KR100901931B1 - Substituted Pyridinones as Modulators of P38 MAP Kinase - Google Patents

Abstract

The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof.

In the above formula,

R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as defined herein. Such compounds are useful for treating diseases and conditions caused or exacerbated by unregulated p38 MAP kinase and / or TNF activity. The present invention also discloses pharmaceutical compositions containing the compounds, methods of making the compounds, and methods of treatment using the compounds.

ｐ38 MAP kinase, TF active, substituted pyridinone

Description

Substituted Pyridinones as Modulators of P38 MAP Kinase as Modulators of PI3 MAP Kinase

Ono, K. and J. Han, Cell Signal. 12: 1, 2000]

Trends in Cell biology 7, 353-361, 1997; Mol Cell Biology 19, 21-30, 1999; EMBO J 20, 466-479, 2001]

Paul et al., Cell Signal. 9: 403-410, 1997]

Lee, J. C. et al, Nature, 372: 376, 1994

J. Biol. Chem. 274, 6272, 1999]

[JPET 293,281, 2000]

See Boehm, J. C. and J. L. Adams, Exp. Opin. Ther. Patents 10: 25, 2000]

European Cytokine Netw 6, 225, 1995

Rev. Infect. Disease, 6, 51 (1984)]

Lymphokine Cytokine Res. (11): 253-256, (1992) and Clin. Exp. Immunol. 989: 244-250, (1992)]

<Cross Reference of Related Application>

This application claims priority to US Provisional Application No. 60 / 357,029, filed February 14, 2002 and US Provisional Application No. 60 / 436,915, filed December 30, 2002, which is incorporated by reference in its entirety herein.

The present invention relates to substituted pyridinones useful for treating diseases and conditions caused or exacerbated by unregulated p38 MAP kinase activity. Also described are pharmaceutical compositions containing the pyridinone compounds, methods of making pyridinone compounds, and methods of treatment using the compounds.

Numerous cell surface receptors use one or more mitogen-activated protein kinase (MAP kinase) sequences during signal transduction. MAP kinases are a family of protein-directed serine / threonine kinases that are activated by double phosphorylation. One subgroup of MAP kinases is the p38 MAP kinase, which is a bacterial lipopolysaccharide and environmental stresses such as osmotic shock and ultraviolet as well as proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1). Activated by various signals including irradiation (Ono, K. and J. Han, Cell Signal. 12: 1, 2000). Among the p38 kinase family, there are four distinct isozymes: p38 alpha, p38 beta, p38 gamma and p38 delta. The p38 kinase family phosphorylates and activates transcription factors (eg, ATF2, CHOP and MEF2C) as well as other kinases (eg, MAPKAP-2 and MAPKAP-3) to flow activation stimuli downstream (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 involves gene expression of several factors related to 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). p38 phosphorylation products can stimulate the production of inflammatory cytokines and other proteins such as TNF and IL-1, and cyclooxygenase-2, and can also modulate the effects of these cytokines on their target cells, thereby inflammation Stimulate the process (Lee, JC et al, Nature, 372: 376, 1994).

P38 MAP kinase has also been shown to promote apoptosis in cardiac muscle cells upon ischemia, suggesting that p38 MAP kinase inhibitors can be used to treat ischemic heart disease (J. Biol. Chem. 274, 6272, 1999). P38 MAP kinase is also required in T-cell HIV-1 replication and may be a useful target for treating AIDS. P38 pathway inhibitors have been used to increase the sensitivity of cancer cells to cancer treatment and have been found to be used in the treatment of asthma (JPET 293,281, 2000).

TNF is a cytokine and is a potent proinflammatory mediator mediated by inflammatory symptoms such as arthritis, asthma, septic shock, non-insulin dependent diabetes mellitus, multiple sclerosis, asthma and inflammatory bowel disease. Thus, inhibitors of p38 MAP kinase (required in TNF production) may be useful for the treatment of inflammatory symptoms due to overproduction of cytokines such as arthritis (Boehm, JC and JL Adams, Exp. Opin. Ther. Patents 10 : 25, 2000 and references cited therein). TNF is also a viral infection such as HIV, influenza virus, and others, herpes simplex virus type 1 (HSV-1), simple herpes virus type 2 (HSV-2), cytomegalovirus (CMV), varicella (varicella-zoster) ) Virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and nonbronchiolitis It is also associated with the herpes virus.

Excessive or unregulated production of TNF has also been shown to increase levels of IL-1. Thus, inhibition of TNF should reduce the level of IL-1 (European Cytokine Netw 6, 225, 1995) and improve disease states by unregulated IL-1 synthesis. These disease states include rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, sepsis, septic shock, endotoxin shock, gram negative sepsis, toxin shock syndrome, adult respiratory distress syndrome, brain malaria, chronic pulmonary inflammatory disease, silicosis, lung sarco Aidosis, bone resorption disease, reperfusion injury, graft-to-host response, allograft rejection, fever and myalgia from infection, secondary cachexia for infection or malignancy, secondary cachexia for acquired immunodeficiency syndrome (AIDS), AIDS-related complications ( ARC), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis and paralysis.

IL-1 has also been shown to modulate a variety of biological activities, such as activation of T-helper cells, heat induction, stimulation of prostaglandin or cholangase production, neutrophil chemotaxis, and inhibition of plasma iron concentrations (Rev. Infect. Disease, 6, 51 (1984)]. Increased levels of IL-1 may also be associated with rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, inflammatory bowel disease, adult respiratory distress syndrome (ARDS), psoriasis, Crohn's disease, ulcerative colitis, hypersensitivity, muscle degeneration, cachexia, lighter syndrome, It is associated with modulating or worsening a number of disease states, including type I and type II diabetes, bone resorption disease, ischemic reperfusion injury, arteriosclerosis, brain trauma, multiple sclerosis, sepsis, septic shock and toxin shock syndrome. Viruses sensitive to TNF inhibition, such as HIV-1, HIV-2, HIV-3, are also affected by IL-1 production. In rheumatoid arthritis, both IL-1 and TNF induce collagenase synthesis, eventually leading to tissue destruction in the joints (Lymphokine Cytokine Res. (11): 253-256, (1992) and Clin. Exp. Immunol. 989: 244-250, (1992)].

IL-6 is another proinflammatory cytokine and is associated with numerous symptoms, including inflammation. Thus, TNF, IL-1 and IL-6 affect a wide range of cells and tissues and are important inflammatory mediators of a wide range of disease states and symptoms. Inhibition of such cytokines by the inhibition or regulation of p38 kinase is beneficial for controlling, reducing and alleviating many of these disease states and symptoms.

Accordingly, the present invention is directed to identifying small molecule inhibitors or modulators of p38 kinase and the p38 kinase pathway.

In a broad aspect, the present invention provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof (Embodiment I):

<Formula 1>

In the above formula,

R ₁ is H, halogen, NO ₂ , 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 independently ₁ , _{2 which} is halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, nitro, CN, haloalkyl, haloalkoxy or C0 ₂ R Substituted or unsubstituted with 3, 4 or 5 groups;

Alkyl moieties of alkyl, hydroxyalkyl, dihydroxyalkyl, arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and arylalkanoyl groups are independently halogen, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxy Substituted or unsubstituted with 1, 2 or 3 groups which are carbonyl or C ₃ -C ₇ cycloalkyl;

R ₂ is H, OH, halogen, -OSO _2- (C ₁ -C ₆ ) alkyl, -OS0 ₂ -aryl, arylalkoxy, aryloxy, arylthio, arylthioalkoxy, arylalkynyl, alkoxy, aryloxy ( C ₁ -C ₆ ) alkyl, alkyl, alkynyl, -OC (O) NH (CH ₂ ) _n aryl, -OC (O) N (alkyl) (CH ₂ ) _n aryl, alkoxyalkoxy, dialkylamino, alkyl , Alkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylalkenyl, heterocycloalkyl, heterocycloalkylalkyl, alkoxyalkoxy, NR ₈ R ₉ , dialkylamino or CO ₂ R,

Where n is 0, 1, 2, 3, 4, 5 or 6;

Each independently halogen,-(C ₁ -C ₆ ) alkyl-N (R) -CO ₂ R ₃₀ , haloalkyl, heteroaryl, heteroarylalkyl, -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-, -C (0) NR ₆ R ₇ ,-(C ₁ -C ₄ ) alkyl-C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -NRC (O NR ₁₆ R ₁₇ , haloalkoxy, alkyl, CN, hydroxyalkyl, dihydroxyalkyl, alkoxy, alkoxycarbonyl, phenyl, -SO ₂ -phenyl (wherein the phenyl and -SO ₂ -phenyl groups are independently halogen Or optionally substituted with 1, 2 or 3 groups which are NO ₂ ) or 1, 2, 3, 4 or 5 groups which are -OC (O) NR ₆ R ₇ , or

Wherein R ₁₆ and R ₁₇ are independently H or C ₁ -C ₆ alkyl;

R ₁₆ , R ₁₇ and the nitrogen to which they are attached form a morpholinyl ring;

R ₆ and R ₇ are independently at each occurrence H, alkyl, hydroxyalkyl, dihydroxyalkyl, alkoxy, alkanoyl, arylalkyl, arylalkoxy, alkoxycarbonyl, -SO ₂ -alkyl, OH, alkoxy, alkoxy Alkyl, arylalkoxycarbonyl,-(C ₁ -C ₄ ) alkyl-CO ₂ -alkyl, heteroarylalkyl or arylalkanoyl, each independently halogen, OH, SH, heterocycloalkyl, heterocycloalkylalkyl 1, 2 which is C ₃ -C ₇ cycloalkyl, alkoxy, NH ₂ , NH (alkyl), N (alkyl) (alkyl), —0-alkanoyl, alkyl, haloalkyl, carboxaldehyde or haloalkoxy Substituted or unsubstituted with 3 groups;

R ₆ , R ₇ and the nitrogen to which they are attached are independently 1 or 2 which are C ₁ -C ₄ alkyl, alkoxycarbonyl, C ₁ -C ₄ alkoxy, hydroxyl, hydroxyalkyl, dihydroxyalkyl or halogen A morpholinyl, pyrrolidinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S, S-oxide, piperidinyl, pyrrolidinyl or piperazinyl ring optionally substituted with a group Forming;

R is independently at each occurrence hydrogen or C ₁ -C ₆ alkyl optionally substituted with 1 or 2 groups independently OH, SH, halogen, amino, monoalkylamino, dialkylamino or C ₃ -C ₆ cycloalkyl ego;

R ₃₀ is independently C ₁ -C ₆ alkyl optionally substituted with 1 or 2 groups which are OH, SH, halogen, amino, monoalkylamino, dialkylamino or C ₃ -C ₆ cycloalkyl;

Each R ₈ is independently hydrogen, alkyl, alkanoyl, arylalkyl and arylalkanoyl, wherein each of said groups is independently 1, 2, 3, 4 or 5, which is alkyl, alkoxy, alkoxycarbonyl, halogen or haloalkyl Optionally substituted with a personal group;

Each R ₉ is hydrogen, alkyl, alkanoyl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, heteroaryl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, arylalkanoyl, -SO ₂ -phenyl and Aryl, wherein each is optionally substituted with 1, 2, 3, 4 or 5 groups independently of alkyl, alkoxy, alkoxycarbonyl, halogen or haloalkyl;

R ₃ is H, halogen, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl, -OC (0) NH (CH ₂ ) _n aryl, arylalkoxy, -OC (O) N (alkyl) ( CH ₂ ) _n aryl, aryloxy, arylthio, thioalkoxy, arylthioalkoxy, alkenyl, -NR ₆ R ₇ , NR ₆ R _7- (C ₁ -C ₆ ) alkyl or alkyl,

Wherein arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl, -OC (O) NH (CH ₂ ) _n aryl, arylalkoxy, -OC (0) N (alkyl) (CH ₂ ) _n aryl and arylthioalkoxy The aryl portion of is independently unsubstituted or substituted with 1, 2, 3, 4 or 5 groups which are halogen, alkoxy, alkyl, haloalkyl or haloalkoxy, where n is 0, 1, 2, 3, 4, 5 Or 6);

R ₄ is hydrogen, or is independently CO ₂ R, —CO ₂ — (C ₁ -C ₆ ) alkyl, —C (0) NR ₆ R ₇ , —C (O) R ₆ , —N (R ₃₀ ) C (O) NR ₁₆ R ₁₇ , -N (R ₃₀ ) C (O)-(C ₁ -C ₆ ) alkoxy or alkyl, arylalkoxy, aryl unsubstituted or substituted with 1 or 2 groups, which is -NR ₆ R ₇ Alkyl, heteroaryl, heteroarylalkyl, hydroxyalkyl, dihydroxyalkyl, haloalkyl, R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-, -NR ₆ R ₇ , alkoxy, carboxaldehyde,- C (O) NR ₆ R ₇ , CO ₂ R, alkoxyalkyl or alkoxyalkoxy, wherein the heteroaryl or aryl moiety of the groups is independently halogen, hydroxy, alkoxy, alkyl, -C0 _2- (C ₁ -C ₆ ) 1, 2, 3, 4 or 5 which is alkyl, -CONR ₆ R ₇ , -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ ) alkyl-, nitro, haloalkyl or haloalkoxy Substituted or unsubstituted with 2 groups;

R ₅ is H; Aryl; Arylalkyl; Arylthioalkyl; Optionally substituted with 1, 2 or 3 groups which are arylalkoxycarbonyl, -NR ₈ R ₉ , halogen, -C (O) NR ₈ R ₉ , alkoxycarbonyl, C ₃ -C ₇ cycloalkyl or alkanoyl Alkyl; Alkoxy; Alkoxyalkyl optionally substituted with one trimethylsilyl group; Amino; Alkoxycarbonyl; Hydroxyalkyl; Dihydroxyalkyl; Alkynyl; -S0 ₂ -alkyl; Alkoxy optionally substituted with one trimethylsilyl group; Heterocycloalkylalkyl; Cycloalkyl; Cycloalkylalkyl; -Alkyl-S-aryl; -Alkyl-SO ₂ -aryl; Heteroarylalkyl; Heterocycloalkyl; Heteroaryl; Or alkenyl optionally substituted with alkoxycarbonyl,

Wherein each independently alkyl, halogen, alkoxy, hydroxyalkyl, dihydroxyalkyl, arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, CO ₂ R, CN, OH, hydroxyalkyl, dihydrate Oxyalkyl, amidinooxime, -NR ₆ R ₇ , -NR ₈ R ₉ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-, carboxaldehyde, SO ₂ alkyl, -SO ₂ H, -SO ₂ NR ₆ R ₇ , alkanoyl, wherein the alkyl moiety is optionally substituted with OH, halogen or alkoxy, -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , amidino, haloalkyl,-(C ₁ -C ₄ alkyl) -NR ₁₅ C (O) NR ₁₆ R ₁₇ ,-(C ₁ -C ₄ alkyl) -NR ₁₅ C (O) R ₁₈ , Substituted or unsubstituted with 1, 2, 3, 4 or 5 groups which are -O-CH ₂ -O, -O-CH ₂ CH ₂ -O- or haloalkoxy;

Wherein R ₁₅ is H or C ₁ -C ₆ alkyl;

R ₁₈ is -O- (C ₂ -C ₆₎ alkanoyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₁ -C ₆ -alkyl optionally substituted C to ₆ alkyl; Amino C ₁ -C ₆ alkyl, mono or dialkylamino C ₁ -C ₆ alkyl.

The invention also includes intermediates useful for preparing the compounds of the invention.

The compound binds and / or interacts with p38 kinase and / or TNF. Preferably, the compound inhibits the activity of p38 kinase and / or TNF. Thus, the compounds are used to treat p38 MAP kinase or TNF mediated disorders. Preferably, it is used for the treatment of p38 alpha or TNF mediated disorder.

The present invention also includes pharmaceutical compositions comprising at least one compound of Formula 1 and at least one pharmaceutically acceptable carrier, solvent, adjuvant or excipient.

The invention also includes a method of treating said disorder or condition comprising treating a subject suffering from or susceptible to TNF mediated disorder, p38 kinase mediated disorder, inflammation and / or arthritis with a therapeutically effective amount of a compound of Formula 1 .

In a preferred aspect, the present invention

R ₂ is benzyloxy, R ₃ is H, R ₄ is H, R ₅ is benzyl or methyl, and R ₁ is not hydrogen;

Up to two of R ₁ , R ₂ , R ₄ and R ₅ are simultaneously hydrogen;

R ₆ and R ₇ are not OH at the same time;

When R ₂ is OH, R ₄ is methyl, R ₅ is phenyl, and R ₁ is not acetyl; And R ₄ and R ₅ are not hydrogen at the same time.

Embodiment 2. A compound of the formula and pharmaceutically acceptable salts thereof.

In the above formula,

R ₁ 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 independently ₁ , _{2 which} is halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, nitro, CN, haloalkyl, haloalkoxy or C0 ₂ R Substituted or unsubstituted with 3, 4 or 5 groups;

Alkyl moieties of alkyl, hydroxyalkyl, dihydroxyalkyl, arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and arylalkanoyl groups are independently halogen, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxy Substituted or unsubstituted with 1, 2 or 3 groups which are carbonyl or cyclopropyl;

R ₂ is H, OH, halogen, -OSO _2- (C ₁ -C ₆ ) alkyl, -OSO ₂ -aryl, arylalkoxy, aryloxy, arylthioalkoxy, arylalkynyl, alkoxy, phenyloxy (C _1- C ₆ ) alkyl, -OC (O) NH (CH ₂ ) _n aryl, -OC (O) N (alkyl) (CH ₂ ) _n aryl, alkyl, alkynyl, alkoxyalkoxy, dialkylamino, heteroaryl, hetero Cycloalkyl, aryloxyalkyl or CO ₂ R,

Wherein each independently halogen, —NR ₆ R ₇ , haloalkyl, haloalkoxy, alkyl, heteroaryl, heteroarylalkyl, — (C ₁ -C ₄ ) alkyl-C (O) NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl) -, -C (O) NR 6 R 7, - (C 1 -C 4 _{alkyl) -NRC (O) NR 16 R} 17, CN, hydroxyalkyl, di Substituted or unsubstituted with 1, 2, 3, 4 or 5 groups which are hydroxyalkyl, -OC (O) NR ₆ R ₇ or-(C ₁ -C ₆ ) alkyl-N (R) -CO ₂ R ₃₀ ; ,

Wherein R ₁₆ and R ₁₇ are independently H or C ₁ -C ₆ alkyl;

R ₁₆ , R ₁₇ , and the nitrogen to which they are attached form a morpholinyl ring;

R ₆ and R ₇ are independently at each occurrence H, alkyl, hydroxyalkyl, dihydroxyalkyl, alkoxy, alkoxyalkyl, alkanoyl, arylalkyl, arylalkoxy, arylalkoxycarbonyl or arylalkanoyl, respectively Is independently substituted or unsubstituted with 1, 2 or 3 groups which are halogen, alkoxy, alkyl, OH, SH, carboxaldehyde, haloalkyl or haloalkoxy;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently morpholinyl optionally substituted with one or two groups which are C ₁ -C ₄ alkyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, dihydroxyalkyl or halogen , Thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S, S-dioxide, piperidinyl, pyrrolidinyl or piperazinyl ring;

n is 0, 1, 2, 3, 4, 5 or 6;

R is independently in each occurrence H, or C ₁ -C ₆ optionally substituted with 1 or 2 groups independently OH, SH, halogen, amino, monoalkylamino, dialkylamino or C ₃ -C ₆ cycloalkyl Alkyl;

R ₃₀ is independently C ₁ -C ₆ alkyl optionally substituted with 1 or 2 groups which are OH, SH, halogen, amino, monoalkylamino, dialkylamino or C ₃ -C ₆ cycloalkyl;

R ₄ is H, or independently CO ₂ R, —CO ₂ alkyl, —C (O) NR ₆ R ₇ , —C (O) R ₆ , —N (R ₃₀ ) C (O) NR ₁₆ R ₁₇ , _{-N (R 30) C (O} ) - (C 1 -C 6) alkoxy or -NR ₆ R ₇ is one or two groups that are optionally substituted alkyl, aryl, alkoxy, heteroaryl, arylalkyl, hydroxyalkyl, di Hydroxyalkyl, haloalkyl, -NR ₆ R ₇ , -C (O) NR ₆ R ₇ , alkoxy, alkoxyalkyl or alkoxyalkoxy,

Wherein the heteroaryl or aryl portions of the group are independently halogen, hydroxy, alkoxy, _{alkyl, -C0 2 - (C 1 -C} 6) _{alkyl, -CONR 6 R 7, -NR 6} R 7, R 6 R ₇ N- (C ₁ -C ₆₎ alkyl-, nitro, haloalkyl or haloalkoxy group of 1, 2, 3, 4, or 5 groups and substituted or unsubstituted hwandoe;

R ₅ is H; Arylalkyl; Alkyl optionally substituted with 1, 2 or 3 groups which are independently arylalkoxycarbonyl, -NR ₈ R ₉ , halogen, -C (O) NR ₈ R ₉ , alkoxycarbonyl or alkanoyl; Alkoxyalkyl optionally substituted with one trimethylsilyl group; Alkoxycarbonyl; Amino; Hydroxyalkyl; Dihydroxyalkyl; Alkenyl optionally substituted with alkoxycarbonyl; Alkynyl; -SO ₂ -alkyl; Aryl; Alkoxy optionally substituted with one trimethylsilyl group; Heterocycloalkylalkyl; Heteroarylalkyl; Heterocycloalkyl; Or heteroaryl,

Wherein each independently alkyl, halogen, alkoxy, arylalkoxy, hydroxyalkyl, dihydroxyalkyl, thioalkoxy, -S0 ₂ alkyl, alkoxycarbonyl, arylalkoxycarbonyl, CO ₂ R, CN, OH, AMI Dinooxime, NR ₈ R ₉ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-, -C (O) NR ₆ R ₇ , amidino, hydroxyalkyl, dihydroxyalkyl, carboxaldehyde, -NR ₆ R ₇ , haloalkyl,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -CO ₂ R,-(C ₁ -C ₄ alkyl )-(C ₁ -C ₆ ) alkoxycarbonyl,-(C ₁ -C ₄ alkyl) -CN,-(C ₁ -C ₄ alkyl) -NR ₁₅ C (O) R ₁₈ , -0-CH _2- Substituted or unsubstituted with 1, 2, 3, 4 or 5 groups which are 0-, -0-CH ₂ CH ₂ -0-, phenyl or haloalkoxy;

R ₈ is hydrogen, alkyl, alkanoyl, arylalkyl and arylalkanoyl;

R ₉ is alkyl, alkanoyl, arylalkyl, heteroaryl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl and arylalkanoyl.

Embodiment 3.

R ₁ is H; halogen; Alkyl optionally substituted with C ₁ -C 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 C ₁ -C ₄ alkoxycarbonyl; Alkoxyalkyl; Haloalkyl; Or phenyl (C ₁ -C ₆ ) alkanoyl,

Wherein the phenyl group is independently substituted or unsubstituted with 1, 2, 3, 4 or 5 groups which are halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, nitro, CN, CF ₃ , OCF ₃ or CO ₂ R Ring;

The alkyl group is unsubstituted or substituted with 1, 2 or 3 groups which are independently halogen, methoxy or ethoxy;

R ₂ is OH, phenyl (C ₁ -C ₆ ) alkoxy, phenyloxy, phenyloxy (C ₁ -C ₆ ) alkyl, phenyl (C ₁ -C ₄ ) thioalkoxy, C ₁ -C ₈ alkoxy, alkoxyalkoxy, -O-SO ₂ phenyl, alkynyl, phenyl (C ₂ -C ₄ ) alkynyl, alkyl, -OC (O) NH (CH ₂ ) _n phenyl, -OC (O) N (alkyl) (CH ₂ ) _n Phenyl, dialkylamino, pyridyl, pyrimidyl, pyridazyl, pyrazolyl, imidazolyl, pyrrolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl, tria Genyl, tetrahydrofuryl, piperidinyl, hexahydropyrimidinyl, thiazolyl, thienyl or CO ₂ R,

Where n is 0, 1, 2, 3, 4, 5 or 6;

Each independently halogen, NR ₆ R ₇ , haloalkyl, haloalkoxy, hydroxyalkyl, di hydroxyalkyl, alkyl, phenyl, pyridyl, piperidinyl, piperazinyl,-(C ₁ -C ₆ ) alkyl -N (R) -CO ₂ R ₃₀ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-, -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ ) alkyl-C (O ) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -NRC (O) NR ₁₆ R ₁₇ or -OC (O) NR ₆ R ₇ substituted or unsubstituted with 1, 2, 3, 4 or 5 groups ,

Wherein R ₆ and R ₇ are independently at each occurrence H, alkyl, (C ₁ -C ₄ ) hydroxyalkyl, (C ₁ -C ₄ ) dihydroxyalkyl, (C ₁ -C ₄ ) alkoxy, ( C ₁ -C ₄ ) alkoxy (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkanoyl, phenyl (C ₁ -C ₄ ) alkyl, phenyl (C ₁ -C ₄ ) alkoxy, phenyl (C ₁ -C ₄ ) alkoxycarbonyl or phenyl (C ₁ -C ₄ ) alkanoyl, each independently halogen, OH, SH, C ₃ -C ₆ cycloalkyl, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkyl, CF ₃ , carboxaldehyde, NH ₂ , NH (C ₁ -C ₆ ) alkyl, N (C ₁ -C ₆ ) alkyl (C ₁ -C ₆ ) alkyl, OCF ₃ 1, 2 Or substituted or unsubstituted with three groups;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently C ₁ -C ₄ alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ dihydroxyalkyl, C ₁ -C ₄ alkoxycar Morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl or piperazinyl rings optionally substituted with 1 or 2 groups that are carbonyl or halogen;

R ₄ is H, independently C0 ₂ R, -CO ₂ alkyl, -C (O) NR ₆ R ₇ , -C (O) R ₆ , -N (R ₃₀ ) C (O) NR ₁₆ R ₁₇ ,- N (R ₃₀ ) C (O) — (C ₁ -C ₆ ) alkoxy or alkyl optionally substituted with 1 or 2 groups, —NR ₆ R ₇ , —C (O) NR ₆ R ₇ , phenyl (C _1- C ₆ ) alkoxy, phenyl (C ₁ -C ₆ ) alkyl, hydroxyalkyl, dihydroxyalkyl, haloalkyl, alkoxy, alkoxyalkyl or alkoxyalkoxy,

Wherein the phenyl group is independently substituted or unsubstituted with 1, 2, 3, 4 or 5 groups being halogen, hydroxy, alkoxy, alkyl, nitro, CF ₃ , OCF ₃ ;

R ₅ is phenyl (C ₁ -C ₆ ) alkyl; Optionally substituted with 1, 2, 3, 4 or 5 groups which are independently phenyl C ₁ -C ₄ alkoxycarbonyl, -NR ₈ R ₉ , halogen, -C (O) NR ₈ R ₉ , alkoxycarbonyl or alkanoyl (C ₁ -C ₆ ) alkyl; Phenyl; Alkoxy; C ₂ -C ₆ alkynyl; Alkoxycarbonyl, indolyl, quinolinyl, isoquinolinyl, isoindolyl, dihydroindolyl, pyrazolyl, imidazolyl, dihydroisoindolyl, indolon-2-yl, indazolyl, benzimida Zolyl, pyridyl, imidazolidine dione, pyrazolyl (C ₁ -C ₆ alkyl), imidazolyl (C ₁ -C ₆ alkyl), piperidinyl (C ₁ -C ₆ ) alkyl, pyrrolidinyl ( C ₁ -C ₆ ) alkyl, imidazolidinyl (C ₁ -C ₆ ) alkyl, tetrahydroisoquinolinyl (C ₁ -C ₆ ) alkyl, 1H-indazolyl (C ₁ -C ₆ ) alkyl, di Hydroindolon-2-yl (C ₁ -C ₆ alkyl), indolinyl (C ₁ -C ₆ alkyl), dihydrobenzimidazolyl (C ₁ -C ₆ alkyl) or dihydrobenzoimidazolonyl ( C ₂ -C ₆ alkenyl optionally substituted with C ₁ -C ₆ alkyl); Pyridyl (C ₁ -C ₆ ) alkyl; Pyridazinyl (C ₁ -C ₆ ) alkyl; Pyrimidinyl (C ₁ -C ₆ ) alkyl; Pyrazinyl (C ₁ -C ₆ ) alkyl; Tetrahydrofuryl (C ₁ -C ₆ ) alkyl; Naphthyl (C ₁ -C ₆ ) alkyl; Morpholinyl (C ₁ -C ₆ ) alkyl; Tetrahydrofuryl (C ₁ -C ₆ ) alkyl; Thienyl (C ₁ -C ₆ ) alkyl; Piperazinyl (C ₁ -C ₆ ) alkyl; Indolyl (C ₁ -C ₆ ) alkyl; Quinolinyl (C ₁ -C ₆ ) alkyl; Isoquinolinyl (C ₁ -C ₆ ) alkyl; Isoindolyl (C ₁ -C ₆ ) alkyl; Dihydroindolyl (C ₁ -C ₆ ) alkyl; Pyrazolyl (C ₁ -C ₄ ) alkyl; Imidazolyl (C ₁ -C ₄ ) alkyl; Dihydroisoindolyl (C ₁ -C ₆ ) alkyl; Indon-2-yl (C ₁ -C ₆ ) alkyl; Indolon-2-yl (C ₁ -C ₆ ) alkyl; Or morpholinyl C ₁ -C ₆ alkyl,

Wherein each independently C ₁ -C ₆ alkyl, halogen, C ₁ -C ₆ alkoxy, phenyl C ₁ -C ₆ alkoxy, C ₁ -C ₆ thioalkoxy, C ₁ -C ₆ alkoxycarbonyl, CO ₂ R , CN, -S0 ₂ (C ₁ -C ₆ ) alkyl, amidinooxime, NR ₈ R ₉ , -NR ₆ R ₇ , NR ₆ R ₇ C ₁ -C ₆ alkyl, -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ ) alkyl-C (O) NR ₆ R ₇ , amidino, C ₁ -C ₄ haloalkyl, hydroxy C ₁ -C ₆ alkyl, C ₁ -C ₆ dihydroxyalkyl or Substituted or unsubstituted with 1, 2, 3, 4 or 5 groups which are C ₁ -C ₄ haloalkoxy;

Wherein R ₈ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl, phenyl C ₁ -C ₆ alkyl and phenyl C ₁ -C ₆ alkanoyl;

R ₉ is aminoalkyl, mono C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl, di C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl , Phenyl C ₁ -C ₆ alkyl, indazolyl and phenyl C ₁ -C ₆ alkanoyl.

Embodiment 4.

R ₁ is H, halogen, C ₁ -C ₄ alkoxycarbonyl optionally substituted by C ₁ -C ₄ alkyl, C ₁ -C ₄ al cock Brassica Viterbo carbonyl optionally substituted C ₂ -C ₄ alkenyl which is to be a, C ₂ -C ₄ alkynyl or carboxaldehyde;

R ₂ is benzyloxy, OH, phenyloxy, phenyloxy (C ₁ -C ₆ ) alkyl, phenyl (C ₁ -C ₄ ) thioalkoxy or pyridyl; Wherein each independently halogen,-(C ₁ -C ₆ ) alkyl-N (R) -CO ₂ R ₃₀ , NR ₆ R ₇ ,-(C ₁ -C ₄ ) alkyl-C (0) NR ₆ R ₇ , (C ₁ -C ₄ ) haloalkyl, -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -NRC (O) NR ₁₆ R ₁₇ , (C ₁ -C ₄ ) haloalkoxy 1, 2, 3, 4 which is, hydroxyalkyl, C ₁ -C ₆ dihydroxyalkyl, (C ₁ -C ₆ ) alkyl, pyridyl or R ₆ R ₇ N- (C ₁ -C ₆ alkyl)- Or a compound according to embodiment 3 optionally substituted with 5 groups.

Embodiment 4a. A compound according to embodiment 4, wherein R ₁ is H.

Embodiment 4b. A compound according to embodiment 4, wherein R ₁ is halogen.

Embodiment 4c. The compound according to embodiment 4, wherein R ₁ is C ₁ -C ₄ alkyl optionally substituted with C ₁ -C ₄ alkoxycarbonyl.

Embodiment 5.

R ₅ is indolyl, pyridyl, pyridazinyl, pyrimidinyl, indazolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, pyrazolyl, imidazolyl, furanyl, quinolinyl, isoquinolinyl, Isoindolyl, dihydroindolyl, dihydroisoindolyl, indolon-2-yl or pyrazinyl, each independently of C ₁ -C ₄ alkyl, halogen, CF ₃ , OCF ₃ , —CO ₂ CH ₃ , C ₁ -C ₄ hydroxy alkyl, dihydroxyalkyl, C ₁ -C ₄ alkoxy, -CO ₂ (C ₁ -C ₅ alkyl), benzyloxy, -NR ₆ R ₇ ,-(C ₁ -C ₄ ) 1, 2, 3 which is alkyl-C (O) NR ₆ R ₇ , -NR ₈ R ₉ , NR ₆ R _7- (C ₁ -C ₄ alkyl), -C (O) NR ₆ R ₇ or amidinooxime Substituted or unsubstituted with 4 or 5 groups;

Wherein, R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ dihydroxy alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl, C ₁ -C ₄ alkanoyl, phenyl C ₁ -C ₄ alkyl, phenyl C ₁ -C ₄ alkoxy or phenyl C ₁ -C ₄ alkanoyl, each independently halogen Substituted or unsubstituted with 1, 2 or 3 substituents that are OH, SH, C ₃ -C ₆ cycloalkyl, aryl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, OH, CF ₃ or OCF ₃ ;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently selected from one or two groups that are C ₁ -C ₄ alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ dihydroxyalkyl or halogen A compound according to embodiment 4, which forms an optionally substituted morpholinyl, thiomorpholinyl, pyrrolidinyl or piperazinyl ring.

Embodiment 6.

R ₅ is indolyl, pyridyl, pyrimidinyl, pyrazolyl, furanyl, indazolyl, dihydroindolyl, dihydroisoindolyl, indolon-2-yl or pyrazinyl, each independently C _1- C ₄ alkyl, _{halogen, CF 3, OCF 3, -CO} 2 CH 3, C 1 -C 4 hydroxyalkyl, C ₁ -C ₄ dihydroxy alkyl, C ₁ -C ₄ alkoxy, -C0 ₂ (C ₁ -C ₅ alkyl), benzyloxy, -C (O) NR ₆ R ₇ , -NR ₈ R ₉ ,-(C ₁ -C ₄ ) alkyl-C (O) NR ₆ R ₇ , -NR ₆ R ₇ , A compound according to embodiment 5, substituted or unsubstituted with 1, 2, 3 or 4 groups which are NR ₆ R _7- (C ₁ -C ₄ alkyl)-and amidinooxime.

Embodiment 7.

R ₅ is indolyl, pyridyl, pyrimidinyl, dihydroindolyl, dihydroisoindolyl, pyrazolyl or pyrazinyl, each independently of C ₁ -C ₄ alkyl, halogen, CF ₃ , OCF ₃ ,- _{CO 2 CH 3, C 1 -C} 4 hydroxyalkyl, C ₁ -C ₄ dihydroxy alkyl, C ₁ -C ₄ alkoxy, -CO ₂ (C ₁ -C ₅ alkyl), benzyloxy, -C (O ) NR ₆ R ₇ , NR ₈ R ₉ ,-(C ₁ -C ₄ ) alkyl-C (O) NR ₆ R ₇ , -NR ₆ R ₇ , NR ₆ R _7- (C ₁ -C ₄ alkyl)- Or substituted or unsubstituted with 1, 2, 3 or 4 groups which are amidinooximes;

Wherein, R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ dihydroxy alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkanoyl, C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl, each independently halogen, OH, SH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ A compound according to embodiment 6, optionally substituted with 1, 2 or 3 groups which are alkyl, OH, CF ₃ or OCF ₃ .

Embodiment 8.

R ₅ is indolyl, pyridyl, pyrimidinyl, dihydroindolyl, dihydroisoindolyl, pyrazolyl or pyrazinyl, each independently of C ₁ -C ₄ alkyl, halogen, CF ₃ , OCF ₃ , C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ dihydroxyalkyl, C ₁ -C ₄ alkoxy, -C (0) NR ₆ R ₇ ,-(C ₁ -C ₄ ) alkyl-C (O) Substituted or unsubstituted with 1, 2 or 3 groups which are NR ₆ R ₇ , NR ₈ R ₉ , -NR ₆ R ₇ or NR ₆ R _7- (C ₁ -C ₄ alkyl)-;

Wherein, R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ dihydroxy alkyl, C ₁ -C ₄ alkanoyl or C _1, C ₄ alkoxy, each independently ₁ , 2 being halogen, OH, SH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, OH, CF ₃ or OCF ₃ Or a compound according to embodiment 7, optionally substituted with three groups.

Embodiment 9.

R ₅ is phenyl, phenyl (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkyl,

Wherein each independently alkyl, halogen, alkoxy, benzyloxy, hydroxyalkyl, dihydroxyalkyl, thioalkoxy, -CO ₂ (C ₁ -C ₅ alkyl), CO ₂ R, CN, amidinooxime,- NR ₈ R ₉ , -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-, -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ ) alkyl-C (O ) Substituted or unsubstituted with 1, 2, 3, 4 or 5 groups which are NR ₆ R ₇ , amidino, CF ₃ or OCF ₃ ;

R ₈ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl, phenyl C ₁ -C ₆ alkyl and phenyl C ₁ -C ₆ alkanoyl;

R ₉ is aminoalkyl, mono C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl, di C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl , Phenyl C ₁ -C ₄ alkyl, indazolyl and phenyl C ₁ -C ₄ alkanoyl.

Embodiment 10.

R ₅ is phenyl; Independently alkyl, halogen, alkoxy, benzyloxy, thioalkoxy, -C0 ₂ (C ₁ -C ₅ alkyl), CO ₂ R, CN, amidinooxime, -NR ₈ R ₉ , -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-, R ₆ R ₇ NC (O)-(C ₁ -C ₄ alkyl)-, R ₆ R ₇ NC (O)-(C ₅ -C ₆ alkyl) Phenyl (C ₁ -C ₆ ) alkyl unsubstituted or substituted with 1, 2, 3, 4 or 5 groups, -C (O) NR ₆ R ₇ , amidino, CF ₃ or OCF ₃ ;

Wherein, R ₆ and R ₇ are independently at each occurrence, H, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ dihydroxy alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl, C ₁ -C ₄ alkanoyl, phenyl C ₁ -C ₄ alkyl, phenyl C ₁ -C ₄ alkoxy or phenyl C ₁ -C ₄ alkanoyl, each independently Substituted or unsubstituted with 1, 2 or 3 groups which are halogen, OH, SH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, CF ₃ or OCF ₃ ;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently selected from one or two groups that are C ₁ -C ₄ alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ dihydroxyalkyl or halogen To form an optionally substituted morpholinyl, thiomorpholinyl or piperazinyl ring;

R ₈ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl, phenyl C ₁ -C ₆ alkyl and phenyl C ₁ -C ₆ alkanoyl;

R ₉ is aminoalkyl, mono C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl, di C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl , Phenyl C ₁ -C ₄ alkyl, indazolyl and phenyl C ₁ -C ₄ alkanoyl.

Embodiment 11.

R ₅ is phenyl, benzyl or phenethyl, each independently C ₁ -C ₆ alkyl, -NR ₆ R ₇ , -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , -NR ₈ R ₉ , halogen, C ₁ -C ₆ alkoxy, C0 ₂ R,-(C ₁ -C ₄ alkyl) -CO ₂ R, C ₁ -C ₆ thioalkoxy, AMI Dinooxime, C ₁ -C ₆ alkoxycarbonyl,-(C ₁ -C ₄ alkyl) -C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ dihydroxyalkyl, - (C ₁ -C ₄ alkyl) -CN, CN, phenyl C ₁ -C ₆ alkoxy, OH, C ₁ -C ₄ haloalkyl, C ₁ -C _{4 haloalkoxy, R 6 R 7 N- (C} 1 - C ₆ alkyl)-,-(C ₁ -C ₄ alkyl) -NR ₁₅ C (O) R ₁₈ , amidinooxime, -SO ₂ (C ₁ -C ₆ alkyl), -O-CH ₂ -O-, Optionally substituted with 1, 2, 3, 4 or 5 groups which are -O-CH ₂ CH ₂ -O-, phenyl C ₁ -C ₄ alkoxy or phenyl;

Wherein, R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ dihydroxy alkyl, C ₁ -C ₄ alkanoyl or C ₁ -C ₄ alkoxy, each independently halogen, OH, SH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, OH, CF ₃ or OCF ₃ , A compound according to embodiment 10, optionally substituted with 2 or 3 groups.

Embodiment 12.

R ₅ is phenyl, benzyl or phenethyl, each independently CN, halogen, C ₁ -C ₄ alkoxy, CF ₃ , OCF ₃ , C ₁ -C ₄ alkyl, -NR ₈ R ₉ , -NR ₆ R ₇ , Substituted or unsubstituted with 1, 2, 3, 4 or 5 groups, wherein R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-or —C (O) NR ₆ R ₇

Wherein R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ dihydroxy alkyl, C ₁ -C ₄ alkanoyl or C ₁ 1, 2 or -C ₄ alkoxy, each independently halogen, OH, SH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, OH, CF ₃ or OCF ₃ A compound according to embodiment 11, optionally substituted with three groups.

Embodiment 13.

이고,R ₅ group is a chemical formula

ego,

Wherein Z ₁ and Z ₂ are independently H, halogen, C ₁ -C ₄ alkyl or CO ₂ R;

Z is —C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ ) alkyl-C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -NR ₁₅ C (O) R ₁₈ , _{-NR 6 R 7, R 6 R} 7 N- (C 1 -C 6 _{alkyl) -, -NR 8 R 9,} C 1 -C 6 hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, C ₁ - C ₆ alkyl, CO ₂ R or halogen;

Wherein R ₆ and R ₇ in each occurrence are independently H, OH, C ₁ -C ₆ alkyl, amino C ₁ -C ₄ alkyl, NH (C ₁ -C ₆ alkyl) alkyl, N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl or - SO ₂ (C ₁ -C ₆ alkyl), each independently halogen, OH, SH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, OH, CF ₃ or OCF ₃ or one, two or three groups optionally substituted or;

R ₆ , R ₇ , and the nitrogen to which they are attached are piperidi optionally substituted with one or two groups which are independently alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ dihydroxyalkyl or halogen To form a nil, pyrrolidinyl, piperazinyl or morpholinyl, thiomorpholinyl ring;

R ₁₈ is —O- (C ₂ -C ₆ ) alkanoyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₄ dihydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₁ -C ₆ -alkyl optionally substituted C to ₆ alkyl; The compound according to embodiment 4, which is amino C ₁ -C ₆ alkyl, mono or dialkylamino C ₁ -C ₆ alkyl.

Embodiment 14.

R ₅ is pyrazolyl (C ₁ -C ₆ alkyl), imidazolyl (C ₁ -C ₆ alkyl), thienyl (C ₁ -C ₆ alkyl), furanyl (C ₁ -C ₆ alkyl), piperidi Neyl (C ₁ -C ₆ ) alkyl, pyrrolidinyl (C ₁ -C ₆ ) alkyl, imidazolidinyl (C ₁ -C ₆ ) alkyl, piperazinyl (C ₁ -C ₆ ) alkyl, pyridyl ( C ₁ -C ₆ ) alkyl, pyrimidyl (C ₁ -C ₆ ) alkyl, pyridazyl (C ₁ -C ₆ ) alkyl, pyrazinyl (C ₁ -C ₆ ) alkyl, isoquinolinyl (C ₁ -C ₆ ) alkyl, tetrahydroisoquinolinyl (C ₁ -C ₆ ) alkyl, indolyl (C ₁ -C ₆ ) alkyl, 1H-indazolyl (C ₁ -C ₆ ) alkyl, dihydroindolyl (C ₁ -C ₆ ) alkyl, dihydroindolon-2-yl (C ₁ -C ₆ alkyl), indolinyl (C ₁ -C ₆ alkyl), dihydroisoindolyl (C ₁ -C ₆ alkyl), dihydrobenz Imidazolyl (C ₁ -C ₆ alkyl) or dihydrobenzoimidazolonyl (C ₁ -C ₆ alkyl),

Wherein each independently represents (C ₁ -C ₆ ) alkyl, halogen, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) hydroxyalkyl, C ₁ -C ₆ dihydroxyalkyl, phenyl (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) thioalkoxy, (C ₁ -C ₆ ) alkoxycarbonyl, phenyl (C ₁ -C ₆ ) alkoxycarbonyl, OH, CO ₂ R, CN, amidino Oxime, -NR ₈ R ₉ , -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-, -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl)- C (O) NR ₆ R ₇ , amidino, piperazinyl, morpholinyl, -SO ₂ (C ₁ -C ₆ ) alkyl, -S0 ₂ NH ₂ , -SO ₂ NH (C ₁ -C ₆ ) alkyl , -S0 ₂ N (C ₁ -C ₆ ) alkyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₄ ) haloalkyl,-(C ₁ -C ₄ alkyl) -NR ₁₅ C (O) NR ₁₆ R ₁₇ ,-(C ₁ -C ₄ alkyl) -NR ₁₅ C (O) R ₁₈ , -O-CH ₂ -O, -O-CH ₂ CH ₂ -O- or (C ₁ -C ₆ ) haloalkoxy Substituted or unsubstituted with 1, 2, 3, 4 or 5 groups of phosphorus;

Wherein R ₆ and R ₇ are independently at each occurrence H, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) hydroxyalkyl, C ₁ -C ₆ dihydroxyalkyl,-(C ₁ -C ₄ ) alkyl-CO _2- (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkanoyl, phenyl (C ₁ -C ₆ ) alkyl, phenyl (C ₁ -C ₆ ) alkoxy or phenyl (C ₁ -C ₆ ) alkanoyl, each independently , Halogen, (C ₁ -C ₄ ) alkoxy, OH, SH, C ₃ -C ₆ cycloalkyl, NH ₂ , NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) (C _1- C ₆ alkyl), (C ₁ -C ₄ ) alkyl, substituted or unsubstituted with 1, 2 or 3 groups which are CF ₃ or OCF ₃ ;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently selected from one or two groups that are C ₁ -C ₄ alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ dihydroxyalkyl or halogen To form an optionally substituted morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl or piperazinyl ring;

R ₁₈ is -O- (C ₂ -C ₆₎ alkanoyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₁ -C ₆ -alkyl optionally substituted C to ₆ alkyl; The compound according to embodiment 4, which is amino C ₁ -C ₆ alkyl, mono or dialkylamino C ₁ -C ₆ alkyl.

That in this embodiment, R ₆ and R ₇ are not simultaneously OH, R ₆ and R ₇ are simultaneously other than -S0 ₂ (C ₁ -C ₆ alkyl) are preferred.

Embodiment 15.

R ₅ is pyrazolyl (C ₁ -C ₆ alkyl), imidazolyl (C ₁ -C ₆ alkyl), benzimidazolyl (C ₁ -C ₆ alkyl), thienyl (C ₁ -C ₆ alkyl), Pyrimidyl (C ₁ -C ₆ ) alkyl, indolyl (C ₁ -C ₆ alkyl), dihydroindolyl (C ₁ -C ₆ alkyl), dihydroisoindolyl (C ₁ -C ₆ alkyl), dihydro Indolon-2-yl (C ₁ -C ₆ alkyl), pyridinyl (C ₁ -C ₆ alkyl), piperazinyl (C ₁ -C ₆ alkyl) or pyrazinyl (C ₁ -C ₆ alkyl), each independently represent a C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ dihydroxy alkyl, _{halogen, -C (O) NR 6 R} 7, - (C 1 -C 4 alkyl ) -C (O) NR ₆ R ₇ , C ₁ -C ₆ alkoxycarbonyl, -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-, haloalkyl, C ₁ -C ₆ Optionally substituted with 1, 2 or 3 groups which are alkanoyl;

R ₆ and R ₇ in each occurrence are independently H, or ₁ , 2 independently of C ₁ -C ₄ alkoxycarbonyl, halogen, C ₃ -C ₆ cycloalkyl, OH, SH or C ₁ -C ₄ alkoxy C ₁ -C ₆ alkyl optionally substituted with three groups;

R ₆ , R ₇ , and the nitrogen to which they are attached are piperidi optionally substituted with one or two groups which are independently alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ dihydroxyalkyl or halogen A compound according to embodiment 14, which forms a silyl, pyrrolidinyl, piperazinyl or morpholinyl ring.

Embodiment 16.

이고,R ₅ is a chemical formula

ego,

Here, Z ₅ is C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ dihydroxy alkyl, _{halogen, -C (O) NR 6 R} 7, - (C 1 -C ₄ alkyl) -C (O) NR ₆ R ₇ , C ₁ -C ₆ alkoxycarbonyl, R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-, -NR ₆ R ₇ , CF ₃ or C _1- C ₆ alkanoyl,

Wherein R ₆ and R ₇ in each occurrence are independently H, or independently C ₁ -C ₄ alkoxycarbonyl, halogen, C ₃ -C ₆ cycloalkyl, OH, SH or C ₁ -C ₄ alkoxy C ₁ -C ₆ alkyl optionally substituted with 2 or 3 groups;

R ₆ , R ₇ , and the nitrogen to which they are attached are piperidi optionally substituted with one or two groups which are independently alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ dihydroxyalkyl or halogen A compound according to embodiment 15 forming a nil, pyrrolidinyl, piperazinyl or morpholinyl ring.

Embodiment 17.

이고,R ₅ is a chemical formula

ego,

Here, Z ₅ is C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ dihydroxy alkyl, _{halogen, -C (O) NR 6 R} 7, - (C 1 -C 4 Alkyl) -C (O) NR ₆ R ₇ , C ₁ -C ₆ alkoxycarbonyl, R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-, -NR ₆ R ₇ , CF ₃ or C ₁ -C ₆ alkanoyl,

Wherein R ₆ and R ₇ in each occurrence are independently H, or independently C ₁ -C ₄ alkoxy carbonyl, halogen, C ₃ -C ₆ cycloalkyl, OH, SH or C ₁ -C ₄ alkoxy C ₁ -C ₆ alkyl optionally substituted with 2 or 3 groups;

R ₆ , R ₇ , and the nitrogen to which they are attached are piperidi optionally substituted with one or two groups which are independently alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ dihydroxyalkyl or halogen A compound according to embodiment 15 forming a nil, pyrrolidinyl, piperazinyl or morpholinyl ring.

Embodiment 18.

Z ₅ is C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ dihydroxy alkyl, halogen, C ₁ -C ₆ alkoxycarbonyl, CF ₃ or C ₁ -C ₆ alkanoyl A compound according to embodiment 16 or 17 which is phosphorus.

Embodiment 19.

Z ₅ is C ₁ -C ₄ alkyl, -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-or -NR ₆ R ₇ , CF ₃ or C ₁ -C ₄ alkanoyl;

Wherein R ₆ and R ₇ in each occurrence are independently H, or independently _{1, which} is C ₁ -C ₄ alkoxycarbonyl, halogen, C ₃ -C ₆ cycloalkyl, OH, SH or C ₁ -C ₄ alkoxy; C ₁ -C ₆ alkyl optionally substituted with 2 or 3 groups;

R _6, R _7, and the nitrogen to which they are attached independently alkyl, hydroxy, hydroxy C ₁ - C ₄ alkyl, C ₁ -C ₄ dihydroxy alkyl or halogen is 1 or 2, l is an optionally substituted piperidinyl group of A compound according to embodiment 16 or 17, which forms a nil, pyrrolidinyl, piperazinyl or morpholinyl ring.

Embodiment 20.

Z ₅ is -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-or -NR ₆ R ₇

Wherein R ₆ and R ₇ are independently at each occurrence H, or independently 1, 2 or 3 groups which are C ₁ -C ₄ alkoxycarbonyl, halogen, cyclopropyl, OH, SH or C ₁ -C ₄ alkoxy The compound according to embodiment 19, which is optionally substituted C ₁ -C ₆ alkyl.

Embodiment 21.

이고,R ₅ is a chemical formula

ego,

Wherein Z ₁₀ is H or methyl;

Z ₂₀ is hydroxy (C ₁ -C ₄ ) alkyl, C ₁ -C ₄ dihydroxyalkyl, OH, halogen, haloalkyl, (C ₁ -C ₄ ) alkyl, OCF ₃ , -NR ₆ R ₇ , R _{6 R 7 N- (C 1 -C} 6 _{alkyl) -, - (C 1 -C} 4 _{alkyl) -C (O) NR 6 R} 7 or -C (O) NR ₆ R _7, and

Wherein R ₆ and R ₇ in each occurrence are independently H, or independently C ₁ -C ₄ alkoxy carbonyl, halogen, C ₃ -C ₆ cycloalkyl, OH, SH or C ₁ -C ₄ alkoxy The compound according to embodiment 15 which is C ₁ -C ₆ alkyl optionally substituted with 2 or 3 groups.

Embodiment 22.

이고,R ₅ is a chemical formula

ego,

Wherein Z ₁₀ is H or methyl;

Z ₂₀ is hydroxy (C ₁ -C ₄ ) alkyl, C ₁ -C ₄ dihydroxyalkyl, OH, halogen, CF ₃ , (C ₁ -C ₄ ) alkyl, OCF ₃ , -NR ₆ R ₇ , R _{6 R 7 N- (C 1 -C} 6 _{alkyl) -, - (C 1 -C} 4 _{alkyl) -C (O) NR 6 R} 7 or -C (O) NR ₆ R _7, and

Wherein R ₆ and R ₇ in each occurrence are independently H, or independently C ₁ -C ₄ alkoxycarbonyl, halogen, C ₃ -C ₆ cycloalkyl, OH, SH or C ₁ -C ₄ alkoxy The compound according to embodiment 15 which is C ₁ -C ₆ alkyl optionally substituted with 2 or 3 groups.

Embodiment 23.

이고,R ₅ is a chemical formula

ego,

Wherein Z ₁₀ is H or methyl;

Z ₂₀ is hydroxy (C ₁ -C ₄ ) alkyl, C ₁ -C ₄ dihydroxyalkyl, OH, halogen, haloalkyl, (C ₁ -C ₄ ) alkyl, OCF ₃ , -NR ₆ R ₇ , R _{6 R 7 N- (C 1 -C} 6 _{alkyl) -, - (C 1 -C} 4 _{alkyl) -C (O) NR 6 R} 7 or -C (O) NR ₆ R _7, and

Wherein R ₆ and R ₇ in each occurrence are independently H, or independently C ₁ -C ₄ alkoxycarbonyl, halogen, C ₃ -C ₆ cycloalkyl, OH, SH or C ₁ -C ₄ alkoxy The compound according to embodiment 15 which is C ₁ -C ₆ alkyl optionally substituted with 2 or 3 groups.

Embodiment 24.

이고,R ₅ is a chemical formula

ego,

Wherein Z ₁₀ is H or methyl;

Z ₂₀ is hydroxy (C ₁ -C ₄ ) alkyl, C ₁ -C ₄ dihydroxyalkyl, OH, halogen, CF ₃ , (C ₁ -C ₄ ) alkyl), OCF ₃ , -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ or -C (O) NR ₆ R ₇ ,

Wherein R ₆ and R ₇ in each occurrence are independently H, or independently C ₁ -C ₄ alkoxycarbonyl, halogen, C ₃ -C ₆ cycloalkyl, OH, SH or C ₁ -C ₄ alkoxy The compound according to embodiment 15 which is C ₁ -C ₆ alkyl optionally substituted with 2 or 3 groups.

Embodiment 25.

이고,R ₅ is a chemical formula

ego,

Wherein Z ₁₀ is H or methyl;

Z ₂₀ is hydroxy (C ₁ -C ₄ ) alkyl, C ₁ -C ₄ dihydroxyalkyl, OH, halogen, haloalkyl, (C ₁ -C ₄ ) alkyl, OCF ₃ , -NR ₆ R ₇ , R _{6 R 7 N- (C 1 -C} 6 _{alkyl) -, - (C 1 -C} 4 _{alkyl) -C (O) NR 6 R} 7 or -C (O) NR ₆ R _7, and

Wherein R ₆ and R ₇ in each occurrence are independently H, or independently C ₁ -C ₄ alkoxycarbonyl, halogen, C ₃ -C ₆ cycloalkyl, OH, SH or C ₁ -C ₄ alkoxy The compound according to embodiment 15 which is C ₁ -C ₆ alkyl optionally substituted with 2 or 3 groups.

Embodiment 26.

이고,R ₅ is a chemical formula

ego,

Wherein Z ₁₀ is H or methyl;

Z ₂₀ is hydroxy (C ₁ -C ₄ ) alkyl, C ₁ -C ₄ dihydroxyalkyl, OH, halogen, CF ₃ , (C ₁ -C ₄ ) alkyl, OCF ₃ , -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ or -C (O) NR ₆ R ₇ ,

Wherein R ₆ and R ₇ in each occurrence are independently H, or independently _{1, which} is C ₁ -C ₄ alkoxycarbonyl, halogen, C ₃ -C ₆ cycloalkyl, OH, SH or C ₁ -C ₄ alkoxy; The compound of embodiment 15 which is C ₁ -C ₆ alkyl optionally substituted with 2 or 3 groups.

Embodiment 27.

이고,R ₅ is a chemical formula

ego,

Wherein Z ₁₀ is H or methyl;

Z ₂₀ is hydroxy (C ₁ -C ₄ ) alkyl, C ₁ -C ₄ dihydroxyalkyl, OH, halogen, haloalkyl, (C ₁ -C ₄ ) alkyl, OCF ₃ , -NR ₆ R ₇ , R _{6 R 7 N- (C 1 -C} 6 _{alkyl) -, - (C 1 -C} 4 _{alkyl) -C (O) NR 6 R} 7 or -C (O) NR ₆ R _7, and

Wherein R ₆ and R ₇ in each occurrence are independently H, or independently _{1, which} is C ₁ -C ₄ alkoxycarbonyl, halogen, C ₃ -C ₆ cycloalkyl, OH, SH or C ₁ -C ₄ alkoxy; A compound according to embodiment 15 which is C ₁ -C ₆ alkyl optionally substituted with 2 or 3 groups.

Embodiment 28.

이고,R ₅ is a chemical formula

ego,

Wherein Z ₁₀ is H or methyl;

Z ₂₀ is hydroxy (C ₁ -C ₄ ) alkyl, C ₁ -C ₄ dihydroxyalkyl, OH, halogen, CF ₃ , (C ₁ -C ₄ ) alkyl, OCF ₃ , -NR ₆ R ₇ , R _{6 R 7 N- (C 1 -C} 6 _{alkyl) -, - (C 1 -C} 4 _{alkyl) -C (O) NR 6 R} 7 or -C (O) NR ₆ R _7, and

Wherein R ₆ and R ₇ in each occurrence are independently H, or independently C ₁ -C ₄ alkoxycarbonyl, halogen, C ₃ -C ₆ cycloalkyl, OH, SH or C ₁ -C ₄ alkoxy The compound of embodiment 15 which is C ₁ -C ₆ alkyl optionally substituted with 2, 3 or 3 groups.

Embodiment 29.

R ₅ is independently C ₁ -C ₄ alkyl, -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , -NR ₆ R ₇ , NR ₆ R ₇ (C ₁ -C ₆ alkyl), C ₁ -C ₆ hydroxyalkyl, dihydroxyalkyl, halogen, C ₁ -C ₄ alkoxy, CO ₂ R, OH, C ₁ -C ₆ alkoxycarbonyl, CF ₃ ,-(C ₁ -C ₄ alkyl) -NR ₁₅ C (O) NR ₁₆ R ₁₇ ,-(C ₁ -C ₄ alkyl) -NR ₁₅ C (O) R ₁₈ which is 1, 2, 3, 4 or 5 Phenyl optionally substituted by groups

Wherein R ₁₅ is H or C ₁ -C ₆ alkyl;

R ₁₆ and R ₁₇ are independently H or C ₁ -C ₆ alkyl;

R ₁₆ , R ₁₇ , and the nitrogen to which they are attached form a morpholinyl ring;

R ₁₈ is -O- (C ₂ -C ₆₎ alkanoyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₁ -C ₆ -alkyl optionally substituted C to ₆ alkyl; The compound of embodiment 4 which is amino C ₁ -C ₆ alkyl, mono or dialkylamino C ₁ -C ₆ alkyl.

Embodiment 30.

이고,R ₅ is a chemical formula

ego,

Wherein, Z ₁ is H, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ dihydroxy alkyl, or C ₁ -C ₄ alkoxy ;

Z ₂ is C ₁ -C ₄ alkyl, -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , -NR ₆ R ₇ , NR ₆ R ₇ ( C ₁ -C ₆ alkyl), C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, halogen, C ₁ -C ₄ alkoxy, CO ₂ R, OH, C ₁ -C ₆ alkoxycarbonyl Or C ₁ -C ₄ haloalkyl;

Z ₃ is H, C ₁ -C ₄ alkyl, -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (0) NR ₆ R ₇ , -NR ₆ R ₇ , NR ₆ R ₇ (C ₁ -C ₆ alkyl), C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, halogen, C ₁ -C ₄ alkoxy, CO ₂ R, OH, C ₁ -C ₆ alkoxy Carbonyl or C ₁ -C ₄ haloalkyl;

Wherein R ₆ and R ₇ in each occurrence are independently H, OH, C ₁ -C ₆ alkyl, amino C ₁ -C ₄ alkyl, NH (C ₁ -C ₆ alkyl) alkyl, N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, - SO ₂ (C ₁ -C ₆ alkyl), -SO ₂ NH ₂ , -SO ₂ NH (C ₁ -C ₆ alkyl), -SO ₂ N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) Or C ₁ -C ₆ alkanoyl, each independently halogen, OH, SH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, OH, CF ₃ Or the compound of embodiment 29 optionally substituted with 1, 2 or 3 groups which are OCF ₃ .

