WO2005018557A2 - Substituted pyridinones - Google Patents

Substituted pyridinones Download PDF

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Publication number
WO2005018557A2
WO2005018557A2 PCT/US2004/026193 US2004026193W WO2005018557A2 WO 2005018557 A2 WO2005018557 A2 WO 2005018557A2 US 2004026193 W US2004026193 W US 2004026193W WO 2005018557 A2 WO2005018557 A2 WO 2005018557A2
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WIPO (PCT)
Prior art keywords
alkyl
methyl
oxy
difluorobenzyl
bromo
Prior art date
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PCT/US2004/026193
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French (fr)
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WO2005018557A3 (en
Inventor
Balekudru Devadas
John Walker
Shaun R. Selness
Terri L. Boehm
Richard C. Durley
Rajesh Devraj
Brian S. Hickory
Paul V. Rucker
Kevin D. Jerome
Heather M. Madsen
Edgardo Alvira
Michele A. Promo
Radhika M. Blevis-Bal
Laura D. Marrufo
Jeff Hitchcock
Thomas Owen
Win Naing
Li Xing
Huey S. Shieh
Aruna Sambandam
Shuang Liu
Ian L. Scott
Kevin F. Mcgee
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Pharmacia Corporation
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Application filed by Pharmacia Corporation filed Critical Pharmacia Corporation
Publication of WO2005018557A2 publication Critical patent/WO2005018557A2/en
Publication of WO2005018557A3 publication Critical patent/WO2005018557A3/en

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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/69—Two or more oxygen atoms
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    • A61P11/00—Drugs for disorders of the respiratory system
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C04B35/63—Preparing or treating the powders individually or as batches ; preparing or treating macroscopic reinforcing agents for ceramic products, e.g. fibres; mechanical aspects section B using additives specially adapted for forming the products, e.g.. binder binders
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    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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Definitions

  • the instant invention relates to substituted pyridinones that are useful for treating diseases and conditions caused or exacerbated by unregulated p38 MAP kinase activity.
  • Pharmaceutical compositions containing the pyridinone compounds, methods of preparing the pyridone compounds and methods of treatment using the compounds are also disclosed.
  • BACKGROUND OF THE INVENTION Numerous cell surface receptors use one or more of the mitogen-activated protein kinase (MAP kinase) cascades during signal transduction.
  • MAP kinases are a family of protein-directed serine/threonine kinases that are activated by dual phosphorylation.
  • p38 MAP kinase which is activated by a variety of signals including proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-1 (E -1), as well as bacterial lipopolysaccharides and environmental stress such as osmotic shock and ultraviolet radiation (Ono, K. and J. Han, Cell Signal. 12: 1, 2000).
  • proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-1 (E -1)
  • E -1 interleukin-1
  • bacterial lipopolysaccharides such as osmotic shock and ultraviolet radiation
  • p38 alpha p38 beta
  • p38 gamma e.g.
  • ATF2, CHOP and MEF2C as well as other kinases (e.g. MAPKAP-2 and MAPKAP-3) (Trends in Cell biology 7, 353-361, 1997;Mol Cell Biology 19, 21-30, 1999; EMBO J 20, 466-479, 2001).
  • MAPKAP-2 and MAPKAP-3 Trends in Cell biology 7, 353-361, 1997;Mol Cell Biology 19, 21-30, 1999; EMBO J 20, 466-479, 2001.
  • the p38 kinase cascade leads to the induction of gene expression of several factors involved in inflammation and immunity including TNF, interleukin-6, granulocyte-macrophage colony stimulating factor (GM-CSF), and HIV long terminal repeat (Paul et al, Cell Signal. 9: 403-410, 1997).
  • the products of the p38 phosphorylation stimulate the production of inflammatory cytokines and other proteins, including TNF and IL-1, and cyclooxygenase-2, and also possibly modulate the effects of these cytokines on their target cells, and thus stimulate inflammation processes (Lee, J.C. et al, Nature, 372: 376, 1994).
  • P38 MAP kinases have also been shown to promote apoptosis during ischemia in cardiac myocytes, which suggests that p38 MAP kinase inhibitors can be used to treat ischemic heart disease (J. Biol. Chem. 274, 6272, 1999). They are also required for T-cell HIV-1 replication and may be useful targets for AIDS therapy.
  • TNF is a cytokine and a potent proinflammatory mediator implicated in inflammatory conditions such as arthritis, asthma, septic shock, non-insulin dependent diabetes mellitus, multiple sclerosis, asthma, and inflammatory bowel disease.
  • inhibitors of p38 MAP kinases may be useful for the treatment of inflammatory conditions resulting from excessive cytokine production such as arthritis.
  • TNF has also been implicated in viral infections, such as HIV, influenza virus, and herpes virus including herpes simplex virus type-1 (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and rhinotracheitis, among others.
  • HSV-1 herpes simplex virus type-1
  • HSV-2 herpes simplex virus type-2
  • CMV cytomegalovirus
  • VZV varicella-zoster virus
  • Epstein-Barr virus Epstein-Barr virus
  • human herpesvirus-6 HHV-6
  • human herpesvirus-7 HHV-7
  • HHV-8 human herpesvirus-8
  • pseudorabies and rhinotracheitis
  • Inhibition of TNF therefore, should reduce levels of EL-l (European Cytokine Netw 6, 225, 1995) and ameliorate disease states caused by unregulated EL-l synthesis.
  • disease states include rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcosis, bone resorption diseases, reperfusion injury, graft versus host reaction, alallograft rejections, fever and myalgias due to infection, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS related complex (ARC), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, and pyresis.
  • AIDS acquired immune deficiency syndrome
  • EL-l has also been shown to mediate a variety of biological activities such as the activation of T-helper cells, induction of fever, stimulation of prostaglandin or coUagenase production, neutrophil chemotaxis, and the suppression of plasma iron levels (Rev. Infect. Disease, 6, 51 (1984)).
  • Elevated levels of EL-l have also been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, inflammatory bowel disease, adult respiratory distress syndrome (ARDS), psoriasis, Crohn's disease, ulcerative colitis, anaphylaxis, muscle degeneration, cachexia, Reiter's syndrome, type I and type II diabetes, bone resorption diseases, ischemia reperfusion injury, arteriosclerosis, brain trauma, multiple sclerosis, sepsis, septic shock, and toxic shock syndrome.
  • ARDS adult respiratory distress syndrome
  • psoriasis Crohn's disease
  • ulcerative colitis anaphylaxis
  • muscle degeneration cachexia
  • Reiter's syndrome type I and type II diabetes
  • bone resorption diseases ischemia reperfusion injury
  • arteriosclerosis arteriosclerosis
  • brain trauma multiple
  • Viruses sensitive to TNF inhibition are also affected by EL-l production.
  • both EL-l and TNF induce coUagenase synthesis and ultimately lead to tissue destruction within arthritic joints ⁇ Lymphokine Cytokine Res. (11): 253-256, (1992) and Clin. Exp. Immunol. 989:244-250, (1992)).
  • EL-6 is another pro-inflammatory cytokine, which is associated with many conditions including inflammation. Consequently, TNF, EL-l and EL-6 affect a wide variety of cells and tissues and are important inflammatory mediators of a wide variety of disease states and conditions.
  • the inhibition of these cytokines by inhibition or modulation of p38 kinase is of benefit in controlling, reducing and alleviating many of these disease states and conditions. Therefore, the present invention concerns finding small molecule inhibitors or modulators of p38 kinase and the p38 kinase pathway.
  • Ri is H, halogen, N0 , alkyl, carboxaldehyde, hydroxyalkyl, dihydroxyalkyl, arylalkoxy, arylalkyl, alkenyl, alkynyl, arylalkynyl, -CN, aryl, alkanoyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, carboxyl, or arylalkanoyl, wherein the aryl portion of arylalkoxy, arylalkyl, and arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, C 1 -C4 alkyl, -C 4 alkoxy, nitro, CN, haloalkyl, haloalkoxy or C0 2 R; wherein the alkyl portion of the alkyl, hydroxyalkyl, dihydroxyalkyl, arylalkoxy,
  • the invention also includes the intermediates that are useful in making the compounds of the invention. These compounds bind and/or interact with p38 kinase and/or TNF. Preferably, they inhibit the activity of p38 kinase and/or TNF. They are therefore used in treating p38 map kinase or TNF mediated disorders. Preferably they are used in treating p38 alpha or TNF mediated disorders.
  • the instant invention also includes pharmaceutical compositions comprising at least one compound of formula I and at least one pharmaceutically acceptable carrier, solvent, adjuvant or excipient.
  • the instant invention also includes methods of treating a TNF mediated disorder, a p38 kinase mediated disorder, inflammation and/or arthritis in a subject, the method comprising treating a subject having or susceptible to such disorder or condition with a therapeutically-effective amount of a compound of Formula I.
  • the invention provides compounds of formula I wherein: when R 2 is benzyloxy, R 3 is H, R 4 is H, and R 5 is benzyl or methyl, Ri is not hydrogen; no more than two of Ri, R 2 , R 4 , and R 5 are simultaneously hydrogen;
  • R and R 7 are not simultaneously OH; when R 2 is OH, R 4 is methyl and R 5 is phenyl, R] is not acetyl; and
  • Ri is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, dihydroxyalkyl, arylalkoxy, arylalkyl, alkenyl, alkynyl, arylalkynyl, CN, alkanoyl, alkoxy, alkoxyalkyl, haloalkyl, carboxyl, or arylalkanoyl, wherein the aryl portion of arylalkoxy, arylalkyl, and arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, C1-C 4 alkyl, -C4 alkoxy, nitro, CN, haloalkyl, haloalkoxy or C0 2 R; wherein the alkyl portion of the alkyl, hydroxyalkyl, dihydroxyalkyl, arylalkoxy, arylalkyl, alkanoyl, alkoxy,
  • R 5 is H, arylalkyl, alkyl optionally substituted with 1 , 2, or 3 groups that are independently arylalkoxycarbonyl, -NR 8 R 9 , halogen, -C(0)NR 8 R 9 , alkoxycarbonyl, or alkanoyl, alkoxyalkyl optionally substituted with one trimethylsilyl group, alkoxycarbonyl, amino, hydroxyalkyl, dihydroxyalkyl, alkenyl optionally substituted with alkoxycarbonyl, alkynyl, -S0 2 -alkyl, aryl, alkoxy optionally substituted with one trimethylsilyl group, heterocycloalkylalkyl, heteroarylalkyl, heterocycloalkyl, or heteroaryl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently
  • R t is H, halogen, alkyl optionally substituted with CrC 4 alkoxycarbonyl, carboxaldehyde, hydroxyalkyl, dihydroxyalkyl, phenyl(C 1 -C 6 )alkoxy, phenyl(C 1 -C 6 )alkyl, CN, alkanoyl, alkoxy, C 2 -C 4 alkynyl, C 2 -C 6 alkenyl optionally substituted with Q- alkoxycarbonyl, alkoxyalkyl, haloalkyl, or phenyl(d-C 6 )alkanoyl, wherein the phenyl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, -C 4 alkyl, C 1 -C 4 alkoxy, nitro, CN, CF 3 , OCF 3 or C0 2 R; wherein the alkyl groups are unsubstituted or substituted with 1, 2,
  • Ri is H, halogen, -C 4 alkyl optionally substituted with C 1 -C 4 alkoxycarbonyl, C 2 -C 4 alkenyl optionally substituted with Ci-C 4 alkoxycarbonyl, C 2 -C 4 alkynyl, or carboxaldehyde;
  • R 2 is benzyloxy, OH, phenyloxy, phenyloxy(C ⁇ -C 6 )alkyl, phenyl (Ci-C ) thioalkoxy, or pyridyl; wherein each of the above is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, -(CrC 6 )alkyl-N(R)-CO 2 R 30 , NR 6 R 7 , -(Cr C 4 )alkyl-C(0)NR 6 R 7 , (C C 4 ) haloalkyl, -C(0)NR 6 R 7 , -(Q-Qalkyl)
  • Embodiment 4a Compounds according to embodiment 4, wherein R t is H.
  • Embodiment 4b Compounds according to embodiment 4, wherein Rj is halogen.
  • Embodiment 4c Compounds according to embodiment 4, wherein R t is -C 4 alkyl optionally substituted with C 1 -C 4 alkoxycarbonyl.
  • Embodiment 5. Compounds according to embodiment 4, wherein
  • R 5 is indolyl, pyridyl, pyridazinyl, pyrimidinyl, indazolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, pyrazolyl, imidazolyl, furanyl, quinolinyl, isoquinolinyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, indolon-2-yl, or pyrazinyl, each of which is unsubstituted or substituted with 1, 2, 3, 4 or 5 groups that are independently C 1 -C 4 alkyl, halogen, CF 3 , OCF 3 , -C0 2 CH 3 , Q-Q hydroxyalkyl, dihydroxyalkyl, C1-C4 alkoxy, -C0 2 (Q-Q alkyl), benzyloxy, -NR 6 R 7 , -(Q- C 4 )al
  • Embodiment 6 Compounds according to embodiment 5, wherein R 5 is indolyl, pyridyl, pyrimidinyl, pyrazolyl, furanyl, indazolyl, dihydroindolyl, dihydroisoindolyl, indolon-2-yl, or pyrazinyl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 groups that are independently Q-Q alkyl, halogen, CF 3 , OCF 3 , -C0 2 CH 3 , Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkoxy, - C0 2 (Q-Q alkyl), benzyloxy, -C(0)NR 6 R 7 , -NR 8 R 9 , -(Q-Q)alkyl-C(0)NR 6 R 7 , -NR 6 R 7 , NR 6 R 7 -(Q-Q alkyl)-, and amidino
  • Embodiment 7 Compounds according to embodiment 6, wherein R 5 is indolyl, pyridyl, pyrimidinyl, dihydroindolyl, dihydroisoindolyl, pyrazolyl, or pyrazinyl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 groups that are independently Q-Q alkyl, halogen, CF 3 , OCF 3 , -C0 2 CH 3 , Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkoxy, -C0 2 (Q-Q alkyl), benzyloxy, -C(0)NR 6 R 7 , NR 8 R 9 , -(Q-Q)alkyl-C(0)NR 6 R 7 , -NR 6 R 7 , NR 6 R 7 -(Q-Q alkyl)-, or amidinooxime; wherein R 6 and R 7 are independently at each occurrence H, Q-Q
  • Embodiment 8 Compounds according to embodiment 7, wherein
  • R 5 is indolyl, pyridyl, pyrimidinyl, dihydroindolyl, dihydroisoindolyl, pyrazolyl, or pyrazinyl, each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently Q-Q alkyl, halogen, CF 3 , OCF 3 , Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkoxy, -C(0)NR 6 R 7 , -(Q-Q)alkyl-C(0)NR 6 R 7 , NR 8 R 9 , - NR 6 R 7 , or NR 6 R 7 -(Q-Q alkyl)-; wherein R 6 and R 7 are independently at each occurrence H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkanoyl, or Q-Q alkoxy, each of which is optionally substituted with
  • Embodiment 9 Compounds according to embodiment 4, wherein
  • R 5 is phenyl, phenyl(Q-C 6 )alkyl, or (Q-C 6 )alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, alkoxy, benzyloxy, hydroxyalkyl, dihydroxyalkyl, thioalkoxy, -C0 2 (Q-C 5 alkyl), C0 2 R, CN, amidinooxime, -NR 8 R 9 , -NR 6 R 7 , R 6 R 7 N-(Q-Q alkyl)-, -C(0)NR 6 R 7 , -(Q-Q)alkyl- C(0)NR 6 R 7 , amidino, CF 3 , or OCF 3 ; R 8 is hydrogen, Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl and phenyl Q-Q alkanoyl; and R 9 is aminoal
  • Embodiment 10 Compounds according to embodiment 4, wherein
  • R 5 is phenyl, phenyl(Q-Q)alkyl, which is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, alkoxy, benzyloxy, thioalkoxy, - C0 2 (Q-Q alkyl), C0 2 R, CN, amidinooxime, -NR 8 R 9 , -NR 6 R 7 , R 6 R 7 N-(Q-Q alkyl)-, R 6 R 7 NC(0)-(Q-Q alkyl)-, R 6 R 7 NC(0)-(Q-Q alkyl)-, -C(0)NR 6 R 7 , amidino, CF 3 , or OCF 3 ; wherein R 6 and R 7 are independently at each occurrence H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl, Q-Q alkanoyl
  • R 5 is phenyl, benzyl or phenethyl, wherein each is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, -NR 6 R 7 , -C(0)NR 6 R 7 , -(Q-Q alkyl)- C(0)NR 6 R 7 , -NR 8 R 9 , halogen, Q-Q alkoxy, C0 2 R, -(Q-Q alkyl)-C0 2 R, Q-Q thioalkoxy, amidinooxime, Q-Q alkoxycarbonyl, -(Q-Q alky ⁇ )-Q-Q alkoxycarbonyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, -(Q-Q alkyl)-CN, CN, phenyl Q-Q alkoxy, OH, Q-Q haloalkyl, Q-Q haloalkoxy, R 6 R 7 N-(Q-Q alkyl)-,
  • R 5 is phenyl, benzyl or phenethyl, each of which is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently CN, halogen, Q-Q alkoxy, CF 3 , OCF 3 , Q-Q alkyl, -NR 8 R 9 , -NR 6 R 7 , R 6 R 7 N-(Q ⁇ Q alkyl)-, or -C(0)NR 6 R 7 , wherein R 6 and R 7 are independently at each occurrence H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkanoyl, or Q-Q alkoxy, each of which is optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH 2 , -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl
  • Zi and Z 2 are independently H, halogen, Q-Q alkyl, or CO 2 R;
  • Z is -C(0)NR 6 R 7 , -(C 1 -C 4 )alkyl-C(0)NR 6 R 7 , -(Q-Q alkyl)-NR 15 C(0)R 18 , -NR 6 R 7 , R 6 R 7 N-(C 1 -C 6 alkyl)-, -NR 8 R 9 , Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkyl, C0 2 R, or halogen; wherein R 6 and R 7 at each occurrence are independently H, OH, Q-Q alkyl, amino Q-Q alkyl, NH(Q-Q alkyl)alkyl, N(Q-Q alkyl)(Q-Q alkyl) Q-Q alkyl, Q- Q hydroxyalkyl, Q-Q alkoxy Q-Q alkyl, or - S0 (Q-Q alkyl) each of which is optionally substituted with 1, 2, or 3 groups that are
  • Embodiment 14 Compounds according to embodiment 4, wherein R 5 is pyrazolyl(Q-Q alkyl), imidazolyl(Q-Q alkyl), fhienyl(Q-C 6 alkyl), furanyl(Q-Q alkyl), piperidinyl(Q-Q)alkyl, pyrrolidinyl(Q-Q)alkyl, imidazolidinyl(Q- Q)alkyl, piperazinyl(Q-Q)alkyl, pyridyl(Q-Q)alkyl, pyrimidyl(Q-Q)alkyl, pyridazyl(Q-Q)a ⁇ kyl, pyrazinyl(Q-Q)alkyl, isoquinolinyl(Q-Q)alkyl, tetrahydroisoquinolinyl(Q-Q)alkyl, indolyl(Q-C 6 )alkyl, lH-indazoly
  • R 6 and R 7 are not simultaneously OH; and R 6 and R 7 are not simultaneously -S0 2 (Q-Q alkyl).
  • Embodiment 15 Compounds according to embodiment 14, wherein R 5 is pyrazolyl(Q-Q alkyl), imidazolyl(Q-Q alkyl), benzimidazolyl(Q-Q alkyl), thienyl(Q-C 6 alkyl), pyrimidyl(Q-Q)alkyl, indolyl(Q-C 6 alkyl), dihydroindolyl(Q-Q alkyl), dihydroisoindolyl(Q-Q alkyl), dihydroindolon-2- yl(Q-Q alkyl), pyridinyl(Q-Q alkyl), pi ⁇ erazinyl(Q-Q alkyl), or pyrazinyl(Q- C 6 alkyl) each of which is optionally substituted with 1, 2, or 3 groups
  • Z 5 is Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, -C(0)NR 6 R 7 , -(Q- Qalkyl)-C(0)NR 6 R 7 ,Q-Q alkoxycarbonyl, R 6 R 7 N-(Q-Q alkyl)-, -NR 6 R 7 , CF 3 , or Q-Q alkanoyl, wherein R 6 and R 7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH 2 , -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(C !
  • R 5 is of the formula: wherein
  • Z 5 is Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, -C(0)NR 6 R 7 , -(Q- Q alkyl)-C(0)NR 6 R 7> Q-Q alkoxycarbonyl, R 6 R 7 N-(Q-Q alkyl)-, -NR 6 R 7 , CF 3 , or Q-Q alkanoyl, wherein R 6 and R 7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH 2 , -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl,
  • Embodiment 18 Compounds according to either embodiment 16 or 17, wherein Z 5 is Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q-Q alkoxycarbonyl, CF 3 , or Q-Q alkanoyl.
  • Z 5 is Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q-Q alkoxycarbonyl, CF 3 , or Q-Q alkanoyl.
  • Z 5 is Q-Q alkyl, -C(0)NR 6 R 7 , -(Q-Q alkyl)-C(0)NR 6 R 7 , R 6 R 7 N-(Q-Q alkyl)-, or - NR 6 R 7 , CF 3 , or Q-Q alkanoyl, wherein R 6 and R 7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH 2 , -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-C 6 alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)
  • Embodiment 20 Compounds according to embodiment 19, wherein Z 5 is -C(0)NR 6 R 7 , -(Q-Qalkyl)-C(0)NR 6 R 7 , R 6 R 7 N-(Q-Q alkyl)-, or -NR 6 R 7 , wherein R 6 and R 7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently Q-Q alkoxycarbonyl, halogen, cyclopropyl, OH, SH, or Q-Q alkoxy.
  • Embodiment 21 Compounds according to embodiment 15, wherein R 5 is of the formula:
  • Z1 0 is H or methyl; and Z 20 is hydroxy(Q-Q)a ⁇ kyl, Q-Q dihydroxyalkyl, OH, halogen, haloalkyl, (Q- Q)alkyl, OCF 3 , -NR 6 R 7 , R 6 R 7 N-(Q-Q alkyl)-, -(Q-Q alkyl)-C(0)NR 6 R 7 , or - C(0)NR 6 R 7 , wherein Re and R at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH 2 , -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidiny
  • Z 10 is H or methyl; and Z 2 0 is hydroxy(Q-Q)alkyl, Q-Q dihydroxyalkyl, OH, halogen, CF3, (Q-Q)alkyl, OCF 3 , -NR 6 R 7 , R 6 R 7 N-(Q-Q alkyl)-, -(Q-Q alkyl)-C(0)NR 6 R 7 , or -C(0)NR 6 R 7 , wherein R 6 and R 7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH 2 , -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholin
  • Z1 0 is H or methyl; and Z 20 is hydroxy(Q-Q)alkyl, C 1 -C 4 dihydroxyalkyl, OH, halogen, haloalkyl, (Q-
  • R 6 and R 7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH 2 , -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy.
  • Embodiment 24 Compounds according to embodiment 15, wherein
  • R 5 is of the formula:
  • Zio is H or methyl; and Z ⁇ o is hydroxy(Q-Q)alkyl, Q-Q dihydroxyalkyl, OH, halogen, CF 3 , (Q-Q)alkyl,
  • R 6 and R 7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH 2 , -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy.
  • Embodiment 25 Embodiment 25.
  • R 5 is of the formula:
  • Z 10 is H or methyl; and Z o is hydroxy(Q-Q)alkyl, Q-Q dihydroxyalkyl, OH, halogen, haloalkyl, (Q- Q)alkyl, OCF 3 , -NR 6 R 7 , R 6 R 7 N-(Q-C 6 alkyl)-, -(Q-Q alkyl)-C(0)NR 6 R 7 , or - C(0)NR 6 R 7 , wherein R 6 and R 7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH 2 , -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidin
  • Z KJ is H or methyl; and Z ⁇ o is hydroxy(Q-Q)a ⁇ kyl, Q-Q dihydroxyalkyl, OH, halogen, CF , (Q-Q)alkyl, OCF 3 , -NR 6 R 7 , R 6 R 7 N-(Q-Q alkyl)-, -(Q-Q alkyl)-C(0)NR 6 R 7 , or -C(0)NR 6 R 7 , wherein R 6 and R 7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH , -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-C 6 alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl
  • Embodiment 27 Compounds according to embodiment 15, wherein R 5 is of the formula: , wherein Z 10 is H or methyl; and Z 20 is hydroxy(Q-Q)arkyl, Q-Q dihydroxyalkyl, OH, halogen, haloalkyl, (Q- C 4 )alkyl, OCF 3 , -NR 6 R 7 , R 6 R 7 N-(Q-Ce alkyl)-, -(Q-C 4 alkyl)-C(0)NR 6 R 7 , or - C(0)NR 6 R 7 , wherein R 6 and R 7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH 2 , -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-C 6 alkyl), Q-Q alk
  • Z 10 is H or methyl; and Z 20 is hydroxy(Ci-C 4 )alkyl, Ci-C 4 dihydroxyalkyl, OH, halogen, CF 3 , (C 1 -C 4 )alkyl, OCF 3 , -NR 6 R 7 , R 6 R 7 N-(Q-C 6 alkyl)-, -(Q-Q alkyl)-C(0)NR 6 R 7 , or -C(0)NR 6 R 7 , wherein R 6 and R 7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH 2 , -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehy
  • Embodiment 29 Compounds according to embodiment 4, wherein R 5 is phenyl, which is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, -C(0)NR 6 R 7 , -(Q-Q alkyl)-C(0)NR 6 R 7; -NR 6 R 7 , NR 6 R 7 (Q-C 6 alkyl), Q-Q hydroxyalkyl, dihydroxyalkyl, halogen, Q-Q alkoxy, C0 2 R, OH, Q-Q alkoxycarbonyl, CF 3 , -(Q-Q alkyl)-NR 15 C(0)NR 16 R 17 , -(Q-Q alkyl)-NR 15 C(0)R 18 ; wherein R 15 is H or Q-Q alkyl; R 16 and R 17 are independently H or Q-Q alkyl; or Ri6, R1 7 , and the nitrogen to which they are attached form a morpholinyl ring; and R 18 is Q-Q alkyl optionally
  • Zi is H, halogen, Q-Q alkyl, Q-Q haloalkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, or Q-Q alkoxy; and Z2 is Q-Q alkyl, -C(0)NR 6 R 7 , -(Q-Q alkyl)-C(0)NR 6 R 7> -NR 6 R 7 , NR 6 R 7 (Q-Q alkyl), Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q-Q alkoxy, C0 2 R, OH, Q- Q alkoxycarbonyl, or Q-Q haloalkyl; Z 3 is H, Q-Q alkyl, -C(0)NR 6 R 7 , -(Q-Q alkyl)-C(0)NR 6 R 7 , -NR 6 R 7 , NR 6 R 7 (Q-Q alkyl), Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q
  • R 5 is of the formula:
  • Z t is H, halogen, Q-Q alkyl, Q-Q haloalkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, or Q-Q alkoxy; and Z 2 is Q-Q alkyl, -C(0)NR 6 R 7 , -(Q-Q alkyl)-C(0)NR 6 R 7 , -NR 6 R 7 , NR 6 R 7 (Q-Q alkyl), Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q-Q alkoxy, C0 2 R, OH, Q- Q alkoxycarbonyl, or Q-Q haloalkyl;
  • Z 3 is H, Q-Q alkyl, -C(0)NR 6 R 7 , -(C ⁇ -C 4 alkyl)-C(0)NR 6 R 7 ,-NR 6 R 7 , NR 6 R 7 (Q-Q alkyl), Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q-Q alkoxy, C0 2 R, OH, Q-Q alkoxycarbonyl, or Q-Q haloalkyl, and wherein R 6 and R 7 at each occurrence are independently H, OH, Q-Q alkyl, amino Q-Q alkyl, NH(Q-Q alkyl)alkyl, N(Q-Q alkyl)(Q-Q alkyl) Q-Q alkyl, Q- Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkoxy Q-Q alkyl, - S0 2 (Q-Q alkyl), -S0 2 NH 2 , -S0 2 NH
  • Z ⁇ is H, halogen, Q-Q alkyl, Q-Q haloalkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, or Q-Q alkoxy; and Z ⁇ is Q-Q alkyl, -C(0)NR 6 R 7 , -(Q-Q alkyl)-C(0)NR 6 R 7 , -NR 6 R 7 , NR 6 R 7 (Q-Q alkyl), Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q-Q alkoxy, C0 2 R, OH, Q- Q alkoxycarbonyl, or Q-Q haloalkyl; Z 3 is H, Q-Q alkyl, -C(0)NR 6 R 7 , -(Q-Q alkyl)-C(0)NR 6 R 7; -NR 6 R 7 , NReR 7 (Q-Q alkyl), Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen
  • R5 is either wherein Zi is H, halogen, Q-Q alkyl, Q-Q haloalkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, or Q-Q alkoxy; and Z 2 is Q-Q alkyl, -C(0)NR 6 R 7 , -(Q-Q alkyl)-C(0)NR 6 R 7> -NR 6 R 7 , NR 6 R 7 (C 1 -C 6 alkyl), Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q-Q alkoxy, C0 2 R, Q-Q alkoxycarbonyl, -(Q-Q alkyl)-NR 15 C(0)NR 16 Ri7, or -(Q-Q alkyl)-NR 15 C(0)Ri 8 ; Z 3 is H, Q-Q alkyl, -C(0)NR 6 R 7 , -(Q-Qalkyl)-C(0)NR 6 R 7 , -NR 6 R 7 ,
  • Embodiment 34 Compounds according to embodiment 33, wherein R 5 is of the formula: Zi is H, halogen, Q-Q alkyl, Q-Q haloalkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, or Q-Q alkoxy; and Z2 is Q-Q alkyl, -C(0)NR 6 R 7 , -(Q-Q alkyl)-C(0)NR 6 R 7 , -NR 6 R 7 , NR 6 R 7 (C 1 -C 6 alkyl), Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q-Q alkoxy, C0 2 R, Q-Q alkoxycarbonyl, -(Q-Q alkyl)-NR 15 C(0)NR 16 R 17 , or -(Q-Q alkyl)-NR 15 C(0)R 18 ; Z 3 is H, Q, Q-Q alkyl, Q-Q haloalkyl, Q-Q hydroxyalkyl
  • Zi is H, halogen, Q-Q alkyl Q-Q haloalkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, or Q-Q alkoxy; and Z2 is Q-Q alkyl, -C(0)NR 6 R 7 , -(Q-Q alkyl)-C(0)NR 6 R 7) -NR 6 R 7 , NR 6 R 7 (Q-C 6 alkyl), Ci-Ce hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q-Q alkoxy, C0 2 R, Q-Q alkoxycarbonyl, -(Q-Q alkyl)-NR 15 C(0)NRieRi7, or -(Q-Q alkyl)-NR 15 C(0)R 18 ; Z 3 is H, Q-Q alkyl, -C(0)NR 6 R 7 , -(Q-Q alkyl)-C(0)NR 6 R 7 , -NR 6 R 7 , NR 6 R 7 (C
  • Xi, X 2 , X a , X b , X c , X d> and X e at are independently selected from -C(0)NR 6 R7, -(Ci-C4 alkyl)-C(0)NR 6 R 7 , -NR 6 R 7 , hydroxy(Q-C 4 )alkyl, Q-Q dihydroxyalkyl, H, OH, halogen, haloalkyl, alkyl, haloalkoxy, heteroaryl, heterocycloalkyl, Q-Q cycloalkyl, R 6 R 7 N-(Q-C 6 alkyl)-, -C0 2 -(Q-Q)alkyl, -N(R)C(0)NR 6 R 7 , - N(R)C(0)-(Q-Q)alkoxy, C0 2 R-(C 1 -C 6 alkyl)-, or -S0 2 NR 6 R 7 ; wherein the heteroaryl and hetero
  • Embodiment 38 Compounds according to embodiment 37, wherein R 5 is
  • Embodiment 39 Compounds according to embodiment 31, wherein Y 2 , Y 4 , and Y are independently halogen; and
  • R 5 is Xi and X 2 are independently H, methyl, NR 6 R 7 , -(Ci-Q alkyl)-C(0)NR 6 R 7 , R 6 R7N-(C 1 -C 6 alkyl)-, -C(0)NR 6 R 7 , Ci-C 6 hydroxyalkyl, Q-Q dihydroxyalkyl, or -(Q-Q alkyl)-morpholinyl; and X a and X e are independently halogen, NH 2 , NH(Ci-C 6 alkyl), N(Q-Q alkyl)(Q-C 6 alkyl), methyl, or hydrogen. In this embodiment, it is preferred that one of X a and X e is not hydrogen.
  • Embodiment 41 Compounds according to embodiment 40, wherein one of X b and X c is hydrogen and the other is -NR 6 R 7 , R ⁇ N ⁇ Q-Q alkyl)-, -C(0)NR 6 R 7 , -S0 2 NR 6 R 7 , or halogen; where R 6 and R 7 are independently at each occurrence H, Q-Q alkyl, Q-Q alkoxy, Ci- Ce alkoxy Q-Q alkyl, Q-Q alkoxycarbonyl, OH, Q-Q hydroxyalkyl, Ci- Ce dihydroxyalkyl, -(Q-Q)alkyl-C0 -alkyl, pyridyl Q-Q alkyl, Q-Q alkanoyl, benzyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q
  • Re and R 7 are independently at each occurrence H, Q-Q alkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl, Q-Q alkoxycarbonyl, OH, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, -(Q-Q)alkyl-C ⁇ 2 -alkyl, pyridyl Q-Q alkyl, Q-Q alkanoyl, benzyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, Q-Q alkoxy, piperidinyl Q-Q alkyl, morpholinyl Ci- Ce alkyl, piperazinyl Q-Q alkyl, OH, NH 2 , NH(alkyl), N(alkyl)(alkyl), -O
  • X a is hydrogen, methyl, fluorine, or chlorine
  • X c and Xa are both hydrogen
  • X b is -NR 6 R 7 , -(Q-Q alkyl)-C(0)NR 6 R 7 , R 6 R 7 N-(Q-C 6 alkyl)-, -C(0)NR 6 R 7 ;
  • R 6 and R 7 are independently at each occurrence H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl, or Q-Q alkanoyl, wherein each of the above is optionally substituted with 1, 2, or 3 groups that are independently OH, SH, halogen, or Q-Q cycloalkyl.
  • Embodiment 44 Compounds according to embodiment 39, wherein
  • X a is H, fluoro, chloro, or methyl
  • X e is hydrogen, halogen, or methyl
  • X b is H
  • X c is -S0 2 NR 6 R 7 , or halogen; wherein Re and R 7 are independently at each occurrence H, Q-Q alkyl, Q-Q alkoxy, Ci- Ce alkoxy Q-Q alkyl, Q-Q alkoxycarbonyl, OH, Q-Q hydroxyalkyl, Ci- Ce dihydroxyalkyl, -(Q-Q)alkyl-C0 2 -alkyl, pyridyl Q-Q alkyl, Q-Q alkanoyl, benzyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, Q-Q alkoxy, piperidinyl Q- Q alkyl, morpholinyl Q-Q alkyl, piperazinyl Q-Q alkyl, OH, SH,
  • Embodiment 46 Compounds according to embodiment 44, wherein X c is -C(0)NR 6 R 7 , -(Q-Q alkyl)-C(0)NR 6 R 7 , -NR 6 R 7 , or R 6 R 7 N-(Q-C 6 alkyl)-; wherein R 6 and R 7 are independently at each occurrence H, Q-Q alkyl, Q-Q alkoxy, Ci- Q alkoxy Q-Q alkyl, Ci-Ce alkoxycarbonyl, OH, Ci-Ce hydroxyalkyl, Ci- Ce dihydroxyalkyl, Q-Q dihydroxyalkyl, -(Q-Q)alkyl-C0 2 -alkyl, pyridyl Q-Q alkyl, Q-Q alkanoyl, benzyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that
  • Embodiment 47 Compounds according to embodiment 46, wherein R 6 is hydrogen; and R 7 is Q-Q alkyl or Q-Q alkanoyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently NH 2 , NH(Q-Q alkyl), N(Q-Q alkyl)(Q-Q alkyl), OH, SH, cyclopropyl, or Ci-C 4 alkoxy; Embodiment 48. Compounds according to embodiment 47, wherein Xc is -C(0)NR 6 R 7 .
  • Embodiment 49 Compounds according to embodiment 47, wherein Xc is NR 6 R 7 , or R 6 R 7 N-(Q-Q alkyl)-.
  • Embodiment 50 Compounds according to embodiment 38, wherein X a is hydrogen; two of X b , Xc, and X d are hydrogen and the other is -C(0)NR 6 R 7 , -(Q-Q alkyl)- C(0)NR 6 R 7 , -NR 6 R 7 , R 6 R 7 N-(Q-Q alkyl)- or -C0 2 -(Ci-C 6 )alkyl; wherein Re and R 7 are independently at each occurrence H, Q-Q alkyl, Q-Q alkoxy, Q- Q alkoxy Q-Q alkyl, Q-Q alkoxycarbonyl, OH, Q-Q hydroxyalkyl, Ci- Ce dihydroxyalkyl, -(Q-C 4 )alkyl-C0 2 -alky
  • Embodiment 51 Compounds according to embodiment 50, wherein X b is -C(0)NR 6 R 7 , -(Ci-Ce alkyl)-C(0)NR 6 R 7 , -NR 6 R 7 , or R 6 R 7 N-(Q-Q alkyl)- wherein Re is hydrogen or Q-Q alkyl;
  • R 7 is OH, Q-Q alkyl or Q-Q alkanoyl, wherein the alkyl and alkanoyl groups substituted with 1, 2, or 3 groups that are independently NH 2 , NH(Q-Q alkyl), N(Q-Q alkyl)(Q-C 6 alkyl), Q-Q cycloalkyl, OH, or Q-Q alkoxy.
  • Embodiment 52 Compounds according to embodiment 38, wherein X a is halogen or methyl;
  • X b is H, -NR 6 R 7 , R 6 R 7 N-(Q-Ce alkyl)-, -C(0)NR 6 R 7 , or -C0 2 -(Q-Q)alkyl;
  • Xc is -NR 6 R 7 , ReR 7 N-(Q-Q alkyl)-, -C(0)NR 6 R 7 , halogen, -C0 2 -(Ci-C 6 )alkyl, NH 2 , NH(Q-C 6 alkyl), N(Q-Q alkyl)(C ⁇ -Q alkyl), -S0 2 NH 2 , -S0 2 NH(Q-C 6 alkyl), - S0 2 N(C 1 -C 6 alkyl)(Ci-C 6 alkyl), or piperazinyl, wherein the piperazinyl group is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, hydroxy, hydroxy Q-Q alkyl, Q-Q dihydroxyalkyl, or halogen; Xc is hydrogen;
  • X e is H, methyl, NH , NH(Q-Q alkyl) or N(Q-Q alkyl)(Q-C 6 alkyl).
  • Embodiment 53 Compounds according to embodiment 38, wherein
  • Xi, X 2 , X a , X b , X c , X d , and X e are independently selected from H, OH, halogen, CF 3 , alkyl, OCF 3 , pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, thienyl, furyl, pyrrolyl, piperidinyl, piperazinyl, or Q-Q cycloalkyl, wherein each of the above is optionally substituted with -NR 6 R 7 , -C(0)NR 6 R 7 , -(Q-Q alkyl)-C(0)NR 6 R 7 , R 6 R 7 N-(Q-Ce alkyl)-, Q-Q alkyl, Q-Q alkoxy, or halogen.
  • Embodiment 54 Compounds according to embodiment 37, wherein R 5 is a heteroaryl or heteroarylalkyl group, where each heteroaryl is pyrazolyl, imidazolyl, furanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, dihydroindolyl, dihydroisoindolyl, indolon-2-yl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, dihydroisoquinolinyl, or indolyl, each of which is optionally substituted with 1, 2, 3, or 4 groups that are independently -C(0)NR 6 R 7 , -(Q-Q alkyl)-C(0)NR 6 R 7 , -NR 6 R 7 , hydroxy(Q-Q)alkyl, Q-Q dihydroxyalkyl, hydrogen, hydroxy, hal
  • Embodiment 55 Compounds according to embodiment 54, wherein Y 2 , Y 4 , and Y are independently halogen; and Y ⁇ and Y 3 are both hydrogen.
  • Embodiment 56 Compounds according to embodiment 55, wherein Xi and X 2 are independently H, methyl, -NR 6 R 7 , ReRyN ⁇ Q-Q alkyl)-, -C(0)NR 6 R 7 , - (Q-Q alkyl)-C(0)NR 6 R 7 , Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, or -(Q-Q alkyl)-morpholinyl.
  • Embodiment 57 Compounds according to embodiment 56, wherein
  • R 5 is pyridyl Q-Q alkyl, pyrimidinyl Ci-Ce alkyl, or pyrazinyl Q-Q alkyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently hydroxy(Q- Q)alkyl, Q-Q dihydroxyalkyl, OH, halogen, CF 3 , (Q-Q)alkyl, OCF 3 , -NR 6 R 7 , - (Q-Q alkyl)-C(0)NR 6 R 7 , ReR7N-(Q-C 6 alkyl)-, or -C(0)NR 6 R 7 .
  • Embodiment 58 Compounds according to embodiment 57, wherein
  • R 5 is of the formula: wherein
  • Z 5 is hydroxy(Q-Q)alkyl, Q-Q dihydroxyalkyl, OH, halogen, CF 3 , (Q-Q)alkyl, OCF 3 , -NR 6 R 7 , ReR 7 N-(Q-Ce alkyl)-, -(Q-Q alkyl)-C(0)NR 6 R 7 , or -C(0)NR 6 R 7 , wherein R 6 and R 7 at each, occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH 2 , -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidiny
  • Z 5 is hydroxy(Q-Q)alkyl, Q-Q dihydroxyalkyl, OH, halogen, CF 3 , (C C 4 )alkyl, OCF 3 , -NR 6 R 7 , R 6 R 7 N-(Q-C 6 alkyl)-, -(Q-Q alkyl)-C(0)NR 6 R 7 , or -C(0)NR 6 R 7 , wherein R 6 and R 7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH 2 , -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-C 6 alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrroli
  • Z 20 is -(Q-Q alkyl)-C(0)NR 6 R 7 , hydroxy(Q-Q)alkyl, Q-Q dihydroxyalkyl, OH, halogen, CF 3 , (Q-Q)alkyl, OCF 3 , -NR 6 R 7 , R 6 R 7 N-(Q-Q alkyl)-, or -C(0)NR 6 R 7 , wherein R 6 and R 7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH 2 , -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl,
  • Embodiment 61 Compounds according to embodiment 57, wherein R 5 is of the formula: , wherein Zio is H or methyl; and Z 20 is -(Q-Q alkyl)-C(0)NR 6 R 7 , hydroxy(C 1 -C 4 )alkyl, Q-C 4 dihydroxyalkyl, OH, , halogen, CF 3 , (Q-C 4 )alkyl, OCF 3 , -NR 6 R 7 , ReR 7 N-(Q-Ce alkyl)-, or -C(0)NR 6 R 7 , wherein R 6 and R 7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH 2 , -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl),
  • Z 10 is H or methyl; and Z 20 is -(Q-Q alkyl)-C(0)NR 6 R 7 , hydroxy(C 1 -C 4 )alkyl, Q-Q dihydroxyalkyl, OH, halogen, CF 3 , (Q-Q)alkyl, OCF 3 , -NR 6 R 7 , R6R 7 N-(Q- alkyl)-, or -C(0)NR 6 R 7 , wherein R 6 and R 7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH 2 , -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-C 4 alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidin
  • Z 10 is H or methyl; and Z20 is -(Q-Q alkyl)-C(0)NR 6 R 7 , hydroxy(Q-Q)alkyl, Q-C 4 dihydroxyalkyl, OH, halogen, CF 3 , (Q-Q)alkyl, OCF 3 , -NR 6 R 7 , R 6 R 7 N-(Q-C 6 alkyl)-, or -C(0)NR 6 R 7 , wherein R 6 and R 7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH 2 , -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl
  • Z 20 is -(Q-Q alkyl)-C(0)NR 6 R 7 , hydroxy(Q-Q)alkyl, Q-Q dihydroxyalkyl, OH, halogen, CF 3 , (Q-Q)alkyl, OCF 3 , -NR 6 R 7 , R 6 R7N-(Q-C 6 alkyl)-, or -C(0)NR 6 R 7 , wherein R 6 and R 7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH 2 , -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-C 4 alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl
  • Z 20 is -(Q-Q alkyl)-C(0)NR 6 R 7 , hydroxy(Q-Q)alkyl, Ci-Q dihydroxyalkyl, OH, halogen, CF 3 , (Q-C )alkyl, OCF 3 , -NR 6 R 7 , R 6 R 7 N-(Q-Q alkyl)-, or -C(0)NR 6 R 7 , wherein R 6 and R 7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH 2 , -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morph
  • R 5 is of the formula:
  • Z 20 is -(Q-Q alkyl)-C(0)NR 6 R 7 , hydroxy(Q-Q)alkyl, Q-C4 dihydroxyalkyl, OH, halogen, CF 3 , (Q-C 4 )alkyl, OCF 3 , -NR 6 R 7 , R6R 7 N-(Q-Q alkyl)-, or -C(0)NR 6 R 7 , wherein R 6 and R 7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH 2 , -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Ci-C 4 alkyl, OH, SH, carboxaldehyde, piperidiny
  • Z ⁇ o is -(Q-Q alkyl)-C(0)NR 6 R 7 , hydroxy(C ⁇ -C 4 )alkyl, Q-Q dihydroxyalkyl, OH, halogen, CF 3 , (Q-Q)alkyl, OCF 3 , -NR 6 R 7 , R ⁇ R 7 N-(Q-Q alkyl)-, or -C(0)NR 6 R 7 , wherein R 6 and R 7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH 2 , -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-C 6 alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperid
  • Embodiment A7 Compounds according to embodiment 1 wherein Ri is H, halogen, alkyl optionally substituted with Q-Q alkoxycarbonyl, Q-Q alkenyl optionally substituted with Q-Q alkoxycarbonyl, Q-Q alkynyl, Q-Q haloalkyl, carboxaldehyde, Q-Q hydroxyalkyl, phenyl(Q-Q)alkoxy, benzyl, phenethyl, phenpropyl, CN, or phenyl(Q-C 6 )alkanoyl, wherein the phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, nitro, CN, CF 3 , OCF 3 or C0 2 H; R 2 is OH, benzyloxy, phenyloxy, phenyloxy(Q-Q)alkyl, phenyl (Q
  • R 2 is benzyloxy
  • R 4 is H
  • R 5 is benzyl or methyl
  • Ri is not hydrogen; and no more than two of R l5 R 2 , R 4 , and R 5 are simultaneously hydrogen.
  • Embodiment A8 Compounds according to embodiment A7 wherein Ri is H, halogen, Q-Q alkyl optionally substituted with Q-Q alkoxycarbonyl, Q-Q alkenyl optionally substituted with Q-Q alkoxycarbonyl, Q-Q alkynyl, or carboxaldehyde;
  • R 2 is benzyloxy, OH, phenyloxy, phenyloxy(Q-Q)alkyl, phenyl (Q-Q) thioalkoxy, or pyridyl; wherein each of the above is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, -(Q-Q)alkyl-N(R)-C0 2 R 3 o, NReR 7 , (Q- Q) haloalkyl, (Q-Q) haloalkoxy, (Q-Q) alkyl, pyridyl, or NR 6 R 7 -(Ci-C 6 alkyl)-.
  • Embodiment A9 Embodiment A9.
  • R is H, (Q-Q)alkyl optionally substituted with one or two groups that are independently C0 2 H, -C0 2 alkyl, -C(0)NRR, -N(R 30 )C(O)NRR, -N(R 30 )C(O)-(Q-C 6 )alkoxy, or - NReR ⁇ , phenyl(Ci-Ce)alkoxy, or hydroxy(C 1 -C 6 )alkyl, wherein the phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, hydroxy, Q-Q alkoxy, Q-Q alkyl, nitro, CF 3 , OCF 3 ; and R 5 is benzyl, phenethyl, phenpropyl, phenbutyl, (Q-Q)alkyl, phenyl, pyridyl, pyrimidyl, indoly
  • R 4 is H, (Q-Q) alkyl optionally substituted with one or two groups that are independently C0 2 H, -COzalkyl, -C(0)NRR, -N(R 30 )C(O)NRR, -N(R 3 o)C(0)-(Q-Q)alkoxy, or - NR 6 R 7 , phenyl(C,-C 6 )alkoxy, benzyl, phenethyl, phenpropyl, or hydroxy(Q- C 6 )alkyl, wherein the phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, hydroxy, Q-Q alkoxy, Q-Q alkyl, nitro, CF 3 , OCF 3 ; and R 5 is indolyl, quinolinyl, isoquinolinyl, isoindolyl, indol-2-onyl, indolyl(Q-Q) alky
  • R 5 is benzyl, phenethyl, phenpropyl, phenyl, quinolinyl, indolyl, isoquinolinyl, isoindolyl, indol-2-onyl, indolyl(Q-Q) alkyl, quinolinyl (Q-Q) alkyl, isoquinolinyl(Q-Q) alkyl, isoindolyl(Q-Q) alkyl, indol-2-onyl(Q-Q) alkyl, piperidinyl C,-Q alkyl, thienyl Q-Q alkyl, -CH 2 -pyridyl, or pyridyl, each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently Q-Q alkyl, halogen, CF 3 , OCF 3 , Q-Q hydroxyalkyl, Q-C 4 alkoxy, -C0 2 (Q
  • Embodiment A 12 Compounds according to embodiment All, wherein R 5 is benzyl, phenethyl, phenpropyl, or phenyl, each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently Q-Q alkyl, halogen, CF 3 , OCF 3 , -C0 2 CH 3 , Q-Q hydroxyalkyl, Q-Q alkoxy, -C0 2 (Q-Q alkyl), benzyloxy, NR 8 R 9 , NR 6 R 7 Ci-C 4 alkyl, -C(0)NR 6 R 7 , and amidinooxime.
  • Embodiment A 13 Compounds according to embodiment All, wherein R 5 is benzyl, phenethyl, phenpropyl, or phenyl, each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently Q-Q alkyl, halogen, CF 3 , OCF 3
  • R 5 is quinolinyl, indolyl, isoquinolinyl, isoindolyl, indol-2-onyl, indolyl(Q-Q) alkyl, quinolinyl(Q-Q) alkyl, isoquinolinyl(Ci-C 6 ) alkyl, isoindolyl(Q-Q) alkyl, indol- 2-onyl(C ⁇ -C 6 ) alkyl, piperidinyl Q-Q alkyl, thienyl Q-Q alkyl, -CH 2 -pyridyl, or pyridyl, each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently Q-Q alkyl, halogen, CF , OCF 3 , -C0 2 CH 3 , Q-Q hydroxyalkyl, Q-Q alkoxy, -C0 2 (Q-Q-Q
  • Embodiment A14 Compounds according to any one of embodiments All, A12, or A13 wherein R is benzyloxy, or phenethyloxy; each of the above is unsubstituted or substituted with 1, 2, or 3, groups that are independently -(Q-Q)alkyl-N(R)-C0 2 R 3 o, fluoro, chloro, bromo, CF 3 , or (Q- Q)alkyl.
  • Embodiment A15 Compounds according to any one of embodiments Al 1, A12 or A13 wherein
  • R 2 is phenyloxy(Q-Q)alkyl, wherein the phenyl group is unsubstituted or substituted with 1, 2, or 3, groups that are independently -(Q-Q)alkyl-N(R)-C0 2 R 3 o, fluoro, chloro, bromo, CF 3 , or (Q-Q)alkyl.
  • R 2 is phenyloxy(Q-Q)alkyl, wherein the phenyl group is unsubstituted or substituted with 1, 2, or 3, groups that are independently -(Q-Q)alkyl-N(R)-C0 2 R 3 o, fluoro, chloro, bromo, CF 3 , or (Q-Q)alkyl.
  • Embodiment A16 Compounds according to embodiment Al, wherein Ri is H, halogen, Q-Q alkyl optionally substituted with Q-Q alkoxycarbonyl, Q-Q alkenyl optionally substituted with Q-Q alk
  • R 2 is benzyloxy, OH, phenyloxy, phenyloxy(Q-C 6 )alkyl, or phenyl (Q-Q) thioalkoxy, wherein each of the above is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, -(Q-Q)alkyl-N(R)-CO 2 R 30 , NR 6 R 7 , (Q-Q) haloalkyl, (Q-Q) haloalkoxy, (Q-Q) alkyl, pyridyl, or NR 6 R 7 -(Q-Q alkyl)-.
  • Embodiment A18 Embodiment A18.
  • R 4 is H, or (Q-Q) alkyl optionally substituted with one or two groups that are independently C0 2 H, -C0 2 alkyl, -C(0)NRR, -N(R 30 )C(O)NRR, -N(R 30 )C(O)-(Q- C 6 )alkoxy, OH, or -NR 6 R 7 .
  • R 4 is H, or (Q-Q) alkyl optionally substituted with one or two groups that are independently C0 2 H, -C0 2 alkyl, -C(0)NRR, -N(R 30 )C(O)NRR, -N(R 30 )C(O)-(Q- C 6 )alkoxy, OH, or -NR 6 R 7 .
  • Embodiment A19 Embodiment A19.
  • R 5 is phenyl, naphthyl, indolyl, pyridyl, quinolinyl, isoquinolinyl, isoindolyl, indol-2-onyl, indolyl(Q-Q) alkyl, quinolinyl(Q-Q) alkyl, isoquinolinyl(Q-Q) alkyl, isoindolyl(Ci-Ce) alkyl, indol-2-onyl(Q-Q) alkyl, pyridazinyl, pyrimidinyl, or pyrazinyl, pyridazinyl(Q-Q) alkyl, pyrimidinyl(Q-Q) alkyl, or pyrazinyl(Q-Q) alkyl, each of which is unsubstituted or substituted with 1, 2, 3, 4 or 5 groups that are independently Q-Q alkyl, hal
  • Embodiment A20 Compounds according to embodiment A 19, wherein R t is H, halogen, methyl, ethyl, Q-Q alkenyl Q-Q alkynyl, or carboxaldehyde; R is benzyloxy, OH, phenyloxy, phenyloxy(Q-Q)alkyl, or phenyl (Q-Q) thioalkoxy, wherein each of the above is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, -(Q-C 6 )alkyl-N(R)-C0 2 R 3 o, NR 6 R 7 , NR 6 R 7 Q-Q alkyl, (Q-Q) haloalkyl, (Q-Q) haloalkoxy, (Q-Q) alkyl, or pyridyl; and R 4 is H, (Q-Q) alkyl optionally substituted with one or two groups that are independently C0 2 H, -C0
  • Embodiment A21 Compounds according to embodiment A20, wherein R 5 is phenyl optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, Q-Q alkyl, -NR 10 Rn, Q-Q alkoxy, -C(O)NR 10 Rii, -C0 2 H, NR 10 Rn Q- C 4 alkyl, Ci-C 6 alkyl, Q-Q alkoxycarbonyl, Q-Q alkoxy, CHO, -S0 2 NH 2 , Q-Q haloalkyl, Q-Q hydroxyalkyl, -Q-Q alkyl-NRi 2 C(0)NR 13 Ri 4 , -Ci-Q alkyl- NR 12 C(0)-(Q-Q alkyl)-NR 13 R 14 , -Q-Q alkyl-NR 12 C(0)OR 15 , or -Q-Q alkyl- NR 12 C(0)-(Q-C 4 alkyl)-R 15 , wherein Rio and
  • Embodiment A22 Compounds according to embodiment A21, wherein R 5 is phenyl optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, Q-Q alkyl, -NR 10 Rii, NR 10 R ⁇ Q-Q alkyl, Q-Q alkoxy, or -C(O)NR 10 R ⁇ , -C0 2 H, -Q-Q alkyl-NR 10 Rii, Q-Q alkyl, Q-Q alkoxycarbonyl, Q-Q alkoxy, CHO, -S0 2 NH 2 , Q-Q haloalkyl, Q-Q hydroxyalkyl, -Q-Q alkyl- NR 12 C(0)NR ⁇ 3 Ri4, -Q-Q alkyl-NR ⁇ 2 C(0)-(Q-Q alkyl)-NR ⁇ 3 R 14 , -Q-Q alkyl- NR ⁇ 2 C(0)OR 15 , or -Q-Q alkyl-NR 12 C(0)-(Ci-C
  • Embodiment A23 Compounds according to embodiment A22, wherein R 5 is phenyl optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, Q-Q alkyl, -NR ⁇ 0 R ⁇ , NR 1 0R 1 1 Q-Q alkyl, Q-Q alkoxy, -C(0)NR,oR ⁇ , wherein Rio and R ⁇ at each occurrence are independently H, Q-Q alkyl, amino Q-Q alkyl, NH(Q-Q alkyl)alkyl, N(Q-Q alkyl)(Q-Q alkyl) Q-Q alkyl, Q- C 6 hydroxyalkyl, Q-Q alkoxy Q-Q alkyl, OH, -S0 2 (Q-Q alkyl), Q-Q alkanoyl.
  • Embodiment A24 Compounds according to embodiment A23, wherein R 5 is phenyl optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, Q-Q alkyl, -NR 10 Rii, or Q-Q alkoxy.
  • Embodiment A25 Compounds according to embodiment A23, wherein
  • R 5 is substituted with at least one -C(0)NR ⁇ oR ⁇ .
  • Embodiment A26 Compounds according to embodiment A25, wherein Rio and R ⁇ at each occurrence are independently H, Q-Q alkyl, amino Q-Q alkyl, NH(Q-Q alkyl)alkyl, N(Q-Q alkyl)(Q-Q alkyl) Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy Q-Q alkyl.
  • Embodiment 27 Compounds according to embodiment A26, wherein Rio is H.
  • Embodiment A28 Compounds according to embodiment A28.
  • Embodiment A30 Compounds according to embodiment A20, wherein R 5 is phenyl optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, -C0 2 H, -Q-Q alkyl-NRioRn, Q-Q alkoxycarbonyl, Q-Q alkoxy, CHO, -S0 2 NH 2 , Q-Q haloalkyl, Q-Q hydroxyalkyl, -Q-Q alkyl-NR ⁇ 2 C(0)NR ⁇ 3 R ⁇ 4 , -Q-Q a ⁇ kyl-NR ⁇ 2 C(0)-(Q-Q alkyl)-NR 13 R,4, -Q-Q alkyl-NR ⁇ 2 C(0)OR ⁇ 5 , or -Q-Q alkyl-NR, 2 C(0)-(Q-Q alkyl)-R, 5 , -OC(0)Q-Q alkyl, or OH wherein R, 2 is H or Q-
  • Embodiment A31 Compounds according to embodiment A30, wherein R 5 is phenyl optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, -C0 H, Q-Q alkoxycarbonyl, Q-Q alkoxy, CHO, -S0 2 NH 2 , Q-Q haloalkyl, Q-Q hydroxyalkyl.
  • Embodiment A32 Compounds according to embodiment A30, wherein
  • R 5 is phenyl optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, -C0 2 H, -Q-Q alkyl-NR 10 Ru, -Q-Q alkyl- NR 12 C(0)NR 13 Ri4, -Q-Q alkyl-NR ⁇ 2 C(0)-(Q-Q alkyl)-NR 13 R ⁇ 4 , -Q-Q alkyl- NR 12 C(0)ORi 5 , or -Q-Q alkyl-NR ⁇ 2 C(0)-(Q-Q alkyl)-R 15 , or -OC(0)Q-Q alkyl, wherein R 12 is H or Q-Q alkyl; R 13 and Ri 4 are independently H or Q-Q alkyl; or R, 3 and R, 4 and the nitrogen to which they are attached form a morpholinyl ring; R 15 is Q-Q alkoxy.
  • Embodiment A33 Compounds according to embodiment A31, wherein R 5 is phenyl optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, -C0 2 H, -Q-Q alkyl- RioRu, -Q-Q alkyl- NR ⁇ 2 C(0)NR ⁇ 3 Ri4, -Q-Q alkyl- Ri 2 C(0)-(Q-Q alkyl)-NR ⁇ 3 R 14 , wherein R 12 is H or Q-Q alkyl; R 13 and R 14 are independently H or Q-Q alkyl; or R1 3 and R 14 and the nitrogen to which they are attached form a morpholinyl ring.
  • Embodiment A34 Embodiment A34.
  • R 5 is indolyl, pyridyl, pyridazinyl, pyrimidinyl, indazolyl, quinolinyl, isoquinolinyl, isoindolyl, indol-2-onyl, pyridazinyl, pyrimidinyl, or pyrazinyl, , each of which is unsubstituted or substituted with 1, 2, 3, 4 or 5 groups that are independently Q-Q alkyl, halogen, CF 3 , OCF 3 , -C0 2 CH 3 , Q-Q hydroxyalkyl, Q-Q alkoxy, -C0 2 (Q- Q alkyl), benzyloxy, NR 8 R 9 , NR 6 R 7 Q-Q alkyl, -C(0)NR 6 R 7 , or amidinooxime; wherein R and R 7 are independently at each occurrence H, Q-Q alkyl, Q-
  • Embodiment A38 Compounds according to embodiment A36, wherein R 5 is indolyl, pyridyl, pyrimidinyl, indazolyl, or pyrazinyl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 groups that are independently Q-Q alkyl, halogen, CF 3 , OCF 3 , -C0 2 CH 3 , Q-Q hydroxyalkyl, Q-Q alkoxy, -C0 2 (Q-Q alkyl), benzyloxy, -C(0)NR 6 R 7 , -NR 8 R 9 , NR 6 R 7 Q-Q alkyl, and amidinooxime; wherein R 6 and R 7 are independently at each occurrence H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, phenyl
  • Embodiment A39 Compounds according to embodiment A38, wherein R 5 is indolyl, pyridyl, or pyrazinyl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 groups that are independently Q-Q alkyl, halogen, CF 3 , OCF 3 , -C0 2 CH 3 , Q-Q hydroxyalkyl, Q-Q alkoxy, -C0 2 (Q-Q alkyl), benzyloxy, -C(0)NR 6 R 7 , NR 8 R 9 , NR 6 R 7 - - alkyl-, and amidinooxime; wherein R 6 and R 7 are independently at each occurrence H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently halogen, OH, SH, Q-Q cycloalkyl,
  • R 5 is indolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each of which is unsubstituted or substituted with 1, 2, 3, 4 or 5 groups that are independently Q-Q alkyl, halogen, CF 3 , OCF 3 , -C0 2 CH 3 , Q-Q hydroxyalkyl, Q-Q alkoxy, -C0 2 (Q- Q alkyl), benzyloxy, -C(0)NH 2 , -C(0)NH(Q-Q alkyl) wherein the alkyl group is optionally substituted with OH or methoxy, -C(0)N(C,-Q alkyl) (Q-Q alkyl) wherein each alkyl group is independently and optionally substituted with OH or methoxy, -C(0)NR 6 R 7 , NR 8 R 9 , NR 6 R 7 Q-Q alkyl, -Q-Q alkyl-NH 2
  • Ri is H, halogen, methyl, or carboxaldehyde
  • R 2 is benzyloxy, phenyloxy, phenyloxy(Q-Q)alkyl, or phenyl (Q-Q) thioalkoxy, wherein each of the above is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, -(Q-Q)alkyl-N(R)-C0 2 R 3 o, NR 6 R 7 , (Q-Q) haloalkyl, (Q-Q) haloalkoxy, (Q-Q) alkyl, NReR 7 (Q-Q)alkyl, pyridyl, morpholinyl, thiomorpholinyl, piperazinyl pyridyl(Q-Q)alkyl, morpholinyl(Q-Q)alkyl, thiomorpholinyl(Q-Q)alkyl, or piperazin
  • Embodiment A43 Compounds according to embodiment A42, wherein Ri is H or halogen.
  • Embodiment A44 Compounds according to embodiment A 18, wherein R 5 is phenyl(Q-Q)alkyl, (Q-Q)alkyl, piperidinyl(C ⁇ -Q) alkyl, thienyl(Q-Q) alkyl, indolyl (Q-Q) alkyl, naphfhyl(Q-Q)alkyl, pyridyl(Q-Q)alkyl, ⁇ yrimidyl(Q- Q)alkyl, quinolinyl(Q-Q) alkyl, isoquinolinyl(Q-Q) alkyl, isoindolyl(Q-Q) alkyl, indol-2-onyl(Q-Q) alkyl, pyridazinyl(Q-Q) alkyl, pyrazinyl(Q-Q) alkyl,
  • R 5 is phenyl(Q-Q)alkyl, which is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, alkoxy, benzyloxy, thioalkoxy, -C0 2 (Q-Q alkyl), C0 2 H, CN, amidinooxime, NR 8 R 9 , NR 6 R 7 -(Q-Q alkyl)-, -C(0)NR 6 R 7 , amidino, CF 3 , or OCF 3 ; wherein R 6 and R 7 are independently at each occurrence H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each is unsubstituted or substituted with 1, 2, or 3 groups
  • Embodiment A46 Compounds according to embodiment A45, wherein R 5 is phenyl(Q-Q)alkyl, which is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently CN, halogen, Q-Q alkoxy, Q-Q thioalkoxy, Q-Q haloalkyl, Q-Q alkyl, Q-Q haloalkyl, Q-Q haloalkoxy, -C(O)NR 20 R 2 ⁇ , wherein R 20 and R 2 ⁇ are independently H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy Q-Q alkyl, or R 20 , R 21 , and the nitrogen to which they are attached form a piperazinyl, or morpholinyl ring, each of which is optionally substituted with 1 or 2 groups that are independently alkyl or halogen.
  • Embodiment A47 Compounds according to embodiment A46, wherein R 5 is phenyl(Q-Q)alkyl, which is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently CN, halogen, Q-Q alkoxy, Q-Q haloalkyl, Q-Q alkyl, Q-Q haloalkoxy, -C(0)NR 2 oR 2 ⁇ , wherein R o and R 21 are independently H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy Q-Q alkyl, or R20, R 2 1, and the nitrogen to which they are attached form a piperazinyl, or morpholinyl ring, each of which is optionally substituted with 1 or 2 groups that are independently alkyl or halogen.
  • Embodiment A48 Compounds according to embodiment A47, wherein R 5 is benzyl or phenethyl, each of which is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently CN, halogen, Q-Q alkoxy, CF 3 , OCF 3 , Q-Q alkyl, * -C(O)NR 20 R2i, wherein R 20 and R 2 ⁇ are independently H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy Q-Q alkyl, or R 20 , R 21 , and the nitrogen to which they are attached form a piperazinyl, or morpholinyl ring, each of which is optionally substituted with 1 or 2 groups that are independently alkyl or halogen.
  • Embodiment A49 Compounds according to embodiment A48, wherein R 5 is benzyl or phenethyl, each of which is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, methoxy, ethoxy, CF 3 , OCF 3 , methyl, ethyl, or -C(O)NR 20 R 2 ⁇ , wherein R 2 o and R 2 ⁇ are independently H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy Q-Q alkyl, Embodiment A50.
  • R 5 is benzyl or phenethyl, each of which is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, methoxy, ethoxy, CF 3 , OCF 3 , methyl, ethyl, or -C(O)NR 20 R 2l , wherein R 2 o, R 21 , and the nitrogen to which they are attached form a piperazinyl, or morpholinyl ring, each of which is optionally substituted with 1 or 2 groups that are independently alkyl or halogen.
  • R 5 is benzyl or phenethyl, each of which is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, methoxy, ethoxy, CF 3 , OCF 3 , methyl, ethyl, or -C(O)NR 20 R 2l , wherein R 2 o, R 21 , and the nitrogen to which they are attached form
  • R 2 is benzyloxy
  • R 4 is H
  • R 5 is benzyl or methyl
  • Ri is not hydrogen; and no more than two of Ri, R 2 , R4, and R 5 are simultaneously hydrogen.
  • Embodiment A53 Compounds according to embodiment A52, wherein R 5 is piperidinyl(Q-Q) alkyl, thienyl(Q-Q) alkyl, indolyl (Q-Q) alkyl, pyridyl(Q- Q)alkyl, pyrimidyl(Q-Q)alkyl, or pyrazinyl(Q-Q)alkyl, each of which is unsubstituted.
  • Embodiment A54 Compounds according to embodiment A52, wherein R 5 is piperidinyl(Q-Q) alkyl, thienyl(Q-Q) alkyl, indolyl (Q-Q) alkyl, pyridyl(Q- Q)alkyl,
  • R 5 is indolyl (Q-Q) alkyl, pyrimidyl(Q-Q)alkyl, or pyrazinyl(Q-Q)alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, or 4 groups that are independently Q-Q alkyl, halogen, Q-Q alkoxy, Q-C 6 hydroxyalkyl, benzyloxy, Q-Q thioalkoxy, -C0 2 (Q-Q alkyl), C0 2 H, CN, amidinooxime, NR 8 R 9 , NR 6 R 7 -(Q-Q alkyl)-, amidino, -C(O)NR 20 R 21 , CF 3 , or OCF 3 ; wherein R 6 and R 7 are independently at each occurrence H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q al
  • R 5 is indolyl (Q-Q) alkyl, or pyrazinyl(Q-Q)alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, or 4 groups that are independently Q-Q alkyl, halogen, Q-Q alkoxy, Q-Q hydroxyalkyl, benzyloxy, Q-Q thioalkoxy, - C0 2 (Q-Q alkyl), C0 2 H, CN, -C(O)NR 20 R2i, CF 3 , or OCF 3 ; wherein R 20 and R2i are independently H, Q-C 6 alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy Q-Q alkyl, or R 20 , R21, and the nitrogen to which they are attached form a piperazinyl, or morpholinyl ring, each of which is optionally substituted with 1 or 2 groups that are independently alkyl or hal
  • Embodiment A56 Compounds according to embodiment A52, wherein R 5 is isoquinolinyl, isoindolyl, indol-2-onyl, quinolinyl(Q-Q) alkyl, isoquinolinyl(Q-Q) alkyl, isoindolyl(Q-Q) alkyl, indol-2-onyl(Q-Q) alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, halogen, Q-Q alkoxy, Q-Q hydroxyalkyl, benzyloxy, Q-Q thioalkoxy, -C0 2 (Q-C 5 alkyl), C0 2 H, CN, amidinooxime, NR 8 R 9 , NReR 7 -(Q-Q alkyl)-, -C(0)NR 6 R 7 , amidino, CF 3 , or OCF
  • Embodiment A57 Compounds according to embodiment Al, wherein Ri is H, halogen, methyl, ethyl, Q-Q alkenyl, Q-Q alkynyl, or carboxaldehyde; R 2 is benzyloxy, OH, phenyloxy, phenyloxy(Q-Q)alkyl, or phenyl (Q-Q) thioalkoxy, wherein each of the above is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, -(Q-C 6 )alkyl-N(R)-CO 2 R 30 , NR 6 R 7 , (Q-Q) haloalkyl, (Q-Q) haloalkoxy, (Q-Q) alkyl, pyridyl, or NR 6 R 7 -(Q-Q alkyl)-; and R 4 is H, (Q-Q) alkyl optionally substituted with one or two groups that are independently C0 2 H,
  • R 5 is Q-Q cycloalkyl or Q-Q cycloalkylalkyl, each of which is optionally substituted with 1 or 2 groups that are independently alkyl, alkoxy, halogen, -NR 6 R 7 , or NR 6 R 7 -(Q-Q alkyl)-, wherein each of the alkyl groups is optionally substituted with 1 or 2 groups that are independently OH, methoxy, NH 2 , or halogen.
  • Embodiment A58 Compounds according to embodiment A57, wherein
  • R 5 is Q-Q cycloalkyl or Q-Q cycloalkyl Q-Q alkyl, each of which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, halogen, -NR 6 R 7 , or NR 6 R 7 -(Q-Q alkyl)- wherein each of the alkyl groups is optionally substituted with 1 or 2 groups that are independently OH, methoxy, or NH 2 ;
  • R 6 and R 7 are independently at each occurrence H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl, Q-Q alkanoyl, benzyl, benzyloxy, or phenyl Q-Q alkanoyl, wherein each is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, OH, SH, Q-Q cycloalkyl, Q-Q alkoxy, Q-Q alkyl, CF 3 , or OCF 3 ; or
  • Ri is H, halogen, methyl, ethyl
  • R 2 is benzyloxy, phenyloxy, phenyloxy(Q-Q)alkyl, or phenyl (Q-Q) thioalkoxy, wherein each of the above is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, -(Q-Q)alkyl-N(R)-CO 2 R 30 , amino, mono or dialkylamino, -NR 6 R 7 , (Q-Q) haloalkyl, (Q-Q) haloalkoxy, (Q-Q) alkyl, or NReR7-(Q-Q alkyl)-; and
  • R 4 is H, methyl, (Q-Q)alkyl optionally substituted with one or two groups that are independently C0 2 H, -C0 2 alkyl, -C(0)NRR, -N(R 30 )C(O)NRR, -N(R 30 )C(O)-(Q- Q)alkoxy, or -NR 6 R 7 or hydroxy(Q-C 2 )alkyl.
  • Embodiment A60 Compounds according to embodiment A59, wherein
  • R 2 is substituted with two halogens and is further optionally substituted with 1 or 2 groups that are independently halogen, -(Q-Q)aikyl-N(R)-C0 2 R 3 o, amino, mono or dialkylamino, -NR 6 R 7 , (Q-Q) haloalkyl, (Q-Q) haloalkoxy, (Q-Q) alkyl, or NReR 7 -(C,-C 6 alkyl).
  • 1 or 2 groups that are independently halogen, -(Q-Q)aikyl-N(R)-C0 2 R 3 o, amino, mono or dialkylamino, -NR 6 R 7 , (Q-Q) haloalkyl, (Q-Q) haloalkoxy, (Q-Q) alkyl, or NReR 7 -(C,-C 6 alkyl).
  • R 5 is H, alkyl optionally substituted with 1, 2, or 3 groups that are independently phenylalkoxycarbonyl, -NR 8 R 9 , halogen, -C(0)NR 8 R 9 , alkoxycarbonyl, or alkanoyl, alkoxyalkyl optionally substituted with one trimethylsilyl group, alkoxycarbonyl, amino, hydroxyalkyl, alkenyl optionally substituted with alkoxycarbonyl, alkynyl, -S0 2 -alkyl, or alkoxy optionally substituted with one trimethylsilyl group, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, alkoxy, phenylalkoxy, thioalkoxy, -S0 2 alkyl, alkoxycarbonyl, phenylalkoxycarbonyl, C0 2 H, CN, OH, amid
  • R 2 is benzyloxy
  • R 4 is H
  • R 5 is benzyl or methyl
  • Ri is not hydrogen; and no more than two of R 1? R 2 , R4, and R 5 are simultaneously hydrogen.
  • R 5 is H, alkyl optionally substituted with 1, 2, or 3 groups that are independently phenylalkoxycarbonyl, -NR 8 R 9 , halogen, -C(0)NR 8 R 9 , alkoxycarbonyl, or alkanoyl, alkoxyalkyl optionally substituted with one trimethylsilyl group, alkoxycarbonyl, amino, hydroxyalkyl, alkenyl optionally substituted with alkoxycarbonyl, alkynyl, -S0 2 -alkyl, alkoxy optionally substituted with one trimethylsilyl group, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, alkoxy, phenylalkoxy, thioalkoxy, -S0 2 alkyl, alkoxycarbonyl, phenylalkoxycarbonyl, C0 2 H, CN, OH, amidin
  • R 2 is benzyloxy
  • R 4 is H
  • R g is benzyl or methyl
  • Ri is not hydrogen
  • no more than two of Ri, R2, R 4 , and R 5 are simultaneously hydrogen.
  • Ri is H, halogen, methyl, ethyl, Q-Q alkenyl, Q-Q alkynyl, or carboxaldehyde
  • R2 is benzyloxy, OH, phenyloxy, phenyloxy(Q-C 6 )alkyl, or phenyl (Q-Q) thioalkoxy, wherein each of the above is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, -(Q-C 6 )alkyl-N(R)-C0 2 R 3 o, NR 6 R 7 , (Q-Q) haloalkyl, (Q-Q) haloalkoxy, (Q-Q) alkyl, pyridyl, or NR 6 R 7 -(C 1 -C 6 alkyl)-; and R4 is H, (Q-Q) alkyl optionally substituted with one or two groups that are independently C0 2 H,
  • Embodiment A64 Compounds according to embodiment A63, wherein / R 5 is H, alkyl optionally substituted with 1, 2, or 3 groups that are independently phenylalkoxycarbonyl, -NR 8 R 9 , halogen, -C(0)NR 8 R 9 , alkoxycarbonyl, or alkanoyl, alkoxyalkyl optionally substituted with one trimethylsilyl group, alkoxycarbonyl, amino, hydroxyalkyl, alkenyl optionally substituted with alkoxycarbonyl, alkynyl, -S0 2 -alkyl, alkoxy optionally substituted with one trimethylsilyl group, wherein wherein R 8 is hydrogen, Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl and phenyl Q-Q alkanoyl; wherein R 9 is Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, pyri
  • Embodiment A65 Compounds according to embodiment A64, wherein R 5 is Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently phenyl Q-Q alkoxycarbonyl, NH 2 , mono Q-Q alkylamino, di Q-Q alkylamino, halogen, -C(0)NH 2 , -C(0)NH(Q-Q alkyl) wherein the alkyl is optionally substituted with OH, NH 2 , or methoxy, -C(0)N (Q-Q alkyl) (Q-Q alkyl) wherein each alkyl is optionally substituted with OH, NH 2 , or methoxy, Q-Q alkoxycarbonyl, and Q-Q alkanoyl, or R 5 is Q-Q alkoxy Q-Q alkyl, Q-Q alkoxycarbonyl, amino, Q-Q hydroxyalkyl, Q-Q alkenyl optionally substituted with Q-Q alkoxycarbonyl,
  • Ri is halogen, NO 2 , alkyl, carboxaldehyde, hydroxyalkyl, arylalkoxy, arylalkyl, CN, aryl, alkanoyl, alkoxy, alkoxyalkyl, haloalkyl, or arylalkanoyl, wherein the aryl portion of arylalkoxy, arylalkyl, and arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, (Q-Q)alkyl, (Q-Q) alkoxy, nitro, CN, haloalkyl, haloalkoxy or C0 2 H; wherein the alkyl portion of the alkyl, hydroxyalkyl, arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and arylalkanoyl groups is unsubstituted or substituted with 1, 2,
  • R 2 is aryl, heteroaryl, arylalkenyl, arylalkoxy, aryloxyalkyl, arylalkyl, OH, alkynyl, aryloxy, aryloxyalkyl, arylthioalkoxy, alkoxy, -OC(0)NH(CH 2 ) n aryl, -OC(0)N(alkyl)(CH 2 ) n aryl, -OS0 2 (Q-Q)alkyl, -OS0 2 aryl, alkyl, alkoxyalkoxy, NR 8 R 9 , or C0 2 H, wherein n is 0, 1, 2, 3, 4, 5 or 6; each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, -(Ci-Q)alkyl-N(R)-C0 2 R 3 o, alkoxy, alkoxycarbonyl, CN, NR 6 R 7 , haloalky
  • R 6 and R 7 are not simultaneously OH; Re and R 7 are not simultaneously -S0 2 (Q-Q alkyl); when R 2 is OH, R 4 is methyl and R 5 is phenyl, Ri is not acetyl; and R 4 and R 5 are not simultaneously hydrogen.
  • R 6 and R 7 are not simultaneously OH; Re and R 7 are not simultaneously -S0 2 (Q-Q alkyl); when R 2 is OH, R 4 is methyl and R 5 is phenyl, Ri is not acetyl; and R 4 and R 5 are not simultaneously hydrogen.
  • Ri is halogen, Q-Q alkyl, phenyl, carboxaldehyde, Q-Q hydroxyalkyl, phenyl Q-Q alkoxy, phenyl Q-Q alkyl, CN, Q-Q alkanoyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl, Q-Q haloalkyl, or phenyl Q-Q alkanoyl, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, (Q-Q)alkyl, (Q-Q) alkoxy, nitro, CN, Q-Q haloalkyl, Q-Q haloalkoxy or C0 2 H; wherein the above alkyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, or ethoxy,
  • R 2 is phenylalkoxy, OH, phenyloxy, phenyloxy(Q-Q)alkyl, phenylthio(Q-Q)aikoxy, alkoxy, alkenyl, phenethyl, -OC(0)NH(CH 2 ) n phenyl, -OC(0)N(alkyl)(CH 2 ) n phenyl, alkyl, alkoxyalkoxy, NR 8 R 9 , pyridyl, pyrimidyl, pyridazyl, pyrazolyl, imidazolyl, pyrrolyl, tetrahydroquinolinyl, amino, tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl, triazinyl, tetrahydrofuryl, piperidinyl, hexahydropyrimidinyl, thiazolyl,
  • R 4 is H, alkyl optionally substituted with one or two groups that are independently C0 2 H, -C0 2 alkyl, -C(0)NRR, -N(R 30 )C(O)NRR, -N(R 30 )C(O)-(Q-Ce)alkoxy, or -NR 6 R 7 , phenylalkoxy, phenylalkyl, hydroxyalkyl, carboxaldehyde, haloalkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy; and R 5 is benzyl, phenethyl, (Q-Q)alkyl, phenyl, naphthyl, alkoxy, piperidinyl, pyrrol
  • R 4 and R 5 are not simultaneously hydrogen.
  • Embodiment A72 Compounds according to embodiment A71 wherein Ri is halogen, alkyl, carboxaldehyde, hydroxyalkyl, phenylalkoxy, phenyl, benzyl, phenethyl, phenpropyl, phenbutyl, CN, (Q-Q)alkanoyl, haloalkyl, or phenylCO-, phenylCH 2 CO-, phenylCH 2 CH 2 CO-, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, (Q-Q)alkyl, (Q-Q) alkoxy, nitro, CN, haloalkyl, haloalkoxy or C0 2 H; wherein the above alkyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, or ethoxy,
  • R is benzyloxy, phenethyloxy, phenpropyloxy, OH, phenyloxy, phenyloxy(Q-Q)alkyl, phenylfhio(Q-Q)a ⁇ koxy, NR 8 R 9 , (Q-Q)alkyl, alkynyl, phenethyl, -OC(0)N(CH 3 )CH 2 phenyl, alkoxyalkoxy, pyridyl, pyrimidyl, pyridazyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazinyl, piperidinyl, hexahydropyrimidinyl, benzimidazolyl, or thienyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, -(Q-Q)alkyl-N(R)-C0 2 R 3 o, CF 3
  • R 5 is benzyl, phenethyl, phenpropyl, phenbutyl, (Q-Q)alkyl, phenyl, piperidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl(Q-Q)alkyl, pyrrolidinyl(Q-Ce)alkyl, imidazolidinyl(Q-Ce)alkyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, pyridyl(Q- Q)alkyl, pyrimidyl(Q-Q)arkyl, pyridazyl(Q-Q)alkyl, or pyrazinyl(Q-Q)alkyl wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, haloalkyl, NR 8 R 9 , NR 6 R
  • R 2 is OH
  • R 4 is methyl
  • R 5 is phenyl
  • R is not acetyl.
  • Embodiment A73 Compounds according to embodiment A72 wherein Ri is halogen, alkyl, carboxaldehyde, hydroxy(Q-Q)alkyl, phenylalkoxy, benzyl, phenethyl, -C(0)CH 3 , phenylCO-, or phenylCH 2 CO-, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, (Q-Q)arkyl, (Q-Q) alkoxy, nitro, CN, CF 3 , or OCF 3 ; wherein the above alkyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, or ethoxy;
  • R 2 is benzyloxy, phenethyloxy, phenpropyloxy, OH, phenyloxy, phenyloxy(Q-Q)alkyl, phenethyl, NR 8 R 9 , -S-benzyl, or (Q-Q)alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, -(Q-Q)alkyl-N(R)-C0 2 R 3 o, CF 3 , OCF 3 , alkyl, thienyl, or pyridyl; R 6 and R 7 are independently at each occurrence H, (Q-Q)alkyl, (Q-Q)alkoxy, (Ci-Ce)alkoxy(Ci-C 6 )alkyl, (Q-Q)alkoxycarbonyl, hydroxy(Q-Q)alkyl, - (Q-Q)alkyl-C0 2 -alky
  • R 2 is benzyloxy, phenethyloxy, phenpropyloxy, OH, phenyloxy, phenyloxy(Q-Q)alkyl, phenethyl, phenylthioalkoxy, or (Q-Q)alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, -(Q-Q)alkyl-N(R)-C0 2 R 3 o, CF 3 , OCF 3 , alkyl, thienyl, or pyridyl;
  • R 4 is H, (Q-Q) alkyl optionally substituted with one or two groups that are independently CO H, -C0 2 alkyl, -C(0)NRR, -N(R 30 )C(O)NRR, -N(R 3 o)C(0)-(Ci-C 6 )alkoxy, or - NR 6 R 7 , benzyloxy, or phenethyloxy, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, hydroxy, (Q-Q)aTkoxy, (Q-Q)alkyl, nitro, CF 3 or OCF 3 ; and R 5 is benzyl, phenethyl, (Q-Q)alkyl, phenyl, indazolyl, or pyridyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently (Q-Q)alkyl,
  • Embodiment A75 Compounds according to embodiment A74 wherein Ri is chloro, bromo, iodo, methyl, Q-Q alkenyl, Q-Q alkynyl; and R 5 is benzyl, phenethyl, phenpropyl, phenyl, or pyridyl, each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently alkyl, OH, halogen, alkoxy, NH 2 , NH(Q-Q)alkyl, N(Q-Q)alkyl(Q-Q)alkyl, NR 8 R 9 , NR 6 R 7 -(Q-Q alkyl)-, CONR 6 R 7 , and amidinooxime; wherein R 6 and R 7 are independently H, Q-Q alkyl, Q-Q alkanoyl, wherein the alkyl and alkanoyl groups are optionally substituted with 1, 2, or 3 groups that are independently OH, hal
  • Embodiment A76 Compounds according to embodiment A75 wherein R 2 is benzyloxy, phenethyl, phenyloxy(Q-Q)alkyl, or phenethyloxy, each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, -(Q-Q)alkyl-N(R)-C0 2 R 3 o, CF 3 , OCF 3 , or (Q-Q)alkyl.
  • R 2 is benzyloxy, phenethyl, phenyloxy(Q-Q)alkyl, or phenethyloxy, each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, -(Q-Q)alkyl-N(R)-C0 2 R 3 o, CF 3 , OCF 3 , or (Q-Q)alkyl.
  • Embodiment A77 Embodiment A77.
  • R 5 is benzyl, phenethyl, thienyl(Q-Q alkyl), piperidinyl(Q-Q)alkyl, pyrrolidinyl(Q- C 6 )alkyl, imidazolidinyl(Ci-C 6 )alkyl, piperazinyl(Q-Ce)alkyl, pyridyl(C,-C 6 )alkyl, pyrimidyl(Ci-Ce)alkyl, pyridazyl(Ci-Ce)alkyl, pyrazinyl(Ci-Ce)alkyl, isoquinolinyl(C,-C 6 )alkyl, tetrahydroisoquinolinyl(C ⁇ -C 6 )alkyl, indolyl(Q- Q)alkyl, or lH-indazolyl(Q-C 6 )alkyl, wherein R 5 is benzyl,
  • R 6 and R 7 are not simultaneously OH; and R 6 and R 7 are not simultaneously -S0 2 (Q-Q alkyl).
  • Embodiment A78 Compounds according to embodiment A77, wherein Ri is halogen, methyl, ethyl, Q-Q alkenyl, Q-Q alkynyl, or carboxaldehyde; R 2 is benzyloxy, OH, phenyloxy, phenyloxy(Ci-Q)alkyl, or phenyl (Q-Q) thioalkoxy, wherein each of the above is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, -(Q-Q)alkyl-N(R)-C0 2 R 3 o, NR 6 R 7 , (Q-Q) haloalkyl, (Q-Q) haloalkoxy, (Q-Q) alkyl, or pyridyl; and R4 is H, (Q
  • R 5 is benzyl, or phenethyl, wherein each is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently (Q-Q)a ⁇ kyl, halogen, (Q-Q)alkoxy, (Q- Q)hydroxyalkyl, phenyl(C ⁇ -Q)alkoxy, (Q-Q)thioalkoxy, (Q-Q)alkoxycarbonyl, phenyl(Q-Q)alkoxycarbonyl, OH, C0 2 H, CN, amidinooxime, NR 8 R 9 , NR 6 R - (Q-Q alkyl)-, -C(0)NR 6 R 7 , -(Q-Q alkyl)-C(0)NR 6 R 7 amidino, piperazinyl, mo ⁇ holinyl, -S0 2 (Q-Q) alkyl, -S0 2 NH 2 , -S0 2 NH(C ⁇ -C 6 )alkyl,
  • R 5 is benzyl or phenethyl, wherein each is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, -C(0)NR 6 R 7> -(Q-Q alkyl)- C(0)NReR 7 , NR 8 R 9 , halogen, Q-Q alkoxy, C0 2 H, -(Q-Q alkyl)-C0 2 H, Q-Q thioalkoxy, amidinooxime, Q-Q alkoxycarbonyl, -(Q-Q alkyl)-Q-Q alkoxycarbonyl, Q-Q hydroxyalkyl, -(Q-Q alkyl)-CN, CN, phenyl Q-Q alkoxy, OH, Q-Q haloalkyl, Q-Q haloalkoxy, NR 6 R 7 -(Q-Q alkyl)-, -(Q-Q alkyl)- NRi 5 C(0)Ri 8 , amid
  • R 6 and R 7 are not simultaneously OH; and R 6 and R 7 are not simultaneously -S0 2 (Q-Q alkyl).
  • Embodiment A81 Compounds according to embodiment A80, wherein R 5 is benzyl or phenethyl, wherein each is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, -C(0)NR 6 R 7> -(Q-Q alkyl)- C(0)NR 6 R 7 , halogen, Ci-Ce alkoxy, C0 2 H, -(Q-Q alkyl)-C0 2 H, Q-Q thioalkoxy, amidinooxime, Q-Q alkoxycarbonyl, -(Q-Q alkyl)-Q-Q alkoxycarbonyl, Q-Q hydroxyalkyl, -(Q-Q alkyl)-CN, CN, phenyl Q-Q alkoxy, OH, Q-Q haloalky
  • R 6 and R 7 are not simultaneously OH; and Re and R 7 are not simultaneously -SOa(Q-Q alkyl).
  • Embodiment A82 Compounds according to embodiment A81, wherein R 5 is benzyl which is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, -C(0)NR 6 R 7 , -(Q-Q alkyl)-C(0)NR 6 R 7 , halogen, Q- Q alkoxy, CO2H, Q-Q thioalkoxy, Q-Q alkoxycarbonyl, Q-Q hydroxyalkyl, CN, OH, NR 6 R 7 -(Q-Q alkyl)-, NR 8 R 9 , -S0 2 (Q-C 6 alkyl), or benzyloxy; wherein R 6 and R 7 at each occurrence are independently H, OH, Q-Q alkyl, amino Q-Q alkyl, NH(Q-Q alkyl)
  • R 5 is benzyl which is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, -C(0)NR 6 R 7> -(Q-Q alkyl)-C(0)NR 6 R 7 , halogen, Q- Q alkoxy, Q-Q thioalkoxy, Q-Q alkoxycarbonyl, Q-Q hydroxyalkyl, CN, NR 8 R 9 , or NReR 7 -(Q-Q alkyl)-; wherein R 6 and R 7 at each occurrence are independently H, OH, Q-Q alkyl, amino Q-Q alkyl, NH(Q-Q alkyl)alkyl, N(Q-Q alkyl)(Q-Q alkyl) Q-Q alkyl, Q- Q hydroxyalkyl, or Q-Q alkoxy Q-Q alkyl each of which is optionally substituted with 1, 2, or 3 groups that are independently halogen, OH, SH, Q-Q cycloalky
  • R 6 and R 7 are not simultaneously OH.
  • Embodiment A84 Compounds according to embodiment A83, wherein the R 5 group is disubstituted with two groups that are meta to each other.
  • Embodiment A86 Compounds according to embodiment A83, wherein the R 5 group is disubstituted with two groups that are meta to each other.
  • R 5 is benzyl which is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, -C(0)NR 6 R 7> -(Q-Q alkyl)-C(0)NR 6 R 7 , NR 8 R 9 , NR 6 R 7 -(Q-Q alkyl)-, halogen, Q-Q alkoxy, C0 2 H, -(Q-Q alkyl)-C0 2 H, -(Q- Q alkyl)-Q-Q alkoxycarbonyl, -(Q-Q alkyl)-CN, CN, phenyl Q-Q alkoxy, CF 3 , OCF3, -(Q-Q alkyl)-NR ⁇ 5 C(0)R ⁇ 8 , amidinooxime, -0-CH 2 -0-, -0-CH 2 CH 2 - O-, or phenyl; wherein R 6 and R 7 at each occurrence are independently H, Q-Q alkyl, -C(0)NR 6 R
  • R 6 and R 7 are not simultaneously OH.
  • Embodiment A87 Compounds according to embodiment A80, wherein R 5 is benzyl or phenethyl, wherein each is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, -C(0)NR 6 R 7 ⁇ -(Q-Q alkyl)- C(0)NR 6 R 7 , halogen, Q-Q alkoxy, C0 2 H, -(Q-Q alkyl)-C0 2 H, Q-Q thioalkoxy, amidinooxime, Q-Q alkoxycarbonyl, -(Q-Q alkyl)-Q-Q alkoxycarbonyl, Q-C 6 hydroxyalkyl, -(Q-Q alkyl)-CN, CN, phenyl Ci-Ce alkoxy, OH, Q-Q haloalkyl, Q-Q haloalkoxy, NR 8 R 9 , NR
  • R 6 and R 7 are not simultaneously OH; and R 6 and R 7 are not simultaneously -S0 2 (Q-Q alkyl).
  • Embodiment A88 Compounds according to embodiment A87, wherein R 5 is benzyl which is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, -C(0)NR 6 R 7 , -(Ci-C 4 alkyl)-C(0)NR 6 R 7 , halogen, Q-Q alkoxy, C0 2 H, Q-Q thioalkoxy, Q-Q alkoxycarbonyl, Q-Q hydroxyalkyl, CN, OH, NR 8 R 9 , NR 6 R 7 -(Q-C 6 alkyl)-, -S0 2 (Q-Q alkyl), or benzyloxy; and wherein R 6 and R 7 at each occurrence are independently H, OH, Q-Q alkyl, amino Q-Q alkyl, NH(Q
  • R 6 and R 7 are not simultaneously OH; and R 6 and R 7 are not simultaneously -S0 2 (Q-Q alkyl).
  • Embodiment A89 Compounds according to embodiment A80, wherein R 5 is benzyl which is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, -C(0)NR 6 R 7 , -(Q-Qalkyl)-C(0)NR 6 R 7 , NR 6 R 7 -(Q-Q alkyl)-, NR 8 R 9 , halogen, Q-Q alkoxy, Q-Q thioalkoxy, Q-Q alkoxycarbonyl, Q-Q hydroxyalkyl, or CN; wherein Re and R 7 at each occurrence are independently H, OH, Q-Q alkyl, amino Q-Q alkyl, NH(Q-Q alkyl)alkyl, N(Q-Q alkyl)(Q-Q alkyl) Q-Q alkyl).
  • R 6 and R 7 are not simultaneously OH.
  • Embodiment A90 Compounds according to embodiment A89, wherein the R 5 group is disubstituted with two groups that are meta to each other.
  • Embodiment A91 Compounds according to embodiment A89, wherein the R 5 group is disubstituted with two groups that are meta to each other.
  • R 5 is phenyl, which is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, -C(0)NR 6 R 7 , -NR 6 R 7 , NR 6 R 7 (Q-Q alkyl), NR 8 R 9 , Ci- Ce hydroxyalkyl, halogen, Q-Q alkoxy, C0 2 H, OH, Q-Q alkoxycarbonyl, carboxaldehyde, Q-Q haloalkyl, -(Q-Q alkyl)-NR ⁇ 5 C(0)NR ⁇ 6 R ⁇ 7 , -(Q-Q alkyl)-NRi 5 C(0)R 18 ; wherein R 6 and R 7 at each occurrence are independently H, OH, Q-Q alkyl, amino Q-Q alkyl, NH(Q-Q alkyl)alkyl, N(Q-Q alkyl)(Q-Q alkyl) Q-Q alkyl, Ci- Ce
  • R 5 is phenyl, which is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, -(Q-Qalkyl)-C(0)NR6R 7 , -C(0)NR 6 R 7 , -NR 6 R 7 , NR 6 R 7 (Q-Q alkyl), NR 8 R 9 , Q-Q hydroxyalkyl, halogen, Q-Q alkoxy, C0 2 H, OH, Q-Q alkoxycarbonyl, carboxaldehyde, Q-Q haloalkyl, -(Q-Q alkyl)- NR 15 C(0)NRieRi 7 , -(Q-Q alkyl)-NR 15 C(0)Ri 8 ; wherein R 6 and R 7 at each occurrence are independently H, OH, Q-Q alkyl, amino Q-Q alkyl, NH(Q-Q alkyl)alkyl, N(Q-Q alkyl)(Q-Q alkyl) Q
  • R 2 is benzyloxy, OH, phenyloxy, phenyloxy(Q-Q)alkyl, or phenyl (Q-Q) thioalkoxy, wherein each of the above is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, -(Q-Q)alkyl-N(R)-CO 2 R 30 , NR 6 R 7 , (Q-Q) haloalkyl, (Q-Q) haloalkoxy, (Q-Q) alkyl, pyridyl, or NReR 7 -(Q-Ce alkyl)-; and R 4 is H, (Q-Q) alkyl optionally substituted with one or two groups that are independently C0 2 H, -C0 2 alkyl, -C(0)NRR, -N(R 30 )C(O)NRR, -N(R 3 o)C(0)-(Ci-Ce)alkoxy, or - NR 6 R
  • Embodiment A94 Compounds according to embodiment A93, wherein R 5 is phenyl, which is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, -C(0)NR 6 R 7 , -(Q-Q alkyl)-C(0)NR 6 R 7) -NR 6 R 7 , NR 6 R7(Ci-C 6 alkyl), Q-Q hydroxyalkyl, halogen, Q-Q alkoxy, C0 2 H, OH, Q- Q alkoxycarbonyl, carboxaldehyde, Q-Q haloalkyl, wherein R 6 and R 7 at each occurrence are independently H, OH, Q-Q alkyl, amino Q-Q alkyl, NH(Q-Q alkyl)alkyl, N(Q-Q alkyl)(Q-Q alkyl) Q-Q alkyl, Q- C 6 hydroxyalkyl, Q-Q alkoxy Q-Q alkyl, -S0
  • Embodiment A101 Compounds according to embodiment A66, wherein R 5 is thienyl(Q-Q alkyl), piperidinyl(Q-Q)alkyl, pyrrolidinyl(Q-Q)alkyl, imidazolidinyl(Q-Q)alkyl, piperazinyl(Q-Q)alkyl, pyridyl(C ⁇ -C 6 )alkyl, pyrimidyl (Q ⁇ Q)alkyl, pyridazyl(C ⁇ -Ce)alkyl, pyrazinyl(C ⁇ -C 6 )alkyl, isoquinolinyl(C ⁇ -Ce)alkyl, tetrahydroisoquinolinyl(Ci-C 6 )alkyl, indolyl(Q- C 6 )alkyl, lH-indazolyl(Q-Q)alkyl, dihydroindolonyl(Ci-C
  • Ri is halogen, methyl, ethyl, Q-Q alkenyl, Q-Q alkynyl, or carboxaldehyde;
  • R 2 is benzyloxy, OH, phenyloxy, phenyloxy(Q-Q)arkyl, or phenyl (Q-Q) thioalkoxy, wherein each of the above is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, -(Q-Q)alkyl-N(R)-C0 2 R 3 o, NR 6 R 7 , (Q-Q) haloalkyl, (Q-Q) haloalkoxy, (Q-Q) alkyl, pyridyl, or NReR 7 -(Q-C 6 alkyl)-; and
  • R 4 is H, (Q-Q) alkyl optionally substituted with one or two groups that are independently C0 2 H, -C0 2 alkyl, -C(0)NRR, -N(R 30 )C(O)NRR, -N(R 30 )C(O)-(Q-C 6 )alkoxy, or - NR 6 R 7 , or hydroxy(Q-Q)alkyl.
  • Embodiment A 103 Embodiment A 103.
  • R 5 is thienyl(Q-Q alkyl), indolyl(Q-Q alkyl), pyridinyl(Q-Q alkyl), piperazinyl(Q-Q alkyl), or pyrazinyl(Q-Q alkyl) each of which is optionally substituted with 1, 2, or 3 groups that are independently Q-Q alkyl, Q-Q hydroxyalkyl, halogen, -C(0)NR 6 R 7 , -(Q-Q alkyl)-C(0)NR 6 R 7> Q-Q alkoxycarbonyl, -NR 6 R 7 , NR 6 R 7 - (Q-Q alkyl)-, haloalkyl, Q-Q alkanoyl, R 6 and R 7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently Q-Q alkoxycarbonyl, halogen, Q-Q cycloalkyl,
  • R 5 is thienyl(Q-Q alkyl), indolyl(Q-Q alkyl), pyridinyl(Q-Q alkyl), piperazinyl(Q-Q alkyl), or pyrazinyl (Q-Q alkyl).
  • Embodiment A 105 is thienyl(Q-Q alkyl), indolyl(Q-Q alkyl), pyridinyl(Q-Q alkyl), piperazinyl(Q-Q alkyl), or pyrazinyl (Q-Q alkyl).
  • R 4 is H, methyl, ethyl, or -CH 2 OH
  • R5 is pyridinyl(Q-Q alkyl), or pyrazinyl(Q-Q alkyl) each of which is optionally substituted with 1, 2, or 3 groups that are independently Q-Q alkyl, Q-Q hydroxyalkyl, halogen, -C(0)NR 6 R 7 , -(Q-Q alkyl)-C(0)NR 6 R 7 , Q-Q alkoxycarbonyl, -NR 6 R 7 , NReR 7 -(Q-Q alkyl)-, CF 3 , Ci-Ce alkanoyl, wherein R 6 and R 7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently Q-Q alkoxycarbonyl, halogen, Q-Q cycloalkyl, OH, SH, or Q-Q alkoxy; or R
  • Embodiment A 106 Compounds according to embodiment A 105, wherein R 4 is H, alkyl substituted with one or two groups that are independently C0 2 H, -C0 2 -(Q- Q)alkyl, -C(0)NRR, -N(R 30 )C(O)NRR, -N(R 30 )C(O)-(C ⁇ -C 6 )alkoxy, or -NR 6 R 7 .
  • Embodiment Al 12 Compounds according to embodiment 16, wherein Ri is halogen, or methyl;
  • R 2 is benzyloxy, which is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, -(Q-Q)alkyl-N(R)-C ⁇ 2R 30 , CF 3 , OCF 3 , or (Q-Q) alkyl,; and R 4 is H, methyl, ethyl, -CH 2 OH, -CH 2 C ⁇ 2 -(Ci-Q alkyl), or Q hydroxyalkyl.
  • Embodiment Al 13 Compounds according to any one of embodiments A85, A95,
  • Ri is halogen, or methyl
  • R 2 is benzyloxy, which is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, -(Q-C 6 )alkyl-N(R)-C0 2 R 3 o, CF 3 , OCF 3 , or (Q-Q) alkyl
  • R4 is alkyl substituted with one group that is C0 2 H, -C0 2 -(Q-Q)alkyl, -C(0)NRR, -N(R 30 )C(O)NRR, -N(R 30 )C(O)-(Q-C 6 )alkoxy, or -NR 6 R 7 .
  • Embodiment Al 14 Compounds according to embodiment A66, wherein R 5 is isoquinolinyl(Q-Q alkyl), tetrahydroisoquinolinyl(C ⁇ -C 6 alkyl), lH-indazolyl(Q-Q alkyl), dihydroindolonyl(Ci-C 6 alkyl), indolinyl(Q-Q alkyl), dihydroisoindolyl(C ⁇ -C 6 alkyl), dihydrobenzimdazolyl(Q-C 6 alkyl), dihydrobenzoimidazolonyl(Q-Ce alkyl), each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently alkyl, alkoxy, halogen, Q- Q alkoxycarbonyl, alkanoyl optionally substituted with 1 or 2 groups that are independently selected from the group consisting of OH, NH 2 , NH(Q-Q alkyl), and
  • Embodiment Al 15 Compounds according to embodiment Al 14, wherein R 5 is isoquinolinyl(Q-Q alkyl), piperidinyl Q-Q alkyl, tetrahydroisoquinolinyl (Q-Q alkyl), lH-indazolyl(C,-Q alkyl), dihydroindolonyl(Q-Q alkyl), indolinyl(Q-Q alkyl), dihydroisoindolyl(Q-Q alkyl), dihydrobenzimdazolyl(Q-Q alkyl), or dihydrobenzoimidazolonyl(C 1 -Q alkyl) .
  • Embodiment Al 16 Compounds according to embodiment Al 14, wherein R 5 is isoquinolinyl(Q-Q alkyl), piperidinyl Q-Q alkyl, tetrahydroisoquinolinyl (Q-Q alkyl), lH-indazolyl
  • R 5 is pyrimidyl, indolinyl, indolyl, lH-isoindolyl, isoquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, dihydro-lH-benzimidazolyl, pyrrolyl, imidazolyl, or each of which is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of Ci-Ce alkoxycarbonyl, Q-Q thioalkoxy, each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently -C(0)NR 6 R 7 , -(Q- C 4 alkyl)-C(0)NR 6 R 7> NReR 7 -(Ci-C 6 alkyl)-, -NR 6 R 7 , alkyl, alkoxy, halogen, Q-Q alkoxycarbonyl, or alkanoyl optionally substituted
  • Embodiment Al 18 Compounds according to embodiment Al 17, wherein R 5 is pyrimidyl, pyrrolyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with 1, 2, or 3 groups independently selected from Q-Q alkoxycarbonyl, Q-Q thioalkoxy, each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently alkyl, alkoxy, halogen, Q-Q alkoxycarbonyl, -C(0)NR 6 R 7 , -(Q-Qalkyl)- C(0)NR 6 R 7 ,NR 6 R 7 -(Q-Ce alkyl)-, or -NR 6 R 7 , or Q-Q alkanoyl optionally substituted with 1 or 2 groups that are independently selected from the group consisting of OH, NH 2 , NH(Q-Ce alkyl), and N(Q-Q alkyl) (Q-Q alkyl), or S0 2 H.
  • Embodiment Al 19 Compounds according to embodiment Al 17, wherein R 5 is pyridyl or pyrazolyl, optionally substituted with 1, 2, or 3 groups that are independently Q-Q alkyl, Q-Q hydroxyalkyl, halogen, -C(0)NReR 7 , -(Q-Q alkyl)-C(0)NReR7,NR 6 R7-(C ⁇ -C 6 alkyl)-, or -NR 6 R 7 , Q-Q alkoxycarbonyl, - NR 6 R 7 , NR 6 R 7 -(C ⁇ -Q alkyl)-, CF 3 , Q-Q alkanoyl, wherein R 6 and R 7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently Q-Q alkoxycarbonyl, halogen, Q-Q cycloalkyl, OH, SH, or Q-Q alkoxy; or R 6 , R 7 , and the nitrogen to
  • Embodiment A 120 Compounds according to embodiment Al 19, wherein R 5 is pyridyl or pyrazolyl, optionally substituted with 1, 2, or 3 groups that are independently Q-Q alkyl, Q-Q hydroxyalkyl, halogen, -C(0)NR 6 R 7 , -(Q-Q alkyl)-C(0)NR 6 R 7; NR 6 R 7 -(Q-Ce alkyl)-, -NR 6 R 7 , Q-Q alkoxycarbonyl, CF 3 , Q- Q alkanoyl, wherein R 6 and R 7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently Q-Q alkoxycarbonyl, halogen, Q-Q cycloalkyl, OH, SH, or Q-Q alkoxy.
  • Embodiment A 121 Compounds according to embodiment Al 19, wherein R 5 is pyridyl or pyrazolyl, optionally substituted with 1, 2, or 3 groups that are independently Q-Q alkyl, Q-Q hydroxyalkyl, halogen, -C(0)NR 6 R 7 , -(Q-Q alkyl)-C(0)NReR 7 ,NR 6 R 7 -(Q-Q alkyl)-, -NR 6 R 7 , Q-Q alkoxycarbonyl, CF 3 , Q- Q alkanoyl, wherein R 6 , R 7 , and the nitrogen to which they are attached form a piperidinyl, pyrrolidinyl, piperazinyl, or a mo ⁇ holinyl ring optionally substituted with 1 or 2 groups that are independently alkyl, hydroxy, hydroxy Q-Q alkyl, or halogen.
  • Embodiment A 122 Compounds according to any one of embodiments Al 14, A115. A116
  • Ri is halogen, methyl, ethyl, Q-Q alkenyl, Q-Q alkynyl, or carboxaldehyde;
  • R 2 is benzyloxy, OH, phenyloxy, phenyloxy(Q-Q)alkyl, or phenyl (Q-Q) thioalkoxy, wherein each of the above is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, -(Q-Q)alkyl-N(R)-C0 2 R 3 o, NR 6 R 7 , (Q-Q) haloalkyl, (Q-Q) haloalkoxy, (Q-Q) alkyl, pyridyl, or NR 6 R 7 -(Q-Q alkyl)-; and R 4 is H, (Q-Q) alkyl substituted with one group that is C0 2 H, -C0 2 -(Q-Q)alkyl, -C(0)NRR
  • R 5 is Q-Q alkoxy, ethyl, methyl, cyclopropylmefhyl, cycloalkyl, or alkynyl, or R 5 is Q-Q alkenyl optionally substituted with Q-Q alkoxycarbonyl or cyclohexyl.
  • Ri is halogen, methyl, ethyl, Q-Q alkenyl, Q-Q alkynyl, or carboxaldehyde
  • R 2 is benzyloxy, OH, phenyloxy, phenyloxy(Q-Q)alkyl, or phenyl (Q-Q) thioalkoxy, wherein each of the above is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, -(Q-Q)alkyl-N(R)-CO 2 R 30 , NR 6 R 7 , (Q-Q) haloalkyl, (Q-Q) haloalkoxy, (Q-Q) alkyl, pyridyl, or NR 6 R 7 -(C ⁇ -Q alkyl)-; and R 4 is H, (Q-Q) alkyl substituted with one group that is C0 2 H, -C0 2 -(Ci-Q)al
  • Embodiment A 125 Compounds according to embodiment A 124, wherein R 5 is Q-Q alkyl optionally substituted with 1 or 2, groups that are independently Q-Q alkoxycarbonyl, or halogen, or R 5 is Q-Q alkoxy, ethyl, methyl, cyclopropylmethyl, cyclohexyl, cyclopentyl, Q-Q alkynyl, or R 5 is Q-Q alkenyl optionally substituted with Q-Q alkoxycarbonyl or cyclohexyl.
  • Embodiment A 126 Embodiment A 126.
  • R 2 is phenylalkynyl, -OC(0)NH(CH 2 ) n aryl, -OC(0)N(alkyl)(CH 2 ) n aryl, -OS0 2 (Q- Q)alkyl, -OS0 2 aryl, or NR 8 R 9 , wherein n is 0, 1, 2, 3, 4, 5 or 6; each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, -(Q-Q)alkyl-N(R)-C0 2 R 3 o, alkoxy, alkoxycarbonyl, CN, NR 6 R 7 , haloalkyl, haloalkoxy, alkyl, heteroaryl, heteroarylalkyl, NReR 7 -(Q-Q alkyl)-, phenyl, -S0 2 -phenyl wherein the phenyl groups are optionally substituted with
  • Embodiment A 127 Compounds according to embodiment A 126, wherein Ri is halogen, methyl, ethyl, Q-Q alkenyl, Q-Q alkynyl, or carboxaldehyde; and R 4 is H, (Q-Q) alkyl substituted with one group that is C0 2 H, -C0 2 -(Q-Q)alkyl, -C(0)NRR, -N(R 30 )C(O)NRR, -N(R 30 )C(O)-(Q-Q)alkoxy, -NR 6 R 7 , NReR 7 -(Q- Q alkyl)-, or hydroxy(Q-Q)alkyl.
  • Embodiment A 128 Embodiment A 128.
  • R 5 is phenyl, optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, CF 3 , OCF 3 , -(C ⁇ -C 4 alkyl)-C(0)NR 6 R 7 ,NR 6 R 7 - (Q-Q alkyl)-, -NR 6 R 7 , or C(0)NR 6 R 7 , wherein R 6 and R 7 are independently at each occurrence H, Q-Q alkyl, Q-Q alkoxy, Q- Q alkoxy Q-Q alkyl, Q-Q alkoxycarbonyl, OH, Q-Q hydroxyalkyl, - (Q-Q)alkyl-C0 -alkyl, pyridyl Q-Q alkyl, Q-Q alkanoyl, benzyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each
  • R 5 is benzyl optionally substituted with 1 ,2 ,3 ,4, or 5 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, CN, CF 3 , OCF 3 , -(Ci-C 4 alkyl)-C(0)NR 6 R 7 , NR 6 R 7 -(Q-Q alkyl)-, -NR 6 R 7 , or C(0)NR 6 R 7 .
  • R 2 is NR 8 R 9 , or NR 8 R 9 -(Q-Q alkyl)-; wherein R 8 at each occurrence is independently hydrogen, Q-Q alkyl, Q-C 6 alkanoyl, phenyl(Q-Q)alkyl or phenyl(Q-Q)alkanoyl wherein each of the above is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Ci-Ce alkyl, Q-Q alkoxy, Q-Q alkoxycarbonyl, halogen, or Q-Q haloalkyl; and R 9 at each occurrence is independently Q-Q alkyl, Q-Q alkanoyl, phenyl(Q- Q)alkyl, Q-Q cycloalkyl, Q-Q alkenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, Q-Q cyclo
  • Embodiment A130 Compounds according to embodiment A129, wherein R 8 is H.
  • Embodiment A131 Compounds according to embodiment A130, wherein R2 is -NH-benzyl option substituted with 1, 2, or 3 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, CF 3 , OCF 3 , or R 2 is -NH-C(0)phenyl, wherein the phenyl group is optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q alkyl, or Q-Q alkoxy; or R 2 is -NH-allyl.
  • Embodiment A 132 Compounds according to embodiment Al 31 , wherein
  • Ri is chloro, bromo, iodo, or methyl; and R 5 is benzyl optionally substituted with 1 ,2 ,3 ,4, or 5 groups that are independently halogen, -(C ⁇ -C4 alkyl)-C(0)NR 6 R 7 ,NReR 7 -(Q-C6 alkyl)-, -NR 6 R 7 , Q-Q alkyl, Q-Q alkoxy, CN, CF 3 , OCF 3 , or C(0)NR 6 R 7 .
  • Embodiment A 133 Compounds according to embodiment A 131 , wherein
  • Ri is chloro, bromo, iodo, or methyl; and R 5 is phenyl, optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, -(Ci-Q alkyl)-C(0)NR 6 R 7f NReR 7 -(Q-Q alkyl)-, -NR 6 R 7 , Q-Q alkyl, Q-Q alkoxy, CF 3 , OCF 3 , or C(0)NR 6 R 7 .
  • Embodiment A 134 A compound of the formula
  • Y 2 , Y 4 , and Y are independently halogen; and Yi and Y 3 are both hydrogen.
  • Embodiment A136 Compounds according to embodiment A135, wherein Xi is H, methyl, -NR 6 R 7 , NR 6 R 7 -(Q-Q alkyl)-, -C(0)NR 6 R 7 , Q-Q hydroxyalkyl, or - (Q-Q alkyl)-mo ⁇ holinyl.
  • Embodiment A137 Compounds according to embodiment A136, wherein X a and X e are independently halogen, is NH 2 , NH(Q-Q alkyl), N(Q-Q alkyl)(Q-Q alkyl) or methyl.
  • Embodiment A138 Compounds according to embodiment A137, wherein X b or X c is -NR 6 R 7 , NR 6 R 7 -(Q-Q alkyl)-, -C(0)NR 6 R 7 , -S0 2 NR 6 R 7 , or halogen; wherein R 6 and R 7 are independently at each occurrence H, Q-Q alkyl, Q-Q alkoxy, Ci- Ce alkoxy Q-Q alkyl, Q-Q alkoxycarbonyl, OH, Q-Q hydroxyalkyl, - (Q-Q)alkyl-C ⁇ 2 -alkyl, pyridyl Q-Q alkyl, Q-Q alkanoyl, benzyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl
  • Embodiment A139 Compounds according to embodiment A138, wherein R 6 , R 7 , and the nitrogen to which they are attached form a mo ⁇ holinyl, thiomo ⁇ holinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, hydroxy, hydroxy Q-Q alkyl, or halogen.
  • R 6 , R 7 , and the nitrogen to which they are attached form a mo ⁇ holinyl, thiomo ⁇ holinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, hydroxy, hydroxy Q-Q alkyl, or halogen.
  • Embodiment A140 Embodiment A140.
  • Embodiment A142 Compounds according to embodiment A138, wherein Re and R 7 are independently at each occurrence H, Ci-Ce alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl, or Q-Q alkanoyl, wherein each of the above is optionally substituted with 1, 2, or 3 groups that are independently OH, SH, halogen, or Q-Q cycloalkyl.
  • Embodiment A143 Compounds according to embodiment A137, wherein X a and X e are independently fluoro, chloro, or methyl; and X c is hydrogen or halogen.
  • Embodiment A144 Compounds according to embodiment A137, wherein X a is halogen;
  • X e is NH 2 , NH(Q-Q alkyl) or N(Q-Q alkyl)(Q-Q alkyl); X b and Xd are both hydrogen.
  • Embodiment A145 Compounds according to embodiment A144, wherein
  • Xc is -NR 6 R 7 , NR 6 R 7 Q-Q alkyl, -S0 2 NR 6 R 7 , or halogen; wherein Re and R 7 are independently at each occurrence H, Q-Q alkyl, Q-Q alkoxy, Ci- Ce alkoxy Q-Q alkyl, Q-Q alkoxycarbonyl, OH, Q-Q hydroxyalkyl, - (Q-Q)alkyl-C0 2 -alkyl, pyridyl Q-Q alkyl, Q-Q alkanoyl, benzyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, Q-Q alkoxy, piperidinyl Q-Q alkyl, mo ⁇ holinyl Q-Q alkyl, piperazinyl Q
  • Embodiment A 146 Compounds according to embodiment A 145, wherein X c is fluoro, chloro, NH 2 , NH(Q-Q alkyl), N(Q-Q alkyl)(Q-Q alkyl), -S0 2 NH 2 , -S0 2 NH(C ⁇ -C 6 alkyl), -S0 2 N(C ⁇ -Ce alkyl)(Q-Q alkyl), or piperazinyl, wherein the piperazinyl group is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, hydroxy, hydroxy Q-Q alkyl, or halogen.
  • X c is fluoro, chloro, NH 2 , NH(Q-Q alkyl), N(Q-Q alkyl)(Q-Q alkyl), -S0 2 NH 2 , -S0 2 NH(C ⁇ -C 6 alkyl), -S0 2 N(
  • Xc is -C(0)NR 6 R 7 , -(Q-Q alkyl)-C(0)NR 6 R 7 , NR 6 R 7 , or NR 6 R 7 -(Q-Ce alkyl)-; wherein R 6 and R 7 are independently at each occurrence H, Q-Q alkyl, Ci-Ce alkoxy, Ci- Ce alkoxy Q-Q alkyl, Ci-Ce alkoxycarbonyl, OH, Q-Q hydroxyalkyl, - (Q-Q)alkyl-C ⁇ 2 -alkyl, pyridyl Q-Q alkyl, Q-Q alkanoyl, benzyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, Q-Q
  • Embodiment A 148 Compounds according to embodiment A 147, wherein R 6 is hydrogen; and R 7 is Q-Q alkyl or Q-Q alkanoyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently NH 2 , NH(Q-Q alkyl), N(Q-Q alkyl)(Q-Q alkyl), OH, SH, cyclopropyl, or Q-Q alkoxy.
  • Embodiment A 148 a Compounds according to embodiment A 148, wherein , R 7 is Ci-Ce alkanoyl optionally substituted with 1, 2, or 3 groups that are independently OH, cyclopropyl, or NH 2 .
  • Embodiment A149 Compounds according to embodiment A135, wherein X a is hydrogen;
  • X b , X c , or X d is -C(0)NR 6 R 7 , -(Q-Q alkyl)-C(0)NR 6 R 7 , NR 6 R 7 , NR 6 R 7 -(Q-Q alkyl)- or -C0 2 -(Q-Q)alkyl; wherein R 6 and R 7 are independently at each occurrence H, Q-Q alkyl, Q-Q alkoxy, Ci- Ce alkoxy Q-Q alkyl, Q-Q alkoxycarbonyl, OH, Q-Q hydroxyalkyl, - (Q-Q)alkyl-C0 2 -alkyl, pyridyl Q-Q alkyl, Q-Q alkanoyl, benzyl, phenyl Ci-Ce alkoxy, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen,
  • Embodiment A150 Compounds according to embodiment A149, wherein X b is NR 6 R 7 , or NR 6 R 7 -(Q-Q alkyl)-, -C(0)NR 6 R 7 or -C0 2 -(Q-Q)alkyl; wherein R 6 is hydrogen or Q-Q alkyl;
  • R 7 is OH, Q-Q alkyl or Q-Q alkanoyl, wherein the alkyl and alkanoyl groups substituted with 1, 2, or 3 groups that are independently NH 2 , NH(Q-Q alkyl), N(Q-Q alkyl)(Q-Q alkyl), Q-Q cycloalkyl, OH, or Q-Q alkoxy.
  • Embodiment A151 Compounds according to embodiment A 137, wherein X a is halogen;
  • X b is NR 6 R 7 , NReR 7 -(Q-Q alkyl)-, -C(0)NR 6 R 7 , or -C0 2 -(Q-Ce)alkyl;
  • X c is NR 6 R 7 , NR 6 R 7 -(Q-C 6 alkyl)-, -C(0)NR 6 R 7 , halogen, -C0 2 -(Ci-Q)alkyl, NH 2 , NH(Q-Q alkyl), N(Q-Q alkyl)(Q-Q alkyl), -S0 2 NH 2 , -S0 2 NH(Q-Q alkyl), - S0 2 N(Q-Q alkylXQ-Q alkyl), or piperazinyl, wherein the piperazinyl group is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, hydroxy, hydroxy Q-Q alkyl, or
  • X e is H, methyl, NH 2 , NH(Q-Q alkyl) or N(Q-Q alkyl)(Q-Q alkyl).
  • Embodiment A152 Compounds according to embodiment A135, wherein Xi, X 2 , X a , X b , Xc, X d , and X e are independently selected from H, OH, halogen, CF3, alkyl, OCF 3 , pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, thienyl, furyl, pyrrolyl, piperidinyl, piperazinyl, or Q-Q cycloalkyl, wherein each of the above is optionally substituted with -NR 6 R 7 , -C(0)NR 6 R 7 , NR 6 R 7 -(Q-C 6 alkyl)-, Q-Q alkyl, Q-Q alkoxy, or
  • Embodiment A153 Compounds according to embodiment A152, wherein at least three of Xi, X 2 , X a , X b , X c , X d , and X e are hydrogen.
  • Embodiment A154 A compound of the formula:
  • Ri is alkanoyl, halogen, arylalkanoyl, arylalkyl, alkoxyalkyl, hydroxyalkyl, or carboxaldehyde, wherein the aryl portion of arylalkyl, and arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, nitro, CN, haloalkyl, haloalkoxy or C0 2 H; the alkyl portion of the hydroxyalkyl, arylalkyl, alkanoyl, alkoxyalkyl and arylalkanoyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, ethoxy or spirocyclopropyl; R 2 is arylalkoxy, aryloxy, phenyloxy(Q-Q)a ⁇ kyl, OH
  • Embodiment A 160 Compounds according to embodiment A 154 wherein Ri is halogen, (Q-Q)alkanoyl, phenyl(Q-Q)alkanoyl, naphthyl(Q-C 6 )alkanoyl, naphfhyl(Q-Q)alkyl, phenyl(Q-Q)arkyl, alkoxyalkyl, hydroxyalkyl, or carboxaldehyde, wherein the phenyl and naphthyl portions of the above are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, nitro, CN, CF 3 , OCF 3 or C0 2 H; the alkyl portion of the above groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, or ethoxy.
  • R 2 is phenylalkoxy, aryloxy, phenyloxy(Q-Q)arkyl, OH, halogen, phenylthioalkoxy, alkoxy, alkyl, alkoxyalkoxy, -OC(0)NH(CH 2 ) n phenyl, -OC(0)N(alkyl)(CH 2 ) n phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazolyl, or thienyl, wherein n is 0, 1, 2, 3, or 4, and the above groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, -(Q-Q)alkyl-N(R)-CO 2 R 30 , halo(Q-Q)alkyl, or thienyl; R 3 is halogen, phenylalkoxycarbonyl, phenyloxycarbonyl, phenyl(Q-Q)al
  • R 4 is H, (Q-Q) alkyl substituted with one group that is C0 2 H, -C0 2 -(Q-Q)alkyl, -C(0)NRR, -N(R 30 )C(O)NRR, -N(R 30 )C(O)-(Q-Q)alkoxy, or -NR 6 R 7 , phenylalkoxy, phenyl(Q-Q)alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, or alkoxyalkoxy, wherein the phenyl portion of the above groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, CF 3 , or OCF 3 .
  • R 5 is phenyl(Ci-C 6 )alkyl, (Q-Q)alkyl, phenyl, naphthyl, pyridyl, (Q-Q)alkoxy, piperidinyl(C ⁇ -Q)alkyl, pyrrolyl(Q-Q)alkyl, imidazolidinyl(C ⁇ -C 6 )alkyl, pyrazolyl(Ci-Ce)alkyl, imidazolyl(Q-C 6 )alkyl, tetrahydropyridinyl(C ⁇ -Ce)alkyl, thienyl(Ci-Q)alkyl, phenylthio(C ⁇ -Ce)alkyl, or pyridyl(C ⁇ -Ce)alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently (Q-Q)alkyl, fluoro, chloro, bromo, (Q
  • Embodiment A161 Compounds according to embodiment A160 wherein Ri is halogen, (Q-Q)alkanoyl, phenyl(Q-Q)alkanoyl, benzyl, phenethyl, phenpropyl, hydroxyalkyl, or carboxaldehyde, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, nitro, CN, CF 3 , OCF 3 or C0 2 H; the alkyl portion of the above groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, or ethoxy;
  • R 2 is benzyloxy, phenethyloxy, phenpropyloxy, phenbutyloxy, phenyloxy, phenyloxy(Q- Q)alkyl, OH, halogen, phenylthioalkoxy, alkoxy, alkyl, alkoxyalkoxy, wherein n is O, 1, 2, 3, or 4, and the above groups are unsubstituted or substituted with 1, 2, or 3, groups that are independently halogen, -(Q-Q)alkyl-N(R)-CO 2 R 30 , halo(Q-Q)alkyl, or thienyl;
  • R 3 is halogen, phenylalkoxycarbonyl, phenyloxycarbonyl, phenyl(C ⁇ -Q)alkyl, phenylalkoxy, phenyloxy, phenylthio, thioalkoxy, phenylthioalkoxy, (Q- Q)alkenyl,
  • R 5 is benzyl, phenethyl, phenpropyl, phenbutyl, (Q-Q)alkyl, phenyl, or pyridyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently (Q-Q)alkyl, fluoro, chloro, bromo, (Q-Q)alkoxy, phenyl(Q- Q)alkoxy, fhio(Q-Q)alkoxy, (Q-Q)a ⁇ koxycarbonyl, C0 2 H, CN, amidinooxime, NR 6 R 7 , NR 6 R 7 -(Q-Q alkyl)-, -C(0)NR 6 R 7 , amidino, CF 3 , or OCF 3 .
  • Embodiment A 162 Compounds according to embodiment A 161 wherein R, is bromo, phenyl(Q-Q)alkanoyl, benzyl, phenethyl, phenpropyl, hydroxyalkyl, or carboxaldehyde, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, nitro, CN, CF 3 , OCF 3 or C0 2 H; R 2 is benzyloxy, phenethyloxy, phenpropyloxy, phenbutyloxy, phenyloxy, phenyloxy(Q- Q)alkyl, OH, halogen, or phenylthioalkoxy, wherein n is 0, 1, 2, 3, or 4, and the above groups are unsubstituted or substituted with 1, 2, or 3, groups that are independently halogen, -(Q-C 6
  • R 5 is benzyl, phenethyl, phenpropyl, (Q-Q)alkyl, phenyl, or pyridyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently (Q-Q)alkyl, fluoro, chloro, bromo, (Q-Q)alkoxy, C0 2 H, CN, amidinooxime, amidino, CF 3 , OCF 3 , NR 6 R 7 , NR 6 R 7 -(Q-Q alkyl)-, or -C(0)NR 6 R 7 ; wherein R 6 and R 7 are independently hydrogen, OH, Q-Q alkoxy, Q-Q alkanoyl, or Q- Q alkyl, wherein each of the above is optionally substituted with 1 or 2 groups that are independently OH, NH 2 , Q-Q cycloalkyl, or halogen; or R 6 , R 7 , and the nitrogen to which
  • Ri is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, arylalkoxy, arylalkyl, CN, alkanoyl, alkoxy, alkoxyalkyl, or arylalkanoyl, wherein the aryl portion of arylalkoxy, arylalkyl, and arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO 2 H; wherein the alkyl portion of the alkyl, hydroxyalkyl, arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and arylalkanoyl groups is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, ethoxy
  • R 5 is arylalkyl, alkyl, aryl, alkoxy, heterocycloalkylalkyl, heteroarylalkyl, arylthioalkyl, heterocycloalkyl, or heteroaryl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, alkoxy, arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, C0 2 H, CN, amidinooxime, NR 6 R 7 , NReR 7 -(Q-Q alkyl)-, -C(0)NR 6 R 7 , amidino, haloalkyl, or haloalkoxy; wherein R 6 and R 7 are independently at each occurrence H, Q-Q alkyl, Q-Q alkoxy, Ci- Ce alkoxy Q-Q alkyl, Q-Q alkoxycarbonyl, OH, Q-
  • Embodiment A168 Compounds according to embodiment A163 wherein R 5 is benzyl, phenethyl, phenpropyl, phenbutyl, alkyl, phenyl, alkoxy, pyridyl(Q-Q)alkyl, phenyl(Q-Q)fhioalkyl, pyrrolyl, pyrrolyl(Q-Q)alkyl, or pyridyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently (Q-Q)alkyl, halogen, (Q-Q)alkoxy, phenyl(Q-C 6 )alkoxy, (Q- Q)thioalkoxy, alkoxycarbonyl, C0 2 H, CN, amidinooxime, amidino, CF 3 , or OCF 3 .
  • Embodiment A 169 Compounds according to embodiment A 163 wherein Ri is H, Cl, Br, (Q-Q)alkyl, carboxaldehyde, hydroxy(Q-Q)alkyl, wherein the alkyl portion of above is unsubstituted or substituted with 1, 2, or 3 , groups that are independently halogen, methoxy, or ethoxy
  • R 2 is H, phenylthio, -OC(0)NH(CH 2 ) » aryl, phenylalkyl, -OC(0)N(alkyl)(CH 2 ) deliberatelyaryl, or phenylthio(Q-Ce)alkoxy, wherein n is 1, 2, 3, or 4; wherein the aryl groups are optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, -(Q-Ce)alkyl-N(R)-C0 2 R 3 o, Q-Q alkoxy, Q- Q alkyl, CF 3 , or OCF 3 ; R 3 is bromo, alkoxycarbonyl, phenylalkoxycarbonyl, phenyloxycarbonyl, phenylalkyl, phenylalkoxy, phenyloxy, phenylthio, thioalkoxy, phenylthioalkoxy, alkenyl, NR 6 R 7 or alkyl,
  • Ri is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, arylalkoxy, arylalkyl, CN, alkanoyl, alkoxy, alkoxyalkyl, or arylalkanoyl, wherein the aryl portion of arylalkoxy, arylalkyl, and arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, nitro, CN, haloalkyl, haloalkoxy or C0 2 H; wherein the alkyl portion of the alkyl, hydroxyalkyl, arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and arylalkanoyl groups is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, eth
  • R 3 is halogen, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl, -OC(0)NH(CH 2 ) promaryl, arylalkoxy, -OC(0)N(alkyl)(CH 2 ) n aryl, aryloxy, arylthio, thioalkoxy, arylthioalkoxy, alkenyl, NR 6 R Q-Q alkyl, NR 6 R 7 or alkyl, wherein the aryl portion of arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl, -OC(0)NH(CH 2 ) tenuaryl, arylalkoxy, -OC(0)N(alkyl)(CH 2 ) n aryl, and arylthioalkoxy, is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy, alkyl, halo
  • Ri is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, benzyloxy, phenethyloxy, phenpropyloxy, benzyl, phenethyl, phenpropyl, CN, alkanoyl, alkoxy, or phenylC(O)-, phenylCH 2 C(0)-, or phenylCH 2 CH 2 C(0), wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, nitro, wherein the above alkyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, or ethoxy; R is benzyloxy, phenethyloxy, phenpropyloxy, phenyloxy, phenyloxy(Q
  • Embodiment A 174 Compounds according to embodiment A 173 wherein R, is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, benzyloxy, phenethyloxy, benzyl, phenethyl, CN, (Q-Q)alkanoyl, alkoxy, or phenylC(O)-, or phenylCH 2 C(0)-, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, nitro, CN, CF 3 , OCF 3 or C0 2 H; R 2 is benzyloxy, phenethyloxy, phenpropyloxy, phenyloxy, phenyloxy(Q-Q)alkyl, halogen, phenyl(Q-Q)fhioalkoxy, -OC(0)NH(CH 2 ) n
  • Embodiment A 175. Compounds according to embodiment A 174 wherein R 5 is substituted with at least one group selected from fluoro, chloro, bromo, and methyl.
  • the invention provides pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier, solvent, adjuvant or excipient and a compound of formula I, embodiment A66, or embodiment A 154.
  • the invention further provides pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier, solvent, adjuvant or excipient and compounds according to any of the preceding embodiments.
  • the invention encompasses methods of treating a TNF mediated disorder, a p38 kinase mediated disorder, inflammation and/or arthritis in a subject, the method comprising treating a subject having or susceptible to such disorder or condition with a therapeutically-effective amount of a compound of formula I or embodiment Al.
  • the invention provides methods for treating or preventing inflammation; arthritis, rheumatoid arthritis, spondylarthropathies, gouty arthritis, osteoarthritis, systemic lupus erthematosus, juvenile arthritis, and other arthritic conditions; neuroinflammation; allergy, Th2 mediated diseases; pain, neuropathic pain; fever; pulmonary disorders, lung inflammation, adult respiratory distress syndrome, pulmonary sarcoisosis, asthma, silicosis, chronic pulmonary inflammatory disease, and chronic obstructive pulmonary disease (COPD); cardiovascular disease, arteriosclerosis, myocardial infarction (including post-myocardial infarction indications), thrombosis, congestive heart failure, cardiac reperfusion injury, as well as complications associated with hypertension and/or heart failure such as vascular organ damage, restenosis; cardiomyopafhy; stroke including ischemic and hemorrhagic stroke; reperfusion injury; renal reperfusion injury; ischemia
  • Compounds of the invention are also useful for preventing the production or expression of cyclooxygenase-2, or cyclooxygenase-2 activity.
  • the invention encompasses methods of treating a p38 kinase or TNF- alpha mediated disorder comprising administering to a patient in need thereof a therapeutically effective amount of Compounds according to embodiment 1 and at least one pharmaceutically acceptable carrier, adjuvant, solvent or excipient.
  • Representative compounds of the invention are: l-benzyl-4-(benzyloxy)-3-bromopyridin-2(lH)-one; 3-bromo-l-(4-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-dimethylphenyl)-6-methylpyridin- 2(lH)-one; 4-(benzyloxy)-3-bromo-l-(4-fluorobenzyl)pyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(3-fluorobenzyl)pyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(pyridin-3-ylmethyl)pyridin
  • Embodiment 57 Compounds according to embodiment 1 or embodiment Al, which is 3-bromo-4-[(4-chlorobenzyl)oxy]-l-(4-fluorobenzyl)pyridin-2(lH)-one; 1 -benzyl-3-bromo-4-[(4-chlorobenzyl)oxy]pyridin-2( lH)-one; 3-bromo-l-(4-chlorobenzyl)-4-[(4-chlorobenzyl)oxy]pyridin-2(lH)-one; 3-bromo-4-[(4-chlorobenzyl)oxy]-l-[2-(phenylthio)ethyl]pyridin-2(lH)-one; 3-bromo-4-[(4-chlorobenzyl)oxy]-l-(2-phenylethyl)pyridin-2(lH)-one; 3-bromo-4-hydroxy- l-(4-hydroxybenzyl)pyridin
  • Embodiment 59 Compounds according to embodiment 1 or embodiment Al, which is 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2-fluorobenzyl)pyridin-2(lH)-one; 3-bromo-4-[(4-r uorobenzyl)oxy]-6-methyl-l-(pyridin-3-ylmethyl)pyridin-2(lH)- one; 3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl- 1 -(pyridin-4-ylmethyl)pyridin-2( 1H)- one; 3-bromo-l-(2,6-dichlorophenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2(lH)- one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(3-methoxybenzyl)pyridin-2(lH)-one; 3-
  • Embodiment 60 A Compound according to embodiment 1, which is l-(l-acetyl-2,3-dihydro-lH-indol-5-yl)-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6- methylpyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(l-glycoloyl-2,3-dihydro-lH-indol-5-yl)- 6-methylpyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[l-(2-hydroxy-2-methylpropanoyl)-2,3- dihydro- lH-indol-5-yl]-6-methylpyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl
  • Embodiment 75 A compound according to Embodiment 17, wherein Z 5 is Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q-Q alkoxycarbonyl, CF 3 , or Q-Q alkanoyl.
  • Embodiment 76 A compound according to Embodiment 17, wherein Z 5 is Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q-Q alkoxycarbonyl, CF 3 , or Q-Q alkanoyl.
  • Embodiment 77 Embodiment 77.
  • R 4 is H, alkyl optionally substituted with one or two groups that are independently C0 2 R, OH, -C0 2 alkyl, -C(0)NR 6 R 7 , -OC(0)NR 6 R 7 , -OC(0)-(Q-Q alkyl), -C(0)R 6 , -N(R 30 )C(O)NR 6 R 7 , -N(R 30 )C(O)-(Q-Q)alkoxy, or -NR 6 R 7 , -C(0)NR 6 R 7 , phenyl(Q-Q)alkoxy, phenyl (Q-Q)alkyl, hydroxyalkyl, dihydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the phenyl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, CF 3 , O
  • Embodiment 78 A compound according to Embodiment 77, wherein R 2 is -OS0 2 -phenyl, phenylalkoxy, phenyloxy, phenylthioalkoxy, phenylalkynyl, phenyloxy(Q-C 6 )alkyl, -OC(0)NH(CH 2 ) classroomphenyl, -OC(0)N(alkyl)(CH 2 ) n ⁇ henyl, pyridyl, pyrimidyl, thienyl, piperazinyl, imidazolidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, or tetrahydrofuranyl, wherein each of the above is substituted with 1, 2, 3, 4, or 5 groups wherein at least one group is of the formula -(Q-Q alkyl)-NR 6 C(0)NR 7 -(Q-Q alkoxy), -(Q- Q alkyl)
  • Zi is H, halogen, Q-Q alkyl, CF 3 , Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, or Q-Q alkoxy; and Z 2 is Q-Q alkyl, -C(0)NR 6 R 7 , -(Q-Q alkyl)-C(0)NR 6 R 7 , -NR 6 R 7 , NR 6 R 7 (Q-Q alkyl), Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q-Q alkoxy, C0 R, OH, Q- Q alkoxycarbonyl, CF 3 , or Q-Q alkenyl optionally substituted with C0 2 H, or - OC(0)NR 16 R ⁇ 7 ; and Z 3 is H, halogen, Q-Q alkyl, Q-Q alkoxy, alkoxyalkyl, -S0 2 -alkyl or C 2 -Q alkenyl, wherein the alkyl, alkoxy, and al
  • Embodiment 79a A compound according to embodiment 79, wherein
  • R 6 and R 7 are independently H, Q-Q alkyl or hydroxyalkyl.
  • Embodiment 79b A compound according to embodiment 79 or 79a, wherein Zi is H, Q-Q alkyl, or fluorine.
  • Embodiment 80 A compound according to embodiment 79 or 79a, wherein Zi is H, Q-Q alkyl, or fluorine.
  • a compound according to Embodiment 79 wherein R 2 is benzyloxy or phenyl Q-Q thioalkoxy, each of which is substituted with 1, 2, 3, 4, or 5 groups wherein at least one group is of the formula -(Q-Q alkyl)-NR 6 C(0)NR 7 - (Q-Q alkoxy) and the other groups, if present, are independently halogen, amino, monoalkylamino, dialkylamino, CF 3 , OCF 3 , Q-Q alkyl, CN, hydroxyalkyl, or dihydroxyalkyl, wherein R 6 and R 7 are independently at each occurrence H, alkyl optionally substituted with NR ⁇ 6 Rj 7 or a heteroaryl group that is selected from thienyl, pyridyl, and furanyl, hydroxyalkyl, dihydroxyalkyl, alkoxy optionally substituted with NR ⁇ 6 R 17 , Q-Q alkoxy Q-Q alkyl, Q-Q alkan
  • k is O, 1, 2, 3, or 4;
  • R 18 is Q-C 6 alkyl;
  • R ⁇ at each occurrence is independently halogen, -NR 6 R 7 , CF 3 , OCF 3 , C ! -C 4 alkyl, -(Q- C 4 )alkyl-C(0)NR 6 R 7 , R 6 R 7 N-(Q-C 6 alkyl)-, -C(0)NR 6 R 7 , -(Q-Q alkyl)- NRC(0)NR ⁇ 6 R ⁇ 7 , CN, hydroxyalkyl, dihydroxyalkyl, -OC(0)NR 6 R 7 , or -(Q- C 6 )alkyl-N(R)-CO 2 R 30 .
  • Embodiment 82 Embodiment 82.
  • a compound according to Embodiment 77 wherein R 2 is benzyloxy or phenyl Q-Q thioalkoxy, each of which is substituted with 1, 2, 3, 4, or 5 groups independently selected from -(Q-Q aikyl)-NR 6 C(0)NR 7 -(Q-Q alkoxy), -(Q-Q alkyl)-NRi 6 C(0)NR 17 -(Q-C 6 cycloalkyl), halogen, amino, monoalkylamino, dialkylamino, CF 3 , OCF 3 , Q-Q alkyl, CN, hydroxyalkyl, or dihydroxyalkyl, wherein R 6 and R 7 are independently at each occurrence H, alkyl optionally substituted with NR ⁇ R 17 or a heteroaryl group that is selected from thienyl, pyridyl, and furanyl, hydroxyalkyl, dihydroxyalkyl, NR ⁇ 6 R 17 , alkoxy optionally substituted with NR 16 R
  • Embodiment 83 A compound according to Embodiment 82, wherein R 2 is benzyloxy substituted with 1, 2, 3, or 4 groups that are independently halogen, -NR 6 R 7 , Q-Q haloalkyl, Q-Q haloalkoxy, Q-Q alkyl optionally substituted with -(Q-Q alkyl)-NR 6 C(0)NR 7 -(Q-Q alkoxy), -(Q-Q)alkyl-C(0)NR 6 R 7 , R 6 R 7 N-(Q-C 6 alkyl)-, -C(0)NR 6 R 7 , -(Q-Q alkyl)-NRC(0)NR 16 Ri 7 , CN, hydroxyalkyl, dihydroxyalkyl, -OC(0)NR 6 R 7 , or -(Q-C 6 )alkyl-N(R)-CO 2 R 30 , R 5 is selected from the group consisting of H, phenyl(Q-Q)alkyl, (Q-Q
  • Embodiment 84 A compound according to Embodiment 83, wherein R 16 and R 17 at each occurrence are independently H or Q-Q alkyl; R 6 and R 7 are independently at each occurrence H, alkyl, hydroxyalkyl, dihydroxyalkyl, alkoxy optionally substituted with NR ⁇ 6 R ⁇ , Q-Q alkoxy Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, tetrahydropyranyloxy, Q-Q alkenyl optionally substituted with -OC(0)NR ⁇ 6 R ⁇ 7 , -S0 2 -phenyl, -S0 2 -Q-Q alkyl, phenyl, pyrrolidinyl Q-Q alkanoyl, piperidinyl Q-Q alkanoyl, phenyl Q-Q alkoxy, phenyl Q-Q alkoxycarbonyl, or phenyl Q-Q alkanoyl, wherein each of
  • R 5 is pyridyl, pyrimidyl, pyrazinyl, pyridyl (Q-Q) alkyl, pyrimidinyl (Q-Q) alkyl, or pyrazinyl (Q-Q) alkyl wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently NR 16 R 17 , Ci-Ce alkyl optionally substituted with 1 or 2 groups that are independently NR 16 R 17 , -NR ⁇ 6 S0 2 -alkyl, - NR 16 S0 2 -phenyl, r OC(0)NH 2 , or -OC(0)NR ⁇ 6 R 17 , halogen, -OC(0)NR 6 R 7 , Ci- Ce alkoxy optionally substituted with NR 16 R 17 , phenyl Q-Q alkoxy, Q-Q thioalkoxy, Q-Q alkoxycarbonyl, C0 2 R, CN, -S(Q
  • Ri is halogen;
  • R 4 is hydroxyalkyl or Q-Q alkyl optionally substituted with one or two groups that are independently C0 2 R, -C0 2 alkyl, -C(0)NH 2 , -C(0)NH(Q-Q alkyl), -C(0)NH(Q- Q alkyl)(Q-Q alkyl), -C(0)-Q-Q alkyl, -N(R 30 )C(O)NR 16 R 17 , or -N(R 30 )C(O)- (Q-Q)alkoxy;
  • R 5 is pyridyl, pyrimidyl, pyrazinyl, pyridyl (Q-Q) alkyl, pyrimidinyl (Q-Q) alkyl, or pyrazinyl (Q-Q) alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3, groups that are independently NRieR ⁇ , Q-Q alkyl optionally substituted with 1 or 2 groups that are independently NR ⁇ 6 R ⁇ 7 , -NR ⁇ 6 S0 2 -alkyl, -NR 16 S0 2 - phenyl, -OC(0)NH 2 , or -OC(0)NR ⁇ 6 R ⁇ 7 , halogen, -OC(0)NR 6 R 7 , Q-Q alkoxy optionally substituted with NR ⁇ 6 R ⁇ 7 , -S0 2 (Q-Q alkyl) optionally substituted with NR ⁇ 6 R ⁇ 7 , -S0 2 (Q-Q)alkyl optionally substituted
  • R 5 o is NRieR ⁇ , alkyl optionally substituted with 1, 2, or 3 groups that are independently - NRieR ⁇ , -NR ⁇ 6 S0 2 alkyl, or -NR 16 C0 2 Q-Q alkyl, alkoxy optionally substituted with NR ⁇ 6 R ⁇ , -S (Q-Q alkyl) optionally substituted with NRieR ⁇ , -S0 2 (Q-Q alkyl) optionally substituted with NRieR ⁇ , piperazinyl optionally substituted with 1 or 2 groups that are independently H, alkyl, alkanoyl, or CONReR 7 , -alkyl- NR 16 S0 2 phenyl wherein the phenyl group is optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, alkyl, alkoxy, or CONR 16 R ⁇ , alkoxyalkyl optionally substituted with NRieR ⁇ , or -alkyl-OC(0)NR 16 R 17 , NR 8 R 9 , CN
  • Re and R 7 are independently H, Q-Q alkyl, hydroxyalkyl, Q-Q alkanoyl, -SO 2 -Q-Q alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH 2 , -C(0)NH(Q-C 6 alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, mo ⁇ holinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q- Q haloalkoxy.
  • Embodiment 88 A compound according to Embodiment 85, wherein R 5 is of the formula:
  • R 55 is -(Q-Q alkyl)-NR 6 R 7 , or -NR 6 R 7 ; wherein R 6 and R 7 are independently H, Q-Q alkyl, hydroxyalkyl, Q-Q alkanoyl, -S0 2 - Q-Q alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH 2 , -C(0)NH(Ci-Q alkyl), - C(0)N(Q-Q alkylXQ-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, mo ⁇ holinyl, pyrrolidinyl, piperazinyl, - OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q
  • Embodiment 88a A compound according to embodiment 88 wherein R 6 is derived from 2-aminopiOpionic acid. More preferably it is derived from (2R)-aminopropionic acid.
  • Embodiment 88b A compound according to embodiment 88 wherein R 6 is derived from 2-amino, 3-hydroxypropionic acid. More preferably, R 6 is derived from the (R) isomer.
  • Embodiment 89 A compound according to Embodiment 85, wherein R 5 is of the formula:
  • each R 60 is independently H, -C(0)NR 6 R 7 , -C0 2 R, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, -(Q-Q alkyl)-NR 6 R 7 , halogen, Q-Q alkenyl, CN, or -NR 6 R 7 , wherein R 6 and R 7 are independently H, Q-Q alkyl, Q-Q alkanoyl, wherein the alkyl portion of each of the above is optionally substituted with OH, or halogen; R at each occurrence is independently H or Q-Q alkyl optionally substituted with 1 or 2 groups that are independently OH, SH, halogen, amino, monoalkylamino, dialkylamino or Q-Q cycloalkyl.
  • Embodiment 90 A compound according to Embodiment 85, wherein
  • R 5 is R 60 is -S0 2 -Q-Q alkyl, or -(Q-Q alkyl)-NR 6 R 7 , wherein Re and R 7 are independently H, Q-Q alkyl, Q-Q alkanoyl, wherein the alkyl portion of each of the above is optionally substituted with OH, or halogen; R at each occurrence is independently H or Q-Q alkyl optionally substituted with 1 or 2 groups that are independently OH, SH, halogen, amino; monoalkylamino, dialkylamino or Q-Q cycloalkyl; and R 61 is H or Q-C alkyl, or Q-Q alkoxy, or halogen.
  • Embodiment 91 Embodiment 91.
  • R 5 is Q-Q alkenyl -alkenyl-C0 2 -alkyl, and -alkenyl-C0 2 H, each of which is optionally substituted with -NR 6 R 7 , OH, -C(0)NR 6 R 7 , wherein R 6 and R 7 at each occurrence are independently H, alkyl optionally substituted with a heteroaryl group that is selected from thienyl, pyridyl, and furanyl, hydroxyalkyl, dihydroxyalkyl, alkoxy optionally substituted with NRieR ⁇ , Q-Q alkoxy Q-Q alkyl, Q- Q alkanoyl, phenyl Q-Q alkyl, tetrahydropyranyloxy, tetrahydrofuranyloxy, piperidinyloxy, pyrrolidinyloxy, Q-Q alkenyl optionally substituted with -OC(0)NR ⁇ 6 R ⁇ , -S0
  • Embodiment 91a A compound according to embodiment 91, wherein R 4 is alkyl which is optionally substituted with one or two groups that are independently C0 2 R, OH, -C(0)NR 6 R 7 , -OC(0)NR 6 R 7 , -OC(0)-(Q-Q alkyl), or -NR 6 R 7 . More preferably, R 4 is methyl or Cl alkyl optionally substituted with with one or two groups that are independently C0 2 R, OH, -C(0)NR 6 R 7 , -OC(0)NR 6 R 7 , -OC(0)-(Q-Q alkyl), or -NR 6 R 7 .
  • Embodiment 91b Embodiment 91b.
  • R 6 and R 7 are H, Q-Q alkyl, phenyl, amino(Q-Q alkyl), alkylamino(C ⁇ -C 4 alkyl), amino(C ⁇ -Ce alkanoyl), and alkylamino(C ⁇ -Q alkanoyl).
  • R 5 is phenyl optionally substituted with 1, 2, 3, 4, or 5 groups that are independently NR ⁇ 6 R 1 , Q-Q alkyl optionally substituted with 1 or 2 groups that are independently NR 16 R ⁇ , -NR 16 S0 2 -alkyl, -NR 16 S0 2 -phenyl, -OC(0)NH 2 , - OC(0)NHR 16 , OH, or -0C(0)NR 16 R 17 , halogen, -OC(0)NR 6 R 7 , Q-Q alkoxy optionally substituted with NRi ⁇ R ⁇ , phenyl Q-Q alkoxy, Q-Q thioalkoxy, Q-Q alkoxycarbonyl, C0 2 R, CN, carboxaldehyde, -S0 2 (Ci-Ce)alkyl optionally substituted with NR ⁇ 6 R 1 , -S0 2 NR 16 Ri7 ) amidinooxime, NR 8 R
  • Embodiment 92a A compound according to embodiment 92, wherein R 4 is alkyl which is optionally substituted with one or two groups that are independently C0 2 R, OH, -C(0)NR 6 R 7 , -OC(0)NR 6 R 7 , -OC(0)-(Q-Q alkyl), -N(R 30 )C(O)-(Q-Q alkyl)-NR 6 R 7 , or -NR 6 R 7 .
  • R 4 is methyl or Cl alkyl optionally substituted with with one or two groups that are independently C0 2 R, OH, -C(0)NR 6 R 7 , -OC(0)NR 6 R 7 , -OC(0)-(Q- Q alkyl), or -NR 6 R 7 .
  • Embodiment 92b A compound according to embodiment 92a, wherein R 6 and R 7 are H, Q-Q alkyl, phenyl, amino(Q-Q alkyl), alkylamino(Q-Q alkyl), amino(Q-Q alkanoyl), and arkylamino(Q-Q alkanoyl).
  • Embodiment 93 Embodiment 93.
  • R 5 is ⁇ henyl(Q-Q)alkyl, which is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently NR ⁇ 6 R ⁇ , Q-Q alkyl optionally substituted with 1 or 2 groups that are independently NR 15 R ⁇ , -NR 16 S0 2 -alkyl, -NR 16 S0 2 - ⁇ henyl, -OC(0)NH 2 , - OC(0)NHR ⁇ e, OH, or -OC(0)NR 16 R ⁇ , halogen, -OC(0)NR 6 R 7 , Q-Q alkoxy optionally substituted with NRieR ⁇ , phenyl Q-Q alkoxy, Q-Q thioalkoxy, Q-Q alkoxycarbonyl, C0 2 R, CN, carboxaldehyde, -S0 2 (Q-Q)alkyl optionally substituted with NR 16 R ⁇ , -S0 2 NR 16 R ⁇ , amidinooxime,
  • R 5 is selected from the group consisting of H, (Q-Q)alkyl optionally substituted with 1, 2, 3, 4, or 5 groups that are independently phenyl Q-Q alkoxycarbonyl, -NR 8 R 9 , halogen, -C(0)NR 8 R 9 , alkoxycarbonyl, or alkanoyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, benzothiazolyl, isoindolyl, dihydroindolyl, pyrazolyl, 3H- isobenzofuran-1-onyl, imidazolyl, pyridyl, pyrimidyl, pyrazinyl, furanyl, dihydroisoindolyl, indolon-2-yl, indazolyl, thienyl, benzimidazolyl, imidazolidine dione, pyrazolyl(Q-Q alkyl), furanyl(Q
  • Embodiment 95 A compound according to Embodiment 94, wherein R 5 is indolyl (Q-Q) alkyl-, indolinyl-(Q-C 4 alkyl)-, isochroman-4-one (Q-Q) alkyl-, indolon-2-yl(Q-Q) alkyl-, benzoxazolyl (Q-Q) alkyl-, 3H-isobenzofuran-l-one (Q-Q) alkyl-, 3H-isobenzofuran-l-one, dihydro-lH-isoindolyl(Q-Q) alkyl, dihydroisoindolyl(Q-Q) alkyl, benzothiazolyl (Q-Q) alkyl-, benzothiazolyl, benzimidazolyl, or benzimidazolyl (Q-Q) alkyl-, optionally substituted with 1, 2, 3, or 4 groups that are independently Q-Q alkyl,
  • Embodiment 96 A compound according to Embodiment 94, wherein R 5 is pyrazolyl Q-Q alkyl, oxazolidin-2-one (Q-Q) alkyl, furanyl, thienyl, or furanyl Q- Q alkyl, which are optionally substituted with 1 or 2 groups independently selected from the group consisting of -C(0)NR 6 R 7 , NR 6 R 7 Q-Q alkyl, Q-Q alkyl, Q-Q alkoxycarbonyl, (Q-Q) alkyl optionally substituted with 1 or 2 groups that are independently NRieR ⁇ , -NRi 6 S0 2 -alkyl, -NR 16 S0 2 -phenyl, - OC(0)NH 2 , -OC(0)NHR 16 , OH, or -OC(0)NR 16 R , hydroxy Q-Q alkyl, heterocycloalkyl which is selected from the group consisting of mo ⁇ holinyl, piperazinyl, te
  • Embodiment 97 A compound according to Embodiment 1 that is selected from (2E)-4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]but-2-enoic acid; 3-[4- ⁇ [2-( ⁇ [(cyclopropylamino)carbonyl]amino ⁇ methyl)-4-fluorobenzyl]oxy ⁇ -6-methyl-2- oxopyridin- 1 (2H)-yl] -N,4-dimefhylbenzamide; 3,5-dibromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[4-methyl-2- (methylsulfonyl)pyrimidin-5-yl]pyridin-2(lH)-one; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
  • Y is CONH(CH 2 ) n OH; CONHCH 2 C(Me) 2 OH; CONH(CH 2 ) n NH 2 ; CONH(CH 2 ) n NHCH 3 ; CONH(CH 2 ) n N(CH 3 ) 2 ; CONHCH 2 CH(OH)CH 2 OH; CH 2 NHCOCH 2 NH 2 ; CH 2 NHCOCH 2 OH; CH 2 NHCOCH(NH 2 )CH 2 OH; and n is 1, 2, or 3.
  • Embodiment 101 A compound according to Embodiment 78, of the formula:
  • R 51 is H, OH, NH 2 , NHR 52 , CONHR 52 , or OR 52 ;
  • R 53 is H or alkyl.
  • Embodiment 102 A compound according to Embodiment 78, of the formula:
  • R 5 o is: CH 2 CONH 2 ; CH 2 CONHCH 3 ;
  • alkenyl refers to a straight or branched hydrocarbon of a designed number of carbon atoms containing at least one carbon-carbon double bond.
  • alkenyl include vinyl, allyl, and 2-methyl-3-heptene.
  • alkoxy represents an alkyl attached to the parent molecular moiety through an oxygen bridge. Examples of alkoxy groups include, for example, methoxy, ethoxy, propoxy and isopropoxy.
  • thioalkoxy represents an alkyl attached to the parent molecular moiety through a sulfur atom. Examples of thioalkoxy groups include, for example, thiomethoxy, thioethoxy, thiopropoxy and thioisopropoxy.
  • alkyl includes those alkyl groups of a designed number of carbon atoms. Alkyl groups may be straight or branched. Examples of “alkyl” include methyl, ethyl, propyl, isopropyl, butyl, iso-, sec- and tert-butyl, pentyl, hexyl, heptyl, 3- ethylbutyl, and the like. "Cx-Cy alkyl” represents an alkyl group of the specified number of carbons. For example, Q-C 4 alkyl includes all alkyl groups that include at least one and no more than four carbon atoms.
  • aryl refers to an aromatic hydrocarbon ring system containing at least one aromatic ring.
  • the aromatic ring may optionally be fused or otherwise attached to other aromatic hydrocarbon rings or non-aromatic hydrocarbon rings.
  • aryl groups include, for example, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalene, indanyl, and biphenyl.
  • Preferred examples of aryl groups include phenyl and naphthyl. The most preferred aryl group is phenyl.
  • aryl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups.
  • aryl groups can be optionally substituted with groups such as, for example, Q-Q alkyl, - alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di-(Q-Q)alkylamino, Q- Qalkenyl, Q-Qalkynyl, Q-Q haloalkyl, Q-Q haloalkoxy, amino(Q-Q)alkyl, mono- or di(C 1 -Q)alkylamino(Q-Q)alkyl.
  • arylalkyl refers to an aryl group, as defined above, attached to the parent molecular moiety through an alkyl group, as defined above.
  • Preferred arylalkyl groups include, benzyl, phenethyl, phenpropyl, and phenbutyl. More preferred arylalkyl groups include benzyl and phenethyl. The most preferred arylalkyl group is benzyl.
  • the aryl portions of these groups are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups.
  • aryl groups can be optionally substituted with groups such as, for example, Q-Q alkyl, Q-Q alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di-(Q-Q)alkylamino, Q-Qalkenyl, Q- Qalkynyl, Q-Q haloalkyl, Q-Q haloalkoxy, amino(Q-Q)alkyl, mono- or di(Q- Q)alkylamino(Q-Q)alkyl.
  • arylalkoxy refers to an aryl group, as defined above, attached to the parent molecular moiety through an alkoxy group, as defined above.
  • Preferred arylaloxy groups include, benzyloxy, phenethyloxy, phenpropyloxy, and phenbutyloxy.
  • the most preferred arylalkoxy group is benzyloxy.
  • cycloalkyl refers to a Q-Q cyclic hydrocarbon. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. More preferred cycloalkyl groups include cyclopropyl.
  • cycloalkylalkyl refers to a Q-Q cycloalkyl group attached to the parent molecular moiety through an alkyl group, as defined above.
  • examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.
  • halogen or halo indicate fluorine, chlorine, bromine, or iodine.
  • heterocycloalkyl refers to a non-aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur, wherein the non-aromatic heterocycle is attached to the core.
  • the heterocycloalkyl ring may be optionally fused to or otherwise attached to other heterocycloalkyl rings, aromatic heterocycles, aromatic hydrocarbons and/or non-aromatic hydrocarbon rings.
  • Preferred heterocycloalkyl groups have from 3 to 7 members. Examples of heterocycloalkyl groups include, for example, piperazine, 1,2,3,4-tetrahydroisoquinoline, morpholine, piperidine, tetrahydrofuran, pyrrolidine, and pyrazole.
  • Preferred heterocycloalkyl groups include piperidinyl, piperazinyl, mo ⁇ holinyl, and pyrolidinyl.
  • heterocycloalkyl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups.
  • heterocycloalkyl groups can be optionally substituted with groups such as, for example, Q-Q alkyl, Q-Q alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di-(Q-Q)alkylamino, Q-Qalkenyl, Q-Qalkynyl, Q-Q haloalkyl, Q- Q haloalkoxy, amino(Q-Q)alkyl, mono- or di(Q-Q)alkylamino(Q-Q)alkyl.
  • heteroaryl refers to an aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur.
  • the heteroaryl ring may be fused or otherwise attached to one or more heteroaryl rings, aromatic or non-aromatic hydrocarbon rings or heterocycloalkyl rings.
  • heteroaryl groups include, for example, pyridine, furan, thiophene, 5,6,7, 8-tetrahydroisoquinoline and pyrimidine.
  • heteroaryl groups include thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl, indolyl, pyrazolyl, and benzopyrazolyl.
  • Preferred heteroaryl groups include pyridyl.
  • heteroaryl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups.
  • heteroaryl groups can be - 225 - optionally substituted with groups such as, for example, Q-Q alkyl, Q-Q alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di-(Q-Q)alkylamino, Q-Qalkenyl, Q- Qalkynyl, Q-Q haloalkyl, Q-Q haloalkoxy, amino(Q-Q)alkyl, mono- or di(Q- Q)alkylamino(Q-Q)alkyl.
  • heteroarylalkyl refers to a heteroaryl group, as defined above, attached to the parent molecular moiety through an alkyl group, as defined above.
  • Preferred heteroarylalkyl groups include, pyrazolemethyl, pyrazoleethyl, pyridylmethyl, pyridylethyl, thiazolemethyl, thiazoleethyl, imidazolemethyl, imidazoleethyl, thienylmethyl, thienylethyl, furanylmethyl, furanylethyl, isoxazolemethyl, isoxazoleethyl, pyrazinemethyl and pyrazineethyl.
  • heteroarylalkyl groups include pyridylmethyl and pyridylethyl.
  • the heteroaryl portions of these groups are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups.
  • heteroaryl groups can be optionally substituted with groups such as, for example, Q-Q alkyl, Q-Q alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di- (Q-Q)alkylamino, Q-Qalkenyl, Q-Qalkynyl, Q-Q haloalkyl, Q-Q haloalkoxy, amino(Q-Q)a kyl, mono- or di(Q-Q)alkylamino(Q-Q)alkyl.
  • p38 mediated disorder refers to any and all disorders and disease states in which p38 plays a role, either by control of p38 itself, or by p38 causing another factor to be released, such as but not limited to IL-1, IL-6 or IL-8.
  • IL-1 IL-6
  • IL-8 IL-8
  • TNF-beta has close structural homology with TNF-alpha (also known as cachectin), and since each induces similar biologic responses and binds to the same cellular receptor, the synthesis of both TNF-alpha and TNF-beta are inhibited by the compounds of the present invention and thus are herein referred to collectively as "TNF” unless specifically delineated otherwise.
  • Non-toxic pharmaceutically acceptable salts include, but are not limited to salts of inorganic acids such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, and nitric or salts of organic acids such as formic, citric, malic, maleic, fumaric, tartaric, succinic, acetic, lactic, methanesulfonic, p-toluenesulfonic, 2-hydroxyethylsulfonic, salicylic and stearic.
  • pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium.
  • the compounds of this invention may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates, chiral non-racemic or diastereomers. In these situations, the single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates.
  • Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent; chromatography, using, for example a chiral HPLC column; or derivatizing the racemic mixture with a resolving reagent to generate diastereomers, separating the diastereomers via chromatography or selective crystallization, and removing the resolving agent to generate the original compound in enantiomerically enriched form. Any of the above procedures can be repeated to increase the enantiomeric purity of a compound.
  • the compounds of the invention may exist as atropisomers, i.e., chiral rotational isomers.
  • the invention encompasses the racemic and the resolved atropisomers.
  • the following illustration generically shows a compound (Z) that can exist as atropisomers as well as its two possible atropisomers (A) and (B). This illustration also shows each of atropisomers (A) and (B) in a Fischer projection.
  • R ls R 2 , and R 4 carry the same definitions as set forth for Formula I
  • R p - is a substituent within the definition of R 5
  • R p is a non-hydrogen substituent within the definition of R 5 .
  • the compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques and the like.
  • a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier.
  • One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants, and if desired other active ingredients.
  • the pharmaceutical compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • the pharmaceutical composition may be in the form of, for example, a tablet, hard or soft capsule, lozenges, dispensable powders, suspension, or liquid.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservative agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques. In some cases such coatings may be prepared by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • Formulations for oral use may also be presented as lozenges.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymefhylcellulose, methylcellulose, hydropropyl- methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain - 229 - aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • dispersing or wetting agents may be a naturally-occurring phosphat
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin, or cetyl alcohol. Sweetening agents and flavoring agents may be added to provide palatable oral preparations.
  • compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents or suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring, and coloring agents, may also be present.
  • Pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil or a mineral oil or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose.
  • Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or - 230 - oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono-or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of general Formula I may also be administered in the form of suppositories, e.g., for rectal administration of the drug.
  • suppositories e.g., for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials include cocoa butter and polyethylene glycols.
  • Compounds of general Formula I may be administered parenterally in a sterile medium.
  • the drug can either be suspended or dissolved in the vehicle.
  • adjuvants such as local anesthetics, preservatives, and buffering agents can be dissolved in the vehicle.
  • the active ingredient may also be administered by injection (IV, LM, subcutaneous or jet) as a composition wherein, for example, saline, dextrose, or water may be used as a suitable carrier.
  • the pH of the composition may be adjusted, if necessary, with suitable acid, base, or buffer.
  • Suitable bulking, dispersing, wetting or suspending agents including mannitol and PEG 400, may also be included in the composition.
  • a suitable parenteral composition can also include a compound formulated as a sterile solid substance, including lyophilized powder, in injection vials.
  • Aqueous solution can be added to dissolve the compound prior to injection.
  • the formulations are preferably applied as a topical gel, spray, ointment or cream, or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w.
  • the active ingredients may be employed with either paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in- water cream base.
  • the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane- 1,3- diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof.
  • the topical formulation may desirably include a compound, which enhances absorption or penetration of the active ingredient through the skin or other affected areas.
  • the compounds of this invention can also be administered by a transdermal device.
  • topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety.
  • the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient.
  • the encapsulating agent may also function as the membrane.
  • the transdermal patch may include the compound in a suitable solvent system with an adhesive system, such as an acrylic emulsion, and a polyester patch.
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier, which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low.
  • the cream should - 232 - preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredients are dissolved or suspended in suitable carrier, especially an aqueous solvent for the active ingredients.
  • suitable carrier especially an aqueous solvent for the active ingredients.
  • the anti-inflammatory active ingredients are preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% and particularly about 1.5% w/w.
  • the active compounds of this combination invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration.
  • the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.
  • Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose.
  • Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration.
  • the compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.
  • Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
  • the amount of therapeutically active compounds that are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and - 233 - medical condition of the subject, the severity of the inflammation or inflammation related disorder, the route and frequency of administration, and the particular compound employed, and thus may vary widely.
  • the pharmaceutical compositions may contain active ingredients in the range of about 0.1 to 1000 mg, preferably in the range of about 7.0 to 350 mg.
  • a daily dose of about 0.01 to 100 mg/kg body weight, preferably between about 0.1 and about 50 mg/kg body weight and most preferably between about 0.5 to 30 mg/kg body weight, may be appropriate.
  • the daily dose can be administered in one to four doses per day.
  • the composition may also be added to the animal feed or drinking water. It may be convenient to formulate the animal feed and drinking water compositions so that the animal takes in a therapeutically appropriate quantity of the composition along with its diet. It may also be convenient to present the composition as a premix for addition to the feed or drinking water.
  • R 5 is as defined above.
  • the compounds of the instant invention can be prepared according to the method outlined in Scheme 2.
  • Q at each occurrence is independently alkyl, halogen, alkoxy, arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, C0 2 H, CN, amidinooxime, NR 6 R 7 , NR 6 R 7 alkyl, -C(0)NR 6 R 7 , amidino, haloalkyl, or haloalkoxy; and n is 0, 1, 2, 3, 4, or 5.
  • compounds of the invention can be prepared using the procedures outlined in Schemes 3-30. Q is as above.
  • Y at each occurrence is independently alkyl, halogen, alkoxy, arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, C0 2 H, CN, amidinooxime, NR 6 R 7 , R 6 R 7 N(Q- Q)alkyl, -C(0)NR 6 R 7 , (Q-Q) alkyl-C(0)NR 6 R 7 , amidino, haloalkyl, or haloalkoxy; and n is 0, 1, 2, 3, 4, or 5; R is aryl, alkyl, heteroaryl, arylalkyl heteroarylalkyl, heterocycloalkyl, or heterocycloalkylalkyl.
  • R may be unsubstituted or substituted with Y.
  • R' is aryl, alkyl, heteroaryl, arylalkyl heteroarylalkyl, heterocycloalkyl, or heterocycloalkylalkyl.
  • R may be unsubstituted or substituted with Q.
  • X is Br or Cl.
  • Suitable protecting groups and methodology for protection and deprotection such as those described in Protecting Groups in Organic Synthesis by Greene and Wuts are well known and appreciated in the art. Unless otherwise specified, all reagents and solvents are of standard commercial grade and are used without further purification. The appropriate atmosphere to run the reaction under, for example, air, nitrogen, hydrogen, argon and the like, will be apparent to those skilled in the art.
  • Example 2 The material prepared in Example 1 (2.1 g, 0.007 mol) and sodium acetate (738 mg, 0.009 mol) in glacial acetic acid (15 mL) were cooled to 15 °C. Bromine (0.412 mL, 0.008) in glacial acetic acid (5 mL) was added dropwise. Contents were stirred 2 hours, coming to room temperature. Water (200 mL) was added and a light yellow solid was filtered. Mp 150.4 - 151.2°C. FABHRMS m/z 384.0599 (M+H, C 20 H 19 BrNO 2 requires 384.0601).
  • Example 11 The material of Example 11 was prepared according to the procedure of Example 2. 1H NMR (CDCl 3 /300 MHz) ⁇ : 7.50-7.30 (m, 6H); 6.20 (d, IH); 5.24 (s, 2H). Anal. Calcd for C 12 H 10 BrNO 2 (0.3H 2 O): C, 50.48; H, 3.74; N, 4.91. Found: C, 50.79; H, 3.41; N, 4.82. Examples 12-19. Preparation of compounds corresponding in structure to the following formula:
  • Example 12 The material of Example 12 (120 mg, 0.25 mmol) and 10% palladium/carbon (30 mg) in glacial acetic acid (2 mL) were shaken at 55 lbs of hydrogen for 4 hours. Contents were filtered and the filtrate was concentrated in vacuo leaving an oil. FABHRMS m/z 295.9952 (M+H, C ⁇ 2 H n BrN0 3 requires 295.9922).
  • Example 22 The material of Example 22 was partitioned between EtOAc and 2.5N sodium hydroxide.
  • Example 17 The material of Example 17 (500 mg, 0.00127 mol), hydroxylamine hydrochloride (90 mg, 0.0013 mol) and sodium bicarbonate (109 mg) were refluxed in ethanol (15 mL) overnight. Contents were allowed to cool and a solid was filtered and washed with water to give the desired as a white solid, 447 mg, (82% yield), mp 210.2-212.2 °C FABHRMS m/z 428.0634 (M+H, C 20 H 19 BrN 3 O 3 requires 428.0610).
  • Example 11 To the material of Example 11 (924 mg, 0.0033 mol) in DMF (5 mL) was added dropwise sodium bis(trimethylsilyl)amide (1M in THF, 3.6 mL). Contents were stirred one hour before adding dropwise a solution of 4-methanesulfonyloxymethyl-l-piperidine-l- carboxylic acid tert-butyl ester (J. Labelled Compd, Radiopharm, 38(7), 1996, 595-606) (1.0 g, 0.0036 mol) in DMF (5 mL). Contents were heated at 75°C overnight. Contents were allowed to cool and poured into water (100 mL). A solid was filtered and recrystallized from EtOAc to give white crystals (546 mg).
  • Example 26 The material of Example 26 was prepared according to the procedure of Example 1. FABHRMS m/z 360.1213 (M+H, C 20 H 17 F 3 NO 2 requires 360.1211). 1H NMR (CDCl 3 /300
  • Example 27 The material of Example 27 was prepared according to the procedure of Example 2. FABHRMS m/z 438.0308 (M+H, C 20 H 16 BrF 3 NO 2 requires 438.0316). 1H NMR (CDCl 3 /300 MHz) ⁇ : 7.65-7.20 (m, 10H); 6.13-6.03 (m, IH); 5.30-5.13 (m, 4H). Anal. Calcd for C 20 H 15 BrF 3 NO 2 : C, 54.81; H, 3.45; N, 3.20. Found: C, 54.69; H, 3.34; N, 3.19.
  • Example 28 Preparation of 4-(benzyloxy)-3-bromo-l-(piperidin-3- ylmethyl)pyridin-2(lH)-one hydrochloride
  • Example 11 To the material of Example 11 (3.1 g, 0.011 mol) in DMF (20 mL) was added dropwise sodium bis(trimethylsilyl)amide (1M in THF, 12 mL). Contents were stirred one hour before adding dropwise a solution of 3-methanesulfonyloxymethyl-l-piperidine-l- carboxylic acid tert-butyl ester (Bioorg.Med.Chem.Lett, 8(13), 1998, 1595-1600) (4.2 g, 0.015 mol) in DMF (5 mL). Contents were heated at 75°C overnight. Contents were allowed to cool, poured into water (100 mL) and a solid was filtered.
  • DMF 3-methanesulfonyloxymethyl-l-piperidine-l- carboxylic acid tert-butyl ester
  • Example 11 To the material of Example 11 (500 mg, 0.0018 mol) in DMF (5 mL) was added dropwise sodium bis(trimethylsilyl)amide (1M in THF, 2 mL). Contents were stirred one hour before adding dropwise a solution of methanesulfonic acid 2-thiophen-3-yl-ethyl ester (J.A.C.S, 109(6), 1987, 1858-1859) (412 mg, 0.002 mol) in DMF (5 mL). Contents were heated at 75 C overnight. Contents were allowed to cool, poured into water (100 mL), and extracted into EtOAc, dried over MgS0 4 , filtered, and concentrated in vacuo leaving a light yellow oil.
  • methanesulfonic acid 2-thiophen-3-yl-ethyl ester J.A.C.S, 109(6), 1987, 1858-1859
  • Example 31 Preparation of 4-(benzyloxy)-3-bromo-l-[3-(trifluoromethyl) benzyl]pyridin-2(l/f)-one.
  • DMF dimethyl methoxyethyl
  • sodium bis(trimethylsilyl)amide 1M in THF, 2 mL.
  • Example 32 The material of Example 32 was prepared according to the procedure of Example 31. FABHRMS m/z 438.0280 (M+H, C 20 H 16 BrF 3 NO 2 requires 438.0316). 1H NMR (CDCl 3 /300 MHz) ⁇ : 7.68 (d, IH); 7.55-7.20 (m, 8H); 7.15 (d, IH); 6.10 (d, IH); 5.40 (s, 2H); 5.13 (s, 2H). Anal. Calcd for C 20 H ⁇ 5 BrF 3 NO 2 : C, 54.81; H, 3.45; N, 3.20. Found: C, 54.48; H, 3.36; N, 3.17.
  • Example 33 Preparation of 4-(benzyloxy)-l-[4- (trifluoromethoxy)benzyl]pyridin-2(lfl r )-one
  • Example 33 The material of Example 33 was prepared according to the procedure of Example 1.
  • Example 34 The material of Example 34 was prepared according to the procedure of Example 2. FABHRMS m/z 454.0240 (M+H, C 20 H 16 BrF 3 NO 3 requires 454.0266). 1H NMR (CDCl 3 /300 MHz) ⁇ : 7.45-7.10 (m, 10H); 6.08 (d, IH); 5.20 (s, 2H); 5.12 (s, 2H). Anal. Calcd for C 20 H 15 BrF 3 NO 3 : C, 52.88; H, 3.33; N, 3.08. Found: C, 52.53; H, 3.09; N, 2.92.
  • Example 35 Preparation of l-benzyl-4-(benzyIoxy)-6-methyIpyridin-2(lH)- one
  • Step 1 Preparation of l-benzyl-4-hydroxy-6-methylpyridin-2(lH)-one.
  • 4- hydroxy-6-methyl-2-pyrone (0.2 mol, 25.2 g) and benzylamine (0.2 mol, 21.4 g) were added to water (800 mL) and heated to reflux with stirring for 2 hours. After cooling to room temperature, a light brown solid was collected by filtration. (33.4 g, 77%): 1H NMR (DMSO-d 6 /300 MHz) ⁇ : 10.5 (s, IH), 7.4-7.1 (m, 5 H), 5.8-5.6 (m, 2H), 5.2 (s,2H), 5.1 (s, 2H), 2.2 (s, 3H).
  • Step 2 Preparation of l-benzyl-4-(benzyloxy)-6-methylpyridin-2(lH)-one.
  • 1- benzyl-4-hydroxy-6-methylpyridin-2(lH)-one (10 mmol, 2.15 g), dichloromethane (100 mL), benzylbromide (11 mmol, 1.88 g), sodium hydroxide (2.5 N, 20 mmol, 8 mL), and benzyltriethylammonium chloride (0.5 g) were vigorously stirred at room temperature for 16h.
  • Step 1 Preparation of l-benzyl-6-methyl-2-oxo-l,2-dihydropyridin-4-yl 4- bromobenzenesulfonate.
  • l-benzyl-4-hydroxy-6-methylpyridin-2(lH)-one (from example 35) (10 mmol, 2.15 g), N,N'-dimethylformamide (30 mL), potassium carbonate (20 mmol, 2.76 g), and 4-bromobenzenesulfonyl chloride (10 mmol, 2.55 g) were stirred at room
  • the reaction mixture was concentrated in vacuo and the residue was partitioned between 5% citric acid (25 mL) and EtOAc (50.0 mL). The organic phase was washed with brine, dried - 267 - (Na 2 S0 4 ), filtered, and concentrated to dryness.
  • Step A Preparation of l-benzyl-2-oxo-l,2-dihydropyridin-4-yl methyl(phenyl)carbamate
  • the compounds were separated by reverse phase HPLC using a 10-90% acetonitrile in water, 30 min gradient at a 100 mL/min flow rate, to afford (after lyophilization) the salt of the desired compound.
  • the salt was diluted in EtOAc and washed with NaHC0 3 .
  • the organic extracts were dried over anhydrous Na 2 S0 , filtered, and concentrated to afford the desired compound (0.271 g, 58%) as a beige solid. MS and ⁇ -NMR were consistent with the desired structure.
  • the reaction mixture was filtered through a bed of celite and the filtrate was concentrated under reduced pressure.
  • the dark brown residue was diluted with CH 2 C1 (100 mL) and washed with water.
  • the organic extracts were combined, dried over anhydrous Na S0 4 , filtered, and concentrated under reduced pressure.
  • the dark brown residue was purified by flash chromatography (silica gel) using 30% EtOAc in hexane. The appropriate fractions were
  • Examples 60-69 Preparation of compounds corresponding in structure to the following formula: - 280 - The compounds of Examples 60-69 are prepared essentially according to the procedures set forth above for Example 59.
  • NHBoc Step 1 Preparation of 3-hydroxymethylbenzonitrile. To an ice-cold solution of 3-cyanobenzaldehyde (5.0 g, 38 mmol) in 1 : 1 MeOH/THF (90 mL) was added NaBIL, (1.6 g, 42 mmol), and the reaction mixture was stirred for 3 h. The reaction mixture was diluted with brine, and the solvent was removed under reduced pressure. The residue was dissolved in water, and the aqueous layer was extracted with Et 0 (3 x 100 mL).
  • Step 1 Preparation of 4-(2,4-difluorobenzyIoxy)pyridine-l-oxide.
  • sodium hydride 1.2 g of a 60% dispersion in mineral oil, 51 mmol
  • Step 5 Preparation of 3-bromo-4-(2,4-difluorobenzyloxy)-l-[(4- dimethylaminomethyl) benzylJ-l.H-pyridin-2-one.
  • 3- bromo-l-(4-chloromethylbenzyl)-4-(2,4-difluoro-benzyloxy)-lH-pyridin-2-one (0.49 g, 1.1 mmol) was added a solution of dimethylamine (5.5 mL of a 2.0 M solution in THF, 11 mmol), and the reaction mixture was stirred for 15 h. The solvent was removed under reduced pressure.
  • Example 70 mp 80-84 °C; 1H NMR (300 MHz, DMSO- 6 ) ⁇ 7.60-7.50 (m, IH), 7.33-
  • Step 3 Preparation of 3-chloro-4-(2,4-difluorobenzyloxy)-l-[4- (isopropyIamino-methyl)benzyl]-l/7-pyridin-2-one.
  • Step 2 Preparation of l-chloromethyl-3-methanesulfonylbenzene.
  • Step 2 Preparation of 4-[3-chIoro-4-(2,4-difluorobenzyloxy)-2-oxo-2fl- pyridin-l-ylmethyl]benzamide.
  • Step 1 Preparation of isoquinolin-5-ylmethanol.
  • MeOH MeOH
  • NaBH NaBH (0.17 g, 4.6 mmol)
  • Step 1 Preparation of 5-(carboxymethyl)-indole-l-carbamic acid tert-butyl ester.
  • methyl indole-5-carboxylate (6.9 g, 39 mmol) and Et 3 N (6.0 mL, 43 mmol) in CH 2 C1 2 (150 mL) was added di-tert-butyl dicarbonate (19 g, 86 mmol), and
  • Step 5 Preparation of 3-Chloro-4-(2,4-difluorobenzyIoxy)-l-(l - r -indol-5- ylmethyl)-l£- r -pyridin-2-one.
  • Step 1 Preparation of 4-(2,4-difluorobenzyloxy)-l-(2,4-difluorobenzyl)-l.ff- pyridin-2-one.
  • K 2 C0 3 2.5 g, 13 mmol
  • 2,4-difluorobenzyl bromide 1.0 mL, 7.6 mmol
  • Step 1 Preparation of methyl 3-cyanomethyIbenzoate.
  • methyl 3-bromomethylbenzoate 9.1 g, 40 mmol
  • CH 3 CN 108 mL
  • tetrabutylammonium fluoride 17.3 mL, 60 mmol
  • trimethylsilylcyanide 8.0 mL, 60 mmol
  • Example 104 Preparation of l-(3-aminomethyl-2-fluorobenzyl)-3-bromo-4- (2,4-difluorobenzyloxy)-lH-pyridin-2-one
  • Step 2 Preparation of l-(3-aminomethyl-2-fluorobenzyl)-3-bromo-4-(2,4- difluoro-benzyloxy)-l J fiT-pyridin-2-one.
  • the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure.
  • Step 1 Preparation of 4-Benzyloxy-l-(3-fluorobenzyl)-lff-pyridin-2-one.
  • 4-benzyloxy-lH-pyridin-2-one 1.0 g, 5 mmol
  • K C0 3 2.0 g, 9.9 mmol
  • 3-fluorobenzyl bromide 1.4 g, 7.5 mmol
  • the reaction mixture was cooled to room temperature, and partitioned between EtOAc and water.
  • the organic solution was washed with water and then brine, dried (Na 2 S0 ), filtered and concentrated under reduced pressure.
  • Step 1 Preparation of 4-(2,4-difluorobenzyloxy)-l-(3-fluorobenzy ⁇ )-LH- pyridin-2-one.
  • l-(3-fluorobenzyl)-4-hydroxy-lH-pyridin-2-one (0.92 g, 4.2 mmol) and K 2 C0 3 ( 1.2 g, 8.4 mmol) in acetone (62 mL) was added 2,4-difluorobenzyl bromide (1.3 g, 6.3 mmol), and the reaction mixture was heated at reflux for 3 h.
  • Step 1 Preparation of 4-(2,4-Difluorobenzyloxy)-l-(3-fluorobenzyl)-lH-pyridin-2-one.
  • EXAMPLE 110 l-(3-fluorobenzyl)-4-hydroxy-lH-pyridin-2-one
  • K 2 C0 3 1.15 g, 8.4 mmol
  • acetone 62 mL
  • 2,4- difluorobenzyl bromide 1.3 g, 6.3 mmol
  • Step 2 Preparation of l-(3-Fluorobenzyl)-4-methoxy-2-oxo-l,2-dihydro-pyridine-3- carbonitrile.
  • Step 3 Preparation of l-(3-Fluorobenzyl)-4-hydroxy-2-oxo-l,2-dihydropyridine-3- carbonitrile.
  • sodium hydride 92 mg of a 60% dispersion in mineral oil, 2.3 mmol
  • DMF 7 mL
  • ethanethiol 92 mg of a 60% dispersion in mineral oil, 2.3 mmol
  • ethanethiol 0.14 g, 2.2 mmol
  • l-(3- fluorobenzyl)-4-methoxy-2-oxo-l,2-dihydropyridine-3-carbonitrile 0.23 g, 0.89 mmol
  • Step 4 Preparation of 4-(2,4-Difluorobenzyloxy)-l-(3-f uorobenzyl)-2-oxo-l,2-dihydro- pyridine-3-carbonitrile.
  • Step 1 Preparation of methyl l-cyclohexyl-4-hydroxy-2,5-dimethyl-6-oxo-l,6- dihydro-pyridine-3-carboxylate.
  • 3-cyclohexylaminobut-2-enoic acid methyl ester (1.12 g, 5.72 mmol) in bromobenzene (20 mL) was added 2-methylmalonic acid bis-(2,4,6-trichloro-phenyl) ester (2.71 g, 5.72 mmol)and the reaction mixture was heated at 170 °C for 3 h. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure.
  • Step 2 Preparation of l-cyclohexyl-4-hydroxy-2,5-dimethyl-6-oxo-l,6- dihydro-pyridine-3-carboxylic acid.
  • a solution of methyl l-cyclohexyl-4-hydroxy-2,5- dimethyl-6-oxo-l,6-dihydro-pyridine-3-carboxylate (0.35 g, 1.25 mmol) in 2 N NaOH (5 mL) was heated at reflux for 3.5 h.
  • the reaction mixture was cooled room temperature, acidified to pH 1-2 with 1 N HCl, and washed with EtOAc.
  • Step 1 Preparation of 4-methyIpyrazole-l-carboxylic acid tert-butyl ester. To a solution of 4-methyl-lH-pyrazole (1 g, 12 mmol) and DMAP (0.15 g, 1.2 mmol) in
  • Step 4 Preparation of 3-chloro-4-(2,4-difluorobenzyloxy)-6-methyl-l-(l/7- pyrazol-4-ylmethyl)-lfl r -pyridin-2-one.
  • 4-[3-Chloro-4-(2,4-difluorobenzyloxy)-6- methyl-2-oxo-2H-pyridin-l-ylmethyl]pyrazole-l -carboxylic acid tert-butyl ester (0.16 g, 0.34 mmol) was heated to 140 °C for 16 h. The reaction mixture was cooled to room temperature.
  • N,N-dimethylformamide (5 mL). ⁇ -Bromo-/?-tolunitrile (0.85g, 4.3 mmol) was added followed by K 2 C0 3 (0.59 g, 4.3 mmol). The resulting mixture was heated to 80 °C for 16 h. The reaction was concentrated to an oil that was partitioned between water and ethyl acetate and extracted with ethyl acetate (3 x 100 ml). The organic extracts were combined, washed with brine, dried over Na 2 S0 4 , and filtered.
  • Example 134 (100 mg, 0.25 mmol) was added to a suspension of potassium fluoride (40% on alumina) in t-butyl alcohol, heated to 85 °C, and stirred for 20h. The alumina was removed by filtration and washed with dichloromethane and water. The resulting filtrate was separated and the aqueous layer was extracted with dichloromethane (2 x 20 mL). The organic extracts were combined, dried over Na 2 S0 4 , and filtered. The filtrate was concentrated to an oil. Trituration with dichloromethane and hexane gave a solid (11.5 mg, 11 ).
  • Example 159 Product from Example 159 (200 mg, 0.39 mmol) was suspended in methanol (3 mL) and cooled to -78°C. Ammonia (g) was bubbled through the mixture for 30 minutes. The reaction vessel was sealed, allowed to reach ambient temperature, and stirred for 4 hours. The solvent and ammonia were removed from the reaction in vacuo with stirring and the resulting oil was triturated with ether to yield a solid (174 mg, 99%).
  • Examples 161-168 are prepared essentially according to the procedures set forth above for Examples 158-160 or by using the compound of Example 158:

Abstract

Disclosed are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, and R5 are defined herein. These compounds are useful for treating diseases and conditions caused or exacerbated by unregulated p38 MAP Kinase and/or TNF activity. Pharmaceutical compositions containing the compounds, methods of preparing the compounds and methods of treatment using the compounds are also disclosed.

Description

SUBSTITUTED PYRIDL ONES
PRIORITY CLA TO RELATED PATENT APPLICATION This patent claims priority to U.S. Provisional Patent Application Serial No. 60/429,959 (filed August 13, 2003). The entire text of U.S. Provisional Patent Application Serial No. 60/429,959 is incorporated by reference into this patent.
FIELD OF THE INVENTION The instant invention relates to substituted pyridinones that are useful for treating diseases and conditions caused or exacerbated by unregulated p38 MAP kinase activity. Pharmaceutical compositions containing the pyridinone compounds, methods of preparing the pyridone compounds and methods of treatment using the compounds are also disclosed. BACKGROUND OF THE INVENTION Numerous cell surface receptors use one or more of the mitogen-activated protein kinase (MAP kinase) cascades during signal transduction. MAP kinases are a family of protein-directed serine/threonine kinases that are activated by dual phosphorylation. One subgroup of the MAP kinases is p38 MAP kinase, which is activated by a variety of signals including proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-1 (E -1), as well as bacterial lipopolysaccharides and environmental stress such as osmotic shock and ultraviolet radiation (Ono, K. and J. Han, Cell Signal. 12: 1, 2000). Within the p38 kinase family, there are four distinct isozymes: p38 alpha, p38 beta, p38 gamma, and p38 delta. The p38 kinase family function downstream of an activating stimulus by phosphorylating and activating transcription factors (e.g. ATF2, CHOP and MEF2C) as well as other kinases (e.g. MAPKAP-2 and MAPKAP-3) (Trends in Cell biology 7, 353-361, 1997;Mol Cell Biology 19, 21-30, 1999; EMBO J 20, 466-479, 2001). Upon activation, the p38 kinase cascade leads to the induction of gene expression of several factors involved in inflammation and immunity including TNF, interleukin-6, granulocyte-macrophage colony stimulating factor (GM-CSF), and HIV long terminal repeat (Paul et al, Cell Signal. 9: 403-410, 1997). The products of the p38 phosphorylation stimulate the production of inflammatory cytokines and other proteins, including TNF and IL-1, and cyclooxygenase-2, and also possibly modulate the effects of these cytokines on their target cells, and thus stimulate inflammation processes (Lee, J.C. et al, Nature, 372: 376, 1994). P38 MAP kinases have also been shown to promote apoptosis during ischemia in cardiac myocytes, which suggests that p38 MAP kinase inhibitors can be used to treat ischemic heart disease (J. Biol. Chem. 274, 6272, 1999). They are also required for T-cell HIV-1 replication and may be useful targets for AIDS therapy. P38 pathway inhibitors have been used to increase cancer cell sensitivity to cancer therapy also find use in the treatment of asthma (JPET 293, 281 , 2000). TNF is a cytokine and a potent proinflammatory mediator implicated in inflammatory conditions such as arthritis, asthma, septic shock, non-insulin dependent diabetes mellitus, multiple sclerosis, asthma, and inflammatory bowel disease. Thus inhibitors of p38 MAP kinases (required for TNF production) may be useful for the treatment of inflammatory conditions resulting from excessive cytokine production such as arthritis. (Boehm, J.C. and J.L. Adams, Exp. Opin. Ther. Patents 10: 25, 2000, and references cited therein). TNF has also been implicated in viral infections, such as HIV, influenza virus, and herpes virus including herpes simplex virus type-1 (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and rhinotracheitis, among others. Excessive or unregulated TNF production has also been shown to produce elevated levels of IL-1. Inhibition of TNF, therefore, should reduce levels of EL-l (European Cytokine Netw 6, 225, 1995) and ameliorate disease states caused by unregulated EL-l synthesis. Such disease states include rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcosis, bone resorption diseases, reperfusion injury, graft versus host reaction, alallograft rejections, fever and myalgias due to infection, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS related complex (ARC), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, and pyresis. EL-l has also been shown to mediate a variety of biological activities such as the activation of T-helper cells, induction of fever, stimulation of prostaglandin or coUagenase production, neutrophil chemotaxis, and the suppression of plasma iron levels (Rev. Infect. Disease, 6, 51 (1984)). Elevated levels of EL-l have also been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, inflammatory bowel disease, adult respiratory distress syndrome (ARDS), psoriasis, Crohn's disease, ulcerative colitis, anaphylaxis, muscle degeneration, cachexia, Reiter's syndrome, type I and type II diabetes, bone resorption diseases, ischemia reperfusion injury, arteriosclerosis, brain trauma, multiple sclerosis, sepsis, septic shock, and toxic shock syndrome. Viruses sensitive to TNF inhibition, such as HEV-1, HEV-2, HEV-3, are also affected by EL-l production. In rheumatoid arthritis, both EL-l and TNF induce coUagenase synthesis and ultimately lead to tissue destruction within arthritic joints {Lymphokine Cytokine Res. (11): 253-256, (1992) and Clin. Exp. Immunol. 989:244-250, (1992)). EL-6 is another pro-inflammatory cytokine, which is associated with many conditions including inflammation. Consequently, TNF, EL-l and EL-6 affect a wide variety of cells and tissues and are important inflammatory mediators of a wide variety of disease states and conditions. The inhibition of these cytokines by inhibition or modulation of p38 kinase is of benefit in controlling, reducing and alleviating many of these disease states and conditions. Therefore, the present invention concerns finding small molecule inhibitors or modulators of p38 kinase and the p38 kinase pathway.
SUMMARY OF THE INVENTION In a broad aspect, the invention provides compounds of Formula I (Embodiment I):
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof, wherein
Ri is H, halogen, N0 , alkyl, carboxaldehyde, hydroxyalkyl, dihydroxyalkyl, arylalkoxy, arylalkyl, alkenyl, alkynyl, arylalkynyl, -CN, aryl, alkanoyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, carboxyl, or arylalkanoyl, wherein the aryl portion of arylalkoxy, arylalkyl, and arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, C1-C4 alkyl, -C4 alkoxy, nitro, CN, haloalkyl, haloalkoxy or C02R; wherein the alkyl portion of the alkyl, hydroxyalkyl, dihydroxyalkyl, arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and arylalkanoyl groups is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, -C4 alkoxy, C1-C alkoxycarbonyl, or C3-C7 cycloalkyl; R2 is H, OH, halogen, -OS02-(C1-C6) alkyl, -OS02-aryl, arylalkoxy, aryloxy, arylthio, arylthioalkoxy, arylalkynyl, alkoxy, aryloxy(C1-C6)alkyl, alkyl, alkynyl, -OC(0)NH(CH2)„aryl, -OC(0)N(alkyl)(CH2)naryl, alkoxyalkoxy, dialkylamino, alkyl, alkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylalkenyl, heterocycloalkyl, heterocycloalkylalkyl, alkoxyalkoxy, NR8R9, dialkylamino, or C02R, wherein n is O, 1, 2, 3, 4, 5 or 6; 1 each of which groups is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, -(C1-C6)alkyl-N(R)-CO2R30, -(C C4 alkyl)- NR6C(0)NR7-(C C6 alkoxy), -(d-C4 alkyl)-NR16C(0)NR17-(C3-C6 cycloalkyl), -( -C4 alkyl)-NR16C(0)NR17-(C3-C6 cycloalkylalkyl), -( - C4 alkyl)-NR16C(0)NR1 -(heteroaryl) wherein the heteroaryl group is optionally substituted with C1-C4 alkyl, --C4 alkoxy, halogen or OH, haloalkyl, heteroaryl, heteroarylalkyl, -NR6R7, R6R7N-(C1-C6 alkyl)-, -( - C4 alkyl)-NR6(CO)NR7-(C1-C6 alkoxy), -C(0)NR6R7, -(C1-C4)alkyl- C(0)NR6R7, -(C C4alkyl)-NRC(0)NR16R17, haloalkoxy, alkyl, CN, hydroxyalkyl, dihydroxyalkyl, alkoxy, alkoxycarbonyl, phenyl, -S02- phenyl wherein the phenyl and -S02-phenyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen or N02, or -OC(0)NR6R7, wherein Rι6 and Rj7 are independently H, -C alkyl, or -C6 alkoxy; or Rι6, R17 and the nitrogen to which they are attached form a morpholinyl ring; R6 and R7 are independently at each occurrence H, alkyl optionally substituted with NRι6Ri7 or a heteroaryl group, hydroxyalkyl, dihydroxyalkyl, alkoxy optionally substituted with NR16R17, alkanoyl, arylalkyl, arylalkoxy, -NR16Sθ2-alkyl, -NR16S02-phenyl, alkoxycarbonyl, -S02-alkyl, -S02-aryl, OH, alkoxy, alkoxyalkyl, arylalkoxycarbonyl, -(C1-C4)alkyl-C02-alkyl, phenyl, heteroarylalkyl, heterocycloalkyloxy, alkenyl optionally substituted with -OC(0)NR6R7, aryl, heterocycloalkylalkanoyl, or arylalkanoyl, wherein each is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, C3-C6 cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(C1-C6 alkyl), -C(0)N(d-C6 alkyl)(C C6 alkyl), Q-C4 alkoxy, Q- alkyl, OH, SH, carboxaldehyde, alkoxy, heterocycloalkyl, heterocycloalkylalkyl, -OC(0)C1-C6 alkyl, -C4 haloalkyl, or - C4 haloalkoxy, or R6, R , and the nitrogen to which they are attached form a morpholinyl, pyrrolidinyl, thiomorpholinyl, thiomorpholinyl S -oxide, thiomorpholinyl S,S-dioxide, piperidinyl, pyrrolidinyl, isoindole 1,3-dionyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently C1-C alkyl, alkoxycarbonyl, Q- C4 alkoxy, hydroxyl, hydroxyalkyl, dihydroxyalkyl, or halogen; R at each occurrence is independently hydrogen or - alkyl optionally substituted with 1 or 2 groups that are independently OH, SH, halogen, amino, monoalkylamino, dialkylamino or C3-C6 cycloalkyl; R3o is -C6 alkyl optionally substituted with 1 or 2 groups that are independently OH, SH, halogen, amino, monoalkylamino, dialkylamino or C3-C6 cycloalkyl; each R8 is independently hydrogen, alkyl, alkanoyl,1 arylalkyl and arylalkanoyl, wherein each of the above is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, alkoxy, alkoxycarbonyl, halogen, or haloalkyl; each R9 is hydrogen, alkyl, alkanoyl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, heteroaryl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, arylalkanoyl, -S02-phenyl, and aryl wherein each of the above is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, alkoxy, alkoxycarbonyl, halogen, or haloalkyl; R3 is H, halogen, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl, -OC(0)NH(CH2)naryl, arylalkoxy, -OC(0)N(alkyl)(CH2)naryl, aryloxy, arylthio, thioalkoxy, arylthioalkoxy, alkenyl, -NR6R7,NR6R7-(C1-C6)alkyl, or alkyl, wherein the aryl portion of arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl, -OC(0)NH(CH2)naryl, arylalkoxy, -OC(0)N(alkyl)(CH2)naryl, and arylthioalkoxy, is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently, halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy, wherein n is 0, 1, 2, 3, 4, 5, or 6; or R is hydrogen or R4 is alkyl unsubstituted or substituted with one or two groups that are independently C02R, OH, -C02-(C C6)alkyl, -C(0)NR6R7, -C(0)R6, -N(R30)C(O)NR6R7, -N(R30)C(O)-(C1-C4 alkyl)-NR6R7, -OC(0)NR6R7, -OC(O)- (Cι-C6 alkyl), -N(R30)C(O)NR16R17, -N(R30)C(O)-(Cι-(^)alkc>xy, -N(R30)C(O)- (C1-C4 alkyl)-NR6R7, or -NR6R7, -OC(0)NR17-alkyl-heteroaryl, arylalkoxy, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyalkyl, dihydroxyalkyl, haloalkyl, R6R7N-(C C6 alkyl)-, -NR6R7, alkoxy, carboxaldehyde, -C(0)NR6R7, C02R, alkoxyalkyl, or alkoxyalkoxy, wherein the heteroaryl or aryl portions of is the above are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, hydroxy, alkoxy, alkyl, -C02-(C1-C6)alkyl, -CONR6R7, - NR6R7, R6R7N-(C1-C6)alkyl-, nitro, haloalkyl, or haloalkoxy; and R5 is H, or R5 is aryl, arylalkyl, arylthioalkyl, alkyl optionally substituted with 1, 2, or 3 groups that are independently arylalkoxycarbonyl, -NR8R9, halogen, -C(0)NR8R9, alkoxycarbonyl, C3-C7 cycloalkyl, or alkanoyl, alkoxy, alkoxyalkyl optionally substituted with one trimethylsilyl group, amino, alkoxycarbonyl, hydroxyalkyl, dihydroxyalkyl, alkynyl, -S02-alkyl, alkoxy optionally substituted with one trimethylsilyl group, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, -alkyl-S- aryl, -alkyl-S02-aryl, heteroarylalkyl, heterocycloalkyl, -heteroaryl- heterocycloalkyl, heteroaryl, or alkenyl optionally substituted with one substituent selected from the group consisting of alkoxycarbonyl, -alkenyl-C02-alkyl, carboxyl, and -OC(0)NR6R7, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl optionally substituted with 1 or 2 groups that are independently NR16R17, -NR16S02-alkyl, -NR16S02-phenyl, -OC(0)NH2, or -OC(0)NR16R17, OH, -OC(0)NR16R17, halogen, alkoxy wherein the alkyl group is optionally substituted with NR16R17, -C(0)NR16R17, OH or Cι-C4 alkoxy, hydroxyalkyl, dihydroxyalkyl, arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, C02R, CN, OH, hydroxyalkyl, dihydroxyalkyl, -S02NR16R17, amidinooxime, -OC(0)NR6R7, -NR6R7, - NR8R9, R6R7N-(CrC6 alkyl)-, carboxaldehyde, -S-alkyl wherein the alkyl group is optionally substituted with NR16R17, -C(0)NR16R1 , OH or - alkoxy, S02alkyl wherein the alkyl group is optionally substituted with NR16R17, -C(0)NR16R17, OH or -C4 alkoxy, -OC(0)-(C1-C6 alkyl), - S02H, -S02NR6R , alkanoyl wherein the alkyl portion is optionally substituted with OH, halogen, -OC(0)-(d-C6 alkyl), or alkoxy, - C(0)NR6R7, -(C1-C4alkyl)-C(0)NR6R7> heterocycloalkyl or heterocycloalkylalkyl, wherein the heterocycloalkyl group is selected from the group consisting of morpholinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, pyrrolidinyl, and imidazolidinyl, heteroaryl which is selected from the group consisting of pyridyl, furanyl, pyrazolyl, and thienyl, alkoxyalkyl optionally substituted with NR16Ri7, amidino, haloalkyl, -( - alkyl)-NR15C(0)NR16R17, -(C1-C4 alkyl)-NR15C(0)R18, - O-CH2-O, C2-C6 alkenyl optionally substituted with -OC(0)NR6R7, d-C4 alkoxy, or OH, -0-CH2CH2-0-, or haloalkoxy; wherein R15 is H or C C6 alkyl; and R18 is C C6 alkyl optionally substituted with -0-(C2-C6 alkanoyl, -C6 hydroxyalkyl, -C6 dihydroxyalkyl, C alkoxy, - alkoxy -C6 alkyl; amino -Cβ alkyl, mono or dialkylamino C C6 alkyl. The invention also includes the intermediates that are useful in making the compounds of the invention. These compounds bind and/or interact with p38 kinase and/or TNF. Preferably, they inhibit the activity of p38 kinase and/or TNF. They are therefore used in treating p38 map kinase or TNF mediated disorders. Preferably they are used in treating p38 alpha or TNF mediated disorders. The instant invention also includes pharmaceutical compositions comprising at least one compound of formula I and at least one pharmaceutically acceptable carrier, solvent, adjuvant or excipient. The instant invention also includes methods of treating a TNF mediated disorder, a p38 kinase mediated disorder, inflammation and/or arthritis in a subject, the method comprising treating a subject having or susceptible to such disorder or condition with a therapeutically-effective amount of a compound of Formula I.
DETAILED DESCRIPTION OF THE INVENTION In a preferred aspect, the invention provides compounds of formula I wherein: when R2 is benzyloxy, R3 is H, R4 is H, and R5 is benzyl or methyl, Ri is not hydrogen; no more than two of Ri, R2, R4, and R5 are simultaneously hydrogen;
R and R7 are not simultaneously OH; when R2 is OH, R4 is methyl and R5 is phenyl, R] is not acetyl; and
R4 and R5 are not simultaneously hydrogen. Embodiment 2. Compounds of the formula:
Figure imgf000009_0001
and the pharmaceutically acceptable salts thereof, wherein
Ri is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, dihydroxyalkyl, arylalkoxy, arylalkyl, alkenyl, alkynyl, arylalkynyl, CN, alkanoyl, alkoxy, alkoxyalkyl, haloalkyl, carboxyl, or arylalkanoyl, wherein the aryl portion of arylalkoxy, arylalkyl, and arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, C1-C4 alkyl, -C4 alkoxy, nitro, CN, haloalkyl, haloalkoxy or C02R; wherein the alkyl portion of the alkyl, hydroxyalkyl, dihydroxyalkyl, arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and arylalkanoyl groups is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, C1-C4 alkoxy, -C4 alkoxycarbonyl, or cyclopropyl; R2 is H, OH, halogen, -OS02-(C C6) alkyl, -OS02-aryl, arylalkoxy, aryloxy, arylthioalkoxy, arylalkynyl, alkoxy, phenyloxy(d-C6)alkyl, -OC(0)NH(CH2)naryl, -OC(0)N(alkyl)(CH2)naryl, alkyl, alkynyl, alkoxyalkoxy, dialkylamino, heteroaryl, heterocycloalkyl, aryloxyalkyl, or CO2R, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, -NR6R7, haloalkyl, haloalkoxy, alkyl, heteroaryl, heteroarylalkyl, -(C1-C4)alkyl-C(0)NR6R7, R6R7N-(C1-C6 alkyl)-, -C(0)NR6R7, -(C1-C4 alkyl)-NRC(0)NR16R17, CN, hydroxyalkyl, dihydroxyalkyl, -OC(0)NR6R7, or -(C1-C6)alkyl-N(R)-CO2R30, wherein R16 and R17 are independently H or - alkyl; or R16, R17 and the nitrogen to which they are attached form a morpholinyl ring; R6 and R are independently at each occurrence H, alkyl, hydroxyalkyl, dihydroxyalkyl, alkoxy, alkoxyalkyl, alkanoyl, arylalkyl, arylalkoxy, arylalkoxycarbonyl, or arylalkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, C3-C6 cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Cι-C6 alkyl), -C(0)N(C C6 alkyl)(C1-C6 alkyl), C1-C4 alkoxy, d-C4 alkyl, OH, SH, carboxaldehyde, alkoxy, heterocycloalkyl, heterocycloalkylalkyl, -OC(0)d-C6 alkyl, C C4 haloalkyl, or Q- C4 haloalkoxy, or R6, R7, and the nitrogen to which they are attached form a morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S- dioxide, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently - C alkyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, dihydroxyalkyl, or halogen; n is O, 1, 2, 3, 4, 5 or 6; R at each occurrence is independently H or -C6 alkyl optionally substituted with 1 or 2 groups that are independently OH, SH, halogen, amino, monoalkylamino, dialkylamino or C3-C6 cycloalkyl; R30 is Cι-C6 alkyl optionally substituted with 1 or 2 groups that are independently OH, SH, halogen, amino, monoalkylamino, dialkylamino or C3-C6 cycloalkyl; R is H, alkyl optionally substituted with one or two groups that are independently C02R, - C02 lkyl, -C(0)NR6R7, -C(0)R6, -N(R3o)C(0)NR16R17, -N(R30)C(O)-(C1- C6)alkoxy, or -NR6R7, arylalkoxy, heteroaryl, arylalkyl, hydroxyalkyl, dihydroxyalkyl, haloalkyl, -NR6R7, -C(0)NR6R7, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the heteroaryl or aryl portions of the above are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, hydroxy, alkoxy, alkyl, -C02-(C1-C6)alkyl, -CONR6R7, -NR6R7, R6R7N-(C!-C6)alkyl-, nitro, haloalkyl, or haloalkoxy; and R5 is H, arylalkyl, alkyl optionally substituted with 1 , 2, or 3 groups that are independently arylalkoxycarbonyl, -NR8R9, halogen, -C(0)NR8R9, alkoxycarbonyl, or alkanoyl, alkoxyalkyl optionally substituted with one trimethylsilyl group, alkoxycarbonyl, amino, hydroxyalkyl, dihydroxyalkyl, alkenyl optionally substituted with alkoxycarbonyl, alkynyl, -S02-alkyl, aryl, alkoxy optionally substituted with one trimethylsilyl group, heterocycloalkylalkyl, heteroarylalkyl, heterocycloalkyl, or heteroaryl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, alkoxy, arylalkoxy, hydroxyalkyl, dihydroxyalkyl, thioalkoxy, -S02alkyl, alkoxycarbonyl, arylalkoxycarbonyl, C02R, CN, OH, amidinooxime, NR8R9, R6R7N-(d-C6 alkyl)-, -C(0)NR6R7, amidino, hydroxyalkyl, dihydroxyalkyl, carboxaldehyde, -NR6R7, haloalkyl, -(C C4 alkyl)-C(0)NR6R7, -(CrC4 alkyl)-C02R, -(C1-C4 alkyl)-d-C6 alkoxycarbonyl, -(CrC4 alkyl)-CN, - (C1-C4 alkyl)-NR15C(0)R18, -0-CH2-0-, -0-CH2CH2-0-, phenyl or haloalkoxy; R8 is hydrogen, alkyl, alkanoyl, arylalkyl and arylalkanoyl; R9 is alkyl, alkanoyl, arylalkyl, heteroaryl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, and arylalkanoyl. Embodiment 3. Compounds according to embodiment 2 wherein
Rt is H, halogen, alkyl optionally substituted with CrC4 alkoxycarbonyl, carboxaldehyde, hydroxyalkyl, dihydroxyalkyl, phenyl(C1-C6)alkoxy, phenyl(C1-C6)alkyl, CN, alkanoyl, alkoxy, C2-C4 alkynyl, C2-C6 alkenyl optionally substituted with Q- alkoxycarbonyl, alkoxyalkyl, haloalkyl, or phenyl(d-C6)alkanoyl, wherein the phenyl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, -C4 alkyl, C1-C4 alkoxy, nitro, CN, CF3, OCF3 or C02R; wherein the alkyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, or ethoxy; R2 is OH; phenyl(C!-C6)alkoxy, phenyloxy, phenyloxy(C1-C6)alkyl, phenyl ( -C4) thioalkoxy, -C8 alkoxy, alkoxyalkoxy, -0-S02phenyl, alkynyl, phenyl ( -C4) alkynyl, alkyl, -OC(0)NH(CH2)nphenyl, -OC(0)N(alkyl)(CH2)nρhenyl, dialkylamino, pyridyl, pyrimidyl, pyridazyl, pyrazolyl, imidazolyl, pyrrolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl, triazinyl, tetrahydrofuryl, piperidinyl, hexahydropyrimidinyl, thiazolyl, thienyl, or CO2R, wherein n is O, 1, 2, 3, 4, 5 or 6; each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, NR6R7, haloalkyl, haloalkoxy, hydroxyalkyl, dihydroxyalkyl, alkyl, phenyl, pyridyl, piperidinyl, piperazinyl, -( - C6)alkyl-N(R)-CO2R30, R6R7N-(C1-C6 alkyl)-, -C(0)NR6R7, -(C1-C4)alkyl- C(0)NR6R7, -(C1-C4alkyl)-NRC(0)NR16R17, or -OC(0)NR6R7, wherein R6 and R are independently at each occurrence H, alkyl, ( -C4) hydroxyalkyl, ( -C ) dihydroxyalkyl, (CrC4) alkoxy, ( -C4) alkoxy (C C4) alkyl, (C1-C4) alkanoyl, phenyl ( - ) alkyl, phenyl (CrC4) alkoxy, phenyl ( -C4) alkoxycarbonyl, or phenyl (C!-C4) alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, OH, SH, C3- C6 cycloalkyl, (C1-C4) alkoxy, ( -C4) alkyl, CF3, carboxaldehyde, NH2, NH(C1-C6)alkyl, N(C C6)alkyl (C1-C6)alkyl, OCF3; or R6, R7, and the nitrogen to which they are attached form a morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently -C4 alkyl, hydroxy, hydroxy -C4 alkyl, C1-C4 dihydroxyalkyl, -C4 alkoxycarbonyl, or halogen; and R4 is H, alkyl optionally substituted with one or two groups that are independently C02R, - C02alkyl, -C(0)NR6R7, -C(0)R6, -N(R30)C(O)NR16R17, -N(R30)C(O)-(d- C6)alkoxy, or -NR6R7, -C(0)NR6R7, pheny -C^alkoxy, phenyl(C1-C6)alkyl, hydroxyalkyl, dihydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the phenyl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, CF3, OCF3; R5 is phenyl(C1-C6)alkyl, (C1-C6)alkyl optionally substituted with 1, 2, 3, 4, or 5 groups that are independently phenyl -C4 alkoxycarbonyl, -NR8R9, halogen, - C(0)NR8R9, alkoxycarbonyl, or alkanoyl, phenyl, alkoxy, C2-C6 alkynyl, C2- alkenyl optionally substituted with alkoxycarbonyl, indolyl, quinolinyl, isoquinolinyl, isoindolyl, dihydroindolyl, pyrazolyl, imidazolyl, dihydroisoindolyl, indolon-2-yl, indazolyl, benzimidazolyl, pyridyl, imidazolidine dione, pyrazolyl(Ci-C6 alkyl), imidazoly -Ce alkyl), piperidinyl(C1-C6)alkyl, pyrrolidinyl(C1-C6)alkyl, imidazolidinyl(C1-C6)alkyl, tetrahydroisoquinoliny^d- C6)alkyl, lH-indazolyl(C C6)alkyl, dihydroindolon-2-yl(C1-C6 alkyl),
Figure imgf000013_0001
alkyl), dihydrobenzimidazoly -Ce alkyl), or dihydrobenzoimidazolony^CrCe alkyl), pyridyl ( - ) alkyl, pyridazinyl ( - C6) alkyl, pyrimidinyl ( -Cβ) alkyl, pyrazinyl ( - ) alkyl, tetrahydrofuryl(Cr C6)alkyl, naphthyl(CrC6)alkyl, morpholinyl ( -Cό) alkyl, tetrahydrofuryl ( - C6) alkyl, thienyl ( -CΘ) alkyl, piperazinyl (CrC6) alkyl, indolyl ( -Ce) alkyl, quinoliny CrCβ) alkyl, isoquinoliny -Ce) alkyl, isoindolyl(Cι-C6) alkyl, dihydroindolyl(Cι-C6) alkyl, pyrazoly -Gi) alkyl, imidazolyl(C1-C4) alkyl, dihydroisoindoly CrCβ) alkyl, indoon-2-yl(C C6) alkyl, indolon-2-yl(C1-C6) alkyl, or morpholinyl - alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently -Cό alkyl, halogen, - alkoxy, phenyl Cι-C6 alkoxy, C\- C6 thioalkoxy, C C6 alkoxycarbonyl, C02R, CN, -S02(CrC6)alkyl, amidinooxime, NR8R9, -NR6R7, NR6R7 - alkyl, -C(0)NR6R7, -(C1-C4)alkyl- C(0)NR6R7, amidino, C C4 haloalkyl, hydroxy C C6 alkyl, CrC6 dihydroxyalkyl, or --C4 haloalkoxy; wherein R8 is hydrogen, C C6 alkyl, -Cβ alkanoyl, phenyl CpC6 alkyl and phenyl Cι-C alkanoyl; and R9 is aminoalkyl, mono Ci-C6 alkylamino -Cό alkyl, di Cι-C6 alkylamino Ci-Cβ alkyl, - s alkyl, - alkanoyl, phenyl Ci-C6 alkyl, indazolyl, and phenyl C Cβ alkanoyl. Embodiment 4. Compounds according to embodiment 3, wherein
Ri is H, halogen, -C4 alkyl optionally substituted with C1-C4 alkoxycarbonyl, C2-C4 alkenyl optionally substituted with Ci-C4 alkoxycarbonyl, C2-C4 alkynyl, or carboxaldehyde; R2 is benzyloxy, OH, phenyloxy, phenyloxy(Cι-C6)alkyl, phenyl (Ci-C ) thioalkoxy, or pyridyl; wherein each of the above is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, -(CrC6)alkyl-N(R)-CO2R30, NR6R7, -(Cr C4)alkyl-C(0)NR6R7, (C C4) haloalkyl, -C(0)NR6R7, -(Q-Qalkyl)- NRC(0)NRι6R17, (C1-C4) haloalkoxy, hydroxyalkyl, Ci-Cβ dihydroxyalkyl, (Ci- C6) alkyl, pyridyl, or R^N^ -Ce alkyl)-.
Embodiment 4a. Compounds according to embodiment 4, wherein Rt is H.
Embodiment 4b. Compounds according to embodiment 4, wherein Rj is halogen.
Embodiment 4c. Compounds according to embodiment 4, wherein Rt is -C4 alkyl optionally substituted with C1-C4 alkoxycarbonyl. Embodiment 5. Compounds according to embodiment 4, wherein
R5 is indolyl, pyridyl, pyridazinyl, pyrimidinyl, indazolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, pyrazolyl, imidazolyl, furanyl, quinolinyl, isoquinolinyl, isoindolyl, dihydroindolyl, dihydroisoindolyl, indolon-2-yl, or pyrazinyl, each of which is unsubstituted or substituted with 1, 2, 3, 4 or 5 groups that are independently C1-C4 alkyl, halogen, CF3, OCF3, -C02CH3, Q-Q hydroxyalkyl, dihydroxyalkyl, C1-C4 alkoxy, -C02(Q-Q alkyl), benzyloxy, -NR6R7, -(Q- C4)alkyl-C(0)NR6R7, -NR8R9, NR6R7-(C C4 alkyl), -C(0)NR6R7, or amidinooxime; wherein R6 and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q hydroxyalkyl, C!-C4 dihydroxyalkyl, C1-C4 alkoxy, C!-C4 alkoxy Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, C3-C6 cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), - C(0)N(Ci-C6 alkyl)(Q-C6 alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, - OC(0)Q-C6 alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy; or R6, R7, and the nitrogen to which they are attached form a morpholinyl, thiomorpholinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, hydroxy, hydroxy Q-Q alkyl, Q-Q dihydroxyalkyl, or halogen.
Embodiment 6. Compounds according to embodiment 5, wherein R5 is indolyl, pyridyl, pyrimidinyl, pyrazolyl, furanyl, indazolyl, dihydroindolyl, dihydroisoindolyl, indolon-2-yl, or pyrazinyl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 groups that are independently Q-Q alkyl, halogen, CF3, OCF3, -C02CH3, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkoxy, - C02(Q-Q alkyl), benzyloxy, -C(0)NR6R7, -NR8R9, -(Q-Q)alkyl-C(0)NR6R7, -NR6R7, NR6R7-(Q-Q alkyl)-, and amidinooxime.
Embodiment 7. Compounds according to embodiment 6, wherein R5 is indolyl, pyridyl, pyrimidinyl, dihydroindolyl, dihydroisoindolyl, pyrazolyl, or pyrazinyl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 groups that are independently Q-Q alkyl, halogen, CF3, OCF3, -C02CH3, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkoxy, -C02(Q-Q alkyl), benzyloxy, -C(0)NR6R7, NR8R9, -(Q-Q)alkyl-C(0)NR6R7, -NR6R7, NR6R7-(Q-Q alkyl)-, or amidinooxime; wherein R6 and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkoxy, Q-Q alkanoyl, Q-Q alkoxy Q-Q alkyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), - C(0)N(Q-C6 alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, - OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy.
Embodiment 8. Compounds according to embodiment 7, wherein
R5 is indolyl, pyridyl, pyrimidinyl, dihydroindolyl, dihydroisoindolyl, pyrazolyl, or pyrazinyl, each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently Q-Q alkyl, halogen, CF3, OCF3, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkoxy, -C(0)NR6R7, -(Q-Q)alkyl-C(0)NR6R7, NR8R9, - NR6R7, or NR6R7-(Q-Q alkyl)-; wherein R6 and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkanoyl, or Q-Q alkoxy, each of which is optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-C6 alkyl), -C(0)N(Q-C6 alkyl)(Q- Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy.
Embodiment 9. Compounds according to embodiment 4, wherein
R5 is phenyl, phenyl(Q-C6)alkyl, or (Q-C6)alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, alkoxy, benzyloxy, hydroxyalkyl, dihydroxyalkyl, thioalkoxy, -C02(Q-C5 alkyl), C02R, CN, amidinooxime, -NR8R9, -NR6R7, R6R7N-(Q-Q alkyl)-, -C(0)NR6R7, -(Q-Q)alkyl- C(0)NR6R7, amidino, CF3, or OCF3; R8 is hydrogen, Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl and phenyl Q-Q alkanoyl; and R9 is aminoalkyl, mono Q-Q alkylamino Q-Q alkyl, di Q-Q alkylamino Q-Q alkyl, Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, indazolyl, and phenyl Q-Q alkanoyl.
Embodiment 10. Compounds according to embodiment 4, wherein
R5 is phenyl, phenyl(Q-Q)alkyl, which is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, alkoxy, benzyloxy, thioalkoxy, - C02(Q-Q alkyl), C02R, CN, amidinooxime, -NR8R9, -NR6R7, R6R7N-(Q-Q alkyl)-, R6R7NC(0)-(Q-Q alkyl)-, R6R7NC(0)-(Q-Q alkyl)-, -C(0)NR6R7, amidino, CF3, or OCF3; wherein R6 and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), - C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, - OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy; or R6, R , and the nitrogen to which they are attached form a morpholinyl, thiomorpholinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, hydroxy, hydroxy Q-Q alkyl, Q-Q dihydroxyalkyl, or halogen; R8 is hydrogen, Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl and phenyl Q-Q alkanoyl; and R9 is aminoalkyl, mono Q-Q alkylamino Q-Q alkyl, di Q-Q alkylamino Q-Q alkyl, Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, indazolyl, and phenyl Q-Q alkanoyl. Embodiment 11. Compounds according to embodiment 10, wherein
R5 is phenyl, benzyl or phenethyl, wherein each is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, -NR6R7, -C(0)NR6R7, -(Q-Q alkyl)- C(0)NR6R7, -NR8R9, halogen, Q-Q alkoxy, C02R, -(Q-Q alkyl)-C02R, Q-Q thioalkoxy, amidinooxime, Q-Q alkoxycarbonyl, -(Q-Q alkyι)-Q-Q alkoxycarbonyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, -(Q-Q alkyl)-CN, CN, phenyl Q-Q alkoxy, OH, Q-Q haloalkyl, Q-Q haloalkoxy, R6R7N-(Q-Q alkyl)-, -(Q-Q alkyl)-NR15C(0)R18, amidinooxime, -S02(Q-C6 alkyl), -0-CH2- O-, -0-CH2CH2-0-, phenyl Q-Q alkoxy, or phenyl; wherein R6 and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkanoyl, or Q-Q alkoxy, each of which is optionally substituted with 1, 2, or 3 groups that are independently halogen, OH, SH, Q-Q cycloalkyl, Q-Q alkoxy, Q-Q alkyl, OH, CF3, or OCF3. Embodiment 12. Compounds according to embodiment 11, wherein
R5 is phenyl, benzyl or phenethyl, each of which is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently CN, halogen, Q-Q alkoxy, CF3, OCF3, Q-Q alkyl, -NR8R9, -NR6R7, R6R7N-(Q~Q alkyl)-, or -C(0)NR6R7, wherein R6 and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkanoyl, or Q-Q alkoxy, each of which is optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q- Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy. Embodiment 13. Compounds according to embodiment 4, wherein the R5 group is of the formula:
Figure imgf000019_0001
wherein Zi and Z2 are independently H, halogen, Q-Q alkyl, or CO2R; and
Z is -C(0)NR6R7, -(C1-C4)alkyl-C(0)NR6R7, -(Q-Q alkyl)-NR15C(0)R18, -NR6R7, R6R7N-(C1-C6 alkyl)-, -NR8R9, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkyl, C02R, or halogen; wherein R6 and R7 at each occurrence are independently H, OH, Q-Q alkyl, amino Q-Q alkyl, NH(Q-Q alkyl)alkyl, N(Q-Q alkyl)(Q-Q alkyl) Q-Q alkyl, Q- Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkoxy Q-Q alkyl, or - S0 (Q-Q alkyl) each of which is optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), - C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, - OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy; or R6, R7, and the nitrogen to which they are attached form a piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl, thiomorpholinyl, ring optionally substituted with 1 or 2 groups that are independently alkyl, hydroxy, hydroxy Q-Q alkyl, Q-Q dihydroxyalkyl, or halogen; and R18 is Q-Q alkyl optionally substituted with -0-(C2-Q alkanoyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl; amino Q-Q alkyl, mono or dialkylamino Q-Q alkyl. Embodiment 14. Compounds according to embodiment 4, wherein R5 is pyrazolyl(Q-Q alkyl), imidazolyl(Q-Q alkyl), fhienyl(Q-C6 alkyl), furanyl(Q-Q alkyl), piperidinyl(Q-Q)alkyl, pyrrolidinyl(Q-Q)alkyl, imidazolidinyl(Q- Q)alkyl, piperazinyl(Q-Q)alkyl, pyridyl(Q-Q)alkyl, pyrimidyl(Q-Q)alkyl, pyridazyl(Q-Q)aιkyl, pyrazinyl(Q-Q)alkyl, isoquinolinyl(Q-Q)alkyl, tetrahydroisoquinolinyl(Q-Q)alkyl, indolyl(Q-C6)alkyl, lH-indazolyl(Q- Q)alkyl, dihydroindolyl(Q-Q alkyl), dihydroindolon-2-yl(C1-C6 alkyl), indolinyl(Q-Q alkyl), dihydroisoindolyl(Q-Q alkyl), dihydrobenzimdazolyl(Q- C6 alkyl), or dihydrobenzoirnidazolonyl(Q-Q alkyl), wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently (Q-Q)alkyl, halogen, (Q-Q)alkoxy, (Q-Q)hydroxyalkyl, Q-Q dihydroxyalkyl, phenyl(Q-Q)alkoxy, (Q-Q)fhioalkoxy, (Q- Q)alkoxycarbonyl, phenyl(Q-Q)alkoxycarbonyl, OH, C02R, CN, amidinooxime, -NR8R9, -NR6R7, R6R7N-(C1-C6 alkyl)-, -C(0)NR6R7, -(Q- C4 alkyl)-C(0)NR6R7> amidino, piperazinyl, morpholinyl, -S02 (Q-Q) alkyl, -S02NH2, -S02NH(Q-C6)alkyl, -S02N(Q-C6)alkyl (Q-C6)alkyl, (C1-C )haloalkyl, -(Q-Q alkyl)-NR15C(0)NR16R17, -(Q-Q alkyl)- NR15C(0)R18, -0-CH2-0, -0-CH2CH2-0-, or (Q-C4)haloalkoxy; wherein R6 and R7 are independently at each occurrence H, (Q-C6)aιkyl, (Q- C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl, (Ci-C6)alkoxycarbonyl, (Q- C6)hydroxyalkyl, Q-C6 dihydroxyalkyl, -(Q-Q)alkyl-C02-(Q- Q)alkyl, (C1-C6)alkanoyl, phenyl(Ci-C6)alkyl, phenyl(Q- C6)alkoxy, or phenyl(Q-Q)alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, (Q-Q)alkoxy, OH, SH, Q-Q cycloalkyl, NH2, NH(Q-Q alkyl), N(Q-Q alkyl)(Q-Q alkyl), (Q-Q)alkyl, CF3 or OCF3; or R6, R7, and the nitrogen to which they are attached form a morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, hydroxy, hydroxy Q-Q alkyl, Q-Q dihydroxyalkyl, or halogen; and R18 is Q-Q alkyl optionally substituted with -0-(Q-Q alkanoyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl; amino Q-Q alkyl, mono or dialkylamino Q-Q alkyl.
In this embodiment, it is preferred that R6 and R7 are not simultaneously OH; and R6 and R7 are not simultaneously -S02(Q-Q alkyl). Embodiment 15. Compounds according to embodiment 14, wherein R5 is pyrazolyl(Q-Q alkyl), imidazolyl(Q-Q alkyl), benzimidazolyl(Q-Q alkyl), thienyl(Q-C6 alkyl), pyrimidyl(Q-Q)alkyl, indolyl(Q-C6 alkyl), dihydroindolyl(Q-Q alkyl), dihydroisoindolyl(Q-Q alkyl), dihydroindolon-2- yl(Q-Q alkyl), pyridinyl(Q-Q alkyl), piρerazinyl(Q-Q alkyl), or pyrazinyl(Q- C6 alkyl) each of which is optionally substituted with 1, 2, or 3 groups that are independently Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7, Q-Q alkoxycarbonyl, -NR6R7, R6R7N- (Q-Q alkyl)-, haloalkyl, Q-Q alkanoyl, R6 and R7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy; or R6, R7, and the nitrogen to which they are attached form a piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl ring optionally substituted with 1 or 2 groups that are independently alkyl, hydroxy, hydroxy Q-Q alkyl, Q-Q dihydroxyalkyl, or halogen. Embodiment 16. Compounds according to embodiment 15, wherein R5 is of the formula:
Figure imgf000021_0001
wherein
Z5 is Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, -C(0)NR6R7, -(Q- Qalkyl)-C(0)NR6R7,Q-Q alkoxycarbonyl, R6R7N-(Q-Q alkyl)-, -NR6R7, CF3, or Q-Q alkanoyl, wherein R6 and R7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(C!-C6 alkyl), C!-C4 alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy; or R6, R7, and the nitrogen to which they are attached form a piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl ring optionally substituted with 1 or 2 groups that are independently alkyl, hydroxy, hydroxy Q-Q alkyl, Q-Q dihydroxyalkyl, or halogen. Embodiment 17. Compounds according to embodiment 15, wherein
R5 is of the formula:
Figure imgf000022_0001
wherein
Z5 is Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, -C(0)NR6R7, -(Q- Q alkyl)-C(0)NR6R7> Q-Q alkoxycarbonyl, R6R7N-(Q-Q alkyl)-, -NR6R7, CF3, or Q-Q alkanoyl, wherein R6 and R7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy; or R6, R7, and the nitrogen to which they are attached form a piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl ring optionally substituted with 1 or 2 groups that are independently alkyl, hydroxy, hydroxy Q-Q alkyl, Q-Q dihydroxyalkyl, or halogen. Embodiment 18. Compounds according to either embodiment 16 or 17, wherein Z5 is Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q-Q alkoxycarbonyl, CF3, or Q-Q alkanoyl. Embodiment 19. Compounds according to either embodiment 16 or 17, wherein Z5 is Q-Q alkyl, -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7, R6R7N-(Q-Q alkyl)-, or - NR6R7, CF3, or Q-Q alkanoyl, wherein R6 and R7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-C6 alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy; or R6, R7, and the nitrogen to which they are attached form a piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl ring optionally substituted with 1 or 2 groups that are independently alkyl, hydroxy, hydroxy Q-Q alkyl, Q-Q dihydroxyalkyl, or halogen. Embodiment 20. Compounds according to embodiment 19, wherein Z5 is -C(0)NR6R7, -(Q-Qalkyl)-C(0)NR6R7, R6R7N-(Q-Q alkyl)-, or -NR6R7, wherein R6 and R7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently Q-Q alkoxycarbonyl, halogen, cyclopropyl, OH, SH, or Q-Q alkoxy. Embodiment 21. Compounds according to embodiment 15, wherein R5 is of the formula:
Figure imgf000023_0001
, wherein Z10 is H or methyl; and Z20 is hydroxy(Q-Q)aιkyl, Q-Q dihydroxyalkyl, OH, halogen, haloalkyl, (Q- Q)alkyl, OCF3, -NR6R7, R6R7N-(Q-Q alkyl)-, -(Q-Q alkyl)-C(0)NR6R7, or - C(0)NR6R7, wherein Re and R at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy. Embodiment 22. Compounds according to embodiment 15, wherein R5 is of the formula:
Figure imgf000024_0001
wherein Z10 is H or methyl; and Z20 is hydroxy(Q-Q)alkyl, Q-Q dihydroxyalkyl, OH, halogen, CF3, (Q-Q)alkyl, OCF3, -NR6R7, R6R7N-(Q-Q alkyl)-, -(Q-Q alkyl)-C(0)NR6R7, or -C(0)NR6R7, wherein R6 and R7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy. Embodiment 23. Compounds according to embodiment 15, wherein R5 is of the formula:
Figure imgf000024_0002
, wherein Z10 is H or methyl; and Z20 is hydroxy(Q-Q)alkyl, C1-C4 dihydroxyalkyl, OH, halogen, haloalkyl, (Q-
C4)alkyl, OCF3, -NR6R7, R6R7N-(Q-C6 alkyl)-, -(Ci-Q alkyl)-C(0)NR6R7, or -
C(0)NR6R7, wherein
R6 and R7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy.