In this embodiment, at least one of Z ₁ , Z ₂ and Z ₃ is preferably not hydrogen.

Embodiment 31.

이고,R ₅ is a chemical formula

ego,

Wherein, Z ₁ is H, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ dihydroxy alkyl, or C ₁ -C ₄ alkoxy ;

Z ₂ is C ₁ -C ₄ alkyl, -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , -NR ₆ R ₇ , NR ₆ R ₇ ( C ₁ -C ₆ alkyl), C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, halogen, C ₁ -C ₄ alkoxy, CO ₂ R, OH, C ₁ -C ₆ alkoxycarbonyl Or C ₁ -C ₄ haloalkyl;

Z ₃ is H, C ₁ -C ₄ alkyl, -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , -NR ₆ R ₇ , NR ₆ R ₇ (C ₁ -C ₆ alkyl), C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, halogen, C ₁ -C ₄ alkoxy, CO ₂ R, OH, C ₁ -C ₆ alkoxy Carbonyl or C ₁ -C ₄ haloalkyl,

Wherein R ₆ and R ₇ in each occurrence are independently H, OH, C ₁ -C ₆ alkyl, amino C ₁ -C ₄ alkyl, NH (C ₁ -C ₆ alkyl) alkyl, N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, -SO ₂ (C ₁ -C ₆ alkyl), -S0 ₂ NH ₂ , -S0 ₂ NH (C ₁ -C ₆ alkyl), -SO ₂ N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl ) Or C ₁ -C ₆ alkanoyl, each independently halogen, OH, SH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, OH, CF ₃ or OCF ₃ The compound of embodiment 30 optionally substituted with one, two or three groups of phosphorus.

In this embodiment, at least one of Z ₁ , Z ₂ and Z ₃ is preferably not hydrogen.

Embodiment 32.

이고,R ₅ is a chemical formula

ego,

Wherein, Z ₁ is H, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ dihydroxy alkyl, or C ₁ -C ₄ alkoxy ;

Z ₂ is C ₁ -C ₄ alkyl, -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , -NR ₆ R ₇ , NR ₆ R ₇ ( C ₁ -C ₆ alkyl), C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, halogen, C ₁ -C ₄ alkoxy, CO ₂ R, OH, C ₁ -C ₆ alkoxycarbonyl Or C ₁ -C ₄ haloalkyl;

Z ₃ is H, C ₁ -C ₄ alkyl, -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , -NR ₆ R ₇ , NR ₆ R ₇ (C ₁ -C ₆ alkyl), C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, halogen, C ₁ -C ₄ alkoxy, CO ₂ R, OH, C ₁ -C ₆ alkoxy Carbonyl or C ₁ -C ₄ haloalkyl,

Wherein R ₆ and R ₇ in each occurrence are independently H, OH, C ₁ -C ₆ alkyl, amino C ₁ -C ₄ alkyl, NH (C ₁ -C ₆ alkyl) alkyl, N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, -SO ₂ (C ₁ -C ₆ alkyl), -SO ₂ NH ₂ , -SO ₂ NH (C ₁ -C ₆ alkyl), -SO ₂ N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl ) Or C ₁ -C ₆ alkanoyl, each independently halogen, OH, SH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, OH, CF ₃ or OCF ₃ A compound according to embodiment 30 optionally substituted with one, two or three groups of phosphorus.

In this embodiment, at least one of Z ₁ , Z ₂ and Z ₃ is preferably not hydrogen.

Embodiment 33.

이고,R ₅

ego,

Wherein, Z ₁ is H, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ dihydroxy alkyl, or C ₁ -C ₄ alkoxy ;

Z ₂ is C ₁ -C ₄ alkyl, -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , -NR ₆ R ₇ , NR ₆ R ₇ ( C ₁ -C ₆ alkyl), C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, halogen, C ₁ -C ₄ alkoxy, CO ₂ R, C ₁ -C ₆ alkoxycarbonyl, - (C ₁ -C ₄ alkyl) -NR ₁₅ C (O) NR ₁₆ R ₁₇ or-(C ₁ -C ₄ alkyl) -NR ₁₅ C (O) R ₁₈ ;

Z ₃ is H, C ₁ -C ₄ alkyl, -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , -NR ₆ R ₇ , NR ₆ R ₇ (C ₁ -C ₆ alkyl), C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, halogen, C ₁ -C _{4 alkoxy, CO 2 R, C 1 -C} 6 alkoxycarbonyl , - (C ₁ -C _{4 alkyl) -NR 15 C (O) NR} 16 R 17 or - (C ₁ -C _{4 alkyl) -NR l5 C (O) R} 18 a;

R ₆ , R ₇ , and the nitrogen to which they are attached are piperidi optionally substituted with one or two groups which are independently alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ dihydroxyalkyl or halogen To form a silyl, pyrrolidinyl, piperazinyl or morpholinyl ring;

R ₁₅ is H or C ₁ -C ₆ alkyl;

R ₁₆ and R ₁₇ are independently H or C ₁ -C ₆ alkyl;

R ₁₆ , R ₁₇ , and the nitrogen to which they are attached form a morpholinyl ring;

R ₁₈ is -O- (C ₂ -C ₆₎ alkanoyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₁ -C ₆ -alkyl optionally substituted C to ₆ alkyl; The compound of embodiment 29 which is amino C ₁ -C ₆ alkyl, mono or dialkylamino C ₁ -C ₆ alkyl.

In this embodiment, at least one of Z ₁ , Z ₂ and Z ₃ is preferably not hydrogen.

Embodiment 34.

이고:R ₅ is a chemical formula

ego:

Z ₁ is H, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ dihydroxy alkyl, or C ₁ -C ₄ alkoxy;

Z ₂ is C ₁ -C ₄ alkyl, -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , -NR ₆ R ₇ , NR ₆ R ₇ ( C ₁ -C ₆ alkyl), C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, halogen, C ₁ -C ₄ alkoxy, CO ₂ R, C ₁ -C ₆ alkoxycarbonyl, - (C ₁ -C ₄ alkyl) -NR ₁₅ C (O) NR ₁₆ R ₁₇ or-(C ₁ -C ₄ alkyl) -NR ₁₅ C (O) R ₁₈ ;

Z ₃ is H, C ₁ -C ₄ alkyl, -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , -NR ₆ R ₇ , NR ₆ R ₇ (C ₁ -C ₆ alkyl), C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, halogen, C ₁ -C _{4 alkoxy, C0 2 R, C 1 -} C 6 alkoxycarbonyl ,-(C ₁ -C ₄ alkyl) -NR ₁₅ C (O) NR ₁₆ R ₁₇ or-(C ₁ -C ₄ alkyl) -NR ₁₅ C (O) R ₁₈ ;

R ₆ , R ₇ , and the nitrogen to which they are attached are piperidi optionally substituted with one or two groups which are independently alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ dihydroxyalkyl or halogen To form a silyl, pyrrolidinyl, piperazinyl or morpholinyl ring;

R ₁₅ is H or C ₁ -C ₆ alkyl;

R ₁₆ and R ₁₇ are independently H or C ₁ -C ₆ alkyl;

R ₁₆ , R ₁₇ , and the nitrogen to which they are attached form a morpholinyl ring;

R ₁₈ is -O- (C ₂ -C ₆₎ alkanoyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₁ -C ₆ -alkyl optionally substituted C to ₆ alkyl; The compound according to embodiment 33, which is amino C ₁ -C ₆ alkyl, mono or dialkylamino C ₁ -C ₆ alkyl.

In this embodiment, at least one of Z ₁ , Z ₂ and Z ₃ is preferably not hydrogen.

Embodiment 35.

이고,R ₅ is a chemical formula

ego,

Wherein, Z ₁ is H, halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ dihydroxy alkyl, or C ₁ -C ₄ alkoxy;

Z ₂ is C ₁ -C ₄ alkyl, -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , -NR ₆ R ₇ , NR ₆ R ₇ ( C ₁ -C ₆ alkyl), C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, halogen, C ₁ -C ₄ alkoxy, CO ₂ R, C ₁ -C ₆ alkoxycarbonyl, - (C ₁ -C ₄ alkyl) -NR ₁₅ C (O) NR ₁₆ R ₁₇ or-(C ₁ -C ₄ alkyl) -NR ₁₅ C (0) R ₁₈ ;

Z ₃ is H, C ₁ -C ₄ alkyl, -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , -NR ₆ R ₇ , NR ₆ R ₇ (C ₁ -C ₆ alkyl), C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, halogen, C ₁ -C _{4 alkoxy, CO 2 R, C 1 -C} 6 alkoxycarbonyl ,-(C ₁ -C ₄ alkyl) -NR ₁₅ C (O) NR ₁₆ R ₁₇ or-(C ₁ -C ₄ alkyl) -NR ₁₅ C (0) R ₁₈ ;

R ₆ , R ₇ and the nitrogen to which they are attached form a piperidinyl, pyrrolidinyl, piperazinyl or morpholinyl ring, each of which is independently alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl Optionally substituted with one or two groups that are C ₁ -C ₄ dihydroxyalkyl or halogen;

R ₁₅ is H or C ₁ -C ₆ alkyl;

R ₁₆ and R ₁₇ are independently H or C ₁ -C ₆ alkyl;

R ₁₆ , R ₁₇ , and the nitrogen to which they are attached form a morpholinyl ring;

R ₁₈ is -O- (C ₂ -C ₆₎ alkanoyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₁ -C ₆ -alkyl optionally substituted C to ₆ alkyl; The compound according to embodiment 33, which is amino C ₁ -C ₆ alkyl, mono or dialkylamino C ₁ -C ₆ alkyl.

In this embodiment, at least one of Z ₁ , Z ₂ and Z ₃ is preferably not hydrogen.

Embodiment 36.

Compounds of the formula or pharmaceutically acceptable salts thereof.

In the above formula,

L and M are independently selected from —O—, —CH ₂ —, —S—, —NR—, N (R) —N (R) —, C (═O) —, —SO ₂ —;

이고,R ₅ is

ego,

here,

X ₁ , X ₂ , X _a , X _b , X _c , X _d and X _e are -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , -NR ₆ R ₇ , hydroxy (C ₁ -C ₄ ) alkyl, C ₁ -C ₄ dihydroxyalkyl, H, OH, halogen, haloalkyl, alkyl, haloalkoxy, heteroaryl, heterocycloalkyl, C ₃ -C ₇ cycloalkyl, R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-, -CO _2- (C ₁ -C ₆ ) alkyl, -N (R) C (0) NR ₆ R ₇ ,- Independently selected from N (R) C (0)-(C ₁ -C ₆ ) alkoxy, C0 ₂ R- (C ₁ -C ₆ alkyl)-or -S0 ₂ NR ₆ R ₇ , wherein heteroaryl and hetero Cycloalkyl groups are -NR ₆ R ₇ , -C (O) NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or halogen Optionally substituted with;

R ₅ is heteroaryl or heteroarylalkyl, wherein the heteroaryl and heteroaryl groups are independently —C (O) NR ₆ R ₇ , — (C ₁ -C ₄ alkyl) -C (0) NR ₆ R ₇ , -NR ₆ R ₇ , hydroxy (C ₁ -C ₄ ) alkyl, C ₁ -C ₄ dihydroxyalkyl, H, OH, halogen, haloalkyl, alkyl, haloalkoxy, R ₆ R ₇ N- (C ₁ -C _{6 alkyl) -, -CO 2 - (C} 1 -C 6) alkyl, -N (R) C (O ) NR 6 R 7 or -N (R) C (O) - (C 1 -C 6) alkoxy Optionally substituted with one, two, three or four groups;

Wherein R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycarbonyl , OH, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₄ dihydroxyalkyl, C ₁ -C ₆ thiohydroxyalkyl,-(C ₁ -C ₄ ) alkyl-CO ₂ -alkyl, pyridyl C _1- C ₆ alkyl, C ₁ -C ₆ alkanoyl, benzyl, phenyl C ₁ -C ₆ alkoxy or phenyl C ₁ -C ₆ alkanoyl, each independently halogen, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, piperidinyl C ₁ -C ₆ alkyl, morpholinyl C ₁ -C ₆ alkyl, piperazinyl C ₁ -C ₆ alkyl, OH, SH, NH ₂ , NH (alkyl), N (alkyl ) (Alkyl), -O-C ₁ -C ₄ alkanoyl, C ₁ -C ₄ alkyl, substituted or unsubstituted with 1, 2 or 3 groups which are CF ₃ or OCF ₃ ;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ dihydroxyalkyl or To form a morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl or piperazinyl ring optionally substituted with one or two groups which are halogen;

R in each occurrence is independently H or C ₁ -C ₆ alkyl;

Y ₁ , Y ₂ , Y ₃ and Y ₄ are independently H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, dihydroxyalkyl, alkenyl, alkynyl, CN, alkanoyl, alkoxy, alkoxyalkyl, halo Alkyl and carboxyl.

Embodiment 37.

A compound of the formula according to embodiment 36 or a pharmaceutically acceptable salt thereof.

Embodiment 38.

인 실시양태 37에 따른 화합물.R ₅

A compound according to embodiment 37 which is phosphorus.

Embodiment 39.

Y ₂ , Y ₄ and Y are independently halogen;

A compound according to embodiment 38, wherein Y ₁ and Y ₃ are both hydrogen.

Embodiment 40.

이고;R ₅

ego;

X ₁ and X ₂ are independently H, methyl, NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl) -, -C (O) NR ₆ R ₇ , C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ dihydroxyalkyl or-(C ₁ -C ₄ alkyl) -morpholinyl;

According to embodiment 39, wherein X _a and X _e are independently halogen, NH ₂ , NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), methyl or hydrogen compound.

In this embodiment, one of X _a and X _e is preferably not hydrogen.

Embodiment 41.

One of X _b and X _c is hydrogen, the other is —NR ₆ R ₇ , R ₆ R ₇ — (C ₁ -C ₆ alkyl)-, —C (O) NR ₆ R ₇ , —S0 ₂ NR ₆ R ₇ or halogen;

Wherein R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycarbonyl , OH, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, - (C ₁ -C ₄₎ alkyl, -CO ₂ - alkyl, pyridyl C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl, benzyl, phenyl C ₁ -C ₆ alkoxy or phenyl C ₁ -C ₆ alkanoyl, each independently halogen, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, piperidinyl C ₁ -C ₆ alkyl, morpholinyl C ₁ -C ₆ alkyl, piperazinyl C ₁ -C ₆ alkyl, OH, SH, NH ₂ , NH (alkyl), N (alkyl) (alkyl), -OC ₁ -C ₄ alkanoyl, C ₁ -C ₄ alkyl, CF ₃ or OCF ₃ in one, two or three groups substituted or unsubstituted;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ dihydroxyalkyl or A compound according to embodiment 40 which forms a morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl or piperazinyl ring optionally substituted with one or two groups which are halogen.

Embodiment 42.

R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycarbonyl, OH , C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, - (C ₁ -C ₄₎ alkyl, -CO ₂ - alkyl, pyridyl C ₁ -C ₆ alkyl, C ₁ -C ₆ alkynyl Noyl, benzyl, phenyl C ₁ -C ₆ alkoxy or phenyl C ₁ -C ₆ alkanoyl, each independently halogen, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, piperidinyl C _1- C ₆ alkyl, morpholinyl C ₁ -C ₆ alkyl, piperazinyl C ₁ -C ₆ alkyl, OH, NH ₂ , NH (alkyl), N (alkyl) (alkyl), -0-C ₁ -C ₄ A compound according to embodiment 41 which is unsubstituted or substituted with 1, 2 or 3 groups which are alkanoyl, C ₁ -C ₄ alkyl, CF ₃ or OCF ₃ .

Embodiment 43.

X _a is hydrogen, methyl, fluorine or chlorine;

X _c and X _d are both hydrogen;

X _b is -NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-, -C (O) NR ₆ R ₇ ;

Wherein R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₄ dihydroxyalkyl, C ₁ -C ₆ alkoxy, C An embodiment optionally substituted with 1, 2 or 3 groups which are _1- C ₆ alkoxy C ₁ -C ₆ alkyl or C ₁ -C ₆ alkanoyl, each independently OH, SH, halogen or C ₃ -C ₆ cycloalkyl A compound according to embodiment 42.

Embodiment 44.

이고;R ₅

ego;

X _a is H, fluoro, chloro or methyl;

X _e is hydrogen, halogen or methyl;

X _b is H;

A compound according to embodiment 39, wherein X _d is H or halogen.

Embodiment 45.

X _c is —SO ₂ NR ₆ R ₇ or halogen;

{Where R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy carbonyl, OH, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, - (C ₁ -C ₄₎ alkyl, -CO ₂ - alkyl, pyridyl C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl, benzyl, phenyl C ₁ -C ₆ alkoxy or phenyl C ₁ -C ₆ alkanoyl, each independently halogen, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, piperidinyl C ₁ -C ₆ alkyl, morpholinyl C ₁ -C ₆ alkyl, piperazinyl C ₁ -C ₆ alkyl, OH, SH, NH ₂ , NH (alkyl), N (alkyl) (alkyl) -OC _1- Substituted or unsubstituted with 1, 2 or 3 groups which are C ₄ alkanoyl, C ₁ -C ₄ alkyl, CF ₃ or OCF ₃ ;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ dihydroxyalkyl or To form a morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl or piperazinyl ring optionally substituted with 1 or 2 groups which are halogen;

X _c is fluoro, chloro, -NH ₂ , -NH (C ₁ -C ₆ alkyl), -N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), -S0 ₂ NH ₂ , -S0 ₂ NH (C ₁ -C ₆ alkyl), —S0 ₂ N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) or piperazinyl, wherein the piperazinyl group is independently C ₁ -C ₄ A compound according to embodiment 44 optionally substituted with one or two groups which are alkyl, C ₁ -C ₄ alkoxy, hydroxy, hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ dihydroxyalkyl or halogen.

Embodiment 46.

X _c is -C (O) NR ₆ R ₇ ,-(C ₁ -C ₆ alkyl) -C (O) NR ₆ R ₇ , -NR ₆ R ₇ or R ₆ R ₇ N- (C ₁ -C ₆ Alkyl)-;

Wherein R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycar carbonyl, OH, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, - (C ₁ -C ₄₎ alkyl, -CO ₂ - alkyl, pyridyl C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl, benzyl, phenyl C ₁ -C ₆ alkoxy or phenyl C ₁ -C ₆ alkanoyl, each independently halogen, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, piperidinyl C ₁ -C ₆ alkyl, morpholinyl C ₁ -C ₆ alkyl, piperazinyl C ₁ -C ₆ alkyl, OH, -NH ₂ , -NH (alkyl), -N Substituted or unsubstituted with 1, 2 or 3 groups which are (alkyl) (alkyl), —OC ₁ -C ₄ alkanoyl, C ₁ -C ₄ alkyl, CF ₃ or OCF ₃ ;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ dihydroxyalkyl or A compound according to embodiment 44, which forms a morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring optionally substituted with one or two groups which are halogen.

Embodiment 47.

R ₆ is hydrogen;

R ₇ is C ₁ -C ₆ alkyl or C ₁ -C ₆ alkanoyl, each independently NH ₂ , NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), OH, SH, cyclopropyl, or C ₁ -C ₄ alkoxy, the compound according to embodiment 46 optionally substituted with 1, 2 or 3 groups.

Embodiment 48.

A compound according to embodiment 47, wherein X _c is —C (O) NR ₆ R ₇ .

Embodiment 49.

A compound according to embodiment 47 wherein X _c is NR ₆ R ₇ or R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-.

Embodiment 50.

X _a is hydrogen;

Two of X _b , X _c and X _d are hydrogen and the other is —C (O) NR ₆ R ₇ , — (C ₁ -C ₆ alkyl) -C (O) NR ₆ R ₇ , -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-or —CO _2- (C ₁ -C ₆ ) alkyl;

Wherein R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycar carbonyl, OH, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, - (C ₁ -C ₄₎ alkyl, -CO ₂ - alkyl, pyridyl C ₁ -C ₆ alkyl, C ₁ - C ₆ alkanoyl, benzyl, phenyl C ₁ -C ₆ alkoxy or phenyl C ₁ -C ₆ alkanoyl, each independently halogen, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, piperidinyl C ₁ -C ₆ alkyl, morpholinyl C ₁ -C ₆ alkyl, piperazinyl C ₁ -C ₆ alkyl, OH, NH ₂ , NH (alkyl), N (alkyl) (alkyl), -OC ₁ -C ₄ Substituted or unsubstituted with 1, 2 or 3 groups which are alkanoyl, C ₁ -C ₄ alkyl, CF ₃ or OCF ₃ ;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ dihydroxyalkyl or To form a morpholinyl, piperidinyl, pyrrolidinyl or piperazinyl ring optionally substituted with 1 or 2 groups that are halogen;

A compound according to embodiment 38, wherein X _e is hydrogen, methyl, C ₁ -C ₂ alkoxy or halogen.

Embodiment 51.

X _b is -C (O) NR ₆ R ₇ ,-(C ₁ -C ₆ alkyl) -C (O) NR ₆ R ₇ , -NR ₆ R ₇ or R ₆ R ₇ N- (C ₁ -C ₆ Alkyl)-

Wherein R ₆ is hydrogen or C ₁ -C ₄ alkyl;

R ₇ is OH, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkanoyl, wherein the alkyl and alkanoyl groups are independently NH ₂ , NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl A compound according to embodiment 50, substituted with 1, 2 or 3 groups which is (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, OH or (C ₁ -C ₄ ) alkoxy.

Embodiment 52.

X _a is halogen or methyl;

X _b is H, -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-, -C (O) NR ₆ R ₇ or -C0 _2- (C ₁ -C ₆ ) alkyl ;

X _c is —NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-, —C (O) NR ₆ R ₇ , halogen, —CO _2- (C ₁ -C ₆ ) alkyl, NH ₂ , NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), -OS ₂ NH ₂ , -SO ₂ NH (C ₁ -C ₆ alkyl), -SO ₂ N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) or piperazinyl, wherein the piperazinyl groups are independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, hydroxide Optionally substituted with one or two groups which are hydroxy C ₁ -C ₄ alkyl, C ₁ -C ₄ dihydroxyalkyl or halogen;

X _d is hydrogen;

A compound according to embodiment 38, wherein X _e is H, methyl, NH ₂ , NH (C ₁ -C ₆ alkyl) or N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl).

Embodiment 53.

X ₁ , X ₂ , X _a , X _b , X _c , X _d and X _e are independently H, OH, halogen, CF ₃ , alkyl, OCF ₃ , pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, Thienyl, furyl, pyrrolyl, piperidinyl, piperazinyl or C ₃ -C ₇ cycloalkyl, each of -NR ₆ R ₇ , -C (O) NR ₆ R ₇ ,-(C _1- Optionally substituted with C ₄ alkyl) -C (0) NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or halogen A compound according to embodiment 38.

Embodiment 54.

R ₅ is a heteroaryl or heteroarylalkyl group, where heteroaryl is pyrazolyl, imidazolyl, furanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, dihydroin Doryl, dihydroisoindolyl, indolon-2-yl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, dihydroisoquinolinyl or indolyl, each independently -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , -NR ₆ R ₇ , hydroxy (C ₁ -C ₄ ) alkyl, C ₁ -C ₄ dihydroxyalkyl , Hydrogen, hydroxy, halogen, haloalkyl, alkyl, haloalkoxy, R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-, -C0 _2- (C ₁ -C ₆ ) alkyl, -N (R) C (O) NR ₆ R ₇ or -N (R) C (O) - (C 1 -C 6) alkoxy of one, two, three or four groups being optionally substituted;

R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycarbonyl, OH, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ di-hydroxyalkyl, C ₁ -C ₆ alkylthio hydroxyalkyl, - (C ₁ -C ₄₎ alkyl, -C0 ₂ - alkyl, pyridyl C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl, benzyl, phenyl C ₁ -C ₆ alkoxy or phenyl C ₁ -C ₆ alkanoyl, each independently halogen, C ₃ -C ₆ cycloalkyl, C _1- C ₆ alkoxy, piperidinyl C ₁ -C ₆ alkyl, morpholinyl C ₁ -C ₆ alkyl, piperazinyl C ₁ -C ₆ alkyl, OH, SH, NH ₂ , NH (alkyl), N (alkyl) A compound according to embodiment 37 which is unsubstituted or substituted with 1, 2 or 3 groups which are (alkyl), -OC ₁ -C ₄ alkanoyl, C ₁ -C ₄ alkyl, CF ₃ or OCF.

Embodiment 55.

Y ₂ , Y ₄ and Y are independently halogen;

A compound according to embodiment 54, wherein Y ₁ and Y ₃ are both hydrogen.

Embodiment 56.

X ₁ and X ₂ are independently H, methyl, -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-, -C (O) NR ₆ R ₇ ,-(C ₁ -C _In embodiment 55, which is ₄ alkyl) -C (O) NR ₆ R ₇ , C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ dihydroxyalkyl or-(C ₁ -C ₄ alkyl) -morpholinyl According to the compound.

Embodiment 57.

R ₅ is pyridyl C ₁ -C ₆ alkyl, pyrimidinyl C ₁ -C ₆ alkyl or pyrazinyl C ₁ -C ₆ alkyl, each independently hydroxy (C ₁ -C ₄ ) alkyl, C _1- C ₄ dihydroxyalkyl, OH, halogen, CF ₃ , (C ₁ -C ₄ ) alkyl, OCF ₃ , -NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ The compound according to embodiment 56, optionally substituted with 1, 2 or 3 groups, which is R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-or —C (0) NR ₆ R ₇ .

Embodiment 58.

이고,R ₅ is a chemical formula

ego,

Wherein Z ₅ is hydroxy (C ₁ -C ₄ ) alkyl, C ₁ -C ₄ dihydroxyalkyl, OH, halogen, CF ₃ , (C ₁ -C ₄ ) alkyl, OCF ₃ , -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ or -C (O) NR ₆ R ₇ ,

Wherein R ₆ and R ₇ in each occurrence are independently H, or independently C ₁ -C ₄ alkoxycarbonyl, halogen, C ₃ -C ₆ cycloalkyl, OH, SH or C ₁ -C ₄ alkoxy The compound according to embodiment 57, which is C ₁ -C ₆ alkyl optionally substituted with 2 or 3 groups.

Embodiment 59.

이고,R ₅ is a chemical formula

ego,

Wherein Z ₅ is hydroxy (C ₁ -C ₄ ) alkyl, C ₁ -C ₄ dihydroxyalkyl, OH, halogen, CF ₃ , (C ₁ -C ₄ ) alkyl, OCF ₃ , -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ or -C (O) NR ₆ R ₇ ,

Wherein R ₆ and R ₇ in each occurrence are independently H, or independently C ₁ -C ₄ alkoxycarbonyl, halogen, C ₃ -C ₆ cycloalkyl, OH, SH or C ₁ -C ₄ alkoxy The compound according to embodiment 57, which is C ₁ -C ₆ alkyl optionally substituted with 2 or 3 groups.

Embodiment 60.

이고,R ₅ is a chemical formula

ego,

Wherein Z ₁₀ is H or methyl;

Z ₂₀ is — (C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , hydroxy (C ₁ -C ₄ ) alkyl, C ₁ -C ₄ dihydroxyalkyl, OH, halogen, CF ₃ , (C ₁ -C ₄ ) alkyl, OCF ₃ , -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-or -C (O) NR ₆ R ₇ ,

Wherein R ₆ and R ₇ in each occurrence are independently H, or independently C ₁ -C ₄ alkoxycarbonyl, halogen, C ₃ -C ₆ cycloalkyl, OH, SH or C ₁ -C ₄ alkoxy The compound according to embodiment 57, which is C ₁ -C ₆ alkyl optionally substituted with 2 or 3 groups.

Embodiment 61.

이고,R ₅ is a chemical formula

ego,

Wherein Z ₁₀ is H or methyl;

Z ₂₀ is — (C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , hydroxy (C ₁ -C ₄ ) alkyl, C ₁ -C ₄ dihydroxyalkyl, OH, halogen, CF ₃ , (C ₁ -C ₄ ) alkyl, OCF ₃ , -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₄ alkyl)-or -C (O) NR ₆ R ₇ ,

Wherein R ₆ and R ₇ in each occurrence are independently H, or independently C ₁ -C ₄ alkoxycarbonyl, halogen, C ₃ -C ₆ cycloalkyl, OH, SH or C ₁ -C ₄ alkoxy The compound according to embodiment 57, which is C ₁ -C ₆ alkyl optionally substituted with 2 or 3 groups.

Embodiment 62.

이고,R ₅ is a chemical formula

ego,

Wherein Z ₁₀ is H or methyl;

Z ₂₀ is — (C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , hydroxy (C ₁ -C ₄ ) alkyl, C ₁ -C ₄ dihydroxyalkyl, OH, halogen, CF ₃ , (C ₁ -C ₄ ) alkyl, OCF ₃ , -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-or -C (O) NR ₆ R ₇ ,

Wherein R ₆ and R ₇ in each occurrence are independently H, or independently C ₁ -C ₄ alkoxycarbonyl, halogen, C ₃ -C ₆ cycloalkyl, OH, SH or C ₁ -C ₄ alkoxy The compound according to embodiment 57, which is C ₁ -C ₆ alkyl optionally substituted with 2 or 3 groups.

Embodiment 63.

이고,R ₅ is a chemical formula

ego,

here,

Z ₁₀ is H or methyl;

Z ₂₀ is — (C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , hydroxy (C ₁ -C ₄ ) alkyl, C ₁ -C ₄ dihydroxyalkyl, OH, halogen, CF ₃ , (C ₁ -C ₄ ) alkyl, OCF ₃ , -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-or -C (0) NR ₆ R ₇ ,

Wherein R ₆ and R ₇ in each occurrence are independently H, or independently _{1, which} is C ₁ -C ₄ alkoxycarbonyl, halogen, C ₃ -C ₆ cycloalkyl, OH, SH or C ₁ -C ₄ alkoxy; The compound according to embodiment 57, which is C ₁ -C ₆ alkyl optionally substituted with 2 or 3 groups.

Embodiment 64.

이고,R ₅ is a chemical formula

ego,

Wherein Z ₁₀ is H or methyl;

Z ₂₀ is — (C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , hydroxy (C ₁ -C ₄ ) alkyl, C ₁ -C ₄ dihydroxyalkyl, OH, halogen, CF ₃ , (C ₁ -C ₄ ) alkyl, OCF ₃ , -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-or -C (O) NR ₆ R ₇ ,

Wherein R ₆ and R ₇ in each occurrence are independently H, or independently C ₁ -C ₄ alkoxycarbonyl, halogen, C ₃ -C ₆ cycloalkyl, OH, SH or C ₁ -C ₄ alkoxy The compound according to embodiment 57, which is C ₁ -C ₆ alkyl optionally substituted with 2 or 3 groups.

Embodiment 65.

이고,R ₅ is a chemical formula

ego,

Wherein Z ₁₀ is H or methyl;

Z ₂₀ is — (C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , hydroxy (C ₁ -C ₄ ) alkyl, C ₁ -C ₄ dihydroxyalkyl, OH, halogen, CF ₃ , (C ₁ -C ₄ ) alkyl, OCF ₃ , -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ ) alkyl- or-(O) NR ₆ R ₇ ,

Wherein R ₆ and R ₇ in each occurrence are independently H, or independently C ₁ -C ₄ alkoxycarbonyl, halogen, C ₃ -C ₆ cycloalkyl, OH, SH or C ₁ -C ₄ alkoxy The compound according to embodiment 57, which is C ₁ -C ₆ alkyl optionally substituted with 2 or 3 groups.

Embodiment 66.

이고,R ₅ is a chemical formula

ego,

Wherein Z ₁₀ is H or methyl;

Z ₂₀ is — (C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , hydroxy (C ₁ -C ₄ ) alkyl, C ₁ -C ₄ dihydroxyalkyl, OH, halogen, CF ₃ , (C ₁ -C ₄ ) alkyl, OCF ₃ , -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-or -C (O) NR ₆ R ₇ ,

Wherein R ₆ and R ₇ in each occurrence are independently H, or independently C ₁ -C ₄ alkoxycarbonyl, halogen, C ₃ -C ₆ cycloalkyl, OH, SH or C ₁ -C ₄ alkoxy The compound according to embodiment 57, which is C ₁ -C ₆ alkyl optionally substituted with 2 or 3 groups.

Embodiment 67.

이고R ₅ is a chemical formula

ego

Wherein Z ₁₀ is H or methyl;

Z ₂₀ is — (C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , hydroxy (C ₁ -C ₄ ) alkyl, C ₁ -C ₄ dihydroxyalkyl, OH, halogen, CF ₃ , (C ₁ -C ₄ ) alkyl, OCF ₃ , -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-or -C (O) NR ₆ R ₇ ,

Wherein R ₆ and R ₇ in each occurrence are independently H, or independently C ₁ -C ₄ alkoxycarbonyl, halogen, C ₃ -C ₆ cycloalkyl, OH, SH or C ₁ -C ₄ alkoxy The compound according to embodiment 57, which is C ₁ -C ₆ alkyl optionally substituted with 2 or 3 groups.

Embodiment A7.

R ₁ is H; halogen; Alkyl optionally substituted with C ₁ -C ₄ alkoxycarbonyl; C ₂ -C ₆ alkenyl optionally substituted with C ₁ -C ₄ alkoxycarbonyl; C ₂ -C ₄ alkynyl; C ₁ -C ₄ haloalkyl; Carboxaldehyde; C ₁ -C ₄ hydroxyalkyl; Phenyl (C ₁ -C ₆ ) alkoxy; benzyl; Phenethyl; Penpropyl; CN or phenyl (C ₁ -C ₆ ) alkanoyl,

Wherein the phenyl group is independently unsubstituted or substituted with 1, 2 or 3 groups which are halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, nitro, CN, CF ₃ , OCF ₃ or C0 ₂ H;

R ₂ is OH, benzyloxy, phenyloxy, phenyloxy (C ₁ -C ₆ ) alkyl, phenyl (C ₁ -C ₄ ) thioalkoxy, -OC (O) NH (CH ₂ ) _n phenyl, -OC (O ) N (alkyl) (CH ₂ ) _n phenyl, di (C ₁ -C ₆ ) alkylamino, C ₂ -C ₆ alkynyl, pyridyl, pyrimidyl, pyridazyl, pyrazolyl, imidazolyl, pyrrolyl, Tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl, triazinyl, tetrahydrofuryl, piperidinyl, hexahydropyrimidinyl, thiazolyl, thienyl or C0 ₂ H to,

Where n is 0, 1, 2, 3, 4, 5 or 6;

Each independently halogen, NR ₆ R ₇ , (C ₁ -C ₄ ) haloalkyl, (C ₁ -C ₄ ) haloalkoxy, (C ₁ -C ₆ ) alkyl, pyridyl,-(C ₁ -C ₆ Substituted or unsubstituted with 1, 2, 3, 4 or 5 groups which is alkyl-N (R) -CO ₂ R ₃₀ or NR ₆ R _7- (C ₁ -C ₆ alkyl)-;

R ₄ is H; Independently CO ₂ H, -CO ₂ alkyl, -C (O) NRR, -N (R ₃₀ ) C (O) NRR, -N (R ₃₀ ) C (O)-(C ₁ -C ₆ ) alkoxy or Alkyl optionally substituted with 1 or 2 groups which is —NR ₆ R ₇ ; Phenyl (C ₁ -C ₆ ) alkoxy; Phenyl (C ₁ -C ₆ ) alkyl; Hydroxyalkyl, wherein the phenyl group is independently substituted or unsubstituted with 1, 2, 3, 4 or 5 groups being halogen, hydroxy, alkoxy, alkyl, nitro, CF ₃ or OCF ₃ ;

R ₅ is phenyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl, phenyl, piperidinyl (C ₁ -C ₆ ) alkyl, thienyl (C ₁ -C ₆ ) alkyl, indolyl, Quinolinyl, isoquinolinyl, isoindolinyl, indol-2-onyl, indazolyl, indolyl (C ₁ -C ₆ ) alkyl, quinolinyl (C ₁ -C ₆ ) alkyl, isoquinolinyl ( C ₁ -C ₆ ) alkyl, isoindolyl (C ₁ -C ₆ ) alkyl, indol-2-onyl (C ₁ -C ₆ ) alkyl, naphthyl (C ₁ -C ₆ ) alkyl, pyridyl (C ₁ -C ₆ ) alkyl, pyrimidyl (C ₁ -C ₆ ) alkyl or pyrazinyl (C ₁ -C ₆ ) alkyl,

Wherein each independently alkyl, halogen, alkoxy, benzyloxy, thioalkoxy, -CO ₂ (C ₁ -C ₅ alkyl), CO ₂ H, CN, amidinooxime, NR ₈ R ₉ , NR ₆ R _7- Substituted or unsubstituted with 1, 2, 3, 4 or 5 groups which are (C ₁ -C ₆ alkyl)-, —C (O) NR ₆ R ₇ , amidino, CF ₃ or OCF ₃ ;

R ₈ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl, phenyl C ₁ -C ₆ alkyl and phenyl C ₁ -C ₆ alkanoyl;

R ₉ is aminoalkyl, mono C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl, di-C ₁ -C ₆ alkylamino C ₁ - C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl , Phenyl C ₁ -C ₄ alkyl, indazolyl and phenyl C ₁ -C ₄ alkanoyl.

In this embodiment, R ₂ is benzyloxy, R ₄ is H, R ₅ is benzyl or methyl, and R ₁ is not hydrogen; At least two of R ₁ , R ₂ , R ₄ and R ₅ are preferably hydrogen.

Embodiment A8.

R ₁ is H; halogen; C ₁ -C ₄ alkyl optionally substituted with C ₁ -C ₄ alkoxycarbonyl; Optionally substituted C ₂ -C ₄ alkenyl is a C ₁ -C ₄ alkoxycarbonyl; C ₂ -C ₄ alkynyl or carboxaldehyde;

R ₂ is benzyloxy, OH, phenyloxy, phenyloxy (C ₁ -C ₆ ) alkyl, phenyl (C ₁ -C ₄ ) thioalkoxy or pyridyl; Wherein each independently halogen,-(C ₁ -C ₆ ) alkyl-N (R) -CO ₂ R ₃₀ , NR ₆ R ₇ , (C ₁ -C ₄ ) haloalkyl, (C ₁ -C ₄ ) Compound according to embodiment A7, optionally substituted with 1, 2, 3, 4 or 5 groups which are haloalkoxy, (C ₁ -C ₆ ) alkyl, pyridyl or NR ₆ R _7- (C ₁ -C ₆ alkyl)- .

Embodiment A9.

R ₄ is H; Independently C0 ₂ H, -C0 ₂ alkyl, -C (O) NRR, -N (R ₃₀ ) C (O) NRR, -N (R ₃₀ ) C (O)-(C ₁ -C ₆ ) alkoxy or (C ₁ -C ₆ ) alkyl optionally substituted with 1 or 2 groups which is —NR ₆ R ₇ ; Phenyl (C ₁ -C ₆ ) alkoxy or hydroxy (C ₁ -C ₆ ) alkyl,

Wherein the phenyl group is independently substituted or unsubstituted with 1, 2 or 3 groups which are halogen, hydroxy, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, nitro, CF ₃ , OCF ₃ ;

R ₅ is benzyl, phenethyl, phenpropyl, phenbutyl, (C ₁ -C ₆ ) alkyl, phenyl, pyridyl, pyrimidyl, indolyl, indazolyl, indolyl (C ₁ -C ₆ ) alkyl, naphthyl (C ₁ -C ₆ ) alkyl, thienyl (C ₁ -C ₆ ) alkyl, pyridyl (C ₁ -C ₆ ) alkyl, pyrimidyl (C ₁ -C ₆ ) alkyl or pyrazinyl (C ₁ -C ₆ Alkyl, where each is independently alkyl, halogen, alkoxy, benzyloxy, thioalkoxy, —C0 ₂ (C ₁ -C ₅ alkyl), CF ₃ , OCF ₃ , CO ₂ H, CN, amidinooxime A compound according to embodiment A7 substituted or unsubstituted with 1, 2 or 3 groups.

In this embodiment, R ₂ is benzyloxy, R ₄ is H, R ₅ is benzyl or methyl, and R ₁ is not hydrogen; At least two of R ₁ , R ₂ , R ₄ and R ₅ are preferably hydrogen.

Embodiment A10.

R ₄ is H; Independently C0 ₂ H, -CO ₂ alkyl, -C (0) NRR, -N (R ₃₀ ) C (O) NRR, -N (R ₃₀ ) C (0)-(C ₁ -C ₅ ) alkoxy or (C ₁ -C ₄ ) alkyl optionally substituted with 1 or 2 groups that is —NR ₆ R ₇ ; Phenyl (C ₁ -C ₆ ) alkoxy; benzyl; Phenethyl; Phenpropyl or hydroxy (C ₁ -C ₆ ) alkyl,

Wherein the phenyl group is independently substituted or unsubstituted with 1, 2 or 3 groups which are halogen, hydroxy, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, nitro, CF ₃ , OCF ₃ ;

R ₅ is indolyl, quinolinyl, isoquinolinyl, isoindolyl, indol-2-onyl, indolyl (C ₁ -C ₅ ) alkyl, quinolinyl (C ₁ -C ₅ ) alkyl, isoqui Nolinyl (C ₁ -C ₅ ) alkyl, isoindolyl (C ₁ -C ₅ 6) alkyl, indole-2-onyl (C ₁ -C ₅ ) alkyl, wherein each independently is C ₁ -C ₄ Alkyl, halogen, CF ₃ , OCF ₃ , -CO ₂ CH ₃ , C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ alkoxy, -C0 ₂ (C ₁ -C ₅ alkyl), benzyloxy, -NR ₈ R ₉ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-, —C (O) NR ₆ R ₇ or amidinooxime which is substituted or unsubstituted with 1, 2 or 3 groups;

Wherein R ₆ and R ₇ are independently at each occurrence H, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, alkanoyl, phenylalkyl, phenylalkoxy or phenylalkanoyl, wherein each independently represents halogen, Substituted or unsubstituted with 1, 2 or 3 groups which are hydroxy, C ₁ -C ₄ alkoxy, OH, SH, C ₃ -C ₅ cycloalkyl, C ₁ -C ₄ alkyl, CF ₃ or OCF ₃ ;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently morpholinyl, thiomorpholi, optionally substituted with 1 or 2 groups which are C ₁ -C ₄ alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen A compound according to embodiment A7, which forms a nil or piperazinyl ring.

Embodiment A11.

R ₁ is chloro, bromo, iodo or H;

R ₅ is benzyl, phenethyl, phenpropyl, phenyl, quinolinyl, indolyl, isoquinolinyl, isoindoleyl, indol-2-onyl, indolyl (C ₁ -C ₆ ) alkyl, quinolinyl ( C ₁ -C ₆ ) alkyl, isoquinolinyl (C ₁ -C ₆ ) alkyl, isoindolyl (C ₁ -C ₆ ) alkyl, indole-2-onyl (C ₁ -C ₆ ) alkyl, piperidinyl C ₁ -C ₄ alkyl, thienyl C ₁ -C ₄ alkyl, —CH ₂ -pyridyl or pyridyl, each independently C ₁ -C ₄ alkyl, halogen, CF ₃ , OCF ₃ , C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ alkoxy, -CO ₂ (C ₁ -C ₅ alkyl), benzyloxy, NR ₈ R ₉ , NR ₆ R ₇ C ₁ -C ₄ alkyl, -C (O) NR ₆ Substituted or unsubstituted with 1, 2 or 3 groups which are R ₇ and amidinooxime;

Wherein R ₆ and R ₇ are independently at each occurrence H, alkyl, hydroxyalkyl, alkoxy, alkoxyalkyl, alkanoyl, phenylalkyl, phenylalkoxy or phenylalkanoyl, wherein each independently represents halogen, Substituted or unsubstituted with 1, 2 or 3 groups which are hydroxy, C ₁ -C ₄ alkoxy, OH, SH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkyl, CF ₃ or OCF ₃ ;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently morpholinyl, thiomorpholi, optionally substituted with 1 or 2 groups which are C ₁ -C ₄ alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen A compound according to embodiment A7, which forms a nil or piperazinyl ring.

Embodiment A12.

R ₅ is benzyl, phenethyl, phenpropyl or phenyl, each independently C ₁ -C ₄ alkyl, halogen, CF ₃ , OCF ₃ , -CO ₂ CH ₃ , C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ alkoxy, -CO ₂ (C ₁ -C ₅ alkyl), benzyloxy, NR ₈ R ₉ , NR ₆ R ₇ C ₁ -C ₄ alkyl, -C (O) NR ₆ R ₇ and amidinooxime A compound according to embodiment A11 substituted or unsubstituted with 1, 2 or 3 groups.

Embodiment A13.

R ₅ is quinolinyl, indolyl, isoquinolinyl, isoindolinyl, indole-2-onyl, indolyl (C ₁ -C ₆ ) alkyl, quinolinyl (C ₁ -C ₆ ) alkyl, isoqui Nolinyl (C ₁ -C ₆ ) alkyl, isoindolyl (C ₁ -C ₆ ) alkyl, indole-2-onyl (C ₁ -C ₆ ) alkyl, piperidinyl C ₁ -C ₄ alkyl, thienyl C ₁ -C ₄ alkyl, -CH ₂ -pyridyl or pyridyl, each independently C ₁ -C ₄ alkyl, halogen, CF ₃ , OCF ₃ , -CO ₂ CH ₃ , C ₁ -C ₄ hydroxyalkyl , C ₁ -C ₄ alkoxy, -CO ₂ (C ₁ -C ₅ alkyl), benzyloxy, NR ₈ R ₉ , NR ₆ R ₇ C ₁ -C ₄ alkyl, -C (O) NR ₆ R ₇ and amino A compound according to embodiment A11 which is unsubstituted or substituted with 1, 2 or 3 groups which are dinooxime.

Embodiment A14.

R ₂ is benzyloxy or phenethyloxy; Each independently 1, 2 or 3 is-(C ₁ -C ₆ ) alkyl-N (R) -CO ₂ R ₃₀ , fluoro, chloro, bromo, CF ₃ or (C ₁ -C ₄ ) alkyl A compound according to one of embodiments A11, A12 or A13, substituted or unsubstituted with a group.

Embodiment A15.

R ₂ is phenyloxy (C ₁ -C ₅ ) alkyl, wherein the phenyl group is independently — (C ₁ -C ₆ ) alkyl-N (R) -CO ₂ R ₃₀ , fluoro, chloro, bromo, CF _A compound according to one of embodiments A11, A12 or A13, which is unsubstituted or substituted with 1, 2 or 3 groups which are ₃ or (C ₁ -C ₄ ) alkyl.

Embodiment A16.

R ₁ is H; halogen; C ₁ -C ₄ alkyl optionally substituted with C ₁ -C ₄ alkoxycarbonyl; Optionally substituted C ₂ -C ₄ alkenyl is a C ₁ -C ₄ alkoxycarbonyl; A compound according to embodiment A1, which is C ₂ -C ₄ alkynyl or carboxaldehyde.

Embodiment A17.

R ₂ is benzyloxy, OH, phenyloxy, phenyloxy (C ₁ -C ₆ ) alkyl or phenyl (C ₁ -C ₄ ) thioalkoxy, each independently halogen,-(C ₁ -C ₆ ) Alkyl-N (R) -CO ₂ R ₃₀ , NR ₆ R ₇ , (C ₁ -C ₄ ) haloalkyl, (C ₁ -C ₄ ) haloalkoxy, (C ₁ -C ₆ ) alkyl, pyridyl or NR _A compound according to embodiment A16, optionally substituted with 1, 2, 3, 4 or 5 groups, which is ₆ R _7- (C ₁ -C ₆ alkyl)-.

Embodiment A18.

R ₄ is H, or independently C0 ₂ H, -CO ₂ alkyl, -C (O) NRR, -N (R ₃₀ ) C (O) NRR, -N (R ₃₀ ) C (O)-(C ₁ -C ₆ ) A compound according to embodiment A17 which is (C ₁ -C ₄ ) alkyl optionally substituted with 1 or 2 groups which are alkoxy, OH or —NR ₆ R ₇ .

Embodiment A19.

R ₅ is phenyl, naphthyl, indolyl, pyridyl, quinolinyl, isoquinolinyl, isoindolyl, indol-2-onyl, indolyl (C ₁ -C ₆ ) alkyl, quinolinyl (C ₁ -C ₆ ) alkyl, isoquinolinyl (C ₁ -C ₆ ) alkyl, isoindolyl (C ₁ -C ₆ ) alkyl, indole-2-onyl (C ₁ -C ₆ ) alkyl, pyridazinyl, pyri Midinyl or pyrazinyl, pyridazinyl (C ₁ -C ₆ ) alkyl, pyrimidinyl (C ₁ -C ₆ ) alkyl or pyrazinyl (C ₁ -C ₆ ) alkyl, wherein each independently is C ₁ -C ₄ alkyl, halogen, CF ₃ , OCF ₃ , -CO ₂ CH ₃ , C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ alkoxy, -CO ₂ (C ₁ -C ₅ alkyl), benzyloxy, Substituted or unsubstituted with 1, 2, 3, 4 or 5 groups which are -NR ₈ R ₉ , -C (O) NR ₆ R ₇ , NR ₆ R ₇ C ₁ -C ₄ alkyl and amidinooxime;

Wherein R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxy C ₁ -C ₄ Alkyl, C ₁ -C ₄ alkanoyl, phenyl C ₁ -C ₄ alkyl, phenyl C ₁ -C ₄ alkoxy or phenyl C ₁ -C ₄ alkanoyl, wherein each independently is halogen, hydroxy, C _1- Substituted or unsubstituted with 1, 2 or 3 groups which are C ₄ alkoxy, C ₁ -C ₄ alkyl, OH, SH, C ₃ -C ₆ cycloalkyl, CF ₃ or OCF ₃ ;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently morpholinyl, thiomorpholi, optionally substituted with 1 or 2 groups which are C ₁ -C ₄ alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen A compound according to embodiment A18, which forms a nil or piperazinyl ring.

Embodiment A20.

R ₁ is H, halogen, methyl, ethyl, C ₂ -C ₄ alkenyl C ₂ -C ₄ alkynyl or carboxaldehyde;

R ₂ is benzyloxy, OH, phenyloxy, phenyloxy (C ₁ -C ₆ ) alkyl or phenyl (C ₁ -C ₄ ) thioalkoxy, each independently halogen,-(C ₁ -C ₆ ) Alkyl-N (R) -C0 ₂ R ₃₀ , NR ₆ R ₇ , NR ₆ R ₇ C ₁ -C ₄ alkyl, (C ₁ -C ₄ ) haloalkyl, (C ₁ -C ₄ ) haloalkoxy, (C ₁ -C ₆₎ alkyl, or pyridyl one, two, three or four groups being optionally substituted;

R ₄ is H, or independently CO ₂ H, —CO ₂ alkyl, —C (O) NRR, —N (R ₃₀ ) C (O) NRR, —N (R ₃₀ ) C (O) — (C ₁ -C ₆ ) A compound according to embodiment A19 which is (C ₁ -C ₄ ) alkyl optionally substituted with 1 or 2 groups which are alkoxy, OH or —NR ₆ R ₇ .

Embodiment A21.

R ₅ is independently halogen, C ₁ -C ₆ alkyl, -NR ₁₀ R ₁₁ , C ₁ -C ₄ alkoxy, -C (O) NR ₁₀ R ₁₁ , -CO ₂ H, NR ₁₀ R ₁₁ C ₁ -C ₄ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkoxy, CHO, -SO ₂ NH ₂ , C ₁ -C ₄ haloalkyl, C ₁ -C ₆ hydroxyalkyl , -C ₁ -C ₄ alkyl-NR ₁₂ C (O) NR ₁₃ R ₁₄ , -C ₁ -C ₄ alkyl-NR ₁₂ C (0)-(C ₁ -C ₄ alkyl) -NR ₁₃ R ₁₄ ,- 1, 2, 3, 4 which is C ₁ -C ₄ alkyl-NR ₁₂ C (O) OR ₁₅ or -C ₁ -C ₄ alkyl-NR ₁₂ C (O)-(C ₁ -C ₄ alkyl) -R ₁₅ Or phenyl optionally substituted with 5 groups,

Wherein R ₁₀ and R ₁₁ are independently at each occurrence H, C ₁ -C ₆ alkyl, amino C ₁ -C ₄ alkyl, NH (C ₁ -C ₆ alkyl) alkyl, N (C ₁ -C ₆ alkyl (C ₁ -C ₆ alkyl) C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, OH, -SO ₂ (C ₁ -C ₆ Alkyl) or C ₁ -C ₆ alkanoyl, or

R ₁₀ , R ₁₁ , and the nitrogen to which they are attached independently form a piperidinyl, pyrrolidinyl, piperazinyl or morpholinyl ring optionally substituted with 1 or 2 groups which are alkyl or halogen;

R ₁₂ is H or C ₁ -C ₆ alkyl;

R ₁₃ and R ₁₄ are independently H or C ₁ -C ₆ alkyl;

R ₁₃ and R ₁₄ , and the nitrogen to which they are attached, form a morpholinyl ring;

R ₁₅ is C ₁ -C ₆ alkoxy; A compound according to embodiment A20, which is -OC (O) C ₁ -C ₆ alkyl, OH.

Embodiment A22.

1 wherein R ₅ is independently halogen, C ₁ -C ₆ alkyl, —NR ₁₀ R ₁₁ , NR ₁₀ R ₁₁ C ₁ -C ₆ alkyl, C ₁ -C ₄ alkoxy or —C (O) NR ₁₀ R ₁₁ , Phenyl optionally substituted with 2, 3, 4 or 5 groups; -C0 ₂ H; -C ₁ -C ₄ alkyl, -NR ₁₀ R _11; C ₁ -C ₆ alkyl; C ₁ -C ₆ alkoxycarbonyl; C ₁ -C ₆ alkoxy; CHO; -SO ₂ NH ₂ ; C ₁ -C ₄ haloalkyl; C ₁ -C ₆ hydroxyalkyl; -C ₁ -C ₄ alkyl, _{-NR 12 C (O) NR 13} R 14; -C ₁ -C ₄ alkyl-NR ₁₂ C (O)-(C ₁ -C ₄ alkyl) -NR ₁₃ R ₁₄ ; -C ₁ -C ₄ alkyl-NR ₁₂ C (O) OR ₁₅ or -C ₁ -C ₄ alkyl-NR ₁₂ C (0)-(C ₁ -C ₄ alkyl) -R ₁₅ ,

Wherein R ₁₀ and R ₁₁ are independently at each occurrence H, C ₁ -C ₆ alkyl, amino C ₁ -C ₄ alkyl, NH (C ₁ -C ₆ alkyl) alkyl, N (C ₁ -C ₆ alkyl ) (C ₁ -C ₆ alkyl) C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, OH, -S0 ₂ (C ₁ -C ₆ alkyl ) Or C ₁ -C ₆ alkanoyl,

R ₁₂ is H or C ₁ -C ₆ alkyl;

R ₁₃ and R ₁₄ are independently H or C ₁ -C ₆ alkyl;

R ₁₃ and R ₁₄ , and the nitrogen to which they are attached, form a morpholinyl ring;

R ₁₅ is C ₁ -C ₆ alkoxy; The compound according to embodiment A21, which is -OC (O) C ₁ -C ₆ alkyl, OH.

Embodiment A23.

1, wherein R ₅ is independently halogen, C ₁ -C ₆ alkyl, —NR ₁₀ R ₁₁ , NR ₁₀ R ₁₁ C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, —C (O) NR ₁₀ R ₁₁ , Phenyl optionally substituted with 2, 3, 4 or 5 groups,

Wherein R ₁₀ and R ₁₁ are independently at each occurrence H, C ₁ -C ₆ alkyl, amino C ₁ -C ₄ alkyl, NH (C ₁ -C ₆ alkyl) alkyl, N (C ₁ -C ₆ alkyl ) (C ₁ -C ₆ alkyl) C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, OH, -SO ₂ (C ₁ -C ₆ alkyl ), C ₁ -C ₆ alkanoyl.

Embodiment A24.

A compound according to embodiment A23, wherein R ₅ is independently halogen, C ₁ -C ₆ alkyl, —NR ₁₀ R ₁₁ or C ₁ -C ₄ alkoxy, phenyl optionally substituted with 1, 2, 3, 4 or 5 groups.

Embodiment A25.

R ₅ is one or more -C (O) compound according to embodiment A23 is substituted with NR ₁₀ R _11.

Embodiment A26.

R ₁₀ And R ₁₁ is independently at each occurrence H, C ₁ -C ₆ alkyl, amino C ₁ -C ₄ alkyl, NH (C ₁ -C ₆ alkyl) alkyl, N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) A compound according to embodiment A25 which is C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl.

Embodiment 27.

A compound according to embodiment A26, wherein R ₁₀ is H.

Embodiment A28.

A compound according to embodiment A25, wherein R ₁₀ and R ₁₁ are independently at each occurrence H, C ₁ -C ₆ alkyl, OH, —SO ₂ (C ₁ -C ₆ alkyl), C ₁ -C ₆ alkanoyl.

Embodiment A29.

R ₅ is independently halogen, C ₁ -C ₆ alkyl, NH ₂ , NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), C ₁ -C ₄ Alkoxy, phenyl optionally substituted with 1, 2, 3, 4 or 5 groups which are —C (O) NR ₁₀ R ₁₁ , wherein the alkyl groups are each optionally substituted with 1 or 2 groups which are each independently OH or methoxy;

Wherein R ₁₀ , R ₁₁ , and the nitrogen to which they are attached form an piperidinyl, pyrrolidinyl, piperazinyl or morpholinyl ring optionally substituted with 1 or 2 groups which are independently alkyl or halogen; Compound according to.

Embodiment A30.

R ₅ is independently halogen, C ₁ -C ₆ alkyl, C ₁ -C ₄ alkoxy, -C0 ₂ H, -C ₁ -C ₄ alkyl-NR ₁₀ R ₁₁ , C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkoxy, CHO, -SO ₂ NH ₂ , C ₁ -C ₄ haloalkyl, C ₁ -C ₆ hydroxyalkyl, -C ₁ -C ₄ alkyl-NR ₁₂ C (O) NR ₁₃ R _l4 ,- C ₁ -C ₄ alkyl, _{-NR 12 C (0) - (} C 1 -C 4 _{alkyl) -NR 13 R l4, -C 1} -C 4 alkyl, -NR ₁₂ C (O) oR ₁₅ or -C ₁ -C Phenyl optionally substituted with 1, 2, 3, 4 or 5 groups which are ₄ alkyl-NR ₁₂ C (O)-(C ₁ -C ₄ alkyl) -R ₁₅ ; -OC (O) C ₁ -C ₆ alkyl or OH,

Wherein R ₁₂ is H or C ₁ -C ₆ alkyl;

R ₁₃ and R ₁₄ are independently H or C ₁ -C ₆ alkyl;

R ₁₃ and R ₁₄ , and the nitrogen to which they are attached, form a morpholinyl ring;

R ₁₅ is a compound according to embodiment A20, wherein C ₁ -C ₆ alkoxy.

Embodiment A31.

R ₅ is independently halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, -CO ₂ H, C ₁ -C ₄ alkoxycarbonyl, C ₁ -C ₄ alkoxy, CHO, -S0 ₂ NH ₂ , A compound according to embodiment A30, which is C ₁ -C ₄ haloalkyl, phenyl optionally substituted with 1, 2, 3, 4 or 5 groups which are C ₁ -C ₄ hydroxyalkyl.

Embodiment A32.

R ₅ is independently halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, -CO ₂ H, -C ₁ -C ₄ alkyl-NR ₁₀ R ₁₁ , -C ₁ -C ₄ alkyl-NR ₁₂ C (O) NR ₁₃ R ₁₄ , -C ₁ -C ₄ alkyl-NR ₁₂ C (O)-(C ₁ -C ₄ alkyl) -NR ₁₃ R ₁₄ , -C ₁ -C ₄ alkyl-NR ₁₂ C (0 Phenyl optionally substituted with 1, 2, 3, 4 or 5 groups which are OR ₁₅ or —C ₁ -C ₄ alkyl-NR ₁₂ C (O) — (C ₁ -C ₄ alkyl) -R ₁₅ ; Or —OC (O) C ₁ -C ₆ alkyl,

Wherein R ₁₂ is H or C ₁ -C ₆ alkyl;

R ₁₃ and R ₁₄ are independently H or C ₁ -C ₆ alkyl;

R ₁₃ and R ₁₄ , and the nitrogen to which they are attached, form a morpholinyl ring;

R ₁₅ is a compound according to embodiment A30, wherein C ₁ -C ₆ alkoxy.

Embodiment A33.

R ₅ is independently halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, -C0 ₂ H, -C ₁ -C ₄ alkyl-NR ₁₀ R ₁₁ , -C ₁ -C ₄ alkyl-NR ₁₂ C (O) NR ₁₃ R ₁₄ , -C ₁ -C ₄ alkyl-NR ₁₂ C (O)-(C ₁ -C ₄ alkyl) -NR ₁₃ R ₁₄ optionally substituted with 1, 2, 3, 4 or 5 groups Phenyl;

Wherein R ₁₂ is H or C ₁ -C ₆ alkyl;

R ₁₃ and R ₁₄ are independently H or C ₁ -C ₆ alkyl;

A compound according to embodiment A31, wherein R ₁₃ and R ₁₄ , and the nitrogen to which they are attached, form a morpholinyl ring.

Embodiment A34.

A compound according to any one of embodiments A30, A31, A32 and A33, wherein the phenyl group is substituted with two groups which are meta positions from one another.

Embodiment A35.

A compound according to any one of embodiments A30, A31, A32 and A33, wherein the phenyl group is substituted with two groups which are para positions of each other.

Embodiment A36.

R ₅ is indolyl, pyridyl, pyridazinyl, pyrimidinyl, indazolyl, quinolinyl, isoquinolinyl, isoindoleyl, indole-2-onyl, pyridazinyl, pyrimidinyl or pyrazinyl Each independently represents C ₁ -C ₄ alkyl, halogen, CF ₃ , OCF ₃ , -C0 ₂ CH ₃ , C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ alkoxy, -CO ₂ (C ₁ -C ₅ alkyl), benzyloxy, NR ₈ R ₉ , NR ₆ R ₇ C ₁ -C ₄ alkyl, -C (O) NR ₆ R ₇ or amidinooxime which is substituted with 1, 2, 3, 4 or 5 groups or Unsubstituted;

Wherein R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxy C ₁ -C ₄ Alkyl, C ₁ -C ₄ alkanoyl, phenyl C ₁ -C ₄ alkyl, phenyl C ₁ -C ₄ alkoxy or phenyl C ₁ -C ₄ alkanoyl, wherein each independently is halogen, OH, SH, C ₃ Substituted or unsubstituted with 1, 2 or 3 groups which are -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, OH, CF ₃ or OCF ₃ ;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently morpholinyl, thiomorph, optionally substituted with one or two groups which are C ₁ -C ₄ alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen A compound according to embodiment A20, which forms a polyyl or piperazinyl ring.

Embodiment A38.

R ₅ is indolyl, pyridyl, pyrimidinyl, indazolyl or pyrazinyl, each independently C ₁ -C ₄ alkyl, halogen, CF ₃ , OCF ₃ , -CO ₂ CH ₃ , C ₁ -C ₄ Hydroxyalkyl, C ₁ -C ₄ alkoxy, -CO ₂ (C ₁ -C ₅ alkyl), benzyloxy, -C (O) NR ₆ R ₇ , -NR ₈ R ₉ , NR ₆ R ₇ C ₁ -C Substituted or unsubstituted with 1, 2, 3 or 4 groups which are ₄ alkyl and amidinooxime;

Wherein R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxy C ₁ -C ₄ Alkyl, C ₁ -C ₄ alkanoyl, phenyl C ₁ -C ₄ alkyl, phenyl C ₁ -C ₄ alkoxy or phenyl C ₁ -C ₄ alkanoyl, each independently halogen, OH, SH, C ₃ − A compound according to embodiment A36, substituted or unsubstituted with 1, 2 or 3 groups, which is C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, OH, CF ₃ or OCF ₃ .

Embodiment A39.

R ₅ is indolyl, pyridyl or pyrazinyl, each independently C ₁ -C ₄ alkyl, halogen, CF ₃ , OCF ₃ , -CO ₂ CH ₃ , C ₁ -C ₄ hydroxyalkyl, C _1- C ₄ alkoxy, -CO ₂ (C ₁ -C ₅ alkyl), benzyloxy, -C (O) NR ₆ R ₇ , NR ₈ R ₉ , NR ₆ R ₇ -C ₁ -C ₄ alkyl- and amidinooxime Substituted or unsubstituted with 1, 2, 3 or 4 groups of phosphorus;

Wherein R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxy C ₁ -C ₄ Alkyl, each independently of one, two or three groups which are halogen, OH, SH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, OH, CF ₃ or OCF ₃ A compound according to embodiment A38, optionally substituted.

Embodiment A40.

R ₅ is indolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, each independently C ₁ -C ₄ alkyl, halogen, CF ₃ , OCF ₃ , -CO ₂ CH ₃ , C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ alkoxy, -C ₂ (C ₁ -C ₅ alkyl), benzyloxy, -C (O) NH ₂ , -C (O) NH (C ₁ -C ₆ alkyl) ( Wherein the alkyl group is optionally substituted with OH or methoxy), -C (O) N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), wherein the alkyl groups are each independently and optionally OH or methoxy Substituted with), -C (O) NR ₆ R ₇ , NR ₈ R ₉ , NR ₆ R ₇ C ₁ -C ₄ alkyl, -C ₁ -C ₄ alkyl-NH ₂ , -C ₁ -C ₄ alkyl- NH (C ₁ -C ₆ alkyl), wherein the alkyl groups are each independently and optionally substituted with OH or methoxy, -C ₁ -C ₄ alkyl-N (C ₁ -C ₆ ) alkyl) (C _1- C ₆ alkyl), wherein the alkyl groups are each independently and optionally optionally substituted with OH or methoxy, and are substituted or unsubstituted with 1, 2, 3, 4 or 5 groups which are amidinooximes;

Wherein R ₆ , R ₇ , and the nitrogen to which they are attached are independently morpholinyl, thio optionally substituted with one or two groups which are C ₁ -C ₄ alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen A compound according to embodiment A36, which forms a morpholinyl or piperazinyl ring.

Embodiment A42.

R ₁ is H, halogen, methyl or carboxaldehyde;

R ₂ is benzyloxy, phenyloxy, phenyloxy (C ₁ -C ₆ ) alkyl or phenyl (C ₁ -C ₄ ) thioalkoxy, each independently halogen,-(C ₁ -C ₆ ) alkyl-N ( R) -CO ₂ R ₃₀ , NR ₆ R ₇ , (C ₁ -C ₄ ) haloalkyl, (C ₁ -C ₄ ) haloalkoxy, (C ₁ -C ₆ ) alkyl, NR ₆ R ₇ (C _1- C ₆ ) alkyl, pyridyl, morpholinyl, thiomorpholinyl, piperazinyl pyridyl (C ₁ -C ₆ ) alkyl, morpholinyl (C ₁ -C ₆ ) alkyl, thiomorpholinyl (C ₁ Optionally substituted with 1, 2, 3 or 4 groups which are -C ₆ ) alkyl or piperazinyl (C ₁ -C ₆ ) alkyl, wherein the pyridyl, morpholinyl, thiomorpholinyl and piperazinyl rings are independent Optionally substituted with 1 or 2 groups that are C ₁ -C ₄ alkyl or halogen;

Wherein R ₆ and R ₇ are independently at each occurrence H; C ₁ -C ₄ alkyl optionally substituted with 1 or 2 groups independently of OH, halogen or methoxy; C ₁ -C ₄ hydroxyalkyl; C ₁ -C ₄ alkoxy; C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl; C ₁ -C ₄ alkanoyl; benzyl; Benzyloxy; Or phenyl C ₁ -C ₄ alkanoyl, wherein each independently is halogen, OH, SH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, CF ₃ or OCF ₃ Substituted or unsubstituted with 1, 2 or 3 groups of phosphorus;

R ₄ is H, or independently C0 ₂ H, -CO ₂ alkyl, -C (O) NRR, -N (R ₃₀ ) C (O) NRR, -N (R ₃₀ ) C (O)-(C ₁ -C _{6) alkoxy, -NR 6 R 7, NR 6} R 7 C 1 -C 4 alkyl or hydroxy (C ₁ -C ₃₎ alkyl with one or two groups (C ₁ -C ₃ optionally substituted) alkyl A compound according to any one of embodiments A37, A38, A39 and A40.

Embodiment A43.

A compound according to embodiment A42, wherein R ₁ is H or halogen.

Embodiment A44.

R ₅ is phenyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl, piperidinyl (C ₁ -C ₆ ) alkyl, thienyl (C ₁ -C ₆ ) alkyl, indolyl (C ₁ -C ₆ ) alkyl, naphthyl (C ₁ -C ₆ ) alkyl, pyridyl (C ₁ -C ₆ ) alkyl, pyrimidyl (C ₁ -C ₆ ) alkyl, quinolinyl (C ₁ -C ₆ ) alkyl , Isoquinolinyl (C ₁ -C ₆ ) alkyl, isoindolyl (C ₁ -C ₆ ) alkyl, indole-2-onyl (C ₁ -C ₆ ) alkyl, pyridazinyl (C ₁ -C ₆ ) Alkyl, pyrazinyl (C ₁ -C ₆ ) alkyl or pyrazinyl (C ₁ -C ₆ ) alkyl,

Each independently alkyl, halogen, alkoxy, benzyloxy, hydroxyalkyl, thioalkoxy, -CO ₂ (C ₁ -C ₅ alkyl), CO ₂ H, CN, amidinooxime, NR ₈ R ₉ , NR ₆ R Substituted or unsubstituted with 1, 2, 3, 4 or 5 groups which are _7- (C ₁ -C ₆ alkyl)-, -C (O) NR ₆ R ₇ , amidino, CF ₃ or OCF ₃ ;

R ₈ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl, phenyl C ₁ -C ₆ alkyl and phenyl C ₁ -C ₆ alkanoyl;

R ₉ is aminoalkyl, mono C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl, di C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl , Phenyl C ₁ -C ₄ alkyl, indazolyl and phenyl C ₁ -C ₄ alkanoyl.

In this embodiment, R ₂ is benzyloxy, R ₄ is H, R ₅ is benzyl or methyl, and R ₁ is not hydrogen; At least two of R ₁ , R ₂ , R ₄ and R ₅ are preferably hydrogen.

Embodiment A45.

R ₅ is independently alkyl, halogen, alkoxy, benzyloxy, thioalkoxy, —CO ₂ (C ₁ -C ₅ alkyl), C0 ₂ H, CN, amidinooxime, NR ₈ R ₉ , NR ₆ R _7- ( C ₁ -C ₆ alkyl)-, -C (O) NR ₆ R ₇ , amidino, CF ₃ or OCF ₃ , substituted or unsubstituted phenyl (C ₁ -C) with 1, 2, 3, 4 or 5 groups ₆ );

Wherein R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxy C ₁ -C ₄ Alkyl, C ₁ -C ₄ alkanoyl, phenyl C ₁ -C ₄ alkyl, phenyl C ₁ -C ₄ alkoxy or phenyl C ₁ -C ₄ alkanoyl, each independently halogen, OH, SH, C ₃ − Substituted or unsubstituted with 1, 2 or 3 groups which are C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, CF ₃ or OCF ₃ ;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently morpholinyl, thiomorpholi, optionally substituted with 1 or 2 groups which are C ₁ -C ₄ alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen To form a silyl or piperazinyl ring;

R ₈ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl, phenyl C ₁ -C ₆ alkyl and phenyl C ₁ -C ₆ alkanoyl;

R ₉ is aminoalkyl, mono C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl, di C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl , Phenyl C ₁ -C ₄ alkyl, indazolyl and phenyl C ₁ -C ₄ alkanoyl.

Embodiment A46.

R ₅ is independently selected from CN, halogen, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ - C ₄ haloalkoxy, phenyl (C ₁ -C ₆ ) alkyl unsubstituted or substituted with 1, 2, 3, 4 or 5 groups, —C (O) NR ₂₀ R ₂₁ ;

Wherein R ₂₀ and R ₂₁ are independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, or

A compound according to embodiment A45, wherein R ₂₀ , R ₂₁ , and the nitrogen to which they are attached each independently form a piperazinyl or morpholinyl ring optionally substituted with one or two groups which are alkyl or halogen.

Embodiment A47.

R ₅ is independently CN, halogen, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkoxy, —C (O) NR ₂₀ R _2l Phenyl (C ₁ -C ₄ ) alkyl unsubstituted or substituted with 2, 3, 4 or 5 groups,

Wherein R ₂₀ and R ₂₁ are independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, or

A compound according to embodiment A46, wherein R ₂₀ , R _2l , and the nitrogen to which they are attached form a piperazinyl or morpholinyl ring, each optionally substituted with one or two groups each independently alkyl or halogen.

Embodiment A48.

R ₅ is benzyl or phenethyl, each independently ₁ , ₂ with CN, halogen, C ₁ -C ₄ alkoxy, CF ₃ , OCF ₃ , C ₁ -C ₄ alkyl, —C (O) NR ₂₀ R _2l Substituted or unsubstituted with 3, 4 or 5 groups;

Wherein R ₂₀ and R ₂₁ are independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, or

The compound according to embodiment A47, wherein R ₂₀ , R ₂₁ , and the nitrogen to which they are attached, each independently form a piperazinyl or morpholinyl ring optionally substituted with one or two groups which are alkyl or halogen.

Embodiment A49.

R ₅ is benzyl or phenethyl, each independently 1, 2, 3, 4 or 5 being halogen, methoxy, ethoxy, CF ₃ , OCF ₃ , methyl, ethyl or —C (O) NR ₂₀ R ₂₁ Substituted or unsubstituted with 2 groups;

Wherein R ₂₀ and R ₂₁ are independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl.

Embodiment A50.

R ₅ is benzyl or phenethyl, each independently 1, 2, 3, 4 or 5 being halogen, methoxy, ethoxy, CF ₃ , OCF ₃ , methyl, ethyl or —C (O) NR ₂₀ R ₂₁ Substituted or unsubstituted with 2 groups;

Wherein R ₂₀ , R ₂₁ , and the nitrogen to which they are attached, each independently form a piperazinyl or morpholinyl ring optionally substituted with one or two groups which are alkyl or halogen.

Embodiment A51.

A compound according to embodiment A49, wherein R ₅ is substituted on the phenyl ring by 1, 2, 3, 4 or 5 groups, said group being in the para position of phenyl.

Embodiment A52.

R ₅ is piperidinyl (C ₁ -C ₆ ) alkyl, thienyl (C ₁ -C ₆ ) alkyl, indolyl (C ₁ -C ₆ ) alkyl, pyridyl (C ₁ -C ₆ ) alkyl, pyrimidyl (C ₁ -C ₆ ) alkyl, quinolinyl (C ₁ -C ₆ ) alkyl, isoquinolinyl (C ₁ -C ₆ ) alkyl, isoindolyl (C ₁ -C ₆ ) alkyl, indole-2- Oyl (C ₁ -C ₆ ) alkyl, pyridazinyl (C ₁ -C ₆ ) alkyl or pyrazinyl (C ₁ -C ₆ ) alkyl or pyrazinyl (C ₁ -C ₆ ) alkyl,

Wherein each independently C ₁ -C ₆ alkyl, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl, benzyloxy, C ₁ -C ₆ thioalkoxy, —CO ₂ (C ₁ -C ₅ alkyl), CO ₂ H, CN, amidinooxime, NR ₈ R ₉ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-, -C (O) NR ₆ R ₇ , amidino, CF ₃ or Substituted or unsubstituted with 1, 2, 3, 4 or 5 groups which are OCF ₃ ;

R ₈ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl, phenyl C ₁ -C ₆ alkyl and phenyl C ₁ -C ₆ alkanoyl;

R ₉ is aminoalkyl, mono C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl, di C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl , Phenyl C ₁ -C ₄ alkyl, indazolyl and phenyl C ₁ -C ₄ alkanoyl.

In this embodiment, R ₂ is benzyloxy, R ₄ is H, R ₅ is benzyl or methyl, and R ₁ is not hydrogen; At least two of R ₁ , R ₂ , R ₄ and R ₅ are preferably hydrogen.

Embodiment A53.

R ₅ is piperidinyl (C ₁ -C ₄ ) alkyl, thienyl (C ₁ -C ₄ ) alkyl, indolyl (C ₁ -C ₄ ) alkyl, pyridyl (C ₁ -C ₄ ) alkyl, pyrimidyl A compound according to embodiment A52, wherein (C ₁ -C ₄ ) alkyl or pyrazinyl (C ₁ -C ₄ ) alkyl are each unsubstituted.

Embodiment A54.

R ₅ is indolyl (C ₁ -C ₄ ) alkyl, pyrimidyl (C ₁ -C ₄ ) alkyl or pyrazinyl (C ₁ -C ₄ ) alkyl, wherein each independently is C ₁ -C ₆ alkyl, Halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl, benzyloxy, C ₁ -C ₆ thioalkoxy, -CO ₂ (C ₁ -C ₅ alkyl), CO ₂ H, CN, amidinooxime , NR ₈ R ₉ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-, amidino, -C (O) NR ₂₀ R ₂₁ , substituted with 1, 2, 3 or 4 groups which are CF ₃ or OCF ₃ Or unsubstituted;

Wherein R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxy C ₁ -C ₄ Alkyl, C ₁ -C ₄ alkanoyl, benzyl, benzyloxy or phenyl C ₁ -C ₄ alkanoyl, each independently halogen, OH, SH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy Or substituted or unsubstituted with 1, 2 or 3 groups which are C ₁ -C ₄ alkyl, CF ₃ or OCF ₃ ;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently morpholinyl, thiomorph, optionally substituted with one or two groups which are C ₁ -C ₄ alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen To form polyyl or piperazinyl;

R ₈ is hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl, phenyl C ₁ -C ₄ alkyl and phenyl C ₁ -C ₄ alkanoyl;

R ₉ is aminoalkyl, mono C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl, di C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl , Phenyl C ₁ -C ₄ alkyl, indazolyl and phenyl C ₁ -C ₄ alkanoyl;

R ₂₀ and R ₂₁ are independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, or

A compound according to embodiment A52, wherein R ₂₀ , R _2l , and the nitrogen to which they are attached each independently form a piperazinyl or morpholinyl ring optionally substituted with 1 or 2 groups which are alkyl or halogen.

Embodiment A55.

R ₅ is indolyl (C ₁ -C ₄ ) alkyl or pyrazinyl (C ₁ -C ₄ ) alkyl, wherein each independently is C ₁ -C ₆ alkyl, halogen, C ₁ -C ₆ alkoxy, C _1- C ₆ hydroxyalkyl, benzyloxy, C ₁ -C ₆ thioalkoxy, -CO ₂ (C ₁ -C ₆ alkyl), CO ₂ H, CN, -C (O) NR ₂₀ R ₂₁ , CF ₃ or OCF ₃ Substituted or unsubstituted with 1, 2, 3 or 4 groups of phosphorus;

R ₂₀ and R ₂₁ are independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, or

A compound according to embodiment A54, wherein R ₂₀ , R ₂₁ and the nitrogen to which they are attached each independently form a piperazinyl or morpholinyl ring optionally substituted with 1 or 2 groups which are alkyl or halogen.

Embodiment A56.

R ₅ is isoquinolinyl, isoindolinyl, indole-2-onyl, quinolinyl (C ₁ -C ₆ ) alkyl, isoquinolinyl (C ₁ -C ₆ ) alkyl, isoindolyl (C _1- C ₆ ) alkyl, indole-2-onyl (C ₁ -C ₆ ) alkyl,

Wherein each independently C ₁ -C ₆ alkyl, halogen, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl, benzyloxy, C ₁ -C ₆ thioalkoxy, —CO ₂ (C ₁ -C ₆ alkyl), CO ₂ H, CN, amidinooxime, NR ₈ R ₉ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-, -C (O) NR ₆ R ₇ , amidino, CF ₃ or A compound according to embodiment A52, unsubstituted or substituted with 1, 2, 3, 4 or 5 groups, which is OCF ₃ .

Embodiment A57.

R ₁ is H, halogen, methyl, ethyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl or carboxaldehyde;

R ₂ is benzyloxy, OH, phenyloxy, phenyloxy (C ₁ -C ₆ ) alkyl or phenyl (C ₁ -C ₄ ) thioalkoxy, each independently halogen,-(C ₁ -C ₆ ) alkyl -N (R) -CO ₂ R ₃₀ , NR ₆ R ₇ , (C ₁ -C ₄ ) haloalkyl, (C ₁ -C ₄ ) haloalkoxy, (C ₁ -C ₆ ) alkyl, pyridyl or NR ₆ Optionally substituted with 1, 2, 3 or 4 groups which are R _7- (C ₁ -C ₆ alkyl)-;

R ₄ is H; Independently CO ₂ H, -CO ₂ alkyl, -C (O) NRR, -N (R ₃₀ ) C (O) NRR, -N (R ₃₀ ) C (O)-(C ₁ -C ₆ ) alkoxy or (C ₁ -C ₄ ) alkyl optionally substituted with 1 or 2 groups which is —NR ₆ R ₇ ; Or hydroxy (C ₁ -C ₄ ) alkyl;

R ₅ is C ₃ -C ₇ cycloalkyl or C ₃ -C ₇ cycloalkylalkyl, each independently of alkyl, alkoxy, halogen, -NR ₆ R ₇ or NR ₆ R _7- (C ₁ -C ₆ alkyl) Optionally substituted with 1 or 2 groups; Wherein the alkyl groups are each optionally substituted with one or two groups, which are independently OH, methoxy, NH ₂ or halogen.

Embodiment A58.

R ₅ is C ₃ -C ₇ cycloalkyl or C ₃ -C ₇ cycloalkyl C ₁ -C ₄ alkyl, each independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, —NR ₆ R _Is optionally substituted with 1 or 2 groups which are ₇ or NR ₆ R _7- (C ₁ -C ₆ alkyl)-, wherein each alkyl group is independently substituted with 1 or 2 groups which are independently OH, methoxy or NH ₂ ;

R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl, C ₁ -C ₄ alkanoyl, benzyl, benzyloxy or phenyl C ₁ -C ₄ alkanoyl, wherein each independently is halogen, OH, SH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, Substituted or unsubstituted with 1, 2 or 3 groups which are C ₁ -C ₄ alkyl, CF ₃ or OCF ₃ ;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently morpholinyl, thiomorpholi, optionally substituted with 1 or 2 groups which are C ₁ -C ₄ alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen A compound according to embodiment A57, which forms a nil or piperazinyl ring.

Embodiment A59.

R ₁ is H, halogen, methyl, ethyl;

R ₂ is benzyloxy, phenyloxy, phenyloxy (C ₁ -C ₆ ) alkyl or phenyl (C ₁ -C ₄ ) thioalkoxy, each independently halogen,-(C ₁ -C ₆ ) alkyl-N (R) -CO ₂ R ₃₀ , amino, mono or dialkylamino, -NR ₆ R ₇ , (C ₁ -C ₄ ) haloalkyl, (C ₁ -C ₄ ) haloalkoxy, (C ₁ -C ₆ ) Optionally substituted with 1, 2, 3 or 4 groups which are alkyl or NR ₆ R _7- (C ₁ -C ₄ alkyl)-;

R ₄ is H; methyl; Independently CO ₂ H, -CO ₂ alkyl, -C (O) NRR, -N (R ₃₀ ) C (O) NRR, -N (R ₃₀ ) C (O)-(C ₁ -C ₆ ) alkoxy or (C ₁ -C ₄ ) alkyl optionally substituted with 1 or 2 groups that is —NR ₆ R ₇ ; Or hydroxy (C ₁ -C ₂ ) alkyl.

Embodiment A60.

R ₂ is substituted with two halogens, independently halogen, — (C ₁ -C ₆ ) alkyl-N (R) —CO ₂ R ₃₀ , amino, mono or dialkylamino, —NR ₆ R ₇ , (C Further optionally substituted with 1 or 2 groups which are _1- C ₄ ) haloalkyl, (C ₁ -C ₄ ) haloalkoxy, (C ₁ -C ₆ ) alkyl or NR ₆ R _7- (C ₁ -C ₆ alkyl) According to embodiment A59.

Embodiment A61.

R ₅ is H; Alkyl optionally substituted with 1, 2 or 3 groups which are independently phenylalkoxycarbonyl, -NR ₈ R ₉ , halogen, -C (O) NR ₈ R ₉ , alkoxycarbonyl or alkanoyl; Alkoxyalkyl optionally substituted with one trimethylsilyl group; Alkoxycarbonyl; Amino; Hydroxyalkyl; Alkenyl optionally substituted with alkoxycarbonyl; Alkynyl; -SO ₂ -alkyl; Or alkoxy optionally substituted with one trimethylsilyl group,

Wherein each independently alkyl, halogen, alkoxy, phenylalkoxy, thioalkoxy, -SO ₂ alkyl, alkoxycarbonyl, phenylalkoxycarbonyl, CO ₂ H, CN, OH, amidinooxime, NR ₈ R ₉ , NR _{1, 2 which is 6} R _7- (C ₁ -C ₆ alkyl)-, -C (O) NR ₆ R ₇ , amidino, hydroxyalkyl, carboxaldehyde, -NR ₆ R ₇ , haloalkyl or haloalkoxy Substituted or unsubstituted with 3, 4 or 5 groups;

Wherein R ₈ is hydrogen, alkyl, alkanoyl, phenylalkyl and arylalkanoyl;

R ₉ is alkyl, alkanoyl, phenylalkyl, heteroaryl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl and arylalkanoyl.

In this embodiment, R ₂ is benzyloxy, R ₄ is H, pentavalent benzyl or methyl, and R ₁ is not hydrogen; At least two of R ₁ , R ₂ , R ₄ and R ₅ are preferably hydrogen.

Embodiment A62.

R ₅ is H; Alkyl optionally substituted with 1, 2 or 3 groups which 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; -SO ₂ -alkyl; Alkoxy optionally substituted with one trimethylsilyl group,

Wherein each independently alkyl, halogen, alkoxy, phenylalkoxy, thioalkoxy, -SO ₂ alkyl, alkoxycarbonyl, phenylalkoxycarbonyl, CO ₂ H, CN, OH, amidinooxime, NR ₈ R ₉ , NR _{1, 2 which is 6} R _7- (C ₁ -C ₆ alkyl)-, -C (O) NR ₆ R ₇ , amidino, hydroxyalkyl, carboxaldehyde, -NR ₆ R ₇ , haloalkyl or haloalkoxy Substituted or unsubstituted with 3, 4 or 5 groups;

Wherein R ₈ is hydrogen, alkyl, alkanoyl, phenylalkyl and arylalkanoyl;

R ₉ is alkyl, alkanoyl, phenylalkyl, heteroaryl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl and arylalkanoyl.

In this embodiment, R ₂ is benzyloxy, R ₄ is H, R ₅ is benzyl or methyl, and R ₁ is not hydrogen; At least two of R ₁ , R ₂ , R ₄ and R ₅ are preferably hydrogen.

Embodiment A63.

R ₁ is H, halogen, methyl, ethyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl or carboxaldehyde;

R ₂ is benzyloxy, OH, phenyloxy, phenyloxy (C ₁ -C ₆ ) alkyl or phenyl (C ₁ -C ₄ ) thioalkoxy, each independently halogen,-(C ₁ -C ₆ ) alkyl -N (R) -CO ₂ R ₃₀ , NR ₆ R ₇ , (C ₁ -C ₄ ) haloalkyl, (C ₁ -C ₄ ) haloalkoxy, (C ₁ -C ₆ ) alkyl, pyridyl or NR ₆ Optionally substituted with 1, 2, 3 or 4 groups which are R _7- (C ₁ -C ₆ alkyl)-;

R ₄ is H; Independently CO ₂ H, -CO ₂ alkyl, -C (O) NRR, -N (R ₃₀ ) C (O) NRR, -N (R ₃₀ ) C (O)-(C ₁ -C ₆ ) alkoxy or (C ₁ -C ₄ ) alkyl optionally substituted with 1 or 2 groups which is —NR ₆ R ₇ ; Or hydroxy (C ₁ -C ₄ ) alkyl.

Embodiment A64.

R ₅ is H; Alkyl optionally substituted with 1, 2 or 3 groups which are independently phenylalkoxycarbonyl, -NR ₈ R ₉ , halogen, -C (O) NR ₈ R ₉ , alkoxycarbonyl or alkanoyl; Alkoxyalkyl optionally substituted with one tri methylsilyl group; Alkoxycarbonyl; Amino; Hydroxyalkyl; Alkenyl optionally substituted with alkoxycarbonyl; Alkynyl; -SO ₂ -alkyl; Alkoxy optionally substituted with one trimethylsilyl group,

Wherein R ₈ is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkanoyl, phenyl C ₁ -C ₄ alkyl and phenyl C ₁ -C ₄ alkanoyl;

R ₉ is C ₁ -C ₄ alkyl, C ₁ -C ₄ alkanoyl, phenyl C ₁ -C ₄ alkyl, pyridyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl and phenyl C ₁ -C ₄ alkanoyl A compound according to embodiment A63.

Embodiment A65.

R ₅ is independently phenyl C ₁ -C ₄ alkoxycarbonyl, NH ₂ , mono C ₁ -C ₄ alkylamino, di C ₁ -C ₄ alkylamino, halogen, -C (O) NH ₂ , -C (O ) NH (C ₁ -C ₆ alkyl optionally substituted with a) a one, two or three groups optionally substituted C ₁ -C ₆ alkyl (wherein alkyl is OH, NH ₂ or methoxy being), -C (O) N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), wherein alkyl is optionally substituted with OH, NH ₂ or methoxy, respectively, C ₁ -C ₄ alkoxycarbonyl and C ₁ -C ₄ Alkanoyl,

R ₅ is C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl; C ₁ -C ₄ alkoxycarbonyl; Amino; C ₁ -C ₄ hydroxyalkyl; Optionally substituted C ₂ -C ₄ alkenyl is a C ₁ -C ₄ alkoxycarbonyl; C ₂ -C ₄ alkynyl; -SO ₂ -C ₁ -C ₄ alkyl; Or C ₁ -C ₄ alkoxy.

Embodiment A66.

의 화합물 또는 제약상 허용되는 그의 염.Chemical formula

Or a pharmaceutically acceptable salt thereof.

In the above formula,

R ₁ is halogen, NO ₂ , alkyl, carboxaldehyde, hydroxyalkyl, arylalkoxy, arylalkyl, CN, aryl, alkanoyl, alkoxy, alkoxyalkyl, haloalkyl or arylalkanoyl,

Wherein the aryl portions of arylalkoxy, arylalkyl and arylalkanoyl are independently halogen, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO ₂ H Substituted or unsubstituted with 1, 2, 3, 4 or 5 groups;

Alkyl moieties of alkyl, hydroxyalkyl, arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and arylalkanoyl groups are independently halogen, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxycarbonyl or spirocyclo Substituted or unsubstituted with 1, 2 or 3 groups which are propyl;

R ₂ is aryl, heteroaryl, arylalkenyl, arylalkoxy, aryloxyalkyl, arylalkyl, OH, alkynyl, aryloxy, aryloxyalkyl, arylthioalkoxy, alkoxy, -OC (O) NH (CH ₂ ) _n aryl, -OC (O) N (alkyl) (CH ₂ ) _n aryl, -OSO ₂ (C ₁ -C ₆ ) alkyl, -OS0 ₂ aryl, alkyl, alkoxyalkoxy, NR ₈ R ₉ or CO ₂ H ,

Where n is 0, 1, 2, 3, 4, 5 or 6;

Each independently represents halogen,-(C ₁ -C ₆ ) alkyl-N (R) -CO ₂ R ₃₀ , alkoxy, alkoxycarbonyl, CN, NR ₆ R ₇ , haloalkyl, haloalkoxy, alkyl, heteroaryl, Heteroarylalkyl, NR ₆ R _7- (C ₁ -C ₆ alkyl)-, phenyl, -SO ₂ -phenyl, wherein the phenyl group is optionally substituted with 1, 2 or 3 groups independently of halogen or NO ₂ , Or substituted or unsubstituted with 1, 2, 3, 4 or 5 groups which are -OC (O) NR ₆ R ₇ ;

Wherein R ₆ and R ₇ are independently at each occurrence H, alkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, -S0 ₂ -alkyl, OH, hydroxyalkyl,-(C ₁ -C ₄ ) alkyl-CO ₂ -alkyl, heteroarylalkyl, alkanoyl, arylalkyl, arylalkoxy or arylalkanoyl, wherein each independently is halogen, alkoxy, heterocycloalkyl, OH, SH, C ₃ -C ₆ cycloalkyl, NH ₂ Or substituted or unsubstituted with 1, 2 or 3 groups which are NH (alkyl), N (alkyl) (alkyl), —0-alkanoyl, alkyl, haloalkyl or haloalkoxy;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently substituted with 1 or 2 groups which are independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen To form a morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl or piperazinyl ring;

R is independently at each occurrence H or C ₁ -C ₆ alkyl;

R ₃₀ is independently C ₁ -C ₆ alkyl optionally substituted with 1 or 2 groups which are OH, SH, halogen, amino, monoalkylamino, dialkylamino or C ₃ -C ₆ cycloalkyl;

R ₄ is H; Independently CO ₂ H, —CO ₂ alkyl, —C (O) NRR, —N (R ₃₀ ) C (O) NRR, —N (R ₃₀ ) C (O) — (C ₁ -C ₆ ) alkoxy or Alkyl optionally substituted with 1 or 2 groups which is —NR ₆ R ₇ ; Arylalkoxy; Arylalkyl; Hydroxyalkyl; Haloalkyl; Alkoxy; Carboxaldehyde; CO ₂ H; Alkoxyalkyl; Or alkoxyalkoxy,

Wherein the aryl portion of arylalkoxy and arylalkyl is independently substituted or unsubstituted with 1, 2, 3, 4 or 5 groups which are halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl or haloalkoxy;

R ₅ is H, arylalkyl, alkyl, aryl, alkoxy, heterocycloalkylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkyl, cycloalkylalkyl, -alkyl-S-aryl, -alkyl-SO ₂ -aryl,- (C ₁ -C ₄ ) alkyl-C (O) -heterocycloalkyl, —SO ₂ -aryl or heteroaryl,

Wherein each independently alkyl, halogen, alkoxy, aryl, arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, OH, CO ₂ H, CN, amidinooxime, NR ₈ R ₉ , NR ₆ R ₇ - (C ₁ -C ₆ alkyl) -, -C (O) NR 6 R, - (C 1 -C 4 _{alkyl) -C (O) NR 6 R} 7, amidino, hydroxyalkyl, -S0 ₂ alkyl , -S0 ₂ H, -SO ₂ NR ₆ R ₇ , -NR ₆ R ₇ , alkanoyl, wherein the alkyl moiety is optionally substituted with OH, halogen or alkoxy, haloalkyl,-(C ₁ -C ₄ Alkyl) -NR ₁₅ C (O) NR ₁₆ R ₁₇ ,-(C ₁ -C ₄ alkyl) -NR ₁₅ C (O) R ₁₈ , -O-CH ₂ -O, -O-CH ₂ CH ₂ -O Or substituted or unsubstituted with 1, 2, 3, 4 or 5 groups which are haloalkoxy;

Wherein R ₈ independently in each occurrence is hydrogen, alkyl, alkanoyl, arylalkyl and arylalkanoyl, wherein each is independently 1, 2, 3, which is alkyl, alkoxy, alkoxycarbonyl, halogen or haloalkyl Optionally substituted with 4 or 5 groups;

R ₉ is independently at each occurrence alkyl, alkanoyl, arylalkyl cycloalkyl, alkenyl, heteroaryl, cycloalkylalkyl, arylalkanoyl, —S0 ₂ -phenyl and aryl, each independently alkyl, alkoxy Optionally substituted with 1, 2, 3, 4 or 5 groups which are alkoxycarbonyl, halogen or haloalkyl;

R ₁₅ is H or C ₁ -C ₆ alkyl;

R ₁₆ and R ₁₇ are independently H or C ₁ -C ₆ alkyl;

R ₁₆ , R ₁₇ , and the nitrogen to which they are attached form a morpholinyl ring;

R ₁₈ is -O- (C ₂ -C ₆₎ alkanoyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl optionally substituted by ₁ C is -C ₆ alkyl; Amino C ₁ -C ₆ alkyl, mono or dialkylamino C ₁ -C ₆ alkyl.

In this embodiment,

R ₆ and R ₇ are not OH at the same time;

R ₆ and R ₇ are not simultaneously —S0 ₂ (C ₁ -C ₆ alkyl);

When R ₂ is OH, R ₄ is methyl and R ₅ is phenyl and R ₁ is not acetyl;

It is preferable that R ₄ and R ₅ are not hydrogen at the same time.

Embodiment A71.

R ₁ is halogen, C ₁ -C ₆ alkyl, phenyl, carboxaldehyde, C ₁ -C ₆ hydroxyalkyl, phenyl C ₁ -C ₆ alkoxy, phenyl C ₁ -C ₆ alkyl, CN, C ₁ -C ₆ Alkanoyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl or phenyl C ₁ -C ₆ alkanoyl,

Wherein the phenyl group is independently halogen, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, nitro, CN, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ haloalkoxy or C0 ₂ H Substituted or unsubstituted with 1, 2 or 3 groups;

Wherein the alkyl group is unsubstituted or substituted with 1, 2 or 3 groups which are independently halogen, methoxy or ethoxy;

R ₂ is phenylalkoxy, OH, phenyloxy, phenyloxy (C ₁ -C ₆ ) alkyl, phenylthio (C ₁ -C ₄ ) alkoxy, alkoxy, alkenyl, phenethyl, -OC (O) NH (CH ₂ ) _n phenyl, -OC (O) N (alkyl) (CH ₂ ) _n phenyl, alkyl, alkoxyalkoxy, NR ₈ R ₉ , pyridyl, pyrimidyl, pyridazyl, pyrazolyl, imidazolyl, pyrrolyl, tetra Hydroquinolinyl, amino, tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl, triazinyl, tetrahydrofuryl, piperidinyl, hexahydropyrimidinyl, thiazolyl, thienyl or CO ₂ H,

Where n is 0, 1, 2 or 3;

Each independently represents halogen,-(C ₁ -C ₆ ) alkyl-N (R) -CO ₂ R ₃₀ , haloalkyl, haloalkoxy, alkyl, thienyl, pyridyl, or 1, 2 or 3 halogens Substituted or unsubstituted with 1, 2, 3, 4 or 5 groups which are substituted phenyl;

R ₆ and R ₇ are independently at each occurrence H, alkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, alkoxycarbonyl,-(C ₁ -C ₄ ) alkyl-CO ₂ -alkyl, alkanoyl, phenylalkyl, Phenylalkoxy or phenylalkanoyl, where each independently is halogen, OH, SH, C ₃ -C ₆ cycloalkyl, alkoxy, NH ₂ , NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ Alkyl) (C ₁ -C ₆ alkyl), alkyl, CF ₃ or OCF ₃ substituted or unsubstituted with 1, 2 or 3 groups;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently morpholinyl, thiomorpholi, optionally substituted with 1 or 2 groups which are C ₁ -C ₄ alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen To form a silyl, piperidinyl, pyrrolidinyl or piperazinyl ring;

R ₄ is H; Independently CO ₂ H, -C0 ₂ alkyl, -C (O) NRR, N (R ₃₀ ) C (O) NRR, -N (R ₃₀ ) C (O)-(C ₁ -C ₆ ) alkoxy or- Alkyl optionally substituted with 1 or 2 groups which are NR ₆ R ₇ ; Phenylalkoxy; Phenylalkyl; Hydroxyalkyl; Carboxaldehyde; Haloalkyl; Alkoxy; Alkoxyalkyl; Or alkoxyalkoxy, wherein the phenyl group is independently substituted or unsubstituted with 1, 2 or 3 groups which are halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl or haloalkoxy;

R ₅ is benzyl, phenethyl, (C ₁ -C ₆ ) alkyl, phenyl, naphthyl, alkoxy, piperidinyl, pyrrolidinyl, imidazolidinyl, piperazinyl, isoquinolinyl, tetrahydroisoqui Nolinyl, indolyl, 1H-indazolyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, piperidinyl (C ₁ -C ₆ ) alkyl, pyrrolidinyl (C ₁ -C ₆ ) alkyl, imidazoli Diyl (C ₁ -C ₆ ) alkyl, piperazinyl (C ₁ -C ₆ ) alkyl, pyridyl (C ₁ -C ₆ ) alkyl, pyrimidyl (C ₁ -C ₆ ) alkyl, pyridazyl (C _1- C ₆ ) alkyl, pyrazinyl (C ₁ -C ₆ ) alkyl, isoquinolinyl (C ₁ -C ₆ ) alkyl, tetrahydroisoquinolinyl (C ₁ -C ₆ ) alkyl, indolyl (C _1- C ₆ ) alkyl or 1H-indazolyl (C ₁ -C ₆ ) alkyl,

Wherein each independently alkyl, halogen, alkoxy, hydroxyalkyl, phenylalkoxy, thioalkoxy, alkoxycarbonyl, phenylalkoxycarbonyl, OH, CO ₂ H, CN, amidinooxime, NR ₈ R ₉ , NR ₆ R ₇ - (C ₁ -C ₆ alkyl) -, -C (O) NR 6 R 7, amidino, piperazinyl, _{morpholinyl, -S0 2 (C 1 -C 6} ) alkyl, -S0 ₂ NH _{2, -S0 2 NH (C 1} -C 6) _{alkyl, -SO 2 N (C 1 -C} 6) alkyl (C ₁ -C ₆₎ alkyl, haloalkyl or haloalkoxy group of 1, 2, 3, 4, or A compound according to embodiment A66 substituted or unsubstituted with 5 groups.

In this embodiment, R ₂ is OH, R ₄ is methyl, R ₅ is phenyl, and R ₁ is not acetyl; It is preferable that R ₄ and R ₅ are not hydrogen at the same time.

Embodiment A72.

R ₁ is halogen, alkyl, carboxaldehyde, hydroxyalkyl, phenylalkoxy, phenyl, benzyl, phenethyl, phenpropyl, phenbutyl, CN, (C ₂ -C ₆ ) alkanoyl, haloalkyl, or phenylCO- , PhenylCH ₂ CO-, phenylCH ₂ CH ₂ CO-,

Wherein the phenyl group is independently substituted with 1, 2 or 3 groups which are halogen, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO ₂ H Unsubstituted;

Wherein said alkyl group is unsubstituted or substituted with 1, 2 or 3 groups which are independently halogen, methoxy or ethoxy;

R ₂ is benzyloxy, phenethyloxy, phenpropyloxy, OH, phenyloxy, phenyloxy (C ₁ -C ₆ ) alkyl, phenylthio (C ₁ -C ₄ ) alkoxy, NR ₈ R ₉ , (C _1- C ₆ ) alkyl, alkynyl, phenethyl, —OC (O) N (CH ₃ ) CH ₂ phenyl, alkoxyalkoxy, pyridyl, pyrimidyl, pyridazyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazinyl, Piperidinyl, hexahydropyrimidinyl, benzimidazolyl or thienyl,

Wherein each independently is halogen,-(C ₁ -C ₆ ) alkyl-N (R) -CO ₂ R ₃₀ , CF ₃ , OCF ₃ , (C ₁ -C ₄ ) alkyl, thienyl, pyridyl, or Substituted or unsubstituted with 1, 2 or 3 groups which are phenyl optionally substituted with 1, 2 or 3 halogens;

R ₆ and R ₇ are independently at each occurrence H, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, ( C ₁ -C ₆ ) alkoxycarbonyl, hydroxy (C ₁ -C ₆ ) alkyl,-(C ₁ -C ₄ ) alkyl-CO ₂ -alkyl, (C ₁ -C ₆ ) alkanoyl, phenyl (C ₁ -C ₆ ) alkyl, phenyl (C ₁ -C ₆ ) alkoxy or phenyl (C ₁ -C ₆ ) alkanoyl, wherein each independently is halogen, (C ₁ -C ₆ ) alkoxy, NH ₂ , OH, Substituted or unsubstituted with 1, 2 or 3 groups which are SH, C ₃ -C ₆ cycloalkyl, (C ₁ -C ₆ ) alkyl, CF ₃ or OCF ₃ ;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently morpholinyl, piperidinyl optionally substituted with 1 or 2 groups which are C ₁ -C ₄ alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen To form pyrrolidinyl or piperazinyl rings;

R ₄ is H, or independently CO ₂ H, —CO ₂ alkyl, —C (O) NRR, —N (R ₃₀ ) C (O) NRR, —N (R ₃₀ ) C (O) — (C ₁ -C ₆ ) alkoxy or -NR ₆ R ₇ , benzyloxy, phenethyloxy phenpropyloxy, benzyl, phenethyl, phenpropyl, hydroxyalkyl, halo (C ₁ -C ₄ ) alkyl, carboxaldehyde, alkoxy, Optionally substituted with one or two groups which are alkoxyalkyl or alkoxyalkoxy,

Wherein said phenyl group is independently substituted or unsubstituted with 1, 2 or 3 groups being halogen, hydroxy, alkoxy, alkyl, nitro, CF ₃ or OCF ₃ ;

R ₅ is benzyl, phenethyl, phenpropyl, phenbutyl, (C ₁ -C ₆ ) alkyl, phenyl, piperidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl (C ₁ -C ₆ ) alkyl, Pyrrolidinyl (C ₁ -C ₆ ) alkyl, imidazolidinyl (C ₁ -C ₆ ) alkyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, pyridyl (C ₁ -C ₆ ) alkyl, pyrimidyl (C ₁ -C ₆ ) alkyl, pyridazyl (C ₁ -C ₆ ) alkyl or pyrazinyl (C ₁ -C ₆ ) alkyl,

Wherein, each independently, alkyl, halogen, haloalkyl, NR ₈ R ₉ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-, carboxaldehyde, morpholinyl, SO ₂ NH ₂ , SO ₂ NH ( Alkyl), SO ₂ N (alkyl) (alkyl), alkoxy, hydroxyalkyl, benzyloxy, thioalkoxy, OH, CO ₂ H, CN, -C0 ₂ (C ₁ -C ₅ alkyl), phenylalkoxycarbonyl, Embodiment A71, substituted or unsubstituted with 1, 2, 3, 4 or 5 groups, which is amidinooxime, amidino, -C (O) NR ₆ R ₇ , CF ₃ , CF ₂ CF ₃ , ClCH ₂ or OCF ₃ Compound according to.

In this embodiment, it is preferred that R ₂ is OH, R ₄ is methyl, R ₅ is phenyl, and R ₁ is not acetyl.

Embodiment A73.

R ₁ is halogen, alkyl, carboxaldehyde, hydroxy (C ₁ -C ₄ ) alkyl, phenylalkoxy, benzyl, phenethyl, -C (O) CH ₃ , phenylCO- or phenylCH ₂ CO-,

Wherein the phenyl group is independently unsubstituted or substituted with 1, 2 or 3 groups which are halogen, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy, nitro, CN, CF ₃ or OCF ₃ ;

The alkyl group is unsubstituted or substituted with 1, 2 or 3 groups which are independently halogen, methoxy or ethoxy;

R ₂ is benzyloxy, phenethyloxy, phenpropyloxy, OH, phenyloxy, phenyloxy (C ₁ -C ₆ ) alkyl, phenethyl, NR ₈ R ₉ , -S-benzyl or (C ₁ -C ₆ ) Alkyl,

Wherein each is independently substituted with 1, 2 or 3 groups which are halogen,-(C ₁ -C ₆ ) alkyl-N (R) -CO ₂ R ₃₀ , CF ₃ , OCF ₃ , alkyl, thienyl or pyridyl Or unsubstituted;

R ₆ and R ₇ are independently at each occurrence H, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, ( C ₁ -C ₆ ) alkoxycarbonyl, hydroxy (C ₁ -C ₆ ) alkyl,-(C ₁ -C ₄ ) alkyl-CO ₂ -alkyl, (C ₁ -C ₆ ) alkanoyl, phenyl (C ₁ -C ₆ ) alkyl, phenyl (C ₁ -C ₆ ) alkoxy or phenyl (C ₁ -C ₆ ) alkanoyl, each independently halogen, (C ₁ -C ₆ ) alkoxy, NH ₂ , OH, SH Or substituted or unsubstituted with 1, 2 or 3 groups which are C ₃ -C ₆ cycloalkyl, (C ₁ -C ₆ ) alkyl, CF ₃ or OCF ₃ ;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently morpholinyl, piperidinyl optionally substituted with 1 or 2 groups which are C ₁ -C ₄ alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen To form pyrrolidinyl or piperazinyl rings;

R ₄ is H; Independently CO ₂ H, —C0 ₂ alkyl, —C (O) NRR, —N (R ₃₀ ) C (O) NRR, —N (R ₃₀ ) C (O) — (C ₁ -C ₆ ) alkoxy or Alkyl optionally substituted with 1 or 2 groups which is —NR ₆ R ₇ ; Benzyloxy; Phenethyloxy; Phenpropyloxy; Benzyl or hydroxyalkyl,

Wherein the phenyl group is independently substituted or unsubstituted with 1, 2 or 3 groups being halogen, hydroxy, alkoxy, alkyl, nitro, CF ₃ or OCF ₃ ;

R ₅ is benzyl, phenethyl, phenpropyl, phenbutyl, (C ₁ -C ₆ ) alkyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazinyl (C ₁ -C ₆ ) alkyl, pyrimidinyl ( C ₁ -C ₆ ) alkyl or pyridyl (C ₁ -C ₄ ) alkyl,

Wherein each independently alkyl, halogen, haloalkyl, morpholinyl, -SO ₂ (C ₁ -C ₆ ) alkyl, -SO ₂ NH ₂ , -SO ₂ NH (C ₁ -C ₆ ), -SO ₂ N (C ₁ -C ₆ ) (C ₁ -C ₆ ), (C ₁ -C ₄ ) alkoxy, phenyl (C ₁ -C ₄ ) alkoxy, thio (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, OH, C0 ₂ H, CN, amidinooxime, amidino, NR ₈ R ₉ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-, hydroxyalkyl, CONR ₆ R ₇ , A compound according to embodiment A72, unsubstituted or substituted with 1, 2, 3, 4 or 5 groups, which is CF ₃ or OCF ₃ .

Embodiment A74.

R ₁ is halogen, alkyl, carboxaldehyde or hydroxyalkyl;

R ₂ is benzyloxy, phenethyloxy, phenpropyloxy, OH, phenyloxy, phenyloxy (C ₁ -C ₆ ) alkyl, phenethyl, phenylthioalkoxy or (C ₁ -C ₆ ) alkyl,

Wherein each is independently substituted with 1, 2 or 3 groups which are halogen,-(C ₁ -C ₆ ) alkyl-N (R) -CO ₂ R ₃₀ , CF ₃ , OCF ₃ , alkyl, thienyl or pyridyl Or unsubstituted;

R ₄ is H; Independently CO ₂ H, -CO ₂ alkyl, -C (O) NRR, -N (R ₃₀ ) C (O) NRR, -N (R ₃₀ ) C (O)-(C ₁ -C ₆ ) alkoxy or (C ₁ -C ₄ ) alkyl optionally substituted with 1 or 2 groups which is —NR ₆ R ₇ ; Benzyloxy; Or phenethyloxy,

Wherein the phenyl group is independently unsubstituted or substituted with 1, 2 or 3 groups which are halogen, hydroxy, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkyl, nitro, CF ₃ or OCF ₃ ;

R ₅ is benzyl, phenethyl, (C ₁ -C ₆ ) alkyl, phenyl, indazolyl or pyridyl, wherein each independently is (C ₁ -C ₄ ) alkyl, halogen, OH, CO ₂ CH, CN, (C ₁ -C ₄ ) alkoxy, -C (O) pyrrolidine, -SO ₂ (C ₁ -C ₆ ) alkyl, benzyloxy, -CO ₂ (C ₁ -C ₅ alkyl), amidino, thio ( C ₁ -C ₄ ) ₁ , ₂ , ₃ , _{4 which} is alkoxy, amidinooxime, CF ₃ , NR ₈ R ₉ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-, CONR ₆ R ₇ or OCF ₃ Or a compound according to embodiment A73 substituted or unsubstituted with 5 groups.

Embodiment A75.

R ₁ is chloro, bromo, iodo, methyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl;

R ₅ is benzyl, phenethyl, phenpropyl, phenyl or pyridyl, each independently alkyl, OH, halogen, alkoxy, NH ₂ , NH (C ₁ -C ₆ ) alkyl, N (C ₁ -C ₆ ) Unsubstituted or substituted with 1, 2 or 3 groups which are alkyl (C ₁ -C ₆ ) alkyl, NR ₈ R ₉ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-, CONR ₆ R ₇ and amidinooxime Become;

Wherein R ₆ and R ₇ are independently H, C ₁ -C ₄ alkyl, C ₁ -C ₆ alkanoyl,

Wherein the alkyl and alkanoyl groups are independently substituted with 1, 2 or 3 groups which are independently OH, halogen or C ₃ -C ₇ cyclopropyl.

Embodiment A76.

R ₂ is benzyloxy, phenethyl, phenyloxy (C ₁ -C ₆ ) alkyl or phenethyloxy, each independently halogen,-(C ₁ -C ₆ ) alkyl-N (R) -CO ₂ R ₃₀ A compound according to embodiment A75 which is unsubstituted or substituted with 1, 2 or 3 groups which are, CF ₃ , OCF ₃ or (C ₁ -C ₄ ) alkyl.

Embodiment A77.

R ₅ is benzyl, phenethyl, thienyl (C ₁ -C ₆ alkyl), piperidinyl (C ₁ -C ₆ ) alkyl, pyrrolidinyl (C ₁ -C ₆ ) alkyl, imidazolidinyl (C ₁ -C ₆ ) alkyl, piperazinyl (C ₁ -C ₆ ) alkyl, pyridyl (C ₁ -C ₆ ) alkyl, pyrimidyl (C ₁ -C ₆ ) alkyl, pyridazyl (C ₁ -C ₆ ) alkyl , Pyrazinyl (C ₁ -C ₆ ) alkyl, isoquinolinyl (C ₁ -C ₆ ) alkyl, tetrahydroisoquinolinyl (C ₁ -C ₆ ) alkyl, indolyl (C ₁ -C ₆ ) alkyl Or 1H-indazolyl (C ₁ -C ₆ ) alkyl,

Wherein each independently represents (C ₁ -C ₆ ) alkyl, halogen, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) hydroxyalkyl, phenyl (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) thioalkoxy, (C ₁ -C ₆ ) alkoxycarbonyl, phenyl (C ₁ -C ₆ ) alkoxycarbonyl, OH, CO ₂ H, CN, amidinooxime, NR ₈ R ₉ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-, -C (O) NR ₆ R ₇ , amidino, piperazinyl, morpholinyl, -S0 ₂ (C ₁ -C ₆ ) alkyl, -SO ₂ NH ₂ , -SO ₂ NH (C ₁ -C ₆ ) alkyl, -S0 ₂ N (C ₁ -C ₆ ) alkyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₄ ) haloalkyl,-(C _1- C ₄ alkyl) -NR ₁₅ C (O) NR ₁₆ R ₁₇ ,-(C ₁ -C ₄ alkyl) -NR ₁₅ C (O) R ₁₈ , -O-CH ₂ -O, -O-CH ₂ CH ₂ Substituted or unsubstituted with 1, 2, 3, 4 or 5 groups which are —O— or (C ₁ -C ₄ ) haloalkoxy;

Wherein R ₆ and R ₇ are independently at each occurrence H, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl , (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) hydroxyalkyl,-(C ₁ -C ₄ ) alkyl-CO _2- (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkanoyl, phenyl (C ₁ -C ₆ ) alkyl, phenyl (C ₁ -C ₆ ) alkoxy or phenyl (C ₁ -C ₆ ) alkanoyl, each independently halogen, (C ₁ -C ₄ Alkoxy, NH ₂ , OH, SH, C ₃ -C ₆ cycloalkyl, NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), (C _1- C ₄ ) alkyl, CF ₃ or OCF ₃ substituted or unsubstituted with 1, 2 or 3 groups;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently morpholinyl, thiomorpholi, optionally substituted with 1 or 2 groups which are C ₁ -C ₄ alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen To form a silyl, piperidinyl, pyrrolidinyl or piperazinyl ring;

R ₁₈ is -0- (C ₂ -C ₆₎ alkanoyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl optionally substituted by ₁ C is -C ₆ alkyl; A compound according to embodiment A66 which is amino C ₁ -C ₆ alkyl, mono or dialkylamino C ₁ -C ₆ alkyl.

In this embodiment, R ₆ and R ₇ are not OH at the same time; It is preferred that R ₆ and R ₇ at the same time are not -S0 ₂ (C ₁ -C ₆ alkyl).

Embodiment A78.

R ₁ is halogen, methyl, ethyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl or carboxaldehyde;

R ₂ is benzyloxy, OH, phenyloxy, phenyloxy (C ₁ -C ₆ ) alkyl or phenyl (C ₁ -C ₄ ) thioalkoxy, each independently halogen,-(C ₁ -C ₆ ) alkyl 1 which is —N (R) —CO ₂ R ₃₀ , NR ₆ R ₇ , (C ₁ -C ₄ ) haloalkyl, (C ₁ -C ₄ ) haloalkoxy, (C ₁ -C ₆ ) alkyl or pyridyl Optionally substituted with 2, 3 or 4 groups;

R ₄ is H; Independently CO ₂ H, -CO ₂ alkyl, -C (O) NRR, -N (R ₃₀ ) C (O) NRR, -N (R ₃₀ ) C (O)-(C ₁ -C ₆ ) alkoxy or (C ₁ -C ₄ ) alkyl optionally substituted with 1 or 2 groups which is —NR ₆ R ₇ ; Or hydroxy (C ₁ -C ₄ ) alkyl.

Embodiment A79.

R ₅ is benzyl or phenethyl, wherein each independently (C ₁ -C ₆ ) alkyl, halogen, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) hydroxyalkyl, phenyl (C _1- C ₆ ) alkoxy, (C ₁ -C ₆ ) thioalkoxy, (C ₁ -C ₆ ) alkoxycarbonyl, phenyl (C ₁ -C ₆ ) alkoxycarbonyl, OH, CO ₂ H, CN, amidinooxime, NR ₈ R ₉ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-, -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ amidino , Piperazinyl, morpholinyl, -SO ₂ (C ₁ -C ₆ ) alkyl, -SO ₂ NH ₂ , -SO ₂ NH (C ₁ -C ₆ ) alkyl, -S0 ₂ N (C ₁ -C ₆ ) Alkyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₄ ) haloalkyl,-(C ₁ -C ₄ alkyl) -NR ₁₅ C (O) R ₁₈ , -O-CH ₂ -O, -O Substituted or unsubstituted with 1, 2, 3, 4 or 5 groups which are -CH ₂ CH ₂ -O- or (C ₁ -C ₄ ) haloalkoxy;

Wherein R ₆ and R ₇ are independently at each occurrence H, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl , (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) hydroxyalkyl,-(C ₁ -C ₄ ) alkyl-CO _2- (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkanoyl, phenyl (C ₁ -C ₆ ) alkyl, phenyl (C ₁ -C ₆ ) alkoxy or phenyl (C ₁ -C ₆ ) alkanoyl, each independently halogen, (C ₁ -C ₄ Alkoxy, NH ₂ , OH, SH, C ₃ -C ₆ cycloalkyl, NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), (C _1- C ₄ ) alkyl, CF ₃ or OCF ₃ substituted or unsubstituted with 1, 2 or 3 groups;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently morpholinyl, thiomorpholi, optionally substituted with 1 or 2 groups which are C ₁ -C ₄ alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen To form a silyl, piperidinyl, pyrrolidinyl or piperazinyl ring;

R ₁₈ is —O- (C ₂ -C ₆ ) alkanoyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, amino C ₁ -C _The compound according to embodiment A78, which is ₆ alkyl or C ₁ -C ₆ alkyl optionally substituted with mono or dialkylamino C ₁ -C ₆ alkyl.

In this embodiment, R ₆ and R ₇ are not OH at the same time; It is preferred that R ₆ and R ₇ at the same time are not -S0 ₂ (C ₁ -C ₆ alkyl).

Embodiment A80.

R ₅ is benzyl or phenethyl, wherein each independently C ₁ -C ₆ alkyl, -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , NR ₈ R ₉ , halogen, C ₁ -C ₆ alkoxy, CO ₂ H, — (C ₁ -C ₄ ) alkyl) -CO ₂ H, C ₁ -C ₆ thioalkoxy, amidinooxime, C ₁ -C ₆ Alkoxycarbonyl,-(C ₁ -C ₄ alkyl) -C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ hydroxyalkyl,-(C ₁ -C ₄ alkyl) -CN, CN, phenyl C _1- C ₆ alkoxy, OH, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ haloalkoxy, NR ₆ R _7- (C ₁ -C ₆ alkyl)-,-(C ₁ -C ₄ alkyl) -NR ₁₅ C (O) R ₁₈ , amidinooxime, -SO ₂ (C ₁ -C ₆ alkyl), -O-CH ₂ -O-, -O-CH ₂ CH ₂ -O-, phenyl C ₁ -C ₄ alkoxy or Optionally substituted by 1, 2, 3, 4 or 5 groups which are phenyl;

Wherein R ₆ and R ₇ in each occurrence are independently H, OH, C ₁ -C ₆ alkyl, amino C ₁ -C ₄ alkyl, NH (C ₁ -C ₆ alkyl) alkyl, N (C ₁ -C ₆ Alkyl) (C ₁ -C ₆ alkyl) C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, -SO ₂ (C ₁ -C ₆ alkyl) Each independently selected from 1, 2 or 3 groups which are halogen, OH, SH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, OH, CF ₃ or OCF ₃ Substituted;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently piperidinyl, pyrrolidinyl, piperazinyl, optionally substituted by one or two groups which are alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen; Morpholinyl, thiomorpholinyl ring;

R ₁₈ is -O- (C ₂ -C ₆₎ alkanoyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl optionally substituted by ₁ C is -C ₆ alkyl; A compound according to embodiment A79 which is amino C ₁ -C ₆ alkyl, mono or dialkylamino C ₁ -C ₆ alkyl.