Embodiment 24. Compounds according to embodiment 15, wherein
R5 is of the formula:
Figure imgf000025_0001
, wherein Zio is H or methyl; and Z^o is hydroxy(Q-Q)alkyl, Q-Q dihydroxyalkyl, OH, halogen, CF3, (Q-Q)alkyl,
OCF3, -NR6R7, R6R7N-(Q-Q alkyl)-, -(Q-Q alkyl)-C(0)NR6R7, or -C(0)NR6R7, wherein R6 and R7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy. Embodiment 25. Compounds according to embodiment 15, wherein
R5 is of the formula:
Figure imgf000025_0002
, wherein Z10 is H or methyl; and Z o is hydroxy(Q-Q)alkyl, Q-Q dihydroxyalkyl, OH, halogen, haloalkyl, (Q- Q)alkyl, OCF3, -NR6R7, R6R7N-(Q-C6 alkyl)-, -(Q-Q alkyl)-C(0)NR6R7, or - C(0)NR6R7, wherein R6 and R7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy. Embodiment 26. Compounds according to embodiment 15, wherein R5 is of the formula:
Figure imgf000026_0001
, wherein ZKJ is H or methyl; and Z^o is hydroxy(Q-Q)aιkyl, Q-Q dihydroxyalkyl, OH, halogen, CF , (Q-Q)alkyl, OCF3, -NR6R7, R6R7N-(Q-Q alkyl)-, -(Q-Q alkyl)-C(0)NR6R7, or -C(0)NR6R7, wherein R6 and R7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH , -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-C6 alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy. Embodiment 27. Compounds according to embodiment 15, wherein R5 is of the formula:
Figure imgf000027_0001
, wherein Z10 is H or methyl; and Z20 is hydroxy(Q-Q)arkyl, Q-Q dihydroxyalkyl, OH, halogen, haloalkyl, (Q- C4)alkyl, OCF3, -NR6R7, R6R7N-(Q-Ce alkyl)-, -(Q-C4 alkyl)-C(0)NR6R7, or - C(0)NR6R7, wherein R6 and R7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-C6 alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy. Embodiment 28. Compounds according to embodiment 15, wherein R5 is of the formula:
Figure imgf000027_0002
, wherein Z10 is H or methyl; and Z20 is hydroxy(Ci-C4)alkyl, Ci-C4 dihydroxyalkyl, OH, halogen, CF3, (C1-C4)alkyl, OCF3, -NR6R7, R6R7N-(Q-C6 alkyl)-, -(Q-Q alkyl)-C(0)NR6R7, or -C(0)NR6R7, wherein R6 and R7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy. Embodiment 29. Compounds according to embodiment 4, wherein R5 is phenyl, which is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7; -NR6R7, NR6R7(Q-C6 alkyl), Q-Q hydroxyalkyl, dihydroxyalkyl, halogen, Q-Q alkoxy, C02R, OH, Q-Q alkoxycarbonyl, CF3, -(Q-Q alkyl)-NR15C(0)NR16R17, -(Q-Q alkyl)-NR15C(0)R18; wherein R15 is H or Q-Q alkyl; R16 and R17 are independently H or Q-Q alkyl; or Ri6, R17, and the nitrogen to which they are attached form a morpholinyl ring; and R18 is Q-Q alkyl optionally substituted with -0-(Q-Q alkanoyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl; amino Q-Q alkyl, mono or dialkylamino Q-Q alkyl. Embodiment 30. Compounds according to embodiment 29, wherein R5 is of the formula:
Figure imgf000028_0001
Zi is H, halogen, Q-Q alkyl, Q-Q haloalkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, or Q-Q alkoxy; and Z2 is Q-Q alkyl, -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7> -NR6R7, NR6R7(Q-Q alkyl), Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q-Q alkoxy, C02R, OH, Q- Q alkoxycarbonyl, or Q-Q haloalkyl; Z3 is H, Q-Q alkyl, -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7, -NR6R7, NR6R7(Q-Q alkyl), Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q-Q alkoxy, C02R, OH, Q-Q alkoxycarbonyl, or Q-Q haloalkyl; and wherein R6 and R7 at each occurrence are independently H, OH, Q-Q alkyl, amino Q-Q alkyl, NH(Q-Q alkyl)alkyl, N(Q-Q alkyl)(Q-Q alkyl) Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkoxy Q-Q alkyl, -S02(Q-Q alkyl), -S02NH2, -S02NH(Q-Q alkyl), -S02N(Q-Q alkyl)(Q-Q alkyl), or Q-Q alkanoyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, - C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-C6 alkyl), Q-C4 alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy. In this embodiment, it is preferred that at least one of Zl5 Z2, and Z3 is not hydrogen. Embodiment 31. Compounds according to embodiment 30, wherein
R5 is of the formula:
Figure imgf000029_0001
wherein
Zt is H, halogen, Q-Q alkyl, Q-Q haloalkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, or Q-Q alkoxy; and Z2 is Q-Q alkyl, -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7, -NR6R7, NR6R7(Q-Q alkyl), Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q-Q alkoxy, C02R, OH, Q- Q alkoxycarbonyl, or Q-Q haloalkyl;
Z3 is H, Q-Q alkyl, -C(0)NR6R7, -(Cι-C4alkyl)-C(0)NR6R7,-NR6R7, NR6R7(Q-Q alkyl), Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q-Q alkoxy, C02R, OH, Q-Q alkoxycarbonyl, or Q-Q haloalkyl, and wherein R6 and R7 at each occurrence are independently H, OH, Q-Q alkyl, amino Q-Q alkyl, NH(Q-Q alkyl)alkyl, N(Q-Q alkyl)(Q-Q alkyl) Q-Q alkyl, Q- Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkoxy Q-Q alkyl, - S02(Q-Q alkyl), -S02NH2, -S02NH(Q-Q alkyl), -S02N(Q-Q alkyl)(Q- Q alkyl), or Q-Q alkanoyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), - C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, - OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy. In this embodiment, it is preferred that at least one of Zi, Z2, and Z3 is not hydrogen. Embodiment 32. Compounds according to embodiment 30, wherein R5 is of the formula:
Figure imgf000030_0001
wherein Z\ is H, halogen, Q-Q alkyl, Q-Q haloalkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, or Q-Q alkoxy; and Zαis Q-Q alkyl, -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7, -NR6R7, NR6R7(Q-Q alkyl), Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q-Q alkoxy, C02R, OH, Q- Q alkoxycarbonyl, or Q-Q haloalkyl; Z3 is H, Q-Q alkyl, -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7; -NR6R7, NReR7(Q-Q alkyl), Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q-Q alkoxy, C02R, OH, Q-Q alkoxycarbonyl, or Q-Q haloalkyl, and wherein R6 and R7 at each occurrence are independently H, OH, Q-Q alkyl, amino Q-Q alkyl, NH(Q-Q alkyl)alkyl, N(Q-Q alkyl)(Q-Q alkyl) Q-Q alkyl, Q- Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkoxy Q-Q alkyl, - S02(Q-Q alkyl), -S02NH2, -S02NH(Q-Q alkyl), -S02N(Q-Q alkyl)(Q- Q alkyl), or Q-Q alkanoyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), - C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, - OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy. In this embodiment, it is preferred that at least one of Zls Z2, and Z3 is not hydrogen. Embodiment 33. Compounds according to embodiment 29, wherein
R5 is either
Figure imgf000031_0001
wherein Zi is H, halogen, Q-Q alkyl, Q-Q haloalkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, or Q-Q alkoxy; and Z2 is Q-Q alkyl, -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7> -NR6R7, NR6R7(C1-C6 alkyl), Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q-Q alkoxy, C02R, Q-Q alkoxycarbonyl, -(Q-Q alkyl)-NR15C(0)NR16Ri7, or -(Q-Q alkyl)-NR15C(0)Ri8; Z3 is H, Q-Q alkyl, -C(0)NR6R7, -(Q-Qalkyl)-C(0)NR6R7, -NR6R7, NR6R7(C1-C6 alkyl), Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q-Q alkoxy, CO2R, Q-Q alkoxycarbonyl, -(Q-Q alkyl)-NR15C(0)NR16R17, or -(Q-Q alkyl)- NR15C(0)R18; R6, R7, and the nitrogen to which they are attached form a piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl ring optionally substituted with 1 or 2 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q- Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy; R15 is H or Q-Q alkyl; R16 and R17 are independently H or Q-Q alkyl; or R16, R17, and the nitrogen to which they are attached form a morpholinyl ring; and Ri8 is Q-Q alkyl optionally substituted with -0-(Q-Q alkanoyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl; amino Q-Q alkyl, mono or dialkylamino Q-Q alkyl. In this embodiment, it is preferred that at least one of Z1; Z2, and Z3 is not hydrogen. Embodiment 34. Compounds according to embodiment 33, wherein R5 is of the formula:
Figure imgf000032_0001
Zi is H, halogen, Q-Q alkyl, Q-Q haloalkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, or Q-Q alkoxy; and Z2 is Q-Q alkyl, -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7, -NR6R7, NR6R7(C1-C6 alkyl), Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q-Q alkoxy, C02R, Q-Q alkoxycarbonyl, -(Q-Q alkyl)-NR15C(0)NR16R17, or -(Q-Q alkyl)-NR15C(0)R18; Z3 is H, Q-C4 alkyl, -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7) -NR6R7, NR6R7(C1-C6 alkyl), Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q-Q alkoxy, C02R, Q-Q alkoxycarbonyl, -(Q-Q alkyl)-NR15C(0)NR16Ri7, or -(Q-Q alkyl)- NRι5C(0)R18; R6, R , and the nitrogen to which they are attached form a piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl ring optionally substituted with 1 or 2 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q- Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy; R15 is H or Q-Q alkyl; R16 and R17 are independently H or Q-Q alkyl; or R16, Rι7, and the nitrogen to which they are attached form a morpholinyl ring; and R18 is Q-Q alkyl optionally substituted with -0-(Q-Q alkanoyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl; amino Q-Q alkyl, mono or dialkylamino Q-Q alkyl. In this embodiment, it is preferred that at least one of Zl5 Z2, and Z3 is not hydrogen. Embodiment 35. Compounds according to embodiment 33, wherein R5 is of the formula:
Figure imgf000033_0001
wherein
Zi is H, halogen, Q-Q alkyl Q-Q haloalkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, or Q-Q alkoxy; and Z2 is Q-Q alkyl, -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7) -NR6R7, NR6R7(Q-C6 alkyl), Ci-Ce hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q-Q alkoxy, C02R, Q-Q alkoxycarbonyl, -(Q-Q alkyl)-NR15C(0)NRieRi7, or -(Q-Q alkyl)-NR15C(0)R18; Z3 is H, Q-Q alkyl, -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7, -NR6R7, NR6R7(Ci-C6 alkyl), Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q-Q alkoxy, C02R, Q-Q alkoxycarbonyl, -(Q-Q alkyl)-NRi5C(0)NR16Ri7, or -(Q-Q alkyl)- NR15C(0)R18; R6, R7, and the nitrogen to which they are attached form a piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl ring, each of which is optionally substituted with 1 or 2 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), - C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, - OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy; R15 is H or Q-Q alkyl; R16 and R17 are independently H or Q-Q alkyl; or R16, R1 , and the nitrogen to which they are attached form a morpholinyl ring; and R18 is Ci-Ce alkyl optionally substituted with -0-(Q-Q alkanoyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Ci-Ce alkyl; amino Q-Q alkyl, mono or dialkylamino Q-Q alkyl. In this embodiment, it is preferred that at least one of Zi, Z2, and Z3 is not hydrogen. Embodiment 36. A compound of the formula
Figure imgf000034_0001
or a pharmaceutically acceptable salt thereof, wherein
L and M are indepedently selected from-O-, -CH2-, -S- -NR-, -N(R)-N(R)-, C(=0)-, - S02-; R5 is
Figure imgf000034_0002
, wherein
Xi, X2, Xa, Xb, Xc, Xd> and Xe at are independently selected from -C(0)NR6R7, -(Ci-C4 alkyl)-C(0)NR6R7, -NR6R7, hydroxy(Q-C4)alkyl, Q-Q dihydroxyalkyl, H, OH, halogen, haloalkyl, alkyl, haloalkoxy, heteroaryl, heterocycloalkyl, Q-Q cycloalkyl, R6R7N-(Q-C6 alkyl)-, -C02-(Q-Q)alkyl, -N(R)C(0)NR6R7, - N(R)C(0)-(Q-Q)alkoxy, C02R-(C1-C6 alkyl)-, or -S02NR6R7; wherein the heteroaryl and heterocycloalkyl groups are optionally substituted with -NR6R7, -C(0)NR6R7, R6R7N-(Q-C6 alkyl)-, Q-Q alkyl, Q-Q alkoxy, or halogen; or R5 is heteroaryl or heteroarylalkyl, wherein the heteroaryl and heteroaryl groups are optionally substituted with 1,2, 3, or 4 groups that are independently -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7, -NR6R7, hydroxy(Q-Q)alkyl, Q-Q dihydroxyalkyl, H, OH, halogen, haloalkyl, alkyl, haloalkoxy, R6R7N-(Q-Q alkyl)-, -C02-(Q- Q)alkyl, -N(R)C(0)NR6R7, or -N(R)C(0)-(C Q)alkoxy; wherein R6 and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q alkoxy, Q- Q alkoxy Q-Q alkyl, Q-Q alkoxycarbonyl, OH, Q-Q hydroxyalkyl, Q- Q dihydroxyalkyl, Q-Q thiohydroxyalkyl, -(Ci-Q)alkyl-C02-alkyl, pyridyl Q-Q alkyl, Q-Q alkanoyl, benzyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, Q-Q alkoxy, piperidinyl Q-Q alkyl, morpholinyl Q-Q alkyl, piperazinyl Q-Q alkyl, OH, SH, NH2, NH(alkyl), N(alkyl)(alkyl), -O-Q- Q alkanoyl, Q-Q alkyl, CF3, or OCF3; or R6, R , and the nitrogen to which they are attached form a morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, hydroxy, hydroxy Q-Q alkyl, Q-Q dihydroxyalkyl, or halogen; R at each occurrence is independently H or Q-Q alkyl; and Y, Yi, Y2, Y3, and Y4 are independently selected from H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, dihydroxyalkyl, alkenyl, alkynyl, CN, alkanoyl, alkoxy, alkoxyalkyl, haloalkyl, and carboxyl. Embodiment 37. Compounds according to embodiment 36 of the formula
Figure imgf000035_0001
or a pharmaceutically acceptable salt thereof. Embodiment 38. Compounds according to embodiment 37, wherein R5 is
Figure imgf000035_0002
Embodiment 39. Compounds according to embodiment 31, wherein Y2, Y4, and Y are independently halogen; and
Yi and Y3 are both hydrogen. Embodiment 40. Compounds according to embodiment 39, wherein
R5 is
Figure imgf000036_0001
Xi and X2 are independently H, methyl, NR6R7, -(Ci-Q alkyl)-C(0)NR6R7, R6R7N-(C1-C6 alkyl)-, -C(0)NR6R7, Ci-C6 hydroxyalkyl, Q-Q dihydroxyalkyl, or -(Q-Q alkyl)-morpholinyl; and Xa and Xe are independently halogen, NH2, NH(Ci-C6 alkyl), N(Q-Q alkyl)(Q-C6 alkyl), methyl, or hydrogen. In this embodiment, it is preferred that one of Xa and Xe is not hydrogen. Embodiment 41. Compounds according to embodiment 40, wherein one of Xb and Xc is hydrogen and the other is -NR6R7, R^N^Q-Q alkyl)-, -C(0)NR6R7, -S02NR6R7, or halogen; where R6 and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q alkoxy, Ci- Ce alkoxy Q-Q alkyl, Q-Q alkoxycarbonyl, OH, Q-Q hydroxyalkyl, Ci- Ce dihydroxyalkyl, -(Q-Q)alkyl-C0 -alkyl, pyridyl Q-Q alkyl, Q-Q alkanoyl, benzyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, Q-Q alkoxy, piperidinyl Q- Q alkyl, morpholinyl Q-Q alkyl, piperazinyl Q-Q alkyl, OH, SH, NH2, NH(alkyl), N(alkyl)(alkyl), -O-Q-Q alkanoyl, Q-Q alkyl, CF3, or OCF3; or R6, R7, and the nitrogen to which they are attached form a morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, hydroxy, hydroxy Q-Q alkyl, Q-Q dihydroxyalkyl, or halogen. Embodiment 42. Compounds according to embodiment 41, wherein
Re and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl, Q-Q alkoxycarbonyl, OH, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, -(Q-Q)alkyl-Cθ2-alkyl, pyridyl Q-Q alkyl, Q-Q alkanoyl, benzyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, Q-Q alkoxy, piperidinyl Q-Q alkyl, morpholinyl Ci- Ce alkyl, piperazinyl Q-Q alkyl, OH, NH2, NH(alkyl), N(alkyl)(alkyl), -O-Q-Q alkanoyl, Q-Q alkyl, CF3, or OCF3. Embodiment 43. Compounds according to embodiment 42, wherein
Xais hydrogen, methyl, fluorine, or chlorine;
Xc and Xa are both hydrogen;
Xb is -NR6R7, -(Q-Q alkyl)-C(0)NR6R7, R6R7N-(Q-C6 alkyl)-, -C(0)NR6R7; wherein
R6 and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl, or Q-Q alkanoyl, wherein each of the above is optionally substituted with 1, 2, or 3 groups that are independently OH, SH, halogen, or Q-Q cycloalkyl. Embodiment 44. Compounds according to embodiment 39, wherein
R5 is
Figure imgf000037_0001
Xa is H, fluoro, chloro, or methyl; Xe is hydrogen, halogen, or methyl; and Xb is H;
X is H or halogen; Embodiment 45. Compounds according to embodiment 44, wherein
Xc is -S02NR6R7, or halogen; wherein Re and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q alkoxy, Ci- Ce alkoxy Q-Q alkyl, Q-Q alkoxycarbonyl, OH, Q-Q hydroxyalkyl, Ci- Ce dihydroxyalkyl, -(Q-Q)alkyl-C02-alkyl, pyridyl Q-Q alkyl, Q-Q alkanoyl, benzyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, Q-Q alkoxy, piperidinyl Q- Q alkyl, morpholinyl Q-Q alkyl, piperazinyl Q-Q alkyl, OH, SH, NH2, NH(alkyl), N(alkyl)(alkyl), -O-Q-Q alkanoyl, Q-Q alkyl, CF3, or OCF3; or R6, R , and the nitrogen to which they are attached form a morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, hydroxy, hydroxy Q-Q alkyl, Q-Q dihydroxyalkyl, or halogen; or Xc is fluoro, chloro, -NH2, -NH(Q-Q alkyl), -N(Q-Q alkyl)(Q-Q alkyl), -S02NH2, -S02NH(Q-Q alkyl), -S02N(Q-Q alkyl)(Q-Q alkyl), or piperazinyl, wherein the piperazinyl group is optionally substituted with 1 or 2 groups that are independently 0,-04 alkyl, Q-Q alkoxy, hydroxy, hydroxy Q-Q alkyl, Q-Q dihydroxyalkyl, or halogen. Embodiment 46. Compounds according to embodiment 44, wherein Xc is -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7, -NR6R7, or R6R7N-(Q-C6 alkyl)-; wherein R6 and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q alkoxy, Ci- Q alkoxy Q-Q alkyl, Ci-Ce alkoxycarbonyl, OH, Ci-Ce hydroxyalkyl, Ci- Ce dihydroxyalkyl, Q-Q dihydroxyalkyl, -(Q-Q)alkyl-C02-alkyl, pyridyl Q-Q alkyl, Q-Q alkanoyl, benzyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, Q-Q alkoxy, piperidinyl Q-Q alkyl, morpholinyl Q-Q alkyl, piperazinyl Q-Q alkyl, OH, -NH2, -NH(alkyl), -N(alkyl)(alkyl), -O-Q-Q alkanoyl, Q-Q alkyl, CF3, or OCF3; or R6, R , and the nitrogen to which they are attached form a morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with! or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, hydroxy, hydroxy Q-Q alkyl, Q-Q dihydroxyalkyl, or halogen. Embodiment 47. Compounds according to embodiment 46, wherein R6 is hydrogen; and R7 is Q-Q alkyl or Q-Q alkanoyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently NH2, NH(Q-Q alkyl), N(Q-Q alkyl)(Q-Q alkyl), OH, SH, cyclopropyl, or Ci-C4 alkoxy; Embodiment 48. Compounds according to embodiment 47, wherein Xc is -C(0)NR6R7. Embodiment 49. Compounds according to embodiment 47, wherein Xc is NR6R7, or R6R7N-(Q-Q alkyl)-. Embodiment 50. Compounds according to embodiment 38, wherein Xa is hydrogen; two of Xb, Xc, and Xd are hydrogen and the other is -C(0)NR6R7, -(Q-Q alkyl)- C(0)NR6R7, -NR6R7, R6R7N-(Q-Q alkyl)- or -C02-(Ci-C6)alkyl; wherein Re and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q alkoxy, Q- Q alkoxy Q-Q alkyl, Q-Q alkoxycarbonyl, OH, Q-Q hydroxyalkyl, Ci- Ce dihydroxyalkyl, -(Q-C4)alkyl-C02-alkyl, pyridyl Q-Q alkyl, Q-Q alkanoyl, benzyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, Q-Q alkoxy, piperidinyl Ci- Ce alkyl, morpholinyl Q-Q alkyl, piperazinyl Q-Q alkyl, OH, NH2, NH(alkyl), N(alkyl)(alkyl), -O-Q-C4 alkanoyl, Q-Q alkyl, CF3, or OCF3; or Re, R7, and the nitrogen to which they are attached form a morpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, hydroxy, hydroxy Q-Q alkyl, Q-Q dihydroxyalkyl, or halogen; and Xe is hydrogen, methyl, Q-Q alkoxy, or halogen. Embodiment 51. Compounds according to embodiment 50, wherein Xb is -C(0)NR6R7, -(Ci-Ce alkyl)-C(0)NR6R7, -NR6R7, or R6R7N-(Q-Q alkyl)- wherein Re is hydrogen or Q-Q alkyl;
R7 is OH, Q-Q alkyl or Q-Q alkanoyl, wherein the alkyl and alkanoyl groups substituted with 1, 2, or 3 groups that are independently NH2, NH(Q-Q alkyl), N(Q-Q alkyl)(Q-C6 alkyl), Q-Q cycloalkyl, OH, or Q-Q alkoxy. Embodiment 52. Compounds according to embodiment 38, wherein Xa is halogen or methyl;
Xb is H, -NR6R7, R6R7N-(Q-Ce alkyl)-, -C(0)NR6R7, or -C02-(Q-Q)alkyl;
Xc is -NR6R7, ReR7N-(Q-Q alkyl)-, -C(0)NR6R7, halogen, -C02-(Ci-C6)alkyl, NH2, NH(Q-C6 alkyl), N(Q-Q alkyl)(Cι-Q alkyl), -S02NH2, -S02NH(Q-C6 alkyl), - S02N(C1-C6 alkyl)(Ci-C6 alkyl), or piperazinyl, wherein the piperazinyl group is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, hydroxy, hydroxy Q-Q alkyl, Q-Q dihydroxyalkyl, or halogen; Xc is hydrogen;
Xe is H, methyl, NH , NH(Q-Q alkyl) or N(Q-Q alkyl)(Q-C6 alkyl). Embodiment 53. Compounds according to embodiment 38, wherein
Xi, X2, Xa, Xb, Xc, Xd, and Xe are independently selected from H, OH, halogen, CF3, alkyl, OCF3, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, thienyl, furyl, pyrrolyl, piperidinyl, piperazinyl, or Q-Q cycloalkyl, wherein each of the above is optionally substituted with -NR6R7, -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7, R6R7N-(Q-Ce alkyl)-, Q-Q alkyl, Q-Q alkoxy, or halogen. Embodiment 54. Compounds according to embodiment 37, wherein R5 is a heteroaryl or heteroarylalkyl group, where each heteroaryl is pyrazolyl, imidazolyl, furanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, dihydroindolyl, dihydroisoindolyl, indolon-2-yl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, dihydroisoquinolinyl, or indolyl, each of which is optionally substituted with 1, 2, 3, or 4 groups that are independently -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7, -NR6R7, hydroxy(Q-Q)alkyl, Q-Q dihydroxyalkyl, hydrogen, hydroxy, halogen, haloalkyl, alkyl, haloalkoxy, R6R7N-(Q- alkyl)-, - C02-(Q-Q)alkyl, -N(R)C(0)NR6R7, or -N(R)C(0)-(Q-Q)alkoxy; wherein R6 and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q alkoxy, Ci- Ce alkoxy Q-Q alkyl, Q-Q alkoxycarbonyl, OH, Q-Q hydroxyalkyl, Q- Q dihydroxyalkyl, Q-Q thiohydroxyalkyl, -(Ci-Q)alkyl-C02-alkyl, pyridyl Q-Q alkyl, Q-Q alkanoyl, benzyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, Q-Q alkoxy, piperidinyl Q-Q alkyl, morpholinyl Q-Q alkyl, piperazinyl Q-Q alkyl, OH, SH, NH2, NH(alkyl), N(alkyl)(alkyl), -O-Q- C4 alkanoyl, Q-Q alkyl, CF3, or OCF. Embodiment 55. Compounds according to embodiment 54, wherein Y2, Y4, and Y are independently halogen; and Y\ and Y3 are both hydrogen. Embodiment 56. Compounds according to embodiment 55, wherein Xi and X2 are independently H, methyl, -NR6R7, ReRyN^Q-Q alkyl)-, -C(0)NR6R7, - (Q-Q alkyl)-C(0)NR6R7, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, or -(Q-Q alkyl)-morpholinyl. Embodiment 57. Compounds according to embodiment 56, wherein
R5 is pyridyl Q-Q alkyl, pyrimidinyl Ci-Ce alkyl, or pyrazinyl Q-Q alkyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently hydroxy(Q- Q)alkyl, Q-Q dihydroxyalkyl, OH, halogen, CF3, (Q-Q)alkyl, OCF3, -NR6R7, - (Q-Q alkyl)-C(0)NR6R7, ReR7N-(Q-C6 alkyl)-, or -C(0)NR6R7. Embodiment 58. Compounds according to embodiment 57, wherein
R5 is of the formula:
Figure imgf000041_0001
wherein
Z5 is hydroxy(Q-Q)alkyl, Q-Q dihydroxyalkyl, OH, halogen, CF3, (Q-Q)alkyl, OCF3, -NR6R7, ReR7N-(Q-Ce alkyl)-, -(Q-Q alkyl)-C(0)NR6R7, or -C(0)NR6R7, wherein R6 and R7 at each, occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy. Embodiment 59. Compounds according to embodiment 57, wherein R5 is of the formula:
Figure imgf000042_0001
wherein
Z5 is hydroxy(Q-Q)alkyl, Q-Q dihydroxyalkyl, OH, halogen, CF3, (C C4)alkyl, OCF3, -NR6R7, R6R7N-(Q-C6 alkyl)-, -(Q-Q alkyl)-C(0)NR6R7, or -C(0)NR6R7, wherein R6 and R7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-C6 alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy. Embodiment 60. Compounds according to embodiment 57, wherein R5 is of the formula:
Figure imgf000042_0002
, wherein Zio is H or methyl; and Z20 is -(Q-Q alkyl)-C(0)NR6R7, hydroxy(Q-Q)alkyl, Q-Q dihydroxyalkyl, OH, halogen, CF3, (Q-Q)alkyl, OCF3, -NR6R7, R6R7N-(Q-Q alkyl)-, or -C(0)NR6R7, wherein R6 and R7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy. Embodiment 61. Compounds according to embodiment 57, wherein R5 is of the formula:
Figure imgf000043_0001
, wherein Zio is H or methyl; and Z20 is -(Q-Q alkyl)-C(0)NR6R7, hydroxy(C1-C4)alkyl, Q-C4 dihydroxyalkyl, OH, , halogen, CF3, (Q-C4)alkyl, OCF3, -NR6R7, ReR7N-(Q-Ce alkyl)-, or -C(0)NR6R7, wherein R6 and R7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy. Embodiment 62. Compounds according to embodiment 57, wherein R5 is of the formula:
Figure imgf000043_0002
, wherein Z10 is H or methyl; and Z20 is -(Q-Q alkyl)-C(0)NR6R7, hydroxy(C1-C4)alkyl, Q-Q dihydroxyalkyl, OH, halogen, CF3, (Q-Q)alkyl, OCF3, -NR6R7, R6R7N-(Q- alkyl)-, or -C(0)NR6R7, wherein R6 and R7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-C4 alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy. Embodiment 63. Compounds according to embodiment 57, wherein R5 is of the formula:
Figure imgf000044_0001
, wherein Z10 is H or methyl; and Z20 is -(Q-Q alkyl)-C(0)NR6R7, hydroxy(Q-Q)alkyl, Q-C4 dihydroxyalkyl, OH, halogen, CF3, (Q-Q)alkyl, OCF3, -NR6R7, R6R7N-(Q-C6 alkyl)-, or -C(0)NR6R7, wherein R6 and R7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy. Embodiment 64. Compounds according to embodiment 57, wherein R5 is of the formula:
Figure imgf000044_0002
, wherein Zio is H or methyl; and Z20 is -(Q-Q alkyl)-C(0)NR6R7, hydroxy(Q-Q)alkyl, Q-Q dihydroxyalkyl, OH, halogen, CF3, (Q-Q)alkyl, OCF3, -NR6R7, R6R7N-(Q-C6 alkyl)-, or -C(0)NR6R7, wherein R6 and R7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-C4 alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy. Embodiment 65. Compounds according to embodiment 57, wherein R5 is of the formula:
Figure imgf000045_0001
wherein Zio is H or methyl; and Z20 is -(Q-Q alkyl)-C(0)NR6R7, hydroxy(Q-Q)alkyl, Ci-Q dihydroxyalkyl, OH, halogen, CF3, (Q-C )alkyl, OCF3, -NR6R7, R6R7N-(Q-Q alkyl)-, or -C(0)NR6R7, wherein R6 and R7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -0C(O)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy. Embodiment 66. Compounds according to embodiment 57, wherein
R5 is of the formula:
Figure imgf000045_0002
5 wherein Zio is H or methyl; and Z20 is -(Q-Q alkyl)-C(0)NR6R7, hydroxy(Q-Q)alkyl, Q-C4 dihydroxyalkyl, OH, halogen, CF3, (Q-C4)alkyl, OCF3, -NR6R7, R6R7N-(Q-Q alkyl)-, or -C(0)NR6R7, wherein R6 and R7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Ci-C4 alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy. Embodiment 67. Compounds according to embodiment 57, wherein R5 is of the formula:
Figure imgf000046_0001
, wherein Zio is H or methyl; and Z^o is -(Q-Q alkyl)-C(0)NR6R7, hydroxy(Cι-C4)alkyl, Q-Q dihydroxyalkyl, OH, halogen, CF3, (Q-Q)alkyl, OCF3, -NR6R7, RδR7N-(Q-Q alkyl)-, or -C(0)NR6R7, wherein R6 and R7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-C6 alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy. Embodiment A7. Compounds according to embodiment 1 wherein Ri is H, halogen, alkyl optionally substituted with Q-Q alkoxycarbonyl, Q-Q alkenyl optionally substituted with Q-Q alkoxycarbonyl, Q-Q alkynyl, Q-Q haloalkyl, carboxaldehyde, Q-Q hydroxyalkyl, phenyl(Q-Q)alkoxy, benzyl, phenethyl, phenpropyl, CN, or phenyl(Q-C6)alkanoyl, wherein the phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, nitro, CN, CF3, OCF3 or C02H; R2 is OH, benzyloxy, phenyloxy, phenyloxy(Q-Q)alkyl, phenyl (Q-Q) thioalkoxy, -OC(0)NH(CH2)„phenyl, -OC(0)N(alkyl)(CH2)nphenyl, di(Q-Q)alkylamino, Q- Q alkynyl, pyridyl, pyrimidyl, pyridazyl, pyrazolyl, imidazolyl, pyrrolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl, triazinyl, tetrahydrofuryl, piperidinyl, hexahydropyrimidinyl, thiazolyl, thienyl, or C02H, wherein n is O, 1, 2, 3, 4, 5 or 6; each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, NR6R7, (Q-Q) haloalkyl, (Q-Q) haloalkoxy, (Ci- Ce) alkyl, pyridyl, -(Q-Ce)alkyl-N(R)-C02R3o, or NR6R7-(Q-Q alkyl)-, R4 is H, alkyl optionally substituted with one or two groups that are independently CO2H, -C02alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R3o)C(0)-(Ci-C6)alkoxy, or -NR6R7, phenyl(Q-Q)alkoxy, phenyl(Q-Q)arkyl, hydroxyalkyl, wherein the phenyl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, CF3, or OCF3; and R5 is phenyl(Q-Q)alkyl, (Q-Q)alkyl, phenyl, piperidinyl(Q-Q) alkyl, thienyl(Q-Q) alkyl, indolyl, quinolinyl, isoquinolinyl, isoindolyl, indol-2-onyl, indazolyl, indolyl (Q-Q) alkyl, quinolinyl(Q-Q) alkyl, isoquinolinyl(Q-Q) alkyl, isoindolyl(Q- C6) alkyl, indoι-2-onyl(Q-Q) alkyl, naphthyl(Q-C6)alkyl, pyridyl(Q-C6)alkyl, pyrimidyl(Ci-Ce)alkyl, pyrazinyl(Ci-C6)alkyl, or wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, alkoxy, benzyloxy, thioalkoxy, -C02(Q-Q alkyl), C02H, CN, amidinooxime, NR8R9, NR6R7-(Q-Q alkyl)-, -C(0)NR6R7, amidino, CF3, or OCF3; R8 is hydrogen, Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl and phenyl Q-Q alkanoyl; and R is aminoalkyl, mono Q-Q alkylamino Q-Q alkyl, di Q-Q alkylamino Q-Q alkyl, Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, indazolyl, and phenyl Q-Q alkanoyl. In this embodiment, it is preferred that when R2 is benzyloxy, R4 is H, and R5 is benzyl or methyl, Ri is not hydrogen; and no more than two of Rl5 R2, R4, and R5 are simultaneously hydrogen. Embodiment A8. Compounds according to embodiment A7 wherein Ri is H, halogen, Q-Q alkyl optionally substituted with Q-Q alkoxycarbonyl, Q-Q alkenyl optionally substituted with Q-Q alkoxycarbonyl, Q-Q alkynyl, or carboxaldehyde;
R2 is benzyloxy, OH, phenyloxy, phenyloxy(Q-Q)alkyl, phenyl (Q-Q) thioalkoxy, or pyridyl; wherein each of the above is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, -(Q-Q)alkyl-N(R)-C02R3o, NReR7, (Q- Q) haloalkyl, (Q-Q) haloalkoxy, (Q-Q) alkyl, pyridyl, or NR6R7-(Ci-C6 alkyl)-. Embodiment A9. Compounds according to embodiment A7 wherein R is H, (Q-Q)alkyl optionally substituted with one or two groups that are independently C02H, -C02alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R30)C(O)-(Q-C6)alkoxy, or - NReRγ, phenyl(Ci-Ce)alkoxy, or hydroxy(C1-C6)alkyl, wherein the phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, hydroxy, Q-Q alkoxy, Q-Q alkyl, nitro, CF3, OCF3; and R5 is benzyl, phenethyl, phenpropyl, phenbutyl, (Q-Q)alkyl, phenyl, pyridyl, pyrimidyl, indolyl, indazolyl, indolyl (Q-Q) alkyl, naphthyl(Q-Q)alkyl, thienyl(Q- C6)alkyl, pyridyl(Q-C6)alkyl, pyrimidyl(Q-Q)aιkyl, or pyrazinyl(C1-C6)alkyl, and wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently alkyl, halogen, alkoxy, benzyloxy, thioalkoxy, -C02(Q-Q alkyl), CF3, OCF3, C02H, CN, amidinooxime. In this embodiment, it is preferred that when R2 is benzyloxy, R4 is H, and R5 is benzyl or methyl, Ri is not hydrogen; and no more than two of Ri, R2, R4, and R5 are simultaneously hydrogen. Embodiment A10. Compounds according to embodiment A7, wherein
R4 is H, (Q-Q) alkyl optionally substituted with one or two groups that are independently C02H, -COzalkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R3o)C(0)-(Q-Q)alkoxy, or - NR6R7, phenyl(C,-C6)alkoxy, benzyl, phenethyl, phenpropyl, or hydroxy(Q- C6)alkyl, wherein the phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, hydroxy, Q-Q alkoxy, Q-Q alkyl, nitro, CF3, OCF3; and R5 is indolyl, quinolinyl, isoquinolinyl, isoindolyl, indol-2-onyl, indolyl(Q-Q) alkyl, quinolinyl(Ci-Ce) alkyl, isoquinolinyl(Ci-Ce) alkyl, isoindolyl(Q-Q) alkyl, indol- 2-onyl(Q-Q) alkyl, each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently Q-Q alkyl, halogen, CF , OCF3, -C02CH3, Q-Q hydroxyalkyl, Q-Q alkoxy, -C02(Q-Q alkyl), benzyloxy, -NR8R9, NR6R7-(Q-Q alkyl)-, -C(0)NR6R7, or amidinooxime; wherein R6 and R7 are independently at each occurrence H, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, alkanoyl, phenylalkyl, phenylalkoxy, or phenylalkanoyl, wherein each is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, hydroxy, Q-Q alkoxy, OH, SH, Q-Q cycloalkyl, Q-Q alkyl, CF3, or OCF3; or Re, R7, and the nitrogen to which they are attached form a morpholinyl, thiomorpholinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, hydroxy, hydroxy Q-Q alkyl, or halogen. Embodiment All. Compounds according to embodiment A7 wherein Ri is chloro, bromo, iodo, or H; and
R5 is benzyl, phenethyl, phenpropyl, phenyl, quinolinyl, indolyl, isoquinolinyl, isoindolyl, indol-2-onyl, indolyl(Q-Q) alkyl, quinolinyl (Q-Q) alkyl, isoquinolinyl(Q-Q) alkyl, isoindolyl(Q-Q) alkyl, indol-2-onyl(Q-Q) alkyl, piperidinyl C,-Q alkyl, thienyl Q-Q alkyl, -CH2-pyridyl, or pyridyl, each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently Q-Q alkyl, halogen, CF3, OCF3, Q-Q hydroxyalkyl, Q-C4 alkoxy, -C02(Q-Q alkyl), benzyloxy, NR8R9, NR6R7 Q-Q alkyl, -C(0)NR6R7, and amidinooxime; wherein R6 and R7 are independently at each occurrence H, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, alkanoyl, phenylalkyl, phenylalkoxy, or phenylalkanoyl, wherein each is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, hydroxy, Q-Q alkoxy, OH, SH, Q-Q cycloalkyl, Q-Q alkyl, CF3, or OCF3; or Re, R7, and the nitrogen to which they are attached form a morpholinyl, thiomorpholinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, hydroxy, hydroxy Q-Q alkyl, or halogen. Embodiment A 12. Compounds according to embodiment All, wherein R5 is benzyl, phenethyl, phenpropyl, or phenyl, each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently Q-Q alkyl, halogen, CF3, OCF3, -C02CH3, Q-Q hydroxyalkyl, Q-Q alkoxy, -C02(Q-Q alkyl), benzyloxy, NR8R9, NR6R7 Ci-C4 alkyl, -C(0)NR6R7, and amidinooxime. Embodiment A 13. Compounds according to embodiment All, wherein R5 is quinolinyl, indolyl, isoquinolinyl, isoindolyl, indol-2-onyl, indolyl(Q-Q) alkyl, quinolinyl(Q-Q) alkyl, isoquinolinyl(Ci-C6) alkyl, isoindolyl(Q-Q) alkyl, indol- 2-onyl(Cι-C6) alkyl, piperidinyl Q-Q alkyl, thienyl Q-Q alkyl, -CH2-pyridyl, or pyridyl, each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently Q-Q alkyl, halogen, CF , OCF3, -C02CH3, Q-Q hydroxyalkyl, Q-Q alkoxy, -C02(Q-Q alkyl), benzyloxy, NR8R9, NR6R7 Q-Q alkyl, - C(0)NReR7, and amidinooxime. Embodiment A14. Compounds according to any one of embodiments All, A12, or A13 wherein R is benzyloxy, or phenethyloxy; each of the above is unsubstituted or substituted with 1, 2, or 3, groups that are independently -(Q-Q)alkyl-N(R)-C02R3o, fluoro, chloro, bromo, CF3, or (Q- Q)alkyl. Embodiment A15. Compounds according to any one of embodiments Al 1, A12 or A13 wherein
R2 is phenyloxy(Q-Q)alkyl, wherein the phenyl group is unsubstituted or substituted with 1, 2, or 3, groups that are independently -(Q-Q)alkyl-N(R)-C02R3o, fluoro, chloro, bromo, CF3, or (Q-Q)alkyl. Embodiment A16. Compounds according to embodiment Al, wherein Ri is H, halogen, Q-Q alkyl optionally substituted with Q-Q alkoxycarbonyl, Q-Q alkenyl optionally substituted with Q-Q alkoxycarbonyl, Q-Q alkynyl, or carboxaldehyde. Embodiment A 17. Compounds according to embodiment A 16, wherein R2 is benzyloxy, OH, phenyloxy, phenyloxy(Q-C6)alkyl, or phenyl (Q-Q) thioalkoxy, wherein each of the above is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, -(Q-Q)alkyl-N(R)-CO2R30, NR6R7, (Q-Q) haloalkyl, (Q-Q) haloalkoxy, (Q-Q) alkyl, pyridyl, or NR6R7-(Q-Q alkyl)-. Embodiment A18. Compounds according to embodiment A 17, wherein R4 is H, or (Q-Q) alkyl optionally substituted with one or two groups that are independently C02H, -C02alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R30)C(O)-(Q- C6)alkoxy, OH, or -NR6R7. Embodiment A19. Compounds according to embodiment A18, wherein R5 is phenyl, naphthyl, indolyl, pyridyl, quinolinyl, isoquinolinyl, isoindolyl, indol-2-onyl, indolyl(Q-Q) alkyl, quinolinyl(Q-Q) alkyl, isoquinolinyl(Q-Q) alkyl, isoindolyl(Ci-Ce) alkyl, indol-2-onyl(Q-Q) alkyl, pyridazinyl, pyrimidinyl, or pyrazinyl, pyridazinyl(Q-Q) alkyl, pyrimidinyl(Q-Q) alkyl, or pyrazinyl(Q-Q) alkyl, each of which is unsubstituted or substituted with 1, 2, 3, 4 or 5 groups that are independently Q-Q alkyl, halogen, CF3, OCF3, -C02CH3, Q-Q hydroxyalkyl, Q-Q alkoxy, -C02(Q-Q alkyl), benzyloxy, -NR8R9, -C(0)NR6R7, NR6R7 Q-Q alkyl, and amidinooxime; wherein R6 and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, hydroxy, Q-C4 alkoxy, Q-Q alkyl, OH, SH, Q- Q cycloalkyl, CF3, or OCF3; or Re, R7, and the nitrogen to which they are attached form a morpholinyl, thiomorpholinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, hydroxy, hydroxy Q-Q alkyl, or halogen. Embodiment A20. Compounds according to embodiment A 19, wherein Rt is H, halogen, methyl, ethyl, Q-Q alkenyl Q-Q alkynyl, or carboxaldehyde; R is benzyloxy, OH, phenyloxy, phenyloxy(Q-Q)alkyl, or phenyl (Q-Q) thioalkoxy, wherein each of the above is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, -(Q-C6)alkyl-N(R)-C02R3o, NR6R7, NR6R7 Q-Q alkyl, (Q-Q) haloalkyl, (Q-Q) haloalkoxy, (Q-Q) alkyl, or pyridyl; and R4 is H, (Q-Q) alkyl optionally substituted with one or two groups that are independently C02H, -C02alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R30)C(O)-(Q-Q)alkoxy, OH, or -NR6R7. Embodiment A21. Compounds according to embodiment A20, wherein R5 is phenyl optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, Q-Q alkyl, -NR10Rn, Q-Q alkoxy, -C(O)NR10Rii, -C02H, NR10Rn Q- C4 alkyl, Ci-C6 alkyl, Q-Q alkoxycarbonyl, Q-Q alkoxy, CHO, -S02NH2, Q-Q haloalkyl, Q-Q hydroxyalkyl, -Q-Q alkyl-NRi2C(0)NR13Ri4, -Ci-Q alkyl- NR12C(0)-(Q-Q alkyl)-NR13R14, -Q-Q alkyl-NR12C(0)OR15, or -Q-Q alkyl- NR12C(0)-(Q-C4 alkyl)-R15, wherein Rio and R at each occurrence are independently H, Q-Q alkyl, amino Q-Q alkyl, NH(Q-Q alkyl)alkyl, N(Q-Q alkyl)(Q-C6 alkyl) Q-Q alkyl, Ci- Ce hydroxyalkyl, Q-Q alkoxy Q-Q alkyl, OH, -S02 (Q-Q alkyl), or Q- Q alkanoyl, or Rio, Rii, and the nitrogen to which they are attached form a piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl ring optionally substituted with 1 or 2 groups that are independently alkyl or halogen, R12 is H or Q-Q alkyl; R13 and R,4 are independently H or Q-Q alkyl; or R13 and Ri4 and the nitrogen to which they are attached form a morpholinyl ring; and Ris is Q-Q alkoxy; -OC(0)Q-Q alkyl, OH. Embodiment A22. Compounds according to embodiment A21, wherein R5 is phenyl optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, Q-Q alkyl, -NR10Rii, NR10Rιι Q-Q alkyl, Q-Q alkoxy, or -C(O)NR10Rιι, -C02H, -Q-Q alkyl-NR10Rii, Q-Q alkyl, Q-Q alkoxycarbonyl, Q-Q alkoxy, CHO, -S02NH2, Q-Q haloalkyl, Q-Q hydroxyalkyl, -Q-Q alkyl- NR12C(0)NRι3Ri4, -Q-Q alkyl-NRι2C(0)-(Q-Q alkyl)-NRι3R14, -Q-Q alkyl- NRι2C(0)OR15, or -Q-Q alkyl-NR12C(0)-(Ci-C4 alkyl)-Rι5 wherein R10 and Rn at each occurrence are independently H, Q-Q alkyl, amino Q-Q alkyl, NH(Q-Q alkyl)alkyl, N(Q-Q alkyl)(Q-Q alkyl) Q-Q alkyl, Ci- Ce hydroxyalkyl, Q-Q alkoxy Q-Q alkyl, OH, -S02 (Q-Q alkyl), or Ci- Ce alkanoyl, R,2 is H or Q-Q alkyl; R13 and Ri4 are independently H or Q-Q alkyl; or R13 and R14 and the nitrogen to which they are attached form a morpholinyl ring; and R15 is Q-Q alkoxy; -OC(0)Q-Q alkyl, OH. Embodiment A23. Compounds according to embodiment A22, wherein R5 is phenyl optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, Q-Q alkyl, -NRι0Rπ, NR10R11 Q-Q alkyl, Q-Q alkoxy, -C(0)NR,oRπ, wherein Rio and Rπ at each occurrence are independently H, Q-Q alkyl, amino Q-Q alkyl, NH(Q-Q alkyl)alkyl, N(Q-Q alkyl)(Q-Q alkyl) Q-Q alkyl, Q- C6 hydroxyalkyl, Q-Q alkoxy Q-Q alkyl, OH, -S02 (Q-Q alkyl), Q-Q alkanoyl. Embodiment A24. Compounds according to embodiment A23, wherein R5 is phenyl optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, Q-Q alkyl, -NR10Rii, or Q-Q alkoxy. Embodiment A25. Compounds according to embodiment A23, wherein
R5 is substituted with at least one -C(0)NRιoRπ. Embodiment A26. Compounds according to embodiment A25, wherein Rio and Rπ at each occurrence are independently H, Q-Q alkyl, amino Q-Q alkyl, NH(Q-Q alkyl)alkyl, N(Q-Q alkyl)(Q-Q alkyl) Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy Q-Q alkyl. Embodiment 27. Compounds according to embodiment A26, wherein Rio is H. Embodiment A28. Compounds according to embodiment A25, wherein Rio and Rπ at each occurrence are independently H, Q-Q alkyl, OH, -S02 (Q-Q alkyl), Q-Q alkanoyl. Embodiment A29. Compounds according to embodiment A20, wherein R5 is phenyl optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, Q-Q alkyl, NH2, NH(Q-Q alkyl), N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, -C(0)NRιoRn, wherein each of the above alkyl groups is optionally substituted with 1 or 2 groups that are independently OH, or methoxy; wherein Rio, Rii, and the nitrogen to which they are attached form a piperidinyl, pyrrolidinyl, piperazinyl, or a morpholinyl ring optionally substituted with 1 or 2 groups that are independently alkyl or halogen. Embodiment A30. Compounds according to embodiment A20, wherein R5 is phenyl optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, -C02H, -Q-Q alkyl-NRioRn, Q-Q alkoxycarbonyl, Q-Q alkoxy, CHO, -S02NH2, Q-Q haloalkyl, Q-Q hydroxyalkyl, -Q-Q alkyl-NRι2C(0)NRι3Rι4, -Q-Q aιkyl-NRι2C(0)-(Q-Q alkyl)-NR13R,4, -Q-Q alkyl-NRι2C(0)ORι5, or -Q-Q alkyl-NR,2C(0)-(Q-Q alkyl)-R,5, -OC(0)Q-Q alkyl, or OH wherein R,2 is H or Q-Q alkyl; R13 and R14 are independently H or Q-Q alkyl; or R13 and Ri4 and the nitrogen to which they are attached form a morpholinyl ring; R15 is CpCe alkoxy. Embodiment A31. Compounds according to embodiment A30, wherein R5 is phenyl optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, -C0 H, Q-Q alkoxycarbonyl, Q-Q alkoxy, CHO, -S02NH2, Q-Q haloalkyl, Q-Q hydroxyalkyl. Embodiment A32. Compounds according to embodiment A30, wherein
R5 is phenyl optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, -C02H, -Q-Q alkyl-NR10Ru, -Q-Q alkyl- NR12C(0)NR13Ri4, -Q-Q alkyl-NRι2C(0)-(Q-Q alkyl)-NR13Rι4, -Q-Q alkyl- NR12C(0)ORi5, or -Q-Q alkyl-NRι2C(0)-(Q-Q alkyl)-R15, or -OC(0)Q-Q alkyl, wherein R12 is H or Q-Q alkyl; R13 and Ri4 are independently H or Q-Q alkyl; or R,3 and R,4 and the nitrogen to which they are attached form a morpholinyl ring; R15 is Q-Q alkoxy. Embodiment A33. Compounds according to embodiment A31, wherein R5 is phenyl optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, -C02H, -Q-Q alkyl- RioRu, -Q-Q alkyl- NRι2C(0)NRι3Ri4, -Q-Q alkyl- Ri2C(0)-(Q-Q alkyl)-NRι3R14, wherein R12 is H or Q-Q alkyl; R13 and R14 are independently H or Q-Q alkyl; or R13 and R14 and the nitrogen to which they are attached form a morpholinyl ring. Embodiment A34. Compounds according to any one of embodiments A30, A31, A32, or A33, wherein the phenyl group is substituted with two groups that are meta to each other. Embodiment A35. Compounds according to any one of embodiments A30, A31, A32, or A33, wherein the phenyl group is substituted with two groups that are para to each other. Embodiment A36. Compounds according to embodiment A20, wherein R5 is indolyl, pyridyl, pyridazinyl, pyrimidinyl, indazolyl, quinolinyl, isoquinolinyl, isoindolyl, indol-2-onyl, pyridazinyl, pyrimidinyl, or pyrazinyl, , each of which is unsubstituted or substituted with 1, 2, 3, 4 or 5 groups that are independently Q-Q alkyl, halogen, CF3, OCF3, -C02CH3, Q-Q hydroxyalkyl, Q-Q alkoxy, -C02(Q- Q alkyl), benzyloxy, NR8R9, NR6R7 Q-Q alkyl, -C(0)NR6R7, or amidinooxime; wherein R and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, OH, SH, Q-Q cycloalkyl, Q-Q alkoxy, Q-Q alkyl, OH, CF3, or OCF3; or R6, R7, and the nitrogen to which they are attached form a morpholinyl, thiomorpholinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, hydroxy, hydroxy Q-Q alkyl, or halogen. Embodiment A38. Compounds according to embodiment A36, wherein R5 is indolyl, pyridyl, pyrimidinyl, indazolyl, or pyrazinyl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 groups that are independently Q-Q alkyl, halogen, CF3, OCF3, -C02CH3, Q-Q hydroxyalkyl, Q-Q alkoxy, -C02(Q-Q alkyl), benzyloxy, -C(0)NR6R7, -NR8R9, NR6R7 Q-Q alkyl, and amidinooxime; wherein R6 and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, OH, SH, Q-Q cycloalkyl, Q-Q alkoxy, Q-Q alkyl, OH, CF3, or OCF3. Embodiment A39. Compounds according to embodiment A38, wherein R5 is indolyl, pyridyl, or pyrazinyl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 groups that are independently Q-Q alkyl, halogen, CF3, OCF3, -C02CH3, Q-Q hydroxyalkyl, Q-Q alkoxy, -C02(Q-Q alkyl), benzyloxy, -C(0)NR6R7, NR8R9, NR6R7- - alkyl-, and amidinooxime; wherein R6 and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently halogen, OH, SH, Q-Q cycloalkyl, Q-Q alkoxy, Q-Q alkyl, OH, CF3, or OCF3. Embodiment A40. Compounds according to embodiment A36, wherein
R5 is indolyl, pyridyl, pyridazinyl, pyrimidinyl, or pyrazinyl, each of which is unsubstituted or substituted with 1, 2, 3, 4 or 5 groups that are independently Q-Q alkyl, halogen, CF3, OCF3, -C02CH3, Q-Q hydroxyalkyl, Q-Q alkoxy, -C02(Q- Q alkyl), benzyloxy, -C(0)NH2, -C(0)NH(Q-Q alkyl) wherein the alkyl group is optionally substituted with OH or methoxy, -C(0)N(C,-Q alkyl) (Q-Q alkyl) wherein each alkyl group is independently and optionally substituted with OH or methoxy, -C(0)NR6R7, NR8R9, NR6R7 Q-Q alkyl, -Q-Q alkyl-NH2, -Q-Q alkyl-NH(Q-Q alkyl) wherein each alkyl group is independently and optionally substituted with OH or methoxy, -Q-Q alkyl-N(Q-Q alkyl)(Q-Q alkyl) wherein each alkyl group is independently and optionally substituted with OH or methoxy, and amidinooxime; wherein R6, R , and the nitrogen to which they are attached form a morpholinyl, thiomorpholinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, hydroxy, hydroxy Q-Q alkyl, or halogen. Embodiment A42. Compounds according to any one of embodiments A37, A38,
A39, or A40, , wherein Ri is H, halogen, methyl, or carboxaldehyde; R2 is benzyloxy, phenyloxy, phenyloxy(Q-Q)alkyl, or phenyl (Q-Q) thioalkoxy, wherein each of the above is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, -(Q-Q)alkyl-N(R)-C02R3o, NR6R7, (Q-Q) haloalkyl, (Q-Q) haloalkoxy, (Q-Q) alkyl, NReR7(Q-Q)alkyl, pyridyl, morpholinyl, thiomorpholinyl, piperazinyl pyridyl(Q-Q)alkyl, morpholinyl(Q-Q)alkyl, thiomorpholinyl(Q-Q)alkyl, or piperazinyl(Q-Q)alkyl wherein the pyridyl, morpholinyl, thiomorpholinyl, and piperazinyl rings are optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, or halogen; wherein R6 and R7 are independently at each occurrence H, Q-Q alkyl optionally substituted with 1 or two groups that are independently OH, halogen or methoxy, Q-Q hydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl, Q- Q alkanoyl, benzyl, benzyloxy, or phenyl Q-Q alkanoyl, wherein each is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, OH, SH, Q-Q cycloalkyl, Q-Q alkoxy, Q-Q alkyl, CF3, or OCF3, and R4 is H, (Q-Q) alkyl optionally substituted with one or two groups that are independently C02H, -C02alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R30)C(O)-(Q-C6)alkoxy, - NR6R7, NR6R7Q-Q alkyl, or hydroxy(Q-C3)alkyl. Embodiment A43. Compounds according to embodiment A42, wherein Ri is H or halogen. Embodiment A44. Compounds according to embodiment A 18, wherein R5 is phenyl(Q-Q)alkyl, (Q-Q)alkyl, piperidinyl(Cι-Q) alkyl, thienyl(Q-Q) alkyl, indolyl (Q-Q) alkyl, naphfhyl(Q-Q)alkyl, pyridyl(Q-Q)alkyl, ρyrimidyl(Q- Q)alkyl, quinolinyl(Q-Q) alkyl, isoquinolinyl(Q-Q) alkyl, isoindolyl(Q-Q) alkyl, indol-2-onyl(Q-Q) alkyl, pyridazinyl(Q-Q) alkyl, pyrazinyl(Q-Q) alkyl, or pyrazinyl(Ci-Q)alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, alkoxy, benzyloxy, hydroxyalkyl, thioalkoxy, -C02(Q-Q alkyl), C02H, CN, amidinooxime, NR8R9, NR6R7-(Q-Q alkyl)-, -C(0)NR6R7, amidino, CF3, or OCF3; R8 is hydrogen, Q-Q alkyl, Q-Q alkanoyl, phenyl Ci-Ce alkyl and phenyl Q-Q alkanoyl; and R9 is aminoalkyl, mono Q-Q alkylamino Q-Q alkyl, di Q-Q alkylamino Q-Q alkyl, Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, indazolyl, and phenyl Q-Q alkanoyl. In this embodiment, it is preferred that when R is benzyloxy, R4 is H, and R5 is benzyl or methyl, Ri is not hydrogen; and no more than two of Ri, R2, R4, and R5 are simultaneously hydrogen. Embodiment A45. Compounds according to embodiment A44, wherein
R5 is phenyl(Q-Q)alkyl, which is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, alkoxy, benzyloxy, thioalkoxy, -C02(Q-Q alkyl), C02H, CN, amidinooxime, NR8R9, NR6R7-(Q-Q alkyl)-, -C(0)NR6R7, amidino, CF3, or OCF3; wherein R6 and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, OH, SH, Q-Q cycloalkyl, Q-Q alkoxy, Q-Q alkyl, CF3, or OCF3; or Re, R7, and the nitrogen to which they are attached form a morpholinyl, thiomorpholinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, hydroxy, hydroxy Q-Q alkyl, or halogen; R8 is hydrogen, Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl and phenyl Q-Q alkanoyl; and R9 is aminoalkyl, mono Q-Q alkylamino Q-Q alkyl, di Q-Q alkylamino Q-Q alkyl, Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, indazolyl, and phenyl Q-Q alkanoyl. Embodiment A46. Compounds according to embodiment A45, wherein R5 is phenyl(Q-Q)alkyl, which is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently CN, halogen, Q-Q alkoxy, Q-Q thioalkoxy, Q-Q haloalkyl, Q-Q alkyl, Q-Q haloalkyl, Q-Q haloalkoxy, -C(O)NR20R2ι, wherein R20 and R2ι are independently H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy Q-Q alkyl, or R20, R21, and the nitrogen to which they are attached form a piperazinyl, or morpholinyl ring, each of which is optionally substituted with 1 or 2 groups that are independently alkyl or halogen. Embodiment A47. Compounds according to embodiment A46, wherein R5 is phenyl(Q-Q)alkyl, which is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently CN, halogen, Q-Q alkoxy, Q-Q haloalkyl, Q-Q alkyl, Q-Q haloalkoxy, -C(0)NR2oR2ι, wherein R o and R21 are independently H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy Q-Q alkyl, or R20, R21, and the nitrogen to which they are attached form a piperazinyl, or morpholinyl ring, each of which is optionally substituted with 1 or 2 groups that are independently alkyl or halogen. Embodiment A48. Compounds according to embodiment A47, wherein R5 is benzyl or phenethyl, each of which is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently CN, halogen, Q-Q alkoxy, CF3, OCF3, Q-Q alkyl, * -C(O)NR20R2i, wherein R20 and R2ι are independently H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy Q-Q alkyl, or R20, R21, and the nitrogen to which they are attached form a piperazinyl, or morpholinyl ring, each of which is optionally substituted with 1 or 2 groups that are independently alkyl or halogen. Embodiment A49. Compounds according to embodiment A48, wherein R5 is benzyl or phenethyl, each of which is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, methoxy, ethoxy, CF3, OCF3, methyl, ethyl, or -C(O)NR20R2ι, wherein R2o and R2ι are independently H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy Q-Q alkyl, Embodiment A50. Compounds according to embodiment A48, wherein R5 is benzyl or phenethyl, each of which is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, methoxy, ethoxy, CF3, OCF3, methyl, ethyl, or -C(O)NR20R2l, wherein R2o, R21, and the nitrogen to which they are attached form a piperazinyl, or morpholinyl ring, each of which is optionally substituted with 1 or 2 groups that are independently alkyl or halogen. Embodiment A51. Compounds according to embodiment A49, wherein R5 is substituted on the phenyl ring with 1, 2, 3, 4, or 5 groups and wherein there is a group at the para position of the phenyl. Embodiment A52. Compounds according to embodiment A43, wherein R5 is piperidinyl(Q-Q) alkyl, thienyl(Q-Q) alkyl, indolyl (Q-Q) alkyl, pyridyl(Q- Q)alkyl, pyrimidyl(Q-Q)arkyl, quinolinyl(Q-Q) alkyl, isoquinolinyl(Q-Q) alkyl, isoindolyl(Q-Q) alkyl, indol-2-onyl(Q-Q) alkyl, pyridazinyl(Q-Q) alkyl, or pyrazinyl(Cι-Q) alkyl, or pyrazinyl(Q-Q)alkyl, or pyrazinyl(Q-Q)alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, halogen, Q-Q alkoxy, Q-Q hydroxyalkyl, benzyloxy, Q-Q thioalkoxy, -C02(Q-Q alkyl), C02H, CN, amidinooxime, NR8R9, NR6R7-(Q-Q alkyl)-, -C(0)NR6R7, amidino, CF3, or OCF3; R8 is hydrogen, Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl and phenyl Q-Q 1 alkanoyl; and R is aminoalkyl, mono Q-Q alkylamino Q-Q alkyl, di Q-Q alkylamino Q-Q alkyl, Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, indazolyl, and phenyl Q-Q alkanoyl. In this embodiment, it is preferred that when R2 is benzyloxy, R4 is H, and R5 is benzyl or methyl, Ri is not hydrogen; and no more than two of Ri, R2, R4, and R5 are simultaneously hydrogen. Embodiment A53. Compounds according to embodiment A52, wherein R5 is piperidinyl(Q-Q) alkyl, thienyl(Q-Q) alkyl, indolyl (Q-Q) alkyl, pyridyl(Q- Q)alkyl, pyrimidyl(Q-Q)alkyl, or pyrazinyl(Q-Q)alkyl, each of which is unsubstituted. Embodiment A54. Compounds according to embodiment A52, wherein R5 is indolyl (Q-Q) alkyl, pyrimidyl(Q-Q)alkyl, or pyrazinyl(Q-Q)alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, or 4 groups that are independently Q-Q alkyl, halogen, Q-Q alkoxy, Q-C6 hydroxyalkyl, benzyloxy, Q-Q thioalkoxy, -C02(Q-Q alkyl), C02H, CN, amidinooxime, NR8R9, NR6R7-(Q-Q alkyl)-, amidino, -C(O)NR20R21, CF3, or OCF3; wherein R6 and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl, Q-Q alkanoyl, benzyl, benzyloxy, or phenyl Q-Q alkanoyl, wherein each is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, OH, SH, Q-Q cycloalkyl, Q-Q alkoxy, Q-Q alkyl, CF3, or OCF3; or R6, R7, and the nitrogen to which they are attached form a morpholinyl, thiomorpholinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, hydroxy, hydroxy Q-Q alkyl, or halogen; R8 is hydrogen, Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl and phenyl Q-Q alkanoyl; and R9 is aminoalkyl, mono Ci-Ce alkylamino Q-Q alkyl, di Ci-Ce alkylamino Q-Q alkyl, Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, indazolyl, and phenyl Q-Q alkanoyl; R2o and R2ι are independently H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy Q-Q alkyl, or R20, R21, and the nitrogen to which they are attached form a piperazinyl, or morpholinyl ring, each of which is optionally substituted with 1 or 2 groups that are independently alkyl or halogen Embodiment A55. Compounds according to embodiment A54, wherein R5 is indolyl (Q-Q) alkyl, or pyrazinyl(Q-Q)alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, or 4 groups that are independently Q-Q alkyl, halogen, Q-Q alkoxy, Q-Q hydroxyalkyl, benzyloxy, Q-Q thioalkoxy, - C02(Q-Q alkyl), C02H, CN, -C(O)NR20R2i, CF3, or OCF3; wherein R20 and R2i are independently H, Q-C6 alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy Q-Q alkyl, or R20, R21, and the nitrogen to which they are attached form a piperazinyl, or morpholinyl ring, each of which is optionally substituted with 1 or 2 groups that are independently alkyl or halogen. Embodiment A56. Compounds according to embodiment A52, wherein R5 is isoquinolinyl, isoindolyl, indol-2-onyl, quinolinyl(Q-Q) alkyl, isoquinolinyl(Q-Q) alkyl, isoindolyl(Q-Q) alkyl, indol-2-onyl(Q-Q) alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, halogen, Q-Q alkoxy, Q-Q hydroxyalkyl, benzyloxy, Q-Q thioalkoxy, -C02(Q-C5 alkyl), C02H, CN, amidinooxime, NR8R9, NReR7-(Q-Q alkyl)-, -C(0)NR6R7, amidino, CF3, or OCF3. Embodiment A57. Compounds according to embodiment Al, wherein Ri is H, halogen, methyl, ethyl, Q-Q alkenyl, Q-Q alkynyl, or carboxaldehyde; R2 is benzyloxy, OH, phenyloxy, phenyloxy(Q-Q)alkyl, or phenyl (Q-Q) thioalkoxy, wherein each of the above is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, -(Q-C6)alkyl-N(R)-CO2R30, NR6R7, (Q-Q) haloalkyl, (Q-Q) haloalkoxy, (Q-Q) alkyl, pyridyl, or NR6R7-(Q-Q alkyl)-; and R4 is H, (Q-Q) alkyl optionally substituted with one or two groups that are independently C02H, -C02alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R30)C(O)-(Q-Q)alkoxy, or - NR6R7, or hydroxy(Q-Q)alkyl;
R5 is Q-Q cycloalkyl or Q-Q cycloalkylalkyl, each of which is optionally substituted with 1 or 2 groups that are independently alkyl, alkoxy, halogen, -NR6R7, or NR6R7-(Q-Q alkyl)-, wherein each of the alkyl groups is optionally substituted with 1 or 2 groups that are independently OH, methoxy, NH2, or halogen. Embodiment A58. Compounds according to embodiment A57, wherein
R5 is Q-Q cycloalkyl or Q-Q cycloalkyl Q-Q alkyl, each of which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, halogen, -NR6R7, or NR6R7-(Q-Q alkyl)- wherein each of the alkyl groups is optionally substituted with 1 or 2 groups that are independently OH, methoxy, or NH2;
R6 and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl, Q-Q alkanoyl, benzyl, benzyloxy, or phenyl Q-Q alkanoyl, wherein each is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, OH, SH, Q-Q cycloalkyl, Q-Q alkoxy, Q-Q alkyl, CF3, or OCF3; or
R6, R7, and the nitrogen to which they are attached form a morpholinyl, thiomoφholinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, hydroxy, hydroxy Q-Q alkyl, or halogen. Embodiment A59. Compounds according to embodiment A58, wherein
Ri is H, halogen, methyl, ethyl;
R2 is benzyloxy, phenyloxy, phenyloxy(Q-Q)alkyl, or phenyl (Q-Q) thioalkoxy, wherein each of the above is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, -(Q-Q)alkyl-N(R)-CO2R30, amino, mono or dialkylamino, -NR6R7, (Q-Q) haloalkyl, (Q-Q) haloalkoxy, (Q-Q) alkyl, or NReR7-(Q-Q alkyl)-; and
R4 is H, methyl, (Q-Q)alkyl optionally substituted with one or two groups that are independently C02H, -C02alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R30)C(O)-(Q- Q)alkoxy, or -NR6R7 or hydroxy(Q-C2)alkyl. Embodiment A60. Compounds according to embodiment A59, wherein
R2 is substituted with two halogens and is further optionally substituted with 1 or 2 groups that are independently halogen, -(Q-Q)aikyl-N(R)-C02R3o, amino, mono or dialkylamino, -NR6R7, (Q-Q) haloalkyl, (Q-Q) haloalkoxy, (Q-Q) alkyl, or NReR7-(C,-C6 alkyl). Embodiment A61. Compounds according to embodiment Al, wherein R5 is H, alkyl optionally substituted with 1, 2, or 3 groups that are independently phenylalkoxycarbonyl, -NR8R9, halogen, -C(0)NR8R9, alkoxycarbonyl, or alkanoyl, alkoxyalkyl optionally substituted with one trimethylsilyl group, alkoxycarbonyl, amino, hydroxyalkyl, alkenyl optionally substituted with alkoxycarbonyl, alkynyl, -S02-alkyl, or alkoxy optionally substituted with one trimethylsilyl group, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, alkoxy, phenylalkoxy, thioalkoxy, -S02alkyl, alkoxycarbonyl, phenylalkoxycarbonyl, C02H, CN, OH, amidinooxime, NR8R9, NR6R7-(Q-Q alkyl)-, -C(0)NR6R7, amidino, hydroxyalkyl, carboxaldehyde, -NR6R7, haloalkyl, or haloalkoxy; wherein R8 is hydrogen, alkyl, alkanoyl, phenylalkyl and arylalkanoyl; and wherein R9 is alkyl, alkanoyl, phenylalkyl, heteroaryl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, and arylalkanoyl. In this embodiment, it is preferred that when R2 is benzyloxy, R4 is H, and R5 is benzyl or methyl, Ri is not hydrogen; and no more than two of R1? R2, R4, and R5 are simultaneously hydrogen. Embodiment A62. Compounds according to embodiment Al, wherein R5 is H, alkyl optionally substituted with 1, 2, or 3 groups that are independently phenylalkoxycarbonyl, -NR8R9, halogen, -C(0)NR8R9, alkoxycarbonyl, or alkanoyl, alkoxyalkyl optionally substituted with one trimethylsilyl group, alkoxycarbonyl, amino, hydroxyalkyl, alkenyl optionally substituted with alkoxycarbonyl, alkynyl, -S02-alkyl, alkoxy optionally substituted with one trimethylsilyl group, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, alkoxy, phenylalkoxy, thioalkoxy, -S02alkyl, alkoxycarbonyl, phenylalkoxycarbonyl, C02H, CN, OH, amidinooxime, NR8R9, NR6R7-(Ci-C6 alkyl)-, -C(0)NR6R7, amidino, hydroxyalkyl, carboxaldehyde, -NR6R7, haloalkyl, or haloalkoxy; wherein R8 is hydrogen, alkyl, alkanoyl, phenylalkyl and arylalkanoyl; and wherein R9 is alkyl, alkanoyl, phenylalkyl, heteroaryl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, and arylalkanoyl. In this embodiment, it is preferred that when R2 is benzyloxy, R4 is H, and Rg is benzyl or methyl, Ri is not hydrogen; and no more than two of Ri, R2, R4, and R5 are simultaneously hydrogen. Embodiment A63. Compounds according to embodiment A62, wherein Ri is H, halogen, methyl, ethyl, Q-Q alkenyl, Q-Q alkynyl, or carboxaldehyde; R2 is benzyloxy, OH, phenyloxy, phenyloxy(Q-C6)alkyl, or phenyl (Q-Q) thioalkoxy, wherein each of the above is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, -(Q-C6)alkyl-N(R)-C02R3o, NR6R7, (Q-Q) haloalkyl, (Q-Q) haloalkoxy, (Q-Q) alkyl, pyridyl, or NR6R7-(C1-C6 alkyl)-; and R4 is H, (Q-Q) alkyl optionally substituted with one or two groups that are independently C02H, -0O2alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R30)C(O)-(Q-Q)alkoxy, or - NR6R7, or hydroxy(Q-Q)alkyl. Embodiment A64. Compounds according to embodiment A63, wherein / R5 is H, alkyl optionally substituted with 1, 2, or 3 groups that are independently phenylalkoxycarbonyl, -NR8R9, halogen, -C(0)NR8R9, alkoxycarbonyl, or alkanoyl, alkoxyalkyl optionally substituted with one trimethylsilyl group, alkoxycarbonyl, amino, hydroxyalkyl, alkenyl optionally substituted with alkoxycarbonyl, alkynyl, -S02-alkyl, alkoxy optionally substituted with one trimethylsilyl group, wherein wherein R8 is hydrogen, Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl and phenyl Q-Q alkanoyl; wherein R9 is Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, pyridyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, and phenyl Q-Q alkanoyl. Embodiment A65. Compounds according to embodiment A64, wherein R5 is Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently phenyl Q-Q alkoxycarbonyl, NH2, mono Q-Q alkylamino, di Q-Q alkylamino, halogen, -C(0)NH2, -C(0)NH(Q-Q alkyl) wherein the alkyl is optionally substituted with OH, NH2, or methoxy, -C(0)N (Q-Q alkyl) (Q-Q alkyl) wherein each alkyl is optionally substituted with OH, NH2, or methoxy, Q-Q alkoxycarbonyl, and Q-Q alkanoyl, or R5 is Q-Q alkoxy Q-Q alkyl, Q-Q alkoxycarbonyl, amino, Q-Q hydroxyalkyl, Q-Q alkenyl optionally substituted with Q-Q alkoxycarbonyl, Q-Q alkynyl, -S02- Q- Q alkyl, or Q-Q alkoxy. Embodiment A66. A compound of the formula
Figure imgf000066_0001
or a pharmaceutically acceptable salt thereof, wherein
Ri is halogen, NO2, alkyl, carboxaldehyde, hydroxyalkyl, arylalkoxy, arylalkyl, CN, aryl, alkanoyl, alkoxy, alkoxyalkyl, haloalkyl, or arylalkanoyl, wherein the aryl portion of arylalkoxy, arylalkyl, and arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, (Q-Q)alkyl, (Q-Q) alkoxy, nitro, CN, haloalkyl, haloalkoxy or C02H; wherein the alkyl portion of the alkyl, hydroxyalkyl, arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and arylalkanoyl groups is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, Q-Q alkoxy, Q-Q alkoxycarbonyl, or spirocyclopropyl;
R2 is aryl, heteroaryl, arylalkenyl, arylalkoxy, aryloxyalkyl, arylalkyl, OH, alkynyl, aryloxy, aryloxyalkyl, arylthioalkoxy, alkoxy, -OC(0)NH(CH2)naryl, -OC(0)N(alkyl)(CH2)naryl, -OS02(Q-Q)alkyl, -OS02aryl, alkyl, alkoxyalkoxy, NR8R9, or C02H, wherein n is 0, 1, 2, 3, 4, 5 or 6; each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, -(Ci-Q)alkyl-N(R)-C02R3o, alkoxy, alkoxycarbonyl, CN, NR6R7, haloalkyl, haloalkoxy, alkyl, heteroaryl, heteroarylalkyl, NR6R7-(Q-Q alkyl)-, phenyl, -S02-phenyl wherein the ■ phenyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen or N02; or -OC(0)NR6R7, wherein R and R7 are independently at each occurrence H, alkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, -S02-alkyl, OH, hydroxyalkyl, -(Q- Q)alkyl-C02-alkyl, heteroarylalkyl, alkanoyl, arylalkyl, arylalkoxy, or arylalkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy, heterocycloalkyl, OH, SH, Q-Q cycloalkyl, NH2, NH(alkyl), N(alkyl)(alkyl), -O-alkanoyl, alkyl, haloalkyl, or haloalkoxy; or R6, R7, and the nitrogen to which they are attached form a morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, hydroxy, hydroxy Q-Q alkyl, or halogen; R at each occurrence is independently H or Q-Q alkyl; R30 is Ci-Ce alkyl optionally substituted with 1 or 2 groups that are independently OH, SH, halogen, amino, monoalkylamino, dialkylamino or C3-Q cycloalkyl; R4 is H, alkyl optionally substituted with one or two groups that are independently C02H, -C02alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R30)C(O)-(Q-C6)alkoxy, or -NR6R7, arylalkoxy, arylalkyl, hydroxyalkyl, haloalkyl, alkoxy, carboxaldehyde, C02H, alkoxyalkyl, or alkoxyalkoxy, wherein the aryl portion of arylalkoxy, arylalkyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy; and R5 is H, arylalkyl, alkyl, aryl, alkoxy, heterocycloalkylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkyl, cycloalkylalkyl, -alkyl-S-aryl, -alkyl-S02-aryl, -(Q- Q) alkyl-C(0)-heterocycloalkyl, -S02-aryl, or heteroaryl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, alkoxy, aryl, arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, OH, C02H, CN, amidinooxime, NR8R9, NReR7-(Cι-Q alkyl)-, -C(0)NR6R7, -(Ci-Qalkyl)-C(0)NR6R7, amidino, hydroxyalkyl, -S02alkyl, -S02H, -S02NR6R7, -NR6R7, alkanoyl wherein the alkyl portion is optionally substituted with OH, halogen or alkoxy, haloalkyl, -(Q-Q alkyl)-NR15C(0)NRi6R17, -(Q-Q alkyl)- NRι5C(0)R18, -O-CH2-O, -O-CH2CH2-O-, or haloalkoxy; wherein R8 at each occurrence is independently hydrogen, alkyl, alkanoyl, arylalkyl and arylalkanoyl wherein each of the above is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, alkoxy, alkoxycarbonyl, halogen, or haloalkyl; and R9 at each occurrence is independently alkyl, alkanoyl, arylalkyl cycloalkyl, alkenyl, heteroaryl, cycloalkylalkyl, arylalkanoyl, -S02-phenyl, and aryl wherein each of the above is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, alkoxy, alkoxycarbonyl, halogen, or haloalkyl; R,5 is H or Q-Q alkyl; Ri6 and Rι are independently H or Q-Q alkyl; or Ri6, Rπ, and the nitrogen to which they are attached form a morpholinyl ring; and Ris is Q-Q alkyl optionally substituted with -0-(Q-Q alkanoyl, Q-Q hydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl; amino Q-Q alkyl, mono or dialkylamino Q-Q alkyl. In this embodiment, it is preferred that: R6 and R7 are not simultaneously OH; Re and R7 are not simultaneously -S02(Q-Q alkyl); when R2 is OH, R4 is methyl and R5 is phenyl, Ri is not acetyl; and R4 and R5 are not simultaneously hydrogen. Embodiment A71. Compounds according to embodiment A66 wherein Ri is halogen, Q-Q alkyl, phenyl, carboxaldehyde, Q-Q hydroxyalkyl, phenyl Q-Q alkoxy, phenyl Q-Q alkyl, CN, Q-Q alkanoyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl, Q-Q haloalkyl, or phenyl Q-Q alkanoyl, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, (Q-Q)alkyl, (Q-Q) alkoxy, nitro, CN, Q-Q haloalkyl, Q-Q haloalkoxy or C02H; wherein the above alkyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, or ethoxy,
R2 is phenylalkoxy, OH, phenyloxy, phenyloxy(Q-Q)alkyl, phenylthio(Q-Q)aikoxy, alkoxy, alkenyl, phenethyl, -OC(0)NH(CH2)nphenyl, -OC(0)N(alkyl)(CH2)nphenyl, alkyl, alkoxyalkoxy, NR8R9, pyridyl, pyrimidyl, pyridazyl, pyrazolyl, imidazolyl, pyrrolyl, tetrahydroquinolinyl, amino, tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl, triazinyl, tetrahydrofuryl, piperidinyl, hexahydropyrimidinyl, thiazolyl, thienyl, or C02H, wherein n is O, 1, 2, or 3; each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, -(Q-Q)alkyl-N(R)-C02R3o, haloalkyl, haloalkoxy, alkyl, thienyl, pyridyl, or phenyl optionally substituted with 1, 2, or 3 halogens; R6 and R7 are independently at each occurrence H, alkyl, alkoxy, alkoxyalkyl, 1 hydroxyalkyl, alkoxycarbonyl, -(Q-Q)alkyl-C02-alkyl, alkanoyl, phenylalkyl, phenylalkoxy, or phenylalkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, OH, SH, Q-Q cycloalkyl, alkoxy, NH2, NH(Q-Q alkyl), N(Q- Q alkyl)(Q-Q alkyl), alkyl, CF3 or OCF3; or Re, R7, and the nitrogen to which they are attached form a morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, hydroxy, hydroxy Q-Q alkyl, or halogen;
R4 is H, alkyl optionally substituted with one or two groups that are independently C02H, -C02alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R30)C(O)-(Q-Ce)alkoxy, or -NR6R7, phenylalkoxy, phenylalkyl, hydroxyalkyl, carboxaldehyde, haloalkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy; and R5 is benzyl, phenethyl, (Q-Q)alkyl, phenyl, naphthyl, alkoxy, piperidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, 1H- indazolyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, piperidinyl(Cι-Q)aιkyl, pyrrolidinyl(Q-Ce)alkyl, imidazolidinyl(Q-C6)alkyl, piperazinyl(C,-Q)alkyl, pyridyl(Q-Q)alkyl, pyrimidyl(C,-Ce)alkyl, pyridazyl(Q-Q)alkyl, pyrazinyl(Q- Q)alkyl, isoquinolinyl(Cι-C6)alkyl, tetrahydroisoquinolinyl(Q-Q)alkyl, indolyl(Cι-C6)alkyl, or lH-indazolyl(Cι-C6)alkyl, and wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, alkoxy, hydroxyalkyl, phenylalkoxy, thioalkoxy, alkoxycarbonyl, phenylalkoxycarbonyl, OH, CO2H, CN, amidinooxime, NR8R9, NR6R7-(Q-Q alkyl)-, -C(0)NReR7, amidino, piperazinyl, morpholinyl, -S02 (Q-Q) alkyl, -S02NH2, -S02NH(Q- Q)alkyl, -S02N(Q-Q)alkyl (Q-C6)alkyl, haloalkyl, or haloalkoxy. In this embodiment, it is preferred that when R2 is OH, R4 is methyl and R5 is phenyl, Ri is not acetyl; and
R4 and R5 are not simultaneously hydrogen. Embodiment A72. Compounds according to embodiment A71 wherein Ri is halogen, alkyl, carboxaldehyde, hydroxyalkyl, phenylalkoxy, phenyl, benzyl, phenethyl, phenpropyl, phenbutyl, CN, (Q-Q)alkanoyl, haloalkyl, or phenylCO-, phenylCH2CO-, phenylCH2CH2CO-, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, (Q-Q)alkyl, (Q-Q) alkoxy, nitro, CN, haloalkyl, haloalkoxy or C02H; wherein the above alkyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, or ethoxy,
R is benzyloxy, phenethyloxy, phenpropyloxy, OH, phenyloxy, phenyloxy(Q-Q)alkyl, phenylfhio(Q-Q)aιkoxy, NR8R9, (Q-Q)alkyl, alkynyl, phenethyl, -OC(0)N(CH3)CH2phenyl, alkoxyalkoxy, pyridyl, pyrimidyl, pyridazyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazinyl, piperidinyl, hexahydropyrimidinyl, benzimidazolyl, or thienyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, -(Q-Q)alkyl-N(R)-C02R3o, CF3, OCF3, (Q- C4)alkyl, thienyl, pyridyl, or phenyl optionally substituted with 1, 2, or 3 halogens; R6 and R7 are independently at each occurrence H, (Q-Q)aιkyl, (Q-Q)alkoxy, (Q-Q)alkoxy(Q-C6)alkyl, (Q-Q)alkoxycarbonyl, hydroxy(Q-Q)alkyl, - (Q-Q)alkyl-C02-alkyl, (Q-Q)alkanoyl, phenyl(Q-Q)alkyl, phenyl(Q- Q)alkoxy, or phenyl(Q-Q)alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, (Q-Q)alkoxy, NH2, OH, SH, Q-Q cycloalkyl, (Q-Q)alkyl, CF3 or OCF3; or R6, R7, and the nitrogen to which they are attached form a morpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, hydroxy, hydroxy Q-Q alkyl, or halogen; R4 is H, alkyl optionally substituted with one or two groups that are independently CO2H, -C02alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R30)C(O)-(Q-Q)alkoxy, or -NR6R7, benzyloxy, phenethyloxy, phenpropyloxy, benzyl, phenethyl, phenpropyl, hydroxyalkyl, halo(Q-Q)alkyl, carboxaldehyde, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, CF3 or OCF3; and
R5 is benzyl, phenethyl, phenpropyl, phenbutyl, (Q-Q)alkyl, phenyl, piperidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl(Q-Q)alkyl, pyrrolidinyl(Q-Ce)alkyl, imidazolidinyl(Q-Ce)alkyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, pyridyl(Q- Q)alkyl, pyrimidyl(Q-Q)arkyl, pyridazyl(Q-Q)alkyl, or pyrazinyl(Q-Q)alkyl wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, haloalkyl, NR8R9, NR6R7-(Q-C6 alkyl)-, carboxaldehyde, morpholinyl, S02NH2, S02NH(alkyl), S02N(alkyl)(alkyl), alkoxy, hydroxyalkyl, benzyloxy, thioalkoxy, OH, C02H, CN, -C02(Q-Q alkyl), phenylalkoxycarbonyl, amidinooxime, amidino, -C(0)NR6R7, CF3, CF2CF3, C1CH2, or OCF3. In this embodiment, it is preferred that when R2 is OH, R4 is methyl and R5 is phenyl, R, is not acetyl. Embodiment A73. Compounds according to embodiment A72 wherein Ri is halogen, alkyl, carboxaldehyde, hydroxy(Q-Q)alkyl, phenylalkoxy, benzyl, phenethyl, -C(0)CH3, phenylCO-, or phenylCH2CO-, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, (Q-Q)arkyl, (Q-Q) alkoxy, nitro, CN, CF3, or OCF3; wherein the above alkyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, or ethoxy;
R2 is benzyloxy, phenethyloxy, phenpropyloxy, OH, phenyloxy, phenyloxy(Q-Q)alkyl, phenethyl, NR8R9, -S-benzyl, or (Q-Q)alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, -(Q-Q)alkyl-N(R)-C02R3o, CF3, OCF3, alkyl, thienyl, or pyridyl; R6 and R7 are independently at each occurrence H, (Q-Q)alkyl, (Q-Q)alkoxy, (Ci-Ce)alkoxy(Ci-C6)alkyl, (Q-Q)alkoxycarbonyl, hydroxy(Q-Q)alkyl, - (Q-Q)alkyl-C02-alkyl, (Q-Q)alkanoyl, phenyl(Q-Q)alkyl, phenyl(Q- C6)alkoxy, or phenyl(Q-Q)alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, (Q-Q)alkoxy, NH2, OH, SH, Q-Q cycloalkyl, (Q-Q)alkyl, CF3 or OCF3; or R6, R7, and the nitrogen to which they are attached form a moφholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, hydroxy, hydroxy Q-Q alkyl, or halogen; R4 is H, alkyl optionally substituted with one or two groups that are independently C02H, -C02alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R3o)C(0)-(Q-Ce)alkoxy, or -NR6R7, benzyloxy, phenethyloxy, phenpropyloxy, benzyl, or hydroxyalkyl, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, CF3 or OCF3; and R5 is benzyl, phenethyl, phenpropyl, phenbutyl, (Q-Q)alkyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazinyl(Q-Q)aιkyl, pyrimidinyl(QτQ)alkyl, or pyridyl(Q- Q)alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, haloalkyl, moφholinyl, -SO2 (Q-Q) alkyl, -S02NH2, -S02NH(Q-Q), -S02N(Q-Q)(Q-Q), (Q-Q)alkoxy, phenyl(Q-Q)alkoxy, thio(Cι-C4)alkoxy, (Q-Q)alkoxycarbonyl, OH, C02H, CN, amidinooxime, amidino, NR8R9, NReR7-(CrC6 alkyl)-, hydroxyalkyl, CONR6R7, CF3, or OCF3. Embodiment A74. Compounds according to embodiment A73 wherein Ri is halogen, alkyl, carboxaldehyde, or hydroxyalkyl;
R2 is benzyloxy, phenethyloxy, phenpropyloxy, OH, phenyloxy, phenyloxy(Q-Q)alkyl, phenethyl, phenylthioalkoxy, or (Q-Q)alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, -(Q-Q)alkyl-N(R)-C02R3o, CF3, OCF3, alkyl, thienyl, or pyridyl;
R4 is H, (Q-Q) alkyl optionally substituted with one or two groups that are independently CO H, -C02alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R3o)C(0)-(Ci-C6)alkoxy, or - NR6R7, benzyloxy, or phenethyloxy, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, hydroxy, (Q-Q)aTkoxy, (Q-Q)alkyl, nitro, CF3 or OCF3; and R5 is benzyl, phenethyl, (Q-Q)alkyl, phenyl, indazolyl, or pyridyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently (Q-Q)alkyl, halogen, OH, C02H, CN, (Q-Q)alkoxy, - C(0)pyrrolidine, -S02 (Q-Q) alkyl, benzyloxy, -C02(Q-Q alkyl), amidino, fhio(Q-Q)alkoxy, amidinooxime, CF3, NR8R9, NR6R7-(C1-C6 alkyl)-, CONR6R7, or OCF3. Embodiment A75. Compounds according to embodiment A74 wherein Ri is chloro, bromo, iodo, methyl, Q-Q alkenyl, Q-Q alkynyl; and R5 is benzyl, phenethyl, phenpropyl, phenyl, or pyridyl, each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently alkyl, OH, halogen, alkoxy, NH2, NH(Q-Q)alkyl, N(Q-Q)alkyl(Q-Q)alkyl, NR8R9, NR6R7-(Q-Q alkyl)-, CONR6R7, and amidinooxime; wherein R6 and R7 are independently H, Q-Q alkyl, Q-Q alkanoyl, wherein the alkyl and alkanoyl groups are optionally substituted with 1, 2, or 3 groups that are independently OH, halogen, or Q-Q cyclopropyl. Embodiment A76. Compounds according to embodiment A75 wherein R2 is benzyloxy, phenethyl, phenyloxy(Q-Q)alkyl, or phenethyloxy, each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, -(Q-Q)alkyl-N(R)-C02R3o, CF3, OCF3, or (Q-Q)alkyl. Embodiment A77. Compounds according to embodiment A66, wherein R5 is benzyl, phenethyl, thienyl(Q-Q alkyl), piperidinyl(Q-Q)alkyl, pyrrolidinyl(Q- C6)alkyl, imidazolidinyl(Ci-C6)alkyl, piperazinyl(Q-Ce)alkyl, pyridyl(C,-C6)alkyl, pyrimidyl(Ci-Ce)alkyl, pyridazyl(Ci-Ce)alkyl, pyrazinyl(Ci-Ce)alkyl, isoquinolinyl(C,-C6)alkyl, tetrahydroisoquinolinyl(Cι-C6)alkyl, indolyl(Q- Q)alkyl, or lH-indazolyl(Q-C6)alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently (Q-Q)alkyl, halogen, (Q-Q)alkoxy, (Q-Ce)hydroxyaTkyl, phenyl(Q-Q)aιkoxy, (Q-Q)thioarkoxy, (Q-C6)alkoxycarbonyl, phenyl(C1-C6)alkoxycarbonyl, OH, C02H, CN, amidinooxime, NR8R , NR6R7-(Ci-C6 alkyl)-, -C(0)NR6R7, amidino, piperazinyl, moφholinyl, - S02 (Ci-Ce) alkyl, -S02NH2, -S02NH(Q-Q)alkyl, -S02N(Q-C6)alkyl (Q- C6)alkyl, (Q-C4)haloalkyl, -(Q-Q alkyl)-NR15C(0)NRi6Ri7, -(Ci-Q alkyl)-NRι5C(0)R18, -0-CH2-0, -0-CH2CH2-0-, or (Q-C4)haloalkoxy; wherein Re and R are independently at each occurrence H, (Q-Q)alkyl, (Q- Q)alkoxy, (Cι-Q)alkoxy(Q-C6)alkyl, (Q-C6)alkoxycarbonyl, (Q- C6)hydroxyalkyl, -(Q-C4)alkyl-C02-(Cι-C6)alkyl, (Q-Ce)alkanoyl, phenyl(Ci-C6)alkyl, phenyl(Ci-C6)alkoxy, or phenyl(Q- Q) alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently,, halo gen, (Q-Q)alkoxy, NH2, OH, SH, Q-Q cycloalkyl, NH(Q-Q alkyl), N(Q-Q alkyl)(Q-Q alkyl), (Q-Q)alkyl, CF3 or OCF3; or Re, R7, and the nitrogen to which they are attached form a moφholinyl, thiomoφholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, hydroxy, hydroxy Q-Q alkyl, or halogen; and Ris is Q-Q alkyl optionally substituted with -0-(Q-Q alkanoyl, Q-Q hydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl; amino Q-Q alkyl, mono or dialkylamino Q-Q alkyl. In this embodiment, it is preferred that R6 and R7 are not simultaneously OH; and R6 and R7 are not simultaneously -S02(Q-Q alkyl). Embodiment A78. Compounds according to embodiment A77, wherein Ri is halogen, methyl, ethyl, Q-Q alkenyl, Q-Q alkynyl, or carboxaldehyde; R2 is benzyloxy, OH, phenyloxy, phenyloxy(Ci-Q)alkyl, or phenyl (Q-Q) thioalkoxy, wherein each of the above is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, -(Q-Q)alkyl-N(R)-C02R3o, NR6R7, (Q-Q) haloalkyl, (Q-Q) haloalkoxy, (Q-Q) alkyl, or pyridyl; and R4 is H, (Q-Q) alkyl optionally substituted with one or two groups that are independently C02H, -C02alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R3o)C(0)-(Q-Q)alkoxy, or - NR6R7, or hydroxy(Q-Q)alkyl. Embodiment A79. Compounds according to embodiment A78, wherein
R5 is benzyl, or phenethyl, wherein each is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently (Q-Q)aιkyl, halogen, (Q-Q)alkoxy, (Q- Q)hydroxyalkyl, phenyl(Cι-Q)alkoxy, (Q-Q)thioalkoxy, (Q-Q)alkoxycarbonyl, phenyl(Q-Q)alkoxycarbonyl, OH, C02H, CN, amidinooxime, NR8R9, NR6R - (Q-Q alkyl)-, -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7amidino, piperazinyl, moφholinyl, -S02 (Q-Q) alkyl, -S02NH2, -S02NH(Cι-C6)alkyl, -S02N(Q- Q)alkyl (Q-Q)alkyl, (Q-Q)haloalkyl, -(Q-Q alkyl)-NRi5C(0)R18, -0-CH2-0, - O-CH2CH2-O-, or (Q-C4)haloalkoxy; wherein Re and R7 are independently at each occurrence H, (Q-Q)alkyl, (Ci-C6)alkoxy, (Q-Q)alkoxy(Q-Q)alkyl, (Q-Q)alkoxycarbonyl, (Q-Q)hydroxyalkyl, - (C1-C4)alkyl-C02-(Ci-Ce)alkyl, (Q-C6)alkanoyl, phenyl(Q-C6)alkyl, phenyl(C,-Q)alkoxy, or phenyl(C,-C6)alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, (Q-Q)alkoxy, NH2, OH, SH, Q-Q cycloalkyl, NH(Q-Q alkyl), N(Q-Q alkyl)(Q-Q alkyl), (Q-Q)alkyl, CF3 or OCF3; or R6, R , and the nitrogen to which they are attached form a moφholinyl, thiomoφholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, hydroxy, hydroxy Q-Q alkyl, or halogen; and Ris is Ci-Ce alkyl optionally substituted with -0-(Q-Q alkanoyl, Q-Q hydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl, amino Q-Q alkyl, or mono or dialkylamino Q-Q alkyl. In this embodiment, it is preferred that R6 and R7 are not simultaneously OH; and R6 and R7 are not simultaneously -S02(Q-Q alkyl). Embodiment A80. Compounds according to embodiment A79, wherein
R5 is benzyl or phenethyl, wherein each is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, -C(0)NR6R7> -(Q-Q alkyl)- C(0)NReR7, NR8R9, halogen, Q-Q alkoxy, C02H, -(Q-Q alkyl)-C02H, Q-Q thioalkoxy, amidinooxime, Q-Q alkoxycarbonyl, -(Q-Q alkyl)-Q-Q alkoxycarbonyl, Q-Q hydroxyalkyl, -(Q-Q alkyl)-CN, CN, phenyl Q-Q alkoxy, OH, Q-Q haloalkyl, Q-Q haloalkoxy, NR6R7-(Q-Q alkyl)-, -(Q-Q alkyl)- NRi5C(0)Ri8, amidinooxime, -S02(Q-Q alkyl), -0-CH2-0-, -0-CH2CH2-0-, phenyl Q-Q alkoxy, or phenyl; wherein R6 and R7 at each occurrence are independently H, OH, Q-Q alkyl, amino Q-Q alkyl, NH(Q-Q alkyl)alkyl, N(Q-Q alkyl)(Q-Q alkyl) Q-Q alkyl, Q- Q hydroxyalkyl, Q-Q alkoxy Q-Q alkyl, -S02(Q-Q alkyl) each of which is optionally substituted with 1, 2, or 3 groups that are independently halogen, OH, SH, Q-Q cycloalkyl, Q-Q alkoxy, Q-Q alkyl, OH, CF3, or OCF3; or R6, R7, and the nitrogen to which they are attached form a piperidinyl, pyrrolidinyl, piperazinyl, or a moφholinyl, thiomoφholinyl, ring optionally substituted with 1 or 2 groups that are independently alkyl, hydroxy, hydroxy Q-Q alkyl, or halogen, R,8 is Q-Q alkyl optionally substituted with -0-(Q-Q alkanoyl, Q-Q hydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl; amino Q-Q alkyl, mono or dialkylamino Q-Q alkyl. In this embodiment, it is preferred that R6 and R7 are not simultaneously OH; and R6 and R7 are not simultaneously -S02(Q-Q alkyl). Embodiment A81. Compounds according to embodiment A80, wherein R5 is benzyl or phenethyl, wherein each is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, -C(0)NR6R7> -(Q-Q alkyl)- C(0)NR6R7, halogen, Ci-Ce alkoxy, C02H, -(Q-Q alkyl)-C02H, Q-Q thioalkoxy, amidinooxime, Q-Q alkoxycarbonyl, -(Q-Q alkyl)-Q-Q alkoxycarbonyl, Q-Q hydroxyalkyl, -(Q-Q alkyl)-CN, CN, phenyl Q-Q alkoxy, OH, Q-Q haloalkyl, Q-Q haloalkoxy, NR6R7-(Q-Ce alkyl)-, NR8R9, -(Q-Q alkyl)-NRι5C(0)R18, amidinooxime, -S02(Q-Q alkyl), -O-CH2-O-, -0-CH2CH2- O-, phenyl Q-Q alkoxy, or phenyl; wherein Re and R7 at each occurrence are independently H, OH, Q-Q alkyl, amino Q-Q alkyl, NH(Q-Q alkyl)alkyl, N(Q-Q alkyl)(Q-C6 alkyl) Q-Q alkyl, Ci- Ce hydroxyalkyl, Q-Q alkoxy Q-Q alkyl, -S02(Q-Q alkyl) each of which is optionally substituted with 1, 2, or 3 groups that are independently halogen, OH, SH, Q-Q cycloalkyl, Q-Q alkoxy, Q-Q alkyl, OH, CF3, or OCF3; and R18 is Q-Q alkyl optionally substituted with -0-(Q-Q alkanoyl, Q-Q hydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl; amino Q-Q alkyl, mono or dialkylamino Q-Q alkyl. In this embodiment, it is preferred that R6 and R7 are not simultaneously OH; and Re and R7 are not simultaneously -SOa(Q-Q alkyl). Embodiment A82. Compounds according to embodiment A81, wherein R5 is benzyl which is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7, halogen, Q- Q alkoxy, CO2H, Q-Q thioalkoxy, Q-Q alkoxycarbonyl, Q-Q hydroxyalkyl, CN, OH, NR6R7-(Q-Q alkyl)-, NR8R9, -S02(Q-C6 alkyl), or benzyloxy; wherein R6 and R7 at each occurrence are independently H, OH, Q-Q alkyl, amino Q-Q alkyl, NH(Q-Q alkyl)alkyl, N(Q-Q alkyl)(Q-Q alkyl) Q-Q alkyl, Q- Q hydroxyalkyl, Q-Q alkoxy Q-Q alkyl, -S02(Q-Q alkyl) each of which is optionally substituted with 1, 2, or 3 groups that are independently halogen, OH, SH, Q-Q cycloalkyl, Q-Q alkoxy, Q-Q alkyl, OH, CF3, or OCF3. In this embodiment, it is preferred that R6 and R7 are not simultaneously OH; and R6 and R7 are not simultaneously -Sθ2(Q-Q alkyl). Embodiment A83. Compounds according to embodiment A82, wherein
R5 is benzyl which is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, -C(0)NR6R7>-(Q-Q alkyl)-C(0)NR6R7, halogen, Q- Q alkoxy, Q-Q thioalkoxy, Q-Q alkoxycarbonyl, Q-Q hydroxyalkyl, CN, NR8R9, or NReR7-(Q-Q alkyl)-; wherein R6 and R7 at each occurrence are independently H, OH, Q-Q alkyl, amino Q-Q alkyl, NH(Q-Q alkyl)alkyl, N(Q-Q alkyl)(Q-Q alkyl) Q-Q alkyl, Q- Q hydroxyalkyl, or Q-Q alkoxy Q-Q alkyl each of which is optionally substituted with 1, 2, or 3 groups that are independently halogen, OH, SH, Q-Q cycloalkyl, Q-Q alkoxy, Q-Q alkyl, OH, CF3, or OCF3. In this embodiment, it is preferred that R6 and R7 are not simultaneously OH. Embodiment A84. Compounds according to embodiment A83, wherein the R5 group is disubstituted with two groups that are meta to each other. Embodiment A86. Compounds according to embodiment A80, wherein R5 is benzyl which is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, -C(0)NR6R7> -(Q-Q alkyl)-C(0)NR6R7, NR8R9, NR6R7-(Q-Q alkyl)-, halogen, Q-Q alkoxy, C02H, -(Q-Q alkyl)-C02H, -(Q- Q alkyl)-Q-Q alkoxycarbonyl, -(Q-Q alkyl)-CN, CN, phenyl Q-Q alkoxy, CF3, OCF3, -(Q-Q alkyl)-NRι5C(0)Rι8, amidinooxime, -0-CH2-0-, -0-CH2CH2- O-, or phenyl; wherein R6 and R7 at each occurrence are independently H, Q-Q alkyl, amino Q-Q alkyl, NH(Q-Q alkyl)alkyl, N(Q-Q alkyl)(Q-Q alkyl) Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy Q-Q alkyl, or OH, each of which is optionally substituted with 1, 2, or 3 groups that are independently halogen, OH, SH, Q-Q cycloalkyl, Q-Q alkoxy, Q-Q alkyl, OH, CF3, or OCF3; and R,8 is Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl; amino Q-Q alkyl, mono or dialkylamino Q-Q alkyl. In this embodiment, it is preferred that R6 and R7 are not simultaneously OH. Embodiment A87. Compounds according to embodiment A80, wherein R5 is benzyl or phenethyl, wherein each is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, -C(0)NR6R7ι -(Q-Q alkyl)- C(0)NR6R7, halogen, Q-Q alkoxy, C02H, -(Q-Q alkyl)-C02H, Q-Q thioalkoxy, amidinooxime, Q-Q alkoxycarbonyl, -(Q-Q alkyl)-Q-Q alkoxycarbonyl, Q-C6 hydroxyalkyl, -(Q-Q alkyl)-CN, CN, phenyl Ci-Ce alkoxy, OH, Q-Q haloalkyl, Q-Q haloalkoxy, NR8R9, NR6R7-(Q-Q alkyl)-, -(Q-Q alkyl)-NRi5C(0)R18, amidinooxime, -S02(Q-Q alkyl), -0-CH2-0-, -0-CH2CH2- O-, phenyl Q-Q alkoxy, or phenyl; wherein R6, R7, and the nitrogen to which they are attached form a piperidinyl, pyrrolidinyl, piperazinyl, or a moφholinyl, thiomoφholinyl, ring optionally substituted with 1 or 2 groups that are independently alkyl, hydroxy, hydroxy Q-Q alkyl, or halogen, Ris is Q-Q alkyl optionally substituted with -0-(Q-Q alkanoyl, Q-Q hydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl; amino Q-Q alkyl, mono or dialkylamino Q-Q alkyl. In this embodiment, it is preferred that R6 and R7 are not simultaneously OH; and R6 and R7 are not simultaneously -S02(Q-Q alkyl). Embodiment A88. Compounds according to embodiment A87, wherein R5 is benzyl which is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, -C(0)NR6R7, -(Ci-C4alkyl)-C(0)NR6R7, halogen, Q-Q alkoxy, C02H, Q-Q thioalkoxy, Q-Q alkoxycarbonyl, Q-Q hydroxyalkyl, CN, OH, NR8R9, NR6R7-(Q-C6 alkyl)-, -S02(Q-Q alkyl), or benzyloxy; and wherein R6 and R7 at each occurrence are independently H, OH, Q-Q alkyl, amino Q-Q alkyl, NH(Q-Q alkyl)alkyl, N(Q-Q alkyl)(Q-Q alkyl) Q-Q alkyl, Q- Q hydroxyalkyl, Q-Q alkoxy Q-Q alkyl, or -S02(Q-Q alkyl), each of which is optionally substituted with 1, 2, or 3 groups that are independently halogen, OH, SH, Q-Q cycloalkyl, Q-Q alkoxy, Q-Q alkyl, OH, CF3, or OCF3. In this embodiment, it is preferred that R6 and R7 are not simultaneously OH; and R6 and R7 are not simultaneously -S02(Q-Q alkyl). Embodiment A89. Compounds according to embodiment A80, wherein R5 is benzyl which is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, -C(0)NR6R7, -(Q-Qalkyl)-C(0)NR6R7, NR6R7-(Q-Q alkyl)-, NR8R9, halogen, Q-Q alkoxy, Q-Q thioalkoxy, Q-Q alkoxycarbonyl, Q-Q hydroxyalkyl, or CN; wherein Re and R7 at each occurrence are independently H, OH, Q-Q alkyl, amino Q-Q alkyl, NH(Q-Q alkyl)alkyl, N(Q-Q alkyl)(Q-Q alkyl) Q-Q alkyl, Ci- Ce hydroxyalkyl, or Q-Q alkoxy Q-Q alkyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently halogen, OH, SH, Q-Q cycloalkyl, Q-Q alkoxy, Q-Q alkyl, OH, CF3, or OCF3. In this embodiment, it is preferred that R6 and R7 are not simultaneously OH. Embodiment A90. Compounds according to embodiment A89, wherein the R5 group is disubstituted with two groups that are meta to each other. Embodiment A91. Compounds according to embodiment A78, wherein R5 is phenyl, which is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, -C(0)NR6R7, -NR6R7, NR6R7(Q-Q alkyl), NR8R9, Ci- Ce hydroxyalkyl, halogen, Q-Q alkoxy, C02H, OH, Q-Q alkoxycarbonyl, carboxaldehyde, Q-Q haloalkyl, -(Q-Q alkyl)-NRι5C(0)NRι6Rι7, -(Q-Q alkyl)-NRi5C(0)R18; wherein R6 and R7 at each occurrence are independently H, OH, Q-Q alkyl, amino Q-Q alkyl, NH(Q-Q alkyl)alkyl, N(Q-Q alkyl)(Q-Q alkyl) Q-Q alkyl, Ci- Ce hydroxyalkyl, Q-Q alkoxy Q-Q alkyl, -S02(Q-Q alkyl), -S02NH2, -S0 NH(Q-Q alkyl), -S02N(Q-Q alkyl)(Q-Q alkyl), or Q-Q alkanoyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently halogen, OH, SH, Q-Q cycloalkyl, Q-Q alkoxy, Q-Q alkyl, OH, CF3, or OCF3; or Re, R7, and the nitrogen to which they are attached form a piperidinyl, pyrrolidinyl, piperazinyl, or a moφholinyl ring optionally substituted with 1 or 2 groups that are independently alkyl, hydroxy, hydroxy Q-Q alkyl, or halogen, R15 is H or Q-Q alkyl; R16 and R17 are independently H or Q-Q alkyl; or Rie, Rπ, and the nitrogen to which they are attached form a moφholinyl ring; R18 is Q-Q alkyl optionally substituted with -0-(Q-Q alkanoyl, Q-Q hydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl; amino Q-Q alkyl, mono or dialkylamino Q-Q alkyl. In this embodiment, it is preferred that R6 and R7 are not simultaneously OH. Embodiment A92. Compounds according to embodiment A91, wherein
R5 is phenyl, which is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, -(Q-Qalkyl)-C(0)NR6R7, -C(0)NR6R7, -NR6R7, NR6R7(Q-Q alkyl), NR8R9, Q-Q hydroxyalkyl, halogen, Q-Q alkoxy, C02H, OH, Q-Q alkoxycarbonyl, carboxaldehyde, Q-Q haloalkyl, -(Q-Q alkyl)- NR15C(0)NRieRi7, -(Q-Q alkyl)-NR15C(0)Ri8; wherein R6 and R7 at each occurrence are independently H, OH, Q-Q alkyl, amino Q-Q alkyl, NH(Q-Q alkyl)alkyl, N(Q-Q alkyl)(Q-Q alkyl) Q-Q alkyl, Ci- Ce hydroxyalkyl, Q-Q alkoxy Q-Q alkyl, -S02(Q-Q alkyl), -S02NH2, -S02NH(Q-Q alkyl), -S02N(Q-Q alkyl)(Q-Q alkyl), or Q-Q alkanoyl each of which is optionally substituted with 1, 2, or 3 groups that are independently halogen, OH, SH, Q-Q cycloalkyl, Q-Q alkoxy, Q-Q alkyl, OH, CF3, or OCF3; Rι5 is H or Q-Q alkyl; R16 and R17 are independently H or Q-Q alkyl; or R16, R17, and the nitrogen to which they are attached form a moφholinyl ring; Ris is Ci-Ce alkyl optionally substituted with -0-(Q-Q alkanoyl, Q-Q hydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl; amino Q-Q alkyl, mono or dialkylamino Q-Q alkyl. Embodiment A93. Compounds according to embodiment A92, wherein Ri is halogen, methyl, ethyl, Q-Q alkenyl, Q-Q alkynyl, or carboxaldehyde;
R2 is benzyloxy, OH, phenyloxy, phenyloxy(Q-Q)alkyl, or phenyl (Q-Q) thioalkoxy, wherein each of the above is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, -(Q-Q)alkyl-N(R)-CO2R30, NR6R7, (Q-Q) haloalkyl, (Q-Q) haloalkoxy, (Q-Q) alkyl, pyridyl, or NReR7-(Q-Ce alkyl)-; and R4 is H, (Q-Q) alkyl optionally substituted with one or two groups that are independently C02H, -C02alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R3o)C(0)-(Ci-Ce)alkoxy, or - NR6R7, or hydroxy(Q-Q)alkyl. Embodiment A94. Compounds according to embodiment A93, wherein R5 is phenyl, which is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7) -NR6R7, NR6R7(Ci-C6 alkyl), Q-Q hydroxyalkyl, halogen, Q-Q alkoxy, C02H, OH, Q- Q alkoxycarbonyl, carboxaldehyde, Q-Q haloalkyl, wherein R6 and R7 at each occurrence are independently H, OH, Q-Q alkyl, amino Q-Q alkyl, NH(Q-Q alkyl)alkyl, N(Q-Q alkyl)(Q-Q alkyl) Q-Q alkyl, Q- C6 hydroxyalkyl, Q-Q alkoxy Q-Q alkyl, -S02(Q-Q alkyl), -S02NH2, -S02NH(Cι-C6 alkyl), -S02N(Cι-Q alkyl)(Q-C6 alkyl), or Q-Q alkanoyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently halogen, OH, SH, Q-Q cycloalkyl, Q-Q alkoxy, Q-Q alkyl, OH, CF3, or OCF3;. Embodiment A101. Compounds according to embodiment A66, wherein R5 is thienyl(Q-Q alkyl), piperidinyl(Q-Q)alkyl, pyrrolidinyl(Q-Q)alkyl, imidazolidinyl(Q-Q)alkyl, piperazinyl(Q-Q)alkyl, pyridyl(Cι-C6)alkyl, pyrimidyl (Q~Q)alkyl, pyridazyl(Cι-Ce)alkyl, pyrazinyl(Cι-C6)alkyl, isoquinolinyl(Cι-Ce)alkyl, tetrahydroisoquinolinyl(Ci-C6)alkyl, indolyl(Q- C6)alkyl, lH-indazolyl(Q-Q)alkyl, dihydroindolonyl(Ci-C6 alkyl), indolinyl(Q- Q alkyl), dihydroisoindoryl(Q-Ce alkyl), dihydrobenzimdazolyl(Ci-C6 alkyl), or dihydrobenzoimidazolonyl(Q-Q alkyl), wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently (Q-Q)alkyl, halogen, (Q-Q)alkoxy, (Q-Q)hydroxyalkyl, phenyl(Q-Q)alkoxy, (Q-Ce)thioalkoxy, (C,-C6)alkoxycarbonyl, phenyl(C,-C6)alkoxycarbonyl, OH, CO2H, CN, amidinooxime, NR8R9, NR6R7-(Q-Q alkyl)-, -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7, amidino, piperazinyl, moφholinyl, -S02 (Q-Q) alkyl, -S02NH2, -S02NH(Q- Q)alkyl, -S02N(Q-Q)alkyl (Q-C6)alkyl, (Q-Q)haloalkyl, -(Q-Q alkyl)- NRι5C(0)NR16R17, -(Q-Q alkyl)-NR15C(0)R18, -0-CH2-0, -0-CH2CH2- O-, or (Q-Q)haloalkoxy; wherein Re and R7 are independently at each occurrence H, (Q-Q)alkyl, (Q- C6)alkoxy, (Q-Q)alkoxy(Cι-Q)alkyl, (C,-C6)alkoxycarbonyl, (Q- Q)hydroxyalkyl, -(Cι-Q)alkyl-Cθ2-(Cι-Q)alkyl, (C,-C6)alkanoyl, phenyl(Q-Q)alkyl, phenyl(Q-C6)alkoxy, or phenyl(Q- C6)alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, (Q-Q)alkoxy, OH, SH, Q-Q cycloalkyl, NH2, NH(Q-Q alkyl), N(Q-Q alkyl)(Q-Q alkyl), (Q-Q)alkyl, CF3 or OCF3; or R6, R7, and the nitrogen to which they are attached form a moφholinyl, thiomoφholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, hydroxy, hydroxy Q-Q alkyl, or halogen; and R18 is Q-Q alkyl optionally substituted with -0-(Q-Q alkanoyl, Q-Q hydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl; amino Q-Q alkyl, mono or dialkylamino Q-Q alkyl. In this embodiment, it is preferred that R6 and R7 are not simultaneously OH; and R6 and R7 are not simultaneously -S02(Q-Q alkyl). Embodiment A102. Compounds according to embodiment A101, wherein
Ri is halogen, methyl, ethyl, Q-Q alkenyl, Q-Q alkynyl, or carboxaldehyde; R2 is benzyloxy, OH, phenyloxy, phenyloxy(Q-Q)arkyl, or phenyl (Q-Q) thioalkoxy, wherein each of the above is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, -(Q-Q)alkyl-N(R)-C02R3o, NR6R7, (Q-Q) haloalkyl, (Q-Q) haloalkoxy, (Q-Q) alkyl, pyridyl, or NReR7-(Q-C6 alkyl)-; and
R4 is H, (Q-Q) alkyl optionally substituted with one or two groups that are independently C02H, -C02alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R30)C(O)-(Q-C6)alkoxy, or - NR6R7, or hydroxy(Q-Q)alkyl. Embodiment A 103. Compounds according to embodiment A 102, wherein R5 is thienyl(Q-Q alkyl), indolyl(Q-Q alkyl), pyridinyl(Q-Q alkyl), piperazinyl(Q-Q alkyl), or pyrazinyl(Q-Q alkyl) each of which is optionally substituted with 1, 2, or 3 groups that are independently Q-Q alkyl, Q-Q hydroxyalkyl, halogen, -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7> Q-Q alkoxycarbonyl, -NR6R7, NR6R7- (Q-Q alkyl)-, haloalkyl, Q-Q alkanoyl, R6 and R7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently Q-Q alkoxycarbonyl, halogen, Q-Q cycloalkyl, OH, SH, or Q-Q alkoxy; or Re, R7, and the nitrogen to which they are attached form a piperidinyl, pyrrolidinyl, piperazinyl, or a moφholinyl ring optionally substituted with 1 or 2 groups that are independently alkyl, hydroxy, hydroxy Q-Q alkyl, or halogen. Embodiment A 104. Compounds according to embodiment A 103, wherein
R5 is thienyl(Q-Q alkyl), indolyl(Q-Q alkyl), pyridinyl(Q-Q alkyl), piperazinyl(Q-Q alkyl), or pyrazinyl (Q-Q alkyl). Embodiment A 105. Compounds according to embodiment A 103, wherein R4 is H, methyl, ethyl, or -CH2OH; R5 is pyridinyl(Q-Q alkyl), or pyrazinyl(Q-Q alkyl) each of which is optionally substituted with 1, 2, or 3 groups that are independently Q-Q alkyl, Q-Q hydroxyalkyl, halogen, -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7, Q-Q alkoxycarbonyl, -NR6R7, NReR7-(Q-Q alkyl)-, CF3, Ci-Ce alkanoyl, wherein R6 and R7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently Q-Q alkoxycarbonyl, halogen, Q-Q cycloalkyl, OH, SH, or Q-Q alkoxy; or R6, R7, and the nitrogen to which they are attached form a piperidinyl, pyrrolidinyl, piperazinyl, or a moφholinyl ring optionally substituted with 1 or 2 groups that are independently alkyl, hydroxy, hydroxy Q-Q alkyl, or halogen. Embodiment A 106. Compounds according to embodiment A 105, wherein R4 is H, alkyl substituted with one or two groups that are independently C02H, -C02-(Q- Q)alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R30)C(O)-(Cι-C6)alkoxy, or -NR6R7. Embodiment Al 12. Compounds according to embodiment 16, wherein Ri is halogen, or methyl;
R2 is benzyloxy, which is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, -(Q-Q)alkyl-N(R)-Cθ2R30, CF3, OCF3, or (Q-Q) alkyl,; and R4 is H, methyl, ethyl, -CH2OH, -CH2Cθ2-(Ci-Q alkyl), or Q hydroxyalkyl. Embodiment Al 13. Compounds according to any one of embodiments A85, A95,
A97, A98, A99, A100, 16 or 17, wherein Ri is halogen, or methyl; R2 is benzyloxy, which is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, -(Q-C6)alkyl-N(R)-C02R3o, CF3, OCF3, or (Q-Q) alkyl,; and R4 is alkyl substituted with one group that is C02H, -C02-(Q-Q)alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R30)C(O)-(Q-C6)alkoxy, or -NR6R7. Embodiment Al 14. Compounds according to embodiment A66, wherein R5 is isoquinolinyl(Q-Q alkyl), tetrahydroisoquinolinyl(Cι-C6 alkyl), lH-indazolyl(Q-Q alkyl), dihydroindolonyl(Ci-C6 alkyl), indolinyl(Q-Q alkyl), dihydroisoindolyl(Cι-C6 alkyl), dihydrobenzimdazolyl(Q-C6 alkyl), dihydrobenzoimidazolonyl(Q-Ce alkyl), each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently alkyl, alkoxy, halogen, Q- Q alkoxycarbonyl, alkanoyl optionally substituted with 1 or 2 groups that are independently selected from the group consisting of OH, NH2, NH(Q-Q alkyl), and N(Q-Q alkyl) (Q-Q alkyl), -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7, NR6R7- (Q-Q alkyl)-, -NR6R7, or S02H; or piperidinyl Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently Q-Q alkyl, Q-Q alkoxy, halogen, -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7) NReR7-(Q-Q alkyl)-, or -NR6R7, or Q-Q alkoxycarbonyl. Embodiment Al 15. Compounds according to embodiment Al 14, wherein R5 is isoquinolinyl(Q-Q alkyl), piperidinyl Q-Q alkyl, tetrahydroisoquinolinyl (Q-Q alkyl), lH-indazolyl(C,-Q alkyl), dihydroindolonyl(Q-Q alkyl), indolinyl(Q-Q alkyl), dihydroisoindolyl(Q-Q alkyl), dihydrobenzimdazolyl(Q-Q alkyl), or dihydrobenzoimidazolonyl(C 1 -Q alkyl) . Embodiment Al 16. Compounds according to embodiment Al 14, wherein R5 is piperidinyl Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently Q-Q alkyl, Q-Q alkoxy, halogen, or Q-Q alkoxycarbonyl. Embodiment Al 17. Compounds according to embodiment A66, wherein R5 is pyrimidyl, indolinyl, indolyl, lH-isoindolyl, isoquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, dihydro-lH-benzimidazolyl, pyrrolyl, imidazolyl, or each of which is optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of Ci-Ce alkoxycarbonyl, Q-Q thioalkoxy, each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently -C(0)NR6R7, -(Q- C4alkyl)-C(0)NR6R7>NReR7-(Ci-C6 alkyl)-, -NR6R7, alkyl, alkoxy, halogen, Q-Q alkoxycarbonyl, or alkanoyl optionally substituted with 1 or 2 groups that are independently selected from the group consisting of OH, NH2, NH(Q-Q alkyl), and N(Q-Q alkyl) (Q-Q alkyl), and S02H; or pyridyl, pyrazolyl, optionally substituted with 1, 2, or 3 groups that are independently -C(0)NR6R7, -(Q-Qalkyl)-C(0)NR6R7,NR6R7-(Q-Q alkyl)-, -NR6R7, Q-Q alkyl, Q-Q hydroxyalkyl, halogen, Q-Q ' alkoxycarbonyl, -NR6R7, NR6R7-(Q-C6 alkyl)-, CF3, Q-Q alkanoyl, wherein Re and R7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently Q-Q alkoxycarbonyl, halogen, Q-Q cycloalkyl, OH, SH, or Q-Q alkoxy; or R6, R7, and the nitrogen to which they are attached form a piperidinyl, pyrrolidinyl, piperazinyl, or a moφholinyl ring optionally substituted with 1 or 2 groups that are independently alkyl, hydroxy, hydroxy Q-Q alkyl, or halogen. Embodiment Al 18. Compounds according to embodiment Al 17, wherein R5 is pyrimidyl, pyrrolyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with 1, 2, or 3 groups independently selected from Q-Q alkoxycarbonyl, Q-Q thioalkoxy, each of which is unsubstituted or substituted with 1, 2, or 3 groups that are independently alkyl, alkoxy, halogen, Q-Q alkoxycarbonyl, -C(0)NR6R7, -(Q-Qalkyl)- C(0)NR6R7,NR6R7-(Q-Ce alkyl)-, or -NR6R7, or Q-Q alkanoyl optionally substituted with 1 or 2 groups that are independently selected from the group consisting of OH, NH2, NH(Q-Ce alkyl), and N(Q-Q alkyl) (Q-Q alkyl), or S02H. Embodiment Al 19. Compounds according to embodiment Al 17, wherein R5 is pyridyl or pyrazolyl, optionally substituted with 1, 2, or 3 groups that are independently Q-Q alkyl, Q-Q hydroxyalkyl, halogen, -C(0)NReR7, -(Q-Q alkyl)-C(0)NReR7,NR6R7-(Cι-C6 alkyl)-, or -NR6R7, Q-Q alkoxycarbonyl, - NR6R7, NR6R7-(Cι-Q alkyl)-, CF3, Q-Q alkanoyl, wherein R6 and R7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently Q-Q alkoxycarbonyl, halogen, Q-Q cycloalkyl, OH, SH, or Q-Q alkoxy; or R6, R7, and the nitrogen to which they are attached form a piperidinyl, pyrrolidinyl, piperazinyl, or a moφholinyl ring optionally substituted with 1 or 2 groups that are independently alkyl, hydroxy, hydroxy Q-Q alkyl, or halogen. Embodiment A 120. Compounds according to embodiment Al 19, wherein R5 is pyridyl or pyrazolyl, optionally substituted with 1, 2, or 3 groups that are independently Q-Q alkyl, Q-Q hydroxyalkyl, halogen, -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7;NR6R7-(Q-Ce alkyl)-, -NR6R7, Q-Q alkoxycarbonyl, CF3, Q- Q alkanoyl, wherein R6 and R7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently Q-Q alkoxycarbonyl, halogen, Q-Q cycloalkyl, OH, SH, or Q-Q alkoxy. Embodiment A 121. Compounds according to embodiment Al 19, wherein R5 is pyridyl or pyrazolyl, optionally substituted with 1, 2, or 3 groups that are independently Q-Q alkyl, Q-Q hydroxyalkyl, halogen, -C(0)NR6R7, -(Q-Q alkyl)-C(0)NReR7,NR6R7-(Q-Q alkyl)-, -NR6R7, Q-Q alkoxycarbonyl, CF3, Q- Q alkanoyl, wherein R6, R7, and the nitrogen to which they are attached form a piperidinyl, pyrrolidinyl, piperazinyl, or a moφholinyl ring optionally substituted with 1 or 2 groups that are independently alkyl, hydroxy, hydroxy Q-Q alkyl, or halogen. Embodiment A 122. Compounds according to any one of embodiments Al 14, A115. A116, or Al 17 wherein
Ri is halogen, methyl, ethyl, Q-Q alkenyl, Q-Q alkynyl, or carboxaldehyde; R2 is benzyloxy, OH, phenyloxy, phenyloxy(Q-Q)alkyl, or phenyl (Q-Q) thioalkoxy, wherein each of the above is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, -(Q-Q)alkyl-N(R)-C02R3o, NR6R7, (Q-Q) haloalkyl, (Q-Q) haloalkoxy, (Q-Q) alkyl, pyridyl, or NR6R7-(Q-Q alkyl)-; and R4 is H, (Q-Q) alkyl substituted with one group that is C02H, -C02-(Q-Q)alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R30)C(O)-(Q-Q)alkoxy, or -NR6R7, hydroxy (C 1 -Q) alkyl . Embodiment A123. Compounds according to embodiment A66, wherein R5 is Q-Q alkyl optionally substituted with 1 or 2, groups that are independently Q-Q alkoxycarbonyl, or halogen, or
R5 is Q-Q alkoxy, ethyl, methyl, cyclopropylmefhyl, cycloalkyl, or alkynyl, or R5 is Q-Q alkenyl optionally substituted with Q-Q alkoxycarbonyl or cyclohexyl. Embodiment A 124. Compounds according to embodiment A 123, wherein Ri is halogen, methyl, ethyl, Q-Q alkenyl, Q-Q alkynyl, or carboxaldehyde; R2 is benzyloxy, OH, phenyloxy, phenyloxy(Q-Q)alkyl, or phenyl (Q-Q) thioalkoxy, wherein each of the above is optionally substituted with 1, 2, 3, or 4 groups that are independently halogen, -(Q-Q)alkyl-N(R)-CO2R30, NR6R7, (Q-Q) haloalkyl, (Q-Q) haloalkoxy, (Q-Q) alkyl, pyridyl, or NR6R7-(Cι-Q alkyl)-; and R4 is H, (Q-Q) alkyl substituted with one group that is C02H, -C02-(Ci-Q)alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R30)C(O)-(Q-Q)alkoxy, or -NR6R7, hydroxy(Q-Q)alkyl; wherein R6 and R7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently Q-Q alkoxycarbonyl, halogen, Q-Q cycloalkyl, OH, SH, or Q-Q alkoxy; or R6, R7, and the nitrogen to which they are attached form a piperidinyl, pyrrolidinyl, piperazinyl, or a moφholinyl ring optionally substituted with 1 or 2 groups that are independently alkyl, hydroxy, hydroxy Q-Q alkyl, or halogen. Embodiment A 125. Compounds according to embodiment A 124, wherein R5 is Q-Q alkyl optionally substituted with 1 or 2, groups that are independently Q-Q alkoxycarbonyl, or halogen, or R5 is Q-Q alkoxy, ethyl, methyl, cyclopropylmethyl, cyclohexyl, cyclopentyl, Q-Q alkynyl, or R5 is Q-Q alkenyl optionally substituted with Q-Q alkoxycarbonyl or cyclohexyl. Embodiment A 126. Compounds according to embodiment A66, wherein R2 is phenylalkynyl, -OC(0)NH(CH2)naryl, -OC(0)N(alkyl)(CH2)naryl, -OS02(Q- Q)alkyl, -OS02aryl, or NR8R9, wherein n is 0, 1, 2, 3, 4, 5 or 6; each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, -(Q-Q)alkyl-N(R)-C02R3o, alkoxy, alkoxycarbonyl, CN, NR6R7, haloalkyl, haloalkoxy, alkyl, heteroaryl, heteroarylalkyl, NReR7-(Q-Q alkyl)-, phenyl, -S02-phenyl wherein the phenyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen or N02; or -OC(0)NR6R7, wherein Re and R7 are independently at each occurrence H, alkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, -S02-alkyl, OH, hydroxyalkyl, -(Q- Q)alkyl-C02-alkyl, heteroarylalkyl, alkanoyl, arylalkyl, arylalkoxy, or arylalkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy, heterocycloalkyl, OH, NH2, Q-Q cycloalkyl, NH(alkyl), N(alkyl)(alkyl), -O-alkanoyl, alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy; or Re, R7, and the nitrogen to which they are attached form a moφholinyl, thiomoφholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, hydroxy, hydroxy Q-Q alkyl, or halogen. Embodiment A 127. Compounds according to embodiment A 126, wherein Ri is halogen, methyl, ethyl, Q-Q alkenyl, Q-Q alkynyl, or carboxaldehyde; and R4 is H, (Q-Q) alkyl substituted with one group that is C02H, -C02-(Q-Q)alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R30)C(O)-(Q-Q)alkoxy, -NR6R7, NReR7-(Q- Q alkyl)-, or hydroxy(Q-Q)alkyl. Embodiment A 128. Compounds according to embodiment A 127, wherein R5 is phenyl, optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, CF3, OCF3, -(Cι-C4alkyl)-C(0)NR6R7,NR6R7- (Q-Q alkyl)-, -NR6R7, or C(0)NR6R7, wherein R6 and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q alkoxy, Q- Q alkoxy Q-Q alkyl, Q-Q alkoxycarbonyl, OH, Q-Q hydroxyalkyl, - (Q-Q)alkyl-C0 -alkyl, pyridyl Q-Q alkyl, Q-Q alkanoyl, benzyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q alkoxy, piperidinyl Q-Q alkyl, moφholinyl Q-Q alkyl, piperazinyl Q-Q alkyl, OH, SH, Q-Q cycloalkyl, NH2, NH(aikyl), N(alkyl)(alkyl), -O-Q-Q alkanoyl, Q-Q alkyl, CF3, or OCF3; or R6, R7, and the nitrogen to which they are attached form a moφholinyl, thiomoφholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, hydroxy, hydroxy Q-Q alkyl, or halogen; or
R5 is benzyl optionally substituted with 1 ,2 ,3 ,4, or 5 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, CN, CF3, OCF3, -(Ci-C4alkyl)-C(0)NR6R7, NR6R7-(Q-Q alkyl)-, -NR6R7, or C(0)NR6R7. Embodiment A 129. Compounds according to embodiment A 128, wherein R2 is NR8R9, or NR8R9-(Q-Q alkyl)-; wherein R8 at each occurrence is independently hydrogen, Q-Q alkyl, Q-C6 alkanoyl, phenyl(Q-Q)alkyl or phenyl(Q-Q)alkanoyl wherein each of the above is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Ci-Ce alkyl, Q-Q alkoxy, Q-Q alkoxycarbonyl, halogen, or Q-Q haloalkyl; and R9 at each occurrence is independently Q-Q alkyl, Q-Q alkanoyl, phenyl(Q- Q)alkyl, Q-Q cycloalkyl, Q-Q alkenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, Q-Q cycloalkyl(Q-Q)alkyl, phenyl(Q-Q)alkanoyl, -Sθ2-phenyl, and phenyl wherein each of the above is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, Q-Q alkoxy, Q-Q alkoxycarbonyl, halogen, or Q-Q haloalkyl. Embodiment A130. Compounds according to embodiment A129, wherein R8 is H. Embodiment A131. Compounds according to embodiment A130, wherein R2 is -NH-benzyl option substituted with 1, 2, or 3 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, CF3, OCF3, or R2 is -NH-C(0)phenyl, wherein the phenyl group is optionally substituted with 1, 2, or 3 groups that are independently halogen, Q-Q alkyl, or Q-Q alkoxy; or R2 is -NH-allyl. Embodiment A 132. Compounds according to embodiment Al 31 , wherein
Ri is chloro, bromo, iodo, or methyl; and R5 is benzyl optionally substituted with 1 ,2 ,3 ,4, or 5 groups that are independently halogen, -(Cι-C4 alkyl)-C(0)NR6R7,NReR7-(Q-C6 alkyl)-, -NR6R7, Q-Q alkyl, Q-Q alkoxy, CN, CF3, OCF3, or C(0)NR6R7. Embodiment A 133. Compounds according to embodiment A 131 , wherein
Ri is chloro, bromo, iodo, or methyl; and R5 is phenyl, optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, -(Ci-Q alkyl)-C(0)NR6R7f NReR7-(Q-Q alkyl)-, -NR6R7, Q-Q alkyl, Q-Q alkoxy, CF3, OCF3, or C(0)NR6R7. Embodiment A 134. A compound of the formula
Figure imgf000091_0001
or pharmaceutically acceptable salts thereof, wherein R5 is
Figure imgf000091_0002
or ; wherein i, X2, Xa, Xb, Xc, Xd, and Xe at are independently selected from -C(0)NR6R7, -NR6R , hydroxy(Cι-C4)alkyl, H, OH, halogen, haloalkyl, alkyl, haloalkoxy, heteroaryl, heterocycloalkyl, Q-Q cycloalkyl, NR6R7-(Q-Q alkyl)-, -C02-(Ci-C6)alkyl, -N(R)C(0)NR6R7, -N(R)C(0)-(Ci-C6)alkoxy, C02H-(Q-C6 alkyl)-, or - S02N 6R7; wherein the heteroaryl and heterocycloalkyl groups are optionally substituted with -NReR7, -C(0)NR6R7, NR6R7-(Q-Q alkyl)-, Ci-C6 alkyl, Q-Q alkoxy, or halogen; Re and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q alkoxy, Ci- Ce alkoxy Q-Q alkyl, Q-Q alkoxycarbonyl, OH, Q-Q hydroxyalkyl, Q- Q thiohydroxyalkyl, -(Q-C4)alkyl-C02-alkyl, pyridyl Q-Q alkyl, Q-Q alkanoyl, benzyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, Q-Q alkoxy, piperidinyl Ci- Ce alkyl, moφholinyl Q-Q alkyl, piperazinyl Q-Q alkyl, OH, SH, NH2, NH(alkyl), N(alkyl)(alkyl), -O-Q-Q alkanoyl, Q-Q alkyl, CF3, or OCF3; or R6, R , and the nitrogen to which they are attached form a moφholinyl, thiomoφholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, hydroxy, hydroxy Q-Q alkyl, or halogen; R at each occurrence is independently H or Q-Q alkyl; and Y, Yi, Y2, Y3, and Y4 are independently selected from H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, alkenyl, alkynyl, CN, alkanoyl, alkoxy, alkoxyalkyl, haloalkyl, and carboxyl. Embodiment A135. Compounds according to embodiment A134, wherein
Y2, Y4, and Y are independently halogen; and Yi and Y3 are both hydrogen. Embodiment A136. Compounds according to embodiment A135, wherein Xi is H, methyl, -NR6R7, NR6R7-(Q-Q alkyl)-, -C(0)NR6R7, Q-Q hydroxyalkyl, or - (Q-Q alkyl)-moφholinyl. Embodiment A137. Compounds according to embodiment A136, wherein Xa and Xe are independently halogen, is NH2, NH(Q-Q alkyl), N(Q-Q alkyl)(Q-Q alkyl) or methyl. Embodiment A138. Compounds according to embodiment A137, wherein Xb or Xc is -NR6R7, NR6R7-(Q-Q alkyl)-, -C(0)NR6R7, -S02NR6R7, or halogen; wherein R6 and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q alkoxy, Ci- Ce alkoxy Q-Q alkyl, Q-Q alkoxycarbonyl, OH, Q-Q hydroxyalkyl, - (Q-Q)alkyl-Cθ2-alkyl, pyridyl Q-Q alkyl, Q-Q alkanoyl, benzyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, Q-Q alkoxy, piperidinyl Q-Q alkyl, moφholinyl Q-Q alkyl, piperazinyl Q-Q alkyl, OH, SH, NH2, NH(alkyl), N(alkyl)(alkyl), -O-Q-Q alkanoyl, Q-Q alkyl, CF3, or OCF3; or R6, R7, and the nitrogen to which they are attached form a moφholinyl, thiomoφholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, hydroxy, hydroxy Q-Q alkyl, or halogen. Embodiment A139. Compounds according to embodiment A138, wherein R6, R7, and the nitrogen to which they are attached form a moφholinyl, thiomoφholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, hydroxy, hydroxy Q-Q alkyl, or halogen. Embodiment A140. Compounds according to embodiment A138, wherein R6, R7, and the nitrogen to which they are attached form a piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, hydroxy, hydroxy Q-Q alkyl, or halogen. Embodiment A 141. Compounds according to embodiment A 138, wherein Re and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl, Q-Q alkoxycarbonyl, OH, Q-Q hydroxyalkyl, -(Q- Q)alkyl-C02-alkyl, pyridyl Q-Q alkyl, Q-Q alkanoyl, benzyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, Q-Q alkoxy, piperidinyl Q-Q alkyl, moφholinyl Q-Q alkyl, piperazinyl Q-Q alkyl, OH, NH2, NH(alkyl), N(alkyl)(alkyl), -O-Q-Q alkanoyl, Q-Q alkyl, CF3, or OCF3. Embodiment A142. Compounds according to embodiment A138, wherein Re and R7 are independently at each occurrence H, Ci-Ce alkyl, Q-Q hydroxyalkyl, Q-Q alkoxy, Q-Q alkoxy Q-Q alkyl, or Q-Q alkanoyl, wherein each of the above is optionally substituted with 1, 2, or 3 groups that are independently OH, SH, halogen, or Q-Q cycloalkyl. Embodiment A143. Compounds according to embodiment A137, wherein Xa and Xe are independently fluoro, chloro, or methyl; and Xc is hydrogen or halogen. Embodiment A144. Compounds according to embodiment A137, wherein Xa is halogen;
Xe is NH2, NH(Q-Q alkyl) or N(Q-Q alkyl)(Q-Q alkyl); Xb and Xd are both hydrogen. Embodiment A145. Compounds according to embodiment A144, wherein
Xc is -NR6R7, NR6R7 Q-Q alkyl, -S02NR6R7, or halogen; wherein Re and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q alkoxy, Ci- Ce alkoxy Q-Q alkyl, Q-Q alkoxycarbonyl, OH, Q-Q hydroxyalkyl, - (Q-Q)alkyl-C02-alkyl, pyridyl Q-Q alkyl, Q-Q alkanoyl, benzyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, Q-Q alkoxy, piperidinyl Q-Q alkyl, moφholinyl Q-Q alkyl, piperazinyl Q-Q alkyl, OH, SH, NH2, NH(alkyl), N(alkyl)(alkyl), -O-Q-Q alkanoyl, Q-Q alkyl, CF3, or OCF3; or R6, R , and the nitrogen to which they are attached form a moφholinyl, thiomoφholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, hydroxy, hydroxy Q-Q alkyl, or halogen. Embodiment A 146. Compounds according to embodiment A 145, wherein Xc is fluoro, chloro, NH2, NH(Q-Q alkyl), N(Q-Q alkyl)(Q-Q alkyl), -S02NH2, -S02NH(Cι-C6 alkyl), -S02N(Cι-Ce alkyl)(Q-Q alkyl), or piperazinyl, wherein the piperazinyl group is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, hydroxy, hydroxy Q-Q alkyl, or halogen. Embodiment A147. Compounds according to either embodiment A137 or A144, wherein Xc is -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7, NR6R7, or NR6R7-(Q-Ce alkyl)-; wherein R6 and R7 are independently at each occurrence H, Q-Q alkyl, Ci-Ce alkoxy, Ci- Ce alkoxy Q-Q alkyl, Ci-Ce alkoxycarbonyl, OH, Q-Q hydroxyalkyl, - (Q-Q)alkyl-Cθ2-alkyl, pyridyl Q-Q alkyl, Q-Q alkanoyl, benzyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, Q-Q alkoxy, piperidinyl Q-Q alkyl, moφholinyl Q-Q alkyl, piperazinyl Q-Q alkyl, OH, NH2, NH(alkyl), N(alkyl)(alkyl), -O-Q-Q alkanoyl, Q-Q alkyl, CF3, or OCF3; or R6, R7, and the nitrogen to which they are attached form a moφholinyl, thiomoφholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, hydroxy, hydroxy Q-Q alkyl, or halogen. Embodiment A 148. Compounds according to embodiment A 147, wherein R6 is hydrogen; and R7 is Q-Q alkyl or Q-Q alkanoyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently NH2, NH(Q-Q alkyl), N(Q-Q alkyl)(Q-Q alkyl), OH, SH, cyclopropyl, or Q-Q alkoxy. Embodiment A 148 a. Compounds according to embodiment A 148, wherein , R7 is Ci-Ce alkanoyl optionally substituted with 1, 2, or 3 groups that are independently OH, cyclopropyl, or NH2. Embodiment A149. Compounds according to embodiment A135, wherein Xa is hydrogen;
Xb, Xc, or Xd is -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7, NR6R7, NR6R7-(Q-Q alkyl)- or -C02-(Q-Q)alkyl; wherein R6 and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q alkoxy, Ci- Ce alkoxy Q-Q alkyl, Q-Q alkoxycarbonyl, OH, Q-Q hydroxyalkyl, - (Q-Q)alkyl-C02-alkyl, pyridyl Q-Q alkyl, Q-Q alkanoyl, benzyl, phenyl Ci-Ce alkoxy, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, Q-Q alkoxy, piperidinyl Q-Q alkyl, moφholinyl Q-Q alkyl, piperazinyl Q-Q alkyl, OH, NH2, NH(alkyl), N(alkyl)(alkyl), -O-Q-Q alkanoyl, Q-Q alkyl, CF3, or OCF3; or R6, R7, and the nitrogen to which they are attached form a moφholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, hydroxy, hydroxy Q-Q alkyl, or halogen; and Xe is hydrogen, methyl, Q-Q alkoxy, or halogen. Embodiment A150. Compounds according to embodiment A149, wherein Xb is NR6R7, or NR6R7-(Q-Q alkyl)-, -C(0)NR6R7 or -C02-(Q-Q)alkyl; wherein R6 is hydrogen or Q-Q alkyl;
R7 is OH, Q-Q alkyl or Q-Q alkanoyl, wherein the alkyl and alkanoyl groups substituted with 1, 2, or 3 groups that are independently NH2, NH(Q-Q alkyl), N(Q-Q alkyl)(Q-Q alkyl), Q-Q cycloalkyl, OH, or Q-Q alkoxy. Embodiment A151. Compounds according to embodiment A 137, wherein Xa is halogen;
Xb is NR6R7, NReR7-(Q-Q alkyl)-, -C(0)NR6R7, or -C02-(Q-Ce)alkyl; Xc is NR6R7, NR6R7-(Q-C6 alkyl)-, -C(0)NR6R7, halogen, -C02-(Ci-Q)alkyl, NH2, NH(Q-Q alkyl), N(Q-Q alkyl)(Q-Q alkyl), -S02NH2, -S02NH(Q-Q alkyl), - S02N(Q-Q alkylXQ-Q alkyl), or piperazinyl, wherein the piperazinyl group is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, hydroxy, hydroxy Q-Q alkyl, or halogen; Xd is hydrogen; ,
Xe is H, methyl, NH2, NH(Q-Q alkyl) or N(Q-Q alkyl)(Q-Q alkyl). Embodiment A152. Compounds according to embodiment A135, wherein Xi, X2, Xa, Xb, Xc, Xd, and Xe are independently selected from H, OH, halogen, CF3, alkyl, OCF3, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, thienyl, furyl, pyrrolyl, piperidinyl, piperazinyl, or Q-Q cycloalkyl, wherein each of the above is optionally substituted with -NR6R7, -C(0)NR6R7, NR6R7-(Q-C6 alkyl)-, Q-Q alkyl, Q-Q alkoxy, or halogen. Embodiment A153. Compounds according to embodiment A152, wherein at least three of Xi, X2, Xa, Xb, Xc, Xd, and Xeare hydrogen. Embodiment A154. A compound of the formula:
Figure imgf000097_0001
or a pharmaceutically acceptable salt thereof, wherein
Ri is alkanoyl, halogen, arylalkanoyl, arylalkyl, alkoxyalkyl, hydroxyalkyl, or carboxaldehyde, wherein the aryl portion of arylalkyl, and arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, nitro, CN, haloalkyl, haloalkoxy or C02H; the alkyl portion of the hydroxyalkyl, arylalkyl, alkanoyl, alkoxyalkyl and arylalkanoyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, ethoxy or spirocyclopropyl; R2 is arylalkoxy, aryloxy, phenyloxy(Q-Q)aιkyl, OH, halogen, arylthioalkoxy, alkoxy, - OC(0)NH(CH2)naryl, -OC(0)N(alkyl)(CH2)naryl, alkyl, alkoxyalkoxy, dialkylamino, pyridyl, pyrimidyl, pyridazyl, pyrazolyl, imidazolyl, pyrrolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl, triazinyl, tetrahydrofuryl, piperidinyl, hexahydropyrimidinyl, thiazolyl, thienyl, or C02H, wherein n is 0, 1, 2, 3, 4, 5 or 6; the aryl portion of arylalkoxy, aryloxy, arylthioalkoxy, -OC(0)NH(CH2)naryl, and -OC(0)N(alkyiχCH2)naryl or the heteroaryl and heterocycloalkyl groups is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, -(Q-Q)alkyl-N(R)-C02R3o, haloalkyl, heteroaryl, heteroarylalkyl, NR6R7, NR6R7-(Q-Q alkyl)-, -0C(0)NR6R7, wherein Re and R7 are independently at each occurrence H, alkyl, alkoxy, alkanoyl, arylalkyl, arylalkoxy, or arylalkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, OH, SH, Q-Q cycloalkyl, alkoxy, alkyl, haloalkyl, or haloalkoxy; or R6, R7, and the nitrogen to which they are attached form a moφholinyl, thiomoφholinyl, thiomoφholinyl S-oxide, thiomoφholinyl S,S- dioxide, piperidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, or halogen; R at each occurrence is independently H or Q-Q alkyl; R o is Q-Q alkyl optionally substituted with 1 or 2 groups that are independently OH, SH, halogen, amino, monoalkylamino, dialkylamino or Q-Q cycloalkyl; R3 is halogen, arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl, -OC(0)NH(CH2)naryl, arylalkoxy,— OC(0)N(alkyl)(CH2)naryl, aryloxy, arylthio, thioalkoxy, arylthioalkoxy, alkenyl, NR6R7, NR6R7-(Q-Q alkyl)-, or alkyl, wherein the aryl portion of arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl, -OC(0)NH(CH2)„aryl, arylalkoxy, -OC(0)N(alkyl)(CH2)naryl, and arylthioalkoxy, is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy, wherein n is 0, 1, 2, 3, 4, 5, or 6; or Rt is H, alkyl substituted with one group selected from C02H, -C02-(Q-Q)alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R30)C(O)-(Q-Q)alkoxy, and -NR6R7, arylalkoxy, arylalkyl, hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the aryl portion of arylalkoxy, arylalkyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy; and R5 is arylalkyl, alkyl, aryl, alkoxy, heterocycloalkylalkyl, heteroarylalkyl, arylthioalkyl, heterocycloalkyl, or heteroaryl, wherein ' each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, alkoxy, arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, C02H, CN, amidinooxime, NR6R7, NR6R7-(Q-Q alkyl)-, -C(0)NR6R7, amidino, haloalkyl, or haloalkoxy. Embodiment A 160. Compounds according to embodiment A 154 wherein Ri is halogen, (Q-Q)alkanoyl, phenyl(Q-Q)alkanoyl, naphthyl(Q-C6)alkanoyl, naphfhyl(Q-Q)alkyl, phenyl(Q-Q)arkyl, alkoxyalkyl, hydroxyalkyl, or carboxaldehyde, wherein the phenyl and naphthyl portions of the above are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, nitro, CN, CF3, OCF3 or C02H; the alkyl portion of the above groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, or ethoxy.
R2 is phenylalkoxy, aryloxy, phenyloxy(Q-Q)arkyl, OH, halogen, phenylthioalkoxy, alkoxy, alkyl, alkoxyalkoxy, -OC(0)NH(CH2)nphenyl, -OC(0)N(alkyl)(CH2)nphenyl, pyridyl, pyrimidyl, pyridazyl, pyrazolyl, or thienyl, wherein n is 0, 1, 2, 3, or 4, and the above groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, -(Q-Q)alkyl-N(R)-CO2R30, halo(Q-Q)alkyl, or thienyl; R3 is halogen, phenylalkoxycarbonyl, phenyloxycarbonyl, phenyl(Q-Q)alkyl, phenylalkoxy, phenyloxy, phenylthio, thioalkoxy, arylthioalkoxy, (Q-Q)alkenyl, NR6R7, NReR7-(Q-Q alkyl)-, or alkyl, wherein the phenyl, naphthyl, and aryl portions of arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl, -OC(0)NH(CH2)naryl, arylthioalkoxy, arylalkoxy, and-OC(0)N(alkyl)(CH2)naryl, are unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy, alkyl, CF3, or OCF3, wherein n is 0, 1, 2, 3, 4, 5, or 6; or
R4 is H, (Q-Q) alkyl substituted with one group that is C02H, -C02-(Q-Q)alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R30)C(O)-(Q-Q)alkoxy, or -NR6R7, phenylalkoxy, phenyl(Q-Q)alkyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, or alkoxyalkoxy, wherein the phenyl portion of the above groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, CF3, or OCF3. R5 is phenyl(Ci-C6)alkyl, (Q-Q)alkyl, phenyl, naphthyl, pyridyl, (Q-Q)alkoxy, piperidinyl(Cι-Q)alkyl, pyrrolyl(Q-Q)alkyl, imidazolidinyl(Cι-C6)alkyl, pyrazolyl(Ci-Ce)alkyl, imidazolyl(Q-C6)alkyl, tetrahydropyridinyl(Cι-Ce)alkyl, thienyl(Ci-Q)alkyl, phenylthio(Cι-Ce)alkyl, or pyridyl(Cι-Ce)alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently (Q-Q)alkyl, fluoro, chloro, bromo, (Q-Q)alkoxy, phenyl(Q- Q)alkoxy, thio(Q-Q)alkoxy, (Cι-C4)alkoxycarbonyl, phenyl(Q- Q)alkoxycarbonyl, C02H, CN, amidinooxime, NR6R7, NR6R7-(Q-Q alkyl)-, - C(0)NR6R7, amidino, CF3, -CF2CF3, OCF3 or OCF2CF3. Embodiment A161. Compounds according to embodiment A160 wherein Ri is halogen, (Q-Q)alkanoyl, phenyl(Q-Q)alkanoyl, benzyl, phenethyl, phenpropyl, hydroxyalkyl, or carboxaldehyde, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, nitro, CN, CF3, OCF3 or C02H; the alkyl portion of the above groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, or ethoxy;
R2 is benzyloxy, phenethyloxy, phenpropyloxy, phenbutyloxy, phenyloxy, phenyloxy(Q- Q)alkyl, OH, halogen, phenylthioalkoxy, alkoxy, alkyl, alkoxyalkoxy, wherein n is O, 1, 2, 3, or 4, and the above groups are unsubstituted or substituted with 1, 2, or 3, groups that are independently halogen, -(Q-Q)alkyl-N(R)-CO2R30, halo(Q-Q)alkyl, or thienyl; R3 is halogen, phenylalkoxycarbonyl, phenyloxycarbonyl, phenyl(Cι-Q)alkyl, phenylalkoxy, phenyloxy, phenylthio, thioalkoxy, phenylthioalkoxy, (Q- Q)alkenyl, NR6R7, NR6R7 Q-Q alkyl, or alkyl, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy, (Q-Q)alkyl, CF3, or OCF3, R4 is H, (Ci-Ce) alkyl substituted with one group that is C02H, -C02-(Q-Q)aTkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R30)C(O)-(Q-C6)alkoxy, or -NR6R7, phenylalkoxy, benzyl, phenethyl, hydroxyalkyl, haloalkyl, alkoxyalkyl, or alkoxyalkoxy, wherein the phenyl portion of the above groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, hydroxy, (Q-Q)aιkoxy, (Q- Q)alkyl, nitro, CF3, or OCF3. R5 is benzyl, phenethyl, phenpropyl, phenbutyl, (Q-Q)alkyl, phenyl, or pyridyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently (Q-Q)alkyl, fluoro, chloro, bromo, (Q-Q)alkoxy, phenyl(Q- Q)alkoxy, fhio(Q-Q)alkoxy, (Q-Q)aιkoxycarbonyl, C02H, CN, amidinooxime, NR6R7, NR6R7-(Q-Q alkyl)-, -C(0)NR6R7, amidino, CF3, or OCF3. Embodiment A 162. Compounds according to embodiment A 161 wherein R, is bromo, phenyl(Q-Q)alkanoyl, benzyl, phenethyl, phenpropyl, hydroxyalkyl, or carboxaldehyde, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, nitro, CN, CF3, OCF3 or C02H; R2 is benzyloxy, phenethyloxy, phenpropyloxy, phenbutyloxy, phenyloxy, phenyloxy(Q- Q)alkyl, OH, halogen, or phenylthioalkoxy, wherein n is 0, 1, 2, 3, or 4, and the above groups are unsubstituted or substituted with 1, 2, or 3, groups that are independently halogen, -(Q-C6)alkyl-N(R)-CO2R30, halo(Q-Q)alkyl, or thienyl; R3 is bromo, phenylalkoxycarbonyl, phenyloxycarbonyl, phenyl(Q-Q)alkyl, phenylalkoxy, phenyloxy, phenylthio, thioalkoxy, phenylthioalkoxy, (Q- Q)alkenyl, NR6R7,NR6R7 Q-Q alkyl, or alkyl, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy, (Q-Q)alkyl, CF3, or OCF3, R4 is H, (Q-Q) alkyl substituted with one group that is C02H, -C02-(Q-Q)alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R3o)C(0)-(Q-Ce)alkoxy, or -NR6R7, phenylalkoxy, benzyl, or phenethyl, wherein the phenyl portion of the above groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, hydroxy, (Ci-Q)alkoxy, (Q- Q)alkyl, nitro, CF3, or OCF3. R5 is benzyl, phenethyl, phenpropyl, (Q-Q)alkyl, phenyl, or pyridyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently (Q-Q)alkyl, fluoro, chloro, bromo, (Q-Q)alkoxy, C02H, CN, amidinooxime, amidino, CF3, OCF3, NR6R7, NR6R7-(Q-Q alkyl)-, or -C(0)NR6R7; wherein R6 and R7 are independently hydrogen, OH, Q-Q alkoxy, Q-Q alkanoyl, or Q- Q alkyl, wherein each of the above is optionally substituted with 1 or 2 groups that are independently OH, NH2, Q-Q cycloalkyl, or halogen; or R6, R7, and the nitrogen to which they are attached form a moφholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, hydroxy, hydroxy Q-Q alkyl, or halogen. Embodiment A 163. Compounds of the formula
Figure imgf000102_0001
or pharmaceutically acceptable salts thereof, wherein
Ri is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, arylalkoxy, arylalkyl, CN, alkanoyl, alkoxy, alkoxyalkyl, or arylalkanoyl, wherein the aryl portion of arylalkoxy, arylalkyl, and arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO2H; wherein the alkyl portion of the alkyl, hydroxyalkyl, arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and arylalkanoyl groups is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, ethoxy or spirocyclopropyl; R2 is H, arylthio, -OC(0)NH(CH2)naryl, arylalkyl, -OC(0)N(alkyl)(CH2)naryl, or arylthioalkoxy, wherein n is 1, 2, 3, 4, or 5; wherein the aryl groups are optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, -(Q- Q)alkyl-N(R)-CO2R30, Q-Q alkoxy, Q-Q alkyl, CF3, or OCF3; R at each occurrence is independently H or Q-Q alkyl; R30 is Q-Q alkyl optionally substituted with 1 or 2 groups that are independently OH, SH, halogen, amino, monoalkylamino, dialkylamino or Q-Q cycloalkyl; R3 is halogen, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl, -OC(0)NH(CH2)naryl, arylalkoxy, -OC(0)N(alkyl)(CH2)naryl, aryloxy, arylthio, thioalkoxy, arylthioalkoxy, alkenyl, NR6R7 Q-Q alkyl, NR6R7 or alkyl, wherein the aryl portion of arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl, -OC(0)NH(CH2)„aryl, arylalkoxy, -OC(0)N(alkyl)(CH2)naryl, and arylthioalkoxy, is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy, wherein n is 0, 1, 2, 3, 4, 5, or 6; or R4 is H, alkyl substituted with one group that is C02H, -C02-(Q-Q)alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R30)C(O)-(Q-Q)alkoxy, or -NR6R7, arylalkoxy, arylalkyl, hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the aryl portion of arylalkoxy, arylalkyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy; and
R5 is arylalkyl, alkyl, aryl, alkoxy, heterocycloalkylalkyl, heteroarylalkyl, arylthioalkyl, heterocycloalkyl, or heteroaryl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, alkoxy, arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, C02H, CN, amidinooxime, NR6R7, NReR7-(Q-Q alkyl)-, -C(0)NR6R7, amidino, haloalkyl, or haloalkoxy; wherein R6 and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q alkoxy, Ci- Ce alkoxy Q-Q alkyl, Q-Q alkoxycarbonyl, OH, Q-Q hydroxyalkyl, - (Q-Q)alkyl-C02-alkyl, pyridyl Q-Q alkyl, Q-Q alkanoyl, benzyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, Q-Q alkoxy, piperidinyl Q-Q alkyl, moφholinyl Q-Q alkyl, piperazinyl Q-Q alkyl, OH, SH, NH2, NH(alkyl), N(alkyl)(alkyl), -0-C1-C4 alkanoyl, Q-Q alkyl, CF3, or OCF3; or R6, R7, and the nitrogen to which they are attached form a moφholinyl, thiomoφholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, hydroxy, hydroxy Q-Q alkyl, or halogen. Embodiment A168. Compounds according to embodiment A163 wherein R5 is benzyl, phenethyl, phenpropyl, phenbutyl, alkyl, phenyl, alkoxy, pyridyl(Q-Q)alkyl, phenyl(Q-Q)fhioalkyl, pyrrolyl, pyrrolyl(Q-Q)alkyl, or pyridyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently (Q-Q)alkyl, halogen, (Q-Q)alkoxy, phenyl(Q-C6)alkoxy, (Q- Q)thioalkoxy, alkoxycarbonyl, C02H, CN, amidinooxime, amidino, CF3, or OCF3. Embodiment A 169. Compounds according to embodiment A 163 wherein Ri is H, Cl, Br, (Q-Q)alkyl, carboxaldehyde, hydroxy(Q-Q)alkyl, wherein the alkyl portion of above is unsubstituted or substituted with 1, 2, or 3 , groups that are independently halogen, methoxy, or ethoxy
R2 is H, phenylthio, -OC(0)NH(CH2)»aryl, phenylalkyl, -OC(0)N(alkyl)(CH2)„aryl, or phenylthio(Q-Ce)alkoxy, wherein n is 1, 2, 3, or 4; wherein the aryl groups are optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, -(Q-Ce)alkyl-N(R)-C02R3o, Q-Q alkoxy, Q- Q alkyl, CF3, or OCF3; R3 is bromo, alkoxycarbonyl, phenylalkoxycarbonyl, phenyloxycarbonyl, phenylalkyl, phenylalkoxy, phenyloxy, phenylthio, thioalkoxy, phenylthioalkoxy, alkenyl, NR6R7 or alkyl, wherein the phenyl portion of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, (Q-Q)alkoxy, (Q-Q)alkyl, halo(Q-Q)arkyl, or halo(Q-Q)alkoxy, wherein n is 0, 1, 2, 3, or 4; R4 is H, alkyl substituted with one group that is C02H, -C02-(Ci-Q)alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R30)C(O)-(Q-Q)alkoxy, or -NR6R7, phenylalkoxy, phenylalkyl, hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, or wherein the phenyl portion of phenylalkoxy, phenylalkyl is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy R5 is benzyl, phenethyl, phenpropyl, phenbutyl, alkyl, phenyl, phenyl(Q-Q)thioalkyl, pyrrolyl, or pyridyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently (Q-Q)alkyl, halogen, (Q-Q)alkoxy, benzyloxy, (Q-C6)thioalkoxy, alkoxycarbonyl, C02H, CN, amidinooxime, amidino, CF3, or OCF3; Re and R7 are independently hydrogen, OH, Q-Q alkoxy, Q-Q alkanoyl, or Q- Q alkyl, wherein each of the above is optionally substituted with 1 or 2 groups that are independently OH, NH2, Q-Q cycloalkyl, or halogen; or Re, R7, and the nitrogen to which they are attached form a moφholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, hydroxy, hydroxy Q-Q alkyl, or halogen. Embodiment A 170. Compounds according to embodiment 1
Figure imgf000105_0001
or a pharmaceutically acceptable salt thereof, wherein
Ri is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, arylalkoxy, arylalkyl, CN, alkanoyl, alkoxy, alkoxyalkyl, or arylalkanoyl, wherein the aryl portion of arylalkoxy, arylalkyl, and arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, nitro, CN, haloalkyl, haloalkoxy or C02H; wherein the alkyl portion of the alkyl, hydroxyalkyl, arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and arylalkanoyl groups is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, ethoxy or spirocyclopropyl; R2 is arylalkoxy, aryloxy, aryloxyalkyl, OH, halogen, arylthioalkoxy, alkoxy, - OC(0)NH(CH2)naryl, -OC(0)N(alkyl)(CH2)naryl, alkyl, alkoxyalkoxy, dialkylamino, or CO2H, wherein n is 0, 1, 2, 3, 4, 5 or 6; the aryl portion of arylalkoxy, aryloxy, arylthioalkoxy, -OC(0)NH(CH2)naryl, and -OC(0)N(alkyl)(CH2)naryl or the heteroaryl and heterocycloalkyl groups is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, -(Q-Q)alkyl-N(R)-C02R3o, haloalkyl, heteroaryl, heteroarylalkyl, NR6R7, NR6R7-(Q-Q alkyl)-, -OC(0)NR6R7, wherein R6 and R7 are independently at each occurrence H, Q-Q alkyl, Q-Q alkoxy, Q- Q alkoxy Q-Q alkyl, Q-Q alkoxycarbonyl, OH, Q-Q hydroxyalkyl, - (Q-Q)alkyl-C02-alkyl, pyridyl Q-Q alkyl, Q-Q alkanoyl, benzyl, phenyl Q-Q alkoxy, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, Q-Q alkoxy, piperidinyl Q-Q alkyl, moφholinyl Q-Q alkyl, piperazinyl Q-Q alkyl, OH, SH, NH2, NH(alkyl), N(alkyl)(alkyl), -O-Q-Q alkanoyl, Q-Q alkyl, CF3, or OCF3; or R6, R7, and the nitrogen to which they are attached form a moφholinyl, thiomoφholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxy, hydroxy, hydroxy Q-Q alkyl, or halogen; R at each occurrence is independently H or Q-Q alkyl; R30 is Q-Q alkyl optionally substituted with 1 or 2 groups that are independently OH, SH, halogen, amino, monoalkylamino, dialkylamino or Q-Q cycloalkyl;
R3 is halogen, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl, -OC(0)NH(CH2)„aryl, arylalkoxy, -OC(0)N(alkyl)(CH2)naryl, aryloxy, arylthio, thioalkoxy, arylthioalkoxy, alkenyl, NR6R Q-Q alkyl, NR6R7 or alkyl, wherein the aryl portion of arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl, -OC(0)NH(CH2)„aryl, arylalkoxy, -OC(0)N(alkyl)(CH2)naryl, and arylthioalkoxy, is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy, wherein n is 0, 1, 2, 3, 4, 5, or 6; or R4 is H, alkyl substituted with one group that is C02H, -C02-(Q-Q)alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R3o)C(0)-(Q-Q)alkoxy, or -NR6R7, arylalkoxy, arylalkyl, hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the aryl portion of arylalkoxy, arylalkyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy; and R5 is aryl, heterocycloalkylalkyl, heteroarylalkyl, arylthioalkyl, heterocycloalkyl, or heteroaryl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, alkoxy, arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, C02H, CN, amidinooxime, NR6R7, NR6R7- (Q-Q alkyl)-, -C(0)NReR7, amidino, haloalkyl, or haloalkoxy. Embodiment A 173. Compounds according to embodiment A 170 wherein Ri is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, benzyloxy, phenethyloxy, phenpropyloxy, benzyl, phenethyl, phenpropyl, CN, alkanoyl, alkoxy, or phenylC(O)-, phenylCH2C(0)-, or phenylCH2CH2C(0), wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, nitro,
Figure imgf000107_0001
wherein the above alkyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, or ethoxy; R is benzyloxy, phenethyloxy, phenpropyloxy, phenyloxy, phenyloxy(Q-Q)alkyl, OH, halogen, phenylthioalkoxy, alkyl, alkoxy, -OC(0)NH(CH2)„phenyl, - OC(0)N(alkyl)(CH2)nphenyl, dialkylamino, or C02H, wherein n is 0, 1, 2, 3, or 4; the above aryl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, -(Q-Q)alkyl-N(R)-C02R3o, CF3, pyridyl, thienyl, NR6R7, or NReR7-(Q-Q alkyl)-, wherein R6 and R7 are independently at each occurrence H, alkyl, alkanoyl, benzyl, or phenylC(O)-, wherein the phenyl portion of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, OH, Q-Q cycloalkyl, alkoxy, alkyl, CF3, or OCF3; R3 is halogen, alkoxycarbonyl, phenylalkoxycarbonyl, phenyloxycarbonyl, phenylalkyl, -OC(0)NH(CH2)nphenyl, phenylalkoxy, -OC(0)N(alkyl)(CH2)nphenyl, phenyloxy, phenylthio, thioalkoxy, phenylthioalkoxy, alkenyl, NR6R7 or alkyl, wherein the phenyl portion of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy, wherein n is 0, 1, 2, 3,or 4; R4 is H, alkyl substituted with one group that is C02H, -C02-(Q-Q)alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R3o)C(0)-(Q-Q)alkoxy, or -NR6R7, phenylalkoxy, phenylalkyl, hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the phenyl portion of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy; and R5 is phenyl, naphthyl, pyrrolylalkyl, piperidinylalkyl pyridinylalkyl, pyrimidinylalkyl, phenylthioalkyl, pyrrolyl, piperidinyl, pyridyl, or thienylalkyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently alkyl, halogen, alkoxy, phenylalkoxy, thioalkoxy, alkoxycarbonyl, phenylalkoxycarbonyl, C02H, CN, amidinooxime, NR6R7, NReR7-(Q-Q alkyl)-, - C(0)NR6R7, amidino, haloalkyl, or haloalkoxy. Embodiment A 174. Compounds according to embodiment A 173 wherein R, is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, benzyloxy, phenethyloxy, benzyl, phenethyl, CN, (Q-Q)alkanoyl, alkoxy, or phenylC(O)-, or phenylCH2C(0)-, wherein the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, Q-Q alkyl, Q-Q alkoxy, nitro, CN, CF3, OCF3 or C02H; R2 is benzyloxy, phenethyloxy, phenpropyloxy, phenyloxy, phenyloxy(Q-Q)alkyl, halogen, phenyl(Q-Q)fhioalkoxy, -OC(0)NH(CH2)nphenyl, - OC(0)N(alkyl)(CH2)nphenyl, or dialkylamino, wherein n is O, 1, 2, 3, or 4; the above phenyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, CF3, NR6R7, or NReR7-(Q-Q alkyl)-, wherein R6 and R7 are independently at each occurrence H, (Q-Q)alkyl, acetyl, benzyl, or phenylC(O)-, wherein the phenyl portion of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, OH, cyclopropyl, alkoxy, alkyl, CF3, or OCF3; R3 is halogen, alkoxycarbonyl, phenylalkoxycarbonyl, phenyloxycarbonyl, phenylalkyl, phenylalkoxy, phenyloxy, phenylthio, thioalkoxy, phenylthioalkoxy, alkenyl, NR6R7 or alkyl, wherein the phenyl portion of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy, wherein n is 0, 1, 2, 3,or 4; R4 is H, alkyl substituted with one group that is C02H, -C02-(Q-Q)alkyl, -C(0)NRR, -N(R30)C(O)NRR, -N(R30)C(O)-(Q-Q)alkoxy, or -NR6R7, phenylalkoxy, phenylalkyl, hydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the phenyl portion of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl, or haloalkoxy; and R5 is phenyl, phenyl(Ci-Q)thioalkyl, pyridyl, or thienyl(Q-Q)alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently (Ci-Q)alkyl, fluoro, chloro, bromo, (Q-Q)alkoxy, CN, amidinooxime, amidino, CF3, or OCF3. Embodiment A 175. Compounds according to embodiment A 174 wherein R5 is substituted with at least one group selected from fluoro, chloro, bromo, and methyl. In another aspect, the invention provides pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier, solvent, adjuvant or excipient and a compound of formula I, embodiment A66, or embodiment A 154. The invention further provides pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier, solvent, adjuvant or excipient and compounds according to any of the preceding embodiments. As noted above, the invention encompasses methods of treating a TNF mediated disorder, a p38 kinase mediated disorder, inflammation and/or arthritis in a subject, the method comprising treating a subject having or susceptible to such disorder or condition with a therapeutically-effective amount of a compound of formula I or embodiment Al. More specifically, the invention provides methods for treating or preventing inflammation; arthritis, rheumatoid arthritis, spondylarthropathies, gouty arthritis, osteoarthritis, systemic lupus erthematosus, juvenile arthritis, and other arthritic conditions; neuroinflammation; allergy, Th2 mediated diseases; pain, neuropathic pain; fever; pulmonary disorders, lung inflammation, adult respiratory distress syndrome, pulmonary sarcoisosis, asthma, silicosis, chronic pulmonary inflammatory disease, and chronic obstructive pulmonary disease (COPD); cardiovascular disease, arteriosclerosis, myocardial infarction (including post-myocardial infarction indications), thrombosis, congestive heart failure, cardiac reperfusion injury, as well as complications associated with hypertension and/or heart failure such as vascular organ damage, restenosis; cardiomyopafhy; stroke including ischemic and hemorrhagic stroke; reperfusion injury; renal reperfusion injury; ischemia including stroke and brain ischemia, and ischemia resulting from cardiac/coronary bypass; neurotrauma and brain trauma including closed head injury; brain edema; neurodegenerative disorders; liver disease and nephritis; gastrointestinal conditions, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis; ulcerative diseases, gastric ulcers; ophthalmic diseases, retinitis, retinopathies, uveitis, ocular photophobia, acute injury to the eye tissue and ocular traumas such as post-traumatic glaucoma, traumatic optic neuropathy, and central retinal artery occlusion (CRAO); periodontal disease; ophthalmological conditions, retinitis, retinopathies (including diabetic retinopathy), uveitis, ocular photophobia, nonglaucomatous optic nerve atrophy, and age related macular degeneration (ARMD) (including ARMD-atrophic form), corneal graft rejection, ocular neovascularization, retinal neovascularization, neovascularization following injury or infection, retrolental fibroplasias, neovascular glaucoma; glaucoma including primary open angle glaucoma (POAG), juvenile onset primary open-angle glaucoma, angle-closure glaucoma, pseudoexfoliative glaucoma, anterior ischemic optic neuropathy (AION), ocular hypertension, Reiger's syndrome, normal tension glaucoma, neovascular glaucoma, ocular inflammation and corticosteroid-induced glaucoma; diabetes; diabetic nephropathy; skin- related conditions, psoriasis, eczema, burns, dermatitis, keloid formation, scar tissue formation, angiogenic disorders; viral and bacterial infections, sepsis, septic shock, gram negative sepsis, malaria, meningitis, HIV infection, opportunistic infections, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (ADDS), ADDS, ARC (AIDS related complex), pneumonia, heφes virus; myalgias due to infection; influenza; endotoxic shock; toxic shock syndrome; autoimmune disease, graft vs. host reaction and allograft rejections; treatment of bone resoφtion diseases, osteoporosis; multiple sclerosis', disorders of the female reproductive system, endometriosis; hemaginomas, infantile hemagionmas, angiofibroma of the nasopharynx, avascular necrosis of bone; benign and malignant tumors/neoplasia, cancer, colorectal cancer, brain cancer, bone cancer, epithelial call-derived neoplasia (epithelial carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, lip cancer, mouth cancer, esophageal cancer, small bowel cancer, stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamus cell and/or basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that affect epithelial cells throughout the body; leukeniia; lymphoma; systemic lupus erfhrematosis (SLE); angiogenesis including neoplasia; metastasis; central nervous system disorders, central nervous system disorders having an inflammatory or apoptotic component, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, and peripheral neuropathy; Canine B-Cell Lymphoma. Compounds of the invention are also useful for preventing the production or expression of cyclooxygenase-2, or cyclooxygenase-2 activity. In this aspect, the invention encompasses methods of treating a p38 kinase or TNF- alpha mediated disorder comprising administering to a patient in need thereof a therapeutically effective amount of Compounds according to embodiment 1 and at least one pharmaceutically acceptable carrier, adjuvant, solvent or excipient. Representative compounds of the invention are: l-benzyl-4-(benzyloxy)-3-bromopyridin-2(lH)-one; 3-bromo-l-(4-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-dimethylphenyl)-6-methylpyridin- 2(lH)-one; 4-(benzyloxy)-3-bromo-l-(4-fluorobenzyl)pyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(3-fluorobenzyl)pyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(pyridin-3-ylmethyl)pyridin- 2(lH)-one; 4-bromo-2-(2,6-dichlorophenyl)-5-[(2,4-difluorobenzyl)oxy]pyridazin-3(2H)-one; 3-bromo-l-(2,6-dichlorophenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-
2(lH)-one; 3-bromo-l-(3-fluorobenzyl)-4-[(3-methylbenzyl)oxy]pyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(pyridin-4-ylmethyl)pyridin- 2(lH)-one; 4-(benzyloxy)-3-bromo-l-(3-fluorobenzyl)pyridin-2(lH)-one; 1 -benzyl-4-(benzyloxy)-3-bromo-6-methylpyridin-2( lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2-methoxy-6-methylphenyl)-6- methylpyridin-2( lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2-fluorobenzyl)pyridin-2(lH)-one; 3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-l-(pyridin-3-ylmethyl)pyridin-2(lH)- one; 3-bromo-l-(2,6-dichlorophenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2(lH)- one; 4-(benzyloxy)-3-bromo-l-(4-methylbenzyl)pyridin-2(lH)-one; 4-(benzyloxy)-3-bromo-l-(4-chlorobenzyl)pyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(3-methoxybenzyl)pyridin-2(lH)-one; 4-{ [4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-yl]methyl Jbenzoic acid; 4-(benzyloxy)-3-bromo- 1 -(2-fluorobenzyl)pyridin-2( lH)-one; 3-bromo-l-(2,6-dimethylphenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2(lH)- one; 4-(benzyloxy)-3-bromo-l-[4-(methylthio)benzyl]pyridin-2(lH)-one; l-benzyl-4-(benzyloxy)-3-chloropyridin-2(lH)-one; 4- { [4-(benzyloxy)-3-bromo-2-oxopyridin- 1 (2H)-yl]methyl } -iV- hydroxybenzenecarboximidamide; methyl 4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-yl]methyl}benzoate; 3-bromo-4-[(3-chlorobenzyl)oxy]-l-(3-fluorobenzyl)pyridin-2(lH)-one; 3-bromo-l-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(lH)-one; 4- { [4-(benzyloxy)-3-bromo-2-oxopyridin- 1 (2H)-yl]methyl Jbenzonitrile; 4-(benzyloxy)-3-bromo-l-(2,6-dichlorophenyl)-6-methylpyridin-2(lH)-one; 3-bromo-4-[(4-fluorobenzyl)oxy]-l-(pyridin-4-ylmethyl)pyridin-2(lH)-one; 4-(benzyloxy)-3-bromo- 1 -(4-bromobenzyl)pyridin-2( lH)-one; 4- {[3-bromo-4-[(4-fluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl jbenzonitrile; l-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]-3-iodopyridin-2(lH)-one; 4-bromo-2-(2,6-dichlorophenyl)-5-{[2-(hydroxymethyl)benzyl]oxy}pyridazin- 3(2H)-one; 3-bromo-4-[(4-fluorobenzyl)oxy]-l-(pyridin-3-ylmethyl)pyridin-2(lH)-one; 3-bromo-l-(2,4-difluorobenzyl)-4-[(2,4-difluorobenzyl)oxy]pyridin-2(lH)-one; 3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-l-(pyridin-2-ylmethyl)pyridin-2(lH)- one; or a pharmaceutically acceptable salt thereof. Embodiment 57. Compounds according to embodiment 1 or embodiment Al, which is 3-bromo-4-[(4-chlorobenzyl)oxy]-l-(4-fluorobenzyl)pyridin-2(lH)-one; 1 -benzyl-3-bromo-4-[(4-chlorobenzyl)oxy]pyridin-2( lH)-one; 3-bromo-l-(4-chlorobenzyl)-4-[(4-chlorobenzyl)oxy]pyridin-2(lH)-one; 3-bromo-4-[(4-chlorobenzyl)oxy]-l-[2-(phenylthio)ethyl]pyridin-2(lH)-one; 3-bromo-4-[(4-chlorobenzyl)oxy]-l-(2-phenylethyl)pyridin-2(lH)-one; 3-bromo-4-hydroxy- l-(4-hydroxybenzyl)pyridin-2( lH)-one; 4-(benzyloxy)-3-bromo-l-(piperidin-3-ylmethyl)pyridin-2(lH)-one hydrochloride; 3-bromo-l-(4-methoxybenzyl)-4-phenoxypyridin-2(lH)-one; l-benzyl-2-oxo-4-phenoxy-l,2-dihydropyridine-3-carbaldehyde; 3-bromo-4-[(4-chlorobenzyl)oxy]-l-(4-methoxybenzyl)pyridin-2(lH)-one; 3-bromo-4-[(4-fluorobenzyl)oxy]-l-(3-phenylpropyl)pyridin-2(lH)-one; 4-(benzyloxy)-l-[4-(benzyloxy)benzyl]-3-bromopyridin-2(lH)-one; 4-(benzyloxy)-3-bromo-l-[2-(trifluoromethyl)benzyl]pyridin-2(lH)-one; 4-(benzyloxy)-3-bromo-l-[3-(trifluoromethyl)benzyl]pyridin-2(lH)-one;
4-(benzyloxy)-3-bromo- l-(piperidin-4-ylmethyl)pyridin-2( lH)-one hydrochloride; l-benzyl-3-bromo-4-{[2-(trifluoromethyl)benzyl]oxy}pyridin-2(lH)-one; l-benzyl-4-[(2,6-dichlorobenzyl)oxy]pyridin-2(lH)-one; 1 -benzyl-4-(benzyloxy)-3-(hydroxymethyl)pyridin-2( lH)-one; l-benzyl-3-bromo-4-[(2,6-dichlorobenzyl)oxy]pyridin-2(lH)-one; l-benzyl-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(lH)-one; l-benzyl-3-bromo-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(lH)-one;
1 -benzyl-3-bromo-4-[(2-chlorobenzyl)oxy]pyridin-2( lH)-one; 4-(benzyloxy)-3-bromo-l-ethylpyridin-2(lH)-one;
4-(benzyloxy)- 1 -(4-bromobenzyl)pyridin-2( lH)-one;
3-bromo-l-(4-methylbenzyl)-4-[(4-methylbenzyl)oxy]pyridin-2(lH)-one; methyl 4- { [4-(benzyloxy)-3-bromo-2-oxopyridin- 1 (2H)-yιjmefhyl Jbenzoate;
4-(benzyloxy)-3-bromo-l-(2-thien-3-ylethyl)pyridin-2(lH)-one; 4-(benzyloxy)-3-bromo-l-(2-thien-2-ylethyl)pyridin-2(lH)-one; l-benzyl-4-[(3-chlorobenzyl)oxy]pyridin-2(lH)-one;
3-bromo-l-(4-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(lH)-one;
4-(benzyloxy)-l-(3-fluorobenzyl)pyridin-2(lH)-one;
4-(benzyloxy)-l-(2-fluorobenzyl)pyridin-2(lH)-one; 4-(benzyloxy)-3-bromo-l-methylpyridin-2(lH)-one hydrobromide;
4-(benzyloxy)-3-bromo-l-methylpyridin-2(lH)-one;
3-bromo-l-(3-chlorobenzyl)-4-[(4-chlorobenzyl)oxy]pyridin-2(lH)-one;
3-bromo-l-(3-chlorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(lH)-one;
4-(benzyloxy)-l-(4-chlorobenzyl)pyridin-2(lH)-one; 4-(benzyloxy)-3-bromo-l-[4-(trifluoromethoxy)benzyl]pyridin-2(lH)-one;
4-(benzyloxy)-3-bromo-l-(4-tert-butylbenzyl)pyridin-2(lH)-one;
1 -benzyl-4-(benzyloxy)-6-methylpyridin-2( lH)-one; l-benzyl-4-(benzyloxy)-3,5-dibromo-6-methylpyridin-2(lH)-one;
4-(benzyloxy)-3-bromo-l-[4-(trifluoromethyl)benzyl]pyridin-2(lH)-one; l-benzyl-4-[(2-chlorobenzyl)oxy]pyridin-2( lH)-one; l-(2-bromobenzyl)-3-[(2-bromobenzyl)oxy]pyridin-2(lH)-one; methyl 5-chloro- 1 -(4-chlorobenzyl)-6-oxo- 1 ,6-dihydropyridine-3-carboxylate; 3-benzyl-4-hydroxy-l-(2-phenylethyl)pyridin-2(lH)-one;
5-bromo-l-(2-chloro-6-fluorobenzyl)-3-methylpyridin-2(lH)-one; l-(2-bromobenzyl)-3-[(2-bromobenzyl)oxy]pyridin-2(lH)-one; l-benzyl-4-(benzyloxy)pyridin-2(lH)-one; l-benzyl-4-(benzyloxy)-3-bromopyridin-2(lH)-one;
1 -benzyl-4-(benzyloxy)-2-oxo- 1 ,2-dihydropyridine-3-carbaldehyde;
1 -benzyl-4-chloro-2-oxo- 1 ,2-dihydropyridine-3-carbaldehyde; l-benzyl-4-hydroxy-2-oxo-l,2-dihydropyridine-3-carbaldehyde; l-benzyl-4-(benzyloxy)-3-methylpyridin-2(lH)-one; 4-(benzyloxy)-l-(4-fluorobenzyl)pyridin-2(lH)-one; l-benzyl-4-(benzyloxy)-3,5-dibromopyridin-2(lH)-one;
4-(benzyloxy)-3-bromo-l-[4-(methylthio)benzyl]pyridin-2(lH)-one;
4-(benzyloxy)-3-bromo-l-(4-fluorobenzyl)pyridin-2(lH)-one; l-benzyl-4-(benzyloxy)-3-chloropyridin-2(lH)-one; 3-bromo-l-(4-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(lH)-one; l-benzyl-3-bromo-2-oxo-l,2-dihydropyridin-4-yl methyl(phenyl)carbamate; l-benzyl-3-bromo-4-(2-phenylethyl)pyridin-2(lH)-one; l-benzyl-3-bromo-4-(3-phenylpropyl)pyridin-2(lH)-one; l-benzyl-3-methyl-4-(2-phenylethyl)pyridin-2(lH)-one; l-benzyl-3-methyl-4-(3-phenylpropyl)pyridin-2(lH)-one; l-benzyl-4-(benzylthio)-3-methylpyridin-2(lH)-one; l-benzyl-4-(benzylthio)-3-bromopyridin-2(lH)-one;
1 -benzyl-2-oxo- 1 ,2-dihydropyridin-4-yl methanesulfonate;
3-acetyl-4-hydroxy-6-methyl-l-[choro]phenylpyridin-2(lH)-one; 6-(benzyloxy)-l-methyl-2-oxo-l,2-dihydropyridine-3-carbonitrile;
3-benzoyl-6-(benzyloxy)-l-methylpyridin-2(lH)-one;
3-benzyl-6-(benzyloxy)-l-methylpyridin-2(lH)-one; l-benzyl-4-hydroxypyridin-2(lH)-one;
1 -benzyl-4-(benzylthio)pyridin-2( lH)-one 4-amino- 1 -benzylpyridin-2( lH)-one; l-benzyl-4-(benzyloxy)pyridin-2(lH)-one;
1 -benzyl-4-hydroxypyridin-2( lH)-one; 1 -benzyl-2-oxo- 1 ,2-dihydropyridin-4-yl methyl (phenyι)carbamate; or a pharmaceutically acceptable thereof. Embodiment 58. Compounds according to embodiment 1 or embodiment Al, which is 4-(benzyloxy)-l-(4-rnefhylbenzyl)pyridin-2(lH)-one; 4-(benzyloxy)-3-bromopyridin-2(lH)-one; methyl 4-{[4-(benzyloxy)-2-oxopyridin-l(2H)-yl]methyl} benzoate; methyl-4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-yl]methyl} benzoate; 4- { [4-(benzyloxy)-2-oxopyridin- 1 (2H)-yl]methyl } benzonitrile; 4-(benzyloxy)- l-(4-tert-butylbenzyl)pyridin-2( lH)-one; 4-(benzyloxy)-l-[4-(trifluoromethyl)benzyl]pyridin-2(lH)-one; 4-(benzyloxy)-3-bromo-l-[4-(trifluoromefhyl) benzyl]pyridin-2(lH)-one; 4-(benzyloxy)-3-bromo-l-[3-(trifluoromethyl) benzyl]pyridin-2(lH)-one; 4-(benzyloxy)-3-bromo-l-[2-(trifluoromethyl) benzyl]pyridin-2(lH)-one; 4-(benzyloxy)-l-[4-(trifluoromethoxy)benzyl]pyridin-2(lH)-one; 4-(benzyloxy)-3-bromo-l-[4-(trifluoromethoxy) benzyl]pyridin-2(lH)-one; l-benzyl-4-hydroxy-6-methylpyridin-2(lΗ)-one; 1 -benzyl-6-methyl-2-oxo- 1 ,2-dihydropyridin-4-yl 4-bromobenzenesulf onate; l-benzyl-3-bromo-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(lH)-one; 1 -benzyl-6-methyl-2-oxo- 1 ,2-dihydropyridin-4-yl 4-bromobenzenesulf onate ; l-benzyl-3-bromo-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(lH)-one; l-Benzyl-4-[2,6-(dichlorobenzyl)oxy]pyridin-2(lH)-one; 4-[(2,6-dichlororbenzyl)oxy]pyridine-l-oxide; 4-[(2,6-dichlorobenzyl)oxy]pyridine 1-oxide; l-Benzyl-3-bromo-4-[2,6-(dichlorobenzyl)oxy]pyridin-2(lH)-one; l-Benzyl-3-bromo-4-[(4-methylbenzyl)oxy]pyridin-2(lH)-one; l-Benzyl-4-[benzylthio]-3-bromopyridin-2(lH)-one; l-benzyl-4-(benzyloxy)-3-iodopyridin-2(lH)-one; l-benzyl-4-(benzyloxy)-3-vinylpyridin-2(lH)-one; l-benzyl-4-(benzyloxy)-3-ethylpyridin-2(lH)-one; 3-acetyl-4-(benzyloxy)- 1 -(2-chlorophenyl)-6-methylpyridin-2( lH)-one; 3-acetyl- 1 -(2-chlorophenyl)-4-hydroxy-6-methylpyridin-2( lH)-one; l-benzyl-3-bromo-4-hydroxypyridin-2(lH)-one; l-benzyl-3-bromo-2-oxo- 1 ,2-dihydropyridin-4-yl trifluoromethanesulfonate; l-benzyl-3-bromo-4-(phenylethynyl)pyridin-2(lH)-one; 3-bromo- 1 -(3-fluorobenzyl)-6-methyl-4-(2-phenylethyl)pyridin-2( 1 H)-one; l-(3-fluorobenzyl)-4-hydroxy-6-methylpyridin-2(lH)-one; 3-bromo-l-(3-fluorobenzyl)-4-hydroxy-6-methylpyridin-2(lH)-one; 3-bromo-l-(3-fluorobenzyl)-6-methyl-2-oxo-l,2-dihydropyridin-4-yl trifluoromethanesulfonate; 3-bromo-l-(3-fluorobenzyl)-6-methyl-4-(phenylethynyl)pyridin-2(lH)-one; 3-acetyl-l-(2,6-dichlorophenyl)-4-hydroxy-6-methylpyridin-2(lH)-one; 1 -(2,6-dichlorophenyl)-4-hydroxy-6-methylpyridin-2( 1 H)-one; 4-(benzyloxy)- 1 -(2,6-dichlorophenyl)-6-methylpyridin-2( lH)-one; 3-bromo-l-(3-fluorobenzyl)-4-(2-phenylethyl)pyridin-2(lH)-one; 3-bromo-l-(3-fluorobenzyl)-4-hydroxypyridin-2(lH)-one; 3-bromo- 1 -(3-fluorobenzyl)-2-oxo- 1 ,2-dihydropyridin-4-yl trifluoromethanesulfonate; 3-bromo- l-(3-fluorobenzyl)-4-(phenylethynyl)pyridin-2( lH)-one; 4-(benzyloxy)-3-ethynyl-l-(3-fluorobenzyl)pyridin-2(lH)-one; 4-(benzyloxy)- 1 -(3-fluorobenzyl)-3-iodopyridin-2( 1 H)-one; 4-(benzyloxy)- 1 -(3 -fluorobenzyl)-3- [(trimethylsilyl)ethynyl]pyridin-2( lH)-one; 4-(benzylamino)-3-bromo-l-(3-fluorobenzyl)pyridin-2(lH)-one; l-(3-fluorobenzyl)-4-hydroxypyridin-2(lH)-one; 4-(benzylamino)- 1 -(3 -fluorobenzyl)pyridin-2 ( 1 H)-one ; or a pharmaceutically acceptable salt thereof. Embodiment 59. Compounds according to embodiment 1 or embodiment Al, which is 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2-fluorobenzyl)pyridin-2(lH)-one; 3-bromo-4-[(4-r uorobenzyl)oxy]-6-methyl-l-(pyridin-3-ylmethyl)pyridin-2(lH)- one; 3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl- 1 -(pyridin-4-ylmethyl)pyridin-2( 1H)- one; 3-bromo-l-(2,6-dichlorophenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2(lH)- one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(3-methoxybenzyl)pyridin-2(lH)-one; 3-bromo-l-(2,6-dimethylphenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2(lH)- one; 3-bromo-4-[(3-chlorobenzyl)oxy]-l-(3-fluorobenzyl)pyridin-2(lH)-one; 3-bromo-4-[(4-fluorobenzyl)oxy]-l-(pyridin-4-ylmethyl)pyridin-2(lH)-one; 3-bromo- 1 -(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2( lH)-one; 4- { [3-bromo-4-[(4-fluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yl]methyl Jbenzonitrile; l-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]-3-iodopyridin-2(lH)-one; 3-bromo-4-[(4-fluorobenzyl)oxy]-l-(pyridin-3-ylmethyl)pyridin-2(lH)-one; 3-bromo-l-(2,4-difluorobenzyl)-4-[(2,4-difluorobenzyl)oxy]pyridin-2(lH)-one; 3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-l-(pyridin-2-ylmethyl)pyridin-2(lH)- one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(3-fluorobenzyl)pyridin-2(lH)-one; 3-bromo-4-[(2,4-difiuorobenzyl)oxy]-6-methyl-l-(pyridin-3-ylmethyl)pyridin- 2(lH)-one; 3-bromo-l-(2,6-dichlorophenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin- 2(lH)-one; 3-bromo-l-(3-fluorobenzyl)-4-[(3-methylbenzyl)oxy]piperidin-2-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(pyridin-4-ylmethyl)pyridin- 2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2-methoxy-6-methylphenyl)-6- methylpyridin-2( lH)-one; or a pharmaceutically acceptable salt thereof. Embodiment 60. A Compound according to embodiment 1, which is l-(l-acetyl-2,3-dihydro-lH-indol-5-yl)-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6- methylpyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(l-glycoloyl-2,3-dihydro-lH-indol-5-yl)- 6-methylpyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[l-(2-hydroxy-2-methylpropanoyl)-2,3- dihydro- lH-indol-5-yl]-6-methylpyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[l-(N-methylglycyl)-2,3- dihydro- lH-indol-5-yl]pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[l-(3-hydroxypropanoyl)-2,3-dihydro- lH-indol-5-yl]-6-methylpyridin-2(lH)-one; 3 -chloro-4- [(2,4-difluorobenzyl)oxy] - 1 - [ 1 -(3-hydroxy-3 -methylbutanoyl)-2 ,3 - dihydro- lH-indol-5-yl]-6-methylpyridin-2( lH)-one; 5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]indoline-l-carboxamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[l-(methylsulfonyl)-2,3- dihydro- lH-indol-5-yl]pyridin-2( lH)-one; 1 -( 1 -acetyl- lH-indol-5-yl)-3-chloro-4-[(2,4-difluorobenzyl)oxy] -6-methylpyridin- 2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(l-glycoloyl-lH-indol-5-yl)-6- methylpyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[l-(2-hydroxy-2-methylpropanoyl)-lH- indol-5-yl]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[l-(N-methylglycyl)-lH-indol- 5-yl]pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[l-(3-hydroxypropanoyl)-lH-indol-5-yl]- 6-methylpyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[l-(3-hydroxy-3-methylbutanoyl)-lH- indol-5-yl]-6-methylpyridin-2(lH)-one; 5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-lH- indole-1-carboxamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[l-(methylsulfonyl)-lH-indol-5- yl]pyridin-2( lH)-one; l-(2-acetyl-2,3-dihydro-lH-isoindol-5-yl)-3-chloro-4-[(2,4-difluorobenzyl)oxy]- 6-methylpyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(2-glycoloyl-2,3-dihydro-lH-isoindol-5- yl)-6-methylpyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[2-(2-hydroxy-2-methylpropanoyl)-2,3- dihydro- lH-isoindol-5-yl]-6-methylpyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[2-(N-methylglycyl)-2,3- dihydro- lH-isoindol-5-yl]pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[2-(3-hydroxypropanoyl)-2,3-dihydro- lH-isoindol-5-yl]-6-methylpyridin-2(lH)-one; i 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[2-(3-hydroxy-3-methylbutanoyl)-2,3- dihydro-lH-isoindol-5-yl]-6-methylpyridin-2(lH)-one; 5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-l,3- dihydro-2H-isoindole-2-carboxamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[2-(methylsulfonyl)-2,3- dihydro- lH-isoindol-5-yl]pyridin-2( lH)-one; l-(2-acetyl-l,2,3,4-tetrahydroisoquinolin-6-yl)-3-chloro-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(2-glycoloyl-l,2,3,4- tetrahydroisoquinolin-6-yl)-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[2-(2-hydroxy-2-methylpropanoyl)- l,2,3,4-tetrahydroisoquinolin-6-yl]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[2-(N-methylglycyl)-l,2,3,4- tetrahydroisoquinolin-6-yl]pyridin-2(lH)-one; ' 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[2-(3-hydroxypropanoyl)-l,2,3,4- tetrahydroisoquinolin-6-yl]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[2-(3-hydroxy-3-methylbutanoyl)-l,2,3,4- tetrahydroisoquinolin-6-yl]-6-methylpyridin-2(lH)-one; 6-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3,4- dihydroisoquinoline-2(lH)-carboxamide; 3-chloro-4- [(2,4-difluorobenzyl)oxy] -6-methyl- 1 - [2-(methylsulf onyl)- 1 ,2,3 ,4- tetrahydroisoquinolin-6-yl]pyridin-2(lH)-one; l-(2-acetyl- 1 ,2,3 ,4-tetrahydroisoquinolin-7-yl)-3-chloro-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(2-glycoloyl-l,2,3,4- tetrahydroisoquinolin-7-yl)-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[2-(2-hydroxy-2-methylpropanoyl)- l,2,3,4-tetrahydroisoquinolin-7-yl]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[2-(N-methylglycyl)-l,2,3,4- tetrahydroisoquinolin-7-yl]pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[2-(3-hydroxypropanoyl)-l,2,3,4- tetrahydroisoquinoiin-7-yl]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[2-(3-hydroxy-3-methylbutanoyl)-l,2,3,4- tetrahydroisoquinolin-7-yl]-6-methylpyridin-2(lH)-one; 7-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3,4- dihydroisoquinoline-2(lH)-carboxamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl- 1 -[2-(methylsulfonyl)- 1 ,2,3,4- tetrahydroisoquinolin-7-yl]pyridin-2(lH)-one; l-(l-acetyl-lH-benzimidazol-5-yl)-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6- methylpyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 -( 1 -glycoloyl- lH-benzimidazol-5-yl)-6- methylpyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[l-(2-hydroxy-2-methylpropanoyl)-lH- benzimidazol-5-yl]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[l-(N-methylglycyl)-lH- benzimidazol-5-yl]pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[l-(3-hydroxypropanoyl)-lH- benzimidazol-5-yl]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[l-(3-hydroxy-3-methylbutanoyl)-lH- benzimidazol-5-yl]-6-methylpyridin-2(lH)-one; 5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl]- 1H- benzimidazole- 1 -carboxamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl- 1 -[ 1 -(methylsulfonyl)- 1H- benzimidazol-5-yl]pyridin-2( lH)-one; 3-chloro-l-(l,3-diacetyl-2,3-dihydro-lH-benzimidazol-5-yl)-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one; l-(3-acetyl-l-glycoloyl-2,3-dihydro-lH-benzimidazol-5-yl)-3-chloro-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one; l-[3-acetyl-l-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-lH-benzimidazol-5- yl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one; l-[3-acetyl-l-(JV-methylglycyl)-2,3-dihydro-lH-benzimidazol-5-yl]-3-chloro-4- [(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one; 1 -[3-acetyl- 1 -(3-hydroxypropanoyl)-2,3-dihydro- lH-benzimidazol-5-yl] -3- chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one; l-[3-acetyl-l-(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-lH-benzimidazol-5-yl]- 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one; 3-acetyl-5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]-2,3-dihydro-lH-benzimidazole-l-carboxamide; l-(l-acetyl-3-glycoloyl-2,3-dihydro-lH-benzimidazol-5-yl)-3-chloro-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(l,3-diglycoloyl-2,3-dihydro-lH- benzimidazol-5-yl)-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxyj-l-[3-glycoloyl-l-(2-hydroxy-2- methylpropanoyl)-2,3-dihydro-lH-benzimidazol-5-yl]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[3-glycoloyl-l-(N-methylglycyl)-2,3- dihydro- lH-benzimidazol-5-yl]-6-methylpyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[3-glycoloyl-l-(3-hydroxypropanoyl)-2,3- dihydro- lH-benzimidazol-5-yl] -6-methylpyridin-2( lH)-one; 5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3- glycoloyl-2,3-dihydro- lH-benzimidazole- 1 -carboxamide; 3 -chloro-4- [(2,4-difluorobenzyl)oxy] - 1 - [3-glycoloyl- 1 -(3 -hydroxy-3 - methylbutanoyl)-2,3-dihydro-lH-benzimidazol-5-yl]-6-methylpyridin-2(lH)-one; 3-chloro-4- [(2,4-difluorobenzyl)oxy] - 1 -[3-glycoloyl- 1 -(methylsulf onyl)-2,3- dihydro- lH-benzimidazol-5-ylj-6-methylpyridin-2( lH)-one; l-[l-acetyl-3-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-lH-benzimidazol-5- yl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[l-glycoloyl-3-(2-hydroxy-2- methylpropanoyl)-2,3-dihydro-lH-benzimidazol-5-yl]-6-methylpyridin-2(lH)-one; 1 -[ 1 ,3-bis(2-hydroxy-2-methylpropanoyl)-2,3-dihydro- lH-benzimidazol-5-yl]-3- chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[3-(2-hydroxy-2-methylpropanoyl)-l-(N- methylglycyl)-2,3-dihydro-lH-benzimidazol-5-yl]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 -[3-(2-hydroxy-2-methylpropanoyl)- 1 -(3- hydroxypropanoyl)-2,3-dihydro-lH-benzimidazol-5-yl]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[l-(3-hydroxy-3-methylbutanoyl)-3-(2- hydroxy-2-methylpropanoyl)-2,3-dihydro-lH-benzimidazol-5-yl]-6-methylpyridin- 2(lH)-one; 5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3-(2- hydroxy-2-methylpropanoyl)-2,3-dihydro-lH-benzimidazole-l-carboxamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 -[3-(2-hydroxy-2-methylpropanoyl)- 1 - (methylsulfonyl)-2,3-dihydro-lH-benzimidazol-5-yl]-6-methylpyridin-2(lH)-one; l-[l-acetyl-3-(N-methylglycyl)-2,3-dihydro-lH-benzimidazol-5-yl]-3-chloro-4- [(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[l-glycoloyl-3-(N-methylglycyl)-2,3- dihydro- lH-benzimidazol-5-yl]-6-methylpyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[l-(2-hydroxy-2-methylpropanoyl)-3-(N- methylglycyl)-2,3-dihydro-lH-benzimidazol-5-yl]-6-methylpyridin-2(lH)-one; l-[l,3-bis(N-methylglycyl)-2,3-dihydro-lH-benzimidazol-5-yl]-3-chloro-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[l-(3-hydroxypropanoyl)-3-(N- methylglycyl)-2,3-dihydro-lH-benzimidazol-5-yl]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[l-(3-hydroxy-3-methylbutanoyl)-3-(N- methylglycyl)-2,3-dihydro-lH-benzimidazol-5-yl]-6-methylpyridin-2(lH)-one; 5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3-(N- methylglycyl)-2,3-dihydro- lH-benzimidazole- 1 -carboxamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[3-(N-methylglycyl)-l- (methylsulfonyl)-2,3-dihydro-lH-benzimidazol-5-yl]pyridin-2(lH)-one; l-[l-acetyl-3-(3-hydroxypropanoyl)-2,3-dihydro-lH-benzimidazol-5-yl]-3- chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[l-glycoloyl-3-(3-hydroxypropanoyl)-2,3- dihydro-lH-benzimidazol-5-yl]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[l-(2-hydroxy-2-methylpropanoyl)-3-(3- hydroxypropanoyl)-2,3-dihydro-lH-benzimidazol-5-yl]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[3-(3-hydroxypropanoyl)-l-(N- methylglycyl)-2,3-dihydro-lH-benzimidazol-5-yl]-6-methylpyridin-2(lH)-one; l-[l,3-bis(3-hydroxypropanoyl)-2,3-dihydro-lH-benzimidazol-5-yl]-3-chloro-4- [(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[l-(3-hydroxy-3-methylbutanoyl)-3-(3- hydroxypropanoyl)-2,3-dihydro-lH-benzimidazol-5-yl]-6-methylpyridin-2(lH)-one; 5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3-(3- hydroxypropanoyl)-2,3-dihydro- lH-benzimidazole- 1-carboxamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[3-(3-hydroxypropanoyl)-l- (methylsulfonyl)-2,3-dihydro-lH-benzimidazol-5-yl]-6-methylpyridin-2(lH)-one; l-[l-acetyl-3-(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-lH-benzimidazol-5-yl]- 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[l-glycoloyl-3-(3-hydroxy-3- methylbutanoyl)-2,3-dihydro-lH-benzimidazol-5-yl]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[3-(3-hydroxy-3-methylbutanoyl)-l-(2- hydroxy-2-methylpropanoyl)-2,3-dihydro-lH-benzimidazol-5-yl]-6-methylpyridin- 2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 -[3-(3-hydroxy-3-methylbutanoyl)- 1 -(N- methylglycyl)-2,3-dihydro-lH-benzimidazol-5-yl]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[3-(3-hydroxy-3-methylbutanoyl)-l-(3- hydroxypropanoyl)-2,3-dihydro-lH-benzimidazol-5-yl]-6-methylpyridin-2(lH)-one; l-[l,3-bis(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-lH-benzimidazol-5-yl]-3- chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one; 5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3-(3- hydroxy-3-methylbutanoyl)-2,3-dihydro-lH-benzimidazole-l-carboxamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[3-(3-hydroxy-3-methylbutanoyl)-l- (methylsulfonyl)-2,3-dihydro-lH-benzimidazol-5-yl]-6-methylpyridin-2(lH)-one; 3-acetyl-6-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]-2,3-dihydro- lH-benzimidazole- 1 -carboxamide; 6- [3 -chloro-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -3- glycoloyl-2,3-dihydro-lH-benzimidazole-l-carboxamide; 6-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3-(2- hydroxy-2-methylpropanoyl)-2,3-dihydro-lH-benzimidazole-l-carboxamide; 6-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxoρyridin-l(2H)-yl]-3-(N- methylglycyl)-2,3-dihydro-lH-benzimidazole-l-carboxamide; 6-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3-(3- hydroxypropanoyl)-2,3-dihydro-lH-benzimidazole-l-cai-boxamide; 6-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3-(3- hydroxy-3-methylbutanoyl)-2,3-dihydro-lH-benzimidazole-l-carboxamide; 5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl]- 1H- benzimidazole-l,3(2H)-dicarboxamide; 6-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3- (methylsulfonyl)-2,3-dihydro- lH-benzimidazole- 1 -carboxamide; l-[l-acetyl-3-(methylsulfonyl)-2,3-dihydro-lH-benzimidazol-5-yl]-3-chloro-4- [(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[l-glycoloyl-3-(methylsulfonyl)-2,3- dihydro- lH-benzimidazol-5-yl]-6-methylpyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 -[ 1 -(2-hydroxy-2-methylpropanoyl)-3- (methylsulfonyl)-2,3-dihydro-lH-benzimidazol-5-yl]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[l-(N-methylglycyl)-3- (methylsulfonyl)-2,3-dihydro-lH-benzimidazol-5-yl]pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[l-(3-hydroxypropanoyl)-3- (methylsulfonyl)-2,3-dihydro-lH-benzimidazol-5-yl]-6-methylpyridin-2(l /)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[l-(3-hydroxy-3-methylbutanoyl)-3- (methylsulfonyl)-2,3-dihydro-lH-benzimidazol-5-yl]-6-methylpyridin-2(lH)-one; 5-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3- (methylsulfonyl)-2,3-dihydro- lH-benzimidazole- 1 -carboxamide; l-[l,3-bis(methylsulfonyl)-2,3-dihydro-lH-benzimidazol-5-yl]-3-chloro-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one; l-[3-acetyl-l-(methylsulfonyl)-2,3-dihydro-lH-benzimidazol-5-yl]-3-chloro-4- [(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one; 1 -( 1 -acetyl- lH-pyrrol-3 -yl)-3 -chloro-4- [(2,4-difluorobenzyl)oxy] -6- methylpyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 -( 1 -glycoloyl- lH-pyrrol-3-yl)-6- methylpyridin-2( lH)-one; 3-chloro-4- [(2,4-difluorobenzyl)oxy]- 1 - [ 1 -(2-hydroxy-2-methylpropanoyl)- 1H- pyrrol-3-yl]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[l-(N-methylglycyl)-lH-pyrrol- 3-yl]ρyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[l-(3-hydroxypropanoyl)-lH-pyrrol-3- yl]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[l-(3-hydroxy-3-methylbutanoyl)-lH- pyrrol-3-yl]-6-methylpyridin-2(lH)-one; 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-lH- pyrrole- 1 -carboxamide; 3-chloro-4- [(2,4-difluorobenzyl)oxy]-6-methyl- 1 - [ 1 -(methylsulf onyl)- lH-pyrrol- 3-yl]pyridin-2(lH)-one; l-(l-acetyl-lH-imidazol-4-yl)-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6- methylpyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(l-glycoloyl-lH-imidazol-4-yl)-6- methylpyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 -[ 1 -(2-hydroxy-2-methylpropanoyl)- 1H- imidazol-4-yl] -6-methylpyridin-2( 1 H)-one ; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[l-(N-methylglycyl)-lH- imidazol-4-yl]pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[l-(3-hydroxypropanoyl)-lH-imidazol-4- yl]-6-methylpyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[l-(3-hydroxy-3-methylbutanoyl)-lH- imidazol-4-yl]-6-methylpyridin-2(lH)-one; 4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl]- 1H- imidazole- 1 -carboxamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[l-(methylsulfonyl)-lH- imidazol-4-yl]pyridin-2( lH)-one; 1 -( 1 -acetyl- lH-pyrazol-4-yl)-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6- methylpyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(l-glycoloyl-lH-pyrazol-4-yl)-6- methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[l-(2-hydroxy-2-methylpropanoyl)-lH- pyrazol-4-yl]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[l-(N-methylglycyl)-lH- pyrazol-4-yl]pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 -[ 1 -(3-hydroxypropanoyl)- lH-pyrazol-4- yl] -6-methylpyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 -[ 1 -(3-hydroxy-3-methylbutanoyl)- 1H- pyrazol-4-yl] -6-methylpyridin-2( lH)-one; 4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-lH- pyrazole- 1 -carboxamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[l-(methylsulfonyl)-lH- pyrazol-4-yl]pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-isoquinolin-7-yl-6-methylpyridin-2(lH)- one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 -(isoquinolin-6-ylmethyl)pyridin-2( 1H)- one; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-l,3- dihydro-2H-indol-2-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(2,3-dihydro-lH-indol-5- ylmethyl)pyridin-2( lH)-one; l-[(l-acetyl-2,3-dihydro-lH-indol-5-yl)methyl]-3-chloro-4-[(2,4- difluorobenzyl)oxy]pyridin-2(lH)-one; 3-chloro-4- [(2,4-difluorobenzyl)oxy]- 1 - [( 1 -glycoloyl-2,3-dihydro- lH-indol-5- yl)methyl]pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[l-(2-hydroxy-2-methylpropanoyl)-2,3- dihydro- lH-indol-5-yl]methyl }pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[l-(N-methylglycyl)-2,3-dihydro-lH- indol-5-yl]methyl }pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 - { [ l-(3-hydroxypropanoyl)-2,3-dihydro- lH-indol-5-yl]methyl}pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 - { [ l-(3-hydroxy-3-methylbutanoyl)-2,3- dihydro- lH-indol-5-yl]methyl }pyridin-2( lH)-one; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)- yljmefhyl } indoline- 1 -carboxamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 - { [ l-(methylsulfonyl)-2,3-dihydro- 1H- indol-5-yl]methyl}pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(2,3-dihydro-lH-isoindol-5- ylmethyl)pyridin-2(lH)-one; l-[(2-acetyl-2,3-dihydro-lH-isoindol-5-yl)methyl]-3-chloro-4-[(2,4- difluorobenzyl)oxy]pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[(2-glycoloyl-2,3-dihydro-lH-isoindol-5- yl)methyl]pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[2-(2-hydroxy-2-methylpropanoyl)-2,3- dihydro-lH-isoindol-5-yl]methyl}pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[2-(N-methylglycyl)-2,3-dihydro-lH- isoindol-5-yl]methyl }pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 - { [2-(3-hydroxypropanoyl)-2,3-dihydro- lH-isoindol-5-yl]methyl }pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[2-(3-hydroxy-3-methylbutanoyl)-2,3- dihydro- lH-isoindol-5-yl]methyl }pyridin-2( lH)-one; 5-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yl]methyl }- 1 ,3- dihydro-2H-isoindole-2-carboxamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[2-(methylsulfonyl)-2,3-dihydro-lH- isoindol-5-yl]methyl}pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(l,2,3,4-tetrahydroisoquinolin-6- ylmethyl)pyridin-2( lH)-one; l-[(2-acetyl-l,2,3,4-tetrahydroisoquinolin-6-yl)methyl]-3-chloro-4-[(2,4- difluorobenzyl)oxy]pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[(2-glycoloyl-l,2,3,4- tetrahydroisoquinolin-6-yl)methyl]pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 - { [2-(2-hydroxy-2-methylpropanoyl)- l,2,3,4-tetrahydroisoquinolin-6-yl]methyl}pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[2-(N-methylglycyl)-l,2,3,4- tetrahydroisoquinolin-6-yl]methyl }pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1- { [2-(3-hydroxypropanoyl)- 1 ,2,3,4- tetrahydroisoquinolin-6-yl]methyl}pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{ [2-(3-hydroxy-3-methylbutanoyl)- l,2,3,4-tetrahydroisoquinolin-6-yl]methyl}pyridin-2(lH)-one; 6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3,4- dihydroisoquinoline-2(lH)-carboxamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[2-(methylsulfonyl)-l,2,3,4- tetrahydroisoquinolin-6-yl]methyl}pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(l,2,3,4-tetrahydroisoquinolin-5- ylmethyl)pyridin-2( lH)-one; l-[(2-acetyl-l,2,3,4-tetrahydroisoquinolin-5-yl)methyl]-3-chloro-4-[(2,4- difluorobenzyl)oxy]pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[(2-glycoloyl-l,2,3,4- tetrahydroisoquinolin-5-yl)methyl]pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 - { [2-(2-hydroxy-2-methylpropanoyl)- 1 ,2,3,4-tetrahydroisoquinolin-5-yl]methyl }pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[2-(N-methylglycyl)-l,2,3,4- tetrahydroisoquinolin-5-yl]methyl }pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{ [2-(3-hydroxypropanoyl)-l,2,3,4- tetrahydroisoquinolin-5-yl]methyl}pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[2-(3-hydroxy-3-methylbutanoyl)- l,2,3,4-tetrahydroisoquinolin-5-yl]methyl}pyridin-2(lH)-one; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3,4- dihydroisoquinoline-2(lH)-carboxamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{ [2-(methylsulfonyl)-l,2,3,4- tetrahydroisoquinolin-5-yl]methyl}pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(2,3-dihydro-lH-benzimidazol-5- ylmethyl)pyridin-2( lH)-one; l-[(l-acetyl-2,3-dihydro-lH-benzimidazol-5-yl)methyl]-3-chloro-4-[(2,4- difluorobenzyl)oxy]pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[(l-glycoloyl-2,3-dihydro-lH- benzimidazol-5-yl)methyl]pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[l-(2-hydroxy-2-methylpropanoyl)-2,3- dihydro- lH-benzimidazol-5-yl]methyl } pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{ [l-(N-methylglycyl)-2,3-dihydro-lH- benzimidazol-5-yl]methyl}pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 - { [ 1 -(3-hydroxypropanoyl)-2,3-dihydro- lH-benzimidazol-5-yl]methyl }pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[l-(3-hydroxy-3-methylbutanoyl)-2,3- dihydro- lH-benzimidazol-5-yl]methyl }pyridin-2( lH)-one; 5- { [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yl]methyl } -2,3- dihydro-lH-benzimidazole-1-carboxamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[l-(methylsulfonyl)-2,3-dihydro-lH- benzimidazol-5-yl]methyl}pyridin-2(lH)-one; l-[(3-acetyl-2,3-dihydro-lH-benzimidazol-5-yl)methyl]-3-chloro-4-[(2,4- difluorobenzyl)oxy]pyridin-2(lH)-one; 3-chloro-l-[(l,3-diacetyl-2,3-dihydro-lH-benzimidazol-5-yl)methyl]-4-[(2,4- difluorobenzyl)oxy]pyridin-2(lH)-one; l-[(3-acetyl-l-glycoloyl-2,3-dihydro-lH-benzimidazol-5-yl)methyl]-3-chloro-4- [(2,4-difluorobenzyl)oxy]pyridin-2(lH)-one; l-{ [3-acetyl-l-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-lH-benzimidazol-5- yl]methyl}-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(lH)-one; 1- { [3-acetyl- 1 -(N-methylglycyl)-2,3-dihydro- lH-benzimidazol-5-yl]methyl } -3- chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(lH)-one; l-{[3-acetyl-l-(3-hydroxypropanoyl)-2,3-dihydro-lH-benzimidazol-5- yl]methyl}-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(lH)-one; l-{ [3-acetyl-l-(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-lH-benzimidazol-5- yljmethyl } -3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2( lH)-one; 3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)- yljmethyl } -2,3-dihydro- lH-benzimidazole- 1 -carboxamide; 1 -{ [3 -acetyl- 1 -(methylsulfonyl)-2, 3-dihydro- lH-benzimidazol-5-yl] methyl } -3 - chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[(3-glycoloyl-2,3-dihydro-lH- benzimidazol-5-yl)methyl]pyridin-2(lH)-one; l-[(l-acetyl-3-glycoloyl-2,3-dihydro-lH-benzimidazol-5-yl)methyl]-3-chloro-4- [(2,4-difluorobenzyl)oxy]pyridin-2(lH)-one; 3 -chloro-4- [(2, 4-difluorobenzyl)oxy]- 1 -[( 1 ,3-diglycoloyl-2,3-dihydro- 1H- benzimidazol-5-yl)methyl]pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{ [3-glycoloyl- l-(2-hydroxy-2- methylpropanoyl)-2,3-dihydro-lH-benzimidazol-5-yl]methyl}pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[3-glycoloyl-l-(iV-methylglycyl)-2,3- dihydro-lH-benzimidazol-5-yl]methyl}pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[3-glycoloyl-l-(3-hydroxypropanoyl)- 2,3-dihydro-lH-benzimidazol-5-yl]methyl}pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[3-glycoloyl-l-(3-hydroxy-3- methylbutanoyl)-2,3-dihydro-lH-benzimidazol-5-yl]methyl}pyridin-2(lH)-one; 5-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3- glycoloyl-2,3-dihydro-lH-benzimidazole-l-carboxamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{ [3-glycoloyl-l-(methylsulfonyl)-2,3- dihydro- lH-benzimidazol-5-yl]methyl } pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[3-(2-hydroxy-2-methylpropanoyl)-2,3- dihydro-lH-benzimidazol-5-yl]methyl}pyridin-2(lH)-one; 1 - { [ 1 -acetyl-3-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro- lH-benzimidazol-5- yl]methyl}-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[l-glycoloyl-3-(2-hydroxy-2- methylpropanoyl)-2,3-dihydro- lH-benzimidazol-5-yl]methyl }pyridin-2( lH)-one; l-{ [l,3-bis(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-lH-benzimidazol-5- yljmethyl } -3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[3-(2-hydroxy-2-methylpropanoyl)-l- (N-methylglycyl)-2,3-dihydro- lH-benzimidazol-5-yl]methyl }pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[3-(2-hydroxy-2-methylpropanoyl)-l-(3- hydroxypropanoyl)-2,3-dihydro-lH-benzimidazol-5-yl]methyl}pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[l-(3-hydroxy-3-methylbutanoyl)-3-(2- hydroxy-2-methylpropanoyl)-2,3-dihydro-lH-benzimidazol-5-yl]methyl}pyridin-2(lH)- one; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3-(2- hydroxy-2-methylpropanoyl)-2,3-dihydro-lH-benzimidazole-l-carboxarnide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{ [3-(2-hydroxy-2-methylpropanoyl)-l- (methylsulfonyl)-2,3-dihydro- lH-benzimidazol-5-yl]methyl }pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[3-(N-methylglycyl)-2,3-dihydro-lH- benzimidazol-5-yl]methyl } pyridin-2( lH)-one; l-{[l-acetyl-3-(N-methylglycyl)-2,3-dihydro-lH-benzimidazol-5-yl]methyl}-3- chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{ [l-glycoloyl-3-(N-methylglycyl)-2,3- dihydro- lH-benzimidazol-5-yl]methyl }pyridin-2( lH)-one; 3 -chloro-4- [(2 ,4-difluorobenzyl)oxy]- 1 - { [ l-(2-hydroxy-2-methylpropanoyl)-3- (7Y-methylglycyl)-2,3-dihydro-lH-benzimidazol-5-yl]methyl}pyridin-2(lH)-one; 1 - { [ 1 ,3-bis(N-methylglycyl)-2,3-dihydro- lH-benzimidazol-5-yl]methyl } -3- chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[l-(3-hydroxypropanoyl)-3-(N- methylglycyl)-2,3-dihydro-lH-benzimidazol-5-yl]methyl}pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 - { [ l-(3-hydroxy-3-methylbutanoyl)-3-(N- methylglycyl)-2,3-dihydro-lH-benzimidazol-5-yl]methyl}pyridin-2(lH)-one; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3-(N- methylglycyl)-2,3-dihydro-lH-benzimidazole-l-carboxamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 - { [3-(N-methylglycyl)- 1 -(methylsulf onyl)- 2,3-dihydro- lH-benzimidazol-5-yl]methyl }pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[[3-(3-hydroxypropanoyl)-2,3-dihydro- lH-benzimidazol-5-yl] methyl }pyridin-2( lH)-one; l-{ [l-acetyl-3-(3-hydroxypropanoyl)-2,3-dihydro-lH-benzimidazol-5- yljmefhyl } -3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[l-glycoloyl-3-(3-hydroxypropanoyl)- 2,3-dihydro-lH-benzimidazol-5-yl]methyl}pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{ [l-(2-hydroxy-2-methylpropanoyl)-3-(3- hydroxypropanoyl)-2,3-dihydro- lH-benzimidazol-5-yl]methyl }pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[3-(3-hydroxypropanoyl)-l-(N- methylglycyl)-2,3-dihydro-lH-benzimidazol-5-yl]methyl}pyridin-2(lH)-one; l-{ [l,3-bis(3-hydroxypropanoyl)-2,3-dihydro-lH-benzimidazol-5-yl]methyl}-3- chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{ [l-(3-hydroxy-3-methylbutanoyl)-3-(3- hydroxypropanoyl)-2,3-dihydro- lH-benzimidazol-5-yl]methyl }pyridin-2( lH)-one; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3-(3- hydroxypropanoyl)-2,3 -dihydro- lH-benzimidazole- 1 -carboxamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[3-(3-hydroxypropanoyl)-l- (methylsulfonyl)-2,3-dihydro-lH-benzimidazol-5-yl]methyl}pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{ [3-(3-hydroxy-3-methylbutanoyl)-2,3- dihydro- lH-benzimidazol-5-yl]methyl } pyridin-2( lH)-one; l-{ [l-acetyl-3-(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-lH-benzimidazol-5- yl]methyl}-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[l-glycoloyl-3-(3-hydroxy-3- methylbutanoyl)-2,3-dihydro-lH-benzimidazol-5-yl]methyl}pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[3-(3-hydroxy-3-methylbutanoyl)-l-(2- hydroxy-2-methylpropanoyl)-2,3-dihydro-lH-benzimidazol-5-yl]methyl}pyridin-2(lH)- one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[[3-(3-hydroxy-3-methylbutanoyl)-l-(N- methylglycyl)-2,3-dihydro-lH-benzimidazol-5-yl]methyl}pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[3-(3-hydroxy-3-methylbutanoyl)-l- (methylsulfonyl)-2,3-dihydro-lH-benzimidazol-5-yl]methyl}pyridin-2(lH)-one; 5-[[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3-(3- hydroxy-3-methylbutanoyl)-2,3-dihydro-lH-benzimidazole-l-carboxamide; l-{[l,3-bis(3-hydroxy-3-methylbutanoyl)-2,3-dihydro-lH-benzimidazol-5- yl]methyl}-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[3-(3-hydroxy-3-methylbutanoyl)-l-(3- hydroxypropanoyl)-2,3-dihydro-lH-benzimidazol-5-yl]methyl}pyridin-2(lH)-one; 6-{ [3-chloro-4-[(2,4-difluorθbenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-2,3- dihydro- lH-benzimidazole- 1 -carboxamide; 3-acetyl-6- { [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)- yljmethyl } -2,3-dihydro- lH-benzimidazole- 1 -carboxamide; 6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3- glycoloyl-2,3-dihydro-lH-benzimidazole-l-carboxamide; 6-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yl]methyl } -3-(2- hydroxy-2-methylpropanoyl)-2,3-dihydro-lH-benzimidazole-l-carboxamide; 6-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3-(N- mefhylglycyl)-2,3-dihydro- lH-benzimidazole- 1 -carboxamide; 6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3-(3- hydroxypropanoyl)-2,3-dihydro- lH-benzimidazole- 1 -carboxamide; 6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3-(3- hydroxy-3-methylbutanoyl)-2,3-dihydro-lH-benzimidazole-l-carboxamide; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-lH- benzimidazole-l,3(2H)-dicarboxamide; , 6-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3- (methylsulfonyl)-2,3-dihydro- lH-benzimidazole- 1 -carboxamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[3-(methylsulfonyl)-2,3-dihydro-lH- benzimidazol-5-yl]methyl }pyridin-2( lH)-one; 1 - { [ 1 -acetyl-3-(methylsulfonyl)-2,3-dihydro- lH-benzimidazol-5-yl]methyl } -3- chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[l-glycoloyl-3-(methylsulfonyl)-2,3- dihydro-lH-benzimidazol-5-yl]methyl}pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 - { [ l-(2-hydroxy-2-methylpropanoyl)-3- (methylsulfonyl)-2,3-dihydro- lH-benzimidazol-5-yl]methyl }pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 - { [ 1 -(N-methylglycyl)-3-(methylsulf onyl)- 2,3-dihydro- lH-benzimidazol-5-yl]methyl } pyridin-2( lH)-one; 3 -chloro-4- [(2 ,4-difluorobenzyl)oxy] - 1 - { [ 1 -(3-hydroxypropanoyl)-3 - (methylsulfonyl)-2,3-dihydro- lH-benzimidazol-5-yl]methyl }pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[l-(3-hydroxy-3-methylbutanoyl)-3- (methylsulfonyl)-2,3-dihydro-lH-benzimidazol-5-yl]methyl}pyridin-2(lH)-one; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3- (methylsulfonyl)-2,3-dihydro-lH-benzimidazole-l-carboxamide; 1 - { [ 1 ,3-bis(methylsulfonyl)-2,3 -dihydro- lH-benzimidazol-5-yl]methyl } -3- chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(lH)-one; 5-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yl]methyl } - 1 ,3- dihydro-2H-benzimidazol-2-one; l-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)- yljmethyl }- 1 ,3-dihydro-2H-benzimidazol-2-one; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-l- glycoloyl- 1 ,3-dihydro-2H-benzimidazol-2-one; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-l-(2- hydroxy-2-methylpropanoyl)- 1 ,3-dihydro-2H-benzimidazol-2-one; 5-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yl]methyl } - 1-(_V- methylglycyl)- 1 ,3-dihydro-2H-benzimidazol-2-one; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-l-(3- hydroxypropanoyl)- 1 ,3-dihydro-2H-benzimidazol-2-one; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-l-(3- hydroxy-3-methylbutanoyl)- 1 ,3-dihydro-2H-benzimidazol-2-one; 5- { [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yl]methyl } -2-oxo- 2,3-dihydro- lH-benzimidazole- 1 -carboxamide; 5- { [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yι]methyl } - 1 - (methylsulfonyl)- 1 ,3-dihydro-2H-benzimidazol-2-one; 1 -acetyl-6- { [3 -chloro-4- [ (2,4-difluorobenzyl)oxy] -2-oxopyridin- 1 (2H)- yljmethyl}-l,3-dihydro-2H-benzimidazol-2-one; 1 ,3-diacetyl-5-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l (2H yljmethyl }- 1 ,3-dihydro-2H-benzimidazol-2-one; 3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)- yl]methyl}-l-glycoloyl-l,3-dihydro-2H-benzimidazol-2-one; 3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)- yl]methyl}-l-(2-hydroxy-2-methylpropanoyl)-l,3-dihydro-2H-benzimidazol-2-one; 3-acetyl-5-[[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)- yljmethyl } - 1 -(N-methylglycyl)- 1 ,3-dihydro-2H-benzimidazol-2-one; 3-acetyl-5-[[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)- yljmethyl } - 1 -(3-hydroxypropanoyl)- 1 ,3-dihydro-2H-benzimidazol-2-one; 3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)- yl]methyl}-l-(3-hydroxy-3-methylbutanoyl)-l,3-dihydro-2H-benzimidazol-2-one; 3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)- yljmethyl } -2-oxo-2,3-dihydro- 1 H-benzimidazole- 1 -carboxamide; 3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)- yl]methyl}-l-(methylsulfonyl)-l,3-dihydro-2H-benzimidazol-2-one; 6- { [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yl]methyl } - 1 - glycoloyl- 1 ,3-dihydro-2H-benzimidazol-2-one; l-acetyl-5-[[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2J )- yljmethyl} -3-glycoloyl- l,3-dihydro-2H-benzimidazol-2-one; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-l,3- diglycoloyl- 1 ,3-dihydro-2H-benzimidazol-2-one; 5- { [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l (2H)-yl]methyl } -3- glycoloyl- 1 -(2-hydroxy-2-methylpropanoyl)- 1 ,3-dihydro-2H-benzimidazol-2-one; 5- { [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yl]methyl } -3- glycoloyl-l-(N-methylglycyl)-l,3-dihydro-2H-benzimidazol-2-one; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxoρyridin-l(2H)-yl]methyl}-3- glycoloyl-l-(3-hydroxypropanoyl)-l,3-dihydro-2H-benzimidazol-2-one; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3- glycoloyl-l-(3-hydroxy-3-methylbutanoyl)-l,3-dihydro-2H-benzimidazol-2-one; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3- glycoloyl-2-oxo-2,3-dihydro-lH-benzimidazole-l-carboxamide; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3- glycoloyl-l-(methylsulfonyl)-l,3-dihydro-2H-benzimidazol-2-one; 6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-l-(2- hydroxy-2-methylpropanoyl)- 1 ,3-dihydro-2H-benzimidazol-2-one; 1 -acetyl-5- { [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)- yljmethyl }-3-(2-hydroxy-2-methylpropanoyl)- 1 ,3-dihydro-2H-benzimidazol-2-one; 5- { [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yl] methyl }- 1- glycoloyl-3-(2-hydroxy-2-methylpropanoyl)-l,3-dihydro-2H-benzimidazol-2-one; 5- { [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l (2H)-yl]methyl }- 1 ,3- bis(2-hydroxy-2-methylpropanoyl)-l,3-dihydro-2H-benzimidazol-2-one; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3-(2- hydroxy-2-methylpropanoyl)- 1 -(N-mefhylglycyl)- 1 ,3-dihydro-2H-benzimidazol-2-one; 5-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yl] methyl } -3-(2- hydroxy-2-methylpropanoyl)-l-(3-hydroxypropanoyl)-l,3-dihydro-2H-benzimidazol-2- one; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-l-(3- hydroxy-3-methylbutanoyl)-3-(2-hydroxy-2-methylpropanoyl)-l,3-dihydro-2H- benzimidazol-2-one ; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3-(2- hydroxy-2-methylpropanoyl)-2-oxo-2,3-dihydro- lH-benzimidazole- 1 -carboxamide; 5- { [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxoρyridin- 1 (2H)-yl] methyl } -3-(2- hydroxy-2-methylpropanoyl)- 1 -(methylsulfonyl)- 1 ,3-dihydro-2H-benzimidazol-2-one; 6-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-l-(N- methylglycyl)- 1 ,3 -dihydro-2H-benzimidazol-2-one; l-acetyl-5-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)- yljmethyl } -3-(N-methylglycyl)- 1 ,3-dihydro-2H-benzimidazol-2-one; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-l- glycoloyl-3-(N-methylglycyl)-l,3-dihydro-2H-benzimidazol-2-one; 5- { [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yl]methyl } - 1-(2- hydroxy-2-methylpropanoyl)-3-(7vr-methylglycyl)-l,3-dihydro-2H-benzimidazol-2-one; 5- { [3-chloro-4- [(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yl]methyl } - 1 ,3- bis(N-methylglycyl)- 1 ,3-dihydro-2H-benzimidazol-2-one; 5-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-l-(3- hydroxypropanoyl)-3-(N-methylglycyl)-l,3-dihydro-2H-benzimidazol-2-one; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-l-(3- hydroxy-3-methylbutanoyl)-3-(N-methylglycyl)-l,3-dihydro-2H-benzimidazol-2-one; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3-(N- methylglycyl)-2-oxo-2,3-dihydro- lH-benzimidazole- 1 -carboxamide; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3-(N- methylglycyl)- 1 -(methylsulfonyl)- 1 ,3-dihydro-2H-benzimidazol-2-one; 6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-l-(3- hydroxypropanoyl)- 1 ,3-dihydro-2H-benzimidazol-2-one; l-acetyl-5-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)- yljmethyl }-3-(3-hydroxypropanoyl)- 1 ,3-dihydro-2H-benzimidazol-2-one; 5- { [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yl]methyl } - 1- glycoloyl-3-(3-hydroxypropanoyl)-l,3-dihydro-2H-benzimidazol-2-one; 5- { [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yl] methyl } - 1 -(2- hydroxy-2-methylpropanoyl)-3-(3-hydroxypropanoyl)-l,3-dihydro-2H-benzimidazol-2- one; 5- { [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yl]methyl } -3-(3- hydroxypropanoyl)-l-(N-methylglycyl)-l,3-dihydro-2H-benzimidazol-2-one; 5-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yl]methyl } - 1 ,3- bis(3-hydroxypropanoyl)- 1 ,3-dihydro-2H-benzimidazol-2-one; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-l-(3- hydroxy-3-methylbutanoyl)-3-(3-hydroxypropanoyl)-l,3-dihydro-2H-benzimidazol-2- one; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3-(3- hydroxypropanoyl)-2-oxo-2,3-dihydro-lH-benzimidazole-l-carboxamide; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3-(3- hydroxypropanoyl)-l-(methylsulfonyl)-l,3-dihydro-2H-benzimidazol-2-one; 6-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxoρyridin- 1 (2H)-yl] methyl } - 1-(3- hydroxy-3-methylbutanoyl)- 1 ,3-dihydro-2H-benzimidazol-2-one; 1 -acetyl-5- { [3-chloro-4-[(2,4-difluorobenzyl)oxy] -2-oxopyridin- 1 (2H)- yl]methyl}-3-(3-hydroxy-3-methylbutanoyl)-l,3-dihydro-2H-benzimidazol-2-one; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-l- glycoloyl-3-(3-hydroxy-3-methylbutanoyl)-l,3-dihydro-2H-benzimidazol-2-one; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3-(3- hydroxy-3-methylbutanoyl)- 1 -(2-hydroxy-2-methylpropanoyl)- 1 ,3-dihydro-2H- benzimidazol-2-one; 5-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yljmefhyl } -3-(3- hydroxy-3-methylbutanoyl)-l-(N-methylglycyl)-l,3-dihydro-2H-benzimidazol-2-one; 5- { [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yl]methyl } -3-(3- hydroxy-3-methylbutanoyl)-l-(3-hydroxypropanoyl)-l,3-dihydro-2H-benzimidazol-2- one; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-l,3- bis(3-hydroxy-3-methylbutanoyl)-l,3-dihydro-2H-benzimidazol-2-one; 5- { [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yl]methyl } -3-(3- hydroxy-3-methylbutanoyl)-2-oxo-2,3-dihydro-lH-benzimidazole-l-carboxamide; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3-(3- hydroxy-3-methylbutanoyl)- 1 -(methylsulfonyl)- 1 ,3-dihydro-2H-benzimidazol-2-one; 6- { [3 -chloro-4-[(2,4-difluorobenzyl)oxy] -2-oxopyridin- 1 (2H)-yl]methyl } -2-oxo- 2,3 -dihydro- 1 H-benzimidazole- 1 -carboxamide ; 3-acetyl-6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)- yljmefhyl } -2-oxo-2,3-dihydro- lH-benzimidazole- 1 -carboxamide; 6-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3- glycoloyl-2-oxo-2,3-dihydro-lH-benzimidazole-l -carboxamide; 6- { [3-chloro-4- [(2,4-difluorobenzyl)oxy] -2-oxopyridin- 1 (2H)-yl]methyl } -3-(2- hydroxy-2-methylpropanoyl)-2-oxo-2,3-dihydro-lH-benzimidazole-l-carboxamide; 6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3-(N- methylglycyl)-2-oxo-2,3-dihydro- lH-benzimidazole- 1 -carboxamide; 6-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yl]methyl } -3-(3- hydroxypropanoyl)-2-oxo-2,3-dihydro-lH-benzimidazole-l-carboxamide; 6-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3-(3- hydroxy-3-methylbutanoyl)-2-oxo-2,3-dihydro-lH-benzimidazole-l-carboxamide; 5- { [3 -chloro-4- [(2,4-difluorobenzyl)oxy] -2-oxopyridin- 1 (2H)-yl] methyl } -2-oxo- lH-benzimidazole- 1 ,3(2H)-dicarboxamide; ' 6-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3- (methylsulf onyl)-2-oxo-2,3-dihydro- lH-benzimidazole- 1 -carboxamide; 6- { [3-chloro-4- [(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yljmethyl } - 1 - (methylsulfonyl)- 1 ,3-dihydro-2H-benzimidazol-2-one; l-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)- yl]methyl}-3-(methylsulfonyl)-l,3-dihydro-2H-benzimidazol-2-one; 5- { [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yl]methyl } - 1 - glycoloyl-3-(methylsulfonyl)-l,3-dihydro-2H-benzimidazol-2-one; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-l-(2- hydroxy-2-methylpropanoyl)-3-(methylsulfonyl)-l,3-dihydro-2H-benzimidazol-2-one; 5- { [3-chloro-4-[(2,4-difluorobenzyl)oxy] -2-oxopyridin- 1 (2H)-yl]methyl } - 1 -(N- methylglycyl)-3-(methylsulfonyl)-l,3-dihydro-2H-benzimidazol-2-one; 5- { [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yl]methyl } - 1-(3- hydroxypropanoyl)-3-(methylsulfonyl)-l,3-dihydro-2H-benzimidazol-2-one; 5- { [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yl]methyl } - 1-(3- hydroxy-3-methylbutanoyl)-3-(methylsulfonyl)-l,3-dihydro-2H-benzimidazol-2-one; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-3- (methylsulfonyl)-2-oxo-2,3-dihydro- lH-benzimidazole- 1 -carboxamide; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-l,3- bis(methylsulf onyl)- 1 ,3-dihydro-2H-benzimidazol-2-one; 3-benzyl-4-hydroxy-l-(2-phenylethyl)pyridin-2(lH)-one; 1 -benzyl-4-hydroxy-2-oxo- 1 ,2-dihydropyridine-3 -carbaldehyde; l-benzyl-4-chloro-2-oxo-l,2-dihydropyridine-3-carbaldehyde; methyl 5-chloro- 1 -(4-chlorobenzyl)-6-oxo- 1 ,6-dihydropyridine-3-carboxylate; 5-bromo- 1 -(2-chloro-6-fluorobenzyl)-3-methylpyridin-2( lH)-one; 3-bromo-l-(2,6-dichlorophenyl)-4-[(4-fluorophenyl)ethynyl]-6-methylpyridin- 2(lH)-one; 3-bromo-l-(2,6-dichlorophenyl)-4-[(4-fluorophenyl)ethynyl]-6-methylpyridin- 2(lH)-one; methyl 3-chloro-4-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)- yljbenzoate; 4-[(2,4-difluorobenzyl)oxy]-l-(3-fluorobenzyl)-2-oxo-l,2-dihydropyridine-3- carbonitrile; 4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-l-(2,4,6-trifluorophenyl)pyridin- 2(lH)-one; 4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[2-(trifluoromethyl)phenyl]pyridin- 2(lH)-one; 3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]benz aldehyde; 4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluoro-4-moφholin-4-ylphenyl)-6- methylpyridin-2( lH)-one; 4-[(2,4-difluorobenzyl)oxy]-l-[2,6-difluoro-4-(4-methylpiperazin-l-yl)phenyl]-6- methylpyridin-2( lH)-one; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]benzoic acid; 4-[(2,4-difluorobenzyl)oxy]-l-[4-(dimethylamino)-2,6-difluorophenyl]-6- methylpyridin-2( lH)-one; 4-[(2,4-difluorobenzyl)oxy]-l-{2,6-difluoro-4-[(2- hydroxyethyl)(methyl)amino]phenyl}-6-methylpyridin-2(lH)-one; methyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yljbenzoate; 3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylbenzoic acid; 4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-6-(hydroxymethyl)pyridin- 2(lH)-one; 3-bromo- 1- { [5-(chloromethyl)pyrazin-2-yljmefhyl } -4-[(2,4-difluorobenzyl)oxy]- 6-methylpyridin-2( lH)-one; l-[2-chloro-5-(hydroxymethyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6- mefhylpyridin-2(lH)-one; 4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluoro-4-hydroxyphenyl)-6-methylpyridin- 2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[4-(hydroxymethyl)-2-methoxyphenyl]-6- methylpyridin-2( lH)-one; methyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl] -4-methylbenzoate ; 3-bromo-4- [(2,4-difluorobenzyl)oxyj -6-methyl- 1 - { 3-[(4-methylpiperazin- 1 - yl)carbonyl]phenyl }pyridin-2( lH)-one; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-[2- (dimethylamino)ethyl]benzamide; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-(2- methoxyethyl)benzamide ; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-[2- (dimethylamino)ethylj-N-methylbenzamide; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxoρyridin-l(2H)-yl]-N-(2- hydroxyethyl)-7Y-methylbenzamide; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-(2- methoxyethyl)-7Y-methylbenzamide; 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yljbenzamide; methyl 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl] -4-fluorobenzoate ; 4-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3- methylbenzoic acid; l-(4-bromo-2-methylphenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)- one; 1 -[( 1 -acetyl- lH-indol-5-yl)methyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin- 2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[(5-methylpyrazin-2- yl)methyl]pyridin-2( lH)-one; methyl 2-( { [3-bromo- 1 -(2,6-difluorophenyl)-6-methyl-2-oxo- 1 ,2-dihydropyridin- 4-yl] oxy } methyl)-3 ,5-difluorobenzylcarbamate; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{[5-(hydroxymethyl)pyrazin-2- yljmethyl } -6-methylpyridin-2( lH)-one; 4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yllmethyl } -N,N-dimethylbenzamide; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-(2- hydroxyethyl)-4-methylbenzamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-{4-[(4-methylpiperazin-l- yl)carbonyl]benzyl }pyridin-2( lH)-one; 3 -chloro-4- [(2,4-difluorobenzyl)oxy]- 1 -( lH-indol-5-ylmethyl)pyridin-2( lH)-one; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N- methylbenzamide; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yljbenzamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[5-(hydroxymethyl)pyrazin-2- yljmethyl } -6-methylpyridin-2( lH)-one; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-(2- methoxyethyl)-4-methylbenzamide; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N,4- dimethylbenzamide; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N,N,4- trimethylbenzamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[2-methyl-5-(moφholin-4- ylcarbonyl)ρhenyl]pyridin-2(lH)-one; 3-bromo-4- [(2,4-difluorobenzyl)oxy]- 1 -[5-( 1 -hydroxy- 1 -methylethyl)-2- methylphenyl] -6-methylpyridin-2( 1 H)-one ; l-(2-bromobenzyl)-3-[(2-bromobenzyl)oxy]pyridin-2(lH)-one; l-(2-bromobenzyl)-3-[(2-bromobenzyl)oxy]pyridin-2(lH)-one; 3-bromo- 1 -(4-methoxybenzyl)-4-phenoxypyridin-2( lH)-one; l-benzyl-2-oxo-4-phenoxy-l,2-dihydropyridine-3-carbaldehyde; 3-Bromo-4-(2,4-difluoro-benzyloxy)-l-(3-dimethylaminomethyl-benzyl)-6- methyl- 1 Η-pyridin-2-one ; N- { 3- [3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin- 1 - ylmefhylj-benzyl } -2-hydroxy-acetamide; 3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-l-[4-(piperidine-l-carbonyl)- benzyl]- lH-pyridin-2-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-6- [(ethoxyamino)methyl]pyridin-2(lH)-one; 4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Η-pyridin-l-ylmethyl]- N-isopropyl-benzamide; N-(3-aminopropyl)-4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]methyl Jbenzamide hydrochloride; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-/V,4- dimethylbenzamide; 4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Η-pyridin-l-ylmethyl]- N,N-bis-(2-hydroxy-ethyl)-benzamide; 3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl- 1 - [4-(pyrrolidine- 1 -carbonyl)- benzyl] - 1 H-pyridin-2-one ; 4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-l-ylmethyl]- N-hydroxy-benzamide ; 4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-l-ylmethyl]- N-methyl-benzamide ; 4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-l-ylmethyl]- N-(2-dimethylamino-ethyl)-benzamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(lH-indazol-5-ylmethyl)pyridin-2(lH)- one; 3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-l-[4-(4-methyl-piperazine-l- carbonyl)-benzyl]-lΗ-pyridin-2-one; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylbenzaldehyde ; 3-Bromo-4-(2,4-difluoro-benzyloxy)-l-(4-dimethylaminomethyl-benzyl)-6- methyl- 1 Η-pyridin-2-one ; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxoρyridin-l(2H)-yl]-N-(2- methoxyethyl)-4-methylbenzamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[2-(dimethylamino)-4,6-difluorophenyl]- 6-methylpyridin-2( lH)-one hydrochloride; N-(2-aminoethyl)-4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]methyl}benzamide hydrochloride; 4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Η-pyridin-l-ylmethyl]- N-(2-hydroxy-ethyl)-benzamide; 3-Bromo-4-(2,4-difluoro-benzyloxy)- 1 -(4-hydroxymethyl-benzyl)-6-methyl- 1 H- pyridin-2-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[2,6-difluoro-4-(4-methylpiperazin-l- yl)phenyl]-6-methylpyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[2-(dimethylamino)-4,6-difluorophenyl]- 6-mefhylpyridin-2( lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[2,6-difluoro-4-(4-methylpiperazin-l- yl)phenyl]-6-methylpyridin-2(lH)-one; 4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Η-pyridin-l-ylmethyl]- N-(2-methoxy-ethyl)-benzamide; 3-Bromo-4-(2,4-difluoro-benzyloxy)- 1 - { 4-[(2-hydroxy-ethylamino)-methyl]- benzyl } -6-methyl- 1 H-pyridin-2-one ; 3-bromo-4-[(2,4-difluorobenzyl)oxy]- 1 -(2,6-difluorophenyl)-6- [(dimethylamino)methyl]pyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[2-methyl-5-(moφholin-4- ylcarbonyl)phenyl]pyridin-2(lH)-one; 3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-l-(4-methylaminomethyl-benzyl)- lΗ-pyridin-2-one; 3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl- 1 - [4-(moφholine-4-carbonyl)- benzyl]- lH-pyridin-2-one; N-(2-aminoethyl)-3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]benzamide; N-(3-aminopropyl)-3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]benzamide hydrochloride; 4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Η-pyridin-l-ylmethyl]- N-(2-methoxy-ethyl)-N-methyl-benzamide; l-(4-Aminomethyl-benzyl)-3-bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-lH- pyridin-2-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[4-(piperazin-l- ylcarbonyl)benzyl]pyridin-2( lH)-one hydrochloride; 3-Bromo-4-(2,4-difluoro-benzyloxy)-l-[4-(isopropylamino-methyl)-benzyl]-6- methyl- 1 Η-pyridin-2-one ; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-dimethylphenyl)-6-methylpyridin- 2(lH)-one; 3-Bromo-4-(2,4-difluoro-benzyloxy)- 1 - { 3-[(2-hydroxy-ethylamino)-methylj- benzyl } -6-methyl- 1 Η-pyridin-2-one; l-(3-Aminomethyl-benzyl)-3-bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-lH- pyridin-2-one; 3-Bromo-4-(2,4-difluoro-benzyloxy)- 1 -(4-hydroxy-benzyl)-6-methyl- lH-pyridin- 2-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 -(2,6-difluorophenyl)-6- [(dimethylamino)methyl]pyridin-2(lH)-one; N-{3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Η-pyridin-l- ylmethylj-benzyl } -acetamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{2,6-difluoro-4-[(2- hydroxyethyl)(methyl)amino]phenyl }-6-methylpyridin-2( lH)-one; ethyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yljbenzoate; l-[3-(aminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]pyridin-2(lH)- one trifluoroacetate; l-(3-{ [Bis-(2-hydroxy-ethyl)-amino]-methyl}-benzyl)-3-bromo-4-(2,4-difluoro- benzyloxy)-6-methyl- 1 H-pyridin-2-one; 3-Bromo-4-(2,4-difluoro-benzyloxy)-l-[3-(isopropylamino-methyl)-benzyl]-6- methyl- 1 H-pyridin-2-one ; {3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-2-oxo-2H-pyridin-l-ylmethyl]-benzyl}- carbamic acid tert-butyl ester; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yljbenzamide; 3-Bromo-4-(2,4-difluoro-benzyloxy)-l-[4-(l-hydroxy-l-methyl-ethyl)-benzyl]-6- methyl-lΗ-pyridin-2-one; 3-Bromo-4-(2,4-difluoro-benzyloxy)-l-(3-dimethylaminomethyl-benzyl)-lH- pyridin-2-one; 3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-l-(3-piperidin-l-ylmethyl- benzyl)- 1 H-pyridin-2-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]- 1 -(2,6-difluorophenyl)-6- { [(2- methoxyethyl)amino]methyl}pyridin-2(lH)-one; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N- methylbenzamide ; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{2,4-difluoro-6-[(2- hydroxyethyl)(methyl)amino]phenyl }-6-methylpyridin-2( lH)-one; 3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-l-(3-moφholin-4-ylmethyl- benzyl)- 1 Η-pyridin-2-one; 3-bromo-l-(2,6-dimethylphenyl)-6-methyl-4-[(2,4,6-trifluorobenzyl)oxy]pyridin- 2(lH)-one; 3-bromo-l-(2,6-dimethylphenyl)-6-methyl-4-[(2,4,6-trifluorobenzyl)oxy]pyridin- 2(lH)-one; l-(4-{ [Bis-(2-hydroxy-ethyl)-amino]-methyl}-benzyl)-3-bromo-4-(2,4-difluoro- benzyloxy)-6-methyl-lΗ-pyridin-2-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluoro-4-moφholin-4-ylphenyl)-6- methylpyridin-2( lH)-one; 4-Benzyloxy-3-bromo-l-(4-fluoro-benzyl)-lΗ-pyridin-2-one; 4-[3-Chloro-4-(2,4-difluoro-benzyloxy)-2-oxo-2H-pyridin-l-ylmethyl]- benzamide; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N,N,4- trimethylbenzamide; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N- isopropylbenzamide; 4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Η-pyridin-l-ylmethyl]- benz amide; 3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-l-ylmethyl]- benzonitrile; 3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-l-(3-piperazin-l-ylmethyl- benzyl)- lH-pyridin-2-one; 4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-l-ylmethyl]- N-(2-hydroxy-ethyl)-N-methyl-benzamide; methyl 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)- yl] -3 -chlorobenzoate; 3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-l-[3-(moφholine-4-carbonyl)- benzyl] - 1 Η-pyridin-2-one ; 3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-l-ylmethyl]- N,N-bis-(2-hydroxy-ethyl)-benzamide; 4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-l-ylmethyl]- benzoic acid methyl ester; 3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-l-ylmethyl]- N-hydroxy-benzamide; 3-Bromo-4-(2,4-difluoro-benzyloxy)-l-(3-hydroxymethyl-benzyl)-6-methyl-lH- pyridin-2-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(3-fluorobenzyl)pyridin-2(lH)-one; 3-Bromo-4-(2,4-difluoro-benzyloxy)-l-(3-fluoro-benzyl)-lΗ-pyridin-2-one; N- { 3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin- 1 - ylmethyl] -benzyl } -methanesulf onamide ; 3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-l-[3-(pyrrolidine-l-carbonyl)- benzyl]-lH-pyridin-2-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(pyridin-3-ylmethyl)pyridin- 2(lH)-one; N-(3-aminopropyl)-3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-1 (2H)-yl]methyl Jbenzamide hydrochloride; 3-bromo-4- [(2,4-difluorobenzyl)oxy]-6-methyl- 1 -(pyridin-3-ylmethyl)pyridin- 2(lH)-one; 3-Bromo-4-(2,4-difluoro-benzyloxy)-l-(3-methylaminomethyl-benzyl)-lΗ- pyridin-2-one; 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3,5- dichlorobenzenesulf onamide ; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[4-(dimethylamino)-2,6-difluorophenyl]- 6-methylpyridin-2( lH)-one; 3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-l-(4-piperidin-l-ylmethyl- benzyl)- 1 Η-pyridin-2-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(pyridin-4-ylmethyl)pyridin-2(lH)-one; N-(2-aminoethyl)-3 - { [3 -bromo-4- [(2,4-dif uorobenzyl)oxy] -6-mefhyl-2- oxopyridin- 1 (2H)-yl] methyl } benzamide hydrochloride ; 3 -bromo- 1 - [2-chloro-5 -(hydroxymethyl)phenyl] -4- [(2,4-difluorobenzyl)oxy] -6- methylpyridin-2( lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-6-methylpyridin- 2(lH)-one; 3-chloro- 1 - [2-chloro-5-(hydroxymethyl)phenyl]-4- [(2,4-difluorobenzyl)oxy] -6- methylpyridin-2( lH)-one; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-(2- hydroxyethyl)-4-methylbenzamide ; 2-{3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-2-oxo-2Η-pyridin-l-ylmethyl]- phenyl } -acetamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[3-(piperazin-l- ylcarbonyl)benzyl]pyridin-2( lH)-one hydrochloride; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-6-methylpyridin- 2(lH)-one; 4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-2-oxo-2Η-pyridin-l-ylmethyl]-benzoic acid methyl ester; l-(3-Aminomethyl-2-fluoro-benzyl)-3-bromo-4-(2,4-difluoro-benzyloxy)-lH- pyridin-2-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-6-(moφholin-4- ylmethyl)pyridin-2( lH)-one; 4-(benzyloxy)-3-bromo-l-(4-fluorobenzyl)pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(lH-indol-5-ylmethyl)pyridin-2(lH)-one; l-[3-(aminomethyl)benzyl]-3-bromo-4-[(4-fluorobenzyl)oxy]pyridin-2(lH)-one trifluoroacetate; l-[3-(2-aminoethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]pyridin-2(lH)- one trifluoroacetate; l-[3-(aminomethyl)benzyl]-3-bromo-4-[(4-fluorobenzyl)oxy]pyridin-2(lH)-one; 3-bromo-l-(2,6-dichlorophenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin- 2(lH)-one; , 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-(2- hydroxyethyl)benzamide ; 3-biOmo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(pyridin-4-ylmethyl)pyridin- 2(lH)-one; 3-Bromo-4-(2,4-difluoro-benzyloxy)-l-(4-methoxy-benzyl)-6-methyl-lΗ-pyridin- 2-one; 4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-l-ylmethyl]- N,N-dimethyl-benzamide; 3-bromo-6-methyl-l-(pyridin-4-ylmethyl)-4-[(2,4,6-trifluorobenzyl)oxy]pyridin- 2(lH)-one; 4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-2-oxo-2Η-pyridin-l-ylmethyl]- benzamide; 3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-l-ylmethyl]- N-methyl-benzamide; { 3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin- 1 - ylmethyl]-benzyl}-carbamic acid methyl ester; 3-bromo-4-[(2,6-difluorobenzyl)oxy]-l-(2,6-dimethylphenyl)-6-methylpyridin- 2(lH)-one; 4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Η-pyridin-l-ylmethyl]- benzonitrile; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(pyridin-4-ylmethyl)pyridin- 2(lH)-one; 1 -benzyl-4-(benzyloxy)-3-bromo-6-methylpyridin-2( lH)-one; l-Benzyl-4-benzyloxy-3-bromo-6-methyl-lΗ-pyridin-2-one; l-benzyl-4-(benzyloxy)-3-bromo-6-methylpyridin-2(lH)-one; 1 -Benzyl-3-bromo-4-(2,4-difluoro-benzyloxy)-6-methyl- 1 H-pyridin-2-one; {3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-2-oxo-2H-pyridin-l-ylmethyl]-phenyl}- acetonitrile; 3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-l-ylmethyl]- N-(2-hydroxy-ethyl)-benzamide; 3-Chloro-4-(2,4-difluoro-benzyloxy)- 1 -(3-fluoro-benzyl)- lH-pyridin-2-one; l-Allyl-3-chloro-4-(2,4-difluoro-benzyloxy)-6-methyl-lH-pyridin-2-one; 3-Chloro-4-(2,4-difluoro-benzyloxy)-l-[4-(isopropylamino-methyl)-benzyl]-lH- pyridin-2-one; methyl 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)- yl]-4-methylbenzoate; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-l-(2,4,6- trifluorophenyl)pyridin-2(lH)-one; 3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl- 1 -(4-piperazin- 1 -ylmethyl- benzyl)-lΗ-pyridin-2-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]- 1 -(2,6-difluorophenyl)-6- (hydroxymethyl)pyridin-2( 1 H)-one ; 3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Η-pyridin-l-ylmethyl]- N,N-dimethyl-benzamide; 3-bromo- 1 -(3-fluorobenzyl)-4-[(3-methylbenzyl)oxy]pyridin-2( lH)-one; 3-Bromo- 1 -(3-fluoro-benzyl)-4-(3-methyl-benzyloxy)- lΗ-pyridin-2-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(l,2,3,4-tetrahydroisoquinolin-5- ylmethyl)pyridin-2(lH)-one; 3-bromo-l-(3-fluorobenzyl)-4-[(3-methylbenzyl)oxy]pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(isoquinolin-5-ylmethyl)pyridin-2(lH)- one trifluoroacetate; 3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Η-pyridin-l-ylmethyl]- benzamide; ' 3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl- 1 -( { 5- [(4-methylpiperazin- 1 - yl)carbonyl]pyrazin-2-yl}methyl)pyridin-2(lH)-one trifluoroacetate; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[5-(hydroxymethyl)-2-methylphenyl]-6- methylpyridin-2(lH)-one; l-allyl-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one; 3 -bromo-4- [(2,4-difluorobenzyl)oxy] - 1 -(pyridin-3 -ylmethyl)pyridin-2( lH)-one ; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2-methoxy-6-methylphenyl)-6- methylpyridin-2( lH)-one ; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2-methoxy-6-methylphenyl)-6- methylpyridin-2( lH)-one; 3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-2-oxo-2Η-pyridin-l-ylmethyl]- benzamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-l-(2,4,6- trifluorophenyl)pyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[2- (trifluoromethyl)phenyl]pyridin-2(lH)-one; 4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Η-pyridin-l-ylmethyl]- benzoic acid; 3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-l-(4-moφholin-4-ylmethyl- benzyl)- lH-pyridin-2-one; 4-(2,4-Difluoro-benzyloxy)- 1 -(3-fluoro-benzyl)-3-iodo- lH-pyridin-2-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(2,4,6-trifluorophenyl)pyridin- 2(lH)-one; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N- hydroxybenzamide; 3-bromo-l-(2,6-dichlorophenyl)-4-[(2,6-difluorobenzyl)oxy]-6-methylpyridin- 2(lH)-one; 3-(4-Benzyloxy-3-bromo-2-oxo-2H-pyridin-l-ylmethyl)-benzonitrile; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[3-(pyrrolidin-l- ylcarbonyl)phenyl]pyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2-fluorobenzyl)pyridin-2(lH)-one; 4-(benzyloxy)-3-bromo- 1 -(4-methylbenzyl)pyridin-2( lH)-one; 3-{[3-chloro-4-[(2,4-difluorobenzyl)amino]-6-methyl-2-oxopyridin-l(2H)- yljmethyl Jbenzonitrile; 3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Η-pyridin-l-ylmethyl]- N-isopropyl-benzamide; 3-bromo-l-(4-bromo-2,6-difluorophenyl)-4-[(2,4-difluorobenzyl)oxy]-6- methylpyridin-2(lH)-one; 3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl- 1 -(pyridin-3-ylmethyl)pyridin-2( 1H)- one; 3-bromo-4-[(4-fluorobenzyl)oxy]-6-methyl-l-(pyridin-4-ylmethyl)pyridin-2(lH)- one; 3 -bromo-4- [(4-fluorobenzyl)oxy]-6-methyl- 1 -(pyridin-4-ylmethyl)pyridin-2( 1H)- one; 4-(benzyloxy)-3-bromo-l-(4-chlorobenzyl)pyridin-2(lH)-one; 4-Benzyloxy-3-bromo-l-(4-chloro-benzyl)-lΗ-pyridin-2-one; 3-bromo- 1 -(4-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2( lH)-one; 3-bromo-l-(2,6-dichlorophenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2(lH)- one; 3-Bromo-l-(4-fluoro-benzyl)-4-(4-fluoro-benzyloxy)-lΗ-pyridin-2-one; methyl 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)- yljbenzoate; 4-(4-Benzyloxy-3-bromo-2-oxo-2Η-pyridin-l-ylmethyl)-benzoic acid; 4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-yl]methyl}benzoic acid; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(2,4,6-trifluorophenyl)pyridin- 2(lH)-one; 4-(benzyloxy)-3-bromo- 1 -(2-fluorobenzyl)pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-6- (hydroxymethyl)pyridin-2(lH)-one; iV-(2-aminoethyl)-4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]benzamide hydrochloride; 4-Benzyloxy-3-bromo-l-(4-methylsulfanyl-benzyl)-lΗ-pyridin-2-one; 1 -Benzyl-4-benzyloxy-3-chloro- lH-pyridin-2-one; 4-(benzyloxy)-3-bromo-l-[4-(methylthio)benzyl]pyridin-2(lH)-one; 1 -benzyl-4-(benzyloxy)-3-chloropyridin-2( lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{[5-(hydroxymethyl)pyrazin-2- yljmefhyl } -6-methylpyridin-2( lH)-one; 3-bromo-l-(2,6-dimethylphenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2(lH)- one; 3-bromo- 1 -(2,6-dimethylphenyl)-4-[(4-fluorobenzyl)oxy]-6-methylpyridin-2( 1H)- one; 3-Bromo-4-(2,4-difluoro-benzyloxy)-l-[3-(isopropylamino-methyl)-benzyl]-lΗ- pyridin-2-one; 3-[3-Chloro-4-(2,4-difluoro-benzyloxy)-2-oxo-2H-pyridin-l-ylmethyl]-2-fluoro- benzamide; 5- { [3-bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)- yl]methyl}-N-(2,3-dihydroxypropyl)pyrazine-2-carboxamide; {3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-2-oxo-2Η-pyridin-l-ylmethyl]-phenyl}- acetic acid ethyl ester; 4-(4-Benzyloxy-3-bromo-2-oxo-2H-pyridin-l-ylmethyl)-N-hydroxy- benzamidine; 4- { [4-(benzyloxy)-3 -bromo-2-oxopyridin- 1 (2H)-yl]methyl } -Ϊ - hydroxybenzenecarboximidamide ; ethyl 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]mefhyl}pyrazine-2-carboxylate; 3-Bromo-4-(2,4-difluoro-benzyloxy)-l-(3-methoxy-benzyl)-lH-pyridin-2-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[(5-methylpyrazin-2- yl)methyl]pyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(3-methoxybenzyl)pyridin-2(lH)-one; 4-(4-Benzyloxy-3-bromo-2-oxo-2Η-pyridin- l-ylmethyl)-benzoic acid methyl ester; 3-Bromo-4-(2,4-difluoro-benzyloxy)- 1 -(4-dimethylaminomethyl-benzyl)- 1 H- pyridin-2-one; 3-Chloro-4-(2,4-difluoro-benzyloxy)- 1 -(3-methanesulfonyl-benzyl)- lH-pyridin- 2-one; 