In this embodiment, R ₆ and R ₇ are not OH at the same time; It is preferred that R ₆ and R ₇ at the same time are not —S0 ₂ (C ₁ -C ₆ alkyl).

Embodiment A81.

R ₅ is benzyl or phenethyl, each independently C ₁ -C ₆ alkyl, —C (O) NR ₆ R ₇ , — (C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , halogen , C ₁ -C ₆ alkoxy, CO ₂ H,-(C ₁ -C ₄ alkyl) -CO ₂ H, C ₁ -C ₆ thioalkoxy, amidinooxime, C ₁ -C ₆ alkoxycarbonyl,-(C ₁ -C ₄ alkyl) -C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ hydroxyalkyl,-(C ₁ -C ₄ alkyl) -CN, CN, phenyl C ₁ -C ₆ alkoxy, OH, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ haloalkoxy, NR ₆ R _7- (C ₁ -C ₆ alkyl)-, NR ₈ R ₉ ,-(C ₁ -C ₄ alkyl) -NR ₁₅ C (O ) R ₁₈ , amidinooxime, -SO ₂ (C ₁ -C ₆ alkyl), -O-CH ₂ -O-, -O-CH ₂ CH ₂ -O-, phenyl C ₁ -C ₄ alkoxy or phenyl Optionally substituted with 1, 2, 3, 4 or 5 groups;

Wherein R ₆ and R ₇ are independently at each occurrence H, OH, C ₁ -C ₆ alkyl, amino C ₁ -C ₄ alkyl, NH (C ₁ -C ₆ alkyl) alkyl, N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, -SO ₂ (C ₁ -C ₆ alkyl Each independently represent 1, 2 or 3 groups which are halogen, OH, SH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, OH, CF ₃ or OCF ₃ Optionally substituted;

R ₁₈ is -O- (C ₂ -C ₆₎ alkanoyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl optionally substituted by ₁ C is -C ₆ alkyl; A compound according to embodiment A80 which is amino C ₁ -C ₆ alkyl, mono or dialkylamino C ₁ -C ₆ alkyl.

In this embodiment, R ₆ and R ₇ are not OH at the same time; It is preferred that R ₆ and R ₇ at the same time are not -S0 ₂ (C ₁ -C ₆ alkyl).

Embodiment A82.

R ₅ is independently C ₁ -C ₄ alkyl, —C (O) NR ₆ R ₇ , — (C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , halogen, C ₁ -C ₄ alkoxy, CO ₂ H, C ₁ -C ₄ thioalkoxy, C ₁ -C ₄ alkoxycarbonyl, C ₁ -C ₆ hydroxyalkyl, CN, OH, NR ₆ R _7- (C ₁ -C ₆ alkyl)-, NR Benzyl optionally substituted with 1, 2, 3, 4 or 5 groups which is ₈ R ₉ , -SO ₂ (C ₁ -C ₆ alkyl) or benzyloxy,

Wherein R ₆ and R ₇ are independently at each occurrence H, OH, C ₁ -C ₆ alkyl, amino C ₁ -C ₄ alkyl, NH (C ₁ -C ₆ alkyl) alkyl, N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxy alkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, -S0 ₂ (C ₁ -C ₆ alkyl Each independently represent 1, 2 or 3 groups which are halogen, OH, SH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, OH, CF ₃ or OCF ₃ A compound according to embodiment A81, optionally substituted.

In this embodiment, R ₆ and R ₇ are not OH at the same time; It is preferred that R ₆ and R ₇ at the same time are not -S0 ₂ (C ₁ -C ₆ alkyl).

Embodiment A83.

R ₅ is independently C ₁ -C ₄ alkyl, —C (O) NR ₆ R ₇ , — (C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , halogen, C ₁ -C ₄ alkoxy, _{1, which is} C ₁ -C ₄ thioalkoxy, C ₁ -C ₄ alkoxycarbonyl, C ₁ -C ₆ hydroxyalkyl, CN, NR ₈ R ₉ or NR ₆ R _7- (C ₁ -C ₆ alkyl)-, As benzyl optionally substituted with 2, 3, 4 or 5 groups;

Wherein R ₆ and R ₇ are independently at each occurrence H, OH, C ₁ -C ₆ alkyl, amino C ₁ -C ₄ alkyl, NH (C ₁ -C ₆ alkyl) alkyl, N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl or C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl, each independently halogen, OH, SH The compound according to embodiment A82, optionally substituted with 1, 2 or 3 groups which are C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, OH, CF ₃ or OCF ₃ .

In this embodiment, it is preferable that R ₆ and R ₇ are not OH at the same time.

Embodiment A84.

A compound according to embodiment A83, wherein the R ₅ groups are disubstituted with two groups which are meta positions from one another.

Embodiment A86.

R ₅ is independently C ₁ -C ₄ alkyl, —C (O) NR ₆ R ₇ , — (C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , NR ₈ R ₉ , NR ₆ R ₇ -(C ₁ -C ₆ alkyl)-, halogen, C ₁ -C ₄ alkoxy, CO ₂ H,-(C ₁ -C ₄ alkyl) -CO ₂ H,-(C ₁ -C ₄ alkyl) -C ₁ -C ₆ alkoxycarbonyl,-(C ₁ -C ₄ alkyl) -CN, CN, phenyl C ₁ -C ₆ alkoxy, CF ₃ , OCF ₃ ,-(C ₁ -C ₄ alkyl) -NR ₁₅ C (0 Benzyl optionally substituted with 1, 2, 3, 4 or 5 groups which are R ₁₈ , amidinooxime, —O—CH ₂ —O—, —O—CH ₂ CH ₂ —O— or phenyl;

Wherein R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₄ alkyl, amino C ₁ -C ₄ alkyl, NH (C ₁ -C ₄ alkyl) alkyl, N (C ₁ -C ₄ alkyl ) (C ₁ -C ₄ alkyl) C ₁ -C ₄ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl or OH, each independently halogen, OH, SH Optionally substituted with 1, 2 or 3 groups which are C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, OH, CF ₃ or OCF ₃ ;

R ₁₈ is C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₄ alkoxy C ₁ -C ₆ alkyl; A compound according to embodiment A80 which is amino C ₁ -C ₆ alkyl, mono or dialkylamino C ₁ -C ₆ alkyl.

In this embodiment, it is preferable that R ₆ and R ₇ are not OH at the same time.

Embodiment A87.

R ₅ is benzyl or phenethyl, each independently C ₁ -C ₆ alkyl, —C (O) NR ₆ R ₇ , — (C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , halogen , C ₁ -C ₆ alkoxy, CO ₂ H,-(C ₁ -C ₄ alkyl) -CO ₂ H, C ₁ -C ₆ thioalkoxy, amidinooxime, C ₁ -C ₆ alkoxycarbonyl,-(C ₁ -C ₄ alkyl) -C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ hydroxyalkyl,-(C ₁ -C ₄ alkyl) -CN, CN, phenyl C ₁ -C ₆ alkoxy, OH, C _1- C ₄ haloalkyl, C ₁ -C ₄ haloalkoxy, NR ₈ R ₉ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-,-(C ₁ -C ₄ alkyl) -NR ₁₅ C (0 ) R ₁₈ , amidinooxime, -SO ₂ (C ₁ -C ₆ alkyl), -O-CH ₂ -O-, -O-CH ₂ CH ₂ -O-, phenyl C ₁ -C ₄ alkoxy or phenyl Optionally substituted with 1, 2, 3, 4 or 5 groups;

Wherein R ₆ , R ₇ , and the nitrogen to which they are attached are independently piperidinyl, pyrrolidinyl, pipera optionally substituted with one or two groups which are alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen Genyl or morpholinyl, thiomorpholinyl ring,

R ₁₈ is -O- (C ₂ -C ₆₎ alkanoyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl optionally substituted by ₁ C is -C ₆ alkyl; A compound according to embodiment A80 which is amino C ₁ -C ₆ alkyl, mono or dialkylamino C ₁ -C ₆ alkyl.

In this embodiment, R ₆ and R ₇ are not OH at the same time; It is preferred that R ₆ and R ₇ at the same time are not -S0 ₂ (C ₁ -C ₆ alkyl).

Embodiment A88.

R ₅ is independently C ₁ -C ₄ alkyl, —C (O) NR ₆ R ₇ , — (C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , halogen, C ₁ -C ₄ alkoxy, CO ₂ CH, C ₁ -C ₄ thioalkoxy, C ₁ -C ₄ alkoxycarbonyl, C ₁ -C ₆ hydroxyalkyl, CN, OH, NR ₈ R ₉ , NR ₆ R _7- (C ₁ -C ₆ As benzyl optionally substituted with 1, 2, 3, 4 or 5 groups which are alkyl)-, -SO ₂ (C ₁ -C ₆ alkyl) or benzyloxy;

Wherein R ₆ and R ₇ are independently at each occurrence H, OH, C ₁ -C ₆ alkyl, amino C ₁ -C ₄ alkyl, NH (C ₁ -C ₆ alkyl) alkyl, N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl or -SO ₂ (C ₁ -C ₆ alkyl Each independently represent 1, 2 or 3 groups which are halogen, OH, SH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, OH, CF ₃ or OCF ₃ A compound according to embodiment A87, which is optionally substituted.

In this embodiment, R ₆ and R ₇ are not OH at the same time; It is preferred that R ₆ and R ₇ at the same time are not -S0 ₂ (C ₁ -C ₆ alkyl).

Embodiment A89.

R ₅ is independently C ₁ -C ₄ alkyl, —C (O) NR ₆ R ₇ , — (C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , NR ₆ R _7- (C _1- C ₆ alkyl) -, NR ₈ R _9, halogen, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxycarbonyl, C ₁ - C ₆ hydroxyalkyl of 1 or CN, As benzyl optionally substituted with 2, 3, 4 or 5 groups;

Wherein R ₆ and R ₇ in each occurrence are independently H, OH, C ₁ -C ₆ alkyl, amino C ₁ -C ₄ alkyl, NH (C ₁ -C ₆ alkyl) alkyl, N (C ₁ -C ₆ Alkyl) (C ₁ -C ₆ alkyl) C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl or C ₁ -C ₄ alkoxy C ₁ -C ₄ alkyl, each independently halogen, OH, SH, A compound according to embodiment A80 optionally substituted with 1, 2 or 3 groups which are C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, OH, CF ₃ or OCF ₃ .

In this embodiment, it is preferable that R ₆ and R ₇ are not OH at the same time.

Embodiment A90.

A compound according to embodiment A89, wherein the R ₅ groups are disubstituted with two groups which are meta positions from one another.

Embodiment A91.

R ₅ is independently C ₁ -C ₄ alkyl, -C (O) NR ₆ R ₇ , -NR ₆ R ₇ , NR ₆ R ₇ (C ₁ -C ₆ alkyl), NR ₈ R ₉ , C ₁ -C ₆ hydroxyalkyl, halogen, C ₁ -C ₄ alkoxy, CO ₂ H, OH, C ₁ -C ₆ alkoxycarbonyl, carboxaldehyde, C ₁ -C ₄ haloalkyl,-(C ₁ -C ₄ alkyl) As phenyl optionally substituted with 1, 2, 3, 4 or 5 groups which is -NR ₁₅ C (O) NR ₁₆ R ₁₇ ,-(C ₁ -C ₄ alkyl) -NR ₁₅ C (O) R ₁₈ ;

Wherein R ₆ and R ₇ in each occurrence are independently H, OH, C ₁ -C ₆ alkyl, amino C ₁ -C ₄ alkyl, NH (C ₁ -C ₆ alkyl) alkyl, N (C ₁ -C ₆ Alkyl) (C ₁ -C ₆ alkyl) C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, -S0 ₂ (C ₁ -C ₆ alkyl) , -SO ₂ NH ₂ , -S0 ₂ NH (C ₁ -C ₆ alkyl), -SO ₂ N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) or C ₁ -C ₆ alkanoyl, Each independently is optionally substituted with 1, 2 or 3 groups which are halogen, OH, SH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, OH, CF ₃ or OCF ₃ ;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently piperidinyl, pyrrolidinyl, piperazinyl, optionally substituted by one or two groups which are alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen; To form a morpholinyl ring,

R ₁₅ is H or C ₁ -C ₆ alkyl;

R ₁₆ and R ₁₇ are independently H or C ₁ -C ₆ alkyl;

R ₁₆ , R ₁₇ , and the nitrogen to which they are attached form a morpholinyl ring;

R ₁₈ is -O- (C ₂ -C ₆₎ alkanoyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl optionally substituted by ₁ C is -C ₆ alkyl; A compound according to embodiment A78 which is amino C ₁ -C ₆ alkyl, mono or dialkylamino C ₁ -C ₆ alkyl.

In this embodiment, it is preferable that R ₆ and R ₇ are not OH at the same time.

Embodiment A92.

R ₅ is independently C ₁ -C ₄ alkyl,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , -C (O) NR ₆ R ₇ , -NR ₆ R ₇ , NR ₆ R ₇ (C ₁ -C ₆ alkyl), NR ₈ R ₉ , C ₁ -C ₆ hydroxyalkyl, halogen, C ₁ -C ₄ alkoxy, CO ₂ H, OH, C ₁ -C ₆ alkoxycarbonyl, carbox Aldehyde, C ₁ -C ₄ haloalkyl,-(C ₁ -C ₄ alkyl) -NR ₁₅ C (0) NR ₁₆ R ₁₇ ,-(C ₁ -C ₄ alkyl) -NR ₁₅ C (O) R ₁₈ phosphorus As phenyl optionally substituted with 1, 2, 3, 4 or 5 groups;

Wherein R ₆ and R ₇ in each occurrence are independently H, OH, C ₁ -C ₆ alkyl, amino C ₁ -C ₄ alkyl, NH (C ₁ -C ₆ alkyl) alkyl, N (C ₁ -C ₆ Alkyl) (C ₁ -C ₆ alkyl) C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, -S0 ₂ (C ₁ -C ₆ alkyl) , -SO ₂ NH ₂ , -SO ₂ NH (C ₁ -C ₆ alkyl), -SO ₂ N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) or C ₁ -C ₆ alkanoyl, Each independently is optionally substituted with 1, 2 or 3 groups which are halogen, OH, SH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, OH, CF ₃ or OCF ₃ ;

R ₁₅ is H or C ₁ -C ₆ alkyl;

R ₁₆ and R ₁₇ are independently H or C ₁ -C ₆ alkyl;

R ₁₆ , R ₁₇ , and the nitrogen to which they are attached form a morpholinyl ring;

R ₁₈ is -O- (C ₂ -C ₆₎ alkanoyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl optionally substituted by ₁ C is -C ₆ alkyl; A compound according to embodiment A91 which is amino C ₁ -C ₆ alkyl, mono or dialkylamino C ₁ -C ₆ alkyl.

Embodiment A93.

R ₁ halogen, methyl, ethyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl or carboxaldehyde;

R ₂ is benzyloxy, OH, phenyloxy, phenyloxy (C ₁ -C ₆ ) alkyl or phenyl (C ₁ -C ₄ ) thioalkoxy, each independently halogen,-(C ₁ -C ₆ ) alkyl- N (R) -CO ₂ R ₃₀ , NR ₆ R ₇ , (C ₁ -C ₄ ) haloalkyl, (C ₁ -C ₄ ) haloalkoxy, (C ₁ -C ₆ ) alkyl, pyridyl or NR ₆ R ₇ - (C ₁ -C ₆ alkyl) - 1, 2, 3 or 4 groups is optionally substituted;

R ₄ is H; Independently CO ₂ H, -CO ₂ alkyl, -C (O) NRR, -N (R ₃₀ ) C (O) NRR, -N (R ₃₀ ) C (0)-(C ₁ -C ₆ ) alkoxy or (C ₁ -C ₄ ) alkyl optionally substituted with 1 or 2 groups which is —NR ₆ R ₇ ; Or hydroxy (C ₁ -C ₄ ) alkyl.

Embodiment A94.

R ₅ is independently C ₁ -C ₄ alkyl, -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , -NR ₆ R ₇ , NR ₆ R ₇ (C ₁ -C ₆ alkyl), C ₁ -C ₆ hydroxyalkyl, halogen, C ₁ -C ₄ alkoxy, C0 ₂ H, OH, C ₁ -C ₆ alkoxycarbonyl, carboxaldehyde, C _1- Phenyl optionally substituted with 1, 2, 3, 4 or 5 groups which are C ₄ haloalkyl,

Wherein R ₆ and R ₇ in each occurrence are independently H, OH, C ₁ -C ₆ alkyl, amino C ₁ -C ₄ alkyl, NH (C ₁ -C ₆ alkyl) alkyl, N (C ₁ -C ₆ Alkyl) (C ₁ -C ₆ alkyl) C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, -SO ₂ (C ₁ -C ₆ alkyl) , -SO ₂ NH ₂ , -SO ₂ NH (C ₁ -C ₆ alkyl), -SO ₂ N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) or C ₁ -C ₆ alkanoyl, Each independently substituted with 1, 2 or 3 groups which are halogen, OH, SH, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, OH, CF ₃ or OCF ₃ A compound according to embodiment A93.

Embodiment A101.

R ₅ is thienyl (C ₁ -C ₆ alkyl), piperidinyl (C ₁ -C ₆ ) alkyl, pyrrolidinyl (C ₁ -C ₆ ) alkyl, imidazolidinyl (C ₁ -C ₆ ) alkyl , Piperazinyl (C ₁ -C ₆ ) alkyl, pyridyl (C ₁ -C ₆ ) alkyl, pyrimidyl (C ₁ -C ₆ ) alkyl, pyridazyl (C ₁ -C ₆ ) alkyl, pyrazinyl (C ₁ -C ₆ ) alkyl, isoquinolinyl (C ₁ -C ₆ ) alkyl, tetrahydroisoquinolinyl (C ₁ -C ₆ ) alkyl, indolyl (C ₁ -C ₆ ) alkyl, 1H-indazolyl (C ₁ -C ₆ ) alkyl, dihydroindolonyl (C ₁ -C ₆ alkyl), indolinyl (C ₁ -C ₆ alkyl), dihydroisoindolyl (C ₁ -C ₆ alkyl), dihydrobenz Imidazolyl (C ₁ -C ₆ alkyl) or dihydrobenzoimidazolonyl (C ₁ -C ₆ alkyl),

Wherein each independently represents (C ₁ -C ₆ ) alkyl, halogen, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) hydroxyalkyl, phenyl (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆₎ thioalkoxy, (C ₁ -C ₆₎ alkoxycarbonyl, phenyl (C ₁ - C ₆₎ alkoxycarbonyl, OH, CO ₂ H, CN, amidino oxime, NR ₈ R _9, NR ₆ R _7- (C ₁ -C ₆ alkyl)-, -C (0) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , amidino, piperazinyl, morpholi Nyl, -SO ₂ (C ₁ -C ₆ ) alkyl, -SO ₂ NH ₂ , -SO ₂ NH (C ₁ -C ₆ ) alkyl, -SO ₂ N (C ₁ -C ₆ ) alkyl (C ₁ -C ₆₎ alkyl, (C ₁ -C ₄₎ haloalkyl, - (C ₁ -C ₄ alkyl) -NR ₁₅ C (O) NR R _{l6 l7,} - (C ₁ -C ₄ alkyl) -NR ₁₅ C (O Substituted or unsubstituted with 1, 2, 3, 4 or 5 groups which are R ₁₈ , —O—CH ₂ —O, —O—CH ₂ CH ₂ —O—, or (C ₁ -C ₄ ) haloalkoxy;

Wherein R ₆ and R ₇ are independently at each occurrence H, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkoxy (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxycarbonyl, (C ₁ -C ₆ ) hydroxyalkyl,-(C ₁ -C ₄ ) alkyl-CO _2- (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ Alkanoyl, phenyl (C ₁ -C ₆ ) alkyl, phenyl (C ₁ -C ₆ ) alkoxy or phenyl (C ₁ -C ₆ ) alkanoyl, each independently halogen, (C ₁ -C ₄ ) Alkoxy, OH, SH, C ₃ -C ₆ cycloalkyl, NH ₂ , NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), (C ₁ -C ₄ ) substituted or unsubstituted with 1, 2 or 3 groups which are alkyl, CF ₃ or OCF ₃ ;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently morpholinyl, thiomorpholi, optionally substituted with 1 or 2 groups which are C ₁ -C ₄ alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen To form a silyl, piperidinyl, pyrrolidinyl or piperazinyl ring;

R ₁₈ is -O- (C ₂ -C ₆₎ alkanoyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl optionally substituted by ₁ C is -C ₆ alkyl; A compound according to embodiment A66 which is amino C ₁ -C ₆ alkyl, mono or dialkylamino C ₁ -C ₆ alkyl.

In this embodiment, R ₆ and R ₇ are not OH at the same time; It is preferred that R ₆ and R ₇ are not simultaneously —SO ₂ (C ₁ -C ₆ alkyl).

Embodiment A102.

R ₁ is halogen, methyl, ethyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl or carboxaldehyde;

R ₂ is benzyloxy, OH, phenyloxy, phenyloxy (C ₁ -C ₆ ) alkyl or phenyl (C ₁ -C ₄ ) thioalkoxy, each independently halogen,-(C ₁ -C ₆ ) alkyl- N (R) -CO ₂ R ₃₀ , NR ₆ R ₇ , (C ₁ -C ₄ ) haloalkyl, (C ₁ -C ₄ ) haloalkoxy, (C ₁ -C ₆ ) alkyl, pyridyl or NR ₆ R Optionally substituted by 1, 2, 3, 4 or 5 groups which are _7- (C ₁ -C ₆ alkyl)-;

R ₄ is H; Independently C0 ₂ H, -C0 ₂ alkyl, -C (O) NRR, -N (R ₃₀ ) C (O) NRR, -N (R ₃₀ ) C (O)-(C ₁ -C ₆ ) alkoxy or (C ₁ -C ₄ ) optionally substituted with 1 or 2 groups that is —NR ₆ R ₇ ; Or hydroxy (C ₁ -C ₄ ) alkyl.

Embodiment A103.

R ₅ is thienyl (C ₁ -C ₆ alkyl), indolyl (C ₁ -C ₆ alkyl), pyridinyl (C ₁ -C ₆ alkyl), piperazinyl (C ₁ -C ₆ alkyl) or pyrazinyl As (C ₁ -C ₆ alkyl), each independently C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, halogen, -C (0) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl ) -C (O) NR ₆ R ₇ , C ₁ -C ₆ alkoxycarbonyl, -NR ₆ R ₇ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-, haloalkyl, C ₁ -C ₆ alka Optionally substituted with 1, 2 or 3 groups which are noyl;

R ₆ and R ₇ are independently at each occurrence H; Or C ₁ -C ₆ alkyl optionally substituted with 1, 2 or 3 groups independently of C ₁ -C ₄ alkoxycarbonyl, halogen, C ₃ -C ₆ cycloalkyl, OH, SH or C ₁ -C ₄ alkoxy ;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently piperidinyl, pyrrolidinyl, piperazinyl, optionally substituted by one or two groups which are alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen; A compound according to embodiment A102, which forms a morpholinyl ring.

Embodiment A104.

R ₅ is thienyl (C ₁ -C ₆ alkyl), indolyl (C ₁ -C ₆ alkyl), pyridinyl (C ₁ -C ₆ alkyl), piperazinyl (C ₁ -C ₆ alkyl) or pyrazinyl A compound according to embodiment A103, which is (C ₁ -C ₆ alkyl).

Embodiment A105.

R ₄ is H, methyl, ethyl or —CH ₂ 0H;

R ₅ is pyridinyl (C ₁ -C ₆ alkyl) or pyrazinyl (C ₁ -C ₆ alkyl), each independently C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, halogen, -C (0) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , C ₁ -C ₆ alkoxycarbonyl, -NR ₆ R ₇ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-, CF ₃ , C ₁ -C ₆ alkanoyl optionally substituted with 1, 2 or 3 groups;

Wherein R ₆ and R ₇ are independently at each occurrence H; Or C ₁ -C ₆ alkyl optionally substituted with 1, 2 or 3 groups independently of C ₁ -C ₄ alkoxycarbonyl, halogen, C ₃ -C ₆ cycloalkyl, OH, SH or C ₁ -C ₄ alkoxy ;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently piperidinyl, pyrrolidinyl, piperazinyl, optionally substituted by one or two groups which are alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen; A compound according to embodiment A103, which forms a morpholinyl ring.

Embodiment A106.

R ₄ is H; Or independently CO ₂ H, -C0 _2- (C ₁ -C ₆ ) alkyl, -C (O) NRR, -N (R ₃₀ ) C (O) NRR, -N (R ₃₀ ) C (O)- A compound according to embodiment A105, which is (C ₁ -C ₆ ) alkoxy or alkyl substituted with one or two groups which is —NR ₆ R ₇ .

Embodiment A112.

R ₁ is halogen or methyl;

1, 2, 3 or 4 R ₂ is independently halogen, — (C ₁ -C ₆ ) alkyl-N (R) —CO ₂ R ₃₀ , CF ₃ , OCF ₃ or (C ₁ -C ₆ ) alkyl Benzyloxy optionally substituted by group;

A compound according to embodiment 16, wherein R ₄ is H, methyl, ethyl, —CH ₂ OH, —CH ₂ CO ₂ — (C ₁ -C ₄ alkyl) or C ₂ hydroxyalkyl.

Embodiment A113.

R ₁ is halogen or methyl;

1, 2, 3 or 4 R ₂ is independently halogen,-(C ₁ -C ₆ ) alkyl-N (R) -CO ₂ R ₃₀ , CF ₃ , OCF ₃ or (C ₁ -C ₄ ) alkyl Benzyloxy optionally substituted by group;

R ₄ is _{CO 2 H, -CO 2 - (} C 1 -C 6) alkyl, -C (O) NRR, -N (R 30) C (O) NRR, -N (R 30) C (O) - The compound according to any one of embodiments A85, A95, A97, A98, A99, A100, 16 and 17, which is (C ₁ -C ₆ ) alkoxy or alkyl substituted with one group -NR ₆ R ₇ .

Embodiment A114.

R ₅ is isoquinolinyl (C ₁ -C ₆ alkyl), tetrahydroisoquinolinyl (C ₁ -C ₆ alkyl), 1H-indazolyl (C ₁ -C ₆ alkyl), dihydroindolinyl ( C ₁ -C ₆ alkyl), indolinyl (C ₁ -C ₆ alkyl), dihydroisoindolyl (C ₁ -C ₆ alkyl), dihydrobenzimidazolyl (C ₁ -C ₆ alkyl), dihydrobenzo Imidazolonyl (C ₁ -C ₆ alkyl) (each independently alkyl; alkoxy; halogen; C ₁ -C ₆ alkoxycarbonyl; OH, NH ₂ , NH (C ₁ -C ₆ alkyl) and N (C Alkanoyl optionally substituted with 1 or 2 groups independently selected from the group consisting of ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl); -C (O) NR ₆ R ₇ ;-(C ₁ -C ₄ Alkyl) -C (O) NR ₆ R ₇ ; NR ₆ R _7- (C ₁ -C ₆ alkyl)-, -NR ₆ R ₇ ; or substituted or unsubstituted with 1, 2 or 3 groups, S0 ₂ H) ; Or independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen, -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , NR ₆ Is a piperidinyl C ₁ -C ₄ alkyl optionally substituted with 1, 2 or 3 groups which are R _7- (C ₁ -C ₆ alkyl)-or —NR ₆ R ₇ , or C ₁ -C ₆ alkoxycarbonyl A compound according to embodiment A66.

Embodiment A115.

R ₅ is isoquinolinyl (C ₁ -C ₄ alkyl), piperidinyl C ₁ -C ₄ alkyl, tetrahydroisoquinolinyl (C ₁ -C ₄ alkyl), 1H-indazolyl (C ₁ -C ₄ alkyl), dihydroindolonyl (C ₁ -C ₄ alkyl), indolinyl (C ₁ -C ₄ alkyl), dihydroisoindolyl (C ₁ -C ₄ alkyl), dihydrobenzimidazolyl (C _A compound according to embodiment A114, which is _1- C ₄ alkyl) or dihydrobenzoimidazolonyl (C ₁ -C ₄ alkyl).

Embodiment A116.

R ₅ is independently piperidinyl C ₁ -C ₄ alkyl optionally substituted with 1, 2 or 3 groups which are C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, halogen or C ₁ -C ₆ alkoxycarbonyl A compound according to embodiment A114.

Embodiment A117.

R ₅ is pyrimidyl, indolinyl, indolyl, 1H-isoindolyl, isoquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, dihydro-1H-benzimidazolyl, pyrrolyl, imida Zolyl (each independently C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₄ thioalkoxy (each independently -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C ( O) NR ₆ R ₇ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-, -NR ₆ R ₇ , alkyl, alkoxy, halogen, C ₁ -C ₆ alkoxycarbonyl, or OH, NH ₂ , NH 1, 2 or 3, which is an alkanoyl optionally substituted with one or two groups independently selected from the group consisting of (C ₁ -C ₆ alkyl) and N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) Unsubstituted or substituted with 1 group) and optionally substituted with 1, 2 or 3 groups independently selected from the group consisting of SO ₂ H); Or pyridyl, pyrazolyl (independently -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , NR ₆ R _7- (C ₁ -C ₆ alkyl )-, -NR ₆ R ₇ , C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, halogen, C ₁ -C ₆ alkoxycarbonyl, -NR ₆ R ₇ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-, CF ₃ , optionally substituted with 1, 2 or 3 groups which are C ₁ -C ₆ alkanoyl),

Wherein R ₆ and R ₇ in each occurrence are independently H, or independently _{1, which} is C ₁ -C ₄ alkoxycarbonyl, halogen, C ₃ -C ₆ cycloalkyl, OH, SH or C ₁ -C ₄ alkoxy; C ₁ -C ₆ alkyl optionally substituted with 2 or 3 groups;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently piperidinyl, pyrrolidinyl, piperazinyl, optionally substituted by one or two groups which are alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen; A compound according to embodiment A66, which forms a morpholinyl ring.

Embodiment A118.

R ₅ is pyrimidyl, pyrrolyl, imidazolyl or pyrazolyl, each independently C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₄ thioalkoxy (each independently alkyl, alkoxy, halogen, C ₁ -C ₆ alkoxycarbonyl, -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , NR ₆ R _7- (C ₁ -C ₆ alkyl)- Or substituted or unsubstituted with 1, 2 or 3 groups being -NR ₆ R ₇ ), or OH, NH ₂ , NH (C ₁ -C ₆ alkyl) and N (C ₁ -C ₆ alkyl) (C ₁ -C C ₁ -C ₄ alkanoyl optionally substituted with 1 or 2 groups independently selected from the group consisting of ₆ alkyl), or in embodiment A117 optionally substituted with 1, 2 or 3 groups independently selected from S0 ₂ H According to the compound.

Embodiment All9.

R ₅ is pyridyl or pyrazolyl, each independently C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, halogen, -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl ) -C (O) NR ₆ R ₇ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-or -NR ₆ R ₇ , C ₁ -C ₆ alkoxycarbonyl, -NR ₆ R ₇ , NR ₆ R Optionally substituted with 1, 2 or 3 groups which are _7- (C ₁ -C ₆ alkyl)-, CF ₃ , C ₁ -C ₆ alkanoyl,

Wherein R ₆ and R ₇ in each occurrence are independently H, or independently _{1, which} is C ₁ -C ₄ alkoxycarbonyl, halogen, C ₃ -C ₆ cycloalkyl, OH, SH or C ₁ -C ₄ alkoxy; C ₁ -C ₆ alkyl optionally substituted with 2 or 3 groups;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently piperidinyl, pyrrolidinyl, piperazinyl, optionally substituted by one or two groups which are alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen; A compound according to embodiment A117, which forms a morpholinyl ring.

Embodiment A120.

R ₅ is pyridyl or pyrazolyl, each independently C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, halogen, -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl ) -C (O) NR ₆ R ₇ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-, -NR ₆ R ₇ , C ₁ -C ₆ alkoxycarbonyl, CF ₃ , C ₁ -C ₆ alka Optionally substituted with 1, 2 or 3 groups which are nil,

Wherein R ₆ and R ₇ in each occurrence are independently H, or independently _{1, which} is C ₁ -C ₄ alkoxycarbonyl, halogen, C ₃ -C ₆ cycloalkyl, OH, SH or C ₁ -C ₄ alkoxy; A compound according to embodiment A119, which is C ₁ -C ₆ alkyl optionally substituted with 2 or 3 groups.

Embodiment A121.

R ₅ is pyridyl or pyrazolyl, each independently C ₁ -C ₄ alkyl, C ₁ -C ₄ hydroxyalkyl, halogen, -C (O) NR ₆ R ₇ ,-(C ₁ -C ₄ alkyl ) -C (O) NR ₆ R ₇ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-, -NR ₆ R ₇ , C ₁ -C ₆ alkoxycarbonyl, CF ₃ , C ₁ -C ₆ alka Optionally substituted with 1, 2 or 3 groups which are noyl;

Wherein R ₆ , R ₇ , and the nitrogen to which they are attached are independently piperidinyl, pyrrolidinyl, pipera optionally substituted with one or two groups which are alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen A compound according to embodiment A119, which forms a genyl or morpholinyl ring.

Embodiment A122.

R ₁ is halogen, methyl, ethyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl or carboxaldehyde;

R ₂ is benzyloxy, OH, phenyloxy, phenyloxy (C ₁ -C ₆ ) alkyl or phenyl (C ₁ -C ₄ ) thioalkoxy, each independently halogen,-(C ₁ -C ₆ ) alkyl- N (R) -CO ₂ R ₃₀ , NR ₆ R ₇ , (C ₁ -C ₄ ) haloalkyl, (C ₁ -C ₄ ) haloalkoxy, (C ₁ -C ₆ ) alkyl, pyridyl or NR ₆ R ₇ - (C ₁ -C ₆ alkyl) - of one, two, three or four groups being optionally substituted;

R ₄ is H; CO ₂ H, -CO _2- (C ₁ -C ₆ ) alkyl, -C (O) NRR, -N (R ₃₀ ) C (O) NRR, -N (R ₃₀ ) C (O)-(C ₁ (C ₁ -C ₄ ) alkyl substituted with one group which is —C ₆ ) alkoxy or —NR ₆ R ₇ ; Or a hydroxy (C ₁ -C ₄ ) alkyl compound according to any one of embodiments A114, A115, A116 and A117.

Embodiment A123.

R ₅ is independently C ₁ -C ₄ alkoxycarbonyl or C ₁ -C ₆ alkyl optionally substituted with 1 or 2 groups which are halogen, or

R ₅ is C ₁ -C ₄ alkoxy, ethyl, methyl, cyclopropylmethyl, cycloalkyl or alkynyl, or

The compound according to embodiment A66, wherein R ₅ is C ₂ -C ₆ alkenyl optionally substituted with C ₁ -C ₄ alkoxycarbonyl or cyclohexyl.

Embodiment A124.

R ₁ is halogen, methyl, ethyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl or carboxaldehyde;

R ₂ is benzyloxy, OH, phenyloxy, phenyloxy (C ₁ -C ₆ ) alkyl or phenyl (C ₁ -C ₄ ) thioalkoxy, each independently halogen,-(C ₁ -C ₆ ) alkyl- N (R) -C0 ₂ R ₃₀ , NR ₆ R ₇ , (C ₁ -C ₄ ) haloalkyl, (C ₁ -C ₄ ) haloalkoxy, (C ₁ -C ₆ ) alkyl, pyridyl or NR ₆ R ₇ - (C ₁ -C ₆ alkyl) - of one, two, three or four groups being optionally substituted;

R ₄ is H; CO ₂ H, -CO _2- (C ₁ -C ₆ ) alkyl, -C (O) NRR, -N (R ₃₀ ) C (0) NRR, -N (R ₃₀ ) C (O)-(C ₁ (C ₁ -C ₄ ) alkyl substituted with one group which is —C ₆ ) alkoxy or —NR ₆ R ₇ ; Or hydroxy (C ₁ -C ₄ ) alkyl,

Wherein R ₆ and R ₇ are independently at each occurrence H; Or C ₁ -C ₆ alkyl optionally substituted with 1, 2 or 3 groups independently of C ₁ -C ₄ alkoxycarbonyl, halogen, C ₃ -C ₆ cycloalkyl, OH, SH or C ₁ -C ₄ alkoxy ;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently piperidinyl, pyrrolidinyl, piperazinyl, optionally substituted by one or two groups which are alkyl, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen; A compound according to embodiment A123, which forms a morpholinyl ring.

Embodiment A125.

R ₅ is independently C ₁ -C ₄ alkoxycarbonyl or C ₁ -C ₆ alkyl optionally substituted with 1 or 2 groups which are halogen, or

R ₅ is C ₁ -C ₄ alkoxy, ethyl, methyl, cyclopropylmethyl, cyclohexyl, cyclopentyl, C ₂ -C ₆ alkynyl, or

A compound according to embodiment A124, wherein R ₅ is C ₂ -C ₆ alkenyl optionally substituted with C ₁ -C ₄ alkoxycarbonyl or cyclohexyl.

Embodiment A126.

R ₂ is phenylalkynyl, -OC (O) NH (CH ₂ ) _n aryl, -OC (O) N (alkyl) (CH ₂ ) _n aryl, -OSO ₂ (C ₁ -C ₆ ) alkyl, -OSO ₂ aryl or NR ₈ R ₉

Where n is 0, 1, 2, 3, 4, 5 or 6;

Each independently represents halogen,-(C ₁ -C ₆ ) alkyl-N (R) -CO ₂ R ₃₀ , alkoxy, alkoxycarbonyl, CN, NR ₆ R ₇ , haloalkyl, haloalkoxy, alkyl, heteroaryl, Heteroarylalkyl, NR ₆ R _7- (C ₁ -C ₆ alkyl)-, phenyl, -SO ₂ -phenyl, wherein the phenyl group is optionally substituted with 1, 2 or 3 groups independently of halogen or NO ₂ , Or substituted or unsubstituted with 1, 2, 3, 4 or 5 groups, which is -OC (O) NR ₆ R ₇ ,

Wherein R ₆ and R ₇ are independently at each occurrence H, alkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, SO ₂ -alkyl, OH, hydroxyalkyl,-(C ₁ -C ₄ ) alkyl-CO _2- Alkyl, heteroarylalkyl, alkanoyl, arylalkyl, arylalkoxy or arylalkanoyl, each independently, halogen, alkoxy, heterocycloalkyl, OH, NH ₂ , C ₃ -C ₆ cycloalkyl, NH (alkyl) Or substituted or unsubstituted with 1, 2 or 3 groups which are N (alkyl) (alkyl), —0-alkanoyl, alkyl, C ₁ -C ₄ haloalkyl or C ₁ -C ₄ haloalkoxy;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently substituted with 1 or 2 groups which are independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen A compound according to embodiment A66, which forms a morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl or piperazinyl ring.

Embodiment A127.

R ₁ is halogen, methyl, ethyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl or carboxaldehyde;

R ₄ is H, or _{C0 2 H, -CO 2 - (} C 1 -C 6) alkyl, -C (O) NRR, -N (R 30) C (O) NRR, -N (R 30) C ( Substituted with one group which is 0)-(C ₁ -C ₆ ) alkoxy, -NR ₆ R ₇ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-or hydroxy (C ₁ -C ₄ ) alkyl ( A compound according to embodiment A126, which is C ₁ -C ₄ ) alkyl.

Embodiment A128.

R ₅ is independently halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, CF ₃ , OCF ₃ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , NR ₆ R ₇ - (C ₁ -C ₆ alkyl) -, a -NR ₆ R ₇ or C (O) NR ₆ R ₇ is 1, 2, 3, 4, or 5 groups that are optionally substituted phenyl,

Wherein R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycarbonyl , OH, C ₁ -C ₆ hydroxyalkyl,-(C ₁ -C ₄ ) alkyl-CO ₂ -alkyl, pyridyl C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl, benzyl, phenyl C _1- C ₆ alkoxy or phenyl C ₁ -C ₆ alkanoyl, wherein each independently, halogen, C ₁ -C ₆ alkoxy, piperidinyl C ₁ -C ₆ alkyl, morpholinyl C ₁ -C ₆ alkyl, p Ferrazinyl C ₁ -C ₆ alkyl, OH, SH, C ₃ -C ₆ cycloalkyl, NH ₂ , NH (alkyl), N (alkyl) (alkyl), —OC ₁ -C ₄ alkanoyl, C ₁ -C Substituted or unsubstituted with 1, 2 or 3 groups which are ₄ alkyl, CF ₃ or OCF ₃ ;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently substituted with 1 or 2 groups which are independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen To form a morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl or piperazinyl ring;

R ₅ is independently halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, CN, CF ₃ , OCF ₃ ,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , NR ₆ R ₇ - (C ₁ -C ₆ alkyl) -, -NR ₆ R ₇ or C (O) NR ₆ R ₇ is 1, the compounds according to 2, 3, 4, or 5 groups that are optionally substituted benzyl embodiment A127 .

Embodiment A129.

R ₂ is NR ₈ R ₉ or NR ₈ R _9- (C ₁ -C ₄ alkyl)-;

Wherein R ₈ in each occurrence is independently hydrogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl, phenyl (C ₁ -C ₆ ) alkyl or phenyl (C ₁ -C ₆ ) alkanoyl, each Is optionally substituted with 1, 2, 3, 4 or 5 groups which are independently C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxycarbonyl, halogen or C ₁ -C ₄ haloalkyl ;

R ₉ independently in each occurrence is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl, phenyl (C ₁ -C ₆ ) alkyl, C ₃ -C ₇ cycloalkyl, C ₂ -C ₆ alkenyl, pyri Dill, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, C ₃ -C ₇ cycloalkyl (C ₁ -C ₆ ) alkyl, phenyl (C ₁ -C ₆ ) alkanoyl, -SO ₂ -phenyl and As phenyl, each independently 1, 2, 3, 4 or 5 is C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxycarbonyl, halogen or C ₁ -C ₄ haloalkyl A compound according to embodiment A128, optionally substituted by group.

Embodiment A130.

A compound according to embodiment A129, wherein R ₈ is H.

Embodiment A131.

R ₂ is independently —NH-benzyl, optionally substituted with 1, 2 or 3 groups being halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, CF ₃ , OCF ₃ , or

R ₂ is —NH—C (O) phenyl, wherein the phenyl group is optionally substituted with 1, 2 or 3 groups independently of halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy,

A compound according to embodiment A130, wherein R ₂ is -NH-allyl.

Embodiment A132.

R ₁ is chloro, bromo, iodo or methyl;

R ₅ is independently halogen,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-, -NR ₆ R ₇ , C _1- A compound according to embodiment A131 which is benzyl optionally substituted with 1, 2, 3, 4 or 5 groups being C ₆ alkyl, C ₁ -C ₆ alkoxy, CN, CF ₃ , OCF ₃ or C (O) NR ₆ R ₇ .

Embodiment A133.

R ₁ is chloro, bromo, iodo or methyl;

R ₅ is independently halogen,-(C ₁ -C ₄ alkyl) -C (O) NR ₆ R ₇ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-, -NR ₆ R ₇ , C _1- A compound according to embodiment A131 which is C ₄ alkyl, C ₁ -C ₄ alkoxy, CF ₃ , OCF ₃ or phenyl optionally substituted with 1, 2, 3, 4 or 5 groups, which is C (O) NR ₆ R ₇ .

Embodiment A134.

의 화합물 또는 제약상 허용되는 그의 염.Chemical formula

Or a pharmaceutically acceptable salt thereof.

In the above formula,

이고,R ₅ is

ego,

Wherein X ₁ , X ₂ , X _a , X _b , X _c , X _d and X _e are independently —C (O) NR ₆ R ₇ , -NR ₆ R ₇ , hydroxy (C ₁ -C ₄ ) Alkyl, H, OH, halogen, haloalkyl, alkyl, haloalkoxy, heteroaryl, heterocycloalkyl, C ₃ -C ₇ cycloalkyl, NR ₆ R _7- (C ₁ -C ₆ alkyl)-, -CO _2- (C ₁ -C ₆ ) alkyl, -N (R) C (O) NR ₆ R ₇ , -N (R) C (O)-(C ₁ -C ₆ ) alkoxy, C0 ₂ H- (C _1- C ₆ alkyl)-or —SO ₂ NR ₆ R ₇ ;

Wherein the heteroaryl and heterocycloalkyl groups are -NR ₆ R ₇ , -C (O) NR ₆ R ₇ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-, C ₁ -C ₆ alkyl, C _1- Optionally substituted with C ₆ alkoxy or halogen;

R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycarbonyl, OH, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ thiohydroxyalkyl,-(C ₁ -C ₄ ) alkyl-CO ₂ -alkyl, pyridyl C ₁ -C ₆ alkyl, C ₁ -C ₆ Alkanoyl, benzyl, phenyl C ₁ -C ₆ alkoxy or phenyl C ₁ -C ₆ alkanoyl, wherein each independently is halogen, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, piperidinyl C ₁ -C ₆ alkyl, morpholinyl C ₁ -C ₆ alkyl, piperazinyl C ₁ -C ₆ alkyl, OH, SH, NH _2, NH (alkyl), N (alkyl) (alkyl), -OC _l - Substituted or unsubstituted with 1, 2 or 3 groups which are C ₄ alkanoyl, C ₁ -C ₄ alkyl, CF ₃ or OCF ₃ ;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently substituted with 1 or 2 groups which are independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen To form a morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl or piperazinyl ring;

R is independently at each occurrence H or C ₁ -C ₆ alkyl;

Y, Y ₁ , Y ₂ , Y ₃ and Y ₄ are independently H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, alkenyl, alkynyl, CN, alkanoyl, alkoxy, alkoxyalkyl, haloalkyl and car Is selected from the compound.

Embodiment A135.

Y ₂ , Y ₄ and Y are independently halogen; A compound according to embodiment A134, wherein Y ₁ and Y ₃ are both hydrogen.

Embodiment A136.

X ₁ is H, methyl, -NR ₆ R ₇ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-, -C (O) NR ₆ R ₇ , C ₁ -C ₆ hydroxyalkyl or-(C _A compound according to embodiment A135, which is ₁ -C ₄ alkyl) -morpholinyl.

Embodiment A137.

_A compound according to embodiment A136, wherein X _a and X _e are independently halogen, NH ₂ , NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) or methyl.

Embodiment A138.

X _b or X _c is —NR ₆ R ₇ , NR ₆ R ₇ — (C ₁ -C ₆ alkyl)-, —C (O) NR ₆ R ₇ , —SO ₂ NR ₆ R ₇ or halogen;

Wherein R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycar Bonyl, OH, C ₁ -C ₆ hydroxyalkyl,-(C ₁ -C ₄ ) alkyl-C0 ₂ -alkyl, pyridyl C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl, benzyl, phenyl C ₁ -C ₆ alkoxy or phenyl C ₁ -C ₆ alkanoyl, wherein each independently, halogen, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, piperidinyl C ₁ -C ₆ alkyl, morpholin Neyl C ₁ -C ₆ alkyl, piperazinyl C ₁ -C ₆ alkyl, OH, SH, NH ₂ , NH (alkyl), N (alkyl) (alkyl), —OC ₁ -C ₄ alkanoyl, C _1- Substituted or unsubstituted with 1, 2 or 3 groups which are C ₄ alkyl, CF ₃ or OCF ₃ ;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently substituted with 1 or 2 groups which are independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen A compound according to embodiment A137, which forms a morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl or piperazinyl ring.

Embodiment A139.

R ₆ , R ₇ , and the nitrogen to which they are attached are optionally substituted with one or two groups which are independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen A compound according to embodiment A138, which forms a morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl ring.

Embodiment A140.

R ₆ , R ₇ , and the nitrogen to which they are attached are optionally substituted with one or two groups which are independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen A compound according to embodiment A138, which forms a piperazinyl ring.

Embodiment A141.

R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycarbonyl, OH, C ₁ -C ₆ hydroxyalkyl,-(C ₁ -C ₄ ) alkyl-CO ₂ -alkyl, pyridyl C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl, benzyl, phenyl C ₁ -C ₆ alkoxy or phenyl C ₁ -C ₆ alkanoyl, each independently, halogen, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, piperidinyl C ₁ -C ₆ alkyl, morpholinyl C ₁ -C ₆ alkyl, piperazinyl C ₁ -C ₆ alkyl, OH, NH ₂ , NH (alkyl), N (alkyl) (alkyl), -OC ₁ -C ₄ alkanoyl, C ₁ -C ₄ alkyl, CF _A compound according to embodiment A138, which is unsubstituted or substituted with 1, 2 or 3 groups which are ₃ or OCF ₃ .

Embodiment A142.

R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₆ alkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl or C _A compound according to embodiment A138, which is optionally substituted with 1, 2 or 3 groups, which are _1- C ₆ alkanoyl, each independently OH, SH, halogen, or C ₃ -C ₆ cycloalkyl.

Embodiment A143.

X _a and X _e are independently fluoro, chloro or methyl; A compound according to embodiment A137, wherein X _c is hydrogen or halogen.

Embodiment A144.

X _a is halogen;

X _e is NH ₂ , NH (C ₁ -C ₆ alkyl) or N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl);

A compound according to embodiment A137, wherein X _b and X _d are both hydrogen.

Embodiment A145.

X _c is —NR ₆ R ₇ , NR ₆ R ₇ C ₁ -C ₆ alkyl, —SO ₂ NR ₆ R ₇ or halogen;

Wherein R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycar Bonyl, OH, C ₁ -C ₆ hydroxyalkyl,-(C ₁ -C ₄ ) alkyl-CO ₂ -alkyl, pyridyl C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl, benzyl, phenyl C ₁ -C ₆ alkoxy or phenyl C ₁ -C ₆ alkanoyl, wherein each independently, halogen, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, piperidinyl C ₁ -C ₆ alkyl, mor Polyyl C ₁ -C ₆ alkyl, piperazinyl C ₁ -C ₆ alkyl, OH, SH, NH ₂ , NH (alkyl), N (alkyl) (alkyl), -OC ₁ -C ₄ alkanoyl, C ₁ Substituted or unsubstituted with 1, 2 or 3 groups which are —C ₄ alkyl, CF ₃ or OCF ₃ ;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently substituted with 1 or 2 groups which are independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen A compound according to embodiment A144, which forms a morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl or piperazinyl ring.

Embodiment A146.

X _c is fluoro, chloro, NH ₂ , NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), -SO ₂ NH ₂ , -SO ₂ NH ( C ₁ -C ₆ alkyl), —S0 ₂ N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) or piperazinyl, wherein the piperazinyl group is independently C ₁ -C ₄ alkyl, C _A compound according to embodiment A145, which is optionally substituted with 1 or 2 groups which are ₁ -C ₄ alkoxy, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen.

Embodiment A147.

X _c is -C (O) NR ₆ R ₇ ,-(C ₁ -C ₆ alkyl) -C (O) NR ₆ R ₇ , NR ₆ R ₇ or NR ₆ R _7- (C ₁ -C ₆ alkyl) -;

Wherein R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycar Bonyl, OH, C ₁ -C ₆ hydroxyalkyl,-(C ₁ -C ₄ ) alkyl-C0 ₂ -alkyl, pyridyl C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl, benzyl, phenyl C ₁ -C ₆ alkoxy or phenyl C ₁ -C ₆ alkanoyl, each independently, halogen, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, piperidinyl C ₁ -C ₆ alkyl, morpholinyl C ₁ -C ₆ alkyl, piperazinyl C ₁ -C ₆ alkyl, OH, NH ₂ , NH (alkyl), N (alkyl) (alkyl), —OC ₁ -C ₄ alkanoyl, C ₁ -C ₄ alkyl Or substituted or unsubstituted with 1, 2 or 3 groups which are CF ₃ or OCF ₃ ;

R ₆ , R ₇ and the nitrogen to which they are attached are independently substituted with one or two groups which are independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen. A compound according to embodiment A137 or A144, which forms a polyyl, thiomorpholinyl, piperidinyl, pyrrolidinyl or piperazinyl ring.

Embodiment A148.

R ₆ is hydrogen;

R ₇ is C ₁ -C ₆ alkyl or C ₁ -C ₆ alkanoyl, each independently NH ₂ , NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), OH, SH, cyclopropyl, or a compound according to embodiment A147 optionally substituted with 1, 2 or 3 groups which are C ₁ -C ₄ alkoxy.

Embodiment A148a.

A compound according to embodiment A148, wherein R ₇ is independently C ₁ -C ₆ alkanoyl optionally substituted with 1, 2 or 3 groups, which are independently OH, cyclopropyl or NH ₂ .

Embodiment A149.

X _a is hydrogen;

X _b , X _c or X _d is -C (O) NR ₆ R ₇ ,-(C ₁ -C ₆ alkyl) -C (O) NR ₆ R ₇ , NR ₆ R ₇ , NR ₆ R _7- (C _{As 1-} C ₆ alkyl)-or -CO _2- (C ₁ -C ₆ ) alkyl;

Wherein R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycarbonyl , OH, C ₁ -C ₆ hydroxyalkyl,-(C ₁ -C ₄ ) alkyl-C0 ₂ -alkyl, pyridyl C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl, benzyl, phenyl C _1- C ₆ alkoxy or phenyl C ₁ -C ₆ alkanoyl, wherein each independently, halogen, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, piperidinyl C ₁ -C ₆ alkyl, morpholinyl C ₁ -C ₆ alkyl, piperazinyl C ₁ -C ₆ alkyl, OH, NH ₂ , NH (alkyl), N (alkyl) (alkyl), —OC ₁ -C ₄ alkanoyl, C ₁ -C ₄ alkyl Or substituted or unsubstituted with 1, 2 or 3 groups which are CF ₃ or OCF ₃ ;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently substituted with 1 or 2 groups which are independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen To form a morpholinyl, piperidinyl, pyrrolidinyl or piperazinyl ring;

X _e is a compound according to embodiment A135 wherein hydrogen, methyl, C ₁ -C ₂ alkoxy or halogen.

Embodiment A150.

X _b is NR ₆ R ₇ or NR ₆ R _7- (C ₁ -C ₆ alkyl)-, —C (O) NR ₆ R ₇ or —CO ₂ — (C ₁ -C ₆ ) alkyl;

Wherein R ₆ is hydrogen or C ₁ -C ₄ alkyl;

R ₇ is OH, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkanoyl, wherein the alkyl and alkanoyl groups are independently NH ₂ , NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl ) A compound according to embodiment A149, which is substituted with 1, 2 or 3 groups which are (C ₁ -C ₆ alkyl), C ₃ -C ₆ cycloalkyl, OH or C ₁ -C ₄ alkoxy.

Embodiment A151.

X _a is halogen;

X _b is NR ₆ R ₇ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-, —C (O) NR ₆ R ₇ or —CO ₂ — (C ₁ -C ₆ ) alkyl;

X _c is NR ₆ R ₇ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-, -C (O) NR ₆ R ₇ , halogen, -CO _2- (C ₁ -C ₆ ) alkyl, NH ₂ , NH (C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl), -SO ₂ NH ₂ , -SO ₂ NH (C ₁ -C ₆ alkyl), -SO ₂ N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) or piperazinyl, wherein the piperazinyl group is independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, hydroxide Optionally substituted with one or two groups that are hydroxy C ₁ -C ₄ alkyl or halogen;

X _d is hydrogen;

A compound according to embodiment A137, wherein X _e is H, methyl, NH ₂ , NH (C ₁ -C ₆ alkyl) or N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl).

Embodiment A152.

X ₁ , X ₂ , X _a , X _b , X _c , X _d and X _e are independently H, OH, halogen, CF ₃ , alkyl, OCF ₃ , pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, Thienyl, furyl, pyrrolyl, piperidinyl, piperazinyl or C ₃ -C ₇ cycloalkyl, wherein each is -NR ₆ R ₇ , -C (O) NR ₆ R ₇ , NR ₆ R ₇ - (C ₁ -C ₆ alkyl) -, C ₁ -C ₆ alkyl compounds according to embodiment A135 which is optionally substituted by C ₁ -C ₆ alkoxy or halogen.

Embodiment A153.

A compound according to embodiment A152, wherein at least three of X ₁ , X ₂ , X _a , X _b , X _c , X _d and X _e are hydrogen.

Embodiment A154.

의 화합물 또는 제약상 허용되는 그의 염.Chemical formula

Or a pharmaceutically acceptable salt thereof.

In the above formula,

R ₁ is an alkanoyl, halogen, arylalkanoyl, arylalkyl, alkoxyalkyl, hydroxyalkyl or carboxaldehyde,

The aryl moiety of arylalkyl and arylalkanoyl is independently 1, 2, 3, 4 or halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO ₂ H Substituted or unsubstituted with 5 groups;

The alkyl moiety of the hydroxyalkyl, arylalkyl, alkanoyl, alkoxyalkyl and arylalkanoyl groups is independently substituted or unsubstituted with 1, 2 or 3 groups which are halogen, methoxy, ethoxy or spirocyclopropyl;

R ₂ is arylalkoxy, aryloxy, phenyloxy (C ₁ -C ₆ ) alkyl, OH, halogen, arylthioalkoxy, alkoxy, -OC (O) NH (CH ₂ ) _n aryl, -OC (0) N ( Alkyl) (CH ₂ ) _n aryl, alkyl, alkoxyalkoxy, dialkylamino, pyridyl, pyrimidyl, pyridazyl, pyrazolyl, imidazolyl, pyrrolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, Tetrazolyl, pyrazinyl, benzimidazolyl, triazinyl, tetrahydrofuryl, piperidinyl, hexahydropyrimidinyl, thiazolyl, thienyl or CO ₂ H,

Where n is 0, 1, 2, 3, 4, 5 or 6;

The aryl moieties or heteroaryl and heterocycloalkyl groups of arylalkoxy, aryloxy, arylthioalkoxy, -OC (0) NH (CH ₂ ) _n aryl and -OC (O) N (alkyl) (CH ₂ ) _n aryl are independent by halogen, - (C ₁ -C ₆₎ alkyl, _{-N (R) -CO 2 R 30} , haloalkyl, heteroaryl, _{heteroaryl-alkyl, NR 6 R 7, NR 6} R 7 - (C 1 -C 6 alkyl )-, -OC (O) NR ₆ R ₇ is substituted or unsubstituted with 1, 2, 3, 4 or 5 groups,

Wherein R ₆ and R ₇ are independently at each occurrence H, alkyl, alkoxy, alkanoyl, arylalkyl, arylalkoxy or arylalkanoyl, wherein each independently is halogen, OH, SH, C ₃ -C ₆ Substituted or unsubstituted with 1, 2 or 3 groups which are cycloalkyl, alkoxy, alkyl, haloalkyl or haloalkoxy;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently morpholinyl, thiomorpholinyl, optionally substituted with 1 or 2 groups, which are C ₁ -C ₄ alkyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl or halogen , Thiomorpholinyl S-oxide, thiomorpholinyl S, S-dioxide, piperidinyl or piperazinyl ring;

R in each occurrence is independently H or C ₁ -C ₆ alkyl;

R ₃₀ is independently C ₁ -C ₆ alkyl optionally substituted with one or two groups which are OH, SH, halogen, amino, monoalkylamino, dialkylamino or C ₃ -C ₆ cycloalkyl;

R ₃ is halogen, arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl, -OC (O) NH (CH ₂ ) _n aryl, arylalkoxy, -OC (0) N (alkyl) (CH ₂ ) _n aryl, Aryloxy, arylthio, thioalkoxy, arylthioalkoxy, alkenyl, NR ₆ R ₇ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-or alkyl, wherein arylalkoxycarbonyl, aryloxycarbonyl , Arylalkyl, -OC (O) NH (CH ₂ ) _n aryl, arylalkoxy, -OC (0) N (alkyl) (CH ₂ ) _n aryl and aryl moieties of arylthioalkoxy are independently halogen, alkoxy Or substituted or unsubstituted with 1, 2 or 3 groups which are alkyl, haloalkyl or haloalkoxy, where n is 0, 1, 2, 3, 4, 5 or 6;

R ₄ is H; CO ₂ H, -CO _2- (C ₁ -C ₆ ) alkyl, -C (O) NRR, -N (R ₃₀ ) C (O) NRR, -N (R ₃₀ ) C (O)-(C ₁ -C ₆ ) alkoxy and alkyl substituted with one group selected from -NR ₆ R ₇ ; Arylalkoxy; Arylalkyl; Hydroxyalkyl; Haloalkyl; Alkoxy; Alkoxyalkyl; Or as alkoxyalkoxy,

Wherein the aryl portion of arylalkoxy and arylalkyl is independently substituted or unsubstituted with 1, 2, 3, 4 or 5 groups which are halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl or haloalkoxy;

R ₅ is arylalkyl, alkyl, aryl, alkoxy, heterocycloalkylalkyl, heteroarylalkyl, arylthioalkyl, heterocycloalkyl or heteroaryl,

Wherein each independently alkyl, halogen, alkoxy, arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, CO ₂ H, CN, amidinooxime, NR ₆ R ₇ , NR ₆ R _7- (C ₁ Unsubstituted or substituted with 1, 2, 3, 4 or 5 groups which are -C ₆ alkyl)-, -C (O) NR ₆ R ₇ , amidino, haloalkyl or haloalkoxy.

Embodiment A160.