4-(4-Benzyloxy-3-bromo-2-oxo-2H-pyridin- l-ylmethyl)-benzoic acid methyl ester; methyl 4- { [4-(benzyloxy)-3-bromo-2-oxopyridin- 1 (2H)-yl]methyl jbenzoate; ethyl 5- { [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)- yl]methyl}pyrazine-2-carboxylate; 4- { [4-(benzyloxy)-3-bromo-2-oxopyridin- 1 (2H)-yl]methyl Jbenzonitrile; 4-(4-Benzyloxy-3-bromo-2-oxo-2Η-pyridin-l-ylmethyl)-benzonitrile; {3-[3-Bromo-4-(4-fluoro-benzyloxy)-2-oxo-2H-pyridin-l-ylmethyl]-benzyl}- carbamic acid tert-butylester; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[5-(l-hydroxy-l-methylethyl)-2- methylphenyl]-6-methylpyridin-2(lH)-one; 4-(benzyloxy)-3-bromo-l-(2,6-dichlorophenyl)-6-methylpyridin-2(lH)-one; l-(3-Aminomethyl-benzyl)-4-benzyloxy-3-bromo-lΗ-pyridin-2-one; 3-bromo-4- [(4-fluorobenzyl)oxy] - 1 -(pyridin-4-ylmethyl)pyridin-2( lH)-one; 4-(benzyloxy)-3-bromo-l-(4-bromobenzyl)pyridin-2(lH)-one; 4-Benzyloxy-3-bromo-l-(4-bromo-benzyl)-lΗ-pyridin-2-one; 5-bromo-4-[(2,4-difluorobenzyl)oxy]- 1 -(2,6-difluorophenyl)-6-oxo- 1 ,6- dihydropyridine-2-carbaldehyde; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 - { [5-(hydroxymethyl)pyrazin-2- yl]methyl}-6-methylpyridin-2(lH)-one; 4-(4-Benzyloxy-3-bromo-2-oxo-2Η-pyridin-l-ylmethyl)-benzamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[3-(piperazin-l- ylcarbonyl)phenyl]pyridin-2( lH)-one hydrochloride; 3-bromo-4-[(2,4-difluorobenzyl)amino]-l-(3-fluorobenzyl)pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[(5-methylpyrazin-2- yl)methyl]pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[5-(hydroxymethyl)-2-methylphenyl]-6- methylpyridin-2( lH)-one; 3-bromo-l-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(lH)-one; 3-Bromo-l-(3-fluoiO-benzyl)-4-(4-fluoro-benzyloxy)-lΗ-pyridin-2-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl- 1 -[3-(moφholin-4- ylcarbonyl)phenyl]pyridin-2(lH)-one; 3-(4-Benzyloxy-3-bromo-2-oxo-2Η-pyridin-l-ylmethyl)-benzoic acid methyl ester; 3-bromo-l-(3-fluorobenzyl)-4-{[2-(hydroxymethyl)benzyl]oxy}pyridin-2(lH)- one; 3-Bromo-l-(3-fluoro-benzyl)-4-(2-hydroxymethyl-benzyloxy)-lΗ-pyridin-2-one; 1 -Benzo [ 1 ,3] dioxol-5-ylmethyl-3-bromo-4-(2,4-difluoro-benzyloxy)- 1 H-pyridin- 2-one; 3-bromo-4-[(2,6-difluorobenzyl)oxy]-6-methyl-l-(pyridin-4-ylmethyl)pyridin- 2(lH)-one; 3-bromo-4-[(3-chlorobenzyl)oxy]-l-(3-fluorobenzyl)pyridin-2(lH)-one; 3-bromo-4-[(3-chlorobenzyl)oxy]-l-(3-fluorobenzyl)pyridin-2(lH)-one; 3-Bromo-4-(3-chloro-benzyloxy)-l-(3-fluoro-benzyl)-lΗ-pyridin-2-one; 4-(benzyloxy)-3-bromo-l-(3-fluorobenzyl)pyridin-2(lH)-one; 4-Benzyloxy-3-bromo-l-(3-fluoro-benzyl)-lΗ-pyridin-2-one; 3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-l-[3-(piperidine-l-carbonyl)- benzyl]-lH-pyridin-2-one; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N,N- dimethylbenzamide; 3-[3-Chloro-4-(2,4-difluoro-benzyloxy)-2-oxo-2H-pyridin-l-ylmethyl]-2-fluoro- benzoic acid methyl ester; l-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]-3-iodopyridin-2(lH)-one; l-(3-Fluoro-benzyl)-4-(4-fluoro-benzyloxy)-3-iodo-lH-pyridin-2-one; N-(3-aminopropyl)-4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]benzamide hydrochloride; 4- { [3 -bromo-4- [(4-fluorobenzyl)oxy] -2-oxopyridin- 1 (2H)- yljmethyl Jbenzonitrile; 4-[3-Bromo-4-(4-fluoro-benzyloxy)-2-oxo-2Η-pyridin-l-ylmethyl]-benzonitrile; 3-Bromo-l-(3-fiuoro-benzyl)-4-(2,3,4-trifluoro-benzyloxy)-lH-pyridin-2-one; l-benzyl-4-(benzyloxy)-3-bromopyridin-2(lH)-one; 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}-N-(2-hydroxyethyl)-7Y-methylpyrazine-2-carboxamide; 4-(4-Benzyloxy-3-bromo-2-oxo-2Η-pyridin-l-ylmethyl)-benzonitrile; 3-bromo- 1 -(2,4-difluorobenzyl)-4-[(2,4-difluorobenzyl)oxy]pyridin-2( lH)-one; 3-Bromo-l-(2,4-difluoro-benzyl)-4-(2,4-difluoro-benzyloxy)-lΗ-pyridin-2-one; 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-(2- hydroxyethyl)benzamide ; 3-bromo-4-[(4-fluorobenzyl)oxy]-l-(pyridin-3-ylmethyl)pyridin-2(lH)-one; l-Benzyl-4-benzyloxy-3-bromo-lΗ-pyridin-2-one; 3-bromo-l-(cyclopropylmethyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin- 2(lH)-one; l-(4-Aminomethyl-benzyl)-4-benzyloxy-3-bromo-lΗ-pyridin-2-one; 3-bromo-l-(4-fluorobenzyl)-4-[(4-fluorobenzyl)amino]-6-methylpyridin-2(lH)- one; 3-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-l-ylmethyl]- benzoic acid methyl ester; 5- { [3-bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)- yljmethyl } -N,N-dimefhylpyrazine-2-carboxamide; 3-bromo-4-[(4-fluorobenzyl)oxy3-6-methyl-l-(pyridin-2-ylmethyl)pyridin-2(lH)- one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-dimethylphenyl)-6-methylpyridin- 2(lH)-one; 3-bromo-l-(2,6-dichlorophenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin- 2(lH)-one; 4-(benzyloxy)-l-(4-bromobenzyl)pyridin-2(lH)-one; 3-bromo-4-hydroxy-l-(4-hydroxybenzyl)pyridin-2(lH)-one; 4-(benzyloxy)-3-bromo-l-[2-(trifluoromethyl)benzyl]pyridin-2(lH)-one; l-benzyl-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(lH)-one; 4-(benzyloxy)-3-bromo- 1 -(piperidin-3-ylmethyl)pyridin-2( lH)-one hydrochloride; l-benzyl-3-bromo-2-oxo-l,2-dihydropyridin-4-yl methyl(phenyl)carbamate; 4-(benzylamino)-l-(3-fluorobenzyl)-6-methyl-3-nitropyridin-2(lH)-one; tert-butyl 4-[3-bromo- l-(3-fluorobenzyl)-2-oxo- 1 ,2-dihydropyridin-4- yljpiperazine- 1 -carboxylate; ethyl [4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-yl]acetate; N-[3-bromo-l-(3-fluorobenzyl)-2-oxo-l,2-dihydropyridin-4- yljbenzenesulfonamide; 3 -bromo-4- [(4-te/ -butylbenzyl)oxy]- 1 -(3-fluorobenzyl)pyridin-2( lH)-one; N-[3 -bromo- 1 -(3 -fluorobenzyl)-2-oxo- 1 ,2-dihydropyridin-4-yl] - 1 - phenylmethanesulfonamide; l-(biphenyl-2-ylmethyl)-3-bromo-4-[(4-fluorobenzyl)oxy]pyridin-2(lH)-one; 4-(biphenyl-2-ylmethoxy)-3-bromo- 1 -(3-fluorobenzyl)pyridin-2( l /)-one; 3-bromo-4-[(2,4rdifluorophenyl)amino]-l-(3-fluorobenzyl)pyridin-2(lH)-one; 4-anilino-3-bromo- 1 -(3-fluorobenzyl)pyridin-2( lH)-one; methyl 4-{[3-bromo-l-(3-fluorobenzyl)-2-oxo-l,2-dihydropyridin-4- yljamino Jbenzoate; 3-bromo- 1 -(3 -fluorobenzyl)-4- [(3 ,4,5-trimethoxyphenyl)amino]pyridin-2( 1H)- one; 3-bromo-l-(3-fluorobenzyl)-4-[4-(4-fluorophenyl)piperazin-l-yl]pyridin-2(lH)- one; 3-bromo-l-(3-fluorobenzyl)-4-(4-methylpiperazin-l-yl)pyridin-2(lH)-one trifluoroacetate; N-[3-bromo-l-(3-fluorobenzyl)-2-oxo-l,2-dihydropyridin-4-yl]-2,5- difluorobenzamide; N-[3-bromo- 1 -(3-fluorobenzyl)-2-oxo- 1 ,2-dihydroρyridin-4-yl]-2,4- difluorobenzamide; 3-bromo- 1 -(cyclohexylmethyl)-4- [(4-fluorobenzyl)oxy]pyridin-2( lH)-one; 3-[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-yl]propanoic acid; N-[3-bromo- l-(3-fluorobenzyl)-2-oxo- 1 ,2-dihydropyridin-4-yl]-N-(2,4- difluorophenyl)urea; 3-[4-(benzyloxy)-3-bromo-2-oxopyridin- 1 (2H)-yl]propanamide; 4-(benzyloxy)-3-bromo-l-(3-moφholin-4-yl-3-oxopropyl)pyridin-2(lH)-one; N-(3-aminopropyl)-3-[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)- yljpropanamide hydrochloride; 4-(benzyloxy)-3-bromo- 1 -(3-oxo-3-piperazin- 1 -ylpropyl)pyridin-2( lH)-one hydrochloride; 4-(benzyloxy)-3-bromo-l-(2-moφholin-4-ylethyl)pyridin-2(lH)-one; 3-bromo-l-(3-fluorobenzyl)-4-{[4-fluoro-2- (trifluoromethyl)benzyl]amino}pyridin-2(lH)-one; N-(2-aminoethyl)-3-[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-yl]propanamide hydrochloride; [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]acetic acid; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(tetrahydrofuran-2- ylmethyl)pyridin-2( lH)-one; 4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(tetrahydrofuran-2-ylmethyl)pyridin- 2(lH)-one; methyl 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridine-l(2H)- carboxylate; l-allyl-3-(2,4-difluorobenzyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin- 2(lH)-one; 4-(benzyloxy)-l-(2,2-diethoxyethyl)pyridin-2(lH)-one; methyl N-acetyl-3-[4-(benzyloxy)-2-oxopyridin-l(2H)-yl]alaninate; benzyl N-acetyl-3-[4-(benzyloxy)-2-oxopyridin-l(2H)-yl]alaninate; benzyl N-[(benzyloxy)carbonyl]-3-[4-(benzyloxy)-2-oxopyridin-l(2H)- yljalaninate; 4-(benzyloxy)-l-(2-oxopropyl)pyridin-2(lH)-one; 5-{[4-(benzyloxy)-2-oxopyridin-l(2H)-yl]methyl}-5-methylimidazolidine-2,4- dione; ethyl [4-(benzyloxy)-2-oxopyridin-l(2H)-yl]acetate; 2-[4-(benzyloxy)-2-oxopyridin-l(2H)-yl]acetamide; l-benzyl-4-(benzyloxy)-3,5-dibromopyridin-2(lH)-one; 4-(benzyloxy)- 1 -ethylpyridin-2( lH)-one; 4-(benzyloxy)- 1 -(4-tert-butylbenzyl)pyridin-2( lH)-one; 4-{ [4-(benzyloxy)-2-oxopyridin-l(2H)-yl]methyl}benzonitrile; tert-butyl 3- { [4-(benzyloxy)-2-oxopyridin- 1 (2H)-yl]methyl } piperidine- 1 - carboxylate; 1 ,3-dibenzyl-4-hydroxy-6-methylpyridin-2( lH)-one; 1 -benzyl-6-methyl-2-oxo- 1 ,2-dihydropyridin-4-yl methanesulfonate; 4-(benzyloxy)-l-(4-bromobenzyl)pyridin-2(lH)-one; 4-(benzyloxy)-3-bromopyridin-2(lH)-one; 4-(benzyloxy)-3-bromo-l-[2-(trifluoromethyl)benzyl]pyridin-2(lH)-one; 1 -benzyl-4-( 1 -naphthylmethoxy)pyridin-2( lH)-one; l-benzyl-4-(benzylthio)-3,5-dibromopyridin-2(lH)-one; 1 -benzyl-4-[(2,6-dichlorobenzyl)oxy]pyridin-2( lH)-one; l-benzyl-3-[(benzylamino)methyl]-4-(benzyloxy)pyridin-2(lH)-one; l-benzyl-4-(benzyloxy)-3-{[(2-cyclohexylethyl)amino]methyl}pyridin-2(lH)- one; 1 -benzyl-4-(benzylthio)-5-methylpyridin-2( lH)-one; 1 -benzyl-3-bromo-6-methyl-2-oxo- 1 ,2-dihydropyridin-4-yl methanesulfonate; l-benzyl-3-bromo-6-methyl-4-{[2-(trifluoromethyl)benzyl]oxy}pyridin-2(lH)- one; l-benzyl-6-methyl-2-oxo-l,2-dihydropyridin-4-yl 4-bromobenzenesulfonate; l-benzyl-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(lH)-one; 1 -benzyl-3-bromo-6-methyl-2-oxo- 1 ,2-dihydropyridin-4-yl 4- bromobenzenesulfonate; 4-phenoxy- 1 - { [2-(trimethylsilyl)ethoxy]methyl } pyridin-2( lH)-one; l-benzyl-4-phenoxypyridin-2(lH)-one; 1 -(4-methoxybenzyl)-4-phenoxypyridin-2( lH)-one; 3-bromo-4-hydroxy-l-(4-hydroxybenzyl)pyridin-2(lH)-one hydrochloride; 4-(benzyloxy)-3-bromo-l-(piperidin-3-ylmethyl)pyridin-2(lH)-one; l-benzyl-4-[(2,6-dichlorobenzyl)oxy]pyridin-2(lH)-one; l-benzyl-4-(benzyloxy)-3,5-dibromopyridin-2(lH)-one; 3-bromo-l-(3-fluorobenzyl)-4-[(E)-2-(4-fluorophenyl)vinyl]pyridin-2(lH)-one; l-benzyl-4-(benzyloxy)-2-oxo-l,2-dihydropyridine-3-carbaldehyde; 1 -benzyl-4-(benzyloxy)pyridin-2( lH)-one; l-benzyl-4-(benzyloxy)pyridin-2(lH)-one; 1 -benzyl-4-(benzylthio)pyridin-2( lH)-one; methyl 4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]benzoate; benzyl (5-nitro-2,6-dioxo-3,6-dihydropyrimidin- 1 (2H)-yl)acetate; ethyl 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxo-2H-l,2'-bipyridine-5'- carboxylate; 4-(benzyloxy)- l-(4-methylbenzyl)pyridin-2( lH)-one; [5-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-2-methyl-6-oxo- 1 ,6-dihydropyridin-3-yl]methyl carbamate; 4-(benzyloxy)- 1 -(4-chlorobenzyl)pyridin-2( lH)-one; methyl (2E)-4-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl]but- 2-enoate; 4-(benzyloxy)-l-(2-fluorobenzyl)pyridin-2(lH)-one; tert-butyl 4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-yl]methyl}piperidine- 1-carboxylate; 4-(benzyloxy)-l-(3-fluorobenzyl)pyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-5-(l,2- dihydroxyethyl)-6-methylpyridin-2(lH)-one; l-benzyl-4-hydroxy-6-methylpyridin-2(lH)-one; 4-( { [3-bromo- 1 -(3-fluorobenzyl)-2-oxo- 1 ,2-dihydropyridin-4- yl]oxy}methyl)benzonitrile; 1 -benzyl-4-(benzyloxy)-6-methylpyridin-2( lH)-one; 5-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-2-methyl-6-oxo-l,6- dihydropyridine-3-carbaldehyde oxime; l-benzyl-4-(benzylthio)-3-methylpyridin-2(lH)-one; l-benzyl-4-[(4-methylbenzyl)oxy]pyridin-2(lH)-one; l-benzyl-4-(benzyloxy)-3,5-dibromo-6-methylpyridin-2(lH)-one; l-benzyl-4-(benzyloxy)-3,5-dibromo-6-methylpyridin-2(lH)-one; 3-bromo- 1 -(3-fluorobenzyl)-4-( 1 -phenylethoxy)pyridin-2( lH)-one; 4-(benzyloxy)-l-[4-(trifluoromethyl)benzyl]pyridin-2(lH)-one; 2-( { [3-bromo-2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridin-4- yl]oxy}methyl)-5-fluorobenzonitrile; 5-bromo-4-[(2,4-difluorobenzyl)oxy]- 1 -(2,6-difluorophenyl)-2-methyl-6-oxo- 1 ,6- dihydropyridine-3-carbonitrile; 4-(benzyloxy)-l-(3-fluorobenzyl)-3-(trifluoromethyl)pyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-6-methyl-5-oxiran- 2-ylpyridin-2( lH)-one; l-benzyl-4-[(3-chlorobenzyl)oxy]pyridin-2(lH)-one; l-benzyl-4-[(3-chlorobenzyl)oxy]pyridin-2(lH)-one; 5-bromo-4-[(2,4-difluorobenzyl)oxy]-l -(2,6-difluorophenyl)-2-methyl-6-oxo- 1 ,6- dihydropyridine-3-carbaldehyde; terf-butyl 3-{ [4-(benzyloxy)-3-bromo-2-oxopyridin- 1 (2H)-yl]methyl Jpiperidine- 1-carboxylate; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-6-methyl-5- vinylpyridin-2(lH)-one; ' 4-(benzyloxy)-l-[4-(trifluoromethoxy)benzyl]pyridin-2(lH)-one; 3-bromo-4-[(4-chlorobenzyl)oxy]-l-[2-(phenylthio)ethyl]pyridin-2(lH)-one; 3-Bromo-4-(4-chloro-benzyloxy)- 1 -(2-phenylsulf anyl-ethyl)- lΗ-pyridin-2-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(2-moφholin-4-ylethyl)ρyridin- 2(lH)-one; 4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-l-(pyridin-3-ylmethyl)pyridin- 2(lH)-one; 4-{[2-(Aminomethyl)-4-fluorobenzyl]oxy}-3-bromo-l-(2,6-difluorophenyl)-6- methylpyridin-2( lH)-one trifluoroacetate; 4-(benzyloxy)-l-(4-fluorobenzyl)pyridin-2(lH)-one; 4-(benzyloxy)-l-(4-fluorobenzyl)pyridin-2(lH)-one; 4-Benzyloxy-3 -bromo- 1 -methanesulf onyl- 1 Η-pyridin-2-one; tert-butyl 4-[4-(benzyloxy)-3-bromo-2-oxopyridin- 1 (2H)-yl]piperidine- 1 - carboxylate; l-benzyl-4-(benzyloxy)-3-vinylpyridin-2(lH)-one; 4-(benzyloxy)- 1 -[4-(methylthio)benzyl]pyridin-2( lH)-one; 3-Bromo-4-(2,4-difluoro-benzyloxy)-l-(2-methyl-4-methylamino-pyrimidin-5- ylmethyl)- lΗ-pyridin-2-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one; 1 -benzyl-3-bromo-4- { [2-(trifluoromethyl)benzyl] oxy } pyridin-2( lH)-one; 1 -benzyl-3 -bromo-4- { [2-(trifluoromethyl)benzyl] oxy } pyridin-2( lH)-one; 4-[(2,4-difluorobenzyl)oxy]-l-[5-(hydroxymethyl)-2-methylphenyl]-6- methylpyridin-2(lH)-one; 4-(benzyloxy)-l-[4-(methylsulfonyl)benzyl]pyridin-2(lH)-one; 4-Phenoxy- 1 Η-pyridin-2-one; 1 -benzyl-4-[(2-chlorobenzyl)oxy]pyridin-2( lH)-one; 1 -benzyl-4-[(2-chlorobenzyl)oxy]pyridin-2( lH)-one; methyl 4-{ [4-(benzyloxy)-2-oxopyridin- 1 (2H)-yl]methyl Jbenzoate; 4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-6-methylpyridin-2(lH)-one; l-(3-fluorobenzyl)-4-(phenylethynyl)pyridin-2(lH)-one; 4-(benzyloxy)-3-bromo-l-(piperidin-4-ylmethyl)pyridin-2(lH)-one hydrochloride; 4-(benzyloxy)-3-bromo-l-(piperidin-4-ylmethyl)pyridin-2(lH)-one hydrochloride; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[2-(methylthio)pyrimidin-4- yl]pyridin-2( lH)-one; 4-(benzyloxy)-3-bromo- l-piperidin-4-ylpyridin-2( lH)-one hydrochloride; 4-B enzyloxy- 1 -difluoromethyl- 1 Η-pyridin-2-one ; 4-Benzyloxy-3-bromo-l-(2-chloro-phenyl)-6-methyl-lH-pyridin-2-one; 3-Bromo-6-methyl-l-pyridin-3-ylmethyl-4-[(pyridin-3-ylmethyl)-amino]-lH- pyridin-2-one; l-(3,4-Dichloro-benzyl)-6-oxo-l ,6-dihydro-pyridine-3-carboxylic acid (2,4- difluoro-phenyl)-amide; l-(2,6-Dichloro-benzyl)-6-oxo-l,6-dihydro-pyridine-3-carboxylic acid (2,4- difluoro-phenyl)-amide; 5-Chloro-l-(2,6-dichloro-benzyl)-6-oxo-l,6-dihydro-pyridine-3-carboxylic acid (2,4-difluoro-phenyl)-amide; 5-Chloro- l-(2,6-dichloro-benzyl)-6-oxo- 1 ,6-dihydro-pyridine-3-carboxylic acid methyl-phenyl-amide; l-(2,6-Dichloro-benzyl)-6-oxo-l,6-dihydro-pyridine-3-carboxylic acid benzylamide; l-(2,6-Dichloro-benzyl)-6-oxo-l,6-dihydro-pyridine-3-carboxylic acid (3- dimethylamino-propyl)-amide; l-(2,6-Dichloro-benzyl)-6-oxo- 1 ,6-dihydro-pyridine-3-carboxylic acid (2- moφholin-4-yl-ethyl)-amide; N-[5-Acetyl-l-(4-chloro-benzyl)-6-methyl-2-oxo-l,2-dihydro-pyridin-3-yl]-4- chloro-benzamide; l-(2,6-Dichloro-benzyl)-6-oxo-l,6 dihydro-pyridine-3-carboxylic acid N'-(3- chloro-5-trifluoromethyl-pyridin-2-yl)-hydrazide; Λ-allyl-2-[(l-benzyl-6-oxo-l,6-dihydropyridin-3- yl)carbonyl]hydrazinecarbothioamide; 1 -B enzyl-5- [5-(3 ,4-dichloro-benzylsulf anyl)- [ 1 ,3 ,4] oxadiazol-2-yl] - 1 H-pyridin-2- one; TV- { [( 1 -benzyl-6-oxo- 1 ,6-dihydropyridin-3-yl)carbonyl]oxy }pyridine-4- carboximidamide; l-(2,6-Dichloro-benzyl)-6-oxo-l,6-dihydro-pyridine-3-carboxylic acid 3- trifluoromethyl-benzylamide; 1 -Benzyl-6-oxo- 1 ,6-dihydro-pyridine-3-carboxylic acid (2-moφholin-4-yl-ethyl)- amide; 5-[4-(3-Chloro-phenyl)-piperazine-l-carbonyl]-l-(3,4-dichloro-benzyl)-lH- pyridin-2-one; 5-Chloro-l-(2,6-dichloro-benzyl)-6-oxo-l,6-dihydro-pyridine-3-carboxylic acid benzylamide; l-(4-Chloro-benzyl)-5-[3-(4-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-lH-pyridin-2- one; l-(4-Chloro-benzyl)-5-[3-(4-chloro-phenyl)-[l,2,4]oxadiazol-5-yl]-lH-pyridin-2- one; 2-Chloro-N-[l-(2,6-dichloro-benzyl)-6-oxo-5-trifluoromethyl-l,6-dihydro- pyridin-3-yl]-4-fluoro-benzamide; N-[l-(2,6-Dichloro-benzyl)-6-oxo-5-trifluoromethyl-l,6-dihydro-pyridin-3-yl]-4- isopropoxy-benzamidE; 1 -(2,6-Dichloro-benzyl)-6-oxo- 1 ,6-dihydro-pyridine-3-carboxylic acid (4- trifluoromethoxy-phenyl)-amide; l-(2,6-Dichloro-benzyl)-6-oxo-l,6-dihydro-pyridine-3-carboxylic acid (3- trifluoromethyl-phenyl)-amide ; 5-Chloro-l-(2,6-dichloro-benzyl)-6-oxo-l,6-dihydro-pyridine-3-carboxylic acid (3-trifluoromethyl-phenyl)-amide; 1 -(2,6-Dichloro-benzyl)-6-oxo- 1 ,6-dihydro-pyridine-3-carboxylic acid (4-chloro- phenyl)-amide; 1 -(2,6-Dichloro-benzyl)-6-oxo- 1 ,6-dihydro-pyridine-3-carboxylic acid (2- dimethylamino-ethyl)-amide; 5-Methyl- 1 -phenyl- 1 H-pyridin-2-one; 3-Bromo-l-(3-fluoro-benzyl)-4-(3-methoxy-phenyl)-lH-pyridin-2-one; 3-Bromo-l-(3-fluoro-benzyl)-4-(3-isopropyl-phenyl)-lH-pyridin-2-one; 3'-Bromo- 1 '-(3-fluoro-benzyl)-6-methoxy- 1 'H-[3,4'jbipyridinyl-2'-one; 4-Benzo[l,3]dioxol-5-yl-3-bromo-l-(3-fluoro-benzyl)-lH-pyridin-2-one; 3-Bromo-l-(3-fluoro-benzyl)-4-thiophen-3-yl-lH-pyridin-2-one; 3-Bromo- 1 -(3-fluoro-benzyl)-4-(3-trifluoromethyl-phenyl)- lH-pyridin-2-one; 3-Bromo-l-(3-fluoro-benzyl)-4-naphthalen-2-yl-lH-pyridin-2-one; 3-Bromo-l-(3-fluoro-benzyl)-4-(4-fluoro-phenyl)-lH-pyridin-2-one; l-Benzenesulfonyl-4-benzyloxy-3-bromo-lH-pyridin-2-one; 4-[3-Amino-l-(2,4-difluoro-phenyl)-propoxy]-3-bromo-6-methyl-l-pyridin-3- ylmethyl- lH-pyridin-2-one; 1 -(4-Bromo-2,6-difluoro-phenyl)-4-(2,4-difluoro-benzyloxy)-6-methyl- 1 H- pyridin-2-one; 2- [ 1 -(4- Amino-2-methyl-pyrimidin-5-ylmethyl)-3 -bromo-6-methyl-2-oxo- 1 ,2- dihydro-pyridin-4-yloxymethyl]-5-fluoro-benzonitrile; 4-(2,4-Difluoro-benzyloxy)-6-methyl- 1 -(2,4,6-trifluoro-phenyl)- 1 H-pyridin-2- one; 1 -(2-Chloro-4-hydroxy-phenyl)-4-(2,4-difluoro-benzyloxy)-6-methyl- 1 H-pyridin- 2-one; 3-[4-(2,4-Difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-l-yl]-benzoic acid methyl ester; 3-Bromo- 1 -(2,6-difluoro-phenyl)-4-methoxy-6-methyl-5-vinyl- 1 H-pyridin-2-one; 3-Bromo-l-(2,6-difluoro-phenyl)-4-methoxy-6-methyl-5-styryl-lH-pyridin-2- one; l-(2,6-Difluoro-phenyl)-4-methoxy-6-methyl-5-phenethyl-lH-pyridin-2-one; 3-Bromo- 1 -(2,6-difluoro-phenyl)-4-methoxy-6-methyl-5-phenethyl- 1 H-pyridin- 2-one; 1 -( lH-indazol-5-yl)-4-( lH-indazol-5-ylamino)-6-methylpyridin-2( lH)-one; 5-Bromo-4-(2,4-difluoro-benzyloxy)-l-(2,6-difluoro-phenyl)-2-[2-(2,4-difluoro- phenyl)-ethyl]-6-oxo-l,6-dihydro-pyridine-3-carbaldehyde; 4-[3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Η-pyridin-l-yl]- pyrimidine-2-carbonitrile; 3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-[l,2']bipyridinyl-5'- carboxylic acid; 3-Bromo-4-(5-carboxy-pyridin-2-yloxy)-6-methyl-2-oxo-2H-[l,2']bipyridinyl-5'- carboxylic acid; 3-Bromo-4-(2,4-difluoro-benzyloxy)-6,6'-dimethyl-2-oxo-2H-[l,2']bipyridinyl-3'- carbonitrile; 3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-[l,2']bipyridinyl-5'- carboxylic acid methylamide; 3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-[l,2']bipyridinyl-5'- carboxylic acid (2-hydroxy-ethyl)-amide; 3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-[l,2']bipyridinyl-5'- carboxylic acid (2-methoxy-ethyl)-amide; 3-Bromo-l-(2,6-difluoro-phenyl)-4-methoxy-6-methyl-5-(4-methyl-benzyl)-lH- pyridin-2-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-5-(l,2-dihydroxy-2- phenylethyl)-6-methylpyridin-2( 1 H)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-5'-(l-hydroxy-l-methylethyl)-6-methyl-2H- 1 ,2'-bipyridin-2-one; 4-Benzyloxy- lH-pyridin-2-one; 4-Benzyloxy-3-methyl-lH-pyridin-2-one; 2-Oxo-6-phenethyl- 1 ,2-dihydro-pyridine-3-carbonitrile; 2-Oxo-6-phenyl- 1 ,2-dihydro-pyridine-3-carbonitrile; 6-Oxo-l,6-dihydro-[2,3']bipyridinyl-5-carbonitrile; 6-Oxo-l,6-dihydro-[2,3']bipyridinyl-5-carboxylic acid; 3-{[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-yl]methyl}benzamide; 3-bromo-4-[(4-fluorobenzyl)oxy]-l-(4-methoxybenzyl)pyridin-2(lH)-one; 3-bromo-4-[(4-fluorobenzyl)oxy]-l-(4-methoxybenzyl)pyridin-2(lH)-one; 3 -bromo-4- [(2,4-difluorobenzyl)oxy] - 1 - [2-fluoro-5-(hydroxymethyl)phenyl] -6- methylpyridin-2( lH)-one; 3-chloro-l-(4-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(lH)-one; 3-chloro-l-(4-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(lH)-one; '3-bromo-l-(3-chlorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(lH)-one; 3 -bromo-4- [(3 ,4-difluorobenzyl)oxy] - 1 -(3 -fluorobenzyl)pyridin-2( 1 H)-one ; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylbenzoic acid; 3-bromo- 1 -(3-chlorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2( lH)-one; 3-bromo- 1 -(3-chlorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2( lH)-one; 4-{[3-chloro-4-[(2,4-difluorobenzyl)amino]-6-methyl-2-oxopyridin-l(2H)- yljmefhyl Jbenzonitrile trifluoroacetate; 3-bromo-4-[(2,4-difluorobenzyl)oxy]- 1 - { [5-( 1 -hydroxy- 1 -mefhylefhyl)pyrazin-2- yl]methyl}-6-methylpyridin-2(lH)-one; 4-(benzylamino)-3-bromo-l-(3-fluorobenzyl)pyridin-2(lH)-one; 4-(benzylamino)-3-bromo-l-(3-fluorobenzyl)pyridin-2(lH)-one; 2-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yljmethyl Jbenzonitrile; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[2-fluoro-6-(4-methylpiperazin-l- yl)phenyl]-6-methylpyridin-2( lH)-one trifluoroacetate; 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-7Y- methylbenzamide; l-[2-(aminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]pyridin-2(lH)- one; 3-bromo- 1 -(4-fluorobenzyl)-4- [(4-fluorobenzyl)oxy]pyridin-2( lH)-one; l-[2-(aminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methylpyridin-2( lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[3-(piperidin-l- ylcarbonyl)phenyl]pyridin-2(lH)-one; l-benzyl-3-bromo-4-[(4-chlorobenzyl)oxy]pyridin-2(lH)-one; 4-[(2,4-difluorobenzyl)oxy]-l-(3-fluorobenzyl)-3-methylpyridin-2(lH)-one; 4-(benzyloxy)- 1 -[4-(benzyloxy)benzyl]-3-bromopyridin-2( lH)-one; 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-7Y- hydroxybenzamide; 4-(benzyloxy)-3-bromo-l-[4-(trifluoromethyl)benzyl]pyridin-2(lH)-one; 3-bromo-l-(cyclopropylmethyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(lH)-one; 3-bromo-l-(cyclopropylmethyl)-4-[(4-fluorobenzyl)oxy]pyridin-2(lH)-one; l-benzyl-3-bromo-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(lH)-one; l-benzyl-3-bromo-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(lH)-one; l-benzyl-3-bromo-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(lH)-one; 2- { [3-bromo-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)- yljmethyl Jbenzonitrile; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-({5- [(methylamino)methyl]pyrazin-2-yl}methyl)pyridin-2(lH)-one trifluoroacetate; 3-bromo-l-(3-fluorobenzyl)-4-[(2-methylbenzyl)oxy]pyridin-2(lH)-one; 3-bromo-l-(3-fluorobenzyl)-4-[(2-methylbenzyl)oxy]pyridin-2(lH)-one; methyl 3-{ [3-bromo-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)- yl]methyl Jbenzoate; 3-bromo-l-(3-fluorobenzyl)-6-methyl-4-(2-phenylethyl)pyridin-2(lH)-one; 3-bromo-l-(3-fluorobenzyl)-6-methyl-4-(2-phenylethyl)pyridin-2(lH)-one; l-benzyl-3-bromo-4-[(4-methylbenzyl)oxy]pyridin-2(lH)-one; 4-(benzyloxy)-l-(3-fluorobenzyl)-3-iodopyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[3-(hydroxymethyl)phenyl]-6- methylpyridin-2( 1 H)-one; 4-(benzyloxy)- 1 -(3-fluorobenzyl)-3-iodopyridin-2( lH)-one; 3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)~ yl]methyl}benzoic acid; 3-bromo-4-[(4-fluorobenzyl)oxy]-l-[2-(hydroxymethyl)benzyl]pyridin-2(lH)- one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]- 1 -[(5- { [(2- hydroxyethyl)(methyl)amino]methyl }pyrazin-2-yl)methyl] -6-methylpyridin-2( lH)-one trifluoroacetate (salt); 4-(benzyloxy)-3-bromo-l-[(6-fluoropyridin-3-yl)methyl]pyridin-2(lH)-one; 3-bromo-4-[(4-chlorobenzyl)oxy]-l-(4-fluorobenzyl)pyridin-2(lH)-one; 3-bromo-4-[(4-chloro-2-fluorobenzyl)amino]-l-(3-fluorobenzyl)pyridin-2(lH)- one; 4-(benzyloxy)-3-bromo- l-ethylpyridin-2( \H)- ne; 4-(benzyloxy)-3-bromo- l-ethylpyridin-2( lH)-one; 4-(benzyloxy)-3-bromo- 1 -ethylpyridin-2( lH)-one; 2-(2-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H yl] methyl } phenyl)acetamide; l-benzyl-3-bromo-4-[(2-chlorobenzyl)oxy]pyridin-2(lH)-one; l-benzyl-3-bromo-4-[(2-chlorobenzyl)oxy]pyridin-2(lH)-one; methyl 2-{ [3-bromo-4-[(4-fluorobenzyl)oxy]-2-oxopyridin-l(2H)- yTjmefhyl Jbenzoate; 3-bromo-l-(2,6-dichlorophenyl)-4-[2-(4-fluorophenyl)ethyl]-6-methylpyridin- 2(lH)-one; 3-bromo-l-(2,6-dichlorophenyl)-4-[2-(4-fluorophenyl)ethyl]-6-methylpyridin- 2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{5-[(isopropylamino)methyl]-2- methylphenylJ-6-methylpyridin-2(lH)-one hydrochloride; 3-bromo- 1 -(3 -fluorobenzyl)-4-(2-phenylethyl)pyridin-2( lH)-one; N- { 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)- yljbenzyl J -N-methylurea; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[3-(hydroxymethyl)phenyl]-6- methylpyridin-2( lH)-one; 3-bromo-l-(3-fluorobenzyl)-4-[(3-fluorobenzyl)oxy]pyridin-2(lH)-one; 4-(benzyloxy)-3-bromo- 1 - [2-(2-thienyl)ethyl]pyridin-2( lH)-one; 4-(benzyloxy)-3-bromo-l-[2-(2-thienyl)ethyl]pyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)amino]-l-(2,6-difluorophenyl)-6-methylpyridin- 2(lH)-one trifluoroacetate; 3-bromo-4-[(2,4-difluorobenzyl)amino]-l-(2,6-difluorophenyl)-6-methylpyridin- 2(lH)-one trifluoroacetate; 3-bromo-4-[(4-chlorobenzyl)oxy]-l-(4-methoxybenzyl)pyridin-2(lH)-one; 3-bromo-4- [(4-chlorobenzyl)oxy] - 1 -(4-methoxybenzyl)pyridin-2( lH)-one; 3-bromo- 1 -(4-chlorobenzyl)-4-[(4-chlorobenzyl)oxy]pyridin-2( lH)-one; 3-bromo-l-(3-fluorobenzyl)-4-[(4-methoxybenzyl)oxy]pyridin-2(lH)-one; 3-bromo-l-(3,5-dibromo-2,6-difluoro-4-hydroxyphenyl)-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one; 4-(benzyloxy)-3-bromo-l-[4-(trifluoromethoxy)benzyl]pyridin-2(lH)-one; 4-(benzyloxy)-3-bromo-l-[4-(trifluoromethoxy)benzyl]pyridin-2(lH)-one; N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yljbenzyl } -N,N~dimethylurea; 3-bromo-4-[(4-fluorobenzyl)oxy]-l-[4-(trifluoromethyl)benzyl]pyridin-2(lH)- one; 2- { [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)- yljmefhyl Jbenzamide; N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yljbenzyl } moφholine-4-carboxamide; N- { 3 - [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)- yljbenzyl } methanesulfonamide; 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N- isopropylbenzamide; 4-(allylamino)-3-bromo-l-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(lH)- one; 4-(allylamino)-3-bromo- 1 -(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2( 1H)- one; (4- { [4-(benzyloxy)-3-bromo-2-oxopyridin- 1 (2H)-yl]mefhyl } phenyl)acetic acid; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[4-(pyrrolidin-l- ylcarbonyi)phenyljpyridin-2(lH)-one; l-benzyl-4-(benzyloxy)-3-iodopyridin-2(lH)-one; l-(biphenyl-4-ylmethyl)-3-bromo-4-[(4-fluorobenzyl)oxy]pyridin-2(lH)-one; 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]benzoic acid; 4-(benzyloxy)-3-bromo-l-[2-(3-thienyl)ethyl]pyridin-2(lH)-one; 4-(benzyloxy)-3-bromo- 1 -[2-(3-thienyl)ethyl]pyridin-2( lH)-one; 3-bromo-4-[(4-fluorobenzyl)oxy]-l-[3-(trifluoromethyl)benzyl]pyridin-2(lH)- one; N-[3-bromo- 1 -(3-fluorobenzyl)-2-oxo- 1 ,2-dihydropyridin-4-yl]-4- fluorobenzamide ; methyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yljbenzylcarbamate; l-benzyl-4-(benzylthio)-3-bromopyridin-2(lH)-one; 4-(benzyloxy)-3-bromo-l-(4-tert-butylbenzyl)pyridin-2(lH)-one; 4-(benzyloxy)-3-bromo- l-(4-tert-butylbenzyl)pyridin-2( lH)-one; N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yljbenzyl }-2-methoxyacetamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]- 1 -( { 5-[(dimethylamino)methyl]pyrazin-2- yl } methyl)-6-methylpyridin-2( lH)-one trifluoroacetate; 3-bromo-4-[(2,4-difluorobenzyl)oxy] -6-methyl- 1 - [4-(piperazin- 1 - ylcarbonyl)phenyl]pyridin-2( lH)-one hydrochloride; 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N,N- bis(2-hydroxyethyl)benz amide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{5-[(dimethylamino)methyl]-2- methylphenylJ-6-methylpyridin-2(lH)-one hydrochloride; 1 -benzyl-3-bromo-4-(2-phenylethyl)pyridin-2( lH)-one; l-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]-3-methylpyridin-2(lH)-one; 4-(benzyloxy)- 1 -(piperidin-3-ylmethyl)pyridin-2( lH)-one trifluoroacetate; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[4-(moφholin-4- ylcarbonyl)phenyl]pyridin-2(lH)-one; 4-(benzyloxy)-l-(3-fluorobenzyl)-3-methylpyridin-2(lH)-one; N1-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yljbenzyl } glycinamide hydrochloride; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-5-iodo-6- methylpyridin-2( lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[4-(piperidin-l- ylcarbonyl)phenyl]pyridin-2(lH)-one; N-[3-bromo-l-(3-fluorobenzyl)-2-oxo-l,2-dihydropyridin-4-yl]-2,6- difluorobenzamide; 2-{ [4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-yl]methylJbenzonitrile; 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}-N-methylpyrazine-2-carboxamide; 3-chloro-4-[(2,4-difluorobenzyl)amino]-l-(2,6-difluorophenyl)-6-methylpyridin- 2(lH)-one; 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]benzoic acid; 3-bromo-l-(3-fluorobenzyl)-4-[(3-fluorobenzyl)amino]pyridin-2(lH)-one; 3-bromo- 1 -(3-fluorobenzyl)-4-[(3-methoxybenzyl)oxy]ρyridin-2( lH)-one; 3-bromo-l-(4-tert-butylbenzyl)-4-[(2,4-difluorobenzyl)oxy]pyridin-2(lH)-one; N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yljbenzyl } acetamide; 2-({3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yljbenzyl } amino)-2-oxoethyl acetate; l-benzyl-4-(benzyloxy)-3-methylpyridin-2(lH)-one; N- { 3- [3-bromo-4-[(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)- yljbenzyljurea; l-benzyl-4-(benzyloxy)-3-ethylpyridin-2(lH)-one; N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yljbenzyl } -2-hydroxyacetamide; 3-bromo-4-[(4-chlorobenzyl)oxy]-l-(2-phenylethyl)pyridin-2(lH)-one; 3-bromo-l-(3-chlorobenzyl)-4-[(4-chlorobenzyl)oxy]pyridin-2(lH)-one; l-[3-(aminomethyl)phenyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methylpyridin-2( lH)-one; 2- { [4-(benzyloxy)-3-bromo-2-oxopyridin- 1 (2H)-yl]methyl Jbenzamide; 1 -(4-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2( lH)-one; l-[2-(aminomethyl)benzyl]-4-(benzyloxy)-3-bromopyridin-2(lH)-one; methyl 3-[4-(benzyloxy)-3-bromo-2-oxopyridin- 1 (2H)-yl]propanoate; l-benzyl-4-(benzyloxy)-3-methylpyridin-2(lH)-one; 4-(allylamino)-l-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(lH)-one; 4-(allylamino)-l-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(lH)-one; 3-bromo-l-(3-fluorobenzyl)-4-(phenylethynyl)pyridin-2(lH)-one; 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N,N- dimethylbenzamide; ι {4-[({4-(benzyloxy)-3-bromo-l-[4-(carboxymethyl)benzyl]-l,2-dihydropyridin- 2-yl } oxy)methyl]phenyl } acetic acid; 4-(benzyloxy)-3-bromo-l-[3-(trifluoromethyl)benzyl]pyridin-2(lH)-one; 4-(benzyloxy)-3-ethynyl- 1 -(3-fluorobenzyl)pyridin-2( lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{3-[(dimethylamino)methyl]phenylJ-6- methylpyridin-2( lH)-one; 4-(benzyloxy)-3-bromo-l-methylpyridin-2(lH)-one; l-benzyl-3-bromo-4-(phenylethynyl)pyridin-2(lH)-one; 4-(benzyloxy)-3-bromo- 1 -methylpyridin-2( lH)-one; 3-biOmo-l-(3-fluorobenzyl)-4-{[4-(trifluoromethyl)benzyl]oxy}pyridin-2(lH)- one; 4-(benzylamino)-3-bromo-l-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(lH)- one; 4-[(2,4-difluorobenzyl)oxy]-l-(4-methoxybenzyl)-6-methylpyridin-2(lH)-one; 4-(benzyloxy)-3-bromo- 1 -methylpyridin-2( lH)-one hydrobromide; 4-(benzyloxy)-3-bromo-l-[4-(moφholin-4-ylcarbonyl)phenyl]pyridin-2(lH)-one; 5-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-6-oxo-l,6- dihydropyridine-2-carboxylic acid; l-benzyl-3-bromo-4-[(2,6-dichlorobenzyl)oxy]pyridin-2(lH)-one; 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-2- methylbenzoic acid; 4-[4-(benzyloxy)-3-bromo-2-oxopyridin- 1 (2H)-yl]benzoic acid; ethyl iV-(5-{ [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}-2-methylpyrimidin-4-yl)glycinate trifluoroacetate; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-6-methyl-5-[(E)-2- phenylvinyl]pyridin-2( lH)-one; 3-bromo-l-(3-fluorobenzyl)-4-{[3-(trifluoromethyl)benzyl]amino}pyridin-2(lH)- one; 3-bromo-4-[(4-fluorobenzyl)oxy] - 1 -(3-phenylρropyl)pyridin-2( lH)-one; 3-bromo- 1 -(4-tert-butylbenzyl)-4-[(4-fluorobenzyl)oxy]pyridin-2( lH)-one; 4-(allylamino)-3-bromo-l-(2,6-difluorophenyl)-6-methylpyridin-2(lH)-one; l-cyclohexyl-4-[(2,4-difluorobenzyl)oxy]-3,6-dimethylpyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-5-(hydroxymethyl)- 6-methylpyridin-2( lH)-one; 1 -benzyl-4-(benzyloxy)-2-oxo- 1 ,2-dihydropyridine-3-carbaldehyde; 4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-prop-2-yn-l-ylpyridin-2(lH)-one; ethyl 3-[4-(benzyloxy)-3-bromo-2-oxopyridin- 1 (2H)-yl]propanoate; l-benzyl-4-(benzyloxy)-3-(hydroxymethyl)pyridin-2(lH)-one; 3-Chloro-4-(2,4-difluoro-benzyloxy)-6-methyl-l-(5-methyl-pyrazin-2-ylmethyl)- lΗ-pyridin-2-one 3-Chloro-4-(2,4-difluoro-benzyloxy)-l-(5-hydroxymethyl-pyrazin-2-ylmethyl)-6- methyl- 1 H-pyridin-2-one 3-Bromo-4-(2,4-difluoro-benzyloxy)-l-(2,3-dihydro-lH-indol-5-ylmethyl)-lH- pyridin-2-one 3-Bromo-4-(2,4-difluoro-benzyloxy)-l-[l-(2-hydroxy-acetyl)-2,3-dihydro-lH- indol-5-ylmethyl]-6-methyl-lH-pyridin-2-one 3-Bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-l-(lH-pyrazol-3-ylmethyl)-lH- pyridin-2-one 3-[3-Chloro-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-l-yl]-4,N- dimethyl-benzamide 3-[3-Chloro-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-l-yl]-4- methyl-benzamide 3-[3-Chloro-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-l-yl]-4- fluoro-N-methyl-benzamide 4-Chloro-3-[3-chloro-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-l- yl] -N-methyl-benzamide 3-[3-Chloro-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-l-yl]-4- ' fluoro-benz amide 4-[3-Chloro-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-l-yl]-3,N- dimethyl-benzamide 3-Chloro-4-(2,4-difluoro-benzyloxy)- 1 - [4-( 1 ,2-dihydroxy-ethyl)-2-methyl- phenyl] -6-methyl- 1 H-pyridin-2-one N-{4-[3-Chloro-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-l- ylmethyl] -phenyl } -2-hydroxy-acetamide 1 -Hydroxy-cyclopropanecarboxylic acid 4-[3-chloro-4-(2,4-difluoro-benzyloxy)- 6-methyl-2-oxo-2H-pyridin- 1 -ylmethyl] -benzylamide N-{4-[3-Chloro-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin-l- ylmethylj-benzyl } -2-hydroxy-acetamide N- { 4- [3-Chloro-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2H-pyridin- 1 - ylmefhylj-phenyl } -acetamide {2-[3-Bromo-l-(2,6-difluoro-phenyl)-6-methyl-2-oxo-l,2-dihydro-pyridin-4- yloxymethyl]-5-fluoro-benzylJ-carbamic acid ethyl ester or a pharmaceutically acceptable salt thereof. The above names were generated using ChemDraw Ultra version 6.0.2, which is put out by CambridgeSoft.com, Cambridge, MA; or ACD Namepro version 5.09, which is put out by ACDlabs.com. Embodiment 75. A compound according to Embodiment 17, wherein Z5 is Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q-Q alkoxycarbonyl, CF3, or Q-Q alkanoyl. Embodiment 76. A compound according to Embodiment 17, wherein Z5 is Q-Q alkyl, -C(0)NR6R7, -(Q-C4alkyl)-C(0)NR6R7, R6R7N-(Q-C6 alkyl)-, or - NR6R7, CF3, or Q-Q alkanoyl, wherein R6 and R7 at each occurrence are independently H, Q-Q alkyl optionally substituted with 1, 2, or 3 groups that are independently Q-Q alkoxycarbonyl, halogen, Q-Q cycloalkyl, OH, SH, or Q-Q alkoxy. Embodiment 77. A compound according to Embodiment 1, wherein Ri is halogen, Q-Q alkyl optionally substituted with Q-Q alkoxycarbonyl, Q-Q alkenyl optionally substituted with Q-Q alkoxycarbonyl, Q-Q alkynyl, or carboxaldehyde; R3 is H; and
R4 is H, alkyl optionally substituted with one or two groups that are independently C02R, OH, -C02alkyl, -C(0)NR6R7, -OC(0)NR6R7, -OC(0)-(Q-Q alkyl), -C(0)R6, -N(R30)C(O)NR6R7, -N(R30)C(O)-(Q-Q)alkoxy, or -NR6R7, -C(0)NR6R7, phenyl(Q-Q)alkoxy, phenyl (Q-Q)alkyl, hydroxyalkyl, dihydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein the phenyl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, hydroxy, alkoxy, alkyl, nitro, CF3, OCF3. Embodiment 78. A compound according to Embodiment 77, wherein R2 is -OS02-phenyl, phenylalkoxy, phenyloxy, phenylthioalkoxy, phenylalkynyl, phenyloxy(Q-C6)alkyl, -OC(0)NH(CH2)„phenyl, -OC(0)N(alkyl)(CH2)nρhenyl, pyridyl, pyrimidyl, thienyl, piperazinyl, imidazolidinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, or tetrahydrofuranyl, wherein each of the above is substituted with 1, 2, 3, 4, or 5 groups wherein at least one group is of the formula -(Q-Q alkyl)-NR6C(0)NR7-(Q-Q alkoxy), -(Q- Q alkyl)-NR6C(0)NR7-(Q-Q alkyl) -(Q-Q alkyl)-NR16C(0)NR17-(C3- Q cycloalkylalkyl), -(Q-Q alkyl)-NRi6C(0)NR17-(heteroaryl) wherein the heteroaryl group is optionally substituted with Q-Q alkyl, Q-Q alkoxy, halogen or OH, haloalkyl, or -(Q-Q aikyl)-NR16C(0)NR17-(C3-Q cycloalkyl) and the other groups, if present, are independently halogen, -NR6R7, CF3, OCF3, Q-Q alkyl, -(Q-C4)alkyl-C(0)NR6R7, R6R7N-(Q-Q alkyl)-, -C(0)NR6R7, -(Q-Q alkyl)-NRC(0)NRi6R17, CN, hydroxyalkyl, dihydroxyalkyl, -OC(0)NR6R7, or -(Q-Q)alkyl-N(R)-CO2R30, wherein Rι6 and R17 at each occurrence are independently H or Q-Q alkyl; or Rι6, Rι7 and the nitrogen to which they are attached form a moφholinyl ring; R6 and R7 are independently at each occurrence H, alkyl optionally substituted with NRι6Rι7 or a heteroaryl group that is selected from thienyl, pyridyl, and furanyl, hydroxyalkyl, dihydroxyalkyl, alkoxy optionally substituted with NR1 Rπ, Q-Q alkoxy Q-Q alkyl, Q- Q alkanoyl, phenyl Q-Q alkyl, heterocycloalkyloxy, Q-Q alkenyl optionally substituted with -OC(0)NR16Rι7, -S02-phenyl, phenyl, heterocyloalkylalkanoyl, phenyl Q-Q alkoxy, phenyl Q- Q alkoxycarbonyl, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, amino, monoalkylamino, dialkylamino, - C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-C6 alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, moφholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy; or R , R7, and the nitrogen to which they are attached form a moφholinyl, thiomoφholinyl, thiomoφholinyl S-oxide, thiomoφholinyl S,S- dioxide, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q- Q alkyl, Q-Q alkoxycarbonyl, hydroxyl, hydroxy Q-Q alkyl, dihydroxy Q-Q alkyl, or halogen; n is 0, 1, 2, 3, 4, 5 or 6; R at each occurrence is independently H or Q-Q alkyl optionally substituted with 1 or 2 groups that are independently OH, SH, halogen, amino, monoalkylamino, dialkylamino or Q-Q cycloalkyl; R3o is Q-Q alkyl optionally substituted with 1 or 2 groups that are independently OH, SH, halogen, amino, monoalkylamino, dialkylamino or Q-Q cycloalkyl. Embodiment 79. A compound according to Embodiment 78, wherein R5 is
Figure imgf000178_0001
wherein
Zi is H, halogen, Q-Q alkyl, CF3, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, or Q-Q alkoxy; and Z2 is Q-Q alkyl, -C(0)NR6R7, -(Q-Q alkyl)-C(0)NR6R7, -NR6R7, NR6R7(Q-Q alkyl), Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q-Q alkoxy, C0 R, OH, Q- Q alkoxycarbonyl, CF3, or Q-Q alkenyl optionally substituted with C02H, or - OC(0)NR16Rι7; and Z3 is H, halogen, Q-Q alkyl, Q-Q alkoxy, alkoxyalkyl, -S02-alkyl or C2-Q alkenyl, wherein the alkyl, alkoxy, and alkenyl portions are optionally substituted with 1, 2, or 3 groups that are independently -OC(0)NR16Rπ, -C(0)NRι6R17, OH, NRι6Rι7, wherein R6 and R7 at each occurrence are independently H, OH, Q-Q alkyl optionally substituted with a heteroaryl group that is selected from thienyl, pyridyl, and furanyl, amino Q-Q alkyl, NH(Q-Q alkyl)alkyl, N(Q-Q alkyl)(Q- C6 alkyl) Q-Q alkyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, Q-Q alkoxy Q-Q alkyl, -S02(Q-Q alkyl), -S02NH2, -S02NH(Q-Q alkyl), -S02N(C!-C6 alkyl)(Q-Q alkyl), or Q-Q alkanoyl, each of which is optionally substituted with 1, 2, or 3 groups that are independently halogen, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-C6 alkyl), Q-Q alkoxy, Q-C4 alkyl, OH, SH, carboxaldehyde, piperidinyl, moφholinyl, pyrrolidinyl, piperazinyl, - OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy. Embodiment 79a. A compound according to embodiment 79, wherein
R6 and R7 are independently H, Q-Q alkyl or hydroxyalkyl. Embodiment 79b. A compound according to embodiment 79 or 79a, wherein Zi is H, Q-Q alkyl, or fluorine. Embodiment 80. A compound according to Embodiment 79, wherein R2 is benzyloxy or phenyl Q-Q thioalkoxy, each of which is substituted with 1, 2, 3, 4, or 5 groups wherein at least one group is of the formula -(Q-Q alkyl)-NR6C(0)NR7- (Q-Q alkoxy) and the other groups, if present, are independently halogen, amino, monoalkylamino, dialkylamino, CF3, OCF3, Q-Q alkyl, CN, hydroxyalkyl, or dihydroxyalkyl, wherein R6 and R7 are independently at each occurrence H, alkyl optionally substituted with NRι6Rj7 or a heteroaryl group that is selected from thienyl, pyridyl, and furanyl, hydroxyalkyl, dihydroxyalkyl, alkoxy optionally substituted with NRι6R17, Q-Q alkoxy Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, tetrahydropyranyloxy, tetrahydrofuranyloxy, piperidinyloxy, pyrrolidinyloxy, Q-Q alkenyl optionally substituted with, -OC(0)NR16Ri7, -S02-phenyl, phenyl, pyrrolidinyl Q-Q alkanoyl, piperidinyl Q-Q alkanoyl, phenyl Q-Q alkoxy, phenyl Q-Q alkoxycarbonyl, or phenyl Q- Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q- Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, moφholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy; and Ri6 and R17 at each occurrence are independently H or Q-Q alkyl. Embodiment 81. A compound according to Embodiment 79, of the formula
Figure imgf000180_0001
wherein k is O, 1, 2, 3, or 4; R18 is Q-C6 alkyl;
Rι at each occurrence is independently halogen, -NR6R7, CF3, OCF3, C!-C4 alkyl, -(Q- C4)alkyl-C(0)NR6R7, R6R7N-(Q-C6 alkyl)-, -C(0)NR6R7, -(Q-Q alkyl)- NRC(0)NRι6Rι7, CN, hydroxyalkyl, dihydroxyalkyl, -OC(0)NR6R7, or -(Q- C6)alkyl-N(R)-CO2R30. Embodiment 82. A compound according to Embodiment 77, wherein R2 is benzyloxy or phenyl Q-Q thioalkoxy, each of which is substituted with 1, 2, 3, 4, or 5 groups independently selected from -(Q-Q aikyl)-NR6C(0)NR7-(Q-Q alkoxy), -(Q-Q alkyl)-NRi6C(0)NR17-(Q-C6 cycloalkyl), halogen, amino, monoalkylamino, dialkylamino, CF3, OCF3, Q-Q alkyl, CN, hydroxyalkyl, or dihydroxyalkyl, wherein R6 and R7 are independently at each occurrence H, alkyl optionally substituted with NRι R17 or a heteroaryl group that is selected from thienyl, pyridyl, and furanyl, hydroxyalkyl, dihydroxyalkyl, NRι6R17, alkoxy optionally substituted with NR16Rι7, Q-Q alkoxy Q-Q alkyl, OH, Q-Q alkanoyl, Q-Q cycloalkyl, phenyl Q-Q alkyl, tetrahydropyranyloxy, tetrahydrofuranyloxy, piperidinyloxy, pyrrolidinyloxy, Q-Q alkenyl optionally substituted with -OC(0)NRι6Rπ, -S02-phenyl, -S02NRι6Rι7, - S02-Q-Q alkyl, phenyl, pyrrolidinyl Q-Q alkanoyl, piperidinyl Q-Q alkanoyl, pyridyl Q-Q alkanoyl, phenyl Q-Q alkoxy, phenyl Q-Q alkoxycarbonyl, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, - C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q- Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, moφholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy; or R6, R7, and the nitrogen to which they are attached form a moφholinyl, thiomoφholinyl, thiomoφholinyl S-oxide, thiomoφholinyl S,S-dioxide, piperidinyl, pyrrolidinyl, isoindole 1,3-dionyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxycarbonyl, hydroxyl, hydroxy Q-Q alkyl, dihydroxy Q-Q alkyl, or halogen; Ri6 and Rπ at each occurrence are independently H or Q-Q alkyl; and R4 is H, hydroxyalkyl, or alkyl which is optionally substituted with one or two groups that are independently C02R, OH, -C02alkyl, -C(0)NR6R7, -OC(0)NR6R7, -OC(O)- (Q-Q alkyl), -C(0)R6, -N(R30)C(O)NR6R7, -N(R30)C(O)-(Q-Q alkyl)-NR6R7, -N(R30)C(O)-(Q-C6)alkoxy, or -NR6R7. Embodiment 83. A compound according to Embodiment 82, wherein R2 is benzyloxy substituted with 1, 2, 3, or 4 groups that are independently halogen, -NR6R7, Q-Q haloalkyl, Q-Q haloalkoxy, Q-Q alkyl optionally substituted with -(Q-Q alkyl)-NR6C(0)NR7-(Q-Q alkoxy), -(Q-Q)alkyl-C(0)NR6R7, R6R7N-(Q-C6 alkyl)-, -C(0)NR6R7, -(Q-Q alkyl)-NRC(0)NR16Ri7, CN, hydroxyalkyl, dihydroxyalkyl, -OC(0)NR6R7, or -(Q-C6)alkyl-N(R)-CO2R30, R5 is selected from the group consisting of H, phenyl(Q-Q)alkyl, (Q-Q)alkyl optionally substituted with 1, 2, 3, 4, or 5 groups that are independently phenyl Q-Q alkoxycarbonyl, -NR8R , halogen, -C(0)NR8R9, alkoxycarbonyl, or alkanoyl, phenyl, alkoxy, Q-Q alkynyl, Q-Q alkenyl optionally substituted with alkoxycarbonyl, C02H, or -OC(0)NR16R17, indolyl, indolinyl, quinolinyl, isoquinolinyl, benzothiazolyl, isoindolyl, dihydroindolyl, pyrazolyl, isobenzofuranonyl, imidazolyl, pyridyl, pyrimidyl, pyrazinyl, dihydroisoindolyl, benzimidazolyl, indolon-2-yl, indazolyl, benzimidazolyl, imidazolidine dione, pyrazolyl(Q-Q alkyl), imidazolyl(Q-Q alkyl), piperidinyl(Cι-C6)alkyl, pyrrolidinyl(Q-C6)alkyl, imidazolidinyl(Cι-C6)alkyl, lH-indazolyl(Cι-C6)alkyl, dihydroindolon-2-yl(Q-Q alkyl), isobenzofuranonyl(Cι-C6 alkyl), benzothiazolyl(Cι-C6 alkyl), indolinyl(Q-Q alkyl), dihydrobenzimidazolyl(Q- Q alkyl), or dihydrobenzoimidazolonyl(Q-Q alkyl), pyridyl (Q-Q) alkyl, pyridazinyl (Q-Q) alkyl, pyrimidinyl (Q-Q) alkyl, pyrazinyl (Q-Q) alkyl, tetrahydrofuryl(Q-C6)alkyl, naphthyl(Q-Q)alkyl, moφholinyl (Q-Q) alkyl, tetrahydrofuryl (Q-Q) alkyl, thienyl (Q-Q) alkyl, piperazinyl (Q-Q) alkyl, indolyl (Q-Q) alkyl, quinolinyl(Q-Q) alkyl, isoquinolinyl(Q-Q) alkyl, isoindolyl(Q-Q) alkyl, dihydroindolyl(Q-Q) alkyl, pyrazolyl(Q-Q) alkyl, imidazolyl(Q-Q) alkyl, dihydroisoindolyl(Q-Q) alkyl, indolon-2-yl(C1-C6) alkyl, moφholinyl Q-Q alkyl, -pyrimidinyl-piperazinyl, -pyridinyl-piperazinyl, alkenyl, -alkenyl-C02-alkyl, and -alkenyl-C02H, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently NR16R17, Q-Q alkyl optionally substituted with 1 or 2 groups that are independently NR16Rπ, -NR16S02-alkyl, -NRi6S02-phenyl, -OC(0)NH2, -OC(0)NHR16, OH, or -OC(0)NR16R17, halogen, -OC(0)NR6R7, Cι-C6 alkoxy optionally substituted with NRj6R17, phenyl Cι-C6 alkoxy, Q-Q thioalkoxy, Q-Q alkoxycarbonyl, C0 R, CN, carboxaldehyde, -S02(Cι-C6)alkyl optionally substituted with NRι6Rι7, - S02NRι6R17, amidinooxime, NR8R9, CN, -NR6R7, NR6R7 Q-Q alkyl, -C(0)NR6R7, -(Q-C4)alkyl-C(0)NR6R7, amidino, Q-Q haloalkyl, phenyl, hydroxy Q-Q alkyl, Q-Q dihydroxyalkyl, Q-Q haloalkoxy, Q-Q alkenyl optionally substituted with -OC(0)NR6R7ι Q-Q alkoxy, or OH, -C(0)C(0)NR16R17, heterocycloalkyl or heterocycloalkylalkyl, wherein the heterocycloalkyl group is selected from the group consisting of moφholinyl, piperazinyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, and imidazolidinyl, heteroaryl which is selected from the group consisting of pyridyl, furanyl, pyrazolyl, and thienyl, alkoxyalkyl optionally substituted with NRι6Rι7, or alkanoyl optionally substituted with OH, halogen, -OC(0)-(Q-Q alkyl), or Q-Q alkoxy; wherein each of the above phenyl or heteroaryl groups are optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, Q-Q alkoxy, halogen, amino, CF3, or OCF3; each of the heterocycloalkyl groups is optionally substituted with 1, 2, 3, or 4 groups that are independently, Q-Q alkyl, Q-Q alkoxy, halogen, Q-Q alkanoyl, -C(0)NR6R7; R8 is hydrogen, Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl and phenyl Q-Q alkanoyl; and R is amino Q-Q alkyl, mono Q-Q alkylamino Q-Q alkyl, di Q-Q alkylamino Q-Q alkyl, Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, indazolyl, and phenyl Q-Q alkanoyl. Embodiment 84. A compound according to Embodiment 83, wherein R16 and R17 at each occurrence are independently H or Q-Q alkyl; R6 and R7 are independently at each occurrence H, alkyl, hydroxyalkyl, dihydroxyalkyl, alkoxy optionally substituted with NRι6Rπ, Q-Q alkoxy Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, tetrahydropyranyloxy, Q-Q alkenyl optionally substituted with -OC(0)NRι6Rι7, -S02-phenyl, -S02-Q-Q alkyl, phenyl, pyrrolidinyl Q-Q alkanoyl, piperidinyl Q-Q alkanoyl, phenyl Q-Q alkoxy, phenyl Q-Q alkoxycarbonyl, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, moφholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy; or R6, R7, and the nitrogen to which they are attached form a moφholinyl, thiomoφholinyl, thiomoφholinyl S-oxide, thiomoφholinyl S,S-dioxide, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxycarbonyl, hydroxyl, hydroxy Q-Q alkyl, dihydroxy Q-Q alkyl, or halogen; n is 0, 1, 2, 3, 4, 5 or 6;
R5 is pyridyl, pyrimidyl, pyrazinyl, pyridyl (Q-Q) alkyl, pyrimidinyl (Q-Q) alkyl, or pyrazinyl (Q-Q) alkyl wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently NR16R17, Ci-Ce alkyl optionally substituted with 1 or 2 groups that are independently NR16R17, -NRι6S02-alkyl, - NR16S02-phenyl, rOC(0)NH2, or -OC(0)NRι6R17, halogen, -OC(0)NR6R7, Ci- Ce alkoxy optionally substituted with NR16R17, phenyl Q-Q alkoxy, Q-Q thioalkoxy, Q-Q alkoxycarbonyl, C02R, CN, -S(Q-Q)alkyl optionally substituted with NRι6Rι7, -S02(Q-Q)alkyl optionally substituted with NRι6Rι7, amidinooxime, NR8R9, CN, -NR6R7, NR6R7 Q-Q alkyl, -C(0)NR6R7, -(Q- Q)alkyl-C(0)NR6R7, amidino, Q-Q haloalkyl, hydroxy Q-Q alkyl, Q-Q dihydroxyalkyl, Q-Q haloalkoxy, -C(0)C(0)NRι6Rι7, heterocycloalkyl which is selected from the group consisting of moφholinyl, piperazinyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, and imidazolidinyl, alkoxyalkyl optionally substituted with NRι6R17, or alkanoyl optionally substituted with OH, halogen, -OC(0)-(Q-Q alkyl), or Q-Q alkoxy; wherein each of the above phenyl or heteroaryl groups are optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, Q-Q alkoxy, halogen, amino, CF3, or OCF3; each of the heterocycloalkyl groups is optionally substituted with 1, 2, 3, or 4 groups that are independently, Q-Q alkyl, Q-Q alkoxy, halogen, Q-Q alkanoyl, -C(0)NR6R7; R8 is hydrogen, Q-Q alkyl, Q-Q alkanoyl, benzyl, and phenyl Q-C4 alkanoyl and R9 is amino Q-Q alkyl, mono Q-Q alkylamino Q-Q alkyl, di Q-Q alkylamino Q-Q alkyl, Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, indazolyl, and phenyl Q-Q alkanoyl. Embodiment 85. A compound according to Embodiment 84, wherein
Ri is halogen; R4 is hydroxyalkyl or Q-Q alkyl optionally substituted with one or two groups that are independently C02R, -C02alkyl, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)NH(Q- Q alkyl)(Q-Q alkyl), -C(0)-Q-Q alkyl, -N(R30)C(O)NR16R17, or -N(R30)C(O)- (Q-Q)alkoxy;
R5 is pyridyl, pyrimidyl, pyrazinyl, pyridyl (Q-Q) alkyl, pyrimidinyl (Q-Q) alkyl, or pyrazinyl (Q-Q) alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3, groups that are independently NRieRπ, Q-Q alkyl optionally substituted with 1 or 2 groups that are independently NRι6Rι7, -NRι6S02-alkyl, -NR16S02- phenyl, -OC(0)NH2, or -OC(0)NRι6Rι7, halogen, -OC(0)NR6R7, Q-Q alkoxy optionally substituted with NRι6Rι7, -S02(Q-Q alkyl) optionally substituted with NRι6Rι7, -S02(Q-Q)alkyl optionally substituted with NRieRπ, NR8R9, CN, NR6R7 Q-Q alkyl, -C(0)NR6R7, -NR6R7, heterocycloalkyl which is selected from the group consisting of piperazinyl, piperidinyl, and pyrrolidinyl, or alkoxyalkyl optionally substituted with NRiβRπ, wherein each of the above phenyl or heteroaryl groups are optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, Q-Q alkoxy, halogen, amino, CF3, or OCF3; each of the heterocycloalkyl groups is optionally substituted with 1, 2, 3, or 4 groups that are independently, Q-Q alkyl, Q-Q alkoxy, halogen, Q-Q alkanoyl, -C(0)NR6R7; R8 is hydrogen, Q-Q alkyl, Q-Q alkanoyl, benzyl, and phenyl Q-Q alkanoyl and R9 is amino Q-Q alkyl, mono Q-Q alkylamino Q-Q alkyl, di Q-C6 alkylamino Q-Q alkyl, Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, and phenyl Q-Q alkanoyl. Embodiment 86. A compound according to Embodiment 85, wherein R5 is of the formula:
Figure imgf000185_0001
wherein
R5o is NRieRπ, alkyl optionally substituted with 1, 2, or 3 groups that are independently - NRieRπ, -NRι6S02alkyl, or -NR16C02Q-Q alkyl, alkoxy optionally substituted with NRι6Rπ, -S (Q-Q alkyl) optionally substituted with NRieRπ, -S02(Q-Q alkyl) optionally substituted with NRieRπ, piperazinyl optionally substituted with 1 or 2 groups that are independently H, alkyl, alkanoyl, or CONReR7, -alkyl- NR16S02phenyl wherein the phenyl group is optionally substituted with 1, 2, 3, 4 or 5 groups that are independently halogen, alkyl, alkoxy, or CONR16Rπ, alkoxyalkyl optionally substituted with NRieRπ, or -alkyl-OC(0)NR16R17, NR8R9, CN, NR6R7 Q-Q alkyl, -C(0)NR6R7, -NR6R7, R51 is H Q-Q alkyl, Q-Q alkoxy, or halogen; wherein R6 and R7 are independently H, Q-Q alkyl, hydroxyalkyl, Q-Q alkanoyl, -S02- Q-Q alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), - C(0)N(Q-Q alkylXQ-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, moφholinyl, pyrrolidinyl, piperazinyl, - OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy. Embodiment 87. A compound according to Embodiment 85, wherein R5 is of the formula:
Figure imgf000186_0001
wherein,
Re and R7 are independently H, Q-Q alkyl, hydroxyalkyl, Q-Q alkanoyl, -SO2-Q-Q alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-C6 alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, moφholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q- Q haloalkoxy. Embodiment 88. A compound according to Embodiment 85, wherein R5 is of the formula:
Figure imgf000186_0002
wherein
R55 is -(Q-Q alkyl)-NR6R7, or -NR6R7; wherein R6 and R7 are independently H, Q-Q alkyl, hydroxyalkyl, Q-Q alkanoyl, -S02- Q-Q alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Ci-Q alkyl), - C(0)N(Q-Q alkylXQ-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, moφholinyl, pyrrolidinyl, piperazinyl, - OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy. Embodiment 88a. A compound according to embodiment 88 wherein R6 is derived from 2-aminopiOpionic acid. More preferably it is derived from (2R)-aminopropionic acid. Embodiment 88b. A compound according to embodiment 88 wherein R6 is derived from 2-amino, 3-hydroxypropionic acid. More preferably, R6 is derived from the (R) isomer. Embodiment 89. A compound according to Embodiment 85, wherein R5 is of the formula:
Figure imgf000187_0001
wherein each R60 is independently H, -C(0)NR6R7, -C02R, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, -(Q-Q alkyl)-NR6R7, halogen, Q-Q alkenyl, CN, or -NR6R7, wherein R6 and R7 are independently H, Q-Q alkyl, Q-Q alkanoyl, wherein the alkyl portion of each of the above is optionally substituted with OH, or halogen; R at each occurrence is independently H or Q-Q alkyl optionally substituted with 1 or 2 groups that are independently OH, SH, halogen, amino, monoalkylamino, dialkylamino or Q-Q cycloalkyl. Embodiment 90. A compound according to Embodiment 85, wherein
R5 is
Figure imgf000187_0002
R60 is -S02-Q-Q alkyl, or -(Q-Q alkyl)-NR6R7, wherein Re and R7 are independently H, Q-Q alkyl, Q-Q alkanoyl, wherein the alkyl portion of each of the above is optionally substituted with OH, or halogen; R at each occurrence is independently H or Q-Q alkyl optionally substituted with 1 or 2 groups that are independently OH, SH, halogen, amino; monoalkylamino, dialkylamino or Q-Q cycloalkyl; and R61 is H or Q-C alkyl, or Q-Q alkoxy, or halogen. Embodiment 91. A compound according to Embodiment 83, wherein R5 is Q-Q alkenyl -alkenyl-C02-alkyl, and -alkenyl-C02H, each of which is optionally substituted with -NR6R7, OH, -C(0)NR6R7, wherein R6 and R7 at each occurrence are independently H, alkyl optionally substituted with a heteroaryl group that is selected from thienyl, pyridyl, and furanyl, hydroxyalkyl, dihydroxyalkyl, alkoxy optionally substituted with NRieRπ, Q-Q alkoxy Q-Q alkyl, Q- Q alkanoyl, phenyl Q-Q alkyl, tetrahydropyranyloxy, tetrahydrofuranyloxy, piperidinyloxy, pyrrolidinyloxy, Q-Q alkenyl optionally substituted with -OC(0)NRι6Rπ, -S02-phenyl, - SOrQ-Q alkyl, phenyl, pyrrolidinyl Q-Q alkanoyl, piperidinyl Q-Q alkanoyl, phenyl Q-Q alkoxy, phenyl Q-Q alkoxycarbonyl, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, moφholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, CF3, or OCF3; or R6, R7, and the nitrogen to which they are attached form a moφholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxycarbonyl, hydroxyl, hydroxy Q-Q alkyl, dihydroxy Q-Q alkyl, or halogen. Embodiment 91a. A compound according to embodiment 91, wherein R4 is alkyl which is optionally substituted with one or two groups that are independently C02R, OH, -C(0)NR6R7, -OC(0)NR6R7, -OC(0)-(Q-Q alkyl), or -NR6R7. More preferably, R4 is methyl or Cl alkyl optionally substituted with with one or two groups that are independently C02R, OH, -C(0)NR6R7, -OC(0)NR6R7, -OC(0)-(Q-Q alkyl), or -NR6R7. Embodiment 91b. A compound according to embodiment 91a, wherein R6 and R7 are H, Q-Q alkyl, phenyl, amino(Q-Q alkyl), alkylamino(Cι-C4 alkyl), amino(Cι-Ce alkanoyl), and alkylamino(Cι-Q alkanoyl). Embodiment 92. A compound according to Embodiment 83, wherein R5 is phenyl optionally substituted with 1, 2, 3, 4, or 5 groups that are independently NRι6R1 , Q-Q alkyl optionally substituted with 1 or 2 groups that are independently NR16Rπ, -NR16S02-alkyl, -NR16S02-phenyl, -OC(0)NH2, - OC(0)NHR16, OH, or -0C(0)NR16R17, halogen, -OC(0)NR6R7, Q-Q alkoxy optionally substituted with NRiβRπ, phenyl Q-Q alkoxy, Q-Q thioalkoxy, Q-Q alkoxycarbonyl, C02R, CN, carboxaldehyde, -S02(Ci-Ce)alkyl optionally substituted with NRι6R1 , -S02NR16Ri7) amidinooxime, NR8R9, -NR6R7, NR6R7 Q-Q alkyl, -C(0)NR6R7, -(Q-C4)alkyl-C(0)NR6R7, amidino, CF3, phenyl, Q-Q hydroxyalkyl, Cι-C6 dihydroxyalkyl, OCF3, C2-Cg alkenyl optionally substituted with-OC(0)NR6R7, Ci-C4 alkoxy, or OH, -C(0)C(0)NRι6R17, heterocycloalkyl which is selected from the group consisting of moφholinyl, piperazinyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, and imidazolidinyl, heteroaryl which is selected from the group consisting of pyridyl, furanyl, pyrazolyl, and thienyl, alkoxyalkyl optionally substituted with NRι6Rπ, or alkanoyl optionally substituted with OH, halogen, -OC(0)-(Q-Q alkyl), or Q-Q alkoxy; wherein each of the above phenyl or heteroaryl groups are optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, Q-Q alkoxy, halogen, amino, CF , or OCF3; each of the heterocycloalkyl groups is optionally substituted with 1, 2, 3, or 4 groups that are independently, Q-Q alkyl, Q-Q alkoxy, halogen, Q-Q alkanoyl, -C(0)NR16Rι7; wherein R6 and R7 are independently at each occurrence H, alkyl optionally substituted with NR16R17 or a heteroaryl group that is selected from thienyl, pyridyl, and furanyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, NR16R1 , alkoxy optionally substituted with NRieRπ, Q-Q alkoxy Q-Q alkyl, OH, Q-Q alkanoyl, Q-Q cycloalkyl, phenyl Q-Q alkyl, tetrahydropyranyloxy, tetrahydrofuranyloxy, piperidinyloxy, pyrrolidinyloxy, Q-Q alkenyl optionally substituted with -OC(0)NRι6Rπ, -S02-phenyl, -S02-Q-Q alkyl, phenyl, pyrrolidinyl Q-Q alkanoyl, piperidinyl Q-Q alkanoyl, pyridyl Q-Q alkanoyl, phenyl Q-Q alkoxy, phenyl Q-Q alkoxycarbonyl, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, - C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q- Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, moφholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy; or R6, R7, and the nitrogen to which they are attached form a moφholinyl, thiomoφholinyl, thiomoφholinyl S-oxide, thiomoφholinyl S,S-dioxide, piperidinyl, pyrrolidinyl, isoindole 1,3-dione, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxycarbonyl, hydroxyl, hydroxy Q-Q alkyl, dihydroxy Q-Q alkyl, or halogen; and R at each occurrence is independently H or Q-Q alkyl optionally substituted with 1 or 2 groups that are independently OH, halogen, amino, monoalkylamino, dialkylamino or Q-Q cycloalkyl. Embodiment 92a. A compound according to embodiment 92, wherein R4 is alkyl which is optionally substituted with one or two groups that are independently C02R, OH, -C(0)NR6R7, -OC(0)NR6R7, -OC(0)-(Q-Q alkyl), -N(R30)C(O)-(Q-Q alkyl)-NR6R7, or -NR6R7. More preferably, R4 is methyl or Cl alkyl optionally substituted with with one or two groups that are independently C02R, OH, -C(0)NR6R7, -OC(0)NR6R7, -OC(0)-(Q- Q alkyl), or -NR6R7. Embodiment 92b. A compound according to embodiment 92a, wherein R6 and R7 are H, Q-Q alkyl, phenyl, amino(Q-Q alkyl), alkylamino(Q-Q alkyl), amino(Q-Q alkanoyl), and arkylamino(Q-Q alkanoyl). Embodiment 93. A compound according to Embodiment 83, wherein R5 is ρhenyl(Q-Q)alkyl, which is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently NRι6Rπ, Q-Q alkyl optionally substituted with 1 or 2 groups that are independently NR15Rπ, -NR16S02-alkyl, -NR16S02-ρhenyl, -OC(0)NH2, - OC(0)NHRιe, OH, or -OC(0)NR16Rπ, halogen, -OC(0)NR6R7, Q-Q alkoxy optionally substituted with NRieRπ, phenyl Q-Q alkoxy, Q-Q thioalkoxy, Q-Q alkoxycarbonyl, C02R, CN, carboxaldehyde, -S02(Q-Q)alkyl optionally substituted with NR16Rπ, -S02NR16Rπ, amidinooxime, NR8R9, CN, -NR6R7, NR6R7 Q-Q alkyl, -C(0)NR6R7, -(Ci-C4)alkyl-C(0)NR6R7, amidino, Q-Q haloalkyl, phenyl, hydroxy Q-Q alkyl, Q-Q dihydroxyalkyl, Q-Q haloalkoxy, Q-Q alkenyl optionally substituted with -OC(0)NR6R7, Q-Q alkoxy, or OH, -C(0)C(0)NRι6Rπ, heterocycloalkyl which is selected from the group consisting of moφholinyl, piperazinyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, and imidazolidinyl, heteroaryl which is selected from the group consisting of pyridyl, furanyl, pyrazolyl, and thienyl, alkoxyalkyl optionally substituted with NRieRπ, or alkanoyl optionally substituted with 1 or 2 groups that are independently OH, halogen, -OC(0)-(Q-Q alkyl), or Q-Q alkoxy; wherein each of the above phenyl or heteroaryl groups are optionally substituted with 1, 2, 3, 4, or 5 groups that are independently Q-Q alkyl, Q-Q alkoxy, halogen, amino, CF3, or OCF3; each of the heterocycloalkyl groups is optionally substituted with 1, 2, 3, or 4 groups that are independently, Q-Q alkyl, Q-Q alkoxy, halogen, Q-Q alkanoyl, -C(0)NR]6Rι7; wherein Re and R7 are independently at each occurrence H, alkyl optionally substituted with NR^Rπ or a heteroaryl group that is selected from thienyl, pyridyl, and furanyl, hydroxyalkyl, dihydroxyalkyl, NRι6R17, alkoxy optionally substituted with NR16Rπ, Q-Q alkoxy Q-Q alkyl, OH, Q-Q alkanoyl, Q-Q cycloalkyl, phenyl Q-Q alkyl, tetrahydropyranyloxy, tetrahydrofuranyloxy, piperidinyloxy, pyrrolidinyloxy, Q-Q alkenyl optionally substituted with -OC(0)NR16R , -S02-phenyl, -S02NRι6Rπ, - S02-Q-Q alkyl, phenyl, pyrrolidinyl Q-C alkanoyl, piperidinyl Q-Q alkanoyl, pyridyl Q-Q alkanoyl, phenyl Q-Q alkoxy, phenyl Q-Q alkoxycarbonyl, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, - C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q- Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, moφholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy; or R6, R7, and the nitrogen to which they are attached form a moφholinyl, thiomoφholinyl, thiomoφholinyl S-oxide, thiomoφholinyl S,S-dioxide, piperidinyl, pyrrolidinyl, isoindole 1,3-dione, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxycarbonyl, hydroxyl, hydroxy Q-Q alkyl, dihydroxy Q-Q alkyl, or halogen; and R at each occurrence is independently H or Q-Q alkyl optionally substituted with 1 or 2 groups that are independently OH, halogen, amino, monoalkylamino, dialkylamino or Q-Q cycloalkyl. Embodiment 94. A compound according to Embodiment 83, wherein
R5 is selected from the group consisting of H, (Q-Q)alkyl optionally substituted with 1, 2, 3, 4, or 5 groups that are independently phenyl Q-Q alkoxycarbonyl, -NR8R9, halogen, -C(0)NR8R9, alkoxycarbonyl, or alkanoyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, benzothiazolyl, isoindolyl, dihydroindolyl, pyrazolyl, 3H- isobenzofuran-1-onyl, imidazolyl, pyridyl, pyrimidyl, pyrazinyl, furanyl, dihydroisoindolyl, indolon-2-yl, indazolyl, thienyl, benzimidazolyl, imidazolidine dione, pyrazolyl(Q-Q alkyl), furanyl(Q-Q alkyl), imidazolyl(Q-C6 alkyl), piperidinyl(Q-Q)alkyl, pyrrolidinyl(Q-Q)alkyl, imidazolidinyl(Q-Q)alkyl, 1H- indazolyl(Q-Q)alkyl, dihydroindolon-2-yl(Q-Q alkyl), 3H- isobenzofuranonyl(Q-Q alkyl), benzothiazolyl(Q-Q alkyl), indolinyl(Q-Q alkyl), dihydrobenzimidazolyl(Q-Q alkyl), benzimidazolyl (Q-Q) alkyl, isochroman-4-one (Q-Q) alkyl, oxazolidin-2-one (Q-Q) alkyl, benzoxazolyl (Q- Q) alkyl, dihydrobenzoimidazolonyl(Q-Q alkyl), pyridyl (Q-Q) alkyl, pyridazinyl (Q-Q) alkyl, pyrimidinyl (Q-C6) alkyl, pyrazinyl (Q-Q) alkyl, tetrahydrofuryl(C1-C6)alkyl, naphfhyl(Q-Q)alkyl, moφholinyl (Q-Q) alkyl, tetrahydrofuryl (Q-Q) alkyl, thienyl (Q-Q) alkyl, piperazinyl (Q-Q) alkyl, indolyl (Q-Q) alkyl, quinolinyl(Q-Q) alkyl, isoquinolinyl(Q-Q) alkyl, dihydro- lH-isoindolyl(Q-Q) alkyl, dihydroindolyl(Ci-C6) alkyl, imidazolyl(Q-Q) alkyl, dihydroisoindolyl(Cι-Ce) alkyl, indolon-2-yl(Q-Q) alkyl, moφholinyl Q-Q alkyl, -pyrimidinyl-piperazinyl, and -pyridinyl-piperazinyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently NR^Rπ, Q-Q alkyl optionally substituted with 1 or 2 groups that are independently NRieRπ, -NRι6S02-alkyl, -NRi6S02-phenyl, -OC(0)NH2, -OC(0)NHRιe, OH, or -OC(0)NR16R17, halogen, -OC(0)NReR7, Q-Q alkoxy optionally substituted with NR16R17, phenyl Q-Q alkoxy, Q-Q thioalkoxy, Q-Q alkoxycarbonyl, C02R, CN, carboxaldehyde, -S02(Q-Q)aTkyl optionally substituted with NR16R17, - S02NRι6R17) amidinooxime, NR8R9, CN, -NR6R7, NR6R7 Ci-Q alkyl, -C(0)NR6R7, -(Q-C4)alkyl-C(0)NR6R7, amidino, Q-Q haloalkyl, phenyl, hydroxy Q-Q alkyl, Q-Q dihydroxyalkyl, Q-Q haloalkoxy, Q-Q alkenyl optionally substituted with -OC(0)NR6R7, Q-Q alkoxy, or OH, -C(0)C(0)NR16Rπ, heterocycloalkyl or heterocycloalkyl(Q-Q)alkyl, wherein the heterocycloalkyl group is selected from the group consisting of moφholinyl, piperazinyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, and imidazolidinyl, heteroaryl which is selected from the group consisting of pyridyl, furanyl, pyrazolyl, and thienyl, alkoxyalkyl optionally substituted with NR16R17, or alkanoyl optionally substituted with OH, halogen, Q-Q cycloalkyl, -OC(0)-(Q-Q alkyl), or Q-Q alkoxy; wherein each of the above phenyl or heteroaryl groups are optionally substituted with 1, 2 3, 4, or 5 groups that are independently Q-Q alkyl, Q-Q alkoxy, halogen, amino, CF3, or OCF3; each of the heterocycloalkyl groups is optionally substituted with 1, 2, 3, or 4 groups that are independently, Q-Q alkyl, Q-Q alkoxy, halogen, Q-Q alkanoyl, -C(0)NRι6Rπ; R6 and R7 are independently at each occurrence H, alkyl optionally substituted with NR16R17 or a heteroaryl group that is selected from thienyl, pyridyl, and furanyl, hydroxyalkyl, dihydroxyalkyl, NRι6Rπ, alkoxy optionally substituted with NRieRπ, Q-Q alkoxy Q-Q alkyl, OH, Q-Q alkanoyl, Q-Q cycloalkyl, phenyl Q-Q alkyl, tetrahydropyranyloxy, tetrahydrofuranyloxy, piperidinyloxy, pyrrolidinyloxy, Q-Q alkenyl optionally substituted with -OC(0)NRι6R17, -S02-phenyl, -S02NR16R17, - S02-Q-Q alkyl, phenyl, pyrrolidinyl Q-Q alkanoyl, piperidinyl Q~Q alkanoyl, pyridyl Q-Q alkanoyl, phenyl Q-Q alkoxy, phenyl Q-Q alkoxycarbonyl, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, - ' C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q- Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, moφholinyl, pyrrolidinyl, piperazinyl, ~OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy; or R6, R , and the nitrogen to which they are attached form a moφholinyl, thiomoφholinyl, thiomoφholinyl S-oxide, thiomoφholinyl S,S-dioxide, piperidinyl, pyrrolidinyl, isoindole 1,3-dione, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxycarbonyl, hydroxyl, hydroxy Q-Q alkyl, dihydroxy Q-Q alkyl, or halogen; and R at each occurrence is independently H or Q-Q alkyl optionally substituted with 1 or 2 groups that are independently OH, halogen, amino, monoalkylamino, dialkylamino or Q-Q cycloalkyl. Embodiment 95. A compound according to Embodiment 94, wherein R5 is indolyl (Q-Q) alkyl-, indolinyl-(Q-C4 alkyl)-, isochroman-4-one (Q-Q) alkyl-, indolon-2-yl(Q-Q) alkyl-, benzoxazolyl (Q-Q) alkyl-, 3H-isobenzofuran-l-one (Q-Q) alkyl-, 3H-isobenzofuran-l-one, dihydro-lH-isoindolyl(Q-Q) alkyl, dihydroisoindolyl(Q-Q) alkyl, benzothiazolyl (Q-Q) alkyl-, benzothiazolyl, benzimidazolyl, or benzimidazolyl (Q-Q) alkyl-, optionally substituted with 1, 2, 3, or 4 groups that are independently Q-Q alkyl, OH, -C(0)C(0)NRι6R17, piperidinyl (Q-Q)alkyl, piperazinyl (Q-Q) alkyl, pyrrolidinyl (Q-Q)alkyl, NR6R7 Q-Q alkyl, moφholinyl Cι-C6 alkyl, Q-Q alkanoyl optionally substituted with 1 or 2 groups that are independently OH, halogen, -OC(0)-(Q-Q alkyl), or Q-Q alkoxy, -S02(Q-Q)alkyl, Q-Q alkoxycarbonyl, R and R7 are independently at each occurrence H, alkyl optionally substituted with NR16R17 or a heteroaryl group that is selected from thienyl, pyridyl, and furanyl, hydroxyalkyl, dihydroxyalkyl, NR16R17, alkoxy optionally substituted with NRieRπ, Q-Q alkoxy Q-Q alkyl, OH, Q-Q alkanoyl, Q-Q cycloalkyl, phenyl Q-Q alkyl, tetrahydropyranyloxy, tetrahydrofuranyloxy, piperidinyloxy, pyrrolidinyloxy, Q-Q alkenyl optionally substituted with -OC^NR^Rπ, -S02- phenyl, -S02NR16Rπ, -S02-Q-Q alkyl, phenyl, pyrrolidinyl Q-Q alkanoyl, piperidinyl Q-Q alkanoyl, pyridyl Q-Q alkanoyl, phenyl Q-C4 alkoxy, phenyl Q-Q alkoxycarbonyl, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, moφholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy. Embodiment 96. A compound according to Embodiment 94, wherein R5 is pyrazolyl Q-Q alkyl, oxazolidin-2-one (Q-Q) alkyl, furanyl, thienyl, or furanyl Q- Q alkyl, which are optionally substituted with 1 or 2 groups independently selected from the group consisting of -C(0)NR6R7, NR6R7 Q-Q alkyl, Q-Q alkyl, Q-Q alkoxycarbonyl, (Q-Q) alkyl optionally substituted with 1 or 2 groups that are independently NRieRπ, -NRi6S02-alkyl, -NR16S02-phenyl, - OC(0)NH2, -OC(0)NHR16, OH, or -OC(0)NR16R , hydroxy Q-Q alkyl, heterocycloalkyl which is selected from the group consisting of moφholinyl, piperazinyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, and imidazolidinyl, C02R, Q-Q cycloalkyl, wherein R6 and R7 are independently at each occurrence H, alkyl optionally substituted with NRiβRπ or a heteroaryl group that is selected from thienyl, pyridyl, and furanyl, hydroxyalkyl, dihydroxyalkyl, NR^Rπ, alkoxy optionally substituted with NR16Rπ, Q-Q alkoxy Q-Q alkyl, OH, Q-Q alkanoyl, Q-Q cycloalkyl, phenyl Q-Q alkyl, tetrahydropyranyloxy, tetrahydrofuranyloxy, piperidinyloxy, pyrrolidinyloxy, Q-Q alkenyl optionally substituted with -OC(0)NR16Rπ, -S02-phenyl, -S02NR16R17, - SO2-Q-Q alkyl, phenyl, pyrrolidinyl C1-C4 alkanoyl, piperidinyl C1-C4 alkanoyl, pyridyl Q-Q alkanoyl, phenyl Q-Q alkoxy, phenyl Q-Q alkoxycarbonyl, or phenyl Q-Q alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, - C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q aikyl)(Q-Q alkyl), Q- Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, moφholinyl, pyrrolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy; or R6, R7, and the nitrogen to which they are attached form a moφholinyl, thiomoφholinyl, thiomoφholinyl S-oxide, thiomoφholinyl S,S-dioxide, piperidinyl, pyrrolidinyl, isoindole 1,3-dione, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently Q-Q alkyl, Q-Q alkoxycarbonyl, hydroxyl, hydroxy Q-Q alkyl, dihydroxy Q- Q alkyl, or halogen; and R at each occurrence is independently H or Q-Q alkyl optionally substituted with 1 or 2 groups that are independently OH, halogen, amino, monoalkylamino, dialkylamino or Q-Q cycloalkyl. Embodiment 97. A compound according to Embodiment 1 that is selected from (2E)-4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]but-2-enoic acid; 3-[4- { [2-( { [(cyclopropylamino)carbonyl]amino } methyl)-4-fluorobenzyl]oxy } -6-methyl-2- oxopyridin- 1 (2H)-yl] -N,4-dimefhylbenzamide; 3,5-dibromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[4-methyl-2- (methylsulfonyl)pyrimidin-5-yl]pyridin-2(lH)-one; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-methyl-4- (moφholin-4-ylcarbonyl)benzamide; 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylpyrimidine-2-carboxylic acid; 2-( { [3-bromo- 1 -(2,6-difluorophenyl)-6-methyl-2-oxo- 1 ,2-dihydropyridin-4-yl]oxy } methyl) 5-fluorobenzarnide; 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4-methyl-N- (tetrahydro-2H-pyran-2-yloxy)benzamide; 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3- (trifluoromethyl)benz amide; 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-methyl-3- (trifluoromethyl)benzamide; 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-hydroxy-4- methylbenzamide; 3 -bromo-4- [(2,4-difluorobenzyl)oxy] - 1 - { 2,6-difluoro-4- [( lE)-3 -hydroxyprop- 1 -en- 1 - yl]phenyl } -6-methylpyridin-2( lH)-one; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yιj-4-mefhyl-N- (tetrahydro-2H-pyran-2-yloxy)benzamide; (2E)-3-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3,5- difluorophenyl }prop-2-en- 1 -yl carbamate; l-[5-(aminomethyl)-2-methylphenyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridi 2(lH)-one hydrochloride; N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylbenzyl}-2-hydroxyacetamide; 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3,5- difluorobenzamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[2,6-difluoro-4-(hydroxymethyl)phenyl]-6- methylpyridin-2( lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[(2E)-4-moφholin-4-yl-4-oxobut-2-en-l- yl]pyridin-2(lH)-one; tert-butyl {3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- fluorophenyl } carbamate ; N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl }phenyl)urea; 2-[(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}phenyl)amino]-l-methyl-2-oxoethyl acetate; methyl 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-2-furoate; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[(l-glycoloyl-2,3-dihydro-lH-indol-5- yl)methyl]pyridin-2( lH)-one; ' N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}phenyl)-2-hydroxypropanamide; N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}phenyl)-2-hydroxy-2-methylpropanamide; 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-l(2H)- yl]benzamide; 2-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3,5- difluorophenyl } -2-hydroxyethyl carbamate; 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3- fluorobenzamide; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylbenzamide; { l-[3-(aminocarbonyl)phenyl]-5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxo-l,6- dihydropyridin-2-yl } methyl carbamate; 2-({3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- fluorophenyl } amino)-2-oxoethyl acetate; 2-({3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- fluorophenyl } amino)- 1 , 1 -dimethyl-2-oxoethyl acetate; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-l(2H)- yl]benzamide; N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl }benzyl)-7V-methylurea; l-[4-(aminomethyl)phenyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)- one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[5-(moφholin-4-ylcarbonyl)-2- furyl]pyridin-2( lH)-one; 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]benzyl carbamate; {5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-2-furyl}methyl carbamate; 3-bromo-2-[2-(2-fluorophenyl)pyridin-4-yl]-l,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4- one trifluoroacetate; N- { 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl]benzyl } -2- hydroxy-2-methylpropaήamide; l-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3,5- difluorophenyl } ethane- 1 ,2-diyl dicarbamate; 1 - [4-(aminomethyl)-2-fluorophenyl] -3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methylpyridin 2(lH)-one hydrochloride; 2-(5- { [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yl]methyl } -2,3-dihydro- lH-indol- 1 -yl)-2-oxoethyl acetate; 2-(5- { [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yl]methyl } -2,3-dihydro- 1 H-indol- 1 -yl)- 1 , 1 -dimethyl-2-oxoethyl acetate ; 5- { [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yl]methyl } - 1 ,3-dihydro-2H- indol-2-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 -( lH-pyrazol-3-ylmethyl)pyridin-2( lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]- 1 -( lH-pyrazol-3-ylmethyl)pyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 - { [ l-(2-hydroxyethyl)- lH-pyrazol-3-yl] methyl } -6- methylpyridin-2( lH)-one; 4- { [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)- yl]methyl jbenzenesulfonamide; { l-[3-(aminocarbonyl)phenyl]-5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxo-l,6- dihydropyridin-2-yl } methyl acetate ; l-(l,3-benzoxazol-6-ylmethyl)-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylρyridin- 2(lH)-one; { l-[3-(aminocarbonyl)phenyl]-5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxo-l,6- dihydropyridin-2-yl } methyl carbamate; 5- { [3-bromo-4- [(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl]mefhyl } -N-(2- hydroxyethyl)-2-furamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-{[5-(moφholin-4-ylcarbonyl)-2- furyl]methyl }pyridin-2( lH)-one; 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-N- methyl-2-furamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(4-vinylphenyl)pyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl- 1 - { [5-(piperazin- 1 -ylcarbonyl)-2- furyljmethyl } pyridin-2( lΗ)-one; methyl 2-bromo-5-{ [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1(2H)- yljmethyl Jbenzoate; N- { 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl]benzyl } urea; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-{[2-(methylamino)pyrimidin-5- yl]methyl}pyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{[5-(hydroxymethyl)-2-furyl]methyl}-6- methylpyridin-2( lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]- 1 -[4-( 1 ,2-dihydroxyethyl)phenyl]-6-methylpyridin- 2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[5-(piperidin-l-ylcarbonyl)-2- furyl]pyridin-2( lH)-one; methyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-l(2H)- yl]benzoate; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-{[l-(methylsulfonyl)-2,3-dihydro-lH- indol-5-yl]methyl}pyridin-2(lH)-one; 2-(5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-2,3- dihydro- lH-indol- 1 -yl)-2-oxoethyl acetate; 2-(5-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-2,3- dihydro- lH-indol- 1 -yl)- 1 , 1 -dimethyl-2-oxoethyl acetate 3-[3-bromo-4-[(2,4-diflubrobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-cyclopropyl-4- methylbenzamide ; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyL-l-(lH-pyrazol-3-ylmethyl)pyridin-2(lH)- one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 - { [ 1 -(methoxyacetyl)- lH-pyrazol-3-yl] methyl J -6- methylpyridin-2( lH)-one; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-7Y-ethyl-4- methylbenz amide; N-allyl-3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylbenzamide; { l-allyl-5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxo-l,6-dihydroρyridin-2-yl}methyl acetate; 4- { [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin- 1 (2H)- yljmefhyl } -N-methylbenzamide; l-{[5-(aminomethyl)pyrazin-2-yl]methyl}-3-bromo-4-[(2,4-difluorobenzyl)oxyj-6- methylpyridin-2( lH)-one; 2- { [(5- { [3-bromo-4- [(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)- yl] methyl }pyrazin-2-yl)methyl] amino } -2-oxoethyl acetate; N-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yljmefhyl } pyrazin-2-yl)methyl]-2-hydroxyacetamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{[2-(dimethylamino)pyrimidin-5-yl]methyl}-6- methylpyridin-2( lH)-one trifluoroacetate; methyl 3-[3-chloro-4-{ [2-({ [(cyclobutylamino)carbonyl] amino }methyl)-4- fluorobenzyl]oxy}-6-methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoate; l-allyl-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)pyridin-2(lH)-one; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-butyl-4- methylbenzamide; 5- { [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)- yl]methyl}pyrimidine-2-carbonitrile; N-(2-aminoethyl)-3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]-4-methylbenzamide hydrochloride; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)- 1 - {4- [(methylamino)methyl]benzyl }pyridin-2( lH)-one; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-isobutyl-4- methylbenzamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[l-(2-hydroxy-2-methylpropyl)-lH-pyrazol-3- yl]methyl}-6-methylpyridin-2(lH)-one; ethyl 3- { [3-bromo-4-[(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl]methyl } - 1 - (tetrahydro-2H-pyran-2-yl)-lH-pyrazole-5-carboxylate; 3-[3-chloro-4-{[2-({[(cyclobutylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6- methyl-2-oxopyridin- 1 (2H)-yl]-N,4-dimethylbenzamide; N-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrazin-2-yl)methyl]acetamide; N-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl] methyl } pyrazin-2-yl)methyl] methanesulf onamide; methyl [(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrazin-2-yl)methyl]carbamate; N-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrazin-2-yl)methyl]-2-hydroxy-2-methylpropanamide; 7Y-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl } pyrazin-2-yl)methyl] - 1 -hydroxycyclopropanecarboxamide; N1-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrazin-2-yl)methyl]glycinamide hydrochloride; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(3-oxo-l,3-dihydro-2-benzofuran-5- yl)pyridin-2( lH)-one; 3-[3-chloro-4-{[2-({[(cyclopropylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6- methyl-2-oxopyridin-l(2H)-yl3-N,4-dimethylbenzamide; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylbenzenesulfonamide; tert-butyl 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yljmethyl }- 1 ,3-dihydro-2H-isoindole-2-carboxylate; methyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-l(2H)-yl] 4-methylbenzoate; l-{[2-(aminomethyl)pyrimidin-5-yl]methyl}-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methylpyridin-2( lH)-one trifluoroacetate; N1-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl }pyrimidin-2-yl)methyl]glycinamide trifluoroacetate; 3-[3-chloro-4-{[2-({[(cyclopropylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6- methyl-2-oxopyridin-l(2H)-yl]-N-[2-hydroxy-l-(hydroxymethyl)ethyl]-4-methylbenzamide; methyl 5-bromo-2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]benzoate; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-[(l,3-dioxo-l,3-dihydro-2H-isoindol-2- yl)methyl] -2-oxopyridin- 1 (2H)-yl]benzamide; 3-bromo-4-[(2,4-difluoiObenzyl)oxy]-6-methyl-l-(2-methyl-5-vinylphenyl)pyridin-2(lH)- one; l-[(2-aminopyrimidin-5-yl)methyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin- 2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[(2-methoxypyrimidin-5-yl)methyl]-6- methylpyridin-2( lH)-one; 3-[6-(aminomethyl)-3-bromo-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]benzamid hydrochloride; methyl 5- { [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl]methyl } - 2-vinylbenzoate; 3-[3-chloro-4-{[2-({[(cyclopropylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6- methyl-2-oxopyridin- 1 (2H)-yl] -N- [2-(dimethylamino)ethyl] -4-methylbenzamide ; 5- { [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl] methyl } -2- vinylbenzoic acid; 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrimidine-2-carboxamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[5-(l,2-dihydroxyethyl)-2-methylphenyl]-6- methylpyridin-2( lH)-one; N1-(4-{ [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl }benzyl)alaninamide hydrochloride; N'-(4- { [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)- yl]methyl }benzyl)-N2-methylglycinamide hydrochloride; N1-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl }benzyl)serinamide hydrochloride; N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yljmefhyl }benzyl)prolinamide hydrochloride; dimethyl 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]isophthalate; methyl 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-5- vinylbenzoate; methyl 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-5-(l,2- dihydroxyethyl)benzoate ; 3-[3-chloro-4-{ [2-({[(cyclopropylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6- methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzamide; N-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl] methyl } pyrimidin-2-yl)methyl] -2-hydroxyacetamide ; 5- { [3-chloro-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl]methyl } - 1 - methyl- 1 ,3-dihydro-2H-indol-2-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(2,3-dihydro-lH-isoindol-5-ylmethyl)-6- methylpyridin-2( lH)-one trifluoroacetate; 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}pyridine- 2-carboxamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]- 1- { 2,6-difluoro-4-[(E)-2-methoxy vinyl]phenyl } -6- methylpyridin-2( lH)-one; 3-bromo-4- [(2,4-difluorobenzyl)oxy] - 1 - { 2,6-difluoro-4-[(Z)-2-methoxy vinyl]phenyl } -6- methylpyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[2,6-difluoro-4-(2-hydroxyethyl)phenyl]-6- methylpyridin-2( lH)-one; 5- { [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl]methyl }-N- methyl-2-vinylbenzamide; 5-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-l-methyl-l,3- dihydro-2H-indol-2-one; methyl 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-5-(l- hydroxy- 1 -methylethyl)benzoate; 5- { [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl]methyl } -2-( 1 ,2- dihydroxyethyl)-N-methylbenzamide; N1-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl }pyrazin-2-yl)methyl]-D-alaninamide hydrochloride; N1-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrazin-2-yl)methyl]-N2-methylglycinamide hydrochloride; N1-[(5-{ [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxoρyridin-l(2H)- yl]methyl }pyrazin-2-yl)methyl]-D-serinamide hydrochloride; 3-[3-bromo-4- { [2-( { [(ethylamino)carbonyl] amino } methyl)-4-fluorobenzyl]oxy } -6-methyl-2 oxopyridin- 1 (2H)-yl]-N,4-dimethylbenzamide; 3 -bromo-4- [(2,4-difluorobenzyl)oxy] - 1 - [4-( 1 ,2-dihydroxyethyl)-2-methylphenyl] -6- methylpyridin-2( lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[4-(l,2-dihydroxyethyl)-2-methylphenyl]-6- methylpyridin-2( lH)-one; 3-[3-bromo-4-{[2-({[(ethylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6-methyl-2 oxopyridin- 1 (2H)-ylj-4-methylbenzamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[2-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro- lH-isoindol-5-yl]methyl}-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-dimethyl-l,3-benzothiazol-5-yl)-6- methylpyridin-2( lH)-one; 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoic acid; 5- { [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl] methyl } -2-furoic acid; 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3- (trifluoromethyl)benzoic acid; 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N,N-dimethyl-3- (trifluoromethyl)benzamide; 4-[3-bromo-4-[(2,4-dif uorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3-fluorobenzoic acid; l-[5-(aminomethyl)-2-fluorophenyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin- 2(lH)-one hydrochloride; 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3,5- difluorobenzoic acid; (2E)-4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-(2- hydroxy-2-methylpropyl)but-2-enamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[5-(5-hydroxy-lH-pyrazol-3-yl)-2-methylphenyl]-6- methylpyridin-2(lH)-one; \ 3-bromo-4-[(2,4-difluorobenzyl)oxy]- 1 -[5-(hydroxymethyl)-2-furyl]-6-methylpyridin-2( 1H) one; methyl 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- [(methylamino)methyl]benzoate; (-)-3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylbenzamide; ' 3 -bromo-4- [(2 ,4-difluorobenzyl)oxy] - 1 - { 2-(hydroxymethyl)-5- [(methylamino)methyl]phenyl}-6-methylpyridin-2(lH)-one; 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-(2- hydroxyethyl)-2-furamide ; l-[4-(aminomethyl)-2-fluorophenyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin- 2(lH)-one hydrochloride; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[4-methyl-2-(methylsulfonyl)pyrimidin-5- yl]pyridin-2(lH)-one; 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N1-(2- hydroxyethy^-iv^-methylterephthalamide; 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylpyrimidine-2-carbonitrile; methyl 3-[4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-l(6H)-yl]-4- methylbenzoate; 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylpyrimidine-2-carboxamide; 3-chloro-l-{[l-(cyclopropylcarbonyl)-lH-pyrazol-3-yl]methyl}-4-[(2,4-difluorobenzyl)oxy] 6-methylpyridin-2( lH)-one; 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylthiophene-3-carboxamide; { 1 -allyl-5-bromo-4- [(2,4-difluorobenzyl)oxy]-6-oxo- 1 ,6-dihydropyridin-2-yl } methyl phenylcarbamate; { l-allyl-5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxo-l,6-dihydropyridin-2-yl}methyl [2-(3- thienyl)ethyl]carbamate; methyl 4-{ l-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]ethyl }benzoate; 4-{ l-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]ethyl}benzoic acid; 4-{ l-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]ethyl}-N- methylbenzamide; 4-{ l-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yljefhyl Jbenzamide; (+)-3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylbenzamide 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{ l-[4-(hydroxymethyl)phenyl]ethyl}-6- methylpyridin-2( lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(2-oxopropyl)pyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]- 1 -[4-(hydroxymethyl)-3-( 1-hydroxy- 1 - methylethyl)phenyl]-6-methylpyridin-2(lH)-one; l-[2,4-bis(l-hydroxy-l-methylethyl)phenyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methylpyridin-2( lH)-one; 5-bromo-2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N- methylbenzamide; 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-methyl-5- vinylbenzamide; 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-5-(l,2- dihydroxyethyl)-N-methylbenzamide; 3-[3-bromo-4-{ [2-({ [(ethylamino)carbonyl] amino }methyl)-4-fluorobenzyl]oxy }-6-methyl- 2-oxopyridin-l(2H)-yl]-4-methyl-N-(2,2,2-trifluoroethyl)benzamide; 3-bromo-l-(3'-chloro-4-methylbiphenyl-3-yl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin- 2(lH)-one; 2-(5- { [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxoρyridin- 1 (2H)-yl]methyl }- lH-indol-3- yl)-N,N-dimethyl-2-oxoacetamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluoro-4-glycoloylphenyl)-6-methylpyridin- 2(lH)-one; N-(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl } pyrazin-2-yl)-2-hydroxy-2-methylpropanamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[3-(piperidin-l-ylmethyl)-lH-indol-5- yl]methyl}pyridin-2(lH)-one; N-(4- { [3-bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)- yljmethyl }phenyl)piperidine-4-carboxamide hydrochloride; N2-(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl } pyrimidin-2-yl)glycinamide; N-(4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}phenyl)-2-hydroxy-2-methylpropan amide; 3-[3-bromo-4-{[2-({[(ethylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6-methyl- 2-oxopyridin-l(2H)-yl]-N-[2-(dimethylamino)ethyl]-4-methylbenzamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 - { [3-(piperazin- 1 -ylmethyl)- lH-indol-5- yl]methyl }pyridin-2( lH)-one hydrochloride; N!-(4- { [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)- yl]methyl}benzyl)-D-serinamide hydrochloride; N1-(4-{[3-bromo-4-[(2,4-difluoiObenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl }benzyl)-L-threoninamide hydrochloride; N1-(4-{ [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)- yl]methyl }phenyl)-2-methylalaninamide hydrochloride; N!-(4- { [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)- yl] methyl } benzyl)-D-alaninamide hydrochloride ; N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl] methyl }benzyl)piperidine-4-carboxamide hydrochloride; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[(2-{[2-(dimethylamino)ethyl]amino}pyrimidin-5- yl)methyl]-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-({3-[(dimethylamino)methyl]-lH-indol-5- yl}methyl)pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-({3-[(methylamino)methyl]-lH-indol-5- yl}methyl)pyridin-2(lH)-one; 7Y1-(4- { [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)- yljmethyl }benzyl)-N~-methyl-L-serinamide hydrochloride; N-(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyridin-2-yl)-2-hydroxy-2-methylpropanamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1-[(3- { [(2-hydroxyethyl)amino]methyl } - lH-indol-5- yl)methyl]pyridin-2( lH)-one; Nl-(4- { [3-chloro-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)- yl]methyl }benzyl)-L-serinamide hydrochloride; N1-(4-{ [3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}phenyl)-2-methylalaninamide hydrochloride; N1-(4-{ [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yljmethyl }benzyl)-D-allothreoninamide hydrochloride; N1-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl] methyl }benzyl)-2-methylalaninamide hydrochloride; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 - { [3-(moφholin-4-ylmethyl)- lH-indol-5- yl]methyl}pyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-({2-[(2-hydroxyethyl)amino]pyrimidin-5- yl }methyl)-6-methylpyridin-2( lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[3-({[2-(dimethylamino)ethyl]amino}methyl)-lH- indol-5-yl] methyl }ρyridin-2( lH)-one; l-({2-[(2-aminoethyl)amino]pyrimidin-5-yl}methyl)-3-bromo-4-[(2,4-difluorobenzyl)oxy]- 6-methylpyridin-2( lH)-one trifluoroacetate; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-hydroxy-iV,4- dimethylbenzamide; N-(5- { [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)- yl]methyl } pyrazin-2-yl)-2-hydroxyacetamide; 3 - [3 -bromo-4- { [4-fluoro-2-( { [(methoxyamino)carbonyl] amino } methyl)benzyl] oxy } -6- methyl-2-oxopyridin- 1 (2H)-yl] -N,4-dimethylbenzamide; l-allyl-6-[(allylamino)methyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]pyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[4-(2-hydroxyethyl)-2-methylphenyl]-6- methylpyridin-2( lH)-one; N'-(4- { [3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H> yl]methyl}benzyl)-L-threoninamide hydrochloride; N1-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yljbenzyl } glycinamide hydrochloride; 3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-N-[2- (dimethylamino)ethyl]-lH-pyrazole-5-carboxamide; 3 -bromo-4- [(2,4-difluorobenzyl)oxy] - 1 - [(2- { [2-hydroxy- 1 - (hydroxymethyl)ethyl]amino}pyrimidin-5-yl)methyl]-6-methylpyridin-2(lH)-one; 3-[3-bromo-4-{[4-fluoro-2-({[(methoxyamino)carbonyl]amino}methyl)benzyl]oxy}-6- methyl-2-oxopyridin- 1 (2H)-yl]-4-methylbenzamide; 5- { [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl]methyl }-N- methylpyridine-2-carboxamide; l-{[5-(aminomethyl)-2-furyl]methyl}-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methylpyridin-2( lH)-one hydrochloride; N-(2- { [(3-bromo- 1 - { 5- [(2,2-dimethylhydrazino)carbonyl] -2-methylphenyl } -6-methyl-2- oxo- 1 ,2-dihydropyridin-4-yl)oxy]methyl } -5-fluorobenzyl)-/Y-ethylurea; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[3-(pyrrolidin-l-ylmethyl)-lH-indol-5- yl] methyl }pyridin-2( 1H) -one; 3- { [3-bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl]methyl } -N-(2- methoxyethyl)-lH-pyrazole-5-carboxamide; 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-methyl-2- vinylbenzamide; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-hydroxy-4- methylbenzamide; 3-[3-bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Η-pyridin-l-yl]-N- carbamoylmethyl-benzamide; N1-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]benzyl}-N2- methylglycinamide hydrochloride; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(2,5-dimethyl-lH-benzimidazol-6-yl)-6- methylpyridin-2( lH)-one; 3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-lH- pyrazole-5-carboxamide; 3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-N-(2,3- dihydroxypropyl)-lH-pyrazole-5-carboxamide; 3- { [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl]methyl } -N- methyl- lH-pyrazole-5-carboxamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 -(2,3-dihydro- lH-isoindol-5-ylmethyl)pyridin- 2(lH)-one trifluoroacetate; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxo-2H-l,4'-bipyridine-2'-carboxamide; 3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-N-(2- hydroxyethyl)-lH-pyrazole-5-carboxamide; N-[(5- { [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl]methyl } -2- furyl)methyl]-2-hydroxy-2-methylpropanamide; N1-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]benzyl } alaninamide hydrochloride ; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl- 1 -(2-methylprop-2-en- l-yl)pyridin-2( 1H)- one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[4-(l,2-dihydroxyethyl)-2-methylphenyl]-6- methylpyridin-2( lH)-one; 5-bromo-6-[(2,4-difluorobenzyl)oxy]-3-isopropyl-2-[4-(2-methylalanyl)piperazin-l- yl]pyrimidin-4(3H)-one trifluoroacetate; methyl 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxo-2H-l,4'-bipyridine-2'- carboxylate; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[5-(2-furyl)-2-methylphenyl]-6-methylpyridin- 2(lH)-one; N1-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yljbenzyl } serinamide hydrochloride; 5- { [3-bromo-4- [(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl]methyl } -N,N- dimethylpyridine-2-carboxamide; 3- { [3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl]methyl } -TV- methyl- lH-pyrazole-5-carboxamide; N1-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl] methyl }pyrazin-2-yl)methyl]-D-alaninamide hydrochloride; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-[(glycylamino)methyl]-2-oxopyridin-l(2H)- yl]benzamide hydrochloride; 3-bromo-4-[(2,4-difluorobenzyl)oxy]- 1 -(4-hydroxy- 1 -oxo-3,4-dihydro- lH-isochromen-7- yl)-6-methylpyridin-2( lH)-one; 6- { [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)- yl]methyl } nicotinamide ; N1-[(5-{ [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrazin-2-yl)methyl]-2-methylalaninamide hydrochloride; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxo-2H-l,4'-bipyridine-2'-carboxylic acid; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- { [(N-methylglycyl)amino]methyl } -2- oxopyridin- 1 (2H)-yl]benzamide hydrochloride; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-2-oxo-6-[(serylamino)methyl]pyridin-l(2H)- yl]benzamide hydrochloride; NI-[(5-{ [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrazin-2-yl)methylj-D-serinamide hydrochloride; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(3-methyl-4-vinylphenyl)pyridin-2(lH)- one; N-[(5- { [3-bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)- yl]methyl}pyrazin-2-yl)methyl]urea; N-[(5-{ [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrazin-2-yl)methyl]piperidine-4-carboxamide hydrochloride; 3-{ [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-N,N- dimethyl-lH-pyrazole-S^carboxamide; {5-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[(2E)-4-hydroxybut-2-en-l-yl]-6-oxo-l,6- dihydropyridin-2-yl } methyl acetate; 3 -[6- [(alanylamino)methyl] -3 -bromo-4- [(2,4-difluorobenzyl)oxy] -2-oxopyridin- 1 (2H)- yl]benzamide hydrochloride; 3-chloro-4- [(2,4-difluorobenzyl)oxy]-6-methyl- 1 -(3-methyl- lH-pyrazol-4-yl)pyridin- 2(lH)-one; N-({ l-[3-(aminocarbonyl)phenyl]-5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxo-l,6- dihydropyridin-2-yl}methyl)pyridine-2-carboxamide; methyl 2-biOmo-5-[3-bromo-4-[(2,4-difluoiObenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yljbenzoate; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-2'-(hydroxymethyl)-6-methyl-2H-l,4'-bipyridin-2- one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[4-(l,2-dihydroxyethyl)-3-methylphenyl]-6- methylpyridin-2( lH)-one; N-({3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxo-2H-l,3'-bipyridin-6'-yl}methyl)- 2-hydroxy-2-methylpropanamide; 6'-(aminomethyl)-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2H-l,3'-bipyridin-2-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-({2-[2-(dimethylamino)ethoxy]pyrimidin-5- yl }methyl)-6-methylpyridin-2( lH)-one; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- { [(2-methylalanyl)amino]methyl } -2-oxopyridin- l(2H)-yl]benzamide hydrochloride; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- { [(2-hydroxy-2- methylpropanoyl)amino] methyl } -2-oxopyridin- 1 (2H)-yl]benzamide; 3-bromo-6'-chloro-4-[(2,4-difluorobenzyl)oxy]-5',6-dimethyl-2H-l,3'-bipyridin-2-one; 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-5- (hydroxymethyl)-N-methylbenzamide; 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3- [(methylamino)carbonyl]benzyl carbamate; 4-[3-bromo-4-[(2,4-dif uorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3- [(methylamino)carbonyl]benzyl carbamate; 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-2-vinylbenzoic acid; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxo-2H-l,3'-bipyridine-6'-carboxamide; methyl 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3- [(methylamino)carbonyl]benzoate; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2'-vinyl-2H-l,4'-bipyridin-2-one; 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-2-(l,2- dihydroxyethyl)-N-methylbenzamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-5',6-dimethyl-6'-vinyl-2H-l,3'-bipyridin-2-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[2-(methylsulfonyl)pyrimidin-5- yl]pyridin-2(lH)-one; 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-5-formyl-N- methylbenzamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxo-2H-l,3'-bipyridine-6'-carbonitrile; methyl 3-bromo-4-[(2,4-difluorobenzyl)oxy]-5',6-dimethyl-2-oxo-2H-l,3'-bipyridine-6'- cai'boxylate; 3-bromo-4- [(2,4-difluorobenzyl)oxy]-6-methyl- 1 - [(2-oxo- 1 ,3-oxazolidin-5- yl)methyl]pyridin-2( lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6'-(l,2-dihydroxyethyl)-5',6-dimethyl-2H-l,3'- bipyridin-2-one; 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-methyl-5- [(methylamino)methyl]benzamide; 3-bromo-2'-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2H-l,4'-bipyridin-2-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-5',6-dimethyl-2-oxo-2H-l,3'-bipyridine-6'- carboxamide; (-)-3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylbenzoic acid; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-2'-(l,2-dihydroxyethyl)-6-methyl-2H-l,4'-bipyridin- 2-one; 2-[3-bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl]-5-( 1 -hydroxy- 1 - methylethyl)-7Y-methylbenzamide ; 3-bromo-4-[(2,4-difluoroberizyl)oxy]-l-(3,3-dimethyl-l-oxo-l,3-dihydro-2-benzofuran-5- yl)-6-methylpyridin-2( lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)pyridin-2(lH)-one; 3-[3-bromo-4-[(2,4-difluorophenoxy)methyl]-6-methyl-2-oxopyridin-l(2H)-yl]-N,4- dimethylbenzamide ; 2-({[3-bromo-l-(2,6-difluorophenyl)-6-methyl-2-oxo-l,2-dihydropyridin-4-yl]oxy}methyl)-5- fluoro-N-( 1-methyl- lΗ-pyrazol-3-yl)benzamide; 2-( { [3-bromo- 1 -(2,6-difluorophenyl)-6-methyl-2-oxo- 1 ,2-dihydropyridin-4-yl]oxy } methyl)- N-(cyclopropylmethyl)-5-fluorobenzamide; 3- { [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl]methyl } - 1 - tetrahydro-2H-pyran-2-yl- lH-pyrazole-5-carboxylic acid; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl- 1 - { [2-(methylsulfonyl)pyrimidin-5- yl]methyl}pyridin-2(lH)-one; and 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-{[2-(methylthio)pyrimidin-5- yl] methyl } pyridin-2( 1 H)-one. Embodiment 98. A compound according to Embodiment 78 of the formula:
Figure imgf000215_0001
wherein,
Figure imgf000216_0001
216-
Figure imgf000217_0001
Embodiment 78, of the formula:
217
Figure imgf000218_0001
wherein Ri is halogen; and Z, R20, and R30 are as defined below:
Figure imgf000218_0002
218 -
Figure imgf000219_0001
219-
Figure imgf000220_0001
-220-
Figure imgf000221_0003
bodiment 78 of the formula:
Figure imgf000221_0001
wherein Y is CONH(CH2)nOH; CONHCH2C(Me)2OH; CONH(CH2)nNH2; CONH(CH2)nNHCH3; CONH(CH2)nN(CH3)2; CONHCH2CH(OH)CH2OH; CH2NHCOCH2NH2; CH2NHCOCH2OH; CH2NHCOCH(NH2)CH2OH; and n is 1, 2, or 3. Embodiment 101. A compound according to Embodiment 78, of the formula:
, wherein
Figure imgf000221_0002
- 221 n
Figure imgf000222_0001
R51 is H, OH, NH2, NHR52, CONHR52, or OR52;
R^is H. Q- alkyl;
R53 is H or alkyl. Embodiment 102. A compound according to Embodiment 78, of the formula:
Figure imgf000222_0002
wherein R5o is: CH2CONH2; CH2CONHCH3;
222 CH2CONH(CH3)2; CH2CONH(CH2)nNH2; CH2CONH(CH2)nNHCH3; CH2NHCONH2; CH2NHCO(CH2)2NH2; CH2NHCH3; CH2N(CH3)2; CH2NHS02 (C1-C3 alkyl); CH2NHS02 phenyl; CH2NHCOCH(alkyl)NH2; CH2NHCOCH(CH2OH )NH2; CH2OCONH2; CH20(CH2)2NH2; CONHCH3; CONH2; CON(CH3)2; CONH(CH2)„NH2; CONH(CH2)nNHCH3; CONH(CH2)nN(CH3)2; and n is 1, 2, or 3. Definitions As used herein, the term "alkenyl" refers to a straight or branched hydrocarbon of a designed number of carbon atoms containing at least one carbon-carbon double bond. Examples of "alkenyl" include vinyl, allyl, and 2-methyl-3-heptene. The term "alkoxy" represents an alkyl attached to the parent molecular moiety through an oxygen bridge. Examples of alkoxy groups include, for example, methoxy, ethoxy, propoxy and isopropoxy. The term "thioalkoxy" represents an alkyl attached to the parent molecular moiety through a sulfur atom. Examples of thioalkoxy groups include, for example, thiomethoxy, thioethoxy, thiopropoxy and thioisopropoxy.
223 As used herein, the term "alkyl" includes those alkyl groups of a designed number of carbon atoms. Alkyl groups may be straight or branched. Examples of "alkyl" include methyl, ethyl, propyl, isopropyl, butyl, iso-, sec- and tert-butyl, pentyl, hexyl, heptyl, 3- ethylbutyl, and the like. "Cx-Cy alkyl" represents an alkyl group of the specified number of carbons. For example, Q-C4 alkyl includes all alkyl groups that include at least one and no more than four carbon atoms. It also contains subgroups, such as, for example, Q- C3 alkyl or Q-Q alkyl. The term "aryl" refers to an aromatic hydrocarbon ring system containing at least one aromatic ring. The aromatic ring may optionally be fused or otherwise attached to other aromatic hydrocarbon rings or non-aromatic hydrocarbon rings. Examples of aryl groups include, for example, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalene, indanyl, and biphenyl. Preferred examples of aryl groups include phenyl and naphthyl. The most preferred aryl group is phenyl. The aryl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. Thus, such aryl groups can be optionally substituted with groups such as, for example, Q-Q alkyl, - alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di-(Q-Q)alkylamino, Q- Qalkenyl, Q-Qalkynyl, Q-Q haloalkyl, Q-Q haloalkoxy, amino(Q-Q)alkyl, mono- or di(C 1 -Q)alkylamino(Q-Q)alkyl. The term "arylalkyl" refers to an aryl group, as defined above, attached to the parent molecular moiety through an alkyl group, as defined above. Preferred arylalkyl groups include, benzyl, phenethyl, phenpropyl, and phenbutyl. More preferred arylalkyl groups include benzyl and phenethyl. The most preferred arylalkyl group is benzyl. The aryl portions of these groups are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. Thus, such aryl groups can be optionally substituted with groups such as, for example, Q-Q alkyl, Q-Q alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di-(Q-Q)alkylamino, Q-Qalkenyl, Q- Qalkynyl, Q-Q haloalkyl, Q-Q haloalkoxy, amino(Q-Q)alkyl, mono- or di(Q- Q)alkylamino(Q-Q)alkyl. The term "arylalkoxy" refers to an aryl group, as defined above, attached to the parent molecular moiety through an alkoxy group, as defined above. Preferred arylaloxy groups include, benzyloxy, phenethyloxy, phenpropyloxy, and phenbutyloxy. The most preferred arylalkoxy group is benzyloxy. - 224 - The term "cycloalkyl" refers to a Q-Q cyclic hydrocarbon. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. More preferred cycloalkyl groups include cyclopropyl. The term "cycloalkylalkyl," as used herein, refers to a Q-Q cycloalkyl group attached to the parent molecular moiety through an alkyl group, as defined above. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl. The terms "halogen" or "halo" indicate fluorine, chlorine, bromine, or iodine. The term "heterocycloalkyl," refers to a non-aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur, wherein the non-aromatic heterocycle is attached to the core. The heterocycloalkyl ring may be optionally fused to or otherwise attached to other heterocycloalkyl rings, aromatic heterocycles, aromatic hydrocarbons and/or non-aromatic hydrocarbon rings. Preferred heterocycloalkyl groups have from 3 to 7 members. Examples of heterocycloalkyl groups include, for example, piperazine, 1,2,3,4-tetrahydroisoquinoline, morpholine, piperidine, tetrahydrofuran, pyrrolidine, and pyrazole. Preferred heterocycloalkyl groups include piperidinyl, piperazinyl, moφholinyl, and pyrolidinyl. The heterocycloalkyl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. Thus, such heterocycloalkyl groups can be optionally substituted with groups such as, for example, Q-Q alkyl, Q-Q alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di-(Q-Q)alkylamino, Q-Qalkenyl, Q-Qalkynyl, Q-Q haloalkyl, Q- Q haloalkoxy, amino(Q-Q)alkyl, mono- or di(Q-Q)alkylamino(Q-Q)alkyl. The term "heteroaryl" refers to an aromatic ring system containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. The heteroaryl ring may be fused or otherwise attached to one or more heteroaryl rings, aromatic or non-aromatic hydrocarbon rings or heterocycloalkyl rings. Examples of heteroaryl groups include, for example, pyridine, furan, thiophene, 5,6,7, 8-tetrahydroisoquinoline and pyrimidine. Preferred examples of heteroaryl groups include thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, benzimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl, indolyl, pyrazolyl, and benzopyrazolyl. Preferred heteroaryl groups include pyridyl. The heteroaryl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. Thus, such heteroaryl groups can be - 225 - optionally substituted with groups such as, for example, Q-Q alkyl, Q-Q alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di-(Q-Q)alkylamino, Q-Qalkenyl, Q- Qalkynyl, Q-Q haloalkyl, Q-Q haloalkoxy, amino(Q-Q)alkyl, mono- or di(Q- Q)alkylamino(Q-Q)alkyl. The term "heteroarylalkyl" refers to a heteroaryl group, as defined above, attached to the parent molecular moiety through an alkyl group, as defined above. Preferred heteroarylalkyl groups include, pyrazolemethyl, pyrazoleethyl, pyridylmethyl, pyridylethyl, thiazolemethyl, thiazoleethyl, imidazolemethyl, imidazoleethyl, thienylmethyl, thienylethyl, furanylmethyl, furanylethyl, isoxazolemethyl, isoxazoleethyl, pyrazinemethyl and pyrazineethyl. More preferred heteroarylalkyl groups include pyridylmethyl and pyridylethyl. The heteroaryl portions of these groups are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. Thus, such heteroaryl groups can be optionally substituted with groups such as, for example, Q-Q alkyl, Q-Q alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di- (Q-Q)alkylamino, Q-Qalkenyl, Q-Qalkynyl, Q-Q haloalkyl, Q-Q haloalkoxy, amino(Q-Q)a kyl, mono- or di(Q-Q)alkylamino(Q-Q)alkyl. If two or more of the same substituents are on a common atom, e.g., di(Q- Q)alkylamino, it is understood that the nature of each group is independent of the other. As used herein, the term "p38 mediated disorder" refers to any and all disorders and disease states in which p38 plays a role, either by control of p38 itself, or by p38 causing another factor to be released, such as but not limited to IL-1, IL-6 or IL-8. A disease state in which, for instance, IL-1 is a major component, and whose production or action, is exacerbated or secreted in response to p38, would therefore be considered a disorder mediated by p38. With reference to the use of the words "comprise" or "comprises" or "comprising" in this patent (including the claims), Applicants note that unless the context requires otherwise, those words are to be interpreted inclusively rather than exclusively. As TNF-beta has close structural homology with TNF-alpha (also known as cachectin), and since each induces similar biologic responses and binds to the same cellular receptor, the synthesis of both TNF-alpha and TNF-beta are inhibited by the compounds of the present invention and thus are herein referred to collectively as "TNF" unless specifically delineated otherwise. - 226 - Non-toxic pharmaceutically acceptable salts include, but are not limited to salts of inorganic acids such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, and nitric or salts of organic acids such as formic, citric, malic, maleic, fumaric, tartaric, succinic, acetic, lactic, methanesulfonic, p-toluenesulfonic, 2-hydroxyethylsulfonic, salicylic and stearic. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts. The compounds of this invention may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates, chiral non-racemic or diastereomers. In these situations, the single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent; chromatography, using, for example a chiral HPLC column; or derivatizing the racemic mixture with a resolving reagent to generate diastereomers, separating the diastereomers via chromatography or selective crystallization, and removing the resolving agent to generate the original compound in enantiomerically enriched form. Any of the above procedures can be repeated to increase the enantiomeric purity of a compound. The compounds of the invention may exist as atropisomers, i.e., chiral rotational isomers. The invention encompasses the racemic and the resolved atropisomers. The following illustration generically shows a compound (Z) that can exist as atropisomers as well as its two possible atropisomers (A) and (B). This illustration also shows each of atropisomers (A) and (B) in a Fischer projection. In this illustration, Rls R2, and R4 carry the same definitions as set forth for Formula I, Rp- is a substituent within the definition of R5, and Rp is a non-hydrogen substituent within the definition of R5.
227 -
Figure imgf000228_0001
When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, it is intended that the compounds include the cis, trans, Z- and E- configurations. Likewise, all tautomeric forms are also intended to be included. The compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques and the like. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier. One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants, and if desired other active ingredients. The pharmaceutical compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
228 For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, hard or soft capsule, lozenges, dispensable powders, suspension, or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservative agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques. In some cases such coatings may be prepared by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed. Formulations for oral use may also be presented as hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil. Formulations for oral use may also be presented as lozenges. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymefhylcellulose, methylcellulose, hydropropyl- methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain - 229 - aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin, or cetyl alcohol. Sweetening agents and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents or suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring, and coloring agents, may also be present. Pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions. The oily phase may be a vegetable oil or a mineral oil or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or - 230 - oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The compounds of general Formula I may also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols. Compounds of general Formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives, and buffering agents can be dissolved in the vehicle. The active ingredient may also be administered by injection (IV, LM, subcutaneous or jet) as a composition wherein, for example, saline, dextrose, or water may be used as a suitable carrier. The pH of the composition may be adjusted, if necessary, with suitable acid, base, or buffer. Suitable bulking, dispersing, wetting or suspending agents, including mannitol and PEG 400, may also be included in the composition. A suitable parenteral composition can also include a compound formulated as a sterile solid substance, including lyophilized powder, in injection vials. Aqueous solution can be added to dissolve the compound prior to injection. For disorders of the eye or other external tissues, e.g., mouth and skin, the formulations are preferably applied as a topical gel, spray, ointment or cream, or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w. When
231 formulated in an ointment, the active ingredients may be employed with either paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in- water cream base. If desired, the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane- 1,3- diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. The topical formulation may desirably include a compound, which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimefhylsulfoxide and related analogs. The compounds of this invention can also be administered by a transdermal device. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane. The transdermal patch may include the compound in a suitable solvent system with an adhesive system, such as an acrylic emulsion, and a polyester patch. The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier, which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base, which forms the oily, dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should - 232 - preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used. Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredients are dissolved or suspended in suitable carrier, especially an aqueous solvent for the active ingredients. The anti-inflammatory active ingredients are preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% and particularly about 1.5% w/w. For therapeutic purposes, the active compounds of this combination invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art. The amount of therapeutically active compounds that are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and - 233 - medical condition of the subject, the severity of the inflammation or inflammation related disorder, the route and frequency of administration, and the particular compound employed, and thus may vary widely. The pharmaceutical compositions may contain active ingredients in the range of about 0.1 to 1000 mg, preferably in the range of about 7.0 to 350 mg. A daily dose of about 0.01 to 100 mg/kg body weight, preferably between about 0.1 and about 50 mg/kg body weight and most preferably between about 0.5 to 30 mg/kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day. In the case of skin conditions, it may be preferable to apply a topical preparation of compounds of this invention to the affected area two to four times a day. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy. For administration to non-human animals, the composition may also be added to the animal feed or drinking water. It may be convenient to formulate the animal feed and drinking water compositions so that the animal takes in a therapeutically appropriate quantity of the composition along with its diet. It may also be convenient to present the composition as a premix for addition to the feed or drinking water. The disclosures in this application of all articles and references, including patents, are incorporated herein by reference. The invention is illustrated further by the following examples, which are not to be construed as limiting the invention in scope or spirit to the specific procedures described in them. The starting materials and various intermediates may be obtained from commercial i sources, prepared from commercially available compounds, or prepared using well-known synthetic methods. The compound names in this application were created using ACD Name Pro version 5.09, or ChemDraw ultra version 6.0.2, software.
234. General Synthetic Procedures Representative procedures for the preparation of compounds of the invention are outlined below in the Schemes The starting materials can be purchased or prepared using methods known to those skilled in the art. Similarly, the preparation of the various intermediates can be achieved using methods known in the art. The starting materials may be varied and additional steps employed to produce compounds encompassed by the invention, as demonstrated by the examples below. In addition, different solvents and reagents can typically be used to achieve the above transformations. Protection of reactive groups may also be necessary to achieve the above transformations. In general, the need for protecting groups, as well as the conditions necessary to attach and remove such groups, will be apparent to those skilled in the art of organic synthesis. When a protecting group is employed, deprotection will generally be required. Suitable protecting groups and methodology for protection and deprotection such as those described in Protecting Groups in Organic Synthesis by Greene and Wuts are known and appreciated in the art.
Figure imgf000235_0001
(ϋ) (iii) (i ) (v)
Z = alkyl, aryl, arylalkyl, hydrogen, heteroarylalkyl, heterocycloalkylalkyl, Hal = halogen alkoxyalkyl, heteroaryl, heterocycloalkyl, -C(0)NH(CH2)naryl, -C(0)N(alkyl)(CH2)naryl,
Figure imgf000235_0002
(viii) (vii) (vi) In this scheme, R5 is as defined above. Alternatively, the compounds of the instant invention can be prepared according to the method outlined in Scheme 2.
235 Scheme 2
Figure imgf000236_0001
(ix) (x) (xi) Q at each occurrence is independently alkyl, halogen, alkoxy, arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, C02H, CN, amidinooxime, NR6R7, NR6R7alkyl, -C(0)NR6R7, amidino, haloalkyl, or haloalkoxy; and n is 0, 1, 2, 3, 4, or 5. Alternatively, compounds of the invention can be prepared using the procedures outlined in Schemes 3-30. Q is as above. Y at each occurrence is independently alkyl, halogen, alkoxy, arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, C02H, CN, amidinooxime, NR6R7, R6R7N(Q- Q)alkyl, -C(0)NR6R7, (Q-Q) alkyl-C(0)NR6R7, amidino, haloalkyl, or haloalkoxy; and n is 0, 1, 2, 3, 4, or 5; R is aryl, alkyl, heteroaryl, arylalkyl heteroarylalkyl, heterocycloalkyl, or heterocycloalkylalkyl. R may be unsubstituted or substituted with Y. R' is aryl, alkyl, heteroaryl, arylalkyl heteroarylalkyl, heterocycloalkyl, or heterocycloalkylalkyl. R may be unsubstituted or substituted with Q. X is Br or Cl.
236 Scheme 3
Figure imgf000237_0001
cιΛrNH
Figure imgf000237_0002
Scheme 4
Figure imgf000237_0003
x = = CI, Br
Scheme 5
Figure imgf000237_0004
237- Scheme 6
Figure imgf000238_0001
Scheme 7
Figure imgf000238_0002
Scheme 8
Figure imgf000238_0003
238 Scheme 9
Figure imgf000239_0001
Scheme 10
Figure imgf000239_0003
Figure imgf000239_0002
Figure imgf000239_0004
-239 Scheme 12
Figure imgf000240_0001
Scheme 13
Figure imgf000240_0002
Scheme 14
Figure imgf000240_0003
-240- Scheme 15
Figure imgf000241_0001
DMF/CH2CI2
Figure imgf000241_0002
Scheme 16
Figure imgf000241_0003
Scheme 17
Figure imgf000241_0004
241 Scheme 18
Figure imgf000242_0001
Scheme 19
Figure imgf000242_0002
(1) lead tetraacetale, toluene (2) Jones reagent, acetone
Figure imgf000242_0003
-242-
Figure imgf000243_0001
R NH5 neat, 190 C s/
Figure imgf000243_0002
Scheme 21
Figure imgf000243_0003
Scheme 22
Figure imgf000243_0004
243- Scheme 23
Figure imgf000244_0001
Scheme 24 1. HC02NH4, PdOH, MeOH H02C U NBπ 2. Boc20, DMAP, N(CH3)3, CH2Ci2 T Boc Patent EP0343580A2-
1.DJBAL.-78C.THF 2. PPh3l CBr4, CHaCl2
Figure imgf000244_0002
2. H÷ or heat
Scheme 25
Figure imgf000244_0003
244 Scheme 26
Figure imgf000245_0001
Figure imgf000245_0002
Scheme 27
Figure imgf000245_0003
Scheme 28
Figure imgf000245_0004
Scheme 29
Figure imgf000245_0005
245 Scheme 30
Figure imgf000246_0001
Ex /H^Zes The invention is illustrated further by the following examples, which are not to be construed as limiting the invention in scope or spirit to the specific procedures described in them. Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the invention, as demonstrated by the following examples. Those skilled in the art will also recognize that it may be necessary to utilize different solvents or reagents to achieve some of the above transformations. In some cases, protection of reactive functionalities may be necessary to achieve the above transformations. In general, such need for protecting groups, as well as the conditions necessary to attach and remove such groups, will be apparent to those skilled in the art of organic synthesis. When a protecting group is employed, adeprotection step may be required. Suitable protecting groups and methodology for protection and deprotection such as those described in Protecting Groups in Organic Synthesis by Greene and Wuts are well known and appreciated in the art. Unless otherwise specified, all reagents and solvents are of standard commercial grade and are used without further purification. The appropriate atmosphere to run the reaction under, for example, air, nitrogen, hydrogen, argon and the like, will be apparent to those skilled in the art.
- 246 - Example 1. Preparation of 4-(benzyloxy)-l-(4-methyIbenzyI)pyridin-2(LH one
Figure imgf000247_0001
4-Benzyloxy-2(lH)-pyridone (3.0 g, 0.015 mol), 4-methylbenzyl bromide (3.15 g, 0.17 mol), and potassium carbonate (3.0 g, 0.022 mol) were heated at 80 °C for 2 hours. Contents were allowed to cool, diluted with water and a solid (5.52 g) was filtered. FABHRMS m/z 306.1494 (M+H, C20H20NO2 requires 306.1494). 1H NMR (CDC13 /300 MHz): 7.50-7.40 (m, 5H); 7.20-7.05 (m, 5H); 6.07-6.00 (m, 1H); 5.95-5.90 (m, 1H); 5.05 (s, 2H); 5.00 (s, 2H); 2.32 (s, 3H). Anal. Calcd for C20H19NO2: C, 78.66; H, 6.27; N, 4.59. Found: C, 78.54; H, 6.38; N, 4.58. Example 2. Preparation of 4-(benzyloxy)-3-bromo-l-(4- methyIbenzyl)pyridin-2(liϊ)-one
Figure imgf000247_0002
The material prepared in Example 1 (2.1 g, 0.007 mol) and sodium acetate (738 mg, 0.009 mol) in glacial acetic acid (15 mL) were cooled to 15 °C. Bromine (0.412 mL, 0.008) in glacial acetic acid (5 mL) was added dropwise. Contents were stirred 2 hours, coming to room temperature. Water (200 mL) was added and a light yellow solid was filtered. Mp 150.4 - 151.2°C. FABHRMS m/z 384.0599 (M+H, C20H19BrNO2 requires 384.0601). 1H NMR (CDCl3/300 MHz) δ: 7.42-7.30 (m, 5H); 7.22-7.08 (m, 5H); 6.02 (d, 1H); 5.20 (s, 2H); 5.12 (s, 2H); 2.32 (s, 3H). Anal. Calcd for C20H18BrNO2: C, 62.51; H, 4.72; N, 3.65. Found: C, 62.11; H, 4.48; N, 3.54. Examples 3-10. Preparation of compounds corresponding in structure to the following formula:
- 247
Figure imgf000248_0001
The compounds of Examples 3-10 are prepared essentially according to the procedure set forth above with respect to Example 1. Compounds wherein Ri = Br are prepared essentially according to the procedure of Example 2.
Figure imgf000248_0002
NMR characterization of compounds of Examples 3-10
Figure imgf000248_0003
- 248
Figure imgf000249_0003
Example 11. Preparation of 4-(benzyloxy)-3-bromopyridin-2(l/Z)-one
Figure imgf000249_0001
The material of Example 11 was prepared according to the procedure of Example 2. 1H NMR (CDCl3/300 MHz) δ: 7.50-7.30 (m, 6H); 6.20 (d, IH); 5.24 (s, 2H). Anal. Calcd for C12H10BrNO2 (0.3H2O): C, 50.48; H, 3.74; N, 4.91. Found: C, 50.79; H, 3.41; N, 4.82. Examples 12-19. Preparation of compounds corresponding in structure to the following formula:
Figure imgf000249_0002
The compounds of Examples 12-19 are prepared essentially according to the procedures set forth above for Example 1. Compounds wherein Rj = Br are prepared essentially according to the procedure of Example 2.
Figure imgf000249_0004
249 - NMR characterization of compounds of Examples 12-19
Figure imgf000250_0002
Example 20. Preparation of 4-(benzyloxy)-3-bromo-l-ethyIpyridin-2(L&r)-one
Figure imgf000250_0001
To 4-benzyloxy-2(lH)-pyridone (1.0 g, 0.005 mol) and potassium carbonate (1.0 g, 0.007 mol) in DMF (10 mL) was added bromoethane (0.82 mL, 0.011 mol). Contents were heated at 75°C overnight. Contents were allowed to cool and partitioned between EtOAc and water. The EtOAc layer was dried over MgS04, filtered, and concentrated in vacuo leaving a waxy solid, which was recrystallized from EtOAc/hexanes to give a white solid (720 mg). To the white solid (700 mg, 0.003 mol) in glacial acetic acid (10 mL), bromine (0.17 mL, 0.00325 mol) in glacial acetic acid (5 mL) was added dropwise at 15°C. Contents were stirred one hour at room temperature and a yellow solid (1.1 g) was filtered. The solid was partitioned between EtOAc and 2.5N sodium hydroxide. The EtOAc layer was dried over MgS04, filtered, and concentrated in vacuo leaving a colorless oil (710 mg), which solidified. FABHRMS m/z 310.0267 (M+H, C14H15BrN02 requires
- 250 - 310.0263). 1H NMR (CDCl3/300 MHz) δ: 7.45-7.30 (m, 6H); 7.22 (d, IH); 6.07 (d, IH); 5.20 (s, 2H); 4.00 (q, 2H); 1.32 (t, 3H). Anal. Calcd for C14H14BrN02: C, 54.56; H, 4.58; N, 4.55. Found: C, 54.21; H, 4.38; N, 4.43. Example 21. Preparation of 3-bromo-4-hydroxy-l-(4-hydroxybenzyl)pyridin- 2(l#)-one
Figure imgf000251_0001
The material of Example 12 (120 mg, 0.25 mmol) and 10% palladium/carbon (30 mg) in glacial acetic acid (2 mL) were shaken at 55 lbs of hydrogen for 4 hours. Contents were filtered and the filtrate was concentrated in vacuo leaving an oil. FABHRMS m/z 295.9952 (M+H, Cι2HnBrN03 requires 295.9922). 1H NMR (DMSO- 6/300 MHz) δ: 11.40 (br s, IH); 9.40 (br s, IH); 7.60 (d, IH); 7.10 (d, 2H); 6.70 (d, 2H); 6.02 (d, IH); 4.93 (s, 2H). Anal. Calcd for C12Hι0BrNO3 (1.4 H20): C, 44.85; H, 4.02; N, 4.36. Found: C, 45.07; H, 4.10; N, 4.35. Example 22. Prepararation of 4-(benzyloxy)-3-bromo-l-methyIpyridin-2(l/f)- one hydrobromide
Figure imgf000251_0002
To 4-benzyloxy-2(lH)-pyridone (1.0 g, 0.005 mol) and potassium carbonate (760 mg, 0.0055 mol) in DMF (10 mL) was added methyl iodide (0.342 mL, 0.0055 mol). Contents were stirred overnight. Contents were partitioned between EtOAc and water. The EtOAc layer was dried over MgS04, filtered, and concentrated in vacuo leaving a white solid (960 mg). To the white solid (332 mg, 0.0015 mol) in glacial acetic acid (10 mL), bromine (256 mg, 0.0016 mol) in glacial acetic acid (5 mL) was added dropwise at 15°C. Contents were stirred one hour at room temperature and the desired was filtered as a white solid, 262 mg (59% yield), mp 105.3- 105.6°C. FABHRMS m/z 296.0097 (M+H, C13H13BrN02 requires 296.0110). 1H NMR (CDCl3/300 MHz) δ: 7.45-7.30 (m, 6H); 7.22 (d, IH); 6.07
251 (d, IH); 5.20 (s, 2H); 4.00 (q, 2H); 1.32 (t, 3H). Anal. Calcd for C13H12BrN02 (HBr, 0.3H2O): C, 41.04; H, 3.60; N, 3.68. Found: C, 41.00; H, 3.87; N, 3.52. Example 23. Prepararation of 4-(benzyloxy)-3-bromo-l-methylpyridin-2(l/-T)- one
Figure imgf000252_0001
The material of Example 22 was partitioned between EtOAc and 2.5N sodium hydroxide.
The EtOAc layer was dried over MgS04, filtered, and concentrated in vacuo leaving a red oil, which solidified. FABHRMS m/z 294.0112 (M+H, C13Hι3BrN02 requires
294.0130). 1H NMR (CDCl3/300 MHz): 7.45-7.30 (m, 6H); 7.22 (d, IH); 6.07 (d, IH); 5.20 (s, 2H); 4.00 (q, 2H); 1.32 (t, 3H). Anal. Calcd for C13H12BrN02: C, 53.08; H, 4.11;
N, 4.76. Found: C, 53.06; H, 4.20; N, 4.74. Example 24. Preparation of 4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2£T)- yl]methyl}-N'-hydroxybenzenecarboximidamide
Figure imgf000252_0002
The material of Example 17 (500 mg, 0.00127 mol), hydroxylamine hydrochloride (90 mg, 0.0013 mol) and sodium bicarbonate (109 mg) were refluxed in ethanol (15 mL) overnight. Contents were allowed to cool and a solid was filtered and washed with water to give the desired as a white solid, 447 mg, (82% yield), mp 210.2-212.2 °C FABHRMS m/z 428.0634 (M+H, C20H19BrN3O3 requires 428.0610). Η NMR (DMSO-^/ 300 MHz): 9.66 (s, IH); 7.98 (d, IH); 7.65 (d, 2H); 7.55-7.35 (m, 5H); 7.30 (d, 2H); 6.54 (d, IH); 5.82 (s, 2H); 5.35 (s, 2H); 5.17 (s, 2H). Anal. Calcd for C20Hι8BrN3O3: C, 56.09; H, 4.24; N, 9.81. Found: C, 55.92; H, 4.01; N, 9.52. Example 25. Preparation of 4-(benzyIoxy)-3-bromo-l-(piperidin-4- ylmethyl)pyridin-2( fiT) -one hydrochloride
252
Figure imgf000253_0001
To the material of Example 11 (924 mg, 0.0033 mol) in DMF (5 mL) was added dropwise sodium bis(trimethylsilyl)amide (1M in THF, 3.6 mL). Contents were stirred one hour before adding dropwise a solution of 4-methanesulfonyloxymethyl-l-piperidine-l- carboxylic acid tert-butyl ester (J. Labelled Compd, Radiopharm, 38(7), 1996, 595-606) (1.0 g, 0.0036 mol) in DMF (5 mL). Contents were heated at 75°C overnight. Contents were allowed to cool and poured into water (100 mL). A solid was filtered and recrystallized from EtOAc to give white crystals (546 mg). The white crystals were refluxed in 4 N HCl/dioxane (10 mL) for 3 hours, allowed to cool and filtered to give the desired as a white solid, 415 mg (30% yield), mp 207.9°C. FABHRMS m/z 377.0852 (M+H, C18H23BrClN202 requires 377.0865). 1H NMR (DMSO-tf«j/300 MHz) δ: 8.90 (br, IH); 8.64 (br, IH); 7.80 (d, IH); 7.50-7.30 (m, 5H); 6.48 (d, IH); 5.30 (s, 2H); 3.83 (d, 2H); 3.20 (d, 2H); 2.88-2.64 (m, 2H); 2.10-1.90 (m, IH); 1.60 (d, 2H); 1.50-1.40 (m, 2H). Anal. Calcd for C18H22BrClN202 (0.3 H20): C, 51.58; H, 5.43; N, 6.68. Found: C, 51.59; H, 5.42; N, 6.81. Example 26. Preparation of 4-(benzyloxy)-l-[4- (trifluoromethyl)benzyl]pyridin-2(lfl)-one
Figure imgf000253_0002
The material of Example 26 was prepared according to the procedure of Example 1. FABHRMS m/z 360.1213 (M+H, C20H17F3NO2 requires 360.1211). 1H NMR (CDCl3/300
MHz) δ: 7.60 (d, 2H); 7.41-7.30 (m, 7H); 7.13 (d, IH); 6.05-6.01 (m, IH); 6.00-5.95 (m,
IH); 5.13 (s, 2H); 5.00 (s, 2H). Anal. Calcd for C20Hι6F3NO2: C, 66.85; H, 4.49; N, 3.90.
Found: C, 66.64; H, 4.26; N, 3.93. Example 27. Preparation of 4-(benzyloxy)-3-bromo-l-[4-(trifluoromethyl) benzyl]pyridin-2(l/f)-one
- 253 -
Figure imgf000254_0001
The material of Example 27 was prepared according to the procedure of Example 2. FABHRMS m/z 438.0308 (M+H, C20H16BrF3NO2 requires 438.0316). 1H NMR (CDCl3/300 MHz) δ: 7.65-7.20 (m, 10H); 6.13-6.03 (m, IH); 5.30-5.13 (m, 4H). Anal. Calcd for C20H15BrF3NO2: C, 54.81; H, 3.45; N, 3.20. Found: C, 54.69; H, 3.34; N, 3.19. Example 28. Preparation of 4-(benzyloxy)-3-bromo-l-(piperidin-3- ylmethyl)pyridin-2(lH)-one hydrochloride
Figure imgf000254_0002
To the material of Example 11 (3.1 g, 0.011 mol) in DMF (20 mL) was added dropwise sodium bis(trimethylsilyl)amide (1M in THF, 12 mL). Contents were stirred one hour before adding dropwise a solution of 3-methanesulfonyloxymethyl-l-piperidine-l- carboxylic acid tert-butyl ester (Bioorg.Med.Chem.Lett, 8(13), 1998, 1595-1600) (4.2 g, 0.015 mol) in DMF (5 mL). Contents were heated at 75°C overnight. Contents were allowed to cool, poured into water (100 mL) and a solid was filtered. The solid was stirred in 4 N HCl/dioxane (15 mL) for 3 hours and filtered to give the desired as a white solid, 752 mg (18% yield), mp 138.1-139.2°C. FABHRMS m/z 377.0859 (M+H, C18H22BrN202 requires 377.0865). Η NMR
Figure imgf000254_0003
MHz): 9.50-9.10 (br, 2H); 8.00 (d, IH); 7.50-7.30 (m, 5H); 6.93 (d, IH); 5.30 (s, 2H); 4.30-3.90 (m, 3H); 3.40-3.10 (m, 3H); 2.80-2.50 (m, 3H); 2.40-2.00 (m, IH); 1.90-1.60 (m, 4H); 1.40-1.10 (m, IH).
Anal. Calcd for C18H21BrN202 (2HC1, 0.25 H20): C, 47.55; H, 5.21; N, 6.16. Found: C, 47.48; H, 5.46; N, 6.27. Example 29. Preparation of 4-(benzyIoxy)-3-bromo-l-(2-thien-3- ylethyι)pyridin-2(lH)-one
254
Figure imgf000255_0001
To the material of Example 11 (500 mg, 0.0018 mol) in DMF (5 mL) was added dropwise sodium bis(trimethylsilyl)amide (1M in THF, 2 mL). Contents were stirred one hour before adding dropwise a solution of methanesulfonic acid 2-thiophen-3-yl-ethyl ester (J.A.C.S, 109(6), 1987, 1858-1859) (412 mg, 0.002 mol) in DMF (5 mL). Contents were heated at 75 C overnight. Contents were allowed to cool, poured into water (100 mL), and extracted into EtOAc, dried over MgS04, filtered, and concentrated in vacuo leaving a light yellow oil. The oil was purified by silica gel chromatography eluting with 50% EtOAc/hexanes to give the desired as a white solid, 199 mg (28% yield), mp 134.0- 134.3°C. FABHRMS m/z 390.0144 (M+H, C18H17BrN02S requires 390.0163). 1H NMR (CDCl3/300 MHz): 7.43-7.20 (m, 6H); 6.92-6.80 (m, 3H); 5.90 (d, IH); 5.20 (s, 2H); 4.13 (t, 2H); 3.10 (t, 2H). Anal. Calcd for Cι8H16BrN02S: C, 55.39; H, 4.13; N, 3.59. Found: C, 55.21; H, 3.87; N, 3.52. Example 30. Preparation of 4-(benzyloxy)-3-bromo-l-(2-thien-2- ylethyl)pyridin-2(lZZ) -one
Figure imgf000255_0002
The title compound was prepared essentially according to the procedure of Example 29. mp 128.0-129.5°C. FABHRMS m/z 390.0160 (M+H, C18H17BrN02S requires 390.0163). 1H NMR (CDCl3/300 MHz) δ: 7.48-7.30 (m, 5H); 7.12 (d, IH); 6.95-6.80 (m, 2H); 6.75- 6.68 (m IH); 5.95 (d, IH); 5.20 (s, 2H); 4.16 (t, 2H); 3.30 (t, 2H). Anal. Calcd for C18H16BrN02S: C, 55.39; H, 4.13; N, 3.59. Found: C, 55.06; H, 4.01; N, 3.56. Example 31. Preparation of 4-(benzyloxy)-3-bromo-l-[3-(trifluoromethyl) benzyl]pyridin-2(l/f)-one. To the material of Example 11 (500 mg, 0.0018 mol) in DMF (5 mL) was added dropwise sodium bis(trimethylsilyl)amide (1M in THF, 2 mL).
- 255 Contents were stirred one hour before adding dropwise a solution of 3- trifluoromethylbenzyl bromide (478 mg, 0.002 mol) in DMF (5 mL). Contents were heated at 75°C for 2 hours. Contents were allowed to cool, poured into water (100 mL), and extracted with EtOAc, which was dried over MgS04, filtered, and concentrated in vacuo leaving a white solid. FABHRMS m/z 438.0301 (M+H, C20H16BrF3NO2 requires 438.0316). 1H NMR (CDCl3/300 MHz): 7.60-7.20 (m, 10H); 6.10 (d, IH); 5.14 (s, 2H); 5.20 (s, 2H). Anal. Calcd for C20H15BrF3NO2: C, 54.81; H, 3.45; N, 3.20. Found: C, 54.81; H, 3.36; N, 3.13. Example 32. Preparation of 4-(benzyloxy)-3-bromo-l-[2-(trifluoromethyl) benzyl]pyridin-2(Lflr)-one
Figure imgf000256_0001
The material of Example 32 was prepared according to the procedure of Example 31. FABHRMS m/z 438.0280 (M+H, C20H16BrF3NO2 requires 438.0316). 1H NMR (CDCl3/300 MHz) δ: 7.68 (d, IH); 7.55-7.20 (m, 8H); 7.15 (d, IH); 6.10 (d, IH); 5.40 (s, 2H); 5.13 (s, 2H). Anal. Calcd for C20Hι5BrF3NO2: C, 54.81; H, 3.45; N, 3.20. Found: C, 54.48; H, 3.36; N, 3.17. Example 33. Preparation of 4-(benzyloxy)-l-[4- (trifluoromethoxy)benzyl]pyridin-2(lflr)-one
Figure imgf000256_0002
The material of Example 33 was prepared according to the procedure of Example 1.
FABHRMS m/z 376.1158 (M+H, C20H17F3NO3 requires 376.1161). 1H NMR (CDCl3/300 MHz) δ: 7.40-7.05 (m, 10H); 6.05-5.95 (m, 2H); 5.06 (s, 2H); 4.98 (s, 2H). Anal. Calcd for C20Hι6F3NO3: C, 64.00; H, 4.30; N, 3.73. Found: C, 63.97; H, 4.26; N, 3.57. Example 34. Preparation of 4-(benzyloxy)-3-bromo-l-[4-(trifluoromethoxy) benzyl]pyridin-2(lfT)-one
- 256 -
Figure imgf000257_0001
The material of Example 34 was prepared according to the procedure of Example 2. FABHRMS m/z 454.0240 (M+H, C20H16BrF3NO3 requires 454.0266). 1H NMR (CDCl3/300 MHz) δ: 7.45-7.10 (m, 10H); 6.08 (d, IH); 5.20 (s, 2H); 5.12 (s, 2H). Anal. Calcd for C20H15BrF3NO3: C, 52.88; H, 3.33; N, 3.08. Found: C, 52.53; H, 3.09; N, 2.92. Example 35. Preparation of l-benzyl-4-(benzyIoxy)-6-methyIpyridin-2(lH)- one
Figure imgf000257_0002
Step 1: Preparation of l-benzyl-4-hydroxy-6-methylpyridin-2(lH)-one. 4- hydroxy-6-methyl-2-pyrone (0.2 mol, 25.2 g) and benzylamine (0.2 mol, 21.4 g) were added to water (800 mL) and heated to reflux with stirring for 2 hours. After cooling to room temperature, a light brown solid was collected by filtration. (33.4 g, 77%): 1H NMR (DMSO-d6/300 MHz) δ: 10.5 (s, IH), 7.4-7.1 (m, 5 H), 5.8-5.6 (m, 2H), 5.2 (s,2H), 5.1 (s, 2H), 2.2 (s, 3H). ESHRMS m/z 216.100 (M+H, Cι2Hι3N02 requires 216.102). Step 2: Preparation of l-benzyl-4-(benzyloxy)-6-methylpyridin-2(lH)-one. 1- benzyl-4-hydroxy-6-methylpyridin-2(lH)-one (10 mmol, 2.15 g), dichloromethane (100 mL), benzylbromide (11 mmol, 1.88 g), sodium hydroxide (2.5 N, 20 mmol, 8 mL), and benzyltriethylammonium chloride (0.5 g) were vigorously stirred at room temperature for 16h. Hydrochloric acid (I N) was added until the mixture produced an acidic reaction to pH paper. The mixture was then extracted with ethyl acetate (3 X 50 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and
- 257 - concentrated. The product was obtained by flash chromatography eluting with ethyl acetate : hexanes (1:2). The appropriate fractions were concentrated to a clear oil. (1.3 g, 43%): 1H NMR (DMSO-d6/300 MHz) δ: 7.4-7.1 (m, 10 H), 6.0-5.9 (m, 2H), 5.2 (s,2H), 5.1 (s, 2H), 2.2 (s, 3H). ESHRMS m/z 306.147 (M+H, C20H,9NO2 requires 306.149). Example 36. Preparation of l-benzyl-4-(benzyloxy)-3-bromo-6- methylpyridin-2(lH)-one
Figure imgf000258_0001
The product from example 35, l-benzyl-4-(benzyloxy)-6-methylpyridin-2(lH)-one (4.2 mmol, 1.3 g), acetic acid (50 mL), and sodium acetate (5.0 mmol, 0.41 g) were stirred at room temperature. Bromine (4.2 mmol, 0.67 g) was added drop wise with stirring. After ¥z hour, water (100 mL) was added and the mixture was extracted with ethyl acetate (3 X 50 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution and brine. After drying over magnesium sulfate and concentrating, the mixture was purified by flash column chromatography eluting with ethyl acetate : hexanes (1 : 2). The appropriate fractions were concentrated to yield a light oil. (1.0 g, 62%): Η NMR (DMSO-d6/300 MHz) 7.4-7.0 (m, 10 H), 6.5 (s, IH), 5.29 (s,2H), 5.27 (s, 2H), 2.2 (s, 3H). ESHRMS m/z 384.057 (M+H, C2oH18N02Br requires 384.060). Example 37. Preparation of l-benzyI-4-(benzy!oxy)-3,5-dibromo-6- methylpyridin-2(lH)-one
258
Figure imgf000259_0001
The product from example 35, l-benzyl-4-(benzyloxy)-6-methylpyridin-2(lH)-one (4.2 mmol, 1.3 g), acetic acid (50 mL), and sodium acetate (5.0 mmol, 0.41 g) were stirred at room temperature. Bromine (4.2 mmol, 0.67 g) was added drop wise with stirring. After V2 hour, water (100 mL) was added and the mixture was extracted with ethyl acetate (3 X 50 mL). The combined organics were washed with saturated aqueous sodium bicarbonate solution and brine. After drying over magnesium sulfate and concentrating, the mixture was purified by flash column chromatography eluting with ethyl acetate : hexanes (1 : 2). The appropriate fractions were concentrated to yield a white solid. (0.3 g, 15%): 1H NMR (DMSO-d6/300 MHz) 7.5-7.0 (m, 10 H), 5.42 (s,2H), 5.07 (s, 2H), 2.45 (s, 3H). ESHRMS m/z 463.966 (M+H, C20H17NO2Br2 requires 463.968). Example 38. Preparation of l-benzyl-4-[(3-chlorobenzyl)oxy]-6- methylpyridin-2(lH)-one
Figure imgf000259_0002
Step 1: Preparation of l-benzyl-6-methyl-2-oxo-l,2-dihydropyridin-4-yl 4- bromobenzenesulfonate. l-benzyl-4-hydroxy-6-methylpyridin-2(lH)-one (from example 35) (10 mmol, 2.15 g), N,N'-dimethylformamide (30 mL), potassium carbonate (20 mmol, 2.76 g), and 4-bromobenzenesulfonyl chloride (10 mmol, 2.55 g) were stirred at room
259 temperature for 16 hours. Hydrochloric acid (IN) was added until the mixture was acidic to pH paper. Brine (50 mL) was added and the mixture extracted with ethyl acetate (3 X 50 mL). The combined organic extracts were washed with brine and dried over magnesium sulfate, and filtered. After concentrating, the material was purified by flash column chromatography eluting with ethyl acetate:hexanes (1:2). The appropriate fractions were concentrated to a clear oil, which solidified upon standing several days to a white solid. (3.3 g, 76%): 1H NMR (DMSO-d6/400 MHz) 7.9 (m, 4H), 7.32-7.00 (m, 5H), 7.3 (m, IH), 6.12 (d, J = 2.4 Hz, IH), 6.02 (d, J = 2.8 Hz, IH), 5.20 (s, 2H), 2.2 (s, 3H). ESHRMS m/z 436.002 (M+H, C19H16N04SBr requires 436.004). Step 2: Preparation of l-benzyl-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-
2(lH)-one. 1 -benzyl-6-methyl-2-oxo- 1 ,2-dihydropyridin-4-yl 4-bromobenzenesulf onate (3.0 mmol, 1.3 g), N,N'-dimethylformamide (30 mL), 3-chlorobenzyl alcohol (3.0 mmol, 0.43 g), and sodium hydroxide (60%, 3.3 mmol, 0.13 g) were stirred at room temperature under nitrogen for 4 hours. Hydrochloric acid (1 N, 10 mL) was added and the mixture extracted with ethyl acetate (3 X 25 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution and brine. After drying over magnesium sulfate and concentrating, the mixture was purified by flash column chromatography eluting with ethyl acetate:hexanes (1:1) to obtain a light yellow oil. (14.3 g, 64%): 1H NMR (DMSO-d6/300 MHz) δ: 7.4-7.0 (m, 10 H), 6.0-5.8 (m, 2H), 5.2 (s,2H), 5.0 (s, 2H), 2.1 (s, 3H). ESHRMS m/z 340.110 (M+H, C20H18NO2Cl requires 340.110). Example 39. Preparation of l-benzyl-3-bromo-4-[(3-chIorobenzyI)oxy]-6- methylpyridin-2(lH)-one
Figure imgf000260_0001
260 The product of example 38, l-benzyl-4-[(3-chlorobenzyl)oxy]-6-methylpyridin-2(lH)-one (0.91 mmol, 310 Mg), acetic acid (20 mL), and sodium acetate (0.91 mmol, 80 Mg) were stirred at room temperature when bromine (0.91 mmol, 145 Mg) was added. After stirring for one hour, the mixture was concentrated, dissolved in ethyl acetate, and washed successively with saturated aqueous sodium bicarbonate solution, brine, and water. After drying over magnesium sulfate and concentrating, the product was recrystallized from tetrahydrofuran / hexanes to yield a white solid. (240 Mg, 63%): 1H NMR (DMSO- d6/300 MHz) 7.6-7.0 (m, 10 H), 6.5 (s, IH), 5.33 (s,2H), 5.33 (s, 2H), 2.3 (s, 3H). ESHRMS m/z 420.019 (M+H, C20H17NO2BrCl requires 420.019). Example 40. Preparation of l-benzyl-4-[2,6-(dichlorobenzyl)oxy]pyridin-
2(lH)-one
Figure imgf000261_0001
The title compound was prepared essentially as described in claim 1. mp 151.6-152.0°C. Η NMR (CDCl3/300MHz) δ: 7.31 (m, 8H), 7.12 (d, IH, J = 7.45 Hz), 6.13 (d, IH, J = 2.42 Hz), 5.90 (dd, IH, J = 2.62 Hz), 5.22 (s, 2H), 5.10 (s, 2H). ESHRMS m/z 360.0551 (M+H C19Hι5Cl2N02 requires 360.0558). Example 41. Preparation of l-benzyl-3-bromo-4-[2,6- (dichlorobenzyl)oxy]pyridin-2(lH)-one
Figure imgf000261_0002
261 l-Benzyl- -[2,6-(dichlorobenzyl)oxy]pyridin-2(lH)-one (0.400 g, 1.11 mmol) was dissolved in acetic acid (10 mL). Sodium acetate (0.091 g, 1.11 mmol was added, and the mixture was cooled to 15 °C. Bromine (0.195 g, 1.22 mmol) was added via syringe. The reaction stirred at room temperature for 2 hours. Water (15 mL) was added, and the mixture transferred to a separatory funnel. Ethyl acetate (50 mL) was added and the layers were separated. The organic phase was washed with aqueous NaHC03 (2 x 25 mL), dried over MgS04, filtered, and evaporated to yield a white solid. 1HNMR (CDCl3/300MHz) δ: 7.34 (m, 9H), 6.24 (d, IH, J = 7.65 Hz), 5.37 (s, 2H), 5.18 (s, 2H). ESHRMS m z 439.9646 (M+H C19H14BrCl2N02 requires 439.9641). Example 42. Preparation of l-benzyl-4-[(2-chlorobenzyl)oxy]pyridin-2(lH)- one
Figure imgf000262_0001
The title compound was prepared by a procedure similar to the one described in Example 1. mp 124.6-125.0 °C. 1HNMR (CDCl3/300MHz) δ: 7.36 (m, 9H), 7.14 (d, IH, J = 7.65 Hz), 6.04 (d, IH, J = 2.62 Hz), 5.98 (d, IH, J = 2.82 Hz), 5.10 (s, 2H), 5.09 (s, 2H). ESHRMS m/z 326.0950 (M+H C19H16C1N02 requires 326.0948). Anal. Calc'd. for Cι9H16ClN02: C, 70.05; H, 4.95; N, 4.30; Cl, 10.88. Found: C, 69.87; H, 4.74; N, 4.42, Cl, 11.08. Example 43. Preparation of l-benzyl-3-bromo-4-[(2- chlorobenzyI)oxy]pyridin-2(lH)-one
- 262
Figure imgf000263_0001
The title compound was prepared by a procedure similar to the one described in Example 2. mp 143.3-145.5 °C. 1HNMR (CDCl3/300MHz) δ: 7.63 (d, 2H, J = 1.81 Hz), 7.44 (m, 9H), 6.06 (d, IH, J = 7.65 Hz), 5.29 (s, 2H), 5.17 (s, 2H). ESHRMS m/z 406.0036 (M+H Cι9H15BrClN02 requires 406.0032). Anal. Calc'd. for Cι9H]5Cl BrN02: C, 56.39; H, 3.74; N, 3.46; Cl, 8.76. Found: C, 56.01; H, 3.38; N, 3.36, Cl, 9.01. Example 44. Preparation of l-benzyl-3-bromo-4-[(4- methylbenzyl)oxy]pyridin-2(lH)-one
Figure imgf000263_0002
The title compound was prepared by a procedure similar to the one described in Example 2. mp 149.0-149.7 °C. 1HNMR (CDCl3/300MHz) δ: 7.25 (m, 10H), 6.04 (d, IH, J = 7.65 Hz), 5.17 (s, 2H), 5.15 (s, 2H), 2.34 (s, 3H). ESHRMS m/z 386.0583 (M+H C20Hι8BrNO2 requires 386.0581). Example 45. Preparation of l-benzyl-4-[(3-chlorobenzyI)oxy]pyridin-2(lH)- one
263
Figure imgf000264_0001
The title compound was prepared by a procedure similar to the one described in Example 1. mp 95.5-95.7 °C. 'HNMR (CDCl3/300MHz) δ: 7.34 (m, 9H), 7.13 (d, IH, J = 7.45 Hz), 5.96 (m, IH), 5.95 (d, IH, J = 7.45 Hz), 5.09 (s, 2H), 4.96 (s, 2H).. ESHRMS m/z 326.0977 (M+H C19H16C1N02 requires 326.0948). Example 46. Preparation of l-benzyl-4-[benzylthio]-3-bromopyridin-2(lH)- one
Figure imgf000264_0002
The title compound was prepared by a procedure similar to the one described in Example 2. mp 180.6-182.1 °C. 1HNMR (CDCl3/300MHz) δ: 7.33 (m, 10H), 7.14 (d, IH, J = 7.45 Hz), 6.08 (d, IH, J = 7.45 Hz), 5.13 (s, 2H), 4.15 (s, 2H). ESHRMS m/z 386.0211 (M+H C19Hι6BrNOS requires 386.0214). Example 47. Preparation of l-benzyl-3-bromo-4-{[2- (trifluoromethyI)benzyl]oxy}pyridin-2(lH)-one
264
Figure imgf000265_0001
The title compound was prepared by a procedure similar to the one described in Example 2. mp 133.2-133.5 °C. 1HNMR (CDC13 / 300MHz) δ: 7.81 (d, IH, J = 7.65 Hz), 7.68 (d, IH, J = 7.65 Hz), 7.61 (t, IH, J = 7.65 Hz), 7.38 (m, 7H), 6.01 (d, IH, J = 7.85 Hz), 5.39 (s, 2H), 5.16 (s, 2H). ESHRMS m/z 438.0313 (M+H C20Hι5BrF3NO2 requires 403.0316). Example 48. Preparation of l-benzyl-4-(benzyloxy)-3-iodopyridin-2(lH)-one
Figure imgf000265_0002
A mixture of N,0-dibenzyl-2-pyridone (2.0 g, 6.87 mmol), N-iodosuccinimide (1.7 g) , dichloroacetic acid (0.15 mL) in acetonitrile (40.0 mL) was heated at 65°C under argon atmosphere for 3.5 h, with constant stirring. The reaction mixture was concentrated to dryness, and the residue was purified by silica gel flash chromatography using EtOAc/ hexanes 1:1 v/v to give the title compound 2.3 g (80%) as a flaky white solid: Η-NMR (CDC13) δ: 7.4 - 7.2 (m, 10 H), 7.19 (IH, d, J = 7.6 Hz), 5.95 (d, IH, J = 7.6 Hz), 5.2 (s, IH), 5.15 (s, 2H); ER-MS m/z = 418 (MH +); HR-MS m/z calcd Cι9H17N02418.0304, found 418.0277. Example 49. Preparation of l-benzyl-4-(benzyloxy)-3-vinylpyridin-2(lH)-one
- 265
Figure imgf000266_0001
A solution of l-benzyl-4-(benzyloxy)-3-iodopyridin-2(lH)-one (1.9 g, 4.56 mmol) and vinyl-tri-butyltin (2.5 mL) in acetonitrile (200 mL) containing DMF (2.0 mL) was degassed using house vacuum and purged with argon. Then added PdCl2(PPh3)2 (0.3 g) and the mixture was heated at 65 °C under argon atmosphere for 4 h, with stirring. The solvents were distilled in vacuo, and the residue was triturated with EtOAc and filtered through a pad of celite. The filtrate was concentrated and the residue was purified by silica gel flash chromatography using 25% EtOAc in hexanes to give the title compound (0.75 g. 50%) as an orange colored solid. 1H-NMR (CDC13) δ: 7.4 - 7.2 (m, 10 H), 7.14 (d, IH, J = 7.6 Hz), 7.05 (dd, IH, J = 12.0 Hz), 6.47 (dd, IH, J = 2.8 Hz), 6.07 (d, IH, J = 7.6 Hz), 5.4 (dd, IH, J = 2.8 Hz), 5.13 (s, 4H); ER-MS m/z = 418 (MH +); ER-MS m/z = 318 (MH +); HR-MS m/z calcd C2ιH20NO2 318.1494, found 318.1480. Example 50. Preparation of l-benzyl-4-(benzyloxy)-3-ethylpyridin-2(lH)-one
Figure imgf000266_0002
To a solution of l-benzyl-4-(benzyloxy)-3-vinylpyridin-2(lH)-one (0.5 g, 1.6 mmol) in EtOH (10.0 mL) and EtOAc (10.0 mL) was added Pd/C (10 %, 0.25 g) and stirred in an atmosphere of hydrogen gas at 30 psi for 16 h. The catalyst was removed by filtration, the filtrate was concentrated to dryness and the resulting residue was purified by silica gel flash chromatography using EtOAc/hexanes (1:1, v/v) to afford the title compound (0.32 g, 64%) as a pale yellow powder: 1H-NMR (CD3OD) δ: 7.52 (d, IH, J = 7.6 Hz), 7.39 - 7.2 (m, 10 H), 6.41 (d, lh, J = 7.6 Hz), 5.18 (s, 2H), 5.15 (s, 2H), 2.58 (q, 2H, J = 7.2 Hz), - 266 - 1.03 (t, 3H, J = 7.2 Hz), ER-MS m/z = 320 (MH +); HR-MS m/z calcd C21H22N02 320.1651, found 320.1648. Example 51. Preparation of 3-acetyI-4-(benzyIoxy)-l-(2-chlorophenyl)-6- methylpyridin-2(lH)-one
Figure imgf000267_0001
Step A. Preparation of 3-acetyl-l-(2-chlorophenyl)-4-hydroxy-6- methy!pyridin-2(lH)-one
Figure imgf000267_0002
A mixture of 2-chlorophenylisocyanate (3.0 g, 19.53 mmol), and diketene (3.3 g, 39.28 mmol) in toluene (10.0 mL) containing triethylamine (0.05 mL) was heated to reflux for 6 h, under an atmosphere of argon. Toluene was distilled in vacuo and the resulting residue was purified by silica gel flash chromatography using 25 % EtOAc in hexanes as the eluent to afford the title compound (0.85 g, see Heterocycles 27 (9), 2063 (1988)) as a pale yellow solid: Η-NMR (CD3OD) δ: 7.63 (m, IH), 7.52 (m, 2H), 7.4 (m, IH), 6.14 (s, IH), 2.58 (s, 3H), and 1.95 (s, 3H); ES-MS m/z = 278 ( MH+ ). Step B. Preparation of 3-acetyl-4-(benzyloxy)-l-(2-chlorophenyl)-6- methylpyridin-2(lH)-one. To a solution of 3 -acetyl- l-(2-chloropheny l)-4-hydroxy-6- methylpyridin-2(lH)-one ( 0.56 g, 2.02 mmol) in DMF (5.0 mL), benzyl bromide (0.3 mL) and potassium carbonate (0.3 g, 2.16 mmol) were added. The mixture was stirred at room temperature for 3 h, and at 65 °C for 1 h under argon atmosphere. The reaction mixture was concentrated in vacuo and the residue was partitioned between 5% citric acid (25 mL) and EtOAc (50.0 mL). The organic phase was washed with brine, dried - 267 - (Na2S04), filtered, and concentrated to dryness. The resulting residue was purified by silica gel flash chromatography using 50% EtOAc in hexanes to afford the title compound (0.58 g, 75%) as a pale yellow amorphous substance: 1H-NMR (CD3OD) δ: 7.65 - 7.3 (m, 9H), 6.5 (s, IH), 5.31 (s, 2H), 2.42 (s, 3H), and 2.01 (s, 3H); ER-MS m/z = 368 (MH +); HR-MS m/z calcd C21H19N03C1 ,368.1060, found 368.1053. Example 52. Preparation of l-benzyl-3-bromo-4-(2-phenylethyl)pyridin- 2(lH)-one
Figure imgf000268_0001
Step A. Preparation of l-benzyl-3-bromo-4-hydroxypyridin-2(lH)-one
Figure imgf000268_0002
A suspension of N-benzyl-4-hydroxy-2-pyridone ((0.75 g, 3.7 mmol), NBS (0.7 g, 1.05 mmol) in dichloromethane was stirred at room temperature for 1.5 h under argon atmosphere. It was diluted with dichloromethane (25 mL), cooled and filtered. The solids were washed with dichloromethane and dried in vacuo. The filtrate and the washings were combined and washed with water, dried (Na2S04), filtered, and concentrated to dryness. The resulting residue was washed with EtOAc, and dried in vacuo to give a combined mass of 0.65 g of the title compound as a white powder: 1H NMR (CD3OD) δ: 7.54 (d, IH, J = 7.6 Hz), 7.27 (m, 5H), 6.12 (d, IH, J = 7.6 Hz), 5.15 (s, 2H); ES-MS: m/z = 280 (MH+). Step B. Preparation of l-benzyl-3-bromo-2-oxo-l,2-dihydropyridin-4-yl trifluoromethanesulfonate
268
Figure imgf000269_0001
To a cold (-30°C ) suspension of l-benzyl-3-bromo-4-hydroxypyridin-2(lH)-one (0.78 g, 2.8 mmol) in dichloromethane (10.0 mL), was added triethylamine (0.6 mL, 4.28 mmol ), followed by the addition of triflic anhydride (0.7 mL, 4.17 mmol). The resulting mixture was stirred at -30 °C under argon atmosphere for 1 h. The reaction mixture was then poured into ice/water mixture (50 mL) and the products were extracted with dichloromethane (2 x 25 mL). The combined organic extracts were washed with water (2 x 20 mL), dried (Na2S0 ), filtered, and concentrated to dryness. The residue was dried in vacuo to afford the desired trifluorosulf onate (1.0 g) as a pale yellow solid which used as such in the next step: 1H- NMR (CDC13) δ: 7.35 (m, 6H), 6.26 (d, IH, J = 8.0 Hz); 19F- NMR (CDC13) δ: -73.73 ppm; ES-MS: m/z = 412 (MH+). Step C. Preparation of l-benzyl-3-bromo-4-(phenylethynyl)pyridin-2(lH)- one.
Figure imgf000269_0002
To a solution of l-benzyl-3-bromo-2-oxo-l,2-dihydropyridin-4-yl trifluoromethanesulfonate (1.0 g) in DMF (5.0 mL) was added phenylacetylene (0.4 mL) and degassed using house vacuum. The reaction flask was then purged with argon, added diisopropylethylamine (0.53 mL), and PdCl2(PPh3)2 (0.35 g) were added. The resulting mixture was stirred at room temperature for 15 min and heated at 65 °C under an argon
269 - atmosphere for 3h. The dark colored reaction mixture was concentrated in vacuo, and the residue was partitioned between EtOAc (50 mL) and 5% aqueous citric acid (25 mL). The organic extracts were washed with water, dried (Na2S0 ), filtered, and concentrated to dryness. The resulting material was purified by silica gel flash chromatography using 25% EtOAc in hexanes as the eluent . The appropriate fractions were combined, concentrated under reduced pressure. 1H NMR (CDC13) δ: 7.57 (m, 2H), 7.38 (m, 8H), 7.21 (d, IH, J = 6.8 Hz), 6.25 (d, IH, J = 6.8 Hz), and 5.16 (d, 2H), ES-MS: m/z = 364 (MH+); HR-MS m/z (MH+) calcd C20H15NOBr 364.0337, found 364.0337. Step D. Preparation of l-benzyl-3-bromo-4-(2-phenylethyl)pyridin-2(lH)- one. A mixture of l-benzyl-3-bromo-4-(phenylethynyl)pyridin-2(lH)-one (0.3 g), and platinum oxide (0.05 g) in a solvent mixture of EtOAc (10.0 mL) and EtOH ( 10.0 mL) was stirred in an atmosphere of hydrogen at 15 psi in a Fischer porter bottle for 45 min. The catalyst was removed by filtration, and filtrate was concentrated. The resulting residue was purified by silica gel flash chromatography using 25% EtOAc in hexanes as the eluent. The appropriate fractions (visualized under an UV lamp) were combined and concentrated under reduced pressure. 1H- NMR (CD3OD) δ: 7.56 (d, IH, J = 6.8 Hz), 7.31 - 7.17 ( , 10 H), 6.24 (d, IH, J = 6.8 Hz), 5.19 (s, 2H), 2.96 (m, 2H), and 2.91 (m, 2H); ES-MS m/z = 368 (MH ); HR-MS m/z (MH+) calcd C20H19NOBr 368.0650, found 368.0630. Example 53. Preparation of 3-bromo-l-(3-fluorobenzyI)-6-methyl-4-(2- phenylethyl)pyridin-2(lH)-one
The title compound was prepared essentially according to the procedure of Example 52. 1H- NMR δ: (CD3OD) δ: 7.35 (m, IH), 7.31-7.16 (m, 5H), 6.99(m, IH), 6.91 (m, IH), 6.81 (m, IH), 6.20 (s, IH), 5.41 (s, 2H), 2.94 (m, 4H), and 2.24 (s, 3H); l9F-NMR
270 - (CD3OD) δ: -115.01 (m); ES-MS, m/z = 400 (MH4); HR-MS m/z calcd C2ιH20NOBrF 400.0712, found 400.0695. Example 54. Preparation of 4-(benzyloxy)-3-bromo-l-(2,6-dichlorophenyl)-6- methylpyridin-2(lH)-one
Figure imgf000271_0001
Step A. Preparation of 3-acetyl-l-(2,6-dichlorophenyl)-4-hydroxy-6- methylpyridin-2(lH)-one
Figure imgf000271_0002
A mixture of 2,6 dichlorophenylisocyanate (4.8 g, 0.025 mol), and diketene (4.3 g, 0.05 mol) in toluene (15.0 mL) was heated to reflux for 4 h under an atmosphere of argon. After removal of the solvent in vacuo, the residue was purified by silica gel flash chromatography using EtOAc/hexanes (1:3 v/v). The appropriate fractions, as monitored by ES mass spectrometry (MH + m/z = 312) were combined and concentrated under reduced pressure. The resulting yellow solid (2.3 g) was further purified by reverse-phase HPLC using 10-90% acetonitrile/water gradient (45 min) at a flow rate of 100 mL/min. The appropriate fractions, as monitored by ES mass spectrometry (MH + m/z = 312) were combined and concentrated to half the volume. The solid that separated was extracted with EtOAc ( 2 x 25 mL). The combined extracts were washed with water, dried (Na S0 ), filtered, and concentrated to dryness to give the title compound (0.77 g) as a pale yellow powder: Η- NMR (CD3OD) δ: 7.62 (m, 2H), 7.52 (m, IH), 6.19 (s, IH), 2.59 (s, 3H), and 1.96 (s, 3H); ES-MS m/z = 312 (MH+); HR-MS, m/z calc C14H12N03C12 312.0189, found 312.0214.
- 271 - Step B. Preparation of l-(2,6-dichlorophenyl)-4-hydroxy-6-methyIpyridin- 2(lH)-one
Figure imgf000272_0001
A mixture of 3-acetyl-l-(2,6-dichlorophenyl)-4-hydroxy-6-methylpyridin-2(lH)-one 0.7 g (0.002mol) in n-butanol(3.0 mL) containing sulfuric acid (1.5 mL) was heated at 120 °C for 4 h. The dark reaction mixture was cooled, added ice/water (25 mL), and extracted with EtOAc (2 x 25 ml). The combined organic extracts were washed with water, dried (Na2S0 ), filtered, concentrated under reduced pressure and the resulting material was purified by silica gel flash chromatography using 25% EtOAc in hexanes as the eluent to afford the title compound (0.14 g) as a pale yellow powder: 1H- NMR (CD30D) δ: 7.6 (m, 2H), 7.48 (m, IH), 6.10 (dd, IH), 5.78 (d, IH, J = 2.4 Hz), 1.91 (s, 3H); ES-MS m/z = 270 (MH+); HR-MS, m/z calc C12Hι0NO2Cl2 270.0083, found 270.0103. Step C. Preparation of 4-(benzyloxy)-l-(2,6-dichlorophenyI)-6-methylpyridin- 2(lH)-one
Figure imgf000272_0002
A mixture of l-(2,6-dichlorophenyl)-4-hydroxy-6-methylpyridin-2(lH)-one (0.125 g, 0.46 mmol) and benzylbromide (0.1 mL) in DMF (2.5 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with water (10.0 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with water, dried (Na2S0 ), filtered, concentrated under reduced pressure and the resulting material was purified by silica gel flash chromatography using 25% EtOAc in hexanes to afford the title compound (0.11 g) as a pale yellow syrup: Η- NMR (CD3OD) δ: 7.61 (m, 2H), 7.55-7.3 (m, 6H),
- 272 - 6.23 (d, IH, J = 2.0 Hz), 6.01 (d, IH, J = 2.0 Hz), 5.12 (s, 2H), and 1.93 (s, 3H); ES-MS m/z=360 (MH4); HR-MS, m/z calc Cι9H16N02Cl2 , 360.0553, found 360.0569. Step D. Preparation of 4-(benzyloxy)-3-bromo-l-(2,6-dichlorophenyl)-6- methylpyridin-2(lH)-one. A mixture of 4-(benzyloxy)-l-(2,6-dichlorophenyl)-6- methylρyridin-2(lH)-one (0.1 g, 0.278 mmol) and N-bromosuccinimide (0.055 g, 0.3 mmol) in dichloroethane (3.0 mL) was stirred at room temperature for 1 h, and heated at 60 °C under argon for 30 min. The reaction mixture was then diluted with dichloroethane (15 mL), washed with water, dried (Na2S0 ), filtered, and concentrated under reduced pressure. 1H NMR (CD3OD) δ: 7.64 (m, 2H), 7.55 (m, 3H), 7.38 (m, 3H), 6.65 (s, IH), 5.34 (s, 2H), and 2.00(s, 3H); ES-MS m/z = 439 (MH+ ); HR-MS, m/z calc Cι9Hι6N02Cl2Br, 439.9635, found 439.9669. Example 55. Preparation of 3-bromo-l-(3-fluorobenzyl)-4-(2- phenylethyl)pyridin-2(lH)-one
Figure imgf000273_0001
The title compound was prepared essentially according to the procedure of Example 52. 1H- NMR (CD3OD) δ: 7.58 (d, IH, J = 6.8 Hz), 7.4-7.0 (m, 9H), 6.26 (d, IH. J = 6.8 Hz), 5.19 (s, 2H), 2.97 (m, 2H), and 2.90 (m, 2H); ES-MS m/z = 386 (MH+); HR-MS, m/z calc C20Hι8NOFBr, 386.0550, found 386.0585. Example 56. Preparation of l-benzyl-3-bromo-2-oxo-l,2-dihydropyridin-4-yl methyl(phenyl)carbamate
273
Figure imgf000274_0001
Step A. Preparation of l-benzyl-2-oxo-l,2-dihydropyridin-4-yl methyl(phenyl)carbamate
Figure imgf000274_0002
To a chilled solution of l-benzyl-4-hydroxypyridin-2(lH)-one (0.375 g, 1.86 mmol) in anhydrous acetonitrile (10 mL) was added triethylamine (0.206 g, 2.04 mmol) followed by N-methyl-N-phenylcarbamoyl chloride (0.379 g, 2.24 mmol). The reaction mixture was stirred under nitrogen atmosphere at 0°C for 30 min then at room temperature for lh. The reaction was monitored by TLC (5% methanol in dichloromethane). The solvent was removed under reduced pressure and the residue was washed with 10% citric acid and extracted with EtOAc. The organic extracts were combined, washed with water dried over anhydrous Na2S04, and filtered. The solvent was removed under reduced pressure to afford a yellow syrup. The residue was purified by flash chromatography (silica gel) using 5% MeOH in CH2C12 to give the desired product (0.382g, 61%) as a white semisolid. MS and 1H-NMR were consistent with the desired structure. 1H-NMR (d6-DMSO, 400 MHz) δ: 7.8 (d, IH), 7.39 (m, 10H), 6.19 (s, 2H), 5.03 (s, 2H), 3.29 (s, 3H); HR-MS (ES) m/z calcd for C20H18N2O3 (MH+)= 335.1396, observed 335.1418.
- 274 - Step B. Preparation of l-benzyl-3-bromo-2-oxo-l,2-dihydropyridin-4-yl methyl(phenyl)carbamate
Figure imgf000275_0001
To a solution of l-benzyl-2-oxo-l,2-dihydropyridin-4-yl methyl(phenyl)carbamate (0.38 g, 1.13 mmol) in anhydrous CH2C12 (7 mL) was added N-Bromosuccinimide (NBS, 0.24 g, 1.34 mmol). The reaction was stirred overnight at room temperature under nitrogen atmosphere. The reaction mixture was purified by flash chromatography (silica gel) using EtOAc/hexanes (1:1 v/v). The appropriate fractions were collected according to ES MS (M+H 413) and concentrated. The dried product showed about 14% of di-brominated product by analytical HPLC. The compounds were separated by reverse phase HPLC using a 10-90% acetonitrile in water, 30 min gradient at a 100 mL/min flow rate, to afford (after lyophilization) the salt of the desired compound. The salt was diluted in EtOAc and washed with NaHC03. The organic extracts were dried over anhydrous Na2S0 , filtered, and concentrated to afford the desired compound (0.271 g, 58%) as a beige solid. MS and Η-NMR were consistent with the desired structure. 1H-NMR (d6-DMSO, 400Hz) δ: 7.83 (d, IH), 7.39 (m, 10H), 6.48 (s, IH), 5.12 (s,2H), 3.33 (s, 3H); HR-MS (ES) m/z calcd for C20H17O3Br (MH+)= 413.0495, observed 413.0496. Example 57. Preparation of 4-(benzyloxy)-3-ethynyl-l-(3- fluorobenzyl)pyridin-2(lH)-one
Figure imgf000275_0002
Step A. Preparation of 4-(benzyloxy)-l-(3-fluorobenzyl)-3-iodopyridin-2(lH)- one
275
Figure imgf000276_0001
Heated a reaction mixture of 4-(benzyloxy)-l-(3-fluorobenzyl)pyridin-2(lH)-one (4.83 g, 15.6 mmol) in anhydrous acetonitrile (55 mL) and N-iodosuccinimide (NIS, 3.86 g, 17.1 mmol) under nitrogen atmosphere at 65° C for 4 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (silica gel) using EtOAc/hexanes (1:1 v:v). The appropriate fractions were collected according to ES MS (M+H 436) and washed with Na2S03 to remove the color impurities. The fractions were concentrated under reduced pressure and dried in vacuo to afford the desired product (6.15 g, 90%) as a light yellow solid. MS and 1H-NMR were consistent with the desired structure. Η-NMR (CD3OD, 400Hz) δ: 7.73 (d, IH), 7.47 (d, 2H), 7.39 (m, 4H), 7.08 (m, 3H), 6.39 (d, IH), 5.29 (s, 2H), 5.19 (s, 2H); HR-MS (ES) m/z calcd for C19H15N02FI (MH+)= 436.0210, observed 436.0196. Step B. Preparation of 4-(benzyloxy)-l-(3-fluorobenzyl)-3- [(trimethyIsilyl)ethynyl]pyridin-2(lH)-one
Figure imgf000276_0002
Degassed a solution of 4-(benzyloxy)-l-(3-fluorobenzyl)-3-iodopyridin-2(lH)-one (2.01 g, 4.62 mmol) in anhydrous acetonitrile (25 mL) under argon atmosphere. Triethylamine (1.11 g, 11 mmol) was added and quickly degassed. The reaction mixture was chilled in an ice bath for 15 minutes before adding bistriphenylphosphine-palladium chloride (0.34 g, 0.48 mmol) and cuprous iodide (0.2 g). The reaction was stirred at room temperature for 30 min before heating at 60° C under an atmosphere of argon for 2 h. The reaction mixture was filtered through a bed of celite and the filtrate was concentrated under reduced pressure. The dark brown residue was diluted with CH2C1 (100 mL) and washed with water. The organic extracts were combined, dried over anhydrous Na S04, filtered, and concentrated under reduced pressure. The dark brown residue was purified by flash chromatography (silica gel) using 30% EtOAc in hexane. The appropriate fractions were
- 276 - combined and concentrated under reduced pressure to afford the desired product (1.34 g, 72%) as a light yellow solid. MS and 1H-NMR were consistent with the desired structure. 1H-NMR (CD3OD, 400Hz) δ: 7.74 (d, IH), 7.47 (d, 2H), 7.35 (m, 4H), 7.09 (m, 3H), 6.46 (d, IH), 5.26 (s, 2H), 5.13 (s, 2H), 0.18 (s, 9H); HR-MS (ES) m/z calcd for C24H24N02FSi (MH+)= 406.1638, observed 406.1610. Step C. Preparation of 4-(benzyloxy)-3-ethynyI-l-(3-fluorobenzyl)pyridin- 2(lH)-one
Figure imgf000277_0001
To a solution of 4-(benzyloxy -l-(3-fluorobenzyl)-3-[(trimethylsilyl)ethynyl]pyridin- 2(lH)-one (1.31 g, 3.2 mmol) in anhydrous acetonitrile (25 mL) at 0° C was added tetrabutylammonium fluoride (0.61 lg, 1.93 mmol). The reaction was stirred at 0° C for 15 min then for 1 h at room temperature. The reaction was concentrated under reduced pressure and the residue was diluted with EtOAc and washed with water. The organic extracts were combined, dried over anhydrous Na2S0 , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel) using EtOAc in hexanes (1:1 v/v). The appropriate fractions were combined and concentrated under reduced pressure to afford the desired product (0.779 g, 72%) as a gold solid. MS and 1H-NMR were consistent with the desired structure. Η-NMR (CD3OD, 400Hz) δ: 7.73 (d, IH), 7.43 (d, 2H), 7.35 (m,4H), 7.09 (m,3H), 6.45 (d, IH), 5.27 (s, 2H), 5.13 (s,2H), 3.78 (s, IH); HR-MS (ES) m/z calcd for C21H16N02F (MH+)= 334.1243, observed 334.1234. Example 58. Preparation of 4-(benzylamino)-3-bromo-l-(3- fluorobenzyl)pyridin-2(lH)-one
277
Figure imgf000278_0001
Step A. Preparation of l-(3-fluorobenzyl)-4-hydroxypyridin-2(lH)-one
Figure imgf000278_0002
In a Fischer-Porter bottle, added a solution of 4-(benzyloxy)-l-(3-fluorobenzyl)pyridin- 2(lH)-one (4.5 g, 14.56 mmol) in absolute ethanol (20 mL). Flushed the solution with nitrogen then added palladium catalyst (1.05 g). Sealed bottle and evacuated system. The system was purged with hydrogen gas (2 X 15 psi) to check for leaks. The reaction was charged with hydrogen (35 psi) and stirred at room temperature for 45 min. The system was evacuated and flushed with nitrogen. The reaction was filtered and the catalyst was carefully washed with fresh ethanol. The filtrate was concentrated under reduced pressure. MS and 1H-NMR were consistent with the desired structure. 1H-NMR (CD3OD, 400Hz) δ: 7.54 (d, IH), 7.32 (m, IH), 7.06 (m, 3H), 6.05 (dd, IH), 5.83 (s, IH), 5.09 (s, 2H); HR-MS (ES) m/z calcd for d2H10NO2F (MH+)= 220.0774, observed 220.0787. Step B. Preparation of 4-(benzylamino)-l-(3-fluorobenzyl)pyridin-2(lH)-one
Figure imgf000278_0003
Heated a reaction mixture of l-(3-fluorobenzyl)-4-hydroxypyridin-2(lH)-one (1.005 g, 4.5 mmol) in benzylamine (15 mL) at reflux (185° C) under nitrogen atmosphere for 24 h.
The reaction was monitored by ES-MS (MH+ 309). The solvent was removed by vacuum distillation to give a yellow residue. MS and 1H-NMR were consistent with the desired structure. Η-NMR (CD3OD, 400Hz) δ: 7.31 (m, 7H), 7.03 (m, 3H), 5.98 (dd, IH), 5.45 (s,
278 IH), 5.00 (s, 2H), 4.30 (s, 2H); HR-MS (ES) m/z calcd for C19H17N2OF (MH+)= 309.1403, observed 309.1375. Step C. Preparation of 4-(benzylamino)-3-bromo-l-(3-fluorobenzyl)pyridin- 2(lH)-one
Figure imgf000279_0001
To a solution of 4-(benzylamino)-l-(3-fluorobenzyl)pyridin-2(lH)-one (0.50 g, 1.62 mmol) in anhydrous CH C12 (10 mL) was added N-bromosuccinimide (NBS, 0.30 g, 1.7 mmol). The reaction was stirred at room temperature under a nitrogen atmosphere for 3 h. The reaction mixture was purified by flash chromatography (silica gel) using EtOAc in hexanes (1:1 v/v). The appropriate fractions were combined and concentrated. MS and 1H-NMR were consistent with the desired structure. 1H-NMR (CD3OD, 400Hz) δ: 7.41 (d, IH), 7.31 (m, 6H), 7.04 (m, 3H), 5.99 (d, IH), 5.08 (s, 2H), 4.53 (s, 2H); HR-MS (ES) m/z calcd for C19Hι6N2OFBr (MH+)= 387.0508, observed 387.0504. Example 59. Preparation of 3-bromo-l-cyclopropylmethyl-4-(4- fluorobenzyloxy)-lfiT-pyridin-2-one
Figure imgf000279_0002
Step 1. Preparation of 4-[(4-fluorobenzyloxy]pyridine-l-oxide. To an ice-cold solution of sodium hydride (1.9 g, of a 60% dispersion in mineral oil, 46 mmol) in DMF
(39 mL) was added 4-fluorobenzyl alcohol (5.1 mL, 46 mmol). The reaction mixture was warmed to room temperature, 4-chloropyridine-l -oxide1 (5.0 g, 39 mmol) was added, and the reaction mixture was stirred for 6 h. The reaction mixture was diluted with a 50% aqueous solution of brine, and extracted with CHC13 (7 x 50 mL). The combined organics were dried (MgS0 ), filtered, and concentrated under reduced pressure. Trituration with Et 0 afforded 4-[(4-fluorobenzyloxy]pyridine-l -oxide as an off-white solid (9.1 g, 90%), which was used in the next step without further purification or characterization.
- 279 - Step 2. Preparation of 4-(4-fluorobenzyloxy)-lH-pyridin-2-one. A solution of 4-[(4-fluorobenzyloxy]pyridine-l -oxide (6.4 g, 29 mmol) in acetic anhydride (97 mL) was heated at reflux for 3 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was diluted with 1 : 1 MeOH/water (34 mL), and the mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. Trituration with Et20/hexanes afforded 4- (4-fluorobenzyloxy)-lH-pyridin-2-one as a brown solid (3.1 g, 48%): 1H NMR (300 MHz, CDC13) δ 7.40-7.36 (m, 2H), 7.22 (d, /= 8 Hz, IH), 7.09 (t, J= 7 Hz, 2H), 6.03 (dd, /= 7, 3 Hz, IH), 5.94 (d, J = 3 Hz, IH), 4.98 (s, 2H). Step 3. Preparation of 3-bromo-4-(4-fluorobenzyloxy)-lfiT-pyridin-2-one. To an ice-cold solution of 4-(4-fluorobenzyloxy)pyridine-2(lH)-one (3.1 g, 14 mmol) in AcOH (26 mL) was added a solution of bromine (0.79 mL, 15 mmol) in AcOH (51 mL), and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure, and purification by flash column chromatography (silica, 1:1 Et 0/hexanes) to afford 3-bromo-4-(4-fluorobenzyloxy)-lH-pyridin-2-one as an orange solid (0.78 g, 48%): MS APCI m/z 298 [M + H]+. Step 4. Preparation of 3-Bromo-l-cyclopropylmethyl-4-(4-fluorobenzyloxy)- Uϊ-pyridin-2-one. To a solution of 3-bromo-4-(4-fluorobenzyloxy)-lH-pyridin-2-one (0.25 g, 0.84 mmol) in DMF (13 mL) was added K2C03 (0.33 g, 1.7 mmol) and cyclopropylmethyl bromide (0.14 g, 1.0 mmol), and the reaction mixture was stirred at
110 °C for 2 h. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was diluted with a 50% aqueous solution of brine, and extracted with CΗC13 (3 x 50 mL). The combined organics were washed with water and then brine, dried (MgS04), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:1 EtOAc/hexanes) afforded 3- bromo-l-cyclopropyl-methyl-4-(4-fluorobenzyloxy)-lH-pyridin-2-one as a yellow solid (0.12 g, 39%): mp 139-141 °C; 1H NMR (300 MHz, CDC13) δ 7.43-7.34 (m, 3H), 7.07 (t, J = 9 Hz, 2H), 6.06 (d, J = 6 Hz, IH), 5.19 (s, 2H), 3.82 (d, J= 9 Hz, 2H), 1.26-1.23 (m, IH), 0.62-0.57 (m, 2H), 0.40-0.36 (m, 2H). ESHRMS m/z 352.0368 (M+H Cι6Hι6BrFN02 requires 352.0343) Examples 60-69. Preparation of compounds corresponding in structure to the following formula: - 280 -
Figure imgf000281_0001
The compounds of Examples 60-69 are prepared essentially according to the procedures set forth above for Example 59.
Figure imgf000281_0002
281
Figure imgf000282_0002
Example 70. Preparation of {3-[3-bromo-4-(4-fluorobenzyloxy)-2-oxo-2fl- pyridin-l-ylmethyl]benzyl}carbamic acid tert-butyl ester
NHBoc
Figure imgf000282_0001
Step 1. Preparation of 3-hydroxymethylbenzonitrile. To an ice-cold solution of 3-cyanobenzaldehyde (5.0 g, 38 mmol) in 1 : 1 MeOH/THF (90 mL) was added NaBIL, (1.6 g, 42 mmol), and the reaction mixture was stirred for 3 h. The reaction mixture was diluted with brine, and the solvent was removed under reduced pressure. The residue was dissolved in water, and the aqueous layer was extracted with Et 0 (3 x 100 mL). The combined organics were washed with brine, dried (MgS0 ), filtered, and concentrated under reduced pressure to provide 3-hydroxymethyl-benzonitrile (4.95 g, 98%) as a clear oil, which was used in the next step without further purification or characterization. Step 2. Preparation of 3-(tert-butyldimethylsilyloxymethyl)benzonitrile. To an ice-cold solution of 3-hydroxymethyl benzonitrile (4.95 g, 37 mmol) in CH2C12 (47 mL) was added imidazole (5.1 g, 74 mmol), DMAP (0.45 g, 3.7 mmol), and TBSC1 (6.2 g, 41 mmol), and the reaction mixture was stirred for 12 h. The reaction mixture was diluted - 282 - with water, and the aqueous layer was extracted with CH2C12 (3 x 150 mL). The combined organics were washed with brine, dried (MgS0 ), filtered, and concentrated under reduced pressure to provide 3-(tert-butyldimethylsilyloxymethyl)-benzonitrile (9.1 g, 99%) as a clear oil: 1H NMR (300 MHz, CDC13) δ 7.51 (s, IH), 7.42 (d, /= 6 Hz, IH), 7.35-7.28 (m, IH), 4.75 (s, 2H), 0.94 (s, 9H), 0.11 (s, 6H). Step 3. Preparation of 3-(fert-butyldimethylsilyloxymethyl)benzylamine. To an ice-cold solution of 3-(tert-butyldimethylsilyloxymethyl)benzonitrile (4.5 g, 18 mmol) in THF (47 mL) was added LiAlE (27 mL, of a 1 M solution in THF, 27 mmol), and the reaction mixture was stirred at reflux for 3 h. The reaction mixture was cooled to 0 °C, and the reaction was quenched with water (25 mL) and 15%NaOH in water (75 mL). The reaction mixture was filtered, concentrated under reduced pressure, and the residue was dissolved in EtOAc. The organic solution was washed with water and then brine, dried (MgS0 ), filtered, and concentrated under reduced pressure to provide 3-(tert- Butyldimethylsilyloxymethyl)benzylamine (1.4 g, 30%) as a clear oil: 1H NMR (300 MHz, CDC13) δ 7.22-7.10 (m, 4H), 4.57 (s, 2H), 3.74 (s, 2H), 0.84 (s, 9H), 0.09 (s, 6H). Step 4. Preparation of 3-(hydroxymethyl)benzylcarbamic acid tert-butyl ester. To a solution of 3-(tert-butyldimemylsilyloxymethyl)benzylarrnne (1.4 g, 5.5 mmol) and Et3N (1.5 mL, 11 mmol) in CH2C12 (28 mL) was added di-tert-butyl dicarbonate (1.3 g, 5.8 mmol), and the reaction mixture was stirred for 12 h. The reaction mixture was diluted with water and extracted with CH2C12 (3 x 100 mL). The combined organics were washed with brine, dried (MgS04), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, CH2C12) to afford 3- (hydroxymethyl)benzylcarbamic acid tert-butyl ester as a yellow oil (1.4 g, 46%): 1H NMR (300 MHz, CDC13) δ 7.32-7.28 (m, IH), 7.18 (d, J = 8 Hz, IH), 7.12 (s, IH), 7.08- 7.01 (m, IH), 4.60 (s, 2H), 4.04 (d, J= 6 Hz, 2H), 1.36 (s, 9H). Step 5. Preparation of 3-(bromomethyl)benzylcarbamic acid tert-butyl ester. To an ice-cold solution of 3-(hydroxymethylbenzyl)carbamic acid tert-butyl ester (0.7 g, 3.0 mmol) and CBr4 (1.0 g, 3.1 mmol) in THF (14 mL) was added Ph3P (0.81 g, 3.1 mmol), and the reaction mixture was stirred for 18 h. The reaction mixture was filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent 5:95 to 15:85 EtOAc/hexanes) to afford the 3-(bromomethyl)benzyl- carbamic acid tert-butyl ester as a white solid (0.42 g, 51%): 1H NMR (300 MHz, MeOD) - 283 - δ 7.55 (s, IH), 7.32-7.27 (m, 2H), 7.21-7.19 (m, IH), 4.54 (s, 2H), 4.21 (s, 2H), 1.28 (s, 9H). Step 6. Preparation of l{3-[3-bromo-4-(4-fluorobenzyloxy)-2-oxo-2iϊ-pyridin- l-ylmethyl]benzyl}carbamic acid tert-butyl ester. To a solution of 3 -bromo-4- (4- fluorobenzyloxy)pyridine-2(lH)-one (from Step 3, synthesis Example 59) (0.2 g, 0.67 mmol) in DMF (11 mL) was added K2C03 (0.26 g, 1.3 mmol) and 3- (bromomethyl)benzylcarbamic acid tert-butyl ester (0.23 g, 0.80 mmol), and the reaction mixture was stirred at 80 °C for 3 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with a 50% aqueous solution of brine (24 mL), and extracted with CHC13 (4 x 50 mL). The combined organics was washed water and then brine, dried (MgS04), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 3:7 EtOAc/hexanes) and recrystallization from MeOH afforded {3-[3-bromo-4-(4- fluorobenzyloxy)-2-oxo-2H-pyridin-l-ylmethyl]benzyl}carbamic acid tert-butyl ester as an off-white solid (0.07 g, 20%): mp 136-138 °C; 1H NMR (300 MHz, CDC13) δ 7.42-7.37 (m, 2H), 7.30-7.20 (m, 5H), 7.08 (t, 7 = 9 Hz, 2H), 6.04 (d, 7 = 9 Hz, IH), 5.16 (s, 2H), 5.14 (s, 2H), 4.28 (d, 7 = 6 Hz, IH), 1.44 (s, 9H). ESHRMS m/z 517.1124 (M+H C25H27BrFN204 requires 517.1133) Example 71. Preparation of l-(3-aminomethylbenzyl)-3-bromo-4-(4- fluorobenzyloxy)-lH-pyridin-2-one
Figure imgf000284_0001
To an ice-cold solution of l-[3-{N-tert-butoxycarbonyl}aminomethylbenzyl]-3-bromo-4-
(4-fluorobenzyloxy)pyridine-2(lH)-one (Example 69) (0.05 g, 0.1 mmol) in CH2C12 (2 mL) was added TFA (2 mL), and the reaction mixture was stirred for 1 h. The solvent was removed under reduced pressure to provide l-(3-aminomethylbenzyl)-3-bromo-4-(4- fluorobenzyloxy)-lH-pyridin-2-one as a tan solid (0.049 g, 100%), as the TFA salt: mp 127-139 °C; 1H NMR (300 MHz, OMSO-d6) δ 8.13 (br s, 2H), 7.94 (d, 7= 6 Hz, IH), 7.52-7.47 (m, 2H), 7.44-7.37 (m, 2H), 7.27 (t, 7 = 8 Hz, 3H), 6.53 (d, 7 = 8 Hz, IH), 5.30
- 284 - (s, 2H), 5.14 (s, 2H), 4.01 (d, 7= 6 Hz, 2H), 3.39 (br s, 2H); Anal. Calcd for C20H17BrF2N2O2 «1.125 TFA: C, 48.99; H, 3.53; N, 5.13. Found: C, 48.80; H, 3.43; N, 4.75. ESHRMS m/z 417.0608 (M+H C20H19BrFN2O2 requires 417.0609). Example 72. Preparation of methyl 2-[3-Bromo-4-(4-fluorobenzyIoxy)-2-oxo- 2/f-pyridin- l-ylmethyl]benzoate
Figure imgf000285_0001
The title compound was prepared by a procedure similar to the one described for EXAMPLE 59 (0.36 g, 48%): mp 161-165 °C; 1H NMR (300 MHz, CDC13) δ 7.98 (d, 7 = 6 Hz, IH), 7.51-7.26 ( , 6H), 7.11-7.05 (m, 2H), 6.05 (d, 7 = 8 Hz, IH), 5.60 (s, 2H), 5.18 (s, 2H), 3.93 (s, 3H). ESHRMS m/z 446.0430 (M+H C2ιH18BrFN04 requires 418.0398) Example 73. Preparation of 3-bromo-4-(4-fluorobenzyloxy)-l-(2- hydroxymethylbenzyl)-lJΪ-pyridin-2-one
Figure imgf000285_0002
To an ice-cold solution of 3-bromo-4-(4-fluorobenzyloxy)-l-(2-hydroxymethylbenzyl)- lH-pyridin-2-one (Example 72) (0.25 g, 0.56 mmol) in THF (1 mL) was added LiBH4 (2.0 M solution in THF, 0.56 mmol), and the reaction mixture was stirred at 40 °C for 6 hours. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the residue was dissolved in EtOAc. The organic solution was washed with brine, dried (MgS04), filtered, and concemtrated under reduced pressure. H NMR (300 MHz, DMSO- 6) δ 7.82 (d, 7 = 8 Hz, IH), 7.54-7.49 (m, 2H), 7.41 (d, 7 = 7 Hz, IH), 7.29-7.21 (m, 4H), 6.81 (d, 7 = 7 Hz, IH), 6.53 (d, 7 = 8 Hz, IH), 5.30-5.25 (m, 3H), 5.18 (s, 2H), 4.60 (d, 7= 7 Hz, 2H). ESHRMS m/z 418.0437 (M+H C20H18BrFNO3 requires 418.0449)
285 Example 74. Preparation of 3-bromo-4-(2,4-difluorobenzyloxy)-l-[(4- dimethylaιninomethyl)benzyI]-lH-pyridin-2-one
Figure imgf000286_0001
Step 1. Preparation of 4-(2,4-difluorobenzyIoxy)pyridine-l-oxide. To an ice- cold solution of sodium hydride (1.2 g of a 60% dispersion in mineral oil, 51 mmol) in
DMF (43 mL) was added 2,4-difluorobenzyl alcohol (5.7 mL, 51 mmol). The reaction mixture was warmed to room temperature, 4-chloropyridine-l-oxide1 (5.5 g, 43 mmol) was added, and the reaction mixture was stirred for 6 h. The reaction mixture was diluted with a 50% aqueous solution of brine, and extracted with CHC13 (7 x 50 mL). The combined organics were dried (MgS0 ), filtered, and the solvent was removed under reduced pressure. Trituration with Et 0 afforded 4-(2,4-difluorobenzyloxy)pyridine-l- oxide as an off-white solid (9.1 g, 90%): 1H NMR (300 MHz, CDC13) δ 8.16-8.08 (m, IH), 7.47-7.36 (m, IH), 6.97-6.81 (m, IH), 5.09 (d, 7= 8 Hz, IH). Step 2. Preparation of 4-(2,4-difluorobenzyloxy)-l 7-pyridin-2-one. A solution of 4-(2,4-difluorobenzyloxy)pyridine-l -oxide (13.4 g, 57 mmol) in acetic anhydride (30 mL) was stirred at reflux for 4 h. The solvent was removed under reduced pressure, the residue was diluted with 1:1 MeOH/water (60 mL), and the mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. Purification by flash column chromatography (silica, eluent methylene chloride to 9: 1 methylene chloride/methanol) provided 4-(2,4-difluorobenzyloxy)-lH-pyridin-2-one as a light brown solid (4.2 g, 31%): 1H NMR (300 MHz, CDC13) δ 7.43 (q, 7= 8 Hz, IH), 7.23 (d, 7 = 7 Hz, IH), 6.91-6.87 (m, 2H), 6.02 (dd, 7 = 8, 2 Hz, IH), 5.97 (d, 7 = 2 Hz, IH), 5.03 (s, 2H). Step 3. Preparation of 3-bromo-4-(2,4-difluorobenzyloxy)-lfl-pyridin-2-one. To an ice-cold solution of 4-(2,4-difluorobenzyloxy)-lH-pyridin-2-one (0.75 g, 3.1 mmol) in AcOH (12 mL) was added a solution of bromine (0.2 mL, 3.5 mmol) in AcOH (6 mL), and the reaction mixture was stirred 10 min. The solvent was removed under reduced
- 286 i pressure to afford 3-bromo-4-(2,4-difluorobenzyloxy)-lH-pyridin-2-one as a white solid (1.0 g, 100%): ESI MS m/z 299 [M + H]+. Step 4. Preparation of 3-bromo-l-(4-chloromethylbenzyl)-4-(2,4- difluorobenzyloxy)-lfl-pyridin-2-one. To a solution of 3-bromo-4-(2,4- difluorobenzyloxy)-lH-ρyridin-2-one (0.60 g, 2.5 mmol) in DMF (40 mL) was added K2C03 (0.70 g, 5.1 mmol) and D D'-dichloro- -xylene (0.53 g, 3.0 mmol), and the reaction mixture was stirred at 110 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with brine, and extracted with CHC13 (4 x 100 mL). The combined organics were washed water and then brine, dried (Na2S0 ), filtered, and concentrated under reduced pressure to afford 3-bromo-l-(4-chloromethylbenzyl)-4-(2,4- difluorobenzyloxy)-lH-ρyridin-2-one as an off-white solid (0.49 g, 43%): 1H NMR (300 MHz, CDC13) δ 7.54 (app q, 7 = 8 Hz, IH), 7.38-7.28 (m, 5H), 6.94 (td, 7 = 8, 2 Hz, IH), 6.85 (td, 7= 8, 2 Hz, IH), 6.10 (d, 7 = 9 Hz, IH), 5.21 (s, 2H), 5.16 (s, 2H), 4.56 (s, 2H). Step 5. Preparation of 3-bromo-4-(2,4-difluorobenzyloxy)-l-[(4- dimethylaminomethyl) benzylJ-l.H-pyridin-2-one. To a sealed tube containing 3- bromo-l-(4-chloromethylbenzyl)-4-(2,4-difluoro-benzyloxy)-lH-pyridin-2-one (0.49 g, 1.1 mmol) was added a solution of dimethylamine (5.5 mL of a 2.0 M solution in THF, 11 mmol), and the reaction mixture was stirred for 15 h. The solvent was removed under reduced pressure. Purification by flash column chromatography (silica, eluent methylene chloride to 92:7.2:0.8 methylene chloride/methanol/ammonia) provided 3-bromo-4-(2,4- difluorobenzyloxy)-l-(4-dimethylaminomethylbenzyl)-lH-pyridin-2-one as a light yellow solid (0.23 g, 46%): mp 111-113 °C; 1H NMR (500 MHz, CDC13) δ 7.50-7.49 (m, IH), 1.26-1.22 (m, 5H), 6.90-6.88 (m, IH), 6.82-6.78 (m, IH), 6.04 (d, 7= 6 Hz, IH), 5.16 (s, 2H), 5.11 (s, 2H), 3.37 (s, 2H), 2.19 (s, 6H). ESHRMS m/z 463.0782 (M+H C22H22BrF2N202 requires 463.0827) Example 75. Preparation of 3-bromo-4-(2,4-difluorobenzyloxy)-l-[3- (isopropyϊaminomethyl)benzyl]-lH-pyridin-2-one
Figure imgf000287_0001
- 287 - The title compound was prepared by a procedure similar to the one described for Example 74 (0.06 g, 35%): mp 109-110 °C; 1H NMR (300 MHz, CDC13) δ 7.54 (d, 7= 6 Hz, IH), 7.33-7.20 (m, 5H), 6.94-6.81 (m, 2H), 6.10 (d, 7= 6 Hz, IH), 5.20 (s, 2H), 5.14 (s, 2H), 3.77 (s, 2H), 2.88 (t, 7 = 6 Hz, IH), 1.13 (d, 7= 6 Hz, 6H). ESHRMS m/z 477.0955 (M+H C23H24BrF2N202 requires 477.0984) Example 76. Preparation of 3-bromo-4-(2,4-difluorobenzyIoxy)-l-[(3- dimethylammomethyl)benzyl]-lfiT-pyridin-2-one
Figure imgf000288_0001
The title compound was prepared by a procedure similar to the one described for Example 74 (0.06 g, 25%): mp 103-107 °C; 1H NMR (300 MHz, CDC13) δ 7.52 (d, 7 = 8 Hz, IH),
7.32-7.24 (m, 5H), 6.94 (td, 7 = 9, 3 Hz, IH), 6.84 (td, 7= 9, 3 Hz, IH), 6.08 (d, 7= 8 Hz,
IH), 5.20 (s, 2H), 5.16 (s, 2H), 3.44 (s, 2H), 2.24 (s, 6H). ESHRMS m/z 463.0801 (M+H
C22H22BrF2N202 requires 463.0827). Example 77. Preparation of 3-Bromo-4-(2,4-difluorobenzyIoxy)-l-[(3- methylaminomethyI)benzyI]-l/7-pyridin-2-one
Figure imgf000288_0002
The title compound was prepared by a procedure similar to the one described for Example
74 (0.05 g, 16%): mp 107-111 °C; 1H NMR (300 MHz, CDC13) δ 7.55 (d, 7 = 6 Hz, IH), 7.31-7.19 (m, 5H), 6.94-6.81 (m, 2H), 6.09 (d, 7= 6 Hz, IH), 5.20 (s, 2H), 5.14 (s, 2H), 3.73 (s, 2H), 2.45 (s, IH). ESHRMS m/z 449.0652 (M+H C21H20BrF2N2O2 requires 449.0671) Example 78. Preparation of {3-[3-bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2flr- pyridin-l-ylmethyl]benzyl}carbamic acid tert-butyl ester
- 288
Figure imgf000289_0001
The title compound was prepared essentially according to the procedure described in
Example 70. mp 80-84 °C; 1H NMR (300 MHz, DMSO- 6) δ 7.60-7.50 (m, IH), 7.33-
7.21 (m, 5H), 6.97-6.81 (m, 2H), 6.10 (dd, 7 = 8, 2 Hz, IH), 5.20 (s, 2H), 5.15 (s, 2H),
4.87 (br s, 2H), 4.30 (s, 2H) 1.45 (s, 9H). ESHRMS m/z 535.1019 (M+H C25H26BrF2N204 requires 535.1039) Example 79. Preparation of l-[(3-aminomethyl)benzyl]-3-bromo-4-(2,4- difluorobenzyloxy)-lH-pyridin-2-one
Figure imgf000289_0002
To an ice-cold solution of {3-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-l- ylmethyl]benzyl}carbamic acid tert-butyl ester (Example 78) (0.05 g, 0.1 mmol) in
CH2C12 (2 mL) was added TFA (2 mL), and the reaction mixture was stirred for 1 hour.
The solvent was removed under reduced pressure to provide l-[(3-aminomethyl)benzyl]-
3-bromo-4-(2,4-difluorobenzyloxy)-lH-pyridin-2-one as a tan solid (0.049 g, 100%), as the TFA salt: mp 80-84 °C; 1H NMR (300 MHz, DMSO-J6) δ 8.15 (br s, 3H), 7.97 (d, 7 = 8 Hz, IH), 7.79-7.60 (m, IH), 7.44-7.30 (m, 4H), 7.20-7.15 (m, IH), 6.61 (d, 7= 6 Hz, IH), 5.31 (s, 2H), 5.16 (s, 2H), 4.03 (s, 2H); 19F NMR (282 MHz, DMSO- ) δ -74.56 (4.8F), -109.63 (IF), -113.61 (IF). ESHRMS m z 435.0540 (M+H C20H18BrF2N2O2 requires 435.0515) Example 80. Preparation of 3-chloro-4-(2,4-difluorobenzyloxy)-l-[4-
(isopropylaminomethy^benzyfJ-lZZ-pyridin^-one
- 289
Figure imgf000290_0001
Step 1. Preparation of 3-chloro-4-(2,4-difluorobenzyIoxy)-l/f-pyridin-2-one.
To a solution of 4-[(4-fluorobenzyl)oxy]pyridine-2(lH)-one (from Step 2, Example 74)
(1.4 g, 5.9 mmol) in AcOH (25 mL) was added N-chlorosuccinimide (0.95 g, 7.1 mmol) , and the reaction mixture was heated at reflux for 2 h. The solvent was removed under reduced pressure. 1H NMR (300 MHz, MeOD) δ 7.63-7.55 (m, IH), 7.45(d, 7 = 8 Hz,
IH), 7.07-7.00 (m, 2H), 6.58 (d, 7= 8 Hz, IH), 5.31 (d, 7= 8 Hz, IH). Step 2. Preparation of 3-chloro-l-(4-chloromethyIbenzyl)-4-(2,4- difluorobenzyloxy)-ljHr-pyridin-2-one. 3-Chloro-l-(4-chloromethylbenzyl)-4-(2,4- difluorobenzyloxy)-lH-pyridin-2-one was prepared by procedure similar to the one described for 3-bromo- 1 -(4-chloromethyl-benzyl)-4-(2,4-difluorobenzyloxy)- lH-pyridin- 2-one (Step 3) as white solid (0.24 g, 34%): 1H NMR (300 MHz, CDC13) δ 7.53 (app q, 7 = 9 Hz, IH), 7.34 (app q, 7= 9 Hz, IH), 7.23 (d, 7= 8 Hz, IH), 6.94 (td, 7= 10, 2 Hz, IH), 6.85 (td, 7 = 10, 2 Hz, IH), 6.14 (d, 7 = 8 Hz, IH), 5.20 (s, 2H), 5.16 (s, 2H), 4.56 (s, 2H). Step 3. Preparation of 3-chloro-4-(2,4-difluorobenzyloxy)-l-[4- (isopropyIamino-methyl)benzyl]-l/7-pyridin-2-one. The title compound was prepared by a procedure similar to the one described for Example 74 (0.17 g, 69 %): mp 146-151 °C; 1H NMR (300 MHz, CDC13) δ 7.52 (app q, 7= 9 Hz, IH), 7.35-7.21 (m, 5H), 6.94 (td, 7 = 8, 2 Hz, IH), 6.85 (td, 7 = 8, 2 Hz, IH), 6.18 (d, 7 = 8 Hz, IH), 5.22 (s, 2H), 5.08 (s, 2H), 3.81 (s, 2H), 2.98 (br s, IH), 1.20 (s, 6H). ESHRMS m/z 433.1481 (M+H C 3H24C1F2N202 requires 433.1489). Example 81. Preparation of 3-chloro-4-(2,4-difluorobenzyloxy)-l-[(3- methanesulfonyl)benzyl]-lH-pyridin-2-one
- 290
Figure imgf000291_0001
Step 1. Preparation of (3-methanesulfonyl)phenyl methanol. To an ice-cold solution of 3-(methylsulfonyl)benzoic acid (1.4 g, 7.1 mmol) in 2:1 Et20/THF (60 mL) was added LiAlELj (8.5 mL of 1.0 M solution in THF, 8.5 mmol), and the reaction mixture was heated at reflux for 1 h. The reaction mixture was cooled to 0 °C, and the reaction was quenched with water (15 mL) and 15%NaOH in water (35 mL). The reaction mixture was filtered, concentrated under reduced pressure, and the residue was dissolved in
EtOAc. The organic solution was washed with water and then brine, dried (MgS0 ), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent 1:2 to 3:1 EtOAc/hexanes) provided (3- methanesulfonyl)phenyl methanol as a clear oil (0.56 g, 42%): Η NMR (300 MHz, CDC13) δ 7.93 (s, IH), 7.83 (d, 7 = 7 Hz, IH), 7.64 (d, 7 = 7 Hz, IH), 7.53 (t, 7 = 7 Hz, IH), 4.78 (d, 7= 6 Hz, 2H), 3.05 (s, 3H), 2.61 (br s, IH). Step 2. Preparation of l-chloromethyl-3-methanesulfonylbenzene. A solution of (3-methanesulfonyl)phenyl methanol (0.21 g, 1.1 mmol) in thionyl chloride (3 mL) was heated at 80°C for 3 h. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure to provide l-chloromethyl-3- methanesulfonylbenzene as a yellow oil (0.23 g, 95%): 1H NMR (300 MHz, CDCI3) δ 7.98 (s, IH), 7.90 (d, 7= 8 Hz, IH), 7.70 (d, 7 = 8 Hz, IH), 7.59 (t, 7= 8 Hz, IH), 4.65 (s, 2H), 3.08 (s, 3H). Step 3. Preparation of 3-chloro-4-(2,4-difluorobenzyloxy)-l-[(3- methanesulfonyl)-benzyl]-liϊ-pyridin-2-one. The title compound was prepared by a procedure similar to the one described for Example 80 (0.14 g, 78%): mp 155-157 °C; 1H NMR (300 MHz, CDC13) δ 7.88 (d, 7 = 8 Hz, IH), 7.83 (m, IH), 7.67 (d, 7 = 8 Hz, IH), 7.58-7.48 (m, 2H), 7.31 (d, 7= 8 Hz, IH), 6.95-6.83 (m, 2H), 6.22 (d, 7 = 8 Hz, IH), 5.22 (s, 4H), 3.08 (s, 3H). ESHRMS m/z 440.0525 (M+H C20H17ClF2NO4S requires 440.0529). Example 82. Preparation of 3-chIoro-4-(2,4-difluorobenzyloxy)-l-[(4- methanesulfonyl)benzyl]-lH-pyridin-2-one
- 291 -
Figure imgf000292_0001
The title compound was prepared by a procedure similar to the one described for Example
81 (0.08 g, 73%): mp 223-225 °C; 1H NMR (300 MHz, CDC13) δ 7.91 (d, 7= 8 Hz, 2H),
7.53-7.47 (m, 3H), 7.30-7.26 (m, IH), 6.94-6.86 (m, 2H), 6.22 (d, 7= 8 Hz, IH), 5.23 (s,
4H), 3.03 (s, 3H). ESHRMS m/z 440.0512 (M+H C20H17ClF2NO4S requires 440.0529) Example 83. Preparation of 4-[3-chloro-4-(2,4-difluorobenzyloxy)-2-oxo-2/Z- pyridin-l-ylmethyl]benzamide
Figure imgf000292_0002
Step 1. Preparation of methyl 4-[3-chloro-4-(2,4-difluorobenzyIoxy)-2-oxo- 2ff-pyridin-l-yImethyl]benzoate. Methyl 4-[3-chloro-4-(2,4-difluorobenzyloxy)-2-oxo- 2H-pyridin-l-ylmethyl]benzoate was prepared by a procedure similar to the one described for Example 81 (0.14 g, 60%): 1H NMR (300 MHz, CDC13) δ 8.01 (dd, 7 = 8, 2 Hz, IH), 7.52 (app q, 7 = 8 Hz, IH), 7.36 (d, 7 = 9 Hz, 2H), 7.26-7.22 (m, 2H), 6.94 (td, 7 = 8, 2 Hz, IH), 6.85 (td, 7 = 8, 2 Hz, IH), 6.16 (d, 7 = 9 Hz, IH), 5.21 (s, 4H), 3.92 (s, 3H). Step 2. Preparation of 4-[3-chIoro-4-(2,4-difluorobenzyloxy)-2-oxo-2fl- pyridin-l-ylmethyl]benzamide. A sealed tube containing a solution of 4-[3-Chloro-4- (2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-l-ylmethyl]benzoic acid methyl ester (0.25 g, 0.60 mmol) and NH3 (20 mL of a 7 N solution in MeOH, 140 mmol) was heated at 75 °C for 16 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. Trituration with Et20/MeOH afforded 4-[3-Chloro-4- (2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-l-ylmethyl]benzamide as a white solid (0.14 g, 60%): mp 235-238 °C; 1H NMR (500 MHz, DMSO- ) δ 7.93 (d, 7 = 8 Hz, 2H), 7.79 (d, 7 = 8 Hz, 2H), 7.60 (app q, 7= 8 Hz, IH), 7.35-7.27 (m, 4H), 7.20-7.10 (m, IH), 6.61 (d, 7 =
- 292 8 Hz, IH), 5.28 (s, 2H), 5.14 (s, 2H). ESHRMS m/z 405.0788 (M+H C20Hι6ClF2N2O3 requires 405.0812) Example 84. Preparation of 3-chloro-4-(2,4-difluorobenzyloxy)-l-isoquinolin- 5-ylmethyl-lH-pyridin-2-one
Figure imgf000293_0001
Step 1. Preparation of isoquinolin-5-ylmethanol. To an ice-cold solution of isoquinoline-5-carb aldehyde2 (0.68 g, 4.3 mmol) in MeOH (15 mL) was added NaBH (0.17 g, 4.6 mmol), and the reaction mixture was stirred for 15 min. The reaction was quenched with brine, the solvent was removed under reduced pressure, and the residue was dissolved in EtOAc. The organic solution was washed with water and then brine, dried (Na2S04), filtered, and concentrated under reduced pressure to afford isoquinolin-5- ylmethanol as a brown solid (0.63 g, 93%): 1H NMR (300 MHz, DMSO- ) δ 9.87(s, IH), 8.82 (d, 7 = 6 Hz, IH), 8.57 (d, 7= 6 Hz, IH), 8.47 (d, 7 = 9 Hz, IH), 8.30 (d, 7 = 6 Hz, IH), 7.95 (t, 7= 9 Hz, IH), 5.34 (s, 2H). Step 2. Preparation of 5-bromomethylisoquinoline. To a solution of isoquinolin-5-ylmethanol (0.63 g, 3.9 mmol) in AcOH (3.3 mL) was added HBr (6.6 mL, a 30% w/w solution in AcOH, 24 mmol), and the reaction mixture was stirred at 75 °C for 45 min. The reaction mixture was cooled to room temperature, and the precipitate was collected to provide the 5-bromomethylisoquinoline hydrobromide acid salt as a brown solid (1.1 g, 87%): lH NMR (300 MHz, CDC13) δ 9.22 (s, IH), 8.58 (d, 7 = 6 Hz, IH), 7.95-7.89 (m, 2H), 7.76 (d, 7=9 Hz, IH), 7.59 (dd, 7= 9, 6 Hz, IH), 5.16 (s, 2H). Step 3. Preparation of 3-chIoro-4-(2,4-difluorobenzyloxy)-l-isoquinolin-5- ylmethyl-l ϊ-pyridin-2-one. The title compound was prepared by a procedure similar to the one described for Example 81, as the TFA salt (0.13 g, 33%): mp 235-238 °C; 1H NMR (300 MHz, DMSO- ) δ 9.55 (s, IH), 8.66 (d, 7 = 6 Hz, IH), 8.29 (d, 7 = 6 Hz, IH), 8.22 (d, 7 = 8 Hz, IH), 7.91 (d, 7= 8 Hz, IH), 7.77 (t, 7= 8 Hz, IH), 7.65-7.63 (m, IH), 7.53 (d, 7= 7 Hz, IH), 7.35-7.25 (m, IH), 7.20-7.10 (m, IH), 6.68 (d, 7 = 8 Hz, IH), 5.67
293 - (s, 2H), 5.32 (s, 2H); 19F NMR (282 MHz, DMSO-J6) δ -74.79 (3F), -109.43 (IF), -113.62 (IF). ESHRMS m/z 413.0868 (M+H C22H16C1F2N203 requires 413.0863) Example 85. Preparation of 3-chloro-4-(2,4-difluorobenzyloxy)-l-(l,2,3,4- tetrahydroisoquinolin-5-yImethyl)-l/7-pyridin-2-one
Figure imgf000294_0001
To a solution of 3-chloro-4-(2,4-difluorobenzyloxy)-l-isoquinolin-5-ylmethyl-lH-pyridin- 2-one (Example 84) (0.14 g, 0.34 mmol) in AcOΗ (1.3 mL) was added NaCNBΗ3 (0.09 g, 1.4 mmol), and the reaction mixture was stirred for 2 h. The reaction mixture was cooled to 0 °C, and diluted with water(10 mL) and 40% aqueous NaOH (10 mL), and the aqueous layer was washed with EtOAc (3 x 50 mL). The combined organics were washed with brine, dried (Na2S04), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent 98:1.8:0.2 to 88:10.8:1.2 CH2Cl2 MeOH/NH3) provided 3-chloro-4-(2,4-difluoro-benzyloxy)-l-(l,2,3,4- tetrahydroisoquinolin-5-ylmethyl)-lH-pyridin-2-one as a white solid (0.13 g, 92%): mp 180-184 °C; 1H NMR (300 MHz, MeOD) δ 7.65-7.55 (m, 2H), 7.16-7.00 (m, 4H), 6.90- 6.80 (m, IH), 6.60 (d, 7= 8 Hz, IH), 5.31 (s, 2H), 5.20 (s, 2H), 4.06 (s, 2H), 3.21 (t, 7= 6 Hz, 2H), 2.82 (t, 7= 6 Hz, 2H). ESHRMS m/z 417.1173 (M+H C22H20ClF2N2O2 requires 417.1176) Example 86. Preparation of 3-chloro-4-(2,4-difluorobenzyloxy)-l-(lff-indol- 5-ylmethyl)-l^T-pyridin-2-one
Figure imgf000294_0002
Step 1. Preparation of 5-(carboxymethyl)-indole-l-carbamic acid tert-butyl ester. To a solution of methyl indole-5-carboxylate (6.9 g, 39 mmol) and Et3N (6.0 mL, 43 mmol) in CH2C12 (150 mL) was added di-tert-butyl dicarbonate (19 g, 86 mmol), and
- 294 - the reaction mixture was stirred for 14 h. The reaction mixture was diluted with CH2C12, washed with water and then brine, dried (Na2S0 ), filtered, and the solvent was removed under reduced pressure. Purification by flash column chromatography (silica, 3:7 EtOAc/hexanes) provided 5-(carboxymethyl)-indole-l -carbamic acid tert-butyl ester as a light yellow oil (11 g, 100%): 1H NMR (300 MHz, CDC13) δ 8.29 (s, IH), 8.15 (d, 7 = 9 Hz, IH), 7.93 (d, 7 = 9 Hz, IH), 7.78 (d, 7= 3 Hz, IH), 6.85 (d, 7= 3 Hz, IH), 3.91 (s, 3H), 1.68 (s, 9H). Step 2. Preparation of 5-hydroxymethylindole-l-carbamic acid tert-butyl ester. To a -78°C solution of 5-(carboxymethyl)-indole-l -carbamic acid tert-butyl ester (10.8 g, 39 mmol) in THF (180 mL) was added DIBAL (127 mL of a 1 M solution in THF, 127 mmol), and the reaction mixture was stirred for 2.5 h. The reaction was quenched with 1:1 1 N HCl/MeOH (100 mL), the reaction mixture was warmed to room temperature, diluted with CH C12 (100 mL), and separated. The organic solution was washed with saturated Rochelle salt, dried (Na2S04), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1: 1
EtOAc/hexanes) provided 5-hydroxymethylindole-l -carbamic acid tert-butyl ester as a yellow oil (6.5 g, 68%): 1H NMR (300 MHz, CDC13) δ 8.07 (d, 7 = 9 Hz, IH), 7.59 (d, 7 = 6 Hz, IH), 7.54 (s, IH), 7.28 (d, 7 = 9 Hz, IH), 6.58 (d, 7= 6 Hz, IH), 4.73 (s, 2H), 1.97 (s, 9H). Step 3. Preparation of 5-bromomethylindole-l-carbamic acid tert-butyl ester.
To an ice-cold solution of 5-hydroxymethylindole-l-carbamic acid tert-butyl ester (0.51 g, 2.1 mmol) in 4:1 Et20/CH2C12 (4 mL) was added PBr3 (0.2 mL, 2.2 mmol), and the reaction mixture was stirred for 40 min. The reaction mixture was diluted with CH2C12, washed a saturated solution of NaHC03 (3 x 10 mL), dried (Na2S04), filtered, and the solvent was removed under reduced pressure to provide 5-bromomethyl-indole-l- carbamic acid tert-butyl ester as a yellow solid (0.59 g, 93%). 1H NMR (300 MHz, CDC13) δ 8.07 (d, 7= 9 Hz, IH), 7.68-7.62 (m, 2H), 7.33 (d, 7= 9 Hz, IH), 6.60 (s, IH), 4.68 (s, 2H), 1.67 (s, 9H). Step 4. Preparation of 5-[3-chloro-4-(2,4-difluorobenzyloxy)-2-oxo-2iϊ- pyridin-l-ylmethyl]indole-l-carbamic acid tert-butyl ester. 5-[3-Chloro-4-(2,4- difluorobenzyloxy)-2-oxo-2H-pyridin-l-ylmethyl]indole-l-carbamic acid tert-butyl ester was prepared by a procedure similar to the one described for Example 81 as an off-white - 295 - solid (0.54 g, 67%): 1H NMR (300 MHz, CDC13) δ 8.10 (d, 7= 8 Hz, IH), 7.60 (d, 7= 3 Hz, 2H), 7.52 (m, IH), 7.26 (m, IH), 6.94 (td, 7= 9, 2 Hz, IH), 6.84 (td, 7= 9, 2 Hz, IH) 6.53 (d, 7= 2 Hz, IH), 6.08 (d, 7= 8 Hz, IH), 5.25 (s, 2H), 5.18 (s, 2H), 1.66 (s, 9H). Step 5. Preparation of 3-Chloro-4-(2,4-difluorobenzyIoxy)-l-(l -r-indol-5- ylmethyl)-l£-r-pyridin-2-one. A flask containing 5-[3-chloro-4-(2,4-difluorobenzyloxy)- 2-oxo-2H-pyridin-l-ylmethyl]indole-l -carbamic acid tert-butyl ester (0.48 g, 0.96 mmol) was heated at 150 °C for 4 h. The reaction mixture was cooled to room temperature, and purification by preparatory HPLC (Phenomenex Luna C18(2) column, 250 x 21.20 mm, 10 μL Solvent A: 0.05% TFA in 95:5 H20/CH3CN; Solvent B: 0.05% TFA in 95:5 CH3CN H20; Eluent: 30-95%o B over 20 min; flow 20.0 mL/min; UV Detector: 254 nm; Retention Time: 15.6 min) provided 3-chloro-4-(2,4-difluorobenzyloxy)-l-(lH-indol-5- ylmethyl)-lH-pyridin-2-one as an off-white solid (0.14 g, 36%): mp 152-153 °C; 1H NMR (300 MHz, DMSO- 6) δ 11.11 (br s, IH), 7.91 (d, 7 = 8 Hz, IH), 7.61 (app q, 7 = 8 Hz, IH, 7.51 (s, IH), 7.36-7.33 (m, 3H), 7.16 (td, 7= 8, 2 Hz, IH), 7.09 (dd, 7= 8, 2 Hz, IH), 6.57 (d, 7= 8 Hz, IH), 6.40 (br s, IH), 5.28 (s, 2H), 5.16 (s, 2H). ESHRMS m/z 401.0845 (M+H C21H16C1F2N202 requires 401.0863). Example 87. Preparation of l-(l-acetyl-lH-indol-5-ylmethyl)-3-chloro-4-(2,4- difluorobenzyloxy)-lflr-pyridin-2-one
Figure imgf000296_0001
To a solution of 3-chloro-4-(2,4-difluorobenzyloxy)-l-(l/ -indol-5-ylmethyl)-lH-pyridin-
2-one (Step 5, synthesis of Example 86) (0.22 g, 0.57 mmol) in CΗ3CN (10 mL) was added acetic anhydride (0.06 mL, 0.58 mmol) and Et N (2 mL) , and the reaction mixture was stirred at 86 °C for 6 h. The reaction mixture was cooled to room temperature, and partitioned between 1 N HC1 and EtOAc. The organic solution was separated, washed with brine, dried (Na2S04), filtered, and concentrated under reduced pressure. 1H NMR (300 MHz, MeOD) δ 8.35 (d, 7 = 9 Hz, IH), 7.77 (d, 7 = 9 Hz, IH), 7.70 (d, 7 = 3 Hz, IH), 7.54 (s, 2H), 7.31 (d, 7 = 9 Hz, IH), 7.01-6.99 (m, 2H), 6.66 (d, 7 = 3 Hz, IH), 6.59 (d, 7 =
- 296 9 Hz, IH), 5.29 (s, 4H), 2.63 (s, 3H). ESHRMS m/z 443.0965 (M+H C23H18C1F2N203 requires 443.0969). Example 88 Preparation of 3-chloro-4-(2,4-difluorobenzyloxy)-l-(2,3- dihydro-lH-indoI-5-ylmethyl)-l -pyridin-2-one
Figure imgf000297_0001
To a solution of 3-chloro-4-(2,4-difluorobenzyloxy)-l-(lH-indol-5-ylmethyl)-lH-pyridin-
2-one (Step 5, synthesis of Example 86) (0.24 g, 0.60 mmol) in AcOΗ (5 mL) was added
NaCNBΗ3 (0.06 g, 1.0 mmol), and the reaction mixture was stirred for 1 h. The reaction mixture was partitioned between water and EtOAc, and the precipitate was collected by filtration. Trituration with CH2C12 afforded 3-Chloro-4-(2,4-difluorobenzyl-oxy)-l-(2,3- dihydro-lH-indol-5-ylmethyl)-lH-pyridin-2-one as a white solid (0.2 g, 81%): mp 137- 139 °C; 1H NMR (300 MHz, CDC13) δ 7.51 (app q, 7= 9 Hz, IH), 7.21 (d, 7= 6 Hz, IH), 7.11 (s, IH), 6.99-6.80 (m, 3H), 6.57 (d, 7= 9 Hz, IH), 6.08 (d, 7 = 9 Hz, IH), 5.18 (s, 2H), 5.02 (s, 2H), 3.83 (br s, IH), 3.55 (t, 7 = 9 Hz, 2H), 2.99 (t, 7 = 9 Hz, 2H). ESHRMS m/z 403.1022 (M+H C21H18C1F2N202 requires 403.1019).
The following example compounds were prepared by procedures similar to that described for Example 74. The yields and the analytical data of the title compounds are reported below. Examples 89-101. Preparation of compounds corresponding in structure to the following formula:
Figure imgf000297_0002
297 The compounds of Examples 89-101 are prepared essentially according to the procedures set forth above for Example 74. The yield (Y), molecular formula (MF) and analytical data for these compounds are shown below.
Figure imgf000298_0002
Example 96. Preparation of 3-bromo-4-(2,4-difluorobenzyloxy)-l-(2,4- difluorobenzyl)-l -pyridin-2-one
Figure imgf000298_0001
Step 1. Preparation of 4-(2,4-difluorobenzyloxy)-l-(2,4-difluorobenzyl)-l.ff- pyridin-2-one. To a solution of 2,4-dihydroxypyridine (0.35 g, 3.2 mmol) in DMF (50 mL) was added K2C03 (2.5 g, 13 mmol) and 2,4-difluorobenzyl bromide (1.0 mL, 7.6 mmol), and the reaction mixture was stirred at 110°C for 4 h. The reaction mixture was cooled to room temperature, diluted with brine, and extracted with CHC13 (4 x 100 mL). The combined organics were washed with water and then brine, dried (Na2S0 ), filtered, and concentrated under reduced pressure. 1H NMR (300 MHz, CDC13) δ 7.54 (app q, 7 = 8 Hz, IH), 7.38-7.28 (m, 5H), 6.94 (td, 7= 8, 2 Hz, IH), 6.85 (td, 7= 8, 2 Hz, IH), 6.10 (d, 7 = 9 Hz, IH), 5.21 (s, 2H), 5.16 (s, 2H), 4.56 (s, 2H). Step 2. Preparation of 3-Bromo-4-(2,4-difluorobenzyloxy)-l-(2,4- fluorobenzyl)-lfl-pyridin-2-one. To an ice-cold solution of 4-(2,4-difluorobenzyloxy)- l-(2,4-difluorobenzyl)-lH-pyridin-2-one (0.72 g, 2.0 mmol) in AcOH (4.0 mL) was added - 298 - a solution of bromine (0.11 mL, 2.2 mmol) in AcOH (7.2 mL), and the reaction mixture was stirred for 40 min. The solvent was removed under reduced pressure. 1H NMR (300 MHz, CDC13) δ 7.63-7.45 (m, 2H), 7.42 (d, 7= 6 Hz, IH), 6.93-6.77 (m, 4H), 6.12 (d, 7 = 6 Hz, IH), 5.20 (s, 2H), 5.12 (s, 2H). ERMS m/z M+H 442. Example 97. Preparation of {3-[3-bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2 - pyridin-l-ylmethyl]-phenyl}acetonitriIe
Figure imgf000299_0001
Step 1. Preparation of methyl 3-cyanomethyIbenzoate. To an ice-cold solution of methyl 3-bromomethylbenzoate (9.1 g, 40 mmol) in CH3CN (108 mL) was added tetrabutylammonium fluoride (17.3 mL, 60 mmol) and trimethylsilylcyanide (8.0 mL, 60 mmol), and the reaction mixture was heated at reflux for 20 h. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. Purification by flash column chromatography (silica, 1 : 1 EtOAc hexanes) provided methyl 3-cyanomethylbenzoate as a clear oil (3.0 g, 43%): 1H NMR (300 MHz, DMSO- 6) δ 7.97 (s, IH), 7.92 (d, 7 = 8 Hz, IH), 7.64 (d, 7 = 8 Hz, IH), 7.56 (t, 7 = 8 Hz, IH), 4.16 (s, 2H), 3.87 (s, 3H). Step 2. Preparation of (3-hydroxymethylphenyl)acetonitrile. To an ice-cold solution of methyl 3-cyanomethylbenzoate (2.8 g, 18 mmol) in THF (23 mL) was added LiBH4 (8.8 mL of a 2 M solution in THF, 18 mmol), and the reaction mixture was heated at reflux for 4 h. The reaction mixture was cooled to room temperature, the reaction was quenched with 1:1 water/1 N HC1, and the aqueous layer was washed with EtOAc (3 x 150 mL). The combined organics were washed with brine, dried (MgS04), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 2: 1 EtOAc hexanes) provided (3-hydroxymethylphenyl)-acetonitrile as a clear oil (0.97 g, 41%): 1H NMR (300 MHz, MeOD) δ 8.15-8.08 (m, IH), 7.47-7.34 (m, IH), 7.27 (s, IH), 6.97-6.82 (m, IH), 4.87 (s, 2H), 3.91 (s, 2H) Step 3. Preparation of (3-bromomethylphenyl)acetonitrile. To an ice-cold solution of (3-hydroxymethylphenyl)acetonitrile (0.97 g, 7.3 mmol) in THF (35 mL) was
- 299 - added CBr4 (2.5 g, 7.7 mmol) and Ph3P (2.0 g, 7.7 mmol), and the reaction mixture was stirred for 3 h. The reaction mixture was filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent 1:9 to 1:4 EtOAc/hexanes) provided (3-bromomethylphenyl)acetonitrile as a clear oil (0.89 g, 58%): 1H NMR (300 MHz, MeOD) δ 7.47-7.29 (m, IH), 7.27 (s, IH), 6.97-6.82 (m, IH), 4.87 (s, 2H), 3.91 (s, 2H). Step 4. Preparation of {3-[3-bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2J&- pyridin-l-ylmethyl]phenyl}acetonitrile. The title compound was prepared by a procedure similar to the one described for Example 74 (0.07 g, 10%): mp 120-121 °C; 1H NMR (300 MHz, CDC13) δ 7.60-7.50 (m, IH), 7.37-7.27 (m, 5H), 6.96 (td, 7 = 9, 3 Hz, IH), 6.82 (td, 7= 9, 3 Hz, IH), 6.13 (d, 7= 8 Hz, IH), 5.21 (s, 2H), 5.16 (s, 2H). ESHRMS m/z 445.0381 (M+H C21H16BrF2N202 requires 445.0358). Example 98. Preparation of 2-[3-bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2/7- pyridin-l-yImethyl]benzonitrile
Figure imgf000300_0001
The title compound was prepared by a procedure similar to the one described for Example
74 (0.13 g, 47%): mp 194-197 °C; 1H NMR (300 MHz, CDC13) δ 7.75 (d, 7= 9 Hz, IH),
7.69-7.49 (m, 4H), 7.42 (t, 7= 8 Hz, IH), 6.96-6.73 (m, 2H), 6.18 (d, 7= 8 Hz, H), 6.17 (s,
2H), 5.30 (s, 2H). ESHRMS m/z 431.0210 (M+H C20H14BrF2N2O2 requires 431.0201. Example 99. Preparation of l-[(2-aminomethyl)benzyl)]-3-bromo-4-(2,4- difluorobenzyIoxy)-l/f-pyridin-2-one
Figure imgf000300_0002
To a solution of 2-[3-bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-l-ylmethyl]- benzonitrile(0.11 g, 0.25 mmol) in THF (3 mL) was added BH3 DMS (0.25 mL of a 2.0 M - 300 - solution in THF, 0.5 mmol), and the reaction mixture was stirred at 70 °C for 1 h. The reaction mixture was cooled to 0 °C, and the reaction was quenched with MeOH. The solvent was removed under reduced pressure, and the residue was partitioned between 2N NaOH and EtOAc. The organic solution was washed with brine, dried (MgS0 ), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent methylene chloride to 90:9:1 methylene chloride/methanol/ammonia) provided l-[(2-aminomethyl)benzyl]-3-bromo-4-(2,4-difluorobenzyloxy)-lH-pyridin-2- one as a white solid (0.15 g, 48%): 1H NMR (300 MHz, CDC13) δ 7.55 (app q, 7= 8 Hz, IH), 7.40-7.26 (m, 4H), 7.14 (d, 7= 8 Hz, IH), 6.94 (td, 7= 8, 2 Hz, IH), 6.85 (td, 7 = 8, 2 Hz, IH), 6.08 (d, 7 = 8 Hz, IH), 5.31 (s, 2H), 5.21 (s, 2H) 4.03 (s, 2H). ESHRMS m/z 435.0517 (M+H C20H18BrF2N2O2 requires 435.0514). Example 100. Preparation of methyl 3-[3-Bromo-4-(2,4-difIuorobenzyloxy)-2- oxo-2/y-pyridin-l-ylmethyl] benzoate
Figure imgf000301_0001
The title compound was prepared by a procedure similar to the one described for Example
74 (0.05 g, 11%): mp 115-117°C; 1H NMR (300 MHz, CDC13) δ 8.15-7.95 (m, 2H), 7.65-
7.50 (m, 2H), 7.45-7.40 (m, IH), 7.32 (d, 7= 6 Hz, IH), 7.00-6.80 (m, 2H), 6.12 (d, 7= 9
Hz, IH), 5.21 (s, 2H), 5.20 (s, 2H), 3.92 (s, 3H). ESHRMS m/z 464.0292 (M+H
C21H17BrF2N04 requires 464.0303). Example 101. Preparation of methyl 4-[3-Bromo-4-(2,4-difluorobenzyloxy)-2- oxo-2£T-pyridin-l-ylmethyl]-benzoate
Figure imgf000301_0002
The title compound was prepared by a procedure similar to the one described for Example 74 (0.17 g, 46%): mpl36-139 °C; 1H NMR (300 MHz, CDC13) δ 8.01 (d, 7 = 8 Hz, 2H),
- 301 - ' 7.60-7.51 (m, IH), 7.37 (d, 7= 8 Hz, 2H), 7.29-7.26 (m, IH), 6.93 (td, 7 = 9, 2 Hz, IH), 6.84 (td, 7= 9, 2 Hz, IH), 6.13 (d, 7= 8 Hz, IH), 5.23 (s, 4H), 3.91 (s, 3H). ESHRMS m/z 464.0306 (M+H C2ιH17BrF2N02 requires 464.0304). Example 102. Preparation of 3-[3-bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2ff- pyridin-l-ylmethyl]benzamide
Figure imgf000302_0001
A sealed tube containing a solution of methyl 3-[3-bromo-4-(2,4-difluorobenzyloxy)-2- oxo-2H-pyridin-l-ylmethyl]benzoate (0.1 g, 0.21 mmol) and NH3 (3 mL of a 7 N solution in MeOH, 21 mmol) was heated at 75 °C for 16 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. Trituration with Et20/MeOH afforded a white solid (0.06 g, 64%): mp 198-201 °C; 1H NMR (300 MHz, DMSO-d6) δ 8.02-8.00 (m, 2H), 7.85-7.75 (m, 2H), 7.70-7.60 (m, IH), 7.45-7.30 (m, 4H), 7.17 (t, 7= 3 Hz, IH), 6.60 (d, 7= 9 Hz, IH), 5.32 (s, 2H), 5.18 (s, 2H). ESHRMS m/z 449.0295 (M+H C20H16BrF2N2O3 requires 449.0307). Example 103. Preparation of 4-[3-bromo-4-(2,4-difluorobenzyIoxy)-2-oxo-2H- pyridin-l-ylmethyl]benzamide
Figure imgf000302_0002
The title compound was prepared by a procedure similar to the one described for Example
102 from Example 101 (0.04 g, 12%): mp 235-238 °C; 1H NMR (300 MHz, DMSO- 6) δ 8.00 (d, 7 = 8 Hz, IH), 7.94 (br s, IH), 7.78 (d, 7 = 8 Hz, IH), 7.64 (app q, 7 = 8 Hz, IH), 7.38-7.30(m, 4H), 7.17 (td, 7= 6, 2 Hz, IH), 6.60 (d, 7= 9 Hz, IH), 5.27 (s, 2H), 5.14 (s, 2H). ESHRMS m/z 449.0291 (M+H C20H16BrF2N2O3 requires 449.0307). Example 104. Preparation of l-(3-aminomethyl-2-fluorobenzyl)-3-bromo-4- (2,4-difluorobenzyloxy)-lH-pyridin-2-one
- 302 -
Figure imgf000303_0001
Step 1. Preparation of 3-Bromo-l-(3-bromomethyl-2-fluorobenzyl)-4-(2,4- difIuoro-benzyIoxy)-l -pyridin-2-one. To a solution of 3-bromo-4-(2,4- difluorobenzyloxy)-lH-pyridin-2-one (from Step 3, Example 74) (0.3 g, 0.95 mmol) in DMF (26 mL) was added K2C03 (0.26 g, 1.9 mmol) and 2,6- bis(bromomethyl)fluorobenzene (1.6 g, 5.7 mmol), and the reaction mixture was stirred at
110 °C for 3 h. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was diluted with a 50% aqueous solution of brine, and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organics were washed with water, dried (Na2S04), filtered, and the solvent was removed under reduced pressure. Purification by flash column chromatography (silica, eluent 99: 1 to 95:5 methylene chloride/methanol) afforded 3-bromo- l-(3-bromomethyl-2- fluorobenzyl)-4-(2,4-difTuorobenzyloxy)-lH-pyridin-2-one as an off-white solid (0.24 g, 49%): Η NMR (300 MHz, CDC13) δ 7.55-7.40 (m, 3H), 7.35-7.25 (m, IH), 7.10-7.05 (m, IH), 7.00-6.80 (m, 2H), 6.14 (d, 7= 6 Hz, IH), 5.22 (s, 2H), 5.19 (s, 2H), 4.50 (s, 2H). Step 2. Preparation of l-(3-aminomethyl-2-fluorobenzyl)-3-bromo-4-(2,4- difluoro-benzyloxy)-lJfiT-pyridin-2-one. A sealed tube containing a solution of 3-bromo- 1 -(3-bromomethyl-2-fluorobenzyl)-4-(2,4-difluorobenzyloxy)- lH-pyridin-2-one (0.24 g, 0.45 mmol) and NΗ3 (24 mL of a 7 N solution in MeOH, 168 mmol) was heated at 80 °C for 1 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. Purification by flash column chromatography (silica, eluent 99.5:0.5 to 96:4 methylene chloride/methanol) afforded a white solid (0.12 g, 60% ): mp 160-163 °C; 1H NMR (300 MHz, CDC13) δ 7.46-7.45 (m, IH), 7.44-7.35 (m, 2H), 7.34-7.26 (m, 1 H), 7.15-7.05 (m, IH), 6.95-6.80 (m, 2H), 6.11 (d, 7= 9 Hz, IH), 5.21 (s, 2H), 5.19 (s, 2H), 3.90 (s, 2H). ESHRMS m/z 453.0442 (M+H C20H BrF3N2O2 requires 453.0420). Example 105. Preparation of methyl 3-[3-chloro-4-(2,4-difluorobenzyloxy)-2- oxo-2#-pyridin-l-ylmethylj-2-fluoro-benzoate
- 303 -
Figure imgf000304_0001
Step 1. Preparation of methyl 2-fluoro-3-methylbenzoate. To a solution of 2- fluoro-3-methyl benzoic acid (3.57 g, 23 mmol) in MeOH (40 mL) was added concentrated sulfuric acid (2.3 mL), and the reaction mixture was heated at reflux for 12 h. The reaction mixture was cooled, the solvent was removed under reduced pressure, and the residue was dissolved in EtOAc. The organic solution was washed with a saturated solution of NaHC03 and then brine, dried (Na2S0 ), filtered and concentrated under reduced pressure to afford methyl 2-fluoro-3-methylbenzoate as a yellow oil (3.2 g, 82%):
1H NMR (300 MHz, CDC13) δ 7.76-7.71 (m, IH), 7.39-7.34 (m, IH), 7.08 (t, 7= 8 Hz, IH), 3.98 (s, 3H), 2.31 (d, 7 = 3 Hz, 3H). Step 2. Preparation of methyl 3-bromomethyl-2-fluorobenzoate. To a mixture of methyl 2-fluoro-3-methylbenzoate (1.5 g, 8.9 mmol) and N-bromosuccinimide (1.67 g, 9.4 mmol) was added carbon tetrachloride (24 mL) and benzoyl peroxide (5 mg), and the mixture was heated at reflux for 16 h. The reaction mixture was cooled, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent 5:95 to 60:40 EtOAc hexanes) afforded methyl 3-bromomethyl-2- fluorobenzoate as a light yellow solid (0.91 g, 41% ): 1H NMR (300 MHz, CDC13) δ 7.93- 7.88 (m, IH), 7.61-7.56 (m, IH), 7.20 (t, 7 = 8 Hz, IH), 4.53 (d, 7 = 3 Hz, 2H), 3.94 (s, 3H). Step 3. Preparation of methyl 3-[3-chloro-4-(2,4-difluorobenzyloxy)-2-oxo-
2#-pyridin-l-ylmethyI]-2-fluorobenzoate. Methyl 3-[3-chloro-4-(2,4- difluorobenzyloxy)-2-oxo-2H-pyridin-l-ylmethyl]-2-fluorobenzoate was prepared by a procedure similar to the one described for Example 81 (0.33 g, 69%): mp 171-174 °C; 1H NMR (300 MHz, CDC13) δ 7.89-7.84 (m, 2H), 7.60-7.45 (m, 2H), 7.25-7.15 (m, IH), 7.00-6.80 (m, 2H), 6.17 (d, 7 = 6.0 Hz, IH), 5.21 (s, 2H), 5.19 (s, 2H), 3.93 (s, 3H). ESHRMS m/z 438.0747 (M+H C21Hι6ClF3N04 requires 438.0714). Example 106. Preparation of 3-[3-chloro-4-(2,4-difluorobenzyloxy)-2-oxo-2fT- pyridin-l-ylmethyl]-2-fluoro-benzamide
- 304 -
Figure imgf000305_0001
The title compound was prepared by a procedure similar to the one described for Example
99 (0.15 g, 62%): mp 252-254 °C; 1H NMR (300 MHz, DMSO- ) δ 8.04 (d, 7= 8 Hz,
IH), 7.92 (br s, IH), 7.79-7.65 (m, 3H), 7.49-7.48 (m, IH), 7.37-7.31 (m, 3H), 6.80 (d, 7 =
8 Hz, IH), 5.46 (s, 2H), 5.33 (s, 2H). ESHRMS m/z 423.0710 (M+H C20H15ClF3N2O3 requires 423.0718). Example 107. Preparation of 3-bromo-4-(2,4-difluorobenzyloxy)-l-(3- fluorobenzyl)-liϊ-pyridin-2-one
Figure imgf000305_0002
Step 1. Preparation of 4-Benzyloxy-l-(3-fluorobenzyl)-lff-pyridin-2-one. To a solution of 4-benzyloxy-lH-pyridin-2-one (1.0 g, 5 mmol) and K C03 (2.0 g, 9.9 mmol) in DMF (30 mL) was added 3-fluorobenzyl bromide (1.4 g, 7.5 mmol), and the reaction mixture was heated to 110 °C for 3 h. The reaction mixture was cooled to room temperature, and partitioned between EtOAc and water. The organic solution was washed with water and then brine, dried (Na2S0 ), filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent 97:3 to 93:7 methylene chloride /methanol) afforded 4-benzyloxy-l-(3-fluorobenzyl)-lH-pyridin-2-one (1.04 g, 67% ): 1H NMR (300 MHz, CDC13) δ 7.45-7.25 (m, 5H), 7.13 (d, 7= 8 Hz, IH), 7.10-6.90 (m, 3H), 6.10-5.95 (m, 2H), 5.07 (s, 2H), 5.00 (s, 2H). Step 2. Preparation of l-(3-Fluorobenzyl)-4-hydroxy-l/-r-pyridin-2-one. To a solution of 4-benzyloxy- 1 -(3-fluorobenzyl)- lH-pyridin-2-one (1.79 g, 5.8 mmol) in EtOH (50 mL) was added 10% Pd/C (0.4 g), and reaction mixture was stirred under a hydrogen atmosphere for 1.5 h. The reaction mixture was filtered through diatomaceous earth and concentrated under reduced pressure to give l-(3-fluorobenzyl)-4-hydroxy-lH-pyridin-2-
- 305 - one (0.92 g, 72% ): 1H NMR (300 MHz, CDC13) δ 7.55 (d, 7 = 6 Hz, IH), 7.40-7.30 (m, IH), 7.10-6.95 (m, 3H), 6.07 (dd, 7= 6, 3 Hz, IH), 5.85 (d, 7= 3 Hz, IH), 5.11 (s, 2H). Step 3. Preparation of 3-Bromo-l-(3-fluorobenzyl)-4-hydroxy-lfl-pyridin-2- one. To an ice-cold solution of l-(3-fluorobenzyl)-4-hydroxy-lH-pyridin-2-one (0.67 g, 3.1 mmol) in AcOH (5.7 mL) was added a solution of bromine (0.52 g, 3.24 mmol) in AcOH (10.8 mL), and the reaction mixture was stirred for 5 min. The reaction mixture was warmed to room temperature and concentrated under reduced pressure to afford 3- bromo-l-(3-fluorobenzyl)-4-hydroxy-lH-pyridin-2-one as a yellow solid (1.07 g, crude): 1H NMR (500 MHz, MeOD) δ 7.64 (d, 7= 8 Hz, IH), 7.35-7.30 (m, IH), 7.05-6.90 (m, 3H), 6.20 (d, 7 = 8 Hz, IH), 5.18 (s, 2H). Step 4. Preparation of 3-Bromo-4-(2,4-difluorobenzyloxy)-l-(3-fluorobenzyl)- lflr-pyridin-2-one. To a solution of 3-bromo-l-(3-fluorobenzyl)-4-hydroxy-lH-pyridin- 2-one (0.20 g, 0.67) and K2C03 (0.27 g, 1.34 mmol) in acetone (10 mL) was added 2,4- difluorobenzyl bromide (0.16 g, 0.8 mmol), and the reaction mixture was heated at reflux for 1 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in EtOAc. The organic solution was washed with water and then brine, dried (Na2S04), filtered and concentrated under reduced pressure. 1H NMR (300 MHz, CDC13) δ 7.65-7.55 (m, IH), 7.40-7.25 (m, 2H), 7.15-6.80 (m, 5H), 6.14 (d, 7= 8 Hz, IH), 5.22 (s, 2H), 5.16 (s, 2H). ESHRMS m/z 424.0159 (M+H C19H14BrF3N02 requires 424.0155). Example 108. Preparation of 3-bromo-l-(3-fluorobenzyι)-4-(2,3,4- trifluorobenzyloxy)-lfiT-pyridin-2-one
Figure imgf000306_0001
The title compound was prepared by a procedure similar to the one described for Example 107 (0.09 g, 39%): mp 176-178 °C; 1H NMR (300 MHz, CDC13) δ 7.40-7.25 (m, 4H), 7.11-6.98 (m, 4H), 6.11 (d, 7 = 9 Hz, IH), 5.23 (s, 2H), 5.16 (s, 2H). ESHRMS m/z 442.0060 (M+H C19H13BrF4N02 requires 442.0061)..
- 306 Example 109. Preparation of l-[3-(2-Aminoethyl) benzyl]-3-bromo-4-(2,4- difluorobenzyloxy)-l/J-pyridin-2-one
Figure imgf000307_0001
The title compound was prepared from compound of Example 97 by a procedure similar to the one described for Example 99, as the TFA salt (0.13 g, 33%): mp 70-74 °C; 1H NMR (300 MHz, DMSO- ) δ 8.21 (br s, IH), 6.60-6.50 (m, IH), 7.52 (d, 7= 6 Hz, IH), 7.30-7.10 (m, 3H), 7.01 (d, 7 = 9 Hz, IH), 6.94-6.85 (m, 2H), 6.20 (d, 7 = 6 Hz, IH), 5.20 (s, 2H), 5.05 (s, 2H), 3.23 (br s, 2H), 2.97 (t, 7= 8 Hz, 2H), 2.05 (br s, 2H). ESHRMS m/z 449.0698 (M+H C21H20BrF2N2O2 requires 449.0671). Example 110. Preparation of 3-chIoro-4-(2,4-difluorobenzyloxy)-l-(3- fluorobenzyl)-lH-pyridin-2-one
Figure imgf000307_0002
Step 1. Preparation of 4-(2,4-difluorobenzyloxy)-l-(3-fluorobenzyι)-LH- pyridin-2-one. To a solution of l-(3-fluorobenzyl)-4-hydroxy-lH-pyridin-2-one (from Step 2 EXAMPLE 107) (0.92 g, 4.2 mmol) and K2C03 ( 1.2 g, 8.4 mmol) in acetone (62 mL) was added 2,4-difluorobenzyl bromide (1.3 g, 6.3 mmol), and the reaction mixture was heated at reflux for 3 h. The reaction mixture was cooled room temperature, concentrated under reduced pressure, and the residue was partitioned between water and EtOAc. The organic solution was washed with brine, dried (Na2S04), filtered, and concentrated under reduced pressure. Purification by flash column chromatography
(silica, eluent methylene chloride to 95:5 methylene chloride/methanol) to provide 4-(2,4- difluorobenzyloxy)-l -(3-fluorobenzyl)- lH-pyridin-2-one as a white solid (1.21 g, 84%): Η NMR (300 MHz, CDC13) δ 7.45-7.20 (m, 2H), 7.14 (d, 7 = 8 Hz, IH), 7.05-6.75 (m, 5H), 6.05 (d, 7 = 3 Hz, IH), 5.95 (dd, 7= 5, 3 Hz, IH), 5.08 (s, 2H), 5.00 (s, 2H). - 307 - Step 2. Preparation of 3-chloro-4-(2,4-difluorobenzyloxy)-l-(3-fluorobenzyl)- lff-pyridin-2-one. To a solution of 4-(2,4-difluorobenzyloxy)-l -(3-fluorobenzyl)- 1H- ρyridin-2-one (0.15 g, 0.4 mmol) in AcOΗ (3 mL) was added N-chlorosuccinimide (70 mg, 0.5 mmol), and the reaction mixture was heated at reflux for 10 min. The reaction mixture was cooled room temperature and the solvent was removed under reduced pressure. 1H NMR (300 MΗz, CDC13) δ 7.60-7.50 (m, 1Η), 7.45-7.20 (m, 2Η), 7.10-6.80 (m, 5H), 6.16 (d, 7= 8 Hz, IH), 5.21 (s, 2H), 5.15 (s, 2H). ESHRMS m/z 380.0641 (M+H C19H14C1F3N02 requires 480.0660). The following example compounds were prepared by procedures similar to that described for Example 107. The yields and the analytical data are described below. Example 111. Preparation of 3-bromo-4-(3-chlorobenzyloxy)-l-(3- fluorobenzyl)-lflr-pyridin-2-one
Figure imgf000308_0001
The title compound was prepared by a procedure similar to the one described for
EXAMPLE 107 (0.12 g, 42%): mp 149-153 °C; 1H NMR (300 MHz, CDC13) δ 7.40-7.23
(m, 6H), 7.09 (d, 7 = 8 Hz, IH), 7.05-6.95 (m, 2H), 6.05 (d, 7 = 8 Hz, IH), 5.19 (s, 2H),
5.14 (s, 2H). ESMS m z M+H 442. Example 112. Preparation of 3-bromo-4-(3,4-difluorobenzyIoxy)-l-(3- fluorobenzyl)-12ϊ-pyridin-2-one
Figure imgf000308_0002
The title compound was prepared by a procedure similar to the one described for
EXAMPLE 107 (0.08 g, 48%): mp 172-174°C; !H NMR (300 MHz, CDC13) δ 7.40-6.95
308 - (m, 8H), 6.05 (d, 7 = 6 Hz, IH), 5.16 (s, 4H). ESHRMS m/z 424.0111 (M+H C19H14BrF3N02 requires 424.0155). Example 113. Preparation of 3-bromo-l-(3-fluorobenzyl)-4-(4- fluorobenzyloxy)-liϊ-pyridin-2-one
Figure imgf000309_0001
The title compound was prepared by a procedure similar to the one described for EXAMPLE 107 (0.07 g, 35%): mp 180-183 °C; 1H NMR (300 MHz, CDC13) δ 7.50-7.25 (m, 5H), 7.15-7.00 (m, 4H), 6.07 (d, 7 = 8 Hz, IH), 5.18 (s, 2H), 5.14 (s, 2H). ESHRMS m/z 406.0258 (M+H C19H15BrF2N02 requires 406.0249). Example 114. Preparation of 3-bromo-l-(3-fluorobenzyl)-4-(3- fluorobenzyIoxy)-liy-pyridin-2-one
Figure imgf000309_0002
To an ice-cold solution of l-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)-lH-pyridin-2-one (0.14 g, 0.43 mmol) in AcOΗ (2 mL) was added a solution of bromine (72 mg, 0.45 mmol) in AcOΗ (1 mL), and the reaction mixture was stirred for 5 min. The reaction mixture was warmed to room temperature and the solvent was removed under reduced pressure. 1H NMR (300 MHz, CDC13) δ 7.45-6.95 (m, 9H), 6.05 (d, 7= 8 Hz, IH), 5.21 (s, 2H), 5.14 (s, 2H). ESHRMS m/z 406.0254 (M+H Cι9H15BrF2N02 requires 406.0249). Examples 115-123. Preparation of compounds corresponding in structure to the following formula:
309
Figure imgf000310_0001
The compounds of Examples 115-123 are prepared essentially according to the procedures set forth above for Example 107
Figure imgf000310_0002
NMR characterization of compounds of Examples 115- 123
Figure imgf000310_0003
- 310 -
Figure imgf000311_0002
Example 124. Preparation of
3-Bromo- 1 -(3-fluorobenzyl)-4-(2-hydroxymethylbenzyloxy)- lH-pyridin-2-one Step 1. Preparation of 3-Bromo-l-(3-fluorobenzyl)-4-(2-hydroxymethylbenzyloxy)-lH- pyridin-2-one. To an ice-cold solution of methyl 2-[3-bromo-l-(3-fluorobenzyl)-2-oxo-l,2-dihydro- pyridin-4-yloxymethyl]benzoate (0.12 g, 0.28 mmol) in TΗF (5 mL) was added LiBΗ (0.15 mL of a 2.0 M solution in THF, 0.30 mmol), and the reaction mixture heated at reflux for 5 hours. The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the residue dissolved in EtOAc. The organic solution was washed with brine, dried (Na2S04), filtered, and concentrated under reduced pressure. 1H NMR (300 MHz, DMSO-</6) δ 7.98 (d, 7 = 8 Hz, IH), 7.46-7.28 (m, 5H), 7.15-7.10 (m, 3H), 6.56 (d, 7 = 8 Hz, IH), 5.35 (s, 2H), 5.25 (br s, IH), 5.14 (s, 2H). ESHRMS m/z 418.0453 (M+H C20H18BrFNO3 requires 418.0449). Example 126. Preparation of
Example 126
311 -
Figure imgf000312_0001
2- { 2- [3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin- 1 -ylmethyl] - phenyl } acetamide
Step 1. Preparation of (2-Bromomethylphenyl)acetic acid.
A solution of isochroman-3-one (1.5 g, 10 mmol) in 30% HBr in acetic acid (13 mL) was stirred at room temperature for 2 h, and 70 °C for 1 h. The reaction mixture was cooled to room temperature, and poured into ice-water. The precipitate was collected to afford (2- bromomethylphenyl)acetic acid as an off-white solid (2.15 g, 93%): 1H NMR (300 MHz, DMSO- ) δ 7.45-7.23 (m, 4H), 4.73 (s, 2H), 3.73 (s, 2H).
Step 2. Preparation of Methyl (2-Bromomethylphenyl)acetate.
To an ice-cold solution of (2-bromomethylphenyl) acetic acid (1 g, 4.4 mmol) in THF (2.4 mL) was added trimethylsilyldiazomethane (3 mL of a 2 M solution in hexanes, 6 mmol), and the reaction mixture was stirred for 14 h. The reaction was quenched with AcOH, and the solvent was removed under reduced pressure. Purification by flash column chromatography (silica, eluent 98:2 to 94:6 methylene chloride/hexanes) afforded methyl (2-bromomethylphenyl)acetate as a light yellow solid (0.34 g, 32%?): 1H NMR (300 MHz, CDC13) δ 7.40-7.20 (m, 4H), 4.59 (s, 2H), 3.81 (s 2H), 3.71 (s, 3H).
Step 3. Preparation of Methyl {2-[3-bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin- 1 -ylmethyl]phenyl } acetate.
Methyl {2-[3-bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-l-ylmethyl]- phenyl} acetate was prepared by a procedure similar to the one described for EXAMPLE 74 (0.41 g, 68%): 1H NMR (300 MHz, CDC13) δ 7.55-6.81 (m, 8 H), 6.10 (d, 7 = 6 Hz, IH), 5.20 (s, 4 H), 3.78 (s, 2H), 3.60 (s, 3H).
312 Step 4. Preparation of 2-{2-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-l- ylmethyl]phenyl } acetamide.
2-{2-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-l-ylmethyl]phenyl}- acetamide was prepared by a procedure similar to the one described for Example 102 (0.07 g, 72%): mp 178-183 °C; 1H NMR (300 MHz, DMSO- )' δ 7.89 (d, 7 = 8 Hz, IH), 7.66 (d, 7 = 9 Hz, 1 H), 7.54 (br s, IH), 7.35 (br s, IH), 7.30-7.15 (m, 4H), 6.98 (br s, IH), 6.85 (d, 7 = 7 Hz, IH), 6.60 (d, 7 = 8 Hz, IH), 5.32 (s, 2H), 5.19 (s, 2H), 3.62 (s, 2H). ESHRMS m/z 463.0442 (M+H C21H18BrF2N203 requires 463.0463). Example 127. Preparation of
Example 127
Figure imgf000313_0001
Ethyl {3-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-l-ylmethyl]- phenyl} acetate
Step 1. Preparation of Ethyl (3-bromomethylphenyl) acetate.
To a mixture of m-tolylacetic acid ethyl ester (3.0 g, 16.8 mmol) and N-bromosuccinimide (3.0 g, 16.8 mmol) was added carbon tetrachloride (45 mL), followed by benzoyl peroxide (5 mg), and the reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent 5:95 to 2:3 EtOAc/hexanes) afforded ethyl (3-bromomethylphenyl) acetate as an off-white solid (0.89 g, 21% ): Η NMR (300 MHz, CDC13) δ 7.32-7.21 (m, 4H), 4.48 (s, 2H), 4.16 (q, 7 = 6 Hz, 2H), 3.63, (s, 2H), 1.27 (t, 7 = 6 Hz, 3H).
Step 2. Preparation of Ethyl {3-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-l- ylmethyljphenyl } acetate.
- 313 Ethyl {3-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-l-ylmethyl]phenyl}- acetate was prepared by a procedure similar to the one described for EXAMPLE 74 (0.27 g, 69%): mp 95-98 °C; 1H NMR (300 MHz, CDC13) δ 7.65-7.55 (m, IH), 7.40-7.20 (m, 5H), 7.00-6.80 (m, 2H), 6.09 (d, 7 = 9 Hz, IH), 5.21 (s, 2H), 5.16 (s, 2H), 4.14 (q, 7 = 6 Hz, 2H), 3.60 (s, 2H), 1.25 (t, 7 = 6 Hz, 3H). ESHRMS m/z 492.0655 (M+H C23H21BrF2N04 requires 435.0617). Example 128. Preparation of
Example 128
Figure imgf000314_0001
2-{3-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin-l-ylmethyl] phenyl} acetamide
The title compound was prepared by a procedure similar to the one described for EXAMPLE 102 (0.07 g, 28%): mp 164-167 °C; 1H NMR (300 MHz, DMSO- 6) δ 7.96 (d, 7 = 9 Hz, IH), 7.70-7.60 (m, IH), 7.60 (br s, IH), 7.50-7.10 (m, 6H), 6.89 (br s, IH), 6.58 (d, 7 = 9 Hz, IH), 5.31 (s, 2H), 5.12 (s, 2H), 3.32 (s, 2H). ESHRMS m/z 463.0485 (M+H C2ιH18BrF2N203 requires 463.0464). Example 129. Preparation of
Example 129
Figure imgf000314_0002
4-(2,4-Difluorobenzyloxy)- 1 -(3-fluorobenzyl)-3-methyl- lH-pyridin-2-one
314 Step 1. Preparation of 4-(2,4-Difluorobenzyloxy)-l-(3-fluorobenzyl)-3-methyl-lH- pyridin-2-one.
To a solution of 3-bromo-4-(2,4-difluorobenzyloxy)-l-(3-fluorobenzyl)-lH-pyridin-2-one
(EXAMPLE 107) (0.14 g, 0.32 mmol), K2C03 (88 mg, 0.64 mmol) and Cs2C03 (0.10 g, 0.32 mmol) in dioxane (2 mL) was added Pd(PPh3)4 (18 mg, 0.12 mmol), followed by trimethylboroxine (40 mg, 0.32 mmol). The reaction mixture was degassed, purged with argon, and heated at reflux for 4 h. The reaction mixture was cooled to room temperature, and partitioned between water and EtOAc. The organic solution was washed with brine, dried (Na2S0 ), filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent methylene chloride to 97:3 methylene chloride/MeOΗ) afforded 4-(2,4-difluorobenzyloxy)- 1 -(3-fluorobenzyl)-3-methyl- 1H- pyridin-2-one as a white solid (0.09 g, 79% ): mp 127-129 °C; !Η NMR (300 MHz, CDC13) δ 7.50-7.40 (m, IH), 7.35-7.25 (m, IH), 7.17 (d, 7 = 9 Hz, IH), 7.06 (d, 7 = 6 Hz, IH), 7.00-6.80 (m, 4H), 6.12 (d, 7 = 9 Hz, IH), 5.12 (s, 4H), 2.07 (s, 3H). ESHRMS m/z 360.1180 (M+H C20H16F3NO2 requires 360.1206). Example 130. Preparation of
Example 130
Figure imgf000315_0001
4-(2,4-Difluorobenzyloxy)- l-(3-fluorobenzyl)-3-iodo- lH-pyridin-2-one
Step 1. Preparation of 4-(2,4-Difluorobenzyloxy)-l-(3-fluorobenzyl)-lH-pyridin-2-one. To a mixture of l-(3-fluorobenzyl)-4-hydroxy-lH-pyridin-2-one (from Step 1, EXAMPLE 110) (0.92 g, 4.2 mmol) and K2C03 (1.15 g, 8.4 mmol) in acetone (62 mL) was added 2,4- difluorobenzyl bromide (1.3 g, 6.3 mmol), and the reaction mixture was heated at reflux for 3 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in EtOAc. The organic solution was washed with water and then brine, dried (Na2S0 ), filtered, and concentrated under - 315 - reduced pressure. Purification by flash column chromatography (silica, eluent methylene chloride to 95:5 methylene chloride/methanol) provided 4-(2,4-difluorobenzyloxy)-l-(3- fluorobenzyl)-lH-ρyridin-2-one as a white solid (1.21 g, 84%): lH NMR (300 MHz, CDC13) δ 7.45-7.20 (m, 2H), 7.14 (d, 7 = 8 Hz, IH), 7.05-6.75 (m, 5H), 6.05 (d, 7 = 3 Hz, IH), 5.95 (dd, 7 = 5, 3 Hz, IH), 5.08 (s, 2H), 5.00 (s, 2H).
Step 2. Preparation of 4-(2,4-Difluorobenzyloxy)-l-(3-fluorobenzyl)-3-iodo-lH-pyridin-
2-one.
To a mixture of 4-(2,4-difluorobenzyloxy)-l-(3-fluorobenzyl)-lH-pyridin-2-one (0.15 g, 0.43 mmol) and N-iodosuccinimide (0.10 g, 0.46 mmol) in CH3CN (3 mL) was added dichloroacetic acid (13 mg, 0.10 mmol), and the reaction mixture was heated to 60 °C for 4 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in methylene chloride. The organic solution was washed with a saturated solution of NaHC03 and then brine, dried (Na2S0 ), filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent 90:10 methylene chloride/hexanes to 99:1 methylene chloride/methanol) provided 4-(2,4-difluorobenzyloxy)-l-(3-fluorobenzyl)-3-iodo-lH-pyridin-2-one as a white solid (0.15 g, 77%): mp 164-167 °C; 1H NMR (300 MHz, CDC13) δ 7.65-7.55 (m, IH), 7.35-7.26 (m, 2H) 7.15-6.80 (m, 5H), 6.05 (d, 7 = 6 Hz, IH), 5.22 (s, 2H), 5.16 (s, 2H). ESHRMS m/z 472.0033 (M+H C19H14F3IN02 requires 472.0018). Example 131. Preparation of
Example 131
Figure imgf000316_0001
4-(2,4-Difluorobenzyloxy)-l-(3-fluorobenzyl)-2-oxo-l,2-dihydropyridine-3-carbonitrile
Step 1. Preparation of 4-Methoxy-2-oxo-l,2-dihydropyridine-3-carbonitrile.
316 - A solution of 2-(dimethylaminoethoxymethylene)malononitrile (1.97 g) in concentrated sulfuric acid (7.0 mL) was stirred at room temperature for 6.5 h. The reaction mixture was poured into water, and the precipitate was collected by filtration. 1H NMR (300 MHz, OMSO-d6) δ 12.14 (br s, IH), 7.79 (d, 7= 9 Hz, IH), 6.35 (d, 7= 9 Hz, IH), 3.98 (s, 3H).
Step 2. Preparation of l-(3-Fluorobenzyl)-4-methoxy-2-oxo-l,2-dihydro-pyridine-3- carbonitrile. l-(3-Fluorobenzyl)-4-methoxy-2-oxo-l,2-dihydro-pyridine-3-carbonitrile was prepared by a procedure similar to the one described for EXAMPLE 74 (0.56 g, 93%): 1H NMR (300 MHz, CDC13) δ 7.48 (d, 7 = 9 Hz, IH), 7.40-7.27 (m, IH), 7.00-6.95 (m, 2H), 6.08 (d, 7 = 9 Hz, IH), 5.10 (s, 2H), 4.00 (s, 3H).
Step 3. Preparation of l-(3-Fluorobenzyl)-4-hydroxy-2-oxo-l,2-dihydropyridine-3- carbonitrile. To a solution of sodium hydride (92 mg of a 60% dispersion in mineral oil, 2.3 mmol) in DMF (7 mL) was added ethanethiol (0.14 g, 2.2 mmol), followed by a solution of l-(3- fluorobenzyl)-4-methoxy-2-oxo-l,2-dihydropyridine-3-carbonitrile (0.23 g, 0.89 mmol) in DMF (2 mL), and the reaction mixture was heated to 100 °C. The reaction mixture was cooled to room temperature, acidified with 3 N HC1, and washed with EtOAc. The organic solution was washed with brine, dried (Na2S0 ), filtered and concentrated under reduced pressure to give l-(3-fluorobenzyl)-4-hydroxy-2-oxo-l,2-dihydro-pyridine-3- carbonitrile as an off-white solid (0.20 g, 91%): 1H NMR (300 MHz, MeOD) δ 8.00 (s, IH), 7.82 (d, 7 = 8 Hz, IH), 7.40-7.30 (m, IH), 7.15-7.00 (m, 2H), 6.13 (d, 7 = 8 Hz, IH), 5.11 (s, 2H).
Step 4. Preparation of 4-(2,4-Difluorobenzyloxy)-l-(3-f uorobenzyl)-2-oxo-l,2-dihydro- pyridine-3-carbonitrile.
4-(2,4-Difluorobenzyloxy)-l-(3-fluorobenzyl)-2-oxo-l,2-dihydro-pyridine-3-carbonitrile was prepared by a procedure similar to the one described for EXAMPLE 107 (0.09 g, 30%): mp 187-190 °C; 1H NMR (300 MHz, CDC13) δ 7.60-7.45 (m, 2H), 7.40-7.30 (m, IH), 7.10-6.50 (m, 5H), 6.13 (d, 7= 9 Hz, IH), 5.27 (s, 2H), 5.10 (s, 2H).
317 Example 132. Preparation of l-cyclohexyl-4-(2,4-difluorobenzyloxy)-3,6- dimethyl-lff-pyridin-2-one
Figure imgf000318_0001
Step 1. Preparation of methyl l-cyclohexyl-4-hydroxy-2,5-dimethyl-6-oxo-l,6- dihydro-pyridine-3-carboxylate. To a solution of 3-cyclohexylaminobut-2-enoic acid methyl ester (1.12 g, 5.72 mmol) in bromobenzene (20 mL) was added 2-methylmalonic acid bis-(2,4,6-trichloro-phenyl) ester (2.71 g, 5.72 mmol)and the reaction mixture was heated at 170 °C for 3 h. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent methylene chloride to 94:6 methylene chloride/MeOH) and recrystallization from hot MeOH provided methyl l-cyclohexyl-4-hydroxy-2,5-dimethyl-6-oxo-l,6- dihydropyridine-3-carboxylate as pale yellow crystals (0.34 g, 21%): 1H NMR (500 MHz, DMSO-d6) δ 9.82 (s, IH), 4.00-3.90 (m, IH), 3.76 (s, 3H), 2.75-2.60 (m, 2H), 2.31 (s, 3H), 1.81 (s, 3H), 1.80-1.70 (m, 2H), 1.65-1.50 (m, 3H), 1.40-1.20 (m, 2H), 1.15-1.05 (m, IH). Step 2. Preparation of l-cyclohexyl-4-hydroxy-2,5-dimethyl-6-oxo-l,6- dihydro-pyridine-3-carboxylic acid. A solution of methyl l-cyclohexyl-4-hydroxy-2,5- dimethyl-6-oxo-l,6-dihydro-pyridine-3-carboxylate (0.35 g, 1.25 mmol) in 2 N NaOH (5 mL) was heated at reflux for 3.5 h. The reaction mixture was cooled room temperature, acidified to pH 1-2 with 1 N HCl, and washed with EtOAc. The organic solution was washed with brine, dried (MgS04), filtered and concentrated under reduced pressure to afford l-cyclohexyl-4-hydroxy-2,5-dimethyl-6-oxo- 1 ,6-dihydropyridine-3 -carboxylic acid as a white solid (0.31 g, 94%): 1H NMR (300 MHz, MeOD) δ 4.30-4.00 (br s, IH), 2.76 (br s, 5H), 1.90 (s, 3H), 1.90-1.80 (m, 2H), 1.75-1.60 (m, 3 H), 1.50-1.15 (m, 3H). Step 3. Preparation of l-cyclohexyl-4-hydroxy-3,6-dimethyl-lJHr-pyridin-2- one. A solution of l-cyclohexyl-4-hydroxy-2,5-dimethyl-6-oxo-l,6-dihydropyridine-3- carboxylic acid (0.15 g, 0.57 mmol) in concentrated HCl (5 mL) was heated at reflux for 4 h. The reaction mixture was cooled to room temperature, diluted with water and washed - 318 - with EtOAc. The organic solution was washed with brine, dried (MgS0 ), filtered and concentrated under reduced pressure to give l-cyclohexyl-4-hydroxy-3,6-dimefhyl-lH- pyridin-2-one as a white solid (0.2 g, 77%): 1H NMR (300 MΗz, DMSO-_i6) δ 9.81 (s, 1Η), 5.73 (s, 1Η), 3.95-3.75 (m, 1Η), 2.80-2.55 (m, 2Η), 2.25 (s, 3H), 1.85-1.40 (m, 5H), 1.72 (s, 3H), 1.38-1.05 (m, 3H). Step 4. Preparation of l-cyclohexyl-4-(2,4-difluorobenzyloxy)-3,6-dimethyl- lfl-pyridin-2-one. l-Cyclohexyl-4-(2,4-difluorobenzyloxy)-3,6-dimethyl-lH-pyridin-2- one was prepared by a procedure similar to the one described for EXAMPLE 107 (0.05 g, 16%): mp 118-120 °C; 1H NMR (300 MΗz, CDC13) δ 7.48-7.41 (m, 1Η), 6.95-6.81 (m, 2Η), 5.87 (s, IH), 5.07 (s, 2H), 4.05-3.85 (m, IH), 3.00-2.80 (m, 2H), 2.35 (s, 3H), 1.98 (s, 3H), 1.95-1.80 (m, 2H), 1.70-1.55 (m, 3H), 1.40-1.20 (m, 3H). Example 133. Preparation of 3-chloro-4-(2,4-difIuorobenzyIoxy)-6-methyl-l- (lflr-pyrazol-4-ylmethyl)-lff-pyridin-2-one
Figure imgf000319_0001
Step 1. Preparation of 4-methyIpyrazole-l-carboxylic acid tert-butyl ester. To a solution of 4-methyl-lH-pyrazole (1 g, 12 mmol) and DMAP (0.15 g, 1.2 mmol) in
CH3CN (20 mL) was added di-tert-butyl dicarbonate (2.8 g, 13 mmol), and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue dissolved in EtOAc. The organic solution was washed with 1 N HCl, water and then brine, dried (MgS0 ), filtered, and concentrated under reduced pressure to provide 4-methyl-pyrazole-l -carboxylic acid tert-butyl ester as a light yellow oil (2.2 g, 100%): 1H NMR (300 MHz, CDC13) δ 7.83 (s, IH), 7.53 (s, IH), 2.09 (s, 3H), 1.64 (s, 9H). Step 2. Preparation of 4-Bromomethylpyrazole-l-carboxylic acid tert-butyl ester. To a solution of 4-methylpyrazole-l -carboxylic acid tert-butyl ester (1.0 g, 5.5 mmol) in carbon tetrachloride (20 mL) was added N-bromosuccinimide (1.0 g, 5.6 mmol) and benzoyl peroxide (50 mg), and the reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced
- 319 - pressure. Purification by flash column chromatography (silica, 1:4 EtOAc/hexanes) provided 4-bromomethylpyrazole-l -carboxylic acid tert-butyl ester as a light yellow oil (0.42 g, 30%): 1H NMR (300 MHz, CDC13) δ 8.10 (s, IH), 7.74 (s, IH), 4.39 (s, 2H), 1.65 (s, 9H). Step 3. Preparation of 4-[3-chIoro-4-(2,4-difluorobenzyloxy)-6-methyl-2-oxo-
2ff-pyridin-l-ylmethyl]pyrazole-l-carboxylic acid tert-butyl ester. 4-[3-Chloro-4-(2,4- difluorobenzyloxy)-6-methyl-2-oxo-27 -pyridin- 1 -ylmefhyljpyrazole- 1 -carboxylic acid tert-butyl ester was prepared by a procedure similar to the one described for EXAMPLE 632: 1H NMR (300 MHz, CDC13) δ 8.09 (s, IH), 7.72 (s, IH), 7.53 (app q, 7 = 6 Hz, IH), 6.97-6.82 (m, 2H), 6.00 (s, IH), 5.19 (s, 2H), 5.13 (s, 2H), 2.43 (s, 3H), 1.63 (s, 9H). Step 4. Preparation of 3-chloro-4-(2,4-difluorobenzyloxy)-6-methyl-l-(l/7- pyrazol-4-ylmethyl)-lflr-pyridin-2-one. 4-[3-Chloro-4-(2,4-difluorobenzyloxy)-6- methyl-2-oxo-2H-pyridin-l-ylmethyl]pyrazole-l -carboxylic acid tert-butyl ester (0.16 g, 0.34 mmol) was heated to 140 °C for 16 h. The reaction mixture was cooled to room temperature. 1H NMR (300 MHz, CDC13) δ 8.33 (s, 2H), 7.68 (d, 7 = 6 Hz, IH), 7.52 (app q, 7 = 6 Hz, IH), 6.93-6.83 (m, 2H), 6.47 68 (d, 7 = 9 Hz, IH), 5.19 (s, 2H), 5.24 (s, 2H), 5.20(s, 2H). Example 134. Preparation of 4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)- yl]methyl}benzonitrile
Figure imgf000320_0001
3-Bromo-4-[benzyloxy]-6-methylpyridin-2(lH)-one(1.0 g, 3.6 mmol) was dissolved in
N,N-dimethylformamide (5 mL). α-Bromo-/?-tolunitrile (0.85g, 4.3 mmol) was added followed by K2C03 (0.59 g, 4.3 mmol). The resulting mixture was heated to 80 °C for 16 h. The reaction was concentrated to an oil that was partitioned between water and ethyl acetate and extracted with ethyl acetate (3 x 100 ml). The organic extracts were combined, washed with brine, dried over Na2S04, and filtered. The filtrate was concentrated to an oil, and purified by chromatography (silica gel, hexane/ethyl acetate) to - 320 - yield a white solid (0.65 g, 46%). 1H NMR (400 MHz, CDC13) δ 7.62 (d, 7 = 8.4 Hz, 2H), 7.41-7.31 (m, 7H), 7.23 (d, 7= 7.6 Hz, IH), 6.11 (d, 7= 8.0 Hz, IH), 5.24 (s, 2H), 5.18 (s, 2H). ES HRMS m/z 395.0404 (M+H C20Hι5BrN2O2 requires 395.0390). Example 135. Preparation of 3-{[4-(benzyIoxy)-3-bromo-2-oxopyridin-l(2H)- yl]methyI}benzonitrile
Figure imgf000321_0001
The title compound was prepared by a procedure essentially as described in example 134.1H NMR (400 MHz, CDC13) δ 7.62-7.54 (m, 3H), 7.45 (d, 7= 7.6Hz, IH), 7.43-7.31 (m, 5H), 7.26 (d, 7= 1.6 Hz, IH), 6.12 (d, 7= 1.6 Hz, IH), 5.24 (s, 2H), 5.15 (s, 2H). ES HRMS m/z 395.0420 (M+H C20H15BrN2O2 requires 395.0390). Example 136. Preparation of 2-{[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)- yl]methyl}benzonitrile
Figure imgf000321_0002
The title compound was prepared by a procedure essentially as described in example 134. 1H NMR (400 MHz, CDC13) δ 7.74 (d, 7 = 8.4 Hz, IH); 7.63 (dd, 7 = 1.2, 8.0 Hz, IH),
7.57 (dt, 7= 1.2, 8.4 Hz, IH), 7.55 (d, 7= 8.0 Hz, IH); 7.43-7.30 (m, 6H), 6.13 (d, 7 = 8.0
Hz, IH,), 5.33 (s, 2H), 5.23 (s, 2H). ES HRMS m/z 395.0398 (M+H C20H15BrN O2 requires 395.0390). Example 137. Preparation of l-[4-(aminomethyl)benzyI]-4-(benzyIoxy)-3- bromopyridin-2(lH)-one
321
Figure imgf000322_0001
Preparation of l-[4-(aminomethyl)benzyl]-4-(benzyloxy)-3-bromopyridin-2(lH)-one. Example 134 (100 mg, 0.25 mmol) was dissolved in tetrahydrofuran (2 mL) under N2. Borane dimethylsulfide complex (0.25 mL, 0.5mmol, 2M in tetrahydrofuran) was added. The reaction was then heated to 70°C and shaken overnight. The mixture was cooled and all the solvent was distilled under vacuum. The resulting residue was partitioned between ethyl acetate and 0.2 N NaOH, and extracted with ethyl acetate (3 x 10 mL). The organic extracts were combined, washed with brine, dried over Na2S04, and filtered. The filtrate was concentrated to an oil, and triturated with dichloromethane and hexane to give an off- white solid. (80 mg, 80%). 1H NMR (400 MHz, d6DMSO) δ 7.90 (d, 7 = 7.6 Hz, IH); 7.43-7.21 (m, 9H), 6.70 (d, 7=7.6 Hz, IH), 5.29 (s, 2H), 5.08 (s, 2H), 3.71 (s, 2H). ES HRMS m/z 399.0721 (M+H C20Hι9BrN2O2 requires 399.0703). Example 138. Preparation of l-[3-(aminbmethyl)benzyl]-4-(benzyIoxy)-3- bromopyridin-2(lH)-one
Figure imgf000322_0002
The title compound was prepared by a procedure essentially as described in Example 137 using the title compound of Example 135 as starting material. 1H NMR (400 MHz, d6DMSO) δ 7.90 (d, 7= 7.6 Hz, IH), 7.44-7.22 (m, 9H), 6.50 (d, 7=7.6 Hz, IH), 5.30 (s,
2H), 5.12 (s, 2H), 3.88 (s, 2H). ES HRMS m/z 399.0730 (M+H C20H19BrN2O2 requires 399.0703). Example 139. Preparation of l-[2-(aminomethyl)benzyl]-4-(benzyloxy)-3- bromopyridin-2( 1 H)-one
322 '
Figure imgf000323_0001
The title compound was prepared by a procedure essentially as described in Example 137 using the title compound of Example 136 as starting material.1H NMR (400 MHz, d6DMSO) δ 7.88 (d, 7 = 8.0 Hz, IH); 7.45-7.34 (m, 5H), 7.26- 7.21 (m, 3H); 6.85 (d, 7=7.2 Hz, IH), 6.53 (d, 7=7.6 Hz, IH), 5.32 (s, 2H), 5.12 (s, 2H), 3.90 (s, 2H). ES HRMS m z 399.0699 (M+H C20H19BrN2O2 requires 399.0703). Example 140. Preparation of 4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)- yl]methyl}benzamide
Figure imgf000323_0002
Preparation of 4-{ [4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-yl]methyl}benzamide.
Example 134 (100 mg, 0.25 mmol) was added to a suspension of potassium fluoride (40% on alumina) in t-butyl alcohol, heated to 85 °C, and stirred for 20h. The alumina was removed by filtration and washed with dichloromethane and water. The resulting filtrate was separated and the aqueous layer was extracted with dichloromethane (2 x 20 mL). The organic extracts were combined, dried over Na2S04, and filtered. The filtrate was concentrated to an oil. Trituration with dichloromethane and hexane gave a solid (11.5 mg, 11 ). 1H NMR (400 MHz, d6DMSO) δ 7.94 (d, 7 = 8.0 Hz, IH), 7.80 (d, 7 = 8.4 Hz, 2H); 7.43-7.29 (m, 7H), 6.51 (d, 7=7.6 Hz, IH), 5.31 (s, 2H), 5.16 (s, 2H). ES HRMS m/z 413.0541 (M+H C20Hι7BrN2O3 requires 413.0495). Example 141. Preparation of 3-{[4-(benzyIoxy)-3-bromo-2-oxopyridin-l(2H)- yl]methyl}benzamide
- 323
Figure imgf000324_0001
The title compound was prepared by a procedure essentially as described in Example 140 using the title compound of Example 135 as starting material. !H NMR (400 MHz, d6DMSO) δ 7.95 (d, 7= 7.6 Hz, 2H), 7.76 (m, 2H); 7.43-7.26 (m, 8H), 6.51 (d, 7=7.6 Hz, IH), 5.31 (s, 2H), 5.15 (s, 2H). ESHRMS m/z 413.0497 (M+H C20H17BrN2θ3 requires 413.0495). Example 142. Preparation of 2-{[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)- yl]methyl}benzamide
Figure imgf000324_0002
The title compound was prepared by a procedure essentially as described in Example 140 using the title compound of Example 136 as starting material. 1H NMR (400 MHz, d6DMSO) δ 7.78 (d, 7 = 7.6 Hz, IH), 7.54 (dd, 7= 1.6, 7.6 Hz, IH); 7.45 (d, 7=7.6 Hz, 2H); 7.44-7.32 (m, 5H), 7.15 (d, 7=7.6 Hz, IH), 6.49 (d, 7=7.6 Hz, IH), 5.39 (s, 2H), 5.30 (s, 2H). ES HRMS m/z 4413.0506 (M+H C20H17BrN2O3 requires 413.0495). Example 143. Preparation of methyl-3-{[4-(benzyloxy)-3-bromo-2- oxopyridin-l(2H)-yI]methyl}benzoate
Figure imgf000324_0003
Product from Example 135 (100 mg, 0.25 mmol) was suspended in methanol and cooled to 0°C. HCl (g) was bubbled through the mixture until saturated (-30 minutes). The
324 reaction was warmed to ambient temperature and stirred for 4 hours. HCl and methanol were removed in vacuo, yielding an oil, that was purified by chromatography (silica gel, hexane/ethyl acetate) to yield a white solid (3 mg, 3%). 1H NMR (400 MHz, ςD3OD) δ 7.98 (app d, 7 = 8.0 Hz, 2H), 7.77 (app d, 7 = 8.0 Hz, IH); 7.55 (app d, 7 = 8.0 Hz, 2H); 7.41-7.35 (m, 5H), 6.52 (d, 7 = 7.6 Hz, IH), 5.31 (s, 2H), 5.27 (s, 2H); 3.88, (s, 3H). API- ES MS m/z 429.0 (M+H C21H18BrN04 requires 428.0492). Example 144. Preparation of methyl-4-{[4-(benzyloxy)-3-bromo-2- oxopyridin-l(2H)-yl]methyl}benzoate
Figure imgf000325_0001
The title compound was prepared by a procedure essentially as described in Example 143 using the title compound of Example 134 as starting material. 1H NMR (400 MHz, CD3OD) δ 7.94 (app d, 7 = 8.4 Hz, 2H), 7.76 (app d, 7 = 7.6 Hz, IH); 7.46 (app d, 7 = 8.0 Hz, 2H); 7.39-7.35 (m, 5H), 6.51 (d, 7=7.6 Hz, IH), 5.31 (s, 2H), 5.26 (s, 2H); 3.88, (s, 3H). ES HRMS m z 428.0492 (M+H C21H18BrN04 requires 428.0492). Example 145. Preparation of 4-[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)- yljbenzonitrile
Figure imgf000325_0002
3-bromo-4-[(benzyloxy]-6-methylpyridin-2(lH)-one(100 mg, 0.36 mmol) was suspended in dimethylsulfoxide (5 mL), cesium carbonate (375 mg, 1.15 mmol) was added and the reaction was shaken for 5 minutes. 4-Fluorobenzonitrile (52 mg, 0.43 mmol was then added, the reaction was heated to 80°C, and stirred. Reaction was monitored by LC/MS, and after 4h was heated to 100°C and stirred for 16 hours. Reaction mixture was partitioned between water and ethyl acetate and extracted with ethyl acetate (5 x 50 mL).
- 325 - The organic extracts were combined, washed with brine, dried over Na2S0 , and filtered. The filtrate was concentrated to an oil, and purified by chromatography (silica gel, hexane/ethyl acetate) to yield a white solid (40 mg, 29%). 1H NMR (400 MHz, CDC13) δ 7.77 (d, 7 = 8.4 Hz, 2H), 7.52 (d, 7= 8.8 Hz, 2H), 7.44-7.42 (m, 4H), 7.28 (d, 7= 7.6 Hz, IH), 7.26 (s, IH), 6.24 (d, 7 = 7.6 Hz, IH); 5.31, (s, 2H). ES HRMS m/z 381.0230 (M+H C19H13BrN202 requires 381.0233). Example 146. Preparation of 2-[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)- yljbenzonitrile
Figure imgf000326_0001
3-bromo-4-[(benzyloxy]-6-methylpyridin-2(lH)-one(100 mg, 0.36 mmol) was suspended in dimethylsulf oxide (5 mL), cesium carbonate (375 mg, 1.15 mmol) was added and the reaction was shaken for 5 minutes. 4-Fluorobenzonitrile (52 mg, 0.43 mmol) was then added and the reaction was heated to 80°C with stirring. Reaction was monitored by LC/MS, and after 4h was heated to 100°C and stirred for 16 hours. The reaction mixture was partitioned between water and ethyl acetate and extracted with ethyl acetate (5 x 50 mL). The organic extracts were combined, washed with brine, dried over Na2S04, and filtered. The filtrate was concentrated to an oil, and purified by chromatography (silica gel, hexane/ethyl acetate) to yield a white solid (18 mg, 13%). 1H NMR (400 MHz, CDC13) δ 7.81 (dd, 7 = 1.2, 8.4 Hz, IH), 7.73 (dt, 7= 1.2, 8.0 Hz, IH), 7.57 (dt, 7= 0.8, 8.0 Hz, IH), 7.50-7.36 (m, 6H), 7.27 (d, 7= 8.0 Hz, IH), 6.28 (d, 7= 8.0 Hz, IH); 5.31 (s, 2H). ES HRMS m/z 381.0249 (M+H C19H13BrN 02 requires 381.0233). Example 147. Preparation of (4-{[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)- yι]methyl}phenyι)acetic acid
Figure imgf000326_0002
3-bromo-4-[(benzyl)oxy]-6-methylpyridin-2(lH)-one(0.5g, 1.78 mmol) was dissolved in N,N-dimethylformamide (5 mL). 4-(Bromomethyl)phenylacetic acid (0.5 g, 2.14 mmol)
- 326 - was added followed by K2C03 (0.3 g, 2.14 mmol). The reaction was heated to 80°C and shaken for 16 hours, then heated to 100°C and shaken for 16 hours more. The reaction mixture was partitioned between water and ethyl acetate and extracted with ethyl acetate (2 x 50 mL). The aqueous layer was acidified (pH 2) with IN HCl and extracted with ethyl acetate (3 x 50 ml). The organic extracts were combined, washed with brine, dried over Na2S04, and filtered. The filtrate was concentrated to an oil, and purified by chromatography (silica gel, hexane/ethyl acetate) followed by reversed phase chromatography (Cι8, 0.1% aqueous trifluoroacetic acid /acetonitrile) to yield a white solid (25 mg, 3%). 1H NMR (400 MHz, CDC13) δ 7.40-7.38 (m, 3H), 7.25-7.20 (m, 7H), 6.05 (d, 7 = 8.0 Hz, IH), 5.21 (s, 2H); 5.13, (s, 2H); 3.62, (s, 2H). ES HRMS m/z 428.0510 (M+H C21Hι8BrN0 requires 428.0492). Example 148. Preparation of {4-[(4-(benzyloxy)-3-bromo-2-{[4- (carboxymethyl)benzyl]oxy}-llambda5-pyridin-l-yl)methyl]phenyl}acetic acid
Figure imgf000327_0001
The desired product was isolated by reversed phase chromatography (C18, 0.1% aqueous trifluoroacetic acid/acetonitrile) using the preparation of Example 147 yielding a white solid (53 mg, 5%). 1H NMR (400 MHz, CDC13) δ 7.40-7.38 (m, 3H), 7.27-7.24 (m, 6H), 7.20 (d, 7= 7.6 Hz, IH), 7.14 (d, 7= 8.0 Hz, 2H), 7.08 (d, 7= 8.4 Hz, IH), 6.06 (d, 7 = 7.6 Hz, IH), 5.21 (s, 2H); 5.11 (s, 2H); 5.11 (s, 2H); 3.63 (s, 2H); 3.58 (s, 2H). ES HRMS m/z 576.1009(M+H C30H28BrNO6 requires 576.1016). Example 149. Preparation of 2-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyI-2-oxopyridin-l(2H)-yl]methyl}benzonitrile
- 327
Figure imgf000328_0001
3-bromo-4-(2,4-difluorophenoxy)-6-methylpyridin-2(lH)-one (50 mg, 0.15 mmol) was dissolved in tetrahydrofuran (2 mL). α-Bromo-o-tolunitrile (44 mg, 0.23 mmol) was added followed by sodium hydride (7.2 mg, 0.18 mmol, 60% in mineral oil) and sodium iodide (56 mg, 0.38 mmol). The reaction was heated to 50°C and stirred for 16 hours. The reaction was filtered through Celite® and the filtrate was concentrated to an oil that was partitioned between water and ethyl acetate and extracted with ethyl acetate (4 x 10 mL). The organic extracts were combined, washed with brine, dried over MgS04, and filtered. The filtrate was concentrated to an oil, and purified by chromatography (silica gel, hexane/ethyl acetate) to yield a white solid (25 mg, 37%). 1H NMR (400 MΗz,
CDC13) δ 7.68 (dd, 7 = 8.0, 1.2 Ηz, 1Η); 7.58 (app q, 7 = 8.8 Ηz, 1Η); 7.52 (dt, 7 = 8.0 & 1.2 Ηz, 1Η), 7.38 (t, 7 = 7.6 Ηz, 1Η); 7.08 (d, 7= 8.8 Ηz, 1Η), 7.00-6.93 (m, 1Η); 6.89- 6.84 (m, 1Η); 6.05 (s, 1Η), 5.57 (s, 2Η), 5.22 (s, 2H); 2.28, (s, 3H). ES HRMS m/z 445.0335 (M+H C21H15BrF2N202 requires 445.0358). Example 150. Preparation of 3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]methyl}benzonitrile
Figure imgf000328_0002
The title compound was prepared by a procedure essentially as described in Example 149 using 3-bromo-4-(2,4-difluorophenoxy)-6-methylpyridin-2(lH)-one (1 g, 3.0 mmol) as starting material. 1H NMR (CDC13, 400 MHz) δ 7.61-7.55 (m, 2H); 7.45-7.41 (m, 3H); 6.98-6.94 (m, IH); 6.89-6.84 (m, IH); 6.03 (s, IH), 5.36 (s, 2H), 5.22 (s, 2H); 2.30, (s, 3H). ES HRMS m/z 445.0349 (M+H C21H15BrF2N202 requires 445.0358) Example 151. Preparation of 4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyI-2-oxopyridin-l(2H)-yl]methyl}benzonitrile
- 328
Figure imgf000329_0001
The title compound was prepared by a procedure essentially as described in Example 149 using 3-bromo-4-(2,4-difluorophenoxy)-6-methylpyridin-2(lH)-one (1 g, 3.0 mmol) as starting material. 1H NMR (400 MHz, CDC13) δ 7.61 (d, 7 = 8.4 Hz, 2H); 7.62-7.56 (m,
IH); 7.27 (d, 7= 8.8 Hz, 2H); 6.95 (app t, 7= 8.4 Hz, IH), 6.88-6.83 (m, IH); 6.03 (s,
IH), 5.39 (s, 2H), 5.21 (s, 2H); 2.28 (s, 3H). ES HRMS m/z 445.0359 (M+H
C21H15BrF2N202 requires 445.0358). Example 152. Preparation of 4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]methyl}benzamide
Figure imgf000329_0002
Product from Example 151 (50 mg, 0.11 mmol) was added to a suspension or potassium fluoride (40% on alumina) in t-butyl alcohol. The reaction was heated to 90°C and stirred for 20 hours. Alumina was removed by filtration and washed with dichloromethane and water. The resulting filtrate was separated and the aqueous layer was extracted with dichloromethane (2 x 20 mL). The organic extracts were combined, dried over Na2S0 and filtered. The filtrate was concentrated to an oil which was purified by chromatography (silica gel, hexane/ethyl acetate) to yield a white solid, yielding the product (13 mg, 25%). 1H NMR (400 MHz, CDC13) δ 7.75 (app d, 7 = 8.4 Hz, 2H), 7.58 (app q, 7 = 8.4 Hz, IH); 7.24 (d, 7= 8.4 Hz, 2H); 6.98-6.94 (m, IH), 6.89-6.83 (m, IH) 6.01 (s, IH); 5.40 (s, 2H), 5.21 (s, 2H); 2.28 (s, 3H). ES HRMS m/z 463.0486 (M+H C21H17BrF2N203 requires 463.0463).
329 Example 153. Preparation of methyl 4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]- 6-methyl-2-oxopyridin-l(2H)-yl]methyl}benzoate
Figure imgf000330_0001
Product from Example 151 (50 mg, 0.11 mmol) was suspended in methanol and cooled to 0°C. HCl (g) was bubbled through the mixture until saturated (-30 minutes). Reaction was sealed, warmed to ambient temperature, and stirred for 2 hours. HCl and methanol were removed in vacuo, yielding an oil, that was purified by chromatography (silica gel, hexane/ethyl acetate) to yield a white solid (19 mg, 36%). 1H NMR (400 MHz, CDC13) δ 7.97 (app d, 7= 8.4 Hz, 2H), 7.58 (app q, 7= 8.0 Hz, IH); 7.22 (d, 7= 8.4 Hz, 2H); 6.95 (app dt, 7= 1.5, 9.6 Hz, IH), 6.89-6.83 (m, IH), 6.00 (s, IH); 5.41 (s, 2H), 5.21 (s, 2H); 3.90, (s, 3H); 2.27 (s, 3H). ES HRMS m/z 478.0461 (M+H C22Hι8BrN04 requires 478.0460). Example 154. Preparation of methyl 3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]- 6-methyl-2-oxopyridin-l(2H)-yl]methyl}benzoate
Figure imgf000330_0002
The title compound was prepared by a procedure essentially as described in Example 149 using the title compound of Example 150 as starting material. Η NMR (400 MHz, CDC13) δ 7.95-7.92 (m, IH); 7.84 (bs, IH); 7.58 (app q, 7 = 8.0 Hz, IH); 7.39-7.37 (m, 2H); 6.95 (app dt, 7= 1.6, 8.4 Hz, IH), 6.88-6.83 (m, IH), 6.00 (s, IH); 5.40 (s, 2H), 5.21 (s, 2H); 3.90, (s, 3H); 2.30 (s, 3H). ES HRMS m/z 478.0449 (M+H C22H18BrN04 requires 478.0460).
330 Example 155. Preparation of 3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]methyl}benzamide
Figure imgf000331_0001
The title compound was prepared by a procedure essentially as described in Example 152 using the title compound of Example 150 as starting material. 1H NMR (400 MHz, CDC13) δ 7.68-7.66 (m, 2H), 7.57 (app q, 7 = 8.4 Hz, IH); 7.42-7.34 (m, 2H); 6.98-6.92 (m, IH), 6.89-6.83 (m, IH) 6.01 (s, IH); 5.39 (s, 2H), 5.21 (s, 2H); 2.28 (s, 3H). ES HRMS m/z 463.0461 (M+H C21H17BrF2N203 requires 463.0463). Example 156. Preparation of 2-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]methyl}benzamide
Figure imgf000331_0002
The title compound was prepared by a procedure essentially as described in Example 152 using the title compound of Example 149 as starting material. 1H NMR (400 MHz, CDC13) δ 7.68-7.66 (m, 2H), 7.57 (app q, 7 = 8.4 Hz, IH); 7.42-7.34 (m, 2H); 6.98-6.92 (m, IH), 6.89-6.83 (m, IH) 6.01 (s, IH); 5.39 (s, 2H), 5.21 (s, 2H); 2.28 (s, 3H). ES
HRMS m/z 463.0461 (M+H C21H17BrF2N203 requires 463.0463). 1H NMR (400 MHz, CDC13) δ 7.56-7.55 (m, 2H); 7.32-7.25 (m, 2H); 7.00-6.94 (m, IH), 6.88-6.84 (m, IH); 6.81-6.79 (m, IH) 6.11 (s, IH); 5.51 (s, 2H), 5.24 (s, 2H); 2.43 (s, 3H). ESHRMS m/z 463.0467 (M+H C2ιH17BrF2N203 requires 463.0463). Example 157. Preparation of l-[2-(aminomethyl)benzyl]-3-bromo-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one
331
Figure imgf000332_0001
Product from Example 149 (50 mg, 0.11 mmol) was dissolved in tetrahydrofuran (2 mL) under N2. Borane-methyl sulfide complex (0.11 mL, 0.22 mmol, 2M in tetrahydrofuran) was added. The reaction was then heated to 70°C and shaken overnight. After cooling to ambient temperature, all the solvent was distilled under vacuum. The resulting residue was partitioned between ethyl acetate and 0.2 N NaOH, and extracted with ethyl acetate (3 x 20 mL). The organic extracts were combined, washed with brine, and dried over Na S0 , and filtered. The filtrate was concentrated to an oil, and purified by chromatography (silica gel, hexane/ethyl acetate) to yield a white solid, to give product (19 mg, 39%). 1H NMR (400 MHz, CDC13) δ 7.56-7.55 (m, 2H); 7.32-7.25 (m, 2H); 7.00- 6.94 (m, IH), 6.88-6.84 (m, IH); 6.81-6.79 (m, IH); 6.11 (s, IH); 5.44 (s, 2H), 5.17 (s, 2H); 4.59 (s, 2H); 2.18 (s, 3H). ESHRMS m/z 449.0692 (M+H C21H19BrF2N202 requires 449.0671). Example 158. Preparation of 3-bromo-l-[3-(bromomethyl)benzyl]-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one
Figure imgf000332_0002
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one (2 g, 6.06 mmol) was suspended in 1,4-dioxane (250 mL). α,α'-Dibromo- -xylene (8 g, 30.3 mmol) was added followed by sodium hydride (0.3 g, 7.5 mmol, 60% in mineral oil). The reaction was heated to 60°C and stirred for 16 hours. The reaction was filtered through Celite® and the filtrate was concentrated to an oil that was partitioned between water and dichloromethane and extracted with dichloromethane (4 x 250 mL). The organic extracts were combined, washed with brine, dried over Na2S04, and filtered. The filtrate was concentrated to an oil, and purified by chromatography (silica gel, hexane/ethyl acetate) to yield a white solid (1.2g, 38%). 1H NMR (400 MHz, CDC13) δ 7.57 (app q, 7= 7.6 Hz, IH); 7.28-7.25
- 332 - (m, 2H); 7.17 (s, IH); 7.08 (m,lH); 6.94 (app dt, 7= 1.2, 9.6 Hz, IH), 6.87-6.82 (m, IH); 5.99 (s, IH), 5.34 (s, 2H), 5.20 (s, 2H); 4.43 (s, 2H); 2.29 (s, 3H). ES HRMS m z 511.9672 (M+H C21H17Br2F2N02 requires 511.9667). Example 159. Preparation of 3-bromo-l-[4-(bromomethyl)benzyI]-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one
Figure imgf000333_0001
The title compound was prepared by a procedure essentially as described in Example 158. 1H NMR (400 MHz, CDC13) δ 7.56 (app q, 7 = 7.6 Hz, IH); 7.32(d, 7 = 8.0 Hz, 2H); 7.14 (d, 7= 8.0 Hz, 2H); 6.94 (app t, 7 = 8.4 Hz, IH), 6.87-6.82 (m, IH); 5.98 (s, IH), 5.33 (s, 2H), 5.19 (s, 2H); 4.44 (s, 2H); 2.29 (s, 3H). ES HRMS m/z 511.9683 (M+H C21H17Br2F2N02 requires 511.9667). Example 160. Preparation of l-[4-(aminomethyl)benzyl]-3-bromo-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one
Figure imgf000333_0002
Product from Example 159 (200 mg, 0.39 mmol) was suspended in methanol (3 mL) and cooled to -78°C. Ammonia (g) was bubbled through the mixture for 30 minutes. The reaction vessel was sealed, allowed to reach ambient temperature, and stirred for 4 hours. The solvent and ammonia were removed from the reaction in vacuo with stirring and the resulting oil was triturated with ether to yield a solid (174 mg, 99%). 1H NMR (400 MHz, CD3OD) δ 7.61 (q, 7 = 7.6 Hz, IH); 7.40 (d, 7 = 8.0 Hz, 2H); 7.20 (d, 7 = 8.0 Hz, 2H); 7.03 (app t, 7 = 8.8 Hz, 2H), 6.51 (s, IH), 5.43 (s, 2H), 5.29 (s, 2H); 4.07 (s, 2H); 2.36 (s, 3H). ES HRMS m/z 449.0673 (C21Hι9BrF2N202 requires 449.0671). Examples 161-168. Preparation of compounds corresponding in structure to the following formula:
333
Figure imgf000334_0001
The compounds of Examples 161-168 are prepared essentially according to the procedures set forth above for Examples 158-160 or by using the compound of Example 158:
Figure imgf000334_0002
NMR characterization of compounds of Examples 161-168
Ex. No. NMR Data
Ex. 161 Η NMR (400 MHz, CD3OD) δ 7.61 (q, J = 7.6 Hz, IH); 7.42-7.35 (m, 2H), 7.24-7.20 (m, 2H), 7.03 (app t, J = 8.4 Hz, 2H), 6.51 (s, IH), 5.43 (s, 2H), 5.29 (s, 2H); 4.07 (s, 2H); 2.04 (s, 3H)
Ex. 162 Η NMR (400 MHz, CD3OD) δ 7.58 (app q, J = 7.6 Hz, IH); 7.26-7.22 (m, 2H), 7.15 (s, 2H), 7.01 (app d, 7 = 6.4 Hz, 2H), 6.95 (app dt, J = 1.2, 8.0 Hz, IH); 6.88-6.82 (m, IH); 5.98 (s, IH), 5.35 (s, 2H), 5.20 (s, 2H); 3.69 (t, J = 8.4 Hz, 4H); 3.46 (s, 2H); 2.41 (m, 4H); 2.29 (s, 3H)
Ex. 163 Η NMR (400 MHz, CD3OD) δ 7.61 (app q, J = 7.6 Hz, IH); 7.25-7.14 (m, 3H); 7.01-6.92 (m, 2H); 6.85 (m, IH); 5.97 (s, IH), 5.36 (s, 2H), 5.20 (s, 2H); 3.38 (s, 2H); 2.28 (s, 3H); 2.21 (s, 6H)
334 - Ex. No. NMR Data
Ex. 164 Η NMR (400 MHz, CDC13) δ 7.61 (app q, 7 = 8.0 Hz, IH); 7.25-7.22 (m, 2H); 7.14 (s, IH), 6.99 (app d, 6.8 Hz, IH), 6.94 (app dt, 7 = 2.0, 8.0 Hz, IH), 6.88-6.80 (m, IH); 5.97 (s, IH), 5.34 (s, 2H), 5.19 (s, 2H); 3.73 (s, 2H); 2.28 (s, 3H); 2.82 (app heptet, 7 = 6.0 Hz, IH), 1.07 (d, 7 = 6.0 Hz, 6H)
Ex. 165 Η NMR (400 MHz, CD3OD) δ 7.61 (app q, 7 = 8.0 Hz, IH); 7.27 (app t, 7 = 8.0 Hz, IH); 7.20 (app d, 7 = 7.6 Hz, IH); 7.08 (bs, IH); 7.01 (app t, 7 = 8.0 Hz, 2H); 6.48 (s, IH), 5.41 (s, 2H), 5.28 (s, 2H); 3.44 (s, 2H); 2.35 (s, 3H); 2.40-2.30 (m, 4H); 1.57-1.53 (m, 4H); 1.48- 1.38 (m, 2H)
Ex. 166 Η NMR (400 MHz, CDC13) δ 7.51 (app q, 7 = 8.0 Hz, IH); 7.22-7.14 (m, 3H); 7.09 (bs, IH); 6.98 (app d, 7 = 7.2 Hz, IH); 6.89 (app dt, 7 = 1.6, 8.0 Hz, IH); 6.81-6.76 (m, IH); 5.92 (s, IH), 5.28 (s, 2H), 5.14 (s, 2H); 3.73 (s, 2H); 3.59 (app t, 7 = 4.8 Hz, 2H); 2.73 (app t, 7 = 4.8 Hz, 2H); 2.24 (s, 3H)
Ex. 167 1H NMR (400 MHz, CD3OD) δ 7.61 (app q, 7 = 8.0 Hz, IH); 7.46 (app d, 7 = 8.8 Hz, 2H); 7.31 (bs, IH); 7.27 (app t, 7 = 8.0 Hz, IH); 7.03 (app t, 7 = 8.8 Hz, 2H); 6.54 (s, IH), 5.44 (s, 2H), 5.30 (s, 2H); 4.47 (s, 2H); 3.90-3.84 (m, 4H); 3.40-3.25 (m, 4H); 2.40 (s, 3H)
Ex. 168 Η NMR (400 MHz, CD3OD) δ 7.62 (app q, 7 = 8.0 Hz, IH); 7.53-7.46 (m, 2H); 7.36 (bs, IH); 7.30 (app d, 7 = 7.6 Hz, IH); 7.05-7.01 (m, 2H); 6.55 (s, IH), 5.44 (s, 2H), 5.30 (s, 2H); 4.47 (s, 2H); 3.58-3.53 (m, 8H); 2.42 (s, 3H) Example 169. Preparation of 3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]methyl}benzoic acid
Figure imgf000335_0001
Product from Example 154 (150 mg, 0.31 mmol) was dissolved in tetrahydrofuran (5 mL). Potassium trimethylsilanolate (80 mg, 0.62 mmol) was added and the reaction was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated to an oil that was partitioned between water and ethyl acetate and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over Na2S0 , and filtered. The filtrate was concentrated to an oil and purified by reversed phase chromatography (Cj8, 0.1% aqueous trifluoroacetic acid/acetonitrile) to yield the product (64 mg, 44%) Η NMR (400 MHz, CD3OD) δ 7.92 (app d, 7= 8.0 Hz, IH); 7.78 (s, IH); 7.62 (app q, 7= 8.0 Hz,
335 IH); 7.44 (t, 7 = 7.6 Hz, IH); 7.36 (app d, 7 = 8.0 Hz, IH); 7.02 (app t, 7 = 7.6 Hz, 2H); 6.51 (s, IH), 5.48 (s, 2H), 5.30 (s, 2H); 2.37 (s, 3H). ES HRMS m/z 464.0328 (C21H16BrF2N04 requires 464.0304). Examples 170-174. Preparation of compounds corresponding in structure to the following formula:
Figure imgf000336_0001
The compounds of Examples 170-174 are prepared using the compound of Example 159 or 161:
Figure imgf000336_0002
NMR characterization of compounds of Examples 170-174
Ex. No. NMR Data
Ex. 170 Η NMR (400 MHz, CD3OD) δ 7.61 (app q, 7 = 8.0 Hz, IH); 7.28 (app t, 7 = 8.0, IH), 7.18 (app d, 7 = 8.0 Hz, IH), 7.05-7.00 (m, 4H); 6.49 (s, IH), 5.41 (s, 2H), 5.29 (s, 2H); 2.37 (s, 3H); 1.94 (s, 3H)
Ex. 171 Η NMR (400 MHz, CDC13) δ 7.57 (app q, 7 = 7.6 Hz, IH); 7.25 (app t, 7 = 8.0, IH), 7.17 (app d, 7 = 8.0 Hz, IH), 7.06-7.02 (m, 2H); 6.97-6.91 (m, IH); 6.87-6.82 (m, IH), 5.98 (s, IH), 5.33 (s, 2H), 5.19 (s, 2H); 4.30 (d, 7 = 6.0 Hz, 2H); 3.67 (s, 3H); 2.28 (s, 3H)
Ex. 172 LH NMR (400 MHz, CD3CN) δ 7.58 (app q, 7 = 7.6 Hz, IH); 7.31 (app t, 7 = 8.0, IH), 7.24 (app d, 7 = 8.0 Hz, IH), 7.11 (s, IH); 7.05-7.00 (m, 3H); 6.32 (s, IH), 6.06 (bs, IH), 5.31 (s, 2H), 5.23 (s, 2H); 4.17 (d, J = 6.4 Hz, 2H); 2.78 (s, 3H); 2.28 (s, 3H)
336
Figure imgf000337_0002
Examples 175-185. Preparation of compounds corresponding in structure to the following formula:
Figure imgf000337_0001
The compounds of Examples 175-185 are prepared using the compounds of Examples 159 or 160:
Figure imgf000337_0003
- 337 NMR characterization of compounds of Examples 175-185
Figure imgf000338_0001
Example 186. Preparation of 4-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-
- 338 methyl-2-oxopyridin-l(2H)-yl]methyl}benzoyl)piperazine-l-carboxamide
Figure imgf000339_0001
3-bromo-4-(2,4-difluorophenoxy)-6-methyl-l-[4-(piperazin-l-ylcarbonyl)benzyl]pyridin- 2(lH)-one (300 mg, 0.54 mmol) was dissolved in N, Y-dimethylacetamide (5 mL). Trimethylsilyl isocyanate (0.15 mL, 1.08 mmol) was added followed by N,N- diisopropylethylamine (0.23 mL, 1.3 mmol) and the reaction was stirred for 1 hour at ambient temperature. The reaction was then diluted with tetrahydrofuran (40 mL) and polyamine resin (1.3 g, 2.81 mmol/g) and methylisocyanate functionalized polystyrene (1 g, 1.38 mmol/g) were added. The mixture was shaken for 6 hours, filtered, and the resulting filtrate was concentrated to a white solid (279 mg, 90%). 1H NMR (400 MHz, CD3OD) δ 7.61 (app q, 7 = 8.0 Hz, IH); 7.41 (d, 7 = 8.0 Hz, 2H), 7.23 (d, 7 = 8.0 Hz, 2H), 7.03 (app t, 7= 8.8 Hz, 2H); 6.51 (s, IH), 5.46 (s, 2H), 5.30 (s, 2H), 3.75-3.35 (m, 8H); 2.37 (s, 3H). ES HRMS m/z 575.1104 (C26H25BrF2N404 requires 575.1100). Example 187. Preparation of N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]methyl}benzyl)-2-methoxyacetamide
Figure imgf000339_0002
Polymer bound carbodiimide resin (2.3 g, 1.18 meq/g, 2.7 mmol) was suspended in N,N- dimethylformamide. Methoxyacetic acid (120 mg, 1.33 mmol) was added, followed by 1- hydroxybenzotriazole (1M in N,N-dimethylformamide, 0.165 mL) and N,N~ diisopropylethylamine (0.3 mL, 2.0 mmol). The reaction was shaken for 1 hour when EXAMPLE 160 (300 mg, 0.67 mmol) was added. The reaction was shaken for 16 hours and then diluted with tetrahydrofuran. Polyamine resin (1 g, 2.81 mmol/g) and methylisocyanate functionalized polystyrene (2 g, 1.38 mmol/g) were added and the mixture was shaken for 72 hours, filtered and the resulting filtrate concentrated. Trituration with water followed by trituration with ether yielded a white solid (125 mg, 36%). 1H NMR (400 MHz, CDC13) δ 7.56 (app q, 7 = 8.0 Hz, IH); 7.21 (d, 7 = 8.0 Hz,
- 339 - 2H), 7.13 (d}, 7= 8.0 Hz, 2H), 6.94 (app t, 7= 8.8 Hz, IH), 6.88-6.81 (m, IH); 5.97(s, IH), 5.33 (s, 2H), 5.19 (s, 2H); 4.43 (d, 7= 6.0 Hz, 2H); 3.92 (s, 2H); 3.39 (s, 3H); 2.29 (s, 3H). ES HRMS m/z 521.0882 (C24H22BrF2N204 requires 521.0882). Examples 188-193. Preparation of compounds corresponding in structure to the following formula:
Figure imgf000340_0001
By following the general method for the preparation of Example 187 and substituting the appropriate carboxylic acid for methoxyacetic acid, the compounds of Examples 188-193 are prepared. These compounds were triturated with water and again with ether and purified by chromatography (silica gel, hexane/ethyl acetate) as appropriate to yield off- white solids. Example 191 was prepared from its N-t-butoxycarbonyl protected intermediate. Deprotection was accomplished with 4N HCl in dioxane to afford the title compound as its hydrochloride salt (86 mg, 24%). Deprotection of the methyl ester from Ex. 188 was accomplished with K2C03 in methanol/water to yield Ex. 192 as a white solid. The yields and analytical data are shown below.
Figure imgf000340_0002
Example 194. Preparation of l- 4-[(4-acetylpiperazin-l-yl)carbonyI]benzyl}- 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one
340
Figure imgf000341_0001
3-bromo-4-(2,4-difluorophenoxy)-6-methyl-l-[4-(piperazin-l-ylcarbonyl)benzyl]pyridin- 2(lH)-one (200 mg, 0.36 mmol) was dissolved in NN-dimethylformamide (5 mL). N,N- Diisopropylethylamine (0.25 mL, 1.44 mmol) was added followed by acetic anhydride (0.10 mL, 1.06 mmol). The reaction was stirred for 2 hours at ambient temperature, and concentrated to an oil that was triturated in ether and again in water to yield an off-white solid (131 mg, 63%) 1H NMR (400 MHz, CD3OD) δ 7.62 (app q, 7= 8.0 Hz, IH); 7.42 (d, 7 = 8.0 Hz, 2H), 7.23 (d, 7 = 8.0 Hz, 2H), 7.62-7.02 (m, IH); 7.02 (app t, 7 = 8.0 Hz, 1 H); 6.52 (s, IH), 5.46 (s, 2H), 5.30 (s, 2H); 3.80-3.65 (m, 8H); 2.37 (s, 3H); 2.11 (s, 3H). ES HRMS m/z 574.1150 (C27H26BrF2N304 requires 574.1148). Example 195. Preparation of 3-bromo-4-[(2,4-difIuorobenzyI)oxy]-6-methyl- l-(4-{[4-(methylsulfonyl)piperazin-l-yl]carbonyl}benzyl)pyridin-2(lH)-one
Figure imgf000341_0002
3-bromo-4-(2,4-difluorophenoxy)-6-methyl- 1 - [4-(piperazin- 1 -ylcarbonyl)benzyl]pyridin- 2(lH)-one (300 mg, 0.54 mmol) was dissolved in NN-dimethylformamide (5 mL). 4-
Methylmorpholine (0.23 mL, 2.2 mmol) was added followed by methanesulfonyl chloride (0.10 mL, 1.33 mmol) and the reaction was stirred for 2 h. The reaction was then diluted with tetrahydrofuran (40 mL) and polyamine resin (1.3 g, 2.81 mmol/g) and methylisocyanate functionalized polystyrene (1 g, 1.38 mmol/g) were added. The mixture was shaken for 16 hours, filtered, and the resulting filtrate concentrated to an oil that was triturated with water. The resulting white solid was collected, washed with ether and dried (172 mg, 52%). 1H NMR (400 MHz, CDC13) δ 7.57 (app q, 7 = 8.2 Hz, IH); 7.34 (d, 7 = 8.0 Hz, 2H), 7.20 (d, 7= 8.0 Hz, 2H), 7.02 (app dt, 7 = 1.2, 8.8 Hz, IH), 6.88-6.82 (m, IH); 6.02 (s, IH), 5.37 (s, 2H), 5.21 (s, 2H); 3.80-3.20 (m, 8H); 2.79 (s, 3H); 2.30 (s, 3H). ES HRMS m/z 610.0851 (C26H26BrF2N305S requires 610.0817). Example 196. Preparation of methyl-4-[4-(benzyloxy)-3-bromo-2-oxopyridin-
- 341 - l(2H)-yl]benzoate
Figure imgf000342_0001
Step 1. Preparation of 4-[4-(benzyloxy)-2-oxopyridin-l(2H)-yI]benzonitrile.
Figure imgf000342_0002
4-benzyloxy-2(lH)-pyridone (12.00 g, 59.63 mmol) was dissolved in dimethyl sulfoxide (100 mL). Potassium carbonate (10.99 g, 79.50 mmol) was added, followed by 4- fluorobenzonitrile (4.81 g, 39.75 mmol). The reaction was stirred at 100 °C for 18 hours. After cooling to room temperature the reaction was diluted with H20 (150 mL) and the solids were collected by filtration washing with diethyl ether. Chromatography (silica gel, hexanes/ethyl acetate) provided an off-white solid (7.78 g, 65%). 1H NMR (300 MHz, CDC13) δ 7.79 (d, 7= 8.3 Hz, 2H), 7.54 (d, 7= 8.5 Hz, 2H), 7.44-7.41 (m, 5H), 7.22 (d, 7 = 13.3, IH), 6.13 (dd, 7= 2.6, 7.7 Hz, IH), 6.06 (d, 7= 2.6 Hz, IH), 5.07 (s, 2H). Step 2. Preparation of 4-[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)- yl]benzonitrile.
Figure imgf000342_0003
4-[4-(benzyloxy)-2-oxopyridin-l(2H)-yl]benzonitrile (Step 1) (2.76 g, 9.13 mmol) was suspended in acetonitrile (50 mL) and cooled in an ice-bath. N-bromosuccinimide (1.71 g, 9.54 mmol) was added. Once the addition was complete the cooling bath was removed. After stirring for 45 minutes the reaction was diluted with acetonitrile and solids were collected by filtration to give a white solid (3.13 g, 90%). Η ΝMR (300 MHz, DMSO- ) δ 8.00 (d, 7 = 8.5 Hz, 2H), 7.84 (d, 7 = 7.9 Hz, IH), 7.66 (d, 7= 8.5, 2H), 7.50-7.37 (m, 5H), 6.63 (d, 7 = 7.9 Hz, IH), 5.41 (s, 2H). - 342 - Step 3. Preparation of methyl-4-[4-(benzyl)oxy-3-bromo-2-oxopyridin-l(2H)- yl]benzoate. 4-[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)-yl]benzonitrile (Step 2) (1.50 g, 3.93 mmol) suspended in methanol (50 mL) was cooled in an ice-bath. HCl (g) was then bubbled through the mixture for 5 minutes. The reaction was then stirred at room temperature overnight, at which time the reaction mixture was concentrated. The residue was suspended in 6NHC1 (60 mL) and heated at reflux for 1.5 hours. After cooling to room temperature the solids were collected by filtration. Chromatography (silica gel, hexanes/ethyl acetate) provided an off-white shiny solid (0.540 g, 61%). 1H ΝMR (400 MHz, DMSO-d6) δ 8.04 (d, 7 = 8.5 Hz, 2H), 7.81 (d, 7 = 7.8 Hz, IH), 7.55 (d, 7 = 8.6 Hz, 2H), 7.47-7.39 (m, 5H), 6.57 (d, 7 = 7.9 Hz, IH), 5.38 (s, 2H), 3.86 (s, 3H). ES-HRMS m/z 416.0355 (M+H caldc for C20H16BrΝO4 requires 414.0341). Example 197. Preparation of 4-[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)- yI]benzoic acid.
Figure imgf000343_0001
Product from Example 196 (0.460 g, 1.11 mmol) was dissolved in tetrahydrofuran (5.0 mL). Potassium trimethylsilanolate (0.285 g, 2.22 mmol) was added. The reaction was stirred at room temperature for 3 hours at which time H 0 (10 mL) was added. The aqueous reaction mixture was acidified (pH-3) with IN HCl. The tetrahydrofuran was evaporated, additional H20 (50 mL) was added and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Νa2S04, filtered and evaporated to provide a rust colored solid (0.444 g, 100%). 1H NMR (400 MHz, DMS0- ) δ 8.02 (d, 7 = 8.6 Hz, 2H), 7.80 (d, 7 = 7.8 Hz, IH), 7.55 (d, 7= 8.6 Hz, 2H), 7.50-7.34 (m, 5H), 6.57 (d, 7 = 7.9 Hz, IH), 5.38 (s, 2H). ES-HRMS m/z 400.0191 (M+H calcd for C19Hι4BrN04 requires 400.0184). Example 198. Preparation of 4-[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)- yfjbenzamide.
343 -
Figure imgf000344_0001
Product from Step 2 of Example 196 (0.238 g, 0.624 mmol) was suspended in tert-butyl alcohol (3.0 mL). KF on 40 wt % A1 03 (0.453 g, 3.12 mmol) was added. The reaction mixture was heated at reflux for 5 days. Additional KF on 40 wt % A1203 (0.453 g, 3.12 mmol) was added and heating was continued at reflux overnight. After cooling to room temperature chloroform and methanol were added and the solids were collected by filtration. Chromatography (reverse-phase, acetonitrile/H20) provided a tan solid (0.073 g, 30%)). 1H NMR (400 MHz, DMSO- 6) δ 8.07 (s, IH), 7.95 (d, 7= 8.6 Hz, 2H), 7.79 (d, 7= 7.8 Hz, IH), 7.47-7.34 (m, 7H), 6.56 (d, 7 = 7.9 Hz, IH), 5.38 (s, 2H). ES-HRMS m/z 399.0372 (M+H calcd for C19H15BrN203 requires 399.0344). Example 199. Preparation of l-[4-(aminomethyl)phenyl]-4-(benzyloxy)-3- bromopyridin-2(lH)-one.
Figure imgf000344_0002
Product from Step 2 of Example 196 (1.25 g, 3.28 mmol) was dissolved in tetrahydrofuran (15 mL). Borane-dimethylsulfide (3.44 mL, 6.89 mmol, 2.0 M in tetrahydrofuran) was added and the mixture heated at reflux. After 14.5 hours the solvent was evaporated. 0.5M NaOH (50 mL) was added followed by ethyl acetate. The aqueous layer was neutralized with IN HCl. Methanol saturated with HCl was added and the mixture was heated at reflux for 5 hours. After cooling to room temperature, diethyl ether was added and the solids were collected by filtration. The solids were treated with AN HCl in dixoane (5 mL) and methanol (1 mL) at room temperature for 1 hour, at which time diethyl ether was added and the solids were collected by filtration to give a tan solid (0.920 g, 67%). !H ΝMR (300 MHz, DMSO- 6) δ 8.67 (br s, 2H), 7.76 (d, 7 = 7.6 Hz, IH), 7.64 (d, 7 = 8.3 Hz, 2H), 7.50-7.37 (m, 7H), 6.56 (d, 7 = 7.6 Hz, IH), 5.41 (s, 2H), 4.09 (br s, 2H). ES- HRMS m/z 385.0555 (M+H calcd for C19Hι7BrΝ202 requires 385.0552).
- 344 - Example 200. Preparation of methyl-4-[3-chloro-4-[(2,4-diflurobenzyl)oxy]-2- oxypyridin-l(2H)-yl]benzoate.
Figure imgf000345_0001
Step 1. Preparation of 4-[4-(benzyloxy)-2-oxopyridin-l(2H)-yl]benzonitrile.
Figure imgf000345_0002
4-benzyloxy-2(lH)-pyridone (50.0 g, 248.47 mmol) was dissolved in dimethyl sulfoxide (300 mL). Potassium carbonate (68.68 g, 496.94 mmol) was added, followed by 4- fluorobenzonitrile (31.60 g, 260.89 mmol). The reaction was stirred at 100 °C for 20 hours. After cooling to room temperature the reaction was diluted with H20 (600 mL) and the solids were collected by filtration washing with diethyl ether. The solids were then washed with hot methanol to provide a tan solid (55.6 g, 74%). 1H NMR (300 MHz, CDC13) δ 7.79 (d, 7= 8.3 Hz, 2H), 7.54 (d, 7 = 8.5 Hz, 2H), 7.44-7.41 (m, 5H), 7.22 (d, 7 = 13.3, IH), 6.13 (dd, 7= 2.6, 7.7 Hz, IH), 6.06 (d, 7= 2.6 Hz, IH), 5.07 (s, 2H). Step 2. Preparation of l-[4-nitrilephenyl]-4-hydroxy-2(lH)-pyridinone.
Figure imgf000345_0003
4-[4-(benzyloxy)-2-oxopyridin-l(2H)-yl]benzonitrile (Step 1) (20.0 g, 66.15 mmol) was dissolved in methanol (300 mL). Ammonium formate (8.34 g, 132.3 mmol) was added followed by 5% Pd/C (6.62 g). The resulting mixture was heated at reflux for 20 minutes at which time the reaction began to exotherm. The reaction was allowed to cool to room temperature at which time it was filtered through a pad of Celite® washing with methanol. The filtrate was evaporated to provide a pale yellow solid (16.2 g, >100%). !H
345 NMR (300 MHz, CDC13) δ. 8.46 (s, IH), 7,95 (d, 7 = 8.5 Hz, 2H), 7.62 (d, 7 = 8.5 Hz, 2H), 7.47 (d, 7 = 7.7 Hz, IH), 5.98 (dd, 7= 2.6, 7.7 Hz, IH), 5.54 (d, 7 = 2.4 Hz, IH). Step 3. Preparation of 4-[4-[(2,4-difluorobenzyloxy)]-2-oxopyridin-l(2H)- yfjbenzonitrile.
Figure imgf000346_0001
l-[4-Nitrilephenyl]-4-hydroxy-2(lH)-pyridinone (Step 2) (16.2 g) was dissolved in NN- dimethylformamide (100 mL). Potassium carbonate (10.06 g, 72.77 mmol) was added followed by α-bromo-2,4-difluorotoluene (8.91 mL, 69.46 mmol). The resulting mixture was heated to 65°C for 1 hour. Additional α-bromo-2,4-difluorotoluene (4.25 mL, 33.08 mmol) was added. The resulting mixture was heated to 65°C for 5 hours. Additional D- bromo-2,4-difluorotoluene (2.12 mL, 16.54 mmol) was added. After stirring at 65°C overnight the reaction was allowed to cool to room temperature. H20 (300 mL) was added and the solid was collected by filtration. A portion (8.0 g) of the solids were washed with hot methanol to give a pale yellow solid (6.22 g, 78%). 1H ΝMR (300 MHz, CDCI3) δ 8.00 (d, 7 = 8.5 Hz, 2H), 7.72-7.64 (m, 2H), 7.66 (d, 7 = 8.5 Hz, 2H), 7.40-7.32 (m, IH), 7.22-7.16 (m, IH), 6.17-6.11 (m, 2H), 5.17 (s, 2H). Step 4. Preparation of methyl-4-[4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- l(2H)-yl]benzoate.
Figure imgf000346_0002
4-[4-[(2,4-difluorobenzyloxy)]-2-oxopyridin- 1 (2H)-yl]benzonitrile (Step 3) (2.00 g, 5.91 mmol) suspended in methanol (20 mL) and H20 (5 mL) was cooled in an ice-bath. HCl (g) was bubbled through the mixture until most of the solids dissolved. The resulting
346 mixture was then heated at reflux for 3 hours. The reaction was then recooled in an ice- bath and HCl was bubbled through the mixture for 5 minutes. The mixture was heated at reflux for 2 hours and then the methanol was evaporated. Additional H20 (50 mL) was added and the aqueous reaction mixture was extracted with ethyl acetate (50 mL) and tetrahydrofuran (50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2S04, filtered and evaporated. Chromatography (silica gel, hexanes/ethyl acetate with 10% methanol) gave an off-white solid (0.630 g, 29%). 1H NMR (300 MHz, DMF- 6) δ 8.15 (d, 7= 8.5 Hz, 2H), 7.80 (app q, 7= 7.9 Hz, IH), 7.74-7.67 (m, IH), 7.68 (d, 7= 8.5 Hz, 2H), 7.42-7.34 (app dt, 7= 2.4, 9.0 Hz, IH), 7.28-7.22 (m, IH), 6.20 (dd, 7 = 2.6, 7.6 Hz, IH), 6.15 (d, 7= 2.4 Hz, IH), 5.28 (s, 2H), 3.98 (s, 3H). Step 5. Preparation of methyl-4-[3-chloro-4-[(2,4-diflurobenzyl)oxy]-2- oxypyridin-l(2H)-yl]benzoate. Methyl-4-[4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- l(2H)-yl]benzoate (Step 4) (0.520 g, 1.40 mmol) was suspended in acetonitrile (10.0 mL). N-chlorosuccinimide (0.196 g, 1.47 mmol) was added followed by several drops of dichloroacetic acid. The resulting mixture was heated at reflux overnight. After cooling to room temperature additional acetonitrile was added and the precipitate was collected by filtration to give an off-white solid (0.331 g, 58%). Η ΝMR (300 MHz, DMF- 6) δ 8.34 (d, 7= 8.5 Hz, 2H), 8.12 (d, 7= 7.9 Hz, IH), 8.04-7.96 (m, IH), 7.88 (d, 7= 8.5 Hz, 2H), 7.59-7.53 (m, IH), 7.52-7.41 (m, IH), 7.05 (d, 7 = 7.9 Hz, IH), 5.70 (s, 2H), 4.15 (s, 3H). ES-HRMS m/z 406.0644 (M+H calcd for C20H14ClF2ΝO4 requires 406.0652). Example 201. Preparation of 3-bromo-4-[(2,4-diflurorbenzyl)oxy]-l-[3- (hydroxymethyl)phenyl]-6-methyIpyridin-2(lH)-one.
Figure imgf000347_0001
Step 1. Preparation of 4-hydroxy-l-[3-(hydroχymethyl)phenyI]6- methylpyridin-2(lH)-one.
Figure imgf000347_0002
347 4-hydroxy-6-methyl-2-pyrone (10.0 g, 79.3 mmol) and 3-aminobenzyl alcohol (9.77g, 79.3 mmol) were combined in H20 (100 mL) and heat at reflux. After 48 hours at reflux the reaction mixture was concentrated. The residue was treated with methanol and the precipitate was collected by filtration to give a pale yellow solid (3.04 g, 17%). 1H NMR (300 MHz, DMSO- ) d 10.6 (br s, IH), 7.46-7.35 (m, 2H), 7.09-7.03 (m, 2H), 5.88 (d, 7 = 1.6 Hz, IH), 5.55 (d, 7= 2.6 Hz, IH), 4.54 (d, 7 = 4.2 Hz, 2H), 1.83 (s, 3H). Step 2. Preparation of l-[3-(hydroxymethyl)phenyl]-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one.
Figure imgf000348_0001
4-Hydroxy-l-[3-(hydroxymet yl)phenyl]6-methylpyridin-2(lH)-one (Step 1) (0.674 g, 2.91 mmol) was suspended in acetone (10 mL). Cesium carbonate (1.04 g, 3.21 mmol) was added followed by α-bromo-2,4-difluorotoluene (0.392 mL, 3.06 mmol). After stirring at room temperature for 2 days the reaction was concentrated. The residue was portioned between H20 (30 mL) and ethyl acetate (30 mL). The aqueous layer was further extracted with ethyl acetate (30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2S04, filtered and concentrated. Chromatography (on silica, hexanes/ethyl acetate with 10% methanol) provided a white solid (0.531 g, 51%). 1H NMR (300 MHz, CDC13) δ 7.51-7.39 (m, 3H), 7.82 (s, IH), 7.16 (d, 7 = 26.8 Hz, IH), 7.08-6.86 (m, 2H), 6.00 (d, 7= 2.6 Hz, IH), 5.92 (d, 7= 2.6 Hz, IH), 5.05 (s, 2H), 4.68 (s, 2H), 1.93 (s, 3H). ES-HRMS m/z 358.1256 (M+H calcd for C20H17F2NO3 requires 358.1249). Step 3. Preparation of 3-bromo-4-[(2,4-diflurorbenzyl)oxy]-l-[3- (hydroxymethyl)phenyl]-6-methylpyridin-2(lH)-one. l-[3-(hydroxymethyl)phenyl]-4- [(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one (Step 2) (0.460 g, 1.29 mmol) was suspended in acetonitrile (5.0 mL) and cooled in an ice-bath. Λ^-bromosuccinimide (0.241 g, 1.35 mmol) was added. Once the addition was complete the cooling bath was removed. After stirring for 1.5 hours the reaction was diluted with acetonitrile and solids were collected by filtration to give a white solid (0.385 g, 68%). 1H NMR (300 MHz, DMSO- d6) d 7.70 (app q, J = 7.9 Hz, IH), 7.49-7.32 (m, 3H), 7.24-7.10 (m, 3H), 6.66 (s, IH), 5.35 - 348 - (s, 2H), 4.56 (d, J = 5.6 Hz, 2H), 1.95 (s, 3H). ES-HRMS m/z 436.0384 (M+H calcd for C20H16BrF2NO3 requires 436.0354). Example 202. Preparation of methyl-4-[3-bromo-4-[(difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]benzoate.
Figure imgf000349_0001
Step 1. Preparation of methyl 4-(4-hydroxy-6-methyI-2-oxypyridin-l(2H)- yl)benzoate.
Figure imgf000349_0002
4-Hydroxy-6-methyl-2-pyrone (21.00 g, 166.70 mmol) and 4-methylaminobenzoate (25.20 g, 166.70 mmol) were combined in 1,2-dichlorobenzene (50 mL) and rapidly heated to 160 °C. After 15 minutes at 160 °C the reaction was allowed to cool to room temperature. The reaction was diluted with dichloromethane (50 mL) and extracted with saturated Na2C03 (2 x 100 mL). The combined aqueous layers were acidified (ρH-2) with concentrated HCl. The precipitate was collected by filtration and washed with diethyl ether to give a yellow/orange solid (10.9 g, 25%). 1H NMR (300 MHz, DMSO- 6) δ 10.8 ( s, IH), 8.07 (d, 7= 8.5 Hz, 2H), 7.40 (d, 7= 8.5 Hz, 2H), 5.95 (d, 7= 2.4 Hz, IH), 5.61 (d, 7 = 2.4, IH), 3.91 (s, 3H), 1.85 (s, 3H). Step 2. Preparation of methyl-4-[4-[(difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]benzoate.
Figure imgf000349_0003
- 349 Methyl 4-(4-hydroxy-6-methyl-2-oxypyridin-l(2H)-yl)benzoate (Step 1) (10.90 g, 42.04 mmol) was dissolved in N,N-dimethylformamide (100 mL). Potassium carbonate (6.97 g, 50.45 mmol) was added, followed by 2,4-difluorobenzyl bromide (5.66 mL, 44.14 mmol). The reaction was stirred at room temperature for 3 days then diluted with H20 (100 mL). The reaction mixture was extracted into ethyl acetate and tetrahydrofuran (2 x 100 mL). The precipitate was collected by filtration and the organic filtrate was washed with brine (50 mL), dried over Νa2S04, filtered and evaporated. The resulting solid was combined with the precipitate to provide a pale pink solid (6.77 g, 42%). 1H NMR (300 MHz, OMSO-de) δ 8.01 (d, 7 = 8.3 Hz, 2H), 7.67 (q, 7 = 7.9 Hz, IH), 7.43 (d, 7 = 8.3 Hz, 2H), 7.35 (m, IH), 7.18 (app dt, 7= 1.6, 8.5 Hz, IH), 6.08 (d, 7= 1.8 Hz, IH), 5.98 (d, 7= 2.4 Hz, IH), 5.14 (s, 2H), 3.91 (s, 3H), 1.87 (s, 3H). Step 3. Preparation of methyl-4-[3-bromo-4-[(difluorobenzyl)oxy]-6-methyl- 2-oxopyridin-l(2H)-yl]benzoate. Methyl-4-[4-[(difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]benzoate (Step 2) (6.74 g, 17.49 mmol) suspended in acetonitrile (100 mL) was cooled in an ice-bath. N-bromosuccinimide (3.27 g, 18.36 mmol) was added. After 1 hour the ice-bath was removed and after an additional 30 minutes the reaction was diluted with acetonitrile (20 mL). The precipitate was collected by filtration to provide the title compound as an off-white solid (6.94 g, 85%). 1H ΝMR (300 MHz, CDC13) δ 8.20 d, 7= 8.7 Hz, 2H), 7.61 (q, 7 = 7.9 Hz, IH), 7.30 (d, 7= 8.7 Hz, 2H), 7.02- 6.96 (m, IH), 6.90 (app dt, 7 = 2.4, 9.5 Hz, IH), 6.14 (s, IH), 5.28 (s, 2H), 3.98 (s, 3H), 2.00 (s, 3H). ES-HRMS m/z 464.0304 (M+H calcd for C21Hι6BrF2Ν04 requires 464.0301). Example 203. Preparation of 4-[3-bromo-4-[(difluorobenzyl)oxy]-6-methyl-2- oxopyridin-1 (2H)-yl]benzoic acid.
Figure imgf000350_0001
Product from Example 202 (7.43 g, 16.00 mmol) was dissolved in tetrahydrofuran (40 mL). Potassium trimethylsilanolate (4.10 g, 32i00 mmol) was added and the reaction mixture was stirred at room temperature for 22 hours. The tetrahydrofuran was - 350 - evaporated and H20 (50 mL) was added. The aqueous reaction mixture was acidified with IN HCl and the precipitate was collected by filtration. The solids were washed with boiling methanol to give an off-white solid (5.05 g, 70%). 1H ΝMR (300 MHz, DMSO- dβ) δ 13.2 (br s, IH), 8.10 (d, 7= 8.5 Hz, 2H), 7.72 (q, 7= 7.9 Hz, IH), 7.45 (d, 7= 8.3 Hz, 2H), 7.38 (app dt, 7= 2.4, 9.9 Hz, IH), 7.23 (app dt, 7 = 1.8, 8.5 Hz, IH), 6.72 (s, IH), 5.37 (s, 2H), 1.97 (s, 3H). ES-HRMS m/z 450.0154 (M+H calcd for C20H14BrF2ΝO4 requires 450.0147). Example 204. Preparation of 4-(benzyloxy)-l-(3-fluorobenzyI)-3- (trifluoromethyl)pyridin-2(lH)-one.
Figure imgf000351_0001
The starting material (0.250 g, 0.591 mmol) was dissolved in l-methyl-2-pyrrolidinone (5.0 mL). Trifluoroacetic acid, sodium salt (0.322 g, 2.36 mmol) was added, followed by copper(I)iodide (0.225 g, 1.18 mmol). The resulting mixture was heated to 180°C for 5 hours and then allowed to cool to room temperature. The reaction was diluted with H20 (50 mL) and brine (50 mL), then extracted into ethyl acetate (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2S0 , filtered and evaporated. Chromatography (reverse-phase, acetonitrile/Η20) provided an off-white solid (0.050 g, 22%). 1H NMR (400 MHz, CDC13) δ 7.40-7.27 (m, 8H), 7.06 (d, 7= 7.7 Hz, IH), 6.97 (d, 7= 9.0 Hz, IH), 6.07 (d, 7= 7.7 Hz, IH), 5.20 (s, 2H), 5.06 (s, 2H). ES- HRMS m/z 378.1097 (M+H calcd for C20H15F4NO2 requires 378.1112). Example 205. Preparation of 4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]methyl}benzoic acid
Figure imgf000351_0002
- 351 Product from Example 153 (50.0 g, 104.54 mmol) was dissolved in methanol (500 mL) and dioxane (100 mL). INNaOH (130 mL, 130 mmol) was added. The resulting mixture was heated to 50 °C for 5.5 hours. The reaction was partially concentrated and the heterogenous mixture was acidified (pH 2) with IN HCl. The precipitate was collected by filtration to afford a white solid (49.2 g, >100 %). 1H ΝMR (300 MHz, OMSO-d6) δ 7.94 (d, 7= 8.3 Hz, 2H), 7.70 (app q, 7= 7.9 Hz, IH), 7.35 (dt, 7= 2.2, 9.9 Hz, IH), 7.18 (app d, 7= 8.3 Hz, 2H), 7.17-7.12 (m, IH), 6.64 (s, IH), 5.41 (s, 2H), 5.33 (s, 2H), 2.32 (s, 3H). ES-HRMS m/z 464.0327 (M+H calcd for C21H16BrF2Ν04 requires 464.0304). Example 206. Preparation of 3-bromo-4-[(2,4-diflurobenzyl)oxy]-l-[4- (hydroxymethyl)benzyl]-6-methylpyridin-2(lH)-one.
Figure imgf000352_0001
Product from example 205 (40.0 g, 86.16 mmol) suspended in tetrahydrofuran (300 mL) was cooled in an ice-bath. Borane dimethylsulfide (129.2 mL, 258.48 mmol, 2.0 M in tetrahydrofuran) was slowly added. The resulting mixture was slowly allowed to warm to room temperature overnight. The mixture was recooled in an ice-bath and quenched by the addition of small pieces of ice. After the evolution of gas ceased additional ice-water was added. The flask was fitted with a distillation apparatus and the dimethylsulfide was removed. After the reaction was cooled to room temperature, H 0 (300 mL), ethyl acetate (200 mL) and tetrahydrofuran (300 mL) were added. The precipitate that formed was collected by filtration and the filtrate was placed in a separatory funnel. The aqueous layer was further extracted with ethyl acetate (300 mL). The combined organic layers were washed with brine (300 mL). The organic phase was dried over Na2S0 and evaporated which was combined with the precipitate to yield an off-white solid (37.8 g, 97%). 1H NMR (400 MHz, CDC13) δ 7.47 (app q, 7 = 7.7 Hz, IH), 7.23 (d, 7 = 7.9 Hz, 2H), 7.05 (d, 7 = 7.9 Hz, 2H), 6.86 (app dt, 7 = 2.3, 8.6 Hz, IH), 6.79 (app dt, 7 = 2.4, 8.4 Hz, IH), 6.00 (s, IH), 5.28 (s, 2H), 5.16 (s, 2H), 4.57 (s, 2H), 2.25 (s, 3H). ES-HRMS m/z 450.0512 (M+H calcd for C2ιH18BrF2N03 requires 450.0511).
- 352 - Example 207. Preparation of 3-bromo-4-[(2,4-diflurobenzyl)oxy]-l-[4-(l- hydroxy-l-methylethyI)benzyI]-6-methylpyridin-2(lH)-one.
Figure imgf000353_0001
Preparation of 3-bromo-4-[(2,4-diflurobenzyl)oxy]-l-[4-(l-hydroxy-l- methylethyl)benzyl]-6-methylpyridin-2(lH)-one. Product from Example 153 (2.00 g, 4.18 mmol) suspended in tetrahydrofuran (20 mL) was cooled in the dry ice/acetone bath. Methyl magnesium bromide (4.32 mL, 12.96 mmol, 3.0 M in diethyl ether) was slowly added. The reaction was slowly allowed to warm to room temperature overnight. The reaction was then cooled in an ice bath and quenched by the addition of saturated NHjCl (50 mL). H20 was added and the reaction was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2S0 , filerted and evaporated. The residue was subjected to chromatography (silica gel, hexanes/ethyl acetate with 10% methanol) to provide an off-white foam. The foam was dissolved in acetonitrile and cooled in an ice bath. N-bromosuccinimide (0.057 g, 0.320 mmol) was added. Once the addition was complete the cooling bath was removed. After 2.5 hours at room temperature the reaction was concentrated. Purification by chromatography (silica gel, hexanes/ethyl acetate with 10% methanol) provided a white foam. lH ΝMR (400 MHz, CDC13) δ 7.56 (app q, 7 = 7.7 Hz, IH ), 7.39 (d, 7 = 78.3 Hz, 2H), 7.11 (d, 7 = 8.2 Hz, 2H), 6.92 (app dt, 7 = 1.7, 8.4 Hz, IH), 6.86-6.81 (m, IH), 5.97 (s, IH), 5.31 (s, 2H), 5.18 (s, 2H), 2.29 (s, 3H), 1.52 (s, 6H). ES-HRMS m/z 478.0811 (M+H C23H22BrF2Ν03 requires 478.0824). Example 208. Preparation of 3-bromo-4-[(2,4-diflurobenzyl)oxy]- 6-methyl-l- {4-[(methylamino)methyI]benzyl}pyridin-2(lH)-one.
353 -
Figure imgf000354_0001
Step 1. Preparation of 4-{[3-bromo-4-[(2,4-difluorobenzyl' loxy]-6-methyl-2- oxopyridin-l(2H)-yI]methyl}benzaldehyde.
Figure imgf000354_0002
Product from Example 206 (1.30 g, 2.89 mmol) was suspended in acetonitrile (10 mL) and cooled in an ice-bath. 1 -hydroxy- l,3-dihydro-3,3-bis(trifluoromethyl)-l,2-benziodoxole 1 -oxide (0.580 g, 1.44 mmol) was added and the reaction mixture was stirred at room temperature overnight. Diethyl ether was added and the solid was collected by filtration to give a white solid (1.14 g, 88%). 1H NMR (400 MHz, CDC13) δ 9.96 (s, IH), 7.80 (d, 7 = 8.2 Hz, 2H), 7.56 (app q, 7 = 7.7 Hz, IH), 7.30 (d, 7 = 8.2 Hz, 2H), 6.93 (app dt, 7 = 1.6, 8.3 Hz, IH), 6.87-6.82 (m, IH), 6.02 (s, IH), 5.41 (s, 2H), 5.20 (s, 2H), 2.27 (s, 3H). Step 2. 3-Bromo-4-[(2,4-diflurobenzyl)oxy]- 6-methyl-l-{4- [(methylamino)methyl]benzyl}pyridin-2(lH)-one. 4- { [3-Bromo-4-[(2,4- difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}benzaldehyde (Step 1) (1.53 g, 3.41 mmol) of step 1 was dissolved in Λ N-dimethylformamie (5.0 mL). Methylamine (3.41 mL, 6.83 mmol, 2.0 M in tetrahydrofuran) was added followed by ΝaHB(OAc) 3 (2.17 g, 10.23 mmol) in NN-dimethylformamide (8.0 mL) and acetic acid (2.0 mL). The reaction was stirred at room temperature overnight at which time IN ΝaOH (50 mL) was added and then extracted with ethyl acetate (2 x 50 mL). The organic layers were washed with brine (25 mL), dried over Νa S04 and evaporated. Chromatography ( on silica, ethyl acetate with 5% methanolic ammonia/hexanes) afforded a tan solid (0.810 g, 53%). 1H
- 354 - NMR (400 MHz, CDC13) δ 7.55 (app q, 7 = 7.8 Hz, IH), 7.22 (d, 7 = 8.1 Hz, 2H), 7.11 (d, 7= 8.1 Hz, 2H), 6.92 (app dt, 7= 2.4, 8.3 Hz, IH), 6.90-6.80 (m, IH), 5.95 (s, IH), 5.32 (s, 2H), 5.17 (s, 2H), 3.68 (s, 2H), 2.40 (s, 3H), 2.27 (s, 3H). ES-HRMS m/z 463.0838 (M+H calcd for C22H21BrF2N204 requires 463.0827). Example 209. Preparation of 4-[(2,4-diflurobenzyl)oxy]-l-(4-methoxybenzyl)- 6-methylpyridin-2-(lH)-one.
Figure imgf000355_0001
Step 1. Preparation of l-(4-methoxybenzyl)-4-hydroxy-6-methylpyridin- 2(lH)-one.
Figure imgf000355_0002
4-Hydroxy-6-methyl-2-pyrone (4.60 g, 36.45 mmol) and 4-methoxybenzylamine (5.00 g, 36.45 mmol) in H 0 (100 mL) were heated to reflux. After 15 hours at reflux the reaction was allowed to cool to room temperature. The precipitate was collected by filtration washing with H20 to give a pale yellow solid (8.00 g, 89 %). 1H NMR (400 MHz, DMSO- ) δ 7.2 (d, 7 = 8.7 Hz, 2H), 6.85 (d, 7 = 8.7 Hz, 2H), 5.74 (d, 7 = 2.0 Hz, IH), 5.56 (d, 7= 2.5 Hz, IH), 5.08 (s, 2H), 3.68 (s, 3H), 2.14 (s, 3H). Step 2. Preparation of 4-[(2,4-diflurobenzyl)oxy]-l-(4-methoxybenzyl)-6- methylpyridin-2(lH)-one. 1 -(4-methoxybenzyl)-4-hydroxy-6-methylpyridin-2( 1 H)-one (Step 1) (7.97 g, 32.49 mmol) was dissolved in NN-dimefhylformamide (60 mL). Potassium carbonate (4.94 g, 35.74 mmol) was added, followed by D-bromo-2,4- difluorotoluene (4.38 mL, 34.11 mmol). The reaction was stirred at room temperature for 20 hours at which time the mixture was filtered through a pad of Celite® washing with acetonitrile and the filtrate was evaporated. The residue was dissolved in H 0 (150 mL)
- 355 - and extracted into ethyl acetate (2 x 100 mL). The organic phase was washed with brine (100 mL), dried over Na2S0 , filtered and evaporated. Chromatography (on silica, hexanes/ethyl acetate with 10% methanol) yielded an off-white solid (3.64 g, 30%). 1H NMR (300 MHz CDC13) δ 7.42 (app q, 7= 7.7 Hz, IH), 7.13 (d, 7= 8.5 Hz, 2H), 6.96- 6.84 (m 2H), 6.85 (app d, 7 = 8.7 Hz, 2H), 6.01 (d, 7 = 2.6 Hz, IH), 5.82 (d, 7 = 2.8 Hz, IH), 5.23 (s, 2H), 5.02 (s, 2H), 3.79 (s, 3H), 2.25 (s, 3H). ES-HRMS m/z 372.1412 (M+H C21H19F2N03 requires 372.1417). Example 210. Preparation of 3-bromo-4-[(2,4-diflurobenzyl)oxy]-l-(4- methoxybenzyl)-6-methylpyridin-2(lH)-one
Figure imgf000356_0001
Product from Example 209 (0.200 g, 0.538 mmol) suspended in acetonitrile (3 mL) was cooled in an ice-bath. N-bromosuccinimide (0.101 g, 0.565 mmol) was added. Once the addition was complete the cooling bath was removed. After 1 hour the reaction was concentrated. Purification by chromatography (silica gel, hexanes/ethyl acetate) provided a white solid (0.240 g, 99%). Η ΝMR (300 MHz, CDC13) δ 7.59 {app q, 7 = 7.8 Hz, IH), 7.16 (d, 7 = 8.7 Hz, 2H), 6.97 (app dt, 7 = 2.4, 8.6 Hz, IH), 6.91-6.83 (m, IH), 6.85 (app d, 7= 8.7 Hz, 2H), 5.98 (s, IH), 5.31 (s, 2H), 5.21 (s, 2H), 3.79 (s, 3H), 2.34 (s, 3H). ESHRMS m/z 450.0491 (M+H C2ιHι8BrF2Ν03 requires 450.0511). Example 211. Preparation of 3-bromo-4-[(2,4-diflurobenzyl)oxy]-l-(4- hydroxybenzyl)-6-methylpyridin-2(lH)-one
Figure imgf000356_0002
356 Product from Example 210 (0.235 g, 0.522 mmol) was suspended in acetonitrile (3 mL). Cerric ammonium nitrate (1.14 g, 2.09 mmol) dissolved in H20 (1 mL) was added. The reaction was stirred at room temperature for 1 hour and then diluted with dichloromethane (25 mL). The reaction was then washed with H20 (10 mL). The aqueous phase was back extracted with dichloromethane (20 mL). The combined organic layers were dried over Na2S04, filtered and evaporated. The residue was washed with hot ethyl acetate to give an off-white solid (0.134 g, 59%). 1H NMR (300 MHz, DMSO- 6) δ 7.75 (app q, 7 = 7.9 Hz, IH), 7.65 (s, IH), 7.45-7.36 (m, IH), 7.36 (d, 7= 10.1Hz, 2H), 7.27-7.20 (m, IH), 6.49 (d, 7 = 10.1 Hz, 2H), 5.60 (s, 2H), 5.07 (s, 2H), 2.63 (s, 3H). ES-HRMS m/z 436.0187 (M+H C20H16BrF2NO3 requires 436.0354). Example 212. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l{4-[(4- hydroxy-4-methylpiperidin-l-yl)carbonyl]benzyl}-6-methylpyridin-2(lH)-one.
Figure imgf000357_0001
Step 1. Preparation of 4-hydroxy-4-methyIpiperidine hydrochloride.
Figure imgf000357_0002
tert-Butyl-4-oxo-l-piperidine (10.0 g, 50.19 mmol) dissolved in diethyl ether (100 mL) was cooled in an ice-bath. Methyl magnesium bromide (18.40 mL, 55.21 mmol, 3.0 M in diethyl ether) was added. After slowly warming to room temperature the reaction was recooled in an ice-bath and quenched by the addition of saturated NH4C1 (75 mL). Additional H20 was added and the organic layer was removed. The aqueous layer was further extracted with diethyl ether (50 mL). The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated. Chromatography ( silica gel, hexanes/ethyl acetate) provided a clear oil. The resulting oil was dissolved in diethyl ether (10 mL) and treated with 4N HCl/dioxane (32.61 mL, 130.43 mmol). After stirring at
357 room temperature for 1 hour the reaction mixture was concentrated to give a pale yellow solid (5.05 g, >100%). Step 2. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l{4-[(4-hydroxy- 4-methylpiperidin-l-yl)carbonyl]benzyl}-6-methylpyridin-2(lH)-one. Product from Example 205 (0.300 g, 0.646 mmol) was suspended in dichloromethane (6.0 mL). 1- hydroxybenzotriazole (0.044 g, 0.323 mmol) was added followed by 3-(l- cyclohexylcarbodiimide)propyl-functionalized silica gel (2.02 g, 1.29 mmol, loading = 0.64 mmol/g), 3-(l-morpholine)propyl functionalized silica gel (1.84 g, 1.29 mmol, loading = 0.7 mmol/g) and dichloromethane (2 mL). After stirring at room temperature for 15 minutes, 4-hydroxy-4-methylpiperidine hydrochloride (0.147 g, 0.969 mmol) was added. The resulting mixture was stirred at room temperature overnight, at which time dimethylamine-3-functionalized silica gel (1.7 g, 2.58 mmol, loading = 1.5 mmol/g) was added followed by isocyanate-3-functionalized silica gel (1.3 g, 1.62 mmol, loading = 1.22 mmol/g). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was then filtered and concentrated. Chromatography (silica gel, hexanes/ethyl acetate with 10% methanol) provided a white foam (0.200 g, 55%). 1H NMR (300 MHz, CDC13) δ 7.58 (app q, 7= 7.7 Hz, IH), 7.33 (d, 7 = 8.1 Hz, 2H), 7.18 (d, 7 = 8.1 Hz, 2H), 6.96 (app t, 7 = 8.3 Hz, IH), 6.87 (app dt, 7= 2.0, 9.5 Hz, IH), 6.06 (s, IH), 5.38 (s, 2H), 5.22 (s, 2H), 4.27 (br m, IH), 3.41 (br m, 3H), 2.30 (s, 3H), 2.06 (s, IH), 1.60 (br m, 4H), 1.28 (s, 3H). ES-HRMS m/z 561.1173 (M+H C27H27BrF2N204 requires 561.1195). Example 213. Preparation of 4-{[3-bromo-4-[(2,4-difluorobenzyι)oxy]- 6- methyl-2-oxypyridin-l(2H)-yl]methyI}-N-(2-hydroxy-2-methylpropyl)benzamide.
Figure imgf000358_0001
The title compound was by a procedure essentially as in Example 212 using l-amino-2- methyl-2-propanol hydrochloride as starting material. Η NMR (400 MHz, CDC13) δ 7.70 (d, J = 8.3 Hz, 2H), 7.53 (app q, 7 = 7.8 Hz, IH), 7.33 (t, 7 = 5.8 Hz, IH), 7.06 (d, 7 = 8.3
- 358 - Hz, 2H), 6.95-6.90 (m, IH), 6.86-6.81 (m, IH), 6.04 (s, IH), 5.30 (s, 2H), 5.19 (s, 2H), 3.40 (d, J = 5.9 Hz, 2H), 2.98 (br s, IH), 2.24 (s, 3H), 1.21 (s, 6H). ES-HRMS m/z 535.1012 (M+H C25H25BrF2N204 requires 535.1039). Example 214. Preparation of 3-bromo-4-[(2,4-difluorobenzyI)oxy]-l{4-[(4- hydroxypiperidin-l-yl)carbonyl]benzyl}-6-methylpyridin-2(lH)-one.
Figure imgf000359_0001
The title compound was produced essentially as in Example 212 using 4- hydroxypiperidine as starting material. 1H NMR (400 MHz, CDC13) δ 7.55 (app q, 7 = 7.7 Hz, IH), 7.30 (d, 7= 8.2 Hz, 2H), 7.15 (d, 7= 8.3 Hz, 2H), 6.94 (app dt, 7 = 2.4, 8.4 Hz, IH), 6.84 (app ddd, 7= 2.6, 8.9, 10.3 Hz, IH), 6.01 (s, IH), 5.36 (s, 2H), 5.19 (s, 2H), 4.12-4.07 (m, IH), 3.96-3.90 (m, IH), 3.60 (br s, IH), 3.33 (br s, IH), 3.13 (br s, IH), 2.27 (s, 3H), 1.91 (br s, 3H), 1.77 (br s, IH), 1.57 (b s, IH), 1.44 (b s, IH). ES-HRMS m/z 547.1006 (M+H C26H25BrF2N204 requires 547.1039). Example 215. Preparation of 4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]methyl}-N-(2-hydroxyethyl)benzamide.
Figure imgf000359_0002
To a reaction vessel (borosilicate culture tube) was added product from Example 205 (0.300 g, 0.646 mmol). A stock solution of 1-hydroxybenzotriazole in N,N- dimethylformamide (3 mL, 0.11 M) was added to the reaction vessel followed by approximately 1.10 g of the polymer bound carbodiimide resin (1.8 mmol/g). Additional NN-dimethylformamide (2 mL) was then added to the reaction vessel. The parallel - 359 - reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 15 minutes. Ethanolamine (0.06 mL, 0.994 mmol) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature overnight. At this time the reaction was diluted with tetrahydrofuran (20 mL) and treated with approximately 2.0 g of polyamine resin (2.63 mmol/g) and approximately 2.6 g of methylisocyanate functionalized polystyrene (1.10 mmol/g) and the orbital shaking was continued at 200 RPM at room temperature for 3 hours. The reaction vessel was then opened and the solution phase product was separated from the insoluble quenched byproducts by filtration and collection into a vial. After partially evaporation the insoluble byproducts were rinsed further with tetrahydrofuran (2 x 10 mL) and combined with the partially reduced filtrate. The resulting filtrate was concentrated by blowing N2 over the vial while heating (60 °C) in a reaction block (KEM- Lab Parallel Reactor) to give an off-white solid. (0.111 g, 34%) 1H NMR (400 MHz, OMΕ-d6) δ 8.45 (t, 7 = 5.4 Hz, IH), 7.94 (d, 7 = 8.2 Hz, 2H), 7.76 (app q, 7 = 7.9 Hz, IH), 7.33-7.27 (m, IH), 7.27 (app d, 7 = 7.9 Hz, 2H), 7.20 (app dt, 7 = 2.4, 8.6 Hz, IH), 6.65 (s, IH), 5.47 (s, 2H), 5.38 (s, 2H), 4.83 (br s, IH), 3.64-3.60 (m, 2H), 2.47-3.42 (m, 2H), 2.40 (s, 3H). ES-HRMS m/z 507.0742 (M+H C23H21BrF2N204 requires 507.0726). Examples 216-231. Preparation of 3-bromo-4-(2,4-difluorophenoxy)-6- methyl-l-[4-(aminocarbonyl)benzyl]pyridin-2(lH)-one compounds
Figure imgf000360_0001
By following the method of Example 215 and substituting the appropriate amine, the compounds of Examples 216-231 are prepared. The deprotection of the protected intermediates was accomplished with 4N HCl in dioxane to afford the compounds as hydrochloride salts.
360
Figure imgf000361_0002
Example 232. Preparation of 4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]- N-(2-hydroxyethyl)benzamide.
Figure imgf000361_0001
To a reaction vessel (borosilicate culture tube) was added EXAMPLE 203 (0.300 g, 0.666 mmol). A stock solution of 1-hydroxybenzotriazole in NN-dimethylformamide (3 mL, 0.11 M) was added to the reaction vessel followed by approximately 1.13 g of the polymer bound carbodiimide resin (1.8 mmol/g). Additional NN-dimethylformamide (2 mL) was then added to the reaction vessel. The parallel reaction apparatus was then orbitally
361 shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 15 minutes. Ethanolamine (0.06 mL, 0.994 mmol) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature overnight. At this time the reaction was diluted with tetrahydrofuran (20 mL) and treated with approximately 2.0 g of polyamine resin (2.63 mmol/g) and approximately 2.7 g of methylisocyanate functionalized polystyrene (1.10 mmol/g) and the orbital shaking was continued at 200 RPM at room temperature for 3 hours. The reaction vessel was then opened and the solution phase products were separated from the insoluble quenched byproducts by filtration and collection into a vial. After partially evaporation the insoluble byproducts were rinsed further with tetrahydrofuran (2 10 mL) and combined with the I partially reduced filtrate. The resulting filtrate was concentrated by blowing N2 over the vial while heating (60 °C) in a reaction block (KEM-Lab Parallel Reactor). Purification by chromatography (silica gel) provided an off-white solid (0.155 g, 47%). 1H NMR (400 MHz, DMF- 6) δ 8.58 (t, 7= 5.5 Hz, IH), 8.10 (d, 7 = 8.3 Hz, 2H), 7.79 (app q, 7= 7.9 Hz, IH), 7.47 (d, 7= 8.3 Hz, 2H), 7.36-7.30 (m, IH), 7.21 (app dt, 7 = 2.4, 8.5 Hz, IH), 6.73 (s, IH), 5.43 (s, 2H), 3.68 (app t, 7= 5.9 Hz, 2H), 3.52-3.49 (m, 2H), 2.03 (s, 3H). ES-HRMS m/z 493.0597 (M+H C22Hι9BrF2N204 requires 493.0569). Example2 233-243. Preparation of compounds corresponding in structure to the following formula:
Figure imgf000362_0001
By following the method of Example 232 and substituting ethanolamine for the appropriate amine, the compounds of Examples 233-243 are prepared. The deprotection of the protected intermediates was accomplished with 4N HCl in dioxane to afford the compounds as hydrochloride salts.
Figure imgf000362_0002
- 362 -
Figure imgf000363_0002
Example 244. Preparation of 4-[3-bromo-4-[(2,4-difluorobenzyι)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]benzamide.
Figure imgf000363_0001
Product from Example 203 (0.500 g, 1.11 mmol) was suspended in tetrahydrofuran (5.0 mL). 2-Chloro-4,6-dimethoxy-l,3,5-triazine (0.234 g, 1.33 mmol) was added followed by 4-methylmorpholine (0.366 mL, 3.33 mmol). The resulting mixture was stirred at room temperature for 1.5 hours at which time NH4OH (2.5 mL) was added. The resulting mixture was stirred at room temperature overnight. H20 (25 mL) and tetrahydrofuran (25 mL) was added. The aqueous layer was further extracted with ethyl acetate (25 mL). The combined organic layers were washed with saturated sodium carbonate solution (25 mL), IN HCl (25 mL), brine (25 mL), dried over Νa2S04, filtered and concentrated to provide a pale yellow solid (0.500 g, 100 %). 1H NMR (400 MHz, OMF-d6) δ 8.13 (s, IH), 8.02 (d, 7 = 8.5 Hz, 2H), 7.70 (app q, 7 = 7.9 Hz, IH), 7.40 (d, 7 = 8.5 Hz, 2H), 7.41-7.34 (m, IH),
363 - 7.22 (app dt, 7 = 1.8, 8.5 Hz, IH), 6.71 (s, IH), 5.37 (s, 2H), 1.97 (s, 3H). ES-HRMS m/z 449.0281 (M+H C20H15BrF2N2O3 requires 449.0307). Example 245. Preparation of 4-(benzyloxy)-3-bromo-l-[4-(morpholin-4- ylcarbonyl)phenyl]pyridin-2(lH)-one
Figure imgf000364_0001
To a reaction vessel (borosilicate culture tube) was added product from Example 197 (0.100 g, 0.250 mmol) which was dissolved in NN-dimethylformamide (2.0 mL). 1- Hydroxybenzotriazole (0.017 g, 0.125 mmol) was added to the reaction vessel followed by approximately 0.423 g of the polymer bound carbodiimide resin (1.8 mmol/g). Additional NN-dimethylformamide (2 mL) was then added to the reaction vessel. The parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 15 minutes. Morpholine (0.033 g, 0.0.375 mmol) dissolved in N,N-dimethlyformamide (0.5 mL) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature overnight. At this time the reaction was diluted with N,N-dimethylformamide (2.0 mL) and dichloromethane (4.0 mL) and treated with approximately 0.770 g of polyamine resin (2.63 mmol/g) and approximately 1.0 g of methylisocyanate functionalized polystyrene (1.10 mmol/g) and the orbital shaking was continued at 200 RPM at room temperature for 3 hours. The reaction vessel was then opened and the solution phase product was separated from the insoluble quenched byproducts by filtration and collection into a vial. After partially evaporation the insoluble byproducts were rinsed with dichloromethane (2 x 10 mL). The filtrate was evaporated by blowing Ν2 over the vial while heating (60 °C) in a reaction block (KEM-Lab Parallel Reactor) to give an off-white solid (0.092 g, 79%). lH NMR (400 MHz, CDC13) δ 7.50 (d, 7 = 8.5 Hz, 2H), 7.48-7.33 (m, 7H), 7.27 (d, 7 = 7.8 Hz, IH), 6.19 (d, 7 = 7.8 Hz, IH), 5.29 (s, 2H), 3.76-3.47 (br m, 8H). ES-HRMS m/z 469.0733 (M+H C23H21BrN204 requires 469.0757). Example 246. Preparation of 4-(benzyloxy)-3-bromo-l-[4-(piperazin-l- ylcarbonyl)phenyl]pyridin-2(lH)-one hydrochloride
- 364 -
Figure imgf000365_0001
By following the method of Example 245 and substituting N-tert-butyl carboxylate piperazine (0.070 g, 0.375 mmol) for morpholine the title compound was prepared as the N-t-butoxycarbonyl protected compound. The deprotection of the Ν-t-butoxycarbonyl intermediate was accomplished with 4N HCl in dioxane to afford the title compound as its hydrochloride salt (0.112 g, >100%). 1H ΝMR (400 MHz, DMSO- 6) δ 9.55 (br s, 2H), 7.78 (d, 7 = 7.8 Hz, IH), 7.58 (d, 7 = 8.5 Hz, 2H), 7.48-7.33 (m, 7H), 6.57 (d, 7 = 7.8 Hz, IH), 5.38 (s, 2H), 3.79-3.36 (br m, 4H), 3.30-3.14 (br s, 4H). ES-HRMS m/z 468.0940 (M+H C23H22BrΝ303 requires 468.0917). Example 247. Preparation of 4-[4-(benzyloxy)-3-bromo-2-oxopyridin-l(2H)- yl] -N-hydoxybenzamide
By following the method of Example 245 and substituting 0-(tetrahydro-2H-pyranyl-2yl) hydroxylamine (0.044 g, 0.375 mmol) for morpholine the title compound was prepared as the tetrahydropyranly protected compound. The deprotection of the tetrahydropyranly intermediate was accomplished with 4N HCl in dioxane to afford the title compound (0.056 g, >71%). Η ΝMR (400 MHz, DMSO- 6) δ 11.03 (br s,lH), 7.83 (d, 7= 8.6 Hz, 2H), 7.78 (d, 7 = 7.8 Hz, IH), 7.48-7.35 (m, 7H), 6.55 (d, 7= 7.8 Hz, IH), 5.37 (s, 2H). ES-HRMS m/z 415.0278 (M+H C19H15BrΝ204 requires 415.0288). Example 248. Preparation of methyl-4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-
6-methyl-2-oxopyridin-l(2H)-yI]methyl}benzoate
365
Figure imgf000366_0001
Step 1. Preparation of 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyIpridin- 2(lH)-one.
Figure imgf000366_0002
4-(2,4-Difluoro-benzyloxy)-lH-pyridin-2-one (5.00 g, 19.90 mmol) was suspended in 1,2- dichloroethane (100 mL). Dichloroacetic acid (0.082 mL, 0.995 mmol) was added, followed by N-chlorosuccinimide (3.19 g, 23..88 mmol). The reaction mixture was heated at 80 °C for 15.5 hours. The 1,2-dichloroethane was evaporated and the remaining solids were washed with acetonitrile to provide a tan solid (4.97 g, 88%). Step 2. Preparation of methyl-4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]methyl}benzoate. 3-Chloro-4-[(2,4-difluorobenzyl)oxy]- 6-methylpridin-2(lH)-one (Step 1) (4.97 g, 17.40 mmol) suspended in tetrahydrofuran (50 mL) was cooled in an ice-bath. Methyl 4-(bromomethyl)benzoate (5.98 g, 26.10 mmol) was added, followed by sodium hydride (0.835 g, 20.88 mmol, 60% dispersion in mineral oil). Once the addition was complete the cooling bath was removed in the mixture was heated to 50 °C for 19 hours. After cooling to room temperature saturated ΝH4C1 (50 mL) was added. Ethyl acetate was added and the precipitate was collected by filtration. The filtrate was further extracted with ethyl acetate. The combined organic layers were washed with brine (50 mL), dried over Na2S04, filtered and evaporated. The resulting solid was combined with the precipitate and washed with hot ethyl acetate to give an off- white solid (5.24 g, 69%). 1H NMR (400 MHz, OMSO-d6) δ 7.90 (d, J = 8.5 Hz, 2H), 7.63 (app q, J = 7.9 Hz, IH), 7.31 (app dt, J = 2.4, 9.9 Hz, IH), 7.21 (d, J = 8.3 Hz, 2H),
366 7.17-7.13 (m, IH), 6.60 (s, IH), 5.36 (s, 2H), 5.27 (s, 2H), 3.81 (s, 3H), 2.27 (s, 3H). ESHRMS m/z 434.0931 (M+H C22Hι8BrF2N0 requires 434.0965). Example 249. Preparation of 3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]methyl}-N-methylbenzamide
Figure imgf000367_0001
To a reaction vessel (borosilicate culture tube) was added product from Example 169 (0.300 g, 0.646 mmol). A stock solution of 1-hydroxybenzotriazole in NN- dimethylformamide (3 mL, 0.11 M) was added followed by approximately 1.10 g of the polymer bound carbodiimide resin (1.8 mmol/g). Additional NN-dimethylformamide (2 mL) was then added to the reaction vessel. The parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 15 minutes. N-Methylamine (0.50 mL, 0.999 mmol) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature overnight. At this time the reaction was diluted with tetrahydrofuran (35 mL) and treated with approximately 2.0 g of polyamine resin (2.63 mmol/g) and approximately 2.6 g of methylisocyanate functionalized polystyrene (1.50 mmol/g) and the orbital shaking was continued at 200 RPM at room temperature for 4 hours. The reaction vessel was then opened and the solution phase products were separated from the insoluble quenched byproducts by filtration and collection into a vial. After partial evaporation the insoluble byproducts were rinsed with tetrahydrofuran (2 x 10 mL). The filtrate was evaporated by blowing Ν2 over the vial while heating (60°C) in a reaction block (KEM-Lab Parallel Reactor). Chromatography (C-18, acetonitrile/H20 with 0.1% trifluoroacetic acid) afforded a white solid (0.178 g, 58%). Η NMR (400 MHz, DMF- ) δ 7.65-7.53 (m, 3H), 7.37-7.28 (m, 2H), 6.97-6.82 (m, 2H), 6.00 (s, IH), 5.36 (s, 2H), 5.19 (s, 3H), 2.96 (t, 7 = 4.83 Hz, 3H), 2.29 (s, 3H). ES-HRMS m/z 477.0635 (M+H C22H19BrF2N203 requires 477.0620). - 367 - Examples 250-261. Preparation of compounds corresponding in structure to the following formula:
Figure imgf000368_0001
By following the method of Example 249 and replacing N-methylamine with the appropriate amine, the compounds of Examples 250-261 are prepared. The deprotection of the protected intermediates was accomplished with 4N HCl in dioxane to afford the compounds as hydrochloride salts.
Figure imgf000368_0002
xample 2 . reparaton o - - - romo- - , - uoro enzy oxy]-6- methyl-2-oxopyridin-l(2H)-yl]methyl}benzyl)-2-methoxyacetamide
-368
Figure imgf000369_0001
To a reaction vessel (borosilicate culture tube) was added methoxyacetic acid (0.09 g, 1.00 mmol). A stock solution of 1-hydroxybenzotriazole (3 mL, 0.16 M) and N- methylmorpholine (3 mL, 0.43 M) in NN-dimethylformamide were added to the reaction vessel followed by approximately 0.97 g of the polymer bound carbodiimide resin (1.38 mmol/g). Additional NN-dimethylformamide (3 mL) was then added to the reaction vessel. The parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 4 hours. l-[3- (aminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one (EXAMPLE 161) (0.30 g, 0.668 mmol) was then added to the reaction vessel followed by additional NN-dimethylformamide (5.0 mL) and the reaction apparatus was orbitally shaken at room temperature overnight. At this time the reaction was diluted with tetrahydrofuran (20 mL) and treated with approximately 2.06 g of polyamine resin (2.63 mmol/g) and approximately 2.67 g of methylisocyanate functionalized polystyrene (1.10 mmol/g) and the orbital shaking was continued at 200 RPM at room temperature for 4 hours. The reaction vessel was then opened and the solution phase products were separated from the insoluble quenched byproducts by filtration and collection into a vial. After partial evaporation the insoluble byproducts were rinsed with tetrahydrofuran (2 x 10 mL). The filtrate was evaporated by blowing Ν2 over the vial while heating (60°C) in a reaction block (KEM-Lab Parallel Reactor) afforded a tan solid (0.321 g, 89.4%). Η
NMR (400 MHz, OMF-d6) δ 8.33 (br s, IH), 7.81 (app q, 7= 7.85 Hz, IH), 7.40-7.23 (m, 5H), 7.09 (d, 7= 7.25 Hz, IH), 6.68 (s, IH), 5.46 (s, 2H), 5.42 (s, 2H), 4.45 (d, 7= 6.24 Hz, 2H), 3.93 (s, 2H), 3.39 (s, 3H), 2.44 (s, 3H). ES-HRMS m/z 521.0891 (M+H C24H23BrF2N20 requires 521.0882). - 369 - Example 263-265. Preparation of compounds corresponding in structure to the following formula:
Figure imgf000370_0001
By following the method of Example 262 and replacing methoxyacetic acid with the appropriate acid, the compounds of Examples 263-265 are prepared. The deprotection of the protected intermediates was accomplished with 4N HCl in dioxane to afford the compounds as hydrochloride salts.
Figure imgf000370_0003
Example 266. Preparation of N-(3-{[3-bromo-4-[(2,4-difIuorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]methyl}benzyl)-2-hydroxy-2-methylpropanamide
Figure imgf000370_0002
l-[3-(aminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)- one (Example 161) (0.300 g, 0.668 mmol), 1-hydroxyisobutyric acid (0.215 g, 2.064 mmol), 1-hydroxybenzotriazole (0.112 g, 0.826 mmol), and l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (0.185 g, 0.963 mmol) were dissolved in NN- - 370 - dimethylacetamide (3 mL). N-methylmorpholine (0.209 g, 2.064 mmol) was added, and the reaction stirred for 1 hour at room temperature. The reaction was diluted with H20 (50 mL) and the aqueous layer extracted with ethyl acetate (3 x 25 mL). The combined organics were then washed with IN HCl (25 mL), saturated Νa2C03 (25 mL), brine (25 mL), dried over Na S0 , and concentrated to yield an off-white solid (0.235 g, 64%). 1H NMR (400 MHz, DMF- 6) δ 8.25 (br s, IH), 7.81 (app q, 7= 7.92 Hz, IH), 7.40-7.21 (m, 5H), 7.09 (d, 7 = 6.84 Hz, IH), 6.67 (s, IH), 5.46 (s, 2H), 5.42 (s, 2H), 4.42 (d, 7 = 6.24 Hz, 2H), 2.44 (s, 3H), 1.38 (s, 6H). ES-HRMS m/z 535.1024 (M+H C25H25BrF2N20 requires 535.1039). Example 267A. Preparation of N-(3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]methyl}benzyl)-l-hydroxycyclopropanecarboxamide
Figure imgf000371_0001
By following the method of Example 266 and substituting 1 -hydroxy- 1-cyclopropane- carboxylic acid for 1-hydroxyisobutyric acid, the title compound was prepared (0.352 g, ■ 96%). 1H NMR (400 MHz, OMF-d6) δ 8.46 (app t, 7 = 6.24 Hz, IH), 7.81 (app q, 7 = 7.92 Hz, IH), 7.40-7.22 (m, 5H), 7.06 (d, 7= 7.05 Hz, IH), 6.67 (s, IH), 5.45 (s, 2H), 5.42 (s, 2H), 4.46 (d, 7 = 6.44 Hz, 2H), 2.45 (s, 3H), 1.17-1.12 (m, 2H), 0.93 (app q, 7= 3.82 Hz, 2H). ES-HRMS m/z 533.0861 (M+H C25H23BrF2N204 requires 533.0882). Example 267B. Preparation of N'-(3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyI-2-oxopyridin-l(2H)-yl]methyl}benzyl)-N,N-dimethylurea
371
Figure imgf000372_0001
Step 1. Preparation of 4-nitrophenyl 3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]- 6-methyl-2-oxopyridin-l(2H)-yl]methyl}benzylcarbamate
Figure imgf000372_0002
l-[3-(aminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)- one (Example 161) (2.00 g, 4.45 mmol) was suspended in dichloromethane (15 mL). Pyridine was added (0.43 mL, 5.34 mmol). After stirring for 10 minutes at room temperature, a stock solution of 4-nitrophenyl chloroformate (10.0 mL, 0.50 M) in dichloromethane was added dropwise. After stirring for 4.5 hours at room temperature, a stock solution of 4-nitrophenyl chloroformate (2.5 mL, 0.50 M) in dichloromethane was again added dropwise and stirring continued at 40 °C overnight. The reaction mixture was concentrated and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) to afford a yellow solid (1.11 g, 66%). Η NMR (400 MHz, DMSO- de) δ 8.56 (app t, 7 = 6.10 Hz, IH), 8.24-8.21 (m, 2H), 7.62 (app q, 7= 7.88 Hz, IH), 7.40- 7.27 (m, 7H), 6.98 (d, 7 = 7.52 Hz, IH), 6.54 (s, IH), 5.30 (s, 2H), 5.24 (s, 2H), 4.25 (d, 7 = 6.18 Hz, 2H),'2.30 (s, 3H). ES-HRMS m/z 614.0753 (M+H C28H22BrF2N306 requires 614.0733). Step 2. Preparation of N'-(3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl- 2-oxopyridin-l(2H)-yl]methyI}benzyl)-N,N-dimethyIurea. To a reaction vessel (borosilicate culture tube) was added 4-nitrophenyl 3-{ [3-bromo-4-[(2,4- difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl]methyl Jbenzylcarbamate (from step
- 372 - 1) (0.350 g, 0.570 mmol) dissolved in dichloromethane (6.0 mL). The parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 15 minutes. A stock solution of NN-dimethylamine in tetrahydorfuran (0.427 mL, 2.0 M) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature overnight. The reaction mixture was concentrated and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) which afforded an off white solid (0.226 g, 63.3%). 1H ΝMR (400 MHz, DMF-de) δ 7.81 (app q, 7= 7.92 Hz, IH), 7.40-7.19 (m, 5H), 7.06 (d, 7= 7.45 Hz, IH), 6.88 (app t, 7 = 5.84 Hz, IH), 6.68 (s, IH), 5.45 (s, 2H), 5.42 (s, IH), 4.35 (d, 7 = 5.84 Hz, IH), 2.92 (s, 6H), 2.44 (s, 3H). ES-HRMS m/z 520.1065 (M+H C24H24BrF2Ν303 requires 520.1042). Examples 268-70. Preparation of compounds corresponding in structure to the following formula:
Figure imgf000373_0001
By following the method of Example 267 and replacing NN-dimethylamine with the appropriate amine, the compounds of Examples 268-270 are prepared. The deprotection of the protected intermediates was accomplished with 4N HCl in dioxane to afford the compounds as hydrochloride salts. Compound No.
Figure imgf000373_0002
Ex. 268 CH2CH2N- CH2CH2N- 66.6 C26H27BrF2N4O3561.1307 561.1309 Ex. 269 H CH3 27.0 C23H22BrF2N303506.0885 506.0898 Ex. 270 CH2CH20- CH2CH20- 64.4 C26H26BrF2N304562.1148 562.1137
- 373 Example 271. Preparation of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]benzoic acid
Figure imgf000374_0001
Step 1: Preparation of methyl 3-(4-hydroxy-6-methyl-2-oxopyridin-l(2H)- yl)benzoate.
Figure imgf000374_0002
Methyl 3-aminobenzoate (75.00 g, 496.13 mmol) and 4-hydroxy-6-methyl-2-pyrone (62.57 g, 496.13 mmol) were suspended in 1,2-dichlorobenzene (150 mL) and heated to 165 °C for 15 minutes. The reaction was cooled to room temperature and extracted with 0.54M K2C03 (4 x 250 mL). The aqueous layers were acidified (pH 2) with 4N HCl. The rjrecipitate was collected by filtration to afford a yellow-orange solid (20.24 g, 16%). The resulting filtrate was extracted with ethyl acetate (3 x 1 L). The organic layers were washed with brine (500 mL), dried over MgS04 and evaporated. The resulting solid was washed with hot H 0 to afford a yellow-orange solid (3.84 g, 3%). The two solids were then combined. 1H ΝMR (400 MHz, OMSO~d6) δ 7.98 (dt, 7= 1.31, 7.79 Hz, IH), 7.69 (app t, 7 = 1.78 Hz, IH), 7.62 (t, 7 = 7.78 Hz, IH) 7.49 (ddd, 7 = 1.07, 1.07, 7.85 Hz, IH), 5.89 (dd, 7= 0.87, 2.48 Hz, IH), 5.55 (app d, 7 = 0.94 Hz, IH), 3.83 (s, 3H), 1.80 (s, 3H). ES-HRMS m/z 260.0895 (M+H C14H13Ν04 requires 260.0917). Step 2: Preparation of methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]benzoate.
Figure imgf000374_0003
374'- Methyl 3-(4-hydroxy-6-methyl-2-oxopyridin-l(2H)-yl)benzoate (from step 1) (24.00 g, 92.57 mmol) and K2C03 (15.35 g, 111.08 mmol) were dissolved in NN- dimethylformamide (220 mL). 2,4-Difluorobenzyl bromide (20.12 g, 97.20 mmol) was then added and the reaction mixture stirred for 48 hours at room temperature. The reaction mixture was diluted with H20 (1 L) and the precipitate collected by filtration to afford a white solid (4.08 g, 11%). The resulting oil was purified by chromatography (silica gel, ethyl acetate with 10% methanol hexanes) to afford an off white solid (11.88 g, 33%). The two solids were combined. 1H ΝMR (400 MHz, CDC13) δ 8.11 (dt, 7 = 1.41, 7.79 Hz, IH), 7.87 (app t, 7= 1.78 Hz, IH), 7.58 (app t, 7 = 7.69 Hz, IH) 7.45-7.38 (m, 2H), 6.94-6.84 (m, 2H), 5.97 (d, 7= 2.68 Hz, IH), 5.90 (ddd, 7= 0.94, 1.74, 1.74 Hz, IH), 5.97 (s, IH), 3.90 (s, 3H), 1.89 (s, 3H). ES-HRMS m/z 386.1179 (M+H C21H17F2Ν04 requires 386.1198). Step 3: Preparation of methyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]benzoate.
Figure imgf000375_0001
Methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]benzoate from step 2) (15.85 g, 41.130 mmol) suspended in acetonitrile (165 mL) was cooled in an ice- bath. N-bromosuccinimide (7.687 g, 43.186 mmol) was added and the ice-bath was removed. The reaction mixture was stirred for 1.5 hours at room temperature. Reaction was concentrated and subjected to chromatography (silica gel, ethyl acetate with 10% methanol hexanes) afforded an off white solid (17.63 g, 92%). 1H ΝMR (400 MHz, CDC13) δ 8.17 (dt, 7= 1.41, 7.85 Hz, IH), 7.90 (t, 7= 1.81 Hz, IH), 7.67-7.41 (m, 3H), 7.05-6.88 (m, 2H), 6.13 (s, IH), 5.30 (s, 2H), 3.95 (s, IH), 2.01 (s, 3H). ES-HRMS m/z 464.0286 (M+H C2ιH,6BrF2Ν0 requires 464.0304). Step 4: Preparation of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]benzoic acid. Methyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yι]benzoate (from step 3) (10.0 g, 21.539 mmol) was
- 375 dissolved in methanol (36 mL) and tetrahydrofuran (14 mL). 4NNaOH (13.5 mL, 53.847 mmol) was added. The resulting mixture was stirred for 1.5 hours at room temperature. The reaction was acidified (pH 2) with 4N HCl. The precipitate was collected by filtration to afford an off white solid (7.83 g, 81%) 1H ΝMR (400 MHz, OMSO-d6) δ 8.01 (dt, 7 = 1.41, 7.65 Hz, IH), 7.76 (app t, 7 = 1.78 Hz, IH), 7.76-7.15 (m, 5H), 6.66 (s, IH), 5.32 (s, 2H), 1.92 (s, 3H). ES-HRMS m/z 450.0134 (M+H C20H14BrF2ΝO4 requires 450.0147). Example 272. Preparation of ethyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]benzoate
Figure imgf000376_0001
By following the method of Example 271 and substituting ethyl 3-aminobenzoate for methyl 3-aminobenzoate, the title compound was prepared (2.66 g, 79%). Η NMR (400 MHz, CDC13) δ 8.13 (dt, 7= 1.41, 7.85 Hz, IH), 7.84 (t, 7= 1.88 Hz, IH), 7.62-7.55 (m, 2H), 7.36 (app dq, 7= 1.07, 7.85 Hz, IH), 6.96 (app dt, 7= 2.55, 8.35 Hz, IH), 6.88-6.84 (m, IH), 6.08 (s, IH), 5.25 (s, 2H), 4.42-4.30 (m, 2H), 1.96 (s, 3H), 1.36 (t, 7= 7.12 Hz, 3H). ES-HRMS m/z 478.0482 (M+H C22H18BrF2N04 requires 478.0460). Example 273. Preparation of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]-N-methylbenzamide
Figure imgf000376_0002
To a reaction vessel (borosilicate culture tube) was added Product from Example 271 (0.300 g, 0.666 mmol). A stock solution of 1-hydroxybenzotriazole in NN- dimethylformamide (3 mL, 0.11 M) was added to the reaction vessel followed by approximately 0.97 g of the polymer bound carbodiimide resin (1.38 mmol/g). Additional N,N-dimethylformamide (2 mL) was then added to the reaction vessel. The parallel
376 reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 15 minutes. N-Methylamine in tetrahydrofuran (0.50 mL, 0.999 mmol) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature overnight. At this time the reaction was diluted with tetrahydrofuran (30 mL) and treated with approximately 2.0 g of polyamine resin (2.63 mmol/g) and approximately 3.6 g of methylisocyanate functionalized polystyrene (1.10 mmol/g) and the orbital shaking was continued at 200 RPM at room temperature for 4 hours. The reaction vessel was then opened and the solution phase products were separated from the insoluble quenched byproducts by filtration and collection into a vial. After partial evaporation the insoluble byproducts were rinsed with tetrahydrofuran (2 x 10 mL). The filtrate was evaporated by blowing Ν2 over the vial while heating (60 °C) in a reaction block (KEM-Lab Parallel Reactor) to give an off-white solid (0.189 g, 61%). 1H NMR (400 MHz, DMF- 6) δ 8.56 (br d, 7 = 4.16 Hz, IH), 8.05-7.76 (m, 3H), 7.66 (t, 7 = 7.79 Hz, IH), 7.56-7.19 (m, 3H), 6.74 (s, IH), 5.43 (s, 2H), 3.46 (s, 3H), 2.03 (s, 3H). ES-HRMS m/z 463.0476 (M+H C2ιH17BrF2N203 requires 463.0463). Examples 274-289. Preparation of compounds corresponding in structure to the following formula:
Figure imgf000377_0001
By following the method of Example 273 and replacing N-methylamine with the appropriate amine, the compounds of Examples 274-289 are prepared. The deprotection of the protected intermediates was accomplished with 4N HCl in dioxane to afford the compounds as their hydrochloride salts.
Figure imgf000377_0002
377
Figure imgf000378_0002
Example 290. Preparation of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]benzamide
Figure imgf000378_0001
Product from Example 271 (2.00 g, 4.44 mmol) and 2-chloro-4,6-dimethoxy-l,3,5-triazine (0.94 g, 5.33 mmol) were suspended in tetrahydrofuran (20 mL). 4-Methylmorpholine (1.5 mL, 13.32 mmol) was added. The resulting mixture was stirred for 1.5 hours at room temperature. NH4OH (10 mL, 148.00 mmol) was added and the reaction was stirred for 0.5 hours at room temperature. H20 (50 mL) and tetrahydrofuran (50 mL) were added and the organic layer was separated. The aqueous phase was extracted with ethyl acetate (75 mL) and the combined organics were washed with saturated Na2C03 (50 mL), IN HCl (50 mL), and brine (50 mL). The organic phase was dried over Νa S04 and evaporated. The - 378 - resulting solid was washed with diethyl ether to give a white solid (1.86 g, 93%). 1H NMR (400 MHz, DMF- ) δ 8.20 (br s, IH), 8.10-8.07 (m, IH), 7.79 (s, IH), 7.79 (app q, 7= 7.83 Hz, IH), 7.66 (app t, 7 = 7.79 Hz, IH), 7.57-7.54 (m, IH), 7.46 (br s, IH), 7.36- 7.19 (m, 2H), 6.74 (s, IH), 5.43 (s, 2H), 2.04 (s, 3H). ES-HRMS m/z 449.0307 (M+H C20H15BrF2N2O3 requires 449.0307). Example 291. Preparation of 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]benzoic acid
Figure imgf000379_0001
Step 1. Preparation of methyl 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]benzoate
Figure imgf000379_0002
Product from step 2, Example 271 (4.54 g, 11.78 mmol) and N-chlorosuccinimide (1.65 g, 12.37 mmol) were suspended in dichloromethane (12 mL). Dichloroacetic acid (0.10 ml, 1.22 mmol) was added and the reaction mixture was stirred overnight at 40 °C. The reaction was cooled to room temperature and a precipitate formed. The precipitate was collected by filtration and washed with dichloromethane (3 x 10 mL) to afford a white solid (1.75 g, 35%). The filtrate was concentrated and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) to afforded an off white solid (1.29 g, 26%). The two solids were then combined. 1H ΝMR (400 MHz, CDC13) δ 8.12 (dt, 7 = 1.38, 7.83 Hz, IH), 7.85 (t, 7= 1.74 Hz, IH), 7.60-7.52 (m, 2H), 7.37 (dq, 7= 0.92, 7.92 Hz, 2H), 6.95 (app dt, 7= 2.55, 8.32 Hz, IH), 6.89-6.83 (m, IH), 6.11 (s, IH), 5.24 (s, 2H), 3.90 (s, 3H), 1.96 (s, 3H). ES-HRMS m/z 420.0783 (M+H C21H16C1F2Ν04 requires 420.0809).
- 379 - Step 2. Preparation of 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]benzoic acid. Methyl 3-[3-chloro-4-[(2,4-difluorobenzyι)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]benzoate (from step 1) (2.90 g, 6.91 mmol) was dissolved in methanol (5 mL) and tetrahydrofuran (12 mL). 4NNaOH (4.3 mL, 17.27 mmol) was added. The resulting mixture was stirred for 1.5 hours at room temperature. The reaction was acidified (pH-2) with 4N HCl. The precipitate was collected by filtration to afford an off white solid (2.36 g, 84%). 1H ΝMR (400 MHz, DMSO- 6 ) δ 8.01 (dt, 7= 1.41, 7.65 Hz, IH), 7.76 (app t, 7= 1.68 Hz, IH), 7.69-7.53 (m, 3H), 7.36-7.14 (m, 2H), 6.69 (s, IH), 5.32 (s, 2H), 1.93 (s, 3H). ES-HRMS m/z 406.0662 (M+H C20H14ClF2ΝO4 requires 406.0652). Example 292. Preparation of 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[3- (hydroxymethyl)phenyl]-6-methylpyridin-2(lH)-one
The starting material (0.550 g, 1.540 mmol) and N-chlorosuccinimide (0.214 g, 1.602 mmol) were suspended in dichloromethane (15 mL). Dichloroacetic acid (0.01 ml, 0.154 mmol) was added and the reaction mixture heated to 40 °C for 9 hours. The reaction was cooled to room temperature and a precipitate formed. The precipitate was collected by filtration and washed with dichloromethane (3 x 10 mL) to afford a white solid (0.286 g, 47%). 1H ΝMR (400 MHz, DMSO-J6) δ 7.38 (app q, 7 = 7.35 Hz, IH), 7.30-7.24 (m, 2H), 7.00 (br s, IH), 6.85 (app dt, 7 = 2.37, 6.24 Hz, IH), 6.82-6.67 (m, 2H), 6.01 (s, IH), 5.07 (s, 2H), 4.48 (d, 7 = 5.24 Hz, 2H), 1.81 (app d, 7 = 0.40 Hz, 3H). ES-HRMS m/z 392.0885 (M+H C20H16ClF2ΝO3 requires 392.0860). Example 293. Preparation of l-[3-(aminomethyl)phenyl]-3-bromo-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one
- 380 -
Figure imgf000381_0001
Step 1. Preparation of l-[3-(chloromethyl)phenyl]-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one.
Figure imgf000381_0002
2,4,6-Trichloro-[l,3,5]-triazine (3.09 g, 16.78 mmol) was dissolved in N,N- dimethylformamide (45 mL). The reaction mixture was stirred at room temperature for 1 hour and then dichloromethane (90 mL) was added. The alcohol (5.72 g, 15.99 mmol) was then added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (200 mL) and the organic phase was washed with H20 (200 mL), saturated Na2C03 (200 mL), IN HCl (200 mL), and brine (200 mL). The organic phase was dried over MgS0 and evaporated to give an orange solid (5.95 g, 99%). Step 2. Preparation of l-[3-(aminomethyl)phenyl]-4-[(2,4- difluorobenzyl)oxy]-6- methylpyridin-2(lH)-one.
Figure imgf000381_0003
l-[3-(chloromethyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one from step 1 (1.00 g, 2.66 mmol) was suspended in methanol (5 mL). The suspension was then brought to -78°C and NH3 was bubbled through the reaction mixture for 10 minutes. The reaction was then slowly allowed to warm to room temperature and stirred at room
- 381 - temperature for 4 days. The reaction was concentrated and the residue taken up in CH2C12 and filtered to remove excess salt. The filtrate was concentrated to afford a tan solid (0.94 g, 99%). Step 3. Preparation of l-[3-(aminomethyϊ)phenyl]-3-bromo-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one. l-[3-(aminomethyl)phenyl]-4-[(2,4- difluorobenzyl)oxy]-6- methylpyridin-2(lH)-one from step 3 (3.89 g, 10.93 mmol) suspended in acetonitrile (42 mL) was cooled in an ice-bath. N-bromosuccinimide (2.04 g, 11.47 mmol) was added and the ice-bath was removed. The reaction mixture was stirred for 1.5 hours at room temperature. The reaction was diluted with acetonitrile (100 mL) and the precipitate that formed was collected by filtration and washed with acetonitrile (3 x 30 mL) to afford an off-white solid (2.74 g, 58%). 1H ΝMR (400 MHz, DMSO-J6) δ 7.67-7.59 (m, 3H), 7.34-7.31 (m, 2H), 7.04 (app t, 7= 8.72 Hz, 2H), 7.05- 6.88 (m, 2H), 6.13 (s, IH), 5.30 (s, 2H), 3.95 (s, IH), 2.01 (s, 3H). ES-HRMS m/z 435.0538 (M+H C20H17BrF2Ν O2 requires 435.0514). Example 294. Preparation of N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]benzyl}methanesuIfonamide
Figure imgf000382_0001
To a reaction vessel (borosilicate culture tube) was added product from Example 293 (0.200 g, 0.459 mmol) and NN-dimethylformamide (4 mL). A stock solution of 4- methylmoipholine in NN-dimethylformamide (1.8 mL, 1.0 M) was added to the reaction vessel and the parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 10 minutes. A stock solution of methanesulfonyl chloride in NN-dimethylformamide (4.50 mL, 0.15 M) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature for 2 hours. At this time the reaction was diluted with dichloromethane (4 mL) and treated with approximately 2.1 g of polyamine resin (2.63 mmol/g) and . approximately 0.8 g of methylisocyanate functionalized polystyrene (1.7 mmol/g) and the
- 382 orbital shaking was continued at 200 RPM at room temperature overnight. The reaction vessel was then opened and the solution phase products were separated from the insoluble quenched byproducts by filtration and collection into a vial. After partial evaporation the insoluble byproducts were rinsed with dichloromethane (2 5 mL). The filtrate was evaporated by blowing N2 over the vial while heating (60 °C) in a reaction block (KEM- Lab Parallel Reactor) to give a yellow solid (0.190 g, 81%). 1H NMR (400 MHz, CD3OD) δ 7.63 (app q, 7= 7.00 Hz, IH), 7.56-7.50 (m, 2H), 7.25 (m, IH), 7.16 (dt, 7= 1.94, 7.25 Hz, IH), 7.04 (app t, 7= 8.59 Hz, 2H), 6.58 (s, IH), 5.34 (s, 2H), 4.30 (s, 2H), 2.87 (s, 3H), 2.03 (s, 3H). ES-HRMS m/z 513.0313 (M+H C2iH19BrF2N204S requires 513.0290). Examples 295-96. Preparation of compounds corresponding in structure to the following formula:
Figure imgf000383_0001
By following the method of Example 294 and replacing methanesulfonyl chloride with the appropriate acid chloride, the compounds of Examples 295-296 are prepared.
Figure imgf000383_0003
methyl-2-oxopyridin-l(2H)-yl]benzyl}-2-methoxyacetamide
Figure imgf000383_0002
383 To a reaction vessel (borosilicate culture tube) was added approximately 2.87 g of polymer bound carbodiimide resin (0.96 mmol/g) followed by a stock solution of methoxyacetic acid (8.0 mL, 0.10 M) in N,N-dimethylacetamide. A stock solution of 1- hydroxybenzotriazole in NN-dimethylacetamide (3.0 mL, 0.10 M) and N- methylmorpholine (6.0 mL, 0.10 M) in 1,2-dichloroethane were added to the reaction vessel. The parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 4 hours. A stock solution of the product from Example 293 in NN-dimethylacetamide (5.0 mL, 0.10 M) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature overnight. At this time the reaction was diluted with 1,2-dichloroethane (10 mL) and treated with approximately 1.70 g of polyamine resin (2.63 mmol/g) and approximately 0.84 g of methylisocyanate functionalized polystyrene (1.50 mmol/g) and > the orbital shaking was continued at 200 RPM at room temperature for 4 hours. The reaction vessel was then opened and the solution phase products were separated from the insoluble quenched byproducts by filtration and collection into a vial. After partial evaporation the insoluble byproducts were rinsed with NN-dimethylacetamide (2 x 5 mL). The filtrate was evaporated by blowing Ν2 over the vial while heating (60 °C) in a reaction block (KEM-Lab Parallel Reactor) and subjected to chromatography (silica gel, ethyl acetate with 10% methanol hexanes) afforded an off white solid (0.081 g, 28%). 1H NMR (400 MHz, DMF-de) δ 7.59 (q, 7 = 7.65 Hz, IH), 7.46 (app t, 7 = 7.55 Hz, IH), 7.40-7.37 (m, IH), 7.11-7.07 (m, 2H), 7.00 (t, 7= 8.56 Hz, 2H), 6.54 (s, IH), 5.30 (s, 2H), 4.43 (s, 2H), 3.88 (s, 2H), 3.35 (app d, 7 = 0.80 Hz, 2H), 1.97 (s, 3H). ES-HRMS m/z 507.0699 (M+H C23H2ιBrF2N204 requires 507.0726). Examples 298-300. Preparation of compounds corresponding in structure to the following formula:
Figure imgf000384_0001
- 384 By following the method of and replacing methoxyacetic acid with the appropriate acid, the compounds of Examples 298-300 are prepared. The deprotection of the protected intermediates was accomplished with 4N HCl in dioxane or 1 M K2C03 in methanol to afford the compounds as hydrochloride salts.
Figure imgf000385_0003
Example 301. Preparation of N'-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]benzyl}-N,N-dimethylurea
Figure imgf000385_0001
Step 1: Preparation of 4-nitrophenyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]benzylcarbamate.
Figure imgf000385_0002
- 385 l-[3-(aminomethyl)phenyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)- one(1.08 g, 2.48 mmol) was suspended in dichloromethane (7.5 mL). Pyridine was added (0.222 mL, 2.74 mmol). After stirring for 10 minutes at room temperature, a stock solution of 4-nitrophenyl chloroformate (5.0 mL, 0.50 M) in dichloromethane was added dropwise. After stirring for 4.5 hours at room temperature, a stock solution of 4- nitrophenyl chloroformate (2.5 mL, 0.50 M) in dichloromethane was again added dropwise and stirring continued at room temperature overnight. The reaction mixture was concentrated and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) afforded a yellow solid (0.85 g, 57%).
Step 2: Preparation of title compound. To a reaction vessel (borosilicate culture tube) was added 4-nitrophenyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]benzylcarbamate (from step 1) (0.150 g, 0.250 mmol) and dichloromethane (2.5 mL). The parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 15 minutes. A stock solution of NN-dimethylamine in tetrahydorfuran (0.15 mL, 2.0 M) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature overnight. The reaction mixture was concentrated and subjected to chromatography (silica gel, ethyl acetate with 10% methanol hexanes) which afforded an off white solid (0.065 g, 51%). 1H ΝMR (400 MHz, DMF-d6) δ 7.58 (app q, 7 = 7.79 Hz, IH), 7.42 (app t, 7 = 7.65 Hz, IH), 7.37 (app d, 7 = 7.79 Hz, IH), 7.08 (s, IH), 7.03 (app dt, 7 = 1.58, 5.37 Hz, IH), 6.96 (app dt, 7 = 2.55, 8.39 Hz, IH), 6.88-6.83 (m, IH), 6.06 (s, IH), 5.24 (s, 2H), 4.95 (app t, 7 = 5.57 Hz, IH), 4.42 (app dddd, 7= 5.10, 5.71, 10.20, 15.17 Hz, 2H), 2.90 (s, 6H), 1.96 (s, 3H). ES-HRMS m/z 506.0848 (M+H C23H22BrF2Ν3θ3 requires 506.0885).
Examples 302-303. Preparation of compounds corresponding in structure to the following formula:
386
Figure imgf000387_0001
By following the method of Example 301 and substituting NN-dimethylamine with the appropriate amine, the compounds of Examples 302-303 are prepared.
Figure imgf000387_0003
Example 304. Preparation of N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]benzyI}urea
Figure imgf000387_0002
To a reaction vessel (borosilicate culture tube) was added EXAMPLE 293 (0.200 g, 0.459 mmol) and tetrahydrofuran (4.0 mL). A stock solution of 4-methylmorpholine in tetrahydrofuran (1.8 mL, 1.0 M) was added to the reaction vessel and the parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 10 minutes. A stock solution of trimethylsilyl isocyanate in tetrahydrofuran (4.0 mL, 0.2 M) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature for two hours. At this time the reaction was diluted with tetrahydrofuran (4.0 mL) and the resulting precipitate - 387 - collected by filtration. The solid was then washed with tetrahydrofuran (3 x 5 mL) to afford a white solid (0.214 g, 97%). 1H NMR (400 MHz, CD3OD) δ 7.72 (app q, 7 = 7.83 Hz, IH), 7.55 (app t, 7= 8.06 Hz, IH), 7.46 (d, 7= 7.52 Hz, IH), 7.25-7.14 (m, 4H), 6.65 (s, IH), 5.65 (app t, 7 = 0.80 Hz, IH), 5.40 (s, 2H), 4.38 (s, 2H), 2.05 (s, 3H). ES-HRMS m/z 478.0594 (M+H C21H18BrF2N303 requires 478.0572).
Example 305. Preparation of 3-bromo-4-[(2,4-difIuorobenzyl)oxy]-l-{3- [(dimethyIamino)methyl]phenyl}-6-methylpyridin-2(lH)-one
Figure imgf000388_0001
Step 1: Preparation of 4-[(2,4-difluorobenzyl)oxy]-l-{3- [(dimethylamino)methyl]phenyl }-6-methylpyridin-2(lH)-one.
Figure imgf000388_0002
l-[3-(chloromethyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one (from step 1 of the synthesis of EXAMPLE 293) (0.500 g, 1.330 mmol) was suspended in a stock solution of NN-dimethylamine in methanol (2.0 mL, 2.0 M) and stirred overnight at room temperature. Reaction was concentrated and the residue partitioned between H20 (25 mL) and ethyl acetate (25 mL). The aqueous layer was further extracted with ethyl acetate (2 x 30 mL), and the combined organics were washed with brine (30 mL), dried over MgS04, and concentrated to afford an off-white solid (0.508 g, 99%).
388 Step 2: Preparation of the title compound. 4-[(2,4-difluorobenzyι)oxy]-l-{3- [(dimethylamino)methyl]phenyl}-6-methylpyridin-2(lH)-one from step 1 (0.200 g, 0.521 mmol) was suspended in acetonitrile (2.5 mL) and cooled in an ice-bath. N- bromosuccinimide (0.097 g, 0.547 mmol) was added and the ice-bath was removed. The reaction mixture was stirred for 1.5 hours at room temperature. The reaction was diluted with acetonitrile (100 mL). The precipitate that formed was collected by filtration and washed with acetonitrile (3 x 15 mL) to afford a yellow solid (0.160 g, 66%). Chromatography (C-18, acetonitrile/H20 with 0.1% trifluoroacetic acid, followed by chromatography silica gel, ethyl acetate with 10% methanol hexanes) afforded an off- white solid (0.024 g, 10%). 1H ΝMR (400 MHz, CD3OD) δ 7.68 (app q, 7 = 7.85 Hz,
IH), 7.58 (app t, 7 = 7.65 Hz, IH), 7.50 (app d, 7 = 7.85 Hz, IH), 7.25-7.05 (m, 4H), 6.63 (s, IH), 5.39 (s, 2H), 3.61 (app q, 7= 12.08 Hz, 2H), 2.32 (s, 6H), 2.08 (s, 3H). ESHRMS m/z 463.0782 (M+H C22H21BrF2Ν202 requires 463.0827). Example 306. Preparation of N-{4-[4-(benzyloxy)-3-bromo-2-oxopyridin- l(2H)-yl]benzyl}acetamide
Figure imgf000389_0001
l-[4-(aminomethyl)phenyl]-4-(benzyloxy)-3-bromopyridin-2(lH)-one hydrochloride(0.150 g, 0.389 mmol) was dissolved in NN-dimethylformamide (3.5 mL). A stock solution of 4-methylmorpholine in NN-dimethylformamide (1.5 mL, 1.0 M) was added and the reaction stirred at room temperature for 10 minutes. A stock solution of acetyl chloride in NN-dimethylformamide (3.0 mL, 0.2 M) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at 200 RPM for 2 hours at room temperature. At this time the reaction was diluted with dichloromethane (4 mL) and treated with approximately 1.8 g of polyamine resin (2.63 mmol/g) and approximately 0.8 g of methylisocyanate functionalized polystyrene (1.7 mmol/g) and the orbital shaking was continued at 200 RPM at room temperature overnight. The reaction vessel was then - 389 - opened and the solution phase products were separated from the insoluble quenched byproducts by filtration and collection into a vial. After partial evaporation the insoluble byproducts were further rinsed with dichloromethane (3 5 mL) and combined with the partially concentrated filtrate. The resulting filtrate was concentrated by blowing N2 over the vial while heating (60 °C) in a reaction block (KEM-Lab Parallel Reactor) to give an off-white solid (0.083 g, 50%). 1H NMR (400 MHz, CD3OD) δ 7.59 (d, 7 = 7.79 Hz, IH), 7.48-7.29 (m, 9H), 6.55 (d, 7 = 7.79 Hz, IH), 5.35 (s, 2H), 4.39 (s, 2H), 1.98 (s, 3H). ESHRMS m/z 427.0625 (M+H C21H19BrN203 requires 427.0652). Example 307. Preparation of N-{4-[4-(benzyloxy)-3-bromo-2-oxopyridin- l(2H)-yl]benzyϊ}-2-hydroxyacetamide
Figure imgf000390_0001
To a reaction vessel (borosilicate culture tube) was added approximately 1.95 g of polymer bound carbodiimide resin (0.96 mmol/g) followed by a stock solution of glycolic acid (5.8 mL, 0.10 M) in N,N-dimethylacetamide. A stock solution of 1- hydroxybenzotriazole in NN-dimethylacetamide (0.4 mL, 0.10 M) and N- methylmorpholine in 1,2-dichloroethane (3.9 mL, 0.10 M) were added to the reaction vessel. The parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 2 hours. A stock solution of l-[4-(aminomethyl)phenyl]-4-(benzyloxy)-3-bromopyridin-2(lH)-one hydrochloride in NN-dimethylacetamide (0.05 M, 7.8 mL) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature overnight. At this time the reaction was diluted with 1,2-dichloroethane (8 mL) and treated with approximately 1.17 g of polyamine resin (2.63 mmol/g) and approximately 0.58 g of methylisocyanate functionalized polystyrene (1.50 mmol/g) and the orbital shaking was continued at 200 RPM at room temperature for 4 hours. The reaction vessel was then opened and the solution phase products were separated from the insoluble quenched byproducts by filtration and collection into a vial. After partial evaporation the insoluble - 390 - byproducts were rinsed with N,N-dimethylacetamide (2 x 5 mL) and combined with the partially concentrated filtrate. The filtrate was concentrated by blowing Ν2 over the vial while heating (60 °C) in a reaction block (KEM-Lab Parallel Reactor) and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) which afforded an off white solid (0.081 g, 21%). 1H NMR (400 MHz, CD3OD) δ 7.55-7.30 (m, 10H), 6.51 (d, 7= 7.85 Hz, IH), 5.37 (s, 2H), 4.52 (s, 2H), 4.08 (s, 2H). ES-HRMS m/z 443.0605 (M+H C21H19BrN204 requires 443.0601). Example 308. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl- l-(2-morpholin-4-ylethyl)pyridin-2(lH)-one
Figure imgf000391_0001
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one (0.100 g, 0.303 mmol), cesium carbonate (0.296 g, 0.909 mmol), and 4-(2-chloroethyl)morpholine (0.059 g, 0.394 mmol) were suspended in acetonitrile (4 mL). The reaction was stirred at 60 °C overnight. H20 (25 mL) was added and the resulting precipitate was collected by filtration. The solid was subjected to chromatography (silica gel, ethyl acetate with 10% methanol) afforded an off-white solid (0.040 g, 30%). 1H NMR (400 MHz, CDC13) δ 7.55 (app q, 7 = 7.92 Hz, IH), 6.93 (app t, 7 = 8.39 Hz, IH), 6.84 (app t, 7 = 9.40 Hz, IH), 5.95 (s, IH), 5.18 (s, 2H), 4.16 (app t, 7= 6.78 Hz, 2H), 3.68 (s, 4H), 2.65 (app t, 7= 6.38 Hz, 2H), 2.54 (s, 4H), 2.43 (s, 3H). ES-HRMS m/z 443.0743 (M+H C19H21BrF2N203 requires 443.0776). Example 309. Preparation of ethyl 3-[4-(benzyloxy)-3-bromo-2-oxopyridin- l(2H)-yl]propanoate
Figure imgf000391_0002
391 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one (0.50 g, 1.78 mmol) and cesium fluoride (0.0027 g, 0.178 mmol) were suspended in tetrahydrofuran (10 mL) followed by dropwise addition of tetraethylortho silicate (0.37 g, 1.78 mmol) at room temperature. After stirring for 10 minutes at room temperature, ethyl acrylate (0.23 g, i2.32 mmol) was added dropwise and the reaction stirred at room temperature overnight. The reaction mixture was filtered through a pad of Celite®. The filtrate was concentrated and the resulting residue subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) to afford a white solid (0.62 g, 92%). 1H NMR (400 MHz, CDC13) δ 7.42 (d, 7 = 7.79 Hz, IH), 7.41-7.29 (m, 5H), 6.03 (d, 7 = 7.65 Hz, IH), 5.20 (s, 2H), 4.17 (t, 7= 5.98 Hz, 2H), 4.07 (q, 7 = 7.16 Hz, 2H), 2.83 (t, 7= 5.98 Hz, 2H), 1.19 (t, 7= 7.18 Hz, 3H). ES-HRMS m/z 380.0523 (M+H C17H18BrN04 requires 380.0492). Example 310. Preparation of methyl 3-[4-(benzyloxy)-3-bromo-2-oxopyridin- l(2H)-yl]propanoate
Figure imgf000392_0001
o o 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one (5.00 g, 17.85 mmol) and cesium fluoride (0.27 g, 1.78 mmol) were suspended in tetrahydrofuran (50 mL) followed by dropwise addition of tetramethylortho silicate (2.70 g, 17.85 mmol) at room temperature. After stirring for 10 minutes at room temperature, methyl acrylate (2.00 g, 23.20 mmol) was added dropwise and the reaction stirred at room temperature for 48 hours. The reaction mixture was filtered through a pad of Celite®. The filtrate was concentrated and the resulting residue subjected to chromatography (silica gel, ethyl acetate with 10% methanol hexanes) to afford a white solid (6.10 g, 93%). 1H NMR (400 MHz, CDC13) δ 7.42 (d, 7 = 7.65 Hz, IH), 7.41-7.29 (m, 5H), 6.04 (d, 7 = 7.65 Hz, IH), 5.20 (s, 2H), 4.17 (t, 7 = 5.91 Hz, 2H), 3.63 (s, 3H), 2.85 (t, 7= 5.91 Hz, 2H). ES-HRMS m/z 366.0350 (M+H C16H16BrN04 requires 366.0335). Example 311. Preparation of N-[3-bromo-l-(3-fluorobenzyl)-2-oxo-l,2- dihydropyridin-4-yl]-2,6-difluorobenzamide
- 392 -
Figure imgf000393_0001
Step 1. Preparation of 3,4-dibromo-l-(3-fluorobenzyl)pyridin-2(lH)-one
Figure imgf000393_0002
3-bromo- l-(3-fluorobenzyl)-2-oxo- 1 ,2-dihydropyridin-4-yl trifluoromethanesulfonate (2.00 g, 4.65 mmol), KBr (5.53 g, 46.49 mmol), and 18-Crown-6 (0.10 g, 0.38 mmol) were dissolved in NN-dimethylacetamide (26 mL). The reaction mixture was then heated at reflux for 16 hours. The reaction was concentrated and the resulting residue was partition between water (50 mL) and ethyl acetate (3 X 50 mL). The combined organics were washed with H20 (2 X 30 mL), brine (50 mL), dried over MgS0 , concentrated, and subjected to chromatography (silica gel, ethyl acetate with 10% methanol/hexane) to afford a brown solid (0.850 g, 51%). Step 2. Preparation of 4-azido-3-bromo-l-(3-fluorobenzyl)pyridin-2(lH)-one
Figure imgf000393_0003
Sodium azide (1.08 g, 16.62 mmol) was suspended in NN-dimethylformamide (10 mL) and a stock solution of 3,4-dibromo-l-(3-fluorobenzyl)pyridin-2(lH)-one (from step 1) in NN-dimethylformamide (33.0 mL, 0.33 M) was added and the resulting mixture was heated to 60 °C for 4 hours. Ice water (30 mL) was added and the aqueous layer was extracted with ethyl acetate (4 X 50 mL). The combined organics were washed with H20 (3 X 50 mL), brine (2 X 25 mL), dried over MgS04, concentrated, and subjected to
393 chromatography (silica gel, ethyl acetate with 10% methanol/hexane) to afford an off- white solid (3.50 g, 98%).
Step 3. Preparation of4-amino-3-bromo-l-(3-fluorobenzyl)pyridin-2(lH)-one hydrochloride
Figure imgf000394_0001
4-azido-3-bromo-l-(3-fluorobenzyl)pyridin-2(lH)-one (from step 2) (4.00 g, 12.38 mmol) was suspended in ethyl acetate (300 mL) and Fe (2.07 g, 37.14 mmol) was added. A stock solution of NB C1 in H20 (300 mL, 0.2 M) was added and the reaction mixture was stirred at room temperature for 36 hours. The reaction was filtered through a pad of Celite® and concentrated. The resulting solid was dissolved in ethyl acetate (150 mL) and washed with water (3 X 50 mL), brine (50 mL), dried over MgS0 , and concentrated. 1H NMR (400 MHz, CD3OD) δ 7.38-7.29 (m, 2H), 7.05 (d, 7 = 7.79 Hz, IH), 6.99 (d, 7= 8.99 Hz, 2H), 6.03 (d, 7= 7.39 Hz IH), 5.09 (s, 2H). ES-HRMS m/z 297.0023 (M+H C20H17BrF2N2O2 requires 297.0033). Step 4: Preparation of N-[3-bromo-l-(3-fluorobenzyl)-2-oxo-l,2-dihydropyridin-4- yl]-2,6-difluorobenzamide. 4-amino-3 -bromo- 1 -(3-fluorobenzyl)pyridin-2( lH)-one (from step 3) (0.30 g, 1.01 mmol) and 4-dimethylaminopyridine (0.002 g, 0.01 mmol) were suspended in acetonitrile (5 mL) followed by dropwise addition of triethylamine (0.2 mL, 1.41 mmol). This reaction mixture was stirred for 10 minutes at room temperature before being cooled to 0 °C. 2,6-difluorobenzoyl chloride (0.37 g, 2.12 mmol) was added dropwise and the reaction was heated at reflux overnight. The reaction was cooled to room temperature and IN NaOH (10 mL) was added. The reaction was then stirred for 45 minutes at room temperature. The reaction mixture was extracted with ethyl acetate (3 x 25 mL) and the organic layer washed with IN NaOH (2 X 25 mL), H20 (until pH neutral), brine (50 mL), dried over MgS04, concentrated, and subjected to chromatography (on C- 18, acetonitrile/ H20 with 0.1% trifluoracetic acid) to afford a white solid (0.19 g, 43%). 1H NMR (400 MHz, CDC13) δ 8.42 (br s, IH), 7.67 (d, 7= 7.65 Hz, IH), 7.49 (app tt, 7 =
394 6.31, 8.60 Hz, IH), 7.33-28 (m, 2H), 7.10-6.97 (m, 5H), 5.17 (s, 2H). ES-HRMS m/z 437.0083 (M+H C19H12BrF3N202 requires 437.0107). Example 312. Preparation of 3-bromo-l-(4-bromo-2,6-difluorophenyl)-4- [(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one
Figure imgf000395_0001
Step 1: Preparation of l-(4-bromo-2,6-difluorophenyl)-4-hydroxy-6- methyIpyridin-2(lH)-one.
Figure imgf000395_0002
4-Hydroxy-6-methyl-2-pyrone (30.0 g, 238 mmol) and 4-bromo-2,6-difluoroaniline (49.5 g, 238 mmol) were suspended in 50 ml of 1,2-dichlorobenzene in a 250 ml, 3-necked, round bottom flask equipped with a J-Kem temperature controller probe, a Dean-Stark trap, and a heating mantle. The reaction was heated to 165°C for 15 minutes, during which, water and some 1,2-dichlorobenzene was collected in the Dean-Stark trap. The reaction was allowed to cool to about 80°C. The flask was placed in an ice bath and about 25 ml of toluene was added and stirred. After about 10 minutes, a precipitate formed. The precipitate was filtered and washed 3 times with toluene, 3 times with hot water to remove excess pyrone, and dried in vacuo to give a tan solid (22.1 g, 29%). 1H NMR (400 MHz, DMSO-d6) δ 11.00 (br s, IH), 7.71 (d, 7 = 6.98 Hz, 2H), 5.97 (t, 7 = 0.88 Hz, IH), 5.55 (d, 7= 2.28 Hz, IH), 1.91 (s, 3H). LC/MS, tr = 1.96 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 316 (M+H). ESHRMS m/z 315.9779 (M+H calcd for C12H8BrF2N02 requires 315.9779). Step 2: Preparation of l-(4-bromo-2,6-difluorophenyl)-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one
395
Figure imgf000396_0001
l-(4-bromo-2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(lH)-one (from Step 1) (5.0 g, 15.8 mmol) was stirred briskly at room temperature with 2,4-difluorobenzyl bromide (2.23 ml, 17.4 mmol) and K2C03 (3.27 g, 23.7 mmol) in 50 ml of dimethylformamide. After stirring overnight, the reaction was poured quickly into 900 ml of cold water. The resulting precipitate was filtered and washed with water and hexane. The product was purified using a Biotage silica chromatography system using 20% ethyl acetate/hexanes to give a beige solid (4.32 g, 62%). XH NMR (400 MHz, CDC13) δ 7.41 (app q, 7= 6.31 Hz, IH), 7.25 (dd, 7 = 8.33, 1.74 Hz, 2H), 6.91 (dt, 7 = 9.2, 0.8 Hz, IH), 6.86 (dt, 7= 9.2, 0.8 Hz, IH), 5.95 (d, 7= 2.56 Hz, IH), 5.92 (dd, 7= 2.56, 0.94 Hz, IH), 5.01 (s, 2H), 1.98 (s, 3H). LC/MS, tr = 3.04 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 442 (M+H). ES-HRMS m/z 442.0057 (M+H calcd for Cι9H12BrF4N02 requires 442.0060). Step 3: Preparation of 3-bromo-l-(4-bromo-2,6-difluorophenyl)-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one. l-(4-bromo-2,6-difluorophenyl)-4- [(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one (from Step 2) (500 mg, 1.13 mmol) was stirred at room temperature with N-bromosuccinimide (221 mg, 1.24 mmol) in 5 ml of CH2C12 for 1.5 hours. The reaction was evaporated on a rotary evaporator and the resulting solid was washed 4 times with acetonitrile and dried in vacuo to yield a white solid (478 mg, 92%). 1H ΝMR (300 MHz, CDC13) δ 7.62 (app q, 7 = 6.64 Hz, IH), 7.31 (d, 7= 6.85 Hz, 2H), 7.01 (app t, 7= 8.36 Hz, IH), 6.96 (dt, 7= 9.46, 2.21 Hz, IH), 6.19 (s, IH), 5.30 (s, 2H), 2.10 (s, 3H); LC/MS, tr = 3.17 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 520 (M+H). ESHRMS m/z 521.9134 (M+H calcd for Cι9HπBr2F4Ν02 requires 521.9146). Example 313. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl- l-(2,4,6-trifluorophenyl)pyridin-2(lH)-one
- 396
Figure imgf000397_0001
The title compound was produced essentially as in Example 313, using 2,4,6- trifluoroaniline instead of 4-bromo-2,6-difluoroaniline. 1H NMR (300 MHz, CDC13) δ 7.62 (app q, 7= 7.79 Hz, IH), 7.01 (app dt, 7= 8.26, 2.01 Hz, IH), 6.95 - 6.85 (m, 3H), 6.19 (s, IH), 5.30 (s, 2H), 2.11 (s, 3H); LC/MS, tr = 2.81 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 460 (M+H). ES-HRMS m/z 459.9954 (M+H calcd for C19HuBrF5N02 requires 459.9966). Example 314. Preparation of 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l- (2,4,6-trifluorophenyl)pyridin-2(lH)-one
Figure imgf000397_0002
4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(2,4,6-trifluorophenyl)pyridin-2(lH)-one (350 mg, 0.92 mmol) was refluxed with N-chlorosuccinimide (147 mg, 1.1 mmol) and dichloroacetic acid (0.038 ml, 0.46 mmol) in 5 ml of CH2C12 overnight. The reaction was evaporated on a rotary evaporator and the resulting solid was washed 4 times with acetonitrile and dried in vacuo to yield a white solid (217 mg, 57%). 1H ΝMR (300 MHz, CDC13) δ 7.60 (app q, 7 = 7.75 Hz, IH), 7.00 (app dt, 7 = 8.23, 2.05 Hz, IH), 6.93 - 6.86 (m, 3H), 6.22 (s, IH), 5.30 (s, 2H), 2.12 (s, 3H); LC MS, tr = 2.78 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 416 (M+H). ES-HRMS m/z 416.0472 (M+H calcd for C19HnClF5Ν02 requires 416.0471). Example 315. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-
(hydroxymethyl)-l-(2,4,6-trifluorophenyl)pyridin-2(lH)-one
Figure imgf000397_0003
397 Step 1. Preparation of 4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-l- (2,4,6-trifluorophenyl)pyridin-2(lH)-one
Figure imgf000398_0001
4- [(2,4-Difluorobenzyl)oxy]-6-methyl- 1 -(2,4,6-trifluorophenyl)pyridin-2( lH)-one (9.0 g, 23.6 mmol) was heated to 135°C overnight with Se02 (13.1 g, 118 mmol) in 75 ml of 1,4- dioxane in a 350 ml sealed glass pressure vessel. The reaction mixture was cooled and placed on a plug of silica gel and washed with 5% methanol in CH C1 . The filtrate was evaporated and the resulting solid was washed with diethyl ether and dissolved in hot ethyl acetate. The insoluble Se salts were filtered off and the organic layer was evaporated. 7.01g (17.6 mmol) of a 3: 1 ratio of aldehyde to desired alcohol was isolated. The mixture was stirred with NaBH4 (802 mg, 21.2 mmol) in 30 ml of methanol at room temperature for 1 hour. The reaction was evaporated and CH2C12 and acetonitrile were used to dissolve the bulk of the solid. The remaining insoluble solid was filtered off. The organic layer was washed 3 times with NH4C1, dried over MgS04 and evaporated. The resulting solid was washed 3 times with diethyl ether and dried in vacuo to yield a light orange solid (4.35 g, 46%). 1H NMR (300 MHz, DMSO- 6) δ 7.68 (app q, 7 = 7.92 Hz, IH), 7.47 (app t, 7= 8.57 Hz, 2H), 7.35 (dt, 7 = 9.87, 2.42 Hz, IH), 7.18 (dt, 7= 8.31, 1.71 Hz, IH), 6.21 (d, 7= 2.42 Hz, IH), 6.07 (d, 7= 2.62 Hz, IH), 5.67 (br s, IH), 5.18 (s, 2H), 3.98 (s, 2H); LC/MS, tr = 2.31 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 398 (M+H). Step 2. Preparation of 4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-l- (2,4,6-trifluorophenyl)pyridin-2(lH)-one. 4-[(2,4-Difluorobenzyl)oxy]-6- (hydroxymethyl)-l-(2,4,6-trifluorophenyl)pyridin-2(lH)-one (from step 1) (2.1 g, 5.28 mmol) was stirred at room temperature with N-bromosuccinimide (1.13 g, 6.34 mmol) in 5 ml CH2C12 for 2 hours. The reaction was evaporated on a rotary evaporator and the resulting solid was washed 4 times with acetonitrile and dried in vacuo to yield a white solid (1.35 g, 54%). 1H ΝMR (300 MHz, CD3OD) δ 7.69 (app q, 7 = 6.65 Hz, IH), 7.20 (app t, 7= 8.36 Hz, 2H), 7.09 (app t, 7= 8.46 Hz, 2H), 6.88 (s, IH), 5.46 (s, 2H), 4.21 (s,
398 2H); LC MS, tr = 2.48 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 476 (M+H). ES-HRMS m/z 475.9907 (M+H calcd for C19HιιBrF5N03 requires 475.9915). Example 316. Preparation of 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6- (hydroxymethyl)-l-(2,4,6-trifluorophenyl)pyridin-2(lH)-one
Figure imgf000399_0001
4-[(2,4-Difluorobenzyl)oxy]-6-(hydroxymethyl)- 1 -(2,4,6-trifluorophenyl)pyridin-2( 1H)- one (2.1 g, 5.28 mmol) was refluxed with N-chlorosuccinimide (846 mg, 6.34 mmol) and dichloroacetic acid (0.87 ml, 10.56 mmol) in 5 ml CH2C12 overnight. The reaction was evaporated on a rotary evaporator and the resulting oil was triturated with diethyl ether to obtain a solid. The solid was washed 4 times with acetonitrile. Chromatography was done using a Biotage silica gel system with 60% ethyl acetate/hexanes. The recovery was poor from the column to give a white solid (109 mg, 5%). 1H ΝMR (300 MHz, CD3OD) δ 7.67 (app q, 7= 7.85 Hz, IH), 7.24 - 7.06 (m, 4H), 6.90 (s, IH), 5.45 (s, 2H), 4.22 (s, 2H); LC/MS, tr = 2.71 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 432 (M+H). ES-HRMS m/z 432.0413 (M+H calcd for C19HnClF5Ν03 requires 432.0420). Example 317. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6- difluoro-4-morpholin-4-ylphenyl)-6-methylpyridin-2(lH)-one
Figure imgf000399_0002
Step 1: Preparation of 4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluoro-4- morpholin-4-ylphenyl)-6-methylpyridin-2(lH)-one.
399
Figure imgf000400_0001
4-[(2,4-Difluorobenzyl)oxy]-6-methyl-l-(2,4,6-trifluorophenyl)pyridin-2(lH)-one (870 mg, 2.28 mmol) was heated to 100°C with K2C03 (630 mg, 4.56 mmol) in 5 ml of morpholine for 36 hours. The reaction was added to 200 ml of cold water and the resulting solid was washed with water and 50:50 diethyl ether/hexanes and dried in vacuo to give a beige solid (738 mg, 72%). 1H NMR (400 MHz, CDC13) δ 7.41 (app q, 7 = 7.70 Hz, IH), 6.93 - 6.85 (m, 2H), 6.49 (d, 7 = 10.47 Hz, 2H), 5.96 (d, 7 = 2.41 Hz, IH), 5.89 (d, 7= 1.75 Hz, IH), 5.00 (s, 2H), 3.83 (t, 7 = 4.83 Hz, 4H), 3.19 (t, 7 = 4.84 Hz, 4H), 1.99 (s, 3H); LC/MS, tr = 3.09 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml min, at 254 nm, at 50°C), ES-MS m/z 449 (M+H). ES-HR/MS m/z 449.1485 (M+H calcd for C23H20F4N2O3 requires 449.1483). Step 2. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluoro-4- morpholin-4-ylphenyl)-6-methylpyridin-2(lH)-one. 4-[(2,4-Difluorobenzyl)oxy]-l- (2,6-difluoro-4-morpholin-4-ylphenyl)-6-methylpyridin-2(lH)-one (from step 1) (500 mg, 1.12 mmol) was stirred at room temperature with N-bromosuccinimide (236 mg, 1.33 mmol) in 5 ml of CH2C12 for 2 hours. The reaction was evaporated on a rotary evaporator and the resulting oil was triturated with diethyl ether to obtain a solid. The solid was washed 4 times with acetonitrile and dried in vacuo to yield a white solid (171 mg, 29%). 1H ΝMR (400 MHz, CDC13) δ 7.58 (app q, 7 = 7.74 Hz, IH), 6.96 (app t, 7 = 8.39 Hz, IH), 6.86 (dt, 7 = 9.46, 2.28 Hz, IH), 6.50 (d, 7 = 10.74 Hz, 2H), 6.09 (s, IH), 5.24 (s, 2H), 3.84 (t, 7 = 4.84 Hz, 4H), 3.20 (t, 7 = 4.83 Hz, 4H), 2.07 (s, 3H); LC/MS, tr = 3.18 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES- MS m/z 527 (M+H). ES-HRMS m/z 527.0570 (M+H calcd for C23H19BrF Ν203 requires 527.0588). Example 318. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[2,6- difluoro-4-(4-methylpiperazin-l-yl)phenyl]-6-methylpyridin-2(lH)-one
- 400
Figure imgf000401_0001
The title compound was prepared essentially as in Example 317, using 1-methylpiperazine instead of morpholine. 1H NMR (400 MHz, CDC13) δ 7.57 (app q, 7 = 7.79 Hz, IH), 6.96 (dt, 7= 8.19, 1.88 Hz, IH), 6.86 (app dt, 7 = 9.44, 2.48 Hz, IH), 6.52 (d, 7 = 10.61 Hz, 2H), 6.14 (s, IH), 5.24 (s, 2H), 3.72 (br s, 4H), 3.51 (d, 7 = 11.27 Hz, 2H), 3.07 (br s, 2H), 2.85 (d, 7 = 4.29 Hz, 3H), 2.06 (s, 3H); LC/MS, tr = 2.50 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 540 (M+H). ES-HRMS m/z 540.0930 (M+H calcd for C24H22BrF4N302 requires 540.0904). Example 320. Preparation of 3-chloro-4-[(2,4-difluorobenzyI)oxy]-l-[2,6- difluoro-4-(4-methylpiperazin-l-yl)phenyl]-6-methylpyridin-2(lH)-one
Figure imgf000401_0002
4-[(2,4-Difluorobenzyl)oxy]-l-[2,6-difluoro-4-(4-methylpiperazin-l-yl)phenyl]-6- methylpyridin-2(lH)-one (1.3 g, 2.82 mmol) was stirred at reflux with N- chlorosuccinimide (451 mg, 3.38 mmol) and dichloroacetic acid (0.17 ml, 1.41 mmol) in 6 ml CH2C12 overnight. LC-MS showed 33% completion. More N-chlorosuccinimide (271 mg, 2.23 mmol) was added and refluxed overnight. The reaction was evaporated on a rotary evaporator and the resulting oil was triturated with ethyl acetate to obtain a solid. The solid was washed 4 times with ethyl acetate and with diethyl ether and dried in vacuo to obtain a white solid (606 mg, 43%). 1H ΝMR (400 MHz, DMSO- ) δ 7.66 (br q, 7 = 7.74 Hz, IH), 7.33 (br t, 7= 9.00 Hz, IH), 7.16 (br t, 7= 7.65 Hz, IH), 6.96 (d, 7= 11.81 Hz, 2H), 6.79 (s, IH), 5.33 (s, 2H), 3.61 (br m, 4H), 3.25 (br m, 4H), 3.21 (br s, 3H), 2.04 (s, 3H); LC MS, tr = 2.45 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min,
401 - at 254 nm, at 50°C), ES-MS m/z 496 (M+H). ES-HRMS m/z 496.1400 (M+H calcd for C24H22C1F4N302 requires 496.1409). Example 321. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[4- (dimethyIamino)-2,6-difluorophenyl]-6-methylpyridin-2(lH)-one
Figure imgf000402_0001
The title compound was prepared essentially as described in Example 317, using dimethylamine instead of morpholine. Η NMR (400 MHz, CDC13) δ 7.59 (q, 7 = 7.74 Hz, IH), 6.95 (dt, 7 = 8.32, 1.61 Hz, IH), 6.85 (app dt, 7= 9.54, 2.41 Hz, IH), 6.27 (d, 7 = 11.01 Hz, 2H), 6.08 (s, IH), 5.23 (s, 2H), 2.98 (s, 3H), 2.07 (s, 3H); LC MS, tr = 3.35 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES- MS m/z 485 (M+H). ES-HRMS m/z 485.0447 (M+H calcd for C21H17BrF4N202 requires 485.0482). Example 322. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{2,6- difluoro-4-[(2-hydroxyethyl)(methyl)amino]phenyl}-6-methylpyridin-2(lH)-one
Figure imgf000402_0002
The title compound was prepared essentially as in Example 317, using 2- (methylamino)ethanol instead of morpholine. 1H NMR (400 MHz, CDC13) δ 7.58 (q, 7 = 7.74 Hz, IH), 6.95 (dt, 7= 8.24, 1.66 Hz, IH), 6.85 (app dt, 7 = 9.49, 2.37 Hz, IH), 6.35 (d, 7= 11.01 Hz, 2H), 6.10 (s, IH), 5.23 (s, 2H), 3.77 (t, 7= 5.77 Hz, 2H), 3.45 (t, 7= 5.78 Hz, 2H), 2.99 (s, 3H), 2.08 (s, 3H); LC/MS, tr = 2.96 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 515 (M+H). ES-HRMS m/z 515.0576 (M+H calcd for C22H19BrF4N203 requires 515.0588). Example 323. Preparation of 3-bromo-l-(3,5-dibromo-2,6-difluoro-4- hydroxyphenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one
- 402 -
Figure imgf000403_0001
Step 1: Preparation of 4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluoro-4- hydroxyphenyl)-6-methylpyridin-2(lH)-one.
Figure imgf000403_0002
4-[(2,4-Difluorobenzyl)oxy]-6-methyl-l-(2,4,6-trifluorophenyl)pyridin-2(lH)-one (step 2 above) (10.0 g, 26.2 mmol) was heated to 45°C with KOSiMe3 (10.08 g, 78.6 mmol) in 50 ml of tetrahydrofuran for 4 days. The reaction was diluted with 30 ml of ethyl acetate and washed with IN HCl and water, dried over MgS04, and evaporated to give an orange solid. The solid was stirred in hot 60% ethyl acetate/hexanes and filtered to give a white solid, which was dried in vacuo to obtain a white solid (3.79 g, 38%). The filtrate was found to contain a mixture of desired product and the ortho substituted regioisomer. 1H NMR (400 MHz, CDC13) δ 7.42 (app q, 7 = 7.70 Hz, IH), 6.95 - 6.83 (m, 2H), 6.34 (d, 7 = 9.40 Hz, 2H), 6.05 (app s, 2H), 5.06 (s, 2H), 2.01 (s, 3H); LC/MS, tr = 2.80 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 380 (M+H). ES-HRMS m/z 380.0926 (M+H calcd for C19Hι3F4N03 requires 380.0904). Step 2. Preparation of 3-bromo-l-(3,5-dibromo-2,6-difluoro-4- hydroxyphenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one. 4-[(2,4- Difluorobenzyl)oxy]-l-(2,6-difluoro-4-hydroxyphenyl)-6-methylpyridin-2(lH)-one (from step 1) (3.73 g, 8.14 mmol) was stirred as a suspension at room temperature with N- bromosuccinimide (1.52 g, 8.55 mmol) in 30 ml CH2C12 overnight. LC-MS showed a 60% starting material. The solid was filtered off, dissolved in 30 ml of CH2C12/NN- dimethylformamide and stirred with more N-bromosuccinimide (0.76 g, 4.28 mmol) overnight. LC-MS showed the tri-brominated product as the major product. The reaction was poured into water and extracted with n-butanol. The combined organic layers were
403 evaporated on a rotary evaporator and the resulting solid was washed with diethyl ether and dried in vacuo to yield a white solid (873 mg, 17%). 1H NMR (400 MHz, CDC13) δ 7.67 (app q, 7= 7.80 Hz, IH), 7.32 (dt, 7= 4.86, 2.11 Hz, IH), 7.16 (dt, 7= 8.48, 1.84 Hz, IH), 6.79 (s, IH), 5.35 (s, 2H), 2.08 (s, 3H); LC/MS, tr = 3.26 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 616 (M+H). ES-HRMS m/z 615.8234 (M+H calcd for C19H10Br3F4NO3 requires 615.8200). Example 324. Preparation of 2-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]-3,5-difluorophenoxy}acetamide
Figure imgf000404_0001
Step 1: Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluoro-4- hydroxyphenyl)-6-methylpyridin-2(lH)-one
Figure imgf000404_0002
3-BiOmo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(2,4,6-trifluorophenyl)pyridin-2(lH)- one (7.5 g, 16.3 mmol) was heated to 45°C with KOSiMe3 (10.08 g, 78.6 mmol) in 50 ml of tetrahydrofuran for 48 hours. The reaction was diluted with 30 ml of ethyl acetate and washed with IN HCl and water, dried over MgS04, and evaporated to give a black oil. The oil was dissolved in ethyl acetate. A precipitate formed upon standing, which was filtered, washed with ethyl acetate and dried in vacuo to obtain a white solid (2.80 g, 37%). The filtrate showed the presence of desired product and the ortho substituted regioisomer. 1H NMR (400 MHz, DMSO- 6) δ 7.66 (q, 7 = 7.92 Hz, IH), 7.32 (dt, 7 = 8.77, 2.19 Hz, IH), 7.15 (m, IH), 6.73 (s, IH), 6.67 (d, 7= 9.66 Hz, 2H), 5.33 (s, 2H), 2.03 (s, 3H); LC/MS, tr = 2.92 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 458 (M+H). ES-HRMS m/z 457.9995 (M+H calcd for C19H12BrF4N03 requires 458.0009).
- 404 Step 2. Preparation of 2-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yI]-3,5-difluorophenoxy}acetamide. 3-Bromo-4-[(2,4- difluorobenzyl)oxy]-l-(2,6-difluoro-4-hydroxyphenyl)-6-methylpyridin-2(lH)-one (from step 1) (500 mg, 1.09 mmol) was stirred briskly with 2-bromoacetamide (196 mg, 1.43 mmol) and K2C03 (282 mg, 2.05 mmol) in 5 ml of NN-dimethylformamide at room temperature for 24 hours. The reaction was poured quickly into cold water and the resulting solid was filtered, washed with water, acetonitrile, and diethyl ether, and dried in vacuo to give a white solid (289 mg, 51%). 1H ΝMR (400 MHz, DMS0- ) δ 7.66 (q, 7 = 7.92 Hz, IH), 7.61 (br s, IH), 7.45 (br s, IH), 7.33 (dt, 7 = 10.07, 2.15 Hz, IH), 7.16 (dt, 7 = 8.53, 1.88 Hz, IH), 6.99 (d, 7= 9.54 Hz, 2H), 6.76 (s, IH), 5.34 (s, 2H), 2.03 (s, 3H); LC/MS, tr = 2.70 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 515 (M+H). ES-HRMS m/z 515.0245 (M+H calcd for C2ιH15BrF4Ν204 requires 515.0224). Example 325. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[2,6- difluoro-4-(2-hydroxyethoxy)phenyl]-6-methylpyridin-2(lH)-one
Figure imgf000405_0001
The title compound was prepared by a procedure similar to the one described for Example 324. 1H NMR (400 MHz, DMSO-d6) δ 7.66 (q, 7 = 7.92 Hz, IH), 7.33 (dt, 7= 10.04, 2.19 Hz, IH), 7.17 (dt, 7= 8.68, 1.84 Hz, IH), 6.99 (d, 7= 9.67 Hz, 2H), 6.75 (s, IH), 5.34 (s, 2H), 4.92 (t, 7 = 4.86 Hz, IH), 4.07 (t, 7 = 4.77 Hz, 2H), 3.70 (t, 7 = 4.83 Hz, 2H), 2.03 (s, 3H); LC/MS, tr = 2.81 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 502 (M+H). ES-HRMS m/z 502.0291 (M+H calcd for C21H16BrF4N04 requires 502.0272). Example 326. Preparation of 3-bromo-l-(2,6-difIuorophenyl)-4-{[4-fluoro-2- (hydroxymethyl)benzyl]oxy}-6-methylpyridin-2(lH)-one
405
Figure imgf000406_0001
Step 1: Preparation o l-(2,6-difluorophenyl)-4-{[4-fluoro-2- (hydroxymethyl)benzyl]oxy}-6-methylpyridin-2(lH)-one.
Figure imgf000406_0002
1 -(2,6-Difluorophenyl)-4-hydroxy-6-methylpyridin-2( 1 H)-one (step 1 ) (3.0 g, 12.65 mmol) was dissolved in NN-dimethylformamide and cooled to 0°C. Triphenylphosphine (3.98 g, 15.18 mmol) and diethyl azodicarboxylate (2.39 ml, 15.18 mmol) were added and stirred for 10 minutes. l,2-Bis(hydroxymethyl)-4-fluorobenzene (2.57 g, 16.44 mmol) was added and stirred at 0°C for 1 hour, then allowed to warm to room temperature and stirred overnight. LC-MS showed only 1 product, not a mixture of regioisomers, as expected. The reaction was added to water and extracted 3 times with ethyl acetate. The combined organic layers were dried over MgS04 and evaporated. A Biotage silica column was done using 60% ethyl acetate/hexanes as an eluent. Desired product, with a substantial impurity was obtained. Another Biotage silica column was ran using 30% ethyl acetate/hexanes to obtain pure product. The resulting oil was triturated with diethyl ether to obtain a white solid (720 mg, 15%). Η ΝMR (300 MHz, CDC13) δ 7.51 - 7.39 (m, 2H), 7.26 (dd, 7 = 9.62, 2.51 Hz, IH), 7.13 - 7.01 (m, 3H), 6.03 (d, 7 = 2.42 Hz, IH), 5.96 (d, 7 = 2.41 Hz, IH), 5.06 (s, 2H), 4.73 (s, 2H), 2.81 (br s, IH), 2.02 (s, 3H); LC/MS, tr = 2.37 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 376 (M+H). ES-HR/MS m/z 376.1181 (M+H calcd for C20H16F3ΝO3 requires 376.1155). Identity of the positional isomer was determined from hmbc, 2-D NMR experiments using H to C 2- and 3- bond coupling. Step 2: Preparation of 3-bromo-l-(2,6-difluorophenyl)-4-{[4-fluoro-2- (hydroxymethyl)benzyl]oxy}-6-methylpyridin-2(lH)-one. l-(2,6-Difluorophenyl)-4- {[4-fluoro-2-(hydroxymethyl)benzyl]oxy}-6-methylpyridin-2(lH)-one (from step 1) (350
- 406 - mg, 0.93 mmol) was stirred at room temperature with N-bromosuccinimide (199 mg, 1.12 mmol) in 1.5 ml CH2C12 for 1.5 hours. The reaction was evaporated on a rotary evaporator and the resulting solid was washed 4 times with acetonitrile and dried in vacuo to yield a white solid (197 mg, 47%). 1H ΝMR (300 MHz, CDC13) δ 7.53 - 7.43 (m, 2H), 7.25 (dd, 7= 9.46, 2.62 Hz, IH), 7.11 - 7.03 (m, 3H), 6.25 (s, IH), 5.31 (s, 2H), 4.81 (s, 2H), 2.28 (br s, IH), 2.10 (s, 3H); LC/MS, tr = 2.38 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 454 (M+H). ES-HRMS m/z 454.0247 (M+H calcd for C20H15BrF3Νθ3 requires 454.0260). Example 327. Preparation of 3-chloro-l-(2,6-difluorophenyl)-4-{[4-fluoro-2- (hydroxymethyl)benzyl]oxy}-6-methylpyridin-2(lH)-one
Figure imgf000407_0001
l-(2,6-Difluorophenyl)-4-{[4-fluoro-2-(hydroxymethyl)benzyl]oxy}-6-methylpyridin- 2(lH)-one (step 1 above) (275 mg, 0.73 mmol) was stirred at reflux with N- chlorosuccinimide (117 mg, 0.88 mmol) and dichloroacetic acid (0.03 ml, 0.36 mmol) in 1.5 ml CH C12 overnight. The reaction was evaporated on a rotary evaporator and the resulting solid was washed 4 times with ethyl acetate and with diethyl ether and dried in vacuo to obtain a white solid (65.5 mg, 22%). 1H ΝMR (300 MHz, CDC13) δ 7.52 - 7.43 (m, 2H), 7.26 (dd, 7 = 9.38, 2.52 Hz, IH), 7.12 - 7.04 (m, 3H), 6.27 (s, IH), 5.32 (s, 2H), 4.82 (s, 2H), 2.29 (br s, IH), 2.11 (s, 3H); LC/MS, tr = 2.32 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 410
(M+H). ES-HRMS m/z 410.0755 (M+H calcd for C20Hi5ClF3ΝO3 requires 410.0765). Example 328. Preparation of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]-2-methyl-N-(2-morpholin-4-ylethyl)benzamide
Figure imgf000407_0002
407 Step 1: Preparation of methyl 3-(4-hydroxy-6-methyl-2-oxopyridin-l(2H)-yι)- 2-methylbenzoate.
Figure imgf000408_0001
4-Hydroxy-6-methyl-2-pyrone (72.6 g, 576 mmol) and methyl-3-amino-2-methylbenzoate (100 g, 605 mmol) were suspended in 75 ml of 1,2-dichlorobenzene in a 500 ml, 3-necked round bottom flask equipped with a J-Kem temperature controller probe, a Dean-Stark trap, and a heating mantle. The reaction was heated to 165°C for 15 minutes, during which, water and some 1,2-dichlorobenzene was collected in the Dean-Stark trap. The reaction was allowed to cool to about 80°C. The flask was placed in an ice bath and about 300 ml of toluene was added and stirred. After about 30 minutes, a precipitate formed. The precipitate was filtered and washed 3 times with toluene, 3 times with hot water to remove excess pyrone, and dried in vacuo to give a tan solid (44.6 g, 28% yield). 1H NMR (400 MHz, DMSO-_i6) δ 10.66 (br s, IH), 7.80 (dd, 7= 7.72, 1.28 Hz, IH), 7.33 (dd, 7= 7.78, 1.34 Hz, IH), 5.91 (dd, 7= 2.41, 0.69 Hz, IH), 5.55 (d, 7 = 2.42 Hz, IH), 3.82 (s, 3H), 2.06 (s, 3H), 1.73 (s, 3H); LC/MS, tr = 1.85 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 274 (M+H). ES-HRMS m/z 274.1078 (M+H calcd for C15H15N04 requires 274.1074). Step 2: Preparation of methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]-2-methylbenzoate.
Figure imgf000408_0002
Methyl-3-(4-hydroxy-6-methyl-2-oxopyridin-l(2H)-yl)-2-methylbenzoate (from Step 1) (42.0 g, 154 mmol) was stirred briskly at room temperature with 2,4-difluorobenzyl bromide (19.7 ml, 154 mmol) and K2C03 (31.8 g, 231 mmol) in 250 ml of NN- dimethylformamide. After stirring overnight, the reaction was poured into 1 L of cold water. The solution was extracted 3 times with ethyl acetate and the organic layers were dried over MgS0 , and evaporated. The product was carried on to the next step as a crude
408 oil (60.4 g, 85%). 1H NMR (400 MHz, CDC13) δ 7.96 (dd, 7 = 7.85, 1.28 Hz, IH), 7.45 - 7.34 (m, 2H), 7.27 - 7.23 (m, IH), 6.94 - 6.84 (m, 2H), 5.98 (d, 7 = 2.68 Hz, IH), 5.92 (dd, 7= 2.69, 0.81 Hz, IH), 5.01 (s, 2H), 3.88 (s, 3H), 2.28 (s, 3H), 1.81 (s, 3H); LC/MS, tr = 2.96 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 400 (M+H). ES-HRMS m/z 400.1341 (M+H calcd for C22H19F2N04 requires 400.1355). Step 3. Preparation of 3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]-2-methylbenzoic acid.
Figure imgf000409_0001
Methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yι]-2- methylbenzoate (from Step 2) (60.0 mg, 150 mmol) was stirred with 2.5 N NaOH (120 ml, 300 mmol) in 375 ml of tetrahydrofuran and 75 ml of water at room temperature overnight. The reaction was acidified with 1 N HCl, 350 ml of water was added and the solution was extracted 3 times with ethyl acetate. The combined organic layers were dried over MgS04, filtered and evaporated. The resulting solid was filtered, washed with ethyl acetate and dried in vacuo to yield a white solid 33.8 g, 58%). 1H NMR (400 MHz, CDC13) δ 7.98 (dd, 7 = 7.92, 1.20 Hz, IH), 7.43 (app q, 7= 7.70 Hz, IH), 7.38 (t, 7= 7.72 Hz, IH), 7.35 (dd, 7 = 7.81, 1.21 Hz, IH), 6.92 - 6.84 (m, 2H), 6.17 (d, 7= 2.56 Hz, IH), 6.00 (dd, 7= 2.55, 0.81 Hz, IH), 5.05 (s, 2H), 2.30 (s, 3H), 1.84 (s, 3H); LC/MS, tr = 2.61 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES- MS m/z 386 (M+H). ES-HR MS m/z 386.1228 (M+H calcd for C2ιH17F2N04 requires 386.1198). Step 4: Preparation of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]-2-methylbenzoic acid.
Figure imgf000409_0002
409 3-[4-[(2,4-Difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-2-methylbenzoic acid (from Step 3) (23.0 g, 59.7 mmol) was stirred at room temperature with N- bromosuccinimide (12.74 g, 71.6 mmol) in 120 ml of CH2C12 for 2 hours. The reaction was evaporated on a rotary evaporator and the resulting solid was stirred in acetonitrile for 1 hour, washed 7 times with acetonitrile and dried in vacuo to yield a white solid (19.14 g, 69%). 1H ΝMR (400 MHz, DMSO- 6) δ 7.87 (dd, 7 = 7.52, 1.61 Hz, IH), 7.67 (app q, J = 7.92 Hz, IH), 7.45 - 7.37 (m, 2H), 7.33 (dt, 7 = 9.87, 2.54 Hz, IH), 7.17 (dt, 7= 8.50, 1.67 Hz, IH), 6.71 (s, IH), 5.32 (s, 2H), 2.08 (s, 3H), 1.86 (s, 3H); LC/MS, tr = 2.69 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES- MS m/z 464 (M+H). ES-HRMS m/z 464.0284 (M+H calcd for C21H16BrF2Ν04 requires 464.0304). Step 5: Preparation of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]-2-methyl-N-(2-morpholin-4-ylethyl)benzamide. 3-[3-Bromo-4- [(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl]-2-methylbenzoic acid (from Step 4 above) (500 mg, 1.08 mmol) was dissolved in 5 ml of CH2C12. 4-(2-
Aminoethyl)morpholine (170 μl, 1.29 mmol) was added, followed, in order, by EDCI (247 mg, 1.29 mmol), 1-hydroxybenzotriazole (174 mg, 1.29 mmol) and triethylamine (301 μl, 2.16 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with NHtCl and extracted 3 times with ethyl acetate. The combined organic layer was dried over MgS04 and evaporated. The resulting oil was triturated with diethyl ether hexane to obtain a solid, which was dried in vacuo to give a white solid (472 mg, 76%). 1H NMR (400 MHz, DMSO- 6) δ 7.64 (app q, 7 = 7.79 Hz, IH), 7.47 (dd, 7 = 7.65, 1.01 Hz, IH), 7.39 (t, 7= 7.75 Hz, IH), 7.17 (dd, 7= 7.65, 0.81 Hz, IH), 7.01 (dt, 7 = 8.26, 1.61 Hz, IH), 6.91 (dt, 7= 9.42, 2.32 Hz, IH), 6.49 (t, 7= 5.04 Hz, IH), 6.18 (s, IH), 5.30 (s, 2H), 3.73 (t, 7 = 4.53 Hz, 4H), 3.68 - 3.47 (m, 2H), 2.59 (t, 7 = 5.94 Hz, 2H), 2.51 (t, 7 = 4.33 Hz, 4H), 2.15 (s, 3H), 1.98 (s, 3H); LC/MS, tr = 2.27 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 576 (M+H). ES-HRMS m/z 576.1313 (M+H calcd for C27H28BrF2N304 requires 576.1304). Examples 329-337. Preparation of compounds corresponding in structure to the following formula:
410
Figure imgf000411_0001
The following compounds are prepared essentially according to the procedure set forth for Example 328: M+H ESHRMS Example No.R MF Requires m/z Ex. 329 τNHCH2CH2OCH3 C24H22BrF2N204 521.0882 521.0906 Ex. 330 -N(CH3)2 C23H20BrF2N2O3 491.0776 491.0752 Ex. 331 -NHCH2CH2OH C23H20BrF2N2O4 507.0726 507.0689 Ex. 332 -NHCH3 C22H18BrF2N203 477.0620 477.0585 Ex. 333 -N(CH3)CH2CH2OH C24H22BrF2N204 521.0882 521.0890 Ex. 334 4-methylpiperazin- 1 -yl C26H25BrF2N303 546.1198 546.1187 Ex. 335 morpholin-4-yl C25H2 BrF2N204 533.0882 533.0856 Ex. 336 -N(CH3)CH2CH2OCH3 C25H24BrF2N204 535.1039 535.1055 Ex. 337 -NH2 C21Hι6BrF2N203 463.0463 463.0492
NMR characterization of compounds of Examples 329-337
Figure imgf000411_0002
411 -
Figure imgf000412_0002
Example 338. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[3- (hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2(lH)-one
- 412 - 3-[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxoρyridin-l(2H)-yl]-2- methylbenzoic acid (Step 4 above) (2.0 g, 4.31 mmol) was cooled to 0°C in 10 ml of tetrahydrofuran. 19.5 ml of 1M BH3 THF in tetrahydrofuran was added and stirred overnight, allowing the temperature to rise to room temperature. The reaction was cooled back down to 0°C and ice chips were added to quench the reaction. The slurry was extracted 3 times with an ethyl acetate/tetrahydrofuran mixture. The combined organic layers were washed with brine, dried over MgS04, filtered and evaporated to give a white solid (1.73 g, 89%). 1H NMR (400 MHz, DMSO- ) δ 7.67 (app q, 7 = 7.92 Hz, IH), 7.46 (d, 7 = 7.52 Hz, IH), 7.32 (dt, 7= 10.74, 2.42 Hz, IH), 7.30 (t, 7= 7.72 Hz, IH), 7.17 (dt, 7= 8.46, 1.88 Hz, IH), 7.03 (d, 7= 7.38 Hz, IH), 6.68 (s, IH), 5.32 (s, 2H), 4.51 (s, 2H), 3.29 (d, 7 = 9.40 Hz, IH), 1.85 (s, 3H), 1.81 (s, 3H), LC/MS, tr = 2.64 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 450 (M+H). ES-HRMS m/z 450.0480 (M+H calcd for C21H18BrF2N03 requires 450.0511). Example 339. Preparation of 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]-N-(2-methoxyethyl)-2-methylbenzamide
Figure imgf000413_0001
Step 1. Preparation of 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]-2-methylbenzoic acid.
Figure imgf000413_0002
3-[4-[(2,4-Difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-2-methylbenzoic acid (Step 3 above) (10.0 g, 25.9 mmol) was refluxed with N-chlorosuccinimide (4.15 g, 31.1 mmol) and dichloroacetic acid (1.06 ml, 12.9 mmol) in 50 ml of CH2C12 overnight. The reaction was evaporated on a rotary evaporator and the resulting solid was stirred in acetonitrile for 30 minutes, washed 4 times with acetonitrile and dried in vacuo to yield a white solid (8.3 g, 78%). 1H ΝMR (300 MHz, DMSO-tf6) δ 7.93 (dd, 7 = 7.15, 1.92 Hz,
413 IH), 7.72 (app q, 7 = 7.92 Hz, IH), 7.52 - 7.35 (m, 3H), 7.22 (dt, 7 = 8.47, 2.01 Hz, IH), 6.80 (s, IH), 5.38 (s, 2H), 2.14 (s, 3H), 1.93 (s, 3H); LC/MS, tr = 2.64 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 420 (M+H). ES-HRMS m/z 420.0806 (M+H calcd for C21H16C1F2N04 requires 420.0809). Step 5. Preparation of 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]-N-(2-methoxyethyl)-2-methylbenzamide. 3-[3-Chloro-4-[(2,4- difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-2-methylbenzoic acid (from Step 1 above) (500 mg, 1.19 mmol) was dissolved in 5 ml of CH C12. 2-Methoxyethylamine (129 μl, 1.49 mmol) was added, followed, in order, by EDCI (286 mg, 1.49 mmol), 1- hydroxybenzotriazole (202 mg, 1.49 mmol) and triethylamine (332 μl, 2.38 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with NH C1 and extracted 3 times with ethyl acetate. The combined organic layer was dried over MgS0 and evaporated. The resulting solid was dried in vacuo to give a white solid (401 mg, 71%). 1H NMR (400 MHz, CDC13) δ 7.56 (app q, 7 = 7.74 Hz, IH), 7.47 (d, 7 = 6.98 Hz, IH), 7.34 (t, 7= 7.72 Hz, IH), 7.11 (d, 7 = 7.25 Hz, IH), 6.95 (dt, 7= 8.23, 1.66 Hz, IH), 6.87 (dt, 7= 9.51, 2.46 Hz, IH), 6.35 (br s, IH), 6.15 (s, IH), 5.25 (s, 2H), 3.72 - 3.63 (m, IH), 3.58 - 3.49 (m, 3H), 3.35 (s, 3H), 2.09 (s, 3H), 1.93 (s, 3H); LC MS, tr = 2.56 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z Ml (M+H). ES-HRMS m/z 477.1363 (M+H calcd for C24H23C1F2N204 requires 477.1387). Example 340. Preparation of 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-m
Figure imgf000414_0001
The title compound was prepared by a procedure similar to the one described for Example 337, where methylamine was used as the amine and the product was obtained in 73% yield. 1H NMR (300 MHz, DMSO-c/6) δ 8.37 (app d, 7 = 4.64 Hz, IH), 7.72 (app q, 7 = 7.92 Hz, IH), 7.44 - 7.35 (m, 4H), 7.22 (dt, 7= 8.54, 1.61 Hz, IH), 6.78 (s, IH), 5.37 (s, 2H), 2.79 (d, 7 = 4.43 Hz, 3H), 1.95 (s, 3H), 1.94 (s, 3H); LC MS, tr = 2.46 minutes (5 to
414 - 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 433 (M+H). ES-HRMS m/z 433.1163 (M+H calcd for C22H19C1F2N203 requires 433.1125). Example 341. Preparation of 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]-N-(2-hydroxyethyl)-2-methylbenzamide
Figure imgf000415_0001
The title compound was prepared by a procedure similar to the one described above, where ethanolamine was used as the amine and the product was obtained in 65% yield. 1H NMR (400 MHz, DMSO- 6) δ 8.39 (t, 7 = 5.51 Hz, IH), 7.67 (app q, 7 = 7.88 Hz, IH), 7.43 - 7.33 (m, 3H), 7.23 (d, 7= 7.25 Hz, IH), 7.17 (dt, 7= 8.39, 1.66 Hz, IH), 6.74 (s, IH), 5.32 (s, 2H), 3.48 (br s, 2H), 3.31 - 3.26 (m, 2H), 1.90 (s, 3H), 1.89 (s, 3H); LC/MS, tr = 2.34 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 463 (M+H). ES-HRMS m/z 463.1220 (M+H calcd for C23H21C1F2N204 requires 463.1231). Example 342. Preparation of 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]-2-methylbenzamide
Figure imgf000415_0002
3-[3-Chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-2- methylbenzoic acid (Step 1 above) (500 mg, 1.19 mmol) was stirred with 2-chloro-4,6- dimethoxy-l,3,5-triazine (251 mg, 1.43 mmol) and N-methylmorpholine (392 μl, 3.57 mmol) in 5 ml of tetrahydrofuran at room temperature for 2 hours. 2.5 ml of ΝH OH was added and stirred at room temperature for 2.5 hours. The reaction was diluted with tetrahydrofuran and ethyl acetate and extracted. The combined organic layers were washed with NaHC03, 1 N HCl, and brine, dried over MgS04, filtered and evaporated. The resulting solid was dried in vacuo to obtain a white solid (313 mg, 63%). 1H NMR (400 MHz, DMSO-de) δ 7.87 (br s, IH), 7.66 (q, 7 = 7.83 Hz, IH), 7.48 - 7.30 (m, 3H),
- 415 - 7.23 (d, 7 = 7.52 Hz, IH), 7.17 (t, 7 = 7.65 Hz, IH), 6.73 (s, IH), 5.32 (s, 2H), 1.94 (s, 3H), 1.88 (s, 3H); LC/MS, tr = 2.44 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 419 (M+H). ES-HRMS m z 419.0963 (M+H calcd for C21H17C1F2N203 requires 419.0969). Example 343. Preparation of 4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2- oxopyridin-l(2H)-yl]-3,5-difluorobenzonitrile
Figure imgf000416_0001
Step 1: Preparation of 4-[(2,4-difluorobenzyl)oxy]pyridine 1-oxide.
Figure imgf000416_0002
2, 4-Difluorobenzyl alcohol (100. g, 0.694 mol) and 4-nitropyridine N-oxide (98. g, 0.700 mol)are combined with 250 g Cs2C03 (1.1 eq) in 2.5 L anhydrous dimethylformamide and heated to 80°C with stirring. The reaction was followed by 19F-NMR (crude reaction mixture with external D20 reference) and complete after 40 h. The mixture was filtered hot; product crystallized out on cooling. 90.21 g (55%) of white plates were collected by filtration and washed with diethyl ether. The mother liquor was diluted with 2.5 L diethyl ether and stored in the freezer overnight, yielding a second crop 68.76 g (41%, combined yield 96%). 1H-NMR (400 MHz, DMSO- 6) δ 8.06 (m, 2 H), 7.61 (quartet, 7= 8.45 Hz, IH), 7.30 (t, 7= 10.37 Hz,lH), 7.12, (t, 7= 8.45 Hz, IH), 7.09 (d, 7= 5.06 Hz, 2H), 5.14 (s, 2H). I9F-NMR (400 MHz, DMSO- 6) δ -109.43 (quintet, 7 = 7.78 Hz, IF), -113.82 (quartet, 7 = 9.55 Hz, IF). LC/MS tr = 3.90 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50°C) ES-MS m/z 238 (M+H). Step 2. Preparation of 4-[(2,4-difluorobenzyl)oxy]-pyridin-2(lH)-one.
416
Figure imgf000417_0001
4-[(2,4-difluorobenzyl)oxy]pyridine 1-oxide (from Step 1) (30.0 g , 0.127 mol), anhydrous potassium acetate (25 g, 0.25 mol), acetic anydride (25 g, 0.25 mol), and 10 ml acetic acid were combined in a 250-ml round-bottomed flask with overhead stirring and heated to 130°C for 4 hours. The mixture was concentrated under vacuum, the solids dissolved in 95 ml acetonitrile: 5 ml water, filtered through charcoal and poured into 600 ml ice with stirring. The mixture was allowed to stand overnight at room temperature, then 9.62 g (30%) product collected by filtration as a medium brown solid (adequate for the next step without purification). 1H-NMR (400 MHz, DMSO-d6) δ 11.10 (s, IH), 7.59 (quartet, 7 = 9.91 Hz, IH), 7.29 (t, 7= 10.36 Hz, IH), 7.21 (d, 7= 8.20 Hz, IH), 7.11 (t, 7 = 8.48 Hz, IH), 5.83 (m, 2H), 5.02 (s, 2H). 19F-NMR (400 MHz, DMSO- 6) δ -109.57(quintet, 7 = 7.66 Hz, IF) -113.88 (quartet, 7 = 8.93 Hz, IF). LC/MS tr = 4.29 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 254 nm, at 50°C) ES-MS m/z 238 (M+H). Step 3: Preparation of 3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(lH)-one
Figure imgf000417_0002
4-[(2,4-difluorobenzyl)oxy]-pyridin-2(lH)-one (from Step 2) (8.60 g, 36.3 mmol) was stirred in 150 ml dimethylformamide and treated with N-chlorosuccinimide (5.4 g, 39.9 mmol). After 15 hours, the precipitate was collected by filtration (5.11 g, 52%) yeilding a lustrous white solid. The mother liquor was diluted to 500 ml with diethyl ether, providing 2.47 g (25%) in a second crop. 1H-NMR (400 MHz, DMSO- 6) δ 11.87 (s, IH), 7.60 (quartet, 7 = 6.34 Hz, IH), 7.43 (d, 7= 7.58 Hz, IH), 7.31 (dt, 7= 10.08, 2.21 Hz, IH), 7.14 (dt, 7 = 8.65, 1.79 Hz, IH), 6.44 (d, 7= 7.49 Hz, IH), 5.28 (s, IH). I9F-NMR (400 MHz, DMSO- ) δ -109.58 (quintet, 7 = 7.75 Hz, IF), -113.68 (quartet, 7 = 8.68 Hz, IF). LC/MS tr = 4.47 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 254 nm, at 50°C) ES-MS m/z 272, 274 3:1 (M+H). - 417 - Step 4. Preparation of 4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- l(2H)-yl]-3,5-difluorobenzonitrile. 3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(lH)- one (from step 3) (3.25 g, 11.9 mmol) was combined with Cs2C03 (3.93 g, 12.1 mmol) in 50 ml dimethylformamide and heated to 70°C, stirring under nitrogen. 3,4,5- trifluorobenzonitrile (1.83 g, 11.9 mmol) was added. After 4 hours, the mixture was filtered, concentrated in vacuo, washed thrice with hot cyclohexane, dissolved in tetrahydrofuran, treated with MgS0 and charcoal, and filtered. The solution was evaporated leaving a fine white solid (3.99 g, 82%). 1H-NMR (400 MHz, DMSO- 6) δ 8.12 (d, 7= 7.59 Hz, 2H), 7.92 (d, 7 = 8.31 Hz, IH), 7.65 (quartet, 7 = 6.77, IH), 7.34 (dt, 7= 9.81, 2.71 Hz, IH), 7.16 (dt, 7= 8.59, 2.50 Hz, IH), 6.87 (d, 7= 8.01 Hz, IH), 5.39 (s, 2H). 19F-NMR (400 MHz, DMSO- ) δ -109.17 (quintet, 7= 8.97 Hz, IF), - 113.51 (quartet, 7= 9.53 Hz, IF), -116.32 (d, 7= 7.69 Hz, 2F). LC/MS tr = 5.51 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50°C) ES-MS m/z 409 (M+H). ES-HRMS m/z 409.0351 (M+H calcd for C19Hι0ClF N2O2 requires 409.0361). Example 344. Preparation of l-[4-(aminomethyl)-2,6-difluorophenyl]-3- chIoro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(lH)-one hydrochloride
Figure imgf000418_0001
Step 1. Preparation of tert-butyl 4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2- oxopyridin-l(2H)-yl]-3,5-difluorobenzylcarbamate.
Figure imgf000418_0002
4- [3 -chloro-4- [(2,4-difluorobenzyl)oxy] -2-oxopyridin- 1 (2H)-yl] -3 ,5-difluorobenzonitrile (2.84 g, 6.95 mmol), di-t-butyl-dicarbonate (3.18 g, 14.6 mmol), and nickel(ϊι) chloride (0.90 g, 6.95 mmol) were combined with 40 ml methanol and 40 ml tetrahydrofuran and
418 cooled to 0°C stirring in an ice bath. Sodium borohydride (1.3,3 g, 35.2 mmol) was added in small portions over 10 minutes to control foaming, and the reaction was stirred 1 hour. Additional sodium borohydride (0.50 g, 13.2 mmol) was required to force the reaction to completion by LC. A color change from yellow to black persisted on completion. The mixture was filtered through a bed of charcoal layered on anhydrous MgS04 and evaporated to dryness. Excess di-t-butyl-dicarbonate and byproduct t-butanol were removed by repeated heating with water to 80°C in vacuo, giving the product as a fine white powder (3.11 g, 87%). 1H-NMR (400 MHz, DMSO- 6) δ 7.89 (d, 7 = 8.04 Hz, IH), 7.65 (quartet, 7 = 6.73 Hz, IH), 7.55 (t, 7 = 6.73 Hz,lH), 7.34, (dt, 7= 10.05, 2.51 Hz, IH), 7.16 (m, 3H), 6.77 (d, 7 = 8.18 Hz, IH), 5.34 (s, 2H), 4.18 (d, 7 = 5.68 Hz, 2H), 1.34 (s, 9H). l9F-NMR (400 MHz, DMSO- ) δ -109.26 (quintet, 7 = 6.91 Hz, IF), -113.53 (quartet, 7 = 7.73 Hz, IF), -120.32(d, 7 = 8.91 Hz, 2F). LC/MS tr = 5.90 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50°C) ES-MS m/z 513 (M+H). ES-HRMS m/z 513.1164 (M+H calcd for C24H22C1F4N204 requires 513.1199). Step 2: Preparation of l-[4-(aminomethyl)-2,6-difluorophenyl]-3-chloro-4- [(2,4-difluorobenzyl)oxy]pyridin-2(lH)-one hydrochloride. Tert-butyl 4-[3-chloro-4- [(2,4-difluorobenzyl)oxy]-2-oxopyridin- l(2H)-yl]-3,5-difluorobenzylcarbamate (from step 3) (1.39 g, 2.71 mmol) was dissolved in 20 ml tetrahydrofuran and treated with 4 ml concentrated hydrochloric acid. The solution was evaporated and dried in vacuo to a fine white solid (1.20 g, 99%). 1H-NMR (400 MHz, DMSO- 6) δ 8.54 (m, 2H), 7.86 (d, 7 = 7.57 Hz, IH), 7.65 (quartet, 7 = 7.62, IH), 7.50 (d, 7 = 9.25 Hz, 2H), 7.34 (dt, 7 = 10.50, 2.45 Hz, IH), 7.16 (dt, 7 = 8.38, 2.55 Hz, IH), 6.78 (d, 7= 7.86 Hz, IH), 5.37 (s, 2H), 4.10 (br s, 2H), 4.97-3.14 (v br s, 3H). 19F-NMR (400 MHz, DMSO-d6) δ -109.21 (quintet, 7 = 7.77 Hz, IF), -113.51 (quartet, 7 = 8.95 Hz, IF), -119.56 (d, 7= 9.44 Hz, 2F). LC/MS tr = 4.33 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50°C) ES-MS m/z 413 (M+H). ES-HRMS m/z 413.0712 (M+H calcd for Cι9Hι4ClF4N202 requires 413.0674). Example 345. Preparation of 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{2,6- difluoro-4- [(methylamino)methyl]phenyl}pyridin-2(lH)-one hydrochloride
419
Figure imgf000420_0001
Step 1. Preparation of tert-butyl 4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2- oxopyridin-l(2H)-yl]-3,5-difluorobenzyl(methyl)carbamate.
Figure imgf000420_0002
Tert-butyl 4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]-3,5- difluorobenzylcarbamate (from Step 1) (252 mg, 0.491 mmol) and iodomethane (75 mg, 0.528 mmol) are combined in 8 ml anhydrous dimethylformamide. Sodium hydride 60% in mineral oil (30 mg, 0.75 mmol) was added and the mixture stirred under nitrogen at room temperaure for 1 hour. Saturated aqueous NH C1 was added (4 ml) followed by 20 ml water and the product was extracted into ethyl acetate, washed with brine, dried over MgS04, filtered, and evaporated to give the product as a white powder (208 mg, 80%). 1H-NMR (400 MHz, DMSO-d6) δ 7.87 (d, 7 = 7.85 Hz, IH), 7.64 (quartet, 7 = 6.66 Hz, IH), 7.32, (dt, 7= 9.39, 3.29 Hz, IH), 7.13 (m, 3H), 6.77 (d, 7= 7.94 Hz, 1), 5.38 (s, 2H), 4.43 (s, 2H), 2.90 (s, 3H), 1.40 (br m, 9H). 19F-NMR (400 MHz, DMSO- 6) δ -109.25 (quintet, 7 = 8.93 Hz, IF), -113.53 (quartet, 7 = 9.73 Hz, IF), -119.89(d, 7 = 9.35 Hz, 2F). LC/MS tr = 6.16 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes, then 95% acetonitrile for 2 minutes, at 1 ml/min with detection at 215 nm, at 50°C) ES-MS m/z 527 (M+H). ES-HRMS m/z 527.1338 (M+H calcd for C25H24C1F4N204 requires 527.1355). Step 2. Preparation of 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{2,6-difluoro-4-
[(methylamino)methyl]phenyl}pyridin-2(lH)-one hydrochloride. Tert-butyl 4-[3- chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]-3,5- difluorobenzyl(methyl)carbamate (from step 1) (188 mg, 0.357 mmol) was subjected to the conditions of Step 2, yielding a fine white solid (165 mg, 100%). 1H-NMR (400
- 420 MHz, DMSO- 6) δ 9.30 (br s, 2H), 7.89 (d, 7 = 7.99 Hz, IH), 7.65 (quartet, 7 = 7.64, IH), 7.55 (d, 7 = 8.66 Hz, 2H), 7.34 (dt, 7= 9.93, 2.57 Hz, IH), 7.17 (dt, 7= 8.49, 2.48 Hz, IH), 6.81 (d, 7= 8.01 Hz, IH), 5.39 (s, 2H), 4.21 (s, 2H), 2.56 (s, 3H). 19F-NMR (400 MHz, DMSO- ) δ -109.20 (quintet, 7= 7.56 Hz, IF), -113.52(quartet, 7= 9.67 Hz, IF), - 119.21 (d, 7 = 8.79 Hz, 2F). LC/MS tr = 4.30 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50°C) ES-MS m/z 427 (M+H). ES-HRMS m/z 427.0816 (M+H calcd for C20H16ClF4N2O2 requires 427.0831). Example 346. Preparation of 3-chloro-l-(4- {[(cyclopropylmethyl)amino]methyl}-2,6-difluorophenyl)-4-[(2,4- difluorobenzyl)oxy]pyridin-2(lH)-one hydrochloride
Figure imgf000421_0001
The title compound was prepared by direct analogy with procedures described above for 3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 - { 2,6-difluoro-4- [(methylamino)methyl]phenyl}pyridin-2(lH)-one hydrochloride, replacing iodomethane with bromocyclopropylmethane and extending the reaction time to 6 hours in Step 1. Step 1. Preparation of tert-butyl 4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2- oxopyridin-l(2H)-yl]-3,5-difluorobenzyl(cyclopropylmethyl)carbamate
Figure imgf000421_0002
1H-NMR (400 MHz, DMSO- 6) δ 7.89 (d, 7= 7.91 Hz, IH), 7.65 (quartet, 7= 6.81 Hz, IH), 7.33, (dt, 7= 9.90, 2.26 Hz, IH), 7.17 (m, 3H), 6.77 (d, 7 = 7.90 Hz, 1), 5.38 (s, 2H), 4.51 (s, 2H), 3.10 (br s, 2H), 1.36 (m, 9H), 0.97 (br s, IH), 0.38 (m, 2H), 0.18 (m, 2H). 19F-NMR (400 MHz, DMSO-d6) δ -109.25 (quintet, 7 = 7.77 Hz, IF), -113.54 (quartet, 7 = 9.02 Hz, IF), -120.24(m, 2F). LC/MS tr = 5.99 minutes (0-95% acetonitrile/water, 0.05%
- 421 - trifluoroacetic acid, over 6 minutes, then 95% acetonitrile for 2 minutes, at 1 ml/min with detection at 215 nm, at 50°C) ES-MS m/z 567 (M+H). ES-HRMS m/z 567.1653 (M+H calcd for C28H28C1F4N204 requires 567.1668). Step 2. Preparation of 3-chloro-l-(4-{[(cyclopropylmethyl)amino]methyl}-2,6- difluorophenyl)-4-[(2,4-difluorobenzyl)oxy]pyridin-2(lH)-one hydrochloride. 1H- NMR (400 MHz, DMSO- ) δ 9.51 (br s, 2H), 7.87 (d, 7= 7.96 Hz, IH), 7.63 (m, 3H), 7.33 (dt, 7= 9.93, 2.65 Hz, IH), 7.16 (dt, 7= 8.36, 2.32 Hz, IH), 6.81 (d, 7 = 7.92 Hz, IH), 5.38 (s, 2H), 4.22 (br s, 2H), 2.82 (br s, 2H), 1.10 (m, IH), 0.57 (m, 2H), 0.36 (m, 2H). 19F-NMR (400 MHz, DMSO- 6) δ -109.25 (quintet, 7 = 7.69 Hz, IF), - 113.54(quartet, 7 = 9.35 Hz, IF), -120.24 (m, 2F). LC MS tr = 4.55 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50°C) ES-MS m/z 467 (M+H). ES-HRMS m/z 467.1119 (M+H calcd for C23H20ClF4N2O2 requires 467.1144). Example 347. Preparation of 4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2- oxopyridin-l(2H)-yl]-3,5-difluoro-N^V-dimethylbenzamide
Figure imgf000422_0001
Step 1: Preparation of 4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- l(2H)-yl]-3,5-difluorobenzamide
Figure imgf000422_0002
4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]-3,5-difluorobenzonitrile (540 mg, 1.32 mmol) and potassium trimethylsilonate 90% (375 mg, 2.63 mmol) are combined in 8 ml anhydrous toluene and heated to reflux with stirring. After 10 minutes, the mixture allowed to cool then partitioned between saturated aqueous ammonium chloride and ethyl acetate. The aqueous layer is extracted twice with ethyl acetate, the - 422 - combined organics are washed with brine, dried over MgS0 , and evaporated in vacuo. The crude product is taken up in tetrahydrofuran and filtered through charcoal layered over silica gel, and the solution evaporated in vacuo to give the product as a white powder (468 mg, 83%). 1H-NMR (400 MHz, DMSO- 6) δ 8.22 (br s, 2H), 7.92 (d, 7 = 7.84 Hz, IH), 7.78 (d, 7 = 8.45, 2H), 7.65 (quartet, 7 = 8.40 Hz, IH), 7.34, (dt, 7 = 10.09, 2.58 Hz, IH), 7.17 (dt, 7= 8.72, 2.30 Hz, IH), 6.83 (d, 7= 7.91 Hz, IH), 5.39 (s, 2H). 19F-NMR (400 MHz, DMSO- 6) δ -109.21 (quintet, 7 = 7.43 Hz, IF), -113.52 (quartet, 7 = 9.62 Hz, IF), -118.74 (d, 7= 8.88 Hz, 2F). LC MS tr = 4.67 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes, then 95% acetonitrile for 2 minutes, at 1 ml/min with detection at 215 nm, at 50°C) ES-MS m/z 427 (M+H). ES-HRMS m/z 427.0454 (M+H calcd for C19H12C1F4N203 requires 427.0467). Step 2. Preparation of 4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- l(2H)-yl]-3,5-difluoro-N^V-dimethylbenzamide. 4-[3-chloro-4-[(2,4- difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]-3,5-difluorobenzamide (from step 1) (243 mg, 0.357 mmol) was subjected to the conditions of Step 1, with the exception that two equivalents of sodium hydride 60% in mineral oil and iodomethane were used instead of one (46 mg, 0.69 mmol and 103 mg, 0.724 mmol respectively). Η-NMR (400 MHz, DMSO-J6) δ 7.92 (d, 7= 7.76 Hz, IH), 7.66 (quartet, 7= 7.33, IH), 7.44 (d, 7= 7.59 Hz, 2H), 7.34 (dt, 7= 9.88, 2.63 Hz, IH), 7.17 (dt, 7= 8.35, 2.06 Hz, IH), 6.83 (d, 7= 7.55 Hz, IH), 5.39 (s, 2H), 2.98 (s, 3H), 2.91 (s, 3H). 19F-NMR (400 MHz, DMSO-d6) δ -
109.22 (quintet, 7 = 8.10 Hz, IF), -113.53(quartet, 7 = 9.18 Hz, IF), -118.88 (d, 7 = 7.77 Hz, 2F). LC/MS tr = 5.13 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50°C) ES-MS m/z 455 (M+H). ES-HRMS m/z 455.0791 (M+H calcd for C21H16C1F4N203 requires 455.0780). Example 348. Preparation of 4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2- oxopyridin-l(2H)-yl]-3-fluoro-5-methoxybenzonitrile
Figure imgf000423_0001
423 Step 1. Preparation of 4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- l(2H)-yl]-3-fluoro-5-hydroxybenzonitrile.
Figure imgf000424_0001
4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]-3,5-difluorobenzonitrile (522 mg, 1.28 mmol) and potassium trimethylsilonate 90% (655 mg, 4.60 mmol) are combined in 8 ml anhydrous tetrahydrofuran and stirred under nitrogen at room temperature for 2 hours. The precipitated potassium salt was collected by filtration, washed with a minimum of tetrahydofuran, and dried in vacuo. A portion of this salt (275 mg, 0.618 mmol) was dissolved in 5 ml water, the pH was adjusted below 6 with concentrated hydrochloric acid, the product collected by filtration, washed with water, sucked dry under a blanket of dry nitrogen, and dried further in vacuo overnight (251 mg, 100%, 98% overall). 1H-NMR (400 MHz, DMSO- ) δ 11.46 (br s, IH), 7.74 (d, 7 = 7.81 Hz, IH), 7.67 (quartet, 7 = 6.76 Hz, IH), 7.52 (d, 7= 8.76, IH), 7.364, (dt, 7= 10.18, 2.37 Hz, IH), 7.24 (br s, IH), 7.17 (br t, 7= 8.75, IH), 6.74 (d, 7 = 8.04 Hz, IH), 5.39 (s, 2H). 19F-NMR (400 MHz, DMSO-dg) δ -109.26 (quintet, 7 = 8.50 Hz, IF), -113.52 (quartet, 7 = 9.29 Hz, IF), -118.06 (d, 7= 9.38 Hz, IF). LC/MS tr = 5.13 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes, then 95% acetonitrile for 2 minutes, at 1 ml/min with detection at 215 nm, at 50°C) ES-MS m/z 407 (M+H). ESHRMS m/z 407.0381 (M+H calcd for
Figure imgf000424_0002
requires 407.0405). Step 2. Preparation of 4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- l(2H)-yl]-3-fluoro-5-methoxybenzonitrile. The potassium salt of 4-[3-chloro-4-[(2,4- difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]-3-fluoro-5-hydroxybenzonitrile (from Step 1) (273 mg, 0.614 mmol) was stirred in 5 ml anhydrous dimethylformamide under nitrogen. Iodomethane (93 mg, 0.66 mmol) was added, and stirring continued for 2 hr. The mixture was diluted to 50 ml with ice-cold water, and the white precipitate collected by filtration. The precipitate was washed thrice with water, sucked dry under a blanket of nitrogen, and dried further in vacuo overnight (242 mg, 87%). Η-NMR (400 MHz, DMSO-d6) δ 7.73 (m, 2H), 7.65 (m, 2H), 7.34 (dt, 7= 9.90, 2.39 Hz, IH), 7.17 (dt, 7= 8.75, 2.47 Hz, IH),
- 424 - 6.75 (d, 7= 7.97 Hz, IH), 5.37 (s, 2H), 3.84 (s, 3H). 19F-NMR (400 MHz, DMSO-d6) δ - 109.24 (quintet, 7= 7.85 Hz, IF), -113.54(quartet, 7= 9.83 Hz, IF), -118.33 (d, 7= 7.77 Hz, IF). LC/MS tr = 5.40 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50°C) ES-MS m/z 421 (M+H). ES-HRMS m/z 421.0522 (M+H calcd for C2oH13ClF3N2θ3 requires 421.0561). Example 349. Preparation of N-{4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2- oxopyridin-l(2H)-yl]-3,5-difluorobenzyl}urea
Figure imgf000425_0001
l-[4-(aminomethyl)-2,6-difluorophenyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin- 2(lH)-one hydrochloride (162 mg, 0.361 mmol) is dissolved in 4 ml 50% aqueous acetic acid and treated with potassium cyanate (59 mg, 0.72 mmol). The mixture was stirred 2 hr, then the mixture was diluted to 50 ml with cold water, and the crude product, contaminated with the acetamide, was purified by silica gel chromatography, eluting first with 20% ethanol in hexane then 40% ethanol in hexane. The 50% fractions were pooled by TLC and evaporated, giving the product as a fine white powder (65 mg, 40%). 1H- NMR (400 MHz, DMSO- 6) δ 7.87 (d, 7= 8.07 Hz, IH), 7.64 (quartet, 7 = 6.53 Hz, IH), 7.33, (dt, 7= 9.47, 1.99 Hz, IH), 7.15 (m, 3H), 6.76 (d, 7 = 7.97 Hz, IH), 6.59 (m, IH), 5.65 (br s, 2H), 5.38 (s, 2H), 4.22 (m, 2H). 19F-NMR (400 MHz, DMSO- 6) δ -109.22 (quintet, 7= 7.86 Hz, IF), -113.51 (quartet, 7 = 9.40 IF), -120.65 (d, 7= 8.75 Hz, 2). LC/MS tr = 4.85 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50°C) ES-MS m/z 456 (M+H). Example 350. Preparation of 2-({4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2- oxopyridin-l(2H)-yl]-3,5-difluorobenzyl}amino)-l,l-dimethyl-2-oxoethyl acetate
Figure imgf000425_0002
- 425 l-[4-(aminomethyl)-2,6-difluorophenyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin- 2(lH)-one hydrochloride (225 mg, 0.501 mmol) is dissolved in a solution of 10 ml tetrahydrofuran and triethylamine (111 mg, 1.10 mmol). 2-acetoxy-2-methyl-propionyl chloride (85 mg, 0.516 mmol) is added, and the mixture stirred for 30 minutes before partitioning between saturated aqueous ammoniom chloride and ethyl acetate. The layers are seperated, and the aqueous phase extracted twice with ethyl acetate. Υ e{ combined organics are washed with water and brine, then dried over MgS04, filtered, and evaporated in vacuo, giving the product as a fine white powder (254 mg, 94%). 1H-NMR (400 MHz, DMSO- 6) δ 8.47 (t, 7= 6.16 Hz, IH), 7.88 (d, 7 = 7.71 Hz, IH), 7.65 (quartet, 7= 7.24 Hz, IH), 7.34, (dt, 7 = 10.04, 2.49 Hz, IH), 7.16 (m, 3H), 6.77 (d, 7 = 7.78 Hz, IH), 5.38 (s, 2H), 4.32 (d, 7 = 5.93 2H), 2.02 (s, 3H), 1.48(s, 6H). 19F-NMR (400 MHz, DMSO- 6) δ -109.26 (quintet, 7= 9.00 Hz, IF), -113.52 (quartet, 7 = 9.52 Hz, IF), -120.62 (d, 7 = 9.09 Hz, 2F). LC/MS tr = 5.43 minutes (0-95%o acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50°C) ES-MS m/z 541 (M+H). ES-HRMS m/z 541.1128 (M+H calcd for C25H22C1F4N205 requires 541.1148). Example 351. Preparation of N-{4-[3-chloro-4-[(2,4-difluorobenzyI)oxy]-2- oxopyridin-l(2H)-yl]-3,5-difluorobenzyl}acetamide
Figure imgf000426_0001
The compound was prepared in the following the produre for Example 350, substituting acetyl chloride (24 mg, 0.30 mmol) for 2-acetoxy-2-methyl-propionyl chloride. (128 mg, 96%). Η-NMR (400 MHz, DMSO- 6) δ 8.48 ( br s, IH), 7.87 (d, 7= 7.28 Hz, IH), 7.64 (quartet, 7= 8.01 Hz, IH), 7.33, (dt, 7= 9.87, 2.25 Hz, IH), 7.17 (m, 3H), 6.76 (d, 7 = 8.25 Hz, IH), 5.38 (s, 2H), 4.30 (m, 2H), 1.88(s, 3H). 19F-NMR (400 MHz, DMSO- ) δ -109.22 (quintet, 7= 8.04 Hz, IF), -113.52 (quartet, 7= 9.91 Hz, IF), -120.43 (d, 7= 8.77 Hz, 2F). LC/MS tr = 5.04 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50°C) ES-MS m/z 555 (M+H). ES-HRMS m/z 455.0824 (M+H calcd for C21Hι6ClF4N203 requires 455.0780).
- 426 Example 352. Preparation of N-{4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2- oxopyridin-l(2H)-yl]-3,5-difluorobenzyl}-2-methoxyacetamide
Figure imgf000427_0001
The compound was prepared in the following the produre for EXAMPLE 350, substituting 2-methoxy-acetyl chloride (45 mg, 0.415 mmol) for 2-acetoxy-2-methyl-propionyl chloride. (124 mg, 78%). 1H-NMR (400 MHz, DMSO- 6) δ 8.56 (t, 7= 6.77 Hz, IH), 7.90 (d, 7 = 7.85 Hz, IH), 7.67 (quartet, 7 = 7.67 Hz, IH), 7.36, (dt, 7= 10.03, 2.36 Hz, IH), 7.20 (m, 3H), 6.79 (d, 7 = 8.07 Hz, IH), 5.40 (s, 2H), 4.37 (d, 7 = 6.28 Hz, 2H), 3.91(s, 2H), 3.35 (s, 3 H). 19F-NMR (400 MHz, DMSO- 6) δ -109.23 (quintet, 7= 8.29 Hz, IF), -113.50 (quartet, 7 = 9.36 Hz, IF), -120.43 (d, 7= 9.07 Hz, 2F). LC/MS tr = 5.13 miinutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50°C) ES-MS m/z 485 (M+H). ES-HRMS m/z 485.0856 (M+H calcd for C22H18C1F4N204 requires 485.0886). Example 353. Preparation of N-{4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2- oxopyridin-l(2H)-yl]-3,5-difluorobenzyl}-2-furamide
Figure imgf000427_0002
The compound was prepared in the following the produre for Example 350, substituting furoyl chloride (62 mg, 0.48 mmol) for 2-acetoxy-2-methyl-propionyl chloride. Yield: 142 mg, 85%. 1H-NMR (400 MHz, DMSO- ) δ 9.07 (t, 7= 6.14 Hz, IH), 7.90 (d, 7= 7.88 Hz, IH), 7.87 (dd, 7 = 1.69, 0.80 Hz, IH), 7.67 (td, 7 = 8.46, 6.80 Hz, IH), 7.35, (dt, 7 = 10.00, 2.81 Hz, IH), 7.26 (d, 7= 8.78 Hz, 2H), 7.18 (ddt, 7 = 8.58, 2.30, 1.07 Hz, IH), 7.16 (dd, 7 = 3.52, 0.77 Hz, IH), 6.79 (d, 7= 8.07 Hz, IH), 6.64 (dd, 7= 3.16, 1.73 Hz, IH), 5.40 (s, 2H), 4.49 (d, 7 = 6.13 Hz, 2H). 19F-NMR (400 MHz, DMSO- 6) δ -109.23 (quintet, 7 = 7.65 Hz, IF), -113.50 (quartet, 7= 9.84 Hz, IF), -120.29 (d, 7= 9.41 Hz, 2F). LC/MS tr = 5.32 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6
- 427 - minutes at 1 ml/min with detection at 215 nm, at 50°C) ES-MS m/z 507 (M+H). ESHRMS m/z 507.0716 (M+H calcd for C24H16C1F4N204 requires 507.0729). Example 354. Preparation of N-{4-[3-chloro-4-[(2,4-difluorobenζyl)oxy]-2- oxopyridin-l(2H)-yl]-3,5-difluorobenzyl}-lH-imidazole-4-carboxamide
Figure imgf000428_0001
Step 1 : Preparation of the title compound l-[4-(aminomethyl)-2,6-difluorophenyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]pyridin- 2(lH)-one hydrochloride (150 mg, 0.334 mmol) is dissolved in a solution of 4 ml tetrahydrofuran and triethylamine (35 mg, 0.35 mmol). 4-imidazolecarboxylic acid (62 mg, 0.56 mmol), 1-hydroxybenzotriazole hydrate (90 mg, 0.67 mmol), l-[3-
(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (128 mg, 0.668 mmol), and triethylamine (100. mg, 0.989 mmol) were combined in 5 ml tetrahydrofuran and stirred under nitrogen. The solution containing l-[4-(aminomethyl)-2,6-difluorophenyl]-3- chloro-4-[(2,4-difluorobenzyl)oxy]pyridin-2(lH)-one hydrochloride was added in one portion, rinsing with 2 ml tetrahydrofuran. Stirring was continued at room temperature overnight, then the reaction was poured into 90 ml of icewater, and the product collected by filtration and dired in vacuo (254 mg, 94%). 1H-NMR (400 MHz, DMSO-d6) δ 12.55 (br s, IH), 8.73 (t, 7= 6.57 Hz, IH), 7.90 (d, 7 = 7.87 Hz, IH), 7.75 (s, IH), 7.67 (m, 2H), 7.35, (dt, 7= 10.04, 2.54 Hz, IH), 7.21 (m, 3H), 6.78 (d, 7= 8.04 Hz, IH), 5.39 (s, 2H), 4.47 (m, 2H). 19F-NMR (400 MHz, DMSO- ) δ -109.26 (quintet, 7 = 7.87 Hz, IF), -
113.52 (quartet, 7 = 9.30 Hz, IF), -120.59 (d, 7 = 9.21 Hz, 2F). LC/MS tr = 4.48 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50°C) ES-MS m/z 507 (M+H). ES-HRMS m/z 507.0818 (M+H calcd for C23Hι6ClF4N403 requires 507.0842). Example 355. Preparation of N-{4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2- oxopyridin-l(2H)-yl]-3,5-difluorobenzyl}-5-oxoprolinamide
428
Figure imgf000429_0001
The compound was prepared following the procedure for Example 354, substituting 2- pyrrolidone-5-carboxylic acid for 4-imidazolecarboxylic acid. 1H-NMR (400 MHz, DMSO- 6) δ 8.67 (t, 7= 6.08 Hz, IH), 7.88 (m, IH), 7.65 (qr, 7= 7.57, IH), 7.34, (dt, 7 =
5. 9.32, 2.63 Hz, IH), 7.22 (d, 7 = 9.36, 2H), 7.17 (dt, 7 = 8.51, 2.55 Hz, IH), 6.77 (d, 7 = 7.66 Hz, IH), 5.73 (s, IH), 5.38 (s, 2H), 4.35 (d, 7 = 5.74, 2H), 4.05 (m, IH), 2.15 (m, 2H), 1.90 (m, 2H). I9F-NMR (400 MHz, DMSO-d6) δ -109.25 (quintet, 7 = 7.72 Hz, IF), -113.52 (quartet, 7= 8.94 Hz, IF), -120.39 (d, 7= 9.11 Hz, 2F). LC/MS tr = 4.81 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with0 detection at 215 nm, at 50°C) ES-MS m/z 524 (M+H). ES-HRMS m/z 524.0998 (M+H calcd for C24H19C1F4N304 requires 524.0995). Example 356. Preparation of
Figure imgf000429_0002
N- { 4- [3 -chloro-4- [(2 ,4-difluorobenzyl)oxy] -2-oxopyridin- 1 (2H)-yl]-3 ,5-difluorobenzyl } -5 3-hydroxy-3-methylbutanamide
Step 1: Preparation of the title compound The compound was prepared following the procedure for , substituting 2-hydroxy-2- methyl butyric acid for 4-imidazolecarboxylic acid. 1H-ΝMR (400 MHz, DMSO- 6) δ0 8.43 (t, 7= 6.04 Hz, IH), 7.88 (d, 7 = 8.01, IH), 7.65 (qr, 7= 6.84, IH), 7.34, (dt, 7 = 10.13, 2.55 Hz, IH), 7.22 (d, 7= 8.74, 2H), 7.16 (dt, 7= 8.57, 2.45 Hz, IH), 6.77 (d, 7 = 7.89 Hz, IH), 5.38 (s, 2H), 4.75 (s, 0.5H (OH)), 4.35 (d, 7= 6.48, 2Η), 2.28 (s, 2H), 1.47 (s, 0.5H(OH)), 1.16 (s, 6Η). I9F-NMR (400 MHz, DMSO- 6) δ -109.26 (quintet, 7 = 7.79
- 429 Hz, IF), -113.53 (quartet, 7 = 9.23 Hz, IF), -120.49 (d, 7 = 9.39 Hz, 2F). LC/MS tr = 5.08 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50°C) ES-MS m/z 513 (M+H). ES-HRMS m/z 513.1177 (M+H calcd for C24H22C1F4N204 requires 513.1199). Example 357. Preparation of iV-{4-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2- oxopyridin-l(2H)-yl]-3,5-difluorobenzyl}-l-hydroxycyclopropanecarboxamide
Figure imgf000430_0001
The compound was prepared following the procedure for , substituting 1 -hydroxy- 1- cyclopropanecarboxylic acid for 4-imidazolecarboxylic acid. 1H-NMR (400 MHz, DMSO- 6) δ 8.70 (t, 7= 6.26 Hz, IH), 7.89 (d, 7 = 6.31, IH), 7.65 (qr, 7= 6.83, IH), 7.34 (t, 7= 10.58 Hz, IH), 7.19 (m, 3H), 6.77 (d, 7 = 7.70 Hz, IH), 5.38 (s, 2H), 4.35 (d, 7 = 5.66, 2H), 1.14 (s, IH), 1.02 (m, 2H), 0.84 (m, 2H). 19F-NMR (400 MHz, DMSO-d6) δ - 109.25 (quintet, 7 = 8.05 Hz, IF), -113.53 (quartet, 7 = 8.27 Hz, IF), -120.59 (d, 7= 8.99 Hz, 2F). LC/MS tr = 5.01 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50°C) ES-MS m/z 497 (M+H). ES-HRMS m/z 497.0873 (M+H calcd for C23H18C1F4N204 requires 497.0886). Example 358. Preparation of N-{4-[3-chIoro-4-[(2,4-difluorobenzyl)oxy]-2- oxopyridin-l(2H)-yl]-3,5-difluorobenzyl}-2-hydroxy-2-methylpropanamide
Figure imgf000430_0002
The compound was prepared following the procedure for , substituting 2- hydroxyisobutyric acid for 4-imidazolecarboxylic acid. 1H-NMR (400 MHz, DMSO- 6) δ 8.48 (t, 7 = 6.41 Hz, IH), 7.89 (d, 7 = 7.78, IH), 7.65 (qr, 7 = 9.10, IH), 7.33 (dt, 7 = 10.12, 2.41 Hz, IH), 7.17 (m, 3H), 6.77 (d, 7= 7.69 Hz, IH), 5.38 (s, 2H), 4.31 (d, 7 =
430 - 6.50, 2H), 1.41 (s, IH), 1.33 (s, 6H). 19F-NMR (400 MHz, DMSO- 6) δ -109.25 (quintet, 7 = 7.49 Hz, IF), -113.53 (quartet, 7 = 9.64 Hz, IF), -120.59 (d, 7 = 8.68 Hz, 2F). LC/MS tr = 5.05 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50°C) ES-MS m/z 499 (M+H). ES-HRMS m/z 499.1020 (M+H calcd for C23H20ClF4N2O4 requires 499.1042). Example 359. Preparation of 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-2- oxopyridin-l(2H)-yl]-3,5-difluorobenzonitrile
Step 1: Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]pyridin-2(lH)- one.
Figure imgf000431_0002
The compound was prepared in the following the produre for 3-chloro-4-[(2,4- difluorobenzyl)oxy]pyridin-2(lH)-one (Step 3), substituting N-bromosuccinimide for N- chlorosuccinimide. 1H-ΝMR (400 MHz, DMSO-d6) δ 11.85 (br s, IH), 7.61 (m, IH), 7.46 (d, 7 = 7.36 Hz, IH), 7.30, (m, IH), 7.14 (m, IH), 6.40 (d, 7= 7.71 Hz, IH), 5.26 (s, 2H). I9F-NMR (400 MHz, DMSO- ) δ -109.69 (quintet, 7 = 7.93 Hz, IF), -113.63 (quartet, 7 = 9.55 Hz, IF). LC MS tr = 4.48 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50°C) ES-MS m/z 316 (M+H). Step 2: Preparation of the title compound. The compound was prepared following the procedure for 4- [3 -chloro-4- [(2, 4-difluorobenzyl)oxy] -2-oxopyridin- 1 (2H)- yl]-3,5-difluorobenzonitrile (Step 4), substituting 3-bromo-4-[(2,4- difluorobenzyl)oxy]pyridin-2(lH)-one (from step 1) (1.92 g, 6.06 mmol) for 3-chloro-4- [(2,4-difluorobenzyl)oxy]pyridin-2(lH)-one (from Step 3). 1H-NMR (400 MHz, DMSO- de) δ 8.13 ( d, 7 = 7.24 Hz, 2H), 7.95 (d, 7= 7.76 Hz, IH), 7.66 (quartet, 7 = 8.71 Hz, IH),
- 431 - 7.34, (dt, 7= 9.94, 2.53 Hz, IH), 7.17 (dt, 7= 8.64, 2.33 Hz, IH), 6.82 (d, 7= 7.77 Hz, IH), 5.39 (s, 2H). 19F-NMR (400 MHz, DMSO- 6) δ -109.28 (quintet, 7 = 7.98 Hz, IF), - 113.45 (quartet, 7 = 9.29 Hz, IF), -116.30 (d, 7 = 7.44 Hz, 2F). LC/MS tr = 5.48 minutes (0-95% acetonitrile/water, 0.05% trifluoroacetic acid, over 6 minutes at 1 ml/min with detection at 215 nm, at 50°C) ES-MS m/z 453 (M+H). ES-HRMS m/z 452.9836 (M+H calcd for C19H10BrF4N2O2 requires 452.9856). Example 360. Preparation of 3-bromo-l-(3-fluorobenzyl)-6-methyl-4-(2- phenylethyl)pyridin-2(lH)-one
Figure imgf000432_0001
Step 1: Preparation of l-(3-fluorobenzyl)-4-hydroxy-6-methylpyridin-2(lH)- one
Figure imgf000432_0002
A mixture of 4-hydroxy-6-methyl-2-pyrone (2.5 g, 0.02 mol) and 3-fluorobenzylamine (2.5 g, 0.02 mol) in n-butanol (15 .0 mL) was heated to reflux for 16 h under argon atmosphere. Butanol wad distilled in vacuo, the residue was triturated with EtOAc, cooled and filterd the precipitate. It was washed with cold EtOAc, and dried to give 0.86 g of the title compound as a pale yellow powder: IH- NMR (CD3OD/400 MHz) δ 7.31 (m, IH), 7.0 - 6.85 (m, 2H), 6.83 (d, IH, J = 9.6 Hz), 5.96 (d, IH, j = 2.0 Hz), 5.80 (d, IH, J = 2.0 Hz), 5.30 (s, 2H), and 2,24 (s, 3H); ESMS m/z = 234 ( MH+). Step 2: Preparation of 3-bromo-l-(3-fluorobenzyl)-4-hydroxy-6- methylpyridin-2(lH)-one
- 432
Figure imgf000433_0001
A mixture of l-(3-fluorobenzyl)-4-hydroxy-6-methylpyridin-2(lH)-one ( 0.8 g, 0.0034 mol), NBS (0.64 g, 0.0036 mol) in dichloromethane (15.0 mL) was stirred at room temperature, under argon atmosphere. After 1.5 h, the reaction mixture was diluted with dichloromethane (15.0 mL), cooled and filterd the solids. The residue was washed with dichloromethane and dried in vacuo to give 0.93 g of the title compound as a white powder: IH- NMR (CD3OD/400 MHzjδ 7.33 (m, IH), 7.2 - 6.8 (m, 3H), 6.07 (s, IH), 5.34 (s, 2H), 2.26 (s, 3H); ESHRMS m/z 312.0016 (M+H C13H12N02BrF requires 312.0035). Step 3: Preparation of 3-bromo-l-(3-fluorobenzyI)-6-methyl-2-oxo-l,2- dihydropyridin-4-yl trifluoromethanesulfonate
Figure imgf000433_0002
To a suspension of 3-bromo-l-(3-fluorobenzyl)-4-hydroxy-6-methylρyridin-2(lH)-one (0.86 g, 0.0028 mol) in dichloromethane (15.0 mL) cooled to -30 °C, triethyl amine (0.5 mL, 0.004 mol) and trflic anhydride (0.7 mL, 0.0042 mol) were added and stirred for 1 h. The resulting orange solution was poured into ice cold water (25 mL) and extracted with dichloromethane ( 2 x 25 mL) The combined organic extracts were washed with water, dried (Na2S04) and concentrated under reduced pressure. The resulting residue was purified by silica gel flash chromatography using 1 : 1 EtOAc/hexane v/v to afford 1.0 g (85%) the title compound as a light brown solid: 1H- NMR (CDC13/400 MHzjδ
7.32 (m,lH), 7.0 - 6.85 (m, 3H), 6.18 (s, IH), 5.32 (s, 2H), and 2.34 (s, 3H); ESHRMS m/z 443.9492 (M+H C14HllN04BrF4S requires 443.9528).
- 433 Step 4: Preparation of 3-bromo-l-(3-fluorobenzyl)-6-methyl-4- (phenylethynyl)pyridin-2(lH)-one
Figure imgf000434_0001
A solution of 3-bromo- l-(3-fluorobenzyl)-6-methyl-2-oxo-l,2-dihydropyridin-4-yl trifluoromethanesulfonate (1.0 g, 0.0022 mol) and phenylacetylene (0.3 mL, 0.0029 mol) in DMF (5.0 mL) was degassed using house vacuum, and purged with argon (3 cycles). Then added diisopropylethylamine, (0.5 mL) followed by the addition of PdC12(PPh3)2 (0.36 g). The reaction mixture was heated at 65 °C for 1.5 h under argon atmosphere. The solvents were distilled in vacuo, and the residue was purified by silica gel flash chromatography using EtOAc/hexane (2:3 v/v) to afford 0.65 g (70%) of the title compound as a brown colored amorphous solid: 1H- NMR (CD3OD/400 MHzjδ7.59 (m, 2H), 7.45 - 7.3 (m, 4H), 7.05 - 6.85 (m, 3H), 6.44 (s, IH), 5.41 (s, 2H), and 2.31 (s, 3H); 19F-NMR (CD3OD/400 MHz) δ -116.33 (m ); ESHRMS m/z 396.0373 (M+H C21H16NOBrF 396.0399). Step 5: Preparation of 3-bromo-l-(3-fluorobenzyl)-6-methyl-4-(2- phenylethyl)pyridin-2(lH)-one. To a solution of 3-bromo- l-(3-fluorobenzyl)-6-methyl- 4-(phenylethynyl)pyridin-2(lH)-one (0.55 g, 0.0014 mol) in EtOAc (10.0 mL) and EtOH (10.0 mL) was added Pt02 (0.05g) and stirred in an atmosphere of hydrogen gas at 15 psi for 30 min. The catalyst was removed by filtration, the filtrate was concentrated and the residue was purified by silica gel flash chromatography using 25% EtOAc in hexane as the eluent. The appropriate fractions were combined (visualized unde^UV) and concentrated to dryness. 1H- NMR (CD3OD/400 MHzjδ 7.35 (m, IH), 7.31 - 7.16 (m, 5H), 6.99(m, IH), 6.91 (m, IH), 6.81 (m, IH), 6.20 (s, IH), 5.41 (s, 2H), 2.94 (m, 4H), and 2.24 (s, 3H); 19F-NMR (CD3OD/400 MHz)δ -115.01 (m ); ESHRMS m/z 400.0695 (M+H C21H20NOBrF 400.0712). Example 361. Preparation of 3-bromo-l-(3-fluorobenzyl)-4-(l- phenylethoxy)pyridin-2(lH)-one
- 434
Figure imgf000435_0001
A mixture of 3-bromo-l-(3-fluorobenzyl)-4-hydroxypyridin-2(lH)-one (0.2 g, 0.72mmol), potassium carbonate (0.1 g, 0.72 mmol) and (l-bromoethyl)benzene (0.19 g, 1 mmol) in DMF (3.0 mL) was stirred at room temperature for 16 h. DMF was distilled in vacuo, and the residue was purified by flash chromatography (EtOAc in hexane (1:3 v/v) to give pale yellow syrup. This material was further purified by reverse-phase HPLC using 10 - 90% acetonitrile/water gradient (30 min), at flow rate of 100 mL/min. The appropriate fractions were combined, concentrated to a small volume (20 mL), added EtOAc (25 mL) and washed successively with satd. sod. bicarbonate, water, and dried (Na2S04). EtOAc was removed under reduced pressure and residue was dried in vacuo to afford the title compound (0.15 g, 52%) as an amorphous substance: Η NMR (CD3OD/ 400 MHz) δ 7.56 (d, IH, J = 7.6 Hz), 7.4 - 7.2 (m, 5H), 7.0 (m, 3H), 6.28 (d, IH, J = 7.6 Hz), 5.65 (m, IH), 5.19 (d x d, 2H, J = 14.8 Hz), and 1.64 (d, 3H, J = 6.4 Hz), ES-HRMS m/z 402.0492(M+H C20H18NO2Br, requires 402.0499). Example 362. Preparation of 3-bromo-l-(3-fluorobenzyl)-4-[(E)-2-(4- fluorophenyl)ethenyl]pyridin-2(lH)-one
Figure imgf000435_0002
A mixture of 3-bromo- l-(3-fluorobenzyl)-2-oxo-l,2-dihydropyridin-4-yl trifluoromethanesulfonate (1.0 g, 0.0023 mol), and 4-fluorostyrene (0.33 mL„ 0.0028 mol) in degassed DMF (10 0 ml) containing dusopropyl ethyl amine (0.37 g, 0.0029 mol) was treated with PdCl2(PPh3)2 (0.32 g, 0.46 mmol) and heated at 65 °C under argon atmosphere for 16 h. DMF was distilled in vacuo, and the residue was purified by flash chromatography (EtOAc/ hexane 1 :4 v/v) to afford a yellow substance which was further
- 435 - purified by by reverse-phase HPLC using 10 - 90% acetonitrile/water gradient (30 min), at flow rate of 100 mL/min. The appropriate fractions were combined, concentrated to a small volume (20 mL), added EtOAc (25 mL) and washed successively with satd. sod. bicarbonate, water, and dried (Na2S04). EtOAc was removed under reduced pressure and residue was dried in vacuo to afford the title compound (0.06 g, 6%) as yellow powder: 1H NMR (CD3OD/ 400 MHzjδ 7.68 (m, 3H), 7.39 (m, 3H), 7.2 - 7.0 (m, 5H), 6.82 (d, IH, J = 7.2 Hz), and 5.22 (s, 2H); 19F NMR(CD3OD/ 400 MHzjδ -113.9(m) and -115 (m); ES-HRMS m/z 402.0305 (M+HC20H15NOF2Br, requires 402.0300). Example 363. Preparation of 4-(benzyloxy)-3-bromo-l-[(6-fluoropyridin-3- yl)methyl]pyridin-2(lH)-one
Figure imgf000436_0001
A mixture of 4-(benzyloxy)-3-bromopyridin-2(lH)-one (0.2 g, 0.00076 mol), 5- bromomethyl-2-fluoropyridine (0.25 g, 0.0013 mol) and pot. Carbonate (0.15 g, 0.0011 mol) in DMF (3.0 ml) was stirred at room temperature for 16 h under argon atmosphere. DMF was distilled in vacuo and the residue was partitioned between water (15 ml) and EtOAc (25 mL). The organic phase was washed with water, dried (Na2S04) and concentrated under reduced pressure. 1H NMR (CD3OD/ 400 MHzjδ 8.22 (m, IH, 2.4 Hz), 7.92(m, IH), 7.82 (d, IH, J = 7.6 Hz), 7.44 - 7.31 (m 5H), 7.03( m, IH) 6.49 (d, IH, J = 7.6 Hz),5.29 (s, 2H), and 5.20 (s, 2H); 19F NMR(CD3OD/ 400 MHzjδ -72.30 (d, J = 6.0 Hz) and -115 (m); ES-HRMS m/z 389.0295 (M+H C18H15N202FBr, requires 389.0309). Example 364. Preparation of 3-bromo-4-[(2,,4-difluorobenzyl)oxy]-l-(2,6- dimethylphenyl)-6-methyIpyridin-2(lH)-one
Figure imgf000436_0002
436 Step 1. Preparation of l-(2,6-dimethylphenyl)-4-hydroxy-6-methylpyridin- 2(lH)-one
Figure imgf000437_0001
A mixture of 4-hydroxy-6-methyl-2-pyrone (2.5 g, 0.02 mol), 2,6 dimethylaniline (2.4 g, 0.02 mol), and p-toluenesulfonic acid (0.2 g) as heated at 140 °C for 3 h under nitrogen atmosphere. The reaction mixture was cooled, triturated with acetonitrile , cooled and filtered the solids. 1H NMR (CD3OD/ 400 MHz) δ 7.22 (m, 3H ), 6.12 (d, IH, J = 1.6 Hz), 5.83 (d, IH, J = 1.8 Hz), 2.00 (s, 6H), and 1.82 (s, 3H); ESMS m/z 229 (M+H). Step 2. Preparation of 3-bromo-l-(2,6-dimethylphenyl)-4-hydroxy-6- methylpyridin-2(lH)-one
Figure imgf000437_0002
A mixture of l-(2,6-dimethylphenyl)-4-hydroxy-6-methylpyridin-2(lH)-one (0.4 g, 0.00175 mol), and NBS (0.35 g, 0.0019 mol) in dichloromethane (10.0 ml) was stirred at room temperature under nitrogen atmosphere. After 1 h, the solids were filtered, washed with dicholoromethane to give 0.42 g (78%) of the title compd as a pale yellow powder: 1H NMR (CD3OD/ 400 MHz) δ 7.22 (m, 3H ), 6.21 (s, IH), 1.99 (s, 6H), and 1.82 (s, 3H); ESMS m/z 308/310 (M+H). Step 3. A mixture of 3-Bromo- l-(2,6-dimethylphenyl)-4-hydroxy-6- methylpyridin-2(lH)-one (0.15 g, 0.00049 mol), 2,4 difluorobenzyl bromide (0.12 g, 0.00058 mol) and potassium carbonate (0.075 g, 0.00054 mol) in DMF 3.00 mL) was stirred at room temperature uder argon atmosphere for 2h. It was then heated at 60 °C for 30 min and concentrated in vacuo. The residue was purified by flash chromatography. 1H NMR (CD3OD/ 400 MHz) δ 7.62 (m, IH), 7.28 ( m,3H), 7.04 (m, 2H), 6.68 (s, IH), 5.35 (m, IH), 1.98 (s, 6H), and 1.92 (s, 3H); ES-HRMS m/z 434.0574 (M+H C2ιH19N02F2Br, requires 434.0562).
437 Example 365. Preparation of 3-bromo-l-(2,6-dimethylphenyl)-4-[(4- fluorobenzyl)oxy]-6-methylpyridin-2(lH)-one
Figure imgf000438_0001
The title compound was prepared by a procedure similar to the one described for Example 364. 1H NMR (CD3OD/ 400 MHz) δ 7.58 (m, 2H), 7.23 (m, 3H), 7.15 (m, 2H), 6.62 (s, IH), 5.32 (s, 2H), 1.98 (m, 6H), and 1.91 (s, 3H); ES-HRMS m/z 416.0670. (M+H C21H20NO2FBr, requires 416.0656). Example 366. Preparation of 3-bromo-l-(2,6-dimethylphenyl)-6-methyl-4- [(2,4,6-trifluorobenzyl)oxy]pyridin-2(lH)-one
Figure imgf000438_0002
The title compound was prepared by a procedure similar to the one described for EXAMPLE 364. 1H NMR (CD3OD/ 400 MHz) δ 7.19 (m, 3H), 6.95 (m, 2H), 6.69 (s, IH), 5.29 (s, 2H), 1.95 (s, 6H), andl.90 (s, 3H); ES-HRMS m/z 452.0471. (M+H C21H18N02F3Br, requires 452.0468). Example 367. Preparation of 3-bromo-4-[(2,6-difluorobenzyl)oxy]-l-(2,6- dimethylphenyl)-6-methylpyridin-2(lH)-one.
Figure imgf000438_0003
The title compound was prepared by a procedure similar to the one described for EXAMPLE 364. 1H NMR (CD3OD/ 400 MHz) δ 7.46 (m, IH), 7.24 (m, 3H), 7.08 (m, 2H), 6.74 (s, IH), 5.38 (s, 2H), 1.99 (s, 6H), and 1.94 (s, 3H); ES-HRMS m/z 434.0589 (M+H C21H,9N02F2Br, requires 434.0562).
- 438 Example 368. Preparation of 3-bromo-l-(2,6-dichlorophenyl)-4-[(4- fluorobenzyl)oxy]-6-methyIpyridin-2(lH)-one
Figure imgf000439_0001
Step 1. Preparation of l-(2,6-dichlorophenyl)-4-hydroxy-6-methylpyridin- 2(lH)-one
Figure imgf000439_0002
This compound was prepared by a procedure similar to the one described in step 1 for Example 364. Yield: 28%, 1H NMR (CD30D) δ 7.6 (m, 2H), 7.48 (m, IH), 6.10 (dd, IH), 5.78 (d, IH, J = 2.4 Hz), 1.91 (s, 3H); ES-MS m/z = 270 (MH+); Step 2. Preparation of 3-bromo-l-(2,6-dichlorophenyl)-4-hydroxy-6- methylpyridin-2(lH)-one
Figure imgf000439_0003
This compound was prepared by a procedure similar to the one described in step 2 for Example 364. Yield: 78%, 1H NMR (400 MHz) CD3OD δ 7.61 (m, 2H), 7.49 (m, IH), 6.2 (s, IH), and 1.91 (s, 3H); ES-MS, m/z = 348 (MH+). Step 3. Preparation of 3-bromo-l-(2,6-dichlorophenyl)-4-[(4- fluorobenzyl)oxy]-6-methylpyridin-2(lH)-one. This compound was prepared by a procedure similar to the one described in step 3 for EXAMPLE 364. Yield: 44%, 1H NMR (CD3OD) δ 7.62 (d, 2H, J = 8.0 Hz), 7.51 (m, 3H), 7.15 (m, 2H), 6.64 (s, IH), 5.33 (s, 2H), and 2.0 (s, 3H); 19F NMR (CD3OD) δ -166.21 (m)DES-HRMS m/z 455.9541(M+H C19Hi4N02Cl2BrF, requires 455.9564). Example 369. Preparation of 3-bromo-l-(2,6-dichlorophenyl)-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one
- 439 -
Figure imgf000440_0001
This compound was prepared by a procedure similar to the one described for EXAMPLE 368. Yield: 64%, 1H NMR (CD3OD/400 MHz δ 7.62 (m, 3H), 7.48 (m, IH), 7.05 (m, 2H), 6.70 (s, IH), 5.36 (s, 2H), and 2.02 (s, 3H), 19F NMR (CD3OD) δ -111.43 (m) and - 115.89 (m); ES-HRMS m/z 473.9450 (M+H C19H13N02Cl2BrF2, requires 473.9469). Example 370. Preparation of 3-Bromo-l-(2,6-dichlorophenyl)-4-[(2,6- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one
Figure imgf000440_0002
This compound was prepared by a procedure similar to the one described for Example 368. Yield: 78%, 1H NMR (CD3OD/400 MHz) δ 7.62 (d, 2H, J = 8.0 Hz), 7.52 (m, 2H), 7.1 (m, 2H), 6.77 (s, IH), and 2.04 (s, 3H); 19F NMR (CD3OD) δ -117.04 (m); ES-HRMS m/z 473.9468 (M+H C19Hi3N02Cl2BrF2, requires 473.9469). Example 371. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2- methoxy-6-methylphenyl)-6-methylpyridin-2(lH)-one
Figure imgf000440_0003
Step 1. Preparation of 4-hydroxy-l-(2-methoxy-6-methylphenyl)-6- methylpyridin-2(lH) -one
Figure imgf000440_0004
440 - This compound was prepared by a procedure similar to the one described in step 1 for Example 368. Yield: 21%, 1H NMR (CD3OD/400 MHz) δ 7.3 l(m, IH), 6.94 (m, 2H), 6.05 (d, IH, J = 2.4 Hz), 5.78 (d, IH, J = 2.4 Hz), 3.76 (s, 3H), 2.00 (s, 3H), and 1.83 (s, 3H); ES-HRMS m/z 246.1092 (M+H C14H16N03, requires 246.1123). Step 2. Preparation of 3-bromo-4-hydroxy-l-(2-methoxy-6-methylphenyl)-6- methylpyridin-2(lH)-one
Figure imgf000441_0001
This compound was prepared by a procedure similar to the one described in step 2 for EXAMPLE 368. Yield: 58%, lH NMR (CD3OD/400 MHz) δ 7.34 (m, IH), 6.96 (m, 2H), 6.15 (s, IH), 3.76 (s, 3H), 1.99 (s, 3H), and 1.83 (s, 3H); ESMS m/z 324 (M+H). Step 3. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2-methoxy-6- methylphenyl)-6-methylpyridin-2(lH)-one. This compound was prepared by a procedure similar to the one described for Example 368. Yield: 60%, 1H NMR (CD3OD/400MHz) δ 7.63 (m, IH), 7.36 (m, IH), 7.01 (m, 4H), 6.61 (s, IH), 5.33 (s, 2H), 3.76 (s, 3H), 1.99(s, 3H), and 1.95 (s, 3H); 19F NMR (CD3OD/400 MHz) δ -111.64 (m), and -116.03 (m); ES-HRMS m/z 450.0532 (M+H C21H19N03Cl2BrF2, requires 450.0511). Example 372. Preparation of 4-[3-bromo-4-[(2,4-difluorobenzyI)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]-3,5-dichlorobenzenesulfonamide
Figure imgf000441_0002
Step 1. Preparation of 3,5-dichloro-4-(4-hydroxy-6-methyl-2-oxopyridin- l(2H)-yl)benzenesulfonamide
Figure imgf000441_0003
441 - A mixture of 4-hydroxy-6-mefhylpyrone ((1.2 g, 0.0095 mol), and 2,6- dichlorosulphanilamide (2.4 g, 0.0099 mol) was heated at 170 °C under argon for 20 min. The resulting dark colored melt was cooled and the crude material was first purified by flash chromatography (EtOAc) to give partially purified material which contained the desired product. This was further purified by reverse-phase HPLC using 10 - 90%
CHsCN/Water (30 min gradient) at a flow rate of 100 mL/min. The appropriate fractions (m/z = 349 )were combined and freeze dried to afford 0.19 g of 3,5-dichloro-4-(4- hydroxy-6-methyl-2-oxopyridin-l(2H)-yl)benzenesulfonamide as pale yellow solid: 1H NMR (CD3OD/400 MHz) δ 8.06 (s, 2H), 6/13 (d, IH, J = 1.6 Hz), 5.78 (d, IH, J = 1.6 Hz), and 1.94 (s, 3H)); ES-HRMS m/z 348.9819 (M+H C12HπN204SCl2 requires 348.9811). Step 2. Preparation of 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]-3,5-dichlorobenzenesulfonamide. A mixture of 3,5-dichloro-4- (4-hydroxy-6-methyl-2-oxopyridin-l(2H)-yl)benzenesulfonamide (0.18 g, 0.0005 mol), N- bromosuccinimide (0.1 g, 0.00056 mol)in acetici acid (2.0 mL) was stirred at room temperature under argon atmosphere for 1 h. Acetic acid was removed in vacuo, the residue was dissolved in DMF (2.0 mL), and added 2,4 difluorobenzyl bromide (0.128 g, 0.0006 mol), potassium carbonate (0.1 g, 0.0007 mol). The resulting mixture was stirred at room temperature for 1 h. The solvents were distilled in vacuo, and the residue was purified by flash chromatography (EtOAc/ hexane 1 : 3 v/v) to give 0.14 g of partially purified product. This was further purified by reverse-phase HPLC using 10 - 90% CH3CN/Water (30 min gradient) at a flow rate of 100 mL/min. The appropriate fractions (m/z = 553 ) were combined and freeze dried to afford 0.045 g of pale yellow powder. This was partitioned between EtOAc (25 ml) and 5% sod. bicarbonate. The organic phase was washed with water, dried (Na2S04) and concentrated under reduced pressure. This material was dried invacuo to afford the title compound (0.033 g) as a white amorphous substance: 1H NMR (CDCl3/400 MHz) δ 7.99 (s, 2H), 7.59 (m, IH), 6.98 (m, IH), 6.85 (m, IH), 6.23 (s, IH), 5.69 (s, 2H), 5.28 (s, 2H), 1.97 (s, 3H), and 1,76 (br, 2H); ESHRMS m/z 552.7214 (M+H Ci9H14BrCl2N204S requires 552.9197).
- 442 Example 373. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6- difluorophenyl)-6-methylpyridin-2(lH)-one
Figure imgf000443_0001
Step 1. Preparation of l-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin- 2(lH)-one
Figure imgf000443_0002
A mixture of 4-hydroxy-6-methyl-2-pyrone (10.0 g, 0.079 mol) and 2,6 difluoroaniline (9.5 g, 0.073 mol) was heated at 170 °C under argon atmosphere for 20 min. The water formed was removed using a Dean-stark apparatus. The melt was cooled, the dark solid was tritutrated with EtOAc, and filtered. This material was washed thoroughly with
EtOAc to afford the desired product l-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin- 2(lH)-one 6.5 g (35%) as a light brown solid: 1H NMR (CD3OD/400 MHz) δ 7.56 (m, IH), 7.19 (m, 2H), 6.09 (m, IH ), 5.77 (d, IH, J = 2.4 Hz), and 1.99 (s, 3H); ES-HRMS m/z 238.0679 (M+H Cι2H10NO2F2 requires 238.0674). Step 2. Preparation of 3-bromo-l-(2,6-difluorophenyl)-4-hydroxy-6- methylpyridin-2(lH)-one
Figure imgf000443_0003
The title compound was prepared by a procedure described in step 2 for Example 364. Yield: 79%, 1H NMR (CD3OD/400 MHz) δ 7.58 (m, IH), 7.21 (m, 2H), 6.19 (d, IH, J = 0.8 Hz), 1.99 (s, 3H); ES-HRMS m/z 315.9811 (M+H C12H9N02F2Br requires 315.9779). Step 3. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6- difluorophenyl)-6-methylpyridin-2(lH)-one. This compound was prepared by a procedure described in step 3 for EXAMPLE 364. Yield : 63%, 1H NMR (CD3OD) δ 7.58
- 443 - (m, 2H), 7.23 (m, 2H), 7,06 (m, 2H), 6.68 (s, IH), 5.36 (s, 2H), and 2.10 (s, 3H); 19F NMR (CD3OD) δ -111.50 (m), -115.96(m), and -121.93 (m); ES-HRMS m/z 442.0061 (M+H C19H13N02F4Br requires 442.0060). Example 374. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6- difluorophenyl)-5-iodo-6-methylpyridin-2(lH)-one
Figure imgf000444_0001
A solution of 3-Bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-6- methylpyridin-2(lH)-one (0.3 g, 0.00068 mol) and N-iodosuccinimide (0.22 g, 0.00098 mol) in dichloroethane , containing dichloroacetic acid (0.1 mL) was heated to reflux for 6 h under argon atmosphere. After the removal of the solvents under reduced pressure, the residue was partitioned between, dichloromethane (20 mL) and 5% sod. sulphite (10 mL). The organic phase was washed with water, dried (Na2S04), and concentrated under reduced pressure. The residue was purified by flash chromatography (25% EtOAc in hexane) to afford the title compound (0.125 g, 32 %) as a pale yellow powder: 1H NMR (CDCl3/400 MHz) δ 7.68 (m, IH), 7.46 (m, IH), 7.11 (m, 2H), 6.95 (m, IH), 6.85 (m, IH), 5.23 (s, 2H), and 2.38 (s, 3H); I9F NMR (CDC13) δ -109.15 (m), -112.95 (m), -118.50 (m); ES-HRMS m/z 567.9014 (M+H C19H12N02F4BrI requires 567.9027). Example 375. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[2- (dimethylamino)-4,6-difluorophenyl]-6-methylpyridin-2(lH)-one
Figure imgf000444_0002
Step 1. Preparation of 3,5-difluoro-N~l~,N~l~-dimethylbenzene-l,2-diamine
Figure imgf000444_0003
444 To a solution of 2,4,6-trifluoronitrobenzene (2.58 g, 0.0145 mol) in THF (20.0 ml) was added a solution of N,N-dimethylamine in THF (8.5 mL of 2M soln) and stirred for 45 min at 0°C. It was then stirred at room temperature for 30 min and concentrated to dryness. The resulting material was dissolved in EtOH (25 mL), added Pd/C (10%, 0.6 g) and hydrogenated at 50 psi for 4 h. The catalyst was removed by filtration, and the filtrate was concentrated to dryness under reducued pressure. Te residue was partitioned between sod. bicarbonate (10%, 25 mL) and EtOAc (30 mL). The organic phase was washed with water, dried (Na2S04), and concentrated to dryness to afford the title compound (1.3 g, 50%) as a dark colored solid: 1H NMR (CDCl3/400 MHz) δ 6.52 (m, 2H), 3.64 ( br, 2H), and 2.65 (s, 6H); ES-HRMS m/z 172.0772 (M+ C8H10N2F2 requires 172.0810). Step 2. l-[2-(dimethyIamino)-4,6-difluorophenyl]-4-hydroxy-6- methylpyridin-2(lH)-one
Figure imgf000445_0001
An intimate mixture of 4-hydroxy-6-methyl-2-pyrone (1.3 g, 0.0103 mol), and 3,5- difluoro-N,N-dimethylbenzene-l,2-diamine (1.4 g, 0.008 mol) was heated at 160 °C under argon for 15 min. The dark colored reaction mixture was cooled, triturated with EtOAc (15 ml), and filtered. The solids were washed with warm EtOAc, followed by hexane and dried to give the title compound as a light blue solid (0.4 g, 14 %). Analalytically pure sample was prepared by reverse-phase HPLC purification using 10-90% CH3CN/Water (30 min gradient) at a flow rate of 100 mL/min. The appropriate fractions were combined and freeze-dried to give the title compound: 1H NMR (CD3OD/400 MHz) δ 6.61 (m, 2H), 6.08 (d, IH, J = 2.0 Hz), 6.78 (d, IH, J = 2.0 Hz), 2.69 (s, 6H), and 1.94 (s, 3H); ESHRMS m/z 281.1084 (M+H C14H15N202F2 requires 281.1096).
445 Step 3. Preparation of 3-bromo-l-[2-(dimethylamino)-4,6-difluorophenyl]-4- hydroxy-6-methylpyridin-2(lH)-one
Figure imgf000446_0001
The title compound was prepared by a procedure described in step 2 for Example 364. Yield: 71%, 1H NMR (CD3OD/400 MHz) δ 6.62 (m, 2H), 6.17 (s, IH), 2.67 (s, 6H), and 1.94 (s, 3H); ES-HRMS m/z 359.0188 (M+H C14H14N202F2Br requires 359.0201). Step 4 The product of Step 3 above was used in the procedure described in step 3 for Example 364. Yield : 34%, 1H NMR (CDCl3/400 MHz) δ 7.62 (m, IH), 6.98 (m, IH), 6.85 (m, IH), 6.46 (m, 2H), 6.1 l(s, IH), 5.24 (s, 2H), 2.66 (s, 6H), and 1.98 (s, 3H); 19F NMR (CDCl3/400 MHz) δ -108.06 (m), -109.60 (m), - 115.02 (m), and -116.01 (m); ESHRMS m/z 485.0451 (M+HC21H18N202F4Br requires 485.0482). Step 5. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[2- (dimethylamino)-4,6-difluorophenyl]-6-methylpyridin-2(lH)-one. The title compound was prepared by stirring a suspension of the product of step 4 above (0.14 g) with 4N HCl in dioxane (0.7 mL) at room temperature for 30 min. The mixture was concentrated to dryness. 1H NMR (CD3OD/400 MHz) δ 7.62 (m, IH), 7.02 (m, 2H), 6.65 (m, 3H), 5.34 (s, 2H), 2.66 (s, 6H), and 2.05 (s, 3H); ESMS m/z = 485. Example 376. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{2,4- difluoro-6-[(2-hydroxyethyl)(methyl)amino]phenyl}-6-methylpyridin-2(lH)-one
Figure imgf000446_0002
The title compound was prepared by a similar procedure described for Example 375, replacing N,N-dimethyl group by N-Methyl-aminoethanol. 1H NMR (CDCl3/400 MHz) δ 7.59 (m, IH), 6.98 (m, IH), 6.85 (m, IH), 6.61(m, IH), 6.52 (m, IH), 6.17 (m, IH), 5.25
446 (s, 2H), 3.63 (m, IH), 3.53 (m, IH), 3.26 (m, IH), 3.0 (m, IH), 2.66 (s, 6H), and 2.09 (s, 3H); ES-HRMS m/z 515.0512 (M+H C22H20N2O3F4Br requires 515.0588). Example 377. Preparation of 2-({[3-bromo-l-(2,6-difluorophenyl)-6-methyl-2- oxo-l,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzonitrile
Figure imgf000447_0001
Step 1. Preparation of 2-(bromomethyl)-5-fluorobenzonitrile
Figure imgf000447_0002
A mixture of 5-fluoro-2-methylbenzonitrile ( 2.0 g, 0.015 mol), NBS (3.2 g, 0.018 mol) and benzoylperoxide (0.25 g) in carbontetrachloride (25.0 ml) was heated to reflux for 6 h, under argon atmosphere. The reaction mixture was cooled and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography (5% EtOAc in hexane ) to afford 2-(Bromomethyl)-5-fluorobenzonitrile (1.9 g, 60%) as a colorless liquid: 1H NMR (CDCl3/400 MHz) m) 7.58 (m, IH), 7.38 (m, IH), and 7.25 (m, IH). Step 2. Preparation of 2-({[3-bromo-l-(2,6-difluorophenyl)-6-methyl-2-oxo- l,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzonitrile. A mixture of 3-bromo-l- (2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(lH)-one (1.0 g, 0.0032 mol), potassium carbonate (0.65 g, 0.0047 mol) and 2-(bromomethyl)-5-fluorobenzonitrile (0.95 g, 0.0045 mol) in dimethylacetamide (15.0 ml) was stirred at room temperature under argon atmosphere. After lh, dimethylacetamide was distilled in vacuo and the residue was partitioned between dichloromethane (50 ml) and 55 citric acid (15 mL). The organic phase was washed with water, dried (Na2S04), and concentrated to dryness. The resulting material was triturated with EtOAc, filtered, washed with EtOAc and dried to afford the title compound (0.86 g, 60%) as a white powder: 1H NMR (DMSO-d6/400 MHz) δ 7.95 (m, IH), 7.81 (m, IH), 7.68 (m, 2H), 7.37 (m, 2H), 6.79(s, IH), 5.45 (s, 2H), and 2.03 (s, 3H); 19F- NMR (DMSO-d6) δ -111.31 (m), -120.34 (m); ESHRMS m/z 449.0094 (M+H C20H13N2O2F3Br requires 449.0107). - 447 - Example 378. Preparation of 4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3- bromo-l-(2,6-difluorophenyl)-6-methylpyridin-2(lH)-one trifluoroacetate
Figure imgf000448_0001
To a cold suspension of 2-({[3-bromo-l-(2,6-difluorophenyl)-6-methyl-2-oxo-l,2- dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzonitrile (0.3 g, 0.00066 mol) in THF (3.0 mL), was added BH3.THF (1.0 mL). After stirring at room temperature for 15 min, the reaction mixture was heated to reflux for 30 min under argon atmosphere. The resulting clear solution cooled, added MeOH (2.0 mL), concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC purification using 10 -90% CH3CN/Water (30 min gradient) at a flow rate of 100 mL/min. The appropriate fractions (m/z= 453 M+H) were combined and freeze-dried to give the title compound (0.16 g, 43%) as its trifluoroacetate salt: 1H NMR (DMSO-d6/400 MHz) δ 8.19 (br, 3H), 7.65 (m, 2H), 7.37 (m, 4H), 6.78 (s, IH), 5.42 (s, 2H), 4.21 (br, 2H), and 2.04 (s, 3H); 19F NMR (DMSO-d6/400 MHz) δ -112.96 (m), and -120.41 (m); ES-HRMS m/z 453.0387 (M+H C20Hι7N2O3F3Br requires 453.0420). Example 379. Preparation of N-[2-({[3-bromo-l-(2,6-difluorophenyl)-6- methyl-2-oxo-l,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzyl]urea
Figure imgf000448_0002
To a suspension of 4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3-bromo-l-(2,6- difluorophenyl)-6-methylpyridin-2( lH)-one trifluoroacetate (0.13g, 0.00023 mol) in THF (3.0 mL), was added triethyl amine (0.07 mL, 0.0005 mol) followed by the addition of trimethylsilylisocyanate (0.066 mL). The reaction mixture was stirred at room temperature for 1 h, and the desired product was isolated by reverse-phase HPLC purification using 10 -90% CH3CN/Water (30 min gradient) at a flow rate of
448 - 100 mL/min. The appropriate fractions (m/z= 496 M+H) were combined and freeze-dried, and the residue was partitioned between 5% sod. bicarbonate (20 mL) and dichloromethane (20 mL). The organic phase was washed with water, dried (Na2S04) and concentrated to dryness under reduced pressure, to afford the title compound as a white amorphous powder (0.065 g): 1H NMR (DMSO-d6/400 MHz) δ 7.62 (m, IH), 7.52 (m, IH), 7.35 (m, 2H), 7.09 (m, 2H), 6.77 (s, IH), 6.51 (t, IH), 5.61 (s, 2H), 5.38 (s. 2H), 4.28 (d, 2H, J = 6.0 Hz), and 2.02 (s, 3H);19F NMR (DMSO-d6/400 MHz) δ -114.044 (m), and -120.31 (m); ES-HRMS m/z 496.0460 (M+HC2iH18N303F3Br requires 496.0478). Example 380. Preparation of methyl 2-({[3-bromo-l-(2,6-difluorophenyl)-6- methyl-2-oxo-l,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzylcarbamate
Figure imgf000449_0001
To solution of 4-{ [2-(aminomethyl)-4-fluorobenzyl]oxy }-3-bromo-l-(2,6-difluorophenyl)- 6-methylpyridin-2(lH)-one trifluoroacetate (0.12g, 0.00021 mol) in dimethylacetamide (2.0 mL) at 0 °C, was added triethylamine (0.06 mL, 0.00043 mol) followed by the addition of methylchloroformate (0.05 mL). The reaction mixture was stirred at room temperature for 30 min under argon atmosphere. Dimethylacetamide was distilled in vacuo and the residue was partitioned between dichloromethane (10 mL) and 5% citric acid (10 mL). The organic phase was washed with water, dried (Na2S04) and concentrated to dryness. The resulting residue was purified by flash chromatography (60%EtOAc in hexane) to afford the title compound (0.09 g, 75%) as a white amorphous powder: 1H NMR (DMSO-d6/400 MHz) δ 7.68 (m, IH), 7.62 (m, IH), 7.59 (m, IH), 7.38 (m, 2H), 7.115 (m, 2H), 6.78 (s, IH), 5.38 (s, 2H), 4.31 (d, 2H, J = 6.0 Hz), 3.53 (s, 3H), and 2.03(s, 3H); 19F NMR (DMSO-d6/400 MHz) δ -113.77 (m), and -120.33 (m); ESHRMS m/z 511.0508 (M+H C22Hι9N204F3Br requires 511.0475).
449 Example 381. Preparation of N-[2-({[3-bromo-l-(2,6-difluorophenyl)-6- methyl-2-oxo-l,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzyl]-2- hydroxyacetamide
Figure imgf000450_0001
To a suspension of 4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3-bromo-l-(2,6- difluoroρhenyl)-6-methylpyridin-2(lH)-one trifluoroacetate (0.12g, 0.00021 mol) in THF (2.0 mL) at 5 °C, was added triethyl amine (0.036 g, 0.00035 mol) followed by the addition of acetoxyacetyl chloride (0.05 mL). The mixture was stirred at room temperature for 30 min, diluted with cold water (10 mL), and extracted the products with dichloromethane ( 2 x 10 mL). The combined organic extracts were washed with water, dried (Na2S04) and concentrated to dryness. The residue was dissolved in ethanol (0.5 mL), added IN NaoH (0.5 mL)and stirred at room temperature for 1 h. The resulting solution was diluted with water (15 mL), and extracted with dichloromethane (2 x 10 mL). The combined dichloromethane extracts were washed with water, dried (Na S04) and concentrated to dryness. The residue was purified by flash chromatography (1 % MeOH in EtOAc) to afford the title compound (0.032 g, 30 %) as a white amorphous powder: 1H NMR (CDCl3/400 Hz) δ 7.45 (m, 2H), 7.18 (m, IH), 7.05 (m, 3H), 6.23 (s, IH), 5.24 (s, 2H), 4.56 (d, 2H, J = 6.4 Hz), 4.08 (d, 2H, J = 5.2 Hz), 2.79 (t, IH), and 2.08 (s, 3H;) 19F NMR (CDCl3/400 MHz) δ -111.88 (m) and -118.62 (m); ES-HRMS m/z 511.0482 (M+H C22H19N204F3Br requires 511.0475). Example 382. Preparation of ethyl 2-({[3-chloro-l-(2,6-difluorophenyl)-6- methyl-2-oxo-l,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzylcarbamate
Figure imgf000450_0002
To solution of 4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3-chloro-l-(2,6-difluorophenyl)- 6-mefhylpyridin-2(lH)-one trifluoroacetate (0.3g, 0.00057 mol) in dimethylacetamide (3.0 - 450 - L) was added N-methymorpholine (0.064 g, 0.00064 mol), followed by addition of ethylchloroformate (0.06 mL) and stirred at - 10 °C, for 30 min. The solvents were distilled in vacuo and the residue was purified by reverse-phase HPLC purification using 10 -90% CH3CN/ ater (30 min gradient) at a flow rate of 100 mL/min. The appropriate fractions (m/z= 481 M+H) were combined and freeze-dried, and the residue was partitioned between 5% sod. bicarbonate (20 mL) and dichloromethane (20 mL). The organic phase was washed with water, dried (Na2S0 ) and concentrated to dryness under reduced pressure, to afford the title compound as a white amorphous powder (0.15 g, 55%): 1H MR (CD3OD/400MHz) δ 7.61 (m, IH), 7.52 (m, IH), 7.26 (~t, 2H, J = 8.4 Hz), 7.12 (dd, IH), 7.05 (3d, IH, J = 2.4 Hz), 6.74 (s, IH), 5.40 (s, 2H), 4.42 (s, 2H), 4.05 (q, 2H, J = 7.2 Hz), 2.12 (s, 3H), and 1.21 (t, 3H, J = 7.2 Hz ); ES-HRMS m/z 481.1118 (M+H C23H21N204F3C1 requires 481.1136). Example 383. Preparation of isobutyl 2-({[3-chloro-l-(2,6-difluorophenyl)-6- methyl-2-oxo-l,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzylcarbamate
Figure imgf000451_0001
The title compound was prepared by a procedure similar to the one described for Example
382. Yield 57 %; 1H NMR (CD3OD/400 MHz) δ 7.61 (m, IH), 7.51 (m, IH), 7.24 (~t, 2H,
J = 8.0 Hz), 7.18 (m, IH), 7.06 (m, IH), 6.74 (s, IH), 5.40 (s, 2H), 4.21 (s, 2H), 3.79 (d.
2H, J = 6.8 Hz), 2.12 (s, 3H), 1.85 (m, IH), and 0.91 (d, 6H, J = 6.4 Hz); ES-HRMS m z 509.1422 (M+H C25H25N204F3C1 requires 509.1449)
- 451 Example 384. Preparation of cyclopropylmethyl 2-({[3-chloro-l-(2,6- difluorophenyl)-6-methyl-2-oxo-l,2-dihydropyridin-4-yl]oxy}methyl)-5- fluorobenzylcarbamate
Figure imgf000452_0001
The title compound was prepared by a procedure similar to the one described for Example 382. Yield 46%; 1H NMR (CD3OD/400 Hz) δ 7.61 (m, IH), 7.55 (m, IH), 7,24 (~ t, 2H, J = 7.6 Hz), 7.18 (m, IH), 7.05 (m, IH), 6.73 (s, IH), 5.40 (s, 2H), 4.42 (s, 2H), 3.83 (d, 2H, J = 7.2 Hz), 2.12 (s, 3H), 1.1 (br, IH), 0.58 (~d, 2H), and 0.22 (~ d, 2H); ES-HRMS m z 507.1316 (M+HC25H23N204F3C1 requires 507.1293). Example 385. Preparation of l-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3- bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one trifluoroacetate
Figure imgf000452_0002
CF3COOH Step 1. Preparation of l-[(4-amino-2-methylpyrimidin-5-yl)methyl]-4- hydroxy-6~methylpyridin-2(lH)-one
Figure imgf000452_0003
A mixture of 4-hydroxy-6-methyl-2-pyrone (0.9 g, 0.007 mol) and 4-amino-5- aminomethyl-2-methylpyrimidine (1.0 g, 0.007 mol) in water (10.0 ml) was heated at 100°C for 1 h under argon atmosphere. The reaction mixture was cooled, and filtered the
452 yellow precipitate. It was washed successively with cold water, ethanol, and dried in vacuo to afford the title compound (1.01 g, 51%) as a pale yellow powder: 1H NMR (DMSO-d6/400 MHz) δ 7.62 (s, IH), 7.04 (s, IH), 5.83 (d, IH, J = 2.0 Hz), 5.58 (d, IH, J = 2.0 Hz), 4.92 (s, 2H), 2.24 (s, 3H), and 2.22 (s, 3H); ES-HRMS m z 325.0304 (M+H C12H14N 02Br requires 325.0295). Step 2. Preparation of l-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-bromo-
4-hydroxy-6-methylpyridin-2(lH)-one
Figure imgf000453_0001
A mixture of l-[(4-amino-2-methylpyrimidin-5-yl)methyl]-4-hydroxy-6-methylpyridin- 2(lH)-one (0.5 g, 0.002 mol), and NBS (0.4 g, 0.002 mol)in glacial acetic acid (5.0 ml) was stirred at room temperature for 1 h under argon atmosphere. Acetic acid was removed in vacuo, residue was triturated with EtOAc containing 10 % EtOH, and filtered. The pale yellow precipitate was washed with EtOAc containing 10% EtOH and dried in vacuo to afford the title compound (0.47 g, 725) as a pale yellow powder: !H NMR (CD3OD/400 MHz) δ 7.62 (s, IH), 6.09 (s, IH), 5.15 (s, 2H), 2.42 (s, 3H), and 2.33 (s, 3H); ES-HRMS m/z 247.1160 (M+H C1 H15N402 requires 247.1190). Step 3. Preparation of l-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-bromo- 4- [(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one trifluoroacetate. To suspension of 1 -[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-bromo-4-hydroxy-6- methylpyridm-2(lH)-one (1.0 g, 0.0031 mol) and potassium carbonate (0.004 mol) in dimethylacetamide (10.0 mL) was added 2,4 difluorobenzyl bromide (0.62 mL, 0.0048 mol) and stirred at room temperature for 2 hours. Dimethylacetamide was distilled in vacuo and the residue was purified by reverse-phase HPLC using 10 - 90% CH3CN/Water (30 min gradient) at a flow rate of 100 mL/min. The appropriate fractions (m z = 566 )were combined and freeze dried to afford 0.65 g (37 %) of the title compound as its trifluoroacetate salt: 1H NMR (CD3OD/400 MHz) δ 7.65 (s, IH), 7.58 (m, IH), 7.05 (m, 2H), 6.61 (s, IH), 5.31 (s, 2H), 5.18 (s, 2H), 2.51 (s. 3H), and 2.46 (s, 3H); 19F NMR
453 (CD3OD/400 MHz) δ -111.39 (m) and -115.98 (m); ES-HRMS m/z 451.0590 (M+H C19H18N402BrF2 requires 451.0576). Example 386. Preparation of l-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3- bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one hydrochloride
Figure imgf000454_0001
Ion exchange (25g) BioRad AG 2X8 resin (200-400 mesh chloride form) was washed with 1M HCl (150 mL), and equilibrated for 2.5 h. This resin was loaded onto a column, and added a solution of Example 385 (3.3 g, 5.8 mmol) in water/CH3CN (1:1). The column was eluted slowly over 1 h, fractions were collected, and freeze dried to afford the desired HCl salt (2.2 g, 72%) as a white solid: 1H-NMR (CD3OD, 400Hz) δ 7.60 (m, 2H), 7.21
(m, 2H), 6.62 (s, IH), 5.31 (s, 2H), 5.18 (s, 2H), 2.52 (s, 3H), 2.47 (s,3H); ES-HRMS m/z 451.0544/453.0577 (M+H C19H17N402F2Br requires 451.0581/453.0563). Example 387. Preparation of l-[(4-amino-2-methylpyrimidin-5-yl)methyI]-3- chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one trifluoroacetate
Figure imgf000454_0002
Step 1. Preparation of l-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-chloro- 4-hydroxy-6-methylpyridin-2(lH)-one
Figure imgf000454_0003
454 1H NMR (CD3OD, 400Hz) δ 7.62 (m, IH), 6.11 (s, IH), 5.13 (s, 2H), 2.66 (s, 3H), 2.42 (s,3H); ES-HRMS m/z 281.0793 (M+H C12H13N402C1 requires 281.0800). Step 2. Preparation of l-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-chloro- 4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one trifluoroacetate. The title compound was prepared from the product of Step 1 by a procedure similar to the one described for Example 385, step 2. 1H NMR (CD3OD, 400Hz) δ 7.59 (m, 2H), 7.03 (m, 2H), 6.63 (s, IH), 5.31 (s, 2H), 5.17 (s, 2H), 2.48 (s, 3H), 2.46 (s, 3H); ES-HRMS m/z 407.1097 (M+H C19H17N402C1F2 requires 407.1081). Example 388. Preparation of l-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3- chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one hydrochloride
Figure imgf000455_0001
Ion exchange (12.5g) BioRad AG 2X8 resin (200-400 mesh chloride form) was washed with 1M HCl (150 mL), and equilibrated for 2.5 h. This resin was loaded onto a column, and added a solution of Example 387 (1.2 g, 2.4 mmol) in water/CH3CN (1:1). The column was eluted slowly over 1 h, fractions were collected,and freeze dried to afford the desired HCl salt (1.03 g, 97%) as a white solid: 1H NMR (CD3OD, 400Hz) δ 7.60 (m, 2H), 7.04 (m, 2H), 6.64 (s, IH), 5.31 (s, 2H), 5.17 (s, 2H), 2.50 (s, 3H), 2.47 (s, 3H); ESHRMS m/z 407.1079 (M+H C19H17N402C1F2 requires 407.1081). Example 389. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(lH- indazol-5-ylmethyl)-6-methylpyridin-2(lH)-one trifluoroacetate
Figure imgf000455_0002
To a mixture of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one (0.55 g, 0.0017 mol) and 5-(bromomefhyl)-l-tetrahydro-2H-pyran-2-yl-lH-indazole (0.5 g, 0.0017 - 455 - mol) in THF (10.0 mL) was added NaH (0.045 g, 0.0019 mOl) and heated at 60°C for 16 h under argon atmosphere. THF was distilled under reduced pressure, and the residue was suspended in EtOAc, added acetic acid (0.5 mL) and the product was purified by flash chromatography (80% EtOAc in hexane). The appropriate fractions were combined and concentrated to give an amorphous substance (0.31 g). This was stirred with trifluoroacetic (0.5 mL) for 30 min, the solution was diluted with acetonitrile (5 mL) and the product was isolated by reverse-phase HPLC using 10 - 90% CH3CN/Water (30 min gradient) at a flow rate of 100 mL/min. The appropriate fractions (m/z = 460 ) were combined and freeze dried to afford 0.14 g (52%) of the title compound as its trifluoroacetate salt: 1H NMR (CD3OD/400 MHz) δ 7.97 (s, IH), 7.62 (m, IH), 7.51 (m, IH), 7.45 (s, IH), 7.25 (m, IH), 7.03 (t, 2H), 6.49 (s, IH), 5.53 (s, 2H), 5.29 (s, 2H), and 2.40 (s, 3H); 19F NMR (CD3OD/400 MHz) δ -111.69 (m), -116.09 (m); ES-HRMS m z 460.0432 (M+HC21H17N302BrF2 requires 460.0467). Example 390. Preparation of N~l~-(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]- 6-methyl-2-oxopyridin-l (2H)-yl] methyl}-2-methylpyrimidin-4-yl)glycinamide trifluoroacetate
Figure imgf000456_0001
CF3COOH To a solution of BOC-Gly-OH (0.19 g, 0.0011 mol) in DMF (2.0 mL), was added N- methylmorpholine (0.14 mL, 0.0011 mol), followed by the addition of isobutylchloroformate (0.15 mL, 0.0011 mol) and stirred at -10 °C for 15 min. Then added a solution of l-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-bromo-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one trifluoroacetate (0/125 g, 0.00022 mol) in DMF ( 2,0 mL) containing diisopropylethylamine (0.1 g, 0.006 mL) and the resulting mixture was stirred for 16 h, at room temperature. The solvents were distilled in vacuo and the residue was purified by by reverse-phase HPLC using 10 - 90% CH3CN/Water (30 min gradient) at a flow rate of 100 mL/min. The appropriate fractions (m z = 608/610) were combined and freeze dried to afford 0.025 g of white powder. This was stirred with - 456 - trifluoroacetic acid (0.5 mL) for 1 h and product was isolated by reverse-phase HPLC using 10 - 90% CH3CN/Water (30 min gradient) at a flow rate of 100 mL/min. The appropriate fractions (m/z = 508/510) were combined and freeze dried to afford the title compound (0.02 g) as a white powder: 1H NMR (CD3OD/400 MHz) δ 8.18 (s, IH), 7.61 (m, IH), 7.02 (m, 2H), 6.59 (s, IH), 5.30 (s, 4H), 4.23 (s, 2H), 2.60 (s, 3H), and 2.47 (s, 3H); ES-HRMS m/z 508.0797 (M+H C21H2ιN503BrF2 requires 508.0790). Example 391. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl- l-{[2-(methylthio)pyrimidin-4-yl]methyl}pyridin-2(lH)-one
Figure imgf000457_0001
Step 1. Preparation of 4-(bromomethyl)-2-(methylthio)pyrimidine
Figure imgf000457_0002
To a solution of 4-methyl-2-methylthiopyrimidine (12.6 g, 0.09 mol) in acetic acid (50.0 mL) was added bromine (5.5 mL, 0.11 mol) and heated at 80°C under argon atmosphere for 2 h. Acetic acid was distilled in vacuo, the residue was triturated with dichloromethane (100.0 mL) and poured into satd. sod.bicarbonate solution (200.0 mL). Additional dichloromethane (100.0 ml) was added and stirred for 15 min. The organic phase was washed with water ( 3 x 100 mL), dried (Na2S04), and concentrated under reduced pressure. The dark colored residue was purified by flash chromatography (EtOAc/hexane 1:4 v/v) to afford 4-(bromomethyl)-2-(methylthio)ρyrimidine (10.9 g, 55%) as a dark colored liquid: 1H NMR (CDCl3/400 MHz) δ 8.50 (d, IH, J = 4.8 Hz), 7.09 (d, IH, J = 4.8 Hz), 4.34 (s, 2H), and 2.56 (s, 3H); ESMS m/z 219 (M+H). Step 2. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-{[2- (methylthio)pyrimidin-4-yl] methyl} pyridin-2(lH)-one. To a mixture of 3-bromo-4- [(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one 5.0 g, 0.015 mol) and 4-
- 457 - (Bromomethyl)-2-(methylthio)ρyrimidine (4.0 g, 0.018 mol) in THF (50.0 mL) was added NaH (0.4 g, 0.0017) and stirred at 55 °C under argon for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between 5% citric acid (25 mL) and EtOAc (50 mL). A precipitate was formed, it was filtered, washed with water, EtOAc, and dried in vacuo to afford the title compound (4.2 g, 59 %) as a light brown powder, 1H NMR (CD3OD/400 MHz) δ (8.45 (d, IH, J = 5.2 Hz), 7.6 (m, IH), 7.06 (d over m, 2H, J = 5.2 Hz), 6.54 (s, IH), 5.39 (s, 2H), 5.32 (s, 2H), 2.43 (s, 3H), 2.33 (s, 3H); ES-HRMS m/z 468.0173 (M+H C19H17N302BrSF2 requires 468.0187). Example 392. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl- l-{[2-(methylsulfonyl)pyrimidin-4-yl]methyI}pyridin-2(lH)-one
Figure imgf000458_0001
A suspension of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-{[2- (methylthio)pyrimidin-4-yl]m:ethyl}pyridin-2(lH)-one 0.28 g, 0.0006 mol), and magnesium monoperoxyphthalate hexahydrate 90.6 g, 0.0012 mol) in acetonitrile (8.0 ml) and water (2.0 ml) was stirred at room temperature for 16 h. The resulting clear solution was concentrated under reduced pressure, and the residue was partitioned between dichloromethane (30 mL) and water (20 mL). The organic phase was washed with water, dried (Na2S04) and concentrated to afford the title compound (0.27 g, 90%) as a pale yellow substance: 1H NMR (CD3OD/400 MHz) δ 8.91 (d, IH, J = 5.2 Hz), 7.63 (d over m, 2H, J = 5.2 Hz), 7.03 (m, 2H), 6.58 (s, IH), 5.54 (s, 2H), 5.33 (s, 2H), 3.28 (s, 3H), and 2.49 (s, 3H); 19F NMR (CD3OD/400 MHz)δ -111.58(m), -115.98 (m)QES-HRMS m/z 500.0113 (M+H C19H17N304BrSF2 requires 500.0086).
458 Example 393. Preparation of 4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l (2H)-yfJ methyl}pyrimidine-2-carbonitrile trifluoroacetate
Figure imgf000459_0001
CF3COOH A mixture of 3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-{[2- (methylsulfonyl)pyrimidin-4-yl]methyl}pyridin-2(lH)-one (1.0 g, 0.002 mol ) and NaCN (0.15 g, 0.0031 mol) in DMF (5.0 mL) was stirred at room temperature for 2 h under argon atmosphere. DMF was distilled in vacuo, the residue was triturated with acetonitrile (10 mL) and water (10 mL), and filtered the red colored precipitate. It was washed with acetonitrile and dried to afford the title compound (0.26 g). The washings and the fitrate were combined and purified by reverse-phase HPLC using 10 - 90% acetonitrile/water gradient (30 min) at a flow rate of 100 mL/min to give an additional 0.5 g of the title compound: 1H NMR (CD3OD/400 MHz) δ 8.83 (d, IH, J = 5.2 Hz), 7.62 (d over m, 2H, J = 5.2 Hz), 7.00 (m, 2H), 6.58 (s, IH), 5.46 (s, 2H), 5.33 (s, 2H), and 2.47 (s, 3H); 19F NMR (CD3OD/400 MHz) δ -111.64 (m), -116.03 (m); ES-HRMS m z 447.0278 (M+H C19H14N402BrF2 requires 447.0263). Example 394. Preparation of 4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3- bromo-l-(2,6-difluorophenyl)-6-methylpyridin-2(lH)-one trifluoroacetate
Figure imgf000459_0002
CF3COOH
To a solution of 4-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrimidine-2-carbonitrile trifluoroacetate (0.3 g. 0.00066mol) in a solvent mixture of EtOAc (15.0 mL) and acetic acid (5.0 mL), was added Pd/C (10 % , 0.18 g) and stirred in an atmosphere of hydrogen at 15 psi for 2 h. The catalyst was removed by - 459 - filtration . The filtrate was concentrated to dryness and the residue was residue was purified by reverse-phase HPLC using 10 - 90% acetonitrile/water gradient (30 min) at a flow rate of 100 mL/min. The appropriate fractions (m/z = 451) were combined and freeze dried to afford (0.32 g, 645) of the title compound as its trifluoroacetate salt: 1H NMR (DMSO-d6/400 mHz) δ 8.78 (d, IH, J = 5.2 Hz), 8.28 (br, 2H), 7.62 (m, IH), 7.38 (m, IH), 7.25 (d, IH, J = 5.2 Hz), 7.18 (m IH), 6.62 (s, IH), 5.32 (s, 2H), 5.29 (s, 2H), 4.24 (s, 2H), and 2.46 (s, 3H); 19F NMR (DMSO-d6/400 MHz) δ -109.59 (m), -113.67 (m); ES-HRMS m z 451.0530 (M+H C19H18N402BrF2 requires 451.0576). Example 395. Preparation of 3-bromo-4-[(2,4-difluorobenzyι)oxy]-l-[(2- methoxypyrimidin-4-yl)methyl]-6-methylpyridin-2(lH)-one trifluoroacetate
Figure imgf000460_0001
CF3COOH A solution of 4-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrimidine-2-carbonitrile trifluoroacetate (0.13 g, 0.00023 mol) in MeOH (2.0 mL) was treated with IN NaOH (0.5 mL). After stirring at room temperature for 3h, it was heated at 60 °C for an additional 3 h and left overnight room temperature. The resulting solution was diluted with acetonitrile, and purified by reverse-phase HPLC using 10 - 90% acetonitrile/water gradient (30 min) at a flow rate of 100 mL/min. The appropriate fractions (m z = 452 ) were combined and freeze dried to afford the title compound ( 0.015 g) as a white powder: 1H NMR (CD3OD) δ 8.84 (d, IH, J = 5.2 Hz) 7.62 (d, IH, J = 5.2 Hz), 7.05 (m, 2H), 6.57 (s, IH), 5.49 (s, 2H), 5.32 (s, 2H), 3.96 (s, 3H), and 2.49 (s, 3H); ES-HRMS m/z 452.0440 (M+H C19H17N303BrF2 requires 452.0416).
460 Example 396. Preparation of Methyl 4-{[3-bromo-4-[(2,4- difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}pyrimidine-2- carboxylate trifluoroacetate
Figure imgf000461_0001
The title compound was obtained as a second product in the formation of 3-Bromo-4- [(2,4-difluorobenzyl)oxy] - 1 - [(2-methoxypyrimidin-4-yl)methyl] -6-methylpyridin-2( 1 H)- one trifluoroacetate. 1H NMR (CD3OD/400 MHz) δ 8.46 (d, IH, J = 5.2 Hz), 7.62 (m, IH), 7.00 (m 2H), 6.93 (d, IH, J = 5.2 Hz), 6.55 (s, IH), 5.39 (s, 2H), 5.32 (s, 2H), 3.85 (s, 3H), and 2.44 (s, 3H); ES-HRMS m z 480.0340 (M+H C20H17N3O BrF2 requires 480.0365). Example 397. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[(2- hy droxypyrimidin-4-yl)methyl] -6-methylpyridin-2(l H)-one trifluoroacetate
Figure imgf000461_0002
A mixture of 4-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrimidine-2-carbonitrile trifluoroacetate (0.2 g, 0.00035 mol) potassium fluoride on aluminum oxide (0.25 g) in t-butanol (5.0 mL) was refluxed for 4 h under argon atmosphere. , The reaction mixture was cooled, filtered the precipitate and washed with ethanol. The combined filtrate and washings were concentrated to dryness and the residue was purified by reverse-phase HPLC using 10 - 90% acetonitrile/water gradient (30 min) at a flow rate of 100 mL/min. The appropriate fractions (m z = 452) were combined and freeze dried to afford the title compound ( 0.05 g) as a white powder: 1H NMR (DMSO-d6/400 Mz) δ 8.75 (d, IH J = 6.4 Hz), 7.64 (m, IH), 7.30 (m IH), 7.15 (m IH), 6.55 (s, IH), 6.22 (d, IH, J = 6.4 Hz), 5.28 (s, 2H), 5.12 (d, 2H), and 2.29 (s, 3H);
- 461 - 19F- NMR (DMSO-d6/400 MHz) δ - 109.69 (m), and -113.67 (m); ES-HRMS m z 438.0228 (M+HC18H15N3θ3BrF2 requires 438.0259). Example 398. Preparation of 4-{[3-bromo-4-[(2,4-difluorobenzyϊ)oxy]-6- methyl-2-oxopyridin-l (2H)-yl] methyl}pyrimidine-2-carboxamide trifluoroacetate
Figure imgf000462_0001
The title compound was obtained by a procedure described for Example 397. 1H NMR (DMSO-d6/400 MHz) δ 8.82 (d, IH J = 5.2 Hz), 8.01 (br, IH), 7.79 (br IH), 7.64 (m, IH), 7.34 (m , 2H), 7.16 (m IH), 6.62 (s, IH), 5.36 (s, 2H), 5.30 (s, 2H), and 2.38 (s, 3H); 19F NMR (DMSO-d6/400 MHz) δ -109.64 (m), and -113.66 (m); ES-HRMS m/z 465.0385 (M+H C19H16N403BrF2 requires 465.0368). Example 399. Preparation of Methyl (4-{[3-bromo-4-[(2,4- difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}pyrimidin-2- yl)methylcarbamate
Figure imgf000462_0002
To a solution of 4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3-bromo-l-(2,6- difluorophenyl)-6-methylpyridin-2(lH)-one trifluoroacetate (0.13 g, 0.00023 mol) in dimethylacetamide (1.0 mL), was added triethylamine (0.04 mL, 0.0003 mol), followed by the addition of methylchloroformate (0.05 mL) and stirred at 0 °C for 30 min under argon atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 20 mL), The combined organic extracts were washed with water, dried (Na2S04) and concentrated to dryness. The resulting residue was purified by flash chromatography (5% MeOH in EtOAc) to afford the title compound (0.055 g, 37%) as pale yellow powder: 1H NMR (DMSO-d6/400 MHz) δ 8.65 (d, IH J = 5.6 Hz), 7.63 (IH), - 462 - 7.5 (m, IH), 7.28 (m IH), 7.13 (m, 2H), 6.59 (s, IH), 5.28 (s, 4H), 5.26 (d, 2H, J = 6.0 Hz), and 2.46 (s, 3H); 19F NMR (DMSO-d6/400 MHz) δ -109.64 (m), and -113.71 (m); ES-HRMS m/z 509.0621 (M+H C21H20N4O4BrF2 requires 509.0630). Example 400. Preparation of 3-bromo-4-[(2,4-difluorobenzyϊ)oxy]-6-methyI- l-[(5-methylpyrazin-2-yl)methyl]pyridin-2(lH)-one
Figure imgf000463_0001
Step 1. Preparation of 4-hydroxy-6-methyl-l-[(5-methylpyrazin-2- yϊ)methyl]pyridin~2(lH)-one
Figure imgf000463_0002
A mixture of 4-hydroxy-6-methyl-2-pyrone (5.0 g, 0.04 mol) and 5-aminomethyl-2- methylpyrazine (5.0 g, 0.041 mol) in water (25.0 ml) was heated at 100 °C for 1 h under argon atmosphere. The reaction mixture was cooled, and filtered the yellow precipitate. It was washed with ethanol, and dried in vacuo to afford the title compound (5.8 g, 63%) as a pale yellow powder: 1H NMR (DMSO-d6/400 MHz) δ 10.43 (br, IH), 8.38(d, 2H, J = 5.2 Hz), 5.77 (d, IH, J = 2.0 Hz), 5.58 (d, IH, J = 2.0 Hz), 4.92 (s, 2H), 2.24 (s, 3H), and 2.22 (s, 3H); ESMS m/z 232 (M+H). Step 2. Preparation of 3-bromo-4-hydroxy-6-methyl-l-[(5-methylpyrazin-2- yl)methyl]pyridin-2(lH)-one
Figure imgf000463_0003
463 - The title compound was prepared by a procedure described in step 2 for Example 385. Yield: 64%, 1H NMR (CD3OD/400 MHz) δ 8.47 (s, IH), 8.42 (s, IH), 6.07 (s, IH), 5.38 (s, 2H), 2.51 (s, 3H), and 2.44 (s, 3H), ESMS m z 310 and 312 (M+H). Step 3. Preparation of 3-bromo-4-[(2,4-difluorobenzyI)oxy]-6-methyl-l-[(5- methylpyrazin-2-yl)methyl]pyridin-2(lH)-one. To a mixture of 3-Bromo-4-hydroxy-6- methyl-l-[(5-methylρyrazin-2-yl)methyl]pyridin-2(lH)-one (0.45 g, 0.0015 mol), and potassium carbonate (0.25 g, 0.0018 mol) in dimethylacetamide (5.0 mL) was added 2,4 difluorobenzyl bromide (0.25 mL. 0.0019 mol)and stirred at room temperature under argon for 1 h. Dimethylacetamide was distilled in vacuo and the residue was partitioned between CH2C12 (20 mL) and water (20 mL). The organic phase was washed with water, dried (Na2S04) and concentrated under reduced pressure. The resulting material was purified by flash chromatography (EtOAc/hexane 4:1 v/v) as the eluent. The appropriate fractions (m z = 451/453) were combined and concentrated under reduced pressure to give a white (0.25 g, 38% )solid. 1H NMR (CD3OD/400 MHz) δ 8.49 (s, IH), 8.40 (s, IH), 7.60 (m, IH), 6.99 (m, 2H), 6.51 (s, IH), 5.42 (s, 2H), 5.29 (s, 2H), 2.54 (s, 3H), and 2.50 (s, 3H); 19F NMR (CD3OD/400 MHz) δ -117.70 (m) and -116.09 (m); ES-HRMS m/z 436.0439 (M+HC19H17N302BrF2 requires 436.0467). Example 401. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl- l-(pyrazin-2-ylmethyl)pyridin-2(lH)-one
Figure imgf000464_0001
Step 1. Preparation of 2- chloromethylpyrazine
Figure imgf000464_0002
A mixture of 2-methylpyrazine (3.5 g, 0.037 mol), NCS (6.3 g, 0.047 mol) and benzoyl peroxide (0.05 g) was heated to reflux for 16 h under argon atmosphere. It was filtered and the filtrate was concentrated to dryness. The resulting residue was purified by flash chromatography using 30 % EtOAc in hexane to afford 2-chloromethylpyrazine as a dark
464 colored liquid (1.7 g, 36 5): 1H NMR (CD3OD/400 MHz) δ 8.75 (d, IH, J = 1.2 Hz), 8.58 (m, IH), 8.56 (m, IH), and 4.75 (s, 2H); ESMS m/z = 129 (M+H). Step 2. Preparation of 3-bromo-4-[(2,4~difluorobenzyι)oxy]-6-methyl-l- (pyrazin-2-ylmethyι)pyridin-2(lH)-one. 3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6- methylρyridm-2(lH)-one (1.8 g, 0.0055 mol) and 2- chloropyrazme (0.8 g, 0.00625) were suspended in THF (25 mL), then added NaH (0.15 g, 0.0062 mol), KI (0.1 g) and the mixture was heated at 65 °C under argon atmosphere for 16 h. The reaction mixture was cooled, added acetic acid (0.5 mL) and concentrated to dryness under reduced pressure. The residue was stirred with a mixture of water (50 mL) and EtoAc (25 mL) and filtered the precipitate. It was washed with water, and acetonitrile an dried in vacuo to afford 1.7 g of light brown powder. 1H NMR (CD3OD/400 MHz) δ 8.65 (d, IH), 8.49 (m, IH), 8.47 9m, IH), 7.61 (~ q, IH), 7.02 (m, 2H), 6.52 (s, IH), 5.47 (s, 2H), 5.23 (s, 2H), and 2.53 (s, 3H); 19F NMR (CD3OD/400 MHz) δ -111.72 (m) and -116.07 (m); ES-HRMS m/z 422.0283 (M+H C18H15N302BrF2 requires 422.0310). Example 402. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{[5-
(hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(lH)-one
Figure imgf000465_0001
Step 1. Preparation of ethyl 5-methylpyrazine-2-carboxylate
Figure imgf000465_0002
A solution of 5-methylpyrazine-2-carboxylic acid (15.0 g, 0.109 mol) in ethanol (70.0 mL) containing (1.5 g, 0.0079 mol) was heated to reflux for 4 h under argon atmosphere. The dark colored solution was cooled, added sod.bicarbonate (1.0 g) and concentrated under reduced pressure. The residue was partitioned between water (50 mL) and EtOAc (100 mL). The organic layer was washed with water (2 x 25 mL), dried (Na2S04), and - 465 - concentrated under reduced pressure to afford ethyl 5-methylpyrazine-2-carboxylate (12.05 g, 67%) as an orange colored liquid: 1H NMR (CD3OD/400 MHz) δ 9.1 (d, IH, J = 1.2 Hz), 8.62 (d, IH, J = 1.2 Hz), 4.45 (q, 2H, J = 7.2 Hz), 2.63 (s, 3H), and 1,41 (t, 3H, J = 7.2 Hz); ESMS m/z 167 (M+H). Step 2. Preparation of ethyl 5-(bromomethyϊ)pyrazine-2-carboxylate
Figure imgf000466_0001
cr oεt A solution of ethyl 5-methylpyrazine-2-carboxylate (12.0 g, 0.072 mol) in glacial acetic acid (60 mL) containing bromine (4.0 mL) was heated at 80 °C under anhydrous conditions for 45 min. After the removal of acetic acid in vacuo, the residue was partitioned between saturated, bicarbonate (100 mL) and EtOAc (3 x 30 mL). The combined EtOAc extracts were washed with water (2 x 25 mL), dried (Na2S04), and concentrated under reduced pressure. The resulting liquid was purified by flash chromatography (20 %EtOAc in hexane) to afford ethyl-(5bromomethylpyrazine-2- carboxylate (7.7 g, 44%) as an orange colored liquid: !H NMR (CD3OD/400 MHz) δ 9.18 (d, IH, J = 1.2 Hz), 8.85 (d, IH, J = 1.2 Hz), 4.71 (d, 2H), 4.47 (q, 2H, J = 7.2 Hz), and
1.42 (t, 3H, J = 7.2 Hz); ES-HRMS m/z 244.9942 (M+H C8H10N2O2Br requires 244.9920). Step 3. Ethyl 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl] methyl}pyrazine-2-carboxylate
Figure imgf000466_0002
To a mixture of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one (6.0 g,
0.018 mol) and ethyl 5-(bromomethyl)pyrazine-2-carboxylate (4.9 g, 0.02 mol) in THF
(50.0 mL) was added NaH (0.5 g) and heated at 55 °C under argon atmosphere for 3 h.
The reaction mixture was cooled, added acetic acid (1.2 ml)and concentrated under
466 reduced pressure. The residue was triturated with water and filtered the solid. It was washed with water, followed by ethanol and dried in vacuo to afford the title compound (3.0 g, 78% )as alight brown powder: 1H NMR (CD3OD/400 MHz) δ 9.10 (d, IH, J = 1.2 Hz), 8.77 (d, IH, J = 1.2 Hz), 7.61 (m, IH), 7.01 (m 2H), 6.54 (s, IH), 5.54 (s, 2H), 5.30 (s, 2H), 4.43 (q, 2H, J = 6.8 Hz), 2.52 (s, 3H), and 1,39 (t, 3H, J = 6.8 Hz); 19F NMR (CD3OD/400 MHz) δ -111.64 (m) and -116.04 (m); ES-HRMS m/z 494.0482 (M+H C21H19N304BrF2 requires 494.0522). Step 4. 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{[5-(hydroxymethyI)pyrazin-2- yl]methyl}-6~methylpyridin-2(lH)-one. To a suspension of ethyl 5-{[3-bromo-4-[(2,4- difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}pyrazine-2-carboxylate (2.0 g, 0.004 mol) in t-butanol (15,0 L and THF (5.0 mL) was added NaBH4 (0.18 g, 0.0047 mol) and the mixture was stirred at room temperature for 16 h under argon atmosphere. It was cooled, added MeOH (5.0 mL) and acetic acid (1.0 mL) and concentrated to dryness . The residue was triturated with water and filtered. It was washed with water, dried in vacuo and purified by flash chromatography (1% MeOH in EtOAc to afford the title compound (0.75 g, 41%) as a pale yellow powder: 1H NMR (CD3OD/400 MHz) δ 8.58 (d, IH, J = 1.6 Hz), 8.56 (d, IH, J = 1.6 Hz), 7.6 (m, IH), 7.01(m, 2H), 6.52 (s, IH), 5.46 (s, 2H), 5.29 (s, 2H), 4.71 (s, 2H), and 2.54 (s, 3H); 19F NMR (CD3OD/400 MHz) δ -111.70 (m) and -116.06 (m); ES-HRMS m/z 452.0394 (M+H C19H17N303BrF2 requires 452.0416). Example 403. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-({5- [(dimethylamino)methyl]pyrazin-2-yl}methyl)-6-methylpyridin-2(lH)-one trifluoroacetate
Figure imgf000467_0001
467 - Step 1. Preparation of 3-bromo-l-{[5-(chloromethyl)pyrazin-2-yl]methyl}-4- [(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one
Figure imgf000468_0001
Cyanurylchloride (0.42g, 0.0023 mol) was added to DMF (0.52 mL) and stirred at room temperature for 15 min. Then added dichloromethane (15 mL) followed by the addition of 3-Bromo-4-[(2,4-difluorobenzyl)oxy]-l-{[5-(hydroxymethyl)pyrazin-2-yl]methyl}-6- methylpyridin-2(lH)-one 1.0 g, 0.0022 mol) and reaction mixture was stirred at room temperature under argon atmosphere. After 1 h, an additional 1.0 mL of DMF was added and the reaction was allowed to proceed for another hour, when a clear solution was obtained. The solution was diluted with dichloromethane (20 mL) and washed with water, dried (Na S04), and concentrated to dryness under reduced pressure. The residue was triturated with EtOAc, filtered, washed with EtOAc and dried to afford 0.79 g ( 77%) of the title compound as a pale yellow powder: 1H NMR (CD3OD/400MHz) δ 8.66 (s, 2H), 7.73 (m, IH), 7.05 (m, 2H), 6.56 (s, IH), 5.52 (s, 2H), 5.33 (s, 2H), 4.74 (s, 2H), and 2.57 (s, 3H); ES-HRMS m z 470.0051 (M+H C19H16N302BrClF2 requires 470.0077). Step 2. Preparation of 3-bromo-l-{[5-(chIoromethyi)pyrazin-2-yf]methyI}-4- [(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one A suspension of 3-bromo-l-{[5- (chloromethyl)pyrazin-2-yl]methyl}-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)- one (0.25 g, 0.00053 mol) in THF (1.0 mL) was treated with N, N,-dimethyl amine (1.0 mL of 2M soln in THF) and stirred at room temperature for 16 h. The reaction mixture was concentrated and the title compound was isolated by reverse-phase HPLC using 10 - 90% acetonitrile/water gradient (30 min) at a flow rate of 100 mL/min. The appropriate fractions (m/z = 479) were combined and freeze dried to afford the title compound (0.27 g, 87%) as a white powder: 1H NMR (CD3OD/400MHz) δ 8.78 (d, IH), 8.56 (d, IH, J = 1.2 Hz), 7.61 (m IH), 7.01 (m, 2H), 6.55 (s, IH), 5.49 (s, 2H), 5.30 (s, 2H), 4.52 (s, 2H), 2.94 (s, 6H) and 2.57 (s, 3H); 19F NMR (CD3OD) δ -111.56 (m) and -116.02 (m); ES-HRMS m/z 479.0885 (M+H C21H22N402BrF2 requires 479.0889). - 468 - Example 404. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[(5-{[(2- hydroxyethyl)(methyl)amino]-methyl}pyrazin-2-yl)methyl]-6-methylpyridin-2(lH)- one trifluoroacetate
Figure imgf000469_0001
The title compound was prepared in a similar manner as described for Example 403, substituting N-methylaminoethanol for N, N-dimethylamine. Yield = 78%, 1H NMR
(CD3OD/400MHz) δ 8.78 (d, IH), 8.59 (d. IH, J = 1.2 Hz), 7.6 (m, IH), 7.01 (m, 2H),
6.55 (s, IH), 5.49 (s, 2H), 5.30 (s, 2H), 3.89 (~t, 2H), 2.97 (s, 3H), and 2.57 (s, 3H); 19F
NMR (CD3OD/4OO MHz) δ -111.56 (m) and -116.04 (m); ES-HRMS m/z 509.0964 (M+H C22H24N403BrF2 requires 509.0994). Example 405. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl- l-({5-[(4-methylpiperazin-l-yl)carbonyl]pyrazin-2-yl}methyl)pyridin-2(lH)-one trifluoroacetate
Figure imgf000469_0002
469 Step 1. Preparation of 5-{[3-bromo-4-[(2,4-difiuorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)~yl]methyl}pyrazine-2-carboxylic acid
Figure imgf000470_0001
A suspension of ethyl 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]methyl}pyrazine-2-carboxylate (0.18 g, 0.002 mol) and INNaOH (0.6 mL in 1:1 v/v EtOH Water) was stirred at room temperature for 1.5 h. The reaction mixture was acidified with 5% citric acid and filtered the precipitate. It was washed with water, followed by ethanol and dried in vacuo to afford the title compound (0.14 g, 77%) as a light brown powder: 1H NMR (CD3OD/400 MHz) δ 9.03 (s, IH), 8.60 (s, IH), 7.61 (m.lH), 7.00 ( , 2H), 6.52 (s, IH), 5.51 (s, 2H), 5.30 (s. 2H), and 2.52 (s, 3H); 19F NMR (CD3OD/400 MHz) δ -111.75 (m) and -116.06 (m); ES-HRMS m z 466.0209 (M+H C19H15N403BrF2 requires 466.0209). Step 2. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-({5- [(4-methylpiperazin-l-yl)carbonyl]pyrazin-2-yl}methyl)pyridin-2(lH)-one trifluoroacetate. To a solution of 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxoρyridin-l(2H)-yl]methyl}pyrazine-2-carboxylic acid (0.28 g, 0.0006 mol) in DMF (3.0 mL), at -15 °C, was added isobutylchloroformate (0.082g, 0.0006 mol), followed by the addition of N-methylmorpholine (0.06 g, 0.00063 mol) and stirred under argon for 15 min. N-methylpiperazine (0.072 g, 0.00072 mol) in DMF (2.0 mL) was then added to the reaction and the mixture was stirred at room temperature for 3 h. After the removal of the solvents in vacuo, the residue was purified by reverse-phase HPLC using 10 - 90% acetonitrile/water gradient (30 min) at a flow rate of 100 mL/min. The appropriate fractions (m/z = 548) were combined and freeze dried to afford the title compound ( 0.32 g, 80%) as a white powder: 1H NMR (CD3OD/400 MHz) δ 8.89 (d, IH, J = 1.6 Hz), 8.73 (d, IH, J = 1.6 Hz), 7.61 (m, IH), 7.01 (m,2H), 6.56 (s, IH), 5.50 (s, 2H), 5.30 (s, 2H), 2.9 (s, 3H), and 2.57 (s, 3H); 19F NMR (CD3OD/400 MHz) = δ -109.36 (m) and -114.91(m); ES-HRMS m/z 548.1090 (M+H C24H25N503BrF2 requires 548.1103).
- 470 - Example 406. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl- l-({5-[(4-methylpiperazin-l-yl)carbonyl]pyrazin-2-yl}methyl)pyridin-2(lH)-one
Figure imgf000471_0001
A solution of 3 -Bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl- 1 -( { 5 -[(4-mefhylpiperazin- l-yl)carbonyl]pyrazin-2-yl}methyl)pyridin-2(lH)-one trifluoroacetate (0.17 g, 0.00026 mol) in 0.1N NaOH (25 mL) was stirred at room temperature for 15 min. and extracted the product in ethyl acetate (2 x 20 mL). The combined organic extracts were washed with water (2 x 20 mL), dried (Na2S04) and concentrated to dryness. The residue was dried in vacuo to afford the title product (0.09 g, 64%) as a white powder: 1H NMR (CD3OD/400 MHz) δ 8.69 (d, IH, J = 1.2 Hz), 8.67 (d, IH, J = 1.2 Hz), 7.60 (m, IH), 7.00 (m, 2H), 6.54 (s, IH), 5.50 (s, 2H), 5.30 (s, 2H), 3.78 (t, 2H, J = 4.8 Hz), 3.58 (t, 2H, J = 4.8 Hz), 2.526 (s, 3H), 2.53 (t, 2H, J = 4.8 Hz), 2.44 (t, 2H, J = 4.8 Hz), and 2.31 (s, 3H); 19F NMR (CD3OD/400 MHz) δ -111.65 (m) and -116.06(m); ES-HRMS m/z 548.1123 (M+H C24H25N503BrF2 requires 548.1103). Example 407. Preparation of 5-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]methyl}-N-(2-hydroxyethyl)-N-methylpyrazine-2- carboxamide
Figure imgf000471_0002
The title compound was prepared in a similar manner as described for Example 405, substituting N-methylpiperazine by N-methylethanolamine. Yield = 60%, 1H NMR
471 - (CD3OD/400 MHz) δ 8.69 (d, IH, J = 1.2 Hz), 8.64 (d. IH, J = 1.2 Hz), 7.61 (m, IH), 7.00 (m, 2H), 6.54 (s, IH), 5.49 (s. 2H), 5.30 (s, 2H), 3.81 (~ t, IH), 3.66 (m, 2H), 3.56 (t, IH, J = 5.2 Hz), 3.12 (d, 3H J = 7.6 Hz), 2.56 (s, 3H); 19F NMR (CD3OD/400 MHz) δ - 109.64 (m) and-113.66(m); ES-HRMS m/z 523.0743 (M+H C22H22N 04BrF2 requires 523.0797). Example 408. Preparation of 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]methyl}-N-(2,3-dihydroxypropyl)pyrazine-2- carboxamide
Figure imgf000472_0001
The title compound was prepared in a similar manner as described for EXAMPLE 405, substituting N-methylpiperazine by 3-amino-l,2-propanediol. Yield = 56%; 1H NMR (CD3OD/400 MHz) δ 9.09 (d, IH, J = 1.2 Hz), 8.70 (d. IH, J = 1.2 Hz), 7.60 (m,lH), 7.00 ( , 2H), 6.54 (s, IH), 5.53 (s. 2H), 5.30 (s, 2H), 3.80 (m, IH), 3.61 (dd, IH), 5.53 (d, 2H), J = 5.2 Hz), 3.42 (dd, IH), and 2.55 (s, 3H); 19F NMR (CD3OD/400 MHz) δ -109.65 (m) and -113.67(m); ES-HRMS m/z 539.0703 (M+H C22H22N404BrF2 requires 539.0736). Example 409. Preparation of 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]methyl}-N-(2-hydroxyethyl)pyrazine-2-carboxamide
Figure imgf000472_0002
The title compound was prepared in a similar manner as described for EXAMPLE 405, substituting N-methylpiperazine by 2-aminoethanol. Yield = 46%; 1H NMR (CD3OD/400 Hz) δ 9.08 (d, IH, J = 1.2 Hz), 8.70 (d, IH, J = 1.2 Hz), 7.601 (m, IH), 7.01 (m, 2H), - 472 - 6.54 (s, IH), 5.53 (s, 2H), 5.30 (s, 2H), 3.69 (t, 2H, J = 6.0 Hz), 3.53 (t, 2H, J = 6.0 Hz),
2.55 (s, 3H); 19F NMR (CD3OD/400 Hz) δ -111.67 (m) and-116.07(m); ES-HRMS m z 509.0616 (M+HC21H20N4O4BrF2 requires 509.0630). Example 410. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{[5- (methoxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(lH)-one
Figure imgf000473_0001
To a solution of 3-Bromo-4-[(2,4-difluorobenzyl)oxy]-l-{[5-(hydroxymethyl)pyrazin-2- yl]methyl}-6-methylpyridin-2(lH)-one (0.35 g, 0.00078 mol) in DMF at 0 °C, was added NaH (0.022 g, 0.00092 mol) and stirred for 10 min. Iodomethane (0.05 mL) was added to the reaction and the mixture was stirred at 10 °C for 3 h. DMF was distilled in vacuo and the residue was partitioned between 5% citric acid and EtOAc (15.0 mL). The organic phase was washed with water, dried (Na2S04) and concentrated to dryness. The residue was purified by flash chromatography (EtOAc), and the appropriate fractions were combined and concentrated to a pale yellow powder. !H NMR (CD3OD/400 MHz) δ 8.59 (s), 8.55 (s, IH), 7.60 (m, IH), 6.99 (m, 2H), 6.52 (s, IH), 5.47 (s, 2H), 5.30 (s, 2H), 4.57 (s, 2H), 3.44 (s, 2H), and 2.54 (s, 3H); 19F NMR (CD3OD/400 Hz) δ -11.69 (m) and- 116.09(m); ES-HRMS m/z 466.0577 (M+H C21H19N303BrF2 requires 466.0572). Example 411. Preparation of 3-bromo~4-[(2,4-difIuorobenzyl)oxy]-l-({5-[(2- methoxyethoxy)methyl]pyrazin-2-yl}methyl)-6-methylpyridin-2(lH)-one
Figure imgf000473_0002
To a solution of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{[5-(hydroxymethyl)pyrazin-2- yl]methyl}-6-methylpyridin-2(lH)-one (0.25 g, 0.00055 mol) in dimethyl acetamide at - 473 - 0 °C, was added NaH (0.016 g, 0.00067 mol) and stirred for 15 min. 2-Methoxyethyl bromide (0.09 g, 0.00-65 mol) was then added , and the mixture was stirred at room temperature for 6 h. Dimethylacetamide was distilled in vacuo and the product was purified by reverse-phase HPLC using 10 - 90% acetonitrile/water gradient (30 min) at a flow rate of 100 mL/min. The appropriate fractions (m/z = 510) were combined and freeze dried to afford the title compound (0.32 g, 80%) as a white powder: 1H NMR (CD3OD/400 Hz) δ 8.59 (s, IH), 8.58 (s, IH), 7.60 (m , IH), 7.02 (m, 2H), 6.52 (s, IH), 5.45 (s, 2H), 5.29 (s, 2H), 4.67 (s, 2H), 3.71 (~t, 2H, ), 3.57 (~t, 2H), 3.34 (s, 3H), and 2.54 (s, 3H); ES-HRMS m/z 510.0852 (M+H C20H18N4O4BrF2 requires 510.0835). Example 412. Preparation of (5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]methyl}pyrazin-2-yl)methyl carbamate
Figure imgf000474_0001
To a suspension of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{[5-(hydroxymethyl)pyrazin- 2-yl]methyl}-6-methylpyridin-2(lH)-one (0.21 g, 0.00055 mol) in THF (5.0 mL) and DMF (2.0 mL), was added 4-nifrophenylchloroformate (0.1 g, 0.0005 mol) and cooled to 0 °C. Triethylamine (0.052g, 0.0005 mol) was then added, stirred at room temperature for 1 h, and at 65 °C for an additional lh. It was cooled in an ice bath and added 2M ammonia in propanol (1.0 mL) and stirred at room temperature for 2 h. After the removal of the solvents under reduced pressure, the residue was partitioned between 5% sod. bicarbonate, and EtOAc (25 mL). The organic phase was washed with 5% sod. bicarbonate, (3 x 25 mL), water (3 x 25 mL), dried (Na2S04) and concentrated under reduced pressure. The resulting substance was purified by isolated by reverse-phase HPLC using 10 -90% CH3CN/ ater (30 min gradient) at a flow rate of 100 mL/min. The appropriate fractions (m/z= 495 M+H) were combined and freeze-dried, and the residue was partitioned between 5% sod. bicarbonate (20 mL) and EtOAc (25 mL). The organic phase was ' washed with water, dried (Na2S0 ) and concentrated to dryness under reduced pressure, to
474. afford the title compound as a white powder (0.065 g): 1H NMR (CD3OD/400 MHz) δ 8.61 (s, IH), 8.54 (br s, IH), 7.60 )m IH), 7.02 (m, 2H), 6.52 (s, IH), 5.47 (s, 2H), 5.29 (s, 2H), 5.15 (s, 2H), and 2.54 (s, 3H): 19F NMR (CD3OD) δ -111.70 (m), and -116.09 (m); ES-HRMS m/z 495.0449 (M+HC20H18N4O4BrF2 requires 495.0474). Example 413. Preparation of l-benzyl-3-bromo-2-oxo-l,2-dihydropyridin-4- yl methyl(phenyι)carbamate
Figure imgf000475_0001
Step 1. Preparation of l-benzyl-2-oxo-l,2-dihydropyridin~4-yl methyl(phenyl)carbamate
Figure imgf000475_0002
To a chilled solution of l-benzyl-4-hydroxypyridin-2(lH)-one (0.375 g, 1.86 mmol) in anhydrous acetonitrile (10 mL) was added triethylamine (0.206 g, 2.04 mmol) followed by N-methyl-N-phenylcarbamoyl chloride (0.379 g, 2.24 mmol). The reaction mixture was stirred under nitrogen atmosphere at 0° C for 30 minutes then at room temperature for lhour. The reaction was monitored by TLC (5% methanol in dichloromethane). The solvent was removed under reduced pressure and the residue was washed with 10% citric acid and extracted with ethyl acetate. The organic extracts were combined, washed with water and dried over anhydrous Na2S04. The solvent was removed under reduced pressure to afford a yellow syrup. The residue was purified by flash chromatography (silica gel) using 5% MeOH in CH2C12 to give the desired product (0.382g, 61%) as a white semisolid. 1H-NMR (d6-DMSO, 400 MHz) δ7.8 (d, IH, J= 7.2 Hz), 7.39 (m, 10H), 6.19 (s, 2H), 5.03 (s, 2H), 3.29 (s, 3H); ES-HRMS m/z 335.1396 (M+H calculated for C20H19N2O3 requires 335.1418).
475 Step 2. Preparation of l-benzyI-3-bromo-2-oxo-l,2-dihydropyridin-4-yl methyl(phenyl)carbamate
Figure imgf000476_0001
To a solution of l-benzyl-2-oxo-l,2-dihydropyridin-4-yl methyl(phenyl)carbamate (0.38 g, 1.13 mmol) in anhydrous CH2C12 (7 mL) was added N-bromosuccinimide (NBS, 0.24 g, 1.34 mmol). The reaction was stirred overnight at room temperature under nitrogen atmosphere. The reaction mixture was purified by flash chromatography (silica gel) using ethyl acetate/hexane (1:1 v/v). The appropriate fractions were collected according to ES MS (M+H 413) and concentrated. The dried product showed about 14% of di-bromonated product by analytical HPLC. The compounds were separated by reverse phase HPLC using a 10-90% acetonitrile in water (30 minute gradient) at a 100 mL/min flow rate to afford (after lyophilization) the salt of the desired compound. The salt was diluted in ethyl acetate and washed with NaHC03. The organic extracts were dried over anhydrous Na2S04 and concentrated to afford the desired compound (0.271 g, 58%) as a beige solid. 1H-NMR (d6-DMSO, 400 MHz) δ7.94 (d, IH, J= 7.2 Hz), 7.29 (m, 10H), 6.48 (s, IH), 5.12 (s, 2H), 3.33 (s, 3H); ES-HRMS m z 413.0495 (M+H calculated for C20H18O3Br requires 413.0496). Example 414. Preparation of 4-(benzyloxy)-3-ethynyl-l-(3- fluorobenzyι)pyridin-2(lH)-one
Figure imgf000476_0002
Step 1. Preparation o 4-(benzyloxy)-l-(3-fluorobenzyι)~3-iodopyridia-2(lH)- one
Figure imgf000476_0003
476 A mixture of 4-(benzyloxy)-l-(3-fluorobenzyl)pyridin-2(lH)-one (4.83 g, 15.6 mmol) in anhydrous acetonitrile (55 mL) and N-iodosuccinimide (NIS, 3.86 g, 17.1 mmol) was heated at 65° C under nitrogen for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (silica gel) using ethyl acetate/hexane (1:1 v:v). The appropriate fractions were collected according to ES MS (M+H 436) and washed with Na2Sθ3 to remove the color impurities. The fractions were concentrated under reduced pressure and dried in vacuo to afford the desired product (6.15 g, 90%) as a light yellow solid. 1H-NMR (CD3OD, 400 MHz) δ7.73 (d, IH, J= 7.6 Hz), 7.47 (d, 2H, J= 7.2 Hz), 7.39 (m, 4H), 7.08 (m, 3H), 6.39 (d, IH, J= 8.0 Hz), 5.29 (s, 2H), 5.19 (s, 2H); ES-HRMS m/z 436.0210 (M+H calculated for C19Hι6N02FI requires 436.0196). Step 2. Preparation of 4-(benzyloxy)-l-(3-fluorobenzyι)-3- [(trimethylsilyl)ethynyl]pyridin-2(lH)-one
Figure imgf000477_0001
Degassed a solution of 4-(benzyloxy)-l-(3-fluorobenzyl)-3-iodopyridin-2(lH)-one (2.01 g, 4.62 mmol) in anhydrous acetonitrile (25 mL) under argon atmosphere. Triethylamine (1.11 g, 11 mmol) was added and quickly degassed. The reaction mixture was chilled in an ice bath for 15 minutes before adding bistriphenylphosphine-palladium chloride (0.34 g, 0.48 mmol) and cuprous iodide (0.2 g). The reaction was stirred at room temperature for 30 minutes before heating at 60° C under an atmosphere of argon for 2 hours. The reaction mixture was filtered through a bed of celite and the filtrate was concentrated under reduced pressure. The dark brown residue was diluted with CH2C12 (100 mL) and washed with water. The organic extracts were combined, dried over anhydrous Na2S04, and concentrated under reduced pressure. The dark brown residue was purified by flash chromatography using 30% ethyl acetate in hexane. The appropriate fractions were combined and concentrated under reduced pressure to afford the desired product (1.34 g, 72%) as a light yellow solid. 1H-NMR (CD3OD, 400 MHz) δ7.74 (d, IH, J= 7.6 Hz), 7.47 (d, 2H, J= 7.6 Hz), 7.35 (m, 4H), 7.09 (m, 3H), 6.46 (d, IH, J= 7.6 Hz), 5.26 (s, 2H), 5.13
477 (s, 2H), 0.18 (s, 9H); ES-HRMS m/z 406.1638 (M+H calculated for C24H25N02FSi requires 406.1610). Step 3. Preparation of 4-(benzyloxy)-3-ethynyl-l-(3-fluorobenzyϊ)pyridin- 2(lH)-one
Figure imgf000478_0001
To a solution of 4-(benzyloxy)-l-(3-fluorobenzyl)-3- [(trimethylsilyl)ethynyl]pyridin-2(lH)-one (1.31 g, 3.2 mmol) in anhydrous acetonitrile (25 mL) at 0° C was added tetrabutylammoniun fluoride (0.61 lg, 1.93 mmol). The reaction was stirred at 0° C for 15 minutes then for 1 hour at room temperature. The reaction was concentrated under reduced pressure and the residue was diluted with ethyl acetate and washed with water. The organic extracts were combined, dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel) using ethyl acetate in hexane (1 : 1 v/v). The appropriate fractions were combined and concentrated under reduced pressure to afford the desired product (0.779 g, 72%) as a gold solid. 1H-NMR (CD3OD, 400 MHz) δ7.73 (d, IH, J= 7.6 Hz), 7.43 (d, 2H, J= 7.2 Hz), 7.35 (m, 4H), 7.09 (m, 3H), 6.45 (d, IH, J= 7.6 Hz), 5.27 (s, 2H), 5.13 (s,2H), 3.78 (s, IH); ES-HRMS m z 334.1243 (M+H calculated for C21H17N02F requires 334.1234). Example 415. Preparation of 4-(benzylamino)-3-bromo-l-(3- fluorobenzyI)pyridin-2(lH)-one
Figure imgf000478_0002
Step 1. Preparation of l-(3-fluorobenzyl)-4-hydroxypyridin-2(lH)-one
Figure imgf000478_0003
478 - In a Fischer-Porter bottle, added a solution of 4-(benzyloxy)-l-(3-fluorobenzyl)pyridin- 2(lH)-one (4.5 g, 14.56 mmol) in absolute ethanol (20 mL). Flushed the solution with nitrogen then added palladium catalyst (1.05 g, 10% Pd/C). Sealed bottle and evacuated system. The system was purged with hydrogen gas (2 X 15 psi) to check for leaks. The reaction was charged with hydrogen (35 psi) and stirred at room temperature for 45 minutes. The system was evacuated and flushed with nitrogen. The reaction was filtered and the catalyst was carefully washed with fresh ethanol. The filtrate was concentrated under reduced pressure. 1H-NMR (CD3OD, 400 MHz) δ7.54 (d, IH, J= 7.6 Hz), 7.32 (m, IH), 7.06 (d, IH, J= 7.6 Hz), 6.99 (m, 2H), 6.05 (dd, IH, J= 2.4 Hz, 2.8 Hz), 5.83 (d, IH, J= 2.4 Hz), 5.09 (s, 2H); ES-HRMS m/z 220.0774 (M+H calculated for C12HπN02F requires 220.0787). Step 2. Preparation of 4-(benzylamino)-l-(3-fluorobenzyl)pyridin-2(lH)-one
Figure imgf000479_0001
A mixture of l-(3-fluorobenzyl)-4-hydroxypyridin-2(lH)-one (1.005 g, 4.5 mmol) in benzylamine (15 mL) was heated at reflux (185° C) under nitrogen atmosphere for 24 hours. The reaction was monitored by ES-MS (MH+ 309). The solvent was removed by vacuum distillation to give a yellow residue. 1H-NMR (CD3OD, 400 MHz) 57.31 (m, 7H), 7.03 (m, 3H), 5.98 (d, IH, J= 7.2 Hz), 5.45 (s, IH), 5.00 (s, 2H), 4.30 (s, 2H); ESHRMS m z 309.1403 (M+H calculated for C19H18N2OF requires 309.1375). Step 3. Preparation of 4-(benzyIamino)-3-bromo-l-(3-fluorobenzyl)pyridin-
2(lH)-one.
Figure imgf000479_0002
To a solution of 4-(benzylamino)-l-(3-fluorobenzyl)pyridin-2(lH)-one (0.50 g, 1.62 mmol) in anhydrous CH2C12 (10 mL) was added N-bromosuccinimide (NBS, 0.30 g, 1.7 mmol). The reaction was stirred at room temperature under a nitrogen atmosphere for 3 hours. The reaction mixture was purified by flash chromatography (silica gel) using ethyl
479 acetate in hexane (1:1 v/v). The appropriate fractions were combined and concentrated. 1H-NMR (CD3OD, 400 MHz) δ7.41 (d, IH, J= 7.6 Hz), 7.31 (m, 6H), 7.04 (m, 3H), 5.99 (d, IH, J= 7.6 Hz), 5.08 (s, 2H), 4.53 (s, 2H); ES-HRMS m/z 387.0508 (M+H calculated for C19Hι7N2OBrF requires 387.0504). Example 416. Preparation of 4-(benzyloxy)-l-(3-fIuorobenzyI)-3- methylpyridin-2(lH)-one
Figure imgf000480_0001
Step 1. Preparation of 4-(benzyloxy)-l-(3-fluorobenzyl)-3-iodopyridin-2(lH)- one
Figure imgf000480_0002
A mixture of 4-(benzyloxy)-l-(3-fluorobenzyl)py din-2(lH)-one (4.83 g, 15.6 mmol) and N-iodosuccinimide (NIS, 3.86 g, 17.1 mmol) in anhydrous acetonitrile (55 mL) was heated at 65° C for 4 hours under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (ethyl acetate/hexane 1:1 v/v). The appropriate fractions were collected according to ES MS (M+H 436) and washed with Na2S03 to remove the color impurities. The fractions were concentrated under reduced pressure and dried in vacuo to afford the desired product (6.15 g, 90%) as a light yellow solid. 1H-NMR (CD3OD, 400 MHz) δ7.73 (d, IH, J= 7.6 Hz), 7.36 (m, 6H), 7.08 (m, 3H), 6.39 (d, IH, J= 8.0 Hz), 5.28 (s, 2H), 5.19 (s, 2H); ES- HRMS m z 436.0196 (M+H calculated for C19H16N02FI requires 436.0210). Step 2. Preparation of 4-(benzyloxy)-l-(3-fluorobenzyl)-3-methylpyridin- 2(lH)-one
Figure imgf000480_0003
480 To a degassed solution of 4-(benzyloxy)-l-(3-fluorobenzyl)-3-iodopyridin-2(lH)-one (1.03 g, 2.36 mmol) in anhydrous DMF (15 mL) under argon atmosphere was added triethylamine (1.11 g, 11 mmol). The reaction mixture was chilled in an ice bath for 15 minutes before adding tetramethyl tin (2.10 g, 11.75 mmol) followed by bistriphenylphosphine-palladium chloride (0.166 g, 0.24 mmol). The reaction was stirred at room temperature for 30 minutes before heating at 95° C under an atmosphere of argon for 3 hours. The reaction mixture was filtered through a bed of celite and the filtrate was concentrated under reduced pressure. The dark brown residue was diluted with ethyl acetate (100 mL) and washed with water. The organic extracts were combined, dried over anhydrous Na2S04, and concentrated under reduced pressure. The dark brown residue was purified by flash chromatography (30% ethyl acetate in hexane). The appropriate fractions were combined and concentrated under reduced pressure to afford the desired product (0.1758 g, 22%) as a light yellow solid. The product was further purified by reverse phase HPLC using a 10-90% acetonitrile/water (30 minute gradient) at a 100 mL/min flow rate, to afford a cleaner product as a light yellow solid (0.0975g, 8%). 1H- NMR (CD3OD, 400 MHz) δ7.58 (d, IH, J= 7.6 Hz)), 7.35 (m, 6H), 6.98 (m, 3H), 6.46 (d, IH, J= 7.6 Hz), 5.19 (s, 2H), 5.15 (s, 2H), 2.0 (s, 3H); ES-HRMS m z 324.1366 (M+H calculated for C 0H19NO2F requires 324.1394). Example 417. Preparation of l-(3-fluorobenzyl)-4-[(4-fluorobenzyι)oxy]-3- iodopyridin-2(lH)-one
Figure imgf000481_0001
Step 1. Preparation of l-(3-fluorobenzyι)-4-hydroxy-3-iodopyridin-2(lH)-one
Figure imgf000481_0002
To a mixture of l-(3-fluorobenzyl)-4-hydroxypyridin-2(lH)-one (1.1 g, 5 mmol) in acetonitrile (15 mL) was added N-iodosuccinimide (1.1 g, 5.5 mmol) along with a ca. amount of dichloroacetic acid (0.1 mL). The reaction mixture stirred at room temperature
- 481 - for 1 hour under nitrogen. The mixture was chilled in an ice bath and filtered cold with fresh MeCl2. The beige solid was dried to afford the desired iodinated intermediate (1.21g, 69%). ES-LRMS m/z 346. Step 2. Preparation of l-(3-fluorobenzyi)-4~[(4-fluorobenzyi)oxy]-3- iodopyridin-2(lH)-one. To a mixture of l-(3-fluorobenzyl)-4-hydroxy-3-iodopyridin- 2(lH)-one (0.5g, 1.44 mmol) in DMF (5 mL) was added K2C03 (0.199g, 1.44 mmol) followed by the addition of 4-fluorobenzyl bromide (0.189 mL, 1.51 mmol). The reaction mixture stirred at room temperature for 30 minutes. The mixture was diluted with ethyl acetate (50 mL) and washed with water. The organic extracts were dried over anhydrous Na2S04 and concentrated to dryness. 1H-NMR (CD3OD, 400 MHz) δ7.75 (d, IH, J= 7.6 Hz), 7.49 (q, 2H), 7.34 (q, IH), 7.1 l(m, 5H), 6.40 (d, IH, J= 7.6 Hz), 5.26 (s, 2H), 5.19 (s, 2H); ES-HRMS m/z 454.0098 (M+H calculated for C19H15N02F2I requires 454.0110). Example 418. Preparation of l-(3-fluorobenzyι)-4-[(4-fluorobenzyϊ)oxy]-3- methylpyridin-2(lH)-one
Figure imgf000482_0001
To a degassed solution of l-(3-fluorobenzyl)-4-[(4-fluorobenzyl)oxy]-3-iodopyridin- 2(lH)-one (0.804g, 1.7 mmol) in DMF (10 mL) and LiCl (0.25g, 5.9 mmol) was added tetramethyltin (0.49 mL, 3.54 mmol) followed by bistriphenylphosphine-palladium chloride catalyst (0.124g, 0.177 mmol). The reaction mixture was heated in an oil bath (85°-90° C) under nitrogen for 3 hours. The solvent was concentrated and the residue was diluted with ethyl acetate and washed with water. The organic extracts were dried over anhydrous Na2S04 and concentrated to dryness. The residue was purified by flash column chromatography (20% ethyl acetate in hexane). The appropriate fractions were concentrated. 1H-NMR (CD3OD, 400 MHz) δ 7.59 (d, IH, J=7.6 Hz), 7.46 (m, 2H), 7.34 (m, IH), 7.10 (m, 4H), 6.46 (d, IH, J=7.6 Hz), 5.17 (s, 2H), 5.15 (s, 2H), 1.99 (s, 3H); ESHRMS m/z 342.1314 (M+H calculated for C20Hι8NO2F2 requires 342.1300).
482 Example 419. Preparation of l-benzyl-3-bromo-4-[(2,4-difluorobenzyϊ)oxy]-6- methylpyridin-2(lH)-one
Figure imgf000483_0001
To a degassed cold solution of DMF (10 mL) and PPh3 (resin, 0.93 g, 2.75 mmol) was added DEAD (0.44 mL, 2.75 mmol). The reaction mixture stirred at -10°C for 20 minutes under nitrogen. A solution of 1 -benzyl-3-bromo-4-hydroxy-6-methylpyridin- 2(lH)-one (0.62 g, 2.1 mmol) and 2,4-difluorobenzylalcohol (0.283 mL, 2.5 mmol) in DMF (10 mL) was added to the resin suspension. The reaction mixture stirred at -10° C for 30 minutes and then allowed to stir at room temperature for 1 hour. The resin was filtered and rinsed with fresh MeOH and the filtrate was concentrated. The residue was dissolved in ethyl acetate and purified by flash column chromatography (ethyl acetate/hexane 1:1 v/v). The appropriate fractions were concentrated. 1H-NMR (CD3OD, 400 MHz) δ 7.62 (m, IH), 7.31 (m, 3H), 7.1 (d, 2H, J= 7.2 Hz), 7.02 (t, 2H, J= 8.6 Hz), 6.48 (s, IH), 5.42 (s, 2H), 5.28 (s, 2H), 2.34 (s, 3H); ES-HRMS m/z 420.0399/422.0380 (M+H calculated for C20H17NO2F2Br requires 420.0405/422.0387). Example 420. Preparation of N-[3-bromo-l-(3-fluorobenzyl)-2-oxo-l,2- dihydropyridin-4-yl]-4-fluorobenzamide
Figure imgf000483_0002
Step 1. Preparation of 4-amino-l-(3-fluorobenzyϊ)pyridin-2(lH)-one
Figure imgf000483_0003
In a Fischer-Porter bottle, added a solution of 4-(benzylamino)-l-(3-fluorobenzyl)pyridin- 2(lH)-one (2.5g, 8.11 mmol) in glacial acetic acid (20 mL). After the solution was
- 483 - flushed with nitrogen, catalyst was added (10%Pd C, 2.0g). The vessel was sealed, evacuated, and purged with hydrogen gas. The system was charged with hydrogen gas (50psi) and the mixture stirred at room temperature for 4 hours. The system was evacuated and flushed with nitrogen. The reaction mixture was filtered through a bed of celite and washed with fresh ethanol. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (hexane/ethyl acetate 3:4 v/v). The filtrate was concentrated. 1H-NMR (CD3OD, 400 MHz) δ 7.32 (q, IH), 7.02 (m, 3H), 5.93 (dd, IH, J= 2.4 Hz, 2.8 Hz), 5.58 (d, IH, J= 2.4 Hz); ES-HRMS m/z 219.0966 (M+H calculated for C1 H12N2OF requires 219.0928). Step 2. Preparation of 4-fluoro-N-[l-(3-fluorobenzyl)-2-oxo-l,2- dihydropyridin-4-yl]benzamide
Figure imgf000484_0001
To a solution of 4-amino-l-(3-fluorobenzyl)pyridin-2(lH)-one (0.263 g, 1.2 mmol) in acetonitrile (7 mL) was added a DMAP (ca.), triethylamine (0.25 mL, 1.8 mmol) and 4- fluorobenzoyl chloride (0.213 mL, 1.8 mmol). The reaction mixture stirred at 0° C for 25 minutes and then filtered. The solid was washed with 10% citric acid and water to afford the desired compound (0.326 g, 79%) after drying. 1H-NMR (d6DMSO, 400 MHz) δ 7.98 (m, 2H), 7.71 (d, IH, J= 7.6 Hz), 7.35 (m, 3H), 7.08 (m, 3H), 6.98 (d, IH, J= 2.4 Hz), 6.61 (dd, IH, J= 2.4 Hz, 2.4 Hz), 5.03 (s, 2H); ESLRMS m/z 341.1. ' Step 3. Preparation of N-[3-bromo-l-(3-fluorobenzyl)-2-oxo-l,2- dihydropyridin-4-yl]-4-fluorobenzamide. To a mixture of 4-fluoro-N-[l-(3- fluorobenzyl)-2-oxo-l,2-dihydropyridin-4-yl]benzamide (0.305g, 0.89 mmol) in acetonitrile (7 mL) was added NBS (0.159g, 0.89 mmol). The reaction mixture stirred at room temperature for 1.5 hours. The filtrate was removed under reduced pressure and the residue was purified by flash column chromatography (ethyl acetate/hexane 1 :1 v/v). The fractions were concentrated. 1H-NMR (CD3OD, 400 MHz) δ 8.03 (m, 2H), 7.79 (d, IH, J= 7.6 Hz), 7.47 (d, IH, J= 8.0 Hz), 7.28 ( , 3H), 7.12 (m, 3H), 5.23 (s, 2H); ES-HRMS m/z 419.0202/421.0191 (M+H calculated for C19H14N202F2Br requires 419.0201/421.0183).
484 Example 421. Preparation of 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(2,6- difluorophenyϊ)-6-methylpyridin-2(lH)-one
Figure imgf000485_0001
Step 1. Preparation of 3-chloro-l-(2,6-difluorophenyl)-4-hydroxy-6- methylpyridin-2(lH)-one ^
Figure imgf000485_0002
To a mixture of l-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(lH)-one (0.30 g, 1.26 mmol) in dichloromethane (5 mL) was added NCS (2.52 g, 1.90 mmol). The reaction mixture stirred at room temperature under nitrogen for 4.5 hours. The suspension was cooled in ice bath, filtered, and the solid was rinsed with fresh dichloromethane to afford the desired product (0.271 g, 79%) as a white solid. 1H-NMR (CD3OD, 400 MHz) δ 7.58 (m, IH), 7.22 (m, 2H), 6.20 (s IH), 2.00 (s, 3H); ES-HRMS m z 272.0287 (M+H calculated for C12H9N02F2C1 requires 272.0290). Step 2. Preparation of 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(2,6- difluorophenyι)-6-methylpyridin~2(lH)-one. To a solution of 3-chloro-l -(2,6- difluorophenyl)-4-hydroxy-6-methylpyridin-2(lH)-one (0.27 g, 1.00 mmol) in DMA (5 L) was added K2CO3 followed by the addition of 2,4-difluorobenzyl bromide (0.128 mL, 1 mmol). The reaction mixture stirred at room temperature for 2 hours and then was diluted in water. The reaction mixture was extracted with ethyl acetate, the organic extracts were dried over Na2S0 and the filfrate was concentrated. The resulting residue was purified by flash column chromatography (ethyl acetate hexane 3:4 v/v) to afford the desired product. 1H-NMR (CD3OD, 400 MHz) δ 7.60 (m, 2H), 7.25 (m, 2H), 7.04 (m, 2H), 6.71 (s, IH), 5.36 (s, 2H), 2.11 (s, 3H); ES-HRMS m/z 398.0551 (M+H calculated for C19H13N02F4C1 requires 398.0571).
485 Example 422. Preparation of 3-bromo-l-(4-fluorobenzyl)-4-[(4- fluorobenzyl)amino]-6-methylpyridin-2(lH)-one
Figure imgf000486_0001
Step 1: Preparation of l-(4-fluorobenzyl)-4-[(4-fluorobenzyl)amino]-6- methylpyridin-2(lH)-one
Figure imgf000486_0002
A mixture of 4-hydroxy-6-methylpyrone (5.0 g, 0.04 mol) and 4-fluorobenzylamine (10.0 g. 0.08 mol) in n-butanol (25.0 mL) was heated to reflux for 24 hours under argon atmosphere. The resulting solution was concentrated to dryness under reduced pressure. The residue was triturated with ethyl acetate and filtered. It was thoroughly washed with ethyl acetate and dried to afford the title compound as a pale yellow powder (4.1 g. 30%). 1H-NMR (CD3OD, 400 MHz) δ 7.33 (q, 2H), 7.04 (m, 5H), 5.85 (d, IH, J= 2.0 Hz), 5.44 (d, 2H, J= 2.4 Hz), 5.20 (s, IH), 4.29 (s, 2H), 2.17 (s, 3H); ES-HRMS m z 341.1488 (M+H calculated for C20H19N2OF2 requires 341.1460). Step 2. Preparation of 3-bromo-l-(4-fluorobenzyl)-4-[(4-fluorobenzyl)amino]-
6-methylpyridin-2(lH)-one. To a solution of l-(4-fluorobenzyl)-4-[(4- fluorobenzyl)amino]-6-methylpyridin-2(lH)-one (0.2857 g, 0.84 mmol) in MeCl2 was added NBS (0.156 g, 0.88 mmol). The reaction stirred at room temperature under nitrogen for 45 minutes. The reaction mixture was diluted with MeCl2 and washed with NaHC03. The organic extracts were washed with water, dried over Na S04, and concentrated to afford the desired product (0.3242 g, 92%) as a yellow solid. 1H-NMR (CD3OD, 400 MHz) δ 7.32 (q, 2H), 7.04 (m, 6H), 5.91 (s, IH), 5.28 (s, 2H), 4.50 (s, 2H), 2.17 (s, 3H); ES-HRMS m/z 419.0549/421.0537 (M+H calculated for C20H18N2OBrF2 requires 419.0565/421.0547).
486 Example 423. Preparation of 3-bromo-l-(cyclopropyImethyι)-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one
Figure imgf000487_0001
To a mixture of 3-bromo-l-(cyclopropylmethyl)-4-hydroxy-6-methylpyridin-2(lH)-one (0.276 g, 1.07 mmol) and K2C03 (0.148 g, 1.07 mmol) in DMA (4 mL) was added 2, 4- difluorobenzyl bromide (0.14 ml, 1.07 mmol). The mixture stirred at room temperature for 1.5 hours. The reaction mixture was diluted in water and extracted with ethyl acetate. The organic extracts were dried over Na2S0 and concentrated. The residue was purified by flash column chromatography (ethyl acetate/hexane 1:1 v/v). The appropriate fractions were combined, and concentrated. 1H-NMR (CD3OD, 400 MHz) δ 7.60 (q, IH), 7.04 (m, 2H), 6.42 (s, IH), 5.26 (s, 2H), 4.06 (s, IH), 4.04 (s, IH), 2.50 (s, 3H), 0.53 (m, 2H), 0.43 (m, 2H); ES-HRMS m/z 384.0392 (M+H calculated for C17H17N20BrF2 requires 384.0405). Example 424. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl- l-(pyridin-4-ylmethyl)pyridin-2(lH)-one
Figure imgf000487_0002
Step 1. Preparation of 3-bromo-4-hydroxy-6-methyl-l-(pyridin-4~ ylmethyι)pyridin-2(l H)-one
Figure imgf000487_0003
Commercially available 4-hydroxy-6-methyl pyrone (10 g, 79.3 mmol) was condensed with commercially available 4-(aminomethyl) pyridine (8 mL, 79.3 mmol) in water
487 (50mL). The mixture was heated in an oil bath at reflux for 1 hour under nifrogen. The solvent was evaporated. MS and 1H-NMR were consistent with the desired desbrominated structure. 1H-NMR (CD3OD, 400 MHz) δ 8.45 (dd, 2H, J= 1.6 Hz, 1.6 Hz), 7.15 (d, 2H, J= 6.0 Hz), 6.00 (d, IH, J= 2.0 Hz), 5.80 (d, IH, J= 2.4 Hz), 5.34 (s, 2H), 2.23 (s, 3H); ES- LRMS (M+H) m/z 217. To a suspension of the above compound (0.801 g, 3.7 mmol) in MeCl2 (10 mL) was added NBS (0.725 g, 4.07 mmol). The reaction mixture stirred at room temperature for 30 minutes under nitrogen. The suspension was chilled in an ice bath and filtered. The solid was washed with fresh MeCl2 and dried to afford a beige solid (0.9663 g, 88%) after drying. 1H-NMR (CD3OD, 400 MHz) δ8.47 (d, 2H, J= 5.2 Hz), 7.16 (d, 2H, J= 6.0 Hz), 6.09 (s, IH), 5.40 (s, 2H), 2.24 (s, 3H); ES-LRMS (M+H) m/z 295/297. Step 2. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l- (pyridin-4-ylmethyϊ)pyridin-2(lH)-one
Figure imgf000488_0001
To a cold solution of 2,4-difluorobenzylalcohol (0.569 mL, 5.1 mmol) in THF (5 mL) was added PPh3 (resin, 2.55 g, 7.65 mmol) followed by the addition of DIAD (1.48 mL, 7.65 mmol). The reaction mixture stirred at -10°C for 15 minutes under nitrogen. A solution of 3-bromo-4-hydroxy-6-methyl-l-(pyridin-4-ylmethyl)pyridin-2(lH)-one (1.0 g, 3.4 mmol), in DMF (10 mL) was added to the resin suspension. The reaction mixture stirred at 0° C for 1.5 hours and then allowed to stir at room temperature overnight. The resin was filtered and rinsed with fresh MeOH and the filtrate was concentrated. The residue was dissolved in ethyl acetate and purified by flash column chromatography (ethyl acetate). The appropriate fractions were concentrated. 1H-NMR (CD3OD, 400 MHz) δ 8.47 (d, 2H, J= 5.6 Hz), 7.63 (q, IH), 7.15 (d, IH, J= 5.6 Hz), 7.05 (m, 2H), 6.55 (s, IH), 5.45 (s, 2H), 5.31 (s, 2H), 2.35 (s, 3H); ES-HRMS m/z 421.0366/423.0355 (M+H calculated for C19H16N202F2Br requires 421.0358/423.0339). Example 428. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyI- l-(pyridin-3-ylmethyl)pyridin-2(lH)-one
- 488 -
Figure imgf000489_0001
Step 1. Preparation of 3-bromo-4-hydroxy-6-methyl-l-(pyridin-3- ylmethyl)pyridin-2(lH)-one
Figure imgf000489_0002
Commercially available 4-hydroxy-6-methyl pyrone (15 g, 119.0 mmol) was condensed with commercially available 3-(aminomethyl) pyridine (12.10 mL, 119.0 mmol) in water (75 mL). The mixture was heated in an oil bath at reflux for 1 hour under nitrogen. The solvent was evaporated. 1H-NMR (CD3OD, 400 MHz) δ 8.43 (d, IH, J= 4.8 Hz), 8.38 (s, IH), 7.60 (d, IH, J= 8.0 Hz), 7.39 (dd, IH, J= 4.8 Hz, 4.8 Hz), 5.97 (d, IH, J= 2.0 Hz), 5.79 (d, IH, J= 2.4 Hz), 5.33 (s, 2H), 2.28 (s, 3H); ES-LRMS (M+H) m/z 217. To a suspension of the above compound (5.01 g, 23.1 mmol) in MeCl2 (50 mL) was added NBS (4.53 g, 25.4 mmol). The reaction mixture stirred at room temperature for 30 minutes under nifrogen. The suspension was chilled in an ice bath and filtered. The solid was washed with fresh MeCl2 and dried to afford a beige solid (7.89 g, 114%) after drying. 1H-NMR (CD3OD, 400 MHz) δ 8.44 (d, IH, J= 4.4 Hz), 8.39 (s, IH), 7.62 (d, IH, J= 7.6 Hz), 7.39 (dd, IH, J= 5.2 Hz, 4.4 Hz), 6.07 (s, IH), 5.39 (s, 2H), 2.29 (s, 3H); ES-LRMS (M+H) m/z 295/297. Step 2. Preparation of 3-bromo-4-[(2,4-difluorobenzyι)oxy]-6-methyl-l- (pyridin-3-ylmethyl)pyridin-2(lH)-one
Figure imgf000489_0003
489 The compound was prepared essentially as described in Step 2 of example 424 using 3- bromo-4-hydroxy-6-methyl-l -(pyridin-3-ylmethyl)pyridin-2(lH)-one. 1H-NMR (CD3OD, 400 MHz) δ 8.45 (d, IH, J= 4.4 Hz), 8.41 (s, IH), 7.63 (m, 2H), 7.41 (dd, IH, J= 5.2 Hz, 4.8 Hz), 7.02 (m, 2H), 6.52 (s, IH), 5.44 (s, 2H), 5.29 (s, 2H), 2.40 (s, 3H); ES-HRMS m/z 421.0355/423.0358 (M+H calculated for C19H16N202F2Br requires 421.0358/423.0339). Example 435A. Preparation of 3-bromo-4-[(2,4-difluorobenzyϊ)oxy]-6-methyl- 1 -(py ridin-2-ylmethyι)pyridin-2(l H)-one
Figure imgf000490_0001
Step 1. Preparation of 3-bromo-4-hydroxy-6-methyl-l-(pyridin-2- ylmethyl)pyridin-2(lH)-one
Figure imgf000490_0002
Commercially available 4-hydroxy-6-methyl pyrone (5 g, 39.6 mmol) was condensed with commercially available 2-(aminomethyl) pyridine (4.03 mL, 39.6 mmol) in water (25 mL). The mixture was heated in an oil bath at reflux for 1.5 hour under nifrogen. The solvent was evaporated. MS and 1H-NMR were consistent with the desired desbromonated structure. 1H-NMR (CD3OD, 400 MHz) δ8.47 (d, IH, J= 4.8 Hz), 7.75 (ddd, IH, J= 2.0 Hz, 1.6 Hz, 1.6 Hz), 7.28 (dd, IH, J= 4.8 Hz, 4.8 Hz), 7.1 l(d, IH, J= 7.6 Hz), 5.98 (d, IH, J= 2.4 Hz), 5.77 (d, IH, J= 2.4 Hz), 5.35 (s, 2H), 2.28 (s, 3H); ES-LRMS (M+H) m/z 217. To a suspension of the above compound (3.0 g, 13.8 mmol) in MeCl2 (30 mL) was added NBS (2.71 g, 15.18 mmol). The reaction mixture stirred at room temperature for 2.5 hours under nitrogen. The suspension was chilled in an ice bath and filtered. The solid was washed with fresh MeCl2 and dried to afford a beige solid (3.18 g, 77%) after drying. 1H- NMR (CD3OD, 400 MHz) δ 8.46 (d, IH, J= 4.8 Hz), 7.76 (ddd, IH, J= 2.0 Hz, 1.6 Hz, 1.6
490 Hz), 7.29 (dd, IH, J= 5.2 Hz, 5.2 Hz), 7.17 (d, IH, J= 8.0 Hz), 6.07 (s, IH), 5.40 (s, 2H), 2.30 (s, 3H); ES-LRMS (M+H) m/z 295/297. Step 2. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l- (pyridin-2-yImethyl)pyridin-2(lH)-one
Figure imgf000491_0001
The compound was prepared essentially as described in Step 2 of example 424 using 3- bromo-4-hyά^oxy-6-methyl-l-(pyridin-2-ylmethyl)pyridin-2(lH)-one 1H-NMR (CD3OD, 400 MHz) δ 8.45 (d, IH, J= 4.4 Hz), 7.76 (ddd, IH, J= 2.0 Hz, 2.0 Hz, 1.6 Hz), 7.62 (q, IH), 7.29 (dd, IH, J= 5.2 Hz, 5.6 Hz), 7.21 (d, IH, J= 8.0 Hz), 7.04 (m, 2H), 6.51 (s, IH), 5.45 (s, 2H), 5.29 (s, 2H), 2.42 (s, 3H); ES-HRMS m/z 421.0354/423.0332 (M+H calculated for C19H16N202F2Br requires 421.0358/423.0339). Examples 425-427 and 429-437. Preparation of compounds corresponding in structure to the following formula:
Figure imgf000491_0002
The following compounds were prepared essentially according to the procedures set forth above for Example 424, using the products of Step 1 of Examples 424, 428, or 435.
Figure imgf000491_0003
491
Figure imgf000492_0001
NMR characterization of compounds of Examples 425-427, 429-435, 436-437
Figure imgf000492_0002
- 492
Figure imgf000493_0004
Example 439. Preparation of 3-bromo-4-[2-(4-fluorophenyϊ)ethyl]-6-methyl- l-(pyridin-3-ylmethyϊ)pyridin-2(lH)-one
Figure imgf000493_0001
Step 1. Preparation of 3-bromo-6-methyl-2-oxq-l-(pyridin-3-ylmethyl)-l,2- dihydropyridin-4-yl trifluoromethanesulfonate
Figure imgf000493_0002
To a chilled suspension (-30° C) of 3-bromo-4-hydroxy-6-methyl-l-(pyridin-3- ylmethyl)pyridin-2(lH)-one (0.481g, 1.63 mmol) in dichloromethane (6 mL) was added triethylamine (0.28 mL, 2.04 mmol), followed by the addition of a solution of trifluoromethanesulfonic anhydride (0.4 mL, 2.44 mmol) in dichloromethane (3 mL). The reaction mixture stirred at -30° C under nitrogen for 1 hour. The reaction mixture was diluted with dichloromethane and washed with cold NaHCOs/water. The organic extracts were dried over Na2S04 and the filtrate was concentrated under reduced pressure to afford the desired compound as a yellow semisolid (0.6675 g, 95%) after drying. ES-LRMS (M+H) m/z 427.1/429.1. Step 2. Preparation of 3-bromo-4-[(4-fluorophenyl)ethynyl]-6~methyl-l- (pyridin~3~ylmethyl)pyridin-2(lH)-one
Figure imgf000493_0003
493 - To a degassed solution of 3-bromo-6-methyl-2-oxo-l-(pyridin-3-ylmethyl)-l,2- dihydropyridin-4-yl trifluoromethanesulfonate (0.6675 g, 1.56 mmol) in DMF (9 mL), DIEA (0.35 mL, 2.03 mmol), 4-fluorophenylacetylene (0.235 mL, 1.95 mmol) and PdCl2(PPh3)2 (0.1 lg) were added. The reaction mixture stirred at room temperature under nitrogen for 1 hour and then heated in an oil bath (65°C) under nitrogen overnight. The solvents were distilled in vacuo and the residue was purified by flash column chromatography (5% methanol in ethyl acetate). The extracts were concentrated to afford the desired compound (0.432 g, 69%) after drying. 1H-NMR (CD3OD, 400 MHz) δ 8.45 (s, 2H), 7.96 (s, IH), 7.64 (m, 3H), 7.41 (dd, IH, J= 4.8 Hz, 4.8 Hz), 7.18 (t, 2H, J= 8.8 Hz), 6.46 (s, IH), 5.45 (s, 2H), 2.37 (s, 3H); ES-HRMS m/z 397.0361/399.0310 (M+H calculated for C20H15N2OFBr requires 397.0346/399.0328). Step 3. Preparation of 3-bromo-4-[2-(4-fluorophenyl)ethyl]-6-methyl-l- (pyridin-3-ylmethyι)pyridin-2(lH)~one
Figure imgf000494_0001
A suspension of 3-bromo-4-[(4-fluorophenyl)ethynyl]-6-methyl-l-(pyridin-3- ylmethyl)pyridin-2(lH)-one (0.430 g, 1.01 mmol) in Ethyl acetate (5 mL) and EtOH (5 mL), containing Pt02 (0.015 g) was stirred in an atmosphere of hydrogen (15 psi) in a Fischer- Porter bottle for 2 hours. The reaction mixture was filtered and the filtrate was concentrated to reduce volume. The material was purified by flash column chromatography (ethyl acetate). The appropriate fractions were combined and concentrated under reduced pressure to afford the desired product (0.0943 g, 22 %) as a sticky semisolid after drying. 1H-NMR (CD3OD, 400 MHz) δ 8.46 (d, 2H, J= 26.4 Hz), 7.60 (d, IH, J= 8.0 Hz), 7.41 (dd, IH, J= 4.8 Hz, 4.8 Hz), 7.21 (m, 2H), 6.97 (t, 2H, J= 8.8 Hz), 6.24 (s, IH), 5.43 (s, 2H), 2.93 (m, 4H), 2.31 (s, 3H); ES-HRMS m/z 401.0645/403.0603 (M+H calculated for C20H19N2OFBr requires 401.0659/403.0641).
- 494 - Example 440. Preparation of 3-bromo-4-[2-(4-fluorophenyl)ethyl]-6-methyl- l-(pyridin-4-ylmethyl)pyridin-2(lH)-one
Figure imgf000495_0001
The title compound was prepared by a procedure similar to the one described for Example 439, steps 1-3 (0.374 g, 25%). MS and 1H-NMR for step 1 were consistent with the desired structure. 1H-NMR (CD3OD, 400 MHz) δ 8.80 (d, 2H, J= 6.8 Hz), 7.89 (d, 2H, J= 6.8 Hz), 6.61 (s, IH), 5.66 (s, 2H), 2.45 (s, 3H); ES-HRMS m/z 427.9645/429.9625 (M+H calculated for C13HπN204SF3Br requires 427.9599/429.9578). MS and 1H-NMR for step 3 were consistent with the desired structure. 1H-NMR (CD3OD, 400 MHz) δ 8.48 (d, 2H, J= 5.2 Hz), 7.21 (m, 2H), 7.13 (d, 2H, J= 5.2 Hz), 6.98 (t, 2H, J= 9.0 Hz), 6.26 (s, IH), 5.43 (s, 2H), 2.95 (m, 4H), 2.25 (s, 3H); ES-HRMS m/z 401.0682/403.0636 (M+H calculated for C20H19N2OFBr requires 401.0659/403.0641). Example 441. Preparation of 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyI~l- (pyridin-3-ylmethyl)pyridin-2(lH)-one
Figure imgf000495_0002
Step 1. Preparation of 3-chloro-4-hydroxy-6-methyl-l-(pyridin-3- ylmethyl)pyridin-2(lH)-one
Figure imgf000495_0003
To a suspension of 4-hydroxy-6-methyl-l-(pyridin-3-ylmethyl)pyridin-2(lH)-one (1.016 g, 4.7 mmol) in MeCl2 (10 mL) was added NCS (1.21 g, 1.78 mmol). The reaction mixture stirred at room temperature for 24 hours under nitrogen. The suspension was chilled in an ice bath and filtered. The solid was washed with fresh MeCl2 and dried to - 495 - afford a yellow solid (1.00 g, 85%) after drying. 1H-NMR (CD3OD, 400 MHz) δ 8.54 (m, 2H), 7.85 (d, IH, J=1.6 Hz), 7.61 (m, IH), 6.10 (s, IH), 5.41 (s, 2H), 2.33 (s, 3H); ES- LRMS (M+H) m/z 251/253. Step 2. Preparation of 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l- (pyridin-3-ylmethyι)pyridin-2(lH)~one
Figure imgf000496_0001
To a degassed cold solution of DMF (10 mL) and PPI13 (resin, 2.2 g, 6.6 mmol) was added DEAD (1.038 mL, 6.6 mmol). The reaction mixture stirred at -10° C for 20 minutes under nitrogen. A solution of 3-chloro-4-hydroxy-6-methyl-l-( yridin-3-ylmethyl)pyridin- 2(lH)-one (1.00 g, 4.0 mmol) and 2,4-difluorobenzylalcohol (0.66 mL, 6.0 mmol) in DMF (10 mL) was added to the resin suspension. The reaction mixture stirred at -10° C for 30 minutes and then allowed to stir at room temperature for 1 hour. The resin was filtered and rinsed with fresh MeOH and the filtrate concentrated. The residue was dissolved in ethyl acetate and purified by flash column chromatography (5% methanol in ethyl acetate). The appropriate fractions were concentrated. 1H-NMR (CD3OD, 400
MHz) δ 8.45 (ddd, 2H, J= 1.6Hz, 1.6 Hz, 1.6 Hz), 7.61 (m, 2H), 7.41 (dd, IH, J= 4.4 Hz, 4.8 Hz), 7.02 (m, 2H), 6.55 (s, IH), 5.43 (s, 2H), 5.29 (s, 2H), 2.41 (s, 3H); ES-HRMS m/z 377.0882/379.0840 (M+H calculated for C19H16N202F2C1 requires 377.0863/379.0840). Example 442. Preparation of l-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3- bromo-6-methyl-4-[(2,4,6-trifluorobenzyι)oxy]pyridin-2(lH)-one trifluoroacetate
Figure imgf000496_0002
The title compound was prepared by a procedure similar to the one described for Example 385, step 2 (0.142 g, 9%). 1H NMR (CD3OD, 400 MHz) δ 7.64 (s, IH), 7.00 (m, 2H), 6.66 (s, IH), 5.29 (s, 2H), 5.18 (s, 2H), 2.50 (s, 3H), 2.47 (s, 3H); ES-HRMS m/z 469.0488/471.0464 (M+H calculated for C19H17N402F3Br requires 469.0481/471.0463).
- 496 - Example 443. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl- l-{[2-methyl-4-(methylamino)pyrimidin-5-yl]methyl}pyridin-2(lH)-one trifluoroacetate
Figure imgf000497_0001
To a solution of l-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-bromo-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one hydrochloride (0.15 g, 0.3 mmol) in DMF (3 mL) was added DBU (0.09 mL, 0.6 mmol). The solution was cooled in an ice bath and iodomethane (0.019 mL, 0.3 mmol) was added. The reaction mixture stirred at room temperature under nitrogen for 2 hours. The reaction was purified by reverse phase HPLC 10-90% CH3CN/water (30 minute gradient) at a flow rate of 100 mL/min. The appropriate fractions (m/z= 465 M+H) were combined and freeze dried to afford the desired product (0.036 g, 25%) as a white powder. 1H NMR (CD3OD, 400 MHz) δ 7.72 (s, IH), 7.60 (m, IH), 7.03 (m, 2H), 6.62 (s, IH), 5.31 (s, 2H), 5.16 (s, 2H), 3.77 (s, 3H), 2.60 (s, 3H), 2.47 (s, 3H); ES-HRMS m/z 465.0717/467.0712 (M+H calculated for C20H20N4O2F2Br requires 465.0732/467.0714). Example 444. Preparation of ethyl N-(5-{[3-bromo-4-[(2,4- difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-2-methylpyrimidin-4- yl)glycinate trifluoroacetate
Figure imgf000497_0002
The title compound was prepared by a procedure similar to the one described for Example 442 with the exception that the reaction mixture had to be heated at oil bath temperature 70° C for 2 days (0.1384 g, 51 %). 1H NMR (CD3OD, 400 MHz) δ 7.78 (s, IH), 7.61 (m, IH), 7.03 (m, 2H), 6.61 (s, IH), 5.30 (s, 2H), 5.18 (s, 2H), 5.03 (s, 2H), 4.27 (q, 2H), 2.55 (s, 3H), 2.46 (s, 3H), 1.28 (t, 3H, J= 7.0 Hz); ES-HRMS m/z 537.0936/539.0932 (M+H calculated for C23H24N404F2Br requires 537.0943/539.0926). • 497 Example 445. Preparation of N-(5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]methyl}-2-methylpyrimidin-4-yl)-2-hydroxyacetamide trifluoroacetate
Figure imgf000498_0001
To a chilled solution of l-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-chloro-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one trifluoroacetate (0.200 g, 0.38 mmol) in DMF (20 mL) and a catalytic amount of DMAP was added triethylamine (0.064 mL, 0.38 mmol). The reaction stirred at -20° C and acetoxyacetyl chloride (0.082 mL, 0.76 mmol) was added. The reaction stirred cold for 15 minutes and then allowed to warm up to room temperature for 3 hours. The reaction was monitored by LR-ESMS m/z = 466. The reaction was incomlete after 3 hours. Added acetoxyacetyl chloride (0.05 mL, 0.466 mmol), and triethylamine (0.2 mL, 1.43 mmol) to the reaction mixture and continued to stir overnight at room temperature. The next morning the reaction heated at 65° C for 3 hours. The solvent was removed in vacuo and IN LiOH (2.5 mL) was added to the residue. The reaction was heated at 60° C for 5 hours. The reaction was diluted with acetonitrile and water (1:1) and purified by reverse phase HPLC in 10-90% CHsCN/water (30 minute gradient) at a flow rate of 50 mL/min. The appropriate fractions were freeze dried to afford the desired product (0.020 g, 9%). 1H NMR (CD3OD, 400 MHz) δ 8.04 (s, IH), 7.6 (m, IH), 7.02 (m, IH), 6.59 (s, IH), 5.30 (s, 2H), 5.24 (s, 2H), 4.26 (s, IH), 2.60 (s, 3H), 2.43 (s, 3H); ES-HRMS m/z 465.1161 (M+H calculated for C21H20N4O4F2Cl requires 465.1136). Example 446. Preparation of 3-chloro-4-[(2,4-difluorobenzyι)oxy]-6-methyl-l- [(5-methylpyrazin-2-yl)methyl]pyridin-2(lH)-one
Figure imgf000498_0002
498 Step 1. Preparation of 3-chloro-4-hydroxy-6-methyl-l-[(5-methylpyrazin-2- yl)methyl]pyridin-2(lH)-one
Figure imgf000499_0001
To a solution of 4-hydroxy-6-methyl-l-[(5-methylpyrazin-2-yl)methyl]pyridin-2(lH)-one (1.00g, 4.3 mmol) in glacial acetic acid (10 mL) was added NCS (0.79 g, 5.94 mmol). The reaction mixture stirred at 60° C for 6 hours. The solvent was removed under reduced pressure and the resulting residue was triturated with ethyl acetate. The desired product was filtered and dried (0.80 g, 69%). 1H NMR (CD3OD, 400 MHz) δ 8.47 (s, IH), 8.42 (s, IH), 6.08 (s, IH), 5.36 (s, 2H), 2.50 (s, 3H), 2.43 (s, 3H); ES-HRMS m/z 266.0691 (M+H calculated for C12H13N302C1 requires 266.0691). Step 2. Preparation of 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[(5- methyIpyrazin-2-yl)methyl]pyridin-2(lH)-one. To a solution of 3-chloro-4-hydroxy-6- methyl-l-[(5-methylpyrazin-2-yl)methyl]ρyridin-2(lH)-one (2.48 g, 9.3 mmol) in DMA (7 mL)was added K2C03 (1.54 g, 11.0 mmol) followed by 2,4-difluorobenzyl bromide (1.2 mL, 9.3 mmol). The reaction mixture stirred at room temperature under nitrogen for 1.5 hours. The solvent was distilled in vacuo. The resulting residue was diluted in dichloromethane and washed with water. The organic extracts were concentrated and the resulting residue was purified by flash column chromatography (ethyl acetate). The appropriate fractions were combined, and concentrated. 1H NMR (CD3OD, 400 MHz) δ 8.49 (d, IH, J=l .2 Hz), 8.40 (s, IH), 7.59 (m, IH), 7.04 (m, 2H), 6.54 (s, IH), 5.41 (s, 2H), 5.28 (s, 2H), 2.54 (s, 3H), 2.40 (s, 3H); ES-HRMS m/z 392.1014 (M+H calculated for C19H17N302C1F2 requires 392.0972).
499 Example 447. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl- l-({5-[(methylamino)methyl]pyrazin-2-yl}methyl)pyridin-2(lH)-one trifluoroacetate
Figure imgf000500_0001
To a suspension of 3-bromo-l-{[5-(chloromethyl)pyrazin-2-yl]methyl}-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one (0.25 g, 0.53 mmol) in THF was added methylamine (1 mL, 2.1 mmol). The reaction was sealed and stirred at room temperature overnight. The reaction mixture was diluted in water: acetonitrile (1:1) and purified by reverse phase HPLC 10-90% CH3CN/water (30 minute gradient) at a flow rate of 70 mL/min. The appropriate fractions were combined and freeze dried to afford the desired product (0.22 g, 71%) as an amorphous solid. 1H NMR (CD3OD, 400 MHz) δ 8.73 (s, IH), 8.55 (s, IH), 7.6 (m, 2H), 7.02 (m, IH), 6.54 (s, IH), 5.47 (s, 2H), 5.29 (s, 2 H), 4.37 (s, 2 H), 2.78 (s, 3H), 2.56 (s, 3H). ES-HRMS m/z 465.0732/467.0709 (M+H calculated for C20H20N4O2BrF2 requires 465.0732/467.0714). Example 448. Preparation of Ethyl 5-{[3-chloro-4-[(2,4-difluorobenzyι)oxy]- 6-methyl-2-oxopyridin-l (2H)-yl] methyl} pyrazine-2-carboxylate
Figure imgf000500_0002
To a mixture of 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one (0.59 g, 2.07 mmol) and ethyl 5-(bromomethyl)pyrazine-2-carboxylate (0.62 g, 2.4 mmol) in THF (15 mL) was added NaH (0.06 g, 2.4 mmol). The reaction stirred at 60° C for 3.5 hours. The solvent was removed under reduced pressure and the residue was partitioned over dichloromethane and citric acid (5%). The organic extracts were washed with water and dried over Na2S04 (anhydrous). The organic extracts were concentrated and the residue was purified by flash column chromatography (100 % ethyl acetate). The appropriate fractions were combined and concentrated under reduced pressure to remove solvent. 1H NMR (CD3OD, 400 MHz) δ 9.11 (d, IH, J= 1.6 Hz), 8.77 (s, IH), 7.52 (m, IH), 7.02 (m, - 500 - 2H), 6.57 (s, IH), 5.53 (s, 2H), 5.30 (s, 2H), 4.49 (q, 2H), 2.52 (s, 3H), 1.39 (t, 3H, J= 7.2 Hz); ES-HRMS m/z 450.1045 (M+H calculated for C21H19N304C1F2 requires 450.01027). Example 449. Preparation of 3-chloro-4-[(2,4-difluorobenzyι)oxy]-l-{[5- (hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(lH)-one
Figure imgf000501_0001
To a suspension of ethyl 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]methyl}pyrazine-2-carboxylate (4.0 g, 8.9 mmol) in THF:t-butanol (1:1) (10 mL) was added NaBH4 (0.46 g, 12.4 mmol). The reaction stirred at room temperature under argon overnight. The reaction mixture was quenched with acetic acid (2 mL) and the solvent was removed in vacuo. The residue was triturated with water and filtered. The solid was washed with fresh water followed by ethanol. The solid was purified by flash column chromatography (100% ethyl acetate). The appropriate fractions were combined and concentrated under reduced pressure to afford the desired compound (1.58 g, 44%) as a white solid. 1H NMR (CD3OD, 400 MHz) δ 8.59 (s, IH), 8.56 (s, IH), 7.52 (m, IH), 7.01 (m, 2H), 6.55 (m, IH), 5.45 (s, 2H), 5.29 (s, 2H), 4.71 (2H), 2.54 (s, 3H); ES-HRMS m/z 408.0940 (M+H calculated for C19H17N303C1F2 requires 408.0921). Example 450. Preparation of 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]methyl}-N,N-dimethylpyrazine-2-carboxamide
Figure imgf000501_0002
To a cold solution of 5- {[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]methyl}pyrazine-2-carboxylic acid (0.175 g, 0.37 mmol) in DMF (5 mL, -10° C) was added IBCF (0.046 mL, 0.35 mmol) followed by NMM (0.041 mL 0.37 mmol). The reaction was activated for 20 minutes at -15° C after which dimethylamine (0.375 mL, 0.74 mmol) was added. The reaction stirred at -10° C to room temperature for 45 - 501 - minutes. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC 10-90% CH3CN/water (30 minute gradient) at a flow rate of 70 mL/min. The appropriate fractions were combined and freeze dried to afford the desired product (0.140g, 75%) as a white solid. 1H NMR (CD3OD, 400 MHz) δ 8.68 (s, IH), 8.67 (s, IH), 7.52 (m, IH), 7.02 (m, 2H), 6.54 (s, IH), 5.50 (s, 2H), 5.30 (s, 2H), 3.11 (s, 3 H), 3.07 (s, 3H), 2.55 (s, 3H); ES-HRMS m/z 493.0680/495.0657 (M+H calculated for C21H20N4O3BrF2 requires 493.0680/495.0657). Example 451. Preparation of 5-{[3-bromo-4-[(2,4-difluorobenzyi)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]methyl}-N-methylpyrazine-2-carboxamide
Figure imgf000502_0001
The title compound was prepared essentially as in Ex. 450, substituting dimethylamine with methylamine. 1H NMR (CD3OD, 400 MHz) δ 9.07 (s, IH), 8.68 (s, IH), 7.54 (m, IH), 7.02 (m, 2H), 6.54 (s, IH), 5.52 (s, 2H), 5.30 (s, 2H), 2.94 (s, 3H), 2.54 (s, 3H); ESHRMS m/z 479.0542/481.0518 (M+H calculated for C20H18N4O3BrF2 requires 479.0525, 481.0507). Example 452. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{[5-(l- hydroxy-l-methylethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(lH)-one
Figure imgf000502_0002
To a cold flask of MeMgBr (1.59 mL, 1.0 mmol) was added a suspension of ethyl 5-{[3- bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}pyrazine-2- carboxylate (0.5 g, 1.0 mmol) in THF (20 mL). The reaction stirred at 0° C for 1.5 hours and then at room temperature overnight. The reaction was quenched with cold citric acid (25 mL, 5%) and extracted with ethyl acetate (2 X 100 mL). The organic extracts were washed with fresh water. The organic extracts were concentrated and purified by reverse - 502 - phase HPLC 10-90% CH3CN/water (30 minute gradient) at a flow rate of 70 mL/min. The appropriate fractions were combined and freeze dried to afford the desired product (29.9 mg, 6%). 1H NMR (CD3OD, 400 MHz) δ 8.76 (d, IH, J= 1.6 Hz), 8.54 (d, IH, J= 1.2 Hz), 7.52 (m, IH), 7.02 (m, 2H), 6.52 (s, IH), 5.45 (s, 2H), 5.29 (s, 2H), 2.55 (s, 3H), 1.52 (s, 6H); ES-HRMS m/z 480.0745/482.0722 (M+H calculated for C21H21N303BrF2 requires 480.0729/482.0711). Example 453. Preparation of 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]methyl}-N-(2-methoxyethyl)pyrazine-2-carboxamide
Figure imgf000503_0001
The title compound was prepared essentially as in Ex. 450, substituting dimethylamine with 2-methoxyethylamine. 1H NMR (CD3OD, 400 MHz) δ 9.08 (d, IH, J= 1.2 Hz), 8.70 (d, IH, J= 1.2 Hz), 7.61 (m, IH), 7.04 (m, 2H), 6.54 (s, IH), 5.53 (s, 2H), 5.30 (s, 2H), 3.56 (m , 4H), 3.30 (s, 3H), 2.54 (s, 3H); ES-HRMS m/z 523.0822/525.0810 (M+H calculated for C22H22N404BrF2 requires 523.0787/525.0770). Example 454 Preparation of 3-bromo-4-[(2,4~difluorobenzyl)oxy]-6-methyl-l-
{[5-(morpholin-4-ylcarbonyl)pyrazin-2-yl]methyl}pyridin-2(lH)-one
Figure imgf000503_0002
The title compound was prepared essentially as in Ex. 450, substituting dimethylamine with morpholine. 1H NMR (CD3OD, 400 MHz) δ 8.77 (d, IH, J= 1.6 Hz), 8.67 (s, IH), 7.54 (m, IH), 7.02 (m, 2H), 6.54 (s, IH), 5.50 (s, 2H), 5.30 (s, 2H), 3.75 (s, 4H), 3.59 (dd, 4H, J= 5.6 Hz, 5.2 Hz), 2.55 (s, 3H); ES-HRMS m/z 535.0816/537.0817 (M+H calculated for C23H22N404BrF2 requires 535.0787/537.0770).
503 Example 450. Preparation of 3-chloro-4-[(2,4~difluorobenzyι)oxy]-l-({5-[(4- hydroxypiperidin-l-yl)carbonyl]pyrazin-2-yl}methyl)-6-methylpyridin-2(lH)-one
Figure imgf000504_0001
Step 1. Preparation of 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]methyl}pyrazine-2-carboxylic acid
Figure imgf000504_0002
A mixture of ethyl 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]methyl}pyrazine-2-carboxylate (1.03g, 2.3 mmol) in IN aOH (3.4 ml, 3.45 mmol, EtOH/water 1:1 v/v) stirred at room temperature for 2 hours. The reaction mixture was quenched with 5% citric acid and filtered. The solid was washed with water and dried to afford the desired product (1.011 g, 100%) as a white solid. 1H NMR (CD3OD, 400 MHz) δ 9.02 (s, IH), 8.60 (s, IH), 7.60 (m, IH), 7.04 (m, 2H), 6.55 (s, IH), 5.50 (s, 2H), 5.30 (s, 2H), 2.52 (s, 3H); ES-HRMS m/z 422.0732 (M+H calculated for C19H15N304C1F2 requires 422.0714). Step 2. Preparation of 3-chloro-4-[(2,4-difluorobenzyι)oxy]-l-({5-[(4- hydroxypiperidin-l-yl)carbonyl]pyrazin-2-yl}methyl)-6-methylpyridin-2(lH)-one The title compound was prepared by a procedure similar to the one described for Example 453 (0.1396 g, 47%). 1H NMR (CD3OD, 400 MHz) δ 8.67 (s, 2H), 7.59 (m, IH), 7.02 (m, 2H), 6.57 (s, IH), 5.49 (s, 2H), 5.30 (s, 2H), 4.16 (m, IH), 3.89 (septet, IH), 3.72 (m, IH), 3.38 (m, 2H), 2.56 (s, 3H), 1.93 (m, IH), 1.83 (m, IH), 1.45 (m, 2H); ES-HRMS m/z 505.1485 (M+H calculated for C24H24N404C1F2 requires 505.1449).
- 504 Example 456. Preparation of 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]methyl}-N-(3-hydroxy-2,2-dimethylpropyl)pyrazine-2- carboxamide
Figure imgf000505_0001
The title compound was prepared by a procedure similar to the one described for Example 455 (0.215 g, 71%). 1H NMR (CD3OD, 400 MHz) δ 9.08 (d, IH, J= 1.2 Hz), 8.71 (d, IH, J= 1.6 Hz), 7.58 (m, IH), 7.02 (m, 2H), 6.57 (s, IH), 5.52 (s, IH), 5.30 (s, IH), 3.31 (s, 4H), 2.55 (s, 3H), 0.912 (s, 6H); ES-HRMS m/z 507.1630 (M+H calculated for C24H26N404C1F2 requires 507.1605). Example 457. Preparation of 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]- 6-methyl-2-oxopyridin-l(2H)-yl]methyl}-N-(2,2,2-trifluoroethyl)pyrazine-2- carboxamide
Figure imgf000505_0002
The title compound was prepared by a procedure similar to the one described for Example 455 except no purification was required, only a NaHC03/ethyl acetate extraction was needed (0.2176 g, 73%). 1H NMR (CD3OD, 400 MHz) δ 9.11 (d, IH, J= 1.6Hz), 8.73 (d, IH, J= 1.3 Hz), 7.59 (m, IH), 7.02 (m, 2H), 6.57 (s, IH), 5.53 (s, 2H), 5.30 (s, 2H), 4.01 (q, 2H), 2.54 (s, 3H); ES-HRMS m/z 503.0930 (M+H calculated for C21H17N403C1F5 requires 503.0904).
505 - Example 458. Preparation of l-allyl-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methylpyridin-2(l H)-one
Figure imgf000506_0001
Step 1. Preparation of l-allyl-4-hydroxy-6-methylpyridin-2(lH)-one. 4- hydroxy-6-methyl-2-pyrone (2g, 16 mmol) was stirred in water (25 mL). AUylamine (1.2 ml, 16mmol) was added to the reaction. The reaction was then heated to 100 °C at which point the reaction became homogeneous. The reaction was stirred at 100 °C for 2h. The reaction was then allowed to cool to rt after which a white precipitate formed. The precipitate was isolated by suction filtration. After additional washing with water, 1.8g (69%) of an off-white solid was obtained. Step 2. l-allyl-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one. To a stirred solution of the above pyrone(4.0g, 24 mmol) in DMF(75ml) was added Cs2C03 (7.8g, 24mmol) followed by addition of 2,4-diflurorbenzyl bromide(3.4 mmol, 26.4 mmol). The resulting mixture was stirred at rt for 2h. Additional Cs2C03 (lg) and bromide (1 ml) was added and the reaction was stirred for an additional 2h. The Cs2C03 was removed by suction filtration. The DMF was removed under vacuum and the crude material was purified by flash chromatography. Elution with ethyl acetate-hexanes (2:1 to 1:1) afforded 1.5 g (21%) of the desired compound. Step 3. l-allyl-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)- one. To a stirred suspension of the above pyridinone (lg, 3.4 mmol) in CH3CN (10 ml) was added n-bromosuccinimide (670 mg, 3.8 mmol). The reaction mixture was stirred, at rt, for 3h. The product was obtained by filtration of the reaction mixture and washing of the solid with diethyl ether. 1H-NMR (DMSOd6/400 MHz) δ 7.62 (app q, J = 8.8 liz, IH), 7.31 (ddd, J = 12.0, 9.6, 2.8 hz, IH); 7.15 (app dtd, J = 8.4, 2.4, 0.8 Hz, IH); 6.50 (s, IH); 5.87 (ddt, J = 12.4, 10.4, 5.6 Hz, IH), 5.30 (s, 2H), 5.10 (dd, J = 10, 1.6 Hz, IH), 4.87 (dd, J = 17.6, 1.6 Hz, IH), 4.64 (m, 2H), 2.34 (s, 3H); 19F-NMR (DMSOd6/282.2 MHz) - 109.68 (quin, J = IH), -113.66(quar, J = IH); HRMS m/z 370.0255 (M + H calcd for C16H15BrF2N02 = 370.0246). - 506 - Example 459. Preparation of l-allyl-3-chloro-4-[(2,4-difluorobenzyϊ)oxy]-6- methylpyridin-2(lH)-one
Figure imgf000507_0001
Step 1. l-allyl-3-chloro-4-hydroxy-6-methylpyridin-2(lH)-one. To a stirred solution of l-allyl-4-hydroxy-6-methylpyridin-2(lH)-one (500 mg, 3.0 mmol) in
CH3CN(10 ml), at rt, was added sequentially n-bromosuccinimide (440 mg, 3.3 mmol) and dichloroacetic acid (546 μl, 6.62 mmol). The resulting mixture was stirred for 2h. The heterogeneous mixture was filtered and the solid was washed with additional CH3CN to give 350 mg (59%) of the desired product as a tan solid. 1H-NMR (DMSOd6/300 MHz) δ 11.16 (s, IH), 5.98-5.86 (m, 2H), 5.12 (dd, J = 10.5, 1.5 Hz, IH), 4.89 (dd, J = 17.1, 1.5 Hz, IH), 4.63-4.61 (m, 2H), 2.29 (s, 3H). ES-HRMS m/z 200.050 (M + H calcd for C9HπClN02 = 200.0470) Step 2. l-alIyI-3-chloro-4-[(2,4-difluorobenzyI)oxy]-6-methylpyridin-2(lH)- one. The title compound was prepared by the procedure outline in the synthesis of Example 458, step 3. 1H-NMR (DMSOd6/300 MHz) δ 7.67 (app q, J = 8.4 hz, IH), 7.36 (app dt, J = 10.2, 2.7 hz, IH); 7.15 (m, IH); 6.58 (s, IH); 5.93 (ddt, J = 15.3, 9.6, 4.8 Hz, IH), 5.30 (s, 2H) 5.15 (dd, J = 10.2, 1.2 Hz, IH), 4.92 (dd, J = 17.4, 1.2 Hz, IH), 4.69- 4.67 (m, 2H), 2.41 (s, 3H). ES-HRMS m/z 326.0760 (M + H calcd for C16H15C1F2N02 = 326.0790). Example 460. Preparation of methyl (2E)-4-[3-bromo-4-[(2,4- difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]but-2-enoate
Figure imgf000507_0002
To a stirred suspension of NaH (277 mg, 11 mmol) in anhydrous THF (30 ml), which was cooled to 0°C, was slowly added 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin- - 507 - 2(lH)-one (3.3g, 10 mmol). The resulting slurry was stirred for 15 min, after which methyl 4-bromocrotonate (1.4 ml, 12 mmol) was added to the reaction. The ice bath was removed and the reaction was heated to reflux for 16h. The reaction was quenched by the addition of IN NH4C1. The layers were separated and the aqueous layer was extracted with CH C12 (5x). The organics were combined, dried, and concentrated in vacuo. The crude yellowish material was then triturated with Et20 to give, after filtration and drying, 1.8g (43%) of a white solid. 1H-NMR (DMSOd6/300 MHz) δ 7.65 (app q, J = 8.7 hz, IH), 7.36 (app dt, J = 12.0, 3.0 hz, IH); 7.17 (dt, J = 8.4, 1.8 Hz, IH); 6.94 (dt, J = 15.9, 4.5 Hz, IH); 6.57 (s, IH), 5.52 (d, J = 15.9 Hz, IH), 5.29 (s, 2H), 4.84 (m, 2H), 3.63 (s, 3H), 2.33 (s, 3H). ES-HRMS m/z 428.0301 (M + H calcd for C18H17BrF2N04 = 428.0310). Example 461. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl- l-prop-2-ynylpyridin-2(lH)-one.
Figure imgf000508_0001
Step 1. 4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-prop-2-ynylpyridin-2(lH)-one. The title compound was prepared by alkylation of 4-[(2,4-difluorobenzyl)oxy] -6- methylpyridin-2(lH)-one (2.5g, 10 mmol) with propargyl bromide (1.3 ml, 11.0 mmol) as described above to give 1.3g (44%) of the desired product. 1H- NMR (DMSOd6/300 MHz) δ 7.60 (app q, J = 8.4 hz, IH), 7.35-7.27 (m, IH); 7.16-7.10 (m, IH); 5.94 (d, J = 2.1 Hz, IH), 5.88 (d, J = 3.0 Hz, IH), 5.03 (s, 2H), 4.76 (d, J = 2.4, Hz, 2H), 3,31 (s, 3H), 3.24 (t, J = 2.4 Hz, IH), 2.39 (s, 3H); ES-HRMS m/z 290.0994 (M + H calcd for C16H14F2N02 = 290.0993). Step 2. Preparation of 3-bromo-4-[(2,4-difluorobenzyϊ)oxy]-6-methyl-l~prop- 2-ynylpyridin-2(lH)-one. Bromination of4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-prop- 2-ynylpyridin-2(lH)-one (500 mg, 1.67 mmol) with NBS (300 mg, 1.67 mmol) was carried out in the manner described above to give 350 mg (57%) of the desired compound. 1H-NMR (DMSOd6/300 MHz) δ 7.67 (app q, J = 9.0 hz, IH), 7.36 (app dt, J = 10.5, 2.4 hz, IH); 7.23-7.16 (m, IH); 6.60 (s, IH), 5.29 (s, 2H), 4.90 (d, J = 2.4, Hz, IH), 3.35 (s, 3H),
508 3.32 (s, IH), 2.53 (s, 3H); ES-HRMS m/z 368.0107 (M + H calcd for C16H13BrF2N02 = 368.0098). Example 462. Preparation of 4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)- l-(pyridin-3-ylmethyι)pyridin-2(lH)-one.
Figure imgf000509_0001
Step 1. To a suspension of (4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(pyridin-3- ylmethyl)pyridin-2(lH)-one) (710 mg, 2 mmol) in dioxane (10 mL) was added selenium dioxide (l.lg 10 mmol). The resulting mixture was heated to 160 °C in a 125 mL sealed tube for lh. The reaction was filtered through a fritted funnel. The filtrate was washed with (10:1) CH2Cl2-MeOH. The organics were combined and concentrated in vacuo. The crude material was purified by flash chromatography. Elution with (50:50 -> 0: 100) hexanes yielded 450 mg (63%) of the aldehyde. 1H-NMR (DMSOd6/400 MHz), δ 9.48 (s, IH, CHO). Step 2. The aldehyde (350 mg, 1 mmol) was dissolved in MeOH (4 mL) and cooled to 0 °C . To this mixture was added NaBH4 (28 mg, 1 mmol) in one portion. After 30 min, additional NaBH4 (20 mg) was added to the reaction. The MeOH was then removed under vacuum. The residue was diluted with IN NH4C1 and then extracted with CH2C12(4X). The organics were combined, dried, and concentrated in vacuo. The yellowish crude product was then taken up in (1:1) CH2C12-Et20. After sitting for a period of time a white precipitate resulted. Filtration and washing with additional Et20 yielded, after drying, 250 mg (55%) of the desired alcohol. 1H-NMR (DMSOd6/400 MHz), δ 8.42 (dd, J = 4.4, 1.6 Hz, IH) 8.37 (d, J = 1.6 Hz, IH), 7.61 (app q, J = 8.0 Hz, IH), 7.45 (d, J = 8.0 Hz, IH), 7.32-7.27(M, 2H), 7.12 (dt, J = 8.4, 1.6 Hz, IH), 6.07 (d, J = 2.8 Hz, IH), 5.99 (d, J = 12.8 Hz, IH), 5.63 (br s, IH), 5.18 (s, 2H), 5.09 (s, 2H), 4.29 (s, 2H). LC/MS, tr = 1.19 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m z 359.1 (M+H)
- 509 Example 463. Preparation of 3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6- (hydroxymethyl)-l-(pyridin-3-ylmethyl)pyridin-2(lH)-one.
Figure imgf000510_0001
The title compound was prepared by bromination of as described above to give a 60% yield. 1H-NMR (DMSOd6/300 MHz) δ 7.93 (d, J = 7.8 Hz, IH), 7.73-7.65 (m, 3H), 7.38 (dt, J = 10.2, 2.4 Hz, IH), 7.21 (app t, J = 8.7 Hz, 2H), 6.74 (s, IH), 5.38.-5.36 (m, 4H), 4.50 (s, 2H); ES-HRMS m/z 437.0311 (M + H cacld for C19H16BrF2N202 = 437.0313). Example 464. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6~ [(dimethylamino)methyl]-l-(pyridin-3-ylmethyl)pyridin-2(lH)-one.
Figure imgf000510_0002
The title compound was prepared in a similar manner to the procedure outlined below for 3 -bromo-4- [(2,4-difluorobenzyl)oxy] - 1 -(2,6-difluorophenyl)-6- [(dimethylamino)- methyl]pyridin-2(lH)-one using the aldehyde (300 mg, 0.85 mmol) described above and 2.0 N THF solution of dimethylamine (500 μL, 1 mmol) to give 110 mg (34%) of a colorless oil. The oil was then dissolved in MeOH (1 mL) and stirred with fumaric acid (25 mg) for lh. The resulting precipitate was filtered, washed with diethyl ether, and dried to give the pure product as it's fumurate salt. 1H-NMR (DMSOd6/400 MHz) δ 8.43-8.41 (m, IH), 8.35 (s, IH), 7.67-7.61 (m, IH), 7.44-7.40 (m, IH), 7.35-7.29 (m, 2H), 7.17-7.12 (m, IH), 6.62 (s, IH), 6.60 (s, IH), 5.41 (s, 2H), 5.32 (s, 2H), 3.13 (s, 2H), 2.12 (s, 6H). LC/MS, tr = 1.55 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m z 464 (M+H).
- 510 Example 465. Preparation of 3-bromo-4- [(2,4-difluorobenzyϊ)oxy]-l-(2,6- difluorophenyl)-6-(hydroxymethyl)pyridin-2(lH)-one
Figure imgf000511_0001
Stepl. 4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyi)-6-oxo-l,6- dihydropy ridine-2-carb aldehyde.
Figure imgf000511_0002
In a 300 ml high-pressure glass reaction vessel 4-[(2,4-difluorobenzyl)oxy]-l-(2,6- difluorophenyl)-6-oxo-l,6-dihydropyridine-2-carbaldehyde (16.3 g, 45 mmol) was dissolved in 1,4-dioxane (90 mL). The reaction vessel was sealed and immersed in a preheated oil bath at 170°C. The reaction was heated at 170° C (165 -170 °C) for 1.5 hours and then cooled to room temperature. The reaction was worked up by filtering the reaction mixture through a plug of celite and silica gel. The plug was then washed with 500 ml of methanol-CH2Cl2 mixture (1 :5). The filtrate was evaporated to give 14.2 g of the desired crude aldehyde.
511 Step 2. Preparation of 4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-6- (hydroxymethyϊ)pyridin-2(lH)-one.
Figure imgf000512_0001
In a 500 ml three neck round bottom flask equipped with a stir bar of 4-[(2,4- difluorobenzyl)oxy] - 1 -(2,6-difluorophenyl)-6-oxo- 1 ,6-dihydropyridine-2-carbaldehyde (14.2 g, 37.7 mmol) was dissolved in methanol (200 mL). The reaction mixture was cooled to 0 °C and to this was added sodium borohydride (2.13g, 56.30 mmol) in a slow portion-wise fashion. The reaction was stirred at 0 °C for 2 hour. Excess amount of sodium borohydride was added to drive the reaction to completion. After stirring for approximately 2.5 hours, the reaction was allowed to warm to room temperature and then concentrated to dryness. The residue was taken up in ethyl acetate (100 mL) and washed with dilute HCl (pH of aqueous layer was approximately 4). Organic extracts were washed with brine (IX 50 ml), dried over MgS04, and concentrated in vacuo. The crude product was recrystallized from ethyl acetate and hexane to yield 7.56 g (44% yield- starting from step 1) of the desired alcohol. \ Step 3. Preparation of 3-bromo-4- [(2,4-difluorobenzyϊ)oxy]-l-(2,6- difluorophenyl)-6-(hydroxymethyl)pyridin-2(lH)-one. In a 100 ml round bottom flask of 4- [(2,4-difluorobenzyl)oxy]- 1 -(2,6-difluorophenyl)-6-(hydroxymethyl)pyridin-2( 1 H)- one (2.49 g, 6.56 mmol), from step 2, was dissolved in acetonitrile (35 mL). The reaction mixture was cooled to 0 °C in ice bath for 10 min. and then charged with N- bomosuccinamide (1.17g, 6.6 mmol) . The mixture was allowed to stir, at 0 °C, under nitrogen atmosphere for 2 hours. The reaction was the worked up by removing the acetonitrile under vacuum. The resulting residue was then filtered, with washing from a small amount of acetonitrile, to give a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.695 - 7.588 (m, 2H), 7.368-7.314 (m, 3H), 7.175 (dt, J = 8.5, 2.5, Hz, IH), 6.760 (s,
- 512 - IH), 5.712 (t, J = 5.674 Hz, IH), 5.384 (s, 2H), 4.004-3.990 (m, 2H); ES-HRMS m/z 458.0013 (M+H-calcd for C19H13BrF4N03, requires 458.0013). Example 466. Preparation of 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(2,6- difluorophenyl)-6-(hydroxymethyι)pyridin-2(lH)-one
The title compound was prepared by taking 4-[(2,4-difluorobenzyl)oxy]-l-(2,6- difluorophenyl)-6-(hydroxymethyl)pyridin-2(lH)-one (1.5g, 3.9 mmol) in acetonitrile (15 mL) and adding to that N-chlorosuccinimide (580 mg, 4.3 mmol). The reaction was stirred at rt for 3h afterwhich a small amount of additional N-chlorosuccinimide (50 mg, 0.4 mmol) was added to the reaction. Stirring was continued for lh. The reaction mixture was filtered through a fritted funnel to obtain the crude material. 1H NMR (400 MHz, DMSO-d6) δ 7.69 - 7.61 (m, 2H), 7.37-7.31 (m, 3H), 7.17 (dt, J = 8.8, 2.0 Hz, IH), 6.80 (s, IH), 5.70 (t, J = 6.0 Hz, IH), 5.38 (s, 2H), 4.01 (d, J = 6.0 Hz, 2H); ES-HRMS m/z 414.0515 (M+H calcd for C19H13C1F4N03; requires 414.0520). Example 467. Preparation of 5-bromo-4-[(2,4-difluorobenzyι)oxy]-l-(2,6- difluorophenyl)-6-oxo-l,6-dihydropyridine-2-carbaldehyde
Figure imgf000513_0002
513 - Preparation of the title compound, a 50 ml one neck round bottom flask 4-[(2,4- difluorobenzyl)oxy] - 1 -(2,6-difluorophenyl)-6-oxo- 1 ,6-dihydropyridine-2-carbaldehyde (0.36 g, 0.95 mmol) was dissolved in acetonitrile (5 mL). The reaction mixture was cooled to 0 °C in ice bath and charged with N-bromosuccinamide (0.17 g, 0.95 mmol). The mixture was allowed to stir at 0 °C for 2 hours under nitrogen atmosphere After 2 hours, the solvent was evaporated under vacuum. 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, IH), 7.73 - 7.67 (m, 2H), 7.62- 7.54 (m, IH), 7.35 (dt, J = 10.40, 2.56 Hz, IH), 7.27 (t, J=8.35 Hz, 2H), 7.19 (dt, J =8.60, 2.44 Hz, IH), 5.72 (s, IH), 5.50 (s, 2H); ES-MS m/z 455.9836 (M+H calcd for C19HnBrF4N03, requires 455.9859). Example 468. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6- difluorophenyl)-6-[(dimethylamino)methyl]pyridin-2(lH)-one
Figure imgf000514_0001
In a 50 ml round bottom flask 5-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6- difluorophenyl)-6-oxo-l,6-dihydropyridine-2-carbaldehyde (0.456 gm, 1.0 mmol) was stirred in dichloromethane (5 mL). To this mixture was added a 2M THF solution of dimethyl amine (1.25ml, 2.5 mmol ). The mixture was allowed to stir under nitrogen atmosphere and at room temperature for 2 hours. To this mixture was then added triacetoxy sodium borohydride (0.37 g, 1.75 mmol) followed by two to three drops of < acetic acid. The mixture was then stirred at rt overnight. The solvents were then removed by evaporation and the residue was taken up in ethyl acetate (30 ml) and washed with aqueous sodium bicarbonate and brine. The organics were then combined, dried over MgS04, and concentrated in vacuo. The crude product was purified by flash column chromatography using a solvent gradient of (3:1) ethyl acetate-hexane to (0:100) ethyl acetate to give 0.14 g (30 % yield) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.73-7.58 (m, 2H), 7.42-7.30 (m, 3H), 7.22 (dt, J=8.73, 2.60 Hz, IH), 6.81 (s, IH), 5.44
- 514 - (s, 2H), 3.04 (s, 2H), 1.96 (s, 6H); ES-MS m/z 485.0 (M+H). ES-HRMS m/z 485.0457 (M+H calcd for C21H18BrF4N20 ; requires 485.0489). Example 469. Preparation of 3-bromo-4-[(2,4-difluorobenzyϊ)oxy]-l-(2,6- difluorophenyl)~6-(morpholin-4-ylmethyl)pyridin-2(lH)-one
Figure imgf000515_0001
The title compound was prepared by reacting 5-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6- difluorophenyl)-6-oxo-l,6-dihydropyridine-2-carbaldehyde (0.456 g, lmmol) with morpholine (0.13 ml, 1.5 mmol) and triacetoxy sodium borohydride (0.42 g, 2.0 mmol) in dichloromethane (7 mL) by using a similar procedure to the one described for Example 468. The crude product was purified by flash column chromatography. Elution with
(50:50 -> 0:100) hexanes-ethyl acetate to give 0.15 g (29% yield) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.75- 7.57 (m, 2H), 7.43-7.31 (m, 3H), 7.20 (dt, J=8.64, 2.48 Hz, 2H), 6.85 (s, IH), 5.44 (s, 2H), 3.37 (app t, J=4.37 Hz, 4H), 3.13 (s,2H), 2.08 (t, J=4.19 Hz, 4H); ES-HRMS m/z 527.0600 (M+H calcd for C23H20BrF4N2O3 requires 527.0594). Example 470. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6- difluorophenyl)-6-{[(2-methoxyethyl)amino]methyl}pyridin-2(lH)-one
Figure imgf000515_0002
515 The title compound was prepared by reacting 5-bromo-4-[(2,4-difluorobenzyl)oxy]-l- (2,6-difluorophenyl)-6-oxo-l,6-dihydropyridine-2-carbaldehyde (0.319 g, 0.7 mmol) with 2-methoxy ethylamine (0.086 ml, 1.0 mmol) and triacetoxy sodium borohydride (0.42 g, 2.0 mmol) in dichloromethane (4 mL)by using a procedure, similar to the one described for Example 468. The crude product was purified by flash column chromatography. Elution with (50:50 - 0:100 hexanes-ethyl acetate to give 0.13 g of the desired product. 1H NMR (400 MHz, CDC13) δ 7.54 (q, J=6.89 Hz, IH), 7.41 - 7.33 (m, IH), 7.19 (s, IH), 6.99 (t, J = 7.90 Hz, 2H), 6.90 (dt, J=7.90, 2.78, Hz, IH), 6.80 (dt, J = 10.60, 2.34 Hz, IH), 6.51 (s,lH), 5.24 (s,2H), 3.33 (t, J=4.69 Hz,lH), 3.30 (s, 3H), 2.57(t, J= 4.86 Hz, 2H), 1.53 (s,2H); ES-HRMS m/z 515.0548 (M+H calcd for C22H20BrF4N2O3, requires 515.0594). Example 471. Preparation of 5-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6- difluorophenyϊ)-6-oxo-l,6-dihydropyridine-2-carboxy lie acid
Figure imgf000516_0001
hi a 100 ml round bottom flask, 3-bromo-4- [(2,4-difluorobenzyl)oxy]-l-(2,6- difluorophenyl)-6 (hydroxymethyl)pyridin-2(lH)-one (1.70 g, 3.7 mmol) was dissolved in acetone (10 mL) and cooled to 0° C in ice bath. To the reaction was added 1M acetone solution of Jones (5 ml, excess amount). Additional Jones reagent was added over time (approximately 6 hours) until the reaction was complete. The reaction was then concentrated down to dryness. The residue was then taken up in ethyl acetate (10 mL) and washed with brine. The dark yellow to brown colored crude product was purified by dissolving in IN aqueous NaOH. The remaining organic impurities were removed by extracting with diethyl ether. The organic layers were discarded and the aqueous layer was acidified with dilute HCl (til pH app 1) to precipitate the pure acid which was then filtered and triturated with ether to obtain 1.17 g (65%) of the desired product. 1H NMR
- 516 - (400 MHz, DMSO-d6) δ 7.66 (q, J= 9.41 Hz, IH), 7.57- 7.50 (m, IH), 7.34 (dt, J= 10.11, 2.78 Hz, IH), 7.28- 7.23 (m, 3H), 7.18 (dt, 8.90, 2.42 Hz, IH), 5.47 (s, 2H). ES-HRMS m/z 471.9814 (M+H calcd for C19HuBrF4N04> requires 471.9808) Example 472. Preparation of methyl 4-[3-bromo-4-[(2.4-difluorobenzyl)oxy]- 6-methyl-2-oxopyridin-l(2H)-yl]-3-methylbenzoate
Figure imgf000517_0001
Step 1: Preparation of methyl 4-(4-hydroxy-6-methyl-2-oxopyridm-l(2H)-yι)-
3-methylbenzoate.
Figure imgf000517_0002
3 In a 50 ml one neck round bottom flask equipped with a stir bar, Dean Stark trap, and condenser 4-amino-2-methyl-methylbenzoate (1.19g, 11.63 mmol) and 4-hydroxy-6- methyl-2H-pyran-2-one (1.61 lg, 12.78 mmol) were mixed together and dissolved in 1,2- dichlorobenzene (5 mL). The mixture was vigorously stirred and then placed in a preheated oil bath at 165 °C. The reaction was maintained at 165 °C for 1.5 hour and cooled to room temperature. The reaction was worked up by diluting with toluene (10 mL) and then stirring at room temperature for 2 hours. A light brown precipitate resulted. The crude product was isolated by filtration and then triturated with ether. 1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, IH), 7.93 (s,lH), 7.85 (dd, 8.46 Hz, IH), 7.26 (d , J= 8.12
517 - Hz, IH), 5.91 (d, J= 2.32 Hz, IH), 5.54 (d, J=2.32 Hz, IH), 3.84 (s, 3H), 1.99 (s, 3H), 1.73 (s,3H). ES-HRMS m/z 272.0880 (M-H calcd for C15H14N04, requires 272.1001). Step 2. Preparation of methyl 4-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin- 1 (2H)-yl)-3-methylbenzoate
Figure imgf000518_0001
3
Methyl 4-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-l(2H)-yl)-3-methylbenzoate was prepared by reacting - methyl 4-(4-hydroxy-6-methyl-2-oxopyridin-l(2H)-yl)-3- methylbenzoate with N-bomosuccinamide in acetonitrile by following a procedure, similar to the one described in Example 465- step 3. 1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, IH), 7.87 (dd, J = 7.76, 2.02 Hz, IH), 7.31 (d, J=8.54, IH), 6.09 (s,lH), 3.85 (s, 3H), 1.99 (s,3H), 1.74 (s, IH). ES-HRMS m/z 352.0195 (M+H calcd for C15H14BrN04, requires 352.0185) Step 3. Preparation of methyl 4-(4-hydroxy-6-methyl-2-oxopyridin-l(2H)-yι)- 3-methylbenzoate. The title compound was prepared by taking methyl 4-(3-bromo-4- hydroxy-6-methyl-2-oxopyridin-l(2H)-yl)-3-methylbenzoate (0.92 g, 2.61 mmol) and dissolving in dry DMF (5 mL). Potassium carbonate (0.432 g, 3.13 mmol) and 2,4 Difluuorobenzyl bromide (0.335 ml, 2.61 mmol) were then added. The mixture was allowed to stir at room temperature for 2 hours. The reaction was then worked up by pouring it into 100 ml of ice-water which resulted in a precipitate forming which was isolated by filtering through a fritted funnel. The crude product was washed with ether and dried in vacuum to give 0.85 g (76.20%) of pure product. 1H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J = 1.6 Hz, IH), 7.88 (dd, J =8.04, 2.0 Hz, IH), 7.69 (q, J = 8.6 Hz, IH), 7.36-7.30 (m, 2H), 7.17 (dt, J = 8.7, 2.3 Hz, IH), 6.71 (s,lH), 5.32 (s,2H), 3.86 (s,3H), 2.00 (s,3H), 1.86 (s, 3H). ES-HRMS m/z 478.0459 (M+H calcd for C22H19BrF2N04 requires 478.0466).
518 Examples 473-476. Preparation of compounds corresponding in structure to the following formula:
Figure imgf000519_0001
The compounds of Examples 473-476 are prepared by derivitazion of the compounds of Example 472.
Figure imgf000519_0002
NMR characterization of compounds of Examples 473-476
Figure imgf000519_0003
- 519
Figure imgf000520_0003
Example 477. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl- l-(2-methyl-4-vinylphenyl)pyridin-2(lH)-one
Figure imgf000520_0001
Step 1. Preparation of -l-(4-bromo-2-methylphenyl)-4-hydroxy-6-methylpyridin- 2(lH)-one
Figure imgf000520_0002
The title compound was prepared in a similar manner to the procedure outlined above for 4-(4-hydroxy-6-methyl-2-oxopyridin-l(2H)-yl)-3-methylbenzoate. 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, IH), 7.59 (d, J= 2.84 Hz, IH), 7.45 (dd, J= 8.39, 2.44 Hz, IH), 7.06 (d, J= 7.44, IH), 5.89 (d, J=2.73 Hz, IH), 5.53(d, J=2.30, IH), 1.91 (s, 3H), 1.75 (s, 3H). ES-HRMS m/z 294.0127 (M+H calcd for C13H13BrN03, requires 294.0130).
- 520 - Step 2. Preparation of - l-(4-bromo-2-methylphenyι)-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one
Figure imgf000521_0001
l-(4-bromo-2-methylphenyl)-4-hydroxy-6-methylpyridin-2 (lH)-one (7.35 g, 25.0 mmol) was dissolved in DMF (15 mL) and stirred with potassium carbonate (4.14 g, 30.0 mmol) and 2,4 difluorobenzyl bromide (3.21 ml (25.0 mmol) at room temperature for 2 hours. The reaction was worked up by pouring in to 300 ml ice water under continuous stirring. A white precipitate was obtained which was isolated by filtering and further purified by triturating with ether to give 3.06 g (29%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 7.65- 7.59 (m, 2H), 7.49 (dd, J=8.45, 2.22 Hz, IH), 7.31 (dt, J= 9.79, 2.22 Hz, IH), 7.16- 7.08 (m, 2H), 6.05 (d, J= 2.58 Hz, IH) , 5.93 (d, J= 2.66 Hz, IH), 5.08 (s, 2H), 1.93 (s, 3H), 1.77 (s, 3H). ES-HRMS m/z 420.0390 (M+H calcd for C20H17BrF2NO2> requires 420.0411). Step 3. Preparation of 4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(2-methyl-4- vinylphenyι)pyridin-2(lH)-one.
Figure imgf000521_0002
521 hi a 50 ml round bottom flask previously evacuated and filled with nitrogen, l-(4-bromo- 2-methylphenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2 (lH)-one (0.420 g, 1.0 mmol) was dissolved in dry THF (10 mL). To this mixture was added Pd (PPh3) (0.173 g, 0.15 mmol). The reaction flask was sealed with a rubber septum, evacuated and filled with nitrogen. Under a nitrogen atmosphere, tributyl(vinyl)tin (0.35 ml, 1.2 mmol) was added to the sealed reaction mixture and stirred overnight at 50 °C. The reaction was worked up by quenching with water and extraction of the product with ethyl acetate. The crude product was purified by column chromatography. Elution with ethyl acetate-hexanes (50:50 ■» 0:100) hexanse gave 0.32 g (69%) of the desired product. Step 4. Preparation of 3-bromo-4-[(2,4-difluorobenzyι)oxy]-6-methyl-l-(2- methyl-4-vinylphenyl)pyridin-2(lH)-one. The title compound was prepared by reacting 4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(2-methyl-4-vinylphenyl)pyridin-2(lH)-one (0.64 g, 1.74 mmol) with N-bromosuccinamide (0.325 g, 1.83 mmol) in acetonitrile (9 mL) at 0°C using a similar procedure as described in step 3 of Example 465, to give 0.423 g (54.5 % after recrystallization) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ
7.67(app q, J= 7.59 Hz, IH), 7.48(s,lH), 7.42(dd, J=8.21,1.98 Hz,lH), 7.33(dt, J=10.00, 2.27 Hz, IH), 7.17(dt, J=8.51, 2.44 Hz, IH), 7.13(d, J=7.88 Hz, IH) 6.74(dd, J=11.29, 6.34 Hz, IH), 6.67 (s,lH), 5.88(d, J= 17.85, IH), 5.32-5.30 (m, 2H), 1.92 (s, 3H), 1.88 (s,3H). ES-HRMS m/z 446.0579 (M+H calcd for C22H19BrF2N02; requires 446.0568). Example 478. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[4-(l,2- dihydroxyethyl)-2-methylphenyl]-6-methylpyridin-2(lH)-one
Figure imgf000522_0001
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(2-methyl-4-vinylphenyl)pyridin-2(lH)- one (0.126 g, 0.28 mmol) was dissolved in a mixture of acetone (3 mL) and water (1 mL).
- 522 - To this was added 4-methylmo holine N-oxide (0.032 g, 0.28 mmol) and catalytic amount (approximately 5 mg) of osmium tetroxide was added, and stirred under nitrogen atmosphere. After approximately 2 hours, the reaction was worked up by evaporation of the acetone. The product was extracted into ethyl acetate and concentrated to give a dark colored solid which was further purified by column chromatography to give 0.049 g (37 % yield)of charcoal colored solid. 1H NMR (400 MHz, DMSO-d6) δ 7.67 (q, J=8.24 Hz, IH), 7.37-7.23 (m, 3H), 7.17 (dt, J= 8.62, 2.62 Hz, IH), 7.07 (dd, J=9.36, 2.24 Hz, IH), 6.65(s,lH), 5.30 (s, 2H), 4.74(t, J=6.16Hz, IH), 4.57- 4.50 (m, IH), 3.45(app t, J=6.12 Hz, 2H), 3.41- 3.37 (m, IH), 1.91(s,3H), 1.85 (s, 3H). ES-HRMS m/z 480.0625 (M+H calcd for C22H21BrF2N04j requires 480.0623). Example 479. Preparation of methyl 3-[3-bromo-4-[(2,4-difluorobenzyι)oxy]-
6-methyl-2-oxopyridin-l(2H)-yl]-4-chlorobenzoate
Figure imgf000523_0001
Step 1. Preparation of methyl 4-chloro-3-(4-hydroxy-6-methyl-2-oxopyridin- l(2H)-yl)benzoate.
Figure imgf000523_0002
A condensation reaction with methyl 3-amino-4-chlorobenzoate (14.5g, 78.2 mmol) and 4- hydroxy-6-methyl pyranone under reaction condition similar to the one described in Example 465- step 3 gave 12.32 (53.8%) of desired product.
523 Step 2. Preparation of methyl-4-chloro-3-[4-[(2,4-difluorobenzyϊ)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]benzoate.
Figure imgf000524_0001
In a 250ml round bottom flask, methyl 4-chloro-3-(4-hydroxy-6-methyl-2-oxopyridin- l(2H)-yl)benzoate (5.28 g, 18.0 mmol) from stepl was reacted with 2,4-difluoro- benzylbromide (3.72 g, 18.0 mmol) in DMF using similar procedure as in Example 472 step 3. After aqueous work up and chromatographic purification, 2.3 g (30%) pure product was obtained. Step 3. Preparation of methyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]-4-chlorobenzoate. Methyl 3-[3-bromo-4-[(2,4- difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4-chlorobenzoate was prepared by reacting methyl-4-chloro-3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]benzoate (2.3 g, 5.47 mmol) with N-bromosuccinamide (0.97 g, 5.47 mmol) in acetonitrile (10 mL) at 0°C, using a similar procedure as described in step 3 of Example 465, to give 1.80g (66.2 %) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.06-8.03 (m, 2H), 7.86 (d, J=9.70 Hz, IH), 7.68 (q, J= 7.62, IH), 7.34(dt, J=10.07, 2.46 Hz, IH), 7.17 (dt,J= 8.72, 2.90 Hz, IH), 6.73 (s,lH), 5.33 (s, 2H), 3.85 (s, 3H), 1.91 (s, 3H). ES-MS m/z 495.9757 (M-H calcd for C21H14BrClF2N04, requires 495.9795).
524 - Example 480. Preparation of 3-[3-bromo-4-[(2,4-difluorobenzyι)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]-4-chlorobenzoic acid
Figure imgf000525_0001
In a 50 ml round bottom flask, methyl-4-chloro-3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl- 2-oxopyridin- l(2H)-yl]benzoate (0.450 g, 0.90 mmol) was stirred in THF (5 mL). To this mixture was added NaOH (0.120 g, 3.0 mmol ) as a solution in water (1.5 mL). The reaction mixture was stirred at room temperature overnight. The THF was evaporated and the residue was acidified with dilute HCl. A white precipitate was obtained. The product was filtered, washed with water and dried in vacuum to give 0.375 g (86 % yield ) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 7.89 (dd, J=7.78, 1.73 Hz, IH), 7.71- 7.65 (m, 2H), 7.53 (d, J=9.08Hz, IH), 7.33 (dt, J=9.95, 2.59 Hz, IH), 7.17 (dt, J=8.22, 2.59 Hz, IH), 6.68 (s, IH), 5.32(s, 2H), 1.89 (s,3H). ES-MS m/z 481.9585 (M-H calcd for C20H12BrClF2NO4, requires 481.9601). Example 481. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[5- (hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2(lH)-one
Figure imgf000525_0002
525 Step 1. Preparation of 4-hydroxy-l-[5-(hydroxymethyl)-2-methylphenyl]-6- methyl pyridin-2(lH)-one.
Figure imgf000526_0001
4-Hydroxy-6-methyl-2-pyrone (23.0 g, 182.2 mmol) and 3-Amino-4-methylbenzyl alcohol (25.0 g, 182.2 mmol) were taken up in 25 ml of 1,2-dichlorobenzene. The solution was heated to 165°C in a 250 ml round bottom flask equipped with a J-Kem temperature controller probe, and a heating mantle, hi a separate 250 ml round bottom flask 4- Hydroxy-6-methyl-2-pyrone (23.0 g, 182.2 mmol) was suspended in 25 ml of 1,2- dichlorobenzene and also heated to 165°C. The pyrone solution was poured into the flask containing the aniline and the reaction stirred at 165°C for 20 minutes. The reaction was allowed to cool to room temperature. Reaction contents were washed with saturated NaHC03 (aq.). Separated the organic and aqueous layers. Aqueous layer was made acidic with dropwise addition of concentrated HCl. The product was extracted from the acidic aqueous layer with n-BuOH. N-BuOH removed in vacuo to produce a reddish brown oil. (8.5 g, 19%). Contents carried forward to next reaction with no further purification. 1H NMR (300 MHz, CD3OD) δ 7.35 (m, 2H), 7.08 (s, IH), 6.08 (br s, IH), 5.81 (br s, IH), 4.60 (s, 2H), 2.01 (s, 3H), 1.87 (s, 3H). LC/MS, tr = 1.42 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 246.1131 (M+H). ES-HRMS m/z 246.1107 (M+H calcd for C14H16N03 requires 246.1125). Step 2. 4-[(2,4-difluorobenzyl)oxy]-l-[5-(hydroxymethyl)-2-methylphenyl]-6- methyl-pyridin-2(lH)-one.
Figure imgf000526_0002
- 526 4-hydroxy-l-[5-(hydroxymethyl)-2-methylphenyl]-6-methyl pyridin-2(lH)-one from Step 1) (8.0 g, 32.6 mmol) was stirred briskly at room temperature with 2,4-difluorobenzyl bromide (4.2 ml, 32.6 mmol) and K2C03 (4.5 g, 32.6 mmol) in 50 ml of dimethylformamide. After stirring for 8 hours, H20 (100 ml) was added to reaction mixture. The product was extracted with ethyl acetate. Ethyl acetate layer was separated and dried over Na2S04. Ethyl acetate was removed in vacuo. A yellow oil was obtained. The oil was passed through a plug of silica gel first eluting with 500 ml of ethyl acetate/hexane (1:1). This eluent was set aside. Next, ethyl acetate (100%) was passed through the plug until desired product was completely flushed from silica (3 liters). Solvent was removed in vacuo. Light yellow oil obtained (7.5 g, 62%). 1H NMR (300
MHz, CD3OD) δ 7.60 (app q, J = 6.44 Hz, IH), 7.42 (d, J = .81 Hz, 2H), 7.15 (s, IH), 7.06 (m, 2H), 6.21 (dd, J = 1.61, 1.00 Hz, IH), 6.12 (d, J = 2.62 Hz, IH), 5.16 (s, 2H), 4.65 (s, 2H), 2.07 (s, 3H), 1.93 (s, 3H); LC/MS, tr = 2.38 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 372 (M+H). Step 3. Preparation of 3-bromo-4-[(2,4~difluorobenzyι)oxy]-l-[5-
(hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2(lH)-one. 4-[(2,4- difluorobenzyl)oxy]-l-[5-(hydroxymethyl)-2-methylphenyl]-6-methyl-pyridin-2(lH)-one (from Step 2) (4.0 g, 10.8 mmol) was stirred at room temperature with N- bromosuccinimide (2.1 g, 11.9 mmol) in 100 ml of CH2C12 for 2.0 hours. The reaction was evaporated on a rotary evaporator and the resulting solid was washed with acetonitrile and dried in vacuo to yield a white solid (3.9 g, 80%). 1H NMR (300 MHz, CDC13) δ 7.67 (app q, J = 6.24 Hz, IH), 7.35 (d, J = 1.01 Hz, 2H), 7.10 (s, IH), 7.04 (m, IH), 6.91 (ddd, J = 11.08, 8.66, 2.42 Hz, IH), 6.15 (d, J = 0.63 Hz, 2H), 5.29 (s, 2H), 4.66 (s, 2H), 2.08 (s, 3H), 1.97 (s, 3H); ES-MS m/z 450 (M+H). ES-HRMS m/z 450.0467 (M+H calcd for C21H19BrF2N03 requires 450.0511).
- 527 Example 482. Preparation of 3-chloro-4-[(2,4-difIuorobenzyϊ)oxy]-l-[5- (hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2(lH)-one
Figure imgf000528_0001
The title compound was prepared by a procedure similar to the one described for Example 481, except that the product from Step 2, Example 481 was chlorinated instead of being brominated. The procedure is as follows: 4-[(2,4-difluorobenzyl)oxy]-l-[5- (hydroxymethyl)-2-methylphenyl]-6-methyl-pyridin-2(lH)-one (from Step 2, Example 481 above) (7.0 g, 18.8 mmol) was refluxed with N-chlorosuccinimide (2.5 g, 18.8 mmol) in 50 ml of CH2C12 overnight. The reaction was evaporated on a rotary evaporator and the resulting solid was stirred in MeOH. The precipitate was collected on a filter pad, washed with MeOH and dried in vacuo to yield a white solid (1.6 g, 21%). 1H NMR (300 MHz, DMF-d7) δ 7.85 (app q, J = 6.44 Hz, IH), 7.43 (d, J = 0.81, IH), 7.42 - 7.23 (m, 3H), 6.84 (s, IH), 5.48 (s, 2H), 4.67 (s, 2H), 2.05 (s, 3H), 2.03 (s, 3H); ES-MS m/z 406 (M+H). ESHRMS m z 406.1033 (M+H calcd for C2ιH16ClF2N04 requires 406.1016). ( Example 483. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[5-
(hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2(lH)-one
Figure imgf000528_0002
Step 1: Preparation of 3-amino-4-chloro-benzyl alcohol.
Figure imgf000528_0003
528 - 3-Nitro-4-chloro-benzyl alcohol (23.0 g, 122.6 mmol) is taken up in isopropyl alcohol (175 ml) and water (35 ml). Iron powder (<10 micron) (68.0 g, 1.2 moles) and NH C1 (66.0 g, 1.2 moles) are added. The suspension is stirred overhead at 70°C in a three neck round bottom flask equipped with a heating mantle and a J-Kem temperature controller probe. After 4 hours, isopropyl alcohol was removed in vacuo. Water (100 ml) and concentrated HCl (10 ml) was added to mixture. Contents are transferred to a separtory funnel and ethyl acetate is used to extract the aqueous layer of impurities. The aqueous layer was then basified with 50% aqueous NaOH. The product was extracted from the basic aqueous layer with ethyl acetate. The ethyl acetate layer was dried over Na S0 and then removed in vacuo. The remaining residue was taken up in 50% ethyl acetate/hexane and the precipitate was collected on a filter pad. Precipitate was washed with 50% ethyl acetate hexane to yield a flocculent brown solid (8.4 g, 44%). 1H NMR (300 MHz, CD3OD) δ 7.17 (d, J = 8.26 Hz, IH), 6.86 (d, J = 2.01 Hz, IH), 6.66 (dd, J = 2.01, 0.61 Hz, IH), 4.51 (s, 2H); LC MS, tr = 0.32 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C); ES-MS m/z 158 (M+H). Step 2. l-[2-chloro-5-(hydroxymethyl)phenyl]~4-hydroxy-6-methyIpyridin- 2(lH)-one.
Figure imgf000529_0001
3-amino-4-chloro-benzyl alcohol (8.0g, 51.0 mmol) and 4-hydroxy-6-methyl-2-pyrone (6.4 g, 51.Ommol) were taken up in 1 ,2-dichlorobenzene (50 ml). The mixture was plunged into a 165°C oil bath where it stirred for 20 minutes. The reaction was cooled to room temperature and the reaction was worked up by washing with saturated NaHC03 (aq.) and extracting impurities with ethyl acetate. The product remained in the aqueous layer. The basic aqueous layer was made acidic with concentrated HCl. The product was extracted from the acidic aqueous layer with ethyl acetate. The ethyl acetate layer was dried over Na2S04 and the solvent removed in vacuo. The product was obtained as a yellow oil in a 26% yield and was carried through to the next step with no further purification. 1H NMR (300 MHz, CD3OD) δ 7.62 (d, J = 8.26 Hz, 2H), 7.51 (dd, J = 8.46,
529 2.22 Hz, IH), 7.36 (d, J = 2.01 Hz, IH), 6.13 (br s, IH), 5.84 (d, J = 2.42 Hz, IH), 4.68 (s, 2H), 1.97 (s, 3H); LC/MS, tr = 0.25 minutes and 1.41 minutes (tautomer), (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 266 (M+H). Step 3. l-[2-chloro-5-(hydroxymethyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6- methylpyridin-2(lH)-one.
Figure imgf000530_0001
1 -[2-chloro-5-(hydroxymethyl)phenyl]-4-hydroxy-6-methylpyridin-2(lH)-one (from step 2) (3.5g, 13.2 mmol) was taken up in DMF (10 ml) and cooled to 0°C. 2,4-Difluorobenzyl bromide (1.7 ml, 13.2 mmol) and K2C03 (1.8 g, 13.2 mmol) were added and the reaction stirred for 6 hours. The reaction was worked up by adding saturated NaHC03 (aq.) and extracting with ethyl acetate. The ethyl acetate extraction was washed with water, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over Na2S04, filtered, and the solvent removed in vacuo. The product was obtained in 83% crude yield and carried through to the next step as a brown oil. LC/MS, tr = 2.48 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 392 (M+H). ES-HRMS m/z 392.0853 (M+H calcd for C20H17ClF2NO3 requires 392.0860). Step 4. Preparation of 3-bromo-4-[(2,4-difluorobenzyι)oxy]~l-[5- (hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2(lH)-one. The title compound was prepared from l-[2-chloro-5-(hydroxymethyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6- methylpyridin-2(lH)-one (from step 3) (1.8g, 4.6 mmol) and N-bromosuccinimide (0.82 g, 4.6 mmol) by dissolving them in CH2C12 (10 ml) and stirring for 2 hours at room temperature. The solvent was removed in vacuo and the residue was taken up in CH3CN. The precipitate was collected on a filter pad and rinsed with CH3CN to yield a white solid (370 mg, 17%). 1H NMR (300 MHz, CDC13) δ 7.65 (app q, J = 6.24 Hz, IH), 7.52 (d, J = 8.26 Hz, IH), 7.40 (dd, J = 8.26, 2.01 Hz IH), 7.26 (d, J = 0.81 Hz, IH), 7.03 (m, IH),
530 6.91 (ddd, J = 11.08, 8.66, 2.42 Hz, IH), 6.17 (d, J = 0.81 IH), 5.29 (s, 2H), 4.63 (s, 2H), 2.02 (s, 3H); ES-MS m/z 471 (M+H). ES-HRMS m/z 471.9953 (M+H calcd for C20H16BrClF2NO3 requires 471.9944). Example 484. Preparation of 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[5- (hydroxymethyl)-2-methylphenyl]-6-methylpyridin-2(lH)-one
Figure imgf000531_0001
The title compound was prepared from l-[2-chloro-5-(hydroxymethyl)phenyl]-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one (2.4 g, 6.1 mmol) and NCS (815.0 mg, 6.1 mmol) in 65°C dichloroethane (20 ml). A catalytic amount of dichloroacetic acid (2 drops) was added. After two hours the solvent was removed in vacuo and the residue was taken up in diethyl ether. The precipitate was collected on a filter pad and then taken up in 50% ethyl acetate/hexanes to remove residual succinimide. The precipitate was collected on a filter pad and then dried in vacuo to produce a white powder (180 mg, 6.9%). 1H NMR (300 MHz, CDC13) δ 7.61 (app q, J = 6.44 Hz, IH), 7.52 (d, J = 8.26 Hz, IH), 7.40 (dd, J = 8.26, 2.01 Hz IH), 7.27 (d, J = 2.01 Hz, IH), 7.00 (m, IH), 6.91 (m, IH), 6.20(s, IH), 5.29 (s, 2H), 4.65 (s, 2H), 2.03 (s, 3H); ES-MS m/z 426 (M+H). ES-HRMS m/z 426.0453 (M+H calcd for C20H16C12F2NO3 requires 426.0470). Example 485. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{5- [(dimethylamino)methyl]-2-methylphenyl}-6-methylpyridin-2(lH)-one hydrochloride
Figure imgf000531_0002
Step 1. Preparation of 3-[3~bromo-4-[(2,4-difluorobenzyι)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]-4-methylbenzaldehyde.
531
Figure imgf000532_0001
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[5-(hydroxymethyl)-2-methylphenyl]-6- methylpyridin-2(lH)-one (1.5g, 3.33 mmol) was dissolved in 75% CH3CN/CH2C12 (20ml) and cooled to 0°C. Dess-Martin Periodinane(2.8 g, 6.66 mmol) was added and the reaction stirred for four hours. At this time, the reaction was quenched with 5% sodium bisulfite (aq.). The product was extracted with ethyl acetate. The combined organic extracts were then washed with saturated NaHC03 (aq.). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over Na2S04, filtered, and concentrated. The resulting residue was taken up in diethyl ether and the precipitate was collected on a filter pad and washed with more diethyl ether to yield a white solid (1.35 g, 91%). 1H NMR (300 MHz, CDC13) δ 10.00 (s, IH), 7.91 (dd, J = 7.65, 1.61 Hz, IH), 7.65 (m, 2H), 7.57 (d, J = 7.85 Hz, IH), 7.03 (m, IH), 6.95 (ddd, J = 12.69, 8.86, 2.62 Hz, IH), 6.19 (s, IH), 5.31 (s, 2H), 2.20 (s, 3H), 1.96 (s, 3H); ES-MS m/z 448 (M+H). ES-HRMS m/z 448.0347 (M+H calcd for C21H17BrF2N03 requires 448.0354). Step 2: Preparation of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopy ridin-1 (2H)-yl] -4-methylbenzaldehy e. 3 - [3 -bromo-4- [(2,4-difluorobenzyl)oxy] - 6-methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzaldehyde (from step 1) (0.50 g, 1.11 mmol) was dissolved in CH2C12 ( 10 ml). N,N-dimethylamine (2.0 M in THF) (1.11 ml, 2.22 mmol) was added. This mixture stirred for at room temperature for 12 hours. Next, sodium tri-acetoxyborohydride (0.47 g, 2.22 mmol) was added and the reaction stirred for two more hours. The reaction was washed with 1 N NaOH (aq.) and then extracted with CH2C1 . The combined organic extracts were washed with water. The aqueous layer was separated and extracted with CH2C12. The combined organic extracts were dried over Na2S04, filtered and concentrated in vacuo. The resulting residue was taken up in diethyl ether. IM HCl in diethyl ether (5 ml) was added and the precipitate was collected on a filter pad. This precipitate was hygroscopic. The hygroscopic solid was then taken up in hot ethyl acetate. Hexane was added until a precipitate crashed out. The precipitate was
532 collected on a filter pad to yield a white solid (150 mg, 26%). 1H NMR (400 MHz, D20) δ 7.42 (m, 3H), 7.17 (s,lH), 6.86 (m, 2H), 6.53(s, IH), 5.20(s, 2H), 4.18(s, IH), 2.72(s, 6H), 1.85(s, 3H), 1.82(s, 3H); ES-MS m/z 477 (M+H). ES-HRMS m/z 477.0955 (M+H calcd for C23H24BrF2N202 requires 477.0984). Example 486. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{5- [(isopropylamino)methyl]-2-methylphenyl}-6-methylpyridin-2(lH)-one hydrochloride
Figure imgf000533_0001
The title compound was prepared by reductive animation of 3-[3-bromo-4-[(2,4- difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzaldehyde (from step 1) (0.50 g, 1.11 mmol) with iso-propyl amine (0.13 g, 2.22) according to the procedure described above for Example 485 (Step 2) to give the desired compound (0.49g, 84%). 1H NMR (400 MHz, CD3OD) δ 7.64 (app quartet, J = 6.58 Hz, IH), 7.53 (m, 2H), 7.29(br s, IH), 7.03(m, IH), 6.68 (s, IH), 5.36 (s, 2H), 4.22(s, 2H), 3.46(m, IH), 2.06 (s, 3H), 2.01 (s, 3H), 1.37 (d, J = 6.58 Hz, 6H) ; ES-MS m/z 491 (M+H). ES-HRMS m/z 491.1107 (M+H calcd for C24H26BrF2N202 requires 491.1140). Example 487. Preparation of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]-N-(2-hydroxyethyl)-4-methylbenzamide
Figure imgf000533_0002
533 - Step 1. Preparation of methyl 3-(4-hydroxy-6-methyl-2-oxopyridin-l(2H)-yl)- 4-methylbenzoate.
Figure imgf000534_0001
4-Hydroxy-6-methyl-2-pyrone (22.9 g, 181.6 mmol) and methyl-3-amino-2- methylbenzoate (25 g, 151.3 mmol) were suspended in 50 ml of 1 ,2-dichlorobenzene in a 250 ml, 3-necked round bottom flask equipped with a J-Kem temperature controller probe, a Dean-Stark trap, and a heating mantle. The reaction was heated to 165°C for 15 minutes, during which, water and some 1,2-dichlorobenzene was collected in the Dean-Stark trap. The reaction was allowed to cool to about 110°C At this point, 200 ml of toluene was added. The flask was plunged into a 0°C ice bath while stirring. "Oiling out" occurred. Perhaps too much toluene was added so some of the solvent was removed in vacuo. The oil went back into solution and a light brown precipitate remained. The toluene mixture was allowed to stir for 72 hours at room temperature. A precipitate was collected on a filter pad. The precipitate was filtered and washed 3 times with toluene, 3 times with 50°C. water to remove excess pyrone, and dried in vacuo to give a tan solid (16.5 g, 40% yield). 1H NMR (300 MHz, CD3OD) δ 8.06 (dd, J = 8.06, 1.61 Hz, IH), 7.80 (d, J = 1.61 Hz, IH), 7.56 (d, J = 8.06, Hz, IH), 6.15 (dd, J = 2.42, 0.81 Hz, IH), 5.86 (d, J = 2.42 IH), 3.94 (s, 3H), 2.15 (s, 3H), 1.91 (s, 3H); ES-MS m/z 274 (M+H). ES-HRMS m/z 274.1066 (M+H calcd for C15H16N04 requires 274.1074). Step 2. Preparation of methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]-4-methylbenzoate.
Figure imgf000534_0002
Methyl 3-(4-hydroxy-6-methyl-2-oxopyridin-l(2H)-yl)-4-methylbenzoate (from Step 1) (16.5 g, 60.4 mmol) 2,4-difluorobenzyl bromide (7.8 ml, 60.4 mmol) were taken up in 250 - 534 - ml of N,N-dimethylformamide and the mixture was cooled to 0°C. K2C03 (8.3g, 60.4 mmol) was added and reaction stirred for 12 hours during which time the reaction was allowed to warm to room temperature. LC/MS indicated the presence of starting material after 12 hours. An excess of K2C03 was added at room temperature along with 0.50 ml of 2,4-difluorobenzyl bromide. The reaction stirred for an additional two hours. Saturated NaHC03 (aq.) was poured into reaction vessel. The solution was extracted with ethyl acetate and the organic layers were combined then washed with water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over Na2S04, and evaporated. The product was carried on to the next step as a crude oil (24.1 g, quantitative yield). 1H NMR (300 MHz, CDC13) δ 8.06 (dd, J = 7.85, 1.61 Hz, IH), 7.82 (d, J = 1.61, IH), 7.52-7.44 (m, 2H), 7.01 - 6.88 (m, 2H), 6.05 (d, J = 2.62 Hz, IH), 5.97 (dd, J = 2.62, 0.81 Hz, IH), 5.08 (s, 2H), 3.93 (s, 3H), 2.20 (s, 3H), 1.89 (s, 3H); ES-MS m/z 400 (M+H). ES-HRMS m/z 400.1374 (M+H calcd for C22H20F2NO4 requires 400.1355). Step 3. Preparation of 3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]-4-methylbenzoic acid.
Figure imgf000535_0001
Methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl]-4- methylbenzoate (14g, 35.0 mmol)(from step 2) was taken up in THF (25 ml) and H20. 2.5 N NaOH (aq.) was added and the reaction stirred for 30 minutes at room temperature. The reaction was made acidic via the addition of concentrated HCl. The product was extracted with ethyl acetate. The ethyl acetate extraction was dried over Na2S0 , filtered, and the solvent removed in vacuo. Upon vacuum removal of the solvent, the product crashed out of the ethyl acetate. This precipitate was collected on a filter pad and washed with a 50 ethyl acetate/hexanes to yield a white powder (9g, 7%). 1H NMR (300 MHz, CDC13) δ 8.01 (dd, J = , 1.61 Hz, IH), 7.84 (d, J = 1.61 Hz, IH), 7.52 - 7.47 (app q, J = 8.26, IH), 7.43 (d, J = 8.06 Hz, IH), 7.00 - 6.88 (m, 2H), 6.19 (d, J = 2.62 Hz, IH), 6.05 (dd, J =
- 535 - 2.62, 1.81 Hz, IH), 5.17 (s, 2H), 2.19 (s, 3H), 1.90 (s, 3H); ES-HR MS m/z 386.12 (M+H calcd for C21H18F2N04 requires 386.1198). Step 4: Preparation of 3-[3-bromo-4-[(2,4-difluorobenzyι)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]-4-methylbenzoic acid.
Figure imgf000536_0001
3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoic acid (5.9 g, 15.2 mmol) (from step 3 above) was taken up in dichloromethane (25 ml). N- Bromosuccinimide was added and the reaction stirred for 14 hours. The dichloromethane was removed in vacuo and the residue was taken up in acetonitrile. The precipitate was collected on a filter pad and rinsed with acetonitrile to yield the desired product as a white solid (5.2 g, 74%). 1H NMR (300 MHz, CD3OD) δ 7.87 (dd, J = 7.85, 1.61,Hz, IH), 7.82 (d, J = 1.81 Hz, IH), 7.69 (app q, J = 8.06 Hz IH), 7.57 (d, J = 8.06 Hz, IH), 7.09 (dt, J = 8.66, 2.22 Hz, IH), 6.70 (s, IH), 5.40 (s, 2H), 2.14 (s, 3H), 2.02 (s, 3H); ES-MS m/z 464 (M+H). ES-HRMS m/z 464.0275 (M+H calcd for C21H17BrF2N04 requires 464.0304). Step 5. Preparation of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]-N-(2-hydroxyethyl)-4-methylbenzamide. 3-[3-bromo-4-[(2,4- difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoic acid (from Step 4 above) (1.9g, 4.10 mmol) was dissolved in 20 ml of CH2C12. Ethanolamine (297 μl, 4.92 mmol) was added, followed, in order, by EDCI (0.764 g, 4.92 mmol), 1- hydroxybenzotriazole (0.665g, 4.92 mmol) and triethylamine (1.14 ml, 8.20 mmol). The reaction was stirred at room temperature overnight. The reaction was quenched with NH4C1 and extracted 3 times with ethyl acetate. The combined organic layer was then washed with saturated NaHC03 (aq.) and extracted 3 times with ethyl acetate. The organic layers were combined and washed with H20 and extracted 3 times with ethyl acetate. The organic layers were combined and dried over Na2S04 and evaporated. The resulting residue was triturated with diethyl ether/hexane to obtain a solid, which was dried in vacuo to give a white solid (1.5g, 72%). 1H NMR (300 MHz, CDC13) δ 7.93 (dd,
- 536 - J = 7.85, 1.61 Hz, IH), 7.65 (d, J = 1.61 Hz, IH), 7.62 (app q, J = 8.26 Hz, IH), 7.40 (d, J = 8.06 Hz, IH), 7.39 - 7.30 (m, IH), 7.03 - 6.97 (m, IH), 6.88 - 6.81 (m, IH), 6.25 (s, IH), 5.20 (s, 2H), 3.70 - 3.52 (m, IH), 3.16 - 3.12 (m, 2H), 2.10 (s, 3H), 1.98 (s, 3H); ES-MS m/z 507 (M+H). ES-HRMS m/z 507.0719 (M+H calcd for C23H22BrF2N204 requires 507.0726). Examples 488-491. Preparation of compounds corresponding in structure to the following formula:
Figure imgf000537_0001
The compounds of Examples 488-491 are prepared essentially according to the procedures set forth for Example 487.
Figure imgf000537_0003
Example 492. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[5-(l hydroxy-l-methylethyl)-2-methylphenyl]-6-methylpyridin-2(lH)-one
Figure imgf000537_0002
537 ■ Step 1. Preparation of methyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoate.
Figure imgf000538_0001
Methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl]-4- methylbenzoate (as prepared above) (1.8g, 4.51 mmol) was taken up in CH2C1 (10 ml). N-bromosuccinimide (0.80 g, 4.51 mmol) was added and the mixture stirred at room temperature for two hours. The CH C1 is removed in vacuo and the residue is taken up in CH3CN. The resulting precipitate is collected on a filter pad and washed with CH3CN to yield a white solid (0.30 g, 14%, first crop). 1H NMR (300 MHz, CDC13) δ 8.06 (dd, J = 8.06, 1.61 Hz, IH), 7.80 (d, J = 1.61 Hz, 2H), 7.65 (app q, J = 8.46 Hz, IH), 7.48 (d, J = 8.06, IH), 7.05 - 6.99 ( , IH), 6.96 - 6.89 (m, IH), 6.16 (s, IH), 5.31 (s, 2H), 3.93 (s, 3H), 2.17 (s, 3H), 1.96 (s, 3H). ES-HRMS m/z 478.0476 (M+H calcd for C22H19BrF2N04 requires 478.0476). Step 2. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[5-(l-hydroxy- l-methylethyl)-2-methylphenyl]-6-methylpyridin-2(lH)-one. Methyl 3-[3-bromo-4- [(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl]-4-methylbenzoate (0.22 g, 0.46 mmol) was taken up in THF and cooled to 0°C. MeMgCl (3.0 M in THF) (0.73 ml, 2.2 mmol) was slowly added to the 0°C solution. The reaction was allowed to proceed without maintaining the 0°C bath temperature. The reaction was complete within two hours. At this time the mixture was quenched with saturated NH C1 (aq.) and extracted with ethyl acetate. The organic layers were combined, washed with H 0, and extracted with ethyl acetate. The organic layers were combined and dried over Na2S0 , filtered, and evaporated. The residue was taken up in 50% ethyl acetate/hexanes. The precipitate was collected on a filter pad and washed with 50% ethyl acetate/hexanes to yield a white solid (0.10 g, 45%). 1H NMR (300 MHz, CD3OD) δ 7.70 (app q, J = 8.26, Hz, IH), 7.54 (dd, J = 8.06, 2.01 Hz, IH), 7.40 (d, J = 1.81 Hz, IH), 7.12 - 7.06 (m, 2H), 6.68 (s, IH), 5.40 (s,
538 2H), 2.05 (s, 3H), 2.02 (s, 3H), 1.57 (s, 6H). ES-HRMS m/z 478.0785 (M+H calcd for C23H23BrF2N03 requires 478.0824). Example 493. Preparation of methyl 3-[3-chloro-4-[(2,4-difluorobenzyι)oxy]- 6-methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoate
Figure imgf000539_0001
The title compound was prepared by taking up methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoate (1.46g, 3.66 mmol) in dichloroethane (25 ml) and adding N-chlorosuccinimide (0.49g, 3.66 mmol), dichloroacetic acid (catalytic), and heating to 50°C for 6 hours. At this time, the solvent was removed in vacuo and the residue taken up in diethyl ether. The precipitate was collected on a filter pad. 1H NMR (300 MHz, CDC13) δ 8.07 (dd, J = 7.85, 1.61 Hz, IH), 7.80 (d, J = 1.81 Hz, 2H), 7.62 (app q, J = 8.46 Hz, IH), 7.48 (d, J = 7.85, IH), 7.05 - 6.95 (m, IH), 6.93 - 6.89 (m, IH), 6.19 (s, IH), 5.30 (s, 2H), 3.93 (s, 3H), 2.17 (s, 3H), 1.97 (s, 3H). ES-HRMS m/z 434.0932 (M+H calcd for C22H19C1F2N04 requires 434.0965). Example 494. Preparation of methyl 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-
6-methyl-2-oxopyridin~l(2H)-yl]-3-chlorobenzoate
Figure imgf000539_0002
Step 1. Preparation of methyl 3~chloro-4-(4-hydroxy-6-methyl-2-oxopyridin- l(2H)-yl)benzoate.
Figure imgf000539_0003
539 4-Hydroxy-6-methyl-2-pyrone (24.5 g, 193.9 mmol) and methyl-3-amino-2- chlorobenzoate (30 g, 161.6 mmol) were suspended in 75 ml of 1,2-dichlorobenzene in a 250 ml, 3-necked round bottom flask equipped with a J-Kem temperature controller probe, a Dean-Stark trap, and a heating mantle. The reaction was heated to 175°C for 20 minutes, during which, water and some 1 ,2-dichlorobenzene was collected in the Dean-Stark trap. The reaction was allowed to cool to about 110°C. At this point, 200 ml of toluene was added. The toluene mixture was allowed to stir for 72 hours at room temperature. A precipitate was collected on a filter pad. The precipitate was filtered and washed 3 times with toluene, 3 times with 50°C. water to remove excess pyrone, and dried in vacuo to give a tan solid (13.0 g, 27% yield). 1H NMR (300 MHz, CD3OD) δ 8.26 (d, J = 1.81 Hz, IH), 8.14 (dd, J = 8.26, 1.81 Hz, IH), 7.54 (d, J = 8.26, Hz, IH), 6.14(dd, J = 2.42, 1.0 Hz, IH), 5.83 (d, J = 2.42 IH), 4.00 (s, 3H), 1.96 (s, 3H); LC/MS, tr = 1.81 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 294 (M+H). Step 2. Preparation of methyl 3-chloro-4-[4-[(2,4-difluorobenzyι)oxy]-6- methyl-2-oxopyridin-l (2H)-yl] benzoate.
Figure imgf000540_0001
Methyl 3-chloro-4-(4-hydroxy-6-methyl-2-oxopyridin-l(2H)-yl)benzoate (from Step 1) (2.4g, 8.17 mmol) was taken up in DMF (10 ml). 2,4-difluorobenzylbromide (1.05 ml, 8.17 mmol) and K2C03 ( 1.13 g, 8.17 mmol) were added. The reaction stirred for 6 hours at room temperature. At this time, the reaction was poured into water (200 ml) and extracted with ethyl acetate. The ethyl acetate layer was dried over Na2S0 , filtered, and the solvent removed in vacuo to give amber oil (2.62 g, 77% crude yield). LC/MS, tr = 2.79 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 294 (M+H). Step 3. Preparation of methyl 4~[3-bromo-4-[(2,4~difluorobenzyι)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]-3-chlorobenzoate. Methyl 3-chloro-4-[4-[(2,4- difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]benzoate (from step 2) (2.60g, 6.21 - 540 - mmol) was taken up in CH2C1 (20 ml). N-bromosuccinimide (1.1 lg, 6.21 mmol) was added and the mixture stirred at room temperature for 4 hours. The CH2C12 is removed in vacuo and the residue is taken up in CH3CN. The resulting precipitate is collected on a filter pad and washed with CH3CN to yield a white solid (0.75 g, 24%). 1H NMR (300 MHz, CDC13) δ 8.22 (d, J = 1.88 Hz, IH), 8.06 (dd, J = 8.19, 1.75 Hz, IH), 7.59 (app q, J = 8.46 Hz, IH), 7.33 (d, J = 8.19, IH), 6.96 (dt, J = 8.06, 1.21 Hz, IH), 6.89 - 6.84 (m, IH), 6.13 (s, IH), 5.26 (s, 2H), 3.95 (s, 3H), 1.95 (s, 3H). ES-HRMS m/z 497.9892 (M+H calcd for C22H16BrClF2N04 requires 497.9914). Example 495. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)amino]-l-(3- fluorobenzyϊ)pyridin-2(lH)-one
Figure imgf000541_0001
Step 1. Preparation of 4-(benzyloxy)-l-(3-fluorobenzyl)pyridin-2(lH)-one
Figure imgf000541_0002
A 100 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with 4-benzyloxy-2(lH)-pyridinone (20 g, 99.6 mmol) and N,N-dimethyl formamide (50 mL). K2C03 (13.7 g, 99.6 mmol) and KI ( 1.6 g, 9.6 mmol) were added followed by 3- fluorobenzyl bromide (14.6 mL, 119.4 mmol). The reaction mixture was heated for 18 h at 80 C. The reaction mixture was concentrated in vacuo and treated with hot ethyl acetate. The solids were filtered off, the filtrate was poured into water and was extracted with ethyl acetate. The organic extract was washed with brine, dried with anhydrous Na2S0 , and concentrated in vacuo. The residue was dissolved in hot ethyl acetate and
- 541 - precipitated with hexanes to give the title compound (10 g, 33%). 1H NMR (400 MHz, CD3OD) δ 7.57 (d, J = 8.4 Hz, IH), 7.37 (m, 5H), 7.07 (d, J = 8.4 Hz, IH), 7.01 (app d, J = 8.4 Hz, 2H), 6.17 (d, J = 2.68 and 7.6 Hz, IH), 6.04 (d, J = 2.68 Hz, IH), 5.10 (s, 2H), 5.08 (s, 2H) ppm. 19 F NMR (400 MHz, CD3OD) δ -114.88 (1 F) ppm. ES-HRMS m/z 310.1271 (M+H calcd for C19H17FN02 requires 310.1238). Step 2. Preparation of l-(3-fluorobenzyι)-4-hydroxypyridin-2(lH)-one
Figure imgf000542_0001
A small Parr bottle was charged with (10 g, 32.3 mmol), ethanol (175 mL) andl0% Pd/C
(0.5 g). The system was flushed twice with both nifrogen and hydrogen. The reaction mixture was hydrogenated at 30 psi until no starting material was visible by LC-MS. The reaction mixture was slurried with Celite and then was filtered through a pad of celite.
The filtrate and ensuing ethanol washes were concentrated in vacuo to give a beige solid.
1H NMR (400 MHz, CD3OD) δ 7.53 (d, J = 7.67 Hz, IH), 7.32 (m, IH), 7.06 (d, J = 7.6
Hz, IH), 6.98 (d, J = 8.4 Hz, 2H), 6.05 (dd, J = 2.58 and 7.67 Hz, IH), 5.83 (d, J = 2.0 Hz, 2H), 5.10 (s, 2H) ppm. 19 F NMR (400 MHz, CD3OD) δ -115.33 (1 F) ppm. ES-HRMS m/z 218.0641 (M+H calcd for C12HπFN02 requires 218.0612). Step 3. Preparation of 4-[(2,4-difluorobenzyl)amino]-l-(3- fluorobenzyl)pyridin-2(lH)-one
Figure imgf000542_0002
The product from Step 2 (0.5 g, 2.28 mmol) and 2,4-difluoro benzylamine (4 mL, 33.6 mmol) were combined in a nitrogen flushed culture tube. The tube was capped and heated
- 542 - at 180 C for 24 h. The excess amine was distilled in vacuo and the residue was chromatographed on silica (95:5 ethyl acetate: methanol). The final compound was isolated as a light yellow solid (0.16 g, 36%). 1H NMR (400 MHz, CD3OD) δ 7.33 (m, 3H), 7.03 (d, J = 8 Hz, IH), 6.96 (m, 3H), 6.95 (m, IH), 5.97 (dd, J = 3.2 and 8.0 Hz, 1 H), 5.48 (d, J = 2.56 Hz, IH), 5.02 (s, 2H), 4.33 (s, 2H) ppm. 19 F NMR (400 MHz, CD3OD) δ -113.88 (1 F), -115.33 (IF), -116.78 (IF) ppm. ES-HRMS m/z 345.1221 (M+H calcd for C19H17F3N20 requires 345.1209). Step 4. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)amino]-l-(3- fluorobenzyι)pyridin-2(lH)-one
Figure imgf000543_0001
N-Bromo succinimide (81 mg, 0.46 mmol) was added to a solution of the product from Step 3 (0.15 g, 0.44 mmol) in methylene chloride (10 mL). After stirring at 25 C for 1 h, the reaction was complete by LC-MS. The reaction mixture was poured into saturated aqueous NaHC03. The aqueous mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous MgS04, and concenfrated in vacuo. 1H NMR (400 MHz, CDC13) δ 7.3-7.2 (m, 4H), 7.07 (app t, J = 7.6 Hz, 2H), 6.97 (m, 2H), 6.80 (m, 2H), 5.78 (d, J = 7.6 Hz, IH), 5.30 (br s, IH), 5.08 (s, 2H), 4.46 (d, J = 6 Hz, 2H) ppm. 19 F NMR (400 MHz, CDC13) δ -110.64 (1 F), -112.75 (IF), -114.79 (IF) ppm. ESHRMS m/z 423.0275 (M+H calcd for C19H15BrF3N20 requires 423.0314).
543 Example 496. Preparation of 3-bromo-l-(3-fluorobenzyl)-4-{[3- (trifluoromethyl)benzyl]amino}pyridin-2(lH)-one
Figure imgf000544_0001
The title compound was prepared essentially as in Example 495. 1H NMR (400 MHz, CDC13) δ 7.54 (m, 2H), 7.48 (m, 2H), 7.27 (q, J = 3.1, 9.0 Hz, IH), 6.96 (app t, J = 8.8 Hz, 2H), 5.71 (d, J = 7.6 Hz, IH), 5.4 (br m, IH), 5.08 (s, 2H), 4.52 (d, J = 5.6 Hz, 2H) ppm. 19 F NMR (400 MHz, CDC13) δ -63 (3 F), -112 (1 F) ppm. ES-HRMS m/z 455.0388 (M+H calcd for C20H16BrF4N2O requires 455.0377). Example 497. Preparation of 3-bromo-l-(3-fluorobenzyl)-4-{[4-fluoro-2- (trifluoromethyϊ)benzyl] amino}pyridin-2(lH)-one
Figure imgf000544_0002
The title compound was prepared essentially as in Example 495. 1H NMR (400 MHz, CDC13) δ 7.43 (m, 2H), 7.27 (m, 3H), 7.07 (m, 2H), 6.99 (m, 2H), 5.65 (d, J = 10Hz, IH), 5.46 (br s, IH), 5.09 (s, 2H), 4.64 (s, 2H) ppm. 19 F NMR (400 MHz, CDC13) δ -61.31 (3 F), -112.69 (1 F), 112.97 (IF) ppm. ES-HRMS m/z 473.0246 (M+H calcd for C20H15BrF5N2O requires 473.0282).
544 Example 498. Preparation of -bromo-4-[(4-chIoro-2-fluorobenzyl)amino]-l- (3-fluorobenzyl)pyridin-2(lH)-one
Figure imgf000545_0001
The title compound was prepared essentially as in Example 495. 1H NMR (400 MHz, CDC13) δ 7.27 (m, IH), 7.19 (app t, J = 8.8 Hz, IH), 7.10 (m, 4H), 6.95 (app t, J = 8.8 Hz, 2H), 5.74 (d, J = 8 Hz, IH), 5.40 (br s, IH), 5.08 (s, 2H), 4.47 (d J = 6 Hz, 2H) ppm. 19 F NMR (400 MHz, CDC13) δ -112.67 (1 F), -116.39 (1 F) ppm. ES-HRMS m/z 439.0047 (M+H calcd for C19H15ClBrF2N20 requires 439.0019). Example 499. Preparation of:
Figure imgf000545_0002
The title compound was prepared essentially as in Example 495. 1H NMR (400 MHz, CDC13) δ 7.35- 7.2 (m, IH), 7.27 (dd, J = 2.5 and 8 Hz, IH), 7.05 (app d, J = 7.2 Hz, 3H), 6.97 (m, 4H), 5.72 (d, J = 7.6 Hz, IH), 5.41 (br s, IH), 5.08 (s, 2H), 4.46 (d, J = 6.4 Hz, 2H) ppm. 19 F NMR (400 MHz, CDC13) δ -112.5 (1 F), -113 (1 F) ppm. ES-HRMS m/z 405.0431 (M+H calcd for C19H16BrF2N20 requires 405.0409).
545 Example 500. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)ammo]-6- methyl-l-(pyridin-4-ylmethyl)pyridin-2(lH)-one
Figure imgf000546_0001
Step 1. Preparation of 4-[(2,4-difluorobenzyl)amino]-6-methyl-l-(pyridin-4- ylmethyϊ)pyridin-2(lH)-one
Figure imgf000546_0002
4-[(2,4-Difluorobenzyl)amino]-6-methyl-l-(pyridin-4-ylmethyl)pyridin-2(lH)-one (0.3 g, 1.39 mmol) and 2,4-difluoro benzylamine (1 mL, 8.4 mmol) were combined in a nitrogen flushed culture tube. The tube was capped and heated at 180 C for 24 h. The excess amine was distilled in vacuo. 1H NMR (400 MHz, CD3OD) δ 8.44 (dd, J = 1.7 and
4.8Hz, 2H), 7.38 (q, J = 10 and 15 Hz, IH), 7.14 (d, J = 4.8 Hz, 2H), 6.95 (m, 2H), 5.90 (dd, J = 1 and 2.5Hz, IH), 5.47 (d, J = 2, IH), 5.28 (s, 2H), 4.33 (s, 2H), 2.27 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) δ -113.73 (1 F), -116.66 (1 F) ppm. ES-HRMS m/z 342.1422 (M+H calcd for C19Hι8F2N30 requires 342.1418). Step 2. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)amino]-6-methyl-l-
(pyridin-4-ylmethyϊ)pyridin-2(lH)-one
Figure imgf000546_0003
546 - N-Bromo succinimide (77 mg, 0.43 mmol) was added to a solution of the product of Step 1 (0.14 g, 0.41 mmol) in methylene chloride (10 mL). After stirring at 25 C for 1 h, the reaction was complete by LC-MS. The reaction mixture was poured into saturated aqueous NaHC03. The aqueous mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous Na2S04, filtered and concentrated in vacuo. The residue was triturated with hexanes to give the title compound as a yellow solid (81 mg, 47 %). 1H NMR (400 MHz, CDC13) δ 8.47 (dd, J = 1.6 and 4.8Hz, 2H), 7.24 (q, J = 6.4 and 13.6 Hz, IH), 7.01 (d, J = 6.4 Hz, 2H), 6.83 (m, 2H), 5.68 (s, IH), 5.25 (s, 2H), 4.45 (d, J = 6.4Hz, 2H), 2.12 (s, 3H) ppm. 19 F NMR (400 MHz, CDC13) δ -110.51 (m, 1 F), -114.66 (m, 1 F) ppm. ES-HRMS m/z 420.0524 (M+H calcd for C19H17BrF2N30 requires 420.0523).
Example 501
Figure imgf000547_0001
Preparation of 3-bromo-4-[(2,4-difluorobenzyl)amino]-6-methyl-l-(pyridin-3- ylmethyl)pyridin-2(lH)-one
The title compound was prepared essentially as in Example 500. !H NMR (400 MHz, CDC13) δ 8.45 (d, J = 4.8Hz, 2H), 7.55 (app t, J = 6 Hz, IH), 7.21 (m, 2H), 6.83 (m, 2H), 5.65 (s, IH), 5.34 (d, J = 5.2Hz, IH), 5.27 (s, 2H), 4.45 (s, 2H), 2.10 (d, J = 4.8Hz, 3H) ppm. 19 F NMR (400 MHz, CDC13) δ -110.74 (1 F), -114.86 (1 F) ppm. ES-HRMS m z 420.0533 (M+H calcd for Cι9Hι7BrF2N30 requires 420.0523).
Example 502
547
Figure imgf000548_0001
Preparation of 3-bromo-4-[(2,4-difluorobenzyl)amino]-l-(2,6-difluorophenyl)-6- methylp yridin-2( 1 H)-one
Step 1 Preparation of 4-[(2,4-difluorobenzyl)amino]-l-(2,6-difluorophenyl)-6- methylpyridin-2( 1 H)-one
Figure imgf000548_0002
l-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(lH)-one (0.3 g, 1.26 mmol) and 2,4-difluoro benzylamine (lmL, 8.4 mmol) were combined in a nitrogen flushed culture tube. The tube was capped and heated at 180 C for 24 h. The excess amine was distilled in vacuo and the residue was chromatographed on silica (1:1 hexanes: ethyl acetate). The compound was approximately 50% pure and was carried on without further purification (0.633 g). 1H NMR (400 MHz, CD3OD) δ 7.53 (m, IH), 7.41 (m, IH), 7.16 (t, J = 8.8Hz, 2H), 6.93 (m, 2H), 6.00 (s, IH), 5.42 (s, IH), 5.42 (s, IH), 4.37 (s, 2H), 1.93 (s, 3H) ppm. LC MS, tr = 4.65 minutes (5 to 95% acetonitrile/water over 8 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m z 363 (M+H).
548 Step 2 Preparation of 3-bromo-4-[(2,4-difluorobenzyl)amino]-l-(2,6-difluorophenyl)-6- methylpyridin-2( 1 H)-one
Figure imgf000549_0001
N-Bromo succinimide (168 mg, 0.945 mmol) was added to a solution of the product of Step 1 (0.633 g) in methylene chloride (10 mL). After stirring at 25 C for 1 h, the reaction was 50 % complete by LC-MS. Additional N-bromo succinimide (150 mg) was added and the reaction was stirred at 25 C for 12 h. The reaction mixture was poured into saturated aqueous NaHC03. The aqueous mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous Na2S04, and concenfrated in vacuo. The residue was purified by reverse phase chromatography (60:40 Acetonitrile: water with 0.05% trifluoroacetic acid). The title compound was isolated as the TFA salt (0.161g, 23%). 1H NMR (400 MHz, CD3OD) δ 7.53 (m, IH), 7.35 (q, J = 8, 15.6Hz, IH), 7.16 (t, J = 8 Hz, 2H), 6.96 (app q, J = 8, 16.4Hz, 2H), 6.12 (s, IH), 4.86 (s, 2H), 1.94 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) δ -77.33 (1 F), -113.60 (1 F), -116.63 (IF), - 121.50 (IF) ppm. ES-HRMS m/z 441.0231 (M+H calcd for C19H14BrF4N20 requires 441.0220).
Example 503
Figure imgf000549_0002
Preparation of 3 -chloro-4- [(2,4-difluorobenzyl)amino]-l -(2,6-difluorophenyι)-6- methylpyridin-2(lH)-one
549 l-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(lH)-one (0.3 g, 1.26 mmol) and 2,4-difluoro benzylamine (lmL, 84 mmol) were combined in an nitrogen flushed culture tube. The tube was capped and heated at 180 C for 24 h. The excess amine was distilled in vacuo and the residue was used without further purification. N-Chloro succinimide (168 mg, 1.26 mmol) was added to a solution of the residue in methylene chloride (10 mL). After stirring at 25 C for 1 h, the reaction mixture was poured into saturated aqueous NaHC03. The aqueous mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous Na2S04, and concentrated in vacuo. The residue was chromatographed on silica (25:75 hexanes: ethyl acetate) to give the title compound (32 mg, 6%). 1H NMR (400 MHz, CD3OD) δ 7.55 (m, IH), 7.36 (q, J = 9.2 and 15.2Hz, IH), 7.18 (t, J = 7.6Hz, 2H), 6.98 (m, 2H), 6.15 (s, IH), 4.62 (s, 2H), 1.96 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) δ -113.78 (1 F), -116.72 (1 F), -121.57 (IF) ppm. ES-HRMS m/z 397.0752 (M+H calcd for C19H14C1F4N20 requires 397.0725).
Example 504
Figure imgf000550_0001
Preparation of 3- { [3 -chloro-4- [(2,4-difluorobenzyl)amino] -6-methyl-2-oxopyridin- 1 (2H)- yl]methyl}benzonitrile
Step 1 Preparation of 3-phthalimidomethyl-benzonitrile
Figure imgf000550_0002
3-Phthalimidomethyl-benzonitrile was prepared as described in the literature. (Bookser, B.C.; Bruice, T.C. J. Am. Chem. Soc. 1991, 113, 4208-18.)
Step 2 Preparation of 3-(aminomethyl)benzonitrile
550
Figure imgf000551_0001
3-(Aminomethyl)benzonitrile was prepared as described in the literature. (Bookser, B.C.; Bruice, T.C. J. Am. Chem. Soc. 1991, 113, 4208-18.)
Step 3 Preparation of 3 - [(4-hydroxy-6-methyl-2-oxopyridin- 1 (2H)-yl)methyl]benzonitrile
Figure imgf000551_0002
A nitrogen flushed pyrex reaction tube was charged with 3- (aminomethyl)benzonitrile (1 g, 7.9 mmol), 4-hydroxy-6-methyl-2-pyrone (1 g, 7.9 mmol) and water (20 mL). The tube was capped and was heated to reflux. After 1.5 h, the product precipitated from solution. The reaction mixture was cooled to room temperature, filtered and washed with water. The product was used without further purification (1.67g, 88 %). 1H NMR (400 MHz, dmso-d6) δ 10.53 (s, IH), 7.61 (d, J = 8Hz, IH), 7.52 (t, J = 8Hz, 2H), 7.38 (d, J = 8 Hz, IH), 5.79 (dd, J = 1 and 2.5 Hz, IH), 5.56 (d, J = 2.7 Hz, IH), 5.18 (s, 2H), 2.14 (s, 3H) ppm. ES-HRMS m/z 241.0968 (M+H calcd for C14H13N202 requires 241.0972).
Step 5 Preparation of 3-{[4-[(2,4-difluorobenzyl)amino]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzonitrile
Figure imgf000551_0003
The product from Step 4 (0.5 g, 2.08 mmol) and 2,4-difluoro benzylamine (2mL, 16.8 mmol) were combined in a nitrogen flushed culture tube. The tube was capped and heated at 180 C for 24 h. The excess amine was distilled in vacuo and the residue was triturated - 551 - with ethyl acetate/ hexanes to precipitate the starting materials. The residue was chromatographed on reverse phase (1:1 water: acetonitrile with 0.05% trifluoroacetic acid ). The product of Step 5 was isolated as a white semi-solid (0.125g, 15%). 1H NMR (400 MHz, CD3OD) δ 7.6 l(d, J = 8Hz, IH), 7.49 (t, J = 8 Hz, IH), 7.41 (m, 3H), 6.94 (m, 2H), 5.89 (dd, J = 0.8 and 2.7Hz, IH), 5.47 (d, J = 2.8Hz, IH), 5.27 (s, 2H), 4.34 (s, 2H), 2.18 (s, 3H) ppm. LC/MS, tr = 4.87 minutes (5 to 95% acetonitrile/water over 8 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 366 (M+H).
Step 6 Preparation of 3-{[3-chloro-4-[(2,4-difluorobenzyl)amino]-6-methyl-2-oxopyridin- l(2H)-yl]methyl}benzonitrile
Figure imgf000552_0001
N-Chloro succinimide (36 mg, 0.27 mmol) was added to a solution of the product of Step 5 (0.125 g, 0.26 mmol) in methylene chloride (10 mL). After stirring at 25 C for 2 h, the reaction was complete by LC-MS. The reaction mixture was poured into saturated aqueous NaHC03. The aqueous mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous Na2S04, and concentrated in vacuo. The residue was triturated with acetonitrile to give the title compound as a tan solid (20 mg, 13%). 1H NMR (400 MHz, CD3OD) δ 7.61 (d, J = 8.4 Hz, IH), 7.49 (m, 2H), 7.40 (d, J = 8.4 Hz, IH), 7.33 (q, J = 8.4 and 14.8 Hz, IH), 6.94 (m, 2H), 6.00 (s, IH), 5.34 (s, 2H), 4.56 (s, 2H), 2.21 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) δ -114.00 (1 F), -116.89 (1 F) ppm. LC/MS, tr = 5.49 minutes (5 to 95% acetonitrile/water over 8 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m z 400 (M+H).
552 . Example 505
Figure imgf000553_0001
Preparation of 4-{[3-chloro-4-[(2,4-difluorobenzyl)amino]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzonitrile
The title compound was prepared essentially as in Example 504. 1H NMR (400 MHz, CD3OD) δ 7.66 (d, J = 8 Hz, 2H), 7.33 (q, J =8 and 15.2 Hz, IH), 7.25 (d, J = 8 Hz, 2H), 6.94 (m, 2H), 6.01 (s, IH), 5.36 (s, 2H), 4.55 (s, 2H), 2.19 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) δ -77.52 (IF), -113.89 (1 F), -116.71 (1 F) ppm. LC/MS, tr = 5.49 minutes (5 to 95% acetonitrile/water over 8 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 400 (M+H).
Example 506
Figure imgf000553_0002
Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[2-fluoro-5- (hydroxymethyDphenyi] -6-methylpyridin-2( 1 H)-one
Step 1 Preparation of (3-amino-4-fluorophenyi)methanol
Figure imgf000553_0003
553 - A flask equipped with overhead stirrer was charged with 4-fluoro-3-nitrobenzyl alcohol (20g, 0.117 mol) and 200 mL of 5:1 isopropanol: water. Ammonium chloride (62 g, 1.17 mol) was added followed by iron filings (65g, 1.17 mol). The mixture was stirred at 70 C for 1.5 H when it was shown to be complete by LC-MS. The liquid was decanted and the solids were washed with additional isopropanol: water. The isopropanol was removed and the residue was diluted with 0.5 N HCl and was extracted with ethyl acetate. The aqueous layer was brought to pH 12-14 with 2.5 N NaOH and was extracted with ethyl acetate. The organic layer was dried with anhydrous Na2S04 and concentrated in vacuo. 3-Amino-4-fluorophenyl methanol was isolated as a brown solid (4.5g, 27%) and was used without further purification. LC/MS, tr = 2.40 minutes (5 to 95% acetonitrile/water over 8 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 142 (M+H).
ES-HRMS m/z 142.0692 (M+H calcd for C7H8FN0 requires 142.0663).
Step 2 Preparation of 1 -[2-fluoro-5-(hydroxymethyl)phenyl]-4-hydroxy-6-methylpyridin- 2(lH)-one
Figure imgf000554_0001
A 100 mL round bottomed flask equipped with stirbar, Dean-Stark trap and reflux condensor was charged with (3-amino-4-fluorophenyl)methanol (4.5 g, 31.9 mmol), 4-hydroxy-6-methyl-2-pyrone (4 g, 31.9 mmol) and o-dichlorobenzene (5 mL). The system was immersed in a 170 C oil bath for 10 minutes. The solvent was removed in vacuo and the residue was chromatographed on reverse phase (75:25 water:acetonitrile with 0.05% TFA). The product contained some starting materials after purification and was used without further purification (1.27g, 15%). 1H NMR (400 MHz, dmso-d6) δ 7.39 (m, IH), 7.20 (dd, J = 2.2 and 7.6 Hz, IH), 6.74 (dd, J = 2.7 and 9.6 Hz, IH), 5.93 (dd, J = 1.2 and 2.2 Hz, IH), 5.22 (dd, J = 0.4 and 2.2 Hz, IH), 2.12 (s, 3H) ppm. ES-HRMS m z 250.0862 (M+H calcd for C13H13FN03 requires 250.0874).
554 ' Step 3 Preparation of 4-[(2,4-difluorobenzyl)oxy]-l-[2-fluoro-5-(hydroxymethyl)phenyl]- 6-methylpyridin-2( 1 H)-one
Figure imgf000555_0001
A 100 mL roundbottomed flask (nifrogen purged) was charged with l-[2-fluoro-5- (hydroxymethyl)phenyl]-4-hydroxy-6-methylpyridin-2(lH)-one (1.2g, 4.82 mmol) and N,N-dimethyl formamide (10 mL). Potassium carbonate (0.6g, 4.4 mmol) and 2,4- difluorobenzyl bromide (0.56 mL, 4.4 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated aqueous NaHC03 and extracted with ethyl acetate. The organic layer was concentrated in vacuo and the residue was chromatographed on silica (9:1 methylene chloride: ethanol). The impure oil (0.3g, 17%) was carried on without further purification. 1H NMR (400 MHz, CD3OD) δ 7.54 (m, 2H), 7.30 (m, 2H), 7.02 (m, 2H), 6.17 (dd, J = 1 and 2.8 Hz, IH), 6.03 (d, J = 2.8 Hz, IH), 5.14 (s, 2H), 4.62 (s, 2H), 2.14 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) δ -111.35 (IF), -115.97 (1 F), -127.31 (1 F) ppm. LC/MS, tr = 5.05 minutes (5 to 95% acetonitrile/water over 8 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 375 (M+H).
Step 4 Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[2-fluoro-5- (hydroxymethyl)phenyl] -6-methylpyridin-2( 1 H)-one
Figure imgf000555_0002
N-Bromo succinimide (50 mg, 0.3 mmol) was added to a solution of the product of Step 3 (0.12 g, 0.32 mmol) in N,N-dimethyl formamide (4 mL). After stirring at 25 C for
- 555 - 2 h, trifluoroacetic acid (50 μL) was added. After 1 h, additional N-Bromo succinimide (30 mg) was added. After 1 h, the reaction was complete by LC-MS. The reaction mixture was poured into brine and was extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous Na2S04, and concenfrated in vacuo. The residue was chromatographed on reverse phase (95:5 methylene chloride: ethanol). The title compound was isolated as the TFA salt (38 mg, 26 %). XH NMR (400 MHz, CD3OD) δ 7.64 (q, J = 7.6 and 14.8 Hz, IH), 7.51 (m, IH), 7.31 (app t, J = 8.4 Hz, IH), 7.04 (t, J = 8.4 Hz, 2H), 6.63 (s, IH), 5.34 (s, 2H), 4.62 (s, 2H), 2.06 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) δ -111.48 (IF), -115.92 (1 F), -127.23 (1 F) ppm. ES-HRMS m/z 454.0228 (M+H calcd for C20H16BrF3NO3 requires 454.0260).
Example 507
Figure imgf000556_0001
Preparation of 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l (2H)-yl]- 4-fluorobenzoic acid
Step 1 Preparation of methyl 4-fluoro-3-nitrobenzoate
Figure imgf000556_0002
A I L 3-necked round bottomed flask equipped with a nitrogen inlet, stirbar, addition funnel and thermocouple was charged with 4-fluoro-3-nitrobenzoic acid (50 g, 0.27 mol) and methanol (300 mL). The system was cooled to 0 C and acetyl choride (27 mL, 0.37 mol) was added dropwise. The system was warmed to room temperature, the addition funnel was replaced with a reflux condensor, and was heated to reflux for 1.5 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NaHC03, and extracted with ethyl acetate. The organic exfract was washed with brine, - 556 - dried with Na2S04 and concentrated in vacuo to give methyl 4-fluoro-3-nitrobenzoate as an orange solid (40.6 g, 75%). 1H NMR (400 MHz, CD3OD) δ 8.67 ((dd, J = 2.2 and 6.8 Hz, IH), 8.34 (dddd, J = 2.2, 4.4, 6.4 and 8.8 Hz, IH), 7.55 (dd, J = 8.8 and 10.8 Hz, IH), 3.94 (s, 3H) ppm. ES-HRMS m/z 200.02446 (M+H calcd for C8H7FN04 requires 200.0354).
Step 2 Preparation of methyl 3-amino-4-fluorobenzoate
Figure imgf000557_0001
A Parr bottle was charged with the product of Step 1 (40 g, 0.2 mol), ethanol (400 mL) andl0% Pd/C (1 g g). The system was flushed twice with mfrogen and hydrogen. The reaction mixture was hydrogenated at 40 psi until no starting material was visible by LC-MS. The reaction mixture was slurried with Celite and then was filtered through a pad of celite. The filtrate and ensuing ethanol washes were concentrated in vacuo to give methyl 3-amino-4-fluorobenzoate as an orange solid (30.6 g, 91%). 1H NMR (400 MHz, CD3OD) δ 7.54 (d, J = 8.7 Hz, IH), 7.35 (m, IH), 7.06 (t, J = 8.7 Hz, IH), 3.09 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) δ -131.02 (IF) ppm. ES-HRMS m z 199.0281 (M+H calcd for C8H7FN04 requires 199.02).
Step 3 Preparation of methyl 4-fluoro-3-(4-hydroxy-6-methyl-2-oxopyridin-l(2H)- yljbenzoate
Figure imgf000557_0002
A 250 mL round bottomed flask equipped with stirbar, Dean-Stark trap and reflux condensor was charged with the product of Step 3 (30 g, 0.18 mol), 4-hydroxy-6-methyl-
2-pyrone (22.6 g, 0.18 mol), and o-dichlorobenzene (90 mL). The system was immersed in a 170 C oil bath for 30 minutes and was then cooled to room temperature. The reaction mixture was washed with aqueous Na2C03 (38 g, 0.36 mol, 300 mL water). The aqueous - 557 - layer was washed with ethyl acetate and then was acidified to pH 1-2 with concentrated HCl. This was extracted with ethyl acetate, which was then dried with MgS04 and concentrated in vacuo. The viscous orange oil was used without further purification (14.4 g, 28%). 1H NMR (400 MHz, CD3OD) δ 8.18 (dddd, J = 2.3, 5.2, 7.2 and 8.8 Hz, IH), 7.97 (dd, J = 2 and 7.2 Hz, IH), 7.44 (t, J = 8.8 Hz, IH), 6.09 (d, J = 1.8 Hz, IH), 5.78 (d, J = 2.4 Hz, IH), 3.9 (s, 3H), 2.14 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) δ -117.29 (IF) ppm. ES-HRMS m/z 278.0796 (M+H calcd for C14H13FN04 requires 278.0823).
Step 4 Preparation of methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]-4-fluorobenzoate
A 100 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with the product of Step 3 (14.4 g, 51.9 mmol) and N,N-dimethyl formamide (40 mL). l,8-diazabicyclo[5.4.0]undec-7-ene (10.9 mL, 72.8 mmol) was added followed by 2,4-difluorobenzyl bromide (9.3 mL, 72.8 mmol). The reaction mixture was stirred at 65 C for 18 h, was poured into saturated aqueous NaHC03 and was extracted with ethyl acetate. The organic layer was washed with brine, dried with Na2S04 and concentrated in vacuo to give the title product, as an orange oil (21.5g), which was carried on to the next reaction without further purification. 1H NMR (400 MHz, CD3OD) δ 8.20 (dddd, J = 2.2, 4.8, 7.2 and 8.8 Hz, IH), 8.00 (dd, J = 2.2 and 7.2 Hz, IH), 7.56 (td, J = 2.4, 6.4 and 9.2 Hz, IH), 7.46 (t, J = 9.2 Hz, IH), 7.02 (m, 2H), 6.18 (dd, J = 0.8 and 2.6 Hz, IH), 6.04 (d, J = 2.7 Hz, IH), 5.14 (s, 2H), 3.90 (s, 3H), 1.98 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) δ -111.34 (IF), -116.00 (1 F), -117.35 (1 F) ppm. ES-HRMS m/z 404.1104 (M+H calcd for C21H17F3N04 requires 404.1104).
Step 5 Preparation of methyl 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]-4-fluorobenzoate - 558 -
Figure imgf000559_0001
A 250 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with the product of Step 4 (21 g, 52 mmol) and N-methyl-2-pyrrolidine (100 mL). N-Chloro succinimide (8.3 g, 62 mmol) was added and the reaction mixture was strrred at 65 C for 2 h. The mixture was then cooled to room temperature, poured into saturated aqueous NaHC03 and extracted with ethyl acetate. The organic layer was washed with brine, dried with Na2S0 , and concentrated in vacuo. The residue was triturated with diethyl ether and filtered to give the title compound, as a white powder (5.9 g, 25%). 1H NMR (400 MHz, CD3OD) δ 8.22 (dddd, J = 2, 4.8, 6.8 and 8.8 Hz, IH), 8.03 (dd, J = 2 and 7.2 Hz, IH), 7.62 (q, J = 8.4 andl4.8 Hz, IH), 7.48 (t, J = 14 Hz, IH), 7.04 (m, 2H), 6.69 (s, IH), 5.36 (s, 2H), 3.91 (s, 3H), 2.08 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) δ -111.38 (IF), -115.97 (1 F), -117.43 (1 F) ppm. ES-HRMS m/z 438.0723 (M+H calcd for C21H16C1F3N04 requires 438.0714).
Step 6 Preparation of 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]-4-fluorobenzoic acid
Figure imgf000559_0002
A 100 mL round bottomed flask was charged with the product of Step 5 (2.5 g, 5.72 mmol), tetrahydrofuran (40 mL), methanol (10 mL), and water (10 mL). To this slurry was added 2.5 N NaOH (4.6 mL, 11.4 mmol). The reaction mixture became clear after 5 minutes and the reaction was complete in 35 minutes by LC-MS. The organics
559 were removed on the rotary evaporator and the remaining solution was acidified to pH 3 with 6N HCl. The desired compound was precipitated by the addition of diethyl ether and subsequent filtration. The title compound was isolated as a white powder (2.5 g, 98%). 1H NMR (400 MHz, dmso-d6) δ 8.10 (dddd, J = 2.1, 4.8, 7.2 and 8.4 Hz, IH), 8.00 (dd, J = 2.1 and 7.6 Hz, IH), 7.66 (q, J = 9.2 and 15.6 Hz, IH), 7.57 (t, J = 8.8 Hz, IH), 7.34 (td, J = 2.4 and 10.4 Hz, IH), 7.17 (tdd, J = 1, 2.7 and 8.4 Hz, IH), 6.76 (s, IH), 5.33 (s, 2H), 1.98 (s, 3H) ppm. 19 F NMR (400 MHz, dmso-d6) δ -109.32 (IF), -113.64 (1 F), -117.22 (1 F) ppm. ES-HRMS m/z 424.0575 (M+H calcd for C20H14ClF3NO4 requires 424.0558).
Example 508
Figure imgf000560_0001
Preparation of 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]- 4-fluoro-N-methylbenzamide To a reaction vessel (borosilicate culture tube) was added 3-[3-chloro-4-[(2,4- difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4-fluorobenzoic acid (0.300 g, 0.708 mmol) and 1-hydroxybenzotriazole (0.048 g, 0.45 mmol). N,N- Dimethylformamide (3 mL) was added to the reaction vessel followed by approximately 1.2 g of the polymer bound carbodiimide resin (1.38 mmol/g). Additional N,N- dimethylformamide (2 mL) was then added to the reaction vessel. The parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 15 minutes. N-Methyl amine (1 mL, 2 mmol) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature overnight. At this time the reaction was diluted with tetrahydrofuran (20 mL) and treated with approximately 2.17 g of polyamine resin (2.63 mmol/g) and approximately 2.8 g of methylisocyanate functionalized polystyrene (1.5 mmol/g) and the
- 560 - orbital shaking was continued at 200 RPM at room temperature for 3 hours. The reaction vessel was then opened and the solution phase product was separated from the insoluble quenched byproducts by filtration and collection into a vial. After partially evaporation the insoluble byproducts were rinsed with tefrahydrofuran (2 x 10 mL). The filtrate was evaporated by blowing N2 over the vial and the resulting solid was triturated with diethyl ether to give an off-white solid. (0.168 g, 59%)
1H NMR (400 MHz, CD3OD) δ 8.02 (dddd, J = 2, 4.4, 7.2 and 8.4 Hz, IH), 7.80 (dd, J = 2 and 6.8 Hz, IH), 7.62 (q, J = 8 and 14.4 Hz, IH), 7.34 (t, J = 8.8 Hz, IH), 7.04 (m, 2H), 6.69 (s, IH), 5.36 (s, 2H), 3.29 (s, 3H), 1.98 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) δ -108.94 (IF), -113.55 (1 F), -117.76 (1 F) ppm. ES-HRMS m/z 437.0861 (M+H calcd for C21H17C1F3N203 requires 437.0874). '
Examples 509-518
Figure imgf000561_0001
By following the method of Example 508 and replacing N-methylamine with the appropriate amine, the compounds of Examples 509-518 are prepared.
Figure imgf000561_0002
561
Figure imgf000562_0003
Example 519
Figure imgf000562_0001
Preparation of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]- 4-fluorobenzoic acid
Stepl Preparation of methyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]-4-fluorobenzoate
Figure imgf000562_0002
- 562 - A 100 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- fluorobenzoate (7.3 g, 18 mmol) and N-methyl-2-pyrrolidine (20 mL). N-Bromo succinimide (3.5 g, 19.8 mmol) was added and the reaction mixture was stirred at room temperature for 30 minutes. The mixture poured into saturated aqueous NaHC03 and extracted with ethyl acetate. The organic layer was washed with brine, dried with Na2S04, and concentrated in vacuo. The residue was triturated with diethyl ether and filtered to give the title compound as a white powder (3.49 g). 1H(NMR (400 MHz, CD3OD) δ 8.16 (qd, J = 3, 6.8 and 15.6 Hz, IH), 7.84 (d, J = 2.12 Hz, IH), 7.64 (q, J = 8.4 andl4.8 Hz, IH), 7.29 (d, J = 8.4 Hz, IH), 7.04 (m, 2H), 6.60 (s, IH), 5.34 (s, 2H), 3.87 (s, 3H), 2.00 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) δ -111.51 (IF), -115.98 (IF), -117.43 (IF) ppm. ES-HRMS m/z 494.0387(M+H calcd for C22H19BrF2N05 requires 494.0409).
Step 2 Preparation of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]-4-fluorobenzoic acid
Figure imgf000563_0001
A 100 mL round bottomed flask was charged with the product of Step 2 (3.4 g, 7.05 mmol), tefrahydrofuran (40 mL), methanol (10 mL), and water (10 mL). To this slurry was added 2.5 N NaOH (5.6 mL, 14.1 mmol). The reaction mixture became clear after 5 minutes and the reaction was complete in 1 h by LC-MS. The organics were removed on the rotary evaporator and the remaining solution was acidified to pH 1-2 with 6N HCl. The desired compound was precipitated by the addition of water and diethyl ether and subsequent filtration. The title compound was isolated as a white powder (2.64 g, 80%). 1H NMR (400 MHz, CD3OD) δ 8.21 (dddd, J = 2.4, 5.2, 7.2 and 9.2 Hz, IH), 8.00 (dd, J = 2.0 and 7.2 Hz, IH), 7.65 (q, J = 8.4 and 14.8 Hz, IH), 7.45 (t, J = 8.4 Hz, IH), 7.04 (appt, J = 9.6 Hz, IH), 6.65 (s, IH), 5.36 (s, 2H), 2.07 (s, 3H) ppm. 19 F NMR
563 (400 MHz, CD3OD) δ -111.40 (IF), -116.00 (1 F), -118.36 (1 F) ppm. ES-HRMS m/z 480.0259 (M+H calcd for C21H17BrF2N05 requires 480.0253).
Example 520
Figure imgf000564_0001
Preparation of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]- 4-methoxybenzoic acid
Step 1 Preparation of methyl 3-amino-4-methoxybenzoate
Figure imgf000564_0002
A I L 3-necked round bottomed flask equipped with a nitrogen inlet, stirbar, addition funnel and thermocouple was charged with 3-amino-4-methoxy benzoic acid (50 g, 0.299 mol) and methanol (300 mL). The system was cooled to 0 C and acetyl choride (30 mL, 0.42 mol) was added dropwise. The system was warmed to room temperature, the addition funnel was replaced with a reflux condensor, and was heated to reflux for 1.5 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NaHC03, and extracted with ethyl acetate. The organic extract was washed with brine, dried with Na2S04 and concentrated in vacuo to give methyl 3-amino-4- methoxybenzoate as a dark solid (47.9 g, 88%). 1H NMR (400 MHz, CD3OD) δ 7.40 (t, J = 2 68 Hz, IH), 7.37 (t, J = 2.0 Hz, IH), 6.86 (d, J = 8.8 Hz, IH), 3.98 (s, 3H), 3.81 (s, 3H) ppm. ES-HRMS m/z 182.0826 (M+H calcd for C9H12C1N03 requires 182.0812).
Step 2 Preparation of methyl 3-(4-hydroxy-6-methyl-2-oxopyridin-l(2H)-yl)-4- methoxybenzoate
564
Figure imgf000565_0001
A 250 mL round bottomed flask equipped with stirbar, Dean-Stark trap and reflux condensor was charged with the product of Step 1 (23.5 g, 0.129 mol), 4-hydroxy-6- methyl-2-pyrone (17.8 g, 0.14 mol), and o-dichlorobenzene (200 mL). The system was immersed in a 170 C oil bath for 2 h and was then cooled to room temperature. The reaction mixture was washed with aqueous Na2C03 (28 g, 0.26 mol, 500 mL water). The aqueous layer was washed with ethyl acetate and then was acidified to pH 1-2 with concentrated HCl. This was extracted with ethyl acetate, which was then dried with Na2S04 and concentrated in vacuo. The viscous orange oil was triturated with MeOH to give the title compound as a yellow solid (1.61 g, 4%). 1H NMR (400 MHz, CD3OD) δ 8.14 (dd, J = 2.2 and 8.8 Hz, IH), 7.79 (d, J = 2.2 Hz, IH), 7.27 (d, J = 8.8 Hz, IH), 6.05 (d, J = 2.3 Hz, IH), 5.77 (d, J = 2.3 Hz, IH), 3.88 (s, 3H), 3.87 (s, 3H), 1.90 (s, 3H) ppm. ES-HRMS m/z 290.0997 (M+H calcd for C15H16N05 requires 290.1023).
Step 3 Preparation of methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl] -4-methoxybenzoate
Figure imgf000565_0002
A 100 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with the product of Step 2 (1.6 g, 5.5 mmol) and N,N-dimethyl formamide (10 mL). l,8-diazabicyclo[5.4.0]undec-7-ene (0.91 mL, 6 mmol) was added followed by 2,4- difluorobenzyl bromide (0.77 mL, 6 mmol). The reaction mixture was stirred at 60 C for 4 h, was poured into saturated aqueous NaHC03 and was extracted with ethyl acetate. The
565 organic layer was washed with brine, dried with Na2S04 and concentrated in vacuo to give the title compound as an orange foam (2.13g, 93%), which was carried on to the next reaction without further purification. 1H NMR (400 MHz, CD3OD) δ 8.17 (dd, J = 2.64 and 11.6 Hz, IH), 7.82 (td, J = 2.7 and 6.8 Hz, IH), 7.57 (m, IH), 7.29 (d, J = 11.6 Hz, IH), 7.02 (m, 2H), 6.16 (m, IH), 6.03 (d, J = 3.5 Hz, IH), 5.14 (s, 2H), 3.89 (s, 6H), 1.93 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) δ -111.43(1F), -116.04 (1 F) ppm. ESHRMS m z 416.1310 (M+H calcd for C22H20F2NO5 requires 416.1304).
Step 4 Preparation of methyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]-4-methoxybenzoate
Figure imgf000566_0001
A 100 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with the product of Step 3 (2.1 g, 5.06 mmol) and N-methyl-2-pynolidine (10 mL). N-Bromo succinimide (1 g, 5.56 mmol) was added and the reaction mixture was stnred at room temperature for 1 h. The mixture poured into saturated aqueous NaHC03 and extracted with ethyl acetate. The organic layer was washed with brine, dried with Na2S04, and concentrated in vacuo. The residue was chromatographed on silica (1 : 1 hexanes: ethyl acetate) to give the title compound as an orange oil (0.77 g, 31%). 1H NMR (400 MHz, CD3OD) δ 8.16 (app qd, J = 2.5 and 7.2 Hz, IH), 7.84 (d, J = 2.6 Hz, IH), 7.64 (m, IH), 7.30 (d, J = 9.2 Hz, IH), 7.04 (appt, J = 8.4 Hz, 2H), 6.60 (s, IH), 5.33 (s, 2H), 3.80 (s, 6H), 1.99 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) δ -111.56 (IF), - 116.00 (1 F) ppm. ES-HRMS m/z 494.0398 (M+H calcd for C22H19BrF2N05 requires 494.0409).
Step 5 Preparation of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]-4-methoxybenzoic acid
566 -
Figure imgf000567_0001
A 100 mL round bottomed flask was charged with the product of Step 4 (0.77 g, 1.55 mmol), tetrahydrofuran (10 mL), methanol (5 mL), and water (5 mL). To this slurry was added 2.5 N NaOH (1.2 mL, 3.1 mmol). The reaction mixture became clear after 30 minutes and the reaction was complete in 1 h by LC-MS. The organics were removed on the rotary evaporator and the remaining solution was acidified to pH 2-3 with 6N HCl. The desired compound was precipitated by the addition of water and diethyl ether and subsequent filtration. The title compound was isolated as a white powder (0.60 g, 81%). 1H NMR (400 MHz, CD3OD) δ 8.17 (dd, J = 2.2 and 8.8 Hz, IH), 7.82 (d, J = 2.2 Hz, IH), 7.64 (q, IH), 7.29 (d, J = 8.8 Hz, IH), 7.34 (t, J = 8.8 Hz, 2H), 6.60 (s, IH), 5.34 (s, 2H), 3.87 (s, 3H), 2.01 (s, 3H) ppm. ES-HRMS m z 480.0259 (M+H calcd for C21H17BrF2N05 requires 480.0253).
Example 521
Figure imgf000567_0002
Preparation of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxoρyridin-l(2H)-yl]- 4-methoxy-N-methylbenzamide
Step 1 To a reaction vessel (borosilicate culture tube) was added Example 520 (0.300 g, 0.624 mmol) and 1-hydroxybenzotriazole (0.042 g, 0.31 mmol). N,N-Dimethylformamide (3
- 567 - mL) was added to the reaction vessel followed by approximately 1.06 g of the polymer bound carbodiimide resin (1.38 mmol/g). Additional N,N-dimethylformamide (2 mL) was then added to the reaction vessel. The parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 15 minutes. N-Methyl amine (2 mL, 4 mmol) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature overnight. At this time the reaction was diluted with tefrahydrofuran (20 mL) and treated with approximately 2 g of polyamine resin (2.63 mmol/g) and approximately 2.5 g of methylisocyanate functionalized polystyrene (1.5 mmol/g) and the orbital shaking was continued at 200 RPM at room temperature for 3 hours. The reaction vessel was then opened and the solution phase product was separated from the insoluble quenched byproducts by filtration and collection into a vial. After partially evaporation the insoluble byproducts were rinsed with tetrahydrofuran (2 x 10 mL). The filfrate was evaporated by blowing N2 over the vial and the resulting solid was triturated with diethyl ether to give the desired product as an off-white solid (0.094 g, 31%). 1H NMR (400 MHz, CD3OD) δ 7.98 (dd, J = 2.2 and 8.8 Hz, IH), 7.64 (m, 2H), 7.28 (d, J = 9.2 Hz, IH), 7.04 (t, J = 9.2 Hz, 2H), 6.60 (s, IH), 5.34 (s, 2H), 3.86 (s, 3H), 2.88 (s, 3H), 2.01 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) δ - 111.59 (IF), -116.01 (1 F) ppm. ES-HRMS m/z 493.0593 (M+H calcd for C22H20BrF2N2O4 requires 493.0569).
Example 522
Figure imgf000568_0001
Preparation of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]- 4-methoxy-N,N-dimethylbenzamide
568 The title compound was prepared essentially as in Example 521. 1H NMR (400 MHz, CD3OD) δ 7.64 (m, IH), 7.61 (dd, J = 2 and 8.8 Hz, IH), 7.33 (d, J = 2.2 Hz, IH), 7.27 (d, J = 8 Hz, IH), 7.04 (t, J = 8 Hz, 2H), 6.59 (s, IH), 5.33 (s, 2H), 3.85 (s, 3H), 3.07 (s, 6H), 2.02 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) δ -111.60 (IF), -116.01 (1 F) ppm. ES-HRMS m z 507.0716 (M+H calcd for C23H22BrF2N204 requires 507.0726).
Example 523 l-[5-(aminomethyl)-2-fluorophenyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6- methylpyridin-2( lH)-one hydrochloride
Figure imgf000569_0001
Step l
Preparation of 3 -[3-chloro-4-[(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -
4-fluorobenzamide
Figure imgf000569_0002
A 250 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4-fluorobenzoic acid (2.58g, 6.1 mmol), 4-methylmorpholine (2.0 mL, 18.3 mmol), 2-chloro-4,6- dimethoxy-l,3,5-triazine (1.28g, 7.3 mmol) and tetrahydrofuran (30 mL). After stirring the mixture for 30 min at 25° C, NH4OH (15.0 mL) was added. The mixture was stirred for 30 min and diluted with water. The product precipitated from solution. The precipitated was filtered and washed with water and diethyl ether to give the title - 569 - compound (2.55g, 78%) as a white solid. 1H NMR (400 MHz, (CD3)2SO) δ 8.10 (m, IH), 7.9 (dd, J = 2.1 and 5.2 Hz, IH), 7.65 (q, 6.7 and 8.5 Hz, IH), 7.56 (t, J = 9.1 Hz, IH), 7.35 (td, J = 2.4 and 8.2 Hz, IH) 7.17 (td, J = 2 and 6.6 Hz, IH) 6.78 (s, IH), 5.36 (s, 2H), 2 (s, 3H) ppm. ES-HRMS m z 423. 0719 (M+H calcd for C20H15ClF3N2O3 requires 423.0718).
Step 2
Preparation of l-[5-(aminomethyl)-2-fluorophenyl]-3-chloro-4-[(2,4 difluorobenzyl)oxy]-
6-methylpyridin-2(lH)-one hydrochloride
Figure imgf000570_0001
A 100 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with the product from step 1 (1.5 g, 3.5 mmol), BH3«THF complex (7.4 mL, 7.4 mmol), and tetrahydrofuran (15 mL). The mixture was refluxed for 6 h, allowed to cool to room temperature and quenched with HCl 6N. The organics were evaporated and the remaining aqueous solution was saturated with NaOH 2.5N and extracted with dichloromethane. The organic phase was dried with Na2S04 and concentrated in vacuo. HCl 6N was added, and concentrated in vacuo. 1H NMR (400 MHz, (CD3)2SO) δ 8.2 (m, IH), 7.6 (m, IH), 7.5 (m, IH), 7.3 (t, J = 9.8 Hz, IH), 7.16 (t, J = 8.6 Hz, IH) 6.78 (s, IH), 5.36 (s, 2H), 4.05 (d, J = 5.8 Hz, 2H), 2 (s, 3H) ppm. ES-HRMS m z 409. 0940 (M+H calcd for C20H17ClF3N2O2 requires 409.0925).
Example 524
3 -[3 -chloro-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -4-fluoro-N- [2- hydroxy- 1 -(hydroxymethyl)ethyl]benzamide
570
Figure imgf000571_0001
Preparation of 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]- 4-fluoro-N-[2-hydroxy- 1 -(hydroxymethyl)ethyl]benzamide
The title compound was prepared essentially as in Example 521. 1H NMR (400 MHz, CD3OD) δ 8.1 (m, IH), 7.8 (dd, J = 2.3 and 5.1 Hz, IH), 7.6 (q, J = 7.4 and 7.0 Hz, IH), 7.41 (t, J = 8.9 Hz, IH), 7.04 (m, 2H) 6.7 (s, IH), 5.36 (s, 2H), 4.1 (t, J = 5.8 Hz, IH), 3.7 (d, J = 5.1 Hz, 4H) 2.1 (s, 3H) ppm. ES-HRMS m/z 497. 1045 (M+H calcd for C23H21C1F3N205 requires 497.1086).
Examples 525-528
Figure imgf000571_0002
The compounds of Examples 525-528 are prepared by derivitazion of Example 523. The analytical data are shown below.
Figure imgf000571_0003
571
Figure imgf000572_0002
NMR characterization of compounds of Examples 525-528
Figure imgf000572_0003
Example 529
Figure imgf000572_0001
2-( { [3-chloro- 1 -(2,6-difluorophenyl)-6-methyl-2-oxo- 1 ,2-dihydropyridin-4- yl]oxy}methyl)-5-fluoroberιzonitrile 2-(bromomethyl)-5-fluorobenzonitrile (3.47 g, 16.2 mmol), 3-chloro-l-(2,6- difluorophenyl)-4-hydroxy-6-methylpyridin-2(lH)-one (3.15 g, 11.6 mmol), K2C03 (2.56 g, 18.6 mmol), and 18-crown-6 (0.15 g) were dissolved in N,N-dimethylacetamide (25 mL). Reaction mixture stirred on 60°C oil bath for 4 hours. Solvent removed by distillation. Reaction neutralized with 5% citric acid. The solid product was washed with hexane followed by 30% EtOAc/hexane. Filtered a brown solid (5.2 g, 79% yield). 1H NMR (CD3OD / 400MHz) δ7.82 (m, 2H), 7.61 (m, 4H), 6.75 (s, IH), 5.49 (s, 2H), 2.13 (s, 3H). ESHRMS m/z 405.0616 (M+H C20H13ClF3N2O2 requires 405.0612).
572 Example 530
Figure imgf000573_0001
4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3-chloro-l-(2,6-difluorophenyl)-6- methylpyridin-2( 1 H)-one trifluoroacetate
BH3THF (17.8 mL, 17.8 mmol) was added dropwise to a chilled (0°C) solution of 2-( { [3 -chloro- 1 -(2,6-difluorophenyl)-6-methyl-2-oxo- 1 ,2-dihydropyridin-4- yl]oxy}methyl)-5-fluorobenzonitrile (3.61 g, 8.92 mmol) in THF (30 mL). Following the addition, the reaction was heated at 60°C for 1.5 hours. The reaction was quenched with MeOH, the solvent evaporated, and the crude product purified by prep HPLC. The product was isolated by freeze-drying and evaporation of the solvent to give a white solid (1.52 g, 32.6%). 1H NMR (CD3OD/ 400MHz) δ7.62 (m, 2H), 7.32 (m, IH), 7.25 (tr, 2H, J = 8.00 Hz), 7.18 (m, IH), 6.78 (s, IH), 5.43 (s, IH), 4.22 (s, IH), 2.14 (s, 3H). ESHRMS m/z 409.0900 (M+H C20H17N2O2F3Cl requires 409.0925).
Examples 531-551
Figure imgf000573_0002
The compounds of Examples 531-551 are prepared by derivitazion of Example 530. The analytical data are shown below.
573 -
Figure imgf000574_0001
NMR characterization of compounds of Examples 531-551
Figure imgf000574_0002
574
Figure imgf000575_0001
575- Example 552
Figure imgf000576_0001
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{[5-(l-hydroxy-l-methylethyl)pyridin-2- yl]methyl}-6-methylpyridin-2(lH)-one
Step 1: Preparation of methyl 6-methylnicotinate 1 -oxide.
Figure imgf000576_0002
Methyl 6-methyhιicotinate (6.0 g, 39.7 mmol) was added into dichloromethane (100 mL) in the round bottom flask under nitrogen. 3-chloroperoxybenzoic acid (10.0 g, 57.9 mmol) was then added into the flask and stirred for 5 hour. Saturated sodium bicarbonate solution (100 ml) was added into the reaction and the mixture was transferred to separatory funnel. Additional 200mL of dichloromethane was added into the funnel and obtained the organic layer. The organic layer was washed with water (150 mL) and dried over anhydrous magnesium sulfate. The resulting solution was evaporated to yield white solid (6 g, 90 %). LC/MS, tr = 0.33 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 168 (M+H). ES-HRMS m/z 168.0628 (M+H calcd for C8H10NO3 requires 168.0655).
Step 2: Preparation of methyl 6-(chloromethyl)nicotinate.
Figure imgf000576_0003
Methyl 6-methylnicotinate 1 -oxide (from Step 1) (6.0 g, 35.9 mmol) was was added into the p-toluenesulfonyl chloride (10 g, 52.4 mmol) in 100 mL of 1,4- dioxane. The mixture was heated to reflux for 20 hours. Saturated sodium bicarbonate solution (200 ml) was added into the reaction and the mixture was transferred to separatory funnel. - 576 - The compound was extracted using ethyl acetate (300ml x 2) and the combined ethyl acetate solution was dried over magnesium sulfate and evaporated to black solid (5.2 g, 78%). LC/MS, tr = 1.52 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 186 (M+H). ES-HRMS m/z 186.0314 (M+H calcd for C8H9C1N02 requires 186.0316).
Step 3: Preparation of methyl 6-{[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl]methyl} nicotinate.
Figure imgf000577_0001
Methyl 6-(chloromethyl)nicotinate (from step 2). (2 g, 10.8 mmol) was added into
4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one in 20 mL of dimethyl formamide followed by addition of cesium carbonate (5g, 15.3 mmol). The mixture was heated to 100 C for 20 hours. It was cooled to room temperature and added 400 mL of water. Brown precipitate came out of from solution. It was filtered and rinsed with water (200 mL x 3) and dried to obtain 4 g of solid. The product was purified using a Gilson
Reversed Phase preparative chromatography to obtain white solid (1.4 g, 32%). 1H NMR (400 MHz, CDC13) δ 9.09 (d, J =1.48 Hz, IH), 8.19 (dd, J = 6.04, 2.15 Hz, IH), 7.37 (app q, J = 8.32 Hz, IH), 7.25 (d, J = 8.33 Hz, IH), 6.84 (m, 2H), 5.94 (d, J = 2.82Hz, IH), 5.83 (d, J = 2.15Hz, IH), 5.36 (s, 2H), 4.97 (s, 2H), 3.90 (s, 3H), 2.27(s, 3H); LC MS, tr = 2.30 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 401 (M+H). ES-HRMS m/z 401.1307 (M+H calcd for C21H19F2N204 requires 401.1307).
Step 4: Preparation of the title compound. 3 molar solution of methyl magnesium bromide in ether (5mL, 15mmol) was added into 5 ml of anhydrous tetrahydrofuran in the round bottom flaks under nitrogen. The mixture was cooled to 0°C. Methyl 6-{[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]methyl}nicotinate (from Step 3) (300mg, 0.75mmol)was dissolved in 5 ml of anhydrous tetrahydrofuran in dropper funnel and the solution was slowly added - 577 - into cold methyl magnesium bromide solution in the round bottom flask. After the addition, the mixture was continue stirring at 0 C for 30 minute and cold solution of saturated ammonium chloride (100 ml) was added slowly into the reaction mixture. The mixture was transferred to separatory funnel and the product was extracted with ethyl acetate (200ml x2). The combined ethyl acetate solution was dried over anhydrous magnesium sulfate and evaporated to dryness. The resulting residue (220 mg) was added into 10 ml of dichloromethane followed by addition of N-bromo succinimide (100 mg, 0.56 mmol). The solution was stirred at room temperature for 3 hours. Saturated sodium bicarbonate solution (100 ml) was added into the reaction mixture and it was transferred to separatory funnel. The product was extracted with ethyl acetate (200ml x2). The combined ethyl acetate solution was dried over anhydrous magnesium sulfate and evaporated to dryness.
1H NMR (400 MHz, CDC13) δ 8.61 (d, J =1.88 Hz, IH), 7.73 (dd, J = 5.77, 2.42 Hz, IH), 7.55 (app q, J = 6.31 Hz, IH), 7.30 (d, J = 8.19b Hz, IH), 6.93 (m, IH), 6.84 (m, IH), 6.00 (s, IH), 5.37 (s, 2H), 5.19 (s, 2H), 2.48 (s, 3H), 1.56 (s, 6H); LC/MS, tr = 2.29 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 479 (M+H). ES-HRMS m/z 479.0791 (M+H calcd for C22H22BrF2N203 requires 479.0776).
Example 553
Figure imgf000578_0001
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{[5-(hydroxymethyl)pyridin-2-yl]methyl}-6- methylp yridin-2( 1 H)-one
Step 1: Preparation of 4-[(2,4-difluorobenzyl)oxy]-l-{[5-(hydroxymethyl)pyridin-2- yl]methyl}-6-methylpyridin-2(lH)-one.
578
Figure imgf000579_0001
Methyl 6-{[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}nicotinate (from preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{[5-(l- hydroxy-l-methylethyl)pyridin-2-yl]methyl}-6-methylpyridin-2(lH)-one, step 3) (350 mg, 0.87 mmol) was added into anhydrous tetrahydrofuran (15 ml) and the solution was cooled to -78 C. Into the cold solution, was added lithium aluminum hydride (100 mg, 2.6 mmol). After the addition, the reaction mixture was warm to 0 C and continue stirring for one additional hour. Potassium hydrogen sulfate (I N solution, 150 ml) was added slowly into the reaction mixture to quench the reaction. The resulting mixture was fransfened to a separatory funnel and the product was extracted with ethyl acetate (200ml x 2). The combine ethyl acetate solution was dried over anhydrous magnesium sulfate and evaporated to dryness. LC/MS, tr = 1.88 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 373 (M+H)
Step 2: Preparation of the title compound.
4-[(2,4-difluorobeιιzyl)oxy]-l-{[5-(hydroxymethyl)pyridin-2-yl]methyl}-6-methylpyridin- 2(lH)-one (from step 1). (230 mg, 0.62 mmol) was added into 10 ml of dichloromethane followed by addition of N-bromo succinimide (110 mg, 0.62 mmol). The solution was stined at room temperature for 3 hours. Saturated sodium bicarbonate solution (100 ml) was added into the reaction mixture and it was fransferred to a separatory funnel. The product was extracted with ethyl acetate (200ml x2). The combined ethyl acetate solution was dried over anhydrous magnesium sulfate and evaporated to dryness. !H NMR (400 MHz, CDC13) δ 8.47 (app s, IH), 7.64 (dd, J = 5.77, 2.29 Hz, IH), 7.55 (app q, J = 6.45 Hz, IH), 7.33 (d, J = 6.05 Hz, IH), 6.93 (m, IH), 6.84 (m, IH), 6.00 (s, IH), 5.39 (s, 2H), 5.19 (s, 2H), 4.68 (s, 2H), 2.46 (s, 3H); LC/MS, tr = 2.01 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 451 (M+H)
579 Example 554
Figure imgf000580_0001
6-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-N-(2- hydroxyethyl)-N-methylnicotinamide
Step 1: Preparation of methyl 6-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)- yl]methyl}nicotinate.
Figure imgf000580_0002
Methyl 6- {[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l (2H)- yl]methyl}nicotinate (from preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{[5-(l- hydroxy-l-methylethyl)pyridin-2-yl]methyl}-6-methylpyridin-2(lH)-one, step 3) (350 mg, 0.87 mmol) (1.0 g, 2.5 mmol) was added into 150 ml of dichloromethane followed by addition of N-bromo succinimide (500 mg, 2.8 mmol). The solution was stined at room temperature for 3 hours. Saturated sodium bicarbonate solution (300 ml) was added into the reaction mixture and it was fransfened to a separatory funnel. The product was extracted with ethyl acetate (500ml x2). The combined ethyl acetate solution was dried over anhydrous magnesium sulfate and evaporated to dryness. 1H NMR (400 MHz, CDC13) δ 9.08 (app d, J = 2.15 Hz, IH), 8.21 (dd, J = 6.04, 2.15 Hz, IH), 7.55 (app qt, J = 6.31 Hz, IH), 7.41 (d, J = 6.31 Hz, IH), 6.91 (m, IH), 6.84 (m, IH), 6.02 (s, IH), 5.42 (s, 2H), 5.19 (s, 2H), 3.91 (s, 3H), 2.45 (s, 3H); LC/MS, tr = 2.85 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 479 (M+H). ES-HRMS m z 479.0415 (M+H calcd for C21H18BrF2N204 requires 479.0413).
Step 2: Preparation of 6- {[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]methyl}nicotinic acid. - 580 -
Figure imgf000581_0001
Methyl 6-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}nicotinate (from step 1) (1.0 g, 2.1 mmol) was added into the mixture of 100 ml tetrahydrofuran and 10 ml of methanol followed by addition of 2.5 N sodium hydroxide(0.85 ml, 2.1 mmol). The solution was heated to 50 C for 2 hours. After the solution was cooled to room temperature and evaporate to completely dried residue. The residue was added into 50 ml of tefrahydrofuran and 4 N HCl in 1,4-dioxane (0.52 ml, 2.1 mmol) and stined the mixture for 30 minute. The mixture was evaporate to dryness. The residue was added 20 ml water and the aqueous solution was neutralized to exactly ph 7 by addition of saturated sodium bicarbonate solution drop wise. The resulting heterogeneous mixture was left standed for 20 hours. Filtered, rinsed with water (30 ml x 3) and dried over high vacuum oven to afford white solid( 950 mg, 97%). 1H NMR (400 MHz, CDC13 and CD3OD) δ 8.98 (app br s, IH), 8.15 (dd, J = 6.17, 2.02 Hz, IH), 7.45 (app q, J = 6.58 Hz, IH), 7.21 (d, J = 8.19 Hz, IH), 6.84 (m, IH), 6.76 (m, IH), 6.04 (s, IH), 5.35 (s, 2H), 5.12 (s, 2H), 2.32 (s, 3H); LC/MS, tr = 2.48 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ESMS m/z 465 (M+H). ES-HRMS m z 465.0254 (M+H calcd for C20H16BrF2N2O4 requires 465.0256).
Step 3: Preparation of the title compound. 6-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}nicotinic acid (from step 2)(230 mg, 0.5 mmol) was added into the 1- hydroxybenzotriazole (lOlmg, 0.75 mmol) in 5 ml of N,N-dimethylforamide. 4 -methyl morpholine (0.16 ml, 1.5 mmol) was added into the mixture followed by addition of l-(3- (dimethylamino) propyl-3-ethylcarbodiimide hydrochloride (143 mg, 0.75 mmol). Stined the mixture for 30 minute to become homogenous solution. To that homogenous solution, was added 2-(methylamino) ethanol(0.06 ml, 0.75 mmol) and the mixture was stined for 20 hours. Water (150 ml) was added into the reaction mixture and the product was extracted using ethyl acetate (400ml x2). The combined ethyl acetate solution was - 581 - dried over anhydrous magnesium sulfate and evaporated to dryness. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (app br s, IH), 7.80 (br d, J = 7.92 Hz, IH), 7.64 (app q, J = 6.58 Hz, IH), 7.30 (m, 2H), 7.15 (m, IH), 6.56 (s, IH), 5.39 (s, 2H), 5.28 (s, 2H), 3.46 (m, 2H), 3.23 (m, 2H) 2.93 (m, 3H), 2.36 (s, 3H); LC/MS, tr = 2.29 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-HRMS m/z 522.0850 (M+H calcd for C23H23BrF2N304 requires 522.0835).
Example 555
Figure imgf000582_0001
6-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxoρyridin-l(2H)-yl]methyl}-N-(2- hydroxyethyl)nicotinamide
Following the method of Example 554 (step 3) and substituting 2- (methylamino)ethanol for the ethanolamine obtained the title compound as a white solid (79% yield). 1H NMR (400 MHz, CD3OD) δ 8.93 (d, J = 2.01 Hz, IH), 8.21 (dd, J = 6.04, 2.21 Hz, IH), 7.67 (app q, J = 6.44 Hz, IH), 7.39 (d, J = 8.06 Hz, IH), 7.08 (m, 2H), 6.58 (s, IH), 5.55 (s, 2H), 5.35 (s, 2H), 3.74 (app t, J = 5.73Hz, 2H), 3.53 (app t, J = 5.73Hz, 2H), 2.49 (s, 3H); LC/MS, tr = 2.26 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-HRMS m/z 508.0673 (M+H calcd for C22H21BrF2N304 requires 508.0678).
Example 556
Figure imgf000582_0002
6-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-N,N- dimethylmcotinamide
582 Following the method of Example 554 (step 3) and substituting dimethylamine for the ethanolamine obtained the title compound as a white solid (75% yield). 1H NMR (400 MHz, CDC13) δ 8.55 (d, J = 1.62 Hz, IH), 7.68 (dd, J = 5.77, 2.15 Hz, IH), 7.55 (app q, J = 6.45 Hz, IH), 7.37 (d, J = 8.06 Hz, IH), 6.93 (m, IH), 6.84 (m, IH), 6.02(s, IH), 5.40 (s, 2H), 5.20 (s, 2H), 3.09 (s, 3H), 2.97 (s, 3H), 2.45 (s, 3H); LC/MS, tr = 2.45 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ESHRMS m z 492.0710 (M+H calcd for C22H21BrF2N303 requires 492.0729).
Example 557
Figure imgf000583_0001
3-bromo-4-[(2,4-difluorobenzy oxy]-6-methyl-l-[2-(trifluoromethyl)phenyl]pyridin- 2(lH)-one
Step 1: Preparation of 4-hydroxy-6-methyl-l-[2-(trifluoromethyl)phenyl]pyridin-2(lH)- one.
Figure imgf000583_0002
4-hydroxy-6-methyl-2 -pyrone (lOg, 79.3 mmol) was added into the 2- (trifluoromethyl) aniline (14 ml, 111.3 mmol) in 10 ml of 1,2-dichlorobenzene in a round bottom flask. The mixture was then placed in a pre-heated oil bath at 165 C. After 30 minute of heating, the mixture was cooled to room temperature and added 250 ml of saturated sodium bicarbonate solution. The mixture was stined at room temperature for 15 minutes and fransfened to a separatory funnel. Ethyl acetate (300ml) was added into the separatory funnel and partitions the layers. The aqueous layer was obtained and the organic layer was added 200 ml of saturated sodium bicarbonate solution. The aqueous layer was obtained again and the combined aqueous solution was neutralized with HCl solution. Upon neutralization, white solid precipitated out of the solution. Filtered the
583 - solid, rinsed with water (100 ml x5) and dried over high vacuum oven to obtain the white solid (7.5 g, 35.5%). LC/MS, tr = 1.77 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 5j0°C). ES-MS m/z 270 (M+H).
Step 2: Preparation of 4-[(2,4-difluorobenzyl)oxy]-6-methyl-l -[2- (trifluoromethyl)phenyl]pyridin-2(lH)-one.
Figure imgf000584_0001
4-hydroxy-6-methyl-l-[2-(trifluoromethyl)phenyl]pyridin-2(lH)-one (from Step 1) (7.3 g, 27.1 mmol) was added into 3,4-difluorobenzyl bromide (5.5 g, 26.5 mmol) in 60 ml of dimethyl formamide. The mixture was cooled to 0 C and cesium carbonate (20g, 61.3 mmol) was added into the mixture. After the addition, the mixture was warmed to room temperature and stined for 4 hours. Water (500ml) was added into the reaction mixture. Yellow solid came out of solution. Filtered and rinsed with water (200ml x 2) to obtain the yellow solid. Dissolved the solid in ethyl acetate (500 ml) and water (300 ml) and transfer to a separatory funnel and obtained the organic layer. The organic layer was washed again with water (200ml) and dried over anhydrous magnesium sulfate. The organic solution was evaporated to dryness. 1H NMR (400 MHz, CDC13) δ 7.82 (d, J =7.65 Hz, IH), 7.7 (t, J = 7.52 Hz, IH), 7.58 (t, J = 7.65 Hz, IH), 7.42 (q, J = 6.45 Hz, IH), 7.27 (d, J = 7.78 Hz, 2H), 6.89 (m, 2H), 5.95 (app d, J = 2.42Hz, IH), 5.90 (app d, J = 2.42Hz, IH), 5.01 (app d, J = 2.94 Hz, 2H), 1.86 (s, 3H); LC/MS, tr = 2.74 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ESMS m/z 396 (M+H)
Step 3: Preparation of the title compound. N-bromosuccinimide (0.24g, 1.36 mmol) was added into 4-[(2,4-difluorobenzyl)oxy]-6- methyl-l-[2-(trifluoromethyl)phenyl]pyridin-2(lH)-one (0.54g, 1.36 mmol) in 20 ml of dichloromethane. The mixture was stined at room temperature for 2 hours. Saturated sodium bicarbonate solution (150 ml) was added into the reaction mixture and the combine solution was fransfened to a separatory funnel. The product was extracted with - 584 - ethyl acetate (250ml). The ethyl acetate solution was dried over anhydrous magnesium sulfate and evaporated to dryness. 1H NMR (400 MHz, CDC13) δ 7.82 (d, J =7.25 Hz, IH), 7.7 (app t, J = 7.66 Hz, IH), 7.60 (m, 2H), 7.26 (s, IH), 6.97 (m, IH), 6.87 (m, IH), 6.09 (s, IH), 5.25 (app d, J = 3.35Hz, 2H), 1.94 (s, 3H); LC/MS, tr = 2.84 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ESHRMS m/z 474.0113 (M+H calcd for C20H14BrF5NO2 requires 474.0123).
Example 558
Figure imgf000585_0001
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-6-methyl-5-vinylpyridin- 2(lH)-one
Step 1 : To a room temperature solution of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6- difluorophenyl)-5-iodo-6-methylpyridin-2(lH)-one (1.00 g, 1.76 mmol) in anhydrous THF (12 mL) was added, sequentially, tributyl(vinyl)tin (1.21 g, 3.81 mmol) and tefrakis(triphenylphosphine)palladium (236 mg, 0.204 mmol) under an argon stream. The reaction vessel was then equipped with a reflux condenser and the reaction system purged with an argon flow. The resulting yellow solution was heated to 68 °C and stined under a positive pressure of argon for 12.0 hours until complete disappearance of starting material by LCMS analysis. The reaction mixture was concentrated in vacuo and the resulting dark residue was subjected to Si02 chromatography with ethyl acetate/hexanes (3:7) to furnish a reddish solid. 1H NMR (400 MHz, CDC13) δ 7.62 (app q, J = 7.8 Hz, IH), 7.45 (app tt, J = 8.4, 6.2, IH), 7.09 (app t, J = 8.8 Hz, 2H), 6.90 (app t, J = 8.0 Hz, IH), 6.83 (app dt, J = 6.8, 2.5 Hz, IH), 6.51 (dd, J = 17.7, 11.4 Hz, IH), 5.53 (dd, J = 11.4, 1.5 Hz, IH), 5.41 (dd, J = 17.8, 1.5 Hz, IH), 5.09 (br s, 2H), 2.09 (s, 3H); LC/MS C-18 column, tr = 3.20 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml min with detection 254 nm, at 50°C). ES-MS m z 468 (M+H). ES-HRMS m/z 468.0210 (M+H calcd for C21H15BrF4N02 requires 468.0217).
585 - Example 560
Figure imgf000586_0001
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-5-(l,2-dihydroxyethyl)-6- methylpyridin-2(lH)-one
Step 1: To a room temperature solution of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6- difluorophenyl)-6-methyl-5-vinylpyridin-2(lH)-one (0.970 g, 2.07 mmol) in water/acetone 1:3 (8.7 mL) was added, sequentially, osmium tefroxide (0.110 g, 0.433 mmol) and N- methyl morpholine oxide (1.32 g, 11.2 mmol). The resulting solution was stined for one hour until complete consumption of starting material by LCMS analysis, and the reaction was concentrated in vacuo. The resulting dark residue was subjected to Si02 chromatography with ethyl acetate/hexanes (3:7) to furnish a solid. 1H NMR (400 MHz, CDC13) δ 7.59 (app q, J = 8.2 Hz, IH), 7.45 (ddd, J = 14.7, 8.5, 6.8 Hz, IH), 7.08 (app t, J = 8.5 Hz, 2H), 6.94 (app t, J = 8.2 Hz, IH), 6.88 (app t, J = 8.5 Hz, IH), 5.31 (AB-q, J = 10.6 Hz, Δ= 38.3 Hz, 2H), 5.07 (dd, J = 9.1, 3.8 Hz, IH), 3.83 (t, J = 10.8 Hz, IH), 3.60 (dd, J = 11.4, 3.9 Hz, IH), 2.94 (br s, IH), 2.16 (s, 3H); LC MS C-18 column, tr = 2.26 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 502 (M+H). ES-HRMS m/z 502.0276 (M+H calcd for C2ιH17BrF N0 requires 502.0272).
Example 561
Figure imgf000586_0002
586 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-5-(hydroxymethyl)-6- methylpyridin-2( 1 H)-one
Step 1: To a -20 °C solution of 5-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6- difluorophenyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carbaldehyde (0.659 g, 1.40 mmol) in methanol (10 mL) was added, portionwise, solid sodium borohyride (3.6 g, 96 mmol) over one hour until complete consumption of starting material by LCMS analysis. Next, the reaction mixture was diluted with 500 mL of ethyl acetate and washed with 3 X 200 mL of water. The resulting organic exfract was Na2S04 dried, filtered, and concenfrated in vacuo to approximately 100 mL volume. The resulting liquid was diluted with hexanes (100 mL) to furnish an amorphous solid that was collected and dried at 1 mm Hg vacuum to furnish (620 mg, 94 %) of the desired product. 1H NMR (400 MHz, d4-MeOH) δ 7.70 (app q, J = 8.3 Hz, IH), 7.62 (app tt, J = 10.4, 6.3 Hz, IH), 7.25 (app t, J = 8.6 Hz, 2H), 7.03 (app t, J = 8.6 Hz, IH), 6.88 (app t, J = 8.5 Hz, IH), 5.31 (s, 2H), 4.58 (s, 2H), 2.17 (s, 3H); LC/MS C-18 column, tr = 2.49 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 472 (M+H). ESHRMS m/z 472.0152 (M+H calcd for C20H15BrF4NO3 requires 472.0166).
Example 562
Figure imgf000587_0001
4-(benzyloxy)-3-bromo-l-(2,6-difluorophenyl)-6-methylpyridin-2(lH)-one
Step 1: Preparation of 4-(benzyloxy)-l-(2,6-difluorophenyl)-6-methylpyridin-2(lH)-one.
Figure imgf000587_0002
- 587 To a briskly stined room temperature solution of l-(2,6-difluorophenyl)-4- hydroxy-6-methylpyridin-2(lH)-one (1.43 g, 6.03 mmol) in dimethylformamide (4.6 mL) was added sequentially K2C03 (2.01 g, 14.5 mmol) and benzyl bromide (2.40 mL, 20.2 mmol). The resulting suspension was stined for 6.5 hours until complete consumption of starting material by LCMS analysis. The reaction was then diluted with ethyl acetate (200 mL) and brine washed (3 X 200 mL). The resulting organic exfract was Na2S04 dried, filtered, and concenfrated in vacuo to approximately 100 mL volume. The resulting mother liquor rapidly precipitated and furnished an amorphous solid that was collected and dried at 1 mm Hg vacuum to provide a solid (1.62 g, 82 %). 1H NMR (300 MHz, MeOH) δ 7.62 (app tt, J = 8.6, 6.4 Hz, IH), 7.52-7.32 (m, 4H), 7.30-7.12 (m, 3H), 6.27 (d, J = 1.6 Hz, IH), 6.04 (d, J = 2.6 Hz, IH), 5.18 (s, 2H), 2.06 (s, 3H). LC/MS C-18 column, tr = 2.51 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 328 (M+H). ES-HRMS m/z 328.1179 (M+H calcd for C19H16F2N02 requires 328.1144).
Step 2: To a room temperature solution of 4-(benzyloxy)-l-(2,6-difluorophenyl)-6- methylpyridin-2(lH)-one (1.52 g, 4.64 mmol) in methylene chloride (15 mL) was added solid N-bromosuccinimide (2.01 g, 11.3 mmol) and the resulting reddish solution was stined for 4.0 hours. At this time the reaction was diluted with ethyl acetate (400 mL) and washed with sodium sulfite (5 % aqueous solution, 100 mL) and brine (3 X 200 mL). The resulting organic extracts were Na S04 dried, filtered, and concenfrated in vacuo to approximately 60 mL volume. The resulting mother liquor rapidly precipitated and furnished an amorphous solid that was collected and dried at 1 mm Hg vacuum to provide a solid 4-(benzyloxy)-3-bromo-l-(2,6-difluorophenyl)-6-methylpyridin-2(lH)-one (1.70 g, 91 %). 1H NMR (300 MHz, d4-MeOH) δ 7.64 (app tt, J = 8.6, 6.4 Hz, IH), 7.57 (br d, J = 7.1 Hz, IH), 7.50-7.34 (m, 4H), 7.27 (app t, J = 8.0 Hz, IH), 7.26-7.21 (m, IH), 6.66 (s, IH), 5.40 (s, 2H), 2.12 (s, 3H); LC/MS C-18 column, tr = 2.63 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 406 (M+H). ES-HRMS m/z 406.0228 (M+H calcd for C19H15BrF2N02 requires 406.0249).
Example 563 - 588 -
Figure imgf000589_0001
5-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-2-methyl-6-oxo-l,6- dihydropyridin-3-yl]methyl carbamate
Step 1 : To a room temperature solution of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6- difluorophenyl)-5-(hydroxymethyl)-6-methylpyridin-2(lH)-one (76.2 mg, 0.161mmol) in methylene chloride (0.4 mL) was added a solution of trichloroacetyl isocyanate (toluene, 0.60 M, 0.5 mL, 0.30 mmol). The resulting solution was stined for one hour until complete consumption of starting material by LCMS analysis. The reaction mixture was then directly applied to A1203 (0.5 g of Broeckman-activity type I) and the slurry was matured for three hours. At this time, the A1203 plug was flushed with ethyl acetate/methanol (95:5) and the resulting mother liquor was concentrated to a residue that was subjected to Si02 chromatography using ethyl acetate/hexanes (1 :1) to furnish a white solid (71.0 mg, 85 %). 1H NMR (400 MHz, αVMeOH) δ 7.71-7.59 (m, 2H), 7.26 (app t, J = 8.5 Hz, 2H), 7.02 (app t, J = 9.2 Hz, 2H), 5.32 (s, 2H), 5.02 (s, 2H), 2.15 (s, 3H); LC/MS C-18 column, tr = 2.35 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m z 515 (M+H). ES-HRMS m/z 515.0188 (M+H calcd for C21H16BrF4N204 requires 515.0224).
Example 564
Figure imgf000589_0002
5-bromo-4-[(2,4 -difluorobenzy oxy] - 1 -(2,6-< iifluorophi snyl)- 2-methyl-6- ■oxo -1,6 dihydropyridine- -3-carbaldehyde
589 - Step 1: To a room temperature solution of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6- difluorophenyl)-5 -(1 ,2-dihydroxyethyl)- 6-methylpyridin-2( 1 H)-one (550 mg, 1.10 mmol) in toluene (10.0 mL) was added lead(IV) acetate (810 mg, 1.82 mmol). The resulting dark brown solution was stined for two hours until complete consumption of starting material by LCMS analysis. The reaction mixture was then diluted with ethyl acetate (400 mL), water washed (3 X 100 mL), and brine washed (3 X 300 mL). The resulting organic extract was separated, Na2S04 dried, and concenfrated. The resulting dark residue was subjected to Si02 chromatography with ethyl acetate/ hexanes (1 :1) to furnish a light yellow solid (321 mg, 62 %). 1H NMR (400 MHz, CDC13) δ 10.08 (s, IH), 7.56-7.48 (m, 2H), 7.12 (app t, J = 7.3 Hz, 2H), 6.94 (app t, J = 8.5 Hz, IH), 6.88 (app t, J = 8.7 Hz, IH), 5.33 (s, 2H), 2.45 (s, 3H); LC/MS C-18 column, tr = 2.94 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 470 (M+H). ES-HRMS m/z 469.9996 (M+H calcd for C20H13BrF4NO3 requires 470.0009).
Example 565
Figure imgf000590_0001
5-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-2-methyl-6-oxo-l,6- dihydropyridine-3-carbaldehyde oxime
Step 1 : To a room temperature solution of 5-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6- difluorophenyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carbaldehyde (316.5 mg, 0.673 mmol) in methanol (10.0 mL) was added solid NH2OH*H2O(300.0 mg, 4.32 mmol) and sodium acetate (480.0 mg, 5.85 mmol). The resulting suspension was stined for 1.5 hours until complete consumption of starting material by LCMS analysis. The reaction mixture was then concentrated in vacuo and the resulting residue was diluted with methylene chloride (300 mL) and water washed (2 X 100 mL). The resulting organic extract was separated, Na2S04 dried, and concenfrated to furnish a light yellow solid (390 mg, 99 %). - 590 - 1H NMR (400 MHz, ( -MeOH with CDC13) δ 8.06 (s, IH), 7.51-7.40 (m, 2H), 7.06 (app dd, J = 8.6, 7.4 Hz, 2H), 6.88 (app dt, J = 8.3, 2.4 Hz, IH), 6.83 (app dt, J = 9.2, 2.4 Hz, IH), 5.13 (s, 2H), 2.76 (s, 3H); LC/MS C-18 column, tr = 2.61 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 485 (M+H). ES-HRMS m/z 485.0093 (M+H calcd for C20H14BrF4N2O3 requires 485.0118).
Example 566
Figure imgf000591_0001
5-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-2-methyl-6-oxo-l,6- dihydrop yridine-3 -carbonitrile
Step 1 : To a room temperature solution of 5-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6- difluorophenyl)-2-methyl-6-oxo-l,6-dihydropyridine-3-carbaldehyde oxime (340.0 mg, 0.701mmol) in methylene chloride (8.0 mL) was added solid 1,1 ' carbonyl diimidazole (290.0 mg, 1.79 mmol) and sodium acetate (480.0 mg, 5.85 mmol). The resulting solution was stined for 1.5 hours until complete consumption of starting material by LCMS analysis. The reaction mixture was then concenfrated in vacuo and the resulting residue was directly applied to Si02 chromatography with ethyl acetate/hexanes (3:7) to furnish a white solid (262 mg, 90 %). 1H NMR (400 MHz, CDC13) δ 7.61 (app q, J = 7.4 Hz, IH), 7.52 (app tt, J = 8.4, 6.3 Hz, IH), 7.14 (app dd, J = 8.6, 7.4 Hz, 2H), 6.94 (app dt, J = 8.5, 2.5 Hz, IH), 6.88 (app dt, J = 8.5, 2.4 Hz, IH), 5.43 (s, 2H), 2.32 (s, 3H); LC/MS C-18 column, tr = 2.95 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). IR (neat) 3111, 3067, 3032, 2914, 2840, 2215 (nitrile stretch), 1678, 1587, 1470 cm _1; ES-MS m/z 467 (M+H). ES-HRMS m/z 467.0037 (M+H calcd for C20H12BrF4N2O2 requires 467.0013).
591 Example 567
Figure imgf000592_0001
4-(benzyloxy)-3-bromo-l-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(lH)-one
Step 1: A solution of 4-(benzyloxy)-3-bromo-l-(2,6-difluorophenyl)-6-methylpyridin- 2(lH)-one (1.42 g, 3.50 mmol) in 1,2 dichloroethane (18 mL) was treated with solid N- iodosuccinimide (1.59 g, 7.06 mmol) and dichloroacetic acid (0.260 g, 2.01 mmol). The resulting solution was stined and heated to 50 °C for 2.5 hours until complete consumption of starting material by LCMS. At this time the reaction was diluted with ethyl acetate (400 mL) and washed with sodium sulfite (5 % aqueous solution, 100 mL) and brine (3 X 200 mL). The resulting organic extracts were Na2S0 dried, filtered, and concenfrated in vacuo to approximately 30 mL volume. The resulting mother liquor rapidly precipitated and furnished an amorphous solid that was collected and dried at 1 mm Hg vacuum to provide a solid (1.49 g, 82 %). 1H NMR (400 MHz, CDC13) δ 7.62 (app d, J = 6.8 Hz, 2H), 7.51-7.38 (m, 4H), 7.09 (app t, J = 8.0 Hz, 2H), 5.20 (s, 2H), 2.39 (s, 3H); LC/MS C-18 column, tr = 3.28 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 532 (M+H). ESHRMS m/z 531.9196 (M+H calcd for C19H14BrF2fN02 requires 531.9215).
Example 568
Figure imgf000592_0002
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-6-methyl-5-oxiran-2- ylpyridin-2(lH)-one
592 Step 1: A sample of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-6- methyl-5-vinylpyridm-2(lH)-one (10.0 mg, 0.0214 mmol) was treated with a solution of dimethyl dioxirane in acetone (approx. 0.1 M, 5 mL, 0.5 mmol). The reaction vessel was capped and sealed, and the resulting solution was stined 6.0 hours. At this time the reaction was concenfrated in vacuo and the resulting residue was subjected to Si0 chromatography with ethyl acetate/hexanes (4:6) to furnish a semi-solid (5.0 mg, 48 %). 1H NMR (400 MHz, CDC13) δ 7.57 (app q, J = 7.4 Hz, IH), 7.46 (app tt, J = 8.5, 6.2, IH), 7.11 (app t, J = 8.0 Hz, 2H), 6.94(app t, J = 8.2 Hz, IH), 6.83 (app t, J = 9.2 Hz, IH), 5.31 (AB-q, J = 10.9 Hz, Δ = 29.0 Hz, 2H), 3.63 (app t, J = 3.5 Hz, IH), 3.03 (dd, J = 9.4, 5.0, IH), 2.85 (dd, J = 5.2, 2.7, IH), 2.14 (s, 3H); LC/MS C-18 column, tr = 2.26 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml min with detection 254 nm, at 50°C). ESMS m/z 484 (M+H) and 502 (M+H30). ES-HRMS m/z 502.0273 (M+H30 calcd for C21H17BrF4N04 requires 502.0272).
Example 569
Figure imgf000593_0001
4-(benzylamino)-3-bromo-l-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(lH)-one
Step 1: A slurry of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-5-iodo-6- methylpyridin-2(lH)-one (80.0 mg, 0.141 mmol) and benzyl amine (300 mg, 2.80 mmol) was heated to 63 °C and stined for 1.0 hours until complete disappearance of starting material by LCMS analysis. The reaction mixture was then diluted with ethyl acetate (300 mL) and brine washed (3 X 200 mL). The resulting organic extracts were Na2S04 dried, filtered, and concenfrated in vacuo to a residue that was then subjected to Si02 chromatography with ethyl acetate/hexanes (3:7) to furnish a brown solid (60.0 mg, 81 %). 1H NMR (400 MHz, CDC13) δ 7.43-7.22 (m, 6H), 7.04 (app t, J = 8.4 Hz, 2H), 5.02 (br t, J = 1.6 Hz, IH), 4.86 (d, J = 5.5 Hz, 2H), 2.37 (s, 3H); LC/MS C-18 column, tr = 3.02 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml min with detection 254 nm, at
593 - 50°C). ES-MS m/z 531 (M+H). ES-HRMS m/z 530.9344 (M+H calcd for C19H15BrF2IN20 requires 530.9375).
Example 570
Figure imgf000594_0001
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-6-methyl-5-[(E)-2- phenylethenyl]pyridin-2( 1 H)-one
Step l: To an anhydrous -78 °C solution of β-bromostyrene (1.80 g, 10.0 mmol) in ether (18 mL) was added sequentially a solution of zinc chloride (10.0 mL, 1.0 M ether, 10.0 mmol) over 1.0 minute and a solution of tert-butyl lithium (15.0 mL, 1.6 M pentanes, 24.0 mmol) over 8.0 minutes. The resulting solution became cloudy and the reaction mixture was allowed to warm to room temperature on its own accord (over 30 minutes). After an additional 1.0 hour, the suspension was fransfened by syringe directly to a separate vessel containing a solution of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6- difluorophenyl)-5-iodo-6-methylpyridin-2(lH)-one (1.50 g, 2.64 mmol) and tefrakis(tripheylphosphine)palladium (294 mg, 0.254 mmol) in anhydrous THF (4 mL). This resulting suspension was heated to 55 °C for 40 minutes and cooled to room temperature, whereby it was stined under a positive pressure of argon for an additional 4.0 hours until complete disappearance of starting material by LCMS analysis. The reaction suspension was subsequently treated with NaHC03 and brine (100 and 200 mL, respectively). The resulting emulsion was extracted with ethyl acetate (3 X 300 mL) and the organic extracts were Na2S04 dried, filtered, and concenfrated in vacuo to a residue that was then subjected to Si02 chromatography with ethyl acetate/hexanes (3:7) to furnish a reddish solid (1.25 g, 86 %). 1H NMR (400 MHz, CDC13) δ 7.51-7.39 (m, 2H), 7.38-7.24 (m, 5H), 7.10 (app t, J = 8.5 Hz, 2H), 6.84 (d, J = 17.2 Hz, IH), 6.82-6.75 (m,
594 IH), 6.74-6.68 (m, IH), 6.69 (d, J = 17.2, IH), 5.11 (br s, 2H), 2.15 (s, 3H); LC/MS C-18 column, tr = 3.74 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m z 544 (M+H). ES-HRMS m/z 544.0565 (M+H calcd for C27H19BrF4N02 requires 544.0530).
Example 574
Figure imgf000595_0001
4-(allylamino)-3-bromo-l-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(lH)-one
Step 1: A slurry of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-5-iodo-6- methylpyridin-2(lH)-one (1.40 g, 2.46 mmol) and allyl amine (1.98 mg, 34.6 mmol) was heated to 50 °C and stined for 1.0 hours until complete disappearance of starting material by LCMS analysis. The reaction mixture was then concentrated in vacuo (1.0 mm Hg) for 2 days at 50 °C to furnish a brown solid (1.18 g, 99 %). 1H NMR (300 MHz, CDC13) δ 7.43 (app tt, J = 8.4, 6.2, IH), 7.09 (app t, J = 8.4 Hz, 2H), 6.02 (app dq, J = 11.0, 6.2 Hz, IH), 5.39 (dd, J = 16.9, 1.8 Hz, IH), 5.30 (dd, J = 11.0, 1.8 Hz, IH), 4.84 (br s, IH), 4.35 (br s, 2H), 2.42 (s, 3H); LC/MS C-18 column, tr = 2.71 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 481 (M+H). ES-HRMS m/z 480.9261 (M+H calcd for C15H13BrF2IN20 requires 480.9219).
Example 575
Figure imgf000595_0002
4-(allylamino)- 1 -(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2( 1 H)-one
595 Step 1: A solution of 4-(allylamino)-3-bromo-l-(2,6-difluorophenyι)-5-iodo-6- methylpyridin-2(lH)-one (1.00 g, 2.07 mmol) and tetrakis(tripheylphosphine)palladium (420 mg, 0.363 mmol) in anhydrous THF (10 mL) under an argon stream was heated to 64 °C and stined for 12 hours until complete disappearance of starting material by LCMS analysis. The reaction suspension was subsequently freated with brine (600 mL). The resulting emulsion was extracted with ethyl acetate (3 X 400 mL) arid the organic extracts were anhy. Na2S04 dried, filtered, and concentrated in vacuo to a residue that was then subjected to Si02 chromatography with ethyl acetate/hexanes (gradient 3:7) to furnish a solid (376 mg, 45 %). 1H NMR (400 MHz, d4-MeOH) δ 7.55 (app tt, J = 8.7, 6.3, IH), 7.18 (app t, J = 7.6 Hz, 2H), 5.89 (app ddd, J = 15.4, 10.3, 5.1 Hz, IH), 5.01 (app d, J = 17.0, Hz, IH), 5.50 (s, IH), 5.22 (app d, J = 11.0 Hz, IH), 4.35 (app d, J = 5.0 Hz , 2H), 2.36 (s, 3H); LC/MS C-18 column, tr = 2.33 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 403 (M+H). ESHRMS m/z 403.0133 (M+H calcd for C15H14F2fN20 requires 403.0113).
Example 576
Figure imgf000596_0001
4-(allylamino)-l-(2,6-difluorophenyl)-5-iodo-6-methylpyridin-2(lH)-one
Step 1: A solution of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-6- methylpyridin-2(lH)-one (197 mg, 0.445 mmol) and allyl amine (1.32 mg, 23.1 mmol) in THF (6.0 mL) was heated to 68 °C and stined for 74.0 hours. The reaction mixture was then concentrated in vacuo (30 mm Hg) to furnish a residue that was subjected to Si02 chromatography with ethyl acetate/hexanes (3:7) to furnish a solid (36.0 mg, 23 %). 1H NMR (400 MHz, d4-MeOH) δ 7.55 (app tt, J = 8.5, 6.5, IH), 7.18 (app t, J = 8.5 Hz, 2H), 6.14 (s, IH), 5.91 (app dq, J = 11.5, 6.4 Hz, IH), 5.23 (dd, J = 17.0, 1.5 Hz, IH), 5.19 (dd, J = 11.0, 1.6 Hz, IH), 4.00 (app d, J = 4.7 Hz , 2H), 1.98 (s, 3H); LC/MS C-18 column, tr = 2.24 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 - 596 - nm, at 50°C). ES-MS m z 355 (M+H). ES-HRMS m/z 355.0257 (M+H calcd for C15H14F2BrF2N20 requires 355.0252).
Example 577
Figure imgf000597_0001
ethyl 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxo-2H-l,2'-bipyridine-5'- carboxylate
Step 1 : To a room temperature suspension of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methylpyridin-2(lH)-one (500.0 mg, 1.51 mmol) and Cs2C03 (1.50 g, 4.60mmol) in 1- t methyl-2-pyrrolidinone (3.0 mL) was added ethyl 6-chloronicotinate (900 mg, 4.85 mmol). The resulting suspension was stined and heated to 106 °C for 36 hours until complete consumption of starting material by LCMS analysis. The reaction mixture was then diluted with ethyl acetate (400 mL), water washed (3 X 200 mL). The resulting organic extract was separated, Na2S04 dried, and concentrated. The resulting dark residue was subjected to Si0 chromatography with ethyl acetate/hexanes (3:7) to furnish a solid. 1H NMR (400 MHz, d4-MeOH) δ 8.68 (app d, J = 2.5 Hz, IH), 8.39 (dd, J = 8.7, 2.3 Hz, IH), 7.62 (app q, J = 8.2 Hz, IH), 7.15 (d, J = 8.6 Hz, IH), 7.08 (s, IH), 7.08-6.99 (m, 2H), 5.31 (s, 2H), 4.37 (q, J = 7.1 Hz, 2H), 2.43 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H); LC/MS C-18 column, tr = 3.44 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 479 (M+H). ES-HRMS m/z 479.0401 (M+H calcd for C21H18BrF2N204 requires 479.0431).
Example 578
597
Figure imgf000598_0001
3-bromo-4-[(2,4-difluorobenzyl)oxy]-5'-(l-hydroxy-l-methylethyl)-6-methyl-2H-l,2'- bipyridin-2-one
Step 1: To a 0 °C solution of methyl magnesium bromide (3.0 M, 3.5 mL, 10.5 mmol) was added dropwise over 15 minutes a solution of ethyl 3 -bromo-4- [(2,4- difluorobenzyl)oxy]-6-methyl-2-oxo-2H-l,2'-bipyridine-5'-carboxylate (500.0 mg, 1.05 mmol) in THF (4.0 mL). The internal temperature of the reaction was never allowed to exceed 0 °C. The resulting solution was maintained for 30 minutes until complete consumption of starting material by LCMS analysis. Next, a solution of ammonium chloride (saturated aqueous, 160 mL) was added. The reaction mixture was exfracted with ethyl acetate (3 X 100 mL) and the resulting organic exfracts were separated, Na2S04 dried, and concentrated in vacuo to a residue that was subjected to Si02 chromatography with ethyl acetate/hexanes (gradient 3:7 to 6:4) to furnish a solid (386 mg, 79 %). 1H NMR (400 MHz, d4-MeOH) δ 8.23 (app d, J = 2.8 Hz, IH), 7.97 (dd, J = 8.6, 2.3 Hz, IH), 7.61 (app q, J = 8.2 Hz, IH), 7.06-7.00 (m, 3H), 7.00 (s, IH), 5.30 (s, 2H), 2.38 (s, 3H), 1.54 (s, 6H); LC/MS C-18 column, tr = 2.75 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml min with detection 254 nm, at 50°C). ES-MS m/z 465 (M+H). ESHRMS m/z 465.0615 (M+H calcd for C21H20BrF2N2O3 requires 465.0620). IR(neat) 3366, 3030, 2974, 1600, 1507, 1362, 1232 cm _1. 13C NMR (400 MHz, d4-MeOH, visible peaks with carbon fluorine coupling present) δ 164.4, 160.7, 158.9, 157.6, 143.6, 141.6, 137.5, 131.61, 131.56, 131.51, 131.46, 119.29, 119.25, 119.15, 119.11, 112.23, 111.55, 111.52, 111.33, 111.29, 106.0, 103.9, 103.7, 103.4, 96.8, 70.3, 64.9, 64.8, 30.5, 22.6.
Example 579
- 598
Figure imgf000599_0001
3-bromo-4-[(2,4-difluoroberizyl)oxy]-l-(2-furylmethyl)-6-methylpyridin-2(lH)-one
Step 1: Preparation of the title compound. To a room temperature suspension of 3-bromo- 4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one (330.0 mg, 1.00 mmol)) and NaH (48.0 mg, 2.0 mmol) in THF (3.0 mL) was added 2-(chloromethyi)furan (461 mg, 3.97 mmol). The resulting suspension was stined and heated to 68 °C for 9 hours until complete consumption of starting material by LCMS analysis. The reaction mixture was then diluted with ethyl acetate (400 mL), water washed (3 X 200 mL). The resulting organic extract was separated, Na2S04 dried, and concentrated. The resulting dark residue was subjected to Si02 chromatography with ethyl acetate/hexanes (4:6) to furnish a solid. 1H NMR (300 MHz, αVMeOH) δ 7.62 (app q, J = 8.4 Hz, IH), 7.46 (s, IH), 7.06 (app t, J = 8.7 Hz, 2H), 6.51 (s, IH), 6.41-6.37 (m, 2H), 5.37 (s, 2H), 5.32 (s, 2H), 2.61 (s, 3H); LC/MS C-18 column, tr = 2.63 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m z 410 (M+H). ES-HRMS m/z 410.0177 (M+H calcd for C18H15BrF2N03 requires 410.0198).
Example 580
Figure imgf000599_0002
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(thien-2-ylmethyl)pyridin-2(lH)-one
Step 1 : To a room temperature suspension of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methylρyridin-2(lH)-one (330.0 mg, 1.00 mmol) and NaH (48.0 mg, 2.0 mmol) in THF (3.0 mL) was added 2-(chloromethyl)thiophene (461 mg, 3.97 mmol). The resulting suspension was stined and heated to 68 °C for 12 hours until complete consumption of - 599 - starting material by LCMS analysis. The reaction mixture was then diluted with ethyl acetate (400 mL), water washed (3 X 200 mL). The resulting organic exfract was separated, Na2S04 dried, and concentrated. The resulting dark residue was subjected to Si02 chromatography with ethyl acetate/hexanes (4:6) to furnish a solid. !H NMR (400 MHz, d4-MeOH) δ 7.58 (app q, J = 8.2 Hz, IH), 7.30 (app dd, J = 5.1, 1.2 Hz, IH), 7.05 (d, J = 2.6 Hz, IH), 7.01 (app t, J = 8.1 Hz, 2H), 6.93 (dd, J = 5.1, 3.4 Hz, IH), 6.43 (s, IH), 5.49 (s, 2H), 5.25 (s, 2H), 2.51 (s, 3H); LC/MS C-18 column, tr = 2.74 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ESMS m/z 426 (M+H). ES-HRMS m/z 425.9936 (M+H calcd for C18H15BrF2N02S requires 425.9969).
Example 581
Figure imgf000600_0001
3-bromo-l-(2,6-difluorophenyl)-4- -furylmet oxy)-6-methylpyridin-2(lH)-one
Step 1: To a suspension of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)- 6-methylpyridin-2(lH)- one (250 mg, 0.445 mmol) and furfuryl alcohol (198 mg, 2.0 mmol) in THF (2.5 mL) was added solid NaH (46.0 mg, 1.92 mmol). Following the evolution of gas, the resulting suspension laws heated to 60 °C and stined for 3.5 hours until complete consumption of starting material by LCMS analysis. The reaction mixture was then diluted with ammonium chloride (saturated aqueous, 100 mL) and exfracted with ethyl acetate (3 X 100 mL). The resulting organic exfracts were separated, Na2S04 dried, and concentrated to provide a residue that was subjected to Si02 chromatography with ethyl acetate/hexanes (3:7) to furnish a solid (110.0 mg, 49 %). 1H NMR (400 MHz, d4- MeOH) δ 7.63 (app tt, J = 8.5, 6.2, IH), 7.62-7.61 (m, IH), 7.28 (app t, J = 8.5 Hz, 2H), 6.77 (s, IH), 6.68 (d, J = 4.1 Hz, IH), 6.51(dd, J = 4.2, 3.9 Hz, IH), 5.34 (s, 2H), 2.15 (s, 3H); LC/MS C-18 column, tr = 2.43 minutes (5 to 95% acetonitrile/water over 5 minutes
600 at 1 ml min with detection 254 nm, at 50°C). ES-MS m/z 396 (M+H). ES-HRMS m/z 396.0044 (M+H calcd for C17H13BrF2N03 requires 396.0041).
Example 582
Figure imgf000601_0001
3 -bromo- 1 - [2-fluoro-6-(3 -furylmethoxy)phenyl] -4-(3 -furylmethoxy)-6-methylpyridin- 2(lH)-one
By following the method of preparation of 3-bromo-l-(2,6-difluorophenyl)-4-(2- furylmethoxy)-6-methylρyridin-2(lH)-one (Example 581) and substituting 3- furylmethanol for furfuryl alcohol, the title compound was prepared in 55 % chemical yield. 1H NMR (400 MHz, VMeOH) δ 7.64 (s, IH), 7.55-7.42 (m, 3H), 7.40 (app t, J = 1.4 Hz, IH), 7.12 (d, J = 9.0 Hz, IH), 6.92 (app t, J = 8.4 Hz, IH), 6.58 (s, 2H), 6.34 (br s, IH), 5.21 (s, 2H), 5.03 (AB-q, J = 14.0 Hz, Δ = 58.0 Hz, 2H), 1.99 (s, 3H); LC/MS C-18 column, tr = 2.67 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m z 474 (M+H). ES-HRMS m/z 474.0346 (M+H calcd for C22H18BrFN05 requires 474.0347).
Example 583
Figure imgf000601_0002
3-bromo-l-[2-fluoro-6-(thien-3-ylmethoxy)phenyl]-6-methyl-4-(thien-3- ylmethoxy)pyridin-2(lH)-one
601 By following the method of preparation of 3-bromo- l-(2,6-difluorophenyl)-4-(2- furylmethoxy)-6-methylpyridin-2(lH)-one Example 581 and substituting thien-3- ylmethanol for furfuryl alcohol, the title compound was prepared in 38 % chemical yield. 1H NMR (400 MHz, dVMeOH) δ 7.50-7.42 (m, 3H), 7.33 (dd, J = 5.0, 3.0 Hz, IH), 7.26 (br d, J = 2.0 Hz, IH), 7.19 (dd, J = 5.0, 1.2 Hz, IH), 7.09 (d, J = 8.6 Hz, IH), 6.98 (dd, J = 14.9, 1.3 Hz, IH), 6.93 (dt, J = 8.7, 1.0 Hz, IH), 6.53 (br s, IH), 5.33 (s, 2H), 5.14 (AB-q, J = 12.1 Hz, Δ = 50.0 Hz, 2H), 1.97 (s, 3H); LC/MS C-18 column, tr = 2.93 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ESMS m/z 506 (M+H). ES-HRMS m/z 505.9881 (M+H calcd for C22H18BrFN03S2 requires 505.9890).
Example 584
Figure imgf000602_0001
methyl 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- [(methylamino)carbonyl]benzoate
Step 1: Preparation of 3-(4-hydroxy-6-methyl-2-oxopyridin-l(2H)-yl)-4- (methoxycarbonyl)benzoic acid.
Figure imgf000602_0002
- 602 4-Hydroxy-6-methyl-2-pyrone (75.0 g, 595 mmol) and 3-amino-4- (methoxycarbonyl)benzoic acid (40.0 g, 0.205 mmol) were suspended in 56 ml of 1,2- dichlorobenzene in a 500 ml, 3-necked, round bottom flask equipped with a J-Kem temperature controller probe, a Dean-Stark trap, and a heating mantle. The reaction was heated to 180 °C over a period of 26 minutes during which time all solids dissolved. Upon reaching an internal temperature of 180 °C, the reaction was allowed to maintain this temperature for an additional 25.0 minutes during which time the evolution of water from the reaction mixture was evident. Next, the heating apparatus was removed and the reaction was allowed to cool on its own accord to about 100 °C. The reaction was then diluted with 160 ml of toluene and stined. After about 10 minutes, the reaction reached room temperature and a gummy solid had formed. The precipitate was filtered, washed with EtOAc (400 mL) and water (200 mL, 55 °C), and dried in vacuo to give a tan solid (30.5 g, 49%). 1H NMR (400 MHz, d4-MeOH) δ 8.20-8.09 (m, 2H), 7.84 (s, IH), 6.08 (app d, J = 1.0 Hz, IH), 5.76 (app d, J = 2.3 Hz, IH), 3.76 (s, 3H), 1.91 (s, 3H). LC/MS, C-18 column, tr = 1.96 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml min with detection 254 nm, at 50 °C). ES-MS m/z 304 (M+H). ES-HRMS m z 304.0803 (M+H calcd for C15H14N06 requires 304.0816).
Step 2: Preparation of methyl 2-(4-hydroxy-6-methyl-2-oxopyridin-l(2H)-yl)-4- [(methylamino)carbonyl]benzoate.
Figure imgf000603_0001
To a solution of 3-(4-hydroxy-6-methyl-2-oxopyridiri-l(2H)-yl)-4- (methoxycarbonyl)benzoic acid (from Step 1) (1.00 g, 3.30 mmol) in dimethylformamide (10 mL) and THF (10 mL) was added cyclohexylcarbodiimide-derivatized silica gel (a product of Silicycle chemical division Quebec, Canada) with a loading of 0.60 mmol/g
(15.2 g, 9.73 mmol). After stirring for 30 minutes, a solution of methylamine (2.0 M, THF, 2.9 mL, 5.8 mmol) was added followed by the addition of 1-hydroxy-benzotriazole (20.0
- 603 - mg, 0.15 mmol). The reaction suspension was allowed to stir for 24 hours until the complete disappearance of starting material by LCMS analysis. The silica suspension was filtered and washed with 300 mL ethyl acetate/methanol (9:1) and 300 mL ethyl acetate/methanol (1:1). The resulting mother liquor was concentrated to furnish a brown semi-solid (898 mg, 86 %). 1H NMR (300 MHz, dj-MeOH) δ 8.22 (d, J = 8.0 Hz, IH), 8.04 (dd, J = 8.3, 1.9 Hz, IH), 7.73 (d, J = 1.6 Hz, IH), 6.13 (d, J = 1.5, Hz, IH), 5.80 (d, J = 2.2 Hz, IH), 3.80 (s, 3H), 3.03 (s, 3H), 1.97 (s, 3H). LC MS, C-18 column, tr = 1.31 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 317 (M+H). ES-HRMS m/z 317.1142 (M+H calcd for C16H17N205 requires 317.1132).
Step 3: Preparation of methyl 2-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-l(2H)-yι)-4- [(methylamino)carbonyl]benzoate.
Figure imgf000604_0001
To a room temperature suspension of methyl 2-(4-hydroxy-6-methyl-2-oxopyridin- l(2H)-yl)-4- [(methylamino)carbonyl]benzoate (from Step 2) (406.0 mg, 1.28 mmol) in CH2C12 (8 mL) was added solid N-bromosuccinimide (251 mg, 1.41 mmol) and stined for 10 minutes until complete consumption of starting material by LCMS analysis. The reaction was next diluted with CH2C12 (5 mL), ethyl acetate (5 mL), and hexanes (1 mL). After approximately 30 minutes the resulting white precipitate was filtered and washed with ethyl acetate (5 mL) to furnish a solid (298 mg, 62%). 1H NMR (400 MHz, MeOH) δ 8.20 (d, J = 8.2 Hz, IH), 8.01 (d, J = 8.1 Hz, IH), 7.69 (s, IH), 6.18 (s IH), 3.75 (s, 3H), 2.91 (s, 3H), 1.91 (s, 3H); LC/MS, tr = 1.27 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 395 (M+H). ES- HRMS m/z 395.0237 (M+H calcd for C16H16BrN205 requires 395.0237).
Step 4: Preparation of the title compound.
- 604 -
Figure imgf000605_0001
To a solution of methyl 2-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-l(2H)-yl)- 4-[(methylamino)carbonyl]benzoate (from Step 3) (241 mg, 0.610 mmol) in dimethylformamide (0.5 mL) was added sequentially K2C03 (240 mg, 1.73 mmol) and 2,4 difluorobenzyl bromide (0.085 mL, 0.66 mmol). The resulting suspension was stined for 6.5 hours until complete consumption of starting material by LCMS analysis. The reaction was then diluted with ethyl acetate (200 mL) and brine washed (3 X 200 mL). The resulting organic exfract was Na2S04 dried, filtered, and concenfrated in vacuo to approximately 5 mL volume. The resulting mother liquor rapidly precipitated and furnished an amorphous solid that was collected. 1H NMR (400 MHz, d -MeOH) δ 8.22 (d, J = 8.2 Hz, IH), 8.03 (dd, J = 8.2, 1.7 Hz, IH), 7.71 (d, J = 1.8 Hz, IH), 7.67 (app q, J = 8.3 Hz, IH), 7.05 (app t, J = 8.6 Hz, 2H), 6.64 (s, IH), 5.37 (s, 2H), 3.74 (s, 3H), 2.90 (s, 3H), 2.01 (s, 3H). LC/MS C-18 column, tr = 2.87 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m z 521 (M+H). ES- HRMS m z 521.0491 (M+H calcd for C23H20BrF2N2O5 requires 521.0518).
Example 585
605 -
Figure imgf000606_0001
3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4-(l-hydroxy- 1 -methylethyl)-N-methylbenzamide
Step 1 : To a -10 °C solution of methyl magnesium bromide (3.0 M, 0.60 mL, 1.8 mmol) was added dropwise over 10 minutes a solution of methyl 2-[3-bromo-4-[(2,4- difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -4-
[(methylamino)carbonyl]benzoate (85.0 mg, 0.163 mmol) in THF (1.0 mL). The internal temperature of the reaction was never allowed to exceed 0°C. The resulting solution was maintained for 10 minutes. Next, a solution of ammonium chloride (saturated aqueous, 100 mL) was added. The reaction mixture was removed from the bath and resulting emulsion was extracted with ethyl acetate (3 X 100 mL) and the resulting organic extracts were separated, Na2S04 dried, and concenfrated in vacuo to a residue that was subjected to Si02 chromatography with ethyl acetate/hexanes (gradient 3:7 to 6:4) to furnish a solid (16 mg, 19 %). 1H NMR (400 MHz, d4-MeOH) δ 7.89 (d, J = 8.5 Hz, IH), 7.78 (d, J = 8.4 Hz, IH), 7.61 (app q, J = 8.2 Hz, IH), 7.41 (s, IH), 7.03-6.99 (m, 2H), 6.57 (s, IH), 5.30 (s, 2H), 2.83 (s, 3H), 2.05 (s, 3H), 1.51 (s, 3H), 1.39 (s, 3H); LC/MS C-18 column, tr = 2.28 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 521 (M+H). ES-HRMS m/z 521.0860 (M+H calcd for C24H24BrF2N204 requires 521.0882).
Example 586
606
Figure imgf000607_0001
3-bromo-l-[2-fluoro-6-(thien-3-ylmethoxy)phenyl]-6-methyl-4-(thien-3- ylmethoxy)pyridin-2(lH)-one By following the method of preparation of 3 -bromo- 1 -(2,6-difluorophenyl)-4-(2- furylmethoxy)-6-methylpyridin-2(lH)-one Example 581 and substituting 4-{[3-bromo-4- [(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzamide for 3- bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluorophenyl)-6-methylpyridin-2(lH)-one, the title compound was prepared in 76 % chemical yield. 1H NMR (400 MHz, d4-MeOH) δ 7.83 (d, J = 8.1 Hz, 2H), 7.54 (app d, J = 1.1 Hz, IH), 7.19 (d, J = 8.1 Hz, 2H), 6.57 (d, J = 3.2 Hz, IH), 6.53 (s, IH), 6.43 (dd, J = 3.1, 1.8 Hz, IH), 5.45 (br s, 2H), 5.22 (s, 2H), 2.34 (s, 3H); LC/MS C-18 column, tr = 1.98 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 417 (M+H). ESHRMS m z 417.0469 (M+H calcd for C19H18BrN204 requires 417.0444).
Example 587
Figure imgf000607_0002
(-)-3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N,4- dimethylbenzamide
607 Example 489 (1.78 g, 4.36 mmol) were separated using a Chiral Technologies Chiralpak AD column (21 mm x 250 mm, 20 μm) eluting with 100% ethanol (isocratic, 20 ml/min), loading 10 mg per injection. Fractions of the early-eluting atropisomer were pooled and concentrated in vacuo to the title compound (718 mg, 80%). Analytical chiral LC (Chiralpak AD, 4.6 mm x 50 mm, lOμm particle size, 0.5 ml/min ethanol) Retention time: 1.70 min, ee 94%. [αD = -23.8° (5 mg/ml DMSO, 22 °C). 1H NMR (400 MHz, DMSO-d6) δ 8.42 (br qr, J = 4.51 Hz, IH), 7.82 (dd, J = 7.92, 1.70 Hz, IH), 7.68 (dt, J = 8.24, 6.58 Hz, IH), 7.58 (d, J = 1.59 Hz, IH), 7.48 (d, J = 7.98 Hz, IH), 7.34 (dt, J = 9.90, 2.50 Hz, IH), 7.18 (dt, J = 8.53, 2.57 Hz, IH), 6.71 (s, IH), 5.33 (s, 2H), 2.74 (s, 3H), 1.98 (s, 3H), 1.88 (s, 3H). 19F-NMR (400 MHz, DMSO-d6) δ -109.58 (quintet, J = 7.49 Hz, IF), - 113.65 (quartet, J = 9.11 Hz, IF). ES-HRMS m/z 477.0612 (M+H calcd for C22H20BrF2N2O3 requires 477.0620).
Example 588
Figure imgf000608_0001
(+)-3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N,4- dimethylbenzamide
The title compound was prepared as in Example 587, pooling the late-eluting atropisomer (722 mg, 81%). Analytical chiral LC (Chiralpak AD, 4.6 mm x 50 mm, lOμm particle size, 0.5 ml/min ethanol) Retention time: 2.00 min, ee 98%. [αp = +28.2° (5 mg/ml DMSO, 22 °C). 1H NMR (400 MHz, DMSO-d6) δ 8.42 (br qr, J = 4.51 Hz, IH), 7.82 (dd, J = 7.92, 1.70 Hz, IH), 7.68 (dt, J = 8.24, 6.58 Hz, IH), 7.58 (d, J = 1.59 Hz, IH), 7.48 (d, J = 7.98 Hz, IH), 7.34 (dt, J = 9.90, 2.50 Hz, IH), 7.18 (dt, J = 8.53, 2.57 Hz, IH), 6.71 (s, IH), 5.33 (s, 2H), 2.74 (s, 3H), 1.98 (s, 3H), 1.88 (s, 3H). 19F-NMR (400 MHz, DMSO-d6) δ -109.58 (quintet, J = 7.49 Hz, IF), -113.65 (quartet, J = 9.11 Hz, IF). ES-HRMS m/z 477.0614 (M+H calcd for C22H20BrF2N2O3 requires 477.0620). - 608 - Example 589
Figure imgf000609_0001
4- [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -3 - chlorobenzamide
Step 1: Preparation of methyl 3-chloro-4-(4-hydroxy-6-methyl-2-oxopyridin-l(2H)- yl)benzoate.
Figure imgf000609_0002
4-Hydroxy-6-methyl-2-pyrone (24.5 g, 193.9 mmol) and methyl-3-amino-2- chlorobenzoate (30 g, 161.6 mmol) were suspended in 75 ml of 1,2-dichlorobenzene in a 250 ml, 3-necked round bottom flask equipped with a J-Kem temperature controller probe, a Dean-Stark frap, and a heating mantle. The reaction was heated to 175°C for 20 minutes, during which, water and some 1,2-dichlorobenzene was collected in the Dean-Stark trap. The reaction was allowed to cool to about 110°C. At this point, 200 ml of toluene was added. The toluene mixture was allowed to stir for 72 hours at room temperature. A precipitate was collected on a filter pad. The precipitate was filtered and washed 3 times with toluene, 3 times with 50°C. water to remove excess pyrone, and dried in vacuo to give a tan solid (13.0 g, 27% yield). 1H NMR (300 MHz, CD3OD) δ 8.26 (d, J = 1.81 Hz, IH), 8.14 (dd, J = 8.26, 1.81 Hz, IH), 7.54 (d, J = 8.26, Hz, IH), 6.14(dd, J = 2.42, 1.0 Hz, IH), 5.83 (d, J = 2.42 IH), 4.00 (s, 3H), 1.96 (s, 3H); LC/MS, tr = 1.81 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 294 (M+H).
609 Step 2: Preparation of methyl 3-chloro-4-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]benzoate.
Figure imgf000610_0001
Methyl 3-chloro-4-(4-hydroxy-6-methyl-2-oxopyridin-l(2H)-yl)benzoate (from Step 1) (2.4g, 8.17 mmol) was taken up in DMF (10 ml). 2,4-difluorobenzylbromide (1.05 ml, 8.17 mmol) and K2C03 (1.13 g, 8.17 mmol) were added. The reaction stined for 6 hours at room temperature. At this time, the reaction was poured into water (200 ml) and extracted with ethyl acetate. The ethyl acetate layer was dried over Na2S04, filtered, and the solvent removed in vacuo to give amber oil (2.62 g, 77% crude yield). LC/MS, tr = 2.79 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m z 294 (M+H).
Step 3: Preparation of methyl 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]-3-chlorobenzoate.
Figure imgf000610_0002
Methyl 3 -chloro-4- [4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)- yl]benzoate (from step 2) (2.60g, 6.21 mmol) was taken up in CH2C12 (20 ml). N- bromosuccinimide (1.1 lg, 6.21 mmol) was added and the mixture stined at room temperature for 4 hours. The CH2C12 is removed in vacuo and the residue is taken up in CH3CN. The resulting precipitate is collected on a filter pad and washed with CH3CN to yield a white solid (0.75 g, 24%). 1H NMR (300 MHz, CDC13) δ 8.22 (d, J = 1.88 Hz, IH), 8.06 (dd, J = 8.19, 1.75 Hz, IH), 7.59 (app q, J = 8.46 Hz, IH), 7.33 (d, J = 8.19, IH), 6.96 (dt, J = 8.06, 1.21 Hz, IH), 6.89 - 6.84 (m, IH), 6.13 (s, IH), 5.26 (s, 2H), 3.95 (s,
610 3H), 1.95 (s, 3H); ES-MS m/z 478 (M+H). ES-HRMS m/z 497.9892 (M+H calcd for C22H16BrClF2N04 requires 497.9914).
Step 4: Preparation of 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]-3-chlorobenzoic acid.
Figure imgf000611_0001
Methyl-4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]- 3-chlorobenzoate (2.30g, 4.61 mmol) was taken up in THF (20 ml) and H20 (4 ml). 2.5 N NAOH (9.2 ml) was added to the vessel and the reaction stined overnight to completion. Concenfrated HCl was added dropwise until reaction was made acidic (pH = 1). H20 (100 ml) and THF (100 ml) were added to the mixture. The contents were poured into a separatory funnel and the aqueous layer was exfracted with ethyl acetate. The organic layer was dried over Na2S04, the solvent removed in vacuo, and the residue was taken up in a 50% mixture of ethyl acetate/hexane. The precipitate was collected on a filter pad to yield a white powder (1.5g, 67%). 1H NMR (300 MHz, DMSO) δ 13.59 (IH), 8.16 (d, J = 1.81 Hz, IH), 8.06 (dd, J = 6.24, 1.81 Hz, IH), 7.73 (app q, J = 8.46, IH), 7.68 (d, J = 8.26 Hz, IH), 7.38 (dt, J = 9.48, 2.62 Hz, IH) 7.26 - 7.18 (hi, IH), 6.80 (s, IH), 5.39 (s, 2H), 3.93 (s, 3H), 1.96 (s, 3H); ES-MS m/z 483 (M+H). ES-HRMS m/z 483.9749 (M+H calcd for C20H14BrClF2NO4 requires 483.9757).
Step 5: 4-[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3- chlorobenzoic acid (0.5 g, 1.03 mmol) was taken up in THF (10 ml). 2-Chloro-4,6- dimethoxy-l,3,5-triazine (0.22 g, 1.24 mmol) and N-methyl morpholine (0.34 ml, 3.09 mmol) were added. The mixture stined at room temperature for 1 hour. At this time, NH4OH (2.5 ml) was added and the reaction stined at room temperature for one more hour. To the reaction mixture was added more THF (50 ml) and water (200 ml). The mixture was extracted with ethyl acetate. The ethyl acetate extraction was washed with saturated brine solution. The brine layer was extracted with ethyl acetate. The organic - 611 - layers were combined, dried over Na2S04, filtered and the solvent was removed in vacuo. The residue was taken up in ethyl acetate and the resulting precipitate was collected on a filter pad to yield a white powder (0.38 g, 76%) 1H NMR (300 MHz, CD3OD) δ 8.18 (d, J = 1.81 Hz, IH), 8.02 (dd, J = 8.26, 2.01 Hz, IH), 7.69 (app q, J = 8.26 Hz, IH), 7.55 (d, J = 8.06 Hz, 1 H) 7.12 - 7.06 (m, 2H), 6.71 (s, IH), 5.40 (s, 2H), 2.07 (s, 3H). ES-MS m/z 482 (M+H). ES-HRMS m/z 482.9919 (M+H calcd for C20H15BrClF2N2O3 requires 482.9917).
Example 590
Figure imgf000612_0001
3 - [3 -chloro-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (H)-yl] -4- methylbenzamide
Stepl : Preparation of 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl] -4-methylbenzoic acid.
Figure imgf000612_0002
3-[4-[(2,4-Difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoic acid (from above) (7.5g,19.4 mmol) and NCS (2.6 g, 19.4 mmol) were taken up in 65°C dichloroethane (100 ml). A catalytic amount of dichloroacetic acid (2 drops) was added. After two hours the solvent was removed in vacuo and the residue was taken up in diethyl ether. The precipitate was collected on a filter pad and then taken up in 50% ethyl acetate/hexanes to remove residual succinimide. The precipitate was collected on a filter pad and then dried in vacuo to produce a white powder (4.2 g, 52%). 1H NMR (300 MHz, - 612 - CD3OD) δ 8.10 (dd, J = 7.85, 1.81 Hz, IH), 7.83 (d, J = 8.26, 1.81 Hz, IH), 7.40 (app q, J = 8.26 Hz, IH), 7.58 (d, J = 7.85 Hz, IH), 7.13 - 7.06 (m, 2H), 6.74 (s, IH), 5.40 (s, 2H), 2.14 (s, 3H), 2.04 (s, 3H); ES-MS m z 420 (M+H). ES-HRMS m/z 420.0786 (M+H calcd for C21H17C1F2N04 requires 420.0809).
Step 2: 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylbenzoic acid (1.5g, 3.57 mmol) was taken up in THF (30 ml). 2-Chloro-4,6- dimethoxy-l,3,5-triazine (0.75 g, 4.28 mmol) and N-methyl morpholine (1.18 ml, 10.72 mmol) were added. The mixture stined at room temperature for 1 hour. At this time, NH4OH (7.5 ml) was added and the reaction stined at room temperature for one more hour. To the reaction mixture was added more THF (100 ml) and water (150 ml). The mixture was exfracted with ethyl acetate. The ethyl acetate extraction was washed with saturated brine solution. The brine layer was exfracted with ethyl acetate. The organic layers were combined, dried over Na2S04, filtered and the solvent was removed in vacuo. The residue was taken up in ethyl acetate and the resulting precipitate was collected on a filter pad to yield a white powder (1.32 g, 88%) 1H NMR (300 MHz, CD3OD) δ 7.96 (dd, J = 7.85, 1.81 Hz, IH), 7.71 (d, J = 1.81 Hz, IH), 7.67 (app q, J = 8.06 Hz, IH), 7.56 (d, J = 8.06 Hz, IH), 7.12 - 7.06 (m, 2H), 6.74 (s, IH), 5.40 (s, 2H), 2.13 (s, 3H) 2.05 (s, 3H). ES-MS m/z 419 (M+H). ES-HRMS m/z 419.0979 (M+H calcd for C21H18C1F2N203 requires 419.0969).
Example 591
Figure imgf000613_0001
3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N,4- dimethylbenzamide
613 The title compound was prepared from 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoic acid (from step 1 above) (1.5 g, 3.57 mmol) in dichloromethane (35 ml). To this mixture, 2.0 M methyl amine in THF (3.6 ml, 7.14 mmol) was added, followed, in order, by EDCI (0.67 g, 4.28 mmol), 1- hydroxybenzotriazole (0.58 g, 4.28 mmol) and triethylamine (0.99 ml, 7.14 mmol). The reaction was stined at room temperature overnight. The reaction was quenched with NH4C1 and extracted 3 times with ethyl acetate. The combined organic layer was then washed with saturated NaHC0 (aq.) and exfracted 3 times with ethyl acetate. The organic layers were combined and washed with H 0 and exfracted 3 times with ethyl acetate. The organic layers were combined and dried over Na2S04 and evaporated. The resulting residue was triturated with diethyl ether/hexane to obtain a solid, which was dried in vacuo to give a white solid (1.5g, 72%). 1H NMR (300 MHz, CD3OD) δ 7.90 (dd, J = 8.06, 1.81 Hz, IH), 7.67 (app q, J = 6.44 Hz, IH), 7.55 (d, J = 8.06 Hz, IH), 7.13 - 7.06 (m, 2H), 6.74 (s, IH), 5.40 (s, 2H), 2.93 (s, 3H), 2.13 (s, 3H), 2.04 (s, 3H); ES-MS m/z 433 (M+H). ES-HRMS m/z 433.1153 (M+H calcd for C22H20ClF2N2O3 requires 433.1125).
Example 592
Figure imgf000614_0001
N-{3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxoρyridin-l(2H)-yl]-4- fluorobenzyl} propanamide
A 10 mL round bottomed flask equipped with stirbar and nifrogen inlet was charged with l-[5-(aminomethyl)-2-fluorophenyl]-3-chloro-4-[(2,4 difluorobenzyl)oxy]-6- methylpyridin-2(lH)-one hydrochloride (250 mg, 0.56 mmol), propionyl chloride (49 μL, 0.56 mmol), triethylamine (195 μL, 1.4 mmol) and tetrahydrofuran (4.0 mL). After - 614 - stirring at 25° C for 5 min the reaction was completed by LC-MS. The reaction mixture was poured into a saturated aqueous NH4C1 solution. The aqueous mixture was extracted with ethyl acetate. The organic phase was dried with Na2S04 and concenfrated in vacuo to obtain the title compound (240 mg, 91%) as a yellow solid. 1H NMR (400 MHz, (CD3)2SO) δ 8.3 (t, J = 5.8 Hz, IH), 7.6 (q, J = 8.7 and 6.58 Hz, IH), 7.38 (d, J = 7.78 Hz, IH), 7.3 (dd, J = 2.6 and 7.6 Hz, IH), 7.22 (d, J = 7.51 Hz, IH), 7.12 (td, J = 2.0 and 6.5 Hz, IH), 6.65 (s, IH), 5.3 (s, 2H), 4.23 (d, J = 3.6 Hz, 2H), 2.1 (q, J = 7.7 Hz 2H), 1.98 (s, 3H), 0.98 (t, J = 7.5 Hz, 3H) ppm. ES-HRMS m/z 465.1203 (M+H calcd for C23H21C1F3N203 requires 465.1187).
Example 593
Figure imgf000615_0001
N-{3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- fluorobenzyl} dimethylurea
A 10 mL round bottomed flask equipped with stirbar and nifrogen inlet was charged with l-[5-(aminomethyl)-2-fluorophenyl]-3-chloro-4-[(2,4 difluorobenzyl)oxy]-6- methylpyridin-2(lH)-one hydrochloride (250 mg, 0.56 mmol), dimethylcarbamyl chloride (52 μL, 0.56 mmol), triethylamine (195 μL, 1.4 mmol) and tetrahydrofuran (4.0 mL). After stirring at 25° C for 5 min the reaction was completed by LC-MS. The reaction mixture was poured into a saturated aqueous NH4C1 solution. The aqueous mixture was exfracted with ethyl acetate. The organic phase was dried with Na2S04 and concentrated in vacuo to obtain the desired product (245 mg, 86%) as a white solid. 1H NMR (400 MHz, (CD3OD) δ 7.61 (q, J = 7.9 and 6.7 Hz, IH), 7.4(m, IH), 7.3 (d, J = 9.3 Hz, IH), 7.21 (m, IH), 7.1 (m, 2H), 6.65 (s, IH), 5.35 (s, 2H), 4.38 (s, 2H), 2.9 (s, 6H), 2.1 (s, 3H) ppm. ESHRMS m z 480.1269 (M+H calcd for C23H22C1F3N303 requires 480.1296). - 615 - Example 594
Figure imgf000616_0001
N-{3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- fluorobenzyl}-2-hydroxyacetamide
A 10 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with l-[5-(aminomethyl)-2-fluorophenyl]-3-chloro-4-[(2,4 difluorobenzyl)oxy]-6- methylpyridin-2(lH)-one hydrochloride (250 mg, 0.56 mmol), acetoxyacetyl chloride (66 μL, 0.62 mmol), triethylamine (195 μL, 1.4 mmol) and tetrahydrofuran (4.0 mL). After stirring at 25° C for 5 min the reaction was completed by LC-MS. NaOH (2.5M, 2.24 mmol, 1.0 mL) and MeOH (2.0mL) was added and stined for 10 min to give the title compound. The reaction mixture was acidified with concenfrated HCl and exfracted with ethyl. The organic phase was dried with Na2S04 and concentrated in vacuo to obtain the title compound (217 mg, 78%) of the desired product as a yellow solid. lR NMR (400 MHz, (CD3OD) δ 7.6 (q, J = 7.6 and 6.9 Hz, IH), 7.44 (m, IH), 7.34 (m, 2H), 7.22 (m, 2H), 6.63 (s, IH), 5.35 (s, 2H), 4.41 (s, 2H), 4.0 (s, 2H), 2.05 (s, 3H) ppm. ES-HRMS m/z 467.0957 (M+H calcd for C22H19C1F3N204 requires 467.0980).
616 Example 595
Figure imgf000617_0001
N-{3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- fluorobenzyl} -2-hydroxy-2-methylpropanamide
The title compound was prepared essentially as described in Example 594, with 1- chlorocarbonyl-1-methylethyl acetate substituting acetoxyacetyl chloride 1H NMR (400 MHz, (CDC13) δ 9.9 (q, J = 8.2 and 6.5 Hz, IH), 9.7 (t, J = 2.6 Hz, IH), 9.5 (t, J = 8.9 Hz, 2H), 9.3 (m, IH), 9.2 (m, IH), 8.6 (s, IH) 7.6 (s, 2H), 6.8 (d, J = 15 Hz, IH), 6.63 (d, J = 15 Hz, IH), 4.42 (d, J = 3.2 Hz, 6H), 3.99 (s, 3H) ppm. ES-HRMS m/z 495.1271 (M+H calcd for C24H23C1F3N204 requires 495.1293).
Example 596
Figure imgf000617_0002
N1-{3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- fluorobenzyl} glycinamide hydrochloride
A 25 mL round bottomed flask equipped with stirbar and nifrogen inlet was charged with boc-glycine (105 mg, 0.6 mmol) and 8 mL of DMF. The mixture was cooled - 617 - to 0° C and isboutylchloroformate (77.5 μL, 0.6 mmol) was added and stined for 20 min. l-[5-(aminomethyl)-2-fluorophenyl]-3-chloro-4-[(2,4 difluorobenzyl)oxy]-6- methylρyridin-2(lH)-one hydrochloride (250 mg, 0.6 mmol) was added and stined for 3h. After completion of the reaction by LC-MS, concentrated HCl (2 mL) and 2 mL of methanol was added to remove the boc group. The reaction was stined for 24 h, neutralized with 2M NaOH and exfracted with ethyl acetate. The organic phase was dried with a2S04 and concentrated in vacuo to obtain the desired product (196 mg, 66%) as an HCl salt. 1H NMR (400 MHz, (CD3OD) δ 7.6 (q, J = 8 and 6.5 Hz, IH), 7.5 ( , IH), 7.3 (m, 2H), 7.0 (m, 2H), 6.63 (s, IH), 5.35 (s, 2H), 4.4 (q, J = 15 and 13.6 Hz, 2H), 3.7 (s, 2H), 2.05 (s, 3H) ppm. ES-HRMS m z 466.1157 (M+H calcd for C22H20ClF3N3O3 requires 466.1140).
Example 597
Figure imgf000618_0001
3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- fluorobenzamide
A 250 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- fluorobenzoic acid (3.65g, 7.8 mmol), 4-methylmorpholine (2.6 mL, 23.4 mmol), 2- chloro-4,6-dimethoxy-l,3,5-triazine (1.64g, 9.36 mmol) and tetrahydrofuran (40 mL). After stirring the mixture for 30 min at 25° C, NH OH (20.0 mL) was added. The mixture was stined for 30 min and diluted with water. The product precipitated from solution. The precipitated was filtered and washed with water and diethyl ether to give the title compound (2.37g, 65%) as a white solid. 1H NMR (400 MHz, (CD3)2SO) δ 7.9 (d, J = 7.3 Hz, IH), 7.61 (q, J = 8.6 and 6.7 Hz, IH), 7.5 (m, 2H), 7.3 (t, J = 9.6 Hz, IH), 7.15 (t, J = - 618 - 8.7 Hz, IH), 6.7 (s, IH), 5.36 (s, 2H), 2 (s, 3H) ppm. ES-HRMS m/z 469.0172 (M+H calcd for C20H15BrF3N2O3 requires 469.0195).
Example 598
Figure imgf000619_0001
3 - [3 -bromo-4-[(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -4-fluoro-N- methylbenzamide
A solution of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]-4-fluorobenzoic acid (1 g, 2.1 mmol) in N,N-dimethylformamide (20 mL) was cooled to -10 C. Isobutyl chloroformate (0.27 mL, 2.1 mmol) and N-methyl morpholine (0.23 mL, 2.1 mmol) were added to the reaction vessel. After stirring at -10 C for 20 minutes, a solution of N-methyl amine (2.1 mL, 4.2 mmol, 2 M in THF) was added and the reaction mixture was warmed to room temperature as it stined for 18 hours. The reaction mixture was concentrated in vacuo, suspended in water, filtered and washed with water, ethyl acetate and diethyl ether. 1H NMR (400 MHz, CD3OD) δ 8.03 (dddd, J = 3.0, 6.4, 9.2 and 11.6 Hz, IH), 7.81 (dd, J = 3.0 and (.2 Hz, IH), 7.66 (q, J = 10.4 Hz, IH), 7.47 (t, J = 12 Hz, IH), 7.06 (t, J = 12 Hz, 2H), 6.67 (s, IH), 5.38 (s, 2H), 2.91 (s, 3H), 2.10 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) δ -111.50 (IF), -115.97 (1 F), -120.16 ppm. ES-HRMS m/z 481.0346 (M+H calcd for C21H17BrF3N203 requires 481.0369).
Example 599
619 -
Figure imgf000620_0001
3 - [3 -bromo-4-[(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -4-fluoro-N,N- dimethylbenzamide A solution of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]-4-fluorobenzoic acid (1 g, 2.1 mmol) in N,N-dimethylformamide (20 mL) was cooled to -10 C. Isobutyl chloroformate (0.27 mL, 2.1 mmol) and N-methyl morpholine (0.23 mL, 2.1 mmol) were added to the reaction vessel. After stirring at -10 C for 20 minutes, a solution of N-methyl amine (2.1 mL, 4.2 mmol, 2 M in THF) was added and the reaction mixture was warmed to room temperature as it stined for 18 hours. The reaction mixture was concentrated in vacuo and partitioned between water and ethyl acetate. The organic layer was washed with brine and concentrated in vacuo. The solid was chromatographed on silica (95:5 methylene chloride : isopropyl alcohol) to give the desired product as a white powder (0.31 g, 30 %). 1H NMR (400 MHz, CD3OD) δ 7.64 (m, IH), 7.50 (dd, J = 2.4 and 7.2 Hz, IH), 7.45 (t, J = 9.6 Hz, IH), 7.04 (t, J = 9.2 Hz, 2H), 6.65 (s, IH), 5.36 (s, 2H), 3.09 (s, 3H), 3.05 (s, 3H), 2.10 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) δ -111.51 (IF), -115.88 (1 F), -121.90 (IF) ppm. ES-HRMS m/z 495.0508 (M+H calcd for C22H19BrF3N203 requires 495.0526).
620 Example 600
Figure imgf000621_0001
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{2-fluoro-5-[(4-methylpiperazin-l- yl)carbonyl]phenyl}-6-methylpyridin-2(lH)-one
Step 1 Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{2-fluoro-5-[(4- methylpiperazin- 1 -yl)carbonyl]phenyl} -6-methylpyridin-2( 1 H)-one
Figure imgf000621_0002
To a reaction vessel (borosilicate culture tube) was added 3-[3-bromo-4-[(2,4- difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4-fluorobenzoic acid (0.300 g, 0.623 mmol) and 1-hydroxybenzotriazole (0.042 g, 0.45 mmol). N,N- Dimethylformamide (3 mL) was added to the reaction vessel followed by approximately 1.1 g of the polymer bound carbodiimide resin (1.38 mmol/g). Additional N,N- dimethylformamide (2 mL) was then added to the reaction vessel. The parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 15 minutes. N-Methyl amine (1 mL, 2 mmol) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature overnight. At this time the reaction was diluted with tetrahydrofuran (20 mL) and freated with approximately 2.0 g of polyamine resin (2.63 mmol/g) and approximately 2.5 g of methylisocyanate functionalized polystyrene (1.5 mmol/g) and the orbital shaking
- 621 - was continued at 200 RPM at room temperature for 3 hours. The reaction vessel was then opened and the solution phase product was separated from the insoluble quenched byproducts by filtration and collection into a vial. After partially evaporation the insoluble byproducts were rinsed with tetrahydrofuran (2 x 10 mL). The filfrate was evaporated by blowing N2 over the vial and the resulting solid was triturated with diethyl ether to give an off-white solid. (0.14g, 41%)
1H NMR (400 MHz, CD3OD) δ 7.63 (m, IH), 7.51 (dd, J = 2.2 and 7.2 Hz, IH), 7.45 (t, J = 8.4 Hz, IH), 7.03 (m, 2H), 6.65 (s, IH), 5.34 (s, 2H), 3.74 (s, 2H), 3.51 (s, 2H), 2.80 (s, 4H), 2.08 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) δ -111.31 (IF), -115.72 (1 F), - 121.41 (1 F) ppm. ES-HRMS m z 550.0946 (M+H calcd for C25H24C1F3N303 requires 550.0948).
Example 601-603
Figure imgf000622_0001
By following the method of Example 600 and replacing N-methylamine with the appropriate amine, the compounds of Examples 601-603 are prepared.
Figure imgf000622_0002
622 Example 604
Figure imgf000623_0001
methyl 4- [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -3 - fluorobenzoate
Step 1 Preparation of 4-amino-3-fluorobenzoic acid
Figure imgf000623_0002
3-Fluoro-4-aminobenzoic acid was prepared as described in the literature. (Schmelkes, F.C.; Rubin, M. J. Am. Chem. Soc. 1944, 66, 1631-2.) I
Step 2 Preparation of methyl 4-amino-3-fluorobenzoate
Figure imgf000623_0003
A 250 mL 3-necked round bottomed flask equipped with a nitrogen inlet, stirbar, addition funnel and thermocouple was charged with 4-amino-3-fluorobenzoic acid (11.8 g, 76 mol) and methanol (100 mL). The system was cooled to 0 C and acetyl choride (7.6 mL, 107 mol) was added dropwise. The system was warmed to room temperature, the addition funnel was replaced with a reflux condensor, and was heated to reflux for 6 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous NaHC03, and extracted with ethyl acetate. The organic extract was washed with brine and concentrated in vacuo to give methyl methyl 4-amino-3-fluorobenzoate as an tan solid (8.2
623 g, 64%). 1H NMR (400 MHz, CD3OD) δ 7.56 (dd, J = 1.6 and 8.0 Hz, IH), 7.52 (dd, J = 1.9 and 12 Hz, IH), 6.76 (t, J = 8.4 Hz, IH), 3.81 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ -139.05 (IF) ppm. ES-HRMS m/z 170.0565 (M+H calcd for C8H9FN02 requires 170.0612).
Step 3 Preparation of methyl 3-fluoro-4-(4-hydroxy-6-methyl-2-oxopyridin-l(2H)- yl)benzoate
Figure imgf000624_0001
A 250 mL round bottomed flask equipped with stirbar, Dean-Stark frap and reflux condensor was charged with the product of Step 2 (8 g, 47.3 mmol), 4-hydroxy-6-methyl- 2-pyrone (12 g, 84.6 mmol), and N-methyl-2-pyrrolidine (8 mL). The system was immersed in a 150 C oil bath for 2 hours and was then cooled to room temperature. The reaction mixture was washed with aqueous K2C03 (8.5 g, 200 mL water). The aqueous layer was washed with ethyl acetate and then was acidified to pH 4-5 with glacial HO Ac. This was exfracted with ethyl acetate, which was then concenfrated in vacuo. The viscous oil was triturated with acetonitrile and filtered to the title compound as a tan solid (2.3 g, 17%). 1H NMR (400 MHz, CD3OD) δ 7.98 (dd, J = 1.8 and 8.0 Hz, IH), 7.91 (dd, J = 1.7 and 10 Hz, IH), 7.46 (t, J = 8Hz, IH), 6.09 (dd, J = 0.9 and 2.4 Hz, IH), 5.77 (d, J = 2.7 Hz, IH), 3.94 (s, 3H), 1.97 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) δ -123.00 (IF) ppm. ES-HRMS m/z 278.0781 (M+H calcd for C14H13FN04 requires 278.0823).
Step 4 Preparation of methyl 4-[4-[(2,4-difluoroberιzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl] -3 -fluorobenzoate
624
Figure imgf000625_0001
A 100 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with the product of Step 4 (2.3 g, 8.3 mmol) and N,N-dimethyl formamide (20 mL). l,8-diazabicyclo[5.4.0]undec-7-ene (1.4 mL, 9.1 mmol) was added followed by 2,4- difluorobenzyl bromide (1.2 mL, 9.1 mmol). The reaction mixture was stined at 60 C for 3 h, was poured into saturated aqueous NaHC03 and was exfracted with ethyl acetate. The organic layer was washed with brine and concentrated in vacuo. The solid was triturated with acetonitrile and filtered to give the title compound (2.15 g, 64%). 1H NMR (400 MHz, CD3OD) δ 7.99 (dd, J = 1.7 and 8.4 Hz, IH), 7.93 (dd, J = 1.8 and 10.4 Hz, IH), 7.55 (m, IH), 7.48 (t, J = 6.8 Hz, IH), 7.02 (m, 2H), 6.18 (dd, J = 1.3 and 2.76 Hz, IH), 6.02 (d, J = 2.7 Hz, IH), 5.14 (s, 2H), 3.94 (s, 3H), 1.98 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) δ -111.34 (IF), -115.97 (1 F), -122.98 (1 F) ppm. ES-HRMS m/z 404.1133 (M+H calcd for C21H17F3N04 requires 404.1104).
Step 5 Preparation of methyl 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl] -3 -fluorobenzoate
Figure imgf000625_0002
A 100 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with the product of Step 4 (2.15 g, 5.3 mmol) and N-methyl-2-pynolidine (15 mL). After cooling to 0 C, a solution of N-bromo succinimide (1.03 g, 5.8 mmol) in 10 mL of N-
- 625 - methyl-2-pynolidine was added over 15 minutes. After 15 additional minutes, the reaction mixture was warmed to room temperature and was stined for 1 hour. The mixture was then poured into saturated aqueous NaHC03 and extracted with ethyl acetate. The organic layer was washed with brine and concentrated in vacuo. The residue was triturated with acetonitrile and filtered to give the title compound as a white powder (1.5 g, 59%). 1H NMR (400 MHz, CD3OD) δ 8.00 (dd, J = 2.0 and 8.4 Hz, IH), 7.95 (dd, J = 1.7 and 10 Hz, IH), 7.64 (q, J = 8.8 and 14.4 Hz, IH), 7.51 (t, J = 7.6 Hz, IH), 7.04 (t, J = 8.4 Hz, 2H), 6.66 (s, IH), 5.36 (s, 2H), 3.95 (s, 3H), 2.01 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) δ -111.50 (IF), -115.97 (1 F), -123.01 (1 F) ppm. ES-HRMS m/z 484.0169 (M+H calcd for C21H16BrF3N04 requires 484.0192).
Example 605
4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzoic acid.
Preparation of 4- {[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]methyl}benzoic acid. Methyl-4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]methyl} benzoate (30.4 g, 70.1 mmol) was suspended in methanol (150 mL) and dioxane (150 mL). 2.5N NaOH (30.8 mL, 77.08 mmol) was added. The resulting mixture was heated to 50 °C for 8.0 hours. The reaction was partially concentrated and the heterogenous mixture was acidified (pH 2) with IN HCl. The precipitate was collected by filtration washing with H20 and diethyl ether to afford a white solid (29.2 g, 99 %). 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 8.3 Hz, 2H), 7.63 (app q, J = 7.9 Hz, IH), 7.31 (dt, J = 2.4, 9.9 Hz, IH), 7.18 (app d, J = 8.3 Hz, 2H), 7.17-7.12 (m, IH), 6.60 (s, IH), 5.35 (s, 2H), 5.27 (s, 2H), 2.28 (s, 3H). ES-HRMS m/z 420.0821 (M+H calcd for C21H17C1F2N04 requires 420.0809). - 626 - Example 606
Figure imgf000627_0001
4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzamide
Preparation of 4- {[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl]methyl}benzamide. 4- {[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]methyl}benzoic acid (12.0 g, 28.58 mmol) was suspended in tetrahydrofuran (100 mL). 2-Chloro-4,6-dimethoxy-l,3,5-triazine (6.02 g, 34.3 mmol) was added followed by 4-methylmorpholine (9.43 mL, 85.74 mmol). The resulting mixture was stined at room temperature for 1.5 hours at which time NH OH (50.0 mL) was added. The resulting mixture was stined at room temperature for 1 hour and then partially concentrated. The precipitate was collected by filtration washing with H20 and diethyl ether to provide an off-white solid (12.11 g, >100 %). 1H NMR (400 MHz,
DMSO-d6) δ 7.91 (br s, IH), 7.80 (d, J = 8.3 Hz, 2H), 7.63 (app q, J = 7.9 Hz, IH), 7.31 (dt, J = 2.6, 10.5 Hz, IH), 7.17-7.12 (m, IH), 7.13 (app d, J = 8.3 Hz, 2H), 6.59 (s, IH), 5.32 (s, 2H), 5.27 (s, 2H), 2.28 (s, 3H). ES-HRMS m/z 419.0968 (M+H calcd for C21H18C1F2N203 requires 419.0969).
627 Example 607
Figure imgf000628_0001
4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-N,N- dimethylbenzamide
Preparation of 4- { [3 -chloro-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)- yljmethyl} }-N,N-dimethylbenzamide. 4- {[3 -chloro-4- [(2,4-difluorobenzyl)oxy] -6- methyl-2-oxopyridin-l(2H)-yl]methyl}benzoic acid (2.00 g, 4.76 mmol) was suspended in N,N-dimethylformamide (20 mL). 1 -Hydroxybenzotriazole (0.773 g, 5.72 mmol) was added followed by 4-methylmorpholine (1.57mL, 14.28 mmol), dimethylamine (7.14 mL, 2.0 M in tetrahydrofuran, 14.28 mmol) and then l-[3-(dimethylamino)propyl]-3- ethylcarbodiimide hydrochloride (1.28 g, 6.66 mmol). The resulting mixture was stined at room temperature for 3 hours at which time the reaction was diluted with H20 (75 mL). The reaction mixture was then exfracted with ethyl acetate. The combined organic extracts were washed with saturated NaHC03, brine, dried over Na2S04, filtered and concenfrated. The resulting solid was washed with ethyl acetate to provide the title compound as a white solid (1.67 g, 78%). 1H NMR (400 MHz, CDC13) δ 7.53 (app q, J = 7.8 Hz, IH), 7.33 (d, J = 8.3 Hz, 2H), 7.16 (d, J = 8.3 Hz, 2H), 6.95-6.90 (m, IH), 6.84 (app dt, J = 2.5, 9.4 Hz, IH), 6.02 (s, IH), 5.35 (s, 2H), 5.19 (s, 2H), 2.97-2.93 (br m, 6H), 2.26 (s, 3H). ES-HRMS m/z 447.1246 (M+H calcd for C23H22C1F2N203 requires 447.1282).
628 - Example 608
Figure imgf000629_0001
4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-N-(2- hydroxy-2-methylpropyl)benzamide
Preparation of 4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yljmethyl} -N-(2-hydroxy-2-methylpropyl)benzamide. 4- {[3-chloro-4-[(2,4- difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}benzoic acid (2.00 g, 4.76 mmol) was suspended in N,N-dimethylformamide (10 mL). 1 -Hydroxybenzotriazole (0.772 g, 5.71 mmol) was added followed by 4-methylmorpholine (1.57mL, 14.28 mmol), l-amino-2-methyl-2-propanol hydrochloride (1.49 g, 11.90 mmol) and then l-[3- (dimethylamino)proρyl]-3-ethylcarbodiimide hydrochloride (1.28 g, 6.66 mmol). The resulting mixture was stined at room temperature for 2 days at which time the reaction was diluted with H20 (50 mL). The reaction mixture was then exfracted with ethyl acetate. The combined organic extracts were washed with saturated NaHC03, brine, dried over Na2S04, filtered and concenfrated. The resulting solid was washed with diethyl ether to provide the title compound as a tan solid (2.08 g, 89%). 1H NMR (400 MHz, CDC13) δ 7.72 (d, J = 8.2 Hz, 2H), 7.51 (app q, J = 7.7 Hz, IH), 7.25-7.21 (m, IH), 7.10 (d, J = 8.2 Hz, 2H), 6.93 (app dt, J = 1.6, 8.3, 9.4 Hz, IH), 6.87-6.82 (m, IH), 6.01 (s, IH), 5.32 (s, 2H), 5.19 (s, 2H), 3.42 (d, J = 5.9 Hz, 2H), 2.26 (s, 3H), 1.23 (s, 6H). ES-HRMS m/z 491.1522 (M+H calcd for C25H26C1F2N20 requires 491.1544).
629 Example 609
Figure imgf000630_0001
N-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]benzyl}-2- hydroxyacetamide.
Step 1. Preparation of l-[4-(aminomethyl)phenyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]- 6-methylpyridin-2(lH)-one.
Figure imgf000630_0002
Example 244 (0.250 g, 0.556 mmol) was suspended in tetrahydrofuran (2.0 mL) and cooled in an ice-bath. Borane dimethyl sulfide (0.500 mL, 2.0 M in tefrahydrofuran, 1.00 mmol) was added. The resulting mixture was heated to reflux overnight and then cooled in an ice-bath. The reaction was quenched by the addition of 6.0 N HCl (5.0 mL) then washed with ethyl acetate. The aqueous layer was made alkaline with 2.5 N NaOH and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na S04, filtered and concenfrated to provide an off-white solid (0.180 g, 74 %). 1H NMR (400 MHz, CDC13) δ 7.58 (app q, J = 7.8 Hz, IH), 7.44 (app d, J = 8.2 Hz, 2H), 7.10 (d, J = 8.2 Hz, 2H), 6.95 (app dt, J = 1.5, 8.5 Hz, IH), 6.88-6.83 (m, IH), 6.06 (s, IH), 5.24 (s, 2H), 3.93 (s, 2H), 1.96 (s, 3H).
Step 2. Preparation of 2-({4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]benzyl} amino)-2-oxoethyl.
- 630
Figure imgf000631_0001
Acetoxyacetic acid (0.037 g, 0.310 mmol) was dissolved in dichloromethane (2.0 mL). 1-hydroxybenzotriazole (0.021 g, 0.155 mmol) was added followed by 3-(l- cyclohexylcarbodiimide)propyl-functionalized silica gel (1.00 g, 0.620 mmol, loading = 0.64 mmol/g). After stining at room temperature for 15 minutes, l-[4-
(aminomethyl)phenyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one
(Step 1) (0.180 g, 0.310 mmol) in dichloromethane (2.0 mL) was added. The resulting mixture was stined at room temperature overnight, at which time the reaction mixture wasfiltered and concenfrated. Chromatography (silica gel, hexanes/ethyl acetate with 10% methanol) provided a white solid (0.130 g, 78%). 1H NMR (400 MHz, CDC13) δ 7.58
(app q, J = 7.8 Hz, IH), 7.33 (d, J = 8.3 Hz, 2H), 7.05 (app d, J = 8.3 Hz, 2H), 6.97-6.92
(m, IH), 6.88-6.83 (m, IH), 6.08 (s, IH), 5.24 (s, 2H), 4.58 (s, 2H), 4.44 (d, J = 6.0 Hz,
2H), 2.13 (s, 3H), 1.95 (s, 3H).
Step 3. Preparation of N-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-1 (2H)-yl]benzyl) -2-hydroxyacetamide. 2-( {4-[3-bromo-4-[(2,4- difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]benzyl} amino)-2-oxoethyl (Step 2) (0.130 g, 0.243 mmol) was dissolved in methanol (5 mL) and H20 (1 mL). K2C03 (0.055 g, 0.398 mmol) was added and the resulting mixture was stined at room temperature for 2 hours. The mixture was then concenfrated and the residue was partitioned between H20 and ethyl acetate. The organic layer was removed and the aqueous layer was further extracted with ethyl acetate. The combined organic layer were washed with brine, dried over Na2S04, filtered and concentrated to provide an off-white solid (0.100 g, 84%). 1H NMR (400 MHz, CDC13) δ 7.56 (app q, J = 7.7 Hz, IH), 7.43 (t, J = 5.8 Hz, IH), 7.33 (d, J = 8.2 Hz, 2H), 7.04 (app d, J = 8.3 Hz, 2H), 6.98-6.93 (m, IH), 6.88-6.83 ( , IH), 6.11 (s, IH), 5.24 (s, 2H), 4.41 (d, J = 6.0 Hz, 2H), 3.87 (s, 2H), 1.96 (s, 3H). ES-HRMS m/z 493.0575 (M+H calcd for C22H20BrF2N2O requires 493.0569).
631 Example 610
Figure imgf000632_0001
3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]benzamide
Example 291 (2.00 g, 4.93 mmol) and 2-chloro-4,6-dimethoxy-l,3,5-triazine (1.04 g, 5.91 mmol) were suspended in tetrahydrofuran (20 mL). 4-Methylmorpholine (1.6 L, 14.79 mmol) was added. The resulting mixture was stined for 1.5 hours at room temperature. NH4OH (10 mL, 148.00 mmol) was added and the reaction was stirred for 0.5 hours at room temperature. H20 (50 mL) and tefrahydrofuran (50 mL) were added and the organic layer was separated. The aqueous phase was extracted with ethyl acetate (75 mL) and the combined organics were washed with saturated Na2C03 (50 mL), IN HCl (50 mL), and brine (50 mL). The organic phase was dried over Na2S04 and evaporated. The resulting solid was washed with diethyl ether to give a white solid (1.96 g, 98%). 1H NMR (400 MHz, DMF-d6) δ 8.24 (br s, IH), 8.10 (dt, J = 1.21, 7.79 Hz, IH), 7.90 (t, J = 1.88 Hz, IH), 7.79 (app dt, J = 6.58, 8.59 Hz, IH), 7.66 (t, J = 7.79 Hz, IH), 7.57-7.55 (m, IH), 7.46 (br s, IH), 7.33 (ddd, J = 2.55, 9.26, 11.82 Hz, IH) 7.24-7.19 (m, IH), 6.78 (s, IH), 5.44 (s, 2H), 2.04 (s, 3H). ES-HRMS m/z 405.0835 (M+H calcd for C20H16BrF2N2O3 requires 405.0812).
Example 611
Figure imgf000632_0002
- 632 l-(4-aminobenzyl)-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one
Step 1: Preparation of l-tert-butyl-4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]methyl}phenylcarbamate.
Figure imgf000633_0001
4- { [3 -bromo-4-[(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)- yl]methyl}benzoic acid (8.00 g, 17.23 mmol) was suspended in 1:1 acetonitrile:t-butanol (172 mL). Diphenylphosphoryl azide (5.69 g, 20.68 mmol) and triethylamine (2.08 g, 20.68 mmol) were added. The reaction was heated to reflux for 1.5 hours. The reaction mixture was cooled to room temperature, concentrated and subjected to chromatography (on silica, ethyl acetate with 10% methanol/hexanes) to afford an off-white solid (6.14 g, 66%).
Step 2: 1 -tert-butyl-4- {[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]methyl}phenylcarbamate (Step 1) (6.14 g, 11.47 mmol) was suspended in 4N HCl in dioxane (5.74 mL, 22.94 mmol). The reaction mixture was stined at room temperature for 1 hour then diluted with diethyl ether. The precipitate was collected by filtration and washed with diethyl ether (3 x 30 mL) to afford a tan solid (3.45 g, 69%). 1H NMR (400 MHz, DMF-d6) δ 7.64 (app dt, J = 6.58, 8.59 Hz, IH), 7.31 (ddd, J = 2.55, 9.53, 10.61 Hz, IH) 7.29-7.12 (m, 5H), 6.56 (s, IH), 5.28 (s, 2H), 5.27 (s, 2H), 2.28 (s, 3H). ES-HRMS m/z 435.0516 (M+H calcd for C20H18BrF2N2O2 requires 435.0514).
- 633 Example 612
Figure imgf000634_0001
l-(3-aminobenzyl)-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one By following the method for Example 611 and substituting 3- {[3 -bromo-4- [(2,4- difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}benzoic acid for 4-{[3- bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}benzoic acid, the title compound was prepared (2.65 g, 67%). 1H NMR (400 MHz, DMF-d6) δ 7.64 (app dt, J = 6.58, 8.59 Hz, IH), 7.39 (t, J = 7.79 Hz, IH), 7.32 (ddd, J = 2.55, 9.53, 10.61 Hz, IH) 7.18-7.08 (m, 3H), 6.96 (s, IH), 6.58 (s, IH), 5.30 (s, 2H), 5.27 (s, 2H), 2.29 (s, 3H). ES-HRMS m/z 435.0513 (M+H calcd for C20H18BrF2N2O2 requires 435.0514).
Example 613
Figure imgf000634_0002
N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxoρyridin-l(2H)- yl]methyl}phenyl)acetamide
To a reaction vessel (borosilicate culture tube) was added Example 611 (0.300 g, 0.689 mmol) and dichloromethane (3.0 mL). A stock solution of N-methylmorpholine
- 634 - (0.30 M, 3.0 mL) was added and the parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 10 minutes. Acetyl chloride (0.074 mL, 1.033 mmol) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature for 1.5 hours. At this time the reaction was diluted with dichloromethane (15 mL) and freated with approximately 2.1 g of polyamine resin (2.63 mmol/g) and approximately 3.8 g of methylisocyanate functionalized polystyrene (1.10 mmol/g) and the orbital shaking was continued at 200 RPM at room temperature overnight. The reaction vessel was then opened and the solution phase products were separated from the insoluble quenched byproducts by filfration and collection into a vial. After partial evaporation the insoluble byproducts were rinsed with dichloromethane (2 x 10 mL). The filtrate was evaporated by blowing N2 over the vial to afford a white solid (0.135 g, 41%). 1H NMR (400 MHz, DMF-d6) δ 7.75 (app dt, J = 6.58, 8.59 Hz, IH), 7.63 (d, J = 8.59 Hz, IH), 7.30 (ddd, J = 2.55, 9.53, 10.61 Hz, IH), 7.22-7.14 (m, 3H), 6.60 (s, IH), 5.37 (s, 4H), 2.40 (s, 3H), 2.06 (s, 3H). ES-HRMS m/z 477.0600 (M+H calcd for C22H21BrF2N203 requires 477.0620).
Preparation of Examples 614-616
Figure imgf000635_0001
By following the method for Example 613 and replacing acetyl chloride with the appropriate acid chloride or sulfarnoyl chloride, the compounds of Examples 614-616 are prepared. The deprotection of the protected intermediate was accomplished with IM 2C03 in methanol to afford the title compound.
635
Figure imgf000636_0002
Example 617
Figure imgf000636_0001
N-(3- {[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxoρyridin- 1 (2H)- yl]methyl}phenyl)acetamide To a reaction vessel (borosilicate culture tube) was added Example 612 (0.300 g,
0.689 mmol) and dichloromethane (3.0 mL). A stock solution of N-methylmo holine (0.30 M, 3.0 mL) was added and the parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 10 minutes. Acetyl chloride (0.074 mL, 1.033 mmol) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature for 1.5 hours. At this time the reaction was diluted with dichloromethane (15 mL) and treated with approximately 2.1 g of polyamine resin (2.63 mmol/g) and approximately 3.8 g of methylisocyanate functionalized polystyrene (1.10 mmol/g) and the orbital shaking was continued at 200 RPM at room temperature overnight. The reaction vessel was then opened and the solution phase products were separated from the insoluble quenched byproducts by filtration and collection into a vial. After partial evaporation the insoluble byproducts were rinsed with dichloromethane (2 10 mL). The filtrate was evaporated by blowing N2 over the vial to afford a white solid (0.167 g, 51 %). 1H NMR (400 MHz,
DMF-d6) δ 7.77 (app dt, J = 6.58, 8.59 Hz, IH), 7.69 (d, J = 8.32 Hz, IH), 7.41 (br s, IH), - 636 - 7.34-7.17 (m, 3H), 6.88 (d, J = 7.65 Hz, IH), 6.63 (s, IH), 5.39 (s, 3H), 5.38 (s, 2H), 2.40 (s, 3H), 2.06 (s, 3H). ES-HRMS m/z 477.0620 (M+H calcd for C22H21BrF2N203 requires 477.0620).
Preparation of Example 618-620
Figure imgf000637_0001
By following the method for Example 617 and replacing acetyl chloride with the appropriate acid chloride or sulfarnoyl chloride, the compounds of Examples 618-620 are prepared. The deprotection of the protected intermediate was accomplished with IM K C03 in methanol to afford the title compound.
Figure imgf000637_0003
Example 621
Figure imgf000637_0002
N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzyl)-N'-methylurea
637 - Preparation of (4- { [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- l(2H)-yl]methyl}benzyl)-N'-methylurea. EXAMPLE 160 (150 mg, 0.33 mmol) was dissolved in N,N-dimethylacetamide (5 mL) and cooled to 0° C. 4-Nitrophenyl chloroformate (100 mg, 0.5 mmol) was added, followed by N,N-diisopropylethylamine (0.15 mL, 0.85 mmol) and the reaction was stined at 0° C for 5 minutes. N-Methylamine (0.5 mL, 1.0 mmol, 2M in tetrahydrofuran) was added and the reaction was allowed to reach ambient temperature and stined for 1 hour. The reaction was then diluted with tefrahydrofuran (40 mL) and polyamine resin (1.3 g, 2.81 mmol/g) and methylisocyanate functionalized polystyrene (1 g, 1.38 mmol/g) were added. The mixture was shaken for 16 hours at ambient temperature, filtered, and the resulting filtrate concenfrated to an oil that was triturated with ether. The resulting white solid was collected, washed with ether, and dried (87 mg, 52%). 1H NMR (400 MHz, CD3OD) δ 7.61 (app q, J = 8.4 Hz, IH); 7.24 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 7.02 (app t, J = 8.4 Hz, 2 H), 6.47 (s, IH), 5.39 (s, 2H), 5.28 (s, 2H), 4.26 (s, 2H); 2.68 (s, 3H); 2.34 (s, 3H). ES-HRMS m/z 506.0862 (M+H calcd for C23H23BrF2N303 requires 506.0885).
Example 622
Figure imgf000638_0001
N-(4- { [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)- yl]methyl}benzyl)-N'-(2-hydroxy-2-methylpropyl)urea
Preparation of N-(4- {[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]methyl}benzyl)-N'-(2-hydroxy-2-methylpropyl)urea. EXAMPLE 160 (300 mg, 0.67 mmol) was dissolved in N,N-dimethylacetamide (5 mL) and cooled to 0° C. 4-Nitrophenyl chloroformate (200 mg, 1.0 mmol) was added, followed by N,N- diisopropylethylamine (0.3 mL, 1.7 mmol) and the reaction was stined at 0° C for 5 minutes. 3-Amino-2-methyl-2-propanol (248 mg, 2.0 mmol) was added and the reaction was allowed to reach ambient temperature and stined for 3 h. The reaction was then diluted with tefrahydrofuran (40 mL) and polyamine resin (1.3 g, 2.81 mmol/g) and
- 638 - methylisocyanate functionalized polystyrene (1 g, 1.38 mmol/g) were added. The mixture was shaken for 16 hours at ambient temperature, filtered, and the resulting filtrate concentrated to an oil that was triturated with ether. The resulting white solid was purified by chromatography (silica gel, hexane/ethyl acetate/methanol) followed by reversed phase chromatography (C18, 0.1% aqueous trifluoroacetic acid/acetonitrile) to yield an off-white solid (43 mg, 11%). 1H NMR (400 MHz, CDC13) δ 7.56 (app q, J = 8.0 Hz, IH); 7.12 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.0 Hz, 2H), 7.02 (app dt, J = 1.6, 8.0 Hz, 2H), 6.83-6.88 (m, IH), 6.06 (s, IH), 5.26 (s, 2H), 5.21 (s, 2H); 4.22 (s, 2H); 3.09 (s, 2H); 2.30 (s, 3H); 1.14 (s, 6H). ES-HRMS m/z 564.1279 (M+H calcd for C26H29BrF2N304 requires 564.1304).-
Example 623
Figure imgf000639_0001
N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzyl)piperidme-l-carboxamide
By following the general method for Example 622 and substituting piperidine (170 mg, 2.0 mmol) for 3-amino-2-methyl-2-propanol the title compound was prepared and purified by chromatography (silica gel, hexane/ethyl acetate/methanol) yielding an oil that was triturated with ether to afford a white solid (107 mg, 28%). 1H NMR (400 MHz, CDC13) δ 7.56 (app q, J = 8.0 Hz, IH); 7.23 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 7.02 (app t, J = 8.0 Hz, 2H), 6.81-6.88 (m, IH), 5.97 (s, IH), 5.32 (s, 2H), 5.19 (s, 2H); 4.37 (s, 2H); 3.34-3.28 (m, 4H); 2.29 (s, 3H); 1.68-1.50 (m, 6H). ES-HRMS m/z 560.1365 (M+H calcd for C27H29BrF2N303 requires 560.1355).
Example 624
Figure imgf000639_0002
639 - N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzyl)morpholine-4-carboxamide
By following the general method for Example 622 and substituting morpholine (175 mg, 2.0 mmol) for 3-amino-2-methyl-2-propanol the title compound was prepared and purified by chromatography (silica gel, hexane/ethyl acetate/methanol) followed by reversed phase chromatography (C18, 0.1% aqueous trifluoroacetic acid/acetonitrile) to yield an off-white solid (51 mg, 13%). 1H NMR (400 MHz, CDC13) δ 7.55 (app q, J = 8.0 Hz, IH); 7.17 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.0 Hz, 2H), 6.94(app dt, J = 2.4, 8.0 Hz, 2H), 6.82-6.87 (m, IH), 6.02 (s, IH), 5.27 (s, 2H), 5.19 (s, 2H); 4.33 (s, 2H); 3.65-3.62 (m, 4H); 3.34-3.36 (m, 4H); 2.28 (s, 3H). ES-HRMS m/z 562.1152 (M+H calcd for C26H27BrF2N304 requires 562.1148).
Example 625
Figure imgf000640_0001
N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzyι)piperazine- 1 -carboxamide hydrochloride
By following the general method for Example 622 and substituting 1-Boc-piperazine (372 mg, 2.0 mmol) for 3-amino-2-methyl-2-propanol the title compound was prepared from its N-t-butoxycarbonyl protected intermediate that was purified by chromatography (silica gel, hexane/ethyl acetate/methanol). Deprotection was accomplished with 4N HCl in dioxane to afford the title compound as its hydrochloride salt (78 mg, 19%). 1H NMR (400 MHz, CD3OD) δ 7.61 (app q, J = 7.6 Hz, IH); 7.26 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 7.08-7.00 (m, 2H), 6.48 (s, IH), 5.41 (s, 2H), 5.28 (s, 2H); 4.31 (s, 2H); 3.65- 3.62 (m, 4H); 3.21-3.17 (m, 4H); 2.35 (s, 3H). ES-HRMS m/z 561.1318 (M+H calcd for C26H28BrF2N403 requires 561.1307).
640 - Example 626
Figure imgf000641_0001
N-(4-{[3-bromo-4- ,4-difluor oxy]-6-methyl-2-oxopyridm-l(2H)- yl]methyl}benzyl)-N'-(2-hydroxyethyl)urea
By following the general method for Example 622 and substituting ethanolamine (121 mg, 2.0 mmol) for 3-amino-2-methyl-2-propanol the title compound was prepared and purified by chromatography (silica gel, hexane/ethyl acetate/methanol) to yield an off- white solid (130 mg, 36%). 1H NMR (400 MHz, CDC13) δ 7.54 (app q, J = 7.6 Hz, IH); 7.13 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.0 Hz, 2H), 6.96-6.92 (m, IH); 6.83-6.88 (m, IH), 6.09 (s, IH), 5.26 (s, 2H), 5.21 (s, 2H); 4.24 (s, 2H); 3.56 (t, J = 4.8 Hz, 2H); 3.21 (t, J = 4.8 Hz, 2H); 2.31 (s, 3H). ES-HRMS m/z 536.0948 (M+H calcd for C24H25BrF2N304 requires 536.0991).
Example 627
Figure imgf000641_0002
N'-(4- { [3 -bromo-4-[(2,4-difluorobenzyl)oxy] -6-methyl-2-oxoρyridin- 1 (2H)- yl]methyl}benzyl)-N,N-dimethylurea
By following the general method for Example 622 and substituting N,N- dimethylamine (1.0 mL, 2.0 mmol, 2M in tetrahydrofuran) for 3-amino-2-methyl-2- propanol the title compound was prepared and purified by chromatography (silica gel, hexane/ethyl acetate/methanol) yielding an oil that was triturated with ether to afford a white solid (65 mg, 19%). 1H NMR (400 MHz, CDC13) δ 7.56 (app q, J = 8.0 Hz, IH); 7.22 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 6.93 (app dt, J = 2.0, 8.0 Hz, IH); 6.87-
- 641 - 6.81 (m, IH); 5.97 (s, IH), 5.31 (s, 2H), 5.19 (s, 2H); 4.36 (s, 2H); 2.89 (s, 6H); 2.28 (s, 3H). ES-HRMS m/z 520.1072 (M+H calcd for C24H25BrF2N303 requires 520.1042).
Example 628
Figure imgf000642_0001
N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzyl)-4-hydroxypiperidine- 1 -carboxamide
By following the general method for Example 622 and substituting 4- Hydroxypiperidine (202 mg, 2.0 mmol) for 3-amino-2-methyl-2-propanol the title compound was prepared and purified by chromatography (silica gel, hexane/ethyl acetate/methanol) yielding an oil that was triturated with ether to afford a white solid (41 mg, 11%). 1H NMR (400 MHz, CDC13) δ 7.56 (app q, J = 8.0 Hz, IH); 7.20 (d, J = 7.6 Hz, 2H), 7.06 (d, J = 8.0 Hz, 2H), 6.94 (app t, J = 8.0 Hz, IH); 6.84 (app t, J = 8.0 Hz, IH); 5.99 (s, IH), 5.29 (s, 2H), 5.19 (s, 2H); 4.34 (s, 2H); 3.84-3.70 (m, 3H); 3.04-2.92 (m,
3H); 2.28 (s, 3H); 1.84-1.81 (m, 2H); 1.47-1.44 (m, 2H). ES-HRMS m/z 576.1348 (M+H calcd for C27H29BrF2N304 requires 576.1304).
Example 629
Figure imgf000642_0002
4- { [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridm- 1 (2H)-yl]methyl} -N,N- dimethylbenzenesulfonamide
Step 1: Preparation of 4-Bromomethyl-N,N-dimethylbenzenesulfonamide
- 642 -
Figure imgf000643_0001
4-(Bromomethyl)benzenesulfonyl chloride (5.0 g, 18.6 mmol) was dissolved in tetrahydrofuran. N,N-dimethylamine (7.7 mL, 15.5 mmol, 2M in tefrahydrofuran) and and N,N-diisoproρylethylamine (3.5 mL, 20.1 mmol) were added, and the reaction was allowed to stir at ambient temperature for 2 hours. The reaction was concentrated to an oil that was partitioned between water and ethyl acetate and exfracted with ethyl acetate. The organic exfracts were combined, washed with brine, dried over Na2S0 , and filtered. The resulting filtrate was concentrated to an oil which deposited needles that were a mixture of the title compound and 4-chloromethyl N,N-dimethylbenzenesulfonamide The resulting needles were collected and dried (2.3 g, 44 %). ES-MS m/z 534 (M+H) and 578 (M+H).
Step 2: Preparation of 4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]methyl}-N,N-dimethylbenzenesulfonamide. 3-bromo-4-(2,4-difluorophenoxy)- 6-methylpyridin-2(lH)-one (300 mg, 0.91 mmol) was suspended in 1,4-dioxane (50 mL). 4-(Bromomethyl)-N,N-dimethylbenzenesulfonamide (from step 1) (300 mg, 1.09 mmol) was added followed by sodium hydride (45 mg, 1.09 mmol, 60% in mineral oil). The reaction was heated to 80°C and stined for 16 hours after which more sodium hydride (45 mg, 1.09 mmol, 60% in mineral oil) and sodium iodide (150 mg, 1.0 mmol) were added. The reaction was allowed to stir at 80°C for 4 hours more. The reaction was then filtered through Celite® and the filtrate was concenfrated to an oil that was purified by chromatography (silica gel, hexane/ethyl acetate) followed by reversed phase chromatography (C18, 0.1% aqueous trifluoroacetic acid/acetonitrile) to yield an off-white solid (41 mg, 8%). 1H NMR (400 MHz, CDC13) δ 7.71(d, J = 8.4 Hz, 2H); 7.57 (app q, J = 7.6 Hz, IH); 7.29 (d, J = 8.0 Hz, 2H); 6.95 (app dt, J = 2.0, 8.0 Hz, IH), 6.88-6.83 (m, IH); 6.05 (s, IH), 5.42 (s, 2H), 5.22 (s, 2H); 2.69 (s, 6H); 2.29 (s, 3H). ES-HRMS m/z 527.0439 (M+H calcd for C22H22Br2F2N204S requires 527.0446).
643 Example 630
Figure imgf000644_0001
4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-N-(2- hydroxyethyl)benzenesulfonamide
Step 1: Preparation of 4-Bromomethyl-N-(2-hydroxyethyl)benzenesulfonamide
Figure imgf000644_0002
4-(Bromomethyl)benzenesulfonyl chloride (5.0 g, 18.6 mmol) was dissolved in tefrahydrofuran. Ethanolamine (1.1 mL, 18.6 mmol) and and N,N-diisopropylethylamine (3.9 mL, 22.3 mmol) were added, and the reaction was allowed to stir at ambient temperature for 30 minutes. The reaction was concentrated to an oil that was partitioned between water and ethyl acetate and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over Na2S04, and filtered. The resulting filtrate was concenfrated to an oil that was a mixture of the title compound and 4-chloromethyl N- (2-hydroxyethyl)benzenesulfonamide. The resulting oil was dried in vacuo (3.7 g, 68 %). ES-MS m/z 250 (M+H) and 294 (M+H).
Step 2: Preparation of 4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-
1 (2H)-yl]methyl} -N-(2-hydroxyethyl)benzenesulfonamide. The title compound was prepared essentially according to the procedure described in Step
2 of Example 629, using 4-Bromomethyl-N-(2-hydroxyethyl) benzenesulfonamide (from step 1). 1H NMR (400 MHz, CDC13) δ 7.81 (d, J = 8.4 Hz, 2H); 7.61 (app q, J = 7.6 Hz, IH); 7.30 (d, J = 8.4 Hz, 2H); 6.95 (app t, J = 8.4 Hz, 2H), 6.53 (s, IH), 5.49 (s, 2H), 5.30 (s, 2H); 3.50 (t, J = 6.0 Hz, 2H); 2.92 (t, J = 6.0 Hz, 2H); 2.36 (s, 3H). ES-HRMS m/z 543.0453 (M+H calcd for C22H22Br2F2N205S requires 543.0395).
644 Example 631
Figure imgf000645_0001
4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-N-(2- hydroxy-2-methylproρyl)benzenesulfonamide
Step 1: Preparation of 4-Bromomethyl-N-(2-hydroxy-2-methylpropyl) benzenesulfonamide
Figure imgf000645_0002
4-(Bromomethyl)benzenesulfonyl chloride (2.0 g, 7.3 mmol) was dissolved in tefrahydrofuran. 3-Amino-2-methyl-2-propanol (1.0 g, 8 mmol) and and N,N- diisopropylethylamine (1.5 mL, 8.8 mmol) were added, and the reaction was allowed to stir at ambient temperature for 30 minutes. The reaction was concentrated to an oil that was partitioned between water and ethyl acetate and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over Na2S0 , and filtered. The resulting filtrate was concentrated to an oil that was a mixture of the title compound and 4- chloromethyl-N-(2-hydroxy-2-methylpropyl) benzenesulfonamide. The resulting oil was dried in vacuo (1.9 g, 81 %).
Step 2: Preparation of 4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]methyl}-N-(2-hydroxy-2-methylpropyl)benzenesulfonamide. The title compound was prepared essentially according to the procedure described in Step 2 of Example 629, using 4-Bromomethyl-N-(2-hydroxy-2-methylpropyl) benzenesulfonamide (from step 1). 1H NMR (400 MHz, CDC13) δ 7.78 (d, J = 8.4 Hz, 2H); 7.56 (app q, J = 7.6 Hz, IH); 7.26 (d, J = 8.4 Hz); 6.95 (app t, J = 8.4 Hz, IH), 6.86-6.83 (m, IH); 6.07 (s, IH), 5.41 (s, 2H), 5.22 (s, 2H); 4.98 (t, J = 6.4 Hz, IH); 2.84 (d, J = 6.4 Hz, 2H); 2.29 (s, 3H); 1.21 (s, 6H). ES-HRMS m/z 571.0684 (M+H calcd for C24H26Br2F2N205S requires 571.0708).
- 645 - Example 632
Figure imgf000646_0001
3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-l-(lH-pyrazol-3-ylmethyl)-lH-pyridin-2- one
Step 1. Preparation of 4-hydroxy-6-methyl-lH-pyridin-2-one.
Figure imgf000646_0002
4-Ηydroxy-6-methyl-pryan-2-one (25.8 g, 0.2 mol) was dissolved in 180 ml of concentrated ammomum hydroxide. The reaction was heated at refluxed for 4 hours. The reaction was cooled to room temperature and evaporated on a rotary evaporator to a quarter of the original volume. The resulting solid was filtered, washed with cold water, hexanes, and dried in a vacuum oven overnight to give a white solid (25 g, 98%): 1H NMR (300 MHz, DMSO- 6) δ 10.94 (br s, IH), 10.34 (s, IH), 5.59 (d, J= 1.4 Hz, IH), 5.32 (d, J= 2.0 Hz, IH), 2.07 (s, 3H).
Step 2. Preparation of 3-Chloro-4-hydroxy-6-methyl-lH-pyridin-2-one.
Figure imgf000646_0003
4-Hydroxy-6-methyl-lH-pyridin-2-one (25g, 0.2 mol) and N-chlorosuccinimide (29.4 g, 0.22 mol) were dissolved in 200 mL of acetic acid. The reaction was heated at 115 °C for 6 hours. The reaction was cooled to room temperature, the solid was filtered, and washed with acetic acid and hexanes. The solid was dried in a vacuum oven overnight to give a white solid (19.2 g, 60%): 1H ΝMR (300 MΗz, DMSO-</6) δ 11.46 (br s, 1Η), 11.04 (s, 1Η), 5.79 (s, 1Η), 2.09 (s, 3Η). - 646 - Step 3. Preparation of 3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-lH-ρyridin-2-one.
Figure imgf000647_0001
3-Chloro-4-hydroxy-6-methyl-lH-pyridin-2-one (19.2 g, 0.12 mol) and DBU (19.9 mL, 0.13 mol) were dissolved in 70 mL of NMP. 2,4-Difluorobenzylbromide (17 mL, 0.13 mol) was added dropwise and the reaction was heated at 80 °C for 6 hours. The reaction was cooled to room temperature, the solid was filtered, and washed with NMP and hexanes. The solid was dried in a vacuum oven overnight to give a white solid (4.4 g, 13%): 1H NMR (300 MΗz, DMSO- ) δ 11.88 (br s, 1Η), 7.63 (app q, J= 9 Ηz, 1Η), 7.33 (app t, J= 10 Ηz, 1Η), 7.16 (app t, J= 9 Ηz, 1Η), 6.37 (s, 1Η), 5.24 (s, 2Η), 2.20 (s, 3H).
Step 4. Preparation of 3 -Methylpyrazole-1 -carboxylic acid tert-butyl ester. ^ ,NBoc N
3-Methyl-lH-pyrazole (5.3 g, 65 mmol), DMAP (0.79 g, 6.5 mmol), and di-tert-butyl dicarbonate (2.8 g, 13 mmol) were at room temperature in 90 mL of CH3CN for 1 hour.. The reaction was evaporated on a rotary evaporator, and the resulting solid dissolved in EtOAc, washed with 1 N HCl, water and brine, dried (MgS0 ), filtered, and evaporated on a rotary evaporator to give a light yellow oil (11.4 g, 96%): 1H NMR (300 MHz, CDC13) δ 7.96 (d, J= 2.7 Hz, IH), 6.17 (d, J= 2.7 Hz, IH), 2.32 (s, 3H), 1.63 (s, 9H).
Step 5. Preparation of 3 -Bromomethylpyrazole-1 -carboxylic acid tert-butyl ester.
^^ N 3-Methylpyrazole-l-carboxylic acid tert-butyl ester (6.0 g, 33 mmol), N- bromosuccinimide (1.0 g, 5.6 mmol) and benzoyl peroxide (50 mg) were dissolved in 20 mL of carbon tetrachloride. The reaction was heated at reflux for 16 h. The reaction was
647 cooled to room temperature, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:4 EtOAc/hexanes) gave a light yellow oil (4.5 g, 53%): 1H NMR (300 MHz, CDC13) δ 8.03 (d, J= 2.6 Hz, 1H), 6.47 (d, J = 2.6 Hz, IH), 4.48 (s, 2H), 1.64 (s, 9H).
Step 6. Preparation of 3-[3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-2-oxo-2H- pyridin-l-ylnιethyl]pyrazole-l -carboxylic acid tert-butyl ester.
Figure imgf000648_0001
3-[3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-2-oxo-2H-pyridin-l-ylmethyl]pyrazole- 1 -carboxylic acid tert-butyl ester was prepared by a procedure similar to the one described for Example 401 gave a yellow solid (1.4 g, 39%): 1H NMR (300 MΗz, CDC13) δ 7.53 -
7.49 (m, 2Η), 6.97 - 6.81 (m, 2H), 6.35 (d, J= 2.0 Hz, IH), 6.01 (s, IH), 5.32 (s, 2H),
5.26 (s, 2H), 2.52 (s, 3H), 1.62 (s, 9H).
Step 7. Preparation of the title compound Example 632 3-[3-Chloro-4-(2,4- difluorobenzyloxy)-6-methyl-2-oxo-2H-pyridin- 1 -ylmethyl]pyrazole- 1 -carboxylic acid tert-butyl ester (0.16 g, 0.34 mmol) was heated to 140 °C for 16 h. The reaction mixture was cooled to room temperature. Recrystallization from methylene chloride/hexanes provided an off-white solid (1.0 g, 91%): 1H NMR (300 MHz, DMSO-^) δ 12.67 (br s, IH), 7.67 - 7.60 (m, 2H), 7.34 (dt, J= 10.5, 2.5 Hz, IH), 7.17 (dt, J= 8.5, 1.6 Hz, IH), 6.52 (s, IH), 6.10 (d, J= 1.9 Hz, IH), 5.27 (s, 2H), 5.20 (s, 2H), 2.48 (s, 2H).
Example 633
Figure imgf000648_0002
648 - 3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-l-(2,3-dihydro-lH-indol-5-ylmethyl)-lH- pyridin-2-one
Step 1. Preparation of 5-[3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-2-oxo-2H- pyridin- 1 -ylmethyljmdole- 1 -carbamic acid tert-butyl ester
Figure imgf000649_0001
5-[3 -Chloro-4-(2,4-difluorobenzyloxy)-2-oxo-2H-pyridin- 1 -ylmethyl]indole- 1 - carbamic acid tert-butyl ester was prepared by a procedure similar to the one described for Example 632 as an off-white solid (2.5 g, 61%): 1H NMR (300 MHz, DMSO-d6) δ 8.00 (d, J = 8.5 Hz, IH), 7.70 - 7.62 (m, 2H), 7.39 - 7.32 (m, 2H), 7.21 - 7.13 (m, 2H), 6.70 (d, J = 3.8 Hz, IH), 6.66 (s, IH), 5.40 (s, 2H), 5.29 (s, 2H), 2.33 (s, 3H), 1.62 (s, 9H).
Step 2. Preparation of 3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-l-(lH-indol-5- ylmethyl)- lH-pyridin-2-one.
Figure imgf000649_0002
5-[3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-2-oxo-2H-pyridin-l- ylmethyl]indole-l -carbamic acid tert-butyl ester (1.08g, 2.1 mmol) dissolved in 40 mL of DMSO was stined at 120 °C for 20 hours. The reaction was cooled to room temperature, diluted with water, and washed 5 times with ethyl acetate. The combined organics were washed 1 time with brine, dried (MgS04), filtered, and concenfrated under reduced pressure. 1H NMR (300 MHz, DMSO-d6) δ 11.1 (br s, IH), 7.67 (d, J = 6.7 Hz, IH), 7.36 - 7.32 (m, 2H), 7.23 (s, IH), 7.18 (d, J = 2.3 Hz, IH), 6.93 (dd, J = 8.4, 1.2 Hz, IH), 6.57 (s, IH), 6.38 (s, IH), 5.37 (s, 2H), 5.29 (s, 2H), 2.35 (s, 3H).
649 Step 3. 3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-l-(lH-indol-5-ylmethyl)-lH- pyridin-2-one (from Step 2) (1.7 g, 4.1 mmol) was stined in 26 mL of acetic acid and NaCNBH3 (0.27 g, 4.3 mmol) was added portionwise. The reaction was stined for 1 hour. The reaction was diluted water, and washed 5 times with ethyl acetate. The combined organics were washed 1 time with brine, dried (MgS04), filtered, and concenfrated under reduced pressure. Purification by flash column chromatography (silica, 100% EtOAc) gave a white solid (1.2 g, 71%): 1H NMR (300 MHz, DMSO-d6) δ 7.64 (app q, J = 8.5 Hz, IH), 7.34 (dt, J = 9.5, 2.6 Hz, IH), 7.17 (app t, J = 8.5, IH), 6.82 (s, IH), 6.72 (d, J = 8.0 Hz, IH), 6.53 (s, IH), 6.42 (d, J = 8.0 Hz, IH), 5.48 (br s, IH), 5.27 (s, 2H), 5.13 (s, 2H), 3.37 (t, J = 8.3 Hz, 2H), 2.82 (t, J = 8.3 Hz, 2H), 2.35 (s, 3H).
Example 634
Figure imgf000650_0001
5 - [3 -Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-2-oxo-2H-pyridin- 1 -ylmethyl] -1,3- dihydro-indol-2-one
Step 1. Preparation of 5-[3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-2-oxo-2H- pyridin- 1 -ylmethyl] -3 ,3 -dibromo- lH-indol-2-one.
Figure imgf000650_0002
3 -Chloro-4-(2,4-difluorobenzyloxy)-6-methyl- 1 -( lH-indol-5 -ylmethyl)- 1 H-ρyridin-2-one
(0.45 mg, 1.1 mmol)(example 633, step 2) was suspended in 11 mL of tert-butanol and pyridinium bromide perbromide (1.04 g, 3.3 mmol) was added portionwise. The reaction was stined for 16 hours. The reaction was diluted with water, and washed 4 times with ethyl acetate. The combined organics were washed 1 time with brine, dried (MgS04),
- 650 - filtered, and concentrated under reduced pressure. Trituration with methylene chloride gave an off-white solid (0.25 g, 39%): 1H NMR (300 MHz, DMSO-d6) δ 11.26 (br s, IH), 7.66 (app q, J = 8.6 Hz, IH), 7.48 (s, IH), 7.35 (dt, J = 10.5, 2.5 Hz, IH), 7.18 (dt, J = 8.7, 1.9, IH), 7.05 (dd, J = 8.2, 1.5, IH), 6.88 (d, J = 8.1 Hz, IH), 6.61 (s, IH), 5.29 (s, 4H), 2.36 (s, 3H).
Step 2. 5-[3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-2-oxo-2H-pyridin-l -ylmethyl]- 3,3-dibromo-lH-indol-2-one (0.2 g, 0.34 mmol) was suspended in 5 mL of acetic acid, and zinc metal (0.22 g, 3.4 mmol) was added. The reaction was stined for 48 hours. The reaction was diluted with water, and washed 2 times with ethyl acetate. The combined organics were washed 1 time with brine, dried (MgS0 ), filtered, and concenfrated under reduced pressure. Purification by flash column chromatography (silica, 100% EtOAc) gave a white solid (0.12 g, 82%): 1H NMR (300 MHz, DMSO-d6) δ 10.37 (br s, IH), 7.65 (app q, J = 6.9 Hz, IH), 7.34 (dt, J = 8.2, 2.5 Hz, IH), 7.18 (dt, J = 7.1, 1.9, IH), 6.98 (br s, 2H), 6.77 (d, J = 8.4 Hz, IH), 6.57 (s, IH), 5.28 (s, 2H), 5.23 (s, 2H), 3.44 (s, 2H), 2.34 (s, 3H).
Example 635
Figure imgf000651_0001
N-[(5-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxoρyridin-l(2H)- yl]methyl}pyrazin-2-yl)methyl]-N-methylmethanesulfonamide
To a suspension of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-({5- [(methylamino)methyl]pyrazin-2-yl}methyl)pyridin-2(lH)-one (0.16 g, 0.34 mmol) in acetonitrile at 0 °C was added triethylamine (0.043 g, 0.42 mmol), followed by the addition of methane sulfonylchloride (0.047 g, 0.41 mmol) and stined at room
651 temperature for 1 h under argon atmosphere. The solvents were removed in vacuo and the residue was triturated with water and filtered. It was washed with water an, acetonitrile and dried in vacuo to afford 0.11 g of material. 1H NMR (CD3OD/ 400 MHz) δ 8.62 (s, IH), 8.55 (s, IH), 7.61 (m, IH), 7.0 (m, 2H), 6.53 (s, IH), 5.47 (s, 2H), 5.29 (s, 2H), 4.49 (s, 2H), 2.95 (s, 3H), 2.85 (s, 3H), and 2.55 (s, 3H); 19F NMR(CD3OD/ 400 MHz) δ -111.70(m) and -116.07 (m); ES-HRMS m z 543.0515(M+H calcd for C21H22BrF2N 0 S requires 543.0508).
Example 636
Figure imgf000652_0001
Methyl (5- {[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)- yl]methyl}pyrazin-2-yl)methyl(methyl)carbamate
To a cold (5 °C) solution of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-({5- [(methylamino)methyl]pyrazin-2-yl}methyl)pyridin-2(lH)-one (0.20 g, 0.4 mmol) in DMF (2.0 ml), was added methylchloroformate (0.049 g, 0.52 mmol), followed by the addition of triethylamine (0.072 g, 0.71 mmol). The mixture was stined at 5 °C for 30 min and at room temperature for an additional 30 min and concentrated in vacuo . The residue was partitioned between water (5.0 mL) and EtOAc (10.0 mL). The organic extract was washed with water, dried (Na2S0 ), and concentrated to dryness. The resulting material was purified by reverse-phase HPLC using 10 -90 % CH3CN/ Water gradient (60 min) at a flow rate of 70 mL/min. The appropriate fractions (m/z = 523 M+H ) were combined and freeze dried to give a white powder. This was partitioned between 5% NaHC03 (10 mL) and EtOAc (15 mL). The organic layer was washed with water, dried (Na2S04), and concentrated to dryness to afford the title compound (0.12 g, 53%) as a white powder: 1H NMR (CD3OD/ 400 MHz) δ 8.59 (s, IH), 8.41(m, IH), 7.60 (m, IH),
- 652 - 7.05 (m, 2H), 6.52 (s, IH), 5.45 (s, 2H), 5.29 (s, 2H), 4.58 (s, 2H), 3.69 and 3.64 (s, 3H), 2.97 (s, 3H), 2.85 (s, 3H), and 2.55 (s, 3H); 19F NMR(CD3OD/ 400 MHz) δ -111.69(m) and -116.09 (m); ES-HRMS m/z 523.0775(M+H calcd for C22H22BrF2N404 requires 523.0787).
Example 637
Figure imgf000653_0001
N-[(5-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrazin-2-yl)methyl]-2-hydroxy-N,2-dimethylpropanamide
To a cold (5 °C) solution of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-({5- [(methylamino)methyl]pyrazin-2-yl}methyl)pyridin-2(lH)-one (0.24 g, 0.52 mmol) in DMF (2.0 ml), was added 2-acetoxyisobutyryl chloride (0.093g, 0.56 mmol), followed by the addition of triethylamine (0.072 g, 0.71 mmol). The mixture was stined at room temperature for an additional 2 h and concenfrated in vacuo . The residue was partitioned between water (5.0 mL) and EtOAc (15.0 mL). The EtOAc extract was washed with water, dried (Na2S0 ), and concentrated to dryness. The resulting material (0.2 g) was stined with IM. LiOH (0.5 mL, MeOH,/Water 1:1 v/v) at room temperature for 3h, cooled, acidified with trifluoroacetic acid and the product was purified by reverse-phase HPLC using 10 -90 % CH3CN/ Water gradient (60 min) at a flow rate of 70 mL/min. The appropriate fractions (m/z = 551 M+H ) were combined and freeze dried to give a white powder. This was partitioned between 5% NaHC03 (10 mL) and EtoAc (15 mL). The organic layer was washed with water, dried (Na2S04), and concentrated to dryness to afford the title compound (0.075 g) as a white powder: 1H NMR (CD3OD/ 400 MHz) δ 8.59 (s, IH), 8.41 (br, IH), 7.60 (m, 2H), 7.01 (m, 2H), 6.52 (s, IH), 5.45 (s, 2h), 5.29 (s, 2H),
- 653 Example 638
Figure imgf000654_0001
5-{[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-N-(2- hydroxy-2-methylpropyl)pyrazine-2-carboxamide
To a solution of 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]methyl}pyrazine-2-carboxylic acid (0.42 g, 0.9 mmol) in DMF (3.0 mL) was added isobutylchloroformate (0.126 g, 0.13 mmol) followed by the addition of N- methylmorpholine (0.11 g, 1.1 mmol ) and stined at -10 °C, under argon atmosphere.
After 20 min, added a solution of 1,1 dimethyl-2-aminoethanol hydrochloride (0.135g, 1.1 mmol) in DMF (2.0 mL) containing N-methylmorpholine (0.11 g, 1.1 mmol). The mixture was stined at room temperature for 1 h, and concentrated to dryness in vacuo. The resulting residue was purified by reverse-phase HPLC using 10 -90 % CH3CN/ Water gradient (60 min) at a flow rate of 70 mL/min. The appropriate fractions (m z = 537 M+H ) were combined and freeze dried to give a white powder. This was partitioned between 5% NaHC03 (10 mL) and EtOAc (15 mL). The organic layer was washed with water, dried (Na S04), and concentrated to dryness to afford the title compound (0.35 g, 75%) as a white powder: 1H NMR (CD3OD/ 400 MHz) δ 9.1 (d, IH, J = 1.6 Hz), 8.71 (d, IH, J = 1.6 Hz), 7.61 (m IH), 7.02 (m, 2H), 6.54 (s, IH), 5.54 (s, 2H), 5.30 (s, 2h). 3.30 (s, 2h), 2.55 (s, 3H), and 1.21 (s, 6H); 19F NMR(CD3OD/ 400 MHz) δ -111.67(m) and -116.05 (m); ES-HRMS m/z 537.0948 (M+H calcd for C23H24BrF2N404 requires 537.0943).
Example 639
- 654. F3CCOOH .H
Figure imgf000655_0001
l-[(5-Aminoρyrazin-2-yl)methyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin- 2(lH)-one trifluoroacetate
A mixture of 5- {[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l (2H)- yl]methyl}pyrazine-2-carboxylic acid (0.70g, 1.5 mmol) diphenylphosphoryl azide (0.51 g, 1.8 mmol) in dimethylacetamide (15.0 mL) and t-butanol (5.0 mL) containing triethylamine (0.18 g, 1.8 mmol) was heated at 90 °C for 6 h under argon atmosphere. The reaction mixture was cooled, filtered the precipitate. It was washed with acetonitrile and dried to obtain 0.22 g of the unreacted acid. The combilned filtrate and the washings were concentrated in vacuo and the resulting material was purified by reverse-phase
HPLC using 10 -90 % CH3CN/ Water gradient (60 min) at a flow rate of 70 mL/min. The appropriate fractions (m/z = 437 M+H ) were combined and freeze dried to give the title compound (0.21 g, 37%) as a white powder: 1H NMR (DMSO-d6/ 400 MHz) δ 7.88 (d, IH, J = 1.2 Hz), 7.75 (d, IH, J = 1.2 Hz), 7.61 (m IH), 7.34 (m, IH), 7.18 (m,lH), 6.49 (s, IH), 5.25 (s, 2H), 5.10 (s, 2H), and 2.49 (s, 3H); 19F NMR(CD3OD/ 400 MHz) δ -111.72(m) and -116.11 (m); ES-HRMS m z 437.0402(M+H calcd for C18H16BrF2N402 requires 437.0419).
Example 640
Figure imgf000655_0002
3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[(3-methyl-l,2,4-triazin-6- yl)methyl]pyridin-2(lH)-one trifluoroacetate
655 Step 1: Preparation of (2-methylpyrimidin-5-yl)methanol trifluoroacetate
Figure imgf000656_0001
To solution of methyl 2-methylpyrimidinecarboxylate (2.6 g, 17.1 mmol) in THF was added dropwise diisobutylaluminumhydride (39.5 mL, IM solution in THF) and stined at -20 °C under argon atmosphere for 1.5 h, and at room temperature for 2 h. The reaction was quenched by the addition of powdered sodiumsulphate decahydrate (25 g), added THF (25 mL) and stined at room temperature for lh. This mixture was allowed to stand in the refrigerator overnight and filtered through a celite pad. The precipitate was thoroughly with warm THF (100 mL) containing 10% ethanol. The combined washings and the filtrate were concentrated to afford ayellow syrup, which was purified by reverse-phase HPLC using 10 -90 % CH3CN/ Water gradient (60 min) at a flow rate of 70 mL/min. The appropriate fractions (m/z = 125 M+H) were combined and lyophilized to give the title compound (0.67 g, 32%) as its trifluoroacetate salt: 1H NMR (CD3OD/ 400 MHz) δ 8.65 (s, 2H ) 4.62 (s, 2H), and 2.66 (s, 3H); ES-HRMS m/z 125.0678 (M+H calcd for C6H9N20 requires 125.0709).
Step 2: Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[(3-methyl-l,2,4- triazin-6-yl)methyl]pyridm-2( 1 H)-one trifluoroacetate To a solution of (2-methylpyrimidin-5-yl)methanol trifluoroacetate (0.9 g, 3.76 mmol) in dichloromethane (10 mL) at 0 °C, was added triethylamine (0.95 g, 9.41 mmol), followed by the addition of methanesulfonyl chloride (0.59 g, 5.17 mmol) and stined at 0 °C for 1 h. After stirring for 1 h at room temperature, additional triethylamine ( 0.22 g) and methanesulfonyl chloride (0.15 g)were added and the mixture was stined at room temperature for another hour under argon atmosphere. The reaction was quenched by the addition of cold water (15 mL) and stined for 15 min. The organic layer was washed with water, followed by 5% sod. bicarbonate (2 15 mL), water, and dried (Na2S04). After the removal of the solvent under reduced pressure, the residue was dried in a desiccator under vacuum for 4 h. This material was suspended in THF (10 mL) and - 656 - DMF (5.0 mL), added 3-bromo-4-(2,4-difluoroρhenoxy)-6-methylpyridin-2(lH)-one (0.5 g, 1.52 mmol) and NaH (0.04 g). The resulting mixture was heated at 65 °C for 16 h under argon atmosphere. The solvents were distilled under vacuum and the residue was purified by reverse-phase HPLC using 10 -90 % CH3CN/ Water gradient (60 min) at a flow rate of 70 mL/min. The appropriate fractions (m z = 436 M+H) were combined and freeze dried to give the title compound (0.045 g,) as its trifluoroacetate salt: 1H NMR (CD3OD/ 400 MHz) δ 8.58 (s, 2H) 7.61 (m, IH), 7.01 (m, 2H), 6.53 (s, IH), 5.37 (s, 2h), 5.29 (s, 2H), 2.65 (s, 3H), and 2.46 (s, 3H); 19F NMR(CD3OD/ 400 MHz) δ -111.62 (m), and -116.08 (m); ES-HRMS m/z 436.0433(M+H calcd for C19H17BrF2N302 requires 436.0467).
Example 641
Figure imgf000657_0001
3-Bromo-4-[(2,4-difluorobenzyl)oxy]-l-(lH-indazol-5-yl)-6-methylpyridin-2(lH)-one
Step 1: Preparation of 4-hydroxy-l-(lH-indazol-5-yl)-6-methylpyridin-2(lH)-one
Figure imgf000657_0002
A mixture of 4- hydoxy-6-methyl-2-pyrone (3.75 g, 0.029 mol) and 5- aminoindazole (4.0 g, 0.03 mol) in water (70 ml) was heated at 90 °C under argon for 1 h. The mixture was cooled, decanted the supernatant and residue was triturated with ethanol, cooled and filtered the solid. It was washed with cold ethanol, and dried. 1H NMR (CD3OD/ 400 MHz) δ 8.11 (s, IH), 7.64 (m, 2H), 7.18 (d, IH, J = 2.0 Hz ), 7.16 (d, IH, J = 2.0 Hz) 6.07 (m, IH), 5.81 (d, IH, J = 2.8 Hz), and 1.94 (s, 3H); ES-HRMS m z 242.0962(M+H calcd for C13H12N302 requires 242.0924).
- 657 Step 2:A mixture of 4-hydroxy-l-(lH-indazol-5-yl)-6-methylpyridin-2(lH)-one (0.2g, 0.83 mmol), N- bromosuccinmide (0.15 g, 0.84 mmol) in dichloromethane (4.0 mL) and acetic acid (1.0 mL) was stined at room temperature under argon atmosphere for 2.5 h. After the removal of the solvents, the residue was dried in vacuo for 4 h in a desiccator. It was then suspended in DMF (3.0 mL), potassium carbonate (0.1 g), and 2,4 difluorobenzyl bromide were added and mixture was stined at room temperature for 3 h. DMF was distilled in vacuo and the residue was purified by reverse-phase HPLC using 10 -90 % CH3CN/ Water gradient (60 min) at a flow rate of 70 mL/min. The appropriate fractions (m z = 537 M+H ) were combined and freeze dried to give a white powder. This was partitioned between 5% NaHC03 (10 mL) and EtOAc (15 mL). The organic layer was washed with water, dried (Na S04), and concentrated to dryness to afford the title compound (0.075 g) as a white powder: 1H NMR (CD3OD/ 400 MHz) δ 8.13 (s, IH ), 7.68 (m, 3H), 7.20 (2d, IH, J = 1.2 Hz), 7.05 (m, 2H), 6.61 (s, IH), 5.35 (s, 2H), and 2.05 (s, 3H); 19F NMR(CD3OD/ 400 MHz) -111.62 (m) and -116.02 (m); ES-HRMS m/z 446.0305(M+H calcd for C20H15BrF2N3O2 requires 446.0310).\
Example 642
Figure imgf000658_0001
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(lH-indazol-6-yl)-6-methylpyridin-2(lH)-one
Step 1: Preparation of 4-hydroxy-l-(lH-indazol-6-yl)-6-methylpyridin-2(lH)-one
Figure imgf000658_0002
The title compound was prepared by a similar procedure described for 4-hydroxy- 1-(1H- indazol-5-yl)-6-methylpyridin-2(lH)-one. Yield = 12%; 1H NMR (CD3OD/ 400 MHz) δ 8.12 (s, IH), 7.90 (d, IH, J = 8.0 Hz), 7.42 (s, IH), 6.94 (d, IH, J = 8.8 Hz) 6.08 (br s,
658 IH), 5.81 (d, IH, J = 2.4 Hz), and 1.96 (s, 3H); ES-HRMS m/z 242.0946(M+H calcd for C13H12N302 requires 242.0924).
Step 2: The title was prepared by a similar procedure described for 3-Bromo-4-[(2,4- difluorobenzyl)oxy]-l-(lH-indazol-5-yl)-6-methylpyridin-2(lH)-one. 1H NMR (CD3OD/ 400 MHz) δ 8.14 (s, IH), 7.93 (d, IH, J = 8.4Hz), 7.61 (m IH), 7.46 (s, IH), 7,04 (m, 2H), 6.98 (m, IH) 6.62 (s, IH), 5.36 (s, 2H), and 2.06 (s, 3H); 19F NMR(CD3OD/ 400 MHz) - 111.62 (m) and -116.03 (m); ES-HRMS m z 446.0302(M+H calcd for C13H12N302 requires 446.0310).
Example 643
Figure imgf000659_0001
Methyl 2- { [(3 -bromo-6-methyl- 1 - {2-methyl- 5 - [(methylamino)carbonyl]phenyl} -2-oxo- 1 ,2-dihydropyridin-4-yl)oxy]methyl} -5-fluorobenzylcarbamate
Step 1: Preparation of methyl 3-[4-[(2-cyano-4-fluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]-4-methylbenzoate.
Figure imgf000659_0002
To a cooled (0°C) solution of 2-(bromomethyl)-5-fluorobenzonitrile (4.31 g, 20.1 mmol) and methyl 3-(4-hydroxy-6-methyl-2-oxopyridin-l(2H)-yl)-4-methylbenzoate - 659 - (5.00 g, 18.3 mmol) in DMF (20 mL) was added K2C03 (3.00 g, 22.0 mmol). The reaction was allowed to warm to RT and stined overnight. Additional 2-(bromomethyl)- 5-fluorobenzonitrile (0.39 g, 1.83 mmol) and K2C03 (0.25 g, 1.83 mmol) were added and the reaction heated at 60°C for 2h. Solvent removed by distillation. Reaction neutralized with 5% citric acid (50 L). Organic products were extracted in DCM (3 x 25 mL), dried over Na S04, filtered, and concentrated to a thick dark brown oil. Purified by silica gel flash column chromatography using EtOAc as the eluent to give the product as a brown solid, dried in vacuo (6.18 g, 76%). 1H NMR (CD3OD/ 400MHz) δ 8.03 (m, IH), 7.76 (m, 2H), 7.66 (m, IH), 7.52 (m, 2H), 6.24 (s, IH), 6.09 (s, IH), 5.27 (s, 2H), 3.89 (s, 3H), 2.12 (s, 3H), 1.90 (s, 3H). ESHRMS m z 407.1408 (M+H calculated for C23H20FN2O4 requires 407.1402).
Step 2: Preparation of methyl 3-[4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-6-methyl-2- oxopyridin- 1 (2H)-yl]-4-methylbenzoate trifluoroacetate.
Figure imgf000660_0001
To a cooled (0°C) solution of methyl 3-[4-[(2-cyano-4-fluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoate (from Step 1) (0.510 g, 1.25 mmol) in THF (5 mL) was added dropwise BH3THF (2.51 mL, 2.51 mmol). The reaction was then stined at RT for 2.5h. Reaction cooled (0°C), quenched by the slow addition of MeOH, concenfrated, and purified by preparatory HPLC. The product was isolated by freeze- drying and evaporation of the solvent to give a white solid, dried in vacuo (0.39 g, 76%). !H NMR (CD3OD/ 400MHz) δ8.04 (m, IH), 7.75 (s, IH), 7.63 (m, IH), 7.55 (d, IH, J = 8.4 Hz), 7.32 (m, IH), 7.24 (m, IH), 6.25 (s, IH), 6.12 (s, IH), 5.23 (s, 2H), 4.25 (s, 2H), 3.90 (s, 3H), 2.11 (s, 3H), 1.90 (s, 3H). ESHRMS m/z 411.1691 (M+H calculated for C23H24FN204 requires 411.1715).
- 660 Step 3: Preparation of methyl 3-[4-[(4-fluoro-2-
{[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylbenzoate.
Figure imgf000661_0001
To a cooled (0°C) solution of methyl 3-[4-{[2-(aminomethyl)-4- fluorobenzyl]oxy}-6-methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoate trifluoroacetate (from Step 2) (0.50 g, 0.95 mmol) in DMA (4 mL) was added 4-methylmorpholine (0.21 mL, 1.9 mmol) and methyl chloroformate (0.08 mL, 1.0 mmol). Reaction was stined at RT for lh. Solvent removed by distillation. Crude product purified by preparatory HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHC03 (30 mL) and extracted in DCM (3 x 25 mL). The organic exfracts were dried over Na2S04, filtered, and concenfrated to a white solid, dried in vacuo (0.36 g, 81%). 1H NMR (CD3OD/ 400MHz) δ8.03 (m, IH), 7.77 (s, IH), 7.53 (d, IH, J = 7.6 Hz), 7.47 (m, IH), 7.12 (m, IH), 7.03 (m, IH), 6.21 (s, IH), 6.08 (s, IH), 5.18 (s, 2H), 4.38 (s, 2H), 3.89 (s, 3H), 3.65 (s, 3H), 2.12 (s, 3H), 1.89 (s, 3H). ESHRMS m/z 469.1767 (M+H calculated for C25H26FN206 requires 469.1769).
Step 4: Preparation of 3-[4-[(4-fluoro-2-{[(methoxycarbonyl)amino]methyl}benzyl)oxy]- 6-methyl-2-oxopyridin- 1 (2H)-yl] -4-methylbenzoic acid.
661
Figure imgf000662_0001
To methyl 3-[4-[(4-fluoro-2- {[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoate (from Step 3) (0.17 g, 0.36 mmol) was added 1.5 N NaOH solution in 1:1 MeOH:water (0.39 mL, 0.59 mmol). The reaction mixture was stined at 60°C for 2.5h. The solution was cooled (0°C), neutralized by the slow addition of 5% citric acid, and organic products exfracted in DCM. A white solid suspended in the organic layer was filtered, washed with DCM and water, dried in vacuo, and found to be the desired product (0.090 g, 55%). 1H NMR (CD3OD/ 400MHz) δ8.03 (m, IH), 7.75 (s, IH), 7.52 (d, IH, J = 8.0 Hz), 7.47 (m, IH), 7.12 (m, IH), 7.03 (m, IH), 6.21 (s, IH), 6.08 (s, IH), 5.18 (s, 2H), 4.38 (s, 2H), 3.65 (s, 3H), 2.12 (s, 3H), 1.90 (s, 3H). ESHRMS m/z 455.1632 (M+H calculated for C24H24FN 06 requires 455.1613).
Step 5: Preparation of 3-[3-bromo-4-[(4-fluoro-2-
{[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylbenzoic acid.
Figure imgf000662_0002
NBS (0.69 g, 3.85 mmol) was added to a solution of 3-[4-[(4-fluoro-2- {[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylbenzoic acid (from Step 4) (1.75 g, 3.85 mmol) in DCM (45 mL). After 1.5h,
- 662 - solvent removed on rotary evaporator. Solid dissolved in EtOAc and hexane added, resulting in a solid precipitate. Solid filtered. Solid subsequently dissolved in DCM and washed with water. Organic layer dried over Na2S04, filtered, and concentrated. Pale yellow solid dried in vacuo (1.47 g, 72%). 1H NMR (CD3OD/ 400MHz) δ8.04 (m, IH), 7.77 (s, IH), 7.54 (m, 2H), 7.13 (m, IH), 7.05 (m, IH), 6.68 (s, IH), 5.40 (s, 2H), 4.44 (s, 2H), 3.64 (s, 3H), 2.09 (s, 3H), 1.99 (s, 3H). ESHRMS m/z 533.0700 and 535.0677 (M+H calculated for C24H23BrFN206 requires 533.0718 and 535.0701).
Step 6: Preparation of the title compound. To a cooled (-10°C) solution of 3-[3-bromo-4-[(4-fluoro-2-
{[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylbenzoic acid (0.07 g, 0.13 mmol) in DMF (2.0 mL) was added isobutyl chloroformate (0.02 mL, 0.16 mmol) and 4-methylmorpholine (0.02 mL, 0.16 mmol). After 15min, 2.0M methylamine in THF (0.01 mL, 0.20 mmol) was added. Solvent removed by distillation after 30min. Crude product purified by preparatory HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHC03 (30 mL) and extracted in DCM (3 x 25 mL). The organic extracts were dried over Na2S04, filtered, concenfrated, and dried in vacuo to give a white foam, (0.061 g, 86%). 1H NMR (CD3OD/ 400MHz) δ7.85 (m, IH), 7.54 (m, 3H), 7.14 (m, IH), 7.05 (m, IH), 6.68 (s, IH), 5.40 (s, 2H), 4.43 (s, 2H), 3.64 (s, 3H), 2.89 (s, 3H), 2.08 (s, 3H), 1.99 (s, 3H). ESHRMS m z 546.0987 and 548.1018 (M+H calculated for C25H26BrFN305 requires 546.1034 and 548.1018).
- 663 Example 644
Figure imgf000664_0001
methyl 2-({[3-bromo- 1 -(5- {[(2-hydroxyethyl)amino] carbonyl} -2-methylphenyl)-6- methyl-2-oxo- 1 ,2-dihydropyridin-4-yl] oxy} methyl)-5 -fluorobenzylcarbamate
The title compound was prepared using a procedure similar to that used in the preparation of Example 643. !H NMR (CD3OD/ 400MHz) δ7.88 (m, IH), 7.61 (s, IH), 7.53 (m, 2H), 7.13 (m, IH), 7.04 (m, IH), 6.68 (s, IH), 5.41 (s, 2H), 4.43 (s, 2H), 3.68 (t, 2H, J = 5.6 Hz), 3.64 (s, 3H), 3.48 (t, 2H, J = 5.6Hz), 2.08 (s, 3H), 2.00 (s, 3H). ESHRMS m z 576.1101 and 578.1072 (M+H calculated for C26H28BrFN306 requires 576.1140 and 578.1124).
Example 645
Figure imgf000664_0002
methyl 2-({[3-bromo-l-(5-{[(2-hydroxy-2-methylpropyl)amino]carbonyl}-2- methylphenyl)-6-methyl-2-oxo- 1 ,2-dihydrop yridin-4-yι]oxy} methyl)-5- fluorobenzylcarbamate
- 664 - The title compound was prepared using a procedure similar to that used in the preparation of Example 643. 1H NMR (CD3OD/ 400MHz) δ7.89 (m, IH), 7.63 (s, IH), 7.54 (m, 2H), 7.13 (m, IH), 7.04 (m, IH), 6.69 (s, IH), 5.41 (s, 2H), 4.43 (s, 2H), 3.64 (s, 3H), 3.38 (s, 2H), 2.09 (s, 3H), 2.01 (d, 6H, J = 3.2 Hz), 1.21 (s, 3H). ESHRMS m/z 604.1412 and 606.1418 (M+H calculated for C28H32BrFN306 requires 604.1453 and 606.1438).
Example 646
Figure imgf000665_0001
methyl 2-( { [3-bromo- 1 -(5 - { [(2-methoxyethyl)amino] carbonyl} -2-methylphenyl)-6- methyl-2-oxo-l,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzylcarbamate
The title compound was prepared using a procedure similar to that used in the preparation of Example 643. 1H NMR (CD3OD/ 400MHz) δ7.87 (m, IH), 7.59 (s, IH), 7.53 (m, 2H), 7.14 (m, IH), 7.05 (m, IH), 6.68 (s, IH), 5.41 (s, 2H), 4.44 (s, 2H), 3.64 (s,
3H), 3.54 (s, 4H), 3.35 (s, 3H), 2.08 (s, 3H), 2.00 (s, 3H). ESHRMS m/z 590.1267 and
592.1219 (M+H calculated for C27H30BrFN3O6 requires 590.1297 and 592.1281).
665 Example 647
Figure imgf000666_0001
methyl 2-[( { 1 -[5-(aminocarbonyl)-2-methylphenyl]-3-bromo-6-methyl-2-oxo- 1 ,2- dihydropyridin-4-yl}oxy)methyl]-5-fluorobenzylcarbamate
The title compound was prepared using a procedure similar to that used in the preparation of Example 643. 1H NMR (CD3OD/ 400MHz) δ7.91 (m, IH), 7.64 (s, IH), 7.54 (m, 2H), 7.14 (m, IH), 7.05 (m, IH), 6.68 (s, IH), 5.40 (s, 2H), 4.44 (s, 2H), 3.64 (s, 3H), 2.09 (s, 3H), 2.00 (s, 3H). ESHRMS m/z 532.0836 and 534.0787 (M+H calculated for C24H24BrFN305 requires 532.0878 and 534.0861).
Example 648
Figure imgf000666_0002
N-[2-( { [3-chloro- 1 -(2,6-difluorophenyl)-6-methyl-2-oxo- 1 ,2-dihydropyridin-4- yl]oxy}methyl)-5-fluorobenzyl]-N'-phenylurea - 666 - To a cooled (0°C) solution of 4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3-chloro- l-(2,6-difluorophenyl)-6-methylpyridin-2(lH)-one trifluoroacetate (0.25 g, 0.48 mmol) in DMA (2.0 mL) was added 4-methylmorpholine (0.06 mL, 0.53 mmol) and phenyl isocyanate (0.06 mL, 0.53 mmol). The reaction was stined at RT for 1.5h. Solvent distilled and crude product purified by preparatory HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHC03 (30 mL) and exfracted in DCM (3 x 25 mL). The organic extracts were dried over Na2S04, filtered, and concentrated to a white solid, dried in vacuo (0.18 g, 71%). 1H NMR (CD3OD/ 400MHz) δ7.60 (m, IH), 7.54 (m, IH), 7.33 (d, 2H, J = 7.6 Hz), 7.22 (m, 5H), 7.06 (m, IH), 6.95 (t, IH, J = 7.2 Hz), 6.73 (s, IH), 5.44 (s, 2H), 4.53 (s, 2H), 2.07 (s, 3H). ESHRMS m z 528.1304 (M+H calculated for C27H22C1F3N303 requires 528.1296).
Example 649
Figure imgf000667_0001
thien-3-ylmethyl 2-({[3-chloro-l-(2,6-difluorophenyl)-6-methyl-2-oxo-l,2- dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzylcarbamate
To a cooled (0°C) solution of 4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-3-chloro- l-(2,6-difluorophenyl)-6-methylpyridin-2(lH)-one trifluoroacetate (0.26 g, 0.50 mmol) and 1, 1-carbonyldiimidazole (0.10 g, 0.60 mmol) in DMA (2.0 mL) was added 4-
- 667 methylmorpholine (0.06 mL, 0.55 mmol). After lh at RT, 3-thioρhenemethanol (0.09 mL, 0.99 mmol) was added. No product was observed after 2h at RT. NaH (0.01 g, 0.50 mmol) was added and the reaction stined at 60°C. Reaction was complete after 20min. The reaction mixture was cooled (0°C) and acetic acid added to quench the reaction. Solvent removed by distillation. Crude product purified by preparatory HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHC03 (30 mL) and extracted in DCM (3 x 25 mL). The organic extracts were dried over Na2S0 , filtered, and concentrated to a white foam, dried in vacuo (0.20 g, 73%). 1H NMR (CD3OD/ 400MHz) δ7.61 (m, IH), 7.52 (m, IH), 7.34 (s, 2H), 7.23 (t, 3H, J = 8.4 Hz), 7.10 (m, 2H), 6.71 (s, IH), 5.40 (s, 2H), 5.07 (s, 2H), 4.43 (s, 2H), 2.10 (s, 3H). ESHRMS m/z 549.0858 (M+H calculated for C26H21C1F3N204S requires 549.0857).
Example 650
Figure imgf000668_0001
ethyl-2-{[(3-bromo-6-methyl-l-{2-methyl-5-[(methylamino)carbonyl]phenyl}-2-oxo-l,2- dihydropyridin-4-yl)oxy]methyl}-5-fluorobenzylcarbamate
Step 1: Preparation of methyl 3-[4-[(2-{[(ethoxycarbonyl)amino]methyl}-4- fluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoate.
668
Figure imgf000669_0001
Prepared using a procedure similar to that used in the preparation of methyl 3-[4- [(4-fluoro-2-{[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]-4-methylbenzoate. 1H NMR (CD3OD/ 400MHz) δ8.03 (m, IH), 7.76 (s, IH), 7.53 (d, IH, J = 8.0 Hz), 7.47 (m, IH), 7.12 (m, IH), 7.03 (m, IH), 6.21 (s, IH), 6.08 (s, IH), 5.18 (s, 2H), 4.38 (s, 2H), 4.08 (q, 2H, J = 6.8 Hz), 3.89 (s, 3H), 2.12 (s, 3H), 1.89 (s, 3H), 1.23 (t, 3H, J = 6.8 Hz). ESHRMS m/z 483.1900 (M+H calculated for C26H28FN206 requires 483.1926).
\ Step 2: Preparation of 3-[4-[(2-{[(ethoxycarbonyl)amino]methyl}-4-fluorobenzyl)oxy]-6- methyl-2-oxopyridin- 1 (2H)-yl]-4-methylbenzoic acid.
Figure imgf000669_0002
Prepared using a procedure similar to that used in the preparation of 3-[4-[(4- fluoro-2-{[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]-4-methylbenzoic acid. 1H NMR (CD3OD/ 400MHz) δ8.03 (m, IH), 7.74 (s, IH), 7.48
(m, 2H), 7.11 (m, IH), 7.03 (m, IH), 6.21 (s, IH), 6.08 (s, IH), 5.18 (s, 2H), 4.38 (s, 2H),
4.08 (q, 2H, J = 7.2 Hz), 2.11 (s, 3H), 1.90 (s, 3H), 1.23 (t, 3H, J = 7.2 Hz). ESHRMS m/z
469.1738 (M+H calculated, for C25H26FN206 requires 469.1769).
669 - Step 3: Preparation of 3-[3-bromo-4-[(2-{[(ethoxycarbonyl)amino]methyl}-4- fluorobenzyl)oxy]-6-methyl-2-oχopyridin-l(2H)-yl]-4-methylbenzoic acid.
Figure imgf000670_0001
Prepared using a procedure similar to that used in Step 5 of the synthesis of Example 643. 1H NMR (CD3OD/ 400MHz) δ8.04 (m, IH), 7.76 (s, IH), 7.55 (m, 2H),
7.13 ( , IH), 7.05 (m, IH), 6.68 (s, IH), 5.40 (s, 2H), 4.43 (s, 2H), 4.07 (m, 2H), 2.09 (s,
3H), 1.99 (s, 3H), 1.22 (t, 3H, J = 7.2 Hz). ESHRMS m/z 547.0842 and 549.0818 (M+H calculated for C25H25BrFN206 requires 547.0875 and 549.0858).
Step 4: ethyl-2-{[(3-bromo-6-methyl-l-{2-methyl-5-[(methylamino)carbonyl]phenyl}-2- oxo-l,2-dihydropyridin-4-yl)oxy]methyl}-5-fluorobenzylcarbamate.Prepared using a procedure similar to that used in the preparation of Example 643. 1H NMR (CD3OD/ 400MHz) δ7.85 (m, IH), 7.54 (m, 3H), 7.13 (m, IH), 7.04 (m, IH), 6.68 (s, IH), 5.40 (s, 2H), 4.43 (s, 2H), 4.07 (q, 2H), 2.89 (s, 3H), 2.08 (s, 3H), 1.99 (s, 3H), 1.23 (t, 3H, J = 7.2 Hz). ESHRMS m/z 560.1215 and 562.1193 (M+H calculated for C26H28BrFN305 requires 560.1191 and 562.1175).
- 670 - Example 651
Figure imgf000671_0001
3-[3-bromo-4-{[2-({[(cyclopropylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6- methyl-2-oxopyridin- 1 (2H)-yl]-N,4-dimethylbenzamide
Step 1: Preparation of methyl 3-[4-{[2-({[(cyclopropylamino)carbonyl]amino}methyl)-4- fluorobenzyl]oxy}-6-methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoate.
Figure imgf000671_0002
To a cooled (0°C) solution of methyl 3-[4-{[2-(aminomethyι)-4- fluorobenzyl] oxy} -6-methyl-2-oxopyridin- 1 (2H)-yl] -4-methylbenzoate trifluoroacetate (1.13 g, 2.16 mmol) and 1,1-carbonyldiimidazole (0.42 g, 2.59 mmol) in DMA (8.0 mL) was added 4-methylmorpholine (0.36 mL, 3.2 mmol). After 30 minutes at room temperature, the reaction was cooled to approximately 0°C and an excess of cyclopropylamine was added. Reaction was stined at RT for 2h. DMA removed by distillation. Crude product purified by preparatory HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHC03 (30 mL) and extracted in DCM (3 x 25 mL).
- 671 - The organic extracts were dried over Na2S04, filtered, concentrated, and dried in vacuo (0.78 g, 73%). 1H NMR (CD3OD/ 400MHz) δ8.03 (m, IH), 7.76 (s, IH), 7.53 (d, IH, J = 8.0 Hz), 7.46 ( , IH), 7.12 (m, IH), 7.01 (m, IH), 6.22 (s, IH), 6.08 (s, IH), 5.19 (s, 2H), 4.44 (s, 2H), 3.89 (s, 3H), 2.48 (m, IH), 2.12 (s, 3H), 1.89 (s, 3H), 0.70 (m, 2H), 0.47 (m, 2H). ESHRMS m z 494.2076 (M+H calculated for C27H29FN305 requires 494.2086).
Step 2: Preparation of 3-[4-{[2-({[(cyclopropylamino)carbonyl]amino}methyl)-4- fluorobenzyl]oxy}-6-methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoic acid.
Figure imgf000672_0001
Prepared using a procedure similar to that used in the preparation of 3-[4-[(4- fluoro-2-{[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]-4-methylbenzoic acid. 1H NMR (CD3OD/ 400MHz) δ8.02 (m, IH), 7.74 (s, IH), 7.48 (m, 2H), 7.12 (m, IH), 7.01 (m, IH), 6.22 (s, IH), 6.08 (s, IH), 5.19 (s, 2H), 4.44 (s, 2H), 2.48 (m, IH), 2.11 (s, 3H), 1.90 (s, 3H), 0.69 (m, 2H), 0.47 (m, 2H). ESHRMS m/z 480.1921 (M+H calculated for C26H27FN305 requires 480.1929).
Step 3: Preparation of 3-[3-bromo-4-{[2-({[(cyclopropylamino)carbonyl]amino}methyl)- 4-fluorobenzyl]oxy}-6-methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoic acid
672
Figure imgf000673_0001
Prepared using a procedure similar to that used in Step 5 of the synthesis of
Example 643. lR NMR (DMSO-d6/ 400MHz) δ7.92 (m, IH), 7.67 (s, IH), 7.54 (m, 2H),
7.12 (m, 2H), 6.71 (s, IH), 5.37 (s, 2H), 4.31 (d, 2H, J = 6.4 Hz), 2.40 (m, IH), 2.00 (s, 3H), 1.88 (s, 3H), 0.56 (m, 2H), 0.33 (m, 2H). ESHRMS m/z 558.0988 and 560.0981
(M+H calculated for C26H26BrFN305 requires 558.1034 and 560.1018).
Step 4 : 3- [3-bromo-4- { [2-( { [(cyclopropylamino)carbonyl] amino } methyl)-4- fluorobenzyl]oxy} -6-rnefhyl-2-oxopyridin- 1 (2H)-yl]-N,4-dimethylbenzamide. Prepared using a procedure similar to that used in the preparation of Example 643.
1H NMR (CD3OD/ 400MHz) δ7.85 (m, IH), 7.54 (m, 3H), 7.14 (m, IH), 7.03 (m, IH), 6.69 (s, IH), 5.41 (s, 2H), 4.48 (s, 2H), 2.89 (s, 3H), 2.48 (m, IH), 2.08 (s, 3H), 1.99 (s, 2H), 0.70 (m, 2H), 0.47 (m, 2H). ESHRMS m/z 571.1348 and 573.1355 (M+H calculated for C27H29BrFN404 requires 571.1351 and 573.1335).
673 - Example 652
Figure imgf000674_0001
3 - [3 -bromo-4- { [2-( { [(cyclopropylamino)carbonyl] amino} methyl)-4-fluorobenzyl] oxy} -6- methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoic acid
Step 1: Preparation of ethyl (5-fluoro-2-methylphenoxy)acetate.
Figure imgf000674_0002
To a solution of 5-fluoro-2-methylphenol (1.00 g, 7.93 mmol) and ethylbromoacetate (1.59 g, 9.51 mmol) in DMF (15 mL) was added K2C03 (1.10 g, 7.93 mmol). After 30min at RT, DMF was removed by distillation. The crude product was washed with 5% citric acid (30 mL) and water (30 mL), exfracted in DCM (3 x 20 mL), dried over Na2S04, filtered, concenfrated, and dried in vacuo. Desired product obtained as yellow oil (1.30 g, 77%). 1H NMR (CD3OD/ 400MHz) δ7.09 (t, IH, J = 8.8 Hz), 6.58 (m, IH), 6.56 (m, IH), 4.71 (s, 2H), 4.23 (q, 2H, J = 7.2 Hz), 2.18 (s, 3H), 1.27 (t, 3H, J = 7.2 Hz). ESHRMS m/z 212.0847 (M+H calculated for CπHι3F03 requires 212.0849).
Step 2: Preparation of ethyl [2-(bromomethyl)-5-fluorophenoxy]acetate.
- 674
Figure imgf000675_0001
A solution of ethyl (5-fluoro-2-methylphenoxy)acetate (from Step 1) (0.65 g, 3.06 mmol), NBS (0.65 g, 3.68 mmol), and benzoyl peroxide (0.05 g, 0.21 mmol) in CC14 (7.0 L) were refluxed at 90°C for 2.5h. Additional NBS (0.16 g, 0.92 mmol) added, and reaction continued overnight. Solid filtered and filfrate concentrated onto silica gel. Purified by flash column chromatography using hexane and 2.5% EtOAc/hexane as eluent. Product obtained as yellow liquid (0.27 g, 30%). 1H NMR (CD3OD/ 400MHz) δ7.37 (m, IH), 6.69 (m, 2H), 4.80 (s, 2H), 4.60 (s, 2H), 4.23 (q, 2H, J = 7.2 Hz), 1.27 (t, 3H, J = 7.2 Hz).
Step 3: Preparation of ethyl [2-({[3-bromo-l-(2,6-difluorophenyl)-6-methyl-2-oxo-l,2- dihydropyridin-4-yl] oxy} methyl)-5-fluorophenoxy] acetate.
Figure imgf000675_0002
To a solution of ethyl [2-(bromomethyl)-5-fluorophenoxy]acetate (from Step 2) (0.59 g, 2.03 mmol) and 3-bromo-l-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin- 2(lH)-one (0.61 g, 1.93 mmol) in DMF (3.0 mL) was added K2C03 (0.34 g, 2.43 mmol). After 2h at RT, DMF was removed by distillation. The crude product was washed with 5% citric acid, extracted in DCM, dried over Na2S0 , filtered, and concentrated onto silica gel. Purified by flash column chromatography using 50% EtOAc hexane as the eluent. Obtained product as a pale yellow solid (0.45 g, 42%). 1H NMR (CD3OD/ 400MHz) - 675 - 87.21 (q, 3H, J = 8.4 Hz), 6.80 (m, 2H), 6.69 (s, IH), 6.15 (s, IH), 5.40 (s, 2H), 4.84 (s, 2H), 4.23 (q, 2H, J = 6.8 Hz), 2.08 (s, 3H), 1.26 (t, 3H, J = 6.8 Hz). ESHRMS m/z 526.0446 and 528.0414 (M+H calculated for C23H20BrF3NO5 requires 526.0471 and 528.0454).
Step 4: Preparation of [2-({[3-bromo-l-(2,6-difluorophenyl)-6-methyl-2-oxo-l,2- dihydropyridin-4-yl]oxy}methyl)-5-fluorophenoxy]acetic acid.
Figure imgf000676_0001
A solution of ethyl [2-({[3-bromo-l-(2,6-difluoroρhenyl)-6-methyl-2-oxo-l,2- dihydropyridin-4-yl]oxy}methyl)-5-fluorophenoxy]acetate (from Step 3) (0.62 g, 1.18 mmol), 1.5 N NaOH solution in 1:1 MeOH:water (1.2 mL, 1.77 mmol), and THF (1.2 mL) were refluxed at 60°C for lh. The solution was concentrated on a rotary evaporator, cooled, and 5% citric acid added. The solid precipitate was filtered and dried in vacuo.
Product obtained as a pale yellow solid (0.35 g, 60%). 1H NMR (CD3OD/ 400MHz) δ7.59 (m, IH), 7.49 (m, IH), 7.22 (m, 2H), 6.75 (m, 2H), 6.72 (s, IH), 5.43 (s, 2H), 4.66 (s, 2H),
2.07 (s, 3H). ESHRMS m/z 498.0143 and 500.0186 (M+H calculated for C21H16BrF3N05 requires 498.0158 and 500.0141).
Step 5: Preparation of 2-[2-({[3-bromo-l-(2,6-difluorophenyl)-6-methyl-2-oxo-l,2- dihydropyridin-4-yl]oxy}methyl)-5-fluorophenoxy]-N-ethylacetamide.
676
Figure imgf000677_0001
To a cooled (-10°C) solution of [2-({[3-bromo-l-(2,6-difluorophenyl)-6-methyl-2- oxo-l,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorophenoxy]acetic acid (from Step 4) (0.15 g, 0.30 mmol) in DMA (2.0 mL) was added 4-methylmorpholine (0.04 mL, 0.36 mmol) and isobutyl chloroformate (0.05 mL, 0.36 mmol). Ethylamine (0.04 mL, 0.45 mmol) was added after 20 minutes. DMF removed by distillation after lh. Crude product purified by preparatory HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHC03 (30 mL) and extracted in DCM (3 x 25 mL). The organic exfracts were dried over Na2S04, filtered, concentrated, and dried in vacuo to give a white solid (0.080 g, 51%). 1H NMR (CD3OD/ 400MHz) δ7.60 (m, IH), 7.53 (t, IH, J = 8.0 Hz), 7.23 (t, 2H, J = 8.4 Hz), 6.82 (m, 2H), 6.71 (s, IH), 5.42 (s, 2H), 4.61 (s, 2H), 3.31 (q, 2H, J = 6.4 Hz), 2.10 (s, 3H), 1.09 (t, 3H, J = 7.2 Hz). ESHRMS m/z 525.0616 and 527.0568 (M+H calculated for C23H21BrF3N204 requires 525.0631 and 527.0614).
Example 653
Figure imgf000677_0002
methyl 3 -[6- [(acetyloxy)methyl] -3 -bromo-4- [(2,4-difluorobenzyl)oxy] -2-oxopyridin- l(2H)-yl]-4-methylbenzoate.
Step 1: Preparation of 3-(2,2-dimethyl-4-oxo-4H-l,3-dioxin-6-yl)-2-oxopropyl acetate. - 677 -
Figure imgf000678_0001
A solution of 2,2,6-trimethyl-4H-l,3-dioxin-4-one (20g, 141 mmol) in dry THF (400 mL) was cooled to -78 °C. To this solution was slowly added a LiHMDS (lM-THF, 160 mL, 160 mmol). The resulting solution was maintained at -78°C with stirring for 30 min. To the reaction mixture was added acetoxy acetylchloride (17 mL, 160 mmol) and the resulting mixture was maintained at -78 °C for at lh. The reaction was then allowed to slowly warm to rt and stir for an additional lh. The reaction was then quenched with addition of a IN solution of ammonium chloride. The layers were sperated and the aqueous layer was extracted with ethyl acetate (5x). The organics were combined, dried, and concentrated in vacuo. The crude product was purified using a medium pressure liquid chromatography biotage system. Elution with hexanes-ethyl acetate (3:1) gave 13.1 g (38%) of a red-brown oil. The product looks clean by NMR. 1H NMR (300 MHz, CDC13) δ 5.42 (s, IH), 4.75 (s, 2H), 3.41 (s, 2H), 2.22 (s, 3H), 1.75 (s, 6H).
Step 2: Preparation of methyl 3-[6-[(acetyloxy)methyl]-4-hydroxy-2-oxoρyridin-l(2H)- yl]-4-methylbenzoate.
Figure imgf000678_0002
To a 100 mL RBF containing methyl 3-amino,4-methylbenzoate (1.65g, 10 mmol) was added the enone from Step 1 (2.6g, 10.7 mmol). The mixture was then dissolved in toluene (40 mL), fitted with a reflux condenser, and placed in an oil bath preset to 115 °C.
The mixture was heated to reflux for 1.5h. The reaction flask was removed from the oil bath and a catalytic amount of TFA (5-6 drops) was added. The reaction was placed back in the oil bath and heated to reflux for an additional 2h. The reaction was then allowed to cool to 0°C. The toluene was then removed under vacuum to give a thick brown residue. The residue was then dissolved in acetonitrile (10-15 mL) and allowed to stand. After 20-
- 678 - 30 min a precipitate results which was filtered and washed with diethyl ether. After drying, an off-white solid (1.9g, 57% yield) was obtained. 1H NMR (300 MHz, DMSO-d6) δ 7.94 (dd, J = 7.8,1.5 Hz, IH), 7.73 (s, IH), 7.54 (d, J = 8.1 Hz, IH), 6.19 (s, IH), 5.73- 5.71 (m, IH), 4.47 (AB quar, J = 10.5 Hz, 2H), 3.87 (s, 3H), 2.09 (s, 3H), 1.91 (s, 3H). ES-HRMS m/z 332.1096 (M+H calcd for C17H18N06 requires 332.1129).
Step3: Preparation of methyl 3-[6-[(acetyloxy)methyl]-3-bromo-4-hydroxy-2-oxopyridin-
1 (2H)-yl]-4-methylbenzoate.
Figure imgf000679_0001
To a s iny of the phenol (2.5g, 7.5 mmol) in dry acetonitrile (50 mL), at rt, was added n-bromosuccinimide (1.33g, 7.5 mmol). The resulting homogeneous mixture was stined at rt for 3h. The resulting precipitate was filtered and washed sequentially with acetonitrile and the diethyl ether. The product was dried in a vacuum oven to yield an off- white solid (2.5g, 81%). 1H NMR (300 MHz, DMSO-d6) δ 11.82 (s, IH), 7.97 (dd, J = 7.8,1.5 Hz, IH), 7.80 (d, J = 1.5 Hz, IH), 7.57 (d, J = 8.1 Hz, IH), 6.38 (s, IH), 4.49 (AB quar, J = 13.8 Hz, 2H), 3.87 (s, 3H), 2.08 (s, 3H), 1.92 (s, 3H). ES-HRMS m/z 410.0225 (M+H calcd for C17H17NBr06 requires 410.0234).
Step 4: Preparation of the title compound. To a solution of the above phenol (2.5g, 6.0 mmol) in dry DMF (25 mL) was added solid potassium carbonate (804 mg, 6.0 mmol). To this mixture was then added, via syringe, 2,4-diflourobenzyl bromide (783 μL, 6.0 mmol). The resulting mixture was allowed to stir at rt overnight. The reaction was then poured into ice water and stined vigorously. The resulting precipitate was filtered and washed sequentially with water and diethyl ether. The solid was dried in a vacuum oven to yield an off-white solid (3.3g, 99%). 1H NMR (400 MHz, DMSO-d6) δ 7.97 (dd, J = 7.6,1.2 Hz, IH), 7.83 (d, J = 1.6 Hz, IH), 7.71 (q, J = 8.8 Hz, IH), 7.57 (d, J = 8.0 Hz, IH), 7.37 (dt, J = 10.4, 2.4 Hz, IH), 7.21 (dt, J = 8.4, 2.0 Hz, IH), 6.90 (s, IH), 5.40 (s,
- 679 - 2H), 4.57 (AB quar, J = 13.6 Hz, 2H), 3.86 (s, 3H), 2.07 (s, 3H), 1.90 (s, 3H). ES-HRMS m/z 536.0484 (M+H calcd for C24H21NF2Br06 requires 536.0515).
Example 654
Figure imgf000680_0001
3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-l(2H)- yl]-4-methylbenzoic acid.
To a stined suspension, at rt, of the Example 643 (2.0g, 3.7 mmol) in THF (10 mL) was added a solution of 2.5N NaOH (3mL, 7.5 mmol). The resulting homogeneous solution was stirred for 2h. The reaction was judged complete and IN HCl was added dropwise until a pH ~ 4 was obtained. The reaction was then diluted with CH2C12 (10 mL). The resulting precipitate was filtered with additional washing from CH2C12. The solid was dried in a vacuum oven to yield a pure white solid (1.8g, 99%). !H NMR (300 MHz, DMSO-d6) δ 7.95 (dd, J = 7.8,1.8 Hz, IH), 7.74-7.66 (m, 2H), 7.54 (d, J = 8.1 Hz, IH), 7.37 (dq, J = 7.8, 2.7 Hz, IH), 7.24-7.17 (m, IH), 6.72 (s, IH), 5.39 (s, 2H), 3.83 (AB quar, J = 15.6 Hz, 2H), 2.02 (s, 3H). ES-HRMS m/z 480.0253 (M+H calcd for C21H17NF2Br05 requires 480.0253).
Example 655
Figure imgf000680_0002
3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-l(2H)- yl]-N-(2-hydroxyethyl)-4-methylbenzamide. - 680 - To a slurry of Example 654 (500mg, 1.04 mmol) in anhydrous CH2C12 was added Et3N (218 μL, 1.56 mmol) and the resulting homogeneous mixture was stined at rt. To this mixture was then added ethanolamine (70 μL, 1.14 mmol) via syringe. HOBt (155mg, 1.14 mmol) was then added followed by addition of EDC (217 mg, 1.14 mmol). The reaction was allowed to stir overnight at rt. The reaction was quenched by addition of a solution of IN NH C1. The biphasic mixture was separated and the aqueous layer was exfracted with CH C12 (4X). The organics were combined, dried, and concentrated in vacuo. The resulting residue was purified by flash chromatography on a 16g Michele- Miller column. Elution with CH Cl2-MeOH (10: I D 12:1) resulted in obtaining the desired product as a viscous oil. The oil was then dissolved in a CH3CN-Et20 combination. After 5-10 minutes, a precipitate resulted which upon filtration and drying yielded a pure white solid (210 mg, 40%). 1H NMR (300 MHz, DMSO-d6) δ 8.46 (t, J = 5.2 Hz, IH), 7.88 (dd, J = 8.0, 2.0 Hz, IH), 7.72-7.65 (m, 2H), 7.50 (d, J = 8.4 Hz, IH), 7.37 (dq, J = 9.6, 2.4 Hz, IH), 7.20 (dq, J = 7.6, 1.6 Hz, IH), 6.71 (s, IH), 5.68 (t, J = 5.6 Hz, -OH), 5.40 (s, 2H), 4.73 (t, J = 5.6 Hz, -OH), 4.02 (dd, J = 16.4, 5.6 Hz, IH), 3.70 (dd, J = 16.4, 5.6 Hz, IH), 3.52-3.48 (m, 2H), 3.39-3.25 (m, 2H), 2.00 (s, 3H). ES-HRMS m/z 523.0674 (M+H calcd for C23H22N2F2Br05 requires 523.0675).
Example 656
Figure imgf000681_0001
3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-l(2H)- yl]-N,4-dimethylbenzamide. The titled compound was prepared from the acid Example 654 (550 mg, 1.07 mmol) in a similar manner to the amide described above using EDC (245 mg, 1.28 mmol), HOBt (171 μL, 1.28 mmol), Et3N (225 mL, 1.6 mmol), and 2.0M MeNH2-THF (1.2 μL, 2.48 mmol). Following work-up with IN NKUCl the product was precipitated out - 681 - of the biphasic mixture after dilution with additional CH2C12 to give a white solid (250 mg, 51% yield). %). 1H NMR (300 MHz, DMS0-d6) δ 8.48 (quar, J = 4.5 Hz, IH), 7.88 (dd, J = 8.1, 1.8 Hz, IH), 7.72 (app quar, J = 6.6 Hz, IH), 7.63 (d, J = 1.8 Hz, IH), 7.52 (d, J = 8.1 Hz, IH), 7.37 (dt, J = 10.2, 2.4 Hz, IH), 7.20 (app dt, J = 8.4, 1.8 Hz, IH), 6.74 (s, IH), 5.71 (t, J = 5.4 Hz, IH), 5.42 (s, 2H), 4.03 (dd, J = 13.8, 5.1 Hz, IH), 3.72 (dd, J = 16.4, 5.1 Hz, IH), 2.78 (d, J = 4.5 Hz, 3H), 2.02 (s, 3H). ES-HRMS m z 493.0575 (M+H calcd for C22H20N2F2BrO4 requires 493.0569).
Example 657
Figure imgf000682_0001
3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-l(2H)-yl]-4- methylbenzamide.
To a stined suspension, at rt, of the carboxylic acid Example 654 (400 mg, 0.80 mmol) in anhydrous THF (4 mL) was added 4-methylmorpholine (274 μL, 2.5 mmol). To the resulting heterogeneous solution was then added 2-Chloro-4,6-dimethyιtriazine (170 mg, 1.0 mmol) and the mixture was allowed to stir for lh at rt. Ammonium hydroxide solution (28-32%, 2 mL) was then added to the reaction and it was allowed to stir at rt overnight. The reaction was then worked up by diluting with H20 (2-3 mL) and stirring vigorously. The resulting precipitate was filtered and washed with H20 and then diethyl ether. After drying with a vacuum oven an off-white solid (140 mg, 32%) was obtained.
%). 1H NMR (300 MHz, DMSO-d6) δ 7.99-7.80 (m, 2H), 7.76 (m, 3H), 7.52 (d, J = 8.1
Hz, IH), 7.43-7.39 (m, 2H), 7.52 (d, J = 8.1 Hz, IH), 7.43-7.36 (m, 2H), 7.20 (dt, J = 8.7,
1.8 Hz, IH), 6.74 (s, IH), 5.41 (s, 2H), 4.02-3.62 (m, 2H), 2.03 (s, 3H). ES-HRMS m z 479.0411 (M+H calcd for C21H18N2F2Br04 requires 479.0413).
682 Example 658
Figure imgf000683_0001
(5-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{2-methyl-5-[(methylamino)carbonyl]phenyl}-6- oxo- 1 ,6-dihydropyridin-2-yl)methyl acetate.
To a solution of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2- oxopyridin-l(2H)-yl]-N,4-dimethylbenzamide (225 mg, 0.50 mmol) stined in CH2C12 was added pyridine (55 μL, 0.69 mmol). To the resulting homogeneous solution was then added acetic anhydride (47 μL, 0.51 mmol). The mixture was stined at rt for 3h. Additional pyridine (150 μL, 1.8 mmol) and acetic anhydride (100 μL, 1.05 mmol) were then added and the reaction was allowed to stir overnight at rt. The reaction was then quenched with IN NHCL and diluted with CH2C12. The layers were separated and the organic layer was then extracted with CH2C12 (3X). The organics were then combined, dried, and concenfrated in vacuo. The residue was then triturated with Et20 and filtered to give (150 mg, 61%) an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.48 (br s, IH), 7.87 (app d, J = 7.8 Hz, IH), 7.74-7.69 (m, 2H), 7.52 (d, J = 7.5 Hz, IH), 7.40 (app t, J = 8.1 Hz, IH), 7.28-7.19 (m, IH), 6.91 (s, IH), 5.43 (s, 2H), 4.60 (s, 2H), 2.79 (s, 3H), 2.06 (s, 3H), 1.94 (s, 3H). ES-HRMS m/z 535.0676 (M+H calcd for C24H22N2F2Br05 requires 535.0675).
Example 659
Figure imgf000683_0002
(2E)-4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N- methylbut-2-enamide.
- 683 Step 1 , (2E)-4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]but-2-enoic acid: The carboxylic acid compo was prepared by stirring the ester (900 mg, 2.1 mmol) in THF (10 mL). To this solution was added IN NaOH (1 mL) and the resulting mixture was stined at rt. After 2 h, additional NaOH (1 mL) was added to the reaction and then allowed to stir at rt overnight. The THF was then concenfrated under vacuum. The remaining aqueous layer was then acidified to pH ~ 4 after which a white precipitate resulted. Filtration and drying under vacuum gave rise to a white solid (900 mg) that was used as in the next step.
The titled compound was prepared by stirring the above acid (480 mg, 1.16 mmol) in CH2C12 at rt. To this mixture was added sequentiallyEt3N (244 μL), HOBt (188 mg, 1.4 mmol), MeNH2 (2.0M-THF, 700 mL, 1.4 mmol), and finally EDC (266 mg, 1.4 mmol). The homogeneous mixture was then allowed to stir at rt overnight. The reaction was quenched with IN HCl. The layers were separated and the aqueous layer was extracted with CH2C12 (4x). The organics were combined, dried, and concenfrated in vacuo. The crude residue was triturated in CH3CN-Et20 combination and filtered to give a pure white solid (330 mg, 67%). 1H-NMR (DMSOd6/300 MHz) δ 8.20-7.90 (m, IH), 7.68 (q, J = 8.4 hz, IH); 7.37 (dt, J = 10.2, 2.4 Hz, IH); 7.20 (dt, J = 15.6, 4.2 Hz, IH); 6.60 (s, IH), 5.63 (d, J = 15.6 Hz, IH), 5.31 (s, 2H), 4.81 (d, J = 2.7 Hz, 2H), 3.33 (d, J = 6.9 Hz, IH), 2.61 (d, J = 4.8 Hz, 3H), 2.37 (s, 3H). ES-HRMS m/z 427.0493 (M + H calcd for C18H18BrF2N203 = 427.0463).
Example 660
Figure imgf000684_0001
methyl 5- {[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l (2H)- yTJmethyl} -2-furoate
684 Step 1: To a room temperature suspension of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methylρyridin-2(lH)-one (330.1 mg, 1.00 mmol)) and NaH (48.0 mg, 2.0 mmol) in THF (1.6 mL) was added methyl-5-chloromethyl-2-furate (400 mg, 2.30 mmol). The resulting suspension was stined and heated to 68 °C for 8 hours until complete consumption of starting material by LCMS analysis. The reaction mixture was then diluted with ammonium chloride (saturated aqueous solution, 10 mL) and water (100 mL). This resulting emulsion was then extracted with with ethyl acetate (3 X 300 mL). The resulting organic extract was separated, Na2S04 dried, and concentrated. The resulting dark residue was subjected to Si02 chromatography with ethyl acetate hexanes (3:7) to furnish a solid. 1H NMR (400 MHz, CDC13) δ 7.53 (app q, J = 8.2 Hz, IH), 7.07 (d, J = 3.5 Hz, IH), 6.93 (app dt, J = 8.4, 1.5 Hz, IH), 6.84 (app ddd, J = 10.2, 8.7, 2.4 Hz, IH), 6.53 (d, J = 3.4 Hz, IH), 6.00 (s, IH), 5.27 (s, 2H), 5.18 (s, 2H), 3.85 (s, 3H), 2.54 (s, 3H); LC/MS C-18 column, tr = 2.64 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m z 468 (M+H). ES-HRMS m z 468.0276 (M+H calcd for C20H17BrF2NO5 requires 468.0253).
Example 661
Figure imgf000685_0001
3 - [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -4- (hydroxymethyl)-N-methylbenzamide
Step 1: Preparation of 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]-4-[(methylamino)carbonyl] benzoic acid.
685
Figure imgf000686_0001
To a room temperature solution of methyl 2- [3 -bromo-4- [(2,4- difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -4-
[(methylamino)carbonyl]benzoate (1.05 g, 2.02 mmol) in THF (10.0 mL) was added dropwise an aqueous solution of sodium hydroxide (3.0 M, 3.5 mL, 10 mmol). The reaction was then heated to 60 °C for 8.0 hours. The resulting suspension was then diluted with 500 mL of ethyl acetate and neutralized with an aqueous solution of hydrochloric acid (2.0 N, 5.0 mL, 10 mmol). The resulting biphasic solution was separated and the resulting aqueous layer was further exfracted with ethyl acetate (2 X 200 mL). The resulting combined organic exfracts were Na2S04 dried, filtered and concentrated in vacuo to a volume of 50 mL. At this time a white solid began to form and the resulting solid suspension was allowed to sit until precipitation appeared to stop (approximately 1.0 hour). The precipitate was collected and dried in vacuo (1.0 mm Hg) to furnish the solid acid as an intermediate (806 mg, 78 %). 1H NMR (400 MHz, d7-DMF) δ 13.19 (s, IH), 8.63 (app d, J = 4.5 Hz, IH), 8.09 (d, J = 8.0 Hz, IH), 8.00 (dd, J = 8.0, 1.6 Hz, IH), 7.71- 7.67 (m, 2H), 7.34 (app dt, J = 9.6, 1.6 Hz, IH), 7.16 (app dt, J = 8.7, 1.8 Hz, IH), 6.66 (s, IH), 5.33 (s, 2H), 3.29 (s, 3H), 1.92 (s, 3H); LC/MS C-18 column, tr = 2.15 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ESMS m/z 507 (M+H). ES-HRMS m/z 507.0344 (M+H calcd for C22H18BrF2N205 requires 507.0362).
Step 2: Preparation of the title compound. To a 0 °C solution of 2- [3 -bromo-4- [(2,4- difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl]-4-[(methylamino)carbonyl] benzoic acid (500 mg, 0.986 mmol) in THF (6.8 mL) was added dropwise a solution of borane-
- 686 - dimethyl sulfide complex (THF solution, 2.0 M, 2.0 mL, 4.0 mmol). The internal temperature of the reaction was never allowed to exceed 0 °C. The resulting solution was maintained for 4.0 hours, at which time the cooling bath was removed and the reaction was maintained at room temperature for an additional two hours. Next, a solution of ammonium chloride (saturated aqueous, 300 mL) was added. The resulting emulsion was extracted with ethyl acetate (3 X 300 mL) and the resulting organic extracts were separated, Na2S04 dried, and concentrated in vacuo to a residue that was subjected to Si02 chromatography with ethyl acetate/hexanes (6:4) to furnish a solid (392 mg, 81 %). 1H NMR (400 MHz, c vleOH) δ 7.96 (dd, J = 8.0, 1.9 Hz, IH), 7.75 (d, J = 8.1 Hz, IH), 7.65 (app q, J = 8.0 Hz, IH), 7.58 (d, J = 1.7 Hz, IH), 7.05 (app t, J = 8.5 Hz, 2H), 6.64 (s, IH), 5.36 (s, 2H), 4.35 (AB-q, J = 14.1 Hz, Δ = 60.8 Hz, 2H), 2.90 (s, 3H), 2.03 (s, 3H); LC/MS C-18 column, tr = 2.16 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 493 (M+H). ES-HRMS m/z 493.0590 (M+H calcd for C22H20BrF2N2O4 requires 493.0596).
Example 662
Figure imgf000687_0001
2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N,N'- dimethylterephthalamide
Step 1: To a room temperature solution of 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]-4-[(methylamino)carbonyl] benzoic acid (500 mg, 0.986 mmol) in DMF (5.0 mL) was added l-(3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (EDC-HC1, 350.0 mg, 1.83 mmol) and 1-hydroxy-benzotriazole (HOBT, 100.0 mg, 0.74 mmol) sequentially. To this resulting suspension was then added a solution of methylamine (2.0 M THF, 1.0 mL, 2.0 mmol). The reaction was stined for 16.0 hours, - 687 - at which time the reaction was diluted with ethyl acetate (600 mL). The mixture was washed with (3 X 200 mL) of water and the organic exfract was separated, Na2S04 dried, and concentrated in vacuo to a volume of approximately 60 mL. At this time a solid precipitate formed and was collected to furnish (289 mg, 56 %). 1H NMR (300 MHz, άV MeOH) δ 8.06 (br d, J = 8.0 Hz, IH), 7.81 (d, J = 8.1 Hz, IH), 7.73 (s, IH), 7.70 (app q, J = 7.4 Hz, IH), 7.09 (app t, J = 8.0 Hz, 2H), 6.65 (s, IH), 5.39 (s, 2H), 2.96 (s, 3H), 2.79 (s, 3H), 2.13 (s, 3H); LC/MS C-18 column, tr = 2.13 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m z 520 (M+H). ESHRMS m/z 520.0700 (M+H calcd for C23H21BrF2N304 requires 520.0678).
Example 663
Figure imgf000688_0001
2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-4- methylterephthalamide
Step 1 : To a room temperature suspension of 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]-4-[(methylamino)carbonyl] benzoic acid (302 mg, 0.595 mmol) in THF (1.8 mL) was added 2-chloro-4,6 dimethoxy-1,3,5 triazine (140.5 mg, 0.800 mmol) and N-methyl morpholine (NMM, 184 mg, 1.824 mmol) sequentially. The resulting solution was matured for 2 hours and then a saturated aqueous solution of ammonium hydroxide (0.60 mL) was added. The reaction was allowed to continue for 1 additional hour at which time a precipitate formed which was collected, washed with 20 mL of diethyl ether, and dried in vacuo to furnish a solid (201 mg, 66 %). lR NMR (400 MHz, d6-DMSO) δ 8.59 (br d, J = 8.0, IH), 7.96 (d, J = 8.0 Hz, IH), 7.83 (s, IH), 7.72 (d, J = 9.0, IH), 7.69-7.64 (m, 2H), 7.39-7.31 (m, IH), 7.19 (app t, J = 8.0 Hz, IH), 6.60 (s, IH), 5.3 l(s, 2H), 3.85 (s, IH), 2.78 (br d, J = 8.0 Hz, 3H), 1.96 (s, 3H); LC/MS C-18 - 688 - column, tτ = 2.20minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 506 (M+H). ES-HRMS m/z 506.0550 (M+H calcd for C22H19BrF2N304 requires 506.0522).
Example 664
Figure imgf000689_0001
methyl 4-(aminocarbonyl)-2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]benzoate
Step 1: To a room temperature solution of 3-(4-hydroxy-6-methyl-2-oxopyridin-l(2H)- yl)-4-(methoxycarbonyl)benzoic acid (3.01 g, 9.93 mmol) in DMF (20 mL) was added 1- (3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (EDC-HC1, 2.00 g, 10.4 mmol) and 1-hydroxy-benzotriazole (HOBT, 50.0 mg, 0.367 mmol) sequentially. To this resulting suspension was then added a solution of ammonia (0.5 M 1,4 dioxane, 30.0 mL, 15.0 mmol). The reaction was stined for 16.0 hours until complete consumption of starting material was seen by LCMS analysis. At this time the reaction vessel was placed on a roto-evaporator at 30 mm Hg vacuum and maintained at 30 °C for 30 minutes to strip off any residual ammonia from the reaction mixture. The reaction vessel was removed from the roto-evaporator and subsequently charged with solid N-bromosuccinimide (1.790 g, 10.06 mmol) and the resulting reddish solution was stined for 3.0 hours. At this time the reaction was charged with K2C03 (3.00 g, 21.7 mmol) and 2,4 difluorobenzyl bromide (1.95 mL, 15.2 mmol). The resulting suspension was stined for 16.0 hours. At this time the reaction suspension was diluted with water (400 mL) and exfracted with ethyl acetate (3 X 300 mL). The organic extracts were separated, Na2S04 dried, and concenfrated to a residue that was subjected to Si02 chromatography using ethyl acetate/hexanes/methanol (6:3.5:0.5) to furnish an off white solid (1.09 g, 21%). 1H NMR (400 MHz, d4-MeOH) δ
- 689 - 8.21 (dd, J = 8.5, 1.5 Hz, IH), 8.09 (dd, J = 7.6, 2.0 Hz, IH), 7.78 (br s, IH), 7.65 (app q, J = 7.9 Hz, IH), 7.03 (app t, J = 8.0 Hz, 2H), 6.63 (s, IH), 5.37 (s, 2H), 3.75 (s, 3H), 2.02 (s, 3H); LC/MS C-18 column, tr = 2.28 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 507 (M+H). ES-HRMS m/z 507.0385 (M+H calcd for C22H18BrF2N205 requires 507.0362).
Example 665
Figure imgf000690_0001
2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N1,N1,N4- trimethylterephthalamide
Step 1: To a room temperature solution of 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]-4-[(methylamino)carbonyl] benzoic acid (300 mg, 0.591 mmol) in DMF (1.8 mL) was added l-(3-dimethylaminopropyl)-ethylcarbodiimide hydrochloride (EDC-HCl, 190.0 mg, 1.0 mmol) and 1-hydroxy-benzotriazole (HOBT, 26.0 mg, 0.191 mmol) sequentially. To this resulting suspension was then added a solution of dimethylamine (2.0 M THF, 0.50 L, 1.0 mmol). The reaction was stined for 16.0 hours, at which time the reaction mixture was directly applied to Si0 chromatography with ethyl acetate/hexanes (6:4) to furnish a solid (206 mg, 65 %). 1H NMR (400 MHz, d4-MeOH) δ 8.01 (dd, J = 8.2, 1.5 Hz, IH), 7.73 (app d, J = 8.1 Hz, IH), 7.61 (app q, J = 7.2 Hz, IH), 7.60 (app d, J = 9.5 Hz, IH), 7.04 (app t, J = 8.0 Hz, 2H), 6.65 (s, IH), 5.32 (s, 2H), 3.64 (s, 3H), 2.92 (s, 6H), 2.13 (s, 3H); LC/MS C-18 column, tr = 2.20 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml min with detection 254 nm, at 50°C). ES-MS m/z 534 (M+H). ES-HRMS m/z 534.0820 (M+H calcd for C24H23BrF2N304 requires 534.0835).
690 Example 666
Figure imgf000691_0001
2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- [(methylamino)carbonyl]benzyl carbamate
Step 1 : To a room temperature solution of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]-4-(hydroxymethyl)-N-methylbenzamide (493 mg, 1.00 mmol) in methylene chloride (5.0 mL) was added a solution of trichloroacetyl isocyanate (toluene, 0.53 M, 1.9 mL, 1.0 mmol). The resulting solution was stined for one hour until complete consumption of starting material by LCMS analysis. The reaction mixture was then directly applied to A1 03 (0.5 g of activity type I) and the slurry was matured for three hours. At this time, the A1203 plug was flushed with ethyl acetate/methanol (95:5) and the resulting mother liquor was concentrated to a residue that was subjected to Si02 chromatography using ethyl acetate/hexanes/methanol (6:3.5:0.5) to furnish a white solid (396 mg, 74 %). 1H NMR (300 MHz, d4-MeOH) δ 8.00 (dd, J = 8.0, 1.7 Hz, IH), 7.75 (d, J = 8.2 Hz, IH), 7.72-7.64 (m, 2H), 7.09 (app t, J = 8.5 Hz, 2H), 6.69 (s, IH), 5.40 (s, 2H), 4.85 (m, 2H), 2.90 (s, 3H), 2.10 (s, 3H); LC/MS C-18 column, tr = 2.15 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m z 536 (M+H). ES-HRMS m z 536.0617 (M+H calcd for C23H21BrF2N305 requires 536.0627).
Example 667
691
Figure imgf000692_0001
3-bromo-4-[(2,4-difluorobenzy oxy]-l-(2,6-difluoro-4-vinylphenyl)-6-methylpyridin- 2(lH)-one
Step 1: Preparation of 4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluoro-4-vinylphenyl)-6- methylpyridin-2(lH)- one.
Figure imgf000692_0002
To a room temperature solution of l-(4-bromo-2,6-difluorophenyl)-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)- one (4.01 g, 9.06 mmol) in anhydrous THF (30mL) was added, sequentially, tributyl(vinyl)tin (5.00 g, 15.7 mmol) and tetrakis(tripheylphosphine)palladium (1.00 g, 0.865 mmol) under an argon stream. The reaction vessel was then equipped with a reflux condenser and the reaction system purged with an argon flow. The resulting yellow solution was heated to 68 °C and stined under a positive pressure of argon for 12.0 hours until complete disappearance of starting material by LCMS analysis. The reaction mixture was diluted with 300 mL of brine and extracted with ethyl acetate (3 X 300 mL). The organic extracts were separated, Na2S04 dried, and concenfrated in vacuo and the resulting dark residue was subjected to Si02 chromatography with ethyl acetate/hexanes (1:1) to furnish a yellowish solid (3.18 g, 90 %). 1H NMR (400 MHz, CDC13) δ 7.41 (app q, J = 8.0 Hz, IH), 7.08 (app d, J = 8.3 Hz, 2H), 6.90 (app t, J =7.2 Hz, IH), 6.85 (app t, J = 7.4 Hz, IH), 6.63 (dd, J = 17.5, 10.9 Hz, IH), 5.96 (app d, 15.8 Hz, IH), 5.94 (app d, J = 15.8 Hz, IH), 5.79 (d, J = 17.4 Hz, IH), 5.43 (d, J = 10.9 Hz, IH), 5.01 (br s, 2H), 1.99 (s, 3H); LC/MS C-18 column, tr = 2.93 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at
692 50°C). ES-MS m/z 390 (M+H). ES-HRMS m z 390.1095 (M+H calcd for C21H16F4N02 requires 390.1112).
Step 2: To a briskly stined room temperature solution of 4-[(2,4-difluorobenzyl)oxy]-l- (2,6-difluoro-4-vinylphenyl)-6-methylpyridin-2(lH)- one (721 mg, 1.85 mmol) in methylene chloride (10 mL) was added solid N-bromosuccinimide (330 mg, 1.86 mmol) and the resulting reddish solution was stined for 10 minutes. At this time the reaction was diluted with ethyl acetate (100 mL) and washed with sodium sulfite (5 % aqueous solution, 50 L) The resulting organic extracts were Na2S04 dried, filtered, and concentrated in vacuo to approximately 50 mL volume. The resulting mother liquor rapidly precipitated and furnished an amorphous solid that was collected and dried at 1 mm Hg vacuum to provide the desired product as a solid (610 mg, 70 %). 1H NMR (400 MHz, CDC13) δ 7.59 (app q, J = 8.0 Hz, IH), 7.09 (app d, J = 8.3 Hz, 2H), 6.95 (app t, J =7.2 Hz, IH), 6.87(app t, J = 7.4 Hz, IH), 6.62 (dd, J = 17.5, 10.9 Hz, IH), 6.12 (s, IH), 5.81 (d, J = 17.4 Hz, IH), 5.43 (d, J = 10.9 Hz, IH), 5.25 (br s, 2H), 2.07 (s, 3H); LC/MS C-18 column, tr = 3.17 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m z 468 (M+H). ES-HRMS m/z 468.0249 (M+H calcd for C21H15BrF4N02 requires 468.0217).