R ₁ is halogen, (C ₁ -C ₆ ) alkanoyl, phenyl (C ₁ -C ₆ ) alkanoyl, naphthyl (C ₁ -C ₆ ) alkanoyl, naphthyl (C ₁ -C ₆ ) alkyl, phenyl (C ₁ -C ₆ ) alkyl, alkoxyalkyl, hydroxyalkyl or carboxaldehyde,

Their phenyl and naphthyl moieties are independently 1, 2, 3, 4 or 5 halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, nitro, CN, CF ₃ , OCF ₃ or C0 ₂ H Substituted or unsubstituted with a group;

Their alkyl moieties are unsubstituted or substituted with 1, 2 or 3 groups which are independently halogen, methoxy or ethoxy;

R ₂ is phenylalkoxy, aryloxy, phenyloxy (C ₁ -C ₆ ) alkyl, OH, halogen, phenylthioalkoxy, alkoxy, alkyl, alkoxyalkoxy, -OC (O) NH (CH ₂ ) _n phenyl, -OC (O) N (alkyl) (CH ₂ ) _n phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazolyl or thienyl,

Where n is 0, 1, 2, 3 or 4,

These groups are independently 1, 2, 3, 4 or 5 halogen,-(C ₁ -C ₆ ) alkyl-N (R) -CO ₂ R ₃₀ , halo (C ₁ -C ₄ ) alkyl or thienyl Substituted or unsubstituted with a group;

R ₃ is halogen, phenylalkoxycarbonyl, phenyloxycarbonyl, phenyl (C ₁ -C ₆ ) alkyl, phenylalkoxy, phenyloxy, phenylthio, thioalkoxy, arylthioalkoxy, (C ₂ -C ₆ ) alkenyl , NR ₆ R ₇ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-or alkyl,

Wherein arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl, -OC (0) NH (CH ₂ ) _n aryl, arylthioalkoxy, arylalkoxy and -OC (O) N (alkyl) (CH ₂ ) _n aryl The phenyl, naphthyl and aryl moieties of are independently substituted or unsubstituted with 1, 2 or 3 groups which are halogen, alkoxy, alkyl, CF ₃ or OCF ₃ , wherein n is 0, 1, 2, 3, 4 , 5 or 6);

R ₄ is H; CO ₂ H, -CO _2- (C ₁ -C ₆ ) alkyl, -C (O) NRR, -N (R ₃₀ ) C (O) NRR, -N (R ₃₀ ) C (O)-(C ₁ (C ₁ -C ₆ ) alkyl substituted with one group which is —C ₆ ) alkoxy or —NR ₆ R ₇ ; Phenylalkoxy; Phenyl (C ₁ -C ₆ ) alkyl; Hydroxyalkyl; Haloalkyl; Alkoxyalkyl; Or as alkoxyalkoxy,

Wherein the phenyl portion of the groups is independently substituted or unsubstituted with 1, 2, 3, 4 or 5 groups being halogen, hydroxy, alkoxy, alkyl, nitro, CF ₃ or OCF ₃ ;

R ₅ is phenyl (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkyl, phenyl, naphthyl, pyridyl, (C ₁ -C ₆ ) alkoxy, piperidinyl (C ₁ -C ₆ ) alkyl , Pyrrolyl (C ₁ -C ₆ ) alkyl, imidazolidinyl (C ₁ -C ₆ ) alkyl, pyrazolyl (C ₁ -C ₆ ) alkyl, imidazolyl (C ₁ -C ₆ ) alkyl, tetrahydro Pyridinyl (C ₁ -C ₆ ) alkyl, thienyl (C ₁ -C ₆ ) alkyl, phenylthio (C ₁ -C ₆ ) alkyl or pyridyl (C ₁ -C ₆ ) alkyl, wherein each independently (C ₁ -C ₄ ) alkyl, fluoro, chloro, bromo, (C ₁ -C ₄ ) alkoxy, phenyl (C ₁ -C ₄ ) alkoxy, thio (C ₁ -C ₄ ) alkoxy, (C _1- C ₄ ) alkoxycarbonyl, phenyl (C ₁ -C ₄ ) alkoxycarbonyl, CO ₂ H, CN, amidinooxime, NR ₆ R ₇ , NR ₆ R _7- (C ₁ -C ₅ alkyl)-,- A compound according to embodiment A154, substituted or unsubstituted with 1, 2 or 3 groups, which is C (0) NR ₆ R ₇ , amidino, CF ₃ , -CF ₂ CF ₃ , OCF ₃ or OCF ₂ CF ₃ .

Embodiment A161.

R ₁ is halogen, (C ₁ -C ₄ ) alkanoyl, phenyl (C ₁ -C ₄ ) alkanoyl, benzyl, phenethyl, phenpropyl, hydroxyalkyl or carboxaldehyde,

Wherein the phenyl group is independently substituted or unsubstituted with 1, 2 or 3 groups which are halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, nitro, CN, CF ₃ , OCF ₃ or CO ₂ H;

The alkyl portion of the group is independently substituted or unsubstituted with 1, 2 or 3 groups which are halogen, methoxy or ethoxy;

R ₂ is benzyloxy, phenethyloxy, phenpropyloxy, phenbutyloxy, phenyloxy, phenyloxy (C ₁ -C ₆ ) alkyl, OH, halogen, phenylthioalkoxy, alkoxy, alkyl, alkoxyalkoxy,

Where n is 0, 1, 2, 3 or 4,

Said groups are independently substituted or unsubstituted with 1, 2 or 3 groups which are halogen,-(C ₁ -C ₆ ) alkyl-N (R) -CO ₂ R ₃₀ , halo (C ₁ -C ₄ ) alkyl or thienyl Ring;

R ₃ is halogen, phenylalkoxycarbonyl, phenyloxycarbonyl, phenyl (C ₁ -C ₆ ) alkyl, phenylalkoxy, phenyloxy, phenylthio, thioalkoxy, phenylthioalkoxy, (C ₂ -C ₆ ) alkenyl , NR ₆ R ₇ , NR ₆ R ₇ C ₁ -C ₆ alkyl or alkyl,

Wherein the phenyl group is independently substituted or unsubstituted with 1, 2 or 3 groups which are halogen, alkoxy, (C ₁ -C ₄ ) alkyl, CF ₃ or OCF ₃ ,

R ₄ is H; C0 ₂ H, -C0 _2- (C ₁ -C ₆ ) alkyl, -C (0) NRR, -N (R ₃₀ ) C (O) NRR, -N (R ₃₀ ) C (O)-(C ₁ (C ₁ -C ₆ ) alkyl substituted with one group which is —C ₆ ) alkoxy or —NR ₆ R ₇ ; Phenylalkoxy; benzyl; Phenethyl; Hydroxyalkyl; Haloalkyl; Alkoxyalkyl; Or as alkoxyalkoxy,

Wherein the phenyl portion of the groups is independently substituted with 1, 2 or 3 groups which are halogen, hydroxy, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkyl, nitro, CF ₃ or OCF ₃ or Unsubstituted;

R ₅ is benzyl, phenethyl, phenpropyl, phenbutyl, (C ₁ -C ₆ ) alkyl, phenyl or pyridyl,

Wherein each independently represents (C ₁ -C ₄ ) alkyl, fluoro, chloro, bromo, (C ₁ -C ₄ ) alkoxy, phenyl (C ₁ -C ₄ ) alkoxy, thio (C ₁ -C ₄ ) Alkoxy, (C ₁ -C ₄ ) alkoxycarbonyl, C0 ₂ H, CN, amidinooxime, NR ₆ R ₇ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-, -C (O) NR ₆ A compound according to embodiment A160 substituted or unsubstituted with 1, 2 or 3 groups which are R ₇ , amidino, CF ₃ or OCF ₃ .

Embodiment A162.

R ₁ is bromo, phenyl (C ₁ -C ₄ ) alkanoyl, benzyl, phenethyl, phenpropyl, hydroxyalkyl or carboxaldehyde,

The phenyl group is independently substituted or unsubstituted with 1, 2 or 3 groups which are halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, nitro, CN, CF ₃ , OCF ₃ or CO ₂ H;

R ₂ is benzyloxy, phenethyloxy, phenpropyloxy, phenbutyloxy, phenyloxy, phenyloxy (C ₁ -C ₆ ) alkyl, OH, halogen or phenylthioalkoxy,

Where n is 0, 1, 2, 3 or 4,

Said groups are independently substituted or unsubstituted with 1, 2 or 3 groups which are halogen,-(C ₁ -C ₆ ) alkyl-N (R) -CO ₂ R ₃₀ , halo (C ₁ -C ₄ ) alkyl or thienyl Ring;

R ₃ is bromo, phenylalkoxycarbonyl, phenyloxycarbonyl, phenyl (C ₁ -C ₆ ) alkyl, phenylalkoxy, phenyloxy, phenylthio, thioalkoxy, phenylthioalkoxy, (C ₂ -C ₆ ) al Kenyl, NR ₆ R ₇ , NR ₆ R ₇ C ₁ -C ₆ alkyl or alkyl,

Wherein the phenyl group is independently substituted or unsubstituted with 1, 2 or 3 groups which are halogen, alkoxy, (C ₁ -C ₄ ) alkyl, CF ₃ or OCF ₃ ;

R ₄ is H; CO ₂ H, -CO _2- (C ₁ -C ₆ ) alkyl, -C (O) NRR, -N (R ₃₀ ) C (O) NRR, -N (R ₃₀ ) C (O)-(C ₁ (C ₁ -C ₆ ) alkyl substituted with one group which is —C ₆ ) alkoxy or —NR ₆ R ₇ ; Phenylalkoxy; benzyl; Or as phenethyl,

Wherein the phenyl portion of the groups is independently substituted with 1, 2 or 3 groups which are halogen, hydroxy, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkyl, nitro, CF ₃ or OCF ₃ or Unsubstituted;

R ₅ is benzyl, phenethyl, phenpropyl, (C ₁ -C ₆ ) alkyl, phenyl or pyridyl, wherein each independently is (C ₁ -C ₄ ) alkyl, fluoro, chloro, bromo, ( C ₁ -C ₄₎ alkoxy, CO ₂ H, CN, amidino oxime, _{amidino, CF 3, OCF 3, NR} 6 R 7, NR 6 R 7 - (C 1 -C 6 alkyl) -, or -C ( O) NR ₆ R ₇ substituted or unsubstituted with 1, 2 or 3 groups;

Wherein R ₆ and R ₇ are independently hydrogen, OH, C ₁ -C ₄ alkoxy, C ₁ -C ₆ alkanoyl or C ₁ -C ₆ alkyl, each independently OH, NH ₂ , C ₃ -C Optionally substituted with 1 or 2 groups which are ₆ cycloalkyl or halogen;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently substituted with 1 or 2 groups which are independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen A compound according to embodiment A161, which forms a morpholinyl, piperidinyl, pyrrolidinyl or piperazinyl ring.

Embodiment A163.

의 화합물 또는 제약상 허용되는 그의 염.Chemical formula

Or a pharmaceutically acceptable salt thereof.

In the above formula,

R ₁ is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, arylalkoxy, arylalkyl, CN, alkanoyl, alkoxy, alkoxyalkyl or arylalkanoyl,

Wherein the aryl portion of arylalkoxy, arylalkyl and arylalkanoyl is independently ₁ , _{2 which} is halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, nitro, CN, haloalkyl, haloalkoxy or C0 ₂ H Substituted or unsubstituted with 3, 4 or 5 groups;

Wherein the alkyl moieties of the alkyl, hydroxyalkyl, arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and arylalkanoyl groups are independently 1, 2 or 3 which are halogen, methoxy, ethoxy or spirocyclopropyl Substituted or unsubstituted with a group;

R ₂ is H, arylthio, —OC (0) NH (CH ₂ ) _n aryl, arylalkyl, —OC (0) N (alkyl) (CH ₂ ) _n aryl or arylthioalkoxy, where n is 1 , 2, 3, 4 or 5; Wherein the aryl group is independently halogen,-(C ₁ -C ₆ ) alkyl-N (R) -CO ₂ R ₃₀ , C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, CF ₃ or OCF ₃ , Optionally substituted with 2, 3, 4 or 5 groups;

R is independently at each occurrence H or C ₁ -C ₆ alkyl;

R ₃₀ is independently C ₁ -C ₆ alkyl optionally substituted with 1 or 2 groups which are OH, SH, halogen, amino, monoalkylamino, dialkylamino or C ₃ -C ₆ cycloalkyl;

R ₃ is halogen, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl, -OC (O) NH (CH ₂ ) _n aryl, arylalkoxy, -OC (O) N (alkyl) (CH ₂ ) _n aryl, aryloxy, arylthio, thioalkoxy, arylthioalkoxy, alkenyl, NR ₆ R ₇ C ₁ -C ₆ alkyl, NR ₆ R ₇ or alkyl,

Wherein arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl, -OC (O) NH (CH ₂ ) _n aryl, arylalkoxy, -OC (O) N (alkyl) (CH ₂ ) _n aryl and arylthioalkoxy The aryl portion of is independently unsubstituted or substituted with 1, 2 or 3 groups which are halogen, alkoxy, alkyl, haloalkyl or haloalkoxy (where n is 0, 1, 2, 3, 4, 5 or 6) ;

R ₄ is H; C0 ₂ H, -C0 _2- (C ₁ -C ₆ ) alkyl, -C (O) NRR, -N (R ₃₀ ) C (O) NRR, -N (R ₃₀ ) C (0)-(C ₁ -C ₆ ) alkoxy or alkyl substituted with one group which is -NR ₆ R ₇ ; Arylalkoxy; Arylalkyl; Hydroxyalkyl; Haloalkyl; Alkoxy; Alkoxyalkyl; Or as alkoxyalkoxy,

Wherein the aryl portion of arylalkoxy and arylalkyl is independently substituted or unsubstituted with 1, 2, 3, 4 or 5 groups which are halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl or haloalkoxy;

R ₅ is arylalkyl, alkyl, aryl, alkoxy, heterocycloalkylalkyl, heteroarylalkyl, arylthioalkyl, heterocycloalkyl or heteroaryl, wherein each independently is alkyl, halogen, alkoxy, arylalkoxy, thioalkoxy , Alkoxycarbonyl, arylalkoxycarbonyl, CO ₂ H, CN, amidinooxime, NR ₆ R ₇ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-, -C (O) NR ₆ R ₇ , Substituted or unsubstituted with 1, 2, 3, 4 or 5 groups which are amidino, haloalkyl or haloalkoxy;

Wherein R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycar Bonyl, OH, C ₁ -C ₆ hydroxyalkyl,-(C ₁ -C ₄ ) alkyl-C0 ₂ -alkyl, pyridyl C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl, benzyl, phenyl C ₁ -C ₆ alkoxy or phenyl C ₁ -C ₆ alkanoyl, wherein each independently, halogen, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, piperidinyl C ₁ -C ₆ alkyl, mor Polyyl C ₁ -C ₆ alkyl, piperazinyl C ₁ -C ₆ alkyl, OH, SH, NH ₂ , NH (alkyl), N (alkyl) (alkyl), -OC ₁ -C ₄ alkanoyl, C ₁ Substituted or unsubstituted with 1, 2 or 3 groups which are —C ₄ alkyl, CF ₃ or OCF ₃ ;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently substituted with 1 or 2 groups which are independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen Form a morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl or piperazinyl ring.

Embodiment A168.

R ₅ is benzyl, phenethyl, phenpropyl, phenbutyl, alkyl, phenyl, alkoxy, pyridyl (C ₁ -C ₆ ) alkyl, phenyl (C ₁ -C ₆ ) thioalkyl, pyrrolyl, pyrrolyl (C ₁ -C ₆ ) alkyl or pyridyl, wherein each independently (C ₁ -C ₆ ) alkyl, halogen, (C ₁ -C ₆ ) alkoxy, phenyl (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) A compound according to embodiment A163 unsubstituted or substituted with one, two or three groups which are thioalkoxy, alkoxycarbonyl, CO ₂ H, CN, amidinooxime, amidino, CF ₃ or OCF ₃ .

Embodiment A169.

R ₁ is H, Cl, Br, (C ₁ -C ₆ ) alkyl, carboxaldehyde, hydroxy (C ₁ -C ₆ ) alkyl,

Wherein the alkyl portion of the groups is independently substituted or unsubstituted with 1, 2 or 3 groups which are halogen, methoxy or ethoxy;

R ₂ is H, phenylthio, -OC (0) NH (CH ₂ ) _n aryl, phenylalkyl, -OC (O) N (alkyl) (CH ₂ ) _n aryl or phenylthio (C ₁ -C ₆ ) alkoxy as,

Wherein n is 1, 2, 3 or 4;

Wherein the aryl group is independently halogen,-(C ₁ -C ₆ ) alkyl-N (R) -CO ₂ R ₃₀ , C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkyl, CF ₃ or OCF ₃ , Optionally substituted with 2, 3, 4 or 5 groups;

R ₃ is bromo, alkoxycarbonyl, phenylalkoxycarbonyl, phenyloxycarbonyl, phenylalkyl, phenylalkoxy, phenyloxy, phenylthio, thioalkoxy, phenylthioalkoxy, alkenyl, NR ₆ R ₇ or alkyl,

Wherein the phenyl portion of the groups is independently halogen, (C ₁ -C ₄ ) alkoxy, (C ₁ -C ₄ ) alkyl, halo (C ₁ -C ₄ ) alkyl or halo (C ₁ -C ₄ ) alkoxy Substituted or unsubstituted with 1, 2 or 3 groups of phosphorus;

Where n is 0, 1, 2, 3 or 4;

R ₄ is H; CO ₂ H, -C0 _2- (C ₁ -C ₆ ) alkyl, -C (O) NRR, -N (R ₃₀ ) C (O) NRR, -N (R ₃₀ ) C (O)-(C ₁ -C ₆ ) alkoxy or alkyl substituted with one group which is -NR ₆ R ₇ ; Phenylalkoxy; Phenylalkyl; Hydroxyalkyl; Haloalkyl; Alkoxy; Alkoxyalkyl;

Wherein the phenyl portion of phenylalkoxy and phenylalkyl is independently substituted or unsubstituted with 1, 2 or 3 groups which are halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl or haloalkoxy;

R ₅ is benzyl, phenethyl, phenpropyl, phenbutyl, alkyl, phenyl, phenyl (C ₁ -C ₆ ) thioalkyl, pyrrolyl or pyridyl, wherein each independently (C ₁ -C ₆ ) alkyl, ₁ , 2 which is halogen, (C ₁ -C ₆ ) alkoxy, benzyloxy, (C ₁ -C ₆ ) thioalkoxy, alkoxycarbonyl, CO ₂ H, CN, amidinooxime, amidino, CF ₃ or OCF ₃ Or substituted or unsubstituted with three groups;

R ₆ and R ₇ are independently hydrogen, OH, C ₁ -C ₄ alkoxy, C ₁ -C ₆ alkanoyl or C ₁ -C ₆ alkyl, wherein each independently is OH, NH ₂ , C ₃ -C ₆ Optionally substituted with one or two groups that are cycloalkyl or halogen;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently substituted with 1 or 2 groups which are independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen A compound according to embodiment A163, which forms a morpholinyl, piperidinyl, pyrrolidinyl or piperazinyl ring.

Embodiment A170.

의 화합물 또는 제약상 허용되는 그의 염인 실시양태 1에 따른 화합물.Chemical formula

A compound according to embodiment 1 which is a compound of or a pharmaceutically acceptable salt thereof.

In the above formula,

R ₁ is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, arylalkoxy, arylalkyl, CN, alkanoyl, alkoxy, alkoxyalkyl or arylalkanoyl,

Wherein the aryl moieties of arylalkoxy, arylalkyl and arylalkanoyl are independently ₁ , _{2 which} is halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO ₂ H Substituted or unsubstituted with 3, 4 or 5 groups;

Wherein the alkyl moieties of the alkyl, hydroxyalkyl, arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and arylalkanoyl groups are independently 1, 2 or 3 which are halogen, methoxy, ethoxy or spirocyclopropyl Substituted or unsubstituted with a group;

R ₂ is arylalkoxy, aryloxy, aryloxyalkyl, OH, halogen, arylthioalkoxy, alkoxy, -OC (0) NH (CH ₂ ) _n aryl, -OC (0) N (alkyl) (CH ₂ ) aryl , Alkyl, alkoxyalkoxy, dialkylamino or CO ₂ H,

Where n is 0, 1, 2, 3, 4, 5 or 6;

The aryl moieties or heteroaryl and heterocycloalkyl groups of arylalkoxy, aryloxy, arylthioalkoxy, -OC (0) NH (CH ₂ ) _n aryl and -OC (O) N (alkyl) (CH ₂ ) _n aryl are independent by halogen, - (C ₁ -C ₆₎ alkyl, _{-N (R) -CO 2 R 30} , haloalkyl, heteroaryl, _{heteroaryl-alkyl, NR 6 R 7, NR 6} R 7 - (C 1 -C 6 alkyl )-, -OC (O) NR ₆ R ₇ substituted or unsubstituted with 1, 2, 3, 4 or 5 groups;

Wherein R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycarbonyl , OH, C ₁ -C ₆ hydroxyalkyl,-(C ₁ -C ₄ ) alkyl-C0 ₂ -alkyl, pyridyl C ₁ -C ₆ alkyl, C ₁ -C ₆ alkanoyl, benzyl, phenyl C _1- C ₆ alkoxy or phenyl C ₁ -C ₆ alkanoyl, wherein each independently, halogen, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, piperidinyl C ₁ -C ₆ alkyl, morpholinyl C ₁ -C ₆ alkyl, piperazinyl C ₁ -C ₆ alkyl, OH, SH, NH ₂ , NH (alkyl), N (alkyl) (alkyl), —OC ₁ -C ₄ alkanoyl, C ₁ -C Substituted or unsubstituted with 1, 2 or 3 groups which are ₄ alkyl, CF ₃ or OCF ₃ ;

R ₆ , R ₇ , and the nitrogen to which they are attached are independently substituted with 1 or 2 groups which are independently C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, hydroxy C ₁ -C ₄ alkyl or halogen To form a morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl or piperazinyl ring;

R is independently at each occurrence H or C ₁ -C ₆ alkyl;

R ₃₀ is independently C ₁ -C ₆ alkyl optionally substituted with 1 or 2 groups which are OH, SH, halogen, amino, monoalkylamino, dialkylamino or C ₃ -C ₆ cycloalkyl;

R ₃ is halogen, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl, -OC (O) NH (CH ₂ ) _n aryl, arylalkoxy, -OC (O) N (alkyl) (CH ₂ ) _n aryl, aryloxy, arylthio, thioalkoxy, arylthioalkoxy, alkenyl, NR ₆ R ₇ C ₁ -C ₆ alkyl, NR ₆ R ₇ or alkyl,

Wherein arylalkoxycarbonyl, aryloxycarbonyl, arylalkyl, -OC (O) NH (CH ₂ ) _n aryl, arylalkoxy, -OC (O) N (alkyl) (CH ₂ ) _n aryl and arylthioalkoxy The aryl portion of is independently substituted or unsubstituted with 1, 2 or 3 groups which are halogen, alkoxy, alkyl, haloalkyl or haloalkoxy where n is 0, 1, 2, 3, 4, 5 or 6 );

R ₄ is H; CO ₂ H, -CO _2- (C ₁ -C ₆ ) alkyl, -C (O) NRR, -N (R ₃₀ ) C (O) NRR, -N (R ₃₀ ) C (O)-(C ₁ -C ₆ ) alkoxy or alkyl substituted with one group which is -NR ₆ R ₇ ; Arylalkoxy; Arylalkyl; Hydroxyalkyl; Haloalkyl; Alkoxy; Alkoxyalkyl; Or as alkoxyalkoxy,

Wherein the aryl portion of arylalkoxy and arylalkyl is independently substituted or unsubstituted with 1, 2, 3, 4 or 5 groups which are halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl or haloalkoxy;

R ₅ is aryl, heterocycloalkylalkyl, heteroarylalkyl, arylthioalkyl, heterocycloalkyl or heteroaryl, wherein each independently is alkyl, halogen, alkoxy, arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycar Carbonyl, CO ₂ H, CN, amidinooxime, NR ₆ R ₇ , NR ₆ R _7- (C ₁ -C ₆ alkyl), -C (O) NR ₆ R ₇ , amidino, haloalkyl or haloalkoxy Substituted or unsubstituted with 1, 2, 3, 4 or 5 groups.

Embodiment A173.

R ₁ is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, benzyloxy, phenethyloxy, phenpropyloxy, benzyl, phenethyl, phenpropyl, CN, alkanoyl, alkoxy or phenyl C (O)-, As phenylCH ₂ C (O)-or phenylCH ₂ CH ₂ C (O),

Wherein the phenyl group is independently substituted or unsubstituted with 1, 2 or 3 groups which are halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, nitro, CN, CF ₃ , OCF ₃ or CO ₂ H;

Wherein said alkyl group is unsubstituted or substituted with 1, 2 or 3 groups which are independently halogen, methoxy or ethoxy;

R ₂ is benzyloxy, phenethyloxy, phenpropyloxy, phenyloxy, phenyloxy (C ₁ -C ₆ ) alkyl, OH, halogen, phenylthioalkoxy, alkyl, alkoxy, -OC (O) NH (CH ₂ ) _n phenyl, -OC (O) N (alkyl) (CH ₂ ) _n phenyl, dialkylamino or CO ₂ H,

Where n is 0, 1, 2, 3 or 4;

The aryl group is independently halogen,-(C ₁ -C ₆ ) alkyl-N (R) -CO ₂ R ₃₀ , CF ₃ , pyridyl, thienyl, NR ₆ R ₇ or NR ₆ R _7- (C _1- C ₆ alkyl) -substituted or unsubstituted with 1, 2, 3, 4 or 5 groups,

Wherein R ₆ and R ₇ are independently at each occurrence H, alkyl, alkanoyl, benzyl or phenylC (O) — wherein the phenyl portion of the groups is independently halogen, OH, C ₃ -C ₆ cyclo Substituted or unsubstituted with 1, 2 or 3 groups which are alkyl, alkoxy, alkyl, CF ₃ or OCF ₃ ;

R ₃ is halogen, alkoxycarbonyl, phenylalkoxycarbonyl, phenyloxycarbonyl, phenylalkyl, -OC (O) NH (CH ₂ ) _n phenyl, phenylalkoxy, -OC (O) N (alkyl) (CH ₂ ) _n phenyl, phenyloxy, phenylthio, thioalkoxy, phenylthioalkoxy, alkenyl, NR ₆ R ₇ or alkyl,

Wherein the phenyl portion of the groups is independently substituted or unsubstituted with 1, 2 or 3 groups which are halogen, alkoxy, alkyl, haloalkyl or haloalkoxy;

Where n is 0, 1, 2, 3 or 4;

R ₄ is H; CO ₂ H, -CO _2- (C ₁ -C ₆ ) alkyl, -C (O) NRR, -N (R ₃₀ ) C (O) NRR, -N (R ₃₀ ) C (O)-(C ₁ -C ₆ ) alkoxy or alkyl substituted with one group which is -NR ₆ R ₇ ; Phenylalkoxy; Phenylalkyl; Hydroxyalkyl; Haloalkyl; Alkoxy; Alkoxyalkyl; Or as alkoxyalkoxy,

Wherein the phenyl portion of the groups is independently substituted or unsubstituted with 1, 2 or 3 groups which are halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl or haloalkoxy;

R ₅ is phenyl, naphthyl, pyrrolylalkyl, piperidinylalkyl pyridinylalkyl, pyrimidinylalkyl, phenylthioalkyl, pyrrolyl, piperidinyl, pyridyl or thienylalkyl, wherein each independently alkyl , Halogen, alkoxy, phenylalkoxy, thioalkoxy, alkoxycarbonyl, phenylalkoxycarbonyl, CO ₂ H, CN, amidinooxime, NR ₆ R ₇ , NR ₆ R _7- (C ₁ -C ₆ alkyl)-, A compound according to embodiment A170, unsubstituted or substituted with 1, 2 or 3 groups, -C (O) NR ₆ R ₇ , amidino, haloalkyl or haloalkoxy.

Embodiment A174.

R ₁ is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, benzyloxy, phenethyloxy, benzyl, phenethyl, CN, (C ₁ -C ₆ ) alkanoyl, alkoxy or phenylC (O)-or PhenylCH ₂ C (0)-,

Wherein the phenyl group is independently substituted or unsubstituted with 1, 2 or 3 groups which are halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, nitro, CN, CF ₃ , OCF ₃ or CO ₂ H;

R ₂ is benzyloxy, phenethyloxy, phenpropyloxy, phenyloxy, phenyloxy (C ₁ -C ₆ ) alkyl, halogen, phenyl (C ₁ -C ₄ ) thioalkoxy, -OC (0) NH (CH ₂ ) _n phenyl, -OC (O) N (alkyl) (CH ₂ ) _n phenyl or dialkylamino,

Where n is 0, 1, 2, 3 or 4;

The phenyl group is independently substituted or unsubstituted with 1, 2 or 3 groups which are halogen, CF ₃ , NR ₆ R ₇ or NR ₆ R _7- (C ₁ -C ₆ alkyl)-,

Wherein R ₆ and R ₇ are independently at each occurrence H, (C ₁ -C ₆ ) alkyl, acetyl, benzyl or phenylC (O) — wherein the phenyl portion of the groups is independently halogen, OH, Substituted or unsubstituted with 1, 2 or 3 groups which are cyclopropyl, alkoxy, alkyl, CF ₃ or OCF ₃ ;

R ₃ is halogen, alkoxycarbonyl, phenylalkoxycarbonyl, phenyloxycarbonyl, phenyl alkyl, phenylalkoxy, phenyloxy, phenylthio, thioalkoxy, phenylthioalkoxy, alkenyl, NR ₆ R ₇ or alkyl,

Wherein the phenyl portion of the groups is independently substituted or unsubstituted with 1, 2 or 3 groups which are halogen, alkoxy, alkyl, haloalkyl or haloalkoxy;

Where n is 0, 1, 2, 3 or 4;

R ₄ is H; CO ₂ H, -CO _2- (C ₁ -C ₆ ) alkyl, -C (O) NRR, -N (R ₃₀ ) C (O) NRR, -N (R ₃₀ ) C (0)-(C ₁ -C ₆ ) alkoxy or alkyl substituted with one group which is -NR ₆ R ₇ ; Phenylalkoxy; Phenylalkyl; Hydroxyalkyl; Haloalkyl; Alkoxy; Alkoxyalkyl; Or as alkoxyalkoxy,

Wherein the phenyl portion of the groups is independently substituted or unsubstituted with 1, 2 or 3 groups which are halogen, hydroxy, alkoxy, alkyl, nitro, haloalkyl or haloalkoxy;

R ₅ is phenyl, phenyl (C ₁ -C ₄ ) thioalkyl, pyridyl or thienyl (C ₁ -C ₄ ) alkyl, wherein each independently is (C ₁ -C ₄ ) alkyl, fluoro, chloro A compound according to embodiment A173 unsubstituted or substituted with 1, 2 or 3 groups which are bromo, (C ₁ -C ₄ ) alkoxy, CN, amidinooxime, amidino, CF ₃ or OCF ₃ .

Embodiment A175.

A compound according to embodiment A174, wherein R ₅ is substituted with one or more groups selected from fluoro, chloro, bromo and methyl.

In another aspect, the present invention provides a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, solvent, adjuvant or excipient and a compound of Formula 1, embodiment A66 or embodiment A154.

The invention also provides a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, solvent, adjuvant or excipient and a compound according to any one of embodiments 1 to A175.

As noted above, the present invention includes treating a subject suffering from or susceptible to TNF mediated disorder, p38 kinase mediated disorder, inflammation and / or arthritis with a therapeutically effective amount of a compound of Formula 1 or a compound of Embodiment A1, It includes a method of treating the disorder or symptoms.

More specifically, the present invention is directed to inflammation; Arthritis, rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, systemic lupus erythematosis, juvenile arthritis and other arthritis symptoms; Neuroinflammatory; Allergy, Th2-mediated disease; Pain, neuropathic pain; Heat; Lung disorders, lung inflammation, adult respiratory distress syndrome, pulmonary sarcoidosis, asthma, silicon pulmonary disease, chronic pulmonary inflammatory disease and chronic obstructive pulmonary disease (COPD); Cardiovascular disease, arteriosclerosis, myocardial infarction (including post-myocardial infarction symptoms), thrombosis, congestive heart failure, cardiac reperfusion injury as well as complications associated with hypertension and / or heart failure, such as vascular damage, restenosis; Cardiomyopathy; Sleepiness, including ischemic and hemorrhagic sleepiness; Reperfusion injury; Kidney reperfusion injury; Ischemia and coronary artery bypass, including sleepiness and cerebral ischemia; Brain trauma including neurotrauma and obstructive brain injury; Brain edema; Neurodegenerative disorders; Liver disease and nephritis; Gastrointestinal symptoms, inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis; Ulcer disease, gastric ulcer; Ocular disease, retinitis, retinopathy, uveitis, eye life, acute damage to eye tissue and ocular trauma such as post-traumatic glaucoma, traumatic ocular neuropathy and central retinal artery occlusion (CRAO); Periodontal disease; Ophthalmic symptoms, retinitis, retinopathy (including diabetic retinopathy), uveitis, ocular life, nonglaucoma optic atrophy and age-related spot degeneration (ARMD) (including ARMD-atrophy form), corneal graft rejection, ocular neovascularization, retinal Angiogenesis, angiogenesis after injury or infection, posterior capsular fibrosis, neovascular glaucoma; Primary open-angle glaucoma (POAG), childhood outbreak Primary open-angle glaucoma, closed-angle glaucoma, deprived-like glaucoma, ischemic anterior optic neuropathy (AION), ocular hypertension, Reiter syndrome, normal pressure glaucoma, angiogenic glaucoma, ocular inflammation and corticosteroid Glaucoma, including steroid-induced glaucoma; diabetes; Diabetic nephropathy; Skin-related symptoms, psoriasis, eczema, burns, dermatitis, keloid formation, scar tissue formation, angiogenic disorders; Secondary cachexia for viral and bacterial infections, sepsis, septic shock, gram negative sepsis, malaria, meningitis, HIB infection, opportunistic infection, infection or malignancy, secondary cachexia for AIDS, AIDS, ARC (AIDS related Complications), pneumonia, herpes virus; Muscle pain due to infection; influenza; Endotoxin shock; Toxin shock syndrome; Autoimmune diseases, graft-versus-host reactions and allograft rejection; Treatment of bone resorption disease, osteoporosis; Multiple sclerosis; Female reproductive system disorders, endometriosis; Hemagglutination, infant hemagglutination, hemangiofibroma of the nasopharynx, avascular necrosis of the bone; Benign and malignant tumors / neoplasms, cancer, colorectal cancer, brain cancer, bone cancer, epithelial cell-derived neoplasms (epithelial carcinoma), basal cell carcinoma, adenocarcinoma, gastrointestinal cancer, cleft lip, oral cancer, esophageal cancer, small intestine cancer, gastric cancer, Colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer, squamous cell carcinoma and / or basal cell cancer, prostate cancer, renal cell carcinoma, and epithelial cells throughout the body Other known cancers; leukemia; Lymphoma; Systemic lupus erythematosus (SLE); Angiogenesis, including neoplasms; transition; Central nervous system disorders, central nervous system disorders with inflammatory or apoptotic components, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, peripheral neuropathy, and canine B-cell lymphoma To provide. The compounds of the present invention are also useful for preventing the production or expression of cyclooxygenase-2 or cyclooxygenase-2 activity.

In this aspect, the present invention provides a method of administering a therapeutically effective amount of a compound according to embodiment 1 and at least one pharmaceutically acceptable carrier, adjuvant, solvent or excipient to a patient in need of treatment for p38 kinase or TNF-alpha mediated disorder. Methods of treating p38 kinase or TNF-alpha mediated disorders, including.

Representative compounds of the invention are:

1-benzyl-4- (benzyloxy) -3-bromopyridin-2 (1H) -one;

3-bromo-1- (4-fluorobenzyl) -4-[(4-fluorobenzyl) oxy] pyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-dimethylphenyl) -6-methylpyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- (4-fluorobenzyl) pyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (3-fluorobenzyl) pyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one;

4-bromo-2- (2,6-dichlorophenyl) -5-[(2,4-difluorobenzyl) oxy] pyridazin-3 (2H) -one;

3-bromo-1- (2,6-dichlorophenyl) -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

3-bromo-1- (3-fluorobenzyl) -4-[(3-methylbenzyl) oxy] pyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (pyridin-4-ylmethyl) pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- (3-fluorobenzyl) pyridin-2 (1H) -one;

1-benzyl-4- (benzyloxy) -3-bromo-6-methylpyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2-methoxy-6-methylphenyl) -6-methylpyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2-fluorobenzyl) pyridin-2 (1H) -one;

3-bromo-4-[(4-fluorobenzyl) oxy] -6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one;

3-bromo-1- (2,6-dichlorophenyl) -4-[(4-fluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- (4-methylbenzyl) pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- (4-chlorobenzyl) pyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (3-methoxybenzyl) pyridin-2 (1H) -one;

4-{[4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] methyl} benzoic acid;

4- (benzyloxy) -3-bromo-1- (2-fluorobenzyl) pyridin-2 (1H) -one;

3-bromo-1- (2,6-dimethylphenyl) -4-[(4-fluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- [4- (methylthio) benzyl] pyridin-2 (1H) -one;

1-benzyl-4- (benzyloxy) -3-chloropyridin-2 (1H) -one;

4-{[4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] methyl} -N'-hydroxybenzenecarboximideamide;

Methyl 4-{[4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] methyl} benzoate;

3-bromo-4-[(3-chlorobenzyl) oxy] -1- (3-fluorobenzyl) pyridin-2 (1H) -one;

3-bromo-1- (3-fluorobenzyl) -4-[(4-fluorobenzyl) oxy] pyridin-2 (1H) -one;

4-{[4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] methyl} benzonitrile;

4- (benzyloxy) -3-bromo-1- (2,6-dichlorophenyl) -6-methylpyridin-2 (1H) -one;

3-bromo-4-[(4-fluorobenzyl) oxy] -1- (pyridin-4-ylmethyl) pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- (4-bromobenzyl) pyridin-2 (1H) -one;

4-{[3-bromo-4-[(4-fluorobenzyl) oxy] -2-oxypyridin-1 (2H) -yl] methyl} benzonitrile;

1- (3-fluorobenzyl) -4-[(4-fluorobenzyl) oxy] -3-iodopyridin-2 (1H) -one;

4-bromo-2- (2,6-dichlorophenyl) -5-{[2- (hydroxymethyl) benzyl] oxy} pyridazin-3 (2H) -one;

3-bromo-4-[(4-fluorobenzyl) oxy] -1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one;

3-bromo-1- (2,4-difluorobenzyl) -4-[(2,4-difluorobenzyl) oxy] pyridin-2 (1H) -one;

3-bromo-4-[(4-fluorobenzyl) oxy] -6-methyl-1- (pyridin-2-ylmethyl) pyridin-2 (1H) -one; Or pharmaceutically acceptable salts thereof.

Embodiment 57.

3-bromo-4-[(4-chlorobenzyl) oxy] -1- (4-fluorobenzyl) pyridin-2 (1H) -one;

1-benzyl-3-bromo-4-[(4-chlorobenzyl) oxy] pyridin-2 (1H) -one;

3-bromo-1- (4-chlorobenzyl) -4-[(4-chlorobenzyl) oxy] pyridin-2 (1H) -one;

3-bromo-4-[(4-chlorobenzyl) oxy] -1- [2- (phenylthio) ethyl] pyridin-2 (1H) -one;

3-bromo-4-[(4-chlorobenzyl) oxy] -1- (2-phenylethyl) pyridin-2 (1H) -one;

3-bromo-4-hydroxy-1- (4-hydroxybenzyl) pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- (piperidin-3-ylmethyl) pyridin-2 (1H) -one hydrochloride;

3-bromo-1- (4-methoxybenzyl) -4-phenoxypyridin-2 (1H) -one;

1-benzyl-2-oxo-4-phenoxy-1,2-dihydropyridine-3-carbaldehyde;

3-bromo-4-[(4-chlorobenzyl) oxy] -1- (4-methoxybenzyl) pyridin-2 (1H) -one;

3-bromo-4-[(4-fluorobenzyl) oxy] -1- (3-phenylpropyl) pyridin-2 (1H) -one;

4- (benzyloxy) -1- [4- (benzyloxy) benzyl] -3-bromopyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- [2- (trifluoromethyl) benzyl] pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- [3- (trifluoromethyl) benzyl] pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- (piperidin-4-ylmethyl) pyridin-2 (1H) -one hydrochloride;

1-benzyl-3-bromo-4-{[2- (trifluoromethyl) benzyl] oxy} pyridin-2 (1H) -one;

1-benzyl-4-[(2,6-dichlorobenzyl) oxy] pyridin-2 (1H) -one;

1-benzyl-4- (benzyloxy) -3- (hydroxymethyl) pyridin-2 (1H) -one;

1-benzyl-3-bromo-4-[(2,6-dichlorobenzyl) oxy] pyridin-2 (1H) -one;

1-benzyl-4-[(3-chlorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

1-benzyl-3-bromo-4-[(3-chlorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

1-benzyl-3-bromo-4-[(2-chlorobenzyl) oxy] pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1-ethylpyridin-2 (1H) -one;

4- (benzyloxy) -1- (4-bromobenzyl) pyridin-2 (1H) -one;

3-bromo-1- (4-methylbenzyl) -4-[(4-methylbenzyl) oxy] pyridin-2 (1H) -one;

Methyl 4-{[4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] methyl} benzoate;

4- (benzyloxy) -3-bromo-1- (2-thien-3-ylethyl) pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- (2-thien-2-ylethyl) pyridin-2 (1H) -one;

1-benzyl-4-[(3-chlorobenzyl) oxy] pyridin-2 (1H) -one;

3-bromo-1- (4-fluorobenzyl) -4-[(4-fluorobenzyl) oxy] pyridin-2 (1H) -one;

4- (benzyloxy) -1- (3-fluorobenzyl) pyridin-2 (1H) -one;

4- (benzyloxy) -1- (2-fluorobenzyl) pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1-methylpyridin-2 (1H) -one hydrobromide;

4- (benzyloxy) -3-bromo-1-methylpyridin-2 (1H) -one;

3-bromo-1- (3-chlorobenzyl) -4-[(4-chlorobenzyl) oxy] pyridin-2 (1H) -one;

3-bromo-1- (3-chlorobenzyl) -4-[(4-fluorobenzyl) oxy] pyridin-2 (1H) -one;

4- (benzyloxy) -1- (4-chlorobenzyl) pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- [4- (trifluoromethoxy) benzyl] pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- (4-tert-butylbenzyl) pyridin-2 (1H) -one;

1-benzyl-4- (benzyloxy) -6-methylpyridin-2 (1H) -one;

1-benzyl-4- (benzyloxy) -3,5-dibromo-6-methylpyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- [4- (trifluoromethyl) benzyl] pyridin-2 (1H) -one;

1-benzyl-4-[(2-chlorobenzyl) oxy] pyridin-2 (1H) -one;

1- (2-bromobenzyl) -3-[(2-bromobenzyl) oxy] pyridin-2 (1H) -one;

Methyl 5-chloro-1- (4-chlorobenzyl) -6-oxo-1,6-dihydropyridine-3-carboxylate;

3-benzyl-4-hydroxy-1- (2-phenylethyl) pyridin-2 (1H) -one;

5-bromo-1- (2-chloro-6-fluorobenzyl) -3-methylpyridin-2 (1H) -one;

1- (2-bromobenzyl) -3-[(2-bromobenzyl) oxy] pyridin-2 (1H) -one;

1-benzyl-4- (benzyloxy) pyridin-2 (1H) -one;

1-benzyl-4- (benzyloxy) -3-bromopyridin-2 (1H) -one;

1-benzyl-4- (benzyloxy) -2-oxo-1,2-dihydropyridine-3-carbaldehyde;

1-benzyl-4-chloro-2-oxo-1,2-dihydropyridine-3-carbaldehyde;

1-benzyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carbaldehyde;

1-benzyl-4- (benzyloxy) -3-methylpyridin-2 (1H) -one;

4- (benzyloxy) -1- (4-fluorobenzyl) pyridin-2 (1H) -one;

1-benzyl-4- (benzyloxy) -3,5-dibromopyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- [4- (methylthio) benzyl] pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- (4-fluorobenzyl) pyridin-2 (1H) -one;

1-benzyl-4- (benzyloxy) -3-chloropyridin-2 (1H) -one;

3-bromo-1- (4-fluorobenzyl) -4-[(4-fluorobenzyl) oxy] pyridin-2 (1H) -one;

1-benzyl-3-bromo-2-oxo-1,2-dihydropyridin-4-ylmethyl (phenyl) carbamate;

1-benzyl-3-bromo-4- (2-phenylethyl) pyridin-2 (1H) -one;

1-benzyl-3-bromo-4- (3-phenylpropyl) pyridin-2 (1H) -one;

1-benzyl-3-methyl-4- (2-phenylethyl) pyridin-2 (1H) -one;

1-benzyl-3-methyl-4- (3-phenylpropyl) pyridin-2 (1H) -one;

1-benzyl-4- (benzylthio) -3-methylpyridin-2 (1H) -one;

1-benzyl-4- (benzylthio) -3-bromopyridin-2 (1H) -one;

1-benzyl-2-oxo-1,2-dihydropyridin-4-yl methanesulfonate;

3-acetyl-4-hydroxy-6-methyl-1- [chloro] phenylpyridin-2 (1H) -one;

6- (benzyloxy) -1-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile;

3-benzoyl-6- (benzyloxy) -1-methylpyridin-2 (1H) -one;

3-benzyl-6- (benzyloxy) -1-methylpyridin-2 (1H) -one;

1-benzyl-4-hydroxypyridin-2 (1H) -one;

1-benzyl-4- (benzylthio) pyridin-2 (1H) -one;

4-amino-1-benzylpyridin-2 (1H) -one;

1-benzyl-4- (benzyloxy) pyridin-2 (1H) -one;

1-benzyl-4-hydroxypyridin-2 (1H) -one;

1-benzyl-2-oxo-1,2-dihydropyridin-4-yl methyl (phenyl) carbamate; Or a pharmaceutically acceptable salt thereof, according to embodiment 1 or embodiment Al.

Embodiment 58.

4- (benzyloxy) -1- (4-methylbenzyl) pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromopyridin-2 (1H) -one;

Methyl 4-{[4- (benzyloxy) -2-oxopyridin-1 (2H) -yl] methyl} benzoate;

Methyl-4-{[4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] methyl} benzoate;

4-{[4- (benzyloxy) -2-oxopyridin-1 (2H) -yl] methyl} benzonitrile;

4- (benzyloxy) -1- (4-tert-butylbenzyl) pyridin-2 (1H) -one;

4- (benzyloxy) -1- [4- (trifluoromethyl) benzyl] pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- [4- (trifluoromethyl) benzyl] pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- [3- (trifluoromethyl) benzyl] pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- [2- (trifluoromethyl) benzyl] pyridin-2 (1H) -one;

4- (benzyloxy) -1- [4- (trifluoromethoxy) benzyl] pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- [4- (trifluoromethoxy) benzyl] pyridin-2 (1H) -one;

1-benzyl-4-hydroxy-6-methylpyridin-2 (1H) -one;

1-benzyl-6-methyl-2-oxo-1,2-dihydropyridin-4-yl 4-bromobenzenesulfonate;

1-benzyl-3-bromo-4-[(3-chlorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

1-benzyl-6-methyl-2-oxo-1,2-dihydropyridin-4-yl 4-bromobenzenesulfonate;

1-benzyl-3-bromo-4-[(3-chlorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

1-benzyl-4- [2,6- (dichlorobenzyl) oxy] pyridin-2 (1H) -one;

4-[(2,6-dichlorobenzyl) oxy] pyridine-1-oxide;

4-[(2,6-dichlorobenzyl) oxy] pyridine 1-oxide;

1-benzyl-3-bromo-4- [2,6- (dichlorobenzyl) oxy] pyridin-2 (1H) -one;

1-benzyl-3-bromo-4-[(4-methylbenzyl) oxy] pyridin-2 (1H) -one;

1-benzyl-4- [benzylthio] -3-bromopyridin-2 (1H) -one;

1-benzyl-4- (benzyloxy) -3-iodopyridin-2 (1H) -one;

1-benzyl-4- (benzyloxy) -3-vinylpyridin-2 (1H) -one;

1-benzyl-4- (benzyloxy) -3-ethylpyridin-2 (1H) -one;

3-acetyl-4- (benzyloxy) -1- (2-chlorophenyl) -6-methylpyridin-2 (1H) -one;

3-acetyl-1- (2-chlorophenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one;

1-benzyl-3-bromo-4-hydroxypyridin-2 (1H) -one;

1-benzyl-3-bromo-2-oxo-1,2-dihydropyridin-4-yl trifluoromethanesulfonate;

1-benzyl-3-bromo-4- (phenylethynyl) pyridin-2 (1H) -one;

3-bromo-1- (3-fluorobenzyl) -6-methyl-4- (2-phenylethyl) pyridin-2 (1H) -one;

1- (3-fluorobenzyl) -4-hydroxy-6-methylpyridin-2 (1H) -one;

3-bromo-1- (3-fluorobenzyl) -4-hydroxy-6-methylpyridin-2 (1H) -one;

3-bromo-1- (3-fluorobenzyl) -6-methyl-2-oxo-1,2-dihydropyridin-4-yl trifluoromethanesulfonate;

3-bromo-1- (3-fluorobenzyl) -6-methyl-4- (phenylethynyl) pyridin-2 (1H) -one;

3-acetyl-1- (2,6-dichlorophenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one;

1- (2,6-dichlorophenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one;

4- (benzyloxy) -1- (2,6-dichlorophenyl) -6-methylpyridin-2 (1H) -one;

3-bromo-1- (3-fluorobenzyl) -4- (2-phenylethyl) pyridin-2 (1H) -one;

3-bromo-1- (3-fluorobenzyl) -4-hydroxypyridin-2 (1H) -one;

3-bromo-1- (3-fluorobenzyl) -2-oxo-1,2-dihydropyridin-4-yl trifluoromethanesulfonate;

3-bromo-1- (3-fluorobenzyl) -4- (phenylethynyl) pyridin-2 (1H) -one;

4- (benzyloxy) -3-ethynyl-1- (3-fluorobenzyl) pyridin-2 (1H) -one;

4- (benzyloxy) -1- (3-fluorobenzyl) -3-iodopyridin-2 (1H) -one;

4- (benzyloxy) -1- (3-fluorobenzyl) -3-[(trimethylsilyl) ethynyl] pyridin-2 (1H) -one;

4- (benzylamino) -3-bromo-1- (3-fluorobenzyl) pyridin-2 (1H) -one;

1- (3-fluorobenzyl) -4-hydroxypyridin-2 (1H) -one;

4- (benzylamino) -1- (3-fluorobenzyl) pyridin-2 (1H) -one; Or a pharmaceutically acceptable salt thereof, according to embodiment 1 or embodiment Al.

Embodiment 59.

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2-fluorobenzyl) pyridin-2 (1H) -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-1- (pyridin-4-ylmethyl) pyridin-2 (1H) -one;

3-bromo-1- (2,6-dichlorophenyl) -4-[(4-fluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (3-methoxybenzyl) pyridin-2 (1H) -one;

3-bromo-1- (2,6-dimethylphenyl) -4-[(4-fluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

3-bromo-4-[(3-chlorobenzyl) oxy] -1- (3-fluorobenzyl) pyridin-2 (1H) -one;

3-bromo-4-[(4-fluorobenzyl) oxy] -1- (pyridin-4-ylmethyl) pyridin-2 (1H) -one;

3-bromo-1- (3-fluorobenzyl) -4-[(4-fluorobenzyl) oxy] pyridin-2 (1H) -one;

4-{[3-bromo-4-[(4-fluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} benzonitrile;

1- (3-fluorobenzyl) -4-[(4-fluorobenzyl) oxy] -3-iodopyridin-2 (1H) -one;

3-bromo-4-[(4-fluorobenzyl) oxy] -1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one;

3-bromo-1- (2,4-difluorobenzyl) -4-[(2,4-difluorobenzyl) oxy] pyridin-2 (1H) -one;

3-bromo-4-[(4-fluorobenzyl) oxy] -6-methyl-1- (pyridin-2-ylmethyl) pyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (3-fluorobenzyl) pyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one;

3-bromo-1- (2,6-dichlorophenyl) -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

3-bromo-1- (3-fluorobenzyl) -4-[(3-methylbenzyl) oxy] piperidin-2-one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (pyridin-4-ylmethyl) pyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2-methoxy-6-methylphenyl) -6-methylpyridin-2 (1H) -one; Or a pharmaceutically acceptable salt thereof, according to embodiment 1 or embodiment Al.

Embodiment 60.

1- (1-acetyl-2,3-dihydro-1H-indol-5-yl) -3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridine-2 ( 1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- (1-glycloyl-2,3-dihydro-1H-indol-5-yl) -6-methylpyridine- 2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1- (2-hydroxy-2-methylpropanoyl) -2,3-dihydro-1H-indole- 5-yl] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [1- (N-methylglycyl) -2,3-dihydro-1H-indole-5- Il] pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1- (3-hydroxypropanoyl) -2,3-dihydro-1H-indol-5-yl] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1- (3-hydroxy-3-methylbutanoyl) -2,3-dihydro-1H-indole-5 -Yl] -6-methylpyridin-2 (1H) -one;

5- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] indoline-1-carboxamide;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [1- (methylsulfonyl) -2,3-dihydro-1H-indol-5-yl] Pyridin-2 (1H) -one;

1- (1-acetyl-1H-indol-5-yl) -3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- (1-glycloyl-1H-indol-5-yl) -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1- (2-hydroxy-2-methylpropanoyl) -1H-indol-5-yl] -6- Methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [1- (N-methylglycyl) -1H-indol-5-yl] pyridine-2 (1H )-On;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1- (3-hydroxypropanoyl) -1H-indol-5-yl] -6-methylpyridine-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1- (3-hydroxy-3-methylbutanoyl) -1H-indol-5-yl] -6-methyl Pyridin-2 (1H) -one;

5- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -1H-indol-1-carboxamide;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [1- (methylsulfonyl) -1H-indol-5-yl] pyridine-2 (1H)- On;

1- (2-acetyl-2,3-dihydro-1H-isoindol-5-yl) -3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridine-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- (2-glycloyl-2,3-dihydro-1H-isoindol-5-yl) -6-methylpyridine -2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [2- (2-hydroxy-2-methylpropanoyl) -2,3-dihydro-1H-isoindole -5-yl] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [2- (N-methylglycyl) -2,3-di hydro-1H-isoindole-5 -Yl] pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [2- (3-hydroxypropanoyl) -2,3-dihydro-1H-isoindol-5-yl ] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [2- (3-hydroxy-3-methylbutanoyl) -2,3-dihydro-1H-isoindole- 5-yl] -6-methylpyridin-2 (1H) -one;

5- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -1,3-dihydro-2H-iso Indole-2-carboxamide;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [2- (methylsulfonyl) -2,3-dihydro-1H-isoindol-5-yl ] Pyridin-2 (1H) -one;

1- (2-acetyl-1,2,3,4-tetrahydroisoquinolin-6-yl) -3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridine- 2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- (2-glycloyl-1,2,3,4-tetrahydroisoquinolin-6-yl) -6-methyl Pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [2- (2-hydroxy-2-methylpropanoyl) -1,2,3,4-tetrahydroiso Quinolin-6-yl] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [2- (N-methylglycyl) -1,2,3,4-tetrahydroisoquinoline- 6-yl] pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [2- (3-hydroxypropanoyl) -1,2,3,4-tetrahydroisoquinoline-6- Il] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [2- (3-hydroxy-3-methylbutanoyl)-1,2,3,4-tetrahydroisoquinoline -6-yl] -6-methylpyridin-2 (1H) -one;

6- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3,4-dihydroisoquinoline-2 (1H) -carboxamide;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [2- (methylsulfonyl) -1,2,3,4-tetrahydroisoquinoline-6- Il] pyridin-2 (1H) -one;

1- (2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridine- 2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- (2-glycoyl-1,2,3,4-tetrahydroisoquinolin-7-yl) -6-methyl Pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [2- (2-hydroxy-2-methylpropanoyl) -1,2,3,4-tetrahydroiso Quinolin-7-yl] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [2- (N-methylglycyl) -1,2,3,4-tetrahydroisoquinoline- 7-yl] pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [2- (3-hydroxypropanoyl) -1,2,3,4-tetrahydroisoquinoline-7- Il] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [2- (3-hydroxy-3-methylbutanoyl) -1,2,3,4-tetrahydroisoquinoline -7-yl] -6-methylpyridin-2 (1H) -one;

7- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3,4-dihydroisoquinoline-2 (1H) -carboxamide;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [2- (methylsulfonyl) -1,2,3,4-tetrahydroisoquinoline-7- Il] pyridin-2 (1H) -one;

1- (1-acetyl-1H-benzimidazol-5-yl) -3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- (1-glycloyl-1H-benzimidazol-5-yl) -6-methylpyridine-2 (1H)- On;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1- (2-hydroxy-2-methylpropanoyl) -1H-benzimidazol-5-yl]- 6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [1- (N-methylglycyl) -1H-benzimidazol-5-yl] pyridine-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1- (3-hydroxypropanoyl) -1H-benzimidazol-5-yl] -6-methylpyridine -2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1- (3-hydroxy-3-methylbutanoyl) -1H-benzimidazol-5-yl] -6 -Methylpyridin-2 (1H) -one;

5- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -1H-benzimidazole-1-carbox amides;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [1- (methylsulfonyl) -1H-benzimidazol-5-yl] pyridine-2 (1H )-On;

3-chloro-1- (1,3-diacetyl-2,3-dihydro-1H-benzimidazol-5-yl) -4-[(2,4-difluorobenzyl) oxy] -6- Methylpyridin-2 (1H) -one;

1- (3-acetyl-1-glycoyl-2,3-dihydro-1H-benzimidazol-5-yl) -3-chloro-4- [(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

1- [3-acetyl-1- (2-hydroxy-2-methylpropanoyl) -2,3-dihydro-1H-benzimidazol-5-yl] -3-chloro-4-[(2 , 4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

1- [3-acetyl-1- (N-methylglycidyl) -2,3-dihydro-1H-benzimidazol-5-yl] -3-chloro-4-[(2,4-difluoro Benzyl) oxy] -6-methylpyridin-2 (1H) -one;

1- [3-acetyl-1- (3-hydroxypropanoyl) -2,3-dihydro-1H-benzimidazol-5-yl] -3-chloro-4-[(2,4-di Fluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

1- [3-acetyl-1- (3-hydroxy-3-methylbutanoyl) -2,3-dihydro-1H-benzimidazol-5-yl] -3-chloro-4-[(2, 4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

3-acetyl-5- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -2,3-dihydro -1H-benzimidazole-1-carboxamide;

1- (1-acetyl-3-glyloyl-2,3-dihydro-1H-benzimidazol-5-yl) -3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- (1,3-diglycoloyl-2,3-dihydro-1H-benzimidazol-5-yl)- 6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [3-glycloyl-1- (2-hydroxy-2-methylpropanoyl) -2,3-di Hydro-1H-benzimidazol-5-yl] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [3-glycloyl-1- (N-methylglycyl) -2,3-dihydro-1H-benzimi Dazol-5-yl] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [3-glycloyl-1- (3-hydroxypropanoyl) -2,3-dihydro-1H- Benzimidazol-5-yl] -6-methylpyridin-2 (1H) -one;

5- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3-glycloyl-2,3- Dihydro-1H-benzimidazole-1-carboxamide;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [3-glycloyl-1- (3-hydroxy-3-methylbutanoyl) -2,3-dihydro -1H-benzimidazol-5-yl] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [3-glycloyl-1- (methylsulfonyl) -2,3-dihydro-1H-benzimidazole- 5-yl] -6-methylpyridin-2 (1H) -one;

1- [1-acetyl-3- (2-hydroxy-2-methylpropanoyl) -2,3-dihydro-1H-benzimidazol-5-yl] -3-chloro-4-[(2 , 4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1-glycloyl-3- (2-hydroxy-2-methylpropanoyl) -2,3-di Hydro-1H-benzimidazol-5-yl] -6-methylpyridin-2 (1H) -one;

1- [1,3-bis (2-hydroxy-2-methylpropanoyl) -2,3-dihydro-1H-benzimidazol-5-yl] -3-chloro-4-[(2, 4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [3- (2-hydroxy-2-methylpropanoyl) -1- (N-methylgylsil) -2 , 3-dihydro-1H-benzimidazol-5-yl] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [3- (2-hydroxy-2-methylpropanoyl) -1- (3-hydroxypropanoyl) -2,3-dihydro-1H-benzimidazol-5-yl] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1- (3-hydroxy-3-methylbutanoyl)-3- (2-hydroxy-2-methylpro Panoyl) -2,3-dihydro-1H-benzimidazol-5-yl] -6-methylpyridin-2 (1H) -one;

5- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3- (2-hydroxy-2- Methylpropanoyl) -2,3-dihydro-1H-benzimidazole-1-carboxamide;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [3- (2-hydroxy-2-methylpropanoyl) -1- (methylsulfonyl) -2,3 -Dihydro-1H-benzimidazol-5-yl] -6-methylpyridin-2 (1H) -one;

1- [1-acetyl-3- (N-methylglycyl) -2,3-dihydro-1H-benzimidazol-5-yl] -3-chloro-4-[(2,4-difluoro Benzyl) oxy] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1-glycloyl-3- (N-methylglycyl) -2,3-dihydro-1H-benzimi Dazol-5-yl] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1- (2-hydroxy-2-methylpropanoyl) -3- (N-methylglysil) -2 , 3-dihydro-1H-benzimidazol-5-yl] -6-methylpyridin-2 (1H) -one;

1- [1,3-bis (N-methylglycyl) -2,3-dihydro-1H-benzimidazol-5-yl] -3-chloro-4-[(2,4-difluorobenzyl ) Oxy] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1- (3-hydroxypropanoyl) -3- (N-methylglycyl) -2,3-di Hydro-1H-benzimidazol-5-yl] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1- (3-hydroxy-3-methylbutanoyl) -3- (N-methylgylsil) -2, 3-dihydro-1H-benzimidazol-5-yl] -6-methylpyridin-2 (1H) -one;

5- [3-Chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3- (N-methylglycyl)- 2,3-dihydro-1H-benzimidazole-1-carboxamide;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [3- (N-methylglycyl) -1- (methylsulfonyl) -2,3-di Hydro-1H-benzimidazol-5-yl] pyridin-2 (1H) -one;

1- [1-acetyl-3- (3-hydroxypropanoyl) -2,3-dihydro-1H-benzimidazol-5-yl] -3-chloro-4-[(2,4-di Fluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1-glycloyl-3- (3-hydroxypropanoyl) -2,3-dihydro-1H- Benzimidazol-5-yl] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1- (2-hydroxy-2-methylpropanoyl) -3- (3-hydroxypropanoyl) -2,3-dihydro-1H-benzimidazol-5-yl] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [3- (3-hydroxypropanoyl) -1- (N-methylglycyl) -2,3-di Hydro-1H-benzimidazol-5-yl] -6-methylpyridin-2 (1H) -one;

1- [1,3-bis (3-hydroxypropanoyl) -2,3-dihydro-1H-benzimidazol-5-yl] -3-chloro-4-[(2,4-difluoro Lobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1- (3-hydroxy-3-methylbutanoyl) -3- (3-hydroxypropanoyl)- 2,3-dihydro-1H-benzimidazol-5-yl] -6-methylpyridin-2 (1H) -one;

5- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3- (3-hydroxypropanoyl ) -2,3-dihydro-1H-benzimidazole-1-carboxamide;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [3- (3-hydroxypropanoyl) -1- (methylsulfonyl) -2,3-dihydro- 1H-benzimidazol-5-yl] -6-methylpyridin-2 (1H) -one;

1- [1-acetyl-3- (3-hydroxy-3-methylbutanoyl) -2,3-dihydro-1H-benzimidazol-5-yl] -3-chloro-4-[(2, 4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1-glycloyl-3- (3-hydroxy-3-methylbutanoyl) -2,3-dihydro -1H-benzimidazol-5-yl] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [3- (3-hydroxy-3-methylbutanoyl) -1- (2-hydroxy-2-methylpro Panoyl) -2,3-dihydro-1H-benzimidazol-5-yl] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [3- (3-hydroxy-3-methylbutanoyl) -1- (N-methylglysil) -2, 3-dihydro-1H-benzimidazol-5-yl] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [3- (3-hydroxy-3-methylbutanoyl) -1- (3-hydroxypropanoyl)- 2,3-dihydro-1H-benzimidazol-5-yl] -6-methylpyridin-2 (1H) -one;

1- [1,3-bis (3-hydroxy-3-methylbutanoyl) -2,3-dihydro-1H-benzimidazol-5-yl] -3-chloro-4-[(2,4 -Difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

5- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3- (3-hydroxy-3- Methylbutanoyl) -2,3-dihydro-1H-benzimidazole-1-carboxamide;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [3- (3-hydroxy-3-methylbutanoyl) -1- (methylsulfonyl) -2,3- Dihydro-1H-benzimidazol-5-yl] -6-methylpyridin-2 (1H) -one;

3-acetyl-6- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -2,3-dihydro -1H-benzimidazole-1-carboxamide;

6- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3-glycloyl-2,3- Dihydro-1H-benzimidazole-1-carboxamide;

6- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3- (2-hydroxy-2- Methylpropanoyl) -2,3-dihydro-1H-benzimidazole-1-carboxamide;

6- [3-Chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3- (N-methylglycyl)- 2,3-dihydro-1H-benzimidazole-1-carboxamide;

6- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3- (3-hydroxypropanoyl ) -2,3-dihydro-1H-benzimidazole-1-carboxamide;

6- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3- (3-hydroxy-3- Methylbutanoyl) -2,3-dihydro-1H-benzimidazole-1-carboxamide;

5- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -1H-benzimidazole-1,3 ( 2H) -dicarboxamide;

6- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3- (methylsulfonyl) -2, 3-dihydro-1H-benzimidazole-1-carboxamide;

1- [1-acetyl-3- (methylsulfonyl) -2,3-dihydro-1H-benzimidazol-5-yl] -3-chloro-4-[(2,4-difluorobenzyl) Oxy] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1-glycloyl-3- (methylsulfonyl) -2,3-dihydro-1H-benzimidazole- 5-yl] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1- (2-hydroxy-2-methylpropanoyl) -3- (methylsulfonyl) -2,3 -Dihydro-1H-benzimidazol-5-yl] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [1- (N-methylglycyl) -3- (methylsulfonyl) -2,3-di Hydro-1H-benzimidazol-5-yl] pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1- (3-hydroxypropanoyl) -3- (methylsulfonyl) -2,3-dihydro- 1H-benzimidazol-5-yl] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1- (3-hydroxy-3-methylbutanoyl) -3- (methylsulfonyl) -2,3- Dihydro-1H-benzimidazol-5-yl] -6-methylpyridin-2 (1H) -one;

5- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3- (methylsulfonyl) -2, 3-dihydro-1H-benzimidazole-1-carboxamide;

1- [1,3-bis (methylsulfonyl) -2,3-dihydro-1H-benzimidazol-5-yl] -3-chloro-4-[(2,4-difluorobenzyl) oxy ] -6-methylpyridin-2 (1H) -one;

1- [3-acetyl-1- (methylsulfonyl) -2,3-dihydro-1H-benzimidazol-5-yl] -3-chloro-4-[(2,4-difluorobenzyl) Oxy] -6-methylpyridin-2 (1H) -one;

1- (1-acetyl-1H-pyrrol-3-yl) -3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- (1-glycloyl-1H-pyrrol-3-yl) -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1- (2-hydroxy-2-methylpropanoyl) -1H-pyrrol-3-yl] -6- Methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [1- (N-methylglycyl) -1H-pyrrol-3-yl] pyridine-2 (1H )-On;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1- (3-hydroxypropanoyl) -1H-pyrrol-3-yl] -6-methylpyridine-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1- (3-hydroxy-3-methylbutanoyl) -1H-pyrrol-3-yl] -6-methyl Pyridin-2 (1H) -one;

3- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -1H-pyrrole-1-carboxamide;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [1- (methylsulfonyl) -1H-pyrrol-3-yl] pyridine-2 (1H)- On;

1- (1-acetyl-1H-imidazol-4-yl) -3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- (1-glycloyl-1H-imidazol-4-yl) -6-methylpyridin-2 (1H) -one ;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1- (2-hydroxy-2-methylpropanoyl) -1H-imidazol-4-yl] -6 -Methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [1- (N-methylglycyl) -1H-imidazol-4-yl] pyridine-2 ( 1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1- (3-hydroxypropanoyl) -1H-imidazol-4-yl] -6-methylpyridine -2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1- (3-hydroxy-3-methylbutanoyl) -1H-imidazol-4-yl] -6- Methylpyridin-2 (1H) -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-1- [1- (methylsulfonyl) -1H-imidazol-4-yl] pyridine-2 (1H) -On;

1- (1-acetyl-1H-pyrazol-4-yl) -3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- (1-glycloyl-1H-pyrazol-4-yl) -6-methylpyridin-2 (1H) -one ;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1- (2-hydroxy-2-methylpropanoyl) -1H-pyrazol-4-yl] -6 -Methylpyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [1- (N-methylglycyl) -1H-pyrazol-4-yl] pyridine-2 ( 1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1- (3-hydroxypropanoyl) -1H-pyrazol-4-yl] -6-methylpyridine- 2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [1- (3-hydroxy-3-methylbutanoyl) -1H-pyrazol-4-yl] -6- Methylpyridin-2 (1H) -one;

4- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -1H-pyrazole-1-carboxamide ;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [1- (methylsulfonyl) -1H-pyrazol-4-yl] pyridine-2 (1H) -On;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isoquinolin-7-yl-6-methylpyridin-2 (1H) -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-1 (2H) -yl] methyl} -1,3-dihydro-2H-indole- 2-one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- (2,3-dihydro-1H-indol-5-ylmethyl) pyridin-2 (1H) -one;

1-[(1-acetyl-2,3-dihydro-1H-indol-5-yl) methyl] -3-chloro-4-[(2,4-difluorobenzyl) oxy] pyridine-2 (1H )-On;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-[(1-glycloyl-2,3-dihydro-1H-indol-5-yl) methyl] pyridine-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[1- (2-hydroxy-2-methylpropanoyl) -2,3-dihydro-1H-indole -5-yl] methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[1- (N-methylglycyl) -2,3-dihydro-1H-indol-5-yl] methyl } Pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- {1- (3-hydroxypropanoyl) -2,3-dihydro-1-indol-5-yl] Methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[1- (3-hydroxy-3-methylbutanoyl) -2,3-dihydro-1H-indole- 5-yl] methyl} pyridin-2 (1H) -one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} indoline-1-carboxamide;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[1- (methylsulfonyl) -2,3-dihydro-1H-indol-5-yl] methyl} pyridine -2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- (2,3-dihydro-1H-isoindol-5-ylmethyl) pyridin-2 (1H) -one;

1-[(2-acetyl-2,3-dihydro-1H-isoindol-5-yl) methyl] -3-chloro-4-[(2,4-difluorobenzyl) oxy] pyridine-2 ( 1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-[(2-glycloyl-2,3-dihydro-1H-isoindol-5-yl) methyl] pyridine- 2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[2- (2-hydroxy-2-methylpropanoyl) -2,3-dihydro-1H-iso Indol-5-yl] methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[2- (N-methylglycyl) -2,3-dihydro-1H-isoindol-5-yl] Methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[2- (3-hydroxypropanoyl) -2,3-dihydro-1H-isoindole-5- Il] methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[2- (3-hydroxy-3-methylbutanoyl) -2,3-dihydro-1H-isoindole -5-yl] methyl} pyridin-2 (1H) -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] -1-{[2- (methylsulfonyl) -2,3-dihydro-1H-isoindol-5-yl] methyl} Pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- (1,2,3,4-tetrahydroisoquinolin-6-ylmethyl) pyridin-2 (1H) -one;

1-[(2-acetyl-1,2,3,4-tetrahydroisoquinolin-6-yl) methyl] -3-chloro-4-[(2,4-difluorobenzyl) oxy] pyridine-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-[(2-glycloyl-1,2,3,4-tetrahydroisoquinolin-6-yl) methyl] pyridine -2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[2- (2-hydroxy-2-methylpropanoyl) -1,2,3,4-tetrahydro Isoquinolin-6-yl] methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[2- (N-methylglycyl) -1,2,3,4-tetrahydroisoquinolin-6-yl ] Methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[2- (3-hydroxypropanoyl) -1,2,3,4-tetrahydroisoquinoline-6 -Yl] methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[2- (3-hydroxy-3-methylbutanoyl) -1,2,3,4-tetrahydroiso Quinolin-6-yl] methyl} pyridin-2 (1H) -one;

6-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3,4-dihydroisoquinoline-2 ( 1H) -carboxamide;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[2- (methylsulfonyl) -1,2,3,4-tetrahydroisoquinolin-6-yl] methyl } Pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- (1,2,3,4-tetrahydroisoquinolin-5-ylmethyl) pyridin-2 (1H) -one;

1-[(2-acetyl-1,2,3,4-tetrahydroisoquinolin-5-yl) methyl-3-chloro-4-[(2,4-difluorobenzyl) oxy] pyridine-2 ( 1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-[(2-glycloyl-1,2,3,4-tetrahydroisoquinolin-5-yl) methyl] pyridine -2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[2- (2-hydroxy-2-methylpropanoyl) -1,2,3,4-tetrahydro Isoquinolin-5-yl] methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[2- (N-methylglycyl) -1,2,3,4-tetrahydroisoquinolin-5-yl ] Methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[2- (3-hydroxypropanoyl) -1,2,3,4-tetrahydroisoquinoline-5 -Yl] methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[2- (3-hydroxy-3-methylbutanoyl) -1,2,3,4-tetrahydroiso Quinolin-5-yl] methyl} pyridin-2 (1H) -one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3,4-dihydroisoquinoline-2 ( 1H) -carboxamide;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[2- (methylsulfonyl) -1,2,3,4-tetra hydroisoquinolin-5-yl] methyl } Pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- (2,3-dihydro-1H-benzimidazol-5-ylmethyl) pyridin-2 (1H) -one;

1-[(1-acetyl-2,3-dihydro-1H-benzimidazol-5-yl) methyl] -3-chloro-4-[(2,4-difluorobenzyl) oxy] pyridine-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-[(1-glycloyl-2,3-dihydro-1H-benzimidazol-5-yl) methyl] pyridine -2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[1- (2-hydroxy-2-methylpropanoyl) -2,3-dihydro-1H-benz Imidazol-5-yl] methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[1- (N-methylglycyl) -2,3-dihydro-1H-benzimidazol-5-yl ] Methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[1- (3-hydroxypropanoyl) -2,3-dihydro-1H-benzimidazole-5 -Yl] methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[1- (3-hydroxy-3-methylbutanoyl) -2,3-dihydro-1H-benzimi Dazol-5-yl] methyl} pyridin-2 (1H) -one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -2,3-dihydro-1H-benzimi Dozol-1-carboxamide;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[1- (methylsulfonyl) -2,3-dihydro-1H-benzimidazol-5-yl] methyl } Pyridin-2 (1H) -one;

1-[(3-acetyl-2,3-dihydro-1H-benzimidazol-5-yl) methyl] -3-chloro-4-[(2,4-difluorobenzyl) oxy] pyridine-2 (1H) -one;

3-chloro-1-[(1,3-diacetyl-2,3-dihydro-1H-benzimidazol-5-yl) methyl] -4-[(2,4-difluorobenzyl) oxy] Pyridin-2 (1H) -one;

1-[(3-acetyl-1-glycoyl-2,3-dihydro-1H-benzimidazol-5-yl) methyl] -3-chloro-4-[(2,4-difluorobenzyl ) Oxy] pyridin-2 (1H) -one;

1-{[3-acetyl-1- (2-hydroxy-2-methylpropanoyl) -2,3-dihydro-1H-benzimidazol-5-yl] methyl} -3-chloro-4- [(2,4-difluorobenzyl) oxy] pyridin-2 (1H) -one;

1-{[3-acetyl-1- (N-methylglycidyl) -2,3-dihydro-1H-benzimidazol-5-yl] methyl} -3-chloro-4-[(2,4- Difluorobenzyl) oxy] pyridin-2 (1H) -one;

1-{[3-acetyl-1- (3-hydroxypropanoyl) -2,3-dihydro-1H-benzimidazol-5-yl] methyl} -3-chloro-4-[(2, 4-difluorobenzyl) oxy] pyridin-2 (1H) -one;

1-{[3-acetyl-1- (3-hydroxy-3-methylbutanoyl) -2,3-dihydro-1H-benzimidazol-5-yl] methyl} -3-chloro-4- [ (2,4-difluorobenzyl) oxy] pyridin-2 (1H) -one;

3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -2,3-dihydro- 1H-benzimidazole-1-carboxamide;

1-{[3-acetyl-1- (methylsulfonyl) -2,3-dihydro-1H-benzimidazol-5-yl] methyl} -3-chloro-4-[(2,4-difluoro Lobenzyl) oxy] pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-[(3-glycloyl-2,3-dihydro-1H-benzimidazol-5-yl) methyl] pyridine -2 (1H) -one;

1-[(1-acetyl-3-glycloyl-2,3-dihydro-1H-benzimidazol-5-yl) methyl] -3-chloro-4-[(2,4-difluoro Benzyl) oxy] pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-[(1,3-diglycoloyl-2,3-dihydro-1H-benzimidazol-5-yl) Methyl] pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[3-glycloyl-1- (2-hydroxy-2-methylpropanoyl) -2,3- Dihydro-1H-benzimidazol-5-yl] methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[3-glycloyl-1- (N-methylglycyl) -2,3-dihydro-1H-benz Imidazol-5-yl] methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[3-glycloyl-1- (3-hydroxypropanoyl) -2,3-dihydro-1H -Benzimidazol-5-yl] methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[3-glycloyl-1- (3-hydroxy-3-methylbutanoyl) -2,3-di Hydro-1H-benzimidazol-5-yl] methyl} pyridin-2 (1H) -one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3-glycoyl-2,3-di Hydro-1H-benzimidazole-1-carboxamide;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[3-glycloyl-1- (methylsulfonyl) -2,3-dihydro-1H-benzimidazole -5-yl] methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[3- (2-hydroxy-2-methylpropanoyl) -2,3-dihydro-1H-benz Imidazol-5-yl] methyl} pyridin-2 (H) -one;

1-{[1-acetyl-3- (2-hydroxy-2-methylpropanoyl) -2,3-dihydro-1H-benzimidazol-5-yl] methyl} -3-chloro-4- [(2,4-difluorobenzyl) oxy] pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[1-glycloyl-3- (2-hydroxy-2- methylpropanoyl) -2,3- Dihydro-1H-benzimidazol-5-yl] methyl} pyridin-2 (1H) -one;

1-{[1,3-bis (2-hydroxy-2-methylpropanoyl) -2,3-dihydro-1H-benzimidazol-5-yl] methyl} -3-chloro-4- [ (2,4-difluorobenzyl) oxy] pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[3- (2-hydroxy-2-methylpropanoyl) -1- (N-methylgylsil)- 2,3-dihydro-1H-benzimidazol-5-yl] methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[3- (2-hydroxy-2-methylpropanoyl) -1- (3-hydroxypropanoyl ) -2,3-dihydro-1H-benzimidazol-5-yl] methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[1- (3-hydroxy-3-methylbutanoyl) -3- (2-hydroxy-2-methyl Propanoyl) -2,3-dihydro-1H-benzimidazol-5-yl] methyl} pyridin-2 (1H) -one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3- (2-hydroxy-2-methyl Propanoyl) -2,3-dihydro-1H-benzimidazole-1-carboxamide;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[3- (2-hydroxy-2-methylpropanoyl) -1- (methylsulfonyl) -2, 3-dihydro-1H-benzimidazol-5-yl] methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[3- (N-methylglycyl) -2,3-dihydro-1H-benzimidazol-5-yl ] Methyl} pyridin-2 (1H) -one;

1-{[1-acetyl-3- (N-methylglycyl) -2,3-dihydro-1H-benzimidazol-5-yl] methyl} -3-chloro-4-[(2,4- Difluorobenzyl) oxy] pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[1-glycloyl-3- (N-methylglycyl) -2,3-dihydro-1H-benz Imidazol-5-yl] methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[1- (2-hydroxy-2-methylpropanoyl) -3- (N-methylglysil)- 2, .3-dihydro-1H-benzimidazol-5-yl] methyl} pyridin-2 (1H) -one;

1-{[1,3-bis (N-methylglycyl) -2,3-dihydro-1H-benzimidazol-5-yl] methyl} -3-chloro-4-[(2,4-di Fluorobenzyl) oxy] pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[1- (3-hydroxypropanoyl) -3- (N-methylglysil) -2,3- Dihydro-1H-benzimidazol-5-yl] methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[1- (3-hydroxy-3-methylbutanoyl) -3- (N-methylgylsil) -2 , 3-dihydro-1H-benzimidazol-5-yl] methyl} pyridin-2 (1H) -one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3- (N-methylglycyl) -2 , 3-dihydro-1H-benzimidazole-1-carboxamide;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[3- (N-methylglycyl) -1- (methylsulfonyl) -2,3-dihydro-1H -Benzimidazol-5-yl] methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[3- (3-hydroxypropanoyl) -2,3-dihydro-1H-benzimidazole-5 -Yl] methyl} pyridin-2 (1H) -one;

1-{[1-acetyl-3- (3-hydroxypropanoyl) -2,3-dihydro-1H-benzimidazol-5-yl] methyl} -3-chloro-4-[(2, 4-difluorobenzyl) oxy] pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[1-glycloyl-3- (3-hydroxypropanoyl) -2,3-dihydro-1H -Benzimidazol-5-yl] methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[1- (2-hydroxy-2-methylpropanoyl) -3- (3-hydroxypropanoyl ) -2,3-dihydro-1H-benzimidazol-5-yl] methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[3- (3-hydroxypropanoyl) -1- (N-methylgylsil) -2,3- Dihydro-1H-benzimidazol-5-yl] methyl} pyridin-2 (1H) -one;

1-{[1,3-bis (3-hydroxypropanoyl) -2,3-dihydro-1H-benzimidazol-5-yl] methyl} -3-chloro-4-[(2,4 -Difluorobenzyl) oxy] pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[1- (3-hydroxy-3-methylbutanoyl) -3- (3-hydroxypropanoyl) -2,3-dihydro-1H-benzimidazol-5-yl] methyl} pyridin-2 (1H) -one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3- (3-hydroxypropanoyl) -2,3-dihydro-1H-benzimidazole-1-carboxamide;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[3- (3-hydroxypropanoyl) -1- (methylsulfonyl) -2,3-dihydro -1H-benzimidazol-5-yl] methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[3- (3-hydroxy-3-methylbutanoyl) -2,3-dihydro-1H-benzimi Dazol-5-yl] methyl} pyridin-2 (1H) -one;

1-{[1-acetyl-3- (3-hydroxy-3-methylbutanoyl) -2,3-dihydro-1H-benzimidazol-5-yl] methyl} -3-chloro-4- [ (2,4-difluorobenzyl) oxy] pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[1-glycloyl-3- (3-hydroxy-3-methylbutanoyl) -2,3-di Hydro-1H-benzimidazol-5-yl] methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[3- (3-hydroxy-3-methylbutanoyl) -1- (2-hydroxy-2-methyl Propanoyl) -2,3-dihydro-1H-benzimidazol-5-yl] methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[3- (3-hydroxy-3-methylbutanoyl) -1- (N-methylgylsil) -2 , 3-dihydro-1H-benzimidazol-5-yl] methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[3- (3-hydroxy-3-methylbutanoyl) -1- (methylsulfonyl) -2,3 -Dihydro-1H-benzimidazol-5-yl] methyl} pyridin-2 (1H) -one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3- (3-hydroxy-3-methyl Butanoyl) -2,3-dihydro-1H-benzimidazole-1-carboxamide;

1-{[1,3-bis (3-hydroxy-3-methylbutanoyl) -2,3-dihydro-1H-benzimidazol-5-yl] methyl} -3-chloro-4-[( 2,4-difluorobenzyl) oxy] pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[3- (3-hydroxy-3-methylbutanoyl) -1- (3-hydroxypropanoyl) -2,3-dihydro-1H-benzimidazol-5-yl] methyl} pyridin-2 (1H) -one;

6-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -2,3-dihydro-1H-benzimi Dozol-1-carboxamide;

3-acetyl-6-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -2,3-dihydro- 1H-benzimidazole-1-carboxamide;

6-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3-glycoyl-2,3-di Hydro-1H-benzimidazole-1-carboxamide;

6-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3- (2-hydroxy-2-methyl Propanoyl) -2,3-dihydro-1H-benzimidazole-1-carboxamide;

6-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3- (N-methylglycyl) -2 , 3-dihydro-1H-benzimidazole-1-carboxamide;

6-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3- (3-hydroxypropanoyl) -2,3-dihydro-1H-benzimidazole-1-carboxamide;

6-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3- (3-hydroxy-3-methyl Butanoyl) -2,3-dihydro-1H-benzimidazole-1-carboxamide;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1H-benzimidazole-1,3 (2H ) -Dicarboxamide;

6-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3- (methylsulfonyl) -2,3 -Dihydro-1H-benzimidazole-1-carboxamide;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[3- (methylsulfonyl) -2,3-dihydro-1H-benzimidazol-5-yl] methyl } Pyridin-2 (1H) -one;

1-{[1-acetyl-3- (methylsulfonyl) -2,3-dihydro-1H-benzimidazol-5-yl] methyl} -3-chloro-4-[(2,4-difluoro Lobenzyl) oxy] pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[1-glycloyl-3- (methylsulfonyl) -2,3-dihydro-1H-benzimidazole -5-yl] methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[1- (2-hydroxy-2-methylpropanoyl) -3- (methylsulfonyl) -2, 3-dihydro-1H-benzimidazol-5-yl] methyl} pyridin-2 (H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[1- (N-methylglycyl) -3- (methylsulfonyl) -2,3-dihydro-1 -Benzimidazol-5-yl] pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy-1- [1- (3-hydroxypropanoyl) -3- (methylsulfonyl) -2,3-dihydro-1H -Benzimidazol-5-yl] methyl} pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[1- (3-hydroxy-3-methylbutanoyl) -3- (methylsulfonyl) -2,3 -Dihydro-1H-benzimidazol-5-yl] methyl} pyridin-2 (1H) -one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3- (methylsulfonyl) -2,3 -Dihydro-1H-benzimidazole-1-carboxamide;

1-{[1,3-bis (methylsulfonyl) -2,3-dihydro-1H-benzimidazol-5-yl] methyl} -3-chloro-4-[(2,4-difluoro Benzyl) oxy] pyridin-2 (1H) -one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1,3-dihydro-2H-benzimi Dazol-2-one;

1-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1,3-dihydro- 2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1-glycoyl-1,3-di Hydro-2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1- (2-hydroxy-2-methyl Propanoyl) -1,3-dihydro-2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1- (N-methylglycyl) -1 , 3-dihydro-2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1- (3-hydroxypropanoyl) -1,3-dihydro-2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1- (3-hydroxy-3-methyl Butanoyl) -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- 1H-benzimidazole-1-carboxamide;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1- (methylsulfonyl) -1,3 -Dihydro-2H-benzimidazol-2-one;

1-acetyl-6-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1,3-dihydro- 2H-benzimidazol-2-one;

1,3-diacetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1,3- Dihydro-2H-benzimidazol-2-one;

3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1-glycloyl-1 , 3-dihydro-2H-benzimidazol-2-one;

3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1- (2-hydroxy -2-methylpropanoyl) -1,3-dihydro-2H-benzimidazol-2-one;

3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1- (N-methylglycol Lysyl) -1,3-dihydro-2H-benzimidazol-2-one;

3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1- (3-hydroxy Propanoyl) -1,3-dihydro-2H-benzimidazol-2-one;

3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1- (3-hydroxy -3-methylbutanoyl) -1,3-dihydro-2H-benzimidazol-2-one;

3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -2-oxo-2,3 -Dihydro-1H-benzimidazole-1-carboxamide;

3-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1- (methylsulfonyl) -1,3-dihydro-2H-benzimidazol-2-one;

6-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1-glycoyl-1,3-di Hydro-2H-benzimidazol-2-one;

1-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3-glycloyl-1 , 3-dihydro-2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1,3-diglyloyl-1, 3-dihydro-2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3-glycloyl-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-glycloyl-1- (N- Methylglycyl) -1,3-dihydro-2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3-glycloyl-1- (3- Hydroxypropanoyl) -1,3-dihydro-2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3-glycloyl-1- (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} -3-glycloyl-2-oxo-2 , 3-dihydro-1H-benzimidazole-1-carboxamide;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3-glycloyl-1- (methylsul Phonyl) -1,3-dihydro-2H-benzimidazol-2-one;

6-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1- (2-hydroxy-2-methyl Propanoyl) -1,3-dihydro-2H-benzimidazol-2-one;

1-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -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-glycloyl-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} -1,3-bis (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- (2-hydroxy-2-methyl Propanoyl) -1- (N-methylglycyl) -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-methyl Propanoyl) -1- (3-hydroxypropanoyl) -1,3-dihydro-2H-benz imidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1- (3-hydroxy-3-methyl Butanoyl) -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} -3- (2-hydroxy-2-methyl Propanoyl) -2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3- (2-hydroxy-2-methyl Propanoyl) -1- (methylsulfonyl) -1,3-dihydro-2H-benzimidazol-2-one;

6-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1- (N-methylglycyl) -1 , 3-dihydro-2H-benzimidazol-2-one;

1-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3- (N-methylglycol Lysyl) -1,3-dihydro-2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1-glycloyl-3- (N- Methylglycyl) -1,3-dihydro-2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1- (2-hydroxy-2-methyl Propanoyl) -3- (N-methylglycosyl) -1,3-dihydro-2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1,3-bis (N-methylglysil ) -1,3-dihydro-2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1- (3-hydroxypropanoyl) -3- (N-methylglycyl) -1,3-dihydro-2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1- (3-hydroxy-3-methyl Butanoyl) -3- (N-methylglycosyl) -1,3-dihydro-2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3- (N-methylglycyl) -2 -Oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (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-1 (2H) -yl] methyl} -1- (3-hydroxypropanoyl) -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 Propanoyl) -1,3-dihydro-2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1-glycloyl-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- (2-hydroxy-2-methyl Propanoyl) -3- (3-hydroxypropanoyl) -1,3-dihydro-2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3 (3-hydroxypropanoyl) -1- (N-methylglycyl) -1,3-dihydro-2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1,3-bis (3-hydroxypro Panoyl) -1,3-dihydro-2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1- (3-hydroxy-3-methyl Butanoyl) -3- (3-hydroxypropanoyl) -1,3-dihydro-2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3- (3-hydroxypropanoyl) 2-oxo-2,3-dihydro-1 H-benzimidazole-1-carboxamide;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3- (3-hydroxypropanoyl) -1- (methylsulfonyl) -1,3-dihydro-2H-benzimidazol-2-one;

6-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1- (3-hydroxy-3-methyl Butanoyl) -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) -1,3-dihydro-2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1-glycloyl-3- (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} -3- (3-hydroxy-3-methyl Butanoyl) -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- (3-hydroxy-3-methyl Butanoyl) -1- (N-methylglycosyl) -1,3-dihydro-2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3- (3-hydroxy-3-methyl Butanoyl) -1- (3-hydroxypropanoyl) -1,3-dihydro-2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1,3-bis (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} -3- (3-hydroxy-3-methyl Butanoyl) -2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3- (3-hydroxy-3-methyl Butanoyl) -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- 1H-benzimidazole-1-carboxamide;

3-acetyl-6-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -2-oxo-2,3 -Dihydro-1H-benzimidazole-1-carboxamide;

6-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3-glycoyl-2-oxo-2 , 3-dihydro-1H-benzimidazole-1-carboxamide;

6-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3- (2-hydroxy-2-methyl Propanoyl) -2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;

6-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3- (N-methylglycyl) -2 -Oxo-2,3-dihydro-1H-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-1 H-benzimidazole-1-carboxamide;

6-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3- (3-hydroxy-3-methyl Butanoyl) -2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxamide;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -2-oxo-1H-benzimidazole-1 , 3 (2H) -dicarboxamide;

6-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3- (methylsulfonyl) -2-oxo -2,3-dihydro-1H-benzimidazole-1-carboxamide;

6-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1- (methylsulfonyl) -1,3 -Dihydro-2H-benzimidazol-2-one;

1-acetyl-5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3- (methylsulfonyl) -1,3-dihydro-2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1-glycoyl-3- (methylsul Phonyl) -1,3-dihydro-2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1- (2-hydroxy-2-methyl Propanoyl) -3- (methylsulfonyl) -1,3-dihydro-2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1- (N-methylgylsil) -3 -(Methylsulfonyl) -1,3-dihydro-2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1- (3-hydroxypropanoyl) 3- (methylsulfonyl) -1,3-dihydro-2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1- (3-hydroxy-3-methyl Butanoyl) -3- (methylsulfonyl) -1,3-dihydro-2H-benzimidazol-2-one;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -3- (methylsulfonyl) -2-oxo -2,3-dihydro-1H-benzimidazole-1-carboxamide;

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -1,3-bis (methylsulfonyl)- 1,3-dihydro-2H-benzimidazol-2-one;

3-benzyl-4-hydroxy-1- (2-phenylethyl) pyridin-2 (1H) -one;

1-benzyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carbaldehyde;

1-benzyl-4-chloro-2-oxo-1,2-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 (1H) -one;

3-bromo-1- (2,6-dichlorophenyl) -4-[(4-fluorophenyl) ethynyl] -6-methylpyridin-2 (1H) -one;

3-bromo-1- (2,6-dichlorophenyl) -4-[(4-fluorophenyl) ethynyl] -6-methylpyridin-2 (1H) -one;

Methyl 3-chloro-4- [4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzoate;

4-[(2,4-difluorobenzyl) oxy] -1- (3-fluorobenzyl) -2-oxo-1,2-dihydropyridine-3-carbonitrile;

4-[(2,4-difluorobenzyl) oxy] -6- (hydroxymethyl) -1- (2,4,6-trifluorophenyl) pyridin-2 (1H) -one;

4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [2- (trifluoromethyl) phenyl] pyridin-2 (1H) -one;

3- [4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzaldehyde;

4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluoro-4-morpholin-4-ylphenyl) -6-methylpyridin-2 (1H) -one;

4-[(2,4-difluorobenzyl) oxy] -1- [2,6-difluoro-4- (4-methylpiperazin-1-yl) phenyl] -6-methylpyridine-2 ( 1H) -one;

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzoic acid;

4-[(2,4-difluorobenzyl) oxy] -1- [4- (dimethylamino) -2,6-difluorophenyl] -6-methylpyridin-2 (1H) -one;

4-[(2,4-difluorobenzyl) oxy] -1- {2,6-difluoro-4-[(2-hydroxyethyl) (methyl) amino] phenyl} -6-methylpyridine- 2 (1H) -one;

Methyl 3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzoate;

3- [4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methylbenzoic acid;

4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6- (hydroxymethyl) pyridin-2 (1H) -one;

3-bromo-1-{[5- (chloromethyl) pyrazin-2-yl] methyl} -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridine-2 (1H)- On;

1- [2-chloro-5- (hydroxymethyl) phenyl] -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluoro-4-hydroxyphenyl) -6-methylpyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [4- (hydroxymethyl) -2-methoxyphenyl] -6-methylpyridin-2 (1H) -one ;

Methyl 3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methylbenzoate;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- {3-[(4-methylpiperazin-1-yl) carbonyl] pyridine-2 (1H )-On;

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N- [2- (dimethylamino) Ethyl] benzamide;

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N- (2-methoxyethyl) Benzamide;

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N- [2- (dimethylamino) Ethyl] -N-methylbenzamide;

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N- (2-hydroxyethyl) -N-methylbenzamide;

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N- (2-methoxyethyl) -N-methylbenzamide;

4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzamide;

Methyl 3- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-fluorobenzoate;

4- [4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3-methylbenzoic acid;

1- (4-bromo-2-methylphenyl) -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

1-[(1-acetyl-1H-indol-5-yl) methyl] -3-chloro-4-[(2,4-difluorobenzyl) oxy] pyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-[(5-methylpyrazin-2-yl) methyl] pyridin-2 (1H) -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] -1-{[5- (hydroxymethyl) pyrazin-2-yl] methyl} -6-methylpyridine-2 (1H) -On;

4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1- (2H) -yl] methyl} -N, N-dimethyl Benzamide;

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N- (2-hydroxyethyl) -4-methylbenzamide;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- {4-[(4-methylpiperazin-1-yl) carbonyl] benzyl} pyridine-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- (1H-indol-5-ylmethyl) pyridin-2 (1H) -one;

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N-methylbenzamide;

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzamide;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[5- (hydroxymethyl) pyrazin-2-yl] methyl} -6-methylpyridine-2 (1H)- On;

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N- (2-methoxyethyl) -4-methylbenzamide;

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N, 4-dimethylbenzamide;

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N, N, 4-trimethylbenzamide ;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [2-methyl-5- (morpholin-4-ylcarbonyl) phenyl] pyridine-2 ( 1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [5- (1-hydroxy-1-methylethyl) -2-methylphenyl] -6-methylpyridine-2 ( 1H) -one;

1- (2-bromobenzyl) -3-[(2-bromobenzyl) oxy] pyridin-2- (1H) -one;

1- (2-bromobenzyl) -3-[(2-bromobenzyl) oxy] pyridin-2- (1H) -one;

3-bromo-1- (4-methoxybenzyl) -4-phenoxypyridin-2 (1H) -one;

1-benzyl-2-oxo-4-phenoxy-1,2-dihydropyridine-3-carbaldehyde;

3-bromo-4- (2,4-difluoro-benzyloxy) -1- (3-dimethylaminomethyl-benzyl) -6-methyl-1H-pyridin-2-one;

N- (3- [3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-yl methyl] -benzyl} -2-hydrate Oxy-acetamide;

3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-1- [4- (piperidine-1-carbonyl) -benzyl] -1 H-pyridin-2-one ;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-[(ethoxyamino) methyl] pyridine-2 (1H) -On;

4- [3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] -N-isopropyl-benzamide;

N- (3-aminopropyl) -4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] Methyl} benzamide hydrochloride;

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N, 4-dimethylbenzamide;

4- [3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-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-1-ylmethyl] -N-hydroxy-benzamide;

4- [3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] -N-methyl-benzamide;

4- [3-Bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] -N- (2-dimethylamino-ethyl ) -Benzamide;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (1H-indazol-5-ylmethyl) pyridin-2 (1H) -one;

3-Bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-1- [4- (4-methyl-piperazine-1-carbonyl) -benzyl] -1 H-pyridine- 2-one;

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methylbenzaldehyde;

3-bromo-4- (2,4-difluoro-benzyloxy) -1- (4-dimethylaminomethyl-benzyl) -6-methyl-1H-pyridin-2-one;

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N- (2-methoxyethyl) -4-methylbenzamide;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [2- (dimethylamino) -4,6-difluorophenyl] -6-methylpyridine-2 (1H) -One hydrochloride;

N- (2-aminoethyl) -4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] Methyl} benzamide hydrochloride;

4- [3-Bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] -N- (2-hydroxy-ethyl ) -Benzamide;

3-bromo-4- (2,4-difluoro-benzyloxy) -1- (4-hydroxymethyl-benzyl) -6-methyl-1H-pyridin-2-one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [2,6-difluoro-4- (4-methylpiperazin-1-yl) phenyl] -6- Methylpyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [2- (dimethylamino) -4,6-difluorophenyl] -6-methylpyridine-2 (1H) -On;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [2,6-difluoro-4- (4-methylpiperazin-1-yl) phenyl] -6- Methylpyridin-2 (1H) -one;

4- [3-Bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] -N- (2-methoxy-ethyl ) -Benzamide;

3-Bromo-4- (2,4-difluoro-benzyloxy) -1- {4-[(2-hydroxy-ethylamino) -methyl] -benzyl} -6-methyl-1 H-pyridine- 2-one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-[(dimethylamino) methyl] pyridine-2 (1H)- On;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [2-methyl-5- (morpholin-4-ylcarbonyl) phenyl] pyridine-2 ( 1H) -one;

3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-1- (4-methylaminomethyl-benzyl) -1H-pyridin-2-one;

3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-1- [4- (morpholin-4-carbonyl) -benzyl] -1 H-pyridin-2-one;

N- (2-aminoethyl) -3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benz amides;

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-2H-pyridin-1-ylmethyl] -N- (2-methoxy-ethyl ) -N-methyl-benzamide;

1- (4-aminomethyl-benzyl) -3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-1H-pyridin-2-one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [4- (piperazin-1-ylcarbonyl) benzyl] pyridin-2 (1H) -one Hydrochloride;

3-bromo-4- (2,4-difluoro-benzyloxy) -1- [4- (isopropylamino-methyl) -benzyl] -6-methyl-1 H-pyridin-2-one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-dimethylphenyl) -6-methylpyridin-2 (1H) -one;

3-Bromo-4- (2,4-difluoro-benzyloxy) -1- {3-[(2-hydroxy-ethylamino) -methyl] -benzyl} -6-methyl-1 H-pyridine- 2-one;

1- (3-aminomethyl-benzyl) -3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-1H-pyridin-2-one;

3-bromo-4- (2,4-difluoro-benzyloxy) -1- (4-hydroxy-benzyl) -6-methyl-1H-pyridin-2-one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-[(dimethylamino) methyl] pyridin-2 (1H) -one ;

N- {3- [3-Bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-yl methyl] -benzyl} -acetamide;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- {2,6-difluoro-4-[(2-hydroxyethyl) (methyl) amino] phenyl}- 6-methylpyridin-2 (1H) -one;

Ethyl 3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzoate;

1- [3- (aminomethyl) benzyl] -3-bromo-4-[(2,4-difluorobenzyl) oxy] pyridin-2 (1H) -one trifluoroacetate;

1- (3-{[bis- (2-hydroxy-ethyl) -amino] -methyl} -benzyl) -3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl -1H-pyridin-2-one;

3-bromo-4- (2,4-difluoro-benzyloxy) -1- [3- (isopropylamino-methyl) -benzyl] -6-methyl-1 H-pyridin-2-one;

{3- [3-Bromo-4- (2,4-difluoro-benzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] -benzyl} -carbamic acid tert-butyl ester;

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzamide;

3-Bromo-4- (2,4-difluoro-benzyloxy) -1- [4- (1-hydroxy-1-methyl-ethyl) -benzyl] -6-methyl-1 H-pyridine-2 -On;

3-bromo-4- (2,4-difluoro-benzyloxy) -1- (3-dimethylaminomethyl-benzyl) -1H-pyridin-2-one;

3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-1- (3-piperidin-1-ylmethyl-benzyl) -1H-pyridin-2-one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-{[(2-methoxyethyl) amino] methyl} pyridine -2 (1H) -one;

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N-methylbenzamide;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- {2,4-difluoro-6-[(2-hydroxyethyl) (methyl) amino] phenyl}- 6-methylpyridin-2 (1H) -one;

3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-1- (3-morpholin-4-ylmethyl-benzyl) -1H-pyridin-2-one;

3-bromo-1- (2,6-dimethylphenyl) -6-methyl-4-[(2,4,6-trifluorobenzyl) oxy] pyridin-2 (1H) -one;

3-bromo-1- (2,6-dimethylphenyl) -6-methyl-4-[(2,4,6-trifluorobenzyl) oxy] pyridin-2 (1H) -one;

1- (4-{[bis- (2-hydroxy-ethyl) -amino] -methyl} -benzyl) -3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl -1H-pyridin-2-one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluoro-4-morpholin-4-ylphenyl) -6-methylpyridine-2 ( 1H) -one;

4-benzyloxy-3-bromo-1- (4-fluoro-benzyl) -1 H-pyridin-2-one;

4- [3-Chloro-4- (2,4-difluoro-benzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] -benzamide;

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N, N, 4-trimethylbenzamide ;

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N-isopropylbenzamide;

4- [3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] -benzamide;

3- [3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] -benzonitrile;

3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-1- (3-piperazin-1-ylmethyl-benzyl) -1H-pyridin-2-one;

4- [3-Bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-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-1- [3- (morpholin-4-carbonyl) -benzyl] -1 H-pyridin-2-one;

3- [3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] -N, N-bis- (2- Hydroxy-ethyl) -benzamide;

4- [3-Bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] -benzoic acid methyl ester;

3- [3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] -N-hydroxy-benzamide;

3-bromo-4- (2,4-difluoro-benzyloxy) -1- (3-hydroxymethyl-benzyl) -6-methyl-1H-pyridin-2-one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (3-fluorobenzyl) pyridin-2 (1H) -one;

3-bromo-4- (2,4-difluoro-benzyloxy) -1- (3-fluoro-benzyl) -1H-pyridin-2-one;

N-3- [3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] -benzyl} -methanesulfonamide;

3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-1- [3- (pyrrolidine-1-carbonyl) -benzyl] -1 H-pyridin-2-one ;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one;

N- (3-aminopropyl) -3-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] Methyl} benzamide hydrochloride;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one;

3-bromo-4- (2,4-difluoro-benzyloxy) -1- (3-methylaminomethyl-benzyl) -1H-pyridin-2-one;

4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3,5-dichlorobenzenesulfonamide;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [4- (dimethylamino) -2,6-difluorophenyl] -6-methylpyridine-2 (1H) -On;

3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-1- (4-piperidin-1-ylmethyl-benzyl) -1H-pyridin-2-one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (pyridin-4-ylmethyl) pyridin-2 (1H) -one;

N- (2-aminoethyl) -3-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] Methyl} benzamide hydrochloride;

3-bromo-1- [2-chloro-5- (hydroxymethyl) phenyl] -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-methylpyridin-2 (1H) -one;

3-chloro-1- [2-chloro-5- (hydroxymethyl) phenyl] -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N- (2-hydroxyethyl) -4-methylbenzamide;

2- {3- [3-Bromo-4- (2,4-difluoro-benzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] -phenyl} -acetamide;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [3- (piperazin-1-ylcarbonyl) benzyl] pyridin-2 (1H) -one Hydrochloride;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-methylpyridin-2 (1H) -one;

4- [3-Bromo-4- (2,4-difluoro-benzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] -benzoic acid methyl ester;

1- (3-aminomethyl-2-fluoro-benzyl) -3-bromo-4- (2,4-difluoro-benzyloxy) -1H-pyridin-2-one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6- (morpholin-4-ylmethyl) pyridine-2 (1H )-On;

4- (benzyloxy) -3-bromo-1- (4-fluorobenzyl) pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- (1H-indol-5-ylmethyl) pyridin-2 (1H) -one;

1- [3- (aminomethyl) benzyl] -3-bromo-4-[(4-fluorobenzyl) oxy] pyridin-2 (1H) -one trifluoroacetate;

1- [3- (2-aminoethyl) benzyl] -3-bromo-4-[(2,4-difluorobenzyl) oxy] pyridin-2 (1H) -one trifluoroacetate;

1- [3- (aminomethyl) benzyl] -3-bromo-4-[(4-fluorobenzyl) oxy] pyridin-2 (1H) -one;

3-bromo-1- (2,6-dichlorophenyl) -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N- (2-hydroxyethyl) Benzamide;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (pyridin-4-ylmethyl) pyridin-2 (1H) -one;

3-bromo-4- (2,4-difluoro-benzyloxy) -1- (4-methoxy-benzyl) -6-methyl-1H-pyridin-2-one;

4- [3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] -N, N-dimethyl-benzamide;

3-bromo-6-methyl-1- (pyridin-4-ylmethyl) -4-[(2,4,6-trifluorobenzyl) oxy] pyridin-2 (1H) -one;

4- [3-bromo-4- (2,4-difluoro-benzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] -benzamide;

3- [3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-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] -1- (2,6-dimethylphenyl) -6-methylpyridin-2 (1H) -one;

4- [3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] -benzonitrile;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (pyridin-4-ylmethyl) pyridin-2 (1H) -one;

1-benzyl-4- (benzyloxy) -3-bromo-6-methylpyridin-2 (1H) -one;

1-benzyl-4-benzyloxy-3-bromo-6-methyl-1H-pyridin-2-one;

1-benzyl-4- (benzyloxy) -3-bromo-6-methylpyridin-2 (1H) -one;

1-benzyl-3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-1H-pyridin-2-one;

{3- [3-bromo-4- (2,4-difluoro-benzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] -phenyl} -acetonitrile;

3- [3-Bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] -N- (2-hydroxy-ethyl ) -Benzamide;

3-chloro-4- (2,4-difluoro-benzyloxy) -1- (3-fluoro-benzyl) -1H-pyridin-2-one;

1-allyl-3-chloro-4- (2,4-difluoro-benzyloxy) -6-methyl-1H-pyridin-2-one;

3-chloro-4- (2,4-difluoro-benzyloxy) -1- [4- (isopropylamino-methyl) -benzyl] -1 H-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) -1- (2,4,6-trifluorophenyl) pyridine-2 (1H)- On;

3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-1- (4-piperazin-1-ylmethyl-benzyl) -1H-pyridin-2-one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6- (hydroxymethyl) pyridin-2 (1H) -one;

3- [3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] -N, N-dimethyl-benzamide;

3-bromo-1- (3-fluorobenzyl) -4-[(3-methylbenzyl) oxy] pyridin-2 (1H) -one;

3-bromo-1- (3-fluoro-benzyl) -4- (3-methyl-benzyloxy) -1H-pyridin-2-one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- (1,2,3,4-tetrahydroisoquinolin-5-ylmethyl) pyridin-2 (1H) -one;

3-bromo-1- (3-fluorobenzyl) -4-[(3-methylbenzyl) oxy] pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- (isoquinolin-5-ylmethyl) pyridin-2 (1H) -one trifluoroacetate;

3- [3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] -benzamide;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-({5-[(4-methylpiperazin-1-yl) carbonyl] pyrazine-2- Methyl} pyridine-2 (1H) -one trifluoroacetate;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [5- (hydroxymethyl) -2-methylphenyl] -6-methylpyridin-2 (1H) -one;

1-allyl-3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2-methoxy-6-methylphenyl) -6-methylpyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2-methoxy-6-methylphenyl) -6-methylpyridin-2 (1H) -one;

3- [3-bromo-4- (2,4-difluoro-benzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] -benzamide;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -6- (hydroxymethyl) -1- (2,4,6-trifluorophenyl) pyridin-2 (1H) -one ;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [2- (trifluoromethyl) phenyl] pyridin-2 (1H) -one;

4- [3-Bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] -benzoic acid;

3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-1- (4-morpholin-4-ylmethyl-benzyl) -1H-pyridin-2-one;

4- (2,4-difluoro-benzyloxy) -1- (3-fluoro-benzyl) -3-iodo-1H-pyridin-2-one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (2,4,6-trifluorophenyl) pyridin-2 (1H) -one;

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N-hydroxybenzamide;

3-bromo-1- (2,6-dichlorophenyl) -4-[(2,6-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

3- (4-benzyloxy-3-bromo-2-oxo-2H-pyridin-1-ylmethyl) -benzonitrile;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [3- (pyrrolidin-1-ylcarbonyl) phenyl] pyridine-2 (1H)- On;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2-fluorobenzyl) pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- (4-methylbenzyl) pyridin-2 (1H) -one;

3-{[3-chloro-4-[(2,4-difluorobenzyl) amino] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzonitrile;

3- [3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] -N-isopropyl-benzamide;

3-bromo-1- (4-bromo-2,6-difluorophenyl) -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -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-1- (pyridin-4-ylmethyl) pyridin-2 (1H) -one;

3-bromo-4-[(4-fluorobenzyl) oxy] -6-methyl-1- (pyridin-4-ylmethyl) pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- (4-chlorobenzyl) pyridin-2 (1H) -one;

4-benzyloxy-3-bromo-1- (4-chloro-benzyl) -1 H-pyridin-2-one;

3-bromo-1- (4-fluorobenzyl) -4-[(4-fluorobenzyl) oxy] pyridin-2 (1H) -one;

3-bromo-1- (2,6-dichlorophenyl) -4-[(4-fluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

3-bromo-1- (4-fluoro-benzyl) -4- (4-fluoro-benzyloxy) -1H-pyridin-2-one;

Methyl 4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzoate;

4- (4-benzyloxy-3-bromo-2-oxo-2H-pyridin-1-ylmethyl) -benzoic acid;

4-{[4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] methyl} benzoic acid;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (2,4,6-trifluorophenyl) pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- (2-fluorobenzyl) pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6- (hydroxymethyl) pyridin-2 (1H) -one;

N- (2-aminoethyl) -4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benz Amide hydrochloride;

4-benzyloxy-3-bromo-1- (4-methylsulfanyl-benzyl) -1 H-pyridin-2-one;

1-benzyl-4-benzyloxy-3-chloro-1H-pyridin-2-one;

4- (benzyloxy) -3-bromo-1- [4- (methylthio) benzyl] pyridin-2 (1H) -one;

1-benzyl-4- (benzyloxy) -3-chloropyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1-{[5- (hydroxymethyl) pyrazin-2-yl] methyl} -6-methylpyridine-2 (1H) -On;

3-bromo-1- (2,6-dimethylphenyl) -4-[(4-fluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

3-bromo-1- (2,6-dimethylphenyl) -4-[(4-fluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

3-bromo-4- (2,4-difluoro-benzyloxy) -1- [3- (isopropylamino-methyl) -benzyl] -1 H-pyridin-2-one;

3- [3-chloro-4- (2,4-difluoro-benzyloxy) -2-oxo-2H-pyridin-1-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-2H-pyridin-1-ylmethyl] -phenyl} -acetic acid ethyl ester;

4- (4-benzyloxy-3-bromo-2-oxo-2H-pyridin-1-ylmethyl) -N-hydroxy-benzamidine;

4-{[4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] methyl} -N'-hydroxybenzenecarboximideamide;

Ethyl 5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} pyrazine-2-carboxylate ;

3-bromo-4- (2,4-difluoro-benzyloxy) -1- (3-methoxy-benzyl) -1H-pyridin-2-one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-[(5-methylpyrazin-2-yl) methyl] pyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (3-methoxybenzyl) pyridin-2 (1H) -one;

4- (4-benzyloxy-3-bromo-2-oxo-2H-pyridin-1-ylmethyl) -benzoic acid methyl ester;

3-bromo-4- (2,4-difluoro-benzyloxy) -1- (4-dimethylaminomethyl-benzyl) -1H-pyridin-2-one;

3-chloro-4- (2,4-difluoro-benzyloxy) -1- (3-methanesulfonyl-benzyl) -1H-pyridin-2-one;

4- (4-benzyloxy-3-bromo-2-oxo-2H-pyridin-1-ylmethyl) -benzoic acid methyl ester;

Methyl 4-{[4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] methyl} benzoate;

Ethyl 5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} pyrazine-2-carboxyl Rate;

4-{[4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] methyl} benzonitrile;

4- (4-benzyloxy-3-bromo-2-oxo-2H-pyridin-1-ylmethyl) -benzonitrile;

{3- [3-Bromo-4- (4-fluoro-benzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] -benzyl} -carbamic acid tert-butylester;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [5- (1-hydroxy-1-methylethyl) -2-methylphenyl] -6-methylpyridine-2 ( 1H) -one;

4- (benzyloxy) -3-bromo-1- (2,6-dichlorophenyl) -6-methylpyridin-2 (1H) -one;

1- (3-aminomethyl-benzyl) -4-benzyloxy-3-bromo-1H-pyridin-2-one;

3-bromo-4-[(4-fluorobenzyl) oxy] -1- (pyridin-4-ylmethyl) pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- (4-bromobenzyl) pyridin-2 (1H) -one;

4-benzyloxy-3-bromo-1- (4-bromo-benzyl) -1 H-pyridin-2-one;

5-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-oxo-1,6-dihydropyridine-2-carb Aldehydes;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[5- (hydroxymethyl) pyrazin-2-yl] methyl} -6-methylpyridine-2 (1H)- On;

4- (4-benzyloxy-3-bromo-2-oxo-2H-pyridin-1-ylmethyl) -benzamide;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [3- (piperazin-1-ylcarbonyl) phenyl] pyridin-2 (1H) -one Hydrochloride;

3-bromo-4-[(2,4-difluorobenzyl) amino] -1- (3-fluorobenzyl) pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-[(5-methylpyrazin-2-yl) methyl] pyridin-2 (1H) -one;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [5- (hydroxymethyl) -2-methylphenyl] -6-methylpyridin-2 (1H) -one;

3-bromo-1- (3-fluorobenzyl) -4-[(4-fluorobenzyl) oxy] pyridin-2 (1H) -one;

3-bromo-1- (3-fluoro-benzyl) -4- (4-fluoro-benzyloxy) -1H-pyridin-2-one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [3- (morpholin-4-ylcarbonyl) phenyl] pyridin-2 (1H) -one ;

3- (4-benzyloxy-3-bromo-2-oxo-2H-pyridin-1-ylmethyl) -benzoic acid methyl ester;

3-bromo-1- (3-fluorobenzyl) -4-{[2- (hydroxymethyl) benzyl] oxy} pyridin-2 (1H) -one;

3-bromo-1- (3-fluoro-benzyl) -4- (2-hydroxymethyl-benzyloxy) -1H-pyridin-2-one;

1-benzo [1,3] dioxol-5-ylmethyl-3-bromo-4- (2,4-difluoro-benzyloxy) -1H-pyridin-2-one;

3-bromo-4-[(2,6-difluorobenzyl) oxy] -6-methyl-1- (pyridin-4-ylmethyl) pyridin-2 (1H) -one;

3-bromo-4-[(3-chlorobenzyl) oxy] -1- (3-fluorobenzyl) pyridin-2 (1H) -one;

3-bromo-4-[(3-chlorobenzyl) oxy] -1- (3-fluorobenzyl) pyridin-2 (1H) -one;

3-bromo-4- (3-chloro-benzyloxy) -1- (3-fluoro-benzyl) -1 H-pyridin-2-one;

4- (benzyloxy) -3-bromo-1- (3-fluorobenzyl) pyridin-2 (1H) -one;

4-benzyloxy-3-bromo-1- (3-fluoro-benzyl) -1 H-pyridin-2-one;

3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-1- [3- (piperidin-1-carbonyl) -benzyl] -1 H-pyridin-2-one ;

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N, N-dimethylbenzamide;

3- [3-chloro-4- (2,4-difluoro-benzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] -2-fluoro-benzoic acid methyl ester;

1- (3-fluorobenzyl) -4-[(4-fluorobenzyl) oxy] -3-iodopyridin-2 (1H) -one;

1- (3-fluoro-benzyl) -4- (4-fluoro-benzyloxy) -3-iodo-1H-pyridin-2-one;

N- (3-aminopropyl) -4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benz Amide hydrochloride;

4-{[3-bromo-4-[(4-fluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} benzonitrile;

4- [3-Bromo-4- (4-fluoro-benzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] -benzonitrile;

3-bromo-1- (3-fluoro-benzyl) -4- (2,3,4-trifluoro-benzyloxy) -1H-pyridin-2-one;

1-benzyl-4- (benzyloxy) -3-bromopyridin-2 (1H) -one;

5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N- (2-hydrate Oxyethyl) -N-methylpyrazine-2-carboxamide;

4- (4-benzyloxy-3-bromo-2-oxo-2H-pyridin-1-ylmethyl) -benzonitrile;

3-bromo-1- (2,4-difluorobenzyl) -4-[(2,4-difluorobenzyl) oxy] pyridin-2 (1H) -one;

3-bromo-1- (2,4-difluoro-benzyl) -4- (2,4-difluoro-benzyloxy) -1H-pyridin-2-one;

4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N- (2-hydroxyethyl) Benzamide;

3-bromo-4-[(4-fluorobenzyl) oxy] -1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one;

1-benzyl-4-benzyloxy-3-bromo-1H-pyridin-2-one;

3-bromo-1- (cyclopropylmethyl) -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

1- (4-aminomethyl-benzyl) -4-benzyloxy-3-bromo-1H-pyridin-2-one;

3-bromo-1- (4-fluorobenzyl) -4-[(4-fluorobenzyl) amino] -6-methylpyridin-2 (1H) -one;

3- [3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] -benzoic acid methyl ester;

5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N, N-dimethylpyrazine -2-carboxamide;

3-bromo-4-[(4-fluorobenzyl) oxy] -6-methyl-1- (pyridin-2-ylmethyl) pyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-dimethylphenyl) -6-methylpyridin-2 (1H) -one;

3-bromo-1- (2,6-dichlorophenyl) -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

4- (benzyloxy) -1- (4-bromobenzyl) pyridin-2 (1H) -one;

3-bromo-4-hydroxy-1- (4-hydroxybenzyl) pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- [2- (trifluoromethyl) benzyl] pyridin-2 (1H) -one;

1-benzyl-4-[(3-chlorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- (piperidin-3-ylmethyl) pyridin-2 (1H) -one hydrochloride;

1-benzyl-3-bromo-2-oxo-1,2-dihydropyridin-4-ylmethyl (phenyl) carbamate;

4- (benzylamino) -1- (3-fluorobenzyl) -6-methyl-3-nitropyridin-2 (1H) -one;

tert-butyl 4- [3-bromo-1- (3-fluorobenzyl) -2-oxo-1,2-dihydropyridin-4-yl] piperazine-1-carboxylate;

Ethyl [4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] acetate;

N- [3-bromo-1- (3-fluorobenzyl) -2-oxo-1,2-dihydropyridin-4-yl] benzenesulfonamide;

3-bromo-4-[(4-tert-butylbenzyl) oxy] -1- (3-fluorobenzyl) pyridin-2 (1H) -one;

N- [3-bromo-1- (3-fluorobenzyl) -2-oxo-1,2-dihydropyridin-4-yl] -1-phenylmethanesulfonamide;

1- (biphenyl-2-ylmethyl) -3-bromo-4-[(4-fluorobenzyl) oxy] pyridin-2 (1H) -one;

4- (biphenyl-2-ylmethoxy) -3-bromo-1- (3-fluorobenzyl) pyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorophenyl) amino] -1- (3-fluorobenzyl) pyridin-2 (1H) -one;

4-anilino-3-bromo-1- (3-fluorobenzyl) pyridin-2 (1H) -one;

Methyl 4-{[3-bromo-1- (3-fluorobenzyl) -2-oxo-1,2-dihydropyridin-4-yl] amino} benzoate;

3-bromo-1- (3-fluorobenzyl) -4-[(3,4,5-trimethoxyphenyl) amino] pyridin-2 (1H) -one;

3-bromo-1- (3-fluorobenzyl) -4- [4- (4-fluorophenyl) piperazin-1-yl] pyridin-2 (1H) -one;

3-bromo-1- (3-fluorobenzyl) -4- (4-methylpiperazin-1-yl) pyridin-2 (1H) -one trifluoroacetate;