Example 668
Figure imgf000693_0001
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[4-(l,2-dihydroxyethyl)-2,6-difluorophenyl]-6- methylpyridm-2( 1 H)-one
Step 1: Preparation of the title compound. To a room temperature solution of 3-bromo-4- [(2,4-difluorobenzyl)oxy]-l-(2,6-difluoro-4-vinylphenyl)-6-methylpyridin-2(lH)-one (408.0 mg, 0.871 mmol) in water/acetone 1:3 (8.0 mL) was added, sequentially, N-methyl morpholine oxide (268.0 mg, 2.29 mmol) and osmium tetroxide (4 % water solution, 0.25 - 693 - mL or approximately 10 mg, 0.039 mmol). The resulting solution was stined for 8 hours until complete consumption of starting material by LCMS analysis, and the reaction was concentrated in vacuo to one- fourth original volume. The resulting solution was diluted with ethyl acetate (300 mL) and washed with water (2 X 100 mL). The organic extract was separated, Na2S04 dried, and concentrated in vacuo and the resulting dark residue was subjected to Si0 chromatography with ethyl acetate/hexanes/ methanol (6:3.5:0.5) to furnish a solid (389 mg, 88 %). 1H NMR (400 MHz, d4-MeOH) δ 7.62 (app q, J = 8.0 Hz, IH), 7.26 (dd, J = 9.6, 4.5 Hz, 2H), 7.04 (app t, J = 8.6 Hz, 2H), 6.67 (s, IH), 5.36 (s, 2H), 4.75 (app t, J = 5.6 Hz, IH), 3.68-3.61 (m, 2H), 2.11 (s, 3H); LC/MS C-18 column, tr = 2.26 minutes (5 to 95%o acetonitrile/water over 5 minutes at 1 ml min with detection 254 nm, at 50°C). ESMS m/z 502 (M+H). ES-HRMS m/z 502.0247 (M+H calcd for C21H BrF4N04 requires 502.0272).
Example 669
Figure imgf000694_0001
4-[3 -bromo-4-[(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -3,5- difluorobenzaldehyde
Step 1: Preparation of the title compound. To a room temperature solution of 3-bromo-4- [(2,4-difluorobenzyl)oxy] - 1 -[4-(l ,2-dihydroxyethyl)-2,6-difluorophenyl] - 6- methylpyridin-2(lH)-one (310 mg, 0.615 mmol) in toluene (3.0 mL) was added lead(IV) acetate (443 mg, 1.63 mmol). The resulting dark brown solution was stined for one hour until complete consumption of starting material by LCMS analysis. The reaction mixture was then diluted with ethyl acetate (100 mL), water washed (3 X 100 mL), and brine washed (3 X 30 mL). The resulting organic extract was separated, Na S04 dried, and concentrated. The resulting dark residue was subjected to Si02 chromatography with ethyl acetate/ hexanes (1:1) to furnish a light yellow solid (269 mg, 93 %). Caution, product is
694 easily air oxidized. 1H NMR (300 MHz, d^MeOH) δ 10.05 (s, IH), 7.68 (app q, J = 7.2 Hz, IH), 7.38 (d, J = 8.0 Hz, 2H), 7.05 (app t, J = 8.2 Hz, 2H), 6.73 (s, IH), 5.40 (s, 2H), 2.15 (s, 3H); LC/MS C-18 column, tr = 2.72 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml min with detection 254 nm, at 50°C). ES-MS m/z 470 (M+H). ES- HRMS m/z 470.0049 (M+H calcd for C20H13BrF4NO3 requires 470.0009).
Example 670
Figure imgf000695_0001
4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3,5- difluorobenzyl carbamate
Step 1: To a room temperature solution of 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]-3,5-difluorobenzaldehyde (220 mg, 0.468 mmol) in methanol (10 mL) was added solid sodium borohydride (60.0 mg, 1.58 mmol). The resulting solution evolved gas for approximately 0.5 minute and was stined for 10 additional minutes until complete consumption of starting material by LCMS analysis. The reaction was then diluted with saturated aqueous solution of ammonium chloride (10 mL) and extracted with ethyl acetate (4 X 50 mL). The organic exfract was separated, Na2S0 dried, and concentrated to a residue. This resulting residue was then diluted with methylene chloride (5.0 mL) and a solution of trichloroacetyl isocyanate (toluene, 0.53 M, 1.0 mL, 0.53 mmol) was added. The resulting solution was stined for one hour until complete consumption of starting material by LCMS analysis. The reaction mixture was then directly applied to A1203 (0.5 g of activity type I) and the slimy was matured for three hours. At this time, the A1203 plug was flushed with ethyl acetate/methanol (95:5) and the resulting mother hquor was concentrated to a residue that was subjected to Si02 chromatography using ethyl acetate/hexanes/methanol (6:3.8:0.2) to furnish a white solid (181 mg, 75 %). 1H NMR (400 MHz, d4-MeOH) δ 7.63 (app q, J = 8.0 Hz, IH), 7.43 (d, J - 695 - = 8.2 Hz, 2H), 7.04 (app t, J = 8.1 Hz, 2H), 6.68 (s, IH), 5.37 (s, 2H), 5.12 (m, 2H), 2.11 (s, 3H); LC/MS C-18 column, tr = 2.54 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m z 515 (M+H). ESHRMS m/z 515.0232 (M+H calcd for C21H16BrF N204 requires 515.0234).
Example 671-687 The following compounds are prepared essentially according to the procedures outlined in the schemes and the above examples .
Figure imgf000696_0001
696
Figure imgf000697_0001
-697
Figure imgf000698_0001
698-
Figure imgf000699_0001
Example 701
699
Figure imgf000700_0001
N-(4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzyl)-2-hydroxyacetamide
Step 1. Preparation of l-[4-(aminomethyl)benzyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]- 6-methylpyridin-2(lH)-one.
Figure imgf000700_0002
The compound of Example 606 (10.0 g, 23.38 mmol) was suspended in tetrahydrofuran (100 mL) and cooled in an ice-bath. Borane dimethyl sulfide (29.9 mL, 2.0 M in tetrahydrofuran, 59.7 mmol) was added. The resulting mixture was heated to reflux overnight and then cooled in an ice-bath. Additional borane dimethyl sulfide (5.85 L, 2.0 M in tetrahydrofuran, 11.7 mmol) was added. The resulting mixtue was heated to reflux overnight and the cooled to room temperature. The flask was fitted with a distillation head and the reaction was partially concentrated. Additional borane dimethyl sulfide (5.85 mL, 2.0 M in tetrahydrofuran, 11.7 mmol) was added. The mixture was heated to reflux overnight and the cooled in an ice-bath. The reaction was quenched by the addition of 1.0 NHC1 (75.0 mL) then partially concentrated. The aqueous layer was made alkaline with 2.5 N ΝaOH and a precipitate developed. The solid was collected by filtration washing with diethyl ether to give a pale purple solid (3.00 g, 32 %). 1H ΝMR (400 MHz, DMSO- 6) δ 7.64 (app q, J= 7.9 Hz, IH), 7.44 (d, J= 7.9 Hz, 2H), 7.32 (app
700 dt, J= 2.4, 9.9 Hz, IH), 7.14 (app dt, J= 1.9, 8.5 Hz, IH), 7.13 (d, J= 7.9 Hz, 2H), 6.61 (s, IH), 5.27 (s, 4H), 3.90 (s, 2H), 2.29 (s, 3H).
Step 2. Preparation of N-(4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]methyl}benzyl)-2-hydroxyacetamide.
Acetoxyacetic acid (1.46 g, 12.35 mmol) was dissolved in NN-dimethylformamide (30 mL) and 1 -Hydroxybenzotriazole (1.84 g, 13.59 mmol) was added followed by 4- methylmorpholine (2.04 mL, 18.53 mmol), l-[4-(aminomethyl)benzyl]-3-chloro-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one (l-[4-(aminomethyl)benzyl]-3-chloro-4- [(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-onecompound of step 1) (2.50 g, 6.18 mmol) and then l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.84 g, 14.83 mmol). The resulting mixture was stined at room temperature for 1 hour at which time the reaction was diluted with Η20 (100 mL). The reaction mixture was then extracted with ethyl acetate. The combined organic exfracts were washed with saturated ΝaHC03, brine, dried over Na S04, filtered and concenfrated. Chromatography (silica gel, hexanes/ethyl acetate with 10% methanol) provided a white foam. The resulting foam was dissolved in 10% aqueous methanol (20 mL). K2C03 (0.653 g, 4.73 mmol) was added and the mixture was stined at room temperature for 2 hours. The reaction mixture was concentrated and H20 (50 mL) was added. The resulting precipitate was collected by filtration washing with diethyl ether to give an off-white solid (1.34 g, 47%). 1H NMR (400 MHz, CDC13) δ 7.50 (app q, J= 7.7 Hz, IH), 7.27 (app t, J= 5.8 Hz, IH), 7.12 (d, J = 8.1 Hz, 2H), 6.97 (d, J = 8.1 Hz, 2H), 6.94-6.89 (m, IH), 6.86-6.81 (m, IH), 6.09 (s, 2H), 5.23 (s, 2H), 5.18 (s, 2H), 4.53 (t, J= 5.8 Hz, IH), 4.33 (d, J= 5.9 Hz, 2H), 3.85 (d, J = 5.6 Hz, 2H), 2.30 (s, 3H). ES-HRMS m/z 463.1256 (M+H calcd for C23H22C1F2N204 requires 463.1231).
701 -
Figure imgf000702_0001
-oxopyridin-l(2H)- yl]methyl}benzyl)- 1 -hydroxycyclopropanecarboxamide
Preparation of N-(4- { [3 -chloro-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)- yl]methyl}benzyl)- 1 -hydroxycyclopropanecarboxamide. 1 -Hydroxy- 1 -cyclopropane- carboxylic acid (1.26 g, 12.35 mmol) was dissolved in NN-dimethylformamide (30 mL). 1 -Hydroxybenzotriazole (1.84 g, 13.59 mmol) was added followed by 4- methylmorpholine (2.04 mL, 18.53 mmol), l-[4-(aminomethyl)benzyl]-3-chloro-4-[(2,4- difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one (Example 701, step 1) (2.50 g, 6.18 mmol) and then l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.84 g, 14.83 mmol). The resulting mixture was stined at room temperature for 24 hours at which time the reaction was diluted with H20 (100 mL). The reaction mixture was then extracted with ethyl acetate. The combined organic exfracts were washed with saturated ΝaHC03, brine, dried over Na2S04, filtered and concentrated. Chromatography (silica gel, hexanes/ethyl acetate with 10% methanol) provided a white foam. The resulting foam was dissolved in 10% aqueous methanol (20 mL) to provide an white foam (1.45 g, 48%). 1H NMR (400 MHz, CDC13) δ 7.52-7.46 (m, IH), 7.34 (t, J= 5.9 Hz, IH), 7.08 (d, J= 8.2 Hz, 2H), 6.92 (app d, J= 8.2 Hz, 2H), 6.92-6.89 (m, IH), 6.86-6.81 (m, IH), 6.11 (s, IH), 5.22 (s, 2H), 5.18 (s, 2H), 4.30 (d, J= 5.9 Hz, 2H), 2.28 (s, 3H), 1.11 (app q, J= 4.1 Hz, 2H), 0.90 (app q, J = 4.1 Hz, 2H). ES-HRMS m/z 489.1420 (M+H calcd for C25H24C1F2N204 requires 489.1387).
702 Example 703
Figure imgf000703_0001
4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}benzyl carbamate
Preparation of 4- { [3 -bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)- yl]methyl}benzyl carbamate Compound of Example 206 (0.868 g, 1.93 mmol) was suspended in dichloromethane (7.0 mL). Trichloroacetyl isocyanate (4.00 mL, 0.53 in toluene, 2.12 mmol) was added. The resulting mixture was stined at room temperature for 3 hours then diluted with tetrahydrofuran (50 mL) and A1203 (5.0 g) was added and the mixture was stined at room temperature overnight. The reaction mixture was filtered through a pad of Celite® washing with methonal. The filtrate was then concentrated and the residue was redissolved in tetrahydrofuran (30 mL). A1203 (5.0 g) was added and the mixture was heated to 40 oC for 3 hours. After cooling to room temperature, the reaction was filtered through a pad of Celite ® washing with methanol. The filtrate was concentrated and the resulting solid was washed with diethyl ether to give an off-white solid (0.831 g, 87%). 1H NMR (400 MΗz, CDC13) δ 7.54 (app q, J= 7.7 Ηz, 1Η), 7.25 (d, J= 8.2 Ηz, 2Η), 7.13 (d, J= 8.2 Hz, 2H), 6.25 (app dt, J = 2.0, 8.3 Hz, IH), 6.86-6.30 (m, IH), 5.97 (s, IH), 5.32 (s, 2H), 5.18 (s, 2H), 5.02 (s, 2H), 4.81 (br s, 2H), 2.25 (s, 3H). ES-HRMS m/z 493.0580 (M+H calcd for C22H2oBrF2N204 requires 493.0569).
703 Example 704
Figure imgf000704_0001
2-[(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}phenyl)amino]-l-methyl-2-oxoethyl acetate
To a reaction vessel (borosilicate culture tube) was added compound of Example 611 (0.300 g, 0.69 mmol) and dichloromethane (3.0 mL). A stock solution of N- methylmorpholine (0.30 M, 3.0 mL) was added and the parallel reaction apparatus was then orbitally shaken (Labline Benchtop Orbital Shaker) at approximately 200 RPM at room temperature for 10 minutes. (S)-(-)-2-Acetoxypropionyl chloride (0.131 mL, 1.04 mmol) was then added to the reaction vessel and the reaction apparatus was orbitally shaken at room temperature for 1.5 hours. At this time the reaction was diluted with dichloromethane (20 mL) and treated with approximately 2.1 g of polyamine resin (2.63 mmol/g) and approximately 3.8 g of methylisocyanate fucntionalized polystyrene (1.10 mmol g) and the orbital shaking was continued at 200 RPM at room temperature overnight. The reaction vessel was then opened and the solution Phase products were separated from the insoluble quenched byproducts by filfration and collection into a vial. After partial evaporation the insoluble byproducts were rinsed with dichloromethane (2 x 10 mL). The filtrate was evaporated by blowing Ν2 over the vial to afford an off-white solid (0.375 g, 99%). 1H NMR (400 MHz, DMF-d6) δ 10.14 (s, IH), 7.75 (app dt, J = 6.98, 8.59 Hz, IH), 7.67-7.64 (m, 2H), 7.30 (ddd, J= 2.55, 9.26, 11.81 Hz, IH), 7.21-7.17 (m, 3H), 6.61 (s, IH), 5.37 (s, 4H), 5.11 (q, J= 6.85 Hz, IH), 2.40 (s, 3H), 2.10 (s, 3H), 1.46 (d, J = 6.85 Hz, 3H). ES-HRMS m/z 549.0790 (M+H calcd for C25H23BrF2N205 requires 549.0831). - 704 -
Example
Figure imgf000705_0001
2-[(4- { [3 -bromo-4-[(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)- yl]methyl}phenyl)amino]-l , 1 -dimethyl-2-oxoethyl acetate
By the method for Example 704 and substituting (S)-(-)-2-acetoxypropionyl chloride with
2-acetoxy-2-methylpropionyl chloride, the title compound was prepared (0.380 g, 98%).
1H NMR (400 MHz, DMF-d6) δ 9.68 (s, IH), 7.75 (app dt, J= 6.72, 8.60 Hz, IH), 7.71-
7.68 (m, 2H), 7.30 (ddd, J= 2.55, 9.40, 11.95 Hz, IH), 7.21-7.15 (m, 3H), 6.61 (s, IH), 5.37 (s, 4H), 2.41 (s, 3H), 2.04 (s, 3H), 1.59 (s, 6H). ES-HRMS m/z 563.1027 (M+H calcd for C26H25BrF2N205 requires 563.0988).
Figure imgf000705_0002
{ 1 -[3-(aminocarbonyl)phenyl]-5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxo- 1 ,6- dihydropyridin-2-yl}methyl acetate
Step 1: Preparation of {l-[3-(aminocarbonyl)phenyl]-4-hydroxy-6-oxo-l,6- dihydropyridin-2-yl} methyl acetate.
705 -
Figure imgf000706_0001
3-(2,2-dimethyl-4-oxo-4H-l,3-dioxin-6-yl)-2-oxopropyl acetate (4.00 g, 16.52 mmol) was dissolved in 1,4-dioxane (160 mL) and 3-aminobenzamide (1.73 g, 12.71 mmol) was added. The reaction was heated to reflux for 1 hour then cooled to 70 °C. Methanesulfonic acid (1.22 g, 12.71 mmol) was added and the reaction brought back to reflux for 1 hour. The reaction was cooled to room temperature, concenfrated and used as crude product for the next step.
Step 2: Preparation of {l-[3-(aminocarbonyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6-oxo- 1 ,6-dihydropyridin-2-yl}methyl acetate.
Figure imgf000706_0002
{l-[3-(aminocarbonyl)phenyl]-4-hydroxy-6-oxo-l,6-dihydropyridin-2-yl}methyl acetate (crude from step 1) (3.61 g, 11.94 mmol) was dissolved in NN-dimethylformamide (40 mL). K2C03 (3.80 g, 27.46 mmol) was added followed by 2,4-difluorobenzyl bromide (5.44 g, 26.27 mmol). The reaction mixture was stined for 48 hours at room temperature. The reaction mixture was then partially concentrated and the residue taken up in dichloromethane/tetrahydrofuran 1:1 and filtered. The filtrate was collected, concentrated and the residue trifrated with dichloromethane to afford a tan solid (1.64 g, 32%). 1H ΝMR (400 MHz, DMF-de) δ 8.19 (br s, IH), 8.07 (app dt, J = 1.35, 7.66 Hz, IH), 7.91 (app t, J= 1.81 Hz, IH), 7.76 (app dt, J = 6.58, 8.59 Hz, IH) 7.62 (t, J = 7.79 Hz, IH), 7.55 (ddd, J = 1.21, 2.01, 7.79 Hz, IH), 7.46 (br s, IH), 7.34 (ddd, J= 2.55, 9.40, 10.47
- 706 Hz, IH), 7.23-7.18 (m, IH), 6.26 (d, J= 2.55 Hz, IH), 6.11 (d, J= 2.69 Hz, IH), 5.23 (s, 2H), 4.62 (AB q, JAB = 14.97 Hz, 2H), 1.96 (s, 3H). ES-HRMS m/z 429.1280 (M+H calcd for C22H18F2N205 requires 429.1257).
Step 3: Preparation of the title compound.
{ 1 -[3-(aminocarbonyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6-oxo- 1 ,6-dihydropyridin-2- yl}methyl acetate (from step 2) (1.02 g, 2.39 mmol) was suspended in dichloromethane (15 mL) and N-chlorosuccinimide (0.37 g, 2.75 mmol) was added. Dichloroacetic acid (0.10 ml, 1.22 mmol) was added and the reaction mixture was stined at 40 °C for 1.5 hours. The reaction was cooled to room temperature and a precipitate formed. The reaction mixture was diluted with diethyl ether and the precipitate was collected by filfration and washed with diethyl ether (3 x 15 mL) to afford a tan solid (0.940 g, 85%). 1H ΝMR (400 MHz, DMF-d6) δ 8.21 (br s, IH), 8.11 (app dt, J= 1.48, 7.52 Hz, IH), 7.95 (app t, J= 1.61 Hz, IH), 7.80 (app dt, J= 6.72, 8.59 Hz, IH) 7.69-7.60 (m, 2H), 7.48 (br s, IH), 7.35 (ddd, = 2.55, 9.53, 10.61 Hz, IH), 7.24-7.19 (m, IH), 6.97 (s, IH), 5.49 (s, 2H), 4.71 (AB q, JAB = 15.04 Hz, 2H), 1.98 (s, 3H). ES-HRMS m/z 463.0883 (M+H calcd for C22H17C1F2Ν205 requires 463.0867).
Example 707
Figure imgf000707_0001
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-{[2-(methylthio)pyrimidin-5- yl]methyl}pyridin-2(lH)-one
Step 1. Preparation of methyl 2-(methylthio)pyrimidine-5-carboxylate
Figure imgf000707_0002
A solution of the sodium salt of 3,3-dimethoxy-2-methoxycarbonylpropen-l-ol
(5.0g, 25 mmol), 2-methyl-2-thiopseudourea sulfate (3.5g, 25 mmol) in anhydrous methanol (25 mL) was refluxed for 3 hours under anhydrous conditions. The reaction mixture was cooled and diluted with ethyl acetate. The reaction mixture was filtered and - 707 - the residue was washed with ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography (silica gel) using 25% ethyl acetate in hexane to afford the desired product (3.5g, 75%) as a white powder. 1H-NMR ( -DMSO, 400 MHz) δ 9.0 (s, 2H), 3.92 (s, 3H), 2.58 (s, 3H); ES-HRMS m/z 185.041 (M+H C7H8N202S requires 185.0379).
Step 2. Preparation of [2-(methylthio)pyrimidin-5-yl]methanol
Figure imgf000708_0001
To a cold suspension of methyl 2-(methylthio)pyrimidine-5-carboxylate (1.74g, 9.4 mmol) in dichloromethane (20 mL, -70° C) was added DIBAL (20.8 mL, 20 mmol) dropwise via an addition funnel. The mixture was stined under nitrogen at -70° C for 1 hour and then at -50° C for 3 hours. The reaction was diluted with dichloromethane (50 mL) and quenched with a suspension of sodium sulfate decahydrate (lOg) in water (50 mL). The sluny was filtered through celite and the filfrate was concentrated. The residue was purified by flash chromatography (silica gel) using 100% ethyl acetate to afford the desired compound (0.7813 g, 39%) as a yellow solid. 1H-NMR ((CD3OD, 400 MHz) δ 8.53 (s, 2H), 4.56 (s, 2H), 2.54 (s, 3H); ES-HRMS m/z 157.0409 (M+H C6H8N2OS requires 157.0430).
Step 3. Preparation of 5-(chloromethyl)-2-(methylthio)pyrimidine
Figure imgf000708_0002
To a cold solution of [2-(methylthio)pyrimidin-5-yl]methanol (0.7813g, 5.0 mmol) in anhydrous dichloromethane (10 mL, 0° C) was added triethylamine (0.836 mL, 8.2 mmol) followed by the addition of methanesulfonyl chloride (0.465mL, 6.0 mmol). The reaction mixture stined at 0° C under a nifrogen atmosphere for 30 minutes then at room temperature for 3.5 hours. The reaction was quenched with sodium bicarbonate (5%, 100 mL)) and extracted with dichloromethane (50 mL). The organic exfracts were concentrated and the residue was purified by flash chromatography (silica gel) using 15% ethyl acetate in hexane to afford the desired compound (0.720 g, 82%) as a white solid.
708 1H-NMR ((CD3OD, 400 MHz) δ 8.60 (s, 2H), 4.64 (s, 2H), 2.54 (s, 3H); ES-HRMS m/z 175.0106 (M+H C6H7N2C1S requires 175.0091).
Step 4. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-{[2- (methylthio)pyrimidin-5-yl]methyl}pyridin-2(lH)-one
To a solution of 5-(chloromethyl)-2-(methylthio)pyrimidine (0.62g, 3.56 mmol) in anhdrous DMF (10 mL) was added KBr (0.424, 3.56 mmol). After the suspension stined at room temperature for 30 minutes, 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methylρyridin-2(lH)-one (1.05g, 3.19 mmol) was added followed by NaH (0.102g, 4.25 mmol). The reaction mixture stined at 70° C under a nitrogen atmosphere for 3.5 hours. The solvent was distilled and the residue was washed with water and exfracted with ethyl acetate. The organic extracts were concenfrated and the residue was purified by reverse phase HPLC using a 10-90% acetonitrile/water (30 minute gradient) at a 70mL/min flow rate to afford the desired TFA salt (0.32 g, 15%) as a white powder. The TFA compound was washed with sodium bicarbonate (5%) and exfracted with dichloromethane. The organic exfract was concentrated to afford the desired compound (0.295g, 18 %) as a yellow solid. 1H-NMR (CD3OD, 400 MHz) δ 8.47 (s, 2H), 7.62 (q, IH, J= 8Hz), 7.03 (m, 2H), 6.51 (s, IH), 5.31 (s, 2H), 5.29 (s, 2H), 2.52 (s, 3H), 2.47 (s, 2H); ES-HRMS m/z 468.0174/470.0156 (M+H C19H16N302F2BrS requires 468.0187/470.0168).
Example 708
Figure imgf000709_0001
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-{[2-(methylsulfonyl)pyrimidin-5- yl]methyl}pyridin-2(lH)-one '
To a solution of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-{[2-
(methylthio)pyrimidin-5-yl]methyl}pyridin-2(lΗ)-one (example 707) (0.26g, 0.55 mmol) in acetonitrile: water (4:1 v/v, 10 mL) was added MMPP (0.549g, 1.1 mmol). The
- 709 - reaction stined at room temperature for 30 hours. The reaction mixture was diluted with ethyl acetate and filtered. The filfrate was concenfrated and the residue was purified by reverse phase HPLC using a 10-90% acetonitrile/water (30 minute gradient) at a 70mL/min flow rate to afford the desired TFA salt of the title copmound (0.13 g, 38%) as a white powder. 1H-NMR ((CD3OD, 400 MHz) δ 8.86 (s, 2H), 7.62 (q, IH, J= 8Hz), 7.02 (m, 2H), 6.56 (s, IH), 5.48 (s, 2H), 5.31 (s, 2H), 3.34 (s, 3H), 2.49 (s, 2H); ES-HRMS m/z 500.0109/502.0066 (M+H C19H16N304F2BrS requires 500.0086/502.0067).
Example 709
Figure imgf000710_0001
Ethyl 2-({[3-bromo-l-(5-{[(2-hydroxyethyl)amino]carbonyl}-2-methylphenyl)-6-methyl- 2-oxo-l,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzylcarbamate
To a cooled (-10°C) solution of 3-[3-bromo-4-[(2-{[(ethoxycarbonyl)amino]methyl}-4- fluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoic acid (0.25 g, 0.46 mmol) and 4-methylmorpholine (0.06 mL, 0.55mmol) in DMF was added isobutyl chloroformate (0.07 mL, 0.55 mmol). The colorless solution gradually turned dark brown. After 30 min, ethaolamine (0.04 mL, 0.69 mmol) was added and the solution warmed to RT. After lh, solvent was removed and the crude product was purified by preparatory ΗPLC. Acetonitrile was evaporated and the solution washed with 5% NaΗC03 (20 mL) and extracted in DCM (3 x 15 mL). The organic extracts were dried over Na2S0 , filtered, and concenfrated to a white solid, dried in vacuo (0.09 g, 33%). 1H NMR (CD3OD/ 400MHz) δ 7.88 (m, IH), 7.61 (s, IH), 7.53 (m, 2H), 7.13 (m, IH), 7.05 (m, IH), 6.68 (s, IH), 5.40 (s, 2H), 4.43 (s, 2H), 4.07 (q, 2H, J= 7.2 Hz), 3.68 (t, 2H, J= 5.6 Hz), 3.48 (t, 2H, J = 5.6 Hz), 2.09 (s, 3H), 2.00 (s, 3H), 1.22 (t, 3H , J = 7.2 Hz). ESHRMS m/z
710 - 590.1266 and 592.1254 (M+H calculated for C27H30BrFN3O6 requires 590.1297 and 592.1281).
Example 710
Figure imgf000711_0001
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[5-(lH-imidazol-2-yl)-2-methylphenyl]-6- methylpyridin-2(lH)-one trifluoroacetate
An oven-dried flask was alternately evacuated and flushed with argon. Toluene (2.18 mL) and trimethyl aluminum (1.25 mL, 2.51 mmol) were added sequentially and the solution cooled to -5°C. Ethylene diamine (0.17 mL, 2.51 mmol) was added dropwise. Methyl 3- [3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoate (0.75 g, 1.57 mmol) was added portionwise to the cooled solution. The reaction mixture was then refluxed at 110°C for 4h. The solution was cooled and water (0.7 mL), DCM (2.2 mL), and MeOΗ (2.2 mL) were added. The solution was refluxed for 15 min following this addition and then dried over Na2S04, filtered, and concenfrated. The residue was dissolved in EtOAc (20 mL), refluxed 15 min, dried over Na2S04, filtered, and concenfrated. The crude product was purified by preparatory ΗPLC. The product was isolated by freeze-drying and evaporation of the solvent to give a white solid, dried in vacuo (0.30 g, 31%). 1H NMR (CD3OD/ 400MΗz) δ 7.88 (m, IH), 7.71 (d, IH, J= 8.0 Hz), 7.64 (m, 2H), 7.05 (m, 2H), 6.70 (s, IH), 5.37 (s, 2H), 4.09 (s, 4H), 2.16 (s, 3H), 2.01 (s, 3H). ESHRMS m/z 488.0750 and 490.0774 (M+H calculated for C23H21BrF2N302 requires 488.0780 and 490.0762).
- 711 - Example 711
Figure imgf000712_0001
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[5-(5-hydroxy-lH-pyrazol-3-yl)-2-methylphenyl]- 6-methylpyridin-2(lH)-one
Step 1: Preparation of ethyl 3-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]-4-methylphenyl} -3 -oxopropanoate.
Figure imgf000712_0002
hi an oven-dried round bottom flask, 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]-4-methylbenzoic acid (see Example 487) (0.75 g, 1.62 mmol), DCM
(2.00 mL), and oxalyl chloride (0.97 mL, 1.94 mmol) were combined under argon. DMF
(3-5 drops) was added to aid in dissolution. Stined at RT overnight. Solvent was removed and the crude acid chloride was coevaporated with DCM (3-5 mL x 3) and dried in vacuo to give an orange solid. In a separate oven-dried flask, in an argon atmosphere, a solution of monoethyl malonate (0.38 mL, 3.23 mmol) in TΗF (3.00 mL) was cooled to -78°C. Isopropyl magnesium chloride (3.23 mL, 6.46 mmol) was added dropwise. The solution was stined for 30 min at -78°C. The acid chloride prepared as described above was added dropwise as a solution in TΗF. The reaction was warmed to RT. After 30 min, the reaction was cooled (0°C) and 10% citric acid (5.0 mL) added. The crude product was extracted in EtOAc, washed with 5% NaΗC03, dried over Na2S04, filtered, and concenfrated to a crude brown oil. Recrystallization from DCM and hexane. Filtered a beige solid, dried in vacuo (0.41 g, 47%). 1H NMR (CD3OD/ 400MHz) δ 8.02 (m, IH), 7.79 (s, IH), 7.65 (m, 2H), 7.05 (t, 2H, J= 9.2 Hz), 6.66 (s, IH), 5.36 (s, 2H), 4.16 (q, 2H, - 712 - J= 7.2 Hz), 2.11 (s, 3H), 2.07 (s, 2H), 1.99 (s, 3H), 1.23 (t, 3H, J = 7.2 Hz). ESHRMS m/z 534.0744 and 536.0746 (M+H calculated for C25H23BrF2N05 requires 534.0722 and 536.0706).
Step 2: Preparation of the title compound.
To a mixture of ethyl 3-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]-4-methylphenyl}-3-oxopropanoate (from Step 1) (0.20 g, 0.37 mmol) in EtOΗ (5.00 mL) was added hydrazine hydrate (0.01 mL, 0.41 mmol). The reaction mixture was heated at 60°C with a condensere. After lh, additional hydrazine hydrate (0.01 mL) was added. After 2h, acetic acid (2 drops) was added. At 4h, additional hydrazine was added (0.1 mL). At 5h, the reaction appeared to be complete. Left in fridge overnight. Precipitate filtered, washed with hexane, found to be product, a white solid (0.10 g, 54%). 1H NMR (CD3OD/ 400MΗz) δ 7.66 (m, 2H), 7.45 (m, 2H), 7.05 (t, 2H, J= 9.6 Hz), 6.65 (s, IH), 5.36 (s, 2H), 2.04 (s, 3H), 2.02 (s, 3H). ESHRMS m/z 502.0552 and 504.0569 (M+H calculated for C23H19BrF2N303 requires 502.0572 and 504.0555).
Example 712
Figure imgf000713_0001
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[5-(5-hydroxyisoxazol-3-yl)-2-methylphenyl]-6- methylpyridin-2(lH)-one
A solution of ethyl 3-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]-4-methylphenyl}-3-oxopropanoate (0.20 g, 0.37 mmol), triethylamine (0.06 mL, 0.41 mmol), and hydroxylamine hydrochloride (0.03 g, 0.41 mmol) in EtOΗ (3.00 mL) was heated overnight at 60°C with a condenser. Additional triethylamine (0.06 mL) and hydroxylamine hydrochloride (0.03 g) were added. After 2.5h, the additions of triethylamine and hydroxylamine hydrochloride were repeated. After lh, the reaction was concentrated and purified by preparatory ΗPLC. The product was isolated by freeze- - 713 - drying and evaporation of the solvent to give a white solid. Dissolved solid in DCM. Upon addition of 5% NaHC03, solution became a milky emulsion. Added additional DCM and some brine. Organic exfracts were dried over Na2S04, filtered, and concentrated to a pink solid, dried in vacuo (120 mg, 64%). 1H NMR (CD3OD/ 400MHz) δ 7.66 (m, 2H), 7.44 (m, 2H), 7.04 (t, 2H, J= 8.8 Hz), 6.64 (s, IH), 5.36 (s, 2H), 2.04 (s, 3H), 2.01 (s, 3H). ESHRMS m/z 503.0415 and 505.0402 (M+H calculated for C23H18BrF2N204 requires 503.0413 and 505.0395).
Example 713
Figure imgf000714_0001
3-[4-{[2-({[(cyclopropylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6-methyl-2- oxopyridin- 1 (2H)-yl] -N,4-dimethylbenzamide
To a cooled (-15°C) solution of 3-[4-{[2-({[(cyclopropylamino)carbonyl]amino}methyl)- 4-fluorobenzyl] oxy} -6-methyl-2-oxopyridin- 1 (2H)-yl] -4-methylbenzoic acid (see Example 651) (0.30 g, 0.63 mmol) and isobutyl chloroformate (0.10 mL, 0.75 mmol) in DMF (3.00 mL) was added 4-methylmorpholine (0.08mL, 0.75 mmol). The solution instantly turned yellow and was dark brown within minutes. After 20 min, methylamine (0.47 mL of 2.0M solution in TΗF, 0.94 mmol) was added. The reaction was carried out at RT. After 2.5h, a catalytic amount of DMAP and additional methylamine (0.47 mL, 0.94 mmol) were added. After an additional 2.5h, the reaction was concenfrated to a dark red oil. The crude product was purified by preparatory ΗPLC. Acetonitrile was evaporated and the solution washed with 5% NaΗC03 (20 mL) and exfracted in DCM (3 x 15 mL). The organic extracts were dried over Na2S04, filtered, and concenfrated to an off-white solid, dried in vacuo (0.06 g, 19%). 1H NMR (CD3OD/ 400MHz) δ 7.85 (m, IH), 7.58 (s, IH), 7.48 (m, 2H), 7.14 (m, IH), 7.02 (m, IH), 6.23 (s, IH), 6.09 (s, IH), - 714 - 5.20 (s, 2H), 4.45 (s, 2H), 2.90 (s, 3H), 2.49 (m, IH), 2.11 (s, 3H), 1.91 (s, 3H), 0.71 (m, 2H), 0.48 (m, 2H). ESHRMS m/z 493.2260 (M+H calculated for C27H30N4O4F requires 493.2246).
Example 714
Figure imgf000715_0001
Methyl 4-{[4-[(2,4-difluorobenzyl)oxy]-2-oxoquinolin-l(2H)-yl]methyl}benzoate
Step 1: Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]quinolin-2(lH)-one.
Figure imgf000715_0002
To a room temperature solution of 4-hydroxy- l,2-dihydroquinolin-2-one (500 mg, 3.10 mmol) in CΗ2C12 (10.0 mL) was added portion- wise solid N-bromosuccinimide (551.5 mg, 3.10 mmol). The reaction was stined vigorously for 1.0 h, followed by the sequential addition of K2C03 (540 mg, 3.90 mmol), DMF (4.0 mL), and 2,4 difluorobenzyl bromide (0.430 mL, 3.30 mmol). The resulting suspension was stined for 4.5 hours until complete formation of desired product was seen by LCMS analysis. The reaction was then diluted with ethyl acetate (400 mL) and brine washed (3 X 200 mL). The resulting organic extract was Νa2S04 dried, filtered, and concentrated in vacuo to a residue that was subjected to Si02 chromatography with ethyl acetate/hexanes/methanol (60:35:5) to furnish a solid (529 mg, 47 %). 1H NMR (300 MHz, </6-DMSO) δ 12.23 (s, IH), 7.68 (app q, J= 7.5 Hz, IH), 7.64 (app q, J = 8.5 Hz, IH), 7.54 (app q, J= 8.3 Hz, IH), 7.38-7.27 (m, 2H), 7.20 (app t, J = 7.4 Hz, IH), 7.13 (app dt, J = 8.4, 2.6 Hz, IH), 5.25 (s, 2H); LC/MS C-18 column, tr = 2.64 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with
715 detection 254 nm, at 50°C). ES-MS m/z 366 (M+H). ES-HRMS m/z 365.9967 (M+H calcd for C16HπBrF2N02 requires 365.9936).
Step 2: Preparation of methyl 4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-2-oxoquinolin- 1(2H)- yl]methyl}benzoate.
Figure imgf000716_0001
To a room temperature solution of 3-bromo-4-[(2,4-difluorobenzyl)oxy]quinolin-2(lH)- one (400 mg, 1.09 mmol) in TΗF (4.5 mL) was added portion-wise solid sodium hydride
(95 % oil-free, 60.0 mg, 2.49 mmol). The reaction was vigorously stined for 30 minutes followed by addition of methyl-4-(bromomethyl)-benzoate (400 mg, 1.75 mmol). This resulting suspension was then heated to 60 °C for 12.0 hours. The resulting solution was then treated with saturated aqueous ammonium chloride (400 mL) and exfracted with ethyl acetate (3 X 300 mL). The resulting organic extracts were Na2S04 dried, filtered, and concentrated in vacuo to a residue that was subjected to Si02 chromatography with ethyl acetate hexanes (60:40) to furnish a solid (396 mg, 71 %). !Η NMR (400 MHz, CDC13) δ 7.97 (app d, J= 8.0 Hz, 2H), 7.87 (d, J= 7.5 Hz, IH), 7.60 (app q, J= 8.4 Hz, IH), 7.49- 7.42 (m, IH), 7.30-7.15 (m, 4H), 6.94 (app t, J= 6.3 Hz, IH), 6.88 (app t, J= 9.4 Hz, IH), 5.64 (s, 2H), 5.33 (s, 2H), 3.88 (s, 3H); LC/MS C-18 column, tr = 3.46 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 514 (M+H). ES-HRMS m/z 514.0451 (M+H calcd for C25H19BrF2N0 requires 514.0460).
Step 3: Preparation of the title compound. In a 25 mL round bottom flask was added, at room temperature, a solution of methyl 4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-2- oxoquinolin-l(2H)- yl]methyl}benzoate (step 2) (120 mg, 0.233 mmol) in MeOH (3.0 mL). Next, a combination of Pd on carbon (10 % Pd, weight by weight 50 % water, 100 mg, 0.047 mmol) and Pd(OAc)2 (15 mg, 0.067 mmol) was added to the reaction vessel that purged with argon and then fitted with a septum. The vessel was then equipped with a
- 716 - 2.0 L hydrogen balloon (c.a. 20 psi). The resulting suspension was allowed to stir of 12.0 hours and was then directly applied to Si02 chromatography using ethyl acetate/ hexanes (3:7) to furnish the desired title compound as a solid (52 mg, 51 %). 1H NMR (300 MHz, CDC13) δ 8.05-7.98 (m, 3H), 7.55 (app q, J = 8.3 Hz, IH), 7.48 (app t, J= 7.5 Hz, IH), 7.30 (d, J= 8.0 Hz 2H), 7.19 (app q, J= 8.5, 2H), 7.05-6.90 (m, 2H), 6.28 (s, IH), 5.60 (s, 2H), 5.26 (s, 2H), 3.91 (s, 3H); LC MS C-18 column, tr = 3.71 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 436 (M+H). ES-HRMS m/z 436.1371 (M+H calcd for C25H20BrF2NO4 requires 436.1355).
Example 715
Figure imgf000717_0001
5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-2- fur amide
Step 1: Preparation of 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]methyl} -2-furoic acid.
Figure imgf000717_0002
To a room temperature solution of methyl 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)- yl]methyl}-2-furoate (Example 660) (608 g, 1.30 mmol) in TΗF (8.0 mL) was added dropwise an aqueous solution of sodium hydroxide (3.0 M, 0.50 mL, 1.50 mmol). The reaction was then heated to 60 °C for 12.0 hours. The resulting suspension was then diluted with 500 mL of ethyl acetate and neutralized with an aqueous solution of hydrochloric acid (1.0 N, 1.5 mL, 10 mmol). The resulting biphasic solution - 717 - was then concenfrated in vacuo to a volume of 50 mL. At this time a white solid began to form and the resulting solid suspension was allowed to sit until precipitation appeared to stop (approximately 1.0 hour). The precipitate was collected and dried in vacuo (1.0 mm Hg) to furnish the solid acid as an intermediate (500 mg, 85 %). !H NMR (300 MHz, d4- MeOH) δ 7.64 (app q, J= 8.3 Hz, IH), 7.18 (d, J= 3.4 Hz, IH), 7.10-7.02 (m, 2H), 6.54 (s, IH), 6.50 (d, J = 3.5 Hz, IH), 5.42 (s, 2H), 5.37 (s, 2H), 2.64 (s, 3H); LC/MS C-18 column, tr = 2.38 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 454 (M+H). ES-HRMS m/z 454.0070 (M+H calcd for C19H15BrF2N05 requires 454.0096).
Step 2: Preparation of the title compound. To a room temperature suspension of 5-{[3- bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-2-furoic acid (500 mg, 1.10 mmol) in THF (6.0 mL) was added 2-chloro-4,6 dimethoxy-1,3,5 triazine (307 mg, 1.75 mmol) and N-methyl morpholine (NMM, 184 mg, 1.82 mmol) sequentially. The resulting solution was matured for 2 hours and then a saturated aqueous solution of ammonium hydroxide (0.70 mL) was added. The resulting suspension was allowed to continue for 1 additional hour. The reaction mixture was diluted with 400 mL of brine and exfracted with ethyl acetate (3 X 400 mL). The organic exfracts were separated, Na2S04 dried, and concenfrated in vacuo and the resulting residue was subjected to Si02 chromatography with ethyl acetate/hexanes/methanol (57:38:5) to provide the title compound (370 mg, 74 %). 1H NMR (300 MHz, d4-MeOH) δ 7.64 (app q, J= 8.1 Hz, IH), 7.10-7.00 (m, 3H), 6.53 (s, IH), 6.52 (d, J= 3.4 Hz, IH), 5.43 (s, 2H), 5.32 (s, 2H), 2.61 (s, 3H); LC/MS C-18 column, tr = 2.15 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 453 (M+H). ES-HRMS m/z 453.0249 (M+H calcd for C19H16BrF2N204 requires 453.0256).
Example 716
- 718 -
Figure imgf000719_0001
5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2/ -yl]-2-furamide
Step 1: Preparation of methyl 5-(4-hydroxy-6-methyl-2-oxopyridin-l(2H)-yl)-2-furoate.
Figure imgf000719_0002
To a room temperature solution of methyl-2-amino-5-furoate (4.85 g, 34.4 mmol) in 1,4 dioxane (28.0 mL) was added 5-(l-hydroxy-3-oxobutylidene)-2,2-dimethyl-l,3-dioxane- 4,6-dione (8.16 g, 44.3 mmol). The reaction was stined vigorously and heated quickly (within 8 minutes) to an internal temperature of 98 °C. Upon reaching temperature, the reaction was maintained for 1.0 hour. At this time, the reaction was cooled to room temperature rapidly using an ice-bath and methane sulfonic acid (3.30 g, 34.4 mmol) was added. The reaction mixture was once again brought to an internal temperature of approximately 100 °C. After 1.0 hour the reaction was diluted with 10 mL of toluene and allowed to cool to room temperature on its own accord. A solid formed after 3.0 hours that was collected and subsequently recrystallized from methanol/ ethyl acetate (1:1). The developing crystals were allowed to form and stand for 12.0 hours prior to collection to furnish the desired product as a solid (3.78 g, 44 %). 1H NMR (400 MHz, 7-DMF) δ 11.34 (s, IH), 7.43 (app d, J = 3.6 Hz, IH), 6.79 (app d, J = 3.6 Hz, IH), 6.01 (s, IH), 5.63 (d, J= 2.0 Hz, IH), 3.87 (s, 3H), 2.02 (s, 3H); LC/MS C-18 column, tr = 1.47 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml min with detection 254 nm, at 50°C). ES-MS m/z 250 (M+H). ES-HRMS m/z 250.0696 (M+H calcd for C12H12N05 requires 250.0710).
Step 2: Preparation of methyl 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]-2-furoate.
719
Figure imgf000720_0001
To a room temperature solution of methyl 5-(4-hydroxy-6-methyl-2-oxopyridin-l(2H)-yl)-
2-furoate (step 1) (3.19 g, 12.8 mmol) in DMF (14 mL) was added portion-wise solid N- bromosuccinimide (2.29 g, 12.9 mmol). The reaction was stined vigorously for 1.0 h, followed by the sequential addition of K2C03 (1.88 g, 13.6 mmol), DMF (4.0 mL), and
2,4 difluorobenzyl bromide (2.00 mL, 15.55 mmol). The resulting suspension was stined for 9.0 hours until complete formation of desired product was seen by LCMS analysis.
The reaction was then diluted with saturated brine (300 mL) and exfracted with ethyl acetate (3 X 300 mL). The resulting organic exfracts were Νa2S04 dried, filtered, and concenfrated in vacuo to a residue that was subjected to Si02 chromatography with a gradient elution using ethyl acetate/hexanes (40:60 to 60:40) to furnish a solid (3.20 mg, 55 %). 1H NMR (400 MΗz, dη-DMF) δ 7.78 (app q, J= 8.6 Ηz, 1Η), 7.48 (app d, J= 3.6 Ηz, 1Η), 7.33 (app dt, J= 10.0, 2.4 Ηz, 1Η), 7.21 (app dt, J= 8.5, 1.8 Ηz, 1Η), 6.92 (d, J = 3.6 Ηz, 1Η), 6.81 (s, 1Η), 5.47 (s, 2Η), 3.88 (s, 3H), 2.15 (s, 3H); LC/MS C-18 column, tr = 3.11 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 454 (M+H). ES-HRMS m/z 454.0117 (M+H calcd for C19H15BrF2N205 requires 454.0096).
Step 3: 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-2- furoic acid.
Figure imgf000720_0002
To a room temperature solution of methyl 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]-2-furoate (step 2) (3.00 g, 6.61 mmol) in TΗF (20 mL) was added dropwise an aqueous solution of sodium hydroxide (3.0 M, 4.00 mL, 12.0
- 720 - mmol). The reaction was then heated to 60 °C for 12.0 hours. The resulting suspension was then diluted with 800 mL of ethyl acetate and neutralized with an aqueous solution of hydrochloric acid (3.0 N, 4.0 mL, 12 mmol). The resulting biphasic solution was then concentrated in vacuo to a volume of 90 mL. At this time a white solid began to form and the resulting solid suspension was allowed to sit until precipitation appeared to stop (approximately 1.0 hour). The precipitate was collected and dried in vacuo (1.0 mm Hg) to furnish the solid acid as an intermediate (2.27 g, 78 %). 1H NMR (400 MHz, dη-DMF) δ 7.79 (app q, J= 8.0 Hz, IH), 7.32 (t, J= 9.2 Hz, IH), 7.20 (app t, J= 7.4 Hz, IH), 6.88 (app d, J= 2.5 Hz, IH), 6.74 (s, IH), 6.51 (d, J= 2.5 Hz, IH), 5.44 (s, 2H), 2.10 (s, 3H); LC/MS C-18 column, tr = 2.77 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 440 (M+H). ES-HRMS m/z 439.9959 (M+H calcd for C18H13BrF2N05 requires 439.9940).
Step 4: Preparation of the title compound.
To a room temperature suspension of 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]-2-furoic acid (1.00 g, 2.27 mmol) in TΗF (8.0 mL) was added 2- chloro-4,6 dimethoxy-1,3,5 triazine (610 mg, 3.47 mmol) and N-methyl morpholine (NMM, 368 mg, 3.62 mmol) sequentially. The resulting solution was matured for 2 hours and then a saturated aqueous solution of ammonium hydroxide (1.5 mL) was added. The resulting suspension was allowed to continue for 1 additional hour. The reaction mixture was diluted with 800 mL of brine and exfracted with ethyl acetate (3 X 600 mL). The organic exfracts were separated, Na2S04 dried, and concenfrated in vacuo and the resulting residue was subjected to Si02 chromatography with ethyl acetate/hexanes/methanol (57:38:5) to provide the title compound (710 mg, 71 %). 1H NMR (400 MΗz, dη-DMF) δ 8.07 (s, 1Η), 7.79 (app q, J= 8.6 Ηz, 1Η), 7.50 (br s, 1Η), 7.32 (app dt, J= 10.1, 2.2 Ηz, 1Η), 7.30 (app dd, J= 8.0, 3.3 Ηz, 1Η), 7.20 (app dt, J= 8.6, 2.0 Ηz, 1Η), 6.81 (s, 1Η), 6.79 (d, J= 3.4 Ηz, 1Η), 5.47 (s, 2Η), 2.14 (s, 3H); LC/MS C-18 column, tr = 2.60 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 439 (M+H). ES-HRMS m/z 439.0088 (M+H calcd for C18H14BrF2N204 requires 439.0010).
Example 717 - 721 -
Figure imgf000722_0001
1 - [3 ,5 -bis(hydroxymethyl)phenyl] -3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methylpyridin-
2(lH)-one
Step 1: Preparation of dimethyl 5-(4-hydroxy-6-methyl-2-oxopyridin-l(2H)- yl)isophthalate
Figure imgf000722_0002
Dimethyl 5-aminoisophthalate (24.45 g, 117 mmol) was dissolved in 500 ml toluene and heated to reflux. 5-(l-hydroxy-3-oxobutylidene)-2,2-dimethyl-l,3-dioxane-4,6-dione (40.0 g, 175.3 mmol) was added and refluxed for 15 minutes. The reaction was evaporated. 500 ml of acetonitrile and p-toluenesulphonic acid (22.25 g, 117 mmol) was added and refluxed for 1 hour. The reaction was allowed to cool to room temperature and stand over night. The resulting precipitate was filtered, washed three times with 250 ml water and 250 ml acetonitrile and dried in vacuo to give a tan solid (18.85 g, 51% yield). 1H NMR (300 MHz, DMSO-dβ) δ 10.70 (br s, IH), 8.47 (t, J= 1.54 Hz, IH), 7.99 (d, J= 1.47 Hz, 2H), 5.90 (d, J = 1.61 Hz, IH), 5.55 (d, J= 2.42 Hz, IH), 3.87 (s, 6H), 1.82 (s, 3H); LC/MS, tr = 1.79 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 318 (M+H). ES-HRMS m/z 318.0994 (M+H calcd for C16H16N06 requires 318.0972).
Step 2: Preparation of dimethyl 5-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-l(2H)- yl)isophthalate
722 ■
Figure imgf000723_0001
Dimethyl-5-(4-hydroxy-6-methyl-2-oxopyridin-l(2H)-yl)isophthalate from Step 1) (18.0 g, 56.7 mmol) was stined at room temperature with N-Bromosuccinimide (10.6 g, 59.6 mmol) in 35 ml of NN-dimethylformamide and 180 ml of methylene chloride. After stirring for 1 hour, a white precipitate had formed. The precipitate was filtered, washed with acetonitrile and dried in vacuo to give a white solid (11.55 g, 51%). 1H ΝMR (400 MHz, DMSO-d6) δ 11.49 (br s, IH), 8.49 (t, J= 1.24 Hz, IH), 8.06 (d, J= 1.47 Hz, 2H), 6.07 (s, IH), 3.88 (s, 6H), 1.82 (s, 3H); LC/MS, tr = 1.81 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 396 (M+H). ES-HRMS m/z 396.0102 (M+H calcd for Cι6H15BrΝ06 requires 396.0077).
Step 3: Preparation of dimethyl 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]isophthalate.
Figure imgf000723_0002
Dimethyl 5-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-l(2H)-yl)isophthalate from Step
2) (11.3 g, 28.5 mmol) was stined briskly with 2,4-difluorobenzylbromide (3.66 ml, 28.5 mmol) and K2C03 (5.91 g, 42.8 mmol) in 50 ml of NN-dimethylformamide at room temperature for 3 hours. The reaction was then poured into 1L of cold water and the resulting precipitate was filtered, washed with water and diethyl ether, and dried in vacuo to yield a white solid (13.8 g, 93%). 1H ΝMR (400 MHz, DMSO- 5) δ 8.51 (t, J= 1.60
Hz, IH), 8.12, (d, J= 1.60 Hz, 2H), 7.67 (app q, J= 7.92 Hz, IH), 7.34 (app dt, J= 9.94,
2.19 Hz, IH), 7.17 (dt, J= 8.53, 2.11 Hz, IH), 6.68 (s, IH), 5.33 (s, 2H), 3.88 (s, 6H), 1.93
(s, 3H); LC/MS, tr = 2.77 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min,
723 at 254 nm, at 50°C), ES-MS m/z 522 (M+H). ES-HR/MS m/z 522.0335 (M+H calcd for C23H19BrF2N06 requires 522.0358).
Step 4: Preparation of 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]isoρhthalic acid.
Figure imgf000724_0001
Dimethyl 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yljisophthalate from Step 3) (5.0 g, 9.57 mmol) was stined at room temperature with 2.5 N
NaOH (15.3 ml, 38.3 mmol) in 30 ml of 5:1 THF/water for 1 hour. The reaction was then acidified with 1 N HCl and the resulting precipitate was filtered, washed with water, and dried in vacuo to yield a white solid (4.48 g, 95%). 1H NMR (400 MHz, DMSO-</6) δ 13.50 (br s, 2H), 8.51 (t, J= 1.41 Hz, IH), 8.02, (d, J= 1.48 Hz, 2H), 7.67 (app q, J= 7.88 Hz, IH), 7.32 (dt, J= 9.94, 2.19 Hz, IH), 7.16 (dt, J= 8.52, 1.99 Hz, IH), 6.68 (s, IH), 5.32 (s, 2H), 1.94 (s, 3H); LC/MS, tr = 2.27 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 494 (M+H). ES-HRMS m/z 494.0054 (M+H calcd for C21H15BrF2N06 requires 494.0045).
Step 5: Preparation of the title compound. 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]isophthalic acid from Step 4 above) (500 mg, 1.01 mmol) was added to a solution of IM borane-dimethylsulfide complex in tetrahydrofuran (9.0 ml, 9.00 mmol) in 2.5 ml tefrahydrofuran at 0°C. The reaction was allowed to warm to room temperature while stirring. After stirring overnight, more IM borane-dimethylsulfide complex in tetrahydrofuran (0.60 ml, 0.60 mmol) was added and stirring at room temperature. After 4 hours, ice chips were added to quench the reaction. The reaction was extracted 2 times with ethyl acetate and the combined organic layers were washed with brine, dried over MgS0 and evaporated. The resulting solid was washed with acetonitrile and diethyl ether and dried in vacuo to give a white solid (281 mg, 60%). R NMR (400 MHz, DMSO- ) δ 7.66 (app q, J= 7.92 Hz, IH), 7.35 (s, IH), 7.33 (dt, J= 9.40, 2.24 Hz,
- 724 - IH), 7.16 (dt, J= 8.52, 1.88 Hz, IH), 6.99 (s, 2H), 6.62 (s, IH), 5.31 (s, 2H), 5.27 (br s, 2H), 4.51 (s, 4H), 1.93 (s, 3H); LC/MS, tr = 2.19 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 466 (M+H). ES-HRMS m/z 466.0454 (M+H calcd for C21H19BrF2N04 requires 466.0460).
Example
Figure imgf000725_0001
5 -[3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] isophthalamide
5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]isophthalic acid (Example 717, step 4) (500 mg, 1.01 mmol) was dissolved in 4 ml of tetrahydrofuran.
0.5M ammonia in 1,4-dioxane (12.12 ml, 6.06 mmol) was added, followed, in order, by
EDCI (494 mg, 2.53 mmol), 1-hydroxybenzotriazole (342 mg, 2.53 mmol) and triethylamine (563 μl, 4.04 mmol). The reaction was stined at room temperature overnight. The reaction evaporated and water was used to triturate the product. The resulting solid was filtered and washed with water, acetonitrile, ethyl acetate and diethyl ether, and dried in vacuo to give a white solid (202 mg, 41%). 1H NMR (400 MHz,
DMSO- ) δ 8.45 (s, IH), 8.08 (br s, 2H), 7.86, (d, J= 1.34 Hz, 2H), 7.67 (app q, J= 7.92
Hz, IH), 7.55 (br s, 2H), 7.33 (dt, J= 9.94, 2.18 Hz, IH), 7.17 (dt, J= 8.59, 1.92 Hz, IH),
6.70 (s, IH), 5.34 (s, 2H), 1.96 (s, 3H); LC MS, tr = 2.10 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 492
(M+H). ES-HRMS m/z 492.0381 (M+H calcd for C 1H17BrF2N304 requires 492.0365).
Example 719
Figure imgf000725_0002
l-[3,5-bis(l-hydroxy-l-methylethyl)phenyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methylpyridin-2( 1 H)-one
Dimethyl 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)- yl]isophthalate (Example 717, step 3) (500 mg, 0.96 mmol) was added dro pwise to a solution of 3M MeMgBr in diethyl ether (1.6 ml, 4.79 mmol) in 15 ml of tefrahydrofuran at -5°C and stined at -5°C. The reaction turned red. After 2.5 hours, the reaction was quenched with a saturated NH4C1 solution and extracted 2 times with ethyl acetate. The combined organic layers were washed with NaHC03 solution and brine, dried over MgS04 and evaporated. The resulting solid was washed with diethyl ether and dried in vacuo to give a white solid (329 mg, 66%). 1H NMR (400 MHz, DMS0- ) δ 7.69 - 7.63 (m, 2H), 7.33 (dt, J= 9.87, 2.41 Hz, IH), 7.16 (dt, J= 8.46, 1.75 Hz, IH), 7.07 (d, J = 1.48 Hz, 2H), 6.61 (s, IH), 5.32 (s, 2H), 5.06 (s, 2H), 1.89 (s, 3H), 1.41 (s, 12H); LC/MS, tr = 2.45 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 522 (M+H). ES-HRMS m/z 522.1098 (M+H calcd for C25H27BrF2N04 requires 522.1086).
Example 720
Figure imgf000726_0001
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[4-(hydroxymethyl)phenyl]-6-methylpyridin- 2(lH)-one
4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]benzoic acid (Example 203) (500 mg, 1.11 mmol) was added to a solution of 2M borane- dimethylsulfide complex in tetrahydrofuran (3.33 ml, 6.66 mmol) in 2.5 ml tetrahydrofuran at 0°C. The reaction was allowed to warm to room temperature while stirring. After 2.5 hours, ice chips were added to quench the reaction. The resulting precipitate was filtered, washed with diethyl ether and dried in vacuo to give a white solid (160 mg, 33%). 1H NMR (400 MHz, DMSO-d6) δ 7.66 (app q, J= 7.88 Hz, IH), 7.42 (d,
- 726 - J= 8.19 Hz, 2H), 7.33 (dt, J= 9.87, 2.06 Hz, IH), 7.19 - 7.14 (m, 3H), 6.62 (s, IH), 5.31 (s, 2H), 5.30 (s, IH), 4.54 (d, J= 5.24, 2H), 1.92 (s, 3H); LC/MS, tr = 2.36 minutes (5 to 95%) acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 436 (M+H). ES-HRMS m/z 436.0374 (M+H calcd for C20H17BrF2NO3 requires 436.0354).
Example 721
Figure imgf000727_0001
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[4-(l-hydroxy-l-methylethyl)phenyl]-6- methylρyridin-2(lH)-one
Methyl-4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxoρyridin-l(2H)- yljbenzoate (Example 202) (500 mg, 1.08 mmol) was added dropwise to a solution of 3M MeMgBr in diethyl ether (0.90 ml, 2.69 mmol) in 15 ml of tetrahydrofuran at -5°C and stined at -5°C. After 2.75 hours, more 3M MeMgBr in diethyl ether (0.45 ml, 1.35 mmol) was added and stined at -5°C. After 4 hours, the reaction was quenched with a saturated NH4C1 solution and extracted 2 times with ethyl acetate. The combined organic layers were washed with NaHC03 solution and brine, dried over MgS04 and evaporated. The resulting solid was washed with diethyl ether and dried in vacuo to give a white solid (268 mg, 53%). 1H NMR (400 MHz, DMSO-i6) δ 7.66 (app q, J= 7.92 Hz, IH), 7.57 (d, J = 8.46 Hz, 2H), 7.33 (dt, J= 9.87, 2.11 Hz, IH), 7.16 (dt, J= 8.59, 2.24 Hz, IH), 7.14 (d, J = 8.63 Hz, 2H), 6.62 (s, IH), 5.31 (s, 2H), 5.12 (s, IH), 1.91 (s, 3H), 1.44 (s, 6H); LC/MS, tr = 2.54 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 464 (M+H). ES-HRMS m/z 464.0604 (M+H calcd for C22H21BrF2N03 requires 464.0667).
- 727. Example 722
Figure imgf000728_0001
l-(5-amino-2-fluorophenyl)-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)- one hydrochloride
Step 1 Preparation of tert-butyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]-4-fluorophenylcarbamate
Figure imgf000728_0002
H solution of the compound of Exam ipl^ was flushed with mfrogen. Diphenyl phosphoryl azide (2 mL, 9.2 mmol) and triethyl amine (1.3 mL, 9.2 mmol) were added. After heating at 90 C for 20 h, the reaction mixture was concenfrated in vacuo. The residue was diluted with methylene chloride and was washed sequentially with aqueous ammonium chloride and aqueous NaHC03. The organic layer was concenfrated in vacuo; the resulting solids were suspended in acetonitrile and filtered to give the title compound (2.9 g, 58%). 1H NMR (400 MHz, CD3OD) δ 7.64 (q, J= 7.2 and 14.4 Hz, IH), 7.49 (m, IH), 7.43 (m, IH), 7.24 (t, J= 9.6 Hz, IH), 7.04 (t, J = 8.4 Hz, 2H), 6.62 (s, IH), 5.35 (s, 2H), 2.09 (s, 3H), 1.49 (s, 9H) ppm. 19 F NMR (300 MHz, CD3OD) δ -111.53 (IF), -115.93 (1 F), -132.58 ppm. ESHRMS m/z 540.0822 (M+H calcd for C24H23BrF3N204 requires 540.0820).
728 Step 2 Preparation of l-(5-amino-2-fluorophenyl)-3-bromo-4-[(2,4-difluorobenzyl)oxy]- 6-methylpyridin-2(lH)-one hydrochloride
Figure imgf000729_0001
The product of Step 1 (2.9 g, 5.3 mmol) was dissolved in tefrahydrofuran (75 mL) and 6N HCl (10 mL). The reaction mixture was heated at 60 C for 18h and was concenfrated in vacuo to give the final product (1.89 g, 75%). 1H NMR (400 MHz, CD3OD) δ 7.64 (q, J= 8.4 and 15.2 Hz, IH), 7.56 (m, 2H), 7.46 (m, IH), 7.05 (m, 2H), 6.69 (s, IH), 5.37 (s, 2H), 2.10 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) δ -111.37 (IF), -115.86 (1 F), -123.16 ppm. ESHRMS m/z 440.0334 (M+H calcd for C19H15BrF3N202 requires 440.0295).
Example 723
Figure imgf000729_0002
N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- fluorophenyl} -2-hydroxyacetamide
Step 1 Preparation of 2-({3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-1 (2H)-yl]-4-fluorophenyl} amino)-2-oxoethyl acetate
729
Figure imgf000730_0001
A solution of the compound of Example 722 (0.5 g, 1.05 mmol) in tetrahydrofuran (20 mL) was treated with triethyl amine (0.3 mL, 2.1 mmol) and acetoxy acetylchloride (0.12 mL, 1.15 mmol). After stirring at room temperature for 2h, the reaction was complete. The reaction mixture was poured into saturated aqueous ammonium chloride. The solids were filtered off and were washed with water and diethyl ether. Title product was isolated as a white solid (0.32 g, 58%). 1H NMR (400 MHz, CD3OD) δ 7.65 (m, 3H), 7.32 (t, J= 8.4 Hz, IH), 7.04 (t, J= 8.4 Hz, 2H), 6.64 (s, IH), 5.35 (s, 2H), 4.68 (s, 2H), 2.15 (s, 3H), 2.10 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) δ -111.56 (IF), -115.99 (1 F), -129.48 (IF) ppm. LC/MS, tr = 5.35 minutes (5 to 95% acetonitrile/water over 8 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 540 (M+H).
Step 2 Preparation of N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]-4-fluorophenyl} -2-
hydroxyacetamide
Figure imgf000730_0002
The product of Step 1 (0.1 g, 0.18 mmol) was suspended in tefrahydrofuran (10 mL), methanol (2 mL), and 2.5 N NaOH (1 mL). After stirring at room temperature for 1 hour, the reaction was complete and the organics were removed in vacuo. The aqueous layer was acidified to pH 1 with 6N HCl, the solids were suspended in water, filtered, and washed with diethyl ether. The title compound, was obtained as a white powder (56.2 mg,
61%). 1H NMR (400 MHz, CD3OD) δ 7.75 (dq, J= 2.9, 4.8 and 9.2 Hz, IH), 7.71 (dd, J - 730 - = 2.4 and 6.8 Hz, IH), 7.64 (q, J= 8 and 14.8 Hz, IH), 7.32 (t, J= 9.6 Hz, IH), 7.04 (t, J = 8.8 Hz, 2H), 6.64 (s, IH), 5.36 (s, 2H), 4.10 (s, 2H), 2.10 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) δ -111.54 (IF), -115.99 (1 F), -129.71 (IF) ppm. LC/MS, tr = 5.04 minutes (5 to 95% acetonitrile/water over 8 minutes at 1 ml min with detection 254 nm, at 50°C). ES-MS m/z 498 (M+H).
Example 724
Figure imgf000731_0001
N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- fluorophenyl} -2-hydroxy-2-methylpropanamide
Step 1 Preparation of 2-({3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl] -4-fluorophenyl} amino)- 1 , 1 -dimethyl-2-oxoethyl acetate
Figure imgf000731_0002
A solution of the compound of Example 722 (0.5 g, 1.05 mmol) in tefrahydrofuran (20 mL) was treated with triethyl amine (0.3 mL, 2.1 mmol) and 1-chlorocarbonyl-l- methylethyl acetate (0.16 mL, 1.15 mmol). After stirring at room temperature for 2h, the reaction was complete. The reaction mixture was poured into saturated aqueous ammonium chloride. The solids were filtered off and were washed with water and diethyl ether. The compound of Step 1 was isolated as a white solid (0.23 g, 39%). 1H NMR (400 MHz, CD3OD) δ 7.64 (m, 2H), 7.54 (dd, J= 2.8 and 6.8 Hz, IH), 7.30 (t, J= 9.2 Hz, IH),
- 731 - 7.04 (t, J= 9.2 Hz, 2H), 6.64 (s, IH), 5.35 (s, 2H), 2.11 (s, 3H), 2.08 (s, 3H), 1.61 (s, 6H) ppm. 19 F NMR (400 MHz, CD3OD) δ -111.57 (IF), -116.00 (1 F), -129.56 (IF) ppm. LC/MS, tr = 5.65 minutes (5 to 95% acetonitrile/water over 8 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 568 (M+H).
Step 2 Preparation of N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl] -4-fluorophenyl} -2-hydroxy-2-methylpropanamide
Figure imgf000732_0001
The product of Step 1 (0.1 g, 0.17mmol) was suspended in tetrahydrofuran (10 mL), methanol (2 mL), and 2.5 N NaOH (1 mL). After stirring at room temperature for 1 hour, the reaction was complete and the organics were removed in vacuo. The aqueous layer was acidified to pH 1 with 6N HCl, the solids were suspended in water, filtered, and washed with diethyl ether. The title compound was obtained as a white powder (56 mg, 61%). lH NMR (400 MHz, CD3OD) δ 7.75 (dq, J= 2.8, 4.4 and 9.2 Hz, IH), 7.69 (dd, J = 2.8 and 6.8 Hz, IH), 7.64 (q, J= 8 and 14.8 Hz, IH), 7.31 (t, J= 9.2 Hz, IH), 7.04 (t, J = 8.4 Hz, 2H), 6.64 (s, IH), 5.35 (s, 2H), 2.10 (s, 3H), 1.43 (s, 6H) ppm. 19 F NMR (400 MHz, CD3OD) δ -111.55 (IF), -115.95 (1 F), -129.80 (IF) ppm. LC MS, tr = 5.34 minutes (5 to 95% acetonitrile/water over 8 minutes at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 526 (M+H).
Example 725
Figure imgf000732_0002
- 732 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3-fiuoro-N,N- dimethylbenzamide
Step 1 Preparation of 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]-3-fluorobenzoic acid
Figure imgf000733_0001
The compound of Example 604 (4.1 g, 8.5mmol) was suspended in tetrahydrofuran (30 mL), methanol (15 mL), water (15 mL) and 2.5 N NaOH (6.8 mL, 17 mmol)). After stirring at room temperature for 2 hour, the reaction was complete and the organics were removed. The aqueous layer was acidified to pH 1 with 3N HCl, the solids were suspended in water, filtered, and washed with diethyl ether. The title compound was obtained as a white powder and used without further purification (4.4 g). 1H NMR (400 MHz, CD3OD) δ 8.00 (dd, J= 1.8 and 8.8 Hz, IH), 7.93 (dd, J= 1.48 and 10 Hz, IH), 7.64 (q, J= 8 and 14.8 Hz, IH), 7.49 (t, J= 7.6 Hz, IH), 7.05 (t, J= 10 Hz, 2H), 6.66 (s, IH), 5.36 (s, 2H), 2.08 (s, 3H) ppm. 19 F NMR (400 MHz, CD3OD) δ -111.48 (IF), - 115.96 (1 F), -123.35 (IF) ppm. ES-HRMS m/z 468.9987 (M+H calcd for C20H14BrF3NO4 requires 469.0086).
Step 2 Preparation of 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl]-3-fluoro-N,N-dimethylbenzamide
733
Figure imgf000734_0001
A solution of the product of Step 1 (0.5 g, 1.07 mmol) in NN-dimethyl formamide was cooled to 0 C. Iso-butyl chloroformate (0.14 mL, 1.07 mmol) and N-methyl morpholine (0.12 mL, 1.07 mmol) were added. After 20 minutes, NN-dimethylamine (2.0 M, 1.1 mL, 2.14 mmol) was added and the reaction mixture was warmed to room temperature over 18 h. The reaction mixture was partitioned between ethyl acetate and saturated aqueous ΝaHC03. The organics were washed with brine and concentrated in vacuo. The resulting semi-solid was freated with ethyl acetate and acetone to precipitate the title compound (90 mg, 17%). 1H NMR (400 MHz, dmso-</d) δ 7.67 (q, J= 8 and 14.8 Hz, IH), 7.52 (m, 2H), 7.35 (m, 2H), 7.18 (td, J = 2.8 and 8.8 Hz, IH), 6.73 (s, IH), 5.34 (s, 2H), 2.98 (s, 3H), 2.91 (s, 3H), 2.00 (s, 3H) ppm. 19 F NMR (400 MHz, dmso-d6) δ -109.50 (IF), -113.63 (1 F), -122.09 (IF) ppm. ES-HRMS m/z 496.0570 (M+H calcd for C22H19BrF3N203 requires 496.0558).
Example 726
Figure imgf000734_0002
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[(l-glycoloyl-2,3-dihydro-lH-indol-5-yl)methyl]-
6-methylp yridin-2( 1 H)-one
A 10 mL round bottomed flask equipped with stirbar and nifrogen inlet was charged with compound of Example 633 (180 mg, 0.43 mmol), acetoxyacetyl chloride (51 μL, 0.47 mmol), triethylamine (119 μL, 0.86 mmol) and tefrahydrofuran (3.0 mL). After stirring at
- 734 - 25° C for 20 min the reaction was completed by LC-MS. NaOH (2.5M, 2.24 mmol, 1.0 mL) and MeOH (2.0mL) was added and stined for 20 min to give the title compound. The compound precipitated out of solution. The precipitated was filtered and washed with water and diethyl ether to obtain the title compound (130 mg, 64%) as a white solid. 1H NMR (400 MHz, (DMSO) δ 7.9 (d, J= 8.2, IH), 7.6 (q, J= 8.5 and 6.9 Hz, IH), 7.3 (t, J = 8.7 Hz, IH), 7.1 (t, J= 7.9 Hz, IH), 6.9 (s, 2H), 6.5 (s, IH), 5.25 (s, 2H), 4.1 (d, J= 5.5 Hz, 2H), 3.9 (t, J= 8.6 Hz, 2H), 3.42 (t, J= 5.4 Hz, IH), 3.35 (t, J = 4.8 Hz, IH), 3.2 (t, J = 8.5 Hz, 2H), 2.3 (s, 3H) ppm. ES-HRMS m/z 475.1220 (M+H calcd for C24H22C1F2N204 requires 475.1231).
Example 727
Figure imgf000735_0001
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[l-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro- lH-indol-5-yl]methyl} -6-methylρyridin-2(lH)-one
A 10 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with compound of Example 633 (200 mg, 0.48 mmol), 1-chlorocarbonyl-l-methylethyl acetate (104.3 μL, 0.72 mmol), triethylamine (133 μL, 0.96 mmol) and tetrahydrofuran (4.0 mL). After stirring at 25° C for 20 min the reaction was completed by LC-MS. NaOH (2.5M, 2.24 mmol, 1.5 mL) and MeOH (2.0mL) was added and stined for 20 min to give the title compound. The compound precipitated out of solution. The precipitate was filtered and washed with water and diethyl ether to obtain a white solid (240 mg, 99%>). 1H NMR (400 MHz, (DMSO) δ 8.0 (d, J= 8.3, IH), 7.6 (q, J= 8.6 and 6.9 Hz, IH), 7.3 (td, J= 2.5 and 7.8 Hz, IH), 7.1 (td, J= 1.75 and 6.7 Hz, IH), 6.95 (s, IH), 6.89 (d, J= 8.5 Hz, IH), 6.58 (s, IH), 5.25 (s, 2H), 4.3 (t, J= 8.3 Hz, 2H), 3.42 (t, J= 5.4 Hz, IH), 3.35 (t, J = 5.2 Hz, IH), 3.0 (t, J= 8.2 Hz, 2H), 2.3 (s, 3H), 1.3 (s, 6H) ppm. ES-HRMS m/z 503.1561 (M+H calcd for C26H26C1F2N204 requires 503.1544).
735 Example 728
Figure imgf000736_0001
3-chloro-4-[(2,4-difluorobenzyl)oxy]- 1 - {[ 1 -(methoxyacetyl)-2,3 -dihydro- 1 H-indol-5- yl]methyl}-6-methylpyridin-2(lH)-one
A 10 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with compound of Example 633 (200 mg, 0.48 mmol), methoxyacetyl chloride (66 μL, 0.72 mmol), triethylamine (134 μL, 0.96 mmol) and tetrahydrofuran (4.0 mL). After stirring at
25° C for 20 min the reaction was completed by LC-MS. The compound precipitated out of solution. The precipitate was filtered and washed with water and diethyl ether to obtain a white solid (195 mg, 83%). 1H NMR (400 MHz, (DMSO) δ 8.0 (d, J= 8.0, IH), 7.6 (q, J = 8.6 and 6.7 Hz, IH), 7.3 (td, J= 2.4 and 6.7 Hz, IH), 7.1 (td, J= 1.88 and 6.6 Hz, IH), 6.9 (s, 2H), 6.58 (s, IH), 5.25 (s, 2H), 4.15 (s, 2H), 3.9 (t, J= 8.3 Hz, 2H), 3.45 (m, IH), 3.4 (m, IH), 3.32 (s, 3H), 3.0 (t, J = 8.5 Hz, 2H), 2.3 (s, 3H) ppm. ES-HRMS m/z 489.1387 (M+H calcd for C25H24C1F2N204 requires 489.1387).
Example 729
Figure imgf000736_0002
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-N,N- dimethylindoline-1 -carboxamide
A 10 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with compound of Example 633 (200 mg, 0.48 mmol), dimethylcarbamyl chloride (66 μL, 0.72 mmol), triethylamine (133 μL, 0.96 mmol) and tetrahydrofuran (4.0 mL). After stirring at 25° C for 5 min the reaction was completed by LC-MS. The compound precipitated out of solution. The precipitate was filtered and washed with water and diethyl ether to obtain a - 736 - white solid (198 mg, 85%). 1H NMR (400 MHz, (DMSO) δ 7.6 (q, J= 7.4 Hz, IH), 7.3 (t, J= 8.9 Hz, IH), 7.1 (t, J= 8.5 Hz, 2H), 6.93 (s, IH), 6.86 (s, IH), 6.58 (s, IH), 5.25 (s, 2H), 3.9 (t, J= 8.2 Hz, 2H), 3.45 (m, IH), 3.4 (m, IH), 2.9 (t, J= 8.3 Hz, 2H), 2.8 (s, 6H), 2.3 (s, 3H) ppm. ES-HRMS m/z 488.1548 (M+H calcd for C25H24C1F2N204 requires 488.1547).
Example 730
Figure imgf000737_0001
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[(l-glycoloyl-2,3-dihydro-lH-indol-5- yl)methyljpyridin-2(lH)-one
A 10 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with compound of Example 88 (200 mg, 0.5 mmol), acetoxyacetyl chloride (59 μL, 0.55 mmol), triethylamine (140 μL, 1.0 mmol) and tefrahydrofuran (3.0 mL). After stirring at 25° C for 20 min the reaction was completed by LC-MS. NaOH (2.5M, 2.24 mmol, 1.0 mL) and MeOH (2.0mL) was added and stined for 20 min to give the title compound. The compound precipitated out of solution. The precipitated was filtered and washed with water and diethyl ether to obtain the title compound (200 mg, 83%) as a white solid. 1H NMR (400 MHz, (DMSO) δ 7.98 (d, J= 8.1, IH), 7.9 (d, J= 7.8 Hz, IH), 7.6 (q, J= 8.6 and 6.6 Hz, IH), 7.3 (dt, J= 2.4 and 7.2 Hz, IH), 7.1 (m, 2H), 6.56 (d, J =7.8 Hz, IH), 5.25 (s, 2H),5.1 (s, 2H), 4.8 (t, J= 5.8 Hz, IH), 4.1 (d, J= 5.6 Hz, 2H), 3.9 (t, J= 7.9 Hz, 2H), 3.1 (t, J = 7.9 Hz, 2H) ppm. ES-HRMS m/z 461.1088 (M+H calcd for C23H20ClF2N2O4 requires 461.1074).
Example 731
Figure imgf000737_0002
Preparation of 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[(l-glycoloyl-2,3-dihydro-lH- indol-5-yl)methyl]pyridin-2(lH)-one
A 10 mL round bottomed flask equipped with stirbar and nifrogen inlet was charged with compound of Example 88 (200 mg, 0.50 mmol), 1-chlorocarbonyl-l-methylethyl acetate (80 μL, 0.55 mmol), triethylamine (140 μL, 1.0 mmol) and tefrahydrofuran (4.0 mL). After stirring at 25° C for 20 min the reaction was completed by LC-MS. NaOH (2.5M, 2.24 mmol, 1.5 mL) and MeOH (2.0mL) was added and stined for 20 min to give the title compound. The compound precipitated out of solution. The precipitated was filtered and washed with water and diethyl ether to obtain the title compound (136 mg, 55%) a white solid. 1H NMR (400 MHz, (DMSO) δ 7.98 (d, J= 8.1, IH), 7.9 (d, J= 7.8 Hz, IH), 7.6 (q, J= 8.6 and 6.6 Hz, IH), 7.3 (m, IH), 7.1 (m, 2H), 6.56 (d, J=7.8 Hz, IH), 5.25 (s, 2H),5.0 (s, 2H), 4.3 (t, J= 7.8 Hz, 2H), 3.0 (t, J= 7.9 Hz, 2H), 1.3 (s, 6H) ppm. ES-HRMS m/z 489.1376 (M+H calcd for C25H24C1F2N204 requires 489.1387).
Example 732
Figure imgf000738_0001
3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[l-(methoxyacetyl)-2,3-dihydro-lH-indol-5- yl]methyl}pyridin-2(lH)-one
A 10 mL round bottomed flask equipped with stirbar and nifrogen inlet was charged with the compound of Example 88 (200 mg, 0.5 mmol), methoxyacetyl chloride (69 μL, 0.75 mmol), triethylamine (139 μL, 1.0 mmol) and tetrahydrofuran (4.0 mL). After stirring at 25° C for 20 min the reaction was completed by LC-MS. The compound precipitated out of solution. The precipitate was filtered and washed with water and diethyl ether to obtain a white solid (195 mg, 83%). 1H NMR (400 MHz, (DMSO) δ 7.98 (d, J= 8.2, IH), 7.9 (d, J = 1.1 Hz, IH), 7.6 (d, J= 8.5 Hz, IH), 7.3 (t, J = 9.6 Hz, IH), 7.1 (m, 3H), 6.56 (d, J =7.8 Hz, IH), 5.25 (s, 2H),5.1 (s, 2H), 4.1 (s, 2H), 3.98 (t, J= 7.9 Hz, 2H), 3.33 (s, 3H),
738 3.0 (t, J= 7.9 Hz, 2H) ppm. ES-HRMS m/z 461.1088 (M+H calcd for C23H20ClF2N2O4 requires 461.1074).
Example 733
Figure imgf000739_0001
5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]2-oxopyridin-l(2H)-yl]methyl}-N,N- dimethylindoline- 1 -carboxamide
A 10 mL round bottomed flask equipped with stirbar and nifrogen inlet was charged with the compound of Example 88 (200 mg, 0.5 mmol), dimethylcarbamyl chloride (69 μL, 0.75 mmol), triethylamine (139 μL, 1.0 mmol) and tefrahydrofuran (4.0 mL). After stirring at 25° C for 5 min the reaction was completed by LC-MS. The compound precipitated out of solution. The precipitate was filtered and washed with water and diethyl ether to obtain a white solid (188 mg, 58%). 1H NMR (400 MHz, (DMSO) δ 7.9 (d, J= 8.1, IH), 7.6 (q, J = 8.6 and 6.6 Hz, IH), 7.3 (t, J= 9.3 Hz, IH), 7.1 (m, 3H), 6.8 (d, J=8.0 Hz, IH), 6.5 (d, J = 7.8 Hz, H), 5.25 (s, 2H),5.0 (s, 2H), 3.7 (t, J= 8.6 Hz, 2H), 2.9(t, J= 7.9 Hz, 2H), 2.8 (s, 6H) ppm. ES-HRMS m/z 474.1387 (M+H calcd for C24H23C1F2N303 requires 474.1391).
Example 734
Figure imgf000739_0002
3 -Bromo-4- [(2,4-difluorobenzyl)oxy] -6-methylpyridin-2( 1 H)-one
Step 1: Preparation of 4-hydroxy-6-methyl-pyridin-2(lH)-one.
- 739 -
Figure imgf000740_0001
Ammonium hydroxide (concentrated, 500 mL) and 4-hydroxy-6-methylpyrone (500 g, (3.96 moles) were stined at 85 °C in a 3L flask filled with a short and wide air condenser with a frap to collect any overflow. Mechanical stirring was used to control extensive foaming during heating. After 2 h the product precipitated and the reaction mixture cooled and filtered. The filfrate was concenfrated to provide additional product. The combined solids were dried (450 g). 1H NMR (300 MHz, DMSO-</6) δ 10.94 (br s, IH), 10.34 (s, IH), 5.59 (d, J= 1.4 Hz, IH), 5.32 (d, J= 2.0 Hz, IH), 2.07 (s, 3H). Step 2: Preparation of 4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one
Figure imgf000740_0002
4-Hydroxy-6-methyl-pyridin-2(lH)-one (375 g, 3 moles) was suspended in NMP (750 mL) and DBU (456 g, 3 moles) added in one portion. The mixture was heated to 60 °C with mechanical stirring. The 2,4-difluorobenzyl chloride (487.5 g, 3 moles) was added during a 20 min. period, and the mixture reached a final temperature of 80 °C. After reaction for 3 h at this temperature, significant precipitation was observed. The mixture was cooled, with continuous stirring, first to ambient temperature then subsequently to 10 °C, and then filtered. The precipitate was washed with cold CH3CN (200 mL) followed by water (4x 400 mL) and dried (373 g, 50 %). MS (M+H) m/z 252.
Step 3: 3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one. To a suspension of 4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one (252 g, 1 mole) in AcOH (500 mL) at 25°C, bromine (160 g, 1 mole) was added drop-wise with stirring. At the end of the addition, 400 mL of water (400 mL) was added and stirring was continued for 30 min. The resulting white suspension was filtered and washed with water (400 mL, twice), saturated sodium bicarbonate (200 mL) and water (300 mL). The white solid was dried (326 g, 98%). 1H NMR (300 MHz, DMSO-</6) δ 11.98 (br s, IH), 7.43 - 740 - (app q, J= 9 Hz, IH), 7.23 (app t, J= 10 Hz, IH), 7.11 (app t, J= 9 Hz, IH), 6.28 (s, IH), 5.20 (s, 2H), 2.25 (s, 3H). ES-HRMS m/z 329.9973 (M+H calcd for C13HnBrF2N02 requires 329.9947).
Example 735
Figure imgf000741_0001
3 -[3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -4- methylbenzamide
3 - [3 -Bromo-4-[(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -4- methylbenzoic acid (see synthesis in Example 487, step 4) (1 g, 2.15 mmol) was dissolved in THF (20 ml), and 2-Chloro-4,6-dimethoxy-l,3,5-triazine (0.45 g, 2.58 mmol) and N- methyl morpholine (0.71 ml, 6.45 mmol) were added. The mixture was stined at room temperature for 1 h. After that time, ΝH4OH (5 ml) was added and the reaction stined at room temperature for an additional hour. To the reaction mixture was added additional THF (50 ml) and water (200 ml). The mixture was extracted with ethyl acetate. The ethyl acetate extraction was washed with saturated brine solution. The brine layer was exfracted with ethyl acetate. The organic layers were combined, dried over Na2S04, filtered and the solvent was removed in vacuo. The residue was taken up in ethyl acetate and the resulting precipitate was collected on a filter pad to yield a white powder (0.71 g, 71%). 1H NMR (300 MHz, CD3OD) δ 7.97 (dd, J= 6.04, 1.81 Hz, IH), 7.70 (m, 2H), 7.57 (d, J= 7.85 Hz,
IH), 7.13 - 7.06 (m, 2H), 6.71 (s, IH), 5.40 (s, 2H), 2.13 (s, 3H) 2.04 (s, 3H). LC/MS, tr =
2.33 min. (5 to 95% acetonitrile/water over 5 min at 1 ml/min with detection 254 nm, at
50°C). ES-MS m/z 463 (M+H).
741 - Example 736
Figure imgf000742_0001
(+)-3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxoρyridin-l(2H)-yl]-4- methylbenzamide
The isolated product from Example 735 was separated using a Chiracel OJ column (50 mm x 500 mm, 20 μm) eluting with 100% methanol, (50 ml/min), pressure 400 psi, with detection at 254 nm. Fractions of the early-eluting atropisomer were pooled and concenfrated in vacuo to the title compound as a white solid (yield 99 %), ee >98 %. [□ DD = + 16.3° (1.0 g/100 mL MeOH, 22 °C). 1H NMR (300 MHz, CD3OD), identical to product from Example 735. ES-HRMS m/z 463.0458 (M+H calcd for C21H18BrF2N203 requires 463.0463).
Example 737
Figure imgf000742_0002
(-)-3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylbenzarnide The title compound was prepared as with the title compound of Example 736, pooling fractions from the late-eluting atropisomer. Recovery by solvent concentration gave a white solid, (yield 90%), ee >98 %. [D DD = - 15.9° (1.0 g/100 mL MeOH, 22 °C).
742 1H NMR (300 MHz, CD3OD), identical to product from Example 735. ES-HRMS m/z 463.0481 (M+H calcd for C21H18BrF2N203 requires 463.0463).
Example 738
Figure imgf000743_0001
4-{l-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]ethyl}-N- methylbenzamide
Step 1: Preparation of methyl 4-(l-bromoethyl)benzoate.
Figure imgf000743_0002
4-(l-Bromoethyl)benzoic acid (14.75 g, 64.4 mmol) was dissolved in 60 ml of methanol. 60 ml of 4 M HCl in 1,4-dioxane was added and stined at room temperature over night. The solvent was evaporated to yield a tan oil (14.96 g, 96% yield). 1H NMR
(400 MHz, CDC13) δ 8.00 - 7.98 (m, 2H), 7.49 - 7.47 (m, 2H), 5.18 (q, J= 6.89 Hz, IH), 3.90 (s, 3H), 2.03 (d, J= 6.85 Hz, 3H); LC/MS, tr = 2.77 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 243 (M+H).
Step 2: Preparation of methyl 4-{l-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin- 1 (2H)-yl] ethyl}benzoate.
Figure imgf000743_0003
3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one (Example 734)
(8.0 g, 24.2 mmol) was stined at room temperature with sodium hydride (60% dispersion in mineral oil) (1.94 g, 48.4 mmol) in 100 ml of tefrahydrofuran for 10 min. Methyl 4-(l- bromoethyl)benzoate (from step 1) (6.48 g, 26.6 mmol) and 60 ml of NMP were then - 743 - added and refluxed at 105 °C over night. The tefrahydrofuran was evaporated and the reaction was then added into 1L of water. No precipitate formed, and the solution was extracted three times with ethyl acetate. The combined organic layer was dried over MgS04 and evaporated. The resulting oil was triturated with diethyl ether and petroleum ether to obtain a solid which was filtered and dried in vacuo to give an off-white solid (7.35 g, 62%). 1H NMR (400 MHz, CDC13) δ 7.98 (d, J= 8.32 Hz, 2H), 7.55 (app q, J= 8.46 Hz, IH), 7.52 (d, J = 8.32 Hz, 2H), 6.92 (dt, J = 8.46, 2.02 Hz, IH), 6.84 (dt, J = 9.40, 2.06 Hz, IH), 6.36 (s, IH), 6.29 (q, J= 6.58 Hz, IH), 5.14 (s, 2H), 3.88.(s, 3H), 2.29 (s, 3H), 1.64 (d, J= 6.57 Hz, 3H); LC/MS, tr = 3.93 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 514 (M+Na). ES-HRMS m/z 492.0629 (M+H calcd for C23H21BrF2N04 requires 492.0617).
Step 3: Preparation of 4-{l-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl] ethyljbenzoic acid.
Figure imgf000744_0001
Methyl 4-{l-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]ethyl}benzoate (from Step 2) (5.0 g, 10.15 mmol) was stined with 8.2 ml of 2.5 N
NaOH, 25 ml of tetrahydrofuran and 5 ml of water at room temperature for 48 h. The reaction was acidified with 1 N HCl and extracted twice with ethyl acetate. The combined organic layer was dried over MgS04 and evaporated. The resulting solid was dried in vacuo to yield a white solid (4.51 g, 93%). 1H NMR (400 MHz, CDC13) δ 8.06 (d, J = 8.46 Hz, 2H), 7.56 (d, J= 8.33 Hz, 2H), 7.55 (app q, J= 7.74 Hz, IH), 6.92 (dt, J= 8.33, 1.52 Hz, IH), 6.84 (dt, J= 9.47, 2.42 Hz, IH), 6.37 (s, IH), 6.31 (q, J= 6.53 Hz, IH), 5.14 (s, 2H), 2.30 (s, 3H), 1.65 (d, J = 6.58 Hz, 3H); LC/MS, tr = 3.25 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 500 (M+Na). ES-HR/MS m/z 476.0311 (M-H calcd for C22H17BrF2N04 requires 476.0309).
Step 4: Preparation of the title compound. 4-{l-[3-bromo-4-[(2,4- difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]ethyl}benzoic acid (from Step 3)
- 744 - (500 mg, 1.04 mmol) was dissolved in 5 ml of methylene chloride. 2.0 M methylamine in tefrahydrofuran (2.09 ml, 4.18 mmol) was added, followed, in order, by EDCI (250 mg, 1.31 mmol), 1-hydroxybenzotriazole (177 mg, 1.31 mmol) and triethylamine (290 μl, 2.08 mmol). The reaction was stined at room temperature overnight. The reaction was quenched with saturated ammonium chloride solution and exfracted twice with ethyl acetate. The combined organic layer was washed with saturated NaHC03 solution and water, dried over MgS04 and evaporated. Water was used to triturate the product. The resulting solid was filtered, washed with water, and dried in vacuo to give a white solid (355 mg, 69%). 1H NMR (400 MHz, DMSO- 6) δ 8.34 (app d, J= 3.75 Hz, IH), 7.75 (d, J= 7.92 Hz, 2H), 7.62 (app q, J= 7.74 Hz, IH), 7.46 (d, J= 7.92 Hz, 2H), 7.30 (app t, J= 9.20 Hz, IH), 7.14 (app t, J= 7.72 Hz, IH), 6.83 (s, IH), 6.23 (q, J= 6.44 Hz, IH), 5.21 (s, 2H), 2.73 (d, J= 3.83 Hz, 3H), 2.28 (s, 3H), 1.54 (d, J= 6.31 Hz, 3H); LC/MS, tr = 3.02 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min, at 254 nm, at 50°C), ESMS m/z 513 (M+Na). ES-HRMS m/z 491.0738 (M+H calcd for C23H22BrF2N203 requires 491.0776).
Example 739
Figure imgf000745_0001
4-{l-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]ethyl}benzamide
4- { 1 - [3 -Bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)- yl]ethyl}benzoic acid (from Example 738, step 3) (500 mg, 1.04 mmol) was dissolved in 5 ml of methylene chloride. 0.5 M ammonia in 1,4-dioxane (20.8 ml, 10.4 mmol) was added, followed, in order, by EDCI (250 mg, 1.31 mmol), 1-hydroxybenzotriazole (177 mg, 1.31 mmol) and triethylamine (290 μl, 2.08 mmol). The reaction was stined at room temperature overnight. The reaction was evaporated and the resulting oil was dissolved in acetonitrile. An impurity precipitated out and was filtered off. The filtrate was evaporated and re-dissolved in diethyl ether/ethyl acetate. A precipitate formed. The resulting solid
- 745 - was filtered and dried in vacuo to give a white solid (300 mg, 60%). 1H NMR (400 MHz, DMSO-</6) δ 7.88 (br s, IH), 7.80 (d, J= 8.19 Hz, 2H), 7.62 (app q, J= 7.92 Hz, IH), 7.46 (d, J= 8.19 Hz, 2H), 7.16 - 7.13 (m, 2H), 7.14 (dt, J= 8.46, 2.01 Hz, IH), 6.84 (s, IH), 6.23 (q, J= 6.44 Hz, IH), 5.22 (s, 2H), 2.28 (s, 3H), 1.54 (d, J= 6.45 Hz, 3H); LC/MS, tr = 2.90 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min, at 254 nm, at 50°C), ESMS m/z 499 (M+Na). ES-HRMS m/z 411.0626 (M+H calcd for C22H20BrF2N2O3 requires 477.0620).
Example 740
Figure imgf000746_0001
3-Bromo-4-[(2,4-difluorobenzyl)oxy]- 1 - { 1 -[4-(hydroxymethyl)phenyl]ethyl} -6- methylpyridin-2(lH)-one
4-{l-[3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]ethyl}benzoic acid (from Example 738, step 3) (500 mg, 1.04 mmol) was added to a solution of IM borane-dimethylsulfide complex in tetrahydrofuran (1.56 ml, 3.12 mmol) in 2.5 ml tetrahydrofuran at 0 °C. The reaction was allowed to warm to room temperature while stirring. After stirring 48 h, ice chips were added to quench the reaction. The reaction was exfracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over MgS04 and evaporated. The resulting oil did not solidify, so it was dried in vacuo to give a clear oil (320 mg, 66%). 1H NMR (400 MHz, DMSO- d6) δ 7.62 (app q, J= 7.92 Hz, IH), 7.35 (d, J= 8.05 Hz, 2H), 7.30 (dt, J= 9.93, 2.46 Hz,
IH), 7.24 (d, J= 7.92 Hz, 2H), 7.14 (dt, J= 8.53, 2.46 Hz, IH), 6.82 (s, IH), 6.19 (q, J =
6.49 Hz, IH), 5.21 (s, 2H), 5.09 (t, J = 5.71 Hz, IH), 4.42 (d, J = 5.64 Hz, 2H), 2.29 (s, 3H), 1.52 (d, j = 6.44 Hz, 3H); LC/MS, tr = 3.14 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min, at 254 nm, at 50 °C), ES-MS m/z 486 (M+Na). ES-HRMS m/z 464.0658
(M+H calcd for C22H21BrF2N03 requires 464.0667).
Example 741
- 746 -
Figure imgf000747_0001
4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-l(2H)- yl]methyl}benzoic acid Step 1: Preparation of Methyl {[4-hydroxy-6-(acetoxymethyl)-2-oxopyridin-
1 (2H)-yl]methyl}benzoate
Figure imgf000747_0002
Methyl-4-(aminomethyl)benzoate (15.5g, 94 mmol) and 3-(2,2-dimethyl-4-oxo- 4H-l,3-dioxin-6-yl)-2-oxopropyl acetate (see synthesis in Example 653, Step 1) (24.9g, 103 mmol) were dissolved in 1,4 dioxane. The reaction was heated to reflux for 3 h with stirring. The reaction was cooled to room temperature and methanesulfonic acid (6.1 L, 94 mmol) was added. The resulting mixture was heated to reflux and stined for 15 min. The reaction was cooled to room temperature acidified with 0.5 NHC1 and exfracted with ethyl acetate (3x 300mL). The organic exfracts were combined washed with brine, dried over Νa2S04 and filtered. The filtrate was concentrated to an oil that was triturated in a mixture of CH2C12 and EtOAc to yield a white solid that was collected and dried (8.5 g, 27%). 1H NMR (400 MHz, CDC13) δ 7.96 (d, J= 8.0 Hz, 2H), 7.17 (d, J= 8.0 Hz, 2H), 6.20 (app d, J= 2.4 Hz, IH), 5.90 (app d, J= 2.4 Hz, IH), 5.33 (br s, 2H), 4.95 (s, 2H); 3.87 (s, 3H); 1.80 (s, 3H). ES-MS m/z 316 (M+H). LC MS, tr = 1.81 min (5 to 95% acetonitrile/water over 6 min. at 1 ml/min with detection 254 nm, at 50 °C). ES-MS m/z 332 (M+H). ES-HRMS m/z 332.1160 (M+H calcd for C17H18N06 requires 332.1129).
- 747 - Step 2: Preparation of Methyl {[3-bromo-4-hydroxy-6-(acetoxymethyl)-2- oxopyridin- 1 (2H)-yl]methyl}benzoate
Figure imgf000748_0001
Methyl{[4-hydroxy-6-(acetoxymethyl)-2-oxopyridin-l(2H)-yl]methyl}benzoate
(from Step 1) (8.3 g, 25.2 mmol) was suspended in acetonitrile and N-bromosuccinimide (4.9 g, 27.7 mmol) was added. The reaction was stined at room temperature for 30 min. after which the reaction was concenfrated on a rotary evaporator and the resulting solid was washed with acetonitrile and dried in vacuo to yield a white solid (10.7 g, 104%). 1H ΝMR (400 MHz, CDC13) δ 7.97 (d, J= 8.4 Hz, 2H), 7.17 (d, J= 8.4 Hz, 2H), 6.26 (s, IH), 5.38 (br s, 2H), 4.85 (s, 2H); 3.88 (s, 3H); 1.94 (s, 3H). LC/MS, tr = 1.86 min. (5 to 95% acetonitrile/water over 6 min. at 1 ml/min with detection 254 nm, at 50 °C). ES-MS m/z 410.3 (M+H). Step 3: Preparation of Methyl{[3-bromo-4-(2,4-difluorobenzyl)oxy]-6-
(acetoxymethyl)-2-oxopyridin-l(2H)-yl]methyl}benzoate
Figure imgf000748_0002
Methyl { [3-bromo-4-hydroxy-6-(acetoxymethyl)-2-oxopyridin- 1 (2H)- yl]methyl}benzoate (from Step 2) (10.7 g, 26 mmol) was suspended in N,N- dimethylformamide and 2,4-difluorobenzyl bromide (5.1 mL, 28.6 mmol) and K2C03 (4 g, 28.6 mmol) were added. The reaction was stined at room temperature for 1 h. after which
- 748 - the reaction was partitioned between water and ethyl acetate and extracted with ethyl acetate (4x 150 mL). The organic exfracts were combined washed with brine, dried over Na2S04, filtered and concenfrated to an oil that deposited a tan solid on standing. This resulting solid was washed with ether and dried (7.9 g, 57%). lR NMR (400 MHz, CDC13) δ 7.96 (d, J= 8.4 Hz, 2H), 7.55 (app q, J= 7.6 Hz, IH), 7.18 (d, J= 8.4 Hz, 2H), 6.94 (app dt, J= 2.0, 8.4 Hz, IH), 6.88-6.83 (m, IH), 6.27 (s, IH), 5.41 (br s, 2H); 5.24 (s, 2H) 4.88 (s, 2H), 3.88 (s, 3H); 1.96 (s, 3H). ES-HRMS m/z 536.0510 (M+H calcd for C24H21F2BrN06 requires 536.0515). Step 4: Preparation of the title compound. Methyl{[3-bromo-4-(2,4- difluorobenzyl)oxy] -6-(acetoxymethyl)-2-oxopyridin- 1 (2H)-yl]methyl}benzoate (from Step 3) (2 g, 3.7 mmol) was suspended in a mixture of methanol: tefrahydrofuran (1:4). Aqueous sodium hydroxide (4 N, 4 mL, 16 mmol) was added and the reaction was stined at room temperature for 6 h. I N Hydrochloric acid was added affording a white precipitate that was collected, washed with water, and dried (1.7 g, 94%). 1H ΝMR (400 MHz, CD3OD) δ 7.97 (d, J= 8.0 Hz, 2H), 7.62 (app q, J= 7.6 Hz, IH), 7.19 (d, J= 8.0 Hz, 2H), 7.05-7.00 (m, 2H), 6.72 (s, IH), 5.48 (br s, 2H); 5.34 (s, 2H) 4.46 (s, 2H). ESHRMS m/z 480.0296 (M+H calcd for C21H17F2BrΝ05 requires 480.0253).
Example
Figure imgf000749_0001
4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-l(2H)- yljmethyl} -N-methylbenzamide
4- { [3 -bromo-4- [(2,4-difluorobenzyι)oxy] -6-(hydroxymethyl)-2-oxopyridin- 1 (2H)- yl]methyl}benzoic acid (from Example 741, Step 4) (1.4 g, 2.9 mmol) was dissolved in NN-dimethylacetamide, and 1-hydroxybenzotriazole (1 M in NN-dimethylacetamide, 2.9 - 749 - mL, 2.9 mmol) was added, followed by methylamine (2 in tefrahydrofuran, 1.75 mL), 4-methylmorpholine (1 mL, 8.7 mmol) and l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (556 mg, 2.9 mmol). The reaction was stined at room temperature overnight. The reaction mixture was then partitioned between water and ethyl acetate and extracted with ethyl acetate (4x 150 mL). The organic exfracts were combined, washed with saturated sodium bicarbonate, brine, and dried over Na2S04. The exfract was filtered and concenfrated to an oil that was triturated with a mixture of methylene chloride, ether, and ethyl acetate to give a tan solid that was dried in vacuo (1.1 g, 80%). 1H NMR (400 MHz, d7 DMF) δ 8.43 (app d, J= 4.0 Hz, IH), 7.89 (d, J= 8.0 Hz, 2H), 7.73 (app q, J= 7.6 Hz, IH), 7.26 (d, J= 8.4 Hz, 2H), 7.33-7.18 (m, 2H), 6.78 (s, IH), 6.13 (br s, IH); 5.47 (br s, 2H); 5.41 (s, 2H) 4.54 (s, 2H), 2.84 (d, J= 4.8 Hz, 3H). ES-HRMS m/z 493.0574 (M+H calcd for C22H20F2BrN2O4 requires 493.0569).
Example ,743
Figure imgf000750_0001
3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-(hydroxymethyl)- 1 - {4-
[(methylamino)methyl]benzyl}pyridin-2(lH)-one
4- {[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin- 1 (2H)- yl]methyl}-N-methylbenzamide (0.5 g, 1.0 mmol) was dissolved in 1,4 dioxane, and borane-methyl sulfide complex (2 M in tefrahydrofuran, 1.5 mL) was added and the reaction was heated to 65 °C with stirring for 6 h. Additional borane-methyl sulfide complex (2 mL) was added and the reaction was stined for 70 h. at 65 °C. The reaction was quenched with IN aqueous hydrochloric acid, and the reaction was concenfrated in vacuo at 50 °C yielding an oil that was partitioned between water and ether. The ether exfract was removed and the aqueous layer was adjusted to pH = 11 with 2.5 N sodium
- 750 - hydroxide. The aqueous was exfracted with ethyl acetate (3x 100 mL) and the organic extracts were combined washed with brine, dried over Na2S04, filtered and concentrated to oil that was triturated with ether to give a tan solid that was dried in vacuo (68 mg, 14%). 1H NMR (400 MHz, CD3OD) δ 7.61 (app q, J= 7.6 Hz, IH), 7.37 (d, J= 8.0 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 7.05-7.01 (m, 2H), 6.71 (s, IH), 5.43 (br s, 2H); 5.34 (s, 2H), 4.47 (s, 2H), 3.98 (s, 2H), 2.57 (s, 3H). ES-HRMS m/z 479.0806 (M+H calcd for C22H22F2BrN203 requires 479.0776).
Exmaple 744
Figure imgf000751_0001
l-{[5-(aminomethyl)pyrazin-2-yl]methyl}-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methylpyridin-2( 1 H)-one
Step 1: Preparation of l-{[5-(chloromethyl)pyrazin-2-yl]methyl}-3-bromo-4- [(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one
Figure imgf000751_0002
Cyanuric chloride (5.1 g, 27.6 mmol) was dissolved in NN-dimethylformamide and stined for 1 hour, after which 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{[5-
(hydroxymethyl)pyrazin-2-yl]methyl}-6-methylpyridin-2(lH)-one (12 g, 26.5 mmol) was added. The reaction was stined at room temperature for 2 h. and was then partitioned between water and ethyl acetate then exfracted with ethyl acetate (3x 200 mL). The - 751 - organic exfracts were combined, washed with 2 Na2C03 (lx 200 mL), 0.5 NHC1 (1 x 200 mL), and brine, then dried over Νa2S04, and filtered. The filfrate was concenfrated in vacuo yielding an oil that was triturated with ether affording an orange solid that was dried (10.4 g, 84%). 1H NMR (400 MHz, CDC13) δ 8.69 (s, IH), 8.58 (s, IH), 7.53 (app q, J = 8.0 Hz, IH), 6.92 (app t, J= 8.0 Hz, IH), 6.87-6.80 (m, IH), 6.03 (s, IH), 5.36 (br s, 2H), 5.19 (s, 2H); 3.45 (s, 2H); 2.52 (s, 3H). ES-MS m/z 470 (M+H). LC/MS, tr = 2.66 min. (5 to 95% acetonitrile/water over 6 min. at 1 ml/min with detection 254 nm, at 50 °C).
Step 2: Preparation of l-{[5-(phthalimidomethyl)pyrazin-2-yl]methyl}-3-bromo- 4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one
Figure imgf000752_0001
1 - { [5 -(chloromethyl)pyrazin-2-yl]methyl} -3 -bromo-4- [(2,4-difluorobenzyl)oxy] - 6-methylpyridin-2(lH)-one (from Step 1) (10.4 g, 22.1 mmol) was suspended in tetrahydrofuran and a solution of potassium phthalimide (4.9 g, 26.5 mmol) in NN- dimethylformamide was added. The reaction was stined at room temperature for 20 h., after which the reaction mixture was concenfrated in vacuo. Addition of water to the resulting oil afforded a precipitate that was collected and dried, yielding a white solid (7.3 g, 57%). 1H ΝMR (400 MHz, CDC13) δ 8.61 (app d, J= 1.6 Hz, IH), 8.49 (app d, J= 1.2 Hz, IH), 7.87-7.84 (m, 2H), 7.75-7.71 (m, 2H), 7.53 (app q, J= 7.6 Hz, IH), 6.92 (app dt, J= 1.6, 8.4 Hz, IH), 6.90-6.80 (m, IH), 5.99 (s, IH), 5.33 (br s, 2H), 5.18 (s, 2H); 4.99 (s, 2H); 2.49 (s, 3H). ES-MS m/z 581 (M+H). LC/MS, tr = 2.85 min. (5 to 95% acetonitrile/water over 6 min. at 1 ml/min with detection 254 nm, at 50 °C).
Step 3: Preparation of the title compound. l-{[5-(phthalimidomethyl)pyrazin-2- yl]methyl}-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one (from Step
- 752 - 2) (7.3 g, 12.5 mmol) was dissolved in 1,4 dioxane and hydrazine monohydrate (0.75 mL, 15 mmol) was added. The reaction was heated to 85 °C with stirring for 22 h. The reaction mixture was concentrated in vacuo yielding a white paste that was freated with IN aqueous hydrochloric acid to afford a white precipitate that was collected and then stined in IN sodium hydroxide for 1 h. The resulting solid was filtered and dried (5.5 g, 98%). 1H ΝMR (400 MHz, CDC13) δ 8.67 (s, IH), 8.43 (s, IH), 7.54 (app q, J = 8.0 Hz, IH), 6.93 (app dt, J= 1.6, 8.4 Hz, IH), 6.87-6.81 (m, IH), 6.02 (s, IH), 5.35 (br s, 2H), 5.19 (s, 2H); 3.96 (s, 2H); 2.53 (s, 3H). ES-HRMS m/z 451.0593 (M+H calcd for C19H18BrF2Ν402 requires 451.0576).
Example 745
Figure imgf000753_0001
2- {[(5- {[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l (2H)- yl]methyl}pyrazin-2-yl)methyl]amino}-2-oxoethyl acetate Acetoxyacetic acid (520 mg, 4.4 mmol) was dissolved in NN-dimethylacetamide, and 1-hydroxybenzotriazole (IM in NN-dimethylacetamide, 4.4 mL) and 4- methylmorpholine (0.725 mL, 6.6 mmol) were added. l-{[5-(aminomethyl)pyrazin-2- yl]methyl}-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one (1 g, 2.2 mmol) and l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (840 mg, 4.4 mmol) were added and the reaction stined at room temperature. After 1 h. the reaction mixture was partitioned between water and ethyl acetate and extracted with ethyl acetate (4x 150 mL). The organic extracts were combined, washed with saturated aqueous sodium bicarbonate, brine, and dried over Νa2S04. The exfract was filtered and concenfrated to an oil that was triturated with ether to give a solid that was dried in vacuo. The resulting solid was purified by chromatography (silica gel, hexane/ethyl acetate) to yield an off-white solid
753 - (350 mg, 30%). 1H NMR (400 MHz, CDC13) δ 8.74 (s, IH); 8.50 (s, IH); 7.53 (app q, J= 8.0 Hz, IH), 7.18 (br s, IH), 6.93 (app t, J= 8.4 Hz, IH), 6.87-6.82 (m, IH); 6.04 (s, IH), 5.35 (s, 2H), 5.20 (s, 2H); 4.61 (s, 2H); 4.60 (s, 2H); 2.57 (s, 3H); 2.19 (s, 3H). ES-HRMS m/z 551.0721 (C23H22BrF2N405 requires 551.0736).
Example 746
Figure imgf000754_0001
N-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrazin-2-yl)methyl]-2-hydroxyacetamide
2-{[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrazin-2-yl)methyl]amino}-2-oxoethyl acetate (255 mg, 0.46 mmol) was suspended in methanol/water (5:1) and K2C03 (35 mg, 0.25 mmol) was added. The reaction was stined at room temperature for 30 min. The reaction was then concentrated to and oil that was triturated with water to yield a white solid that was filtered and dried (175 mg, 75%). 1H NMR (400 MHz, CD3OD) δ 8.58 (s, IH); 8.47 (s, IH); 7.60 (app q, J = 8.0 Hz, IH), 7.14-6.98 (m, 2H); 6.50 (s, IH), 5.45 (s, 2H), 5.29 (s, 2H); 4.61 (s, 2H); 4.01 (s, 2H); 2.54 (s, 3H). ES-HRMS m/z 509.0628 (C21H20BrF2N4O4 requires 509.0630).
Example 747
754
Figure imgf000755_0001
N-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yljmethyl} pyrazin-2-yl)methyl] acetamide l-{[5-(aminomethyl)pyrazin-2-yl]methyl}-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methylpyridin-2(lH)-one (500 mg, 1.1 mmol) was dissolved in NN-dimethylformamide (5 mL). NN-Diisopropylethylamine (0.75 mL, 4.4 mmol) was added followed by acetic anhydride (0.3 mL, 3.2 mmol). The reaction was stined at room temperature for 2 h. and concenfrated in vacuo to an oil, that was triturated in ether to yield an off-white solid that was collected and dried (252 mg, 46%). 1H ΝMR (400 MHz, CDC13) δ 8.69 (s, IH); 8.44 (s, IH); 7.54 (app q, J= 8.0 Hz, IH), 6.93 (app t, J= 8.4 Hz, IH), 6.85 (app t, J= 8.4 Hz, IH), 6.03 (s, IH), 5.33 (s, 2H), 5.19 (s, 2H); 4.53 (d, J= 5.2 Hz, 2H); 2.52 (s, 3H); 2.03 (s, 3H). ES-HRMS m/z 493.0692 (C21H20BrF2Ν4O3 requires 493.0681).
Example 748
Figure imgf000755_0002
N-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrazin-2-yl)methyl] methanesulfonamide
- 755 - l-{[5-(aminomethyl)pyrazin-2-yl]methyl}-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methylpyridin-2(lH)-one (500 mg, 1.1 mmol) was dissolved in NN-dimethylformamide (5 mL). 4-Methylmorpholine (0.48 mL, 4.4 mmol) was added followed by methanesulfonyl chloride (0.17 mL, 2.2 mmol). The reaction was stined at room temperature for 2 h. The reaction was then diluted with tetrahydrofuran (40 mL) and polyamine resin (1 g, 2.81 mmol/g) and methylisocyanate functionalized polystyrene (2 g, 1.38 mmol/g) were added. The mixture was shaken for 20 h., filtered, and the resulting filtrate concentrated to an oil that was purified by chromatography (silica gel, hexane/ethyl acetate) to yield an off-white solid (133 mg, 23%). 1H ΝMR (400 MHz, CDC13) δ 8.70 (s, IH); 8.48 (s, IH); 7.54 (app q, J= 8.0 Hz, IH), 6.93 (app t, J= 8.4 Hz, IH), 6.86-6.82 (m, IH), 6.04 (s, IH), 5.35 (s, 2H), 5.19 (s, 2H); 4.46 (s, 2H); 2.96 (s, 3H); 2.54 (s, 3H). ESHRMS m/z 529.0354 (C20H20BrF2Ν4O4S requires 529.0351).
Example 749
Figure imgf000756_0001
Methyl (5- {[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l (2H)- yl]methyl}pyrazin-2-yl)methylcarbamate l-{[5-(aminomethyl)pyrazin-2-yl]methyl}-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methylpyridin-2(lH)-one (500 mg, 1.1 mmol) was dissolved in NN-dimethylformamide (5 mL). NN-Diisopropylethylamine (0.75 mL, 4.4 mmol) was added, followed by methyl chloroformate (0.1 mL, 1.37 mmol) and the reaction was stined at room temperature for 15 min. The reaction was then diluted with tetrahydrofuran (40 mL) and polyamine resin (1 g, 2.81 mmol/g) and methylisocyanate functionalized polystyrene (2 g, 1.38 mmol/g) were added. The mixture was shaken for 20 h., filtered, and the resulting filfrate concentrated to an oil that was purified by chromatography (silica gel, hexane/ethyl
- 756 - acetate) to yield an off-white solid (137 mg, 24%). 1H NMR (400 MHz, CDC13) δ 8.69 (s, IH); 8.46 (s, IH); 7.54 (app q, J= 8.0 Hz, IH), 6.93 (app t, J= 8.4 Hz, IH), 6.87-6.82 (m, IH), 6.02 (s, IH), 5.35 (s, 2H), 5.20 (s, 2H); 4.48 (d, J= 5.2 Hz, 2H); 3.68 (s, 3H); 2.54 (s, 3H). ES-HRMS m/z 509.0619 (C21H20BrF2N4O4 requires 509.0630).
Example 750
Figure imgf000757_0001
N- [(5 - { [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)- yl]methyl}pyrazin-2-yl)methyl]-2-hydroxy-2-methylpropanamide 2-Hydroxyisobutyric acid (230 mg, 2.2 mmol) was dissolved in NN- dimethylformamide, and 1-hydroxybenzotriazole (IM in NN-dimethylacetamide, 2.2 mL) and 4-methylmo holine (0.36 mL, 3.3 mmol) were added. l-{[5- (aminomethyl)pyrazin-2-yl]methyl}-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methylpyridin-2(lH)-one (0.5 g, 1.1 mmol) and l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (425 mg, 2.2 mmol) were then added. The reaction was stined at room temperature. After 3 h., the reaction mixture was partitioned between water and ethyl acetate and extracted with ethyl acetate (4x 150 mL). The organic exfracts were combined, washed with saturated aqueous sodium bicarbonate, brine, and dried over Νa2S04. The exfract was filtered and concentrated to an oil that was triturated with ether to give a solid that was dried in vacuo (275 mg, 46%). 1H NMR (400 MHz, CDC13) δ 8.68 (s, IH); 8.44 (s, IH); 7.60-7.53 (m, 2H), 6.93 (app t, J= 8.4 Hz, IH), 6.87-6.82 (m, IH); 6.03 (s, IH), 5.34 (s, 2H), 5.19 (s, 2H); 4.55 (d, J= 5.6 Hz, 2H); 2.54 (s, 3H); 1.45 (s, 6H). ES-HRMS m/z 537.0988 (C23H24BrF2N404 requires 537.0943).
- 757 Example
Figure imgf000758_0001
N-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrazin-2-yl)methyl]-l-hydroxycyclopropanecarboxamide By following the general method of Example 750 and substituting 1-hydroxy-l- cyclopropanecarboxylic acid (225 mg, 2.2 mmol) for 2-hydroxyisobutyric acid, the title compound was prepared and purified by chromatography (silica gel, hexane/ethyl acetate/methanol) yielding an off-white solid (90 mg, 15%). 1H NMR (400 MHz, CDC13) δ 8.68 (s, IH); 8.47 (s, IH); 7.40 (app q, J = 8.4 Hz, IH), 6.93 (app t, J = 8.4 Hz, IH), 6.87-6.82 (m, IH); 6.04 (s, IH), 5.34 (s, 2H), 5.20 (s, 2H); 4.59 (d, J= 5.6 Hz, 2H); 2.55 (s, 3H); 1.32(q, J = 4.4 Hz, 2H), 1.04 (q, J = 4.4 Hz, 2H). ES-HRMS m/z 535.0779 (C 3H22BrF2N404 requires 535.0787).
Example 752
Figure imgf000758_0002
N1-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrazin-2-yl)methyl] glycinamide hydrochloride
758 - By following the general method of Example 750 and substituting Boc-glycine (385 mg, 2.2 mmol) for 2-hydroxyisobutyric acid and allowing the reaction to proceed for 20 h., the title compound was prepared as its Boc-protected intermediate which was purified by chromatography (silica gel, hexane/ethyl acetate/methanol) yielding an off- white solid. Deprotection was accomplished with 4NHC1 in 1,4 dioxane to afford the title compound as its hydrochloride salt (105 mg, 18%). 1H ΝMR (400 MHz, CD3OD) δ 8.60 (s, IH); 8.50 (s, IH); 7.60 (app q, J= 8.4 Hz, IH), 7.06-6.94 (m, 2H); 6.52 (s, IH), 5.44 (s, 2H), 5.29 (s, 2H); 4.56 (s, 2H); 3.72 (s, 2H); 2.54 (s, 3H). ES-HRMS m/z 508.0799 (C21H21BrF2Ν503 requires 508.0790).
Example 753
Figure imgf000759_0001
N1-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrazin-2-yl)methyl]-L-alanineamide hydrochloride Polymer-bound carbodiimide resin (3.4 g, 1.18 meq/g, 4 mmol) was suspended in
NN-dimethylacetamide. Boc-L-Alanine (378 mg, 2 mmol) was added, followed by 1- hydroxybenzotriazole (IM in NN-dimethylacetamide, 0.25 mL), l-{[5- (aminomethyl)pyrazin-2-yl]methyl}-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methylpyridin-2(lH)-one (0.45 g, 1 mmol) and NN-diisopropylethylamine (0.52 mL, 3 mmol). The reaction was shaken for 4 h. and then diluted with tefrahydrofuran. Polyamine resin (1 g, 2.81 mmol g) and methylisocyanate functionalized polystyrene (2 g, 1.38 mmol/g) were added and the mixture was shaken for 72 h., filtered and the resulting filtrate concenfrated in vacuo. The crude product was purified by chromatography (silica gel, hexane/ethyl acetate/methanol) yielding an off-white solid. Deprotection was
- 759 - accomplished with 4NHC1 in 1,4 dioxane to afford the title compound as its hydrochloride salt (116 mg, 22%). 1H ΝMR (400 MHz, CD3OD) δ 8.61 (s, IH); 8.50 (s, IH); 7.61 (app q, J= 8.4 Hz, IH), 7.05-6.99 (m, 2H); 6.53 (s, IH), 5.45 (s, 2H), 5.29 (s, 2H); 4.55 (d, J= 4.4 Hz, 2H); 3.98 (q, J= 8.0 Hz, IH); 2.55 (s, 3H); 1.50 (d, J= 7.2 Hz, 3H). ES-MS m/z 522 (M+H). LC/MS, tr = 1.92 min. (5 to 95% acetonitrile/water over 6 min. at 1 ml/min with detection 254 nm, at 50 °C).
Figure imgf000760_0001
Ν1-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrazin-2-yl)methyl]-N-methylglycineamide hydrochloride
By following the general method of Example 753 and substituting Boc-sarcosine (378 mg, 2 mmol) for Boc-L-alanine the title compound was prepared as its Boc-protected intermediate that was purified by chromatography (silica gel, hexane/ethyl acetate/methanol) yielding an off-white solid. Deprotection was accomplished with 4N HCl in 1,4 dioxane to afford the title compound as its hydrochloride salt (155 mg, 30%). 1H ΝMR (400 MHz, CD3OD) δ 8.61 (s, IH); 8.52 (s, IH); 7.60 (app q, J= 8.4 Hz, IH), 7.05-6.99 (m, 2H); 6.53 (s, IH), 5.45 (s, 2H), 5.29 (s, 2H); 4.56 (s, 2H); 3.85 (s, 2H), 2.71 (s, 3H), 2.55 (s, 3H). ES-MS m/z 522 (M+H). LC/MS, tr = 1.86 min. (5 to 95% acetonitrile/water over 6 min. at 1 ml/min with detection 254 nm, at 50 °C).
760 - Example 755
Figure imgf000761_0001
N1-[(5- {[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)- yl]methyl}pyrazin-2-yl)methyl]-L-serineamide hydrochloride By following the general method of Example 753 and substituting Boc-serine (410 mg, 2 mmol) for Boc-L-alanine the title compound was prepared as its Boc-protected intermediate that was purified by chromatography (silica gel, hexane/ethyl acetate/methanol) yielding an off-white solid. Deprotection was accomplished with 4N HCl in 1,4 dioxane to afford the title compound as its hydrochloride salt (95 mg, 17%). 1H ΝMR (400 MHz, CD3OD) δ 8.60 (s, IH); 8.51 (s, IH); 7.61 (app q, J= 8.4 Hz, IH), 7.05- 6.99 (m, 2H); 6.53 (s, IH), 5.45 (s, 2H), 5.29 (s, 2H), 4.57 (s, 2H), 4.05-3.85 (m, 3H), 2.55 (s, 3H). ES-MS m/z 538 (M+H). LC/MS, tr = 1.92 min. (5 to 95% acetonitrile/water over 6 min. at 1 ml min with detection 254 nm, at 50 °C)
Example 756
Figure imgf000761_0002
761 N1-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzyl)alaninamide hydrochloride
Polymer-bound carbodiimide resin (2.3 g, 1.18 meq/g, 2.7 mmol) was suspended in NN-dimethylacetamide. Boc-L-Alanine (251 mg, 1.33 mmol) was added, followed by 1-hydroxybenzotriazole (IM in NN-dimethylacetamide, 0.16 mL), l-[4- (aminomethyl)benzyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one (0.3 g, 0.67 mmol) and NN-diisopropylethylamine (0.35 mL, 2 mmol). The reaction was shaken for 4 h. and then diluted with tefrahydrofuran. Polyamine resin (1 g, 2.81 mmol/g) and methylisocyanate functionalized polystyrene (2 g, 1.38 mmol/g) were added and the mixture was shaken for 22 h., filtered and the resulting filfrate concentrated in vacuo to an oil that was triturated in ether yielding an off-white solid. The solid was purified by chromatography (silica gel, hexane/ethyl acetate/methanol) yielding the Boc-protected intermediate as an off-white solid. Deprotection was accomplished with 4N HC1 in 1,4 dioxane to afford the title compound as its hydrochloride salt (134 mg, 36%). 1H ΝMR (400 MHz, CD3OD) δ 7.59 (app q, J= 8.4 Hz, IH), 7.50 (d, J= 7.2 Hz, 2H); 7.08 (d, J = 7.2 Hz, 2H); 7.00 (app t, J= 8.4 Hz, 2H); 6.48 (s, IH), 5.38 (s, 2H), 5.27 (s, 2H); 4.36 (s, 2H), 3.89 (app d, J= 5.6 Hz, IH); 2.34 (s, 3H); 1.47 (d, J= 6.0 Hz, 3H). ES-MS m/z 520 (M+H). LC/MS, tr = 2.15 min. (5 to 95% acetonitrile/water over 6 min. at 1 ml/min with detection 254 nm, at 50 °C).
Example 757
Figure imgf000762_0001
762 N1-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzyl)-N -methylglycinamide hydrochloride
By following the general method of Example 756 and substituting Boc-sarcosine (251 mg, 1.33 mmol) for Boc-L-alanine the title compound was prepared as its Boc- protected intermediate that was purified by chromatography (silica gel, hexane/ethyl acetate/methanol) yielding an off-white solid. Deprotection was accomplished with 4N HCl in 1,4 dioxane to afford the title compound as its hydrochloride salt (160 mg, 39%). 1H ΝMR (400 MHz, CD3OD) δ 7.61 (q, J= 8.4 Hz, IH), 7.27 (d, J= 8.0 Hz, 2H); 7.96 (d, J= 8.0 Hz, 2H); 7.05-7.00 (m, 2H); 6.50 (s, IH), 5.40 (s, 2H), 5.29 (s, 2H); 4.39 (s, 2H), 3.79 (s, 2H), 2.70 (s, 3H); 2.35 (s, 3H). ES-MS m/z 520 (M+H). LC/MS, tr = 2.15 min. (5 to 95% acetonitrile/water over 6 min. at 1 ml/min with detection 254 nm, at 50 °C).
Example 758
Figure imgf000763_0001
N*-(4- {[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzyl)serinamide hydrochloride
By following the general method of Example 756 and substituting Boc-serine (273 mg, 1.33 mmol) for Boc-L-alanine the title compound was prepared as its Boc-protected intermediate that was purified by chromatography (silica gel, hexane/ethyl acetate/methanol) yielding an off-white solid. Deprotection was accomplished with 4N HCl in 1,4 dioxane to afford the title compound as its hydrochloride salt (95 mg, 25%). 1H ΝMR (400 MHz, CD3OD) δ 7.60 (q, J= 8.4 Hz, IH), 7.27 (d, J= 8.0 Hz, 2H); 7.08 (d, J= 8.0 Hz, 2H); 7.03-6.98 (m, 2H); 6.49 (s, IH), 5.39 (br s, 2H), 5.28 (s, 2H); 4.39 (app d, J= - 763 - 2.4 Hz, 2H), 3.93 (s, 2H), 3.92-3.82 (m, IH); 2.35 (s, 3H). ES-MS m/z 536 (M+H). LC/MS, tr = 2.14 min. (5 to 95%o acetonitrile/water over 6 min. at 1 ml/min with detection 254 nm, at 50 °C).
Example 759
Figure imgf000764_0001
N1-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzyl)prolineamide hydrochloride By following the general method of Example 756 and substituting Boc-proline
(286 mg, 1.33 mmol) for Boc-L-alanine the title compound was prepared as its Boc- protected intermediate that was triturated in ether yielding an off-white solid. Deprotection was accomplished with 4N HCl in 1,4 dioxane to afford the title compound as its hydrochloride salt (220 mg, 56%). 1H ΝMR (400 MHz, CD3OD) δ 7.60 (q, J = 8.4 Hz, IH), 7.25 (d, J= 7.6 Hz, 2H); 7.08 (d, J= 7.6 Hz, 2H); 7.03-6.98 (m, 2H); 6.50 (s, IH), 5.38 (br s, 2H), 5.27 (s, 2H); 4.38 (s, 2H), 4.29-4.26 (m, IH), 3.70-3.32 (m, 2H); 2.34 (s, 3H), 2.04-1.97 (m, 4H). ES-MS m/z 546 (M+H). LC MS, tr = 2.18 min. (5 to 95% acetonitrile/water over 6 min. at 1 ml/min with detection 254 nm, at 50 °C).
764 - Example 760
Figure imgf000765_0001
4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzenesulfonamide Step 1. Preparation of 4-[(4-hydroxy-6-methyl-2-oxopyridin-l(2H)- yl)methyl]benzenesulfonamide
Figure imgf000765_0002
^-Aminomethyl benzene sulfonamide hydrochloride (17.66 g, 79.3 mmol) was suspended in H20 (100 mL) and then 2.5 NNaOH was added to adjust the solution to pH 8. 4-Hydroxy-6-methyl-2-pyrone (10.0 g, 79.3 mmol) was added and the resulting mixture was heated at reflux for 22 h. The reaction mixture was cooled in an ice-bath and the precipitate that developed was collected by filfration washing with acetonitrile and then diethyl ether to give a tan solid (5.27 g, 23%). 1H NMR (400 MHz, DMSO-c?6) δ 10.56 (s, IH), 7.44 (d, J= 8.3 Hz, 2H), 7.22 (d, J= 8.3 Hz, 2H), 5.81 (d, J= 2.0 Hz, IH), 5.58 (d, J= 2.6 Hz, IH), 5.22 (s, 2H), 2.13 (s, 3H).
Step 2. Preparation of 4-{[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]methyl}benzenesulfonamide.
765 -
Figure imgf000766_0001
4-[(4-hydroxy-6-methyl-2-oxopyridin- 1 (2H)-yl)methyl]benzenesulfonamide (Step 1) (1.00 g, 3.40 mmol) was suspended in dichloromethane (30 mL) and cooled in an ice- bath. To the suspension was added 2.83 g of polymer-bound triphenylphosphine (loading = 3.0 mmol/g), 2,4-difluorobenzyl alcohol (0.980 g, 6.80 mmol), followed by di-tert- butylaziocarboxylate (1.57 g, 6.80 mmol). After 5 min. the cooling bath was removed. The resulting mixture was stined for 1.5 h. and then trifluoroacetic acid (10 mL) was added. After 1 h. the reaction mixture was filtered through a pad of Celite® and washed with dichloromethane. The filfrate was concentrated then suspended in H20 (50 mL) and made alkaline with 1.0 N NaOH. The aqueous reaction was exfracted with ethyl acetate. The combined organic exfracts were washed with brine, dried over Na2S0 , filtered and concentrated. The residue was dissolved in methanol, absorbed onto silica gel and subjected to chromatography (silica gel, hexanes/ethyl acetate with 10% methanol) to provide a white solid (0.250 g, 17%). 1H NMR (400 MHz, DMSO-</6) δ 7.75 (d, J= 8.3 Hz, 2H), 7.60 (app q, J= 7.9 Hz, IH), 7.32-7.30 (m, IH), 7.27-7.23 (m, IH), 7.24 (app d, J= 8.3 Hz, 2H), 7.12 (app dt, J= 1.9, 8.3 Hz, IH), 5.95 (s, 2H), 5.26 (s, 2H), 5.07 (s, 2H), 2.16 (s, 3H).
Step 3. Preparation of 4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-1 (2H)-yl]methyl}benzenesulfonamide. 4- {[4-[(2,4-difluorobenzyl)oxy]-6- methyl-2-oxopyridin-l(2H)-yl]methyl}benzenesulfonamide (Step 2) (0.270 g, 0.523 mmol) was suspended in acetonitrile (3.0 mL). N-Bromosuccinimide (0.098 g, 0.549 mmol) was added and the resulting mixture was stined at room temperature for 1 h., at which time the reaction mixture was concenfrated. Chromatography (silica gel, hexanes/ethyl acetate with 10% methanol) provided a white solid (0.210 g, 81%). 1H
- 766 - NMR (400 MHz, CDC13) δ 7.76 (d, J= 8.5 Hz, 2H), 7.64 (app q, J= 7.9 Hz, IH), 7.34- 7.29 (m, IH), 7.25 (d, J= 8.5 Hz, 2H), 7.16 (app dt, J = 2.4, 8.5 Hz, IH), 6.57 (s, IH), 5.35 (s, 2H), 5.28 (s, 2H), 2.28 (s, 3H). ES-HRMS m/z 499.0160 (M+H calcd for C20H18BrF2N2O4S requires 499.0133).
Example 761
Figure imgf000767_0001
N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzyl)-N-methylurea
Preparation of N-(4- {[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-
2oxopyridinl(2H)-yl]methyl}benzyl)-N-methylurea. The product from Example 208 (0.300 g, 0.648 mmol) was suspended in tefrahydrofuran (3.0 mL). 4-methylmorpholine (0.142 mL, 1.30 mmol) and trimethylsilylisocyanate (0.176 mL, 1.30 mmol) were added and the resulting mixture was stined at room temperature for 2 days at which time additional trimethylsilylisocyanate (0.176 mL, 1.30 mmol) was added. The resulting reaction mixture was stined at room temperature for 24 h. and then heated to 40 °C for 2 h. at which time the reaction was concenfrated. The residue was absorbed onto silica gel and subjected to chromatography (silica gel, hexanes/ethyl acetate with 10% methanol) to give the title compound as a white solid (0.147 g, 45%). 1H NMR (400 MHz, CDC13) δ 7.63 (app q, J= 7.9 Hz, IH), 7.31 (dt, J= 2.5, 9.9 Hz, IH), 7.17-7.12 (app m, IH), 7.13 (app d, J= 8.2 Hz, 2H), 7.03 (d, J= 8.1 Hz, 2H), 6.53 (s, IH), 5.88 (s, 2H), 5.26 (s, 4H), 4.33 (s, 2H), 2.68 (s, 3H), 2.28 (s, 3H). ES-HRMS m/z 506.0898 (M+H calcd for C23H23BrF2N303 requires 506.0885).
Example 762
767 .
Figure imgf000768_0001
5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyridine-2-carboxamide
Step 1. Preparation of 2-iodo-5-(iodomethyl)pyridine.
Figure imgf000768_0002
5-Hydroxymethyl-2-chloropyridine (20.3 g, 141.4 mmol) was dissolved in acetonitrile (250 mL). Sodium iodide (74.2 g, 494.9 mmol) and acetyl chloride (35.2 mL,
494.9 mmol) were added and the resulting mixture was heated at reflux for 24 h. The reaction mixture was cooled in an ice-bath and the solids were collected by filfration washing with acetonitrile. The solids were then suspended in H20 and treated with K2C03 (pH-8). The resulting solids were collected by filfration washing with diethyl ether and dichloromethane to provide a pale yellow solid (5.70 g, 12%). LC/MS, tr = 2.47 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min with detection 254 nm, at 50 °C). ES-MS m/z 346 (M + H).
Step 2. Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[(6-iodopyridin-3- yl)methyl] -6-methylpyridin-2( 1 H)-one.
Figure imgf000768_0003
768 2-Iodo-5-(iodomethyl)pyridine (Step 1) (3.00 g, 8.70 mmol) and the product from Example 734 (1.91 g, 5.80 mmol) were suspended in tefrahydrofuran (15 mL) and NN- dimethylformamide (5.0 mL). Sodium hydride (0.510 g, 12.76 mmol, 60% dispersion in mineral oil) was added at room temperature. The resulting mixture was heated to 60 °C for 15 h. and then allowed to cool to room temperature. Additional 2-iodo-5- (iodomethyl)pyridine (1.00 g, 2.90 mmol) and sodium hydride (0.232 g, 5.80 mmol, 60% dispersion in mineral oil) were added and the resulting mixture was heated to 60 °C for 2 , h. After cooling to room temperature the reaction was diluted with H20 and exfracted with ethyl acetate. The combined organic layers were washed with brine, dried over Νa2S0 , filtered and concenfrated. The resulting solid was washed with diethyl ether to give a brown solid (2.32 g, 73%). 1H NMR (400 MHz, CDCla)δ 8.23 (d, J= 2.3 Hz, IH), 7.77 (d, J= 8.1 Hz, IH), 7.62 (q, J= 7.9 Hz, IH), 7.30 (dt, J= 2.4, 9.9 Hz, IH), 7.20 (app dt, J = 2.4, 8.1 Hz, IH), 7.14 (app dt, J= 1.8, 8.3 Hz, IH), 6.56 (s, IH), 5.26 (s, 2H), 5.23 (s, 2H), 2.32 (s, 3H).
Step 3. Preparation of 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]methyl}pyridine-2-carbonitrile.
Figure imgf000769_0001
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[(6-iodopyridin-3-yl)methyl]-6- methylpyridin-2(lH)-one (from Step 2) (1.50 g, 2.74 mmol) was dissolved in NN- dimethylformamide (6.0 mL). Zinc cyanide (0.193 g, 1.64 mmol) and tefrakis(triphenylphosphine)palladium (0) (0.317 g, 0.274 mmol) were added and the resulting mixture was heated to 80 °C for 16 h. and then cooled to room temperature. The reaction was diluted with H20 and 2M ΝH4OH (30 mL). The aqueous reaction mixture was exfracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated. Chromatography (silica gel, hexanes/ethyl acetate with 10% methanol) provided a pale yellow solid (0.700 g, 57%). %). 1H NMR
769 (400 MHz, CDC13) δ 8.61 (d, J= 1.6 Hz, IH), 7.96 (d, J= 8.3 Hz, IH), 7.69-7.66 (m, IH), 7.65-7.60 (m, IH), 7.30 (app dt, J= 2.4, 9.9 Hz, IH), 7.14 (app dt, J= 1.7, 8.5 Hz, IH), 6.59 (s, IH), 5.38 (s, 2H), 5.27 (s, 2H), 2.32 (s, 3H). Step 4. Preparation of 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]methyl}pyridine-2-carboxamide. 5-{[3-bromo-4-[(2,4- difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}pyridine-2-carboriifrile (from Step 3) (0.300 g, 0.672 mmol) was suspended in tetrahydrofuran (3.0 mL). Potassium trimethylsilanolate (0.172 g, 1.34 mmol) was added and the resulting mixture was stined at room temperature for 23 h. H20 was added and the tefrahydrofuran was removed by blowing N2 over the reaction mixture. The solids were collected by filfration to provide the title compound as a tan solid (0.225 g, 72%). 1H NMR (400 MHz, CDC13) δ 8.47 (d, J = 1.7 Hz, IH), 8.04 (br s, IH), 7.96 (d, J= 8.2 Hz, IH), 7.67-7.60 (m, 2H), 7.31 (app dt, J= 2.5, 9.9 Hz, IH), 7.14 (app dt, J= 1.7, 8.5 Hz, IH), 6.58 (s, IH), 5.38 (s, 2H), 5.27 (s, 2H), 2.32 (s, 3H). ES-HRMS m/z 464.0416 (M+H calcd for C20H17BrF2N3O3 requires 464.0436).
Example 763
Figure imgf000770_0001
N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}phenyl)-2-hydroxypropanamide
To a reaction vessel (borosilicate culture tube) was added the product from Example 704 (0.332 g, 0.604 mmol) and methanol (2.0 mL) followed by a saturated
- 770 solution of K2C03 (1 mL). The reaction was stined for 1 h. at room temperature. The reaction mixture was then extracted with ethyl acetate (3x 10 mL). The combined organics were washed with brine (15 mL), dried with Na2S04, and concentrated to afford an off-white solid (0.264 g, 86%). 1H NMR (400 MHz, DMF-d6) δ 7.79-7.73 (m, 3H), 7.30 (ddd, J = 2.55, 9.40, 10.47 Hz, IH), 7.21-7.17 (m, 3H), 6.61 (s, IH), 5.37 (s, 4H), 4.22 (q, J = 6.76 Hz, IH), 2.41 (s, 3H), 1.35 (d, J = 6.71 Hz, 3H). ES-HRMS m/z 507.0721 (M+H calcd for C23H21BrF2N204 requires 507.0726).
Example 764
Figure imgf000771_0001
N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}phenyl)-2-hydroxy-2-methylpropanamide
By following the method of Example 763 and substituting the compound from Example 704 with the compound from Example 705, the title compound was prepared (0.293 g, 95%). 1H NMR (400 MHz, DMF-de) δ 9.58 (s, IH), 7.81-7.74 (m, 3H), 7.33- 7.17 (m, 4H), 6.61 (s, IH), 5.78 (s, IH), 5.38 (s, 4H), 2.41 (s, 3H), 1.39 (s, 6H). ESHRMS m/z 521.0880 (M+H calcd for C24H23BrF2N204 requires 521.0882).
771 Example 765
Figure imgf000772_0001
N-(4- {[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)- yl]methyl}phenyl)urea
To a reaction vessel (borosilicate culture tube) was added the compound from Example 611 (0.500 g, 1.149 mmol) and tefrahydrofuran (10.0 mL) followed by N- methylmorpholine (0.232 g, 2.298 mmol) and trimethylsilyl isocynate (0.199 g, 1.724 mmol). The reaction was stined for 20 days at room temperature. The reaction mixture was then diluted with tefrahydrofuran and the solids collected by filtration. The filfrate was concenfrated and purified by chromatography (silica gel, hexane\ethyl acetate containing 10%> methanol). The two solids were combined to afford a white solid (0.140 g, 25%). 1H ΝMR (400 MHz, DMF-d6) δ 8.78 (s, IH), 7.75 (app q, J= 7.83 Hz, IH), 7.46 (app d, J = 8.59 Hz, 2H), 7.31 (ddd, J = 2.55, 10.61, 11.95 Hz, IH), 7.28-7.08 (m, 3H), 6.59 (s, IH), 5.93 (s, 2H), 5.36 (s, 2H), 5.33 (s, 2H), 2.41 (s, 3H). ES-HRMS m/z 478.0571 (M+H calcd for C21H18BrF2Ν303 requires 478.0572).
Example 766
Figure imgf000772_0002
■ 772 - 3 - [3 -chloro-4- [(2,4-difluorobenzyl)oxy] -6-(hydroxymethyl)-2-oxopyridin- 1 (2H)- yljbenzamide
Step 1: Preparation of the title compound. {l-[3-(aminocarbonyι)phenyl]-5- chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxo-l,6-dihydropyridin-2-yl}methyl acetate (1.09 g, 2.36 mmol) was dissolved in methanol (10 mL) and K C03 (0.69 g, 5.19 mmol) was added. H20 (1 mL) was added and the reaction mixture was stined at room temperature for 1 h. The reaction was then diluted with H20 (30 mL) and the precipitate was collected by filfration washing with H20 (3x 20 mL) to afford a tan solid (0.820 g, 83%). 1H NMR (400 MHz, DMF- 6) δ 8.21 (br s, IH), 8.09 (d, J= 7.79 Hz, IH), 7.90 (s, IH), 7.78 (app dt, J = 6.71, 8.45 Hz, IH) 7.67-7.56 (m, 2H), 7.46 (br s, IH), 7.34 (ddd, J= 2.55, 9.53, 10.34 Hz, IH), 7.24-7.19 (m, IH), 6.83 (s, IH), 5.85 (s, 2H), 4.10 (AB q, JAB = 15.04 Hz, 2H). ES-HRMS m/z 421.0766 (M+H calcd for C20H15ClF2N2O4 requires 421.0761).
Example 767 /
Figure imgf000773_0001
{l-[3-(aminocarbonyl)phenyl]-5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxo-l,6- dihydropyridin-2-yl}methyl carbamate Step 1: Preparation of the title compound. 3-[3-chloro-4-[(2,4- difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-l(2H)-yl]benzamide (0.350 g, 0.832 mmol) was suspended in tefrahydrofuran (3 mL) and trichloroacetyl chloride (0.170 g, 0.902 mmol) was added. The reaction mixture was stined at room temperature for 1.5 h. A1203 (2.11 g, 20.75 mmol) was added followed by tefrahydrofuran (3 mL) and the reaction was stined for 1.5 h. at room temperature. The reaction was then heated to reflux for 1 h. The reaction mixture was then filtered through Celite®, washed with methanol,
- 773 - and the filfrate concentrated. The resulting residue was dissolved in 1,4-dioxane (5 mL) and A1203 (2.11 g, 20.75 mmol) was added. The reaction mixture was refluxed for 1 h., filtered through Celite®, washed with methanol, and the filtrate concenfrated. The resulting residue was trifrated with diethyl ether to afford a white solid (0.195 g, 51%). 1H NMR (400 MHz, DMF- ) δ 8.18 (br s, IH), 8.11 (d, J= 7.79 Hz, IH), 7.93 (s, IH), 7.81 (app dt, J = 6.58, 8.59 Hz, IH) 7.67-7.58 (m, 2H), 7.46 (br s, IH), 7.34 (ddd, J = 2.55, 9.53, 10.61 Hz, IH), 7.24-7.20 (m, IH), 6.87 (s, IH), 5.45 (s, 2H), 4.58 (AB q, JAB = 15.98 Hz, 2H). ES-HRMS m/z 464.0842 (M+H calcd for C21H16C1F2N305 requires 464.0819).
Example 768
Figure imgf000774_0001
3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-l(2H)- yljbenzamide Step 1: Preparation of methyl 3-[6-[(acetyloxy)methyl]-4-hydroxy-2-oxopyridin- l(2H)-yl jbenzoate.
Figure imgf000774_0002
3-(2,2-dimethyl-4-oxo-4H-l,3-dioxin-6-yl)-2-oxopropyl acetate (from Example
653, step 1) (12.25 g, 50.57 mmol) was dissolved in 1,4-dioxane (300 mL) and methyl 3- aminobenzoate (5.88 g, 38.90 mmol) was added. The reaction was heated to reflux for 1 h. then cooled to 70 °C. Methanesulfonic acid (3.74 g, 38.90 mmol) was added and the
774 reaction brought back to reflux for 1 h. The reaction was cooled to room temperature, concenfrated and used as crude product for the next step.
Step 2: Preparation of methyl 3-[6-[(acetyloxy)methyl]-3-bromo-4-hydroxy-2- oxopyridin-l(2H)-yl]benzoate.
Figure imgf000775_0001
Methyl 3-[6-[(acetyloxy)methyl]-4-hydroxy-2-oxopyridin-l(2H)-yl]benzoate
(crude from step 1) (12.34 g, 38.90 mmol) dissolved in acetonitrile (110 mL) was cooled in an ice-bath. N-bromosuccinimide (7.27 g, 40.85 mmol) was added and the ice-bath was removed. The reaction mixture was stined for 1 h. at room temperature. The reaction was diluted with diethyl ether and the solids collected by filfration. The solid was then washed with diethyl ether (3x 50 mL) to afford a tan solid (8.38 g, 54% over two steps). 1H ΝMR (400 MHz, DMSO- 6) δ 8.01 (app dt, J = 1.48, 7.92 Hz, IH), 7.81 (app t, J= 1.68 Hz, IH), 7.66-7.59 (m, 2H), 6.29 (s, IH), 4.49 (AB q, JAB = 14.97 Hz, 2H), 3.84 (s, 3H), 1.88 (s, 3H). ES-HRMS m/z 396.0118 (M+H calcd for C16H14BrΝ06 requires 396.0077).
Step 3: Preparation of methyl 3-[6-[(acetyloxy)methyl]-3-bromo-4-[(2,4- difluorobenzyl)oxy] -2-oxopyridin- 1 (2H)-yl]benzoate.
Figure imgf000775_0002
Methyl 3 - [6-[(acetyloxy)methyl] -3 -bromo-4-hydroxy-2-oxopyridin- 1 (2H)- yljbenzoate (from step 2) (8.30 g, 20.95 mmol) was dissolved in NN-dimethylformamide (42 mL). K2C03 (3.08 g, 23.05 mmol) was added followed by 2,4-difluorobenzyl bromide
- 775 - (5.64 g, 27.24 mmol). The reaction mixture was stined for 24 h. at room temperature. The reaction mixture was then diluted with diethyl ether and the solids collected by filtration. The solid was then washed with H20 (3x 50 mL) to afford a white solid (8.81 g, 80%). 1H NMR (400 MHz, DMSO- 6) δ 8.03 (d, J= 7.52 Hz, IH), 7.85 (s, IH), 7.70- 7.60 (m, 3H), 7.33 (ddd, J= 2.55, 8.32, 10.88 Hz, IH), 7.16 (app dt, J= 1.61, 7.79 Hz, IH), 6.83 (s, IH), 5.37 (s, 2H), 4.57 (AB q, JAB = 15.44 Hz, 2H), 3.85 (s, 3H), 1.88 (s, 3H). ES-HRMS m/z 522.0388 (M+H calcd for C23H18BrF2N06 requires 522.0358).
Step 4: Preparation of methyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- (hydroxymethyl)-2-oxopyridin- 1 (2H)-yl]benzoate.
Figure imgf000776_0001
Methyl 3-[6-[(acetyloxy)methyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-2- oxopyridin-l(2H)-yl]benzoate (from step 3) (15.50 g, 29.68 mmol) was dissolved in methanol (120 mL) and K2C03 (8.72 g, 65.29 mmol) was added. The reaction mixture was stined for 1 h. at room temperature and diluted with H20. The solids were collected by filfration and washed with H20 (3x 50 mL) to afford a white solid (13.24 g, 93%). 1H NMR (400 MHz, DMSO- 6) δ 8.03 (app dt, J= 1.21, 7.65 Hz, IH), 7.81 (app t, J= 1.88 Hz, IH), 7.67-7.57 (m, 3H), 7.34 (app t, J= 1.28 Hz, IH), 7.16 (app t, J= 1.28 Hz, IH), 6.66 (s, IH), 5.62 (app t, J= 5.37 Hz, IH), 5.35 (s, 2H), 3.88 (app t, J = 5.17 Hz, 2H), 3.84 (s, 3H). ES-HRMS m/z 480.0258 (M+H calcd for C21H16BrF2N05 requires 480.0253).
Step 5: Preparation of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-
(hydroxymethyl)-2-oxopyridin- 1 (2H)-yl]benzoic acid.
776
Figure imgf000777_0001
Methyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin- l(2H)-yl]benzoate (from step 4) (5.00 g, 10.41 mmol) was dissolved in tefrahydrofuran\methanol (3.5:1) (21 mL). 4N NaOH (6.5 mL, 26.03 mmol) was added and the reaction mixture was stined for 1 h. at room temperature. The reaction was acidified (pH 2) with 4N HCl and the solids collected by filfration washing with H20 (3x
50 mL) to afford a white solid (4.54 g, 93%). 1H ΝMR (400 MHz, DMF-d6) δ 8.29 (app dt, J= 1.61, 7.38 Hz, IH), 8.11 (app t, J= 1.54 Hz, IH), 7.99-7.82 (m, 3H), 7.49 (ddd, J=
1.21, 9.40, 10.61 Hz, IH), 7.38 (ddd, J= 2.55, 9.53, 10.61 Hz, IH), 6.97 (s, IH), 5.95 (s, IH), 5.63 (s, 2H), 4.26 (s, 2H). ES-HRMS m/z 466.0097 (M+H calcd for C20H14BrF2ΝO5 requires 466.0096).
Step 6: Preparation of the title compound. 3-[3-bromo-4-[(2,4- difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-l(2H)-yl]benzoic acid (from step 5) (0.200 g, 0.429 mmol) was suspended in tefrahydrofuran (2 mL). 2-Chloro-4,6- dimethoxy-l,3,5-triazine (0.090 g, 0.515 mmol) was added followed by N- methylmorpholine (0.130 g, 1.287 mmol). The reaction mixture was stined at room temperature for 1.5 h. Reagent grade ΝH4OH (1 mL) was added and the reaction was stined overnight at room temperature. The reaction was then diluted with H20 (50 mL) and the precipitate was collected by filfration washing with diethyl ether (3x 20 mL) to afford a white solid (0.184 g, 93%). 1H NMR (400 MHz, DMF-d6) δ 8.20 (br s, IH), 8.09 (app dt, J= 1.41, 8.05 Hz, IH), 7.89 (t, J= 1.74 Hz, IH), 7.78 (app dt, J= 6.58, 8.59 Hz, IH) 7.65 (t, J= 7.85 Hz, IH), 7.58-7.55 (m, IH), 7.46 (br s, IH), 7.34 (ddd, J= 2.55, 9.26, 10.47 Hz, IH), 7.22 (ddd, J= 1.16, 8.46, 10.34 Hz, IH), 6.80 (s, IH), 5.80 (br s, IH), 5.47 (s, 2H), 4.08 (s, 2H). ES-HRMS m/z 465.0234 (M+H calcd for C20H15BrF2N2O4 requires 465.0256).
777 Example 769
Figure imgf000778_0001
{ 1 - [3 -(aminocarbonyl)phenyl] -5 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-oxo- 1,6- dihydropyridin-2-yl}methyl acetate
Step 1: Preparation of the title compound. 3-[3-bromo-4-[(2,4- difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-l(2H)-yl]benzamide (from Example 768, above) (0.300 g, 0.643 mmol) was suspended in pyridine (3 mL) and acetic anhydride (0.099 g, 0.965 mmol) was added. The reaction mixture was stined at room temperature overnight. The reaction was then diluted with H20 (50 mL) and the precipitate was collected by filtration washing with H20 (2x 30 mL) followed by diethyl ether (3x 30 mL) to afford a white solid (0.251 g, 77%). 1H NMR (400 MHz, DMSO- 6) δ 8.02 (br s, IH), 7.95 (app d, J = 7.79 Hz, IH), 7.75 (app d, J= 1.75 Hz, IH), 7.67 (app q, J= 8.01 Hz, IH), 7.48-7.15 (m, 5H), 6.82 (s, IH), 5.38 (s, 2H), 4.58 (AB q, JAB = 15.35 Hz, 2H), 1.89 (s, 3H). ES-HRMS m/z 507.0389 (M+H calcd for C22H17BrF2N205 requires 507.0362).
Example 770
Figure imgf000778_0002
{l-[3-(aminocarbonyl)phenyl]-5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxo-l,6- dihydropyridin-2-yl}methyl carbamate - 778 - Step 1: Preparation of the title compound. 3 -[3 -bromo-4- [(2,4- difluorobenzyl)oxy] -6-(hydroxymethyl)-2-oxopyridin- 1 (2H)-yl]benzamide (from Example 768, above) (0.300 g, 0.643 mmol) was suspended in tefrahydrofuran (3 mL) and trichloroacetyl chloride (0.133 g, 0.707 mmol) was added. The reaction mixture was stined at room temperature 1.5 h. Reagent grade NH4OH (1.5 mL) was added and the reaction was stined overnight at room temperature. The reaction was then diluted with H20 (50 mL) and the precipitate was collected by filfration washing with H20 (2x 30 mL) followed by diethyl ether (3x 30 mL) to afford a white solid (0.255 g, 78%). 1H NMR (400 MHz, DMSO- 6) δ 8.00 (br s, IH), 7.96 (app d, J= 7.92 Hz, IH), 7.72 (m, 2H), 7.58 (app t, J= 7.79 Hz, IH), 7.47-7.15 (m, 4H), 6.72 (s, IH), 5.35 (s, 2H), 4.43 (AB q, JAB = 18.12 Hz, 2H). ES-HRMS m/z 508.0328 (M+H calcd for C21H16BrF2N305 requires 508.0314).
Example 771
Figure imgf000779_0001
3-[6-(aminomethyl)-3-bromo-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)- yljbenzamide hydrochloride Step 1: Preparation of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-[(l,3-dioxo-l,3- dihydro-2H-isoindol-2-yl)methyl]-2-oxopyridin-l(2H)-yl]benzamide.
779
Figure imgf000780_0001
3 - [3-bromo-4- [(2,4-difluorobenzyl)oxy] -6-(hydroxymethyl)-2-oxopyridin- 1 (2H)- yljbenzamide (from Example 768, above) (4.00 g, 8.60 mmol), triphenylphosphine (4.96 g, 18.91 mmol), and phthalimide (1.39 g, 9.46 mmol) dissolved in tefrahydrofuran/1- methyl-2-pynolidinone (1:1) (34.4 mL) were cooled in an ice bath. Diethyl azodicarboxylate (3.29 g, 18.91 mmol) was added and the ice bath removed. The reaction mixture was stined at room temperature 1.5 h. The reaction was then diluted with ethyl acetate (75 mL) and the organic washed with H20 (2x 50 mL), IN HCl (2x 50 mL), saturated ΝaHC03 (2x 50 mL), brine (50 mL), dried with Na2S04, and concentrated. The resulting residue was trifrated with dichloromethane to afford an off-white solid (3.19 g, 62%). 1H NMR (400 MHz, DMSO-rf6) δ 7.98-7.79 (m, 7H), 7.60-7.49 (m, 3H), 7.42 (s, IH), 7.17 (app dt, J= 2.55, 9.53 Hz, IH), 7.07 (app dt, J = 2.55, 8.46 Hz, IH), 6.45 (s, IH), 5.28 (s, 2H), 4.24 (AB q, JAB = 21.08 Hz, 2H). ES-HRMS m/z 594.0477 (M+H calcd for C28H18BrF2N305 requires 594.0471).
Step 2: Preparation of the title compound. 3 -[3 -bromo-4- [(2,4- difluorobenzyl)oxy]-6-[(l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)methyl]-2-oxopyridin- l(2H)-yl]benzamide (from step 1) (3.92 g, 6.59 mmol) was suspended in 1,4-dioxane (22 mL). Hydrazine (0.660 g, 13.191 mmol) was added and the reaction mixture was stined at reflux for 4 h. The reaction was cooled to room temperature and the resulting solids collected by filtration. The impure solid was suspended in 1,4-dioxane (50 mL) and IN ΝaOH (20 mL) and was stined at room temperature for 1 h. The solids were filtered and washed with 1,4-dioxane (2x 25 mL) and H 0 (2x 25 mL). The filfrate was diluted with ethyl acetate (100 mL) and washed with H20 (25 mL), brine (25 mL), dried with Νa2S0 , and concentrated. The two solids were combined and washed with diethyl ether (3x 30
- 780 mL) to afford an off-white solid (1.86 g, 61%). 1H NMR (400 MHz, DMF-d6) δ 9.35 (br s, 2H), 8.31 (br s, IH), 8.11-8.08 (m, 2H), 7.89 (app q, J= 7.88 Hz, 21), 7.70-7.64 (m, 2H), 7.53 (s, IH), 7.47 (br s, IH), 7.36-7.31 (m, IH), 7.22-7.18 (m, IH), 5.52 (s, 2H), 3.96 (s, 2H). ES-HRMS m/z 464.0427 (M+H calcd for C20H16BrF2N3O3 requires 464.0416).
Example 772
Figure imgf000781_0001
5-[[3-Chloro-4-(2,4-difluorobenzyloxy)-2-oxo-ρyridin-l(2H)-yl]methyl]-l,3-dihydro-2H- indol-2-one
Step 1: Preparation of 3,3-dibromo-5-[[3-chloro-4-(2,4-difluorobenzyloxy)-2-oxo- pyridin- 1 (2H)-yl]methyl]- 1 ,3-dihydroindol-2-one.
Figure imgf000781_0002
3 -Chloro-4-(2,4-difluorobenzyloxy)- 1 -( 1 H-indol-5 -ylmethyl)-pyridin-2( 1 H)-one (1.2 g, 3.0 mmol) was diluted with 25mL of t-BuOH and pyridinium bromide perbromide (2.51g, 7.83 mmol) was added portion-wise over a period of 20 min. The reaction was stined at room temperature for 16.5 h. The reaction was evaporated on a rotary evaporator, and the resulting solid dissolved in water, extracted with EtOAc, dried (Na2S04), filtered, and concentrated under reduced pressure to give a dark, tan solid (1.37 g, 87%), which was carried forward without further purification or analysis.
Step 2. Preparation of title compound. 3,3-Dibromo-5-[3-chloro-4-(2,4- difluorobenzyloxy)-2-oxo-pyridin-l(2H)-ylmethyl]-l,3-dihydroindol-2-one (1.75 g, 3.04 mmol) and zinc dust (1.98 g, 30.4 mmol) was diluted with 60 mL acetic acid, and the
- 781 - reaction was stined at room temperature for 17.5 h. The reaction was diluted with water, extracted with EtOAc, washed with brine, dried (Na2S04), filtered and evaporated on a rotary evaporator. Purification by flash column chromatography (silica, 95:5 CH2Cl2/MeOH) gave a tan solid (0.10 g, 9%): 1H NMR (300 MHz, DMSO-</6) δ 10.38 (s, IH), 7.92 (d, J= 8 Hz, IH), 7.62 (app q, J= 9 Hz, IH), 7.33 (app t, J= 9 Hz, IH), 7.19- 7.13 (m, 3H), 6.76 (d, J = 9 Hz, IH), 6.59 (d, J = 8 Hz, IH), 5.29 (s, 2H), 5.04 (s, 2H), 3.45 (s, 2H). ES-HRMS m/z 417.0823 (M+H calcd for C21H16C1F2N203 requires 417.0812).
Example 773
Figure imgf000782_0001
3 -Chloro-4-(2,4-difluorobenzyloxy)- 1 -( lH-pyrazol-3 -ylmethyl)-pyridin-2( 1 H)-one
Step 1. Preparation of the title compound. 3-Chloro-4-(2,4-difluorobenzyloxy)- pryidin-2(lH)-one (see Example 80) (1.9 g, 6.9 mmol) and K2C03 (1.9 g, 13.8 mmol) were stined in 60 mL of anhydrous DMF, and 3 -bromomethyl-pyrazole-1 -carboxylic acid tert-butyl ester (2.2 mL, 8.3 mmol) was added dropwise. The reaction was stined at 80 °C for 15.5 h. The reaction was cooled to room temperature and diluted with brine, exfracted with EtOAc, washed with 5% LiCl, brine, dried (Na2S04), filtered and evaporated on a rotary evaporator. Purification by preparatory HPLC (Phenomenex Luna 10 μ, C18(2)
250 21.2 mm) provided a white solid (0.30 g, 10%): 1H NMR (300 MHz, DMSO- ) δ
7.80 (d, J= 7.8 Hz, IH), 7.66-7.58 (m, 2H), 7.34 (app t, J= 7.8 Hz, IH), 7.16 (app t, J=
8.5 Hz, IH), 6.57 (d, J= 7.7 Hz, IH), 6.15 (s, IH), 5.29 (s, 2H), 5.10 (s, 2H), 2.07 (s, IH).
ES-HRMS m/z 352.0661 (M+H calcd for C16H13C1F2N302 requires 352.0659).
782 Example 774
Figure imgf000783_0001
3-Bromo-4-(2,4-difluorobenzyloxy)-l-(lH-pyrazol-3-ylmethyl)-pyridin-2(lH)-one
Step 1. Preparation of 3-bromo-4-(2,4-difluorobenzyloxy)-pyridin-2(lH)-one.
Figure imgf000783_0002
4-(2,4-Difluorobenzyloxy)-pyridin-2(lH)-one (see Example 74) (2.4 g, 10.2 mmol) was dissolved in 19 ml of acetic acid, cooled to 0 °C, and bromine (0.53 mL, 10.3 mmol) in 34 mL acetic acid was added dropwise. The reaction was stined at room temperature for 2 h. The reaction was evaporated on a rotary evaporator. The resulting solid was recrystallized from EtOAc and hexanes to give a white solid (3.3 g, 100%): 1H NMR (300
MHz, DMSO- ) δ 7.62 (app q, J = 6.7 Hz, IH), 7.50 (d, J = 7.4 Hz, IH), 7.34 (dt, J =
10.4, 2.5 Hz, IH), 7.17 (dt, J= 8.6, 2.3 Hz, IH), 6.44 (d, J= 7.4 Hz, IH), 5.29 (s, 2H). Step 2. Preparation of 3-[3-bromo-4-(2,4-difluorobenzyloxy)-2-oxo-pyridin- l(2H)-ylmethyl]pyrazole-l -carboxylic acid tert-butyl ester
Figure imgf000783_0003
3-[3-Bromo-4-(2,4-difluorobenzyloxy)-2-oxo-pyridin-l(2H)-ylmethyl]pyrazole-l- carboxylic acid tert-butyl ester was prepared by a procedure similar to the one described for Example 74 (Step 4) to provide a white solid (1.3 g, 21%): 1H NMR (300 MHz,
- 783 - DMSO- 6) δ 8.19 (d, J= 2.7 Hz, IH), 7.93 (d, J= 7.7 Hz, IH), 7.64 (app q, J= 6.8 Hz, IH), 7.34 (dt, J = 10.4, 2.5 Hz, IH), 7.17 (dt, J= 8.6, 2.3 Hz, IH), 6.59 (d, J= 7.8 Hz, IH), 6.39 (d, J = 2.7 Hz, IH), 5.31 (s, 2H), 5.16 (s, 2H), 1.56 (s, 9H). HRMS m/z 497 (M+H).
Step 3. Preparation of the title compound. 3-[3-Bromo-4-(2,4-difluorobenzyloxy)- 2-oxo-pyridin-l(2H)-ylmethyl]pyrazole-l -carboxylic acid tert-butyl ester (1.2 g, 2.5 mmol) was heated to 130 °C for 16 h. The reaction was cooled to room temperature and partitioned between water and ethyl acetate. The separated organic layer was washed with brine, dried (MgS04), filtered, and evaporated on a rotary evaporator to give an off-white solid. Trituration from methanol provided a white solid (0.59 g, 60%): 1H NMR (300 MHz, DMSO- 6) δ 12.73 (br s, IH), 7.83 (d, J= 7.7 Hz, IH), 7.66-7.59 (m, 2H), 7.34 (dt, J= 12.8, 2.5 Hz, IH), 7.16 (dt, J= 8.5, 2.4 Hz, IH), 6.52 (d, J= 7.7 Hz, IH), 6.15 (s, IH), 5.29 (s, 2H), 5.11 (s, 2H). ES-HRMS m/z 396.0172 (M+H calcd for C21H13BrF2N302 requires 396.0153).
Example 775
Figure imgf000784_0001
3-Chloro-4-(2,4-difluorobenzyloxy)- 1 -[ 1 -(2-hydroxyethyl)-lH-pyrazol-3-ylmethyι]-6- methyl-pyridin-2(lH)-one
Step 1. Preparation of the title compound. 3-[3-Chloro-4-(2,4-difluorobenzyloxy)-2-oxo- pyridin-l(2H)-ylmethyl]pyrazole (0.53 mg, 1.5 mmol), 2N NaOH (1.5 mL, 2.9 mmol), benzyltriethylammomum chloride (0.17 g, 0.72 mmol), sodium iodide (10 mg), and 2- chloroethanol (0.15 mL, 2.2 mmol) were stined in 5 mL of 1,4-dioxane at 85 °C for 19 h. The reaction was cooled to room temperature, neutralized with IN HCl, and evaporated on a rotary evaporator. Purification by flash column chromatography (silica, 1:9 MeOH chloroform) provided a white solid (0.11 g, 19%): 1H NMR (300 MHz, DMSO-d6)
- 784 - δ 7.65-7.60 (m, 2H), 7.34 (dt, J= 10.4, 2.5 Hz, IH), 7.17 (dt, J= 8.5, 1.7 Hz, IH), 6.52 (s, IH), 6.05 (d, J= 2.2 Hz, IH), 5.27 (s, 2H), 5.16 (s, 2H), 4.85 (t, J= 5.3 Hz, IH), 4.06 (t, J = 5.6 Hz, 2H), 3.67 (q, J = 5.5 Hz, 2H), 2.50 (s, 3H). ES-HRMS m/z 410.1065 (M+H calcd for C19H19C1F2N303 requires 410.1078).
Example 776
Figure imgf000785_0001
l-Benzooxazol-6-ylmethyl-3-chloro-4-(2,4-difluorobenzyloxy)-6-methyl-pyridin-2(lH)- one
Step 1. Preparation of 6-bromomethylbenzooxazole.
Figure imgf000785_0002
6-Methylbenzoxazole (2.5 g, 19 mmol), N-bromosuccinimide (3.7 g, 21 mmol) and benzoyl peroxide (50 mg) were dissolved in 32 mL of carbon tefrachloride. The reaction was stined at reflux for 6 h. The reaction was cooled to room temperature, filtered, and evaporated on a rotary evaporator. Purification by flash column chromatography (silica, 1:3 EtOAc/hexanes) gave a light yellow oil (1.1 g, 28%): 1H NMR (300 MHz, CDC13) δ 8.12 (s, IH), 7.76 (d, J= 9.0 Hz, IH), 7.64 (d, J= 1.5 Hz, IH), 7.42 (dd, J= 8.1, 1.5 Hz, IH), 4.63 (s, 2H).
Step 2. Preparation of the title compound. l-Benzooxazol-6-ylmethyl-3-chloro-4- (2,4-difluorobenzyloxy)-6-methyl-pyridin-2(lH)-one was prepared by a procedure similar to the one described for Example 777 (below) to provide an off-white solid (0.75 g, 50%): 1H NMR (300 MHz, DMSO-d6) δ 8.73 (s, IH), 7.77 (d, J= 8.2 Hz, IH), 7.67 (app q, J = 8.6 Hz, IH), 7.52 (br s, IH), 7.36 (dt, J = 10.4, 2.5 Hz, IH), 7.21-7.15 (m, 2H), 6.62 (s, IH), 5.45 (s, 2H), 5.30 (s, 2H), 2.35 (s, 3H). ES-HRMS m/z 417.0812 (M+H calcd for C21H16C1F2N203 requires 417.0794).
- 785 - Example 777
Figure imgf000786_0001
3 -Bromo-4-(2,4-difluorobenzyloxy)-6-methyl- 1 -( 1 H-pyrazol-3 -ylmethyl)-p yridin-2( 1 H)- one.
Step 1. Preparation of 3-[3-bromo-4-(2,4-difluoro-benzylozy)-6-methyl-2-oxo- pyridin-l(2H)-ylmethyl]-pyrazole-l-carboxylic acid tert-butyl ester.
Figure imgf000786_0002
3-Bromo-4-(2,4-difluorobenzyloxy)-6-methyl-lH-pyridin-2-one (3.72g, 11.3 mmol) was diluted with 80 mL of THF, cooled to 0 °C, and NaH (0.90g, 22.5 mmol) was added portionwise over a period of 30 min. The reaction was warmed to room temperature, and 3-bromomethyl-pyrazole-l-carboxylic acid tert-butyl ester (4.41g, 16.9 mmol) was added to the reaction. The reaction was stined at 70 °C for 16 h. The reaction was quenched with a saturated solution of NH C1 and diluted with EtOAc. The organic layer was washed with brine, dried (Mg2S04), filtered and evaporated on a rotary evaporator. Purification by flash column chromatography (silica, 1:1 EtOAc/hexanes) provided a light yellow solid (1.94g, 34%): 1H NMR (300 MHz, DMSO-d6) δ 8.17 (d, J= 2.7 Hz, IH), 7.65 (app q, J= 8.5 Hz, IH), 7.34 (app t, J= 8.0, IH), 7.17 (app t, J= 8.2 Hz, IH), 6.56 (s, IH), 6.35 (d, J= 2.7 Hz, IH), 5.29 (s, 2H), 5.25 (s, 2H), 2.45 (s, 3H), 1.55 (s, 9H).
Step 2. Preparation of the title compound. 3-[3-Bromo-4-(2,4-difluoro- benzylozy)-6-methyl-2-oxo-pyridin-l (2H)-ylmethyl]-pyrazole-l -carboxylic acid tert-butyl
- 786 - ester (1.94g, 3.81 mmol),,was diluted in 15 mL of anhydrous DMSO and stined at reflux for 17 h. The reaction was cooled to room temperature and partitioned between water and EtOAc. The aqueous layer was extracted 3 times with EtOAc, dried (Mg2S04), filtered, and evaporated on a rotary evaporator. The reaction was diluted with EtOAc and hexanes. The solid was filtered to provide a tan solid (1.13g, 75%): 1H NMR (300 MHz, DMSO- 6) δ 12.67 (br s, IH), 7.68-7.60 (m, 2H), 7.34 (app t, J= 9 Hz, IH), 7.17 (app t, J = 9 Hz, IH), 6.49 (s, IH), 6.11 (s, IH), 5.27 (s, 2H), 5.21 (s, 2H), 2.49 (s, 3H). ES-HRMS m/z 410.0295 (M+H calcd for C17H15BrF2N302 requires 410.0313).
Example 778
Figure imgf000787_0001
3-Chloro-4-(2,4-difluorobenzyloxy)-l-[l-(2-methoxyacetyl)-lH-pyrazol-3-ylmethyl]-6- methyl-pyridin-2( 1 H)-one Step l. Preparation of the title compound. 3-[3-Chloro-4-(2,4-difluorobenzyloxy)-
2-oxo-pyridin-l(2H)-ylmethyl]pyrazole (0.25 mg, 0.68 mmol), NMM (0.15 mL, 1.4 mmol), and methoxyacetyl chloride (0.07 mL, 0.75 mmol) were stined in 5 mL of THF for 14 h. The solid was filtered, and washed with water. The solid was dried in a vacuum oven overnight to provide a white solid (0.19 g, 64%): 1H NMR (300 MHz, DMSO- ) δ 8.35 (d, J= 2.8 Hz, IH), 7.65 (app q, J= 6.7 Hz, IH), 7.34 (dt, J= 10.3, 2.5 Hz, IH), 7.19 (dt, J= 8.5, 2.0 Hz, IH), 6.60 (s, IH), 6.46 (d, J= 2.8 Hz, IH), 5.29 (s, 2H), 5.26 (s, 2H), 4.78 (s, 2H), 3.39 (s, 3H), 2.48 (s, 3H). ES-HRMS m/z 438.1043 (M+H calcd for C20H19ClF2N3O0 requires 438.1027).
Example 779
- 787 ^
Figure imgf000788_0001
3-Chloro-l-(l-cyclopropanecarbonyl-lH-pyrazol-3-ylmethyl)-4-(2,4-difluorobenzyloxy)- 6-methyl-pyridin-2(lH)-one Step l. Preparation of the title compound. 3-[3-Chloro-4-(2,4-difluorobenzyloxy)-
2-oxo-pyridin-l(2H)-ylmethyl]pyrazole (0.18 mg, 0.49 mmol), NMM (0.11 mL, 0.98 mmol), and cyclopropanecarbonyl chloride (0.05 mL, 0.54 mmol) were stined in 5 mL of THF for 14 h. The solid was filtered, and washed with water. The solid was dried in a vacuum oven overnight to provide a white solid (0.15 g, 68%): 1H NMR (300 MHz, DMSO- 6) δ 8.33 (d, J= 2.8 Hz, IH), 7.64 (app q, J= 6.7 Hz, IH), 7.35 (dt, J= 10.5, 2.5 Hz, IH), 7.17 (dt, J= 7.9, 1.8 Hz, IH), 6.61 (s, IH), 6.49 (d, J= 2.8 Hz, IH), 5.30 (s, 2H), 5.29 (s, 2H), 2.92 (q, J= 4.6 Hz, IH), 2.50 (s, 3H), 1.20-1.14 (m, 2H), 1.12-1.08 (m, 2H). ES-HRMS m/z 434.1090 (M+H calcd for C21H19C1F2N303 requires 434.1078).
Example 780
Figure imgf000788_0002
3-Chloro-4-(2,4-difluorobenzyloxy)-l-[l-(2-hydroxy-2-methyl-propyl)-H-pyrazol-3- ylmethyl] -6-methyl-pyridin-2( 1 H)-one Step l. Preparation of the title compound. 3-[3-Chloro-4-(2,4-difluorobenzyloxy)-
2-oxo-pyridin-l(2H)-ylmethyl]ρyrazole (0.24 mg, 0.65 mmol), 2N NaOH (1.5 mL, 3 mmol), benzyltriethylammonium chloride (0.1 g, 0.44 mmol), sodium iodide (10 mg), and l-chloro-2-methyl propan-2-ol (0.07 mL, 0.71 mmol) were stined in 5 mL of 1,4-dioxane at 85 °C for 19 h. The reaction was cooled to room temperature and evaporated on a
- 788 - rotary evaporator. Purification by flash column chromatography (silica, 1:9 MeOH/chloroform) provided a white solid (0.17 g, 58%): 1H NMR (300 MHz, DMSO- 6) δ 7.65 (app q, J= 8.5 Hz, IH), 7.56 (d, J= 2.2 Hz, IH), 7.34 (dt, J= 10.5, 2.5 Hz, IH), 7.17 (dt, J= 7.8, 1.7 Hz, IH), 6.52 (s, IH), 6.06 (d, J= 2.2 Hz, IH), 5.26 (s, 2H), 5.18 (s, 2H), 4.64 (s, IH), 3.94 (s, 2H), 2.48 (s, 3H), 1.01 (s, 6H). ES-HRMS m/z 438.1378 (M+H calcd for C21H23C1F2N303 requires 438.1390).
Example 781
Figure imgf000789_0001
5-[3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-2-oxo-pyridin-l(2H)-ylmethyl]-l,3- dihydroisoindole-2-carboxylic acid tert-butyl ester
Step 1. Preparation of 2,3-dihydro-lH-isoindole-5-carboxylic acid methyl ester hydrochloride salt.
Figure imgf000789_0002
2-Benzyl-2,3-dihydro-lH-isoindole-5-carboxylic acid methyl ester (see, e.g., European patent EP 0343560A2) (3.0 g, 11.2 mmol), ammonium formate (1.4 g, 22.4 mmol) and palladium hydroxide (112 mg) were dissolved in 50 mL of methanol. The reaction was stined at reflux for 15 h. The reaction was cooled to room temperature, the catalyst was filtered over Celite®, and the filfrate was evaporated on a rotary evaporator. The residue was dissolved in methanol, IM HCl in Et20 was added to provide a light yellow solid (1.6 g, 67%): 1H NMR (300 MHz, DMSO-tf6) δ 9.80 (br s, 2H), 8.00 (s, IH), 7.95 (d, J= 8.0 Hz, IH), 7.55 (d, J= 7.9 Hz, IH), 4.55 (d, J= 4.1 Hz, 4H), 3.86 (s, 3H). Step 2. Preparation of l,3-dihydro-isoindole-2,5-dicarboxylic acid 2-tert-butyl ester 5 -methyl ester
789
Figure imgf000790_0001
2,3-Dihydro-lH-isoindole-5-carboxylic acid methyl ester hydrochloride salt (1.6 g, 7.5 mmol), triethylamine (2.1 mL, 15 mmol), DMAP (92 mg, 0.8 mmol) and Boc20 (2.5 g, 11.3 mmol) were stined in 15 mL of methylene chloride for 12 h. The reaction was diluted with methylene chloride, washed with 10% citric acid, brine, dried (MgS04), filtered, and evaporated on a rotary evaporator. Purification by flash column chromatography (silica, 1:3 EtOAc/hexanes) gave a light yellow oil (1.34 g, 64%): 1H NMR (300 MHz, CDC13) δ 7.97-7.90 (m, 2H), 7.35-7.27 (m, IH), 4.72 (s, 2H), 4.68 (s, 2H), 3.92 (s, 3H), 1.52 (s, 9H).
Step 3. Preparation of 5-hydroxymethyl-l,3-dihydroisoindole-2-carboxylic acid tert-butyl ester
Figure imgf000790_0002
l,3-Dihydroisoindole-2,5-dicarboxylic acid 2-tert-butyl ester 5-methyl ester (1.3 g, 4.7 mmol) was dissolved in 15 mL of THF, cooled to -78 °C, and DIBAL (15.2 mL of a IM solution in toluene, 15.2 mmol) was added dropwise. The reaction was warmed room temperature and stined for 12 h. The reaction was quenched with a 1:1 solution of 10% citric acid/methanol, and was evaporated on a rotary evaporator. The residue was dissolved in EtOAc, washed with (3 times) Rochelle salt, brine, dried (MgS04), and evaporated on a rotary evaporator. Trituration with EtOAc gave a white solid (0.35 g, 29%): 1H NMR (300 MHz, DMSO- ) δ 7.24 (s, 3H), 5.19 (s, IH), 4.55 (s, 4H), 4.48 (d, J = 5.7, 2H), 1.45 (s, 9H).
Step 4. Preparation of 5-bromomethyl-l,3-dihydroisoindole-2-carboxylic acid tert- butyl ester.
Figure imgf000790_0003
5-Hydroxymethyl-l,3-dihydroisoindole-2-carboxylic acid tert-butyl ester (0.63 g, 2.5 mmol), triphenylphosphine (0.79 g, 3.0 mmol) and carbon tefrabromide (0.99 g, 3.0
790 mmol) were stined in 10 mL of methylene chloride for 20 min. The reaction was evaporated on a rotary evaporator. Purification by flash column chromatography (silica, 1:3 EtOAc/hexanes) gave a white solid (0.56 g, 72%): 1H NMR (300 MHz, DMSO- ) δ 7.44-7.24 (m, 3H), 4.71 (s, 2H), 4.57 (s, 2H), 4.55 (s, 2H), 1.45 (s, 9H).
Step 5. Preparation of the title compound. 5-[3-Chloro-4-(2,4-difluorobenzyloxy)- 6-methyl-2-oxo-pyridin-l(2H)-ylmethyl]-l,3-dihy(hOisoindole-2-carboxylic acid tert-butyl ester was prepared by a procedure similar to the one described in Example 777 gave a yellow solid (1.4 g, 39%): 1H NMR (300 MHz, DMSO- 6) δ 7.64 (app q, J= 6.7 Hz, IH), 7.39-7.27 (m, 2H), 7.17 (dt, J= 8.5, 2.6 Hz, IH), 7.08-7.03 (m, 2H), 6.59 (s, IH), 5.29 (s, 4H), 4.55 (s, 2H), 4.53 (s, 2H), 2.32 (s, 3H), 1.44 (s, 9H). ES-HRMS m/z 517.1728 (M+H calcd for C27H28C1F2N204 requires 438.1700).
Example 782
Figure imgf000791_0001
5-[3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-2-oxo-pyridin-l(2H)-ylmethyl]-l- methyl- 1 ,3 -dihydroindol-2-one
Step 1. Preparation of the 3-chloro-4-(2,4-difluorobenzyloxy)-6-methyl-l-(l- methyl-lH-indol-5-ylmethyl)-pyridin-2(lH)-one.
Figure imgf000791_0002
3 -Chloro-4-(2,4-difluoro-benzyloxy)- 1 -( 1 H-indol-5-ylmethyl)-6-methyl-pyridin- 2(lH)-one (see Example 633) (1.2 g, 2.9 mmol) was dissolved in 12 mL of anhydrous DMF, cooled to 0 °C, and NaH (0.14 g, 3.5 mmol) was added. The reaction was stined at
- 791 - room temperature for 30 min., then dimethylsulfate (0.33 mL, 3.5 mmol), was added dropwise and the reaction was stined at room temperature for 17.5 h. The reaction was diluted with water, and the precipitate was filtered off to afford a light, yellow solid (1.12 g, 90%): 1H NMR (300 MHz, DMSO-d6) δ 7.66 (app q, J= 9 Hz, IH), 7.41-7.30 (m, 3H), 7.23-7.15 (m, 2H), 7.00 (d, J= 8 Hz, IH), 6.57 (s, IH), 6.38 (s, IH), 5.39 (s, 2H), 5.29 (s, 2H), 3.76 (s, 3H), 2.34 (s, 3H).
Step 2. Preparation of 3,3-dibromo-5-[3-chloro-4-(2,4-difluorobenzyloxy)-6- methyl-2-oxo-2H-pyridin-l-ylmethyl]-l-methyl-l,3-dihydroindol-2-one.
Figure imgf000792_0001
3-Chloro-4-(2,4-difluoro-benzyloxy)-6-methyl-l-(l-methyl-lΗ-indol-5-ylmethyl)- pyridin-2(lH)-one (1.12g, 2.61 mmol) was diluted with 25mL of t-BuOH, and pyridinium bromide perbromide (2.51g, 7.83 mmol) was added portionwise over a period of 20 min.
The reaction was stined at room temperature for 16.5 h. The reaction was evaporated on a rotary evaporator, and the resulting solid dissolved in water, exfracted with EtOAc, dried
(Na2S04), filtered, and concenfrated under reduced pressure to give a dark, tan solid (1.4 g, 87%), which was carried forward without further purification or characterization.
Step 3. Preparation of the title compound. 3,3-Dibromo-5-[3-chloro-4-(2,4- difluoro-benzyloxy)-6-methyl-2-oxo-pyridin- 1 (H)-ylmethyl] - 1 -methyl- 1 ,3-dihydro-indol- 2-one (1.37g, 2.27 mmol) and zinc dust (1.5 g, 23 mmol) were dissolved in 30 mL of acetic acid. The reaction was stined at room temperature for 20 h. The reaction was diluted with water and exfracted with EtOAc, washed with brine, dried (Na2S04), filtered, and evaporated on a rotary evaporator to give a yellow solid (0.19 g, 19%): 1H NMR (300 MHz, DMSO-</6) δ 7.63 (app q, J= 8 Hz, IH), 7.35 (app t, J= 9 Hz, IH), 7.21-7.08 (m, 2H), 7.03 (s, IH), 6.93 (d, J= 8 Hz, IH), 6.57 (s, IH), 5.28 (br s, 4H), 3.52 (s, 2H), 3.09 (s, 3H), 2.34 (s, 3H).
792 Example 783
Figure imgf000793_0001
3-Chloro-4-(2,4-difluorobenzyloxy)-l-(2,3-dihydro-lH-isoindol-5-ylmethyl)-6-methyl- pyridin-2(lH)-one, trifluoroacetic acid salt
Step 1. Preparation of the title compound. 5-[3-Chloro-4-(2,4-difluorobenzyloxy)- 6-methyl-2-oxo-pyridin-l(2H)-ylmethyl]-l,3-dihydroisoindole-2-carboxylic acid tert-butyl ester (0.14 mg, 0.27 mmol) was stined in 10 mL of 9:1 dioxane/H2S0 for 48 h. The reaction was evaporated on a rotary evaporator. Purification by preparatory HPLC (Phenomenex Luna 10 μ, C18(2) 250 x 21.2 mm) provided a white solid (0.05 g, 34%): 1H NMR (300 MHz, DMSO-</6) δ 9.41 (br s, 2H), 7.66 (app q, J= 6.1 Hz, IH), 7.39-7.32 (m, 2H), 7.21-7.11 (m, 3H), 6.62 (s, IH), 5.32 (s, 2H), 5.29 (s, 2H), 4.47 (s, 4H), 2.32 (s, 3H).
Example 784
Figure imgf000793_0002
5-[3-Chloro-4-difluorobenzyloxy)-2-oxo-pyridin-l(2H)-yhnethyl]-l-methyl-l,3- dihydroindol-2-one
Step 1. Preparation of 3-chloro-4-(2,4-difluorobenzyloxy)-l-(l-methyl-lH-indol- 5-ylmethyl)-pyridin-2(lΗ)-one.
793
Figure imgf000794_0001
3-Chloro-4-(2,4-difluoro-benzyloxy)-l-(lH-indol-5-ylmethyl)-pyridin-2(lH)-one (0.26 g, 0.64 mmol), was dissolved with 4 mL of anhydrous DMF, cooled to 0 °C, and NaH (0.03 lg, 0.77 mmol) was added to the reaction. The reaction was stined at 0 °C for 30 min., and then dimethyl sulfate (0.07 mL, 0.77 mmol) was added dropwise to the reaction. The reaction was allowed to warm to room temperature and stined for 21 h. The reaction was diluted with water, and the precipitate was filtered and washed with water to afford an orange solid (0.230g, 87%), which was carried forward without further purification or analysis.
Step 2. Preparation of 3,3-dibromo-5-[3-chloro-4-(2,4-difluorobenzyloxy)-2-oxo- pyridin- 1 (2H)-ylmethyl] - 1 -methyl- 1 ,3 -dihydroindol-2-one.
Figure imgf000794_0002
3 -Chloro-4-(2,4-difluorobenyloxy)- 1 -( 1 -methyl- 1 H-indol-5 -ylmethyl)-pyridine- 2(lΗ)-one (0.230g, 0.554 mmol) was diluted with 5 mL of t-BuOH, and pryidinium bromide perbromide was added portionwise over a period of 15 min. The reaction was stined at room temperature for 7 h. The reaction was evaporated on a rotary evaporator. The residue was diluted with water and exfracted with EtOAc, dried over dried (Na2S04), filtered, and evaporated on a rotary evaporator to provide an orange solid (0.329g, 100%), which was carried forward without further purification or analysis.
Step 3. Preparation of title compound. 3,3-Dibromo-5-[3-chloro-4-(2,4- difluorobenzyloxy)-2-oxo-pyridin-l(2H)-ylmethyl]-l-methyl-l,3-dihy{hOindol-2-one (0.33g, 0.55 mmol) and zinc dust (0.36 g, 5.5 mmol) were diluted with lOmL of acetic
- 794 - acid. The reaction was stined at room temperature for 15 h. The reaction was diluted with water and exfracted with EtOAc, washed with brine, dried (Na2S04), filtered, and evaporated on a rotary evaporator. Purification by flash column chromatography (silica, 100% EtOAc) provided an off-white solid (0.05g, 21%). 1H NMR (300 MHz, DMSO- 6) δ 7.94 (d, J= 8 Hz, IH), 7.62 (app q, J= 9 Hz, IH), 7.37 - 7.28 (m, 2H), 7.24 (s, IH), 7.15 (app t, J= 9 Hz, IH), 6.93 (d, J= 8Hz, IH), 6.59 (d, J= 8 Hz, IH), 5.29 (s, 2H), 5.08 (s, 2H), 3.53 (s, 2H), 3.08 (s, 2H).
Example 785
Figure imgf000795_0001
3-Chloro-4-(2,4-difluorobenzyloxy)-l-[2-(2-hydroxy-2-methyl-propionyl)-2,3-dihydro- lH-isoindol-5-ylmethyl]-6-methyl-pyridin-2(lH)-one
Step 1. Preparation of title compound. 3-Chloro-4-(2,4-difluorobenzyloxy)-l- (2,3-dihydro-lH-isoindol-5-ylmethyl)-6-methyl-ρyridin-2(lH)-one (0.061 g, 0.12 mmol), 1-chlorocarbonyl-l-methyethyl acetate (0.02 mL, 0.13 mmol), and NMM ( 0.03 mL, 0.23 mmol) were stined in 3.0 mL of THF for 1.5 h. 2N Sodium hydroxide (0.300 mL) and MeOH (0.338 mL) were added to the reaction. The reaction continued to stir at room temperature for an additional 1 h. The reaction was evaporated on a rotary evaporator to afford an off-white solid (0.05 g, 82%): 1H NMR (300 MHz, DMSO-</6) δ 7.66 (app q, J= 8.6 Hz, IH), 7.39-7.29 (m, 2H), 7.18 (app t, J= 8.7 Hz, IH), 7.11-7.02 (m, 2H), 6.60 (s, IH), 5.33-5.29 (m, 4H), 5.08 (s, 2H), 4.64 (s, 2H), 2.33 (s, 3H), 1.33 (s, 6H).
795 Example 786
Figure imgf000796_0001
3-Chloro-4-(2,4-difluorobenzyloxy)-l-(2,5-dimethyl-l,3-benzothiazol-6-yl)-6- methylpyridin-2( 1 H)-one Step l. Preparation of 2,5-dimethyl-6-nifro-l,3-benzothiazole.
Figure imgf000796_0002
2,5-Dimethyl-l,3-benzothiazole ( 5.0 g, 31 mmol) and potassium nitrate (3.4 g, 34 mmol) were added, separately, in small portions to sulfuric acid at -5 °C and stined for
19.5 h. The reaction was quenched with NH4OH at 0 °C, the solid was collected, and dried in a vacuum oven to provide a tan solid (2.5 g, 40%): 1H NMR (300 MHz, DMSO- d6) δ 8.84 (s, IH), 7.99 (s, IH), 2.63 (s, 3H), 2.42 (s, 3H).
Step 2. Preparation of 2,5-dimethyl-l,3-benzothiazol-6-ylamine.
Figure imgf000796_0003
2,5-Dimethyl-6-nitro-l,3-benzothiazole (0.60 g, 2.9 mmol) and zinc dust (1.9 g, 29 mmol) were stined in 30 mL of acetic acid at room temperature for 48 h. The reaction was diluted with water and exfracted with EtOAc, washed with brine, dried (Na2S04), filtered and evaporated on a rotary evaporator to give a tan solid (0.510g, 99%): 1H NMR (300 MHz, DMS0- ) δ 7.46 (s, IH), 7.05 (s, IH), 5.05 (br s, 2H), 2.64 (s, 3H), 2.15 (s, 3H).
Step 3. Preparation of l-(2,5-dimethyl-l,3-benzothiazol-6-yl)-4-hydroxy-6- methyl-pyridin-2(lH)-one.
796.
Figure imgf000797_0001
2,5-Dimethyl-l,3-benzothiazol-6-ylamine (0.51 g, 2.9 mmol), and 4-hydroxy-6- methyl-2-pyrone (0.36 g, 2.6 mmol) were diluted with 10 mL of trifluoroethanol, and the reaction was heated to 85 °C for 18.5 h. The reaction was cooled to room temperature, and evaporated on a rotary evaporator to give a brown solid (0.88 g, 100%): 1H NMR (300 MHz, DMSO-tf6) δ 10.75 (br s, IH), 7.89(s, IH), 7.84 (s, IH), 5.94 (d, J = 1.5 Hz, IH), 5.59 (d, J= 2.4 Hz, IH), 2.81(s, 3H), 2.05 (s, 3H), 1.78 (s, 3H).
Step 4. Preparation of 3-chloro-l-(2,5-dimethyl-l,3benzothiazol-6-yl)-4-hydroxy- 6-methyl-pyridin-2(lH)-one.
Figure imgf000797_0002
l-(2,5-Dimethyl-l,3-benzothiazol-6-yl)-4-hydroxy-6-methyl-pyridin-2(lH)-one (0.82 g, 2.9 mmol) and NCS (0.46 g, 3.4 mmol) were stined in 10 mL of DMF for 50 h. The reaction was diluted with an 5% LiCl, extracted with EtOAc, washed with brine, dried (Na2S04), filtered, and evaporated on a rotary evaporator that gave a brown semi-solid (0.23 g, 25%), which was carried forward without further purification or analysis.
Step 5. Preparation of title compound. 3-Chloro-l-(2,5-dimethyl-l,3- benzothiazol-6-yl)-4-hydroxy-6-methyl-pyridin-2(lH)-one (0.23 g, 0.71 mmol), cesium carbonate (0.46 g, 1.4 mmol) and 2,4-difluorobenzyl bromide (0.11 mL, 0.86 mmol), were diluted with 5 mL of anhydrous dioxane, and the reaction was heated at reflux for 21 h. The reaction was cooled to room temperature and diluted with EtOAc. The reaction was washed with water, brine, dried (Na2S04), filtered, and evaporated on a rotary evaporator. Purification by flash column chromatography (silica gel, 100% EtOAc) to provide an orange solid (0.03 g, 8%): 1H NMR (300 MHz, DMSO-. 6) δ 7.95 (d, J= 4.7 Hz, 2H), 7.71
- 797 - (app q, J = 8.6 Hz, IH), 7.38 (app t, J= 7.9 Hz, IH), 7.21 (app t, J= 8.5 Hz, IH), 6.78 (s, IH), 5.35(s, 2H), 2.83 (s, 3H), 2.06 (s, 3H), 1.92 (s, 3H).
Example 787
Figure imgf000798_0001
3 -Chloro-4-(2,4-difluorobenzyloxy)-6-methyl- 1 -(3 -methyl- 1 H-pyrazol-4-yl)p yridin- 2(lH)-one
Step 1. Preparation of 3-methyl-4-nifro-lH-pyrazole.
Figure imgf000798_0002
3-Methylpyrazole (4.9 mL, 61 mmol) was dissolved in 30 mL of H2S04 cooled to -5 °C. KN03 (6.8 g, 67 mmol) was added to the reaction portion-wise. The reaction was warmed to room temperature and stined for 16 h. The reaction was neutralized with concentrated NH4OH at 0 °C, the solid was collected, and dried in a vacuum oven to provide a white solid (4.93 g, 64%): 1H NMR (300 MHz, DMSO-c?6) δ 13.55 (br s, IH), 8.39 (s, IH), 2.50 (s, 3H).
Step 2. Preparation of 3 -methyl-4-nifro-pyrazole-l -carboxylic acid tert-butyl ester.
Figure imgf000798_0003
3-Methyl-4-nitro-lH-pyrazole (4.9 g, 39 mmol), triethylamine (6.0 mL, 43 mmol),
DMAP (0.48 g, 3.9 mmol) and Boc20 (17.8 g, 82 mmol) were stined in 65 mL of acetonitrile for 20 h. The reaction was evaporated on a rotary evaporator. The residue was dissolved in EtOAc, washed with 10% citric acid, brine, dried (MgS0 ), filtered, and evaporated on a rotary evaporator. Purification by flash column chromatography (silica,
798 1:1 EtOAc/hexanes) gave a yellow oil (8.8 g, 100%): 1H NMR (300 MHz, DMSO-</6) δ 9.19 (s, IH), 2.48 (s, 3H), 1.47 (s, 9H).
Step 3. Preparation of 4-amino-3-methyl-pyrazole-l -carboxylic acid tert-butyl ester
Figure imgf000799_0001
3 -Methyl-4-nifro-pyrazole-l -carboxylic acid tert-butyl ester (4.4 g, 19.4 mmol), and 10% palladium on carbon (250 mg) were suspended in 150 mL of methanol and subject to 20 psi of hydrogen on a Pan shaker for 24 h. The catalyst was removed over celite, and the filfrate was evaporated on a rotary evaporator. Purification by flash column chromatography (silica, EtOAc) gave a yellow oil (1.6 g, 42%): 1H NMR (300 MHz, DMSO- ) δ 7.25 (s, IH), 4.28 (s, 2H), 2.07 (s, 3H), 1.51 (s, 9H).
Step 4. Preparation of 4-hydroxy-6-methyl-l-(3-methyl-lH-pyrazol-4-yl)-pyridin- 2(lH)-one.
Figure imgf000799_0002
4-Amino-3-methyl-pyrazole-l -carboxylic acid tert-butyl ester (2.0 g, 10 mmol) and 4-hydroxy-6-methyl-2-pyrone (1.3 g, 10 mmol) were diluted with 30 mL of trifluoroethanol, and the reaction was heated to 85 °C for 24 h. The reaction was cooled to room temperature, and evaporated on a rotary evaporator to give a brown solid (3.1 g,
100%), which was used without further purification or analysis.
Step 5. Preparation of 4-(2-4-difluorobenzyloxy)-6-methyl-l-(3-methyl-lH- pyrazol-4-yl)-pyridin-2( 1 H)-one.
Figure imgf000799_0003
4-Hydroxy-6-methyl-l-(3-methyl-lH-pyrazol-4-yl)-pyridin-2(lH)-one (3.1 g, 10 mmol), cesium carbonate (6.6 g, 20 mmol) and 2,4-difluorobenzyl bromide (1.6 mL, 12 mmol), were diluted with 50 mL of anhydrous 1,4-dioxane, and the reaction was heated at reflux for 22 h. The reaction was cooled to room temperature and diluted with water. The reaction was exfracted 3 times with EtOAc, washed with brine, dried (Na2S04), filtered, and evaporated on a rotary evaporator. Purification by flash column chromatography (silica gel, 1:9 MeOH/chloroform) to provide an off-white solid (0.47 g, 14%): 1H NMR (300 MHz, DMSO- ) δ 12.72 (br s, IH), 8.32 (s, IH), 7.63 (app q, J= 8.6 Hz, IH), 7.34 (dt, J= 10.4, 2.5 Hz, IH), 7.16 (dt, J= 8.5, 1.8 Hz, IH), 6.01 (d, J= 2.0 Hz, IH), 5.90 (d, J= 2.6 Hz, IH), 5.09 (s, 2H), 1.95 (s, 3H), 1.90 (s, 3H).
Step 6. Preparation of the title compound. 4-(2-4-Difluorobenzyloxy)-6-methyl-l- (3-methyl-lH-pyrazol-4-yl)-ρyridin-2(lH)-one (0.46 mg, 1.4 mmol) and NCS (0.20 g, 1.5 mmol) were diluted with 5 mL of DMF, and stined for 14 h. The reaction was diluted with water, and exfracted 3 times with EtOAc. The combined organics were washed with brine, dried (MgS04), filtered, and evaporated on a rotary evaporator. Purification (silica, 1:9 MeOH/chloroform) provided an off-white solid (0.10 g, 18%): IH NMR (300 MHz, DMSO-dβ) δ 8.17 (br s, IH), 7.57 (app q, J= 6.4 Hz, IH), 7.30 (s, IH), 6.97 (dt, J= 10.4, 2.0 Hz, IH), 6.88 (dt, J= 10.3, 2.4 Hz, IH), 6.16 (s, IH), 5.26 (s, 2H), 2.04 (s, 3H), 2.01 (s, 3H).
Example 788
Figure imgf000800_0001
3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-l- tefrahydro-2H-pyran-2-yl-lH-pyrazole-5-carboxylic acid
- 800 - Step 1 Preparation diethyl l-tefrahydro-2H-pyran-2-yl-lH-pyrazole-3,5- dicarboxylate Et02C^^ -C02Et N-N THP Trifluoro acetic acid (5.4 mL, 70 mmol) and dihydropyran (7.2 mL, 77.7 mmol) were added sequentially to a room temperature solution of diethyl-3,5-pyrazole dicarboxylate (15 g, 70.7 mmol) in methylene chloride. After three hours, the reaction mixture was poured into saturated aqueous NaHC03 and exfracted with additional methylene chloride. The organic exfract was washed with brine, dried over anhydrous
Na2S04, decanted and concentrated in vacuo to give diethyl l-tefrahydro-2H-pyran-2-yl- lH-pyrazole-3,5-dicarboxylate as a white solid. 1H NMR (400 MHz, CDC13) δ 7.35 (s,
IH), 6.31 (dd, J= 2.76 and 10 Hz, IH), 4.37 (q, J= 7.2 Hz, 4H), 4.03 ( m, IH), 3.71 (dt, J
= 3.2 Hz, IH), 2.53 (m, IH), 2.1 (m, IH), 1.97 (m, IH), 1.71 (m, 2H), 1.57 (m, IH), 1.37 ( t, J= 7.2 Hz, 6H) . Step 2. Preparation of ethyl 3-(hydroxymethyl)-l-tefrahydro-2H-pyran-2-yl-lH- pyrazole-5-carboxylate
Figure imgf000801_0001
Diisobutyl aluminum hydride (110 mL, 110 mmol, 1.0M solution in hexanes) was added dropwise to a -78 C solution of l-tefrahydro-2H-pyran-2-yl-lH-pyrazole-3,5- dicarboxylate (14.7g, 49.6 mmol) in THF (100 mL). The reaction mixture was stined at - 78 C for 1 h., was wanned to 0 °C and was quenched by the drop wise addition of 30 mL of H20. This mixture was poured into saturated aqueous sodium potassium tarfrate (300 mL) and was stined for 30 min. at room temperature. Ethyl acetate was added, the layers were separated and the organic layer was washed with additional saturated sodium potassium tarfrate solution. The ethyl acetate exfract was dried with anhydrous Na2S04, decanted and concentrated in vacuo to give the title product, ethyl 3-(hydroxymethyl)-l- tetrahydro-2H-pyran-2-yl-lH-pyrazole-5-carboxylate, as a white solid. (11 g, 87%) 1H NMR (400 MHz, CDC13) δ 6.88 (s, IH), 6.26 (dd, J= 2.4 and 10.4 Hz, IH), 4.69 (s, 2H), 4.33 (q, J = 8.4 Hz, 2H), 4.08 (m, IH), 3.71 (t, J = 9.6 Hz, IH), 2.40 (m, IH), 2.05 (m, - 801 - IH), 1.91 (m, IH), 1.71 (m, 2H), 1.55 (m, IH), 1.35 (t, J = 8 Hz, 3H) . ES-HRMS m/z 255.1323 (M+H calcd for C12H19N204 requires 255.1339.)
Step 3 Preparation of ethyl 3-{[(methylsulfonyl)oxy]methyl}-l-tefrahydro-2H- pyran-2-yl-lH-pyrazole-5-carboxylate
Figure imgf000802_0001
A solution of ethyl 3-(hydroxymethyl)-l-tetrahydro-2H-pyran-2-yl-lH-pyrazole-5- carboxylate (6 g, 23.6 mmol), and triethylamine (4 mL, 28.3 mmol) in methylene chloride (100 mL) was cooled to 0 °C. Methane sulfonyl chloride (2 mL, 25.9 mmol) was added and the reaction mixture was stined at 0 °C for 2 h. The solution was poured into saturated aqueous NaHC03 and exfracted additional methylene chloride. The organic extract was washed with brine, dried with anhydrous Na2S04, decanted and concentrated in vacuo to give ethyl 3-{[(methylsulfonyl)oxy]methyl}-l-tefrahydro-2H-pyran-2-yl-lH- pyrazole-5-carboxylate as a colorless oil which was used without further purification. (7.4 g, 95%) 1H NMR (400 MHz, CDC13) δ 6.99 (s, IH), 6.27 (dd, J= 2.2 and 10 Hz, IH), 5.26 (d, J= 2.6 Hz, 2H), 4.33 (q, J= 7.6 Hz, 2H), 4.06 (d, J= 12 Hz, IH), 3.71 (t , J= 12 Hz, IH), 2.98 (s, 3H), 2.37 (m, IH), 2.06 (m, IH), 1.91 (m, IH), 1.70 (m, 2H), 1.56 (m, IH), 1.36 (t, J= 6.8 Hz, 3H). LC/MS, tr = 5.05 min. (5 to 95% acetonitrile/water over 8 min. at 1 ml/min with detection 254 nm, at 50 °C).
Step 4 Preparation of ethyl 3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]methyl} - 1 -tetrahydro-2H-pyran-2-yl- 1 H-pyrazole-5 -carboxylate
Figure imgf000802_0002
802 Sodium hydride (0.73 g, 30.6 mmol) was added to a 0 °C suspension of the compound from Example 734 (5 g, 15.3 mmol) in tefrahydrofuran (100 mL). After 5 minutes, a solution of ethyl 3-{[(methylsulfonyl)oxy]methyl}-l-tefrahydro-2H-pyran-2-yl- lH-ρyrazole-5-carboxylate (7.4 g, 23 mmol) in tefrahydrofuran (20 mL) was added and the reaction mixture was refluxed for 2h. The solution was cooled to room temperature, poured into saturated aqueous NaHC03 and exfracted with ethyl acetate. The organic exfract was washed with brine, dried with anhydrous Na2S04, decanted and concenfrated in vacuo. The semi-solid residue was freated with acetonitrile and filtered. The filfrate was concenfrated and treated with diethyl ether/ hexanes and the title product, ethyl 3-{[3- bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl]methyl} - 1 - tefrahydro-2H-pyran-2-yl-lH-pyrazole-5-carboxylate, was isolated by filfration as a tan solid. (4.4 g, 51 %) 1H NMR (400 MHz, CDC13) δ 7.54 (td, J= 6.5 and 8.5 Hz, IH), 7.00 (s, IH), 6.92 (m, IH), 6.83 (dddd, J= 2.6, 2.6, 8.9Hz, IH), 6.23 (dd, J= 2.5 and 10.5 Hz, IH), 5.93 (s, IH), 5.27 (dd, IH), 5.17 (s, 2H), 4.28 (q, J= 6.5 Hz, 2H), 4.05 (m, IH), 3.71 (td, J= 2.5 Hz, IH), 2.53 (s, 3H), 2.34 (m, IH), 2.04 (m, IH), 1.87 (d, IH), 1.69 (t, IH), 1.57 (m, 2H), 1.33 (t, J= 7.3 Hz, 3H). 19 F NMR (300 MHz, CD3OD)δ -109.79 (IF), - 115.06 (1 F). ES-HRMS m/z 566.1089 (M+H calcd for C25H27BrF2N305 requires 566.1097). ' Step 5 Preparation of 3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]methyl} - 1 -tefrahydro-2H-pyran-2-yl- 1 H-pyrazole-5 -carboxylic acid Sodium hydroxide (0.57 mL, 1.44 mmol, 2.5 M) was added to a solution of ethyl 3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-l- tetrahydro-2H-pyran-2-yl-lH-pyrazole-5-carboxylate (0.68g, 1.2 mmol) in tefrahydrofuran (10 mL), ethanol, and water (2 mL). After stirring at room temperature for 1 h., the reaction mixture was poured into saturated aqueous ammonium chloride, which was extracted with ethyl acetate. The organic extract was concenfrated in vacuo to give a cloudy solution, which was freated with diethyl ether. The white powder was filtered and washed with additional ether to give 3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl- 2-oxopyridin-l(2H)-yl]methyl}-l-tefrahydro-2H-pyran-2-yl-lH-pyrazole-5-carboxylic acid, which was used without further purification. (0.7 g) 1H NMR (400 MHz, dmso-dβ) δ 7.62 (q, J= 8.4 Hz, IH), 7.30 (m, IH), 7.13 (td, J= 2.3 and 8.8 Hz, IH), 6.61 (dd, J= 2.4 - 803 - and 10.4 Hz, IH), 6.49 (s, IH), 6.14 (s, IH), 5.25 (s, 2H), 5.12 (s, 2H), 4.0 (q, J= 7.2 Hz, 2H), 3.84 (d, IH), 3.46 (m, IH), 3.33 (m, IH), 2.15 (m, IH), 1.96 (s, 3H), 1.90 (m, IH), 1.66 (m, IH), 1.45 ( , IH), 1.14 (m, IH) . 19 F NMR (300 MHz, dmso-d6) δ -109.76 (IF), -113.72 (1 F). ES-HRMS m/z 538.0786 (M+H calcd for C23H23BrF2N305 requires 538.0784).
Example 789
Figure imgf000804_0001
CH3 3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-N- methyl-lH-pyrazole-5-carboxamide
Step 1 Preparation of 3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]methyl} -N-methyl- lH-pyrazole-5-carboxamide A nitrogen flushed flask containing a solution of 3-{[3-bromo-4-[(2,4- difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl]methyl} - l-tetrahydro-2H-pyran-2- yl-lH-ρyrazole-5-carboxylic acid (0.6 g, 1.1 mmol) in NN-dimethyl formamide (30 mL) was cooled to 0 °C. Triethylamine (0.12 mL, 1.1 mmol) and isobutyl chloroformate (0.14 mL, 1.1 mmol) were added and the reation mixture was stined as it warmed to room temperature overnight. The reaction mixture was partitioned between ethyl acetate and saturated aqueous ΝaHC03. The organic exfract was washed with brine and was concentrated in vacuo to give a white solid that was dissolved in tetrahydrofuran (15 mL), methanol (5 mL), water (5 mL) and concenfrated HCl (1 mL). After stirring at room temperature for 2 h., the reaction mixture was brought to pH 12 with 2.5 N NaOH. The solution was partitioned between ethyl acetate and brine and the organic layer was concenfrated in vacuo. The white solid was triturated with diethyl ether and filtered to give the desired product (0.23 g, 85%). 1H NMR (400 MHz, CD3OD) δ 7.59 (q, J= 8.4
- 804 - Hz, IH), 7.01 (m, 2H), 6.59 (s, IH), 6.47 (s, IH), 5.36 (s, 2H), 5.27 (s, 2H), 2.84 (s, 3H), 2.50 (s, 3H). 19 F NMR (300 MHz, CD3OD) δ -111.64 (IF), -116.07 (1 F). ES-HRMS m/z 467.0558 (M+H calcd for C19H18BrF2N403 requires 467.0525).
Example 790
Figure imgf000805_0001
3 - { [3 -bromo-4-[(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl]methyl} - 1 H- pyrazole-5-carboxamide Step 1 Preparation of 3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]methyl} - 1 H-pyrazole-5 -carboxamide
Figure imgf000805_0002
N-methyl morpholine (0.6 mL, 5.4 mmol) was added to a suspension of the compound from Example 788 (1 g, 1.8 mmol) in tefrahydrofuran (30 mL). When the solution became clear, 2-chloro-4,6-dimethoxy-l,3,5-triazine (0.4 g, 2.2 mmol) was added. After the reaction mixture was stined at room temperature for 2 h., concentrated ammonium hydroxide (14 mL) was added. The mixture was stined at room temperature for an additional h. and was then diluted with water and filtered. The white solid was
- 805 - suspended in a mixture of tetrahydrofuran (20 mL), methanol (15 mL), water (5 mL) and concenfrated HCl (2 mL). After stirring at room temperature for 1 h., the solution was brought to pH 12 with 2.5 N NaOH. The solution was extracted with ethyl acetate and the organic exfract was concentrated in vacuo. The resulting solid was triturated with diethyl ether to give the title compound as a white powder (0.5g). 1H NMR (400 MHz, dmso-dβ) δ 7.93 (s, IH), 7.62 (q, J= 8 Hz, IH), 7.30 (m, 2H), 7.14 (t , J= 9.6 Hz, IH), 6.57 (s, IH), 6.50 (s, IH), 5.24 (s, 2H), 5.19 (s, 2H), 1.59 (s, 3H). 19 F NMR (300 MHz, dmso-ά6) δ - 109.71 (IF), -113.71 (1 F). ES-HRMS m/z 453.0385 (M+H calcd for C18H16BrF2N403 requires 453.0368).
Example 791
Figure imgf000806_0001
3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-N,N- dimethyl-lH-pyrazole-5-carboxamide
Step 1 Preparation of 3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxoρyridin-l(2H)-yl]methyl}-N,N-dimethyl-lH-pyrazole-5-carboxamide
Figure imgf000806_0002
806 To a solution of the compound from Example 788 (0.35g, 0.65 mmol) in NN'- dimethylformamide (20 mL) was added N-methyl morpholine (0.1 mL, 0.97 mmol) and zsobutyl chloroformate (0.13 mL, 0.97 mmol). After stirring the mixture at room temperature for 15 min., NN'-dimethyl amine (0.65 mL, 1.3 mmol, 2.0M in THF) was added. When the reaction was complete, the solution was partitioned between saturated aqueous ΝaHC03 and ethyl acetate. The organic extract was washed with brine, dried with anhydrous Na2S04, decanted and concenfrated. The resulting oil was dissolved in a mixture of tetrahydrofuran (20 mL), methanol (10 mL), water (2 mL) and concentrated HCl (1 mL). After stirring at room temperature for 1 h., the reaction mixture was poured into saturated aqueous NaHC0 and was exfracted with ethyl acetate. The organic extract was washed with brine, dried with anhydrous Na2S04 and concentrated in vacuo. The resulting solid was triturated with diethyl ether and the title compound was isolated as a white powder (0.217 g, 69%). 1H NMR (400 MHz, CD3OD) δ 7.59 (q, J= 7.6 Hz, IH), 7.01 (m, 2H), 6.53 (s, IH), 6.47 (s, IH), 5.37 (s, 2H), 5.27 (s, 2H), 3.23 (s, 3H), 3.06 (s, 3H), 2.52 (s, 3H). 19 F NMR (300 MHz, CD3OD) δ -111.72 (IF), -116.07 (1 F). ESHRMS m/z 481.0687 (M+H calcd for C20H20BrF2N4O3 requires 481.0673).
Example 792
Figure imgf000807_0001
3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-N-(2- methoxyethyl)-lH-pyrazole-5-carboxamide
Step 1. Preparation of 3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]methyl} -N-(2-methoxyethyl)- 1 H-pyrazole-5 -carboxamide To a solution of the compound from Example 788 (0.35g, 0.65 mmol) in N,N'- - 807 - dimethylformamide (20 mL) was added N-methyl morpholine (0.1 mL, 0.97 mmol) and ώøbutyl chloroformate (0.13 mL, 0.97 mmol). After stirring the mixture at room temperature for 15 min., 2-methoxy ethylamine (0.11 mL, 1.3 mmol) was added. When the reaction was complete, the solution was partitioned between saturated aqueous ΝaHC03 and ethyl acetate. The organic exfract was washed with brine, dried with anhydrous Na2S04, decanted and concenfrated. The resulting oil was dissolved in a mixture of tetrahydrofuran (20 mL), methanol (10 mL), water (2 mL) and concentrated HCl (1 mL). After stirring at room temperature for 1 h., the reaction mixture was poured into saturated aqueous NaHC03 and was extracted with ethyl acetate. The organic extract was washed with brine, dried with anhydrous Na2S04 and concenfrated in vacuo. The resulting solid was triturated with diethyl ether and the product was isolated as a white powder (43 mg, 13%). 1H NMR (400 MHz, CD3OD) δ 7.60 (q, J= 7.6 Hz, IH), 7.01 (m, 2H), 6.62 (s, IH), 6.47 (s, IH), 5.37 (s, 2H), 5.27 (s, 2H), 3.49 (m, 4H), 3.33 (s, 3H), 2.49 (s, 3H) . 19 F NMR (300 MHz, CD3OD) δ -111.69 (IF), -116.08 (1 F) . ES-HRMS m/z 511.0793 (M+H calcd for C21H22BrF2N404 requires 511.0793).
The following table of non-limiting compounds can be made from the compound of Example 788 by coupling with the appropriate amine and cleavage of the tetrahydropyranyl protecting group.
Figure imgf000808_0001
Figure imgf000808_0002
- 808
Figure imgf000809_0003
n = l-3
The following table of compounds can be made from the compound of Example 790 by reduction of the amide and coupling acids including amino acids to the resulting amine residue. Non-limiting compounds are:
Figure imgf000809_0001
Figure imgf000809_0004
Example 793
Figure imgf000809_0002
3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-{[l-(methylsulfonyl)-2,3-dihydro-lH- indol-5-yl]methyl}pyridin-2(lH)-one
A 10 mL round bottomed flask equipped with stirbar and nifrogen inlet was charged with the compound of Example 88 (200 mg, 0.5 mmol), methanesulfonyl chloride (41 μL, 0.52 mmol), triethylamine (134 μL, 1.1 mmol) and tefrahydrofuran (4.0 mL). After stirring at 25 °C for 20 min. the reaction was completed by LC-MS. The compound precipitated out of solution. The precipitated was filtered and washed with water and diethyl ether to obtain the title compound (200 mg, 84%) as a solid. 1H NMR (400 MHz, - 809 - (c/6-DMSO) δ 7.7 (q, J= 8.6 and 6.7 Hz, IH), 7.3 (t, J= 9.5 Hz, IH), 7.3 (m, 2H), 7.0 (m, 2H), 6.6 (s, IH), 5.3 (s, 2H), 3.9 (t, J= 8.3 Hz, 2H), 2.9(m, 2H), 2.8 (s, 3H), 2.3 (s, 3H), 1.0 (t, J=7.25 Hz, 2H) ppm. ES-HRMS m/z 495.0970 (M+H calcd for C 3H22C1F2N204S requires 495.0951).
Example 794
Figure imgf000810_0001
2-(5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}- 2,3-dihydro- 1 H-indol- 1 -yl)-2-oxoethyl acetate A 10 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with the compound from Example 88 (200 mg, 0.5 mmol), acetoxyacetyl chloride (59 μL, 0.55 mmol), triethylamine (140 μL, 1.0 mmol) and tefrahy<kofuran (3.0 mL). After stirring at 25 °C for 20 min. the reaction was completed as determined by LC-MS. The compound precipitated out of solution. The precipitated solid was filtered and washed with water and diethyl ether to obtain the title compound (180 mg, 72%) as a white solid. 1H NMR (400 MHz, ( -DMS0) δ 7.9 (d, J= 8.3, IH), 7.6 (q, J= 7.5 and 8.0 Hz, IH), 7.3 (t, J= 9.7 Hz, IH), 7.1 (t, J= 8.3 Hz, IH), 6.8 (m, 2H), 6.5 (s,lH), 5.2 (s, 2H), 4.7 (s, 2H), 3.9 (t, J= 7.9 Hz, 2H), 3.5(s, 2H), 3.0 (t, J=7.8 Hz, 2H), 2.3 (s, 3H), 1.9 (s, 3H) ppm. ES-HRMS m/z 517.1343 (M+H calcd for C26H24C1F2N205 requires 517.1336).
Example 795
Figure imgf000810_0002
810 2-(5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}- 2,3 -dihydro- 1 H-indol- 1 -yl)- 1 , 1 -dimethyl-2-oxoethyl acetate
A 10 mL round bottomed flask equipped with stirbar and nifrogen inlet was charged with the compound from Example 88 (200 mg, 0.5 mmol), 1-chlorocarbonyl-l- methylethyl acetate (80 μL, 0.55 mmol), triethylamine (140 μL, 1.0 mmol) and tetrahydrofuran (3.0 mL). After stirring at 25 °C for 20 min., the reaction was completed as determined by LC-MS. The compound precipitated out of solution. The precipitated solid was filtered and washed with water and diethyl ether to obtain the title compound (180 mg, 72%) as a white solid. 1H NMR (400 MHz, (< -DMSO) δ 7.9 (d, J= 8.3, IH), 7.6 (d, J= 6.4 Hz, IH), 7.3 (t, J= 9.8 Hz, IH), 7.1 (s, IH), 6.9 (m, 2H), 6.5 (s, IH), 5.1 (s, 4H), 3.9 (s, 2H), 2.9 (s, 2H), 2.3 (s, 3H), 2.0 (s, 3H), 1.5 (s, 6H) ppm. ES-HRMS m/z 545.1632 (M+H calcd for C28H28C1F2N205 requires 545.1649).
Example 796
Figure imgf000811_0001
N-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3- fluorobenzyl} acetamide Step 1: Preparation of 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]-3-fluorobenzamide.
- 811 -
Figure imgf000812_0001
A 25 mL round bottomed flask equipped with stirbar and nifrogen inlet was charged with the acid (Example 725, step 1) (785 mg, 1.7 mmol), 4-methylmorpholine (0.55 mL, 5 mmol), 2-chloro-4,6-dimethoxy-l,3,5-triazine (353 mg, 2 mmol) and tefrahydrofuran (9 mL). After stirring the mixture for 30 min. at 25 °C, NH4OH (4 mL) was added. The mixture was stined for 12 h. and diluted with water. The product precipitated from solution. The precipitated solid was filtered and washed with water and diethyl ether to give the title compound (624 mg, 78%) as a white solid. lR NMR (400 MHz, ( -DMSO) δ 7.8 (t, J= 11.8 Hz, 2H), 7.65 (m, 2H), 7.56 (t, J= 7.9 Hz, IH), 7.35 (td, J= 2.5 and 9.3 Hz, IH) 7.17 (q, J= 8.5 and 2.6 Hz, IH), 5.4 (s, 2H), 2 (s, 3H) ppm. ES-HRMS m/z 467.0215 (M+H calcd for C20H15BrF3N2O3 requires 467.0213).
Step 2: Preparation of l-[4-(aminomethyl)-2-fluorophenyl]-3-bromo-4-[(2,4- difluorobenzyl)oxy] -6-methylpyridin-2( 1 H)-one hydrochloride
Figure imgf000812_0002
812 A 100 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with the compound from Example 725, Step 1 (2.31 g, 4.9 mmol), BH3»DMS complex (0.7 mL, 7.4 mmol), and dichloromethane(49 mL). The mixture was refluxed for 24 h., allowed to cool to room temperature and quenched with HCl (6N). The organics were evaporated and the remaining aqueous solution was saturated with NaOH (2.5N) and exfracted with dichloromethane. The organic phase was dried with Na S0 and concentrated in vacuo. HCl (6N) was added, concentrated in vacuo, and recrystallized from acetonitrille to furnish the title compound (1.5 g, 70%) as a white solid. 1H NMR (400 MHz, ( -DMS0) δ 7.6 (q, J= 8.5 and 6.8 Hz IH), 7.5 (d, 11 Hz, IH), 7.4 (t, J= 7.9 Hz, IH), 7.3 (d, J= 7.9 Hz, IH), 7.2 (t, J=10 Hz, IH), 7.0 (t, J=8.6 Hz IH), 6.7 (s, IH) 5.36 (s, 2H), 4.1 (d, J= 5.4 Hz, 2H), 2 (s, 3H) ppm. ES-HRMS m/z 453.0398 (M+H calcd for C20H17BrF3N2O2 requires 453.0420).
Step 3: Preparation of N-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]-3-fluorobenzyl} acetamide
Figure imgf000813_0001
A 10 mL round bottomed flask equipped with stirbar and nifrogen inlet was charged with the compound from Step 2 (above) (180 mg, 0.37 mmol), acetyl chloride (26 μL, 0.37 mmol), triethylamine (103 μL, 1.7 mmol) and tetrahydrofuran (4.0 mL). After stirring at 25 °C for 15 min. the reaction was completed as determined by LC-MS. The reaction mixture was poured into a saturated aqueous NH4C1 solution. The aqueous mixture was extracted with ethyl acetate. The organic phase was dried with Na2S0 and concentrated in vacuo to obtain the title compound (110 mg, 60%) as a solid. !H NMR (400 MHz, CD3OD) δ 7.6 (s, IH), 7.5-6.9 (m, 6H), 6.6 (s, IH), 5.2 (s, 2H), 4.2 (s, 2H),
813 - 2.1-1.7 (m, 6H) ppm. ES-HRMS m/z 495.0541 (M+H calcd for C22H19BrF3N203 requires 495.0526).
Example 797
Figure imgf000814_0001
5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-N- methyl-2-vinylbenzamide
Step 1: Preparation of methyl 2-bromo-5 -methylbenzoate
Figure imgf000814_0002
Acetyl chloride (16.5 mL, 232.6 mmol) was added to a 0 C solution of 2-bromo-5- methyl benzoic acid (25g, 116.3 mmol) in methanol (200 mL). After the reaction mixture was warmed to room temperature, the solution was refluxed for 2 h. The reaction mixture was cooled to room temperature and was concenfrated to lA the original volume. The residue was diluted with ethyl acetate and saturated aqueous NaHC03. After exfracting with ethyl acetate, the organic extract was washed with brine, dried with MgS04 and concenfrated in vacuo to give methyl 2-bromo-5 -methylbenzoate which was used without further purification. 1H NMR (400 MHz, CD3OD) δ 7.54 (m, 2H), 7.21 (m, IH), 3.88 (s, 3H), 2.32 (s, 3H). LC/MS, tr = 5.97 min. (5 to 95% acetonitrile/water over 8 min. at 1 ml min with detection 254 nm, at 50°C).
Step 2: Preparation of methyl 2-bromo-5-(bromomethyl)benzoate
814
Figure imgf000815_0001
A mixture of solid N-bromo succinimide (4.3 g, 24 mmol) and benzoylperoxide (0.5g, 2.1 mmol) was added to a 75 °C solution of the product of Step 1 (5 g, 21.8 mmol) in carbon tefrachloride (50 mL). After the reaction mixture was refluxed for 2 h., it was cooled to room temperature and the solution was filtered. The filtrate was concentrated in vacuo and the product, methyl 2-bromo-5-(bromomethyl)benzoate, was used without further purification. 1H NMR (400 MHz, CDC13) δ 7.60 (m, 3H), 4.42 (s, 2H), 3.93 (s, 3H). LC/MS, tr = 5.73 min. (5 to 95% acetonitrile/water over 8 min. at 1 ml/min with detection 254 nm, at 50 °C).
Step 3: Preparation of methyl 2-bromo-5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-
6-methyl-2-oxopyridin- 1 (2H)-yl]methyl}benzoate
Figure imgf000815_0002
Sodium hydride (0.22 g, 9.2 mmol, 60% in mineral oil) was added to a 0 C slurry of the compound from Example 734 (1.5g, 4.6 mmol) in 1,4-dioxane (40 mL). A solution of the product of Step 2 (2.2 g, 7 mmol) in 1,4-dioxane (10 mL) was added and the reaction mixture was heated to 100 °C for 18 h. The solution was cooled to room temperature, poured into water and exfracted with ethyl acetate. The organic extract was washed with brine and concentrated in vacuo. The resulting solid was triturated with acetonitrile and diethyl ether to give the title compound as a tan solid (1.2g, 48%). 1H NMR (400 MHz, CDC13) δ 7.57 (m, 3H), 7.15 (dd, J= 2.2 and 8 Hz, IH), 6.95 (m, IH), 6.85 (m, IH), 6.00 (s, IH), 5.31 (s, 2H), 5.20 (s, 2H), 3.91 (s, 3H), 2.29 (s, 3H). 19F NMR (400 MHz, CDC13) δ -109.53 (IF), -114.97 (IF). LC/MS, tr = 6.01 min. (5 to 95% acetonitrile/water over 8 min. at 1 ml min with detection 254 nm, at 50 °C). - 815 - Step 4: Preparation of methyl 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl- 2-oxopyridin-l(2H)-yl]methyl}-2-vinylbenzoate
Figure imgf000816_0001
A 50 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with the compound from Step 3 (4.3 g, 7.7 mmol), ethylene glycol dimethyl ether (62 mL) and Pd(PPh3)4 (5mg, cat.). The mixture was stined for 20 min at room temperature. Potassium carbonate (1.1 g, 7.7 mmol), water (19 mL) and trivinylcyclofriboroxane-pyridine complex (1.8 g, 7.7 mmol) were added and the mixture was refluxed. After 4 h. the reaction was completed as determined by LC-MS. The reaction was cooled to room temperature and extracted with ethyl acetate and dried over sodium sulfate. The crude was evaporated to dryness, the residue suspended with methanol and filtered to give the product as a white solid(2.1 g, 71%). 1H NMR (400 MHz, CDC13) δ 7.7 (s, IH), 7.6 (m, IH), 7.5 (d, J=8.1 Hz, IH), 7.4 (m, IH), 7.3 (m, IH), 7.0 (t, J=8.4 Hz, IH), 6.8 (t, J=8.1 Hz, IH), 6.0 (s, IH), 5.6 (d, J=17 Hz, IH), 5.3 (m, 3H), 5.2 (s, 2H), 3.8 (s, 3H), 2.4 (s, 3H) ppm. ES-HRMS m/z 504.0588 (M+H calcd for C22H21BrF2N04 requires 504.0617).
Step 5: Preparation of 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-
oxopyridin- 1 (2H)-yl]methyl} -2-vinylbenzoic acid
Figure imgf000816_0002
816 A 50 mL round bottomed flask equipped with stirbar was charged with the compound from Step 4 (1.3g, 2.6 mmol), NaOH (2.5 mL, 5.2 mmol, 2.5N), tefrahydrofuran (13 mL), methanol (5 mL) and water (5 mL). The mixture was stined for 1 h., acidified with HCl, exfracted with ethylacetate and dried over sodium sulfate. The solution was concenfrated and the product precipitated with methanol to give the title compound as a solid (640 mg, 51%). 1H NMR (400 MHz, CDC13) δ 7.8 (s, IH), 7.6-7.4 (m, 3H), 7.3 (d, J=7.9 Hz, IH), 7.0 (t, J=8.3 Hz, IH), 6.8 (t, J=8.2 Hz, IH), 6.0 (s, IH), 5.6 (d, J=17 Hz, IH), 5.3 (m, 3H), 5.2 (s, 2H), 2.4 (s, 3H) ppm. ES-HRMS m/z 490.0479 (M+H calcd for C23H19BrF2N04 requires 490.0460).
Step 6: Preparation of 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]methyl} -N-methyl-2-vinylbenzamide
Figure imgf000817_0001
A 50 mL round bottomed flask equipped with stirbar and nifrogen inlet was charged with the compound from Step 5 (640 mg, 1.3 mmol) in dimethylformamide (13 mL) was cooled to -10 °C. Isobutylchloroformate (0.17 mL, 1.3 mmol) and 4- methylmorpholine (0.14 mL, 1.3 mmol) were added and stined for 20 min. Methylamine (1.3 mL. 2.6 mmol, 2M in THF) was added and stined for 12 h. The solvent was evaporated and the residue was suspended with methanol to give the title product (657 mg, 79%) as a solid. 1H NMR (400 MHz, CDC13) δ 7.56 (q, J=8.5 and 6.5 Hz, IH), 7.5 (d, J=8 Hz, IH), 7.2 (m, 2H), 6.9 (m, 2H), 6.8 (t, J=7.9 Hz, IH), 6.0 (s, IH), 5.6 (d, J=17.5 Hz, IH), 5.3 (d, J=ll Hz, 3H), 5.2 (s, 2H), 2.9 (s, 3H), 2.3 (s, 3H) ppm. ES-HRMS m/z 503.0780 (M+H calcd for C24H22BrF2N203 requires 503.0776).
Example 798
817
Figure imgf000818_0001
5 - { [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl]methyl} -2- (l,2-dihydroxyethyl)-N-methylbenzamide A 50 mL round bottomed flask equipped with stirbar was charged with the compound Example 797 (above) (500mg, 0.99 mmol), N-methylmorpholine oxide (291 mg, 2.47 mmol), and osmium tefroxide (91 μL, 25% in water, cat.). The mixture was stined for 12 h. and the volatiles were evaporated. The water residue was exfracted with ethylacetate and the organic phase washed with water and dried over sodium sulfate. Half of the volume of the ethyl acetate was evaporated and the product precipitated upon standmgand the solid was filtered to give the title compound (323 mg, 61 %). 1H NMR (400 MHz, -DMS0) δ 8.2 (d, J=4 Hz, IH), 7.6 (q, J=8.3 and 7.6 Hz, IH), 7.4 (d, J=8.0 Hz, IH), 7.25 (t, J=9.5 Hz, IH), 7.13 (t, J=8.7 Hz, IH), 7.09 (d, J=8.5 Hz, IH), 7.05 (s, IH), 6.5 (s, IH), 5.2 (s, 2H), 4.75 (m, 2H), 3.4 (m, 2H), 2.7 (s, 3H), 2.3 (s, 3H) ppm. ES- HRMS m/z 537.0848 (M+H calcd for C24H24BrF2N205 requires 537.0831).
Example 799
Figure imgf000818_0002
3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl- 1 - { [2-(methylthio)pyrimidin-5 - yl]methyl}pyridin-2(lH)-one
Step 1. Preparation of methyl 2-(methylthio)pyrimidine-5-carboxylate
- 818 -
Figure imgf000819_0001
A solution of the sodium salt of 3,3-dimethoxy-2-methoxycarbonylpropen-l-ol (5.0g, 25 mmol), 2-methyl-2-thiopseudourea sulfate (3.5g, 25 mmol) in anhydrous methanol (25 mL) was refluxed for 3 h. under anhydrous conditions. .The reaction mixture was cooled and diluted with ethyl acetate. The reaction mixture was filtered and the residue was washed with ethyl acetate. The filtrate was concenfrated and the residue was purified by flash chromatography (silica gel) using 25% ethyl acetate in hexane to afford the desired product (3.5g, 75%) as a white powder. 1H-NMR (d6-DMSO, 400 MHz) δ 9.0 (s, 2H), 3.92 (s, 3H), 2.58 (s, 3H); ES-HRMS m/z 185.041 (M+H calcd for C7H8N202S requires 185.0379).
Step 2. Preparation of [2-(methylthio)pyrimidin-5-yl]methanol
Figure imgf000819_0002
To a cold suspension of methyl 2-(methylthio)pyrimidine-5-carboxylate (from Step 1) (1.74g, 9.4 mmol) in dichloromethane (20 mL, -70 °C) was added DIBAL (20.8 mL, 20 mmol) dropwise via an addition funnel. The mixture was stined under nifrogen at -70 °C for 1 h. and then at -50 °C for 3 h. The reaction was diluted with dichloromethane (50 mL) and quenched with a suspension of sodium sulfate decahydrate (lOg) in water (50 mL). The slurry was filtered through Celite® and the filfrate was concenfrated. The residue was purified by flash chromatography (silica gel) using 100% ethyl acetate to afford the desired compound (0.7813 g, 39%) as a yellow solid. 1H-NMR (CD3OD, 400 MHz) δ 8.53 (s, 2H), 4.56 (s, 2H), 2.54 (s, 3H); ES-HRMS m/z 157.0409 (M+H calcd for C6H9N2OS requires 157.0430). Step 3. Preparation of 5-(chloromethyl)-2-(methylthio)pyrimidine
Figure imgf000819_0003
To a cold solution of [2-(methylthio)pyrimidin-5-yl]methanol (from Step 2) (0.7813g, 5.0 mmol) in anhydrous dichloromethane (10 mL, 0 °C) was added triethylamine (0.836 mL, 8.2 mmol) followed by the addition of methanesulfonyl chloride - 819 - (0.465mL, 6.0 mmol). The reaction mixture stined at 0 °C under a nitrogen atmosphere for 30 min. then at room temperature for 3.5 h. The reaction was quenched with sodium bicarbonate (5%, 100 mL)) and exfracted with dichloromethane (50 mL). The organic exfracts were concenfrated and the residue was purified by flash chromatography (silica gel) using 15% ethyl acetate in hexane to afford the desired compound (0.720 g, 82%>) as a white solid. 1H-NMR ((CD3OD, 400 MHz) δ 8.60 (s, 2H), 4.64 (s, 2H), 2.54 (s, 3H); ES-HRMS m/z 175.0106 (M+H calcd for C6H7N2C1S requires 175.0091).
Step 4. Preparation of title compound 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methyl-l-{[2-(methylthio)pyrimidin-5-yl]methyl}pyridin-2(lH)-one
To a solution of 5-(chloromethyl)-2-(methylthio)pyrimidine (from Step 3) (0.62g, 3.56 mmol) in anhdrous DMF (10 mL) was added KBr (0.424, 3.56 mmol). After the suspension stined at room temperature for 30 min., 3-bromo-4-[(2,4-difluorobenzyl)oxy]- 6-methylpyridin-2(lH)-one (1.05g, 3.19 mmol) was added followed by NaH (0.102g, 4.25 mmol). The reaction mixture stined at 70 °C under a nifrogen atmosphere for 3.5 h. The solvent was distilled and the residue was washed with water and exfracted with ethyl acetate. The organic exfracts were concenfrated and the residue was purified by reverse phase HPLC using a 10-90%) acetonitrile/water (30 min. gradient) at a 70 mL/min flow rate to afford the desired TFA salt (0.32 g, 15%) as a white powder. The TFA compound was washed with sodium bicarbonate (5%) and exfracted with dichloromethane. The organic exfract was concenfrated to afford the desired compound (0.295g, 18 %) as a yellow solid. 1H-NMR (CD3OD, 400 MHz) δ 8.47 (s, 2H), 7.62 (q, IH, J= 8Hz), 7.03 (m, 2H), 6.51 (s, IH), 5.31 (s, 2H), 5.29 (s, 2H), 2.52 (s, 3H), 2.47 (s, 3H); ES-HRMS m/z 468.0174 (M+H calcd for C19H17N302F2BrS requires 468.0187.
Example 800
Figure imgf000820_0001
820 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-{[2-(methylsulfonyl)pyrimidin-5- yl]methyl} pyridin-2( 1 H)-one
To a solution of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-{[2- (methylthio)pyrimidin-5-yl]methyl}pyridin-2(lH)-one (0.26g, 0.55 mmol) in acetonitrile: water (4:1 v/v, 10 mL) was added MMPP (0.549g, 1.1 mmol). The reaction stined at room temperature for 30 h. The reaction mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated and the residue was purified by reverse phase HPLC using a 10-90%) acetonitrile/water (30 min. gradient) at a 70 mL/min flow rate to afford the desired TFA salt (0.13 g, 38%) as a white powder. 1H-NMR (CD3OD, 400 MHz) δ 8.86 (s, 2H), 7.62 (q, IH, J= 8Hz), 7.02 (m, 2H), 6.56 (s, IH), 5.48 (s, 2H), 5.31 (s, 2H), 3.34 (s, 3H), 2.49 (s, 3H); ES-HRMS m/z 500.0109 (M+H calcd for C19H17N304F2BrS requires 500.0086).
Example 801
Figure imgf000821_0001
l-[(2-aminopyrimidin-5-yl)methyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methylpyridin-2(lH)-one To a cold solution of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-{[2-
(methylsulfonyl) pyrimidin-5-yl]methyl}pyridin-2(lH)-one (Example 800) (0.50g, 1 mmol) in methanol (30mL) was bubbled in ammonia gas. The reaction mixture was stoppered and stined at room temperature over weekend. Concentrated to remove methanol and purified residue by reverse phase HPLC using a 10-90% acetonitrile in water (30 min. gradient) at a 100 mL/min flow rate to isolate two compounds. Each were washed with NaHC03 and exfracted with ethyl acetate. The organic extracts were dried over anhydrous Na2S0 and concenfrated to afford two products, one of which was the desired compound (0.040 g). 1H-NMR (CD3OD, 400 MHz) δ 8.26 (s, 2H), 7.60 (q, IH,
821 J= 8Hz), 7.01 (m, 2H), 6.48 (s, IH), 5.27 (s, 2H), 5.19 (s, 2H), 2.48 (s, 3H); ES-HRMS m/z 437.0415 (M+H calcd for C18H16N402F2Br requires 437.0419).
Example 802
Figure imgf000822_0001
3 -bromo-4- [(2,4-difluorobenzyl)oxy] - 1 -[(2-methoxypyrirnidin-5 -yl)methyι] -6- methylpyridin-2( 1 H)-one
A second compound was isolated from the synthesis detailed in Example 801, above. 1H-NMR (CD3OD, 400 MHz) δ 8.5 (s, 2H), 7.60 (q, IH, J= 8Hz), 7.01 (m, 2H), 6.50 (s, IH), 5.31 (s, 2H), 5.28 (s, 2H), 3.97 (s, 3H), 2.48 (s, 3H); ES-HRMS m/z 452.0440 (M+H calcd for C19H17N303F2Br requires 452.0416).
Example 803
Figure imgf000822_0002
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-{[2-(methylamino)pyrimidin-5- yl]methyl}pyridin-2(lH)-one
To a solution of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-{[2- (methylsulfonyl)pyrimidin-5-yl]methyl}pyridin-2(lH)-one (Example 800) (0.35g, 0.7 mmol) in anhydrous THF (5mL) was added methylamine (1.4 mL of 2M solution in THF).
The reaction mixture was stoppered and stined at room temperature over the 2-3 days.
The reaction mixture became turbid upon stirring. The reaction mixture was diluted in water (15 mL) and chilled in an ice bath. The solid was filtered and washed with ethyl acetate to afford the desired product (0.1074g, 34%> yield) as a white solid. 1H-NMR
(CD3OD, 400 MHz) δ 8.24 (s, 2H), 7.60 (q, IH, J= 8Hz), 7.01 (m, 2H), 6.47 (s, IH), 5.27
822 (s, 2H), 5.18 (s, 2H), 2.87 (s, 3H), 2.48 (s, 3H); ES-HRMS m/z 451.0575 (M+H calcd for C19H17N404F2Br requires 451.0576).
Example 804
Figure imgf000823_0001
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{[2-(dimethylamino)pyrimidin-5-yl]methyl}-6- methylpyridin-2( 1 H)-one
To a solution of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-{[2- (methylsulfonyl)pyrimidin-5-yl]methyl}pyridin-2(lH)-one (0.325g, 0.65 mmol) in anhydrous THF (5mL) was added N,N-dimethylamine (1.6 mL of 2M solution in THF). The reaction mixture was stoppered and stined at room temperature over the weekend. Reaction mixture became turbid upon stirring. The reaction mixture was diluted in water (20 mL) and chilled in an ice bath. The white solid was purified by reverse phase HPLC 10-90% acetonitrile/water (30 min. gradient) at a 70 mL/min flow rate to afford the desired TFA salt (0.40 g, 11%). 1H-NMR (CD3OD, 400 MHz) δ 8.33 (s, 2H), 7.62 (q, IH, J= 8Hz), 7.02 (m, 2H), 6.56 (s, IH), 5.27 (s, 2H), 5.20 (s, 2H), 3.10 (s, 6H), 2.49 (s, 3H); ES-HRMS m/z 465.0732 (M+H calcd for C20H20N4O4F2Br requires 465.0732).
Example 805
Figure imgf000823_0002
5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrimidine-2-carbonitrile
To a suspension of 3-bromo-4-[(2,4-difluorobenzyl) oxy]-6-methyl-l-{[2- (methylsulfonyl)pyrimidin-5-yl]methyl}pyridin-2(lH)-one (Example 800) (1.355 g, 0.27 mmol) in anhydrous DMF (lOmL) was added sodium cyanide (0.132 g, 0.27 mmol).
823 Shortly after beginning the stirring of the suspension at room temperature, the reaction mixture became dark orange. The mixture was stined at room temperature for 1 h. The solvent was distilled and the residue was washed with a water/acetonitrile (1:1 v/v, 30 mL). The residue was chilled and filtered to afford the desired product as an orange solid (0.942 g, 91% yield). 1H-NMR (CD3OD, 400 MHz) δ 8.77 (s, 2H), 7.61 (q, IH, J= 8Hz), 7.02 (m, 2H), 6.55 (s, IH), 5.44 (s, 2H), 5.30 (s, 2H), 2.47 (s, 3H); ES-HRMS m/z 441.0261 (M+H calcd for C19H13N404F2Br requires 447.0263).
Further Non-limiting Compounds
The following compounds can be prepared similarly using the compound (3-bromo-4-
[(2,4-difluorobenzyl)oxy]-6-methyl-l-{[2(methylsulfonyl)pyrimidin-5-yl]methyl}pyridin-
2(lH)-one) from Example 800.
Figure imgf000824_0001
Figure imgf000824_0002
824
Figure imgf000825_0001
The non-limiting compounds in the following table can also be made from the intermediate (3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-{[2(methylsulfonyl) pyrimidin-5-yl]methyl}pyridin-2(lH)-one) by freatment with ZnBrCH2COOt-Bu, hydrolysis and coupling with the appropriate amine.
Figure imgf000825_0002
Figure imgf000825_0004
n = l-3
Example 806
Figure imgf000825_0003
l-{[2-(aminomethyl)pyrimidin-5-yl]methyl}-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methylpyridin-2(lH)-one
825 hi a Fischer-Porter bottle, added a solution of 5-{[3-bromo-4-[(2,4- difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl]methyl}pyrimidine-2-carbonitrile (Example 805 above) (0.40g, 0.89 mmol) in ethyl acetate/ acetic acid ((3:1 v/v) (20 ml)). Flushed the solution with nifrogen then added palladium catalyst (0.18 g, 10% Pd/C). The bottle was sealed and evacuated. The system was purged with hydrogen gas (2x 15 psi) to check for leaks. The reaction was charged with hydrogen (15 psi) and stined at room temperature for 2 h. The system was evacuated and flushed with nifrogen. The reaction was filtered and the catalyst was carefully washed with fresh ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase HPLC using a 10-90% acetonitrile in water (30 min. gradient) at a 100 mL/min flow rate to afford (after lyophilization) the salt of the desired compound (0.35 g, 70% yield). 1H- NMR (CD3OD, 400 MHz) δ 8.71(s, 2H), 7.61 (q, IH, J= 8Hz), 7.02 (m, 2H), 6.55 (s, IH), 5.40 (s, 2H), 5.30 (s, 2H), 4.35, (s, 2H), 2.49 (s, 3H); ES-HRMS m/z 447.0255/453.0543 (M+H calcd for C19H18N402F2Br requires 447.0263).
Example 807
Figure imgf000826_0001
N-l-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrimidin-2-yl)methyl]glycinamide To a cold solution of l-{[2-(aminomethyl)pyrimidin-5-yl]methyl}-3-bromo-4-
[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one (0.1634 g, 0.36 mmol) in anhydrous DMF (5 mL) was added NMM (0.1 mL) followed by the addition of t-Boc glycine-N- hydroxysuccinimide ester (0.0987g, 0.36 mmol). The reaction mixture was stined at room temperature for 2.5 h. The reaction was diluted with water and exfracted with ethyl acetate. The organic exfracts were concenfrated and the Boc group was removed with TFA (2 mL). The residue was diluted with acetonitrile and water and purified by reverse phase HPLC using a 10-90% acetonitrile in water (30 min. gradient) at a 70 mL/min flow rate to afford (after lyophilization) the salt of the desired compound (0.040 g). 1H-NMR (CD3OD, 400 MHz) δ 8.64(s, 2H), 7.61 (q, IH, J= 8Hz), 7.02 (m, 2H), 6.53 (s, IH), 5.38
- 826 - (s, 2H), 5.29 (s, 2H), 4.64, (s, 2H), 3.76 (s, 2H), 2.47 (s, 3H); ES-HRMS m/z 508.0822/ (M+H calcd for C21H21N503F2Br requires 508.0790).
Example
Figure imgf000827_0001
N-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrimidin-2-yl)methyl]-2-hydroxyacetamide
To a cold solution of l-{[2-(aminomethyl)pyrimidin-5-yl]methyl}-3-bromo-4- [(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one (0.130 g, 0.23 mmol) in anhydrous DMF (5 mL) was added NMM (0.06 mL) followed by the addition of acetoxyacetyl chloride (0.026 mL, 0.23 mmol). The reaction mixture was stined cold to room temperature for 3 h. The solvent was removed and the residue was hydrolyzed to the alcohol with 1 N NaOH (3 mL). The reaction mixture was stined at room temperature for 1.5 h. The residue was diluted with acetonitrile and water (TFA) and purified by reverse phase HPLC using a 10-90% acetonitrile in water (30 min. gradient) at a 70 mL/min flow rate to afford (after lyophilization) the salt of the desired compound (0.080 g). The TFA salt was washed with NaHC03 and water and exfracted with MeCl2. The solvent was removed in vacuo to afford the desired product (0.055 g) as a white solid. 1H-NMR (CD3OD, 400 MHz) δ 8.64 (s, 2H), 7.61 (q, IH, J= 8Hz), 7.04 (m, 2H), 6.52 (s, IH), 5.39 (s, 2H), 5.29 (s, 2H), 4.63, (s, 2H), 4.035 (s, 2H), 2.46 (s, 3H); ES-HRMS m/z 509.0621 (M+H calcd for C21H20N4O F2Br requires 509.0630).
The following table of non-limiting compounds can be made from the compound below (Example 807) using similar and/or known methodology.
Figure imgf000827_0002
827
Figure imgf000828_0002
Example 809
Figure imgf000828_0001
5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrimidine-2-carboxamide
To a solution of 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]methyl}pyrimidine-2-carbonitrile (0.20, 0.44mmol) in anhydrous THF (5 mL) was added potassium trimethylsilanolate (0.114 g, 0.88 mmol). The reaction mixture was heated at 60 °C for 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic exfracts were concenfrated and the residue was purified by reverse phase HPLC using a 10-90% acetonitrile in water (30 min. gradient) at a 70 mL/min flow rate. The TFA salt was washed with NaHC03 and water and extracted with ethyl acetate. The solvent was removed in vacuo to afford the desired product (0.020 g) as a white solid. 1H-NMR (CD3OD, 400 MHz) δ8.78 (s, 2H), 7.62 (q, IH, J= 8Hz), 7.02 (m, 2H), 6.55 (s, IH), 5.47 (s, 2H), 5.30 (s, 2H), 2.47 (s, 3H); ES-HRMS m/z 465.0394 (M+H calcd for C19H16N403F2Br requires 465.0368).
828 The following table of non-limiting compounds can be made from the following compound (Example 809) by hydrolysis to the acid and coupling with the appropriate amine.
Figure imgf000829_0001
Figure imgf000829_0004
n = l-3
Example 810
Figure imgf000829_0002
4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3- (trifluoromethyl)benzamide Step 1: Preparation of 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]-3-(trifluoromethyl)benzamide.
Figure imgf000829_0003
4-Hydroxy-6-methyl-2-pyrone (10.0 g, 78.7 mmol) and 4-bromo-2- (trifluoromethyl)aniline (25 g, 104.1 mmol) were suspended in 25 ml of 1,2- dichlorobenzene in a 250 ml, 3-necked, round bottom flask equipped with a J-Kem - 829 - temperature controller probe, a Dean-Stark trap, and a heating mantle. The reaction was heated to 165 °C for 15 min., during which some water and 1,2-dichlorobenzene was collected in the Dean-Stark frap. The reaction was allowed to cool to about 80 °C. Toluene (100 mL) was added to the reaction with stirring. The reaction was allowed to stand for 16 h. at room temperature and a precipitate formed. The precipitate was filtered and washed 3 times with toluene, 3 times with hot water to remove excess pyrone, and dried in vacuo to give a solid (9 g, 33%). 1H NMR (400 MHz, Acetone- 6) δ 8.02 (m, 2H), 7.43 (d, J = 8.19 Hz, IH), 5.93 (m, IH), 5.62 (d, J = 2.42 Hz, IH), 1.91 (s, 3H). LC/MS, tr = 2.54 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 348 (M+H).
Step 2: Preparation of (4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]-3-(trifluoromethyl)benzamide.
Figure imgf000830_0001
4-[3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -3 -
(trifluoromethyl)benzamide (from Step 1) (7.5 g, 21.6 mmol) was stined at 0 °C with 2,4- difluorobenzyl bromide (2.78 ml, 21.6 mmol) and K2C03 (3.5 g, 25.3 mmol) in 80 mL of dimethylformamide. The reaction was warmed to room temperature and stined overnight. 300 mL of water was added into the reaction. The resulting mixture was extracted with ethyl acetate (500 ml). The ethyl acetate solution was dried over MgS04 and evaporated to dryness. The residue was crystallized overnight from ethyl acetate and hexane to afford white solid (7.3 g, 71%). LC/MS, tr = 3.16 min. (5 to 95%> acetonitrile/water over 5 min. at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 474 (M+H). Step 3: Preparation of methyl 4-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]-3-(trifluoromethyl)benzoate.
830 -
Figure imgf000831_0001
Isopropyl magnesium chloride (2 M solution in THF) (7.5 ml, 15 mmol) was added into (4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxoρvridin-l(2H)-yl]-3-
(trifluoromethyl)benzamide (from Step 2) (6 g, 12.6 mmol) in anhydrous THF at room temperature under nifrogen. After 2 h., N-methyl morpholine (2.8 ml, 25 mmol) was added into the reaction and followed by slow addition of methyl chloroformate (1.5 ml, 19 mmol). The reaction was stined at room temperature for 16 h. 300 mL of water was added into the reaction. The resulting mixture was exfracted with ethyl acetate (500 mL).
The ethyl acetate solution was dried over MgS04 and evaporated to dryness to obtain 5.5 g of crude residue. The residue was purified using Gilson preparative LC system to afford white solid (1.5g, 26%). LC/MS, tr = 3.05 min. (5 to 95% acetonitrile/water over 5 min. at
1 ml/min with detection 254 nm, at 50 °C). ES-MS m/z 454 (M+H).
Step 4: Preparation of 4-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- l(2H)-yl]-3-(trifluoromethyl)benzoic acid.
Figure imgf000831_0002
2.5 N NaOH solution (1.5 mL, 3.75 mmol) was added to methyl 4-[4-[(2,4- difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3-(trifluoromethyl)benzoate (from
Step 3) (1.1 g, 2.4 mmol) in 100 mL of 9:1 THF/water at room temperature. The reaction was stined at room temperature for 16 h. 200 mL of water was added into the reaction.
The resulting solution was acidified to pH 2 using concenfrated hydrochloric acid. The resulting suspension was extracted with ethyl acetate (500 mL). The ethyl acetate solution was dried over MgS04 and evaporated to afford white solid (0.85g, 80%). LC/MS, tr =
831 2.68 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml min with detection 254 nm, at 50 °C). ES-MS m/z 440 (M+H).
Step 5: Preparation of 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]-3-(trifluoromethyl)benzoic acid.
Figure imgf000832_0001
N-Bromo succinimide (0.45 g, 2.5 mmol) was added into 4-[4-[(2,4- difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl]-3-(trifluoromethyl)benzoic acid (from Step 4) (0.85 g, 1.9 mmol) in 15 mL of dichloromethane at room temperature. The reaction was stined at room temperature for 16 h. 300 mL of water was added into the reaction. The resulting mixture was extracted with ethyl acetate (2x 500 mL). The combined ethyl acetate solution was dried over MgS04 and evaporated to a dry residue. The residue was crystallized from ethyl acetate and hexane to afford white solid (0.82g, 82%). 1H NMR (400 MHz, CD3OD) δ 8.47 (br s, IH), 8.42 (dd, J= 6.58, 1.47 Hz, IH), 7.62 (m, 2H), 7.04 (m, 2H), 6.65 (s, IH), 5.36 (s, 2H), 2.01 (s, 3H). LC/MS, tr = 2.77 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min with detection 254 nm, at 50 °C). ESMS m/z 518 (M+H). ES-HRMS m/z 518.0017 (M+H calcd for C21H14BrF5N04 requires 518.0021). Step 6: Preparation of the title compound. 2-chloro- 4,6- dimethoxy- 1,3,5- triazine (0.14 g, 0.81 mmol) was added into the mixture of 4-[3-bromo-4-[(2,4- difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3-(trifluoromethyl)benzoic acid (from Step 5) (0.35g, 0.67 mmol) and N-methyl morpholine (0.22 ml, 2.0 mmol) in 10 mL of THF. The mixture was stined for 1 h. Ammonium hydroxide (28%, 1.5 ml) was added into the reaction and continued stirring for additional 16 h. 150 mL of water was added into the reaction and the resulting mixture was extracted with ethyl acetate (2x 300 L). The combined ethyl acetate solution was dried over MgS04 and evaporated to dried residue. The residue was crystallized from ethyl acetate and hexane to afford white solid - 832 - (0.32g, 92%). 1H NMR (400 MHz, CDC13) δ 8.29 (s, IH), 8.09 (app dd, J= 6.72, 1.34 Hz, IH), 7.59 (app dt, J= 8.46, 6.31 Hz, IH), 7.44 (br s, IH), 7.19 (d, J= 8.19 Hz, IH), 6.99 (m, IH), 6.88 (m, IH), 6.17 (s, IH), 5.27 (d, J= 2.55 Hz, 2H), 1.91(s, 3H). LC/MS, tr = 2.54 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 517 (M+H). ES-HRMS m/z 517.0186 (M+H calcd for C21H15BrF5N203 requires 517.0181).
Example 811
Figure imgf000833_0001
4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-methyl-3- (trifluoromethyl)benzamide l-[3-(dimthylamino)propyl]3-ethyl carbodiimide hydrogen chloride (88 mg, 0.46 mmol) was added into the mixture of 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]-3-(trifluoromethyl)benzoic acid (from Example 810, step 5 above) (200 mg, 0.38 mmol), 1- hydroxy benzotriazole (62 mg, 0.46 mmol) and N-methyl morpholine (0.15 ml, 1.36 mmol) in 2.5 ml of dimethylformamide. The mixture was stined for 1 h. Methylamine (2 M solution in THF) (2.5 ml, 0.5 mmol) was added into the mixture and continued stirring for 16 h. 150 ml of water was added into the reaction and white precipitate came out. Filtered and dried to obtain the white solid (155 mg, 77 %). 1H NMR (400 MHz, CDC13) δ 8.21 (s, IH), 8.01 (app d, J= 8.05 Hz, IH), 7.59 (app dt, J = 8.46, 6.45 Hz, IH), 7.42 (m, IH), 7.18 (d, J= 8.19 Hz, IH), 6.97 (m, IH), 6.90 (m, IH), 6.16 (s, IH), 5.26 (br s, 2H), 2.90 (d, J= 4.56 Hz, 3H), 1.90(s, 3H). LC/MS, tr = 2.66 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min with detection 254 nm, at 50°C). ES- MS m/z 531 (M+H). ES-HRMS m/z 531.0354 (M+H calcd for C22H17BrF5N203 requires 531.0337).
Example 812 - 833 -
Figure imgf000834_0001
4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N,N-dimethyl- 3-(trifluoromethyl)benzamide l-[3-(dimthylamino)propyl]3-ethyl carbodiimide hydrogen chloride (76 mg, 0.4 mmol) was added into the mixture of 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]-3-(trifluoromethyl)benzoic acid (from Example 810, step 5 above) (175 mg, 0.33 mmol), 1- hydroxy benzotriazole (55 mg, 0.4 mmol) and N-methyl morpholine (0.15 ml, 1.36 mmol) in 2.5 ml of dimethylformamide. The mixture was stined for 1 h. Dimethylamine (2 M solution in THF) (2.5 ml, 0.5 mmol) was added into the mixture and continued stirring for 16 h. 150 ml of water was added into the reaction and white precipitate came out. Filtered and dried to obtain the white solid (135 mg, 75 %). 1H NMR (400 MHz, CDC13) δ 7.86 (app d, J= 1.47 Hz, IH), 7.72 (app dd, J= 6.44, 1.48 Hz, IH), 7.58 (app dt, J= 8.46, 6.45 Hz, IH), 7.30 (m, IH), 6.95 (m, IH), 6.85 (m, IH), 6.11 (s, IH), 5.24 (br s, 2H), 3.12 (s, 3H), 2.99 (s, 3H), 1.94(s, 3H). LC/MS, tr = 2.70 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min with detection 254 nm, at 50 °C). ES-MS m/z 545 (M+H). ES-HRMS m/z 545.0503 (M+H calcd for C23H19BrF5N203 requires 545.0494).
Example 813
Figure imgf000834_0002
5- [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -4- methylpyrimidine-2-carboxamide
Step 1: Preparation of 4-methyl-2-(methylthio)pyrimidin-5-amine. - 834 -
Figure imgf000835_0001
Ethyl 4-methyl-2-(methylthio)pyrimidine-5-carboxylate (prepared similarly to the compound of Example 799, step 1) (5 g, 23.6 mmol) was added into the 100 ml of 9:1 THF/water. NaOH solution (2.5 N, 10 ml, 25 mmol) was added into the reaction and the reaction was stined for 16 h. The solvent was evaporated to a dry residue to which 75 ml of acetonitrile was added, followed by addition of 50 ml of tert-butanol and diphenylphosphoryl azide (8.5 ml, 40 mmol). The mixture was heated to 90 °C for 16 h. The white suspension was filtered and the filtrate was evaporated to dried residue. The residue was added 300 ml of water and 500 ml of ethyl acetate. The organic layer was isolated and exfracted several times with 500 ml of ethyl acetate. The combined ethyl acetate solution was dried over MgS04 and evaporated to a dry residue. This residue was dissolved in minimal amount of dichloromethane and loaded onto a bed of activated alumina and eluted with 3 L of dichloromethane. The dichloromethane solution was evaporated to a dry residue. HCl (4N) in 1,4-dioxane (50 ml) was added into the residue with stirring. After 3 h., diethyl ether (200 ml) was added to the reaction. The reaction stood for 1 h., and was filtered to isolate the formed solid. The solid was dissolved in 20 ml of water and was basified with saturated sodium bicarbonate solution. The basic solution was exfracted with ethyl acetate (2x 300 ml). The combined ethyl acetate solution was dried over MgS04 and evaporated to an amber oil (2.2 g, 60%). LC/MS, tr = 0.58 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min with detection 254 nm, at 50 °C). ES-MS m/z 156 (M+H).
Step 2: Preparation of 4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[4-methyl-2- (methylthio)pyrimidin-5-yl]pyridin-2(lH)-one.
Figure imgf000835_0002
4-methyl-2-(methylthio)pyrimidin-5-amine (from Step 1) (2 g, 12.9 mmol) was added into 5-(l-hydroxy-3-oxobutylidene)-2,2-dimethyl-l,3-dioxane-4,6-dione (Monatshefte fuer - 835 - Chemie, 113, 1213-6, 1982) (3.5 g, 15.3 mmol) in 100 ml of 1,4- dioxane. The mixture was heated to 100 °C for 16 h. The reaction was cooled to room temperature and HCl in 1,4-dioxane (4N, 10 ml, 40 mmol) was added to the reaction. After 1 h. of stirring, the reaction was evaporated to a dry residue. The residue was added into 2,4-difluorobenzyl bromide (1.9 ml, 15 mmol) and potassium carbonate (lOg, 72.5 mmol) in 30 ml of dimethylformamide. The reaction was stined for 16 h. To the reaction was added 150 ml of water and the resulting mixture was extracted with ethyl acetate (2x 300 ml). The combined ethyl acetate solution was dried over MgS0 and evaporated to a crude brown oil (4.5g, 89%). LC MS, tr = 2.53 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min with detection 254 nm, at 50 °C). ES-MS m/z 390 (M+H).
Step 3: Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[4- methyl-2-(methylsulfonyl)pyrimidin-5-yl]pyridin-2(lH)-one.
Figure imgf000836_0001
N-bromo succinimide (3 g, 16.9 mmol) was added into a 100 mL dichloromethane solution of 4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[4-methyl-2-(methylthio) pyrimidin-5- yl]pyridin-2(lH)-one (from Step 2) (5.5 g, 14.1 mmol). The reaction was stined for 1 h. Water (30 mL) and magnesium monoperoxyphthalate hexahydrate (17.5g, 35 mmol) was then added. The reaction was stined vigorously for 16 h. 300 ml of water was added into the reaction and the resulting mixture was extracted with dichloromethane (2x 700 ml). The combined organic solution was dried over MgS04 and evaporated to crude residue. The crude residue was purified using Waters Prep 2000 system to obtain the compound (l.lg, 16%). 1H NMR (400 MHz, CDC13) δ 8.59 (s, IH), 7.54 (app dt, J= 8.46, 6.45 Hz, IH), 6.93 (m, IH), 6.85 (m, IH), 6.25 (s, IH), 5.25 (s, 2H), 3.35 (s, 3H), 2.42 (s, 3H), 1.93(s, 3H). LC/MS, tr = 2.36 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 500 (M+H). ES-HRMS m/z 500.0090 (M+H calcd for C19H17BrF2N304S requires 500.0086).
836 Step 4: Preparation of 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]-4-methylpyriιnidine-2-carbonitrile.
Figure imgf000837_0001
Potassium cyanide (0.24 g, 3.7 mmol) was added into 3-bromo-4-[(2,4- difluorobenzyl)oxy]-6-methyl-l-[4-methyl-2-(methylsulfonyl)pyrimidin-5-yl]pyridin-
2(lH)-one (from Step 3) (0.97 g, 1.93 mmol) was added into 15 ml of dimethylformamide. The reaction was stined for 16 h. 200 ml of water was added into the reaction and the resulting mixture was extracted with ethyl acetate (2x 300 ml). The combined organic solution was dried over MgS04 and evaporated to a dry residue. The crude residue was crystallized from methanol and ether to obtain the compound (0.8g, 92%). lR NMR (400 MHz, CDC13) δ 8.52 (s, IH), 7.59 (app dt, J= 8.46, 6.45 Hz, IH), 6.97 (m, IH), 6.88 (m, IH), 6.21 (s, IH), 5.28 (s, 2H), 2.41 (s, 3H), 1.95(s, 3H). LC/MS, tr = 2.65 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 447 (M+H). ES-HRMS m/z 447.0257 (M+H calcd for C19H14BrF2N402 requires 447.0263).
Step 5: Preparation of 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]-4-methylpvrimidine-2-carboxylic acid.
Figure imgf000837_0002
5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylpyrimidine-2-carbonitrile (from Step 4) (0.7 g, 1.56 mmol) was added into 20 ml of methanol and 20 ml of hydrochloric acid. The reaction was heated to 80 °C for 2 h. The reaction was cooled to room temperature and 300 ml saturated sodium carbonate solution was added. The mixture was stined for 1 h. and neutralized with aqueous HCl.
837 The mixture was exfracted with ethyl acetate (2x 300 ml). The combined organic solution was dried over MgS0 and evaporated to a dry residue. The crude residue was crystallized from methanol, ethyl acetate and hexane to obtain the compound (0.45g, 62%). 1H NMR (400 MHz, CDOD) δ 8.75 (s, IH), 7.62 (m, IH), 7.00 (m, 2H), 6.67 (s, IH), 5.36 (s, 2H), 2.40 (s, 3H), 2.03(s, 3H). LC MS, tr = 2.16 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min with detection 254 nm, at 50 °C). ES-MS m/z 466 (M+H). ES-HRMS m/z 466.0206 (M+H calcd for C19H15BrF2N304 requires 466.0209). Step 6: Preparation of the title compound. 2-chloro-4,6-dimethoxy-l,3,5-triazine
(0.10g, 0.56 mmol) was added into a mixture of 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]- 6-methyl-2-oxopyridin-l(2H)-yl]-4-methylpyrimidine-2-carboxylic acid (from Step 5) (0.22g, 0.47 mmol) and N-methyl morpholine (0.22 ml, 2.0 mmol) in 10 ml of tetrahydrofuran. The mixture was stined for 1 h. Ammonium hydroxide (28%, 1.5 ml) was added into the reaction and stirring continued for additional 16 h. Water (150 ml) was added to the reaction and the resulting mixture was extracted with ethyl acetate (2x 300 ml). The combined ethyl acetate solution was dried over MgS04 and evaporated to dryness. The resulting residue was crystallized from methanol, dichloromethane and hexane to afford yellow needle-like solid (0.16g, 73%). 1H NMR (400 MHz, CDOD) δ 8.66 (s, IH), 7.59 (m, IH), 6.96 (m, 2H), 6.57 (s, IH), 5.33 (s, 2H), 2.39 (s, 3H), 2.01(s, 3H). LC MS, tr = 2.16 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 465 (M+H). ES-HRMS m/z 465.0363 (M+H calcd for C19H16BrF2N403 requires 465.0368).
Example 814
Figure imgf000838_0001
4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]benzyl carbamate - 838 - 3 -bromo-4- [(2,4-difluorobenzyl)oxy] - 1 - [4-(hydroxymethyl)phenyl] -6- methylpyridin-2(lH)-one (500 mg, 1.15 mmol) was stined with trichloroacetyl isocyanate (2.4 ml, 1.27 mmol) in 5 ml of methylene chloride at room temperature. After 1 h., the reaction was quenched with ammonium hydroxide solution and was stined vigorously at room temperature for 1 h. The reaction was then poured into 100 ml of cold water and the resulting precipitate was filtered, washed with diethyl ether and dried in vacuo to give a white solid (425 mg, 77%). 1H NMR (400 MHz, DMSO-d6) δ 7.66 (app q, J= 7.92 Hz, IH), 7.45 (d, J= 8.19 Hz, 2H), 7.33 (dt, J= 9.87, 2.15 Hz, IH), 7.24 (d, J= 8.19 Hz, 2H), 7.16 (dt, J= 8.12, 2.19 Hz, IH), 6.81 - 6.38 (br s, 2H), 6.64 (s, IH), 5.31 (s, 2H), 5.03 (s, 2H), 1.92 (s, 3H); LC/MS, tr = 2.41 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min, at 254 nm, at 50 °C), ES-MS m/z 479 (M+H). ES-HRMS m/z 479.0387 (M+H calcd for C21H18BrF2N204 requires 479.0413).
Example 815
Figure imgf000839_0001
N-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]benzyl}-2- hydroxy-2-methylpropanamide
Step 1: Preparation of methyl 4-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin- l(2H)-yl)benzoate.
Figure imgf000839_0002
Methyl 4-(4-hydroxy-6-methyl-2-oxopyridin-l(2H)-yl)benzoate (see Example 202, step 1) (10.0 g, 38.6 mmol) was stined at room temperature with N-bromosuccinimide
(6.87 g, 38.6 mmol) in 80 ml of NN-dimethylformamide and 100 ml of methylene chloride. After stirring as a slurry overnight, the precipitate was filtered, washed with
- 839 - diethyl ether, and dried in vacuo to give a white solid (10.38 g, 80%). 1H NMR (400 MHz, DMSO-d6) δ 11.53 (s, IH), 8.05 (d, J = 8.46 Hz, 2H), 7.39 (d, J = 8.45 Hz, 2H), 6.11 (s, IH), 3.86 (s, 3H), 1.81 (s, 3H); LC/MS, tr = 1.69 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min, at 254 nm, at 50 °C), ES-MS m/z 338 (M+H). ES-HRMS m/z 338.0044 (M+H calcd for C14H13BrN04 requires 338.0022).
Step 2: Preparation of methyl 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-
2-oxopyridin- 1 (2H)-yl]benzoate.
Figure imgf000840_0001
Methyl 4-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-l(2H)-yl)benzoate (from
Step 1) (10.25 g, 30.3 mmol) was stined vigorously with 2,4-difluorobenzylbromide (3.89 ml, 30.3 mmol) and K2C03 (6.28 g, 45.4 mmol) in 50 ml of NN-dimethylformamide at room temperature for 1.5 h. The reaction was then poured into 1 L of cold water and the resulting precipitate was filtered, washed with water and diethyl ether, and dried in vacuo to yield a white solid (10.13 g, 72%). See Example 202.
Step 3: Preparation of 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin-l(2H)-yl]benzoic acid.
Figure imgf000840_0002
See the protocol detailed in Example 203.
Step 4: Preparation of 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl]benzamide. - 840 -
Figure imgf000841_0001
This compound can be synthesized according to the protocol detailed in Example
244.
Step 5: Preparation of l-[4-(aminomethyl)phenyl]-3-bromo-4-[(2,4- difluorobenzyl)oxy] -6-methylpyridin-2( 1 H)-one.
Figure imgf000841_0002
4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]benzamide (from Step 4) (1.82 g, 4.05 mmol) was added to a solution of 2 M borane- dimethylsulfide complex in tetrahydrofuran (6.07 ml, 12.15 mmol) in 12 ml tetrahydrofuran at 0 °C. The reaction was allowed to warm to room temperature with stirring. After stirring for 4 days, ice chips were added to quench the reaction. The reaction was exfracted 2 times with ethyl acetate, which removed some non-polar impurities. The aqueous layer was then exfracted 5 times with n-butanol and the combined organic layers were evaporated. The resulting solid was washed with diethyl ether and dried in vacuo to give a white solid (865 mg, 49%). 1H NMR (400 MHz, DMSO- 6) δ 7.71 (app q, J= 7.99 Hz, IH), 7.50 (d, J= 8.26 Hz, 2H), 7.38 (dt, J= 9.87, 2.15 Hz, IH), 7.25 - 7.19 (m, 3H), 6.67 (s, IH), 5.36 (s, 2H), 3.82 (s, 2H), 2.45 (br s, 2H), 1.97 (s, 3H); LC/MS, tr = 2.03 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 435 (M+H). ES-HRMS m/z 435.0508 (M+H calcd for C20H18BrF2N2O2 requires 435.0514).
Step 6: Preparation of the title compound.
- 841 - l-[4-(aminomethyl)phenyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin- 2(lH)-one (from Step 5) (400 mg, 0.92 mmol) was dissolved in 8 ml of NN- dimethylformamide and 5 ml of methylene chloride. 2-hydroxyisobutyric acid (96 mg, 0.92 mmol) was added, followed, in order, by EDCI (225 mg, 1.15 mmol), 1- hydroxybenzotriazole (155.4 mg, 1.15 mmol) and triethylamine (257 μl, 1.84 mmol). The reaction was stined at room temperature overnight. The methylene chloride was evaporated and the reaction was then poured into 200 ml of cold water. The resulting solid was filtered and washed with water and diethyl ether and dried in vacuo to give a white solid (276 mg, 53%). 1H ΝMR (400 MHz, DMSO- ) δ 8.30 (t, J= 6.38 Hz, IH), 7.67 (app q, J= 7.82 Hz, IH), 7.35 - 7.26 (m, 3H), 7.18 - 7.14 (m, 3H), 6.62 (s, IH), 5.42 (s, IH), 5.31 (s, 2H), 4.31 (d, J = 6.24 Hz, 2H), 1.91 (s, 3H), 1.26 (s, 6H); LC/MS, tr = 2.36 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min, at 254 nm, at 50°C), ESMS m/z 521 (M+H). ES-HRMS m/z 521.0876 (M+H calcd for C24H24BrF2Ν204 requires 521.0882).
Example 816
Figure imgf000842_0001
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[4-(l,2-dihydroxyethyl)phenyl]-6-methylpyridin-
2(lH)-one Step 1: Preparation of 4-hydroxy-6-methyl-l-(4-vinylphenyl)pyridin-2(lH)-one.
Figure imgf000842_0002
5-(l-hydroxy-3-oxobutylidene)-2,2-dimethyl-l,3-dioxane-4,6-dione (43.1 g, 189 mmol) and 4-vinylaniline (15.0 g, 125.9 mmol) were dissolved in 500 ml 1,4-dioxane and heated to reflux for 45 min. Methane sulphonic acid (8.17 g, 125.9 mmol) was added and refluxed for 1 h. The reaction was -allowed to cool to room temperature and stand
842 overnight. The reaction was added to an amount of water and exfracted with ethyl acetate and n-butanol. The combined organic layers were dried over MgS04 and evaporated. The resulting oil was triturated with ethyl acetate/diethyl ether to obtain a solid. The resulting precipitate was filtered and washed with ethyl acetate, acetonitrile, acetone and diethyl ether and dried in vacuo to give a tan solid (8.57 g, 20% yield). 1H NMR (300 MHz, DMSO-</6) δ 10.65 (br s, IH), 7.59 (d, J= 8.46 Hz, 2H), 7.18 (d, J= 8.26 Hz, 2H), 6.82 (dd, J= 17.72, 10.88 Hz, IH), 5.92 (d, J= 17.52 Hz, IH), 5.92 (d, J= 2.41 Hz, IH), 5.58 (d, J= 2.61 Hz, IH), 5.36 (d, J= 10.88 Hz, IH), 1.87 (s, 3H); LC/MS, tr = 1.85 min. (5 to 95% acetonitrile/water over' 5 min. at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 228 (M+H). ES-HRMS m/z 228.1023 (M+H calcd for Cι4Hι4N02 requires 228.1019).
Step 2: Preparation of 3-bromo-4-hydroxy-6-methyl-l-(4-vinylphenyl)pyridin- 2(lH)-one.
4-hydroxy-6-methyl-l-(4-v Binrylphenylι)pyridin-2(lH)-one (from Step 1) (8.0 g, 35.2 mmol) was stined at room temperature with N-bromosuccinimide (6.26 g, 35.2 mmol) in 75 ml of NN-dimethylformamide. After stirring overnight, the reaction was poured into cold water. The resulting precipitate was filtered, washed with water and diethyl ether, and dried in vacuo to give a white solid (7.99 g, 74%). 1H ΝMR (300 MHz, DMSO- ) δ 11.41 (br s, IH), 7.62 (d, J= 8.46 Hz, 2H), 7.23 (d, J= 8.45 Hz, 2H), 6.82 (dd, J= 17.72, 11.08 Hz, IH), 6.09 (s, IH), 5.94 (d, J= 17.52 Hz, IH), 5.37 (d, J= 11.08 Hz, IH), 1.88 (s, 3H); LC/MS, tr = 1.90 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 306 (M+H). ES-HRMS m/z 306.0103 (M+H calcd for C14H13BrΝ02 requires 306.0124).
Step 3: Preparation of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(4- vinylphenyl)pyridin-2(lH)-one.
843 -
Figure imgf000844_0001
3-Bromo-4-hydroxy- -methyl-l-( (from Step 2) (7.75 g, 25.3 mmol) was stined vigorously with 2,4-difluorobenzylbromide (3.25 ml, 25.3 mmol) and K2C03 (5.25 g, 38.0 mmol) in 40 ml of NN-dimethylformamide at room temperature overnight. The reaction was then poured into 1 L of cold water and the resulting precipitate was filtered, washed with water and ethyl acetate, and dried in vacuo to yield a white solid (2.52 g, 23%). 1H ΝMR (300 MHz, DMSO- /6) δ 7.71 (app q, J = 7.65 Hz, IH), 7.64 (d, J= 8.26 Hz, 2H), 7.38 (dt, J= 9.97, 2.42 Hz, IH), 7.27 (d, J= 8.26 Hz, 2H), 7.23 (app t, J= 8.26 Hz, IH), 6.84 (dd, J= 17.72, 11.07 Hz, IH), 6.69 (s, IH), 5.96 (d, J= 17.72 Hz, IH), 5.40 - 5.37 (m, 3H), 1.99 (s, 3H); LC/MS, tr = 2.96 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 432 (M+H). ES-HR/MS m/z 432.0390 (M+H calcd for C21H17BrF2Ν02 requires 432.0405).
Step 4: Preparation of the title compound. 3-Bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(4-vinylphenyl)ρyridin-2(lH)- one (from Step 3) (500 mg, 1.16 mmol) was stined as a suspension in 13 ml acetone and 3.25 ml water. 4-methylmorpholine N-oxide (311.6 mg, 2.66 mmol) was added, followed by 4% w/w water solution of Os04 (0.1 ml, 1.3 mol%) and the reaction was stined at room temperature overnight. The reaction was diluted with 150 ml of ethyl acetate, washed with water, dried over MgS04 and evaporated to near dryness. The resulting precipitate was filtered, washed with diethyl ether and dried in vacuo to yield a white solid (297 mg, 55%). 1H NMR (300 MHz, DMSO-rf6) δ 7.71 (app q, J= 7.92 Hz, IH), 7.52 - 7.48 (m, 2H), 7.38 (dt, J= 9.87, 2.42 Hz, IH), 7.24 - 7.20 (m, 3H), 6.67 (s, IH), 5.40 (d, J = 5.43 Hz, IH), 5.36 (m, 2H), 4.80 (t, J= 5.74 Hz, IH), 4.63 (dd, J= 10.07, 5.44 Hz, IH), 3.51 (t, J= 5.74 Hz, 2H), 1.96 (s, 3H); LC/MS, tr = 2.24 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min, at 254 nm, at 50°C), ES-MS m/z 466 (M+H). ES-HR/MS m/z 466.0451 (M+H calcd for C21H19BrF2N04 requires 466.0460).
Exmaple 817 - 844 -
Figure imgf000845_0001
3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4-methyl-N- (hydroxyl) benzamide Step 1: Preparation of 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2- oxopyridin- 1 (2H)-yl] -4-methyl-N-(tetrahydro-2H-pyran-2-
yloxy)benzamide.
Figure imgf000845_0002
The title compound of Step 1 was prepared by a procedure similar to the one described for the compound of Example 487, where 0-(tefrahydro-2H-pyran-2- yl)hydroxylamine was used as the amine instead of ethanolamine to yield the desired product (350 mg, 56%). 1H NMR (300 MHz, CDC13) δ 10.0-9.86 (m, IH), 7.71-7.67 (m, IH), 7.63-7.58 (m, IH), 7.55 (br s, IH), 7.32 (d, J = 8.06 Hz, IH), 7.04-6.98 (m, IH), 6.96-6.89 (m, IH), 6.23 (s, IH), 5.31 (s, 2H), 5.10 (br s, IH), 4.17-4.0 (m, 2H), 3.71-3.59 (dd, J= 11.28, 26.78 Hz, 2H), 2.12 (s, 3H), 1.94 (s, 3H), 1.85-1.61 (m, 2H), 1.32-1.27 (m, 2H); LC MS, tr = 2.67 min. (5 to 95%> acetonitrile/water over 5 min. at 1 ml/min with detection 254 nm, at 50°C); ES-MS m/z 519 (M+H).
Step 2: Preparation of the title compound. 3-[3-chloro-4-[(2,4- difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4-methyl-N-(tetrahydro-2H-pyran- 2-yloxy)benzamide (from Step 1) (250 mg, 0.48 mmol) was stined at room temperature with 12 N HCl (0.12 ml, 1.44 mmol) in 5 ml of dioxane for 2.0 h. Upon quenching the - 845 - reaction with water, a precipitate formed and was collected. The precipitate was purified by dissolving it in ethyl acetate and triturating with diethyl ether. The precipitate was collected and dried to yield a white solid (50 mg, 24%). 1H NMR (300 MHz, CD3OD) δ 7.79 (d, J= 7.93 Hz, IH), 7.66 (app q, J = 6.72, IH), 7.52-7.51 (m, 2H), 7.07-7.02 (m, 2H), 5.35 (s, 2H), 2.07 (s, 3H), 2.00 (s, 3H); LC MS, tr = 2.24 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min with detection 254 nm, at 50°C); ES-MS m/z 435 (M+H).
Example 818
Figure imgf000846_0001
3 - [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -4-methyl-
N-(tefrahydro-2H-pyran-2-yloxy) benzamide
The title compound was prepared by a procedure similar to the one described for the compound of Example 487, where 0-(tefrahydro-2H-pyran-2-yl)hydroxylamine was used as the amine to yield the desired product (800 mg, 62%). XR NMR (400 MHz, CDC13) δ 10.12-9.96 (m, IH), 7.62-7.56 (m, IH), 7.51 (br s, IH), 7.26(m, IH), 6.98-6.89 (m, IH), 6.86-6.83 (m, IH), 6.15 (s, IH), 5.25 (s, 2H), 5.06 (d, J= 14.24 Hz, IH), 4.09- 3.98 (m, 2H), 3.58 (dd, J= 30.09, 11.55 Hz, 2H) 2.04 (d, J= 9.94 Hz, 3H), 1.87 (s, 3H), 1.83-1.70 (m, 2H), 1.62-1.50 (m, 3H); LC/MS, tr = 2.73 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min with detection 254 nm, at 50°C); ES-MS m/z 563 (M+H). This compound can be converted to the N-OH analogue by hydrolysis with HCl.
Example 819
846
Figure imgf000847_0001
N- {3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridfn- 1 (2H)-yl]-4- methylbenzyl} -2-hydroxyacetamide Step 1: Preparation of l-[5-(aminomethyl)-2-methylphenyl]-3-bromo-4-[(2,4- difluorobenzyl)oxy] -6-methylpyridin-2( 1 H)-one hydrochloride.
Figure imgf000847_0002
The title compound of Step 1 was prepared by the addition of 3 -[3 -bromo-4- [(2,4- difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzamide (2.0 g, 4.32 mmol) to a 0 °C solution of 1 M BH3-THF (9.1 ml, 9.10 mmol). THF (20 ml) was added and the mixture was heated to reflux. No reaction was observed after 3 h. 2 M BH3-DMS (10 ml) was added and the reaction mixture became completely soluble. After 2 additional hours, 6 N HCl was added to reaction. The organic solvent was removed in vacuo. The aqueous layer was made basic with 2.5 N NaOH and exfracted with dichloromethane. The aqueous layer separated and the dichloromethane was removed in vacuo. The residue was taken up in acetonitrile. 1.0 N HCl in diethethyl ether was added to the acetonitrile mixture and the resulting precipitate was collected on a filter pad to yield the desired product (1.2 g, 53%). 1H NMR (400 MHz, CD3OD) δ 7.65 (app q, J= 6.56 Hz, IH), 7.50 (s, IH), 7.49 (s, IH), 7.24 (s, IH), 7.07-7.02 (m, 2H), 6.68 (s, IH)), 5.36 (s, 2H), 4.13 (s, 2H), 2.05 (s, 3H), 2.00 (s, 3H); LC/MS, tr = 1.96 min. (5 to 95% acetonifrile/water over 5 min. at 1 ml/min with detection 254 nm, at 50°C); ES-MS m/z 450 (M+H).
847 Step 2: Preparation of the title compound. l-[5-(aminomethyl)-2-methylphenyl]- 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)-one hydrochloride (from Step 1) (500 mg, 1.03 mmol), glycolic acid, (94.3 mg, 1.24 mmol), EDC (192.5 mg, 1.24 mmol), HOBt (135.1 mg, 1.24 mmol), and N-methyl morpholine (0.45 ml, 4.12 mmol) were stined together in DMF (10 ml) for 3 h. The reaction was quenched with saturated ammonium chloride (aq.) and extracted with dichloromethane. The dichloromethane layer was separated and dried over Νa S04. The solvent was removed in vacuo. The residue was taken up in ethyl acetate and triturated with diethyl ether. The precipitate was collected on a filter pad to yield a white solid (325 mg, 62%). 1H NMR (400 MHz, CDC13) δ 7.59 (app q, J= 6.98 Hz, IH), 7.28 (m, 2H), 6.98-6.94 (m, 2H), 6.84 (t, J= 8.19 Hz, IH), 6.14 (br s, IH), 5.21 (s, 2H), 4.46 (dd, J = 9.67, 5.91 Hz, IH), 4.24 (dd, J= 11.00, 5.24 Hz, IH), 3.88 (dd, j = 16.11, 11.14 Hz, 2H), 3.00 (m, 3H), 1.98 (s, 3H), 1.90 (s, 3H); LC/MS, tr = 2.35 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min with detection 254 nm, at 50 °C); ES-MS m/z 507 (M+H).
Example 820
Figure imgf000848_0001
3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N,4- cyclopropylbenzamide
The title compound was prepared by a procedure similar to the one described for the compound of Example 487, where cyclopropylamine was used as the amine to yield the desired product (0.74 g, 57%). 1H NMR (400 MHz, CDC13) δ 7.70 (dd, J= 7.92, 1.75 Hz, IH), 7.59 (app q, J= 8.59 Hz, IH), 7.50 (d, J= 1.88, IH), 7.31 (d, J= 8.19, IH), 6.95 - 6.90 (m, 2H), 6.78 (dt, J= 8.73, 2.55 Hz, IH), 6.13 (s, IH), 6.18 (s, IH), 5.24 (s, 2H), 2.68-2.62 (m, IH), 2.06(s, 3H), 1.89 (s, 3H), 0.71-0.59 (m, 2H), 0.49-0.40 (m, 2H);
848 - LC MS, tr = 2.59 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml min with detection 254 nm, at 50 °C); ES-MS m/z 503 (M+H).
Example 821
Figure imgf000849_0001
3 - [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -N-ethyl-4- methylbenzamide
The title compound was prepared by a procedure similar to the one described for Example 487, where ethylamine was used as the amine to yield the desired product (0.25 g, 19%). 1H NMR (400 MHz, CDC13) δ 7.80 (dd, J= 8.06, 1.48Hz, IH), 7.59 (app q, J = 8.46 Hz, IH), 7.51 (br s, IH), 7.33 (d, J= 7.92, IH), 6.96 - 6.93 (m, IH), 6.85-6.79 (m, IH), 6.71-6.91 (m, IH), 6.14 (s, IH), 5.20 (s, 2H), 3.30 (m, 2H), 2.06 (s, 3H), 1.89 (s, 3H), 1.10 (t, J= 7.25 Hz, 3H); LC/MS, tr = 2.45 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min with detection 254 nm, at 50 °C); ES-MS m/z 491 (M+H).
Example 822
Figure imgf000849_0002
N-allyl-3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylbenzamide
The title compound was prepared by a procedure similar to the one described for Example 487, where allylamine was used as the amine to yield the desired product (0.55 g, - 849 - 42%). 1H NMR (400 MHz, CDC13) δ 7.76 (dd, J= 6.18, 1.75 Hz, IH), 7.60 (app q, J = 8.46 Hz, IH), 7.54 (d, J= 1.75, IH), 7.28 (d, J= 8.06, IH), 6.96-6.90 (m, 2H), 6.81 (dt, J = 8.60, 2.55 Hz, IH), 6.14 (s, IH), 5.83-5.74 (m, IH), 5.20 (s, 2H), 5.05 (dd, J = 10.20, 1.34 Hz, IH), 5.03 (dd, J= 10.20, 1.34 Hz, IH), 3.93-3.78 (m, 2H), 2.05 (s, 3H), 1.89 (s, 3H); LC/MS, tr = 2.65 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min with detection 254 nm, at 50 °C); ES-MS m/z 503 (M+H).
Example 823
Figure imgf000850_0001
3 - [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -N-butyl-4- methylbenzamide
The title compound was prepared by a procedure similar to the one described for Example 487, where n-butylamine was used as the amine to yield the desired product (0.65 g, 50%). 1H NMR (400 MHz, CDC13) δ 7.77 (dd, J= 7.79, 1.75 Hz, IH), 7.61 (app q, J= 8.46 Hz, IH), 7.49 (d, J= 1.61, IH), 7.34 (d, J= 8.06, IH), 6.97 - 6.93 (m, IH), 6.83 (dt, J= 8.73, 2.42 Hz, IH), 6.55, (t, J = 5.37 Hz, IH) 6.12 (s, IH), 5.21 (s, 2H), 3.28 (m, 2H), 2.07 (s, 3H), 1.90 (s, 3H), 1.45 (m, 2H), 1.32 (m, 2H), 0.90 (t, J= 7.25Hz, 3H); LC/MS, tr = 2.76 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml min with detection 254 nm, at 50 °C); ES-MS m/z 519 (M+H).
- 850 - Example 824
Figure imgf000851_0001
3 - [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -N-isobutyl-4- methylbenzamide
The title compound was prepared by a procedure similar to the one described in Example 487, where isobutylamine was used as the amine to yield the desired product (0.60 g, 46%). 1H NMR (400 MHz, CDC13) δ 7.75 (dd, J= 7.92, 1.75 Hz, IH), 7.60 (app q, J= 8.46 Hz, IH), 7.51 (d, J= 1.75, IH), 7.33 (d, J = 8.06, IH), 6.98 - 7.93 (m, 2H), 6.84 (dt, J= 8.73, 2.42 Hz, IH), 6.65 (t, J= 5.77 Hz, IH), 6.71 (s, IH), 6.12 (s, IH), 5.21 (s, 2H), 3.13 (m, 2H), 2.07 (s, 3H), 1.90 (s, 3H), 1.79, (m, IH), 0.88 (dd, J= 6.71, 1.21) Hz ; LC/MS, tr = 2.76 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml min with detection 254 nm, at 50 °C); ES-MS m/z 519 (M+H).
Example 825
Figure imgf000851_0002
(2E)-4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]but-2- enoic acid. To a sluny of the ester from Example 460(940 mg, 2.1 mmol), in THF (4 mL) at r.t, was added a 2.5 N NaOH solution (1.0 mL). The resulting homogeneous solution was allowed to stir at r.t. overnight. The reaction was quenched by dropwise addition of a 3 N
- 851 HCl solution until the pH was ~ 4. The solvent was concentrated by passing N gas over the reaction to give a white precipitate. The reaction was filtered to give a white solid which was washed with diethyl ether and dried to give an off-white solid (757 mg, 86%) of >95% purity. 1H-NMR (DMSOd6/300 MHz) δ 7.68 (app quar, J = 8.7 Hz, IH), 7.36 (dt, J = 10.5, 2.4 Hz, IH); 7.23-7.10 (m IH); 6.90 (dt, J = 15.9, 4.2 Hz, IH), 6.60 (s, IH), 5.45 (d, J = 15.6 Hz, IH), 5.32 (s, 2H), 4.90-4.80 (m, 2H), 2.32 (s, 3H). ES-HRMS m/z 414.0126 (M + H calcd for C17H15BrF2N04 = 414.0147).
Example 826
Figure imgf000852_0001
(2E)-4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxoρyridin-l(2H)-yl]-N-(2- hydroxy-2-methylpropyl)but-2-enamide.
The title compound above was prepared similar to the method as described for the synthesis for the compound of Example 659. Starting from the acid described in Example 825 (300 mg, 0.72 mmol) and the appropriate amino alcohol, the desired product was obtained in 95% purity as a tan colored solid (225 mg, 55%> yield). 1H-NMR (DMSOd6/300 MHz) δ 7.92 (t, J = 6.0 Hz, IH), 7.68 (q, J = 8.7 Hz, IH); 7.37 (dt, J = 10.5, 2.4 Hz, IH); 7.20 (dt, J = 10.5, 1.8 Hz, IH); 6.71 (dt, J = 15.3, 4.2 Hz, IH), 6.61 (s, IH), 5.82 (d, J = 15.6 Hz, IH), 5.31 (s, 2H), 4.82 (d, J = 2.4 Hz, 2H), 3.07 (d, J = 6.9 Hz, IH), 2.61 (d, J = 6.0 Hz, 3H), 2.37 (s, 3H), 1.04 (s, 6H). ES-HRMS m z 485.0875 (M + H calcd for C21H24BrF2N204 = 485.0882).
Example 827
852
Figure imgf000853_0001
{5-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[(2E)-4-hydroxybut-2-enyl]-6-oxo-l,6- dihydropyridin-2-yl}methyl acetate The title compound was prepared by adding cw-butene-l,4-diol (100 μl, 1.1 mmol) to a slimy of the compound from Example 832 (0.43g, 1 mmol) in 5 ml of benzene. Grubbs catalyst, tricyclohexylphosphine[l,3-bis(2,4,6-trimethylphenyl)-4,5- dihydroimidazol-2-ylidene][benzylidine]ruthenium(rV)chloride, (0.015g, 0.05 mmol) was added to the reaction. The mixture was then heated to 60 °C. After 3 h., the reaction was about 50-60% complete. Additional diol (200 ml) and Schrock catalyst (0.015 g) were added and the reaction was maintained at 60 °C for 12 h. The reaction was quenched by addition of water. The layers were separated and the organic layer was extracted with CH2C12 (4X). The organics were combined, dried, and concenfrated in vacuo. The crude residue was purified by flash chromatography on a 35 g Michelle-Miller column. Eluting with hexanes-ethyl acetate (2:1 → 0:100) gave the desired product (0.21g, 46%) as a tan solid. 1H-NMR (DMSOd6/500 MHz) δ 7.64 (q, J = 8.5 Hz, IH); 7.33 (dt, J = 10.5, 2.5 Hz, IH); 7.16 (dt, J = 8.5, 2.0 Hz,lH), 6.66 (s, IH), 5.69-5.64 (m, IH), 5.51 (dt, J = 16.0, 4.5 Hz, IH), 5.32 (s, 2H), 5.01 (s, 2H), 4.61 (d, J = 4.5 Hz, IH), 3.89 (d, J = 3.5 Hz, IH), 2.12 (s, 3H). ES-HRMS m z 458.0392 (M + H calcd for C19H19BrF2N05 = 458.0409).
Example 828
Figure imgf000853_0002
(2E)-4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-(2- hydroxy-2-methylpropyl)but-2-enamide.
853 The titled compound was prepared using a similar method to that described in Example 659. Starting from the acid described in Example 825 (315 mg, 0.76 mmol), the desired product was obtained in 90-95% purity as an off-white solid (250 mg, 68% yield). 1H-NMR (DMSOd6/300 MHz) δ 7.62 (q, J = 6.3 Hz, IH); 7.31 (dt, J = 8.1, 2.1 Hz, IH); 7.17-7.10 (m, IH), 6.59 (dt, J = 15.6, 3.9 Hz, IH); 6.55 (s, IH), 6.37 (d, J = 11.4 Hz, IH), 5.26 (s, 2H), 4.78 (d, J = 3.0 Hz, 2H), 3.53-3.50 (m, , 4H), 3.45-3.43 (m, 4H), 2.34 (s, 3H). ES-HRMS m/z 483.0700 (M + H calcd for C21H22BrF2N204 = 483.0726).
Example 829
Figure imgf000854_0001
Methyl-3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-l(2H)- yl]-4-methylbenzoate. A solution of the compound of Example 653 (1.4g, 2.6 mmol) was slurried in methanol (13 mL). To this solution was added solid potassium carbonate (770mg, 5.7 mmol). The mixture was stined at room temperature. After 1.5 h., the reaction was poured into a flask containing deionized water. The resulting solid was filtered through a fritted funnel. The solid was dried under vacuum to give the desired product as an off- white solid (950 mg, 74% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.00 (dd, J = 8.1, 1.8 Hz, IH), 7.79 (d, J = 1.5 Hz, IH), 7.72 (app q, J = 6.9 Hz, IH), 7.59 (d, J = 8.1 Hz, IH), 7.40 (dt, J = 9.9, 2.4 Hz, IH), 7.26-7.19 (m, IH), 6.75 (s, IH), 5.41 (s, 2H), 3.87 (s, 3H), 3.85 (AB quar, J = 15.6 Hz, 2H), 2.06 (s, 3H). ES-HRMS m/z 536.0484 (M+H calcd for C24H21NF2Br06 requires 536.0515).
Example 830
854
Figure imgf000855_0001
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(2-methyl-5-vinylphenyl)pyridin-2(lH)- one Step 1-Preperation of -l-(5-bromo-2-methylphenyl) -4-hydroxy-6-methylpyridin-
2(lH)-one.
Figure imgf000855_0002
To a 500 mL round-bottom flask containing 2-methyl, 5-bromo aniline (2.79g, 15 mmol) was added 5-(l-hydroxy-3-oxobutylidene)-2,2-dimethyl-l,3-dioxane-4,6-dione (5.0 g, 20.7 mmol). This mixture was then slurried in toluene (75 mL) along with a catalytic amount of p-toluenesulfonic acid and heated to reflux under a nifrogen environment for 2 h. The reaction was then allowed to cool to r.t., resulting in formation of a precipitate. The reaction mixture was further diluted with 50 ml ether and the solid was isolated by filtration of the reaction mixture. The solid was washed with diethyl ether to give the desired product (3.39 g, 77% yield) as a white solid. lR NMR (400 MHz, CDC13) δ 7.51 (dd, J= 8.60, 2.19 Hz, IH), 7.37 (d, J= 2.01 Hz, IH), 7.31 (d, J=8.23, IH), 5.89 (dd, J=1.35, 0.97 Hz, IH), 5.53 (d, J=2.53 Hz, IH), 1.86 (s,3H), 1.76 (s,3H), ES- LCMS m/z 294 (M+H calcd for C13H13BrN02 , requires 294). Step 2: Preparation of l-(5-bromo-2-methylphenyl) -4-[(2,4-difluorobenzyl)oxy]-
6-methylpyridin-2(lH)-one.
Figure imgf000855_0003
- 855 hi a 500 ml round-bottom flask, the compound from Step 1 (12.6g, 43.0 mmol) was dissolved in 180 ml of DMF. To this mixture was added anhydrous potassium carbonate (1.91g, 13.83 mmol) followed by addition of 2,4-difluorobenzyl bromide (6.9 g, 50 mmol). The reaction was allowed to stir at room temperature overnight. The reaction was then poured into 300 ml of ice water. The aqueous solution was extracted with ethyl acetate (4x 100 mL) and combined. The organic layer was washed with brine (2x 100 mL), dried and concentrated in vacuo. The resulting solid was triturated with diethyl ether and filtered to yield a tan solid, which was used in the next step without further purification.
Step 3: Preparation of 4-[(2,4-difluorobenzyl)oxy] -6-methyl-l-(2-methyl-5- vinylphenyl)pyridin-2( 1 H)-one.
Figure imgf000856_0001
4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(2-methyl-5-vinylphenyl)pyridin-2(lH)- one was prepared by reacting the compound of Step 2 (3.0g, 7.15 mmol) with vinyltributyl tin (2.64 ml, 9 mmol) via a Stille coupling procedure, similar to that described for Example 477 (step 3) to yield the desired product (4 g, 54 % yield) after filtration through a plug of silica. The crude material was then used as is in Step 4. Step 4: The title compound was prepared by reacting 4-[(2,4-difluorobenzyl)oxy] -
6-methyl-l-(2-methyl-5-vinylphenyl)pyridin-2(lH)-one (1.4g, 3.8 mmol) and N- bromosuccinimide (0.67g, 3.8 mmol) as described in Example 477 Step 4. Recrystallization from ethyl acetate-hexanes gave the desired product (1.8 g, ~99%). 1H NMR (400 MHz, CDC13) δ 7.66 (q, J=8.47 Hz, IH), 7.46 (dd, J=7.70, 0.77 Hz, IH), 7.36 - 7.30 (m, 3H), 7.17 (dt, J=7.71, 2.69,Hz, IH), 6.72 - 6.65 (m, 2H), 5.84 (d, J=19.41 Hz, - 856 - IH), 5.31(s, IH), 5.25(d, J=10.97 Hz, IH), 1.91(s, 3H), 1.88(s, 3H). ES-HRMS m/z 446.0560 (M+H calcd for C22H19BrF2N02 requires 446.0562).
Example 831
Figure imgf000857_0001
3 -bromo-4- [(2,4-difluorobenzyl)oxy] -l-[5-(l ,2-dihydroxyethyl)-2-methylphenyl] -6- methylpyridin-2( 1 H)-one
The title compound was prepared by dihydroxylation of the compound from Example 830 (1.0 g, 2.47 mmol) as described in the procedure in Example 478. 1H NMR (400 MHz, CDC13) δ 7.67 (q, J= 8.46 Hz, IH), 7.36 - 7.30 (m, 3H), 7.17 (ddt, J= 8.59, 2.59, 1.10 Hz, IH), 7.04 (d, J= 13.74, IH), 6.66 (s,lH), 5.31 (s,2H), 5.28-5.24 (m, IH), 4.72-4.60 (m,lH), 4.56-4.50 (m, IH), 3.42-3.38 (m, 2H), 1.90 (s, 3H), 1.84, (s 3H). ESHRMS m/z 480.0611 (M+H calcd for C22H21BrF2N04 , requires 480.0617).
Example 832
Figure imgf000857_0002
{l-allyl-5-bromo-4-[(2,4-difluorobenzyl) oxy]-6-oxo-l,6-dihydropyridin-2-yl}methyl acetate Step 1: Preparation of (4-hydroxy-2-oxo-2H-pyran-6-yl)methyl acetate.
857
Figure imgf000858_0001
A sluny of 3-(2,2-dimethyl-4-oxo-4H-l,3-dioxin-6-yl)-2-oxopropyl acetate (Example 653 Step 1) (5 g, 20 mmol) in 30 mL of toluene was heated to reflux under nifrogen environment. LC-MS of the reaction mixture showed 100 % conversion to the desired product after 2 h. Heating was stopped and the mixture was allowed to cool to room temperature and stand overnight. The resulting precipitate was filtered and washed with 15 ml of a 1:1 ether / hexane mixture and dried under house vacuum to give desired product (2.95g, 80%) as off-white solid. 1H NMR (400 MHz, CDC13) δl0.62(s, IH), 6.16 (s, IH), 5.28 (s, IH), 4.80 (s, 2H), 2.07 (s, 3H). ES-LCMS m/z 185 (M+H calcd for C8H905 requires 185)
Step 2: Synthesis of l-allyl-4-hydroxy-6-oxo-l,6-dihydropyridin-2-yl)methyl acetate.
Figure imgf000858_0002
In a 100 ml round bottom flask the compound from Step 1 (1.0 g, 5.45 mmol) and allylamine (0.259g, 4.54 mmol) were mixed together and dissolved in 27 ml of water. The reaction mixture was heated to reflux under a nitrogen atmosphere for 1.5 h. The reaction was then allowed to cool to room temperature. The solvent was partially concentrated under high vacuum to give a white precipitate. The solid was obtained by filfration through a fritted funnel to yield a (0.625g, 52 % yield) white solid. 1H NMR (400 MHz, CDC13) δ 10.62 (s, IH), 5.94 (d, J= 2.4 Hz, IH), 5.88 - 5.78 (m, IH), 5.58 (d, J= 3.0 Hz, IH), 5.06 (dd, J = 10.4, 1.4 Hz, IH), 4.92(s, 2H), 4.82 (dd, J= 17.3, 1.7 Hz, IH), 4.48- 4.46 (m, IH), 2.06 (s, 3H). ES-LCMS m/z 224 (M+H calcd for CπH14N04, requires 224). Step 3: Preparation of (l-allyl-5-bromo-4-hydroxy-6-oxo-l,6-dihydropyridin-2- yl)methyl acetate.
- 858 -
Figure imgf000859_0001
The title compound was prepared by bromination of the product from Step 2 (4.01g, 18 mmol) as outlined previously in the preparation described in Example 477. The crude product was triturated with diethyl ether to give after filtration the desired product (5.4 g, 99%) as a white solid. 1H NMR (400 MHz, CDC13) δ 11.46 (s, IH), 6.14 (s, IH), 5.81 - 5.91 (m, IH), 5.09(dd, J =11.87, 1.75 Hz, IH), 4.96 (s, 2H), 4.85(dd, J =18.03, 1.31, IH), 4.55-4.56(m, 2H), 2.07(s,3H). ES-LCMS m/z 302 (M+H calcd for CπH13BrN04, requires 302). Step 4: Preparation of {l-allyl-5-bromo-4-[(2,4-difluorobenzyl) oxy]-6-oxo-l,6- dihydropyridin-2-yl}methyl acetate.
In a 250 ml round bottom flask l-allyl-5-bromo-4-hydroxy-6-oxo-l,6- dihydropyridin-2-yl)methyl acetate (5.4 g, 17.94 mmol) was dissolved in 90 mL of DMF. To this reaction was added anhydrous potassium carbonate (2.97g, 21.52 mmol) followed by addition of 2,4-difluorobenzyl bromide (2.3 ml, 17.94 mmol). The reaction mixture was allowed to stir at room temperature and nifrogen atmosphere for 2.5 h. The reaction was worked up by pouring it into 1 L of ice water. A white fluffy precipitate resulted. The solid was isolated by filtering the reaction mixture through a fritted funnel to give the desired product (7.5g, 98%) as a white solid. 1H NMR (400 MHz, CDC13) δ 7.62 (q, J = 8.33 Hz, IH), 7.32 (dt, J= 9.87, 2.46, Hz, IH), 7.15 (dt, J = 8.3, 2.2, Hz, IH), 6.64 (s,lH), 5.90 - 6.82 (m, IH), 5.30 (s, 2H), 5.11 (dd, J=10.7, 1.3 Hz, IH), 5.03 (s, IH), 4.88 (dd, J= 17.3, 1.5, Hz, IH), 4.60 (d, J= 4.8Hz, 2H), 2.09 (s, 3H). ES-MS m/z 428 (M+H calcd for C18H17BrF2N04 requires 428).
- 859 -
Example 833
Figure imgf000860_0001
1 -allyl-3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-(hydroxymethyl)pyridin-2( 1 H)-one
The title compound was prepared by slunying the above acetate (7.27g, 17 mmol), Example 832, Step 4 in 100 ml of methanol. To this slurry was added potassium carbonate (4.69g, 34 mmol). The mixture was allowed to stir at room temperature for 2 h. The reaction was worked up by partially concentrating methanol to approximately 60 ml and cooling the mixture to ~ 5 °C in ice bath. Filtration of the reaction gave a white solid, which was washed with water, to give the desired product. (6.3g, 96% yield). XR NMR (400 MHz, CDC13) δ 7.62 (q, J= 8.1 Hz, IH), 7.31 (dt, J= 10.6, 2.6, Hz, IH), 7.14 (dt, J= 8.8, 2.20, Hz, IH), 6.57 (s,lH), 5.92 - 6.83 (m, IH), 5.27 (s, 2H), 5.09 (d, J = 10.7, Hz, IH), 4.86 (d, J= 6.8, Hz, IH), 4.63 (s, 2H), 4.24 (s, 2H). ES-HRMS m/z 386.0122 (M+H calcd for C16H15BrF2N03 , requires 386.0198).
Example 834
Figure imgf000860_0002
l-allyl-5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxo-l,6-dihydropyridin-2-yl}methyl phenylcarbamate
860 The title compound was prepared by dissolving l-allyl-3-bromo-4-[(2,4- difluorobenzyl)oxy]-6-(hydroxymethyl)pyridin-2(lH)-one (0.27g, 0.7 mmol), in a 50 ml round bottom flask, with 2 ml of pyridine. To this mixture was slowly added phenyl isocyanate (0.11 mL, 1 mmol) and the reaction was maintained at room temperature. Within 10 min. the reaction was judged complete by LC-MS analysis. The reaction was poured into ice water (-25 ml) and diluted with ethyl acetate. The layers were separated and the aqueous layer was exfracted with ethyl acetate (2x 25 ml). The organics were combined, dried, and concenfrated in vacuo. The crude product was purified by flash chromatography. Elution with hexanes-ethyl acetate (3:1 → 0:100) gave the desired product (0.135g, 39%) as a white crystalline solid. 1H NMR (400 MHz, CDC13) δ 7.60 (q, J= 8.1 Hz, IH), 7.44 (d, J= 7.7, 2H), 7.30-7.23 (m, 3H), 7.09 (dt, J= 7.74, 2.5 Hz, IH), 7.00 (t, J= 7.7\ Hz, IH), 6.71 (s, IH), 5.94 - 5.87 (m, IH), 5.29(s, 2H), 5.14-5.1 l(m, 3H), 4.91 (d, J = 17.0, Hz, IH), 4.66 (d, J = 4.5, Hz, IH). ES-HRMS m/z 505.0572 (M+H calcd for C23H20BrF2N2O4.requires 505.0569).
Example 835
Figure imgf000861_0001
l-allyl-5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxo-l,6-dihydropyridin-2-yl}methyl thien-3 -ylethylcarbamate
The title compound was prepared from l-allyl-3-bromo-4-[(2,4- difluorobenzyl)oxy]-6-(hydroxymethyl)pyridin-2(lH)-one (0.27 g, 0.7 mmol) and 3-(2- isocyanato-l-methylethyl)thiophene (0.13 g, 0.84 mmol) as described above in the preparation described in Example 834. 1H NMR (400 MHz, CDC13) δ 7.63-7.60(m, IH), 7.30-7.27 (m, 2H), 7.13 (dt, J = 8.4, 2.1 Hz, IH), 6.93-6.28 (m, 2H), 6.60 (s,lH), 5.94-
- 861 - 5.82 (m, IH), 5.26 (s, 2H), 5.11 (d, J= 11.1 Hz, IH), 4.98 (s, 2H), 4.90 (d, J= 17.8 Hz, 1H),4.60 (dd, J= 4.63, 0.9 Hz, 2H), 3.23-3.18 (m,2H), 2.90 (t, J= 7.3 Hz, 2H) 2.85 (t, J= 6.8 Hz, 2H). ES-HRMS m/z 539.0454 (M+H calcd for C23H22BrF2N204S, requires 539.0446).
Example 836
Figure imgf000862_0001
5-{[3-bromo-4-[(2,4-difluoro enzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-N- methyl-2-furamide Step 1 : Preparation of the title compound. To a room temperature suspension of 5-
{[3-bromo-4-[(2,4-difluoroberιzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]memyl}-2-furoic acid (Example 715, step 1) (1.00 g, 2.20 mmol) in THF (20.0 mL) was added 2-chloro-4,6 dimethoxy-1,3,5 triazine (476 mg, 2.70 mmol) and N-methyl morpholine (NMM, 763 mg, 7.28 mmol) sequentially. The resulting solution was matured for 2 h. and then treated with a 2.0 M solution of methylamine (THF, 4.0 mL, 8.0 mmol). The resulting suspension was allowed to continue for 1 additional h. The reaction mixture was diluted with 400 mL of brine and extracted with ethyl acetate (3x 400 mL). The organic exfracts were separated, Na2S04 dried, and concenfrated in vacuo and the resulting residue was subjected to a series of washes: 100 mL water (45 °C), 100 mL diethyl ether, 100 mL ethyl acetate/hexanes (1:1). The final remaining solid was the desired compound (591 mg, 54 %). 1H NMR (300 MHz, rf4-MeOH) δ 7.59-7.49 (m, IH), 7.70-7.69 (m, 3H), 6.45 (s, 2H), 5.33 (s, 2H), 5.20 (s, 2H), 3.60 (s, 3H), 2.61 (s, 3H); LC/MS C-18 column, tr = 2.81 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min with detection 254 nm, at 50 °C). ES-MS m/z 467 (M+H). ES-HRMS m/z 467.0415 (M+H calcd for C20H18BrF2N2O4 requires 467.0413).
Example 837
862 -
Figure imgf000863_0001
5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-N-(2- hydroxyethyl)-2-furamide Step 1 : Preparation of the title compound was performed by an identical method as that described for Example 836 by substitution of ethanolamine instead of methylamine. The solid desired title compound was achieved (611 mg, 56 %). ES-HRMS m/z 497.0490 (M+H calcd for C21H20BrF2N2O5 requires 497.0518).
Example 838
Figure imgf000863_0002
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-{[5-(morpholin-4-ylcarbonyl)-2- furyl]methyl}pyridin-2(lH)-one Step 1: The title compound was made by an identical method as that described in
Example 836 but with substitution of 4-morpholine for the methylamine. The solid desired title compound was achieved (506 mg, 44 %). ES-HRMS m/z 523.0644 (M+H calcd for C23H22BrF2N205 requires 523.0675).
Example 839
- 863
Figure imgf000864_0001
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-{[5-(piperazin-l-ylcarbonyl)-2- furyl]methyl}pyridin-2( 1 H)-one
Step 1 : Preparation of the title compound was completed by an identical method as that described for Example 836 with substitution of 1,4 piperazine instead of methylamine. The solid desired title compound was achieved (348 mg, 30 %). ES-HRMS m/z 522.0818 (M+H calcd for C23H23BrF2N304 requires 522.0835).
Example 840
Figure imgf000864_0002
3-bromo-4-[(2,4-difluoroberιzyl)oxy]-l-{[5-(hydroxymethyl)-2-fiιryl]methyl}-6- methylpyridin-2(l H)-one Step 1 : Preparation of the title compound. To a room temperature suspension of 5-
{[3-bromo-4-[(2,4-difluoroberιzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-2-furoic acid (Example 715, Step 1) (600.8 g, 1.32 mmol) in THF (8.0 mL) was added a solution of borane-dimethyl sulfide adduct (THF, 2.0 M, 3.0 mL, 6.0 mmol). The reaction was warmed to 58 °C and maintained for 12 h. The reaction was quenched with a saturated aqueous solution of ammonium chloride (300 mL) and exfracted with ethyl acetate (3x 200 mL). The organic exfracts were separated, Na2S04 dried, and concenfrated in vacuo and the resulting residue was subjected to normal phase silica chromatography ethyl acetate/hexanes/methanol (57:38:5) to furnish the desired title compound (218 mg, 54 %>). 1H NMR (400 MHz, d -DMF) δ 7.75 (app q, J = 7.3 Hz, IH), 7.30 (app t, J = 8.0 Hz,
- 864 - IH), 7.19 (app t, J = 7.0 Hz, IH), 6.60 (s, IH), 6.27 (s, IH), 6.25 (s, IH), 5.35 (s, 2H), 5.32 (s, 2H), 5.30 (s, IH), 4.40 (s, 2H), 2.61 (s, 3H); LC/MS C-18 column, tr = 2.70 min. (5 to 95%o acetonitrile/water over 5 min. at 1 ml/min with detection 254 nm, at 50 °C). ESMS m/z 440 (M+H). ES-HRMS m/z 440.0291 (M+H calcd for C19H17BrF2N04 requires 440.0304).
Example 841
Figure imgf000865_0001
3 -bromo-4- [(2,4-difluorobe - 1 - [5 -(hydroxymethyl)-2-furyl] -6-methylpyridin-
2(lH)-one
Step 1 : Preparation of the title compound was done from 5-[3-bromo-4-[(2,4- difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-2-furoic acid (Example 716, Step
3) by an identical method as protocol established for Example 840. The title compound was achieved as a solid (325 mg, 67 %). ES-HRMS m/z 426.0104 (M+H calcd for C18H15BrF2N04 requires 426.0147).
Example 842
Figure imgf000865_0002
5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-(2- hydroxyethyl)-2-furamide
Step 1 : Preparation of the title compound was performed by an identical method as that described for Example 716 with substitution of ethanolamine for ammonium
865 hydroxide. The solid title compound was isolated (591 mg, 54 %>). ES-HRMS m/z 483.0343 (M+H calcd for C20H18BrF2N2O5 requires 483.0362).
Example 843
Figure imgf000866_0001
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[5-(morpholin-4-ylcarbonyl)-2- furyl]pyridin-2( lH)-one
Step 1 : The title compound was prepared by an identical method as that described for Example 716, with substitution of 4-morpholine for ammonium hydroxide. The solid desired title compound was achieved (563 mg, 49 %). ES-HRMS m/z 509.0525 (M+H calcd for C22H20BrF2N2O5 requires 509.0518).
Example 844
Figure imgf000866_0002
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[5-(piperidin-l-ylcarbonyl)-2- furyl]pyridm-2(lH)-one
Step 1 : The title compound was made by an identical method as that described for Example 716 by substituting piperdine for ammonium hydroxide. The solid desired title compound was achieved (211 mg, 42 %). ES-HRMS m/z 507.0707 (M+H calcd for C23H22BrF2N204 requires 507.0726).
866 Example 845
Figure imgf000867_0001
4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3,5- difluorobenzoic acid
Step 1: Preparation of the title compound. To a room temperature solution of 4- [3- bromo-4-[(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -3,5- difluorobenzaldehyde (943 mg, 2.01 mmol) in acetone (10.0 mL) was added 1.5 mL of a 3.0 M solution of Jones Reagent (4.5 mmol). The resulting dark brown solution was stined for 0.5 h. until complete consumption of starting material was indicated by LC-MS analysis. At this time a gray solid began forming. After an additional 0.5 h., the solid was collected and washed with 10 mL of EtOAc. The resulting solid was the desired product, (787 mg, 81 %). Note: the compound showed signs of trace chromium contamination. 1H NMR (400 MHz, d4-MeOR) δ 7.80 (br s, 2H), 7.63 (br s, IH), 7.08 (br s, 2H), 6.70 (br s, IH), 5.40 (s, 2H), 2.15 (s, 3H); LC/MS C-18 column, tr = 2.60 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min with detection 254 nm, at 50 °C). ES-MS m/z 486 (M+H). ES-HRMS m/z 485.9973 (M+H calcd for C20H13BrF4NO4 requires 485.9959).
Example 846
Figure imgf000867_0002
4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3,5- difluorobenzamide
867 Step 1: Preparation of the title compound. To a room temperature solution of 4-[3- bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3,5-difluorobenzoic acid (311.0 mg, 0.637 mol) in THF (6.0 mL) was added 2-chloro-4,6 dimethoxy-1,3,5 triazine (175 mg, 1.00 mmol) and N-methyl morpholine (NMM, 184 mg, 1.82 mmol) sequentially. The resulting solution was matured for 2 h. and then freated with ammonium hydroxide saturated aqueous solution (0.50 ml). The resulting suspension rested for 1 additional hour. The reaction mixture was diluted with 100 mL of brine and exfracted with ethyl acetate (3x 100 mL). The organic exfracts were separated, Na2S04 dried, and concenfrated in vacuo and the resulting residue was subjected to a series of washes: 20 mL water (45 °C) and 20 mL diethyl ether. The final remaining solid was the desired compound (226 mg, 73 %). 1H NMR (400 MHz, d4-DMF) δ 7.92 (d, J = 8.3 Hz, 2H), 7.80 (app q, J= 7.3 Hz, 2H), 7.40 (br s, IH), 7.35 (dt, J= 8.3, 2.4 Hz, IH), 7.20 (app t, J = 7.3 Hz, IH), 6.80 (s, IH), 5.49 (s, 2H), 2.20 (s, 3H); LC/MS C-18 column, tr = 2.40 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml min with detection 254 nm, at 50°C). ES- MS m/z 485 (M+H). ES-HRMS m/z 485.0098 (M+H calcd for C20H14BrF4N2O3 requires 485.0118).
Example 847
Figure imgf000868_0001
3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{2,6-difluoro-4-[(lE)-3-hydroxyprop-l- enyl]phenyl}-6-methylpyridin-2(lH)-one Step 1: Preparation of the title compound. To a room temperature solution of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6- difluoro-4-vinylphenyl)-6- methylpyridin-2(lH)-one (489.0 mg, 1.04 mmol) in benzene (10.0 mL) was added, sequentially, (2E)-but-2-ene-l,4-diol (0.298g, 3.38 mmol) and Grubb's catalyst (trichlorohexylphosphine [1,3 bis-(2,4,6 trimethylphenyl)-4,5-dichlorohydroimidazol- 2ylidene]-ruthehenium (IV) dichloride (Sourced by Strem Chemicals, Catalog # 44-777-0)
868 (30.0 mg, 0.0353 mmol). The resulting biphasic mixture was heated to 56 °C and subsequent addition of ruthenium catalyst was made over a 4 h. period of time (25.0 mg, 0.0294 mmol). Complete consumption of starting material, determined by LC-MS analysis, was seen after a total reaction time of 8 h. The reaction was diluted with saturated brine (200 ml) and water (200 mL). This mixture was then exfracted with ethyl acetate (3x 200 mL) and the organic exfracts were separated, Na2S04 dried, and concentrated in vacuo to a volume of approximately 10 mL at which time a solid precipitate formed (310 mg, 60%). lR NMR (400 MHz, 4-MeOH) δ 7.62 (app q, J= 8.0 Hz, IH), 7.30 (d, J = 8.8 Hz, 2H), 7.04 (app t, J= 9.0 Hz, 2H), 6.70-6.64 (m, 2H), 6.58 (dt, J=16.6, 4.5 Hz, IH), 5.36 (s, 2H), 4.28 (app d, J= 4.6 Hz, 2H), 2.12 (s, 3H); LC/MS C-18 column, tr = 2.87 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 498 (M+H). ES-HRMS m/z 498.0303 (M+H calcd for C22H17BrF4N03 requires 498.0322).
Example 848
Figure imgf000869_0001
(2E)-3-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3,5- difluorophenyl}prop-2-enyl carbamate Step 1: Preparation of the title compound. To a room temperature solution of 3- bromo-4-[(2,4-difluorobenzyl)oxy]-l-{2,6-difluoro-4-[(lE)-3-hydroxyprop-l- enyl]phenyl}-6-methylρyridin-2(lH)-one (189 mg, 0.379 mmol) in CH2C12 (5.0 mL) was added a solution of trichloroacetyl isocyanate (toluene, 0.53 M, 0.91 mL, 0.48 mmol). The resulting solution was stined for 1 h. until complete consumption of starting material (LC- MS analysis). The reaction mixture was then directly applied to A1203 (0.5 g of activity type I) and the slurry was matured for 3 h. At this time, the A1203 plug was flushed with EtOAc/MeOH (95:5) and the resulting mother liquor was concenfrated to a residue that was subjected to Si02 chromatography using EtOAc/hexanes/MeOH (6:3.8:0.2) to furnish - 869 - the title compound as a white solid (190 mg, 94 %). 1H NMR (400 MHz, CDC13) δ 7.59 (app q, J= 7.9 Hz, IH), 7.06 (d, J= 8.3 Hz, 2H), 6.96 (app dt, J= 8.5, 6.0 Hz, IH), 6.85 (app dt, J= 10.0, 3.5 Hz, IH), 6.55 (d, J= 16.0 Hz, IH), 6.35 (dt, J= 16.0, 5.8 Hz, IH), 6.12 (s, IH), 5.24 (s, 2H), 4.73 (d, J = 6.0, 1.2 Hz, 2H), 2.03 (s, 3H); LC/MS C-18 column, tr = 2.90 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 541 (M+H). ES-HRMS m/z 541.0406 (M+H calcd for C23H18BrF4N204 requires 541.0381).
Ecample 849
Figure imgf000870_0001
2-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxoρyridin-l(2H)-yl]-3,5- difluorophenyl} -2-hydroxyethyl carbamate
Step 1: Preparation of the title compound was made from the compound of Example 668 by an identical method as protocol established for Example 848. The solid desired title compound was achieved (283 mg, 74 %). ES-HRMS m/z 545.0321 (M+H calcd for C22H18BrF4N205 requires 545.0330).
Example 850
Figure imgf000870_0002
l-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3,5- difluorophenyl} -ethyl 1 ,2-dicarbamate
870 Step 1: Preparation of the title compound was made from the compound of
Example 668 by an identical method as protocol established for Example 848, substituting
2.5 equivalents of the trichloroacetyl isocyanate. This gave the title compound as a solid
(368 mg, 82 %). ES-HRMS m/z 588.0356 (M+H calcd for C23H19BrF4N306 requires 588.0388).
Example 851
Figure imgf000871_0001
{5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-2- furyl}methyl carbamate
Step 1: Preparation of the title compound was made from the compound of Example 841 by an identical method as protocol established for Example 848. The solid desired title compound was achieved (211 mg, 75 %). ES-HRMS m/z 469.0192 (M+H calcd for C19H16BrF2N205 requires 469.0205).
Examle 852
Figure imgf000871_0002
3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl- 1 -(3-oxo- 1 ,3-dihydro-2-benzofuran-5- yl)pyridin-2(lH)-one
Step 1: Preparation of the title compound was made from 5-(l-hydroxy-3- oxobutylidene)-2,2-dimethyl-l,3-dioxane-4,6-dione and 6-aminophthalide by the method described in steps 1 and 2 of Example 716, yielding a solid (1.10 g, 53 % over two steps). ES-HRMS m/z 462.0149 (M+H calcd for C21H15BrF2N04 requires 462.0147).
- 871 Example 853
Figure imgf000872_0001
3 - [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -4- methylbenzenesulfonamide
Step 1: Preparation of the title compound was made from 5-(l-hydroxy-3- oxobutylidene)-2,2-dimethyl-l,3-dioxane-4,6-dione and 3-amino-4- methylbenzenesulfonamide by the method described for Example 716 (Steps 1 and 2), giving a solid (689 mg, 30 % over two steps). ES-HRMS m/z 499.0134 (M+H calcd for C20H18BrF2N2O4S requires 499.0133).
Example 854
Figure imgf000872_0002
methyl 5-bromo-2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yljbenzoate
Step 1: Preparation of the title compound was made from 5-(l-hydroxy-3- oxobutylidene)-2,2-dimethyl-l,3-dioxane-4,6-dione and methyl 2-amino-5-bromobenzoate by the method described for Example 716 (Steps 1 and 2), giving a solid (8.10 g, 51 % over two steps). ES-HRMS m/z 541.9430 (M+H calcd for C21H16Br2F2N04 requires 541.9409).
872
Figure imgf000873_0001
dimethyl 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]isophthalate Step 1 : Preparation of the title compound. At room temperature in a Paar Pressure Bottle (150 psi pressure maximum specification) was added a solution of methyl 5-bromo- 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl] benzoate (Example 854) (543 g, 1.00 mmol) in anhydrous THF (8 mL) and MeOH (18 mL). Next was added tefrakis(tripheylphosphine) palladium (511 mg, 0.442 mmol) and the pressure bottle was purged with CO gas. The bottle was next pressurized to 60 psi and heated to 61 °C. The final pressure of the bottle at this temperature was 72 psi. The reaction mixture was maintained for 36 h. and then vented and cooled. The black solution was concenfrated in vacuo and the resulting dark residue was subjected to Si02 chromatography with ethyl acetate/hexanes (1:1) to furnish a yellow solid (1.10 g, 63 %). 1H NMR (400 MHz, CDC13) δ 8.77 (app d, J= 2.3 Hz, IH), 8.28 (app dd, J= 8.3, 2.1 Hz, IH), 7.43-7.40 (m, IH), 7.25 (app d, J= 9.0 Hz, IH), 6.93 (app t, J =7.2 Hz, IH), 6.83 (app t, J= 7.4 Hz, IH), 6.18 (s, IH), 5.22 (br s, 2H), 3.96 (s, 3H), 3.78 (s, 3H), 1.93 (s, 3H); LC/MS C-18 column, tr = 2.52 min. (5 to 95% acetonitrile/water over 5 min. at 1 ml/min with detection 254 nm, at 50°C). ES-MS m/z 522 (M+H). ES-HRMS m/z 522.0361 (M+H calcd for C23H19BrF2N06 requires 522.0358).
Example 856
Figure imgf000873_0002
873 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylthiophene-3 -carboxamide
Step 1: The title compound was made from 5-(l-hydroxy-3-oxobutylidene)-2,2- dimethyl- l,3-dioxane-4,6-dione and 2-amino-4-methyl-thiophene-3-carboxamide by the method described in Example 716 (Steps 1 and 2), giving a solid (612 mg, 27 % over two steps). ES-HRMS m/z 469.0036 (M+H calcd for C19H16BrF2N203S requires 469.0028).
Example 857
Figure imgf000874_0001
3-bromo-2'-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2H-l,4l-bipyridin-2-one
Step 1: The title compound was made from 5-(l-hydroxy-3-oxobutylidene)-2,2- dimethyl-l,3-dioxane-4,6-dione and 4-amino-2-chloropyridine by the method described for Example 716 (Steps 1 and 2), with a substitution of 18.0 M sulfuric acid instead of methane sulfonic acid, giving a solid (1.67 g, 24 % over two steps). ES-HRMS m/z
440.9790 (M+H calcd for C18H13BrClF2N202 requires 440.9811).
Example 858
Figure imgf000874_0002
3-bromo-2'-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2H-l,4'-bipyridin-2-one
Step 1: The title compound was made from 5-(l-hydroxy-3-oxobutylidene)-2,2- dimethyl-l,3-dioxane-4,6-dione and 5-amino-2-chloro-3-picoline by the method described for Example 716 (Steps 1 and 2), with a substitution of 18.0 M sulfuric acid instead of
874 - methane sulfonic acid, giving a solid (5.56 g, 44 % over two steps). ES-HRMS m/z 454.9986 (M+H calcd for C19H15BrClF2N202 requires 454.9968).
Example 859
Figure imgf000875_0001
3 -[3 -chloro-4- {[2-({[(cyclobutylamino)carbonyl] amino} methyl)-4-fluorobenzyl]oxy}-6- methyl-2-oxopyridin- 1 (2H)-yl] -N,4-dimethylbenzamide
Step 1: Preparation of methyl 3-[4-{[2-
({[(cyclobutylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6-methyl-2- oxopyridin-l(2H)-yl]-4-methylbenzoate.
Figure imgf000875_0002
To a cooled (0 °C) solution of methyl 3-[4-{[2-(aminomethyl)-4- fluorobenzyl]oxy}-6-methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoate trifluoroacetate (1.03 g, 1.96 mmol) and 1,1-carbonyldiimidazole (0.38 g, 2.4 mmol) in DMA (6.0 mL)
875 was added 4-methylmorpholine (0.32 mL, 3.0 mmol). After 30 min. at ambient temperature, the mixture was cooled (0 °C), cyclobutylamine (0.34 mL, 3.9 mmol) was added, and stined at room temperature for 3 h. DMA was removed by distillation, and the product was purified by preparatory HPLC using a 10-90% CH3CN/H20 (30 min) gradient containing 0.5%» TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z = 508) were combined and concenfrated under reduced pressure to approximately 20 mL. Added 5% NaHC03 (20 mL) and extracted with DCM (3x 20 mL). The combined organic extracts were dried over Na2S04, filtered, concentrated under reduced pressure, and dried in vacuo to give the desired product as a white foam (0.74 g, 74%). 1H NMR (CD3OD/ 400MHz) δ8.03 (d, IH, J= 8.0 Hz), 7.76 (s, IH), 7.53 (d, IH, J= 8.0 Hz), 7.46 (m, IH), 7.10 (m, IH), 7.01 (m, IH), 6.22 (s, IH), 6.07 (s, IH), 5.17 (s, 2H), 4.39 (s, 2H), 4.13 (m, IH), 3.89 (s, 3H), 2.26 (m, 2H), 2.12 (s, 3H), 1.89 (s, 3H), 1.86 (m, 2H), 1.65 (m, 2H). ESHRMS m/z 508.2262 (M+H calculated for C28H31FN305 requires 508.2242). Step 2: Preparation of methyl 3 -[3 -chloro-4- {[2-
({[(cyclobutylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6-methyl-2- oxopyridin- 1 (2H)-yl] -4-methylbenzoate.
Figure imgf000876_0001
Methyl 3-[4-{[2-({[(cyclobutylamino)carbonyl]amino} methyl)-4- fluorobenzyl]oxy}-6-methyl-2-oxoρyridin-l(2H)-yl]-4-methylbenzoate (from Step 1)
(0.60 g, 1.18 mmol) and NCS (0.16 g, 1.18 mmol) were dissolved in acetic acid (10 mL).
Dichloroacetic acid (4 drops) was added in a catalytic amount. The mixture was stirred overnight at ambient temperature. Additional NCS (0.02g, 0.12 mmol) was added and the
- 876 - solution heated at 60 °C for 6.5 h., then stined at room temperature overnight. The reaction mixture was concenfrated under reduced pressure and purified by preparatory HPLC using a 10-90% CH3CN/H20 (30 min) gradient containing 0.5% TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z = 543) were combined and concenfrated under reduced pressure to approximately 20 mL. To the fractions was added 5% NaHC03 (20 mL), which was then exfracted with DCM (3x 15 mL). The organic exfracts were dried over Na2S04, filtered, concentrated under reduced pressure, and dried in vacuo to give a white solid with one major impurity. The product was further purified by recrystallization from DCM/MeOH using hexane to precipitate the desired product as a white solid (0.33 g, 52%). 1H NMR (CDC13/ 400MHz) δ7.99 (d, IH, J= 8.0 Hz), 7.70 (s, IH), 7.38 (m, 2H), 7.05 (m, IH), 6.93 (m, IH), 6.34 (s, IH), 5.21 (s, 2H), 4.37 (s, 2H), 4.04 (quintet, IH,. J= 8.0 Hz), 3.84 (s, 3H), 2.20 (m, 2H), 2.07 (s, 3H), 1.91 (s, 3H), 1.72 (m, 2H), 1.58 (m, 2H). ESHRMS m/z 542.1851 (M+H calculated for C28H30ClFN3O5 requires 542.1853).
Step 3: Preparation of 3 -[3 -chloro-4- {[2-
({[(cyclobutylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6-methyl-2- oxopyridin- 1 (2H)-yl] -4-methylbenzoic acid.
Figure imgf000877_0001
To methyl 3-[3-chloro-4-{[2-({[(cyclobutylamino) carbonyl]amino}methyl)-4- fluorobenzyl]oxy}-6-methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoate (from Step 2) (0.21 g, 0.39 mmol) was added 1.5 N NaOH solution in 1:1 MeOH:water (0.31 mL, 0.46 mmol) and THF (0.41 mL). The reaction mixture was heated with a condenser at 60 °C
- 877 - for 35 min. The solution was cooled (0 °C) and a white solid precipitated by the slow addition of 5% citric acid. Solid was isolated by filfration, washed with H20, and dried in vacuo to give the desired product (0.18 g, 87%). 1H NMR (CD3OD/ 400MHz) δ8.04 (m, IH), 7.76 (s, IH), 7.52 (m, 2H), 7.11 (m, IH), 7.03 (m, IH), 6.70 (s, IH), 5.38 (s, 2H), 4.43 (s, 2H), 4.10 (quintet, IH, J= 8.0 Hz), 2.25 (m, 2H), 2.10 (s, 3H), 2.00 (s, 3H), 1.85 (m, 2H), 1.65 (m, 2H). ESHRMS m/z 528.1730 (M+H calculated for C27H28C1FN305 requires 528.1696).
Step 4: Preparation of the title compound. To a cooled (0 °C) solution of 3-[3-chloro-4-{[2-
({[(cyclobutylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6-methyl-2- oxopyridin-l(2H)-yl]-4-methylbenzoic acid (from Step 3) (0.12 g, 0.23 mmol) in DMA (2.0 mL) was added isobutyl chloroformate (0.35 mL of a stock solution prepared 0.1 mL in 0.9 mL DCM, 0.27 mmol) and 4-methylmorpholine (0.33 mL of a stock solution prepared 0.1 mL in 0.9 mL DMA, 0.30 mmol). The reaction mixture was stined for 5 min. at 0 °C, then for 25 min. at room temperature. The solution was cooled (0 °C), and methylamine (0.17 mL of a 2.0M solution in THF, 0.34 mmol) was added with stirring at ambient temperature for 1.5 h. DMA was removed by distillation under reduced pressure, and the product was purified by preparatory HPLC using a 10-90% CH3CN/H20 (30 min.) gradient containing 0.5% TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z = 542) were combined, concenfrated under reduced pressure, freeze-dried, and lyophilized. The resulting solid was washed with 5%> NaHC03 (10 mL) and extracted with DCM (3x 10 mL). The organic exfracts were dried over Na2S04, filtered, concentrated, and dried in vacuo to give the desired product as a white solid (0.06 g, 48%). 1H NMR (CD3OD/ 400MHz) δ7.85 (m, IH), 7.57 (s, IH), 7.52 (m, 2H), 7.11 (m, IH), 7.03 (m, IH), 6.70 (s, IH), 5.39 (s, 2H), 4.43 (s, 2H), 4.11 (quintet, IH, J= 8.4 Hz), 2.89 (s, 3H), 2.26 (m, 2H), 2.08 (s, 3H), 2.00 (s, 3H), 1.86 (m, 2H), 1.65 (m, 2H). ESHRMS m/z 541.2011 (M+H calculated for C28H31C1FN404 requires 541.2012).
Example 860
878
Figure imgf000879_0001
3 -[3 -chloro-4- { [2-( { [(cyclopropylamino)carbonyl] amino } methyl)-4-fluorobenzyl] oxy} -6- methyl-2-oxopyridin-l(2H)-yl]-N,4-dimethylbenzamide
Step 1: Preparation of methyl 3-[3-chloro-4-{[2-
({[(cyclopropylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6-methyl-2- oxopyridin-l(2H)-yl]-4-methylbenzoate.
Figure imgf000879_0002
Methyl 3-[4- {[2-( {[(cyclopropylamino)carbonyl]amino} methyl)-4-fluorobenzyl]oxy} -6- methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoate (0.82 g, 1.66 mmol) and NCS (0.22 g, 1.66 mmol) were dissolved in acetic acid (10 mL). Dichloroacetic acid (8 drops) was added in a catalytic amount. The mixture was stined at ambient temperature overnight. The reaction was not completed by that time, so additional dichloroacetic acid (6 drops) was added and the mixture was again stined at room temperature overnight. When reaction was still not complete, additional NCS (0.02 g, 0.17 mmol) was added. The reaction was complete 6 h. later, and was concentrated under reduced pressure and
879 purified by preparatory HPLC using a 10-90% CH3CN/H20 (30 min) gradient containing 0.5% TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z - 528) were combined and concenfrated to approximately 20 mL under reduced pressure. Added 5% NaHC03 (20 mL) and exfracted with DCM (3x 15 mL). The organic exfracts were dried over Na2S0 , filtered, concenfrated under reduced pressure, and dried in vacuo to give the desired product as a white foam (0.59 g, 67%). 1H NMR (CD3OD/ 400MHz) δ8.04 (m, IH), 7.79 (s, IH), 7.54 (m, 2H), 7.14 (m, IH), 7.03 (m, IH), 6.72 (s, IH), 5.41 (s, 2H), 4.48 (s, 2H), 3.89 (s, 3H), 2.47 (m, IH), 2.10 (s, 3H), 1.99 (s, 3H), 0.69 (m, 2H), 0.46 (m, 2H). ESHRMS m/z 528.1715 (M+H calculated for C27H28C1FN305 requires 528.1696).
Step 2: Preparation of 3-[3-chloro-4-{[2-
({[(cyclopropylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6-methyl-2- oxopyridin- 1 (2H)-yl]-4-methylbenzoic acid.
Figure imgf000880_0001
Preparation was done according to a procedure similar to that used in the synthesis detailed in Step 3 of Example 859. 1H NMR (DMSO-tf6/ 400MHz) δ7.92 (m, IH), 7.67 (s, IH), 7.51 (m, 2H), 7.09 (m, 2H), 6.73 (s, IH), 5.36 (s, 2H), 4.31 (s, 2H), 2.41 (m, IH), 2.01 (s, 3H), 1.89 (s, 3H), 0.56 (m, 2H), 0.34 (m, 2H). ESHRMS m/z 514.1537 (M+H calculated for C26H26C1FN305 requires 514.1540).
Step 3: Preparation of the title compound. The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis detailed in Example 859. 1H NMR (CD3OD/ 400MHz) δ7.85 (m, IH), 7.58 (s, IH), 7.52 (m, 2H), 7.14 (m, IH), 7.03
880 (m, IH), 6.72 (s, IH), 5.41 (s, 2H), 4.48 (s, 2H), 2.89 (s, 3H), 2.47 (m, IH), 2.08 (s, 3H), 2.00 (s, 3H), 0.69 (m, 2H), 0.47 (m, 2H). ESHRMS m/z 527.1865 (M+H calculated for C27H29C1FN404 requires 527.1856).
Example 861
Figure imgf000881_0001
3 -[3 -chloro-4- { [2-( { [(cyclopropylamino)carbonyl] amino } methyl)-4-fluorobenzyl] oxy} -6- methyl-2-oxopyridin-l(2H)-yl]-N-[2-hydroxy-l-(hydroxymethyl)ethyl]-4- methylbenzamide
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis described in Example 859. lR NMR (CD3OD/ 400MHz) δ7.90 (m, IH), 7.64 (s, IH), 7.52 (m, 2H), 7.14 (m, IH), 7.03 (m, IH), 6.72 (s, IH), 5.42 (s, 2H), 4.48 (s, 2H), 4.14 (m, IH), 3.70 (m, 4H), 2.47 (m, IH), 2.09 (s, 3H), 2.02 (s, 3H), 0.69 (m, 2H), 0.47 (m, 2H). ESHRMS m/z 587.2083 (M+H calculated for C29H33C1FN406 requires 587.2067).
881 -
Example
Figure imgf000882_0001
3 -[3 -chloro-4- { [2-( { [(cyclopropylamino)carbonyl] amino } methyl)-4-fluorobenzyl] oxy} -6- methyl-2-oxopyridin- 1 (2H)-yl] -N- [2-(dimethylamino)ethyl] -4-methylbenzamide The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis detailed in Example 859. 1H NMR (CD3OD/ 400MHz) δ7.88 (m, IH), 7.63 (s, IH), 7.52 (m, 2H), 7.14 (m, IH), 7.03 (m, IH), 6.72 (s, IH), 5.42 (s, 2H), 4.48 (s, 2H), 3.51 (t, 2H, J= 6.8 Hz), 2.56 (t, 2H, J= 6.8 Hz), 2.47 (m, IH), 2.29 (s, 6H), 2.09 (s, 3H), 2.01 (s, 3H), 0.69 (m, 2H), 0.47 (m, 2H). ESHRMS m/z 584.2437 (M+H calculated for C30H36ClFN5O4 requires 584.2434).
Example 863
Figure imgf000882_0002
3 - [3 -chloro-4- { [2-( { [(cyclopropylamino)carbonyl] amino } methyl)-4-fluorobenzyl] oxy} -6- methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzamide
882 The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis detailed in Example 859. 1H NMR (CD3OD/ 300MHz) δ7.93 (m, IH), 7.66 (s, IH), 7.53 (m, 2H), 7.15 (m, IH), 7.04 (m, IH), 6.73 (s, IH), 5.42 (s, 2H), 4.49 (s, 2H), 2.48 (m, IH), 2.09 (s, 3H), 2.02 (s, 3H), 0.70 (m, 2H), 0.47 (m, 2H). ESHRMS m/z 513.1663 (M+H calculated for C26H27C1FN404 requires 513.1699).
Example 864
Figure imgf000883_0001
2-( { [3-bromo- 1 -(2,6-difluorophenyl)-6-methyl-2-oxo- 1 ,2-dihydropyridin-4- yl] oxy} methyl)-5 -fluoro-N-( 1 -methyl- lH-pyrazol-3 -yι)benzamide
Step 1: Preparation of methyl 5-fluoro-2-methylbenzoate.
Figure imgf000883_0002
5-fluoro-2-methylbenzoic acid (2.00 g, 13.0 mmol) was combined with 4.0 M hydrogen chloride in 1,4-dioxane (2.5 mL) in MeOH (11 mL) and heated at 70 °C with a condenser overnight. The mixture was concentrated, cooled (0 °C), neutralized with 5%NaHC03, exfracted with DCM, dried over Na2S04, filtered, concenfrated under reduced pressure, and dried in vacuo. The resulting product was obtained as pale yellow oil (1.69 g, 77%). 1H NMR (CD3OD/ 400MHz) δ7.55 (d, IH, J= 2.4 Hz), 7.28 (t, IH, J= 6.0 Hz), 7.16 (t, IH, J= 8.4 Hz), 3.87 (s, 3H), 2.51 (s, 3H).
- 883 Step 2: Preparation of methyl 2-(bromomethyl)-5-fluorobenzoate.
Figure imgf000884_0001
Methyl-5-fluoro-2-methylbenzoate (Step 1) (1.64 g, 9.75 mmol), NBS (2.08 g, 11.7 mmol), and benzoyl peroxide (0.16 g, 0.68 mmol) in CC14 (15 mL) were heated overnight at 80 °C. Solid was removed by filfration and subsequently washed with DCM. The filfrate was concenfrated and purified by flash column chromatography using hexane and a gradient up to 5% ethyl acetate/hexane as eluent. The resuting product was obtained as colorless liquid (1.79g, 74%). 1H NMR (CD3OD/ 400MHz) δ7.63 (m, IH), 7.54 (m, IH), 7.28 (m, IH), 4.95 (s, 2H), 3.92 (s, 3H).
Step 3: Preparation of methyl 2-({[3-bromo-l-(2,6-difluorophenyl)-6-methyl-2- oxo- 1 ,2-dihydropyridin-4-yl] oxy} methyl)-5 -fluorobenzoate.
Figure imgf000884_0002
Methyl-2-(bromomethyl)-5-fluorobenzoate (from Step 2) (1.76 g, 7.12 mmol), 3- bromo-l-(2,6-difluorophenyl)-4-hy(hOxy-6-methylpyridin-2(lH)-one (1.61 g, 5.09 mmol), K2C03 (1.13 g, 8.14 mmol), and 18-crown-6 (0.12 g) were combined in DMA (12 mL) and heated with a condenser at 60 °C. After 1 h., DMA was removed by distillation under reduced pressure. The resulting residue was cooled (0 °C), neufralized with 5% citric acid, washed with cold 20% ethyl acetate/hexane, filtered, and dried in vacuo. The product was obtained as a white solid (2.42 g, 99%). 1H NMR (CD3OD/ 400MHz) δ7.82 (m, IH), 7.75 (m, IH), 7.61 (m, IH), 7.41 (m, IH), 7.23 (t, 2H, J= 8.4 Hz), 6.61 (s, IH), 5.68 (s, 2H), 3.91 (s, 3H), 2.10 (s, 3H). ESHRMS m/z 482.0221 and 484.0208 (M+H calculated for C21H16BrF3N04 requires 482.0209 and 484.0192). - 884 - Step 4: Preparation of 2-({ [3-bromo- l-(2,6-difluorophenyl)-6-mefhyl-2-oxo- 1,2- dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzoic acid.
Figure imgf000885_0001
A solution of methyl-2-({[3-bromo-l-(2,6-difluorophenyl)-6-methyl-2-oxo-l,2- dihydropyridin-4-yl]oxy}methyl)-5-fluorobenzoate (from Step 3) (1.88 g, 3.90 mmol) and 2.0 N NaOH (2.9 mL) in dioxane (2.9 mL) was heated at 55 °C for 1.5 h. The reaction mixture was cooled (0 °C), neufralized with 5% citric acid, washed with water, and the product was obtained by filfration as a white solid (1.60 g, 88%). 1H NMR (CD3OD/ 400MHz) δ7.79 (m, IH), 7.69 (m, IH), 7.60 (m, IH), 7.34 (m, IH), 7.23 (t, 2H, J = 8.8 Hz), 6.62 (s, IH), 5.70 (s, 2H), 2.08 (s, 3H). ESHRMS m/z 468.0061 and 470.0052 (M+H calculated for C20H14BrF3NO4 requires 468.0053 and 470.0035).
Step 5: Preparation of the title compound. To a cooled (0 °C) solution of 2-({[3- bromo-l-(2,6-difluorophenyl)-6-methyl-2-oxo-l,2-dihydropyridin-4-yl]oxy}methyl)-5- fluorobenzoic acid (from Step 4) (0.22 g, 0.47 mmol) in DMA (2.0 mL) was added isobutyl chloroformate (0.73 mL of a stock solution prepared 0.1 mL in 0.9 mL DCM, 0.56 mmol) and 4-methylmorpholine (0.67 mL of a stock solution prepared 0.1 mL in 0.9 mL DMA, 0.61 mmol). The mixture was stined for 5 min. at 0 °C then for 25 min. at ambient temperature. The reaction was cooled (0 °C) and 1 -methyl- lH-pyrazol-3 -amine (0.07 g, 0.70 mmol) was added. The mixture was stined at room temperature for 1.5 h., and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by preparatory HPLC using a 10-90% CH3CN/H20 (30 min.) gradient containing 0.5% TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z = 548) were combined, concenfrated under reduced pressure, freeze-dried, and lyophilized. The resulting solid was washed with 5% NaHC03 (10 mL), exfracted in DCM (3x 10 mL), dried over Na2S04, filtered, concentrated under reduced pressure, and dried in vacuo to give the desired product as a peach-colored solid (0.15 g, 58%). 1H NMR (CD3OD/ 300 - 885 - MHz) δ7.79 (m, IH), 7.64 (m, IH), 7.50 (m, 2H), 7.38 (m, IH), 7.27 (t, 2H, J= 7.8 Hz), 6.68 (s, IH), 6.60 (s, IH), 5.61 (s, 2H), 3.85 (s, 3H), 2.11 (s, 3H). ESHRMS m/z 547.0560 and 549.0530 (M+H calculated for C24H19BrF3N403 requires 547.0587 and 549.0570).
Example 865
Figure imgf000886_0001
2-( { [3-bromo- 1 -(2,6-difluorophenyl)-6-methyl-2-oxo- 1 ,2-dihydropyridin-4- yl] oxy} methyl)-5 -fluorobenzamide The title compound was prepared using a procedure similar to that used in Step 5 of the synthesis described in Example 864. 1H NMR (CD3OD/ 300 MHz) δ7.72 (m, IH), 7.60 (m, IH), 7.38 (m, IH), 7.29 (m, IH), 7.23 (t, 2H, J= 7.6 Hz), 6.64 (s, IH), 5.54 (s, 2H), 2.08 (s, 3H). ESHRMS m/z 467.0199 and 469.0176 (M+H calculated for C20H15BrF3N2O3 requires 467.0213 and 469.0195).
Example 866
Figure imgf000886_0002
2-( { [3-bromo- 1 -(2,6-difluorophenyl)-6-methyl-2-oxo- 1 ,2-dihydropyridin-4- yl]oxy}methyl)-N-(cyclopropylmethyl)-5-fluorobenzamide
The title compound was prepared using a procedure similar to that used in Step 5 of the synthesis detailed in Example 864. 1H NMR (CD3OD/ 400 MHz) δ7.68 (m, IH), 7.60 (m, IH), 7.29 (m, 2H), 7.23 (t, 2H, J = 8.4 Hz), 6.64 (s, IH), 5.49 (s, 2H), 3.19 (d, - 886 - 2H, J= 7.2 Hz), 2.09 (s, 3H), 1.04 (m, IH), 0.49 (m, 2H), 0.24 (m, 2H). ESHRMS m/z 521.0693 and 523.0676 (M+H calculated for C24H21BrF3N203 requires 521.0682 and 523.0665).
Example 867
Figure imgf000887_0001
3-[3-bromo-4-{[2-({[(ethylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6- methyl-2-oxopyridin-l(2H)-yl]-N,4-dimethylbenzamide
Step 1: Preparation of methyl 3-[4-{[2-({[(ethylamino)carbonyl]amino}methyl)-4- fluorobenzyl]oxy}-6-methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoate.
Figure imgf000887_0002
To a cooled (0 °C) solution of methyl 3-[4-{[2-(aminomethyl)-4- fluorobenzyl]oxy}-6-methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoate trifluoroacetate (1.94 g, 3.7 mmol) and 1,1-carbonyldiimidazole (0.72 g, 4.4 mmol) in DMA (23 mL) was added 4-methylmorpholine (0.61 mL, 5.5 mmol). The mixture was stined at room temperature for 30 min., cooled (0 °C), and ethylamine (3.7 mL of a 2.0 M solution in THF, 7.4 mmol) added. Solution was stined for 2 h. at ambient temperature, and solvent
887 was removed by distillation under reduced pressure. Residue was purified by preparatory HPLC using a 10-90% CH3CN/H20 (30 min.) gradient containing 0.5% TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z = 482) were combined and concenfrated under reduced pressure to approximately 30 mL. Added 5% NaHC03 (30 mL) and exfracted with DCM (3x 15 mL). The organic exfracts were dried over Na2S04, filtered, concenfrated under reduced pressure, and dried in vacuo to give the desired product as a gummy, pale yellow solid in quantitative yield. 1H NMR (CD3OD/ 400 MHz) δ8.03 (m, IH), 7.76 (s, IH), 7.53 (d, IH, J= 8.0 Hz), 7.45 (m, IH), 7.11 (m, IH), 7.01 (m, IH), 6.22 (s, IH), 6.07 (s, IH), 5.18 (s, 2H), 4.40 (s, 2H), 3.89 (s, 3H), 3.15 (q, 2H, J = 7.2 Hz), 2.11 (s, 3H), 1.89 (s, 3H), 1.09 (t, 3H, J = 7.2 Hz). ESHRMS m/z 482.2049 (M+H calculated for C26H29FN305 requires 482.2086).
Step 2: Preparation of methyl 3 -[3 -bromo-4- {[2-
({[(ethylamino)carbonyl]amino}mefhyl)-4-fluorobenzyl]oxy}-6-methyl-2-oxopyridin- l(2H)-yl]-4-methylbenzoate.
Figure imgf000888_0001
NBS (0.77 g, 4.3 mmol) was added portionwise to a solution of methyl 3-[4-{[2- ({[(ethylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6-methyl-2-oxopyridin- l(2H)-yl]-4-methylbenzoate (from Step 1) (2.08 g, 4.3 mmol) in DCM (25 mL). The solution was stined at room temperature for 30 min., washed with water (20 mL), exfracted in DCM (2x 10 mL), dried over Na2S04, filtered, and concenfrated under reduced pressure. The resulting yellow foam was purified by filtration from a cooled (0 °C) solution in ethyl acetate and was washed with a cold solution of 30% ethyl acetate in hexane to give the desired product as an off-white solid (1.51 g, 63%). 1H NMR (CD3OD/
- 888 - 400MHz) δ8.04 (m, IH), 7.78 (s, IH), 7.54 (m, 2H), 7.13 (m, IH), 7.03 (m, IH), 6.67 (s, IH), 5.39 (s, 2H), 4.46 (s, 2H), 3.89 (s, 3H), 3.13 (q, 2H, J= 7.2 Hz), 2.10 (s, 3H), 1.98 (s, 3H), 1.09 (t, 3H, J= 7.2 Hz). ESHRMS m/z 560.1223 and 562.1183 (M+H calculated for C26H28FBrN305 requires 560.1191 and 562.1175).
Step 3: Preparation of 3-[3-bromo-4-{[2-({[(ethylamino)carbonyl]amino}methyl)- 4-fluorobenzyl]oxy}-6-methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoic acid.
Figure imgf000889_0001
To methyl 3 -[3 -bromo-4- { [2-( { [(ethylamino)carbonyl] amino}methyl)-4- fluorobenzyl]oxy}-6-methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoate (from Step 2) (1.47 g, 2.6 mmol) was added 1.5 N NaOH solution in 1:1 MeOH:H20 (2.6 mL, 3.9 mmol) and THF (3.6 mL). The mixture was heated at 60 °C with a condenser for 1 h. White solid was precipitated from the cooled (0 °C) solution by the slow addition of 5% citric acid, filtered, and dried in vacuo to give the product as a pale yellow solid (1.40 g, 99%). 1H NMR (CD3OD/ 400MHz) δ8.04 (d, IH, J= 9.6 Hz), 7.76 (s, IH), 7.54 (m, IH), 7.13 (m, IH), 7.03 (m, IH), 6.67 (s, IH), 5.39 (s, 2H), 4.46 (s, 2H), 3.14 (q, 2H, J= 7.2 Hz), 2.09 (s, 3H), 1.99 (s, 3H), 1.09 (t, 3H, J = 6.8 Hz). ESHRMS m/z 546.1060 and 548.1049 (M+H calculated for C25H26BrFN305 requires 546.1034 and 548.1018). Step 4: Preparation of the title compound.
To a cooled (0 °C) solution of 3-[3-bromo-4-{[2-({[(ethylamino)carbonyl]amino}methyl)- 4-fluorobenzyl]oxy}-6-methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoic acid (from Step 3) (0.22 g, 0.40 mmol) in DMA (2 mL) was added isobutyl chloroformate (0.63 mL of a stock solution prepared 0.1 mL in 0.9 mL DCM, 0.56 mmol) and 4-methylmorpholine
- 889 (0.58 mL of a stock solution prepared 0.1 mL in 0.9 mL DMA, 0.61 mmol). The mixture was stined for 5 min. at 0 °C then for 25 min. at ambient temperature. The solution was cooled (0 °C), methylamine (0.30 mL, 0.60 mmol) was added as a 2.0 M solution in THF, and the mixture was stined at room temperature for 2.5 h. DMA was removed by distillation under reduced pressure and the resulting residue was purified by preparatory HPLC using a 10-90% CH3CN/H20 (30 min.) gradient containing 0.5% TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z - 560) were combined and concentrated under reduced pressure to approximately 20 mL. Added 5% NaHC03 (10 mL) and exfracted in DCM (3x 10 mL). The organic extracts were dried over Na2S04, filtered, concentrated under reduced pressure, and dried in vacuo to give the desired product as a white solid (0.12 g, 54%). 1H NMR (CD3OD/ 400MHz) δ7.85 (m, IH), 7.54 (m, 3H), 7.12 (m, IH), 7.02 (m, IH), 6.67 (s, IH), 5.40 (s, 2H), 4.45 (s, 2H), 3.14 (q, 2H, J = 7.2 Hz), 2.89 (s, 3H), 2.08 (s, 3H), 1.99 (s, 3H), 1.09 (t, 3H, J= 6.8 Hz). ESHRMS m/z 559.1353 and 561.1324 (M+H calculated for C26H29BrFN404 requires 559.1351 and 561.1334).
Example 868
Figure imgf000890_0001
3 - [3 -bromo-4- { [2-( { [(ethylamino)carbonyl] amino } methyl)-4-fluorobenzyl] oxy} -6- methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzamide
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis described in Example 867. 1H NMR (CD3OD/ 400MHz) 87.91 (m, IH), 7.64 (s, IH), 7.53 (m, 2H), 7.13 (m, IH), 7.03 (m, IH), 6.68 (s, IH), 5.40 (s, 2H), 4.45 (s,
890 2H), 3.14 (q, 2H, J = 7.2 Hz), 2.09 (s, 3H), 2.00 (s, 3H), 1.09 (t, 3H, J = 7.2 Hz). ESHRMS m/z 545.1183 and 547.1198 (M+H calculated for C25H27BrFN 04 requires 545.1194 and 547.1178).
Example 869
Figure imgf000891_0001
3 -[3 -bromo-4- { [2-( { [(ethylamino)carbonyl] amino } methyl)-4-fluorobenzyl] oxy} -6- methyl-2-oxopyridin-l(2H)-yl]-N-[2-(dimethylamino)ethyl]-4-methylbenzamide The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis in Example 867. 1H NMR (CD3OD/ 400MHz) δ7.88 (m, IH), 7.62 (s, IH), 7.53 (m, 2H), 7.12 (m, IH), 7.03 (m, IH), 6.68 (s, IH), 5.40 (s, 2H), 4.45 (s, 2H), 3.51, (t, 2H, J= 5.6 Hz), 3.14 (q, 2H, J= 7.2 Hz), 2.56 (t, 2H, J= 6.8 Hz), 2.30 (s, 6H), 2.08 (s, 3H), 2.00 (s, 3H), 1.09 (t, 3H, J= 7.2 Hz). ESHRMS m/z 616.1933 and 618.1900 (M+H calculated for C29H36BrFN504 requires 616.1929 and 618.1914).
Example 870
Figure imgf000891_0002
891 - N-(2-{[(3-bromo-l-{5-[(2,2-dimethylhydrazino)carbonyl]-2-mefhylphenyl}-6-methyl-2- oxo-l,2-dihydropyridin-4-yl)oxy]mefhyl}-5-fluoroberιzyl)-N'-ethylurea
The title compound was prepared using a procedure similar to that used in Step 4 of ώe "synthesis described in Example 867. 1H NMR (CD3OD/ 400MHz) δ7.82 (m, IH), 7.53 (m, 3H), 7.13 (m, IH), 7.03 (m, IH), 6.68 (s, IH), 5.40 (s, 2H), 4.45 (s, 2H), 3.14 (q, 2H, J = 7.6 Hz), 2.62 (s, 6H), 2.08 (s, 3H), 2.00 (s, 3H), 1.09 (t, 3H, J = 7.2 Hz). ESHRMS m/z 588.1663 and 590.1605 (M+H calculated for C27H32BrFN504 requires 588.1616 and 590.1600).
Example 871
Figure imgf000892_0001
3-[3-bromo-4-{[4-fluoro-2-({[(methoxyamino)carbonyl]amino}methyl)benzyl]oxy}-6- methyl-2-oxopyridin- 1 (2H)-yl] -N,4-dimethylbenzamide
Step 1: Preparation of methyl 3-[4-{[4-fluoro-2-
({[(methoxyamino)carbonyl]amino}methyl)benzyl]oxy}-6-methyl-2-oxopyridin-l(2H)- yl]-4-methylbenzoate. ,
Figure imgf000892_0002
892 Prepared using a procedure similar to that used in Step 1 of the synthesis described in Example 867. 1H NMR (CD3OD/ 400MHz) δ8.03 (m, IH), 7.77 (s, IH), 7.53 (d, IH, J
= 8.0 Hz), 7.47 (m, IH), 7.13 (m, IH), 7.02 (m, IH), 6.22 (s, IH), 6.09 (s, IH), 5.21 (s,
2H), 4.47 (s, 2H), 3.89 (s, 3H), 3.67 (s, 3H), 2.11 (s, 3H), 1.89 (s, 3H). ESHRMS m/z 484.1888 (M+H calculated for C25H27FN306 requires 484.1878).
Step 2: Preparation of methyl 3-[3-bromo-4-{[4-fluoro-2-
( { [(methoxyamino)carbonyl] amino } methyl)benzyl] oxy} -6-methyl-2-oxopyridin- 1 (2H)- yl] -4-methylbenzoate.
Figure imgf000893_0001
This compound was prepared using a procedure similar to that used in Step 2 of the synthesis described in Example 867. 1H NMR (CD3OD/ 400MHz) δ8.04 (m, IH), 7.78 (s,
IH), 7.55 (m, 2H), 7.16 (m, IH), 7.04 (m, IH), 6.68 (s, IH), 5.43 (s, 2H), 4.52 (s, 2H),
3.89 (s, 3H), 3.67 (s, 3H), 2.09 (s, 3H), 1.97 (s, 3H). ESHRMS m/z 562.0971 and 564.0980 (M+H calculated for C25H26BrFN306 requires 562.0984 and 564.0967).
Step 3: Preparation of 3-[3-bromo-4-{[4-fluoro-2-
( {[(methoxyamino)carbonyl]amino}methyl)benzyl]oxy} -6-methyl-2-oxopyridin- 1 (2H)- yl]-4-methylbenzoic acid.
- 893
Figure imgf000894_0001
This compound was prepared using a procedure similar to that used in Step 3 of the synthesis described in Example 867. 1H NMR (CD3OD/ 400MHz) δ8.03 (m, IH), 7.75 (s,
IH), 7.53 (m, 2H), 7.16 (m, IH), 7.04 (m, IH), 6.67 (s, IH), 5.43 (s, 2H), 4.53 (s, 2H), 3.67 (s, 3H), 2.09 (s, 3H), 1.98 (s, 3H). ESHRMS m/z 548.0830 and 548.0827 (M+H calculated for C24H24BrFN306 requires 548.0827 and 550. 0810).
Step 4: Preparation of the title compound. The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis described in Example 867. 1H NMR (CD3OD/ 400MHz) δ7.85 (m, IH), 7.54 (m, 3H), 7.15 (m, IH), 7.04 (m, IH), 6.68 (s, IH), 5.43 (s, 2H), 4.52 (s, 2H), 3.67 (s, 3H), 2.89 (s, 3H), 2.08 (s, 3H), 1.99 (s, 3H). ESHRMS m/z 561.1126 and 563.1108 (M+H calculated for C25H27BrFN405 requires 561.1143 and 563.1127).
Example
Figure imgf000894_0002
3 -[3 -bromo-4- { [4-fluoro-2-( { [(methoxyamino)carbonyl] amino } methyl)benzyl] oxy} -6- methyl-2-oxopyridin- 1 (2H)-yl]-4-methylbenzamide
894 The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis described in Example 867. 1H NMR (CD3OD/ 400MHz) 87.91 (m, IH),
7.64 (s, IH), 7.53 (m, 2H), 7.15 (m, IH), 7.04 (m, IH), 6.68 (s, IH), 5.44 (s, 2H), 4.52 (s, 2H), 3.67 (s, 3H), 2.08 (s, 3H), 1.99 (s, 3H). ESHRMS m/z 547.0959 and 549.0950 (M+H calculated for C24H25BrFN405 requires 547.0987 and 549.0970).
Example 873
Figure imgf000895_0001
3 -Chloro-4-(2,4-difluorobenzyloxy)- 1 -(2,6-dimethyl-3H-benzoimidazol-5-yl)-6-methyl- pyridin-2(lH)-one
Step 1. Preparation of 4-(2,4-difluorobenzyloxy)-l-(2,6-dimethyl-3H- benzoimidazol-5-yl)-6-methyl-pyridin-2(lH)-one.
Figure imgf000895_0002
l-(2,6-Dimethyl-3H-benzoimidazol-5-yl)-4-hydroxy-6-methyl-pyridin-2(lH)-one (El Kihel, A. et al. Synthetic. Commun.1999, 29, 2435-2445) (1.4 g, 5.2 mmol) and DBU (0.8 mL, 5.5 mmol) was dissolved in 10 mL of NMP and 2,4-difluorobenzyl bromide (0.7 mL, 5.5 mmol) was added. The reaction was stined at 80 °C for 12 h. The reaction was cooled room temperature, diluted with water, and exfracted 3 times with EtOAc. The combined organics were washed with brine, dried (MgS04), filtered, and evaporated on a rotary evaporator. Purification by flash column chromatography (silica, 89:10:1 CHCl3/MeOH concenfrated ammonium hydroxide) provided a tan solid (0.54 g, 25%): 1H NMR (300 MHz, DMSO- ) δ 12.47 (s, IH), 7.86 (app q, J= 8.5 Hz, IH), 7.60 - 7.51 (m, - 895 - 2H), 7.41 - 7.34 (m, 2H), 6.25 (d, J= 2.3 Hz, IH), 6.16 (d, J= 2.6 Hz, IH), 5.31 (s, 2H), 2.62 (s, 3H), 2.19 (s, 3H), 1.97 (s, 3H).
Step 2. Preparation of title compound. 4-(2,4-Difluorobenzyloxy)-l-(2,6-dimethyl-3H- benzoimidazol-5-yl)-6-methyl-pyridin-2(lH)-one (0.53 g, 1.3 mmol) and NCS (0.2 g, 1.5 mmol) were dissolved in 7 mL DMF, and the reaction was stined at room temperature for 18 h. The reaction was diluted with water, and exfracted 3 times with EtOAc. The combined organics were washed with brine, dried (MgS04), filtered and evaporated on a rotary evaporator. Purification by flash column chromatography (silica, 89:10:1 CHCl3/MeOH/concenfrated ammonium hydroxide) gave an off-white solid (0.06 g, 10%): 1H NMR (300 MHz, DMSO-tf6) δ 12.14 (br s, IH), 7.70 (d, J= 6.7 Hz, IH), 7.44 - 7.34 (m, 2H), 7.30 (s, IH), 7.21 (d, J = 1.8 Hz, IH), 6.73 (s, IH), 5.34 (s, 2H), 2.50 (s, 3H), 1.95 (s, 3H), 1.89 (s, 3H). ES-HRMS m/z 430.1126 (M+H calcd for C22H19C1F2N302 requires 430.1128).
Example
Figure imgf000896_0001
2-{5-[3-Chloro-4-(2,4-difluorobenzyloxy)-2-oxo-pyridin-l(2H)-ylmethyl]-lH-indol-3- yl} -N,N-dimethyl-2-oxo-acetamide Step l. Preparation of the title compound. 3-Chloro-4-(2,4-difluorobenzyloxy)-l-
(lH-indol-5-ylmethyl)-pyridin-2(lH)-one (0.3 g, 0.75 mmol) was dissolved in 4 mL of CH2C12 at 0 °C and oxalyl chloride (0.07 mL, 0.82 mmol) was added dropwise. After 30 min. the solvent was evaporated on a rotary evaporator and the residue was suspended in 4 mL THF. To this suspension was added a solution of dimethylamine (0.94 mL of a 2.0 M solution in THF, 1.9 mmol). The reaction was stined at room temperature for 12 h. The reaction was partitioned between water and ethyl acetate, and separated. The organic layer was washed with brine, dried (MgS04), filtered and evaporated on a rotary evaporator.
896 Purification by flash column chromatography (silica, 84:15:1 CHCl3/MeOH/concenfrated ammonium hydroxide) gave an off-white solid (0.05 g, 13%): lR NMR (300 MHz, DMSO-< ) δ 12.32 (br s, IH), 8.10 (d, J= 6.4 Hz, IH), 7.99 (d, J= 7.8 Hz, IH), 7.49 (d, J = 8.4 Hz, IH), 7.36 - 7.26 (m, 2H), 7.15 (app t, J= 6.3 Hz, IH), 6.62 (d, J= 7.9 Hz, IH), 5.30 (s, 2H), 5.25 (s, 2H), 2.98 (s, 3H), 2.86 (s, 3H). ES-HRMS m/z 500.1213 (M+H calcd for C25H21C1F2N304 requires 500.1183).
Example 875
Figure imgf000897_0001
3-Chloro-4-(2,4-difluorobenzyloxy)-l-(3-dimethylaminomethyl-lH-indol-5-yhnethyl)- ρyridin-2(lH)-one
Step 1. Preparation of the title compound. A suspension of paraformaldehyde (0.03 mg, 0.85 mmol), acetic acid (0.05 mL, 0.85 mmol), and a solution of dimethylamine (0.43 mL of a 2.0 M in THF, 0.85 mmol) in 3 mL of EtOH was stined at 80 °C until a homogeneous solution formed. The reaction was cooled to room temperature, a solution of 3-Chloro-4-(2,4-difluorobenzyloxy)-l-(lH-indol-5-ylmethyl)-pyridin-2(lH)-one from Example 874, Step 1 (0.3 g, 0.75 mmol) in 3.0 mL EtOH was added, and the resulting reaction mixture was stined at 80 °C for 18 h. The reaction was cooled to room temperature and evaporated on a rotary evaporator. Purification by flash column chromatography (silica, 84:15:1 CHCl3/MeOH/concenfrated ammonium hydroxide) gave a white solid (0.14 g, 41%): 1H NMR (300 MHz, DMSO-</6) δ 10.98 (s, IH), 7.90 (d, J = 7.8 Hz, IH), 7.62 - 7.57 (m, 2H), 7.36 - 7.23 (m, 3H), 7.15 (app t, J= 8.5 Hz, IH), 7.06 (dd, J= 8.4, 1.5 Hz, IH), 6.57 (d, J= 7.8 Hz, IH), 5.28 (s, 2H), 5.18 (s, 2H), 3.54 (s, 2H), 2.16 (s, 6H). ES-HRMS m/z 458.1430 (M+H calcd for C2 H23C1F2N302 requires 458.1441).
- 897 Example 876
Figure imgf000898_0001
3-Chloro-4-(2,4-difluorobenzyloxy)-l-(3-pynolidin-l-ylmethyl-lH-indol-5-yhnethyl)- pyridin-2( 1 H)-one
Step 1. The title compound was prepared by a procedure similar to the one described for Example 875 (0.24 g, 66%): 1H NMR (300 MHz, DMSO-d6) δ 11.24 (br s, IH), 7.91 (d, J= 9 Hz, IH), 7.63 - 7.60 (m, 2H), 7.32 - 7.05 (m, 5H), 6.57 (d, J= 8 Hz, IH), 5.23 (s, 2H), 5.18 (s, 2H), 3.78 (s, 2H), 2.50 (s, 4H), 1.69 (s, IH). ES-HRMS m/z 484.1595 (M+H calcd for C26H25C1F2N302 requires 454.1598).
Example
Figure imgf000898_0002
3 -Chloro-4-(2,4-difluorobenzyloxy)- 1 -(2,3 -dihydro- 1 H-isoindol-5 -ylmethyl)-pyridin- 2(lH)-one Trifluoroacetic acid salt Step 1. Preparation of l,3-dihydroisoindole-2,5-dicarboxylic acid 5-methyl ester
2-(2,2,2-trichloroetliyl) ester.
Figure imgf000898_0003
2,3-Dihydro-lH-isoindole-5-carboxylic acid methyl ester (3.0 g, 17 mmol) and triethylamine (3.5 mL, 25 mmol) dissolved in 60 mL of THF was cooled to 0 °C. The reaction mixture was treated with 2,2,2-trichloroethyl chloroformate (3.4 mL, 25 mmol).
The reaction mixture was warm to room temperature and stined for 1.5 h. The precipitate
898 was filtered and the filfrate was diluted with EtOAc. The organics were washed with a solution of 10% citric acid, brine, dried (Na2S04), filtered and evaporated on a rotary evaporator. Purification by flash column chromatography (silica, 1:4 EtOAc/hexanes) afforded a light tan solid (5.74g, 97%): 1H NMR (300 MHz, DMSO- 6) δ 7.98 (s, IH), 7.92 (d, J= 8 Hz, IH), 7.52 (t, J= 7 Hz, IH), 4.92 (s, 2H), 4.83 (s, 2H), 4.76 (s, 2H), 3.86 (s, 3H). '
Step 2. Preparation of 5-hydroxymethyl-l,3-dihydroisoindole-2-carboxylic acid 2,2,2-trichloroethyl ester.
Figure imgf000899_0001
l,3-Dihydroisoindole-2,5-dicarboxylic acid 5-methyl ester 2-(2,2,2-trichloroethyl) ester (7.3 g, 21 mmol) was dissolved in 70 mL of THF, cooled to -78 °C, and DIBAL (67.3 mL of a 1.0 M solution in toluene, 67.3 mmol) was added dropwise. The reaction continued to stir at -78 °C for 5 h. The reaction mixture was warmed to room temperature and quenched with a 1:1 solution of 10% citric acid in wate /methanol, and evaporated on a rotary evaporator. The residue was dissolved in EtOAc, washed 3 times with Rochelle salt, brine, dried (Na2S04), filtered, and evaporated on a rotary evaporator. Purification by flash column chromatography (silica, 1:1 EtOAc/Hexanes) gave a light yellow solid (3.90g, 58%): 1H NMR (300 MHz, DMSO-</6) δ 7.30 - 7.25 (m, 3H), 5.24 - 5.20 (m, IH), 5.06 (s, 2H), 4.91 (s, 2H), 4.75 (s, 2H), 4.68 (s, 2H).
Step 3. Preparation of 5-bromomethyl-l,3-dihydroisoindole-2-carboxylic acid 2,2,2-trichloroethyl ester.
Figure imgf000899_0002
5-Hydroxymethyl-l,3-dihydroisoindole-2-carboxylic acid 2,2,2-trichloroethyl ester
(2.0 g, 6.2 mmol), was dissolved in 25 mL of CH2C1 , followed by treatment of triphenylphosphine and carbon tetrabromide. The reaction was stined at room temperature for 30 min. The solvent was evaporated on a rotary evaporator. Purification by flash column chromatography (silica, 1:1 EtOAc Hexanes) provided a viscous orange oil, which was carried forwarded without further characterization.
- 899 - Step 4. Preparation of 5-[3-chloro-4-(2,4-difluorobenzyloxy)-2-oxo-pyridin- l(2H)-ylmethyl]-l,3-dihydroisoindole-2-carboxylic acid 2,2,2-trichloroethyl ester.
Figure imgf000900_0001
3-Chloro-4-(2,4-difluoro-benzyloxy)-pyridin-2(lH)-one (1.1 g, 4.8 mmol) and potassium carbonate (1.3 g, 9.5mmoι) were dissolved in 40 mL of DMF, followed by freatment of 5-bromomethyl-l,3-dihydroisoindole-2-carboxylic acid 2,2,2-trichloroethyl ester (2.2 g, 5.7 mmol). The reaction was stined at 80 °C for 21 h. The reaction was cooled to room temperature, diluted with brine and exfracted 3 times with EtOAc. The combined organics were washed with water, brine, dried (Na2S04), filtered, and evaporated on a rotary evaporator. Purification by flash column chromatography (silica; CH2C12) afforded an off-white solid, (1.1 g, 38%): 1H NMR (300 MHz, DMSO-c?6) δ 7.96 - 7.92 (, IH), 7.63 (app q, J= 8 Hz, IH), 7.37 - 7.28 (m, 4H), 7.16 (app t, J= 6 Hz, IH), 6.62 (d, J= 8 Hz, IH), 5.30 (s, 2H), 5.14 (s, 2H), 4.90 (s, 2H), 4.74 (s, 2H), 4.67 (s, 2H).
Step 5. Preparation of title compound. To solution of zinc dust (0.6 g, 9.1 mmol) in a 5 mL solution of NH4OAc (1.0 M in water) was added a solution of 5-[3-chloro-4- (2,4-difluorobenzyloxy)-2-oxo-pyridin-l(2H)-ylmethyl]-l,3-dihydroisoindole-2- carboxylic acid 2,2,2-trichloroethyl ester (1.1 g, 1.8 mmol) in 25 mL of THF. The reaction mixture stined at room temperature for 4.5 hr. The solution was adjusted to pH 8 using a saturated solution of NaHC03, and extracted 3 times with CH2C12. The combined organics were washed with brine, dried (Na2S04), filtered and evaporated on a rotary evaporator. Purification by preparatory HPLC (Phenomenex Luna 10 μ, C18(2) 250 x 21.2 mm) provided an off-white solid (0.08 g, 11%): 1H NMR (300 MHz, DMSO- ) δ 9.30 (br s, IH), 7.96 (d, J= 8 Hz, IH), 7.63 (app q, J = 9 Hz, IH), 7.39 - 7.30 (m, 4H), 7.16 (app t, J= 2 Hz, IH), 6^64 (d, J= 8 Hz, IH), 5.30 (s, 2H), 5.15 (s, 2H), 4.47 (br s, 4H). ES-HRMS m/z 403.1004 (M+H calcd for C21H18C1F2N202 requires 403.1019).
900 Example 878
Figure imgf000901_0001
3-Chloro-4-(2,4-difluorobenzyloxy)-l-(3-morpholin-4-ylmethyl-lH-indol-5-ylmethyl)- pyridin-2 ( 1 H)-one
Step 1. The title compound was prepared by a procedure similar to the one described for Example 875 (0.16 g, 43%): 1H NMR (300 MHz, DMSO-d6) δ 10.97 (br s, IH), 7.91 (d, J = 8 Hz, IH), 7.63 - 7.57 (m, 2H), 7.37 - 7.05(m, 5H), 6.58 (d, J= 8 Hz, IH), 5.28 (s, 2H), 5.19 (s, 2H), 3.58 - 3.53 (m, 6H), 2.33 (br s, 4H). ES-HRMS m/z 500.1443 (M+H calcd for C26H25C1F2N303 requires 500.1547).
Example 879
Figure imgf000901_0002
3-Chloro-4-(2,4-difluoro-benzyloxy)-l-(3-piperidin-l-ylmethyl-lH-indol-5-ylmethyl)- pyridin-2( 1 H)-one
Step 1. The title compound was prepared by a procedure similar to the one described for Example 875 (0.18 g, 48%): 1H NMR (300 MHz, DMSO-d6) δ 10.92 (br s, IH), 7.90 (d, J = 8 Hz, IH), 7.62 - 7.57 (m, 2H), 7.37 - 7.27 (m, 2H), 7.18 - 7.12 (m, 2H), 7.05 (d, J= 8 Hz, IH), 6.58 (d, J= 8 Hz, IH), 5.28 (s, 2H), 5.18 (s, 2H), 3.53 (s, 2H), 2.30 (br s, 4H), 1.43 - 1.35 (m, 6H). ES-HRMS m/z 498.1727 (M+H calcd for C27H27C1F2N302 requires 498.1754).
- 901 - Example
Figure imgf000902_0001
3-Chloro-4-(2,4-difluorobenzyloxy)-l-(3-methylaminomethyl-lH-indol-5-ylmethyl)- pyridin-2( 1 H)-one
Step 1. The title compound was prepared by a procedure similar to the one described for Example 875 (0.06 g, 18%): 1H NMR (300 MHz, DMSO- 6) δ 11.05 (s, IH), 7.90 (d, J= 7.7 Hz, IH), 7.67 - 7.57 (m, 2H), 7.37 - 7.29 (m, 3H), 7.17 - 7.07 (m, 2H), 6.57 (d, J= 7.8 Hz, IH), 5.40 (br s, IH), 5.28 (s, 2H), 5.18 (s, 2H), 3.91 (s, 2H), 2.38 (s, 3H). ES-HRMS m/z 444.1266 (M+H calcd for C23H21C1F2N302 requires 444.1285).
Example 881
Figure imgf000902_0002
3-[3-Bromo-4-(2,4-difluorophenoxymethyl)-6-methyl-2-oxo-pyridin-l(2H)-yl]-4,N- dimethyl benzamide Step 1. Preparation of l-(5-methoxycarbonyl-2-methylphenyl)-6-methyl-2-oxo-
1 ,2-dihydropyridine-4-carboxylic acid.
Figure imgf000902_0003
6-Methyl-2-oxo-2H-pyran-4-carboxylic acid (Hasizume, K. et al. Chem. Pharm.
Bull. 1968, 16, 2292-2296) (3.4g, 22 mmol) and 3-amino-4-methyl-benzoic acid methyl
902 ester (3.6 g, 22 mmol) were suspended 110 mL of 1-butanol, and stined at 120 °C for 24 h. The reaction was cooled room temperature, and the solvent was evaporated on a rotary evaporator. The residue was diluted with a saturated solution of NaHC03, and washed 3 times with EtOAc. The aqueous layer was acidified to pH 3 the concenfrated HCl, and exfracted 3 times with EtOAc. The combined organics were washed with brine, dried (MgS04), filtered, and evaporated on a rotary evaporator to provide a white solid (2.1 g, 32%): 1H NMR (300 MHz, DMSO-dβ) δ 14.01 (br s, IH), 7.98 (dd, J= 7.9, 1.6 Hz, IH), 7.76 (d, J= 1.4 Hz, IH), 7.60 (d, J= 7.9, IH), 6.84 (s, IH), 6.67 (s, IH), 3.85 (s, 3H), 2.04 (s, 3H), 1.90 (s, 3H).
Step 2. Preparation of 3-(4-hydroxymethyl-6-methyl-2-oxo-pyridin-l(2H)-yl)-4- methyl benzoic acid methyl ester.
Figure imgf000903_0001
1 -(5-Methoxycarbonyl-2-methylphenyl)-6-methyl-2-oxo- 1 ,2-dihydropyridine-4- carboxylic acid (2.1 g, 7.0 mmol) and triethylamine (1.5 mL, 10 mmol) were dissolved in 20 mL of THF, and cooled to 0 °C. To this reaction mixture was added ethyl chloroformate (1.0 mL, 10 mmol). After 1 h. the solid was filtered, the filtrate was cooled to 0 °C, sodium borohydride (0.26 g, 7.0 mmol) was added, and 20 mL of water was added dropwise. The reaction was warmed to room temperatures stined for 3 h. The reaction solvent was evaporated on a rotary evaporator to provide a light yellow oil (1.6 g, 80%): 1H NMR (300 MHz, CDC13) δ 8.02 (dd, J = 7.9, 1.7 Hz, IH), 7.77 (d, J = 1.6 Hz, IH), 7.45 (d, J= 7.9 Hz, IH), 6.55 (s, IH), 6.18 (s, IH), 4.51 (d, J= 5.0 Hz, 2H), 3.89 (s, 3H), 2.14 (s, 3H), 1.88 (s, 3H). Step 3. Preparation of 3-(4-bromomethyl-6-methyl-2-oxo-pyridin-l(2H)-yl)-4- methyl benzoic acid methyl ester.
903
Figure imgf000904_0001
3 -(4-Hydroxymethyl-6-methyl-2-oxo-pyridin- 1 (2H)-yl)-4-methyl benzoic acid methyl ester (1.6 g, 5.6 mmol), triphenylphosphine (1.8 g, 6.7 mmol), and carbon tetrabromide (2.2 g, 6.7 mmol) were dissolved in 20 mL of methylene chloride, and stined for 30 min. The solvent was evaporated on a rotary evaporator. Purification by flash column chromatography (silica; EtOAc) provided a light yellow solid (0.3 g, 16%): !H NMR (300 MHz, CDC13) δ 8.05 (dd, J= 8.0, 1.7 Hz, IH), 7.79 (d, J= 1.7 Hz, IH), 7.45 (d, J= 8.0, IH), 6.54 (d, J= 1.0 Hz, IH), 6.20 (d, J= 1.0 Hz, IH), 4.23 (s, 2H), 3.89 (s, 3H), 2.15 (s, 3H), 1.90 (s, 3H).
Step 4. Preparation of 3-[4-(2,4-difluorophenoxymethyl)-6-methyl-2-oxo-pyridin- l(2H)-yl]-4-methyl benzoic acid methyl ester.
Figure imgf000904_0002
3-(4-Bromomethyl-6-methyl-2-oxo-pyridin-l(2H)-yl)-4-methyl benzoic acid methyl ester (0.3 g, 0.86 mmol), cesium carbonate (0.56 g, 1.7 mmol), and 2,4- difluorophenol (0.1 mL, 1.0 mmol) were dissolved in 10 mL of dioxane, and stined at 105 °C for 12 h. The reaction was cooled room temperature, diluted with EtOAc, washed with water, brine, dried (MgS04), filtered, and evaporated on a rotary evaporator to provide a light yellow oil (0.27 g, 80%): 1H NMR (300 MHz, CDC13) δ 8.04 (dd, J = 8.0, 1.7 Hz, IH), 7.79 (d, J= 1.7 Hz, IH), 7.45 (d, J= 8.0, IH), 6.96 - 6.80 (m, 3H), 6.62 (s, IH), 6.28 (s, IH), 4.95 (s, 2H), 3.89 (s, 3H), 2.15 (s, 3H), 1.92 (s, 3H).
Step 5. Preparation of 3-[3-bromo-4-(2,4-difluorophenoxymethyl)-6-methyl-2- oxo-pyridin-l(2H)-yl]-4-methyl benzoic acid methyl ester.
904 -
Figure imgf000905_0001
3-[4-(2,4-Difluorophenoxymethyl)-6-methyl-2-oxo-pyridin-l(2H)-yl]-4-methyl benzoic acid methyl ester (0.27 g, 0.68 mmol) was dissolved in 3 mL of acetic acid, cooled to 0 °C, and a solution of bromine (0.04 mL, 0.72 mmol) in 1 mL of acetic acid was added dropwise. The reaction was warmed to room temperature, and stined for 2 h. The solvent was evaporated on a rotary evaporator to provide a yellow oil (0.32 g, 100%): lR NMR (300 MHz, CDC13) δ 8.06 (dd, J= 6.6, 1.3 Hz, IH), 7.75 (d, J= 1.1 Hz, IH), 7.47 (d, J= 7.9, IH), 7.13 - 7.08 (m, IH), 6.94 - 6.81 (m, 2H), 6.62 (s, IH), 5.39 (s, 2H), 3.90 (s, 3H), 2.16 (s, 3H), 2.15 (s, 3H).
Step 6. Preparation of 3-[3-bromo-4-(2,4-difluorophenoxymethyl)-6-methyl-2- oxo-pyridin-l(2H)-yl]-4-methyl benzoic acid.
Figure imgf000905_0002
3-[3-Bromo-4-(2,4-difluorophenoxymethyl)-6-methyl-2-oxo-pyridin-l(2H)-yl]-4- methyl-benzoic acid methyl ester (0.32 g, 0.68 mmol) was dissolved in 2.0 mL of MeOH, and a solution of KOH (2.0 mL of a 1.0 M solution in water, 2.0 mmol). After 3 h. the solvent was evaporated on a rotary evaporator. The residue was dissolved in water and washed 2 times with diethyl ether. The aqueous layer was acidified to pH 3 with 1 N HCl, and extracted 3 times with 3:1 CHCl3/isopropanol. The combined organics were washed with brine, dried (MgS04), filtered, and evaporated on a rotary evaporator to provide a off- white solid (0.27 g, 87%): 1H NMR (300 MHz, CDC13) δ 8.10 (dd, J= 7.9, 1.4 Hz, IH), 7.80 (d, J= 1.4 Hz, IH), 7.50 (d, J= 7.9, IH), 7.13 - 7.08 (m, IH), 6.95 - 6.90 (m, IH), 6.88 - 6.81 (m, IH), 6.62 (s, IH), 5.40 (s, 2H), 2.16 (s, 3H), 2.15 (s, 3H).
905 - Step 7. The title compound was prepared by a procedure similar to the one described for Example 656 (0.02 g, 7%): 1H NMR (300 MHz, DMSO-d6) δ 7.76 - 7.43 (m, 3H), 6.97 - 6.81 (m, 4H), 6.39 (br s, IH), 5.01 (s, 2H), 2.91 (s, 3H), 2.13 (s, 3H), 2.11 (s, 3H). ). ES-HRMS m/z 477.0610 (M+H calcd for C22H20BrF2N2O3 requires 477.0620).
Example 882
Figure imgf000906_0001
3-Chloro-4-(2,4-difluorobenzyloxy)-l-(3-piperazin-l-ylmethyl-lH-indol-5-yl-methyl)- pyridin-2(lH)-one dihydrochloride salt
Step 1. Preparation of 4-{5-[3-Chloro-4-(2,4-difluorobenzyloxy)-2-oxo-pyridin- l(2H)-ylmethyl]-lH-indol-3-yl-methyl}-piperazine-l-carboxylic acid tert-butyl ester.
Figure imgf000906_0002
A suspension of paraformaldehyde (0.03 mg, 0.85 mmol), acetic acid (0.05 mL, 0.85 mmol), and tert-Butyl 1-piperazine-carboxylate (0.16, 0.85 mmol) in 3 mL of EtOH was stined at 80 °C until a homogeneous solution formed. The reaction was cooled to room temperature, a solution of the compound from Example 874 (0.3 g, 0.75 mmol) in 3.0 mL EtOH was added, and the resulting reaction mixture was stined at 80 °C for 18 h. The reaction was cooled to room temperature and evaporated on a rotary evaporator. Purification by flash column chromatography (silica, 90:10 CHCl3/MeOH) gave an off- white solid (0.17 g, 38%): 1H NMR (300 MHz, DMSO- ) δ 10.97 (s, IH), 7.91 (d, J= 8
- 906 - Hz, IH) 7.63 - 7.57 (m, 2H), 7.35 - 7.04 (m, 5H), 6.58 (d, J= 8 Hz, IH), 5.28 (s, 2H), 5.18 (s, 2H), 3.60 (s, 2H), 3.26 (br s, 4H), 2.29 (br s, 4H), 1.36 (s, 9H).
Step 2. Preparation of title compound. 4-{5-[3-Chloro-4-(2,4-difluorobenzyloxy)- 2-oxo-pyridin-l(2H)-yl-methyl]-lH-indol-3-ylmethyl}-piperazine-l-carboxylic acid tert- butyl ester (0.17 g, 0.28 mmol) was diluted with a solution of HCl (4 mL of a 4.0 M solution in dioxane, 1.0 mmol) and the reaction was stined at room temperature for 2 h. The solvent was evaporated on a rotary evaporator to afford a tan solid (0.15 g, 99%): H NMR (300 MHz, DMSO-d6) δ 11.62 (br s, 2H), 9.57 br s, IH), 9.21 (br s, IH), 7.96 - 7.91 (m, 2H) 7.69 - 7.60 (m, 2H), 7.43 - 7.31 (m, 2H), 7.19 - 7.12 (m, 2H), 6.57 (d, J= 8 Hz, IH), 5.29 (s, 2H), 5.20 (s, 2H), 4.54 (br s, 2H), 3.70 - 3.30 (m, 7H). ES-HRMS m/z 499.1718 (M+H calcd for C26H26C1F2N402 requires 499.1707).
Example 883
Figure imgf000907_0001
3-Chloro-4-(2,4-difluorobenzyloxy)-l-{3-[(2-hy(hOxyethylamino)methyl]-lH-indol-5- ylmethyl} -pyridin-2( 1 H)-one
Step 1. The title compound was prepared by a procedure similar to the one described for Example 875 (0.04 g, 13%): 1H NMR (300 MHz, DMSO-d6) δ 11.05 (br s, 2H), 7.90 (d, J= 7.7 Hz, IH), 7.68 - 7.57 (m, 2H), 7.37 - 7.29 (m, 3H) 7.16 (app t, J= 8.7 Hz, IH), 7.09 (d, J= 8.5 Hz, IH), 6.57 (d, J= 7.8 Hz, IH), 5.28 (s, 2H), 5.19 (s, 2H), 4.65 (br s, IH), 3.97 (s, 2H), 3.53 (br s, 2H), 2.73 (t, J= 5.5 Hz, 2H). ES-HRMS m/z 474.1418 (M+H calcd for C24H23C1F2N303 requires 474.1391).
907 Example 884
Figure imgf000908_0001
3-Chloro-4-(2,4-difluorobenzyloxy)-l-{3-[(2-dimethylaminoethylamino)methyl]-lH- indol-5-ylmethyl}-pyridin-2(lH)-one Step 1. The title compound was prepared by a procedure similar to the one described for Example 875 (0.11 g, 29%): 1H NMR (300 MHz, DMSO-d6) δ 10.98 (s, IH), 7.89 (d, J= 8 Hz, IH), 7.63 - 7.57 (m, 2H), 7.36 - 7.29 (m, 3H), 7.18 - 7.07 (m, 2H), 6.56 (d, J= 8 Hz, IH), 5.28 (s, 2H), 5.18 (s, 2H), 3.90 (s, 2H), 3.39 (br s, IH), 2.68 (t, J= 6 Hz, 2H), 2.34 (t, J= 6 Hz, 2H), 2.10 (s, 6H). ES-HRMS m/z 501.1870 (M+H calcd for C26H18C1F2N402 requires 501.1863).
BIOLOGICAL EVALUATION p38 Kinase Assay Cloning of human p38a: The coding region of the human p38a cDNA was obtained by PCR-amplification from RNA isolated from the human monocyte cell line THP.l. First strand CDNA was synthesized from total RNA as follows: 2 μg of RNA was annealed to 100 ng of random hexamer primers in a 10 μl reaction by heating to 70° C. for 10 minutes followed by 2 minutes on ice. cDNA was then synthesized by adding 1 μl of RNAsin (Promega, Madison Wis.), 2 μl of 50 mM dNTP's, 4 μl of 5X buffer, 2 μl of 100 mM DTT and 1 μl (200 U) of Superscript II™ AMV reverse transcriptase. Random primer, dNTP's and Superscript II™ reagents were all purchased from Life-Technologies, Gaithersburg, Mass. The reaction was incubated at 42° C. for 1 hour. Amplification of p38 cDNA was performed by aliquoting 5 μl of the reverse transcriptase reaction into a 100 μl PCR reaction containing the following: 80 μl dH.sub.2 O, 2 . μl 50 mM dNTP's, 1 μl each of forward and reverse primers (50 pmol/μl), 10 μl of 10X buffer and 1 μl Expand™
- 908 - polymerase (Boehringer Mannheim). The PCR primers incorporated Bam HI sites onto the 5' and 3' end of the amplified fragment, and were purchased from Genosys. The sequences of the forward and reverse primers were 5'- GATCGAGGATTCATGTCTCAGGAGAGGCCCA-3' and 5'GATCGAGGATTCTCAGGACTCCATCTCTTC-3' respectively. The PCR amplification was carried out in a DNA Thermal Cycler (Perkin Elmer) by repeating 30 cycles of 94° C. for 1 minute, 60° C. for 1 minute and 68° C. for 2 minutes. After amplification, excess primers and unincorporated dNTP's were removed from the amplified fragment with a Wizard™ PCR prep (Promega) and digested with Bam HI (New England Biolabs). The Bam HI digested fragment was ligated into BamHI digested pGEX 2T plasmid DNA (PharmaciaBiotech) using T-4 DNA ligase (New England Biolabs) as described by T. Maniatis, Molecular Cloning: A Laboratory Manual, 2nd ed. (1989). The ligation reaction was transformed into chemically competent E. coli DH10B cells purchased from Life-Technologies following the manufacturer's instructions. Plasmid DNA was isolated from the resulting bacterial colonies using a Promega Wizard™ miniprep kit. Plasmids containing the appropriate Bam HI fragment were sequenced in a DNA Thermal Cycler (Perkin Elmer) with Prism™ (Applied Biosystems Inc.). cDNA clones were identified that coded for both human p38a isoforms (Lee et al. Nature 372, 739). One of the clones that contained the cDNA for p38a-2 (CSB-2) inserted in the cloning site of PGEX 2T, 3' of the GST coding region was designated pMON 35802. The sequence obtained for this clone is an exact match of the cDNA clone reported by Lee et al. This expression plasmid allows for the production of a GST-p38a fusion protein. Expression of human p38a GST/p38a fusion protein w as expressed from the plasmid pMON 35802 in E. coli, stain DH10B (Life Technologies, Gibco-BRL). Overnight cultures were grown in Luria Broth (LB) containing 100 mg/ml ampicillin. The next day, 500 ml of fresh LB was inoculated with 10 ml of overnight culture, and grown in a 2 liter flask at 37° C. with constant shaking until the culture reached an absorbance of 0.8 at 600 nm. Expression of the fusion protein was induced by addition of isopropyl b-D-thiogalactosidase TPTG) to a final concenfration of 0.05 mM. The cultures were shaken for three hours at room temperature, and the cells were harvested by centrifugation. The cell pellets were stored frozen until protein purification. - 909 - Purification of P38 Kinase-alpha All chemicals were from Sigma Chemical Co. unless noted. Twenty grams of E. coli cell pellet collected from five 1 L shake flask fermentations was resuspended in a volume of PBS (140 mM NaCl, 2.7 mM KC1, 10 mM Na.sub.2 HPO.sub.4, 1.8 mM KH.sub.2 PO.sub.4, pH 7.3) up to 200 ml. The cell suspension was adjusted to 5 mM DTT with 2 M DTT and then split equally into five 50 ml Falcon conical tubes. The cells were sonnicated (Ultrasonics model W375) with a 1 cm probe for 3. times.1 minutes (pulsed) on ice. Lysed cell material was removed by centrifugation (12,000 x g, 15 minutes) and the clarified supernatant applied to glutathione-sepharose resin (Pharmacia).
Glutathione-Sepharose Affinity Chromatography Twelve ml of a 50% glutathione sepharose-PBS suspension was added to 200 ml clarified supernatant and incubated batchwise for 30 minutes at room temperature. The resin was collected by centrifugation (600.times.g, 5 min) and washed with 2.times.l50 ml PBS/1% Triton X-100, followed by 4.times.40 ml PBS. To cleave the p38 kinase from the GST-p38 fusion protein, the glutathione-sepharose resin was resuspended in 6 ml PBS containing 250 units thrombin protease (Pharmacia, specific activity >7500 units/mg) and mixed gently for 4 hours at room temperature. The glutathione-sepharose resin was removed by centrifugation (600.times.g, 5 min) and washed 2.times.6 ml with PBS. The PBS wash fractions and digest supernatant containing p38 kinase protein were pooled and adjusted to 0.3 mM PMSF.
Mono Q Anion Exchange Chromatography The thrombin-cleaved p38 kinase was further purified by FPLC-anion exchange chromatography. Thrombin-cleaved sample was diluted 2-fold with Buffer A (25 mM HEPES, pH 7.5, 25 mM beta-glycerophosphate, 2 mM DTT, 5% glycerol) and injected onto a Mono Q HR 10/10 (Pharmacia) anion exchange column equilibrated with Buffer A. The column was eluted with a 160 ml 0.1 M-0.6 M NaCl/Buffer A gradient (2 ml/minute flowrate). The p38 kinase peak eluting at 200 mM NaCl was collected and concenfrated to 3-4 ml with a Filtron 10 concentrator (Filfron Corp.).
910 Sephacryl SI 00 Gel Filfration Chromatography The concentrated Mono Q- p38 kinase purified sample was purified by gel filfration chromatography (Pharmacia HiPrep 26/60 Sephacryl SI 00 column equilibrated with Buffer B (50 mM HEPES, pH 7.5, 50 mM NaCl, 2 mM DTT, 5% glycerol)). Protein was eluted from the column with Buffer B at a 0.5 ml/minute flowrate and protein was detected by absorbance at 280 nm. Fractions containing p38 kinase (detected by SDS- polyacrylamide gel electrophoresis) were pooled and frozen at -80° C. Typical purified protein yields from 5 L E. coli shake flasks fermentations were 35 mg p38 kinase.
In Vitro Assay ' The ability of compounds to inhibit human p38 kinase alpha was evaluated using two in vitro assay methods. In the first method, activated human p38 kinase alpha phosphorylates a biotinylated substrate, PHAS-I (phosphorylated heat and acid stable protein-insulin inducible), in the presence of gamma 32P-ATP (32P-ATP). PHAS-I was biotinylated prior to the assay and provides a means of capturing the substrate, which is phosphorylated during the assay. p38 Kinase was activated by MKK6. Compounds were tested in 10 fold serial dilutions over the range of 100 μM to 0.001 μM using 1% DMSO. Each concenfration of inhibitor was tested in triplicate. All reactions were carried out in 96 well polypropylene plates. Each reaction well contained 25 mM HEPES pH 7.5, 10 mM magnesium acetate and 50 μM unlabeled ATP.
Activation of p38 was required to achieve sufficient signal in the assay. Biotinylated
PHAS-I was used at 1-2 μg per 50 μl reaction volume, with a final concentration of 1.5 μM. Activated human p38 kinase alpha was used at 1 μg per 50 μl reaction volume representing a final concentration of 0.3 μM. Gamma 32P-ATP was used to follow the phosphorylation of PHAS-I. 32P-ATP has a specific activity of 3000 Ci/mmol and was used at 1.2 μCi per 50 μl reaction volume. The reaction proceeded either for one hour or overnight at 30° C. Following incubation, 20 μl of reaction mixture was fransfened to a high capacity streptavidin coated filter plate (SAM-sfreptavidin-matrix, Promega) prewetted with phosphate buffered saline. The fransfened reaction mix was allowed to contact the streptavidin membrane of the Promega plate for 1-2 minutes. Following capture of biotinylated PHAS-I with 32P incorporated, each well was washed to remove - 911 - unincorporated 32P-ATP three times with 2M NaCl, three washes of 2M NaCl with 1% phosphoric, three washes of distilled water and finally a single wash of 95% ethanol. Filter plates were air-dried and 20 μl of scintillant was added. The plates were sealed and counted. A second assay format was also employed that is based on p38 kinase alpha induced phosphorylation of EGFRP (epidermal growth factor receptor peptide, a 21 mer) in the presence P-ATP. Compounds were tested in 10 fold serial dilutions over the range of 100 μM to 0.001 μM in 1%> DMSO. Each concentration of inhibitor was tested in triplicate. Compounds were evaluated in 50 μl reaction volumes in the presence of 25 mM Hepes pH 7.5, 10 mM magnesium acetate, 4% glycerol, 0.4% bovine serum albumin, 0.4mM DTT, 50 μM unlabeled ATP, 25 μg EGFRP (200 μM), and 0.05 μCi 33P-ATP. Reactions were initiated by addition of 0.09 μg of activated, purified human GST-p38 kinase alpha. Activation was carried out using GST-MKK6 (5:l,p38:MKK6) for one hour at 30° C. in the presence of 50 μM ATP. Following incubation for 60 minutes at room temperature, the reaction was stopped by addition of 150 μl of AG l.times.8 resin in 900 mM sodium formate buffer, pH 3.0 (1 volume resin to 2 volumes buffer). The mixture was mixed three times with pipetting and the resin was allowed to settle. A total of 50 μl of clarified solution head volume was fransfened from the reaction wells to Microlite-2 plates. 150 μl of Microscint 40 was then added to each well of the Microlite plate, and the plate was sealed, mixed, and counted. Representative compounds that exibit ICso values between 1 and 25 μM (p38 alpha kinase assay) are: Example Nos. 20, 22, 23, 39, 43, 44, 48, 50, 52, 53, 55, 57, 58, 62, 92, 115, 118, 136, 139, 141, 142, 149, 156, 157, 169, 174, 219, 220, 244, 245, 387, 288, 289, 291, 292, 293, 294, 295, 296, 298, 297, 300, 301, 302 304, 305, 309, 310, 311, 323, 360, 394, 403, 414, 415, 416, 418, 420, 444, 447, 449, 451, 452, 471, 485, 486, 496, 498, 499, 503, 506, 561, 569, 574, 575, 576, 738, 812, and 837. Representatve compounds that exibit IC50 values between 25 and 100 μM (p38 alpha kinase assay) are: Example Nos. 1, 25, 33, 35, 37, 42, 45, 47, 49, 119, 204, 308, 558, 560, 564, 565, 566, 568, 577, and 865. Representatve compounds that exibit ICso values less than 1 μM (p38 alpha kinase assay) are: Example Nos. 6, 14, 8, 17, 10, 15, 4, 117, 161, 162, 165, 170, 171, 172, 173 176, 179, 217, 218, 219, 220, 221, 223, 225, 230, 231, 234, 235, 272, 273, 275, 276, 278, - 912 - 280, 282, 286, 285, 290, 312, 313, 314, 315, 316, 317, 318, 320, 321, 322, 364, 366, 400, 402, 405, 421, 422, 423, 446, 448, 450, 458, 466, 467, 468, 469, 470, 481, 482, 483, 484, 487, 489, 492, 493, 494, 495, 504, 521, 522, 523, 557, 587, 589, 590, 591,, 597, 609, 610, 613, 629, 642, 643, 736, 757, 777, 785, 804, 807, 815, 838, 847, 849, and 863. Representatve compounds that exibit IC50 values greater than 100 μM (p38 alpha kinase assay) are: Example Nos. 3, 11, 38, 56, 116, 121, 237, 236, 413, 497 and 578.
TNF Cell Assays
Method of Isolation of Human Peripheral Blood Mononuclear Cells: Human whole blood was collected in Vacutainer tubes containing EDTA as an anticoagulant. A blood sample (7 ml) was carefully layered over 5 ml PMN Cell Isolation Medium (Robbins Scientific) in a 15 ml round bottom centrifuge tube. The sample was cenfrifuged at 450-500.times.g for 30-35 minutes in a swing out rotor at room temperature. After centrifugation, the top band of cells were removed and washed 3 times with PBS w/o calcium or magnesium. The cells were cenfrifuged at 400 .times.g for 10 minutes at room temperature. The cells were resuspended in Macrophage Serum Free Medium (Gibco BRL) at a concenfration of 2 million cells/mi. LPS Stimulation of Human PBMs PBM cells (0.1 ml, 2 million ml) were co-incubated with 0.1 ml compound (10- 0.41 μM, final concenfration) for 1 hour in flat bottom 96 well microtiter plates. Compounds were dissolved in DMSO initially and diluted in TCM for a final concenfration of 0.1% DMSO. LPS (Calbiochem, 20 ng/ml, final concenfration) was then added at a volume of 0.010 ml. Cultures were incubated overnight at 37° C. Supernatants were then removed and tested by ELISA for TNF-a and ILl-b. Viability was analyzed using MTS. After 0.1 ml supernatant was collected, 0.020 ml MTS was added to remaining 0.1 ml cells. The cells were incubated at 37° C. for 2-4 hours, then the O.D. was measured at 490-650 nM.
Maintenance and Differentiation of the U937 Human Histiocytic Lymphoma Cell Line U937 cells (ATCC) were propagated in RPMI 1640 containing 10% fetal bovine serum, 100 IU/ml penicillin, 100 μg/ml streptomycin, and 2 mM glutamine (Gibco). Fifty - 913 - million cells in 100 ml media were induced to terminal monocytic differentiation by 24 hour incubation with 20 ng/ml phorbol 12-myristate 13-acetate (Sigma). The cells were washed by centriftigation (200.times.g for 5 min) and resuspended in 100 ml fresh medium. After 24-48 hours, the cells were harvested, cenfrifuged, and resuspended in culture medium at 2 million cells/ml.
LPS Stimulation of TNF production by U937 Cells U937 cells (0.1 ml, 2 million/ml) were incubated with 0.1 ml compound (0.004-50 μM, final concentration) for 1 hour in 96 well microtiter plates. Compounds were prepared as 10 mM stock solutions in DMSO and diluted in culture medium to yield a final DMSO concenfration of 0.1% in the cell assay. LPS (E coli, 100 ng/ml final concenfration) was then added at a volume of 0.02 ml. After 4 hour incubation at 37° C, the amount of TNF-. alpha, released in the culture medium was quantitated by ELISA. Inhibitory potency is expressed as IC50 (μM).
Rat Assay The efficacy of the novel compounds in blocking the production of TNF also was evaluated using a model based on rats challenged with LPS. Male Harlen Lewis rats [Sprague Dawley Co.] were used in this model. Each rat weighed approximately 300 g and was fasted overnight prior to testing. Compound administration was typically by oral gavage (although infraperitoneal, subcutaneous and intravenous administration were also used in a few instances) 1 to 24 hours prior to the LPS challenge. Rats were administered 30 μg/kg LPS [salmonella typhosa, Sigma Co.] intravenously via the tail vein. Blood was collected via heart puncture 1 hour after the LPS challenge. Serum samples were stored at -20° C. until quantitative analysis of TNF-. alpha, by Enzyme Linked-Immuno-Sorbent Assay ("ELISA") [Biosource]. Additional details of the assay are set forth in Penetti, M., et al., Br. J. Pharmacol. (1993), 110, 868-874, which is incorporated by reference in this application.
914 Mouse Assay
Mouse Model of LPS-Induced TNF Alpha Production TNF alpha was induced in 10-12 week old BALB/c female mice by tail vein injection with 100 ng lipopolysaccharide (from S. Typhosa) in 0.2 ml saline. One hour later mice were bled from the refroorbital sinus and TNF concentrations in serum from clotted blood were quantified by ELISA. Typically, peak levels of serum TNF ranged from 2-6 ng/ml one hour after LPS injection. The compounds tested were administered to fasted mice by oral gavage as a suspension in 0.2 ml of 0.5% methylcellulose and 0.025% Tween 20 in water at 1 hour or 6 hours prior to LPS injection. The 1 hour protocol allowed evaluation of compound potency at Cmax plasma levels whereas the 6 hour protocol allowed estimation of compound duration of action. Efficacy was determined at each time point as percent inhibition of serum TNF levels relative to LPS injected mice that received vehicle only.
Induction and Assessment of Collagen-Induced Arthritis in Mice Arthritis was induced in mice according to the procedure set forth in J. M. Stuart, Collagen Autoimmune Arthritis, Annual Rev. Immunol. 2:199 (1984), which is incorporated herein by reference. Specifically, arthritis was induced in 8-12 week old DBA/1 male mice by injection of 50 μg of chick type II collagen (CH) (provided by Dr. Marie Griffiths, Univ. of Utah, Salt Lake City, Utah) in complete Freund's adjuvant (Sigma) on day 0 at the base of the tail. Injection volume was 100 μl. Animals were boosted on day 21 with 50 μg of CII in incomplete Freund's adjuvant (100 μl volume). Animals were evaluated several times each week for signs of arthritis. Any animal with paw redness or swelling was counted as arthritic. Scoring of arthritic paws was conducted in accordance with the procedure set forth in Wooley et al., Genetic Control of Type II Collagen Induced Arthritis in Mice: Factors Influencing Disease Suspectibility and Evidence for Multiple MHC Associated Gene Control, Trans. Proc, 15:180 (1983). Scoring of severity was carried out using a score of 1-3 for each paw (maximal score of 12/mouse). Animals displaying any redness or swelling of digits or the paw were scored as 1. Gross swelling of the whole paw or deformity was scored as 2. Ankylosis of joints was scored as 3. Animals were evaluated for 8 weeks. 8-10 animals per group were used. - 915 - The invention and the manner and process of making and using it, are now described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains, to make and use the same. It is to be understood that the foregoing describes prefened embodiments of the present invention and that modifications may be made therein without departing from the spirit or scope of the present invention as set forth in the claims. To particularly point out and distinctly claim the subject matter regarded as invention, the following claims conclude this specification.
916

Claims

We claim:
1. A compound or a pharmaceutically acceptable salt thereof, wherein: the compound conesponds in structure to the following formula:
Figure imgf000917_0001
Ri is H, halogen, N02, alkyl, carboxaldehyde, hydroxyalkyl, dihydroxyalkyl, arylalkoxy, arylalkyl, alkenyl, alkynyl, arylalkynyl, -CN, aryl, alkanoyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, carboxyl, or arylalkanoyl, wherein: the aryl portion of arylalkoxy, arylalkyl, and arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents that are independently halogen, Q- C4 alkyl, Q-Q alkoxy, nitro, CN, haloalkyl, haloalkoxy or C02R; the alkyl portion of the alkyl, hydroxyalkyl, dihydroxyalkyl, arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and arylalkanoyl is unsubstituted or substituted with 1, 2, or 3 substituents that are independently halogen, Q-Q alkoxy, Q-Q alkoxycarbonyl, or Q-Q cycloalkyl; R2 is H, OH, halogen, -OS02-(Q-Q) alkyl, -OS02-aryl, arylalkoxy, aryloxy, arylthio, arylthioalkoxy, arylalkynyl, alkoxy, aryloxy(Q-C6)alkyl, alkyl, alkynyl, -OC(0)NH(CH2)naryl, -OC(0)N(alkyl)(CH2)naryl, alkoxyalkoxy, dialkylamino, alkyl, alkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylalkenyl, heterocycloalkyl, heterocycloalkylalkyl, alkoxyalkoxy, NR8R9, dialkylamino, or C02R, wherein: each such substituent is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents that are independently halogen, -(Q-C6)alkyl-N(R)-CO2R30, -(Q-Q alkyl)-NR6C(0)NR7-(Q-C6 alkoxy), -(Q-Q alkyl)-NR16C(0)NR17-(C3-C6 cycloalkyl), -{Q-Q alkyl)-NR16C(0)NR17-(C3-C6 cycloalkylalkyl), -(Q-Q alkyl)-NR16C(0)NR17-(heteroaryl) wherein the heteroaryl is optionally substituted with Q-Q alkyl, Q-Q alkoxy, halogen or OH, haloalkyl, heteroaryl, heteroarylalkyl, -NReR7, R6R7N-(Q-Q alkyl)-, -(Q-Q alkyl)-NR6(CO)NR7-(Q- Q alkoxy), -C(0)NR6R7, -(Q-Q)alkyl-C(0)NR6R7, -(Q-Q alkyl)- NRC(0)NR16R17, haloalkoxy, alkyl, CN, hydroxyalkyl, dihydroxyalkyl, alkoxy,
- 917 - alkoxycarbonyl, phenyl, -S0 -phenyl wherein the phenyl and -S02-phenyl substituents are optionally substituted with 1, 2, or 3 substituents that are independently halogen or N02, or -OC(0)NR<5R7; ' n is O, 1, 2, 3, 4, 5 or 6; as to R16 and R17: R1 and R17 are independently H, Q-Q alkyl, or Q-Q alkoxy; or R16, Rn, and the nitrogen to which they are attached form a morpholinyl ring; as to Rό and R^ R6 and R7 are independently at each occunence H, alkyl optionally substituted with NRι6R17 or heteroaryl, hydroxyalkyl, dihydroxyalkyl, alkoxy optionally substituted with NR16R17, alkanoyl, arylalkyl, arylalkoxy, -NR16S02- alkyl, -NR16S0 -phenyl, alkoxycarbonyl, -S02-alkyl, -S02-aryl, OH, alkoxy, alkoxyalkyl, arylalkoxycarbonyl, -(Q-Q)alkyl-C02-alkyl, phenyl, heteroarylalkyl, heterocycloalkyloxy, alkenyl optionally substituted with -OC(0)NR6R7, aryl, heterocycloalkylalkanoyl, or arylalkanoyl, wherein: each such substituent is unsubstituted or substituted with 1, 2, or 3 substituents that are independently halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), - C(0)N(Q-Q alkylXQ-Q alky Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, alkoxy, heterocycloalkyl, heterocycloalkylalkyl, - OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy, or Re, R7, and the nitrogen to which they are attached form a moφholinyl, pynolidinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S- dioxide, piperidinyl, pynolidinyl, isoindole 1,3-dionyl, or piperazinyl ring which is optionally substituted with 1 or 2 substituents that are independently Q-Q alkyl, alkoxycarbonyl, Q-Q alkoxy, hydroxyl, hydroxyalkyl, dihydroxyalkyl, or halogen; R at each occunence is independently hydrogen or Q-Q alkyl optionally substituted with 1 or 2 substituents that are independently OH, SH, halogen, amino, monoalkylamino, dialkylamino or Q-Q cycloalkyl;
918 R30 is Q-Q alkyl optionally substituted with 1 or 2 substituents that are independently OH, SH, halogen, amino, monoalkylamino, dialkylamino or Q-Q cycloalkyl; each R8 is independently hydrogen, alkyl, alkanoyl, arylalkyl and arylalkanoyl, wherein: each such substituent is optionally substituted with 1, 2, 3, 4, or 5 substituents that are independently alkyl, alkoxy, alkoxycarbonyl, halogen, or haloalkyl; each R9 is hydrogen, alkyl, alkanoyl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, heteroaryl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, arylalkanoyl, - S02-phenyl, and aryl wherein: each such substituent is optionally substituted with 1, 2, 3, 4, or 5 substituents that are independently alkyl, alkoxy, alkoxycarbonyl, halogen, or haloalkyl; R3 is H, halogen, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl, -OC(0)NH(CH2)naryl, arylalkoxy, -OC(0)N(alkyl)(CH2)naryl, aryloxy, arylthio, thioalkoxy, arylthioalkoxy, alkenyl, -NR6R7,NR6R7-(C1-C6)alkyl, or alkyl, wherein: the aryl portion of arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl, -OC(0)NH(CH2)naryl, arylalkoxy, -OC(0)N(alkyl)(CH2)naryl, and arylthioalkoxy is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents that are independently, halogen, alkoxy, alkyl, haloalkyl, or haloalkoxy; R4 is hydrogen or Rj is alkyl unsubstituted or substituted with one or two substituents that are independently C02R, OH, -C02-(Q-Q)alkyl, -C(0)NR6R7, -C(0)R<s, -N(R30)C(O)NR6R7, -N(R30)C(O)-(Q-Q alkyl)-NR6R7, -OC(0)NR6R7, -OC(0)-(Q-Q alkyl), -N(R30)C(O)NR16R17, -N(R30)C(O)-(Q-C6)alkoxy, -N(R30)C(O)-(Q-Q alkyl)- NR6R7, or -NR6R7, -OC(0)NR17-alkyl-heteroaryl, arylalkoxy, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyalkyl, dihydroxyalkyl, haloalkyl, R6R7N-(Q-Q alkyl)-, -NR6R7, alkoxy, carboxaldehyde, -C(0)NR6R7, C02R, alkoxyalkyl, or alkoxyalkoxy, wherein: the heteroaryl or aryl portions of the above substituents are unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents that are independently halogen, hydroxy, alkoxy, alkyl, -C02-(Q-Q)alkyl, -CONReR/, -NReR7, R6R7N-(Q- Q)alkyl-, nitro, haloalkyl, or haloalkoxy; - 919 - R5 is H, or R5 is aryl, arylalkyl, arylthioalkyl, alkyl optionally substituted with 1, 2, or 3 substituents that are independently arylalkoxycarbonyl, -NR8R9, halogen, - C(0)NR8R9, alkoxycarbonyl, Q-Q cycloalkyl, or alkanoyl, alkoxy, alkoxyalkyl optionally substituted with one trimethylsilyl, amino, alkoxycarbonyl, hydroxyalkyl, dihydroxyalkyl, alkynyl, -S02-alkyl, alkoxy optionally substituted with one trimethylsilyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, -alkyl-S-aryl, -alkyl-S02-aryl, heteroarylalkyl, heterocycloalkyl, -heteroaryl-heterocycloalkyl, heteroaryl, or alkenyl optionally substituted with one substituent selected from the group consisting of alkoxycarbonyl, carboxyl, and -OC(0)NR6R7, wherein: each such substituent is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents that are independently alkyl optionally substituted with 1 or 2 substituents that are independently NR16R17, -NR16S02-alkyl, -NR16S02-phenyl, - OC(0)NH2, or-OC(0)NR16R17, OH, -OC(0)NR16R17, halogen, alkoxy wherein the alkyl is optionally substituted with NR16R17, -C(0)NR16R17, OH or Q-Q alkoxy, hydroxyalkyl, dihydroxyalkyl, arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, C02R, CN, OH, hydroxyalkyl, dihydroxyalkyl, -S02NR16R17j amidinooxime, -OC(0)NR6R7, -NR6R7, -NRsR9, R6R7N-(Q-C6 alkyl)-, carboxaldehyde, -S-alkyl wherein the alkyl is optionally substituted with NR16R17, -C(0)NR16R17, OH or Q-Q alkoxy, S02alkyl wherein the alkyl is optionally substituted with NR16R17, -C(0)NR16R17, OH or Q-Q alkoxy, -OC(0)-(Q-Q alkyl), -S02H, -S02NR6R7, alkanoyl wherein the alkyl portion is optionally substituted with OH, halogen, -OC(0)-(Q-Q alkyl), or alkoxy, -C(0)NR6R7, -(Q- Q alkyl)-C(0)NR6R7; heterocycloalkyl or heterocycloalkylalkyl, wherein the heterocycloalkyl is selected from the group consisting of morpholinyl, piperazinyl, tefrahydropyranyl, tefrahydrofuranyl, piperidinyl, pynolidinyl, and imidazolidinyl, heteroaryl which is selected from the group consisting of pyridyl, furanyl, pyrazolyl, and thienyl, alkoxyalkyl optionally substituted with NR16R17, amidino, haloalkyl, -(Q-Q alkyl)-NR15C(0)NR16R17, -(Q-Q alkyl)-NR15C(0)R18, -O- CH2-0, Q-Q alkenyl optionally substituted with -OC(0)NR6R7, Q-Q alkoxy, or OH, -0-CH2CH2-0-, or haloalkoxy; R15 is H or Q-Q alkyl; and
920 R18 is Q-Q alkyl optionally substituted with -0-(C2-Q alkanoyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, Ci-Ce alkoxy, Q-Q alkoxy Q-Q alkyl; amino Ci- Ce alkyl, mono or dialkylamino Q-Q alkyl. 2. A compound according to claim 1, wherein: Ri is halogen, Q-Q alkyl optionally substituted with Q-Q alkoxycarbonyl, Q-Q alkenyl optionally substituted with Q-Q alkoxycarbonyl, Q-Q alkynyl, or carboxaldehyde; R3 is H; and R is H, alkyl optionally substituted with one or two substituents that are independently C02R, OH, -C02alkyl, -C(0)NReR7, -OC(0)NReR7, -OC(0)-(Q-Q alkyl), -C(0)Re, -N(R30)C(O)NR6R7, -N(R3o)C(0)-(Q-C6)alkoxy, or -NR6R7, -C(0)NReR7, phenyl(Q-C6)alkoxy, phenyl(Q-Ce)alkyl, hydroxyalkyl, dihydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl, or alkoxyalkoxy, wherein: the phenyls are unsubstituted or substituted with 1,
2, 3, 4, or 5 substituents that are independently halogen, hydroxy, alkoxy, alkyl, nitro, CF3, or OCF3.
3. A compound according to claim 2, wherein: R2 is -OS02-phenyl, phenylalkoxy, phenyloxy, phenylthioalkoxy, phenylalkynyl, phenyloxy(Q-C6)alkyl, -OC(0)NH(CH2)nphenyl, -OC(0)N(alkyl)(CH2)nphenyl, pyridyl, pyrimidyl, thienyl, piperazinyl, imidazolidinyl, pynolidinyl, piperidinyl, tetrahydropyranyl, or tefrahydrofuranyl, wherein: each such substituent is substituted with 1, 2, 3, 4, or 5 substituents wherein at least one substituent is of the formula -(Q-Q aikyl)-NReC(0)NR7-(Q-Ce alkoxy), -(Q-Q alkyl)-NR6C(0)NR7-(Q-C6 alkyl) -(Q-Q alkyl)- NR16C(0)NR17-(C3-Q cycloalkylalkyl), -(Q-Q alkyl)-NRi6C(0)NR17- (heteroaryl) wherein the heteroaryl is optionally substituted with Q-Q alkyl, Q- Q alkoxy, halogen or OH, haloalkyl, or -(Q-Q alkyl)-NRieC(0)NR17-(C3-Ce cycloalkyl) and the other substituents, if present, are independently halogen, -NReR7, CF3, OCF3, Q-Q alkyl, -(Q-C4)alkyl-C(0)NR6R7, ReR7N-(Q-Q alkyl)-, -C(0)NReR7, -(Ci-C4 alkyl)-NRC(0)NRi6R17, CN, hydroxyalkyl, dihydroxyalkyl,
921 -OC(0)NReR7, or -(Q-Ce)alkyl-N(R)-CO2R30; as to R16 and R17: R16 and R17 at each occunence are independently H or Q-Q alkyl; or R16, R17 and the nifrogen to which they are attached form a morpholinyl ring; as to Re and R7: Re and R7 are independently at each occunence H, alkyl optionally substituted with NR16R17 or a heteroaryl group that is selected from thienyl, pyridyl, and furanyl, hydroxyalkyl, dihydroxyalkyl, alkoxy optionally substituted with NR16Ri75 Q-Q alkoxy Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, heterocycloalkyloxy, Q-Q alkenyl optionally substituted with -OC(0)NR16R17, - S02-phenyl, phenyl, heterocyloalkylalkanoyl, phenyl Q-Q alkoxy, phenyl Q-Q alkoxycarbonyl, or phenyl Q-Q alkanoyl, wherein: each such substituent is unsubstituted or substituted with 1, 2, or 3 substituents that are independently, halogen, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-C6 alkyl), -C(0)N(Q-C6 alkyl)(Q- Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, morpholinyl, pynolidinyl, piperazinyl, -OC(0)Q-C6 alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy; or R , R7, and the nifrogen to which they are attached form a morpholinyl, thiomoφholinyl, thiomoφholinyl S-oxide, thiomoφholinyl S,S-dioxide, piperidinyl, pynolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 substituents that are independently Q-Q alkyl, Q-Q alkoxycarbonyl, hydroxyl, hydroxy Q-Q alkyl, dihydroxy Q-Q alkyl, or halogen; n is 0, 1, 2, 3, 4, 5, or 6; R at each occurrence is independently H or Q-Q alkyl optionally substituted with 1 or 2 substituents that are independently OH, SH, halogen, amino, monoalkylamino, dialkylamino or Q-Q cycloalkyl; and R30 is Q-Q alkyl optionally substituted with 1 or 2 substituents that are independently OH, SH, halogen, amino, monoalkylamino, dialkylamino or Q-Q cycloalkyl.
922 -
4. A compound according to claim 3, wherein: R5 is:
Figure imgf000923_0001
Zi is H, halogen, Q-Q alkyl, CF3, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, or Q-Q alkoxy; and Z2 is Q-Q alkyl, -C(0)NReR7, -(Q-Q alkyl)-C(0)NReR7, -NR6R7, NR6R7(C1-C6 alkyl), Q-C6 hydroxyalkyl, Q-Q dihydroxyalkyl, halogen, Q-Q alkoxy, C02R, OH, Q- C6 alkoxycarbonyl, CF3, or C2-C6 alkenyl optionally substituted with C02H, or - OC(0)NR16R17; Z3 is H, halogen, Q-Q alkyl, Q-Q alkoxy, alkoxyalkyl, -S02-alkyl or Q-Q alkenyl, wherein: the alkyl, alkoxy, and alkenyl portions of such substituents are optionally substituted with 1, 2, or 3 substituents that are independently -OC(0)NR16Ri7, -C(0)NR16R17, OH, orNR16R17; and R6 and R7 at each occurrence are independently H, OH, Q-Q alkyl optionally substituted with heteroaryl that is selected from thienyl, pyridyl, and furanyl, amino Q-Q alkyl, NH(Q-C6 alkyl)alkyl, N(Q-Q alkyl)(Q-C6 alkyl) Q-Q alkyl, Q-Q hydroxyalkyl, Q-Ce dihydroxyalkyl, Q-Q alkoxy Q-Q alkyl, -S02(Q-Q alkyl), -S02NH2, -S02NH(Q-C6 alkyl), -S02N(Q-Q alkyl)(Q-C6 alkyl), or Q-Q alkanoyl, each of which is optionally substituted with 1, 2, or 3 substituents that are independently halogen, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-C6 alkyiXQ-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, moφholinyl, pynolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy.
5. A compound according to claim 4, wherein: R2 is benzyloxy or phenyl Q-Q thioalkoxy, each of which is substituted with 1, 2, 3, 4, or 5 substituents, wherein:
923 at least one substituent has the formula -(Q-Q alkyl)-NReC(0)NR7-(Q-Ce alkoxy) and the other substituents, if present, are independently halogen, amino, monoalkylamino, dialkylamino, CF3, OCF3, Q-Q alkyl, CN, hydroxyalkyl, or dihydroxyalkyl; R6 and R7 are independently at each occunence H, alkyl optionally substituted with
NR16R17 or heteroaryl that is selected from thienyl, pyridyl, and furanyl, hydroxyalkyl, dihydroxyalkyl, alkoxy optionally substituted withNR16Ri7, Q-Q alkoxy Q-Q alkyl, Q- Q alkanoyl, phenyl Q-Q alkyl, tetrahydropyranyloxy, tetrahydrofuranyloxy, piperidinyloxy, pynolidinyloxy, Q-Q alkenyl optionally substituted with -OC(0)NRι6R17, -S02-phenyl, phenyl, pynolidinyl Q-Q alkanoyl, piperidinyl Q-Q alkanoyl, phenyl Q-Q alkoxy, phenyl Q-Q alkoxycarbonyl, or phenyl Q-Q alkanoyl, wherein: each such substituent is unsubstituted or substituted with 1, 2, or 3 substituents that are independently, halogen, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-C6 alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, moφholinyl, pynolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q- Q haloalkoxy; and R16 and R17 at each occunence are independently H or Q-Q alkyl.
6. A compound according to claim 4, wherein: the compound conesponds in structure to the following formula:
Figure imgf000924_0001
k is O, 1, 2, 3, or 4; R18 is Q-Q alkyl; and
924 - R19 at each occunence is independently halogen, -NReR7, CF3, OCF3, Ci-C4 alkyl, -(Q-C4)alkyl-C(0)NReR7, ReR7N-(Q-C6 alkyl)-, -C(0)NReR7, -(Q-C4 alkyl)- NRC(0)NR16R17, CN, hydroxyalkyl, dihydroxyalkyl, -OC(0)NReR7, or -(Q-C6)alkyl- N(R)-CO2R30.
7. A compound according to claim 2, wherein: R2 is benzyloxy or phenyl Q-Q thioalkoxy, each of which is substituted with 1, 2, 3, 4, or 5 substituents independently selected from -(Q-Q aιkyι)-NR6C(0)NR7-(Q-C6 alkoxy), -(Q-Q alkyl)-NR16C(0)NRi7-(C3-C6 cycloalkyl), halogen, amino, monoalkylamino, dialkylamino, CF3, OCF3, Q-Q alkyl, CN, hydroxyalkyl, or dihydroxyalkyl; as to Re and R7: Re and R7 are independently at each occurrence H, alkyl optionally substituted with NR16R17 or heteroaryl that is selected from thienyl, pyridyl, and furanyl, hydroxyalkyl, dihydroxyalkyl, NR16R17, alkoxy optionally substituted with NRi6Ri7, Q-Q alkoxy Q-Q alkyl, OH, Q-Q alkanoyl, Q-Q cycloalkyl, phenyl Q-Q alkyl, tefrahydropyranyloxy, tetrahydrofuranyloxy, piperidinyloxy, pynolidinyloxy, Q-Q alkenyl optionally substituted with -OC(0)NR16R17, -S02- phenyl, -S02NR16Rι , -S02-Q-Q alkyl, phenyl, pynolidinyl Q-Q alkanoyl, piperidinyl Q-Q alkanoyl, pyridyl Q-Q alkanoyl, phenyl Q-Q alkoxy, phenyl Q-Q alkoxycarbonyl, or phenyl Q-Q alkanoyl, wherein: each such substituent is unsubstituted or substituted with 1, 2, or 3 substituents that are independently, halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), - C(0)N(Q-Q alkylXQ-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, moφholinyl, pynolidinyl, piperazinyl, - OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy; or Re, R , and the nitrogen to which they are attached form a moφholinyl, thiomoφholinyl, thiomoφholinyl S-oxide, thiomoφholinyl S,S-dioxide, piperidinyl, pyrrolidinyl, isoindole 1,3-dionyl, or piperazinyl ring which is optionally substituted with 1 or 2 substituents that are independently Q-Q alkyl,
925 Q-Q alkoxycarbonyl, hydroxyl, hydroxy Q-Q alkyl, dihydroxy Q-Q alkyl, or halogen; R16 and R17 at each occunence are independently H or Q-Q alkyl; and • ^ is H, hydroxyalkyl, or alkyl which is optionally substituted with one or two substituents that are independently C02R, OH, -C02alkyl, -C(0)NR6R7, -OC(0)NR6R7, - OC(0)-(Q-Q alkyl), -C(0)Re, -N(R30)C(O)NR6R7, -N(R30)C(O)-(Q-Q alkyl)-NReR7, -N(R30)C(O)-(C1-C6)alkoxy, or -NReR7.
8. A compound according to claim 7, wherein: R2 is benzyloxy substituted with 1, 2, 3, or 4 substituents that are independently halogen, -N 6R7, Q-Q haloalkyl, Q-Q haloalkoxy, Q-Q alkyl optionally substituted with -(Q-Q alkyl)-NReC(0)NR7-(C1-C6 alkoxy), -(C1-C4)alkyl-C(0)NR6R7, R6R7N-(C1- Q alkyl)-, -C(0)NR6R7, -(Q-C4 alkyl)-NRC(0)NR16R17, CN, hydroxyalkyl, dihydroxyalkyl, -OC(0)NReR7, or -(Q-C6)alkyl-N(R)-CO2R30; R5 is selected from the group consisting of H, phenyl(Q-Q)alkyl, (Q-Ce)alkyl optionally substituted with 1, 2, 3, 4, or 5 substituents that are independently phenyl Q-Q alkoxycarbonyl, -NR8R9, halogen, -C(0)NR8R , alkoxycarbonyl, or alkanoyl, phenyl, alkoxy, Q-Q alkynyl, Q-Q alkenyl optionally substituted with alkoxycarbonyl, C02H, or -OC(0)NR16Ri7, indolyl, indolinyl, quinolinyl, isoquinolinyl, benzothiazolyl, isoindolyl, dihydroindolyl, pyrazolyl, isobenzofuranonyl, imidazolyl, pyridyl, pyrimidyl, pyrazinyl, dihydroisoindolyl, benzimidazolyl, indolon-2-yl, indazolyl, benzimidazolyl, imidazolidine dione, pyrazolyl(Q-C6 alkyl), imidazoryl(Q-Ce alkyl), piperidinyl(Q- Q)alkyl, pynoιidinyl(Ci-C6)alkyl, imidazolidinyl(Q-C6)alkyl, lH-indazolyl(Q-C6)alkyl, dihydroindolon-2-yl(Ci-C6 alkyl), isobenzofuranonyl(Q-C6 alkyl), benzothiazolyl(Q-C6 alkyl), indofinyl(Q-C6 alkyl), dihydrobenzimidazolyl(Q-C6 alkyl), or dihydrobeιιzoinιidazoιonyl(Q-Ce alkyl), pyridyl (Q-Q) alkyl, pyridazinyl (Q-Q) alkyl, pyrimidinyl (Q-Q) alkyl, pyrazinyl (Q-Q) alkyl, tetrahydrofuryl(Q-C6)alkyl, naphthyl(Q-C6)alkyl, moφholinyl (Q-Q) alkyl, tetrahydrofuryl (Q-Q) alkyl, thienyl (Ci-Ce) alkyl, piperazinyl (Q-Q) alkyl, indolyl (Q-Q) alkyl, quinolinyl(Q-Ce) alkyl, isoquinolinyl(Ci-Q) alkyl, isoindolyl(Q-C6) alkyl, dihydroindolyl(Q-Ce) alkyl, pyrazolyl(Q-Q) alkyl, imidazoryl(Q-Q) alkyl, dihydroisoindolyl(Cι-C6) alkyl, indolon-
926 2-yl(Q-Q) alkyl, moφholinyl Q-Q alkyl, -pyrimidinyl-piperazinyl, -pyridinyl- piperazinyl, alkenyl, -alkenyl-C02-alkyl, and -alkenyl-C02H, wherein: each such substituent is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents that are independently NR16Ri7, Q-Q alkyl optionally substituted with 1 or 2 substituents that are independently NR16Ri7, -NR1eS02-alkyl, -NR16S02-phenyl, -OC(0)NH2, -OC(0)NHR16, OH, or -OC(0)NR16Ri7, halogen, -OC(0)NR6R7, Q-Q alkoxy optionally substituted with NR16Ri7, phenyl Q-Q alkoxy, Q-Q thioalkoxy, Q-Q alkoxycarbonyl, C0 R, CN, carboxaldehyde, - S02(Q-C6)alkyl optionally substituted withNR16R17, -S02NR16R17, amidinooxime, NR8R9, CN, -NReR7, NReR7 Ci-C6 alkyl, -C(0)NReR7, -(Q- C4)alkyl-C(0)NReR7, amidino, CrC4 haloalkyl, phenyl, hydroxy Ci-C6 alkyl, Ci- Ce dihydroxyalkyl, Q-Q haloalkoxy, Q-Q alkenyl optionally substituted with - OC(0)NReR7) Q-Q alkoxy, or OH, -C(0)C(0)NR16R17, heterocycloalkyl or heterocycloalkylalkyl, wherein the heterocycloalkyl is selected from the group consisting of moφholinyl, piperazinyl, tefrahydropyranyl, piperidinyl, pynolidinyl, and imidazolidinyl, heteroaryl which is selected from the group consisting of pyridyl, furanyl, pyrazolyl, and thienyl, alkoxyalkyl optionally substituted with NR16Ri7, or alkanoyl optionally substituted with OH, halogen, -OC(0)-(Q-C6 alkyl), or Q-Q alkoxy, wherein: each phenyl and heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 substituents that are independently Q-Q alkyl, Q-Q alkoxy, halogen, amino, CF3, or OCF3; each heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents that are independently, Q-Q alkyl, Q-Q alkoxy, halogen, Q- Q alkanoyl, -C(0)NReR7; R8 is hydrogen, Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl and phenyl Q-Q alkanoyl; and R9 is amino Ci-Ce alkyl, mono Ci-Ce alkylamino Q-Q alkyl, di Q-Q alkylamino Ci-Ce alkyl, Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, indazolyl, and phenyl Q-Q alkanoyl.
9. A compound according to claim 8, wherein: - 927 - R16 and R17 at each occunence are independently H or Q-Q alkyl; as to Re and R7: R<5 and R7 are independently at each occunence H, alkyl, hydroxyalkyl, dihydroxyalkyl, alkoxy optionally substituted with NR16Rι7, Q-Q alkoxy Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, tefrahydropyranyloxy, Q-Q alkenyl optionally substituted with -OC(0)NRi6Ri7, -S02-ρhenyl, -S02-Q-Q alkyl, phenyl, pynolidinyl Q-Q alkanoyl, piperidinyl Q-Q alkanoyl, phenyl Q-Q alkoxy, phenyl Q-Q alkoxycarbonyl, or phenyl Q-Q alkanoyl, wherein: each such substituent is unsubstituted or substituted with 1, 2, or 3 substituents that are independently, halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Ci-C6 alkyl), - C(0)N(Q-Q alkyl)(Q-Ce alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, moφholinyl, pynolidinyl, piperazinyl, - OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy; or R6, R7, and the nifrogen to which they are attached form a moφholinyl, thiomoφholinyl, thiomoφholinyl S-oxide, thiomoφholinyl S,S-dioxide, piperidinyl, pynolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 substituents that are independently Q-Q alkyl, Q-Q alkoxycarbonyl, hydroxyl, hydroxy Q-Q alkyl, dihydroxy Q-Q alkyl, or halogen; n is 0, 1, 2, 3, 4, 5 or 6; R5 is pyridyl, pyrimidyl, pyrazinyl, pyridyl (Q-Q) alkyl, pyrimidinyl (Q-Q) alkyl, or pyrazinyl (Q-Q) alkyl wherein: each such substituent is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents that are independently NRieRπ, Q-Q alkyl optionally substituted with 1 or 2 substituents that are independently NR16Rπ, -NRieS02-alkyl, - NRi6S02-phenyl, -OC(0)NH2, or -OC(0)NR16Rι7, halogen, -OC(0)NReR7, Q-Q alkoxy optionally substituted with NR16Ri7, phenyl Q-Q alkoxy, Q-Q thioalkoxy, Q-Q alkoxycarbonyl, C02R, CN, -S(Q-C6)alkyl optionally substituted with NR16Rπ, -S02(Q-Q)alkyl optionally substituted with NR16Ri7, amidinooxime, NR8R9, CN, -N eR7, NReR7 Q-Q alkyl, -C(0)NReR7, -(Q- Q)alkyl-C(0)NReR7, amidino, Q-Q haloalkyl, hydroxy Q-Q alkyl, Q-Q dihydroxyalkyl, Q-Q haloalkoxy, -C(0)C(0)NR16Ri7, heterocycloalkyl which is - 928 - selected from the group consisting of moφholinyl, piperazinyl, tefrahydropyranyl, piperidinyl, pynolidinyl, and imidazolidinyl, alkoxyalkyl optionally substituted with NRi6R17, or alkanoyl optionally substituted with OH, halogen, -OC(0)-(Q-Q alkyl), or Q-Q alkoxy, wherein: each phenyl and heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 substituents that are independently Q-Q alkyl, Q-Q alkoxy, halogen, amino, CF3, or OCF3; each heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents that are independently, Q-Q alkyl, Q-Q alkoxy, halogen, Q-Q alkanoyl, - C(0)NReR?; R8 is hydrogen, Q-Q alkyl, Q-Q alkanoyl, benzyl, and phenyl Q-Q alkanoyl; and R9 is amino Q-Q alkyl, mono Q-Q alkylamino Q-Q alkyl, di Q-Q alkylamino Q-Q alkyl, Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, indazolyl, and phenyl Q-Q alkanoyl.
10. A compound according to claim 9, wherein: Ri is halogen; R4 is hydroxyalkyl or Q-Q alkyl optionally substituted with one or two substituents that are independently C02R, -C02alkyl, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)NH(Q-Q alkyl)(Ci-Ce alkyl), -C(0)-Q-Q alkyl, -N(R30)C(O)NR16Ri7, or -N(R3o)C(0)-(Q-C6)alkoxy; R5 is pyridyl, pyrimidyl, pyrazinyl, pyridyl (Q-Q) alkyl, pyrimidinyl (Q-Q) alkyl, or pyrazinyl (Q-Q) alkyl, wherein: each such substituent is unsubstituted or substituted with 1, 2, or 3 substituents that are independently NR16Rπ, Q-Q alkyl optionally substituted with 1 or 2 substituents that are independently NR16Ri7, -NR16S02-alkyl, - NR16S02-phenyl, -OC(0)NH2, or -OC(0)NR16Ri7, halogen, -OC(0)NReR7, Q-Q alkoxy optionally substituted with NRieRπ, -S02(Q-Q alkyl) optionally substituted with NR16Rπ, -S02(Q-C6)alkyl optionally substituted with NR16R17, NR8R9, CN, NReR7 Q-Q alkyl, -C(0)NR6R7, -NR6R7, heterocycloalkyl which is
929 selected from the group consisting of piperazinyl, piperidinyl, and pynolidinyl, or alkoxyalkyl optionally substituted with N ieRπ, wherein: each phenyl and heteroaryl are optionally substituted with 1, 2, 3, 4, or 5 substituents that are independently Q-Q alkyl, Q-Q alkoxy, halogen, amino, CF3, or OCF3; each heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents that are independently, Q-Q alkyl, Q-Q alkoxy, halogen, Q- Q alkanoyl, -C(0)NReR7; R8 is hydrogen, Q-Q alkyl, Q-Q alkanoyl, benzyl, and phenyl Q-Q alkanoyl; and R9 is amino Q-Q alkyl, mono Q-Q alkylamino Q-Q alkyl, di Q-Q alkylamino Q-Q alkyl, Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, and phenyl Q-Q alkanoyl.
11. A compound according to claim 10, wherein: R5 is of the formula:
Figure imgf000930_0001
R50 is NR16Rπ, alkyl optionally substituted with 1, 2, or 3 substituents that are independently -NR16Rπ, -NR16S02alkyl, or-NRi6C02Ci-Q alkyl, alkoxy optionally substituted with NRi6Rπ, -S (Q-Q alkyl) optionally substituted with NR16Ri7, -S02(Q- Q alkyl) optionally substituted with N i6Rπ, piperazinyl optionally substituted with 1 or 2 substituents that are independently H, alkyl, alkanoyl, or CONReR7, -alkyl- NR16S02phenyl wherein the phenyl is optionally substituted with 1, 2, 3, 4 or 5 substituents that are independently halogen, alkyl, alkoxy, or CONR16Ri7, alkoxyalkyl optionally substituted with NR16R17, or -alkyl-OC(0)NR16Rπ, NR8R9, CN, NR6R7 Q-Q alkyl, -C(0)NR6R7, -NReR7,
R51 is H Q-Q alkyl, Q-Q alkoxy, or halogen; and R6 and R7 are independently H, Q-Q alkyl, hydroxyalkyl, Q-Q alkanoyl, -S02- Q-Q alkyl, wherein: each such substituent is unsubstituted or substituted with 1, 2, or 3 substituents that are independently, halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q - 930 - alkyl)(Ci-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, moφholinyl, pynolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy.
12. A compound according to claim 10, wherein: R5 is of the formula:
Figure imgf000931_0001
Re and R7 are independently H, Q-Q alkyl, hydroxyalkyl, Q-Q alkanoyl, -S02-
Q-Q alkyl, wherein: each such substituent is unsubstituted or substituted with 1, 2, or 3 substituents that are independently, halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyι)(Q-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, moφholinyl, pynolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy.
13. A compound according to claim 10, wherein: R5 is of the formula:
Figure imgf000931_0002
R55 is -(Q-Ce alkyl)-NReR7, or -NReR7; and Re and R7 are independently H, Q-C4 alkyl, hydroxyalkyl, Q-Q alkanoyl, -S02- Q-Q alkyl, wherein: each such substituent is unsubstituted or substituted with 1, 2, or 3 substituents that are independently, halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-Q alkyl), -C(0)N(Q-Q alkyl)(Q-C6 alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, moφholinyl, pynolidinyl, piperazinyl, -OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy.
- 931 -
14. A compound according to claim 10, wherein: R5 is of the formula:
Figure imgf000932_0001
each R60 is independently H, -C(0)NReR7, -C02R, Ci-C hydroxyalkyl, Q-Q dihydroxyalkyl, -(Ci-Ce alkyl)-NR6R7, halogen, Q-Q alkenyl, CN, or- R?; Re and R7 are independently H, Q-Q alkyl, Q-Q alkanoyl, wherein the alkyl portion of each of the above is optionally substituted with OH, or halogen; and R at each occurrence is independently H or Q-Q alkyl optionally substituted with 1 or 2 substituents that are independently OH, SH, halogen, amino, monoalkylamino, dialkylamino or Q-Q cycloalkyl.
15. A compound according to claim 10, wherein: R5 is:
Figure imgf000932_0002
Reo is -S02-Q-Q alkyl, or -(Ci-Ce alkyl)-NR6R7; Re and R7 are independently H, Q-Q alkyl, Q-Q alkanoyl, wherein: the alkyl portion of each of the above substituents is optionally substituted with OH or halogen; R at each occunence is independently H or Q-Q alkyl optionally substituted with
1 or 2 substituents that are independently OH, SH, halogen, amino; monoalkylamino, dialkylamino or Q-Q cycloalkyl; and R61 is H, Q-Q alkyl, Q-Q alkoxy, or halogen.
16. A compound according to claim 8, wherein: R5 is Q-Q alkenyl -alkenyl-C02-alkyl, and -alkenyl-C02H, each of which 1S optionally substituted with -NReR7, OH, -C(0)NR6R7; and as to R6 andR7:
- 932 - Re and R7 at each occunence are independently H, alkyl optionally substituted with heteroaryl that is selected from thienyl, pyridyl, and furanyl, hydroxyalkyl, dihydroxyalkyl, alkoxy optionally substituted with NR16Rπ, Q-Q alkoxy Q-Q alkyl, Q-Q alkanoyl, phenyl Q-Q alkyl, tefrahydropyranyloxy, tetrahydrofuranyloxy, piperidinyloxy, pynolidinyloxy, Q-Q alkenyl optionally substituted with -OC(0)NR16Ri7, -S02-ρhenyl, -S02-Q-Q alkyl, phenyl, pynolidinyl Q-Q alkanoyl, piperidinyl Q-Q alkanoyl, phenyl Q-Q alkoxy, phenyl Q-Q alkoxycarbonyl, or phenyl Q-Q alkanoyl, wherein: each of the above is unsubstituted or substituted with 1, 2, or 3 substituents that are independently, halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-C6 alkyl), - C(0)N(Q-Q alkylXQ-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, moφholinyl, pynolidinyl, piperazinyl, -OC(0)Q-Q alkyl, CF3, or OCF3; or R6, R7, and the nitrogen to which they are attached form a moφholinyl, piperidinyl, pynolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 substituents that are independently Q-Q alkyl, Q-Q alkoxycarbonyl, hydroxyl, hydroxy Q-Q alkyl, dihydroxy Q-Q alkyl, or halogen.
17. A compound according to claim 8, wherein: R5 is phenyl optionally substituted with 1, 2, 3, 4, or 5 substituents that are independently NR16Ri7, Q-Q alkyl optionally substituted with 1 or 2 substituents that are independently NR16Ri7, -NR16S02-alkyl, -NR16S02-phenyl, -OC(0)NH2, -OC(0)NHR16, OH, or -OC(0)NRι6R17, halogen, -OC(0)NReR7, Q-Q alkoxy optionally substituted with NR16Rπ, phenyl Q-Q alkoxy, Q-Q thioalkoxy, Q-Q alkoxycarbonyl, C02R, CN, carboxaldehyde, -S02(Q-Ce)alkyl optionally substituted with NR16Rπ, -S02NR16R17j amidinooxime, NR8R9, -NRβR.?, NReR7 Q-Q alkyl, -C(0)NReR7, -(Q-Q)alkyl- C(0)NR6R7, amidino, CF3, phenyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, OCF3, Q- C6 alkenyl optionally substituted with -OC(0)NReR7, Q-Q alkoxy, or OH, -C(0)C(0)NR16R17, heterocycloalkyl which is selected from the group consisting of moφholinyl, piperazinyl, tefrahydropyranyl, piperidinyl, pynolidinyl, and imidazolidinyl, heteroaryl which is selected from the group consisting of pyridyl, furanyl, pyrazolyl, and - 933 - thienyl, alkoxyalkyl optionally substituted with NRieRπ, or alkanoyl optionally substituted with OH, halogen, -OC(0)-(Q-Q alkyl), or Q-Q alkoxy, wherein: each phenyl and heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 substituents that are independently Q-Q alkyl, Q-Q alkoxy, halogen, amino, CF3, or OCF3; and each heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents that are independently, Q-Q alkyl, Q-Q alkoxy, halogen, Q-Q alkanoyl, - C(0)NR16R17; as R6 and R7: Re and R7 are independently at each occurrence H, alkyl optionally substituted with RieRπ or heteroaryl that is selected from thienyl, pyridyl, and furanyl, Q-Q hydroxyalkyl, Q-Q dihydroxyalkyl, N ^Rn, alkoxy optionally substituted with NRieRπ, Q-Q alkoxy Q-Q alkyl, OH, Q-Q alkanoyl, Q-Q cycloalkyl, phenyl Q-Q alkyl, tefrahydropyranyloxy, tefrahydrofuranyloxy, piperidinyloxy, pynolidinyloxy, Q-Q alkenyl optionally substituted with -OC(0)NR16Ri75 -S02-ρhenyl, -S02-Q-C6 alkyl, phenyl, pynolidinyl Q-Q alkanoyl, piperidinyl Q-Q alkanoyl, pyridyl Q-Q alkanoyl, phenyl Q-Q alkoxy, phenyl Q-Q alkoxycarbonyl, or phenyl Q-Q alkanoyl, wherein: each of the above substituents is unsubstituted or substituted with 1, 2, or 3 substituents that are independently, halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(0)NH(Q-C6 alkyl), -C(0)N(Q-Q alkylXQ-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, moφholinyl, pynolidinyl, piperazinyl, - OC(O)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy; or Re, R7, and the nifrogen to which they are attached form a moφholinyl, thiomoφholinyl, thiomoφholinyl S-oxide, thiomoφholinyl S,S-dioxide, piperidinyl, pynolidinyl, isoindole 1,3-dione, or piperazinyl ring which is optionally substituted with 1 or 2 substituents that are independently Q-Q alkyl, Q-Q alkoxycarbonyl, hydroxyl, hydroxy Q-Q alkyl, dihydroxy Q-Q alkyl, or halogen; and
934 R at each occunence is independently H or Q-Q alkyl optionally substituted with 1 or 2 substituents that are independently OH, halogen, amino, monoalkylamino, dialkylamino or C3-C6 cycloalkyl.
18. A compound according to claim 8, wherein: R5 is phenyl(Ci-Q)alkyl, which is optionally substituted with 1, 2, 3, 4, or 5 substituents that are independently NRieRπ, Q-Q alkyl optionally substituted with 1 or 2 substituents that are independently NR16Rπ, -NR16SO2-alkyl, -NRι6SO2-phenyl, -OC(O)NH2, -OC(O)NHR16, OH, or -OC(O) t16Rπ, halogen, -OC(O)NR6R7, Q-Q alkoxy optionally substituted with NR16Rπ, phenyl Q-Q alkoxy, Q-Q thioalkoxy, Q-Q alkoxycarbonyl, CO2R, CN, carboxaldehyde, -SO2(Q-C6)alkyl optionally substituted with NR16Rπ, -SO2NR16Rπ, amidinooxime, NR8R9, CN, -NR6R7, N eR? Q-Q alkyl, -C(O)NR6R7, -(Ci-Q)aιkyl-C(O)NReR7, amidino, Q-Q haloalkyl, phenyl, hydroxy Q-Q alkyl, Q-Q dihydroxyalkyl, Q-Q haloalkoxy, Q-Q alkenyl optionally substituted with -OC(O)NR6R7; Q-Q alkoxy, or OH, -C(O)C(O)NR16R17, heterocycloalkyl which is selected from the group consisting of moφholinyl, piperazinyl, tefrahydropyranyl, piperidinyl, pynolidinyl, and imidazolidinyl, heteroaryl which is selected from the group consisting of pyridyl, furanyl, pyrazolyl, and thienyl, alkoxyalkyl optionally substituted with RieRn, or alkanoyl optionally substituted with 1 or 2 substituents that are independently OH, halogen, -OC(O)-(Q-Q alkyl), or Q-Q alkoxy; wherein: each phenyl and heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 substituents that are independently Q-Q alkyl, Q-Q alkoxy, halogen, amino, CF3, or OCF3; each heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents that are independently, Q-Q alkyl, Q-Q alkoxy, halogen, Q-Q alkanoyl, - C(O)NR16R17; as to R6 and R7: Re and R are independently at each occunence H, alkyl optionally substituted with NR16Rι7 or heteroaryl that is selected from thienyl, pyridyl, and furanyl, hydroxyalkyl, dihydroxyalkyl, NRieRπ, alkoxy optionally substituted with 16R17, Q-Q alkoxy Q-Q alkyl, OH, Q-Q alkanoyl, Q-Q cycloalkyl, phenyl Q-Q alkyl, tetrahydropyranyloxy, tefrahydrofuranyloxy, piperidinyloxy, - 935 - pyrrolidinyloxy, C2-C6 alkenyl optionally substituted with -OC(O)NR16R17, -SO - phenyl, -SO2NR16R17, -SO2-Ci-C6 alkyl, phenyl, pyrrolidinyl Q-Q alkanoyl, piperidinyl Q-Q alkanoyl, pyridyl Q-Q alkanoyl, phenyl Q-Q alkoxy, phenyl Q-Q alkoxycarbonyl, or phenyl Q-Q alkanoyl, wherein: each of the above substituents is unsubstituted or substituted with 1, 2, or 3 substituents that are independently, halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(O)NH2, -C(O)NH(Q-Q alkyl), -C(O)N(Q-Q alkyl)(Q-C6 alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, moφholinyl, pynolidinyl, piperazinyl, - OC(0)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy; or R6, R7, and the nifrogen to which they are attached form a moφholinyl, thiomoφholinyl, thiomoφholinyl S-oxide, thiomoφholinyl S,S-dioxide, piperidinyl, pynolidinyl, isoindole 1,3-dione, or piperazinyl ring which is optionally substituted with 1 or 2 substituents that are independently Q-Q alkyl, Q-Q alkoxycarbonyl, hydroxyl, hydroxy Q-Q alkyl, dihydroxy Q-Q alkyl, or halogen; and ' R at each occurrence is independently H or Q-Q alkyl optionally substituted with 1 or 2 substituents that are independently OH, halogen, amino, monoalkylamino, dialkylamino or Q-Q cycloalkyl.
19. A compound according to claim 8, wherein: R5 is selected from the group consisting of H, (Q-Ce)alkyl optionally substituted with 1, 2, 3, 4, or 5 substituents that are independently phenyl Q-Q alkoxycarbonyl, - NR8R9, halogen, -C(O)NR8R , alkoxycarbonyl, or alkanoyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, benzothiazolyl, isoindolyl, dihydroindolyl, pyrazolyl, 3H-isobenzofuran-l- onyl, imidazolyl, pyridyl, pyrimidyl, pyrazinyl, furanyl, dihydroisoindolyl, indolon-2-yl, indazolyl, thienyl, benzimidazolyl, imidazolidine dione, pyrazolyl(Ci-C6 alkyl), furanyl(Q-Ce alkyl), imidazolyl(Q-C6 alkyl), piperidinyl(Q-Ce)alkyl, pynolidinyl(Q- Q)alkyl, imidazolidinyl(Q-C6)alkyl, lH-indazolyl(Cι-C6)alkyl, dihydroindolon-2-yl(Q- Q alkyl), 3H-isobenzofuranonyl(Q-Ce alkyl), benzothiazolyl(Q-C6 alkyl), indolinyl(Q- Q alkyl), dihydrobenzimidazolyl(Ci-C6 alkyl), benzimidazolyl (Q-Q) alkyl, isochroman- 4-one (Q-Q) alkyl, oxazolidin-2-one (Q-Q) alkyl, benzoxazolyl (Q-Q) alkyl, - 936 - dihydrobenzoimidazolonyl(Ci-C6 alkyl), pyridyl (Q-Q) alkyl, pyridazinyl (Q-Q) alkyl, pyrimidinyl (Q-Q) alkyl, pyrazinyl (Q-Q) alkyl, tefrahydrofiιryl(Q-C6)alkyl, naphthyl(Cι-C6)alkyl, moφholinyl (Q-Q) alkyl, tefrahydrofuryl (Q-Q) alkyl, thienyl (Q-Q) alkyl, piperazinyl (Q-Q) alkyl, indolyl (Q-Q) alkyl, quinoiiny Q-Q) alkyl, isoquinolinyl(Q-Ce) alkyl, dihydro- lH-isoindolyl(Q-C6) alkyl, dihydroindolyl(Q-C6) alkyl, imidazoryl(Q-Q) alkyl, dihydroisoindoIyXQ-Ce) alkyl, indolon-2-yl(Q-C6) alkyl, moφholinyl Q-Q alkyl, -pyrimidinyl-piperazinyl, and -pyridinyl-piperazinyl, wherein: each of the above substituents is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents that are independently NR16Rπ, Q-Q alkyl optionally substituted with 1 or 2 substituents that are independently NR16R17, -NR16SO2-alkyl, -NR16SO2-phenyl, -OC(O)NH2, -OC(O)NHR16, OH, or -OC(O)NR16R17, halogen, -OC(O)NR6R7, Q-Q alkoxy optionally substituted with NRieRπ, phenyl Q-Q alkoxy, Q-Q thioalkoxy, Q-Q alkoxycarbonyl, CO2R, CN, carboxaldehyde, - SO2(Q-Ce)alkyl optionally substituted with NR16R17, -SO2NR16Ri7) amidinooxime, NR8R9, CN, -NReR7, NReR7 Q-Q alkyl, -C(O)NReR7, -(Q- C4)alkyl-C(O)NR6R7, amidino, C!-C4 haloalkyl, phenyl, hydroxy Q-Q alkyl, Q- Q dihydroxyalkyl, Q-Q haloalkoxy, Q-Q alkenyl optionally substituted with - OC(O)NReR7; Q-Q alkoxy, or OH, -C(O)C(O)NR16R17, heterocycloalkyl or heterocycloalkyl(Q-C6)alkyl, wherein the heterocycloalkyl is selected from the group consisting of moφholinyl, piperazinyl, tefrahydropyranyl, piperidinyl, pynolidinyl, and imidazolidinyl, heteroaryl which is selected from the group consisting of pyridyl, furanyl, pyrazolyl, and thienyl, alkoxyalkyl optionally substituted with NR^Rn, or alkanoyl optionally substituted with OH, halogen, Q- Q cycloalkyl, -OC(O)-(Q-Q alkyl), or Q-Q alkoxy; wherein: each phenyl and heteroaryl is optionally substituted with 1, 2, 3, 4, or 5 substituents that are independently Q-Q alkyl, Q-Q alkoxy, halogen, amino, CF3, or OCF3; each heterocycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents that are independently, Q-Q alkyl, Q-Q alkoxy, halogen, Q- Q alkanoyl, -C(O)NR16R17; as to Re and R7:
937 Re and R7 are independently at each occunence H, alkyl optionally substituted with NRKSRΠ or heteroaryl that is selected from thienyl, pyridyl, and furanyl, hydroxyalkyl, dihydroxyalkyl, NR16R17, alkoxy optionally substituted with NRieRπ, Q-Q alkoxy Q-Q alkyl, OH, Q-Q alkanoyl, Q-Q cycloalkyl, phenyl Q-Q alkyl, tefrahydropyranyloxy, tefrahydrofuranyloxy, piperidinyloxy, pyrrolidinyloxy, Q-Q alkenyl optionally substituted with -OC(0)NRi6Rπ, -S0 - phenyl, -S02NR16R17, -S02-Q-Q alkyl, phenyl, pynolidinyl Q-Q alkanoyl, piperidinyl Q-Q alkanoyl, pyridyl Q-Q alkanoyl, phenyl Q-Q alkoxy, phenyl Q-Q alkoxycarbonyl, or phenyl Q-Q alkanoyl, wherein: each of the above substituents is unsubstituted or substituted with 1 , 2, or 3 substituents that are independently, halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(0)NH2, -C(O)NH(Q-Q alkyl), -C(0)N(Q-Q alkylXQ-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, moφholinyl, pynolidinyl, piperazinyl, - OC(O)Q-C6 alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy; or Re, R7, and the nifrogen to which they are attached form a moφholinyl, thiomoφholinyl, thiomoφholinyl S-oxide, thiomoφholinyl S,S-dioxide, piperidinyl, py olidinyl, isoindole 1,3-dione, or piperazinyl ring which is optionally substituted with 1 or 2 substituents that are independently Q-Q alkyl, Q-Q alkoxycarbonyl, hydroxyl, hydroxy Q-Q alkyl, dihydroxy Q-Q alkyl, or halogen; and R at each occurrence is independently H or Q-Q alkyl optionally substituted with 1 or 2 substituents that are independently OH, halogen, amino, monoalkylamino, dialkylamino or Q-Q cycloalkyl.
20. A compound according to claim 19, wherein: R5 is indolyl (Q-Q) alkyl-, indolinyl-(Q-C4 alkyl)-, isochroman-4-one (Q-Q) alkyl-, indolon-2-yl(Cι-Q) alkyl-, benzoxazolyl (Q-Q) alkyl-, 3H-isobenzofuran-l-one (Q-Q) alkyl-, 3H-isobenzofuran-l-one, dihydro-lH-isoindolyl(Q-C6) alkyl, dihydroisoindolyl(Q-Q) alkyl, benzothiazolyl (Ci-Ce) alkyl-, benzothiazolyl, benzimidazolyl, or benzimidazolyl (Q-Q) alkyl-, optionally substituted with 1, 2, 3, or 4 substituents that are independently Q-Q alkyl, OH, -C(O)C(O)NRι6R17, piperidinyl (Q- - 938 - Q)alkyl, piperazinyl (Q-Q) alkyl, pynolidinyl (Q-Q)alkyl, NReR7 Q-Q alkyl, moφholinyl Q-Q alkyl, Q-Q alkanoyl optionally substituted with 1 or 2 substituents that are independently OH, halogen, -OC(O)-(Q-Q alkyl), or Q-Q alkoxy, -SO2(Q- Q)alkyl, Q-Q alkoxycarbonyl; and Re and R7 are independently at each occunence H, alkyl optionally substituted with
NR16Ri7 or heteroaryl that is selected from thienyl, pyridyl, and furanyl, hydroxyalkyl, dihydroxyalkyl, NRi6Rπ, alkoxy optionally substituted with NR16Rπ, Q-Q alkoxy Q-Q alkyl, OH, Q-Q alkanoyl, Q-Q cycloalkyl, phenyl Q-Q alkyl, tefrahydropyranyloxy, tefrahydrofuranyloxy, piperidinyloxy, pynolidinyloxy, Q-Q alkenyl optionally substituted with -OC(O)NP 6RΠ, -SO2-ρhenyl, -SO2NR16Rπ, -SO2-Q-Q alkyl, phenyl, pynolidinyl Q-Q alkanoyl, piperidinyl Q-Q alkanoyl, pyridyl Q-Q alkanoyl, phenyl Q-Q alkoxy, phenyl Q-Q alkoxycarbonyl, or phenyl Q-Q alkanoyl, wherein: each of the above substituents is unsubstituted or substituted with 1, 2, or 3 substituents that are independently, halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(O)NH2, -C(O)NH(Q-Q alkyl), -C(O)N(Q-Q alkylXQ-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, moφholinyl, pynolidinyl, piperazinyl, -OC(O)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy. '
21. A compound according to claim 19, wherein: R5 is pyrazolyl Q-Q alkyl, oxazolidin-2-one (Q-Q) alkyl, furanyl, thienyl, or furanyl Ci-Ce alkyl, wherein: each such substituent is optionally substituted with 1 or 2 substituents independently selected from the group consisting of-C(O)NReR7, N e z Q-Q alkyl, Q-Q alkyl, Q-Q alkoxycarbonyl, (Q-Q) alkyl optionally substituted with 1 or 2 substituents that are independently NR16Rπ, -NR16SO2-alkyl, -NR16SO2- phenyl, -OC(O)NH2, -OC(O)NHR16, OH, or -OC(O)NRι6R17, hydroxy Q-Q alkyl, heterocycloalkyl which is selected from the group consisting of moφholinyl, piperazinyl, tefrahydropyranyl, piperidinyl, pynolidinyl, and imidazolidinyl, CO2R, Q-Q cycloalkyl, as to R6 and R7:
939 Re and R7 are independently at each occunence H, alkyl optionally substituted with NR16Rπ or a heteroaryl group that is selected from thienyl, pyridyl, and furanyl, hydroxyalkyl, dihydroxyalkyl, NR16Rπ, alkoxy optionally substituted with NR16Rπ, Q-Q alkoxy Q-Q alkyl, OH, Ci-Ce alkanoyl, Q-Q cycloalkyl, phenyl Q-Q alkyl, tefrahydropyranyloxy, tefrahydrofuranyloxy, piperidinyloxy, pynolidinyloxy, Q-Q alkenyl optionally substituted with -OC(O)NR16R17, -SO2-phenyl, -SO2NR16R17, -SO2-Q-Q alkyl, phenyl, pynolidinyl Q-Q alkanoyl, piperidinyl Q-Q alkanoyl, pyridyl Q-Q alkanoyl, phenyl Q-Q alkoxy, phenyl Q-Q alkoxycarbonyl, or phenyl Q-Q alkanoyl, wherein: each of the above substituents is unsubstituted or substituted with 1, 2, or 3 substituents that are independently, halogen, Q-Q cycloalkyl, amino, monoalkylamino, dialkylamino, -C(O)NH2, -C(O)NH(Q-Q alkyl), -C(O)N(Q-Q alkylXQ-Q alkyl), Q-Q alkoxy, Q-Q alkyl, OH, SH, carboxaldehyde, piperidinyl, moφholinyl, pyrrolidinyl, piperazinyl, - OC(O)Q-Q alkyl, Q-Q haloalkyl, or Q-Q haloalkoxy; or Re, R7, and the nifrogen to which they are attached form a moφholinyl, thiomoφholinyl, thiomoφholinyl S-oxide, thiomoφholinyl S,S-dioxide, piperidinyl, pynolidinyl, isoindole 1,3-dione, or piperazinyl ring which is optionally substituted with 1 or 2 substituents that are independently Q-Q alkyl, Q-Q alkoxycarbonyl, hydroxyl, hydroxy Q-Q alkyl, dihydroxy Q-Q alkyl, or halogen; and R at each occunence is independently H or Q-Q alkyl optionally substituted with 1 or 2 substituents that are independently OH, halogen, amino, monoalkylamino, dialkylamino or Q-Q cycloalkyl.
22. A compound according to claim 1, wherein the compound is selected from the group consisting of: (2E)-4- [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl]but-2-enoic , acid;
- 940 3 - [4- { [2-( { [(cyclopropylamino)carbonyl] amino } methyl)-4-fluorobenzyl] oxy} -6-methyl-2- oxopyridin- 1 (2H)-yl] -N,4-dimethylbenzamide; 3,5-dibromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[4-methyl-2- (methylsulfonyl)pyrimidin-5-yl]pyridin-2(lH)-one; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-methyl-4- (moφholin-4-ylcarbonyl)benzamide; 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylpyrimidine-2-carboxylic acid; 2-( { [3 -bromo- 1 -(2, 6-difluorophenyl)-6-methyl-2-oxo- 1 ,2-dihydropyridin-4-yl] oxy} methyl)- 5-fluorobenzamide; 3 - [3 -chloro-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -4-methyl-N- (tefrahydro-2H-pyran-2-yloxy)benzamide; 4- [3 -bromo-4- [(2,4-difluorobenzyι)oxyj -6-methyl-2-oxopyridin- 1 (2H)-yl] -3 - (trifluoromethyl)benzamide; 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-methyl-3- (trifluoromethyl)benzamide; 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-hydroxy-4- methylbenzamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{2,6-difluoro-4-[(lE)-3-hydroxyprop-l-en-l- yl]phenyl}-6-methylpyridin-2(lH)-one; 3 - [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -4-methyl-N- (tefrahydro-2H-pyran-2-yloxy)benzamide; (2E)-3-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxoρyridin-l(2H)-yl]-3,5- difluorophenyl}prop-2-en-l-yl carbamate; l-[5-(aminomethyl)-2-methylphenyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin 2(lH)-one hydrochloride; N-{3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylbenzyl} -2-hydroxyacetamide; 4- [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -3,5- difluorobenzamide;
941 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[2,6-difluoro-4-(hydroxymethyl)phenyl]-6- methylpyridin-2( lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[(2E)-4-moφholin-4-yl-4-oxobut-2-en-l- yl]pyridin-2(lH)-one; tert-butyl {3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- fluorophenyl} carbamate; N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}phenyl)urea; 2-[(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}phenyl)amino]-l-methyl-2-oxoethyl acetate; methyl 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2/^-yl]-2-furoate; 3 -chloro-4- [(2,4-difluorobenzyl)oxy] - 1 - [( 1 -glycoloyl-2,3 -dihydro- lH-indol-5- yl)methyl]pyridin-2( 1 H)-one; N-(4-{[3-bromo-4-[(2,4-m*fluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}phenyl)-2-hydroxypropanamide; N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}phenyl)-2-hydroxy-2-methylpropanamide; 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-l(2H)- yljbenzamide; 2-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3,5- difluorophenyl} -2-hydroxyethyl carbamate; 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3- fluorobenzamide; 3 - [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -4- methylbenzamide; { 1 - [3 -(aminocarbonyl)phenyl] -5-chloro-4- [(2,4-difluorobenzyl)oxy] -6-oxo- 1,6- dihydropyridin-2-yl} methyl carbamate; 2-({3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- fluorophenyl} amino)-2-oxoethyl acetate; 2-({3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- fluorophenyl} amino)- 1 , 1 -dimethyl-2-oxoethyl acetate;
942 - 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-l(2H)- yljbenzamide; N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzyl)-N-methylurea; l-[4-(aminomethyl)phenyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(lH)- one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[5-(moφholin-4-ylcarbonyl)-2- furyl]pyridin-2(lH)-one; 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]benzyl carbamate { 5 - [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -2 furyl} methyl carbamate; 3-bromo-2-[2-(2-fluorophenyl)pyridin-4-yl]-l,5,6,7-tefrahydro-4H-pyrrolo[3,2-c]pyridin-4- one trifluoroacetate; N-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]benzyl}-2- hydroxy-2-methylpropanamide; l-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3,5- difluorophenyl} ethane- 1 ,2-diyl dicarbamate; l-[4-(aminomethyl)-2-fluorophenyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin 2(lH)-one hydrochloride; 2-(5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]methyl}-2,3-dihydro- lH-indol- 1 -yl)-2-oxoethyl acetate; 2-(5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxoρyridin-l(2H)-yl]methyl}-2,3-dihydro- lH-indol- 1 -yl)- 1 , 1 -dimethyl-2-oxoethyl acetate; 5- { [3-chloro-4-[(2,4-difluorobenzyl)oxy] -2-oxopyridin- 1 (2H)-yl]methyl} - 1 ,3-dihydro-2H- indol-2-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(lH-pyrazol-3-ylmethyl)pyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(lH-pyrazol-3-ylmethyl)pyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[l-(2-hydroxyethyl)-lH-pyrazol-3-yl]methyl}-6- methylpyridin-2(lH)-one; 4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzenesulfonamide;
943 {l-[3-(aminocarbonyl)phenyl]-5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxo-l,6- dihydropyridin-2-yl} methyl acetate; l-(l,3-benzoxazol-6-ylmethyl)-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin- 2(lH)-one; {l-[3-(aminocarbonyl)phenyl]-5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxo-l,6- dihydropyridin-2-yl} methyl carbamate; 5- { [3-bromo-4-[(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl]methyl} -N-(2- hydroxyethyl)-2-furamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-{[5-(moφholin-4-ylcarbonyl)-2- furyl]methyl}pyridin-2(lH)-one; 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-N- methyl-2-furamide; 3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl- 1 -(4-vinylphenyl)pyridin-2( lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-{[5-(piperazin-l-ylcarbonyl)-2- furyl]methyl}pyridin-2(lH)-one; methyl 2-bromo-5- {[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l (2H)- yl]methyl}benzoate; N-{4-[3-bromo-4-[(2,4-difluoroberιzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]benzyl}urea; 3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl- 1 - { [2-(methylamino)pyrimidin-5- yl]methyl}pyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{[5-(hyαj-oxymethyl)-2-furyl]methyl}-6- methylpyridin-2( lH)-one; 3 -bromo-4- [(2,4-difluorobenzyl)oxy] - 1 - [4-( 1 ,2-dihydroxyethyl)phenyl] -6-methylpyridin- 2(lH)-one; 3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl- 1 - [5-(piperidin- 1 -ylcarbonyl)-2- furyl]pyridin-2(lH)-one; methyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-l(2H)- yljbenzoate; 3-chloro-4-[(2,4-difluorobenzyl)oxy] -6-methyl- 1 - { [ 1 -(methylsulfonyl)-2,3-dihydro- 1H- indol-5-yl]methyl}pyridin-2(lH)-one;
944 - 2-(5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-2,3- dihydro- lH-indol- 1 -yl)-2-oxoethyl acetate; 2-(5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-2,3- dihydro- lH-indol- 1 -yl)- 1 , 1 -dimethyl-2-oxoethyl acetate 3 - [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -N-cyclopropyl-4- methylbenzamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(lH-pyrazol-3-ylmethyl)pyridin-2(lH)- one; 3 -chloro-4-[(2,4-difluorobenzyl)oxy] - 1 - { [ 1 -(methoxyacetyl)- 1 H-pyrazol-3 -yljmethyl} -6- methylpyridin-2(lH)-one; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-ethyl-4- methylbenzamide; N-allyl-3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylbenzamide; {l-allyl-5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxo-l,6-dihydropyridin-2-yl}methyl acetate; 4- { [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-(hydroxymethyl)-2-oxopyridin- 1 (2H)- yl]methyl} -N-methylbenzamide; 1 - {[5-(aminomethyl)pyrazin-2-yl]methyl} -3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methylpyridin-2(lH)-one; 2-{[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl} pyrazin-2-yl)methyl] amino } -2-oxoethyl acetate; N-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrazin-2-yl)methyl]-2-hydroxyacetamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{[2-(dimethylamino)pyrimidin-5-yl]methyl}-6- methylpyridin-2(lH)-one trifluoroacetate; methyl 3 - [3 -chloro-4- { [2-( { [(cyclobutylamino)carbonyl] amino } methyl)-4- fluorobenzyl]oxy} -6-methyl-2-oxopyridin- 1 (2H)-yl]-4-methylbenzoate; 1 -allyl-3 -bromo-4-[(2,4-difluorobenzyl)oxy] -6-(hydroxymethyl)pyridin-2( lH)-one; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-butyl-4- methylbenzamide;
945 - 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl} pyrimidine-2-carbonitrile; N-(2-aminoethyl)-3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl] -4-methylbenzamide hydrochloride; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)- 1 - {4- [(methylamino)methyl]benzyl}pyridin-2(lH)-one; 3 - [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -N-isobutyl-4- methylbenzamide; 3 -chloro-4- [(2,4-difluorobenzyl)oxy] - 1 - { [ 1 -(2-hydroxy-2-methylpropyl)- lH-pyrazol-3 - yl]methyl}-6-methylpyridin-2(lH)-one; ethyl 3 - { [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl]methyl} - 1 - (tefrahydro-2H-pyran-2-yl)-lH-pyrazole-5-carboxylate; 3 -[3 -chloro-4- { [2-( { [(cyclobutylamino)carbonyl] amino } methyl)-4-fluorobenzyl] oxy} -6- methyl-2-oxopyridin- 1 (2H)-yl] -N,4-dimethylbenzamide; N-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrazin-2-yl)methyl]acetamide; N-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrazin-2-yl)methyl]methanesulfonamide; methyl [(5 - { [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)- yl]methyl}pyrazin-2-yl)methyl]carbamate; N-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrazin-2-yl)methyl]-2-hydroxy-2-methylpropanamide; N-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrazin-2-yl)methyl]-l-hydroxycyclopropanecarboxamide; N1 - [(5 - { [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)- yl]methyl}pyrazin-2-yl)methyl]glycinamide hydrochloride; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(3-oxo-l,3-dihydro-2-berιzofuran-5- yl)pyridin-2( 1 H)-one; 3 - [3 -chloro-4- { [2-( { [(cyclopropylamino)carbonyl] amino } methyl)-4-fluorobenzyl] oxy} -6- methyl-2-oxopyridin- 1 (2H)-yl]-N,4-dimethylbenzamide;
- 946 - 3-[3-bromo-4-[(2,4-mfluoroberιzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylbenzenesulfonamide; tert-butyl 5 - { [3 -chloro-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)- yl]methyl} - 1 ,3 -dihydro-2H-isoindole-2-carboxylate; methyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-(hydroxymethyl)-2-oxopyridin-l(2H)-yl]- 4-methylbenzoate; l-{[2-(aminomethyl)pyrimidin-5-yl]methyl}-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methylpyridin-2(lH)-one trifluoroacetate; N1-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrimidin-2-yl)methyl]glycinamide trifluoroacetate; 3-[3-chloro-4-{[2-({[(cyclopropylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6- methyl-2-oxopyridin-l(2H)-yl]-N-[2-hydroxy-l-(hydroxymethyl)ethyl]-4-methylbenzamide; methyl 5 -bromo-2-[3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)- yl]benzoate; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-[(l,3-dioxo-l,3-dihydro-2H-isoindol-2- yl)methyl]-2-oxopyridin-l(2H)-yl]benzamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(2-methyl-5-vinylphenyl)pyridin-2(lH)- one; l-[(2-aminopyrimidin-5-yl)methyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin- 2(lH)-one; 3 -bromo-4- [(2 ,4-difluorobenzyl)oxy] - 1 - [(2-methoxypyrimidin-5 -yl)methyl] -6- methylpyridin-2(lH)-one; 3-[6-(aminomethyl)-3-bromo-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin-l(2H)-yl]benzamide hydrochloride; methyl 5 - { [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl]methyl} - 2-vinylbenzoate; 3-[3-chloro-4-{[2-({[(cyclopropylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6- methyl-2-oxopyridin- 1 (2H)-yl] -N- [2-(dimethylamino)ethyl] -4-methylbenzamide; 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-2- vinylbenzoic acid;
947 5- { [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)- yl]methyl}pyrimidine-2-carboxamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[5-(l,2-dihydroxyethyl)-2-methylphenyl]-6- methylpyridin-2(lH)-one; N1-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzyl)alaninamide hydrochloride; N1-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzyl)-N2-methylglycinamide hydrochloride; N1-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzyl)serinamide hydrochloride; N-(4- { [3 -bromo-4-[(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)- yl]methyl}benzyl)prolinamide hydrochloride; dimethyl 4- [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)- yljisophthalate; methyl 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-5- vinylbenzoate; methyl 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl]-5-(l ,2- dihydroxyethyl)benzoate; 3-[3-chloro-4-{[2-({[(cyclopropylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6- methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzamide; N-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrimidin-2-yl)methyl]-2-hydroxyacetamide; 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-l- methyl-l,3-dihydro-2H-indol-2-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(2,3-dihydro-lH-isoindol-5-ylmethyl)-6- methylpyridin-2( lH)-one trifluoroacetate; 5-{[3-bromo-4-[(2,4-difluoroberιzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}pyridine- 2-carboxamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{2,6-difluoro-4-[(E)-2-methoxyvinyl]phenyl}-6- methylpyridin-2(lH)-one;
948 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{2,6-difluoro-4-[(Z)-2-methoxyvinyl]phenyl}-6- methylpyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[2,6-difluoro-4-(2-hydroxyethyl)phenyl]-6- methylpyridin-2(lH)-one; 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-N- methyl-2-vinylbenzamide; 5- { [3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxopyridin- 1 (2H)-yl]nιethyl} - 1 -methyl- 1 ,3 - dihydro-2H-indol-2-one; methyl 2- [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -5-( 1 - hydroxy- 1 -methylethyl)benzoate; 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxoρyridin-l(2H)-yl]methyl}-2-(l,2- dihydroxyethyl)-N-methylbenzamide; N1-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl} pyrazin-2-yl)methyl] -D-alaninamide hydrochloride; N1-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrazin-2-yl)methyl] -N2-methylglycinamide hydrochloride; N1-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrazin-2-yl)methyl]-D-serinamide hydrochloride; 3-[3-bromo-4-{[2-({[(ethylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6-methyl-2- oxopyridin- 1 (2H)-yl] -N,4-dimethylbenzamide; 3 -bromo-4- [(2,4-difluorobenzyl)oxy] - 1 - [4-( 1 ,2-dihydroxyethyl)-2-methylphenyl] -6- methylpyridin-2(lH)-one; 3 -bromo-4- [(2,4-difluorobenzyl)oxy] - 1 - [4-( 1 ,2-dihydroxyethyl)-2-methylphenyl] -6- methylpyridin-2(lH)-one; 3 - [3 -bromo-4- { [2-( { [(ethylamino)carbonyl] amino } methyl)-4-fluorobenzyl] oxy} -6-mefhyl-2- oxopyridin-l(2H)-yl]-4-methylbenzamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[2-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro- lH-isoindol-5-yl]methyl}-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-dimethyl-l,3-benzothiazol-5-yl)-6- methylpyridin-2(lH)-one;
949 - 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4-methylbenzoic acid; 5-{[3-bromo-4-[(2,4-difluoroberιzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-2-furoic acid; 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3- (trifluoromethyl)benzoic acid; 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N,N-dimethyl-3- (trifluoromethyl)benzamide; 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl]-3-fluorobenzoic ■ acid; 1 - [5-(aminomethyl)-2-fluorophenyl] -3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methylpyridin- 2(lH)-one hydrochloride; 4- [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -3,5- difluorobenzoic acid; (2E)-4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-(2- hydroxy-2-methylpropyl)but-2-enamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[5-(5-hydroxy-lH-pyrazol-3-yl)-2-methylphenyl]-6- methylpyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[5-(hydroxymethyl)-2-furyl]-6-methylpyridin-2(lH)- one; methyl 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- [(methylamino)methyl]benzoate; (-)-3 -[3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -4- methylbenzamide; 3 -bromo-4- [(2,4-difluorobenzyl)oxy] - 1 - {2-(hydroxymethyl)-5 - [(methylamino)methyl]phenyl}-6-methylpyridin-2(lH)-one; 5 - [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -N-(2- hydroxyethyl)-2-furamide; l-[4-(aminomethyl)-2-fluorophenyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin- 2(lH)-one hydrochloride;
950 - 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[4-methyl-2-(methylsulfonyl)pyrimidin-5- yl]pyridin-2(lH)-one; 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N1-(2- hydroxyethy^-Λ^-methylterephthalamide; 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylpyrimidine-2-carbonitrile; methyl 3-[4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin- 1 (6H)-yl]-4- methylbenzoate; 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylpyrimidine-2-carboxamide; 3 -chloro- 1 - { [ 1 -(cyclopropylcarbonyl)- lH-pyrazol-3 -yljmethyl} -4- [(2,4-difluorobenzyl)oxy] - 6-methylpyridin-2(lH)-one; 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-4- methylthiophene-3 -carboxamide; { 1 -allyl-5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxo- 1 ,6-dihydropyridin-2-yl} methyl phenylcarbamate; {l-allyl-5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxo-l,6-dihydropyridin-2-yl}methyl [2-(3- thienyl)ethyl] carbamate; methyl 4- { 1 - [3-bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)- yl] ethyl}benzoate; 4-{l-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]ethyl}benzoic acid; 4- { 1 -[3 -bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl] ethyl} -N- methylbenzamide; 4- { 1 - [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxop yridin- 1 (2H)- yl]ethyl}benzamide; (+)-3 - [3 -bromo-4- [(2 ,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -4- methylbenzamide 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-{l-[4-(hydroxymethyl)phenyl]ethyl}-6- methylpyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(2-oxopropyl)pyridin-2(lH)-one;
951 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[4-(hydroxymethyl)-3-(l-hydroxy-l- methylethyl)phenyl]-6-methylpyridin-2(lH)-one; 1 -[2,4-bis( 1 -hydroxy- 1 -methylethyl)phenyl] -3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6- methylpyridin-2(lH)-one; 5-bromo-2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N- methylbenzamide; 2- [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -N-methyl-5 - vinylbenzamide; 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl]-5-(l ,2- dihydroxyethyl)-N-methylbenzamide; 3 - [3 -bromo-4- { [2-( { [(ethylamino)carbonyl] amino } methyl)-4-fluorobenzyl] oxy} -6-methyl- 2-oxopyridin- 1 (2H)-yl] -4-methyl-N-(2,2,2-trifluoroethyl)benzamide; 3-bromo-l-(3'-chloro-4-methylbiphenyl-3-yl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin- 2(lH)-one; 2-(5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-2-oxoρyridin-l(2H)-yl]methyl}-lH-indol-3- yl)-N,N-dimethyl-2-oxoacetamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(2,6-difluoro-4-glycoloylphenyl)-6-methylpyridin- 2(lH)-one; N-(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrazin-2-yl)-2-hydroxy-2-methylpropanamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[3-(piperidin-l-ylmethyl)-lH-indol-5- yl]methyl}pyridin-2(lH)-one; N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}phenyl)piperidine-4-carboxamide hydrochloride; N2-(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrimidin-2-yl)glycinamide; N-(4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}phenyl)-2-hydroxy-2-methylpropanamide; 3 - [3 -bromo-4- { [2-( { [(ethylamino)carbonyl] amino} methyl)-4-fluorobenzyl] oxy} -6-methyl- 2-oxopyridin-l(2H)-yl]-N-[2-(dimethylamino)ethyl]-4-methylbenzamide;
952 3 -chloro-4- [(2,4-difluorobenzyl)oxy] - 1 - { [3-(piperazin- 1 -ylmethyl)- lH-indol-5 - yl]methyl}pyridin-2(lH)-one hydrochloride; N1-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzyl)-D-serinamide hydrochloride; N1-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzyl)-L-threoninamide hydrochloride; N1-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}phenyl)-2-methylalaninamide hydrochloride; N1-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzyl)-D-alaninamide hydrochloride; N-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzyl)piperidine-4-carboxamide hydrochloride; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[(2-{[2-(dimethylamino)ethyl]amino}pyrimidin-5- yl)methyl]-6-methylpyridin-2(lH)-one; 3 -chloro-4- [(2,4-difluorobenzyl)oxy] - 1 -( {3 - [(dimethylamino)methyl] - lH-indol-5 - yl}methyl)pyridin-2(lH)-one; 3 -chloro-4- [(2,4-difluorobenzyl)oxy] - 1 -( {3 - [(methylamino)methyl] - lH-indol-5- yl}methyl)pyridin-2(lH)-one; N1-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzyl)-N2-methyl-L-serinamide hydrochloride; N-(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyridin-2-yl)-2-hydroxy-2-methylpropanamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-[(3-{[(2-hydroxyethyl)amino]methyl}-lH-indol-5- yl)methyl]pyridin-2(lH)-one; N1-(4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzyl)-L-serinamide hydrochloride; N1-(4-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}phenyl)-2-methylalaninamide hydrochloride; N1 "(4- { [3-bromo-4-[(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)- yl]methyl}benzyl)-D-allothreoninamide hydrochloride;
953 - N1-(4-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}benzyl)-2-methylalaninamide hydrochloride; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[3-(moφholin-4-ylmethyl)-lH-indol-5- yl]methyl}pyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-({2-[(2-hydroxyethyl)amino]pyrimidin-5- yl}methyl)-6-methylpyridin-2(lH)-one; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[3-({[2-(dimethylamino)ethyl]amino}methyl)-lH- indol-5-yl]methyl}pyridin-2(lH)-one; l-({2-[(2-aminoethyl)amino]pyrimidin-5-yl}methyl)-3-bromo-4-[(2,4-difluorobenzyl)oxy]- 6-methylpyridin-2(lH)-one trifluoroacetate; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-hydroxy-N,4- dimethylbenzamide; N-(5- {[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l (2H)- yl]methyl}pyrazin-2-yl)-2-hydroxyacetamide; 3-[3-bromo-4-{[4-fluoro-2-({[(methoxyamino)carbonyl]amino}methyl)benzyl]oxy}-6- methyl-2-oxopyridin-l(2H)-yl]-N,4-dimethylbenz amide; l-allyl-6-[(allylamino)methyl]-3-bromo-4-[(2,4-difluorobenzyl)oxy]pyridin-2(lH)-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[4-(2-hy(hOxyethyl)-2-methylphenyl]-6- methylpyridin-2(lH)-one; N1 -(4- { [3-chloro-4-[(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)- yl]methyl}benzyl)-L-threoninamide hydrochloride; N1-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]benzyl} glycinamide hydrochloride; 3- {[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxoρyridin- 1 (2H)-yl]methyl} -N-[2- (dimethylamino)ethyl]-lH-pyrazole-5-carboxamide; 3-bromo-4- [(2,4-difluorobenzyl)oxy] - 1 - [(2- { [2-hydroxy- 1 - (hydroxymethyl)ethyl]amino}pyrimidin-5-yl)methyl]-6-methylpyridin-2(lH)-one; 3 - [3 -bromo-4- { [4-fluoro-2-( { [(methoxyamino)carbonyl] amino } methyl)benzyl] oxy} -6- methyl-2-oxopyridin- 1 (2H)-yl]-4-methylbenzamide; 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-N- methylpyridine-2-carboxamide;
954 - l-{[5-(aminomethyl)-2-furyl]methyl}-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6- methylpyridin-2(lH)-one hydrochloride; N-(2-{[(3-bromo-l-{5-[(2,2-dimethylhydrazino)carbonyl]-2-methylphenyl}-6-methyl-2- oxo- 1 ,2-dihydropyridin-4-yl)oxy]methyl} -5-fluorobenzyl)-N-ethylurea; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-{[3-(pynolidin-l-ylmethyl)-lH-indol-5- yl]methyl}pyridin-2(lH)-one; 3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-N-(2- methoxyethyl)-lH-pyrazole-5-carboxamide; 5 -[3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -N-methyl-2- vinylbenzamide; 3 - [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -N-hydroxy-4- methylbenzamide; 3 - [3 -bromo-4-(2,4-difluoro-benzyloxy)-6-methyl-2-oxo-2Η-pyridin- 1 -yl] -Ν- carbamoylmethyl-benzamide; N1-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]benzyl}-N2- methylglycinamide hydrochloride; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(2,5-dimethyl-lH-benzimidazol-6-yl)-6- methylpyridin-2(lH)-one; 3 - { [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl]methyl} - 1 H- pyrazole-5-carboxamide; 3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-N-(2,3- dihydroxypropyl)- lH-pyrazole-5 -carboxamide; 3- {[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)-yl]methyl} -N- methyl- lH-pyrazole-5-carboxamide; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-l-(2,3-dihydro-lH-isoindol-5-ylmethyl)pyridin- 2(lH)-one trifluoroacetate; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxo-2H-l,4'-bipyridine-2'-carboxamide; 3 - { [3 -bromo-4-[(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl]methyl} -N-(2- hydroxyethyl)-lH-pyrazole-5-carboxamide; N-[(5- { [3-bromo-4-[(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl]methyl} -2- furyl)methyl]-2-hydroxy-2-methylpropanamide;
955 N1-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]benzyl}alaninamide hydrochloride; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(2-methylprop-2-en-l-yl)pyridin-2(lH)- one; ' 3 -chloro-4- [(2,4-difluorobenzyl)oxy] - 1 - [4-( 1 ,2-dihydroxyethyl)-2-methylphenyl] -6- methylpyridin-2(lH)-one; 5-bromo-6-[(2,4-difluorobenzyl)oxy]-3-isopropyl-2-[4-(2-methylalanyl)piperazin-l- yl]pyrimidin-4(3H)-one trifluoroacetate; methyl 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxo-2H-l,4'-bipyridine-2'- carboxylate; 3 -bromo-4- [(2,4-difluorobenzyl)oxy] - 1 - [5 -(2-furyl)-2-methylphenyl] -6-methylpyridin- 2(lH)-one; N1-{4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]benzyl}serinamide hydrochloride; 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-N,N- dimethylpyridine-2-carboxamide; 3-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-N- methyl- lH-pyrazole-5-carboxamide; N1-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrazin-2-yl)methyl]-D-alaninamide hydrochloride; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-[(glycylamino)methyl]-2-oxopyridin-l(2H)- yl]benzamide hydrochloride; 3 -bromo-4-[(2,4-difluorobenzyl)oxy]- 1 -(4-hydroxy- 1 -oxo-3 ,4-dihydro- lH-isochromen-7- yl)-6-methylpyridin-2(lH)-one; 6-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}nicotinamide; N1_[(5- {[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin- 1 (2H)- yl]methyl}pyrazin-2-yl)methyl]-2-methylalaninamide hydrochloride; 3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxo-2H- 1 ,4'-bipyridine-2'-carboxylic acid;
956 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-{[(N-methylglycyl)amino]methyl}-2- oxopyridin- 1 (2H)-yl]benzamide hydrochloride; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-2-oxo-6-[(serylamino)methyl]pyridin-l(2H)- yl]benzamide hydrochloride; N1-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrazin-2-yl)methyl] -D-serinamide hydrochloride; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(3-methyl-4-vinylphenyl)pyridin-2(lH)- one; N-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrazin-2-yl)methyl]urea; N-[(5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]methyl}pyrazin-2-yl)methyl]piperidine-4-carboxamide hydrochloride; 3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-N,N- dimethyl-lH-pyrazole-5-carboxamide; {5-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[(2E)-4-hydroxybut-2-en-l-yl]-6-oxo-l,6- dihydropyridin-2-yl} methyl acetate; 3 -[6- [(alanylamino)methyl] -3 -bromo-4- [(2,4-difluorobenzyi)oxy] -2-oxopyridin- 1 (2H)- yljbenzamide hydrochloride; 3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-(3-methyl-lH-pyrazol-4-yl)pyridin- 2(lH)-one; N-( { 1 - [3 -(aminocarbonyl)phenyl] -5-bromo-4- [(2,4-difluorobenzyl)oxy] -6-oxo- 1,6- dihydropyridin-2-yl}methyl)pyridine-2-carboxamide; methyl 2-bromo-5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)- yl]benzoate; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-2'-(hydroxymethyl)-6-methyl-2H-l,4'-bipyridin-2- one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-[4-(l,2-dihydroxyethyl)-3-methylphenyl]-6- methylpyridin-2( lH)-one; N-({3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxo-2H-l,3'-bipyridin-6'-yl}methyl)- 2-hydroxy-2-methylpropanamide; 6'-(aminomethyl)-3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2H-l,3'-bipyridin-2-one;
- 957 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-({2-[2-(dimethylamino)ethoxy]pyrimidin-5- yl}methyl)-6-methylpyridin-2(lH)-one; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-{[(2-methylalanyl)amino]methyl}-2-oxopyridin- l(2H)-yl]benzamide hydrochloride; 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-{[(2-hydroxy-2- methylpropanoyl)amino]methyl} -2-oxopyridin- 1 (2H)-yl]benzamide; 3-bromo-6'-chloro-4-[(2,4-difluorobenzyl)oxy]-5',6-dimethyl-2H-l,3'-bipyridin-2-one; 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-5- (hydroxymethyl)-N-methylbenzamide; 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3- [(methylamino)carbonyl]benzyl carbamate; 4-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-3- [(methylamino)carbonyl]benzyl carbamate; 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-2-vinylbenzoic acid; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxo-2H-l,3'-bipyridine-6'-carboxamide; methyl 4- [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -3 - [(methylamino)carbonyl]benzoate; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2'-vinyl-2H-l,4'-bipyridin-2-one; 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-2-(l,2- dihydroxyethyl)-N-methylbenzamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-5',6-dimethyl-6'-vinyl-2H-l,3'-bipyridin-2-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[2-(methylsulfonyl)pyrimidin-5- yl]pyridin-2(lH)-one; 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-5-formyl-N- methylbenzamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxo-2H-l,3,-bipyridine-6'-carbonitrile; methyl 3-bromo-4-[(2,4-difluorobenzyl)oxy]-5',6-dimethyl-2-oxo-2H-l,3'-bipyridine-6'- carboxylate; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-l-[(2-oxo-l,3-oxazolidin-5- yl)methyl]pyridin-2(lH)-one;
958 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6'-(l,2-dihychOxyethyl)-5',6-dimethyl-2H-l,3*- bipyridin-2-one; 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]-N-mefhyl-5- [(methylamino)methyl]benzamide; ' 3-bromo-2'-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2H-l,4'-bipyridin-2-one; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-5',6-dimethyl-2-oxo-2H-l,3'-bipyridine-6'- carboxamide; (-)-3 - [3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl] -4- methylbenzoic acid; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-2'-(l,2-dihydroxyethyl)-6-methyl-2H-l,4,-bipyridin- 2-one; 2-[3-bromo-4-[(2,4-difluorobenzyl)oxy] -6-methyl-2-oxopyridin- 1 (2H)-yl]-5-( 1 -hydroxy- 1 - methylethyl)-N-methylbenzamide; 3-bromo-4-[(2,4-difluorobenzyl)oxy]-l-(3,3-dimethyl-l-oxo-l,3-dihydro-2-berιzofuran-5- yl)-6-methylpyridin-2(lH)-one; 3-bromo-4-[(2,4-difluoroberizyl)oxy]-6-(hydroxymethyl)pyridin-2(lH)-one; 3 - [3 -bromo-4- [(2,4-difluorophenoxy)methyl] -6-methyl-2-oxopyridin- 1 (2H)-yl] -N,4- dimethylbenzamide; 2-({[3-bromo-l-(2,6-difluorophenyl)-6-methyl-2-oxo-l,2-dihydropyridin-4-yl]oxy}methyl)- 5-fluoro-Ν-( 1 -methyl- 1 Η-pyrazol-3 -yl)benzamide; 2-( { [3 -bromo- 1 -(2,6-difluorophenyl)-6-methyl-2-oxo- 1 ,2-dihydropyridin-4-yl] oxy} methyl) N-(cyclopropylmethyl)-5-fluorobenzamide; 3-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-l(2H)-yl]methyl}-l- tetrahydro-2H-pyran-2-yl-lH-pyrazole-5-carboxylic acid; 3 -bromo-4- [(2,4-difluorobenzyl)oxy] -6-methyl- 1 - { [2-(methylsulfonyl)pyrimidin-5 - yl]methyl}pyridin-2(lH)-one; and 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl- 1 - {[2-(methylthio)pyrimidin-5- yl]methyl}pyridin-2(lH)-one.
23. A compound according to claim 3, wherein: the compound conesponds in structure to the following formula:
959
Figure imgf000960_0001
Ri is halogen; and Z, R20, and R30 are as defined below;
Figure imgf000960_0002
960
Figure imgf000961_0001
961
Figure imgf000962_0001
-962
Figure imgf000963_0002
24. A compound according to claim 3, wherein: the compound conesponds in structure to the following formula:
Figure imgf000963_0001
Rt is halogen; and Z, R2o, and R30 are as defined below:
Figure imgf000963_0003
963 -
Figure imgf000964_0001
964
Figure imgf000965_0001
-965
Figure imgf000966_0002
25. A compound according to claim 3, wherein: the compound conesponds in structure to the following formula:
Figure imgf000966_0001
Y is: CONH(CH2)„OH; CONHCH2C(Me)2OH; CONH(CH2)nNH2; CONH(CH2)„NHCH3; CONH(CH2)nN(CH3)2; CONHCH2CH(OH)CH2OH; CH2NHCOCH2NH2;
966 CH2NHCOCH2OH; or CH2NHCOCH(NH2)CH2OH; and n is 1, 2, or 3.
26. A compound according to claim 3, wherein: the compound conesponds in structure to the following formula:
Figure imgf000967_0001
R5o is: -O(CH2)nR51; -NH(CH2)nR51; - N(CH3)(CH2)nR51; -S(CH2)„R51; -SO2(CH2)nR51; CH3
^NH -
Figure imgf000967_0002
— NH
Figure imgf000967_0003
— N O or
Figure imgf000967_0004
n is 2,3, or 4;
R51 is H, OH, NH2, NHR52, CONHR52, or OR52;
- 967 R52 is H or d-C alkyl; and R53 is H or alkyl.
27. A compound according to claim 3, wherein: the compound conesponds in structure to the following formula:
Figure imgf000968_0001
R50 is: CH2CONH2; CH2CONHCH3; CH2CONH(CH3)2; CH2CONH(CH2)„NH2; CH2CONH(CH2)„NHCH3; CH2NHCONH2; CH2NHCO(CH2)2NH2; CH2NHCH3; CH2N(CH3)2; CH2NHSO2 (C1-C3 alkyl); CH2NHSO2 phenyl; CH2NHCOCH(alkyl)NH2; CH2NHCOCH(CH2OH)NH2; CH2OCONH2; CH2O(CH2)2NH2; CONHCH3; CONH2; CON(CH3)2; CONH(CH2)nNH2; CONH(CH2)nNHCH3; or CONH(CH2)nN(CH3)2; and n is 1, 2, or 3.
968 -
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