N- [3-bromo-1- (3-fluorobenzyl) -2-oxo-1,2-dihydropyridin-4-yl] -2,5-difluorobenzamide;

N- [3-bromo-1- (3-fluorobenzyl) -2-oxo-1,2-dihydropyridin-4-yl] -2,4-difluorobenzamide;

3-bromo-1- (cyclohexylmethyl) -4-[(4-fluorobenzyl) oxy] pyridin-2 (1H) -one;

3- [4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] propanoic acid;

N- [3-bromo-1- (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-1- (3-morpholin-4-yl-3-oxopropyl) pyridin-2 (1H) -one;

N- (3-aminopropyl) -3- [4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] propanamide hydrochloride;

4- (benzyloxy) -3-bromo-1- (3-oxo-3-piperazin-1-ylpropyl) pyridin-2 (1H) -one hydrochloride;

4- (benzyloxy) -3-bromo-1- (2-morpholin-4-ylethyl) pyridin-2 (1H) -one;

3-bromo-1- (3-fluorobenzyl) -4-{[4-fluoro-2- (trifluoromethyl) benzyl] amino} pyridin-2 (1H) -one;

N- (2-aminoethyl) -3- [4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] propanamide hydrochloride;

[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] acetic acid;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (tetrahydrofuran-2-ylmethyl) pyridin-2 (1H) -one;

4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (tetrahydrofuran-2-ylmethyl) pyridin-2 (1H) -one;

Methyl 3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridine-1 (2H) -carboxylate;

1-allyl-3- (2,4-difluorobenzyl) -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

4- (benzyloxy) -1- (2,2-diethoxyethyl) pyridin-2 (1H) -one;

Methyl N-acetyl-3- [4- (benzyloxy) -2-oxopyridin-1 (2H) -yl] alanineate;

Benzyl N-acetyl-3- [4- (benzyloxy) -2-oxopyridin-1 (2H) -yl] alanineate;

Benzyl N-[(benzyloxy) carbonyl] -3- [4- (benzyloxy) -2-oxopyridin-1 (2H) -yl] alanineate;

4- (benzyloxy) -1- (2-oxopropyl) pyridin-2 (1H) -one;

5-{[4- (benzyloxy) -2-oxopyridin-1 (2H) -yl] methyl} -5-methylimidazolidine-2,4-dione;

Ethyl [4- (benzyloxy) -2-oxopyridin-1 (2H) -yl] acetate;

2- [4- (benzyloxy) -2-oxopyridin-1 (2H) -yl] acetamide;

1-benzyl-4- (benzyloxy) -3,5-dibromopyridin-2 (1H) -one;

4- (benzyloxy) -1-ethylpyridin-2 (1H) -one;

4- (benzyloxy) -1- (4-tert-butylbenzyl) pyridin-2 (1H) -one;

4-{[4- (benzyloxy) -2-oxopyridin-1 (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 (1H) -one;

1-benzyl-6-methyl-2-oxo-1,2-dihydropyridin-4-yl methanesulfonate;

4- (benzyloxy) -1- (4-bromobenzyl) pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromopyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- [2- (trifluoromethyl) benzyl] pyridin-2 (1H) -one;

1-benzyl-4- (1-naphthylmethoxy) pyridin-2 (1H) -one;

1-benzyl-4- (benzylthio) -3,5-dibromopyridin-2 (1H) -one;

1-benzyl-4-[(2,6-dichlorobenzyl) oxy] pyridin-2 (1H) -one;

1-benzyl-3-[(benzylamino) methyl] -4- (benzyloxy) pyridin-2 (1H) -one;

1-benzyl-4- (benzyloxy) -3-{[(2-cyclohexylethyl) amino] methyl} pyridin-2 (1H) -one;

1-benzyl-4- (benzylthio) -5-methylpyridin-2 (1H) -one;

1-benzyl-3-bromo-6-methyl-2-oxo-1,2-dihydropyridin-4-yl methanesulfonate;

1-benzyl-3-bromo-6-methyl-4-{[2- (trifluoromethyl) benzyl] oxy} pyridin-2 (1H) -one;

1-benzyl-6-methyl-2-oxo-1,2-dihydropyridin-4-yl 4-bromobenzenesulfonate;

1-benzyl-4-[(3-chlorobenzyl) oxy] -6-methylpyridin-2 (1H) -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 (1H) -one;

1-benzyl-4-phenoxypyridin-2 (1H) -one;

1- (4-methoxybenzyl) -4-phenoxypyridin-2 (1H) -one;

3-bromo-4-hydroxy-1- (4-hydroxybenzyl) pyridin-2 (1H) -one hydrochloride;

4- (benzyloxy) -3-bromo-1- (piperidin-3-ylmethyl) pyridin-2 (1H) -one;

1-benzyl-4-[(2,6-dichlorobenzyl) oxy] pyridin-2 (1H) -one;

1-benzyl-4- (benzyloxy) -3,5-dibromopyridin-2 (1H) -one;

3-bromo-1- (3-fluorobenzyl) -4-[(E) -2- (4-fluorophenyl) vinyl] pyridin-2 (1H) -one;

1-benzyl-4- (benzyloxy) -2-oxo-1,2-dihydropyridine-3-carbaldehyde;

1-benzyl-4- (benzyloxy) pyridin-2 (1H) -one;

1-benzyl-4- (benzyloxy) pyridin-2 (1H) -one;

1-benzyl-4- (benzylthio) pyridin-2 (1H) -one;

Methyl 4- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (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-1,2'-bipyridine-5'-carboxylate;

4- (benzyloxy) -1- (4-methylbenzyl) pyridin-2 (1H) -one;

[5-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -2-methyl-6-oxo-1,6-dihydropyridine -3-yl] methyl carbamate;

4- (benzyloxy) -1- (4-chlorobenzyl) pyridin-2 (1H) -one;

Methyl (2E) -4- [4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] but-2-enoate;

4- (benzyloxy) -1- (2-fluorobenzyl) pyridin-2 (1H) -one;

tert-butyl 4-{[4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] methyl} piperidine-1-carboxylate;

4- (benzyloxy) -1- (3-fluorobenzyl) pyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -5- (1,2-dihydroxyethyl) -6-methyl Pyridin-2 (1H) -one;

1-benzyl-4-hydroxy-6-methylpyridin-2 (1H) -one;

4-({[3-bromo-1- (3-fluorobenzyl) -2-oxo-1,2-dihydropyridin-4-yl] oxy} methyl) benzonitrile;

1-benzyl-4- (benzyloxy) -6-methylpyridin-2 (1H) -one;

5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -2-methyl-6-oxo-1,6-dihydropyridine- 3-carbaldehyde oxime;

1-benzyl-4- (benzylthio) -3-methylpyridin-2 (1H) -one;

1-benzyl-4-[(4-methylbenzyl) oxy] pyridin-2 (1H) -one;

1-benzyl-4- (benzyloxy) -3,5-dibromo-6-methylpyridin-2 (1H) -one;

1-benzyl-4- (benzyloxy) -3,5-dibromo-6-methylpyridin-2 (1H) -one;

3-bromo-1- (3-fluorobenzyl) -4- (1-phenylethoxy) pyridin-2 (1H) -one;

4- (benzyloxy) -1- [4- (trifluoromethyl) benzyl] pyridin-2 (1H) -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) -1- (3-fluorobenzyl) -3- (trifluoromethyl) pyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-methyl-5-oxirane-2-ylpyridine-2 ( 1H) -one;

1-benzyl-4-[(3-chlorobenzyl) oxy] pyridin-2 (1H) -one;

1-benzyl-4-[(3-chlorobenzyl) oxy] pyridin-2 (1H) -one;

5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -2-methyl-6-oxo-1,6-dihydropyridine- 3-carbaldehyde;

tert-butyl 3-{[4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] methyl} piperidine-1-carboxylate;

3-bromo-4-[(2,4-difluorobenzyloxy] -1- (2,6-difluorophenyl) -6-methyl-5-vinylpyridin-2 (1H) -one;

4- (benzyloxy) -1- [4- (trifluoromethoxy) benzyl] pyridin-2 (1H) -one;

3-bromo-4-[(4-chlorobenzyl) oxy] -1- [2- (phenylthio) ethyl] pyridin-2 (1H) -one;

3-bromo-4- (4-chloro-benzyloxy) -1- (2-phenylsulfanyl-ethyl) -1 H-pyridin-2-one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (2-morpholin-4-ylethyl) pyridin-2 (1H) -one;

4-[(2,4-difluorobenzyl) oxy] -6- (hydroxymethyl) -1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one;

4-{[2- (aminomethyl) -4-fluorobenzyl] oxy} -3-bromo-1- (2,6-difluorophenyl) 6-methylpyridin-2 (1H) -one trifluor Low acetate;

4- (benzyloxy) -1- (4-fluorobenzyl) pyridin-2 (1H) -one;

4- (benzyloxy) -1- (4-fluorobenzyl) pyridin-2 (1H) -one;

4-benzyloxy-3-bromo-1-methanesulfonyl-1H-pyridin-2-one;

tert-butyl 4- [4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] piperidine-1-carboxylate;

1-benzyl-4- (benzyloxy) -3-vinylpyridin-2 (1H) -one;

4- (benzyloxy) -1- [4- (methylthio) benzyl] pyridin-2 (1H) -one;

3-bromo-4- (2,4-difluorobenzyloxy) -1- (2-methyl-4-methylamino-pyrimidin-5-ylmethyl) -1H-pyridin-2-one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

1-benzyl-3-bromo-4-{[2- (trifluoromethylbenzyl] oxy} pyridin-2 (1H) -one;

1-benzyl-3-bromo-4-{[2- (trifluoromethyl) benzyl] oxy} pyridin-2 (1H) -one;

4-[(2,4-difluorobenzyl) oxy] -1- [5- (hydroxymethyl) -2-methylphenyl] -6-methylpyridin-2 (1H) -one;

4- (benzyloxy) -1- [4- (methylsulfonyl) benzyl] pyridin-2 (1H) -one;

4-phenoxy-1H-pyridin-2-one;

1-benzyl-4-[(2-chlorobenzyl) oxy] pyridin-2 (1H) -one;

1-benzyl-4-[(2-chlorobenzyl) oxy] pyridin-2 (1H) -one;

Methyl 4-{[4- (benzyloxy) -2-oxopyridin-1 (2H) -yl] methyl} benzoate;

4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-methylpyridin-2 (1H) -one;

1- (3-fluorobenzyl) -4- (phenylethynyl) pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- (piperidin-4-ylmethyl) pyridin-2 (1H) -one hydrochloride;

4- (benzyloxy) -3-bromo-1- (piperidin-4-ylmethyl) pyridin-2 (1H) -one hydrochloride;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [2- (methylthiopyrimidin-4-yl] pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1-piperidin-4-ylpyridin-2 (1H) -one hydrochloride;

4-benzyloxy-1-difluoromethyl-1 H-pyridin-2-one;

4-benzyloxy-3-bromo-1- (2-chloro-phenyl) -6-methyl-1 H-pyridin-2-one;

3-bromo-6-methyl-1-pyridin-3-ylmethyl-4-[(pyridin-3-ylmethyl) -amino] -1 H-pyridin-2-one;

1- (3,4-Dichloro-benzyl) -6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (2,4-difluoro-phenyl) -amide;

1- (2,6-Dichloro-benzyl) -6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (2,4-difluoro-phenyl) -amide;

5-Chloro-1- (2,6-dichloro-benzyl) -6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (2,4-difluoro-phenyl) -amide;

5-chloro-1- (2,6-dichloro-benzyl) -6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl-phenyl-amide;

1- (2,6-dichloro-benzyl) -6-oxo-1,6-dihydro-pyridine-3-carboxylic acid benzylamide;

1- (2,6-Dichloro-benzyl) -6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (3-dimethylamino-propyl) -amide;

1- (2,6-Dichloro-benzyl) -6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (2-morpholin-4-yl-ethyl) -amide;

N- [5-acetyl-1- (4-chloro-benzyl) -6-methyl-2-oxo-1,2-dihydro-pyridin-3-yl] -4-chloro-benzamide;

1- (2,6-Dichloro-benzyl) -6-oxo-1,6-dihydro-pyridine-3-carboxylic acid-N '-(3-chloro-5-trifluoromethyl-pyridine-2- One) -hydrazide;

N-allyl-2-[(1-benzyl-6-oxo-1,6-dihydropyridin-3-yl) carbonyl] hydrazinecarbothioamide;

1-benzyl-5- [5- (3,4-dichloro-benzylsulfanyl)-[1,3,4] oxadiazol-2-yl] -1 H-pyridin-2-one;

N '-{[(1-benzyl-6-oxo-1,6-dihydropyridin-3-yl) carbonyl] oxy} pyridine-4-carboximideamide;

1- (2,6-Dichloro-benzyl) -6-oxo-1,6-dihydro-pyridine-3-carboxylic acid 3-trifluoromethyl-benzylamide;

1-benzyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (2-morpholin-4-yl-ethyl) -amide;

5- [4- (3-Chloro-phenyl) -piperazine-1-carbonyl] -1- (3,4-dichloro-benzyl) -1 H-pyridin-2-one;

5-chloro-1- (2,6-dichloro-benzyl) -6-oxo-1,6-dihydro-pyridine-3-carboxylic acid benzylamide;

1- (4-chloro-benzyl) -5- [3- (4-chloro-phenyl)-[1,2,4] oxadiazol-5-yl] -1 H-pyridin-2-one;

1- (4-chloro-benzyl) -5- [3- (4-chloro-phenyl)-[1,2,4] oxadiazol-5-yl] -1 H-pyridin-2-one;

2-Chloro-N- [1- (2,6-dichloro-benzyl) -6-oxo-5-trifluoromethyl-1, 6-dihydro-pyridin-3-yl] -4-fluoro-benz amides;

N- [1- (2,6-Dichloro-benzyl) -6-oxo-5-trifluoromethyl-1, 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;

1- (2,6-Dichloro-benzyl) -6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (3-trifluoromethyl-phenyl) -amide;

5-chloro-1- (2,6-dichloro-benzyl) -6-oxo-1,6-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-1H-pyridin-2-one;

3-bromo-1- (3-fluoro-benzyl) -4- (3-methoxy-phenyl) -1H-pyridin-2-one;

3-bromo-1- (3-fluoro-benzyl) -4- (3-isopropyl-phenyl) -1H-pyridin-2-one;

3'-bromo-1 '-(3-fluoro-benzyl) -6-methoxy-1'H- [3,4'] bipyridinyl-2'-one;

4-benzo [1,3] dioxol-5-yl-3-bromo-1- (3-fluoro-benzyl) -1H-pyridin-2-one;

3-bromo-1- (3-fluoro-benzyl) -4-thiophen-3-yl-1H-pyridin-2-one;

3-bromo-1- (3-fluoro-benzyl) -4- (3-trifluoromethyl-phenyl) -1 H-pyridin-2-one;

3-bromo-1- (3-fluoro-benzyl) -4-naphthalen-2-yl-1H-pyridin-2-one;

3-bromo-1- (3-fluoro-benzyl) -4- (4-fluoro-phenyl) -1H-pyridin-2-one;

1-benzenesulfonyl-4-benzyloxy-3-bromo-1H-pyridin-2-one;

4- [3-Amino-1- (2,4-difluoro-phenyl) -propoxy] -3-bromo-6-methyl-1-pyridin-3-ylmethyl-1H-pyridin-2-one ;

1- (4-bromo-2,6-difluoro-phenyl) -4- (2,4-difluoro-benzyloxy) -6-methyl-1H-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) -1H-pyridin-2-one;

1- (2-chloro-4-hydroxy-phenyl) -4- (2,4-difluoro-benzyloxy) -6-methyl-1H-pyridin-2-one;

3- [4- (2,4-Difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-yl] -benzoic acid methyl ester;

3-bromo-1- (2,6-difluoro-phenyl) -4-methoxy-6-methyl-5-vinyl-1H-pyridin-2-one;

3-bromo-1- (2,6-difluoro-phenyl) -4-methoxy-6-methyl-5-styryl-1H-pyridin-2-one;

1- (2,6-difluoro-phenyl) -4-methoxy-6-methyl-5-phenethyl-1H-pyridin-2-one;

3-bromo-1- (2,6-difluoro-phenyl) -4-methoxy-6-methyl-5-phenethyl-1H-pyridin-2-one;

1- (1H-indazol-5-yl) -4- (1H-indazol-5-ylamino) -6-methylpyridin-2 (1H) -one;

5-bromo-4- (2,4-difluoro-benzyloxy) -1- (2,6-difluoro-phenyl) -2- [2- (2,4-difluoro-phenyl) -Ethyl] -6-oxo-1,6-dihydro-pyridine-3-carbaldehyde;

4- [3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-yl] -pyrimidine-2-carbonitrile;

3-Bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H- [1,2 '] bipyridinyl-5'-carboxylic acid;

3-bromo-4- (5-carboxy-pyridin-2-yloxy) -6-methyl-2-oxo-2H- [1,2 '] bipyridinyl-5'-carboxylic acid;

3-bromo-4- (2,4-difluoro-benzyloxy) -6,6'-dimethyl-2-oxo-2H- [1,2 '] bipyridinyl-3'-carbonitrile;

3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H- [1,2 '] bipyridinyl-5'-carboxylic acid methylamide;

3-Bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H- [1,2 '] bipyridinyl-5'-carboxylic acid (2-hydric Oxy-ethyl) -amide;

3-Bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H- [1,2 '] bipyridinyl-5'-carboxylic acid (2-meth Oxy-ethyl) -amide;

3-bromo-1- (2,6-difluoro-phenyl) -4-methoxy-6-methyl-5- (4-methyl-benzyl) -1H-pyridin-2-one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -5- (1,2-dihydroxy-2-phenylethyl) -6-methylpyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -5 '-(1-hydroxy-1-methylethyl) -6-methyl-2H-1,2'-bipyridine- 2-one;

4-benzyloxy-1H-pyridin-2-one;

4-benzyloxy-3-methyl-1 H-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-1,6-dihydro- [2,3 '] bipyridinyl-5-carbonitrile;

6-oxo-1,6-dihydro- [2,3 '] bipyridinyl-5-carboxylic acid;

3-{[4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] methyl} benzamide;

3-bromo-4-[(4-fluorobenzyl) oxy] -1- (4-methoxybenzyl) pyridin-2 (1H) -one;

3-bromo-4-[(4-fluorobenzyl) oxy] -1- (4-methoxybenzyl) pyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [2-fluoro-5- (hydroxymethyl) phenyl] -6-methylpyridin-2 (1H) -one ;

3-chloro-1- (4-fluorobenzyl) -4-[(4-fluorobenzyl) oxy] pyridin-2 (1H) -one;

3-chloro-1- (4-fluorobenzyl) -4-[(4-fluorobenzyl) oxy] pyridin-2 (1H) -one;

3-bromo-1- (3-chlorobenzyl) -4-[(4-fluorobenzyl) oxy] pyridin-2 (1H) -one;

3-bromo-4-[(3,4-difluorobenzyl) oxy] -1- (3-fluorobenzyl) pyridin-2 (1H) -one;

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methylbenzoic acid;

3-bromo-1- (3-chlorobenzyl) -4-[(4-fluorobenzyl) oxy] pyridin-2 (1H) -one;

3-bromo-1- (3-chlorobenzyl) -4-[(4-fluorobenzyl) oxy] pyridin-2 (1H) -one;

4-{[3-chloro-4-[(2,4-difluorobenzyl) amino] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzonitrile trifluoroacetate;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1-{[5- (1-hydroxy-1-methylethyl) pyrazin-2-yl] methyl} -6-methyl Pyridin-2 (1H) -one;

4- (benzylamino) -3-bromo-1- (3-fluorobenzyl) pyridin-2 (1H) -one;

4- (benzylamino) -3-bromo-1- (3-fluorobenzyl) pyridin-2 (1H) -one;

2-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzonitrile;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [2-fluoro-6- (4-methylpiperazin-1-yl) phenyl] -6-methylpyridine- 2 (1H) -one trifluoroacetate;

4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N-methylbenzamide;

1- [2- (aminomethyl) benzyl] -3-bromo-4-[(2,4-difluorobenzyl) oxy] pyridin-2 (1H) -one;

3-bromo-1- (4-fluorobenzyl) -4-[(4-fluorobenzyl) oxy] pyridin-2 (1H) -one;

1- [2- (aminomethyl) benzyl] -3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) -oxy] -6-methyl-1- [3- (piperidin-1-ylcarbonyl) phenyl] pyridine-2 (1H) -On;

1-benzyl-3-bromo-4-[(4-chlorobenzyl) oxy] pyridin-2 (1H) -one;

4-[(2,4-difluorobenzyl) oxy] -1- (3-fluorobenzyl) -3-methylpyridin-2 (1H) -one;

4- (benzyloxy) -1- [4- (benzyloxy) benzyl] -3-bromopyridin-2 (1H) -one;

4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N-hydroxybenzamide;

4- (benzyloxy) -3-bromo-1- [4- (trifluoromethyl) benzyl] pyridin-2 (1H) -one;

3-bromo-1- (cyclopropylmethyl) -4-[(4-fluorobenzyl) oxy] pyridin-2 (1H) -one;

3-bromo-1- (cyclopropylmethyl) -4-[(4-fluorobenzyl) oxy] pyridin-2 (1H) -one;

1-benzyl-3-bromo-4-[(3-chlorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

1-benzyl-3-bromo-4-[(3-chlorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

1-benzyl-3-bromo-4-[(3-chlorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

2-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} benzonitrile;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-({5-[(methylamino) methyl] pyrazin-2-yl} methyl) pyridine-2 ( 1H) -one trifluoroacetate;

3-bromo-1- (3-fluorobenzyl) -4-[(2-methylbenzyl) oxy] pyridin-2 (1H) -one;

3-bromo-1- (3-fluorobenzyl) -4-[(2-methylbenzyl) oxy] pyridin-2 (1H) -one;

Methyl 3-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} benzoate;

3-bromo-1- (3-fluorobenzyl) -6-methyl-4- (2-phenylethyl) pyridin-2 (1H) -one;

3-bromo-1- (3-fluorobenzyl) -6-methyl-4- (2-phenylethyl) pyridin-2 (1H) -one;

1-benzyl-3-bromo-4-[(4-methylbenzyl) oxy] pyridin-2 (1H) -one;

4- (benzyloxy) -1- (3-fluorobenzyl) -3-iodopyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [3- (hydroxymethyl) phenyl] -6-methylpyridin-2 (1H) -one;

4- (benzyloxy) -1- (3-fluorobenzyl) -3-iodopyridin-2 (1H) -one;

3-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzoic acid;

3-bromo-4-[(4-fluorobenzyl) oxy] -1- [2- (hydroxymethyl) benzyl] pyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1-[(5-{[(2-hydroxyethyl) (methyl) amino] methyl} pyrazin-2-yl) Methyl] -6-methylpyridin-2 (1H) -one trifluoroacetate (salt);

4- (benzyloxy) -3-bromo-1-[(6-fluoropyridin-3-yl) methyl] pyridin-2 (1H) -one;

3-bromo-4-[(4-chlorobenzyl) oxy] -1- (4-fluorobenzyl) pyridin-2 (1H) -one;

3-bromo-4-[(4-chloro-2-fluorobenzyl) amino] -1- (3-fluorobenzyl) pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1-ethylpyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1-ethylpyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1-ethylpyridin-2 (1H) -one;

2- (2-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} phenyl) acetamide;

1-benzyl-3-bromo-4-[(2-chlorobenzyloxy] pyridin-2 (1H) -one;

1-benzyl-3-bromo-4-[(2-chlorobenzyl) oxy] pyridin-2 (1H) -one;

Methyl 2-([3-bromo-4-[(4-fluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} benzoate;

3-bromo-1- (2,6-dichlorophenyl) -4- [2- (4-fluorophenyl) ethyl] -6-methylpyridin-2 (1H) -one;

3-bromo-1- (2,6-dichlorophenyl) -4- [2- (4-fluorophenyl) ethyl] -6-methylpyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyloxy] -1- {5-[(isopropylaminomethyl] -2-methylphenyl} -6-methylpyridin-2 (1H) -one hydro Chloride;

3-bromo-1- (3-fluorobenzyl) -4- (2-phenylethyl) pyridin-2 (1H) -one;

N- {3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzyl} -N'-methyl Urea;

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [3- (hydroxymethyl) phenyl] -6-methylpyridin-2 (1H) -one;

3-bromo-1- (3-fluorobenzyl) -4-[(3-fluorobenzyl) oxy] pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- [2- (2-thienyl) ethyl] pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- [2- (2-thienyl) ethyl] pyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) amino] -1- (2,6-difluorophenyl) -6-methylpyridin-2 (1H) -one trifluoroacetate;

3-bromo-4-[(2,4-difluorobenzyl) amino] -1- (2,6-difluorophenyl) -6-methylpyridin-2 (1H) -one trifluoroacetate;

3-bromo-4-[(4-chlorobenzyl) oxy] -1- (4-methoxybenzyl) pyridin-2 (1H) -one;

3-bromo-4-[(4-chlorobenzyl) oxy] -1- (4-methoxybenzyl) pyridin-2 (1H) -one;

3-bromo-1- (4-chlorobenzyl) -4-[(4-chlorobenzyl) oxy] pyridin-2 (1H) -one;

3-bromo-1- (3-fluorobenzyl) -4-[(4-methoxybenzyl) oxy] pyridin-2 (1H) -one;

3-bromo-1- (3,5-dibromo-2,6-difluoro-4-hydroxyphenyl) -4-[(2,4-difluorobenzyl) oxy] -6-methyl Pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- [4- (trifluoromethoxy) benzyl] pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- [4- (trifluoromethoxy) benzyl] pyridin-2 (1H) -one;

N '-{3- [3-bromo-4-[(2,4-difluorobenzyloxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzyl} -N, N- Dimethylurea;

3-bromo-4-[(4-fluorobenzyl) oxy] -1- [4- (trifluoromethyl) benzyl] pyridin-2 (1H) -one;

2-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzamide;

N- {3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzyl} morpholine-4- Carboxamides;

N- {3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzyl} methanesulfonamide;

4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N-isopropylbenzamide;

4- (allylamino) -3-bromo-1- (2,6-difluorophenyl) -5-iodo-6-methylpyridin-2 (1H) -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] methyl} phenyl) acetic acid;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [4- (pyrrolidin-1-ylcarbonyl) phenyl] pyridine-2 (1H)- On;

1-benzyl-4- (benzyloxy) -3-iodopyridin-2 (1H) -one;

1- (biphenyl-4-ylmethyl) -3-bromo-4-[(4-fluorobenzyl) oxy] pyridin-2 (1H) -one;

4- [3-bromo-4-[(2,4-difluorobenzyl) oxyl-6-methyl-2-oxopyridin-1 (2H) -yl] benzoic acid;

4- (benzyloxy) -3-bromo-1- [2- (3-thienyl) ethyl] pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- [2- (3-thienyl) ethyl] pyridin-2 (1H) -one;

3-bromo-4-[(4-fluorobenzyl) oxy] -1- [3- (trifluoromethyl) benzyl] pyridin-2 (1H) -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-1 (2H) -yl] benzylcarbamate;

1-benzyl-4- (benzylthio) -3-bromopyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- (4-tert-butylbenzyl) pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1- (4-tert-butylbenzyl) pyridin-2 (1H) -one;

N- {3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzyl} -2-methoxy Acetamide;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1-({5-[(dimethylamino) methyl] pyrazin-2-yl} methyl) -6-methylpyridine-2 ( 1H) -one trifluoroacetate;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [4- (piperazin-1-ylcarbonyl) phenyl] pyridin-2 (1H) -one Hydrochloride;

4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N, N-bis (2-hydric Oxyethyl) benzamide;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- {5-[(dimethylamino) methyl] -2-methylphenyl} -6-methylpyridin-2 (1H) -one Hydrochloride;

1-benzyl-3-bromo-4- (2-phenylethyl) pyridin-2 (1H) -one;

1- (3-fluorobenzyl) -4-[(4-fluorobenzyl) oxy] -3-methylpyridin-2 (1H) -one;

4- (benzyloxy) -1- (piperidin-3-ylmethyl) pyridin-2 (1H) -one trifluoroacetate;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [4- (morpholin-4-ylcarbonyl) phenyl] pyridin-2 (1H) -one ;

4- (benzyloxy) -1- (3-fluorobenzyl) -3-methylpyridin-2 (1H) -one;

N ^1- {3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzyl} glycinamide hydrochloride ;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -5-iodo-6-methylpyridin-2 (1H) -one ;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [4- (piperidin-1-ylcarbonyl) phenyl] pyridine-2 (1H)- On;

N- [3-bromo-1- (3-fluorobenzyl) -2-oxo-1,2-dihydropyridin-4-yl] -2,6-difluorobenzamide;

2-{[4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] methyl} benzonitrile;

5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N-methylpyrazine-2 Carboxamides;

3-chloro-4-[(2,4-difluorobenzyl) amino] -1- (2,6-difluorophenyl) -6-methylpyridin-2 (1H) -one;

3- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzoic acid;

3-bromo-1- (3-fluorobenzyl) -4-[(3-fluorobenzyl) amino] pyridin-2 (1H) -one;

3-bromo-1- (3-fluorobenzyl) -4-[(3-methoxybenzyloxy] pyridin-2 (1H) -one;

3-bromo-1- (4-tert-butylbenzyl) -4-[(2,4-difluorobenzyl) oxy] pyridin-2 (1H) -one;

N- {3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzyl} acetamide;

2-({3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzyl} amino) -2 Oxoethyl acetate;

1-benzyl-4- (benzyloxy) -3-methylpyridin-2 (1H) -one;

N- {3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzyl} urea;

1-benzyl-4- (benzyloxy) -3-ethylpyridin-2 (1H) -one;

N- {3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzyl} -2-hydroxy Acetamide;

3-bromo-4-[(4-chlorobenzyl) oxy] -1- (2-phenylethyl) pyridin-2 (1H) -one;

3-bromo-1- (3-chlorobenzyl) -4-[(4-chlorobenzyl) oxy] pyridin-2 (1H) -one;

1- [3- (aminomethyl) phenyl] -3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one;

2-{[4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] methyl} benzamide;

1- (4-fluorobenzyl) -4-[(4-fluorobenzyl) oxy] pyridin-2 (1H) -one;

1- [2- (aminomethyl) benzyl] -4- (benzyloxy) -3-bromopyridin-2 (1H) -one;

Methyl 3- [4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] propanoate;

1-benzyl-4- (benzyloxy) -3-methylpyridin-2 (1H) -one;

4- (allylamino) -1- (2,6-difluorophenyl) -5-iodo-6-methylpyridin-2 (1H) -one;

4- (allylamino) -1- (2,6-difluorophenyl) -5-iodo-6-methylpyridin-2 (1H) -one;

3-bromo-1- (3-fluorobenzyl) -4- (phenylethynyl) pyridin-2 (1H) -one;

4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N, N-dimethylbenzamide;

{4-[({4- (benzyloxy) -3-bromo-1- {4- (carboxymethyl) benzyl] -1,2-dihydropyridin-2-yl} oxy) methyl] phenyl} acetic acid;

4- (benzyloxy) -3-bromo-1- [3- (trifluoromethyl) benzyl] pyridin-2 (1H) -one;

4- (benzyloxy) -3-ethynyl-1- (3-fluorobenzyl) pyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- {3-[(dimethylamino) methyl] phenyl} -6-methylpyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1-methylpyridin-2 (1H) -one;

1-benzyl-3-bromo-4- (phenylethynyl) pyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1-methylpyridin-2 (1H) -one;

3-bromo-1- (3-fluorobenzyl) -4-{[4- (trifluoromethyl) benzyl] oxy} pyridin-2 (1H) -one;

4- (benzylamino) -3-bromo-1- (2,6-difluorophenyl) -5-iodo-6-methylpyridin-2 (1H) -one;

4-[(2,4-difluorobenzyl) oxy] -1- (4-methoxybenzyl) -6-methylpyridin-2 (1H) -one;

4- (benzyloxy) -3-bromo-1-methylpyridin-2 (1H) -one hydrobromide;

4- (benzyloxy) -3-bromo-1- [4- (morpholin-4-ylcarbonyl) phenyl] pyridin-2 (1H) -one;

5-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-oxo-1,6-dihydropyridine-2-carboxyl mountain;

1-benzyl-3-bromo-4-[(2,6-dichlorobenzyl) oxy] pyridin-2 (1H) -one;

3- [3-Chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl]-2-methylbenzoic acid;

4- [4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] benzoic acid;

Ethyl N- (5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -2- Methylpyrimidin-4-yl) glycinate trifluoroacetate;

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-methyl-5-[(E) -2-phenylvinyl] Pyridin-2 (1H) -one;

3-bromo-1- (3-fluorobenzyl) -4-{[3- (trifluoromethyl) benzyl] amino} pyridin-2 (1H) -one;

3-bromo-4-[(4-fluorobenzyl) oxy] -1- (3-phenylpropyl) pyridin-2 (1H) -one;

3-bromo-1- (4-tert-butylbenzyl) -4-[(4-fluorobenzyl) oxy] pyridin-2 (1H) -one;

4- (allylamino) -3-bromo-1- (2,6-difluorophenyl) -6-methylpyridin-2 (1H) -one;

1-cyclohexyl-4-[(2,4-difluorobenzyl) oxy] -3,6-dimethylpyridin-2 (1H) -one;

3-bromo-4-[(2,4-difluorobenzyloxy] -1- (2,6-difluorophenyl) -5- (hydroxymethyl) -6-methylpyridine-2 (1H) -On;

1-benzyl-4- (benzyloxy) -2-oxo-1,2-dihydropyridine-3-carbaldehyde;

4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-prop-2-yn-1-ylpyridin-2 (1H) -one;

Ethyl 3- [4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] propanoate;

1-benzyl-4- (benzyloxy) -3- (hydroxymethyl) pyridin-2 (1H) -one;

3-chloro-4- (2,4-difluoro-benzyloxy) -6-methyl-1- (5-methyl-pyrazin-2-ylmethyl) -1H-pyridin-2-one;

3-chloro-4- (2,4-difluoro-benzyloxy) -1- (5-hydroxymethyl-pyrazin-2-ylmethyl) -6-methyl-1H-pyridin-2-one;

3-bromo-4- (2,4-difluoro-benzyloxy) -1- (2,3-dihydro-1H-indol-5-ylmethyl) -1H-pyridin-2-one;

3-bromo-4- (2,4-difluoro-benzyloxy) -1- [1- (2-hydroxy-acetyl) -2,3-dihydro-1H-indol-5-ylmethyl] -6-methyl-1H-pyridin-2-one;

3-bromo-4- (2,4-difluoro-benzyloxy) -6-methyl-1- (1H-pyrazol-3-ylmethyl) -1H-pyridin-2-one;

3- [3-chloro-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-yl] -4, N-dimethyl-benzamide;

3- [3-chloro-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-yl] -4-methyl-benzamide;

3- [3-chloro-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-yl] -4-fluoro-N-methyl-benzamide ;

4-chloro-3- [3-chloro-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-yl] -N-methyl-benzamide;

3- [3-chloro-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-yl] -4-fluoro-benzamide;

4- [3-chloro-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-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-pyridine 2-one;

N- {4- [3-Chloro-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] -phenyl} -2-hydroxy Acetamide;

1-hydroxycyclopropanecarboxylic 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-1-ylmethyl] -benzyl} -2-hydroxy Acetamide;

N- {4- [3-Chloro-4- (2,4-difluoro-benzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] -phenyl} -acetamide;

{2- [3-Bromo-1- (2,6-difluoro-phenyl) -6-methyl-2-oxo-1,2-dihydro-pyridin-4-yloxymethyl] -5-fluoro Rho-benzyl} -carbamic acid ethyl ester; Or a pharmaceutically acceptable salt thereof.

The compound name was prepared using ChemDraw Ultra version 6.0.2 from CambridgeSoft.com, Cambridge, Mass., Or ACD Namepro version 5.09 from ACDlabs.com.

<Definition>

As used herein, the term "alkenyl" refers to a linear or branched hydrocarbon of a planned number of carbon atoms containing one or more carbon-carbon double bonds. Examples of "alkenyl" include vinyl, allyl and 2-methyl-3-heptene.

The term "alkoxy" refers to alkyl attached to the parent molecule site via an oxygen bridge. Examples of alkoxy groups include, for example, methoxy, ethoxy, propoxy and isopropoxy.

The term "thioalkoxy" refers to alkyl attached to the parent molecule site via a sulfur atom. Examples of thioalkoxy groups include, for example, thiomethoxy, thioethoxy, thiopropoxy and thioisopropoxy.

As used herein, the term "alkyl" includes alkyl groups of a predetermined number of carbon atoms. Alkyl groups may be linear 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 a specific number of carbons. For example, C ₁ -C ₄ alkyl includes all alkyl groups containing at least one and up to four carbon atoms. It also contains subgroups such as, for example, C ₂ -C ₃ alkyl or C ₁ -C ₃ alkyl.

The term "aryl" means an aromatic hydrocarbon ring system containing at least one aromatic ring. The aromatic ring may optionally be fused to or otherwise attached to another aromatic hydrocarbon ring or non-aromatic hydrocarbon ring. Examples of aryl groups include, for example, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalene, indanyl and biphenyl. Preferred examples of the aryl group include phenyl and naphthyl. Most preferred aryl group is phenyl. Aryl groups herein are unsubstituted or substituted with various groups at one or more substitutable positions as described above. Thus, such aryl groups are, for example, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di- (C ₁ -C ₆ ) alkylamino, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, amino (C ₁ -C ₆ ) alkyl, mono- or di (C _1- Optionally substituted with a group such as C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl.

The term "arylalkyl" means 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. Most preferred arylalkyl group is benzyl. The aryl portion of the group is unsubstituted or substituted with various groups at one or more substitutable positions as described above. Thus, such aryl groups are, for example, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di- (C ₁ -C ₆ ) alkylamino, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, amino (C ₁ -C ₆ ) alkyl, mono- or di (C _1- Optionally substituted with a group such as C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl.

The term "arylalkoxy" means an aryl group as defined above attached to the parent molecular moiety through an alkoxy group as defined above. Preferred arylalkoxy groups include benzyloxy, phenethyloxy, phenpropyloxy and phenbutyloxy. Most preferred arylalkoxy groups are benzyloxy.

The term "cycloalkyl" refers to a C ₃ -C ₈ cyclic hydrocarbon. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. More preferred cycloalkyl groups include cyclopropyl.

As used herein, the term "cycloalkylalkyl" refers to a C ₃ -C ₈ cycloalkyl group attached to the parent molecular moiety through an alkyl group as defined above. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.

The term "halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

The term “heterocycloalkyl” means a non-aromatic ring system containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the non-aromatic heterocycle is attached to the core. Heterocycloalkyl rings may optionally be fused to or otherwise attached to other heterocycloalkyl rings, aromatic heterocycles, aromatic hydrocarbons, and / or non-aromatic hydrocarbon rings. Preferred heterocycloalkyl groups have 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, morpholinyl and pyrrolidinyl. Heterocycloalkyl groups herein are unsubstituted or substituted with various groups at one or more substitutable positions as described above. Thus, such heterocycloalkyl groups are, for example, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di- (C ₁ -C ₆ ) alkyl Amino, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, amino (C ₁ -C ₆ ) alkyl, mono- or di (C ₁ -C ₆₎ it may be optionally substituted by a group such as alkyl-amino (C ₁ -C ₆₎ alkyl.

The term "heteroaryl" means an aromatic ring system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur. Heteroaryl rings may be fused to 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, isox Sazolyl, oxadiazolyl, isothiazolyl, benzisothiazolyl, triazolyl, tetrazolyl, pyrrolyl, indolyl, pyrazolyl and benzopyrazolyl. Preferred heteroaryl groups include pyridyl. Heteroaryl groups herein are unsubstituted or substituted with various groups at one or more substitutable positions as described above. Thus, such heteroaryl groups are for example C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di- (C ₁ -C ₆ ) alkylamino, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, amino (C ₁ -C ₆ ) alkyl, mono- or di- (C ₁ -C ₆₎ it may be optionally substituted by a group such as alkyl-amino (C ₁ -C ₆₎ alkyl.

The term "heteroarylalkyl" means 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 portion of the group is unsubstituted or substituted with various groups at one or more substitutable positions as described above. Thus, such heteroaryl groups are for example C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di- (C ₁ -C ₆ ) alkylamino , C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, amino (C ₁ -C ₆ ) alkyl, mono- or di (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl may be optionally substituted.

When two or more identical substituents are present on a common atom, for example in the case of di (C ₁ -C ₆ ) alkylamino, it is understood that the nature of each group is independent of the other groups.

As used herein, the term “p38 mediated disorder” refers to p38 by the control of p38 itself or by allowing p38 to release other factors such as, but not limited to, IL-1, IL-6 or IL-8. It means some and all disorders and disease states that function. Thus, for example, a disease state in which IL-1 is a major factor and the production or action of the disease state is exacerbated or secreted in response to p38 will be considered a disorder mediated by p38.

TNF-beta has structural homology close to TNF-alpha (also known as capetine), each induces a similar biological response and binds to the same cellular receptor, thus both TNF-alpha and TNF-beta synthesis Inhibited by the compounds of the invention, and therefore collectively referred to herein as "TNF", unless specifically stated otherwise.

Non-toxic pharmaceutically acceptable salts include salts of inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid and nitric acid or formic acid, citric acid, malic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, acetic acid, lactic acid, methanesulfonic acid salts of organic acids such as, but not limited to, p-toluenesulfonic acid, 2-hydroxyethylsulfonic acid, salicylic acid and stearic acid. 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 range of non-toxic pharmaceutically acceptable addition salts.

Since the compounds of the present invention may contain one or more asymmetric carbon atoms, the compounds may exist in various stereoisomeric forms. Such compounds can be, for example, racemates, chiral non-racemates or diastereomers. In such a situation, the enantiomers alone, ie optically active forms, can be obtained by asymmetric synthesis or by separation of racemates. Separation of the racemates can be carried out, for example, by conventional methods such as crystallization in the presence of a separating agent; Chromatography using, for example, chiral HPLC columns; Or to generate diastereomers by achieving derivatization of the racemic mixture using a separation reagent, and to separate the diastereomers by chromatography or selective crystallization and to remove the separating agent to produce the original compound in enantiomeric rich form. can do. Any of the above methods can be repeated to increase the enantiomeric purity of the compound.

The compounds of the present invention may exist as atropisomers, ie chiral rotamers. The present invention includes racemates and isolated atropisomers. The following schemes generally show compounds (Z), which may exist as atropisomers, as well as two possible atropisomers (A) and (B). This scheme also shows each of the atropisomers (A) and (B) in a Fischer projection. In this scheme, R ₁ , R ₂ and R ₄ are defined the same as described for Formula 1, R _{p '} is a substituent within the definition of R ₅ , and R _p is a non-hydrogen substituent within the definition of R ₅ . .

Where the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include cis, trans, Z- and E-configurations. Likewise, it is intended to include all tautomeric forms.

The compound of formula 1 may be administered orally, topically, parenterally, inhaled or nebulized or rectally in a dosage unit formulation containing a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and vehicle. . The term parenteral, as used herein, includes transdermal, subcutaneous, intravascular (eg intravenous), intramuscular, or intrathecal injection or infusion techniques and the like. Also provided is a pharmaceutical formulation comprising a compound of Formula 1 and a pharmaceutically acceptable carrier. One or more compounds of Formula 1 may be present in combination with one or more non-toxic pharmaceutically acceptable carriers and / or diluents and / or adjuvants, and other active ingredients, if desired. Pharmaceutical compositions containing a compound of formula (1) may be in a form suitable for oral use, for example tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or It may be an elixir.

For oral administration, the pharmaceutical composition may be in the form of a tablet, hard or soft capsule, lozenge, dispensable powder, suspension or liquid, for example. Pharmaceutical compositions are preferably prepared in the form of dosage units containing a specific amount of active ingredient. Examples of such dosage units are tablets or capsules.

Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, which compositions can be used as sweetening, flavoring, coloring and It may contain one or more agents selected from the group consisting of preservatives. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. The excipient may be, for example, an inert diluent such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; Granulating and disintegrating agents such as corn starch or alginic acid; Binders such as starch, gelatin or acacia; And lubricating agents, for example magnesium stearate, stearic acid or talc. Tablets may not be coated or may be coated by known techniques. In some cases, such coatings may be prepared by known techniques to provide longer lasting action by delaying disintegration and absorption in the gastrointestinal tract. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be used.

In addition, formulations for oral use are provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or the active ingredient is water or an oil medium such as peanut oil, It may be provided as a soft gelatin capsule mixed with liquid paraffin or olive oil.

Formulations for oral use may also be provided as lozenges.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; Dispersants or wetting agents may be natural phospholipids, such as lecithin, or condensation products of alkylene oxides and fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide and long chain aliphatic alcohols, for example heptadecaethylene Condensation products of oxycetanol or partial esters and hexitols derived from ethylene oxide with fatty acids, for example polyoxyethylene sorbitol monooleate, or condensation of partial esters and hexitol anhydrides derived from ethylene oxide with fatty acids Product, for example polyethylene sorbitan monooleate. Aqueous suspensions also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweetening agents such as sucrose or saccharin can do.

Oily suspensions can be formulated by suspending the active ingredient in vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil, or mineral oils such as liquid paraffin. The oily suspension may contain thickeners such as beeswax, hard paraffin or cetyl alcohol. Sweetening and flavoring agents may be added to provide a delicious oral formulation. The composition can be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparing an aqueous suspension by addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Examples of suitable dispersing or wetting agents or suspending agents have already been mentioned above. Additional excipients may also be present, such as sweetening, flavoring and coloring agents.

Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oil phase can be vegetable or mineral oil, or mixtures thereof. Suitable emulsifiers are natural gums such as gum acacia or gum tragacanth, natural phospholipids such as soybeans, lecithin, and esters or partial esters derived from fatty acids and hexitols, anhydrides such as sorbitan monooleate And condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations may contain analgesics, preservatives, flavors and coloring agents. The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension. Such suspensions may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example 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 nonvolatile oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid have been found to be used in the preparation of injectables.

The compounds of formula 1 may also be administered in the form of suppositories, eg suppositories for rectal administration of the drug. The composition may be prepared by mixing the drug with a suitable non-irritating excipient which will be solid at ordinary temperatures or liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.

The compound of formula 1 may be administered parenterally in sterile medium. Depending on the vehicle and concentration used, the drug may be suspended or dissolved in the vehicle. Advantageously, adjuvant such as local anesthetics, preservatives and buffers can be dissolved in the vehicle.

In addition, the active ingredient may be administered as a composition by injection (IV, IM, subcutaneous or jet), where, for example, saline, dextrose or water can be used as a suitable carrier. If necessary, the pH of the composition can be adjusted with a suitable acid, base or buffer. Suitable bulking, dispersing, wetting or suspending agents can also be included in the compositions, including mannitol and PEG 400. Suitable parenteral compositions may also include formulated compounds in the injection vials as sterile solid materials comprising lyophilized powder. Aqueous solutions may be added to dissolve the compound prior to injection.

In the case of disorders of the eyes or other external tissues, such as the mouth and skin, the preparation may contain, for example, 0.075 to 30% by weight, preferably 0.2 to 20% by weight, most preferably 0.4 to 15% by weight of the active ingredient. Preference is given to applying as a topical gel, spray, ointment or cream, or suppository containing in a total amount of. When formulated into an ointment, the active ingredient can be used with paraffinic or water miscible ointment bases.

Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base. If desired, the cream based aqueous phase may comprise at least 30% by weight of polyhydric alcohols such as, for example, propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. Topical formulations may preferably include compounds which enhance the absorption or penetration of the active ingredient through the skin or other site of action. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs. The compounds of the present invention may also be administered by transdermal devices. Preferably, topical administration will be achieved using a reservoir and a patch of porous membrane type or solid matrix variant. In any case, the active agent is continuously transferred from the reservoir or microcapsules through the membrane to the active agent permeable adhesive that contacts the recipient's skin or mucous membranes. When the active agent is absorbed through the skin, a controlled and predetermined flow of active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as a membrane. Transdermal patches may comprise the compound in suitable solvent systems with adhesive systems, such as acrylic emulsions and polyester patches. The oil phase of the emulsions of the invention may be constituted from known ingredients in a known manner. The oil phase may comprise only emulsifiers, but may comprise fats or oils or mixtures of one or more emulsifiers containing both fats and oils. Preferably, hydrophilic emulsifiers are included together with lipophilic emulsifiers that act as stabilizers. It is also desirable to include both oils and fats. With or without stabilizer (s), the emulsifier (s) together constitute the so-called emulsifying wax, and together with the oil and the fat the wax constitutes the so-called emulsifying ointment base, which is an oily dispersion of the cream formulation. Form the phase. Suitable emulsifiers and emulsion stabilizers for the formulations of the present invention include, among others, tween 60, span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. Used in Pharmaceutical Emulsion Formulations Since the solubility of the active compounds in very likely oils is very low, the selection of suitable oils or fats for such formulations is based on achieving the desired molding properties. Thus, the cream should preferably be a non-greasy, non-polluting and washable product with a suitable consistency so as not to leak out of the tube or other container. Straight or branched chain, monobasic or dibasic alkyl esters, for example di-isoadiate, isocetyl stearate, propylene glycol diesters of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl Blends of stearate, 2-ethylhexyl palmitate or branched chain esters can 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 ingredient is dissolved or suspended in a carrier suitable for the active ingredient, in particular an aqueous solvent. The anti-inflammatory active ingredient is preferably present in such formulations at a concentration of 0.5 to 20%, advantageously 0.5 to 10% and especially about 1.5% by weight. For the purpose of treatment, the active compounds of the present invention are usually combined with one or more adjuvants appropriate for the indicated route of administration. When administered orally, the compounds are lactose, sucrose, starch powder, cellulose esters of cellulose alkanoic acid, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfuric acid, gelatin, acacia After mixing with gum, sodium alginate, polyvinylpyrrolidone and / or polyvinyl alcohol, it can be tableted or encapsulated for conventional administration. Such capsules or tablets may contain controlled-release preparations which may be provided as a dispersion of the active compound in hydroxypropylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injectable solutions or suspensions. Such solutions and suspensions may be prepared from sterile powders or granules containing one or more carriers or diluents mentioned for use in the formulation for oral administration. The compound can 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 known in the pharmaceutical art.

The amount and dosing regimen of a therapeutically active compound administered to treat a disease state with a compound and / or composition of the present invention may include the age, weight, sex and medical condition of the subject, the severity of the inflammation or inflammation-related disorder, the route of administration And frequency, and the particular compound used, and therefore can vary widely. The pharmaceutical composition may contain the active ingredient in the range of about 0.1 to 1000 mg, preferably in the range of about 7.0 to 350 mg. A daily dosage of about 0.01 to 100 mg / kg body weight, preferably about 0.1 to about 50 mg / kg body weight and most preferably about 0.5 to 30 mg / kg body weight may be suitable. The daily dose may be administered in one to four doses per day. Depending on the skin condition, it may be desirable to apply a topical formulation of a compound of the invention to the site of action twice to four times daily.

However, the specific dosage level for any particular patient may vary depending on the activity, age, weight, general health, sex, diet, time of administration, route of administration and rate of administration, drug combination and therapy of the specific compound used. It will be appreciated that this will vary depending on various factors, including severity.

When administered to non-human animals, the compositions may be added to animal feed or beverages. It may be convenient to formulate animal feed and beverage compositions such that the animal consumes a therapeutically suitable amount of the composition with its diet. It may also be convenient to provide the composition as a premix for addition to the feed or beverage.

All articles and references, including patents described in this application, are incorporated herein by reference.

The invention is further illustrated by the following examples, which should not be construed to limit the invention to the specific methods set forth in the Examples in terms of scope or spirit.

Starting materials and various intermediates can be obtained from commercial sources, prepared from commercially available compounds, or prepared using well known synthetic methods.

Compound names in this application were determined using either software ACD Name Pro version 5.09 or ChemDraw Ultra version 6.0.2.

<Common Synthesis Method>

Representative methods of preparing the compounds of the present invention are summarized in the following schemes. 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 accomplished using methods known in the art. As demonstrated by the examples below, the compounds included in the present invention can be prepared using varying starting materials and additional steps. In addition, various solvents and reagents may typically be used to achieve this modification. It may also be necessary to protect the reactive groups to achieve this modification. In general, the conditions required for attaching and removing such groups as well as those required for protecting groups will be apparent to those skilled in the art of organic synthesis. If protecting groups are used, deprotection will generally be required. Suitable protecting groups and methods for protection and deprotection, for example those described for protecting groups in Greene and Watts' Organic Synthesis, are known and recognized in the art.

In the above scheme, R ₅ is as defined above.

Alternatively, the compounds of the present invention can be prepared according to the methods outlined in Scheme 2.

In Scheme 2, in each case Q is independently alkyl, halogen, alkoxy, arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, CO 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.

Alternatively, the compounds of the present invention can be prepared using the methods outlined in Schemes 3-25. In Schemes 3-25, the X, X ', R, R' and R "substituents on groups such as aryl, heteroaryl, amine and alkyl are the same as defined above for the substituents on these groups.

The invention is further illustrated by the following examples, which should not be construed to limit the invention to the specific methods set forth in the Examples in terms of scope or spirit. One of ordinary skill in the art will recognize that the compounds included in the present invention can be prepared using varying starting materials and using additional steps, as demonstrated by the examples below. Those skilled in the art will also recognize that it may be necessary to use various solvents and reagents to achieve some of these modifications. In some cases, protection of reaction functionality may be necessary to achieve this modification. In general, not only what is required for such protecting groups, but also the conditions necessary for attaching and removing such groups will be apparent to those skilled in the art of organic synthesis. If a protecting group is used, a deprotection step may be required. Suitable protecting groups and methods for protection and deprotection, such as those described for the protecting groups in Green and Watts of Organic Synthesis, are well known and recognized in the art.

Unless otherwise specified, all reagents and solvents are of standard commercial grade and used without further purification. Suitable atmospheres for carrying out the reaction, for example under air, under nitrogen, under hydrogen, under argon and the like will be apparent to those skilled in the art.

<Example>

Example 1

4- (benzyloxy) -1- (4-methylbenzyl) pyridin-2 (1H) -one

4-benzyloxy-2 (1H) -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. It was. The contents were cooled, diluted with water and the solid (5.52 g) was filtered off. FABHRMS m / z 306.1494 (M + H required for C ₂₀ H ₂₀ NO ₂ : 306.1494). _{^{1 H NMR (CDCl 3/300}} MHz): 7.50-7.40 (m, 5H); 7.20-7.05 (m, 5 H); 6.07-6.00 (m, 1 H); 5.95-5.90 (m, 1 H); 5.05 (s, 2 H); 5.00 (s, 2 H); 2.32 (s, 3 H).

Anal. Calcd. For C ₂₀ H ₁₉ NO ₂ : C, 78.66; H, 6. 27; N, 4.59. Found: C, 78.54; H, 6. 38; N, 4.58.

Example 2

4- (benzyloxy) -3-bromo-1- (4-methylbenzyl) pyridin-2 (1H) -one

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. The contents were stirred for 2 hours to reach room temperature. Water (200 mL) was added and the light yellow solid was filtered off. Mp 150.4-151.2 ° C. FABHRMS m / z 384.0599 (M + H required for C ₂₀ H ₁₈ BrNO ₂ : 384.0601). _{^{1 H NMR (CDCl 3/300}} MHz) δ: 7.42-7.30 (m, 5H); 7.22-7.08 (m, 5 H); 6.02 (d, 1 H); 5.20 (s, 2 H); 5.12 (s, 2 H); 2.32 (s, 3 H).

Anal. Calcd. For C ₂₀ H ₁₈ BrNO ₂ : C, 62.51; H, 4.72; N, 3.65. Found: C, 62.11; H, 4. 48; N, 3.54.

Examples 3 to 10

The compounds of Examples 3 to 10 were prepared essentially according to the method described above for Example 1. According to the method of Example 2 essentially prepared a compound wherein R ₁ = Br.

NMR Properties of the Compounds of Examples 3 to 10

Example 11

4- (benzyloxy) -3-bromopyridin-2 (1H) -one

The material of Example 11 was prepared according to the method of Example 2. _{^{1 H NMR (CDCl 3/300}} MHz) δ: 7.50-7.30 (m, 6H); 6.20 (d, 1 H); 5.24 (s, 2 H).

Anal calculated 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

The compounds of Examples 12-19 were prepared essentially according to the method described above for Example 1. According to the method of Example 2 essentially a compound was prepared wherein R ₁ = Br.

NMR Properties of the Compounds of Examples 12-19

Example 20

4- (benzyloxy) -3-bromo-1-ethylpyridin-2 (1H) -one

Bromoethane (0.82 mL, 0.011 mol) was added to 4-benzyloxy-2 (1H) -pyridone (1.0 g, 0.005 mol) and potassium carbonate (1.0 g, 0.007 mol) in DMF (10 mL). The contents were heated at 75 ° C. overnight. The contents were left to cool and partitioned between EtOAc and water. The EtOAc layer was dried over MgSO ₄ , filtered and concentrated in vacuo to give a waxy solid which was recrystallized from EtOAc / hexanes to give a white solid (720 mg). To a white solid (700 mg, 0.003 mol) in glacial acetic acid (10 mL) was added dropwise bromine (0.17 mL, 0.00325 mol) in glacial acetic acid (5 mL) at 15 ° C. The contents were stirred for 1 hour at room temperature and the yellow solid (1.1 g) was filtered off. The solid was partitioned between EtOAc and 2.5 N sodium hydroxide. The EtOAc layer was dried over MgSO ₄ , filtered and concentrated in vacuo to give a colorless oil (710 mg) which solidified. FABHRMS m / z 310.0267 (M + H required for C ₁₄ H ₁₅ BrNO ₂ : 310.0263). _{^{1 H NMR (CDCl 3/300}} MHz) δ 7.45-7.30 (m, 6H); 7.22 (d, 1 H); 6.07 (d, 1 H); 5.20 (s, 2 H); 4.00 (q, 2 H); 1.32 (t, 3 H).

Anal. Calcd. For C ₁₄ H ₁₄ BrNO ₂ : C, 54.56; H, 4.58; N, 4.55. Found: C, 54.21; H, 4.38; N, 4.43.

Example 21

3-bromo-4-hydroxy-1- (4-hydroxybenzyl) pyridin-2 (1H) -one

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. The contents were filtered and the filtrate was concentrated in vacuo to give an oil. FABHRMS m / z 295.9952 (M + H required for C ₁₂ H ₁₁ BrNO ₃ : 295.9922). _{^{1 H NMR (DMSO-d 6}} /300 MHz) δ 11.40 (br s, 1H); 9.40 (br s, 1 H); 7.60 (d, 1 H); 7.10 (d, 2 H); 6.70 (d, 2 H); 6.02 (d, 1 H); 4.93 (s, 2 H).

Anal calculated for C ₁₂ H ₁₀ BrNO ₃ (1.4 H ₂ O): C, 44.85; H, 4.02; N, 4.36. Found: C, 45.07; H, 4.10; N, 4.35.

Example 22

4- (benzyloxy) -3-bromo-1-methylpyridin-2 (1H) -one hydrobromide

Methyl iodide (0.342 mL, 0.0055 mol) was added to 4-benzyloxy-2 (1H) -pyridone (1.0 g, 0.005 mol) and potassium carbonate (760 mg, 0.0055 mol) in DMF (10 mL). The contents were stirred overnight. The contents were partitioned between EtOAc and water. The EtOAc layer was dried over MgSO ₄ , filtered and concentrated in vacuo to give a white solid (960 mg).

To a white solid (332 mg, 0.0015 mol) in glacial acetic acid (10 mL) was added dropwise bromine (256 mg, 0.0016 mol) in glacial acetic acid (5 mL) at 15 ° C. The contents were stirred for 1 hour at room temperature, and the desired product was filtered out as 262 mg (yield 59%) of white solid. mp 105.3 ° C. to 105.6 ° C. FABHRMS m / z 296.0097 (M + H required for C ₁₃ H ₁₃ BrNO ₂ : 296.0110). _{^{1 H NMR (CDCl 3/300}} MHz) δ 7.45-7.30 (m, 6H); 7.22 (d, 1 H); 6.07 (d, 1 H); 5.20 (s, 2 H); 4.00 (q, 2 H); 1.32 (t, 3 H).

C ₁₃ H ₁₂ BrNO ₂ Anal. Calculated for (HBr, 0.3 H ₂ O): C, 41.04; H, 3. 60; N, 3.68. Found: C, 41.00; H, 3.87; N, 3.52.

Example 23

4- (benzyloxy) -3-bromo-1-methylpyridin-2 (1H) -one

The material of Example 22 was partitioned between EtOAc and 2.5 N sodium hydroxide. The EtOAc layer was dried over MgSO ₄ , filtered and concentrated in vacuo to give a red oil which solidified. FABHRMS m / z 294.0112 (M + H required for C ₁₃ H ₁₃ BrNO ₂ : 294.0130). _{^{1 H NMR (CDCl 3/300}} MHz): 7.45-7.30 (m, 6H); 7.22 (d, 1 H); 6.07 (d, 1 H); 5.20 (s, 2 H); 4.00 (q, 2 H); 1.32 (t, 3 H).

Anal. Calcd. For C ₁₃ H ₁₂ BrNO ₂ : C, 53.08; H, 4.11; N, 4.76. Found: C, 53.06; H, 4. 20; N, 4.74.

Example 24

4-{[4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] methyl} N'-hydroxybenzenecarboximideamide

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. The contents were left to cool and the solids were filtered and washed with water to afford the desired product as a white solid of 447 mg (yield 82%). mp 210.2 ° C to 212.2 ° C. FABHRMS m / z 428.0634 (M + H required for C ₂₀ H ₁₉ BrN ₃ O ₃ : 428.0610). _{^{1 H NMR (DMSO-d 6}} /300 MHz): 9.66 (s, 1H); 7.98 (d, 1 H); 7.65 (d, 2 H); 7.55-7.35 (m, 5 H); 7.30 (d, 2 H); 6.54 (d, 1 H); 5.82 (s, 2 H); 5.35 (s, 2 H); 5.17 (s, 2 H).

Anal. Calcd. For C ₂₀ H ₁₈ BrN ₃ O ₃ : C, 56.09; H, 4. 24; N, 9.81. Found: C, 55.92; H, 4.01; N, 9.52.

Example 25

4- (benzyloxy) -3-bromo-1- (piperidin-4-ylmethyl) pyridin-2 (1H) -one hydrochloride

To the material of Example 11 (924 mg, 0.0033 mol) in DMF (5 mL) was added dropwise sodium bis (trimethylsilyl) amide (1 M in THF, 3.6 mL). After stirring the contents for 1 hour, 4-methanesulfonyloxymethyl-1-piperidine-1-carboxylic acid tert-butyl ester in DMF (5 mL) (J. Labelled Compd, Radiopharm, 38 ( 7), 1996, 595-606] (1.0 g, 0.0036 mol) solution was added dropwise. The contents were heated at 75 ° C. overnight. The contents were left to cool and poured into water (100 mL). The 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, left to cool and filtered to afford the desired product as a white solid, 415 mg (30% yield). mp 207.9 ° C. FABHRMS m / z 377.0852 (M + H required for C ₁₈ H ₂₃ BrClN ₂ O ₂ : 377.0865). _{^{1 H NMR (DMSO-d 6}} /300 MHz) δ 8.90 (br, 1H); 8.64 (br, 1 H); 7.80 (d, 1 H); 7.50-7.30 (m, 5 H); 6.48 (d, 1 H); 5.30 (s, 2 H); 3.83 (d, 2 H); 3.20 (d, 2 H); 2.88-2.64 (m, 2 H); 2.10-1.90 (m, 1 H); 1.60 (d, 2 H); 1.50-1.40 (m, 2 H).

C ₁₈ H ₂₂ BrClN ₂ O ₂ Anal. Calculated for (0.3 H ₂ O): C, 51.58; H, 5. 43; N, 6.68. Found: C, 51.59; H, 5. 42; N, 6.81.

Example 26

4- (benzyloxy) -1- [4- (trifluoromethyl) benzyl] pyridin-2 (1H) -one

The material of Example 26 was prepared according to the procedure of Example 1. FABHRMS m / z 360.1213 (M + H required for C ₂₀ H ₁₇ F ₃ NO ₂ : 360.1211). _{^{1 H NMR (CDCl 3/300}} MHz) δ 7.60 (d, 2H); 7.41-7.30 (m, 7 H); 7.13 (d, 1 H); 6.05-6.01 (m, 1 H); 6.00-5.95 (m, 1 H); 5.13 (s, 2 H); 5.00 (s, 2 H).

Anal. Calcd. For C ₂₀ H ₁₆ F ₃ NO ₂ : C, 66.85; H, 4. 49; N, 3.90. Found: C, 66.64; H, 4. 26; N, 3.93.

Example 27

4- (benzyloxy) -3-bromo-1- [4- (trifluoromethyl) benzyl] pyridin-2 (1H) -one

The material of Example 27 was prepared according to the procedure of Example 2. FABHRMS m / z 438.0308 (M + H required for C ₂₀ H ₁₆ BrF ₃ NO ₂ : 438.0316). _{^{1 H NMR (CDCl 3/300}} MHz) δ 7.65-7.20 (m, 10H); 6.13-6.03 (m, 1 H); 5.30-5.13 (m, 4 H).

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

4- (benzyloxy) -3-bromo-1- (piperidin-3-ylmethyl) pyridin-2 (1H) -one hydrochloride

To the material of Example 11 (3.1 g, 0.011 mol) in DMF (20 mL) was added dropwise sodium bis (trimethylsilyl) amide (1 M in THF, 12 mL). After stirring the contents for 1 hour, 3-methanesulfonyloxymethyl-1-piperidine-1-carboxylic acid tert-butyl ester in DMF (5 mL) (Bioorg. Med. Chem. Lett, 8 (13), 1998, 1595-1600]) (4.2 g, 0.015 mol) was added dropwise. The contents were heated at 75 ° C. overnight. The contents were left to cool and poured into water (100 mL) and the solids were filtered off. The solid was stirred for 3 h in 4 N HCl / dioxane (15 mL) and filtered to afford the desired product as 752 mg (yield 18%) of white solid. mp 138.1 ° C to 139.2 ° C. FABHRMS m / z 377.0859 (M + H required for C ₁₈ H ₂₂ BrN ₂ O ₂ : 377.0865). _{^{1 H NMR (DMSO-d 6}} /300 MHz): 9.50-9.10 (br, 2H); 8.00 (d, 1 H); 7.50-7.30 (m, 5 H); 6.93 (d, 1 H); 5.30 (s, 2 H); 4.30-3.90 (m, 3 H); 3.40-3.10 (m, 3 H); 2.80-2.50 (m, 3 H); 2.40-2.00 (m, 1 H); 1.90-1.60 (m, 4 H); 1.40-1.10 (m, 1 H).

C ₁₈ H ₂₁ BrN ₂ O ₂ (2HCl, 0.25 H ₂ O): C, 47.55; H, 5. 21; N, 6.16. Found: C, 47.48; H, 5. 46; N, 6.27.

Example 29

4- (benzyloxy) -3-bromo-1- (2-thien-3-ylethyl) pyridin-2 (1H) -one

To the material of Example 11 (500 mg, 0.0018 mol) in DMF (5 mL) was added dropwise sodium bis (trimethylsilyl) amide (1 M in THF, 2 mL). After stirring the contents for 1 hour, methanesulfonic acid 2-thiophen-3-yl-ethyl ester in DMF (5 mL) (JAC S, 109 (6), 1987, 1858-1859]) (412 mg, 0.002 mol) solution was added dropwise. The contents were heated at 75 ° C. overnight. The contents were left to cool, poured into water (100 mL), extracted with EtOAc, dried over MgSO ₄ , filtered and concentrated in vacuo to give a light yellow oil. The oil was purified by silica gel chromatography eluting with 50% EtOAc / hexanes to give 199 mg (28% yield) of the title compound as a white solid. mp 134.0 ° C. to 134.3 ° C.

FABHRMS m / z 390.0144 (M + H required for C ₁₈ H ₁₇ BrNO ₂ S: 390.0163). _{^{1 H NMR (CDCl 3/300}} MHz): 7.43-7.20 (m, 6H); 6.92-6.80 (m, 3 H); 5.90 (d, 1 H); 5.20 (s, 2 H); 4.13 (t, 2 H); 3.10 (t, 2 H).

Anal. Calcd. For C ₁₈ H ₁₆ BrNO ₂ S: C, 55.39; H, 4.13; N, 3.59. Found: C, 55.21; H, 3.87; N, 3.52.

Example 30

4- (benzyloxy) -3-bromo-1- (2-thien-2-ylethyl) pyridin-2 (1H) -one

The title compound was prepared essentially according to the procedure of Example 29. mp 128.0 ° C. to 129.5 ° C. FABHRMS m / z 390.0160 (M + H required for C ₁₈ H ₁₇ BrNO ₂ S: 390.0163). _{^{1 H NMR (CDCl 3/300}} MHz) δ 7.48-7.30 (m, 5H); 7.12 (d, 1 H); 6.95-6.80 (m, 2 H); 6.75-6.68 (m, 1 H); 5.95 (d, 1 H); 5.20 (s, 2 H); 4.16 (t, 2 H); 3.30 (t, 2 H).

Anal. Calcd. For C ₁₈ H ₁₆ BrNO ₂ S: C, 55.39; H, 4.13; N, 3.59. Found: C, 55.06; H, 4.01; N, 3.56.

Example 31

4- (benzyloxy) -3-bromo-1- [3- (trifluoromethyl) benzyl] pyridin-2 (1H) -one

To the material of Example 11 (500 mg, 0.0018 mol) in DMF (5 mL) was added dropwise sodium bis (trimethylsilyl) amide (1 M in THF, 2 mL). After the contents were stirred for 1 hour, a solution of 3-trifluoromethylbenzyl bromide (478 mg, 0.002 mol) in DMF (5 mL) was added dropwise. The contents were heated at 75 ° C. for 2 hours. The contents were left to cool and poured into water (100 mL), extracted with EtOAc, which was dried over MgSO ₄ , filtered and concentrated in vacuo to give a white solid. FABHRMS m / z 438.0301 (M + H required for C ₂₀ H ₁₆ BrF ₃ NO ₂ : 438.0316). _{^{1 H NMR (CDCl 3/300}} MHz): 7.60-7.20 (m, 10H); 6.10 (d, 1 H); 5.14 (s, 2 H); 5.20 (s, 2 H).

Anal. Calcd. For C ₂₀ H ₁₅ BrF ₃ NO ₂ : C, 54.81; H, 3. 45; N, 3.20. Found: C, 54.81; H, 3. 36; N, 3.13.

Example 32

4- (benzyloxy) -3-bromo-1- [2- (trifluoromethyl) benzyl] pyridin-2 (1H) -one

The material of Example 32 was prepared according to the procedure of Example 31.

FABHRMS m / z 438.0280 (M + H required for C ₂₀ H ₁₆ BrF ₃ NO ₂ : 438.0316). _{^{1 H NMR (CDCl 3/300}} MHz) δ 7.68 (d, 1H); 7.55-7.20 (m, 8 H); 7.15 (d, 1 H); 6.10 (d, 1 H); 5.40 (s, 2 H); 5.13 (s, 2 H).

Anal. Calcd. For C ₂₀ H ₁₅ 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

4- (benzyloxy) -1- [4- (trifluoromethoxy) benzyl] pyridin-2 (1H) -one

The material of Example 33 was prepared according to the procedure of Example 1.

FABHRMS m / z 376.1158 (M + H required for C ₂₀ H ₁₇ F ₃ NO ₃ : 376.1161). _{^{1 H NMR (CDCl 3/300}} MHz) δ 7.40-7.05 (m, 10H); 6.05-5.95 (m, 2 H); 5.06 (s, 2 H); 4.98 (s, 2 H).

Anal. Calcd. For C ₂₀ H ₁₆ F ₃ NO ₃ : C, 64.00; H, 4. 30; N, 3.73. Found: C, 63.97; H, 4. 26; N, 3.57.

Example 34

4- (benzyloxy) -3-bromo-1- [4- (trifluoromethoxy) benzyl] pyridin-2 (1H) -one

The material of Example 34 was prepared according to the procedure of Example 2.

FABHRMS m / z 454.0240 (M + H required for C ₂₀ H ₁₆ BrF ₃ NO ₃ : 454.0266). _{^{1 H NMR (CDCl 3/300}} MHz) δ 7.45-7.10 (m, 10H); 6.08 (d, 1 H); 5.20 (s, 2 H); 5.12 (s, 2 H).

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

1-benzyl-4- (benzyloxy) -6-methylpyridin-2 (1H) -one

Step 1. Preparation of 1-benzyl-4-hydroxy-6-methylpyridin-2 (1H) -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 for 2 hours with stirring. After cooling to room temperature, a light brown solid was collected by filtration (33.4 g, 77%): 1 H NMR (DMSO-d 6/300 MHz) δ 10.5 (s, 1H), 7.4-7.1 (m, 5H) , 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 required for C ₁₂ H ₁₃ NO ₂ : 216.102).

Step 2. Preparation of 1-benzyl-4- (benzyloxy) -6-methylpyridin-2 (1H) -one

1-benzyl-4-hydroxy-6-methylpyridin-2 (1H) -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 sufficiently stirred at rt for 16 h. Hydrochloric acid (IN) was added until the mixture showed an acidic reaction to the pH test paper. Then the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. The product is obtained by flash chromatography eluting with ethyl acetate: hexanes (1: 2). The appropriate fractions were concentrated to a clear oil (1.3 g, 43%): 1 H NMR (DMSO-d 6/300 MHz) δ 7.4-7.1 (m, 10H), 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 required for C ₂₀ H ₁₉ NO ₂ : 306.149).

Example 36

1-benzyl-4- (benzyloxy) -3-bromo-6-methylpyridin-2 (1H) -one

Product from Example 35, 1-benzyl-4- (benzyloxy) -6-methylpyridin-2 (1H) -one (4.2 mmol, 1.3 g), acetic acid (50 mL) and sodium acetate (5.0 mmol, 0.41 g) was stirred at room temperature. Bromine (4.2 mmol, 0.67 g) was added dropwise with stirring. After ½ hour, water (100 mL) was added and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution and brine. After drying over magnesium sulfate and concentration, the mixture was purified by flash column chromatography eluting with ethyl acetate: hexanes (1: 2). Concentration of the appropriate fractions to give a light color oil (1.0 g, 62%): 1 H NMR (DMSO-d 6/300 MHz) 7.4-7.0 (m, 10H), 6.5 (s, 1H), 5.29 (s , 2H), 5.27 (s, 2H), 2.2 (s, 3H). ESHRMS m / z 384.057 (M + H required for C ₂₀ H ₁₈ NO ₂ Br: 384.060).

Example 37

1-benzyl-4- (benzyloxy) -3,5-dibromo-6-methylpyridin-2 (1H) -one

Product from Example 35, 1-benzyl-4- (benzyloxy) -6-methylpyridin-2 (1H) -one (4.2 mmol, 1.3 g), acetic acid (50 mL) and sodium acetate (5.0 mmol, 0.41 g) was stirred at room temperature. Bromine (4.2 mmol, 0.67 g) was added dropwise with stirring. After ½ hour, water (100 mL) was added and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organics were washed with saturated aqueous sodium bicarbonate solution and brine. After drying over magnesium sulfate and concentration, the mixture was purified by flash column chromatography eluting with ethyl acetate: hexanes (1: 2). Concentration of the appropriate fractions to give a white solid (0.3 g, 15%): 1 H NMR (DMSO-d 6/300 MHz) 7.5-7.0 (m, 10H), 5.42 (s, 2H), 5.07 (s, 2H), 2.45 (s, 3H). ESHRMS m / z 463.966 (M + H required for C ₂₀ H ₁₇ NO ₂ Br ₂ : 463.968).

Example 38

1-benzyl-4-[(3-chlorobenzyl) oxy] -6-methylpyridin-2 (1H) -one

Step 1. Preparation of 1-benzyl-6-methyl-2-oxo-1,2-dihydropyridin-4-yl 4-bromobenzenesulfonate

1-benzyl-4-hydroxy-6-methylpyridin-2 (1H) -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 rt for 16 h. Hydrochloric acid (IN) was added until the mixture became acidic against the pH test paper. Brine (50 mL) was added and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate and filtered. After concentration, the material was purified by flash column chromatography eluting with ethyl acetate: hexanes (1: 2). The appropriate fractions was concentrated to a clear oil, solidifying them, while left stand for several days to give a white solid (3.3 g, 76%): 1 H NMR (DMSO-d 6/400 MHz) 7.9 (m, 4H), 7.32- 7.00 (m, 5H), 7.3 (m, 1H), 6.12 (d, J = 2.4 Hz, 1H), 6.02 (d, J = 2.8 Hz, 1H), 5.20 (s, 2H), 2.2 (s, 3H ). ESHRMS m / z 436.002 (M + H required for C ₁₉ H ₁₆ NO ₄ SBr: 436.004).

Step 2. Preparation of 1-benzyl-4-[(3-chlorobenzyl) oxy] -6-methylpyridin-2 (1H) -one

1-benzyl-6-methyl-2-oxo-1,2-dihydropyridin-4-yl 4-bromobenzenesulfonate (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 (IN, 10 mL) was added and the mixture was extracted with ethyl acetate (3 × 25 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution and brine. After drying over magnesium sulfate and concentration, the mixture was purified by flash column chromatography eluting with ethyl acetate: hexanes (1: 1) to give a light yellow oil (14.3 g, 64%): ¹ H NMR (DMSO-d _{6/300 MHz) δ 7.4-7.0 (} m, 10H), 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 requirement for C ₂₀ H ₁₈ NO ₂ Cl: 340.110).

Example 39

1-benzyl-3-bromo-4-[(3-chlorobenzyl) oxy] -6-methylpyridin-2 (1H) -one

When bromine (0.91 mmol, 145 Mg) is added, the product of Example 38 (SC-83316), 1-benzyl-4-[(3-chlorobenzyl) oxy] -6-methylpyridine-2 (1H)- Warm (0.91 mmol, 310 Mg), acetic acid (20 mL) and sodium acetate (0.91 mmol, 80 Mg) were stirred at room temperature. After stirring for 1 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 concentrated, and the product was recrystallized from tetrahydrofuran / hexane to give a white solid (240 Mg, 63%): 1 H NMR (DMSO-d 6/300 MHz) 7.6-7.0 (m, 10H), 6.5 (s, 1H), 5.33 (s, 2H), 5.33 (s, 2H), 2.3 (s, 3H). ESHRMS m / z 420.019 (M + H required for C ₂₀ H ₁₇ NO ₂ BrCl: 420.019).

Example 40

1-benzyl-4- [2,6- (dichlorobenzyl) oxy] pyridin-2 (1H) -one

The title compound was prepared essentially as described in claim 1. mp 151.6 ° C. to 152.0 ° C. _{^{1 H NMR (CDCl 3/300}} MHz) δ 7.31 (m, 8H), 7.12 (d, 1H, J = 7.45 Hz), 6.13 (d, 1H, J = 2.42 Hz), 5.90 (dd, 1H, J = 2.62 Hz), 5.22 (s, 2H), 5.10 (s, 2H). ESHRMS m / z 360.0551 (M + H required for C ₁₉ H ₁₅ Cl ₂ NO ₂ : 360.0558).

Example 41

1-benzyl-3-bromo-4- [2,6- (dichlorobenzyl) oxy] pyridin-2 (1H) -one

1-benzyl-4- [2,6- (dichlorobenzyl) oxy] pyridin-2 (1H) -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 was stirred at rt for 2 h. Water (15 mL) was added and the mixture was transferred to a separating funnel. Ethyl acetate (50 mL) was added and the layers separated. The organic phase was washed with aqueous NaHCO ₃ solution (2 × 25 mL), dried over MgSO ₄ , filtered and evaporated to give a white solid. _{^{1 H NMR (CDCl 3/300}} MHz) δ 7.34 (m, 9H), 6.24 (d, 1H, J = 7.65 Hz), 5.37 (s, 2H), 5.18 (s, 2H). ESHRMS m / z 439.9646 (M + H required for C ₁₉ H ₁₄ BrCl ₂ NO ₂ : 439.9646).

Example 42

1-benzyl-4-[(2-chlorobenzyl) oxy] pyridin-2 (1H) -one

The title compound was prepared by a procedure similar to that described in Example 1. mp 124.6 ° C. to 125.0 ° C. _{^{1 H NMR (CDCl 3/300}} MHz) δ 7.36 (m, 9H), 7.14 (d, 1H, J = 7.65 Hz), 6.04 (d, 1H, J = 2.62 Hz), 5.98 (d, 1H, J = 2.82 Hz), 5.10 (s, 2H), 5.09 (s, 2H). ESHRMS m / z 326.0950 (M + H required for C ₁₉ H ₁₆ ClNO ₂ : 326.0948).

Anal. Calcd. For C ₁₉ H ₁₆ ClNO ₂ : 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

1-benzyl-3-bromo-4-[(2-chlorobenzyl) oxy] pyridin-2 (1H) -one

The title compound was prepared by a procedure similar to that described in Example 2. mp 143.3 ° C. to 145.5 ° C. _{^{1 H NMR (CDCl 3/300}} MHz) δ 7.63 (d, 2H, J = 1.81Hz), 7.44 (m, 9H), 6.06 (d, 1H, J = 7.65 Hz), 5.29 (s, 2H), 5.17 (s, 2H). ESHRMS m / z 406.0036 (M + H required for C ₁₉ H ₁₅ BrClNO ₂ : 406.0032).

Anal. Calcd. For C ₁₉ H ₁₅ Cl BrNO ₂ : 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

1-benzyl-3-bromo-4-[(4-methylbenzyl) oxy] pyridin-2 (1H) -one

The title compound was prepared by a procedure similar to that described in Example 2. mp 149.0 ° C. to 149.7 ° C. _{^{1 H NMR (CDCl 3/300}} MHz) δ 7.25 (m, 10H), 6.04 (d, 1H, J = 7.65 Hz), 5.17 (s, 2H), 5.15 (s, 2H), 2.34 (s, 3H) . ESHRMS m / z 386.0583 (M + H requirement for C ₂₀ H ₁₈ BrNO ₂ : 386.0581).

Example 45

1-benzyl-4-[(3-chlorobenzyl) oxy] pyridin-2 (1H) -one

The title compound was prepared by a procedure similar to that described in Example 1. mp 95.5 ° C. to 95.7 ° C. _{^{1 H NMR (CDCl 3/300}} MHz) δ 7.34 (m, 9H), 7.13 (d, 1H, J = 7.45 Hz), 5.96 (m, 1H), 5.95 (d, 1H, J = 7.45 Hz), 5.09 (s, 2H), 4.96 (s, 2H). ESHRMS m / z 326.0977 (M + H required for C ₁₉ H ₁₆ ClNO ₂ : 326.0948).

Example 46

1-benzyl-4- [benzylthio] -3-bromopyridin-2 (1H) -one

The title compound was prepared by a procedure similar to that described in Example 2. mp 180.6 ° C. to 182.1 ° C. _{^{1 H NMR (CDCl 3/300}} MHz) δ 7.33 (m, 10H), 7.14 (d, 1H, J = 7.45 Hz), 6.08 (d, 1H, J = 7.45 Hz), 5.13 (s, 2H), 4.15 (s, 2H). ESHRMS m / z 386.0211 (M + H required for C ₁₉ H ₁₆ BrNOS: 386.0214).

Example 47

1-benzyl-3-bromo-4-{[2- (trifluoromethyl) benzyl] oxy} pyridin-2 (1H) -one

The title compound was prepared by a procedure similar to that described in Example 2. mp 133.2 ° C to 133.5 ° C. _{^{1 H NMR (CDCl 3/300}} MHz) δ 7.81 (d, 1H, J = 7.65 Hz), 7.68 (d, 1H, J = 7.65 Hz), 7.61 (t, 1H, J = 7.65 Hz), 7.38 (m , 7H), 6.01 (d, 1H, J = 7.85 Hz), 5.39 (s, 2H), 5.16 (s, 2H). ESHRMS m / z 438.0313 (M + H required for C ₂₀ H ₁₅ BrF ₃ NO ₂ : 403.0316).

Example 48

1-benzyl-4- (benzyloxy) -3-iodopyridin-2 (1H) -one

Stirring a mixture of N, O-dibenzyl-2-pyridone (2.0 g, 6.87 mmol), N-iodosuccinimide (1.7 g), dichloroacetic acid (0.15 mL) in acetonitrile (40.0 mL) Heated at 65 ° C. under an argon atmosphere for 3.5 hours. 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 2.3 g (80%) of the title compound as a flaky white solid. : ¹ H NMR (CDCl ₃ ) δ 7.4-7.2 (m, 10H), 7.19 (1H, d, J = 7.6 Hz), 5.95 (d, 1H, J = 7.6 Hz), 5.2 (s, 1H), 5.15 (s, 2H); ER-MS m / z = 418 (MH ⁺ ); C ₁₉ H ₁₇ calculated for _{NO 2 HR-MS m / z} : 418.0304, Found: 418.0277.

Example 49

1-benzyl-4- (benzyloxy) -3-vinylpyridin-2 (1H) -one

1-benzyl-4- (benzyloxy) -3-iodopyridin-2 (1H) -one (1.9 g, 4.56 mmol) and vinyl-tri in acetonitrile (20 0 mL) containing DMF (2.0 mL) A solution of butyltin (2.5 mL) was degassed using a house vacuum and purged with argon. Thereafter, the added PdCl ₂ (PPh ₃ ) ₂ (0.3 g) and the mixture were heated at 65 ° C. under an argon atmosphere for 4 hours with stirring. The solvent was distilled under vacuum 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 solid.

¹ H NMR (CDCl ₃ ) δ 7.4-7.2 (m, 10H), 7.14 (d, 1H, J = 7.6 Hz), 7.05 (dd, 1H, J = 12.0 Hz), 6.47 (dd, 1H, J = 2.8 Hz), 6.07 (d, 1H, J = 7.6 Hz), 5.4 (dd, 1H, J = 2.8 Hz), 5.13 (s, 4H); ER-MS m / z = 418 (MH ⁺ ); ER-MS m / z = 318 (MH ⁺ ); C ₂₁ calculated for _{H 2O NO 2 HR-MS m} / z: 318.1494, Found: 318.1480.

Example 50

1-benzyl-4- (benzyloxy) -3-ethylpyridin-2 (1H) -one

Pd / C (10%, in a solution of 1-benzyl-4- (benzyloxy) -3-vinylpyridin-2 (1H) -one (0.5 g, 1.6 mmol) in EtOH (10.0 mL) and EtOAc (10.0 mL) 0.25 g) was added and stirred for 16 h at 30 psi under hydrogen gas atmosphere. 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 give the title compound (as a light yellow powder). 0.32 g, 64%): ¹ H NMR (CD ₃ OD) δ 7.52 (d, 1H, J = 7.6 Hz), 7.39-7.2 (m, 10H), 6.41 (d, 1h, J = 7.6 Hz) , 5.18 (s, 2H), 5.15 (s, 2H), 2.58 (q, 2H, J = 7.2 Hz), 1.03 (t, 3H, J = 7.2 Hz), ER-MS m / z = 320 (MH ⁺ ); HR-MS m / z calculated for C ₂₁ H ₂₂ NO ₂ : 320.1651, found 320.1648.

Example 51

3-acetyl-4- (benzyloxy) -1- (2-chlorophenyl) -6-methylpyridin-2 (1H) -one

Step A. Preparation of 3-acetyl-1- (2-chlorophenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one

A mixture of diketene (3.3 g, 39.28 mmol) in toluene (10.0 mL) containing 2-chlorophenylisocyanate (3.0 g, 19.53 mmol), and triethylamine (0.05 mL) was heated to reflux under an argon atmosphere for 6 hours. I was. Toluene was distilled under vacuum and the resulting residue was purified by silica gel flash chromatography using 25% EtOAc in hexane as eluent to give the title compound (0.85 g, Heterocycles 27 (9), 2063, 1988) as a light yellow solid. ]]: ¹ H NMR (CD ₃ OD) δ 7.63 (m, 1H), 7.52 (m, 2H), 7.4 (m, 1H), 6.14 (s, 1H), 2.58 (s, 3H) and 1.95 (s, 3 H); ES-MS m / z = 278 (MH ⁺ ).

Step B. Preparation of 3-acetyl-4- (benzyloxy) -1- (2-chlorophenyl) -6-methylpyridin-2 (1H) -one

Benzyl bromide (0.3 mL) in a solution of 3-acetyl-1- (2-chlorophenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one (0.56 g, 2.02 mmol) in DMF (5.0 mL) And potassium carbonate (0.3 g, 2.16 mmol). The mixture was stirred at rt for 3 h and stirred 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 (Na ₂ SO ₄ ) filtered and concentrated to dryness. The resulting residue was purified by silica gel flash chromatography using 50% EtOAc in hexanes to give the title compound (0.58 g, 75%) as light yellow amorphous material: ¹ H NMR (CD ₃ OD) δ 7.65-7.3 ( m, 9H), 6.5 (s, 1H), 5.31 (s, 2H), 2.42 (s, 3H) and 2.01 (s, 3H); ER-MS m / z = 368 (MH ⁺ ); HR-MS m / z calculated for C ₂₁ H ₁₉ NO ₃ Cl: 368.1060, found: 368.1053.

Example 52

1-benzyl-3-bromo-4- (2-phenylethyl) pyridin-2 (1H) -one

Step A. Preparation of 1-benzyl-3-bromo-4-hydroxypyridin-2 (1H) -one

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 for 1.5 h at room temperature under argon atmosphere. It was diluted with dichloromethane (25 mL), cooled and filtered. The solid was washed with dichloromethane and dried under vacuum. The filtrate and washes were combined, washed with water, dried (Na ₂ SO ₄ ), filtered and concentrated to dryness. The resulting residue was washed with EtOAc and dried in vacuo to give the title compound as a white powder with a combined mass of 0.65 g: ¹ H NMR (CD ₃ OD) δ 7.54 (d, 1H, J = 7.6 Hz), 7.27 (m, 5H), 6.12 (d, 1H, J = 7.6 Hz), 5.15 (s, 2H); ES-MS: m / z = 280 (MH ⁺ ).

Step B. Preparation of 1-benzyl-3-bromo-2-oxo-1,2-dihydropyridin-4-yl trifluoromethanesulfonate

Triethylamine (0.6 mL) in a cold (-30 ° C.) suspension of 1-benzyl-3-bromo-4-hydroxypyridin-2 (1H) -one (0.78 g, 2.8 mmol) in dichloromethane (10.0 mL). , 4.28 mmol), followed by triflic anhydride (0.7 mL, 4.17 mmol). The resulting mixture was stirred at −30 ° C. for 1 h under argon atmosphere. Thereafter, the reaction mixture was poured into an ice / water mixture (50 mL) and the product was extracted with dichloromethane (2 × 25 mL). The combined organic extracts were washed with water (2 × 20 mL), dried (Na ₂ SO ₄ ) filtered and concentrated to dryness. The residue was dried under vacuum to give the desired trifluorosulfonate (1.0 g) as a light yellow solid, used in the next step: ¹ H NMR (CDCl ₃ ) δ 7.35 (m, 6H), 6.26 (d, 1H , J = 8.0 Hz); ¹⁹ F NMR (CDCl ₃ ) δ −73.73 ppm; ES-MS: m / z = 412 (MH ⁺ ).

Step C. Preparation of 1-benzyl-3-bromo-4- (phenylethynyl) pyridin-2 (1H) -one

To a solution of 1-benzyl-3-bromo-2-oxo-1,2-dihydropyridin-4-yl trifluoromethanesulfonate (1.0 g) in DMF (5.0 mL) was added phenylacetylene (0.4 mL). Add and degas using house vacuum. The reaction flask was then purged with argon, diisopropylethylamine (0.53 mL) was added, followed by PdCl ₂ (PPh ₃ ) ₂ (0.35 g). The resulting mixture was stirred at room temperature for 15 minutes and heated at 65 ° C. under an argon atmosphere for 3 hours. The dark reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc (50 mL) and 5% aqueous citric acid (25 mL). The organic extract was washed with water, dried (Na ₂ SO ₄ ) filtered and concentrated to dryness. The resulting material was purified by silica gel flash chromatography using 25% EtOAc in hexane as eluent. Appropriate fractions were combined and concentrated under reduced pressure. ¹ H NMR (CDCl ₃ ) δ 7.57 (m, 2H), 7.38 (m, 8H), 7.21 (d, 1H, J = 6.8 Hz), 6.25 (d, 1H, J = 6.8 Hz) and 5.16 (d, 2H), ES-MS: m / z = 364 (MH ⁺ ); HR-MS m / z (M−H ⁺ ) calculated for C ₂₀ H ₁₅ NOBr: 364.0337. Found: 364.0337.

Step D. Preparation of 1-benzyl-3-bromo-4- (2-phenylethyl) pyridin-2 (1H) -one

Of 1-benzyl-3-bromo-4- (phenylethynyl) pyridin-2 (1H) -one (0.3 g), and platinum oxide (0.05 g) in solvent EtOAc (10.0 mL) and EtOH (10.0 mL). The mixture was stirred for 45 min in a Fischer porter bottle at 15 psi under hydrogen atmosphere. The catalyst was removed by filtration and the filtrate was concentrated. The resulting residue was purified by silica gel flash chromatography using 25% EtOAc in hexane as eluent. Appropriate fractions (visualized under UV lamp) were combined and concentrated under reduced pressure. ¹ H NMR (CD ₃ OD) δ 7.56 (d, 1H, J = 6.8 Hz), 7.31-7.17 (m, 10H), 6.24 (d, 1H, 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 ⁺ ) calculated for C ₂ oH ₁₉ NOBr: 368.0650. Found: 368.0630.

Example 53

3-bromo-1- (3-fluorobenzyl) -6-methyl-4- (2-phenylethyl) pyridin-2 (1H) -one

The title compound was prepared essentially according to the procedure of Example 52. ¹ H NMR δ (CD ₃ OD) δ 7.35 (m, 1H), 7.31-7.16 (m, 5H), 6.99 (m, 1H), 6.91 (m, 1H), 6.81 (m, 1H), 6.20 (s , 1H), 5.41 (s, 2H), 2.94 (m, 4H) and 2.24 (s, 3H); ¹⁹ F NMR (CD ₃ OD) δ −115.01 (m); ES-MS, m / z = 400 (MH ⁺ ); C ₂₁ calculated for _{H 2O NOBrF HR-MS m /} z: 400.0712, Found: 400.0695.

Example 54

4- (benzyloxy) -3-bromo-1- (2,6-dichlorophenyl) -6-methylpyridin-2 (1H) -one

Step A. Preparation of 3-acetyl-1- (2,6-dichlorophenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one

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 hours under argon atmosphere. After the solvent was removed in vacuo, the residue was purified by silica gel flash chromatography using EtOAc / hexanes (1: 3 v / v). The appropriate fractions were combined and concentrated under reduced pressure, monitoring by ES mass spectrometer (MH ⁺ m / z = 312). The resulting yellow solid (2.3 g) was further purified by reverse phase HPLC using a 10-90% acetonitrile / water gradient (45 min) at 100 mL / min flow rate. Appropriate fractions monitored by ES mass spectrometer (MH ⁺ m / z = 312) were combined and concentrated until half the volume. The separated solid was extracted with EtOAc (2 × 25 mL). The combined extracts were washed with water, dried (Na ₂ SO ₄ ), filtered and concentrated to dryness to give the title compound (0.77 g) as a light yellow powder: ¹ H NMR (CD ₃ OD) δ 7.62 ( m, 2H), 7.52 (m, 1H), 6.19 (s, 1H), 2.59 (s, 3H) and 1.96 (s, 3H); ES-MS m / z = 312 (MH ⁺ ); C ₁₄ H ₁₂ NO ₃ calculated for _{Cl 2 HR-MS, m /} z: 312.0189, Found: 312.0214.

Step B. Preparation of 1- (2,6-dichlorophenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one

0.7 g of 3-acetyl-1- (2,6-dichlorophenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one in n-butanol (3.0 mL) containing sulfuric acid (1.5 mL) ( 0.002 mol) was heated at 120 ° C. for 4 hours. The dark reaction mixture was cooled, ice / water (25 mL) was added and then extracted with EtOAc (2 × 25 ml). The combined organic extracts were washed with water, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure and the resulting material was purified by silica gel flash chromatography using 25% EtOAc in hexane as eluent to give a light yellow powder. The title compound (0.14 g) was obtained: ¹ H NMR (CD ₃ OD) δ 7.6 (m, 2H), 7.48 (m, 1H), 6.10 (dd, 1H), 5.78 (d, 1H, J = 2.4 Hz ), 1.91 (s, 3 H); ES-MS m / z = 270 (MH ⁺ ); HR-MS calculated for C ₁₂ H ₁₀ NO ₂ Cl ₂ , m / z: 270.0083. Found: 270.0103.

Step C. Preparation of 4- (benzyloxy) -1- (2,6-dichlorophenyl) -6-methylpyridin-2 (1H) -one

A mixture of 1- (2,6-dichlorophenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one (0.125 g, 0.46 mmol) and benzylbromide (0.1 mL) in DMF (2.5 mL) Stir at room temperature for 16 hours. The reaction mixture was diluted with water (10.0 mL) and extracted with EtOAc (2 × 20 mL). The combined organic extracts were washed with water, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure and the resulting material was purified by silica gel flash chromatography using 25% EtOAc in hexanes to give the title compound as a light yellow syrup. (0.11 g) was obtained: ¹ H NMR (CD ₃ OD) δ 7.61 (m, 2H), 7.55-7.3 (m, 6H), 6.23 (d, 1H, J = 2.0 Hz), 6.01 (d, 1H , J = 2.0 Hz), 5.12 (s, 2H) and 1.93 (s, 3H); ES-MS m / z = 360 (MH ⁺ ); HR-MS calculated for C ₁₉ H ₁₆ NO ₂ Cl ₂ , m / z: 360.0553, found: 360.0569.

Step D. Preparation of 4- (benzyloxy) -3-bromo-1- (2,6-dichlorophenyl) -6-methylpyridin-2 (1H) -one

4- (benzyloxy) -1- (2,6-dichlorophenyl) -6-methylpyridin-2 (1H) -one (0.1 g, 0.278 mmol) and N-bromosuccicin in dichloroethane (3.0 mL) The mixture of mead (0.055 g, 0.3 mmol) was stirred at rt 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 (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. ¹ H NMR (CD ₃ OD) δ 7.64 (m, 2H), 7.55 (m, 3H), 7.38 (m, 3H), 6.65 (s, 1H), 5.34 (s, 2H) and 2.00 (s, 3H) ; ES-MS m / z = 439 (MH ⁺ ); HR-MS calculated for C ₁₉ H ₁₆ NO ₂ Cl ₂ Br, m / z: 439.9635. Found: 439.9669.

Example 55

3-bromo-1- (3-fluorobenzyl) -4- (2-phenylethyl) pyridin-2 (1H) -one

The title compound was prepared essentially according to the procedure of Example 52. ¹ H NMR (CD ₃ OD) δ 7.58 (d, 1H, J = 6.8 Hz), 7.4-7.0 (m, 9H), 6.26 (d, 1H, 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 calculated for C ₂₀ H ₁₈ NOFBr, m / z: 386.0550. Found: 386.0585.

Example 56

1-benzyl-3-bromo-2-oxo-1,2-dihydropyridin-4-yl methyl (phenyl) carbamate

Step A. Preparation of 1-benzyl-2-oxo-1,2-dihydropyridin-4-yl methyl (phenyl) carbamate

To a cold solution of 1-benzyl-4-hydroxypyridin-2 (1H) -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) was added. The reaction mixture was stirred for 30 minutes at 0 ° C. under a nitrogen atmosphere and then for 1 hour at room temperature. 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 Na ₂ SO ₄ and filtered. The solvent was removed under reduced pressure to give a yellow syrup. The residue was purified by flash chromatography (silica gel) using 5% MeOH in CH ₂ Cl ₂ to afford the desired product (0.382 g, 61%) as a white semisolid.

MS and ¹ H NMR matched the desired structure. ¹ H NMR (d ₆ -DMSO, 400 MHz) δ 7.8 (d, 1H), 7.39 (m, 10H), 6.19 (s, 2H), 5.03 (s, 2H), 3.29 (s, 3H); C ₂₀ H ₁₈ N ₂ O ₃ HR-MS (ES) calculated for (MH ⁺ ) m / z = 335.1396. Found: 335.1418.

Step B. Preparation of 1-benzyl-3-bromo-2-oxo-1,2-dihydropyridin-4-yl methyl (phenyl) carbamate

N-bromosuccicin in a solution of 1-benzyl-2-oxo-1,2-dihydropyridin-4-yl methyl (phenyl) carbamate (0.38 g, 1.13 mmol) in anhydrous CH ₂ Cl ₂ (7 mL). Imide (NBS, 0.24 g, 1.34 mmol) was added. The reaction was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was purified by flash chromatography (Silica gel) using EtOAc / hexanes (1: 1 v / v). Appropriate fractions were collected and concentrated according to ES MS (M + H 413). The dry product appeared to be about 14% dibrominated product by analytical HPLC. The compound was separated by reverse phase HPLC using a 30 minute gradient, 10-90% acetonitrile in water at a flow rate of 100 mL / min to give a salt of the desired compound (after freeze drying). The salt was diluted with EtOAc and washed with NaHCO ₃ . The organic extract was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to afford the desired compound (0.271 g, 58%) as a beige solid.

MS and ¹ H NMR matched the desired structure. ¹ H NMR (d ₆ -DMSO, 400 Hz) δ 7.83 (d, 1H), 7.39 (m, 10H), 6.48 (s, 1H), 5.12 (s, 2H), 3.33 (s, 3H); HR-MS (ES) calculated for C ₂₀ H ₁₇ O ₃ Br (MH ⁺ ) m / z = 413.0495. Found: 413.0496.

Example 57

4- (benzyloxy) -3-ethynyl-1- (3-fluorobenzyl) pyridin-2 (1H) -one

Step A. Preparation of 4- (benzyloxy) -1- (3-fluorobenzyl) -3-iodopyridin-2 (1H) -one

4- (benzyloxy) -1- (3-fluorobenzyl) pyridin-2 (1H) -one (4.83 g, 15.6 mmol) and N in anhydrous acetonitrile (55 mL) for 4 hours at 65 ° C. under a nitrogen atmosphere. The reaction mixture of iodosuccinimide (NIS, 3.86 g, 17.1 mmol) was heated. 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). Appropriate fractions were collected according to ES MS (M + H 436) and washed with Na ₂ SO ₃ to remove colored impurities. Fractions were concentrated under reduced pressure and dried under vacuum to afford the desired product (6.15 g, 90%) as a light yellow solid.

MS and ¹ H NMR matched the desired structure. ¹ H NMR (CD ₃ OD, 400 Hz) δ 7.73 (d, 1H), 7.47 (d, 2H), 7.39 (m, 4H), 7.08 (m, 3H), 6.39 (d, 1H), 5.29 (s , 2H), 5.19 (s, 2H); HR-MS (ES) calculated for Ci ₉ H ₁₅ NO ₂ FI (MH ⁺ ) m / z = 436.0210, found 436.0196.

Step B. Preparation of 4- (benzyloxy) -1- (3-fluorobenzyl) -3-[(trimethylsilyl) ethynyl] pyridin-2 (1H) -one

A solution of 4- (benzyloxy) -1- (3-fluorobenzyl) -3-iodopyridin-2 (1H) -one (2.01 g, 4.62 mmol) in anhydrous acetonitrile (25 mL) under argon atmosphere It was degassed. Triethylamine (1.11 g, 11 mmol) was added and quickly degassed. After the reaction mixture was cooled in an ice bath for 15 minutes, bistriphenylphosphine-palladium chloride (0.34 g, 0.48 mmol) and cuprous iodide (0.2 g) were added. The reaction was stirred at rt for 30 min and then heated at 60 ° C. for 2 h under argon atmosphere. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The dark brown residue was diluted with CH ₂ Cl ₂ (100 mL) and washed with water. The organic extracts were combined, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The dark brown residue was purified by flash chromatography (silica gel) using 30% EtOAc in hexanes. Appropriate fractions were combined and concentrated under reduced pressure to afford the desired product (1.34 g, 72%) as a light yellow solid.

MS and ¹ H NMR matched the desired structure. ¹ H NMR (CD ₃ OD, 400 Hz) δ 7.74 (d, 1H), 7.47 (d, 2H), 7.35 (m, 4H), 7.09 (m, 3H), 6.46 (d, 1H), 5.26 (s , 2H), 5.13 (s, 2H), 0.18 (s, 9H); HR-MS (ES) calculated for C ₂₄ H ₂₄ NO ₂ FSi (MH ⁺ ) m / z = 406.1638. Found: 406.1610.

Step C. Preparation of 4- (benzyloxy) -3-ethynyl-1- (3-fluorobenzyl) pyridin-2 (1H) -one

4- (benzyloxy) -1- (3-fluorobenzyl) -3-[(trimethylsilyl) ethynyl] pyridin-2 (1H) -one (1.31 g, in anhydrous acetonitrile (25 mL) at 0 ° C. 3.2 mmol) was added tetrabutylammonium fluoride (0.611 g, 1.93 mmol). The reaction was stirred at 0 ° C. for 15 minutes and then further at room temperature for 1 hour. 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 Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel) using EtOAc in hexanes (1: 1 v / v). Appropriate fractions were combined and concentrated under reduced pressure to afford the desired product (0.779 g, 72%) as a gold solid.

MS and ¹ H NMR matched the desired structure. ¹ H NMR (CD ₃ OD, 400 Hz) δ 7.73 (d, 1H), 7.43 (d, 2H), 7.35 (m, 4H), 7.09 (m, 3H), 6.45 (d, 1H), 5.27 (s , 2H), 5.13 (s, 2H), 3.78 (s, 1H); HR-MS (ES) calculated for C ₂₁ H ₁₆ NO ₂ F (MH ⁺ ) m / z = 334.1243. Found: 334.1234.

Example 58

4- (benzylamino) -3-bromo-1- (3-fluorobenzyl) pyridin-2 (1H) -one

Step A. Preparation of 1- (3-fluorobenzyl) -4-hydroxypyridin-2 (1H) -one

In a Fischer-Porter bottle, a solution of 4- (benzyloxy) -1- (3-fluorobenzyl) pyridin-2 (1H) -one (4.5 g, 14.56 mmol) in anhydrous ethanol (20 mL) was added. . After the solution was washed with nitrogen, palladium catalyst (1.05 g) was added. The bottle was sealed and the system evacuated. The system was checked for leaks by purging the system with hydrogen gas (2 × 15 psi). The reaction was charged with hydrogen (35 psi) and stirred at room temperature for 45 minutes. The system was evacuated and washed with nitrogen. The reaction was filtered and the catalyst was carefully washed with fresh ethanol. The filtrate was concentrated under reduced pressure.

MS and ¹ H NMR matched the desired structure. ¹ H NMR (CD ₃ OD, 400 Hz) δ 7.54 (d, 1H), 7.32 (m, 1H), 7.06 (m, 3H), 6.05 (dd, 1H), 5.83 (s, 1H), 5.09 (s , 2H); HR-MS (ES) calculated for C ₁₂ H ₁₀ NO ₂ F (MH ⁺ ) m / z = 220.0774, found 220.0787.

Step B. Preparation of 4- (benzylamino) -1- (3-fluorobenzyl) pyridin-2 (1H) -one

Reaction of 1- (3-fluorobenzyl) -4-hydroxypyridin-2 (1H) -one (1.005 g, 4.5 mmol) in benzylamine (15 mL) at reflux (185 ° C.) under nitrogen atmosphere for 24 hours. The mixture was heated. The reaction was monitored by ES-MS (MH + 309). The solvent was removed by vacuum distillation to give a yellow residue.

MS and ¹ H NMR matched the desired structure. ¹ H NMR (CD ₃ OD, 400 Hz) δ 7.31 (m, 7H), 7.03 (m, 3H), 5.98 (dd, 1H), 5.45 (s, 1H), 5.00 (s, 2H), 4.30 (s , 2H); HR-MS (ES) calculated for Ci ₉ H ₁₇ N ₂ OF (MH ⁺ ) m / z = 309.1403, found: 309.1375.

Step C. Preparation of 4- (benzylamino) -3-bromo-1- (3-fluorobenzyl) pyridin-2 (1H) -one

N-bromosuccin was added to a solution of 4- (benzylamino) -1- (3-fluorobenzyl) pyridin-2 (1H) -one (0.50 g, 1.62 mmol) in anhydrous CH ₂ Cl ₂ (10 mL). Mid (NBS, 0.30 g, 1.7 mmol) was added. The reaction was stirred at room temperature under nitrogen atmosphere for 3 hours. The reaction mixture was purified by flash chromatography (silica gel) using EtOAc in hexanes (1: 1 v / v). Appropriate fractions were combined and concentrated.

MS and ¹ H NMR matched the desired structure. ¹ H NMR (CD ₃ OD, 400 Hz) δ 7.41 (d, 1H), 7.31 (m, 6H), 7.04 (m, 3H), 5.99 (d, 1H), 5.08 (s, 2H), 4.53 (s , 2H); HR-MS (ES) calculated for Ci ₉ H ₁₆ N ₂ OFBr (MH ⁺ ) m / z = 387.0508, found 387.0504.

Example 59

3-bromo-1-cyclopropylmethyl-4- (4-fluorobenzyloxy) -1H-pyridin-2-one

Step 1. Preparation of 4- (4-fluorobenzyloxy) pyridine-1-oxide

To a ice cold solution of sodium hydride (1.9 g, 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 allowed to warm to room temperature, 4-chloropyridine-1-oxide ¹ (5.0 g, 39 mmol) was added and the reaction mixture was stirred for 6 hours. The reaction mixture was diluted with 50% aqueous solution of brine and extracted with CHCl ₃ (7 × 50 mL). The combined organics were dried (MgSO ₄ ) filtered and concentrated under reduced pressure. 4- (4-fluorobenzyloxy) pyridine-1-oxide (9.1 g, 90%) obtained by trituration with Et ₂ O as an off-white solid was used in the next step without further purification or characterization.

Step 2. Preparation of 4- (4-fluorobenzyloxy) -1 H-pyridin-2-one

A solution of 4- (4-fluorobenzyloxy) pyridine-1-oxide (6.4 g, 29 mmol) in acetic anhydride (97 mL) was heated at reflux for 3 hours. The reaction mixture was cooled to rt 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 rt for 1 h. The solvent was removed under reduced pressure. Trituration with Et ₂ O / hexanes afforded 4- (4-fluorobenzyloxy) -1H-pyridin-2-one (3.1 g, 48%) as a brown solid: ¹ H NMR (300 MHz, CDCl ₃₎ ) δ 7.40-7.36 (m, 2H), 7.22 (d, J = 8 Hz, 1H), 7.09 (t, J = 7 Hz, 2H), 6.03 (dd, J = 7, 3 Hz, 1H), 5.94 (d, J = 3 Hz, 1 H), 4.98 (s, 2 H).

Step 3. Preparation of 3-bromo-4- (4-fluorobenzyloxy) -1H-pyridin-2-one

A solution of bromine (0.79 mL, 15 mmol) in AcOH (51 mL) in an ice cold solution of 4- (4-fluorobenzyloxy) pyridin-2 (1H) -one (3.1 g, 14 mmol) in AcOH (26 mL) Was added and the reaction mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure and purified by flash column chromatography (silica, 1: 1 Et ₂ O / hexane) to give 3-bromo-4- (4-fluorobenzyloxy) -1H-pyridine-2 as an orange solid. -One (0.78 g, 48%) was obtained: MS APCI m / z 298 [M + H] ⁺ .

Step 4. Preparation of 3-bromo-1-cyclopropylmethyl-4- (4-fluorobenzyloxy) -1H-pyridin-2-one

K ₂ CO ₃ (0.33 g, 1.7 mmol) in a solution of 3-bromo-4- (4-fluorobenzyloxy) -1H-pyridin-2-one (0.25 g, 0.84 mmol) in DMF (13 mL) And cyclopropylmethyl bromide (0.14 g, 1.0 mmol) was added and the reaction mixture was stirred at 110 ° C. for 2 hours. The reaction mixture was cooled to rt and the solvent was removed under reduced pressure. The residue was diluted with a 50% aqueous solution of brine and extracted with CHCl ₃ (3 × 50 mL). The combined organics were washed with water followed by brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1: 1 EtOAc / hexanes) affords 3-bromo-1-cyclopropyl-methyl-4- (4-fluorobenzyloxy) -1H-pyridin-2-one as a yellow solid. (0.12 g, 39%) was obtained: mp 139 ° C. to 141 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.43-7.34 (m, 3H), 7.07 (t, J = 9 Hz, 2H), 6.06 (d, J = 6 Hz, 1H), 5.19 (s, 2H) , 3.82 (d, J = 9 Hz, 2H), 1.26-1.23 (m, 1H), 0.62-0.57 (m, 2H), 0.40-0.36 (m, 2H). ESHRMS m / z 352.0368 (M + H required for C ₁₆ H ₁₆ BrFNO ₂ : 352.0343)

Examples 60-69

The mixture of Examples 60-69 was prepared essentially according to the procedure described in Example 59 above.

Example 70

{3- [3-bromo-4- (4-fluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] benzyl} carbamic acid tert-butyl ester

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 NaBH ₄ (1.6 g, 42 mmol) and the reaction mixture was stirred for 3 hours. 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 ₂ O (3 × 100 mL). The combined organics are washed with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure to afford 3-hydroxymethyl-benzonitrile (4.95 g, 98%) as a clear oil, which is further purified or characterized. It was used in the next step without work.

Step 2. Preparation of 3- (tert-butyldimethylsilyloxymethyl) benzonitrile

In an ice cold solution of 3-hydroxymethyl benzonitrile (4.95 g, 37 mmol) in CH ₂ Cl ₂ (47 mL) imidazole (5.1 g, 74 mmol), DMAP (0.45 g, 3.7 mmol) and TBSCl (6.2 g) , 41 mmol) was added and the reaction mixture was stirred for 12 hours. The reaction mixture was diluted with water and the aqueous layer was extracted with CH ₂ Cl ₂ (3 × 150 mL). The combined organics were washed with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure to afford 3- (tert-butyldimethylsilyloxymethyl) -benzonitrile (9.1 g, 99%) as a clear oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.51 (s, 1H), 7.42 (d, J = 6 Hz, 1H), 7.35-7.28 (m, 1H), 4.75 (s, 2H), 0.94 (s, 9H), 0.11 (s, 6H).

Step 3. Preparation of 3- (tert-butyldimethylsilyloxymethyl) benzylamine

To an ice cold solution of 3- (tert-butyldimethylsilyloxymethyl) benzonitrile (4.5 g, 18 mmol) in THF (47 mL) was added LiAlH ₄ (27 mL, 1 M solution in THF, 27 mmol) and reaction The mixture was stirred at reflux for 3 hours. The reaction mixture was cooled to 0 ° C. and the reaction was quenched with water (25 mL) and 15% NaOH (75 mL) in water. The reaction mixture was filtered and then concentrated under reduced pressure and the residue was dissolved in EtOAc. The organic solution was washed with water followed by brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure to afford 3- (tert-butyldimethylsilyloxymethyl) benzylamine (1.4 g, 30%) as a clear oil. Were: ¹ H NMR (300 MHz, CDCl ₃ ) 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

Di-tert-butyl dicarbo in a solution of 3- (tert-butyldimethylsilyloxymethyl) benzylamine (1.4 g, 5.5 mmol) and Et ₃ N (1.5 mL, 11 mmol) in CH ₂ Cl ₂ (28 mL). Nate (1.3 g, 5.8 mmol) was added and the reaction mixture was stirred for 12 hours. The reaction mixture was diluted with water and extracted with CH ₂ Cl ₂ (3 × 100 mL). The combined organics were washed with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, CH ₂ Cl ₂ ) gave 3- (hydroxymethyl) benzylcarbamic acid tert-butyl ester (1.4 g, 46%) as a yellow oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.32-7.28 (m, 1H), 7.18 (d, J = 8 Hz, 1H), 7.12 (s, 1H), 7.08-7.01 (m, 1H), 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

Ph ₃ P (0.81 g, 3.1 mmol) in an ice cold solution of 3- (hydroxymethylbenzyl) carbamic acid tert-butyl ester (0.7 g, 3.0 mmol) and CBr ₄ (1.0 g, 3.1 mmol) in THF (14 mL) ) Was added and the reaction mixture was stirred for 18 hours. The reaction mixture was filtered and then concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent: 5:95 to 15:85 EtOAc / hexanes) gave 3- (bromomethyl) benzyl-carbamic acid tert-butyl ester (0.42 g, 51%) as a white solid. ¹ H NMR (300 MHz, MeOD) δ 7.55 (s, 1H), 7.32-7.27 (m, 2H), 7.21-7.19 (m, 1H), 4.54 (s, 2H), 4.21 (s, 2H) , 1.28 (s, 9 H).

Step 6. Preparation of 1 {3- [3-bromo-4- (4-fluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] benzyl} carbamic acid tert-butyl ester

K in a solution of 3-bromo-4- (4-fluorobenzyloxy) pyridin-2 (1H) -one (synthesized from step 3 of Example 59) (0.2 g, 0.67 mmol) in DMF (11 mL) ₂ CO ₃ (0.26 g, 1.3 mmol) and 3- (bromomethyl) benzylcarbamic acid tert-butyl ester (0.23 g, 0.80 mmol) were added and the reaction mixture was stirred at 80 ° C. for 3 hours. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was diluted with a 50% aqueous solution of brine (24 mL) and extracted with CHCl ₃ (4 × 50 mL). The combined organics were diluted with water followed by brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, 3: 7 EtOAc / hexanes) and recrystallization from MeOH yields {3- [3-bromo-4- (4-fluorobenzyloxy) -2-oxo-2H as off-white solid. -Pyridin-1-ylmethyl] benzyl} carbamic acid tert-butyl ester (0.07 g, 20%) was obtained: mp 136 ° C. to 138 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.42-7.37 (m, 2H), 7.30-7.20 (m, 5H), 7.08 (t, J = 9 Hz, 2H), 6.04 (d, J = 9 Hz, 1H), 5.16 (s, 2H), 5.14 (s, 2H), 4.28 (d, J = 6 Hz, 1H), 1.44 (s, 9H). ESHRMS m / z 517.1124 (M + H required for C ₂₅ H ₂₇ BrFN ₂ O ₄ : 517.1133)

Example 71

1- (3-aminomethylbenzyl) -3-bromo-4- (4-fluorobenzyloxy) -1H-pyridin-2-one

1- [3- {N-tert-butoxycarbonyl} aminomethylbenzyl] -3-bromo-4- (4-fluorobenzyloxy) pyridine-2 (1H) in CH ₂ Cl ₂ (2 mL) To an on-cold (Example 69) (0.05 g, 0.1 mmol) ice-cold solution was added TFA (2 mL) and the reaction mixture was stirred for 1 h. Solvent was removed under reduced pressure to give 1- (3-aminomethylbenzyl) -3-bromo-4- (4-fluorobenzyloxy) -1H-pyridin-2-one as a tan solid as a TFA salt (0.049 g, 100 %) Were prepared: mp 127 ° C. to 139 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.13 (br s, 2H), 7.94 (d, J = 6 Hz, 1H), 7.52-7.47 (m, 2H), 7.44-7.37 (m, 2H) , 7.27 (t, J = 8 Hz, 3H), 6.53 (d, J = 8 Hz, 1H), 5.30 (s, 2H), 5.14 (s, 2H), 4.01 (d, J = 6 Hz, 2H) , 3.39 (br s, 2 H); C ₂₀ H ₁₇ BrF ₂ N ₂ O _2. Anal. Calcd. For 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 required for C ₂₀ H ₁₉ BrFN ₂ O ₂ : 417.0609).

Example 72

Methyl 2- [3-bromo-4- (4-fluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] benzoate

The title compound was prepared in a procedure similar to that described in Example 59 (0.36 g, 48%): mp 161 ° C. to 165 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.98 (d, J = 6 Hz, 1H), 7.51-7.26 (m, 6H), 7.11-7.05 (m, 2H), 6.05 (d, J = 8 Hz, 1H), 5.60 (s, 2H), 5.18 (s, 2H), 3.93 (s, 3H). ESHRMS m / z 446.0430 (M + H required for C ₂₁ H ₁₈ BrFNO ₄ : 418.0398)

Example 73

3-bromo-4- (4-fluorobenzyloxy) -1- (2-hydroxymethylbenzyl) -1H-pyridin-2-one

3-Bromo-4- (4-fluorobenzyloxy) -1- (2-hydroxymethylbenzyl) -1H-pyridin-2-one (Example 72) in THF (1 mL) (0.25 g, 0.56 LiBH ₄ (2.0 M solution in THF, 0.56 mmol) was added to an ice cold solution, and the reaction mixture was stirred at 40 ° C. for 6 hours. The reaction mixture is cooled to room temperature, the solvent is removed under reduced pressure and the residue is dissolved in EtOAc. The organic solution was washed with brine, dried (MgSO ₄ ) filtered and concentrated under reduced pressure. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.82 (d, J = 8 Hz, 1H), 7.54-7.49 (m, 2H), 7.41 (d, J = 7 Hz, 1H), 7.29-7.21 ( m, 4H), 6.81 (d, J = 7 Hz, 1H), 6.53 (d, J = 8 Hz, 1H), 5.30-5.25 (m, 3H), 5.18 (s, 2H), 4.60 (d, J = 7 Hz, 2H). ESHRMS m / z 418.0437 (M + H required for C ₂₀ H ₁₈ BrFNO ₃ : 418.0449)

Example 74

3-bromo-4- (2,4-difluorobenzyloxy) -1-[(4-dimethylaminomethyl) benzyl] -1 H-pyridin-2-one

Step 1. Preparation of 4- (2,4-difluorobenzyloxy) pyridine-1-oxide.

To an ice cold solution of sodium hydride (1.2 g, 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 allowed to warm to room temperature, 4-chloropyridine-1-oxide ¹ (5.5 g, 43 mmol) was added and the reaction mixture was stirred for 6 hours. The reaction mixture was diluted with 50% aqueous solution of brine and extracted with CHCl ₃ (7 × 50 mL). The combined organics were dried (MgSO ₄ ) and filtered, then the solvent was removed under reduced pressure. Trituration with Et ₂ O afforded 4- (2,4-difluorobenzyloxy) pyridine-1-oxide (9.1 g, 90%) as off-white solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.16-8.08 (m, 1H), 7.47-7.36 (m, 1H), 6.97-6.81 (m, 1H), 5.09 (d, J = 8 Hz, 1H).

Step 2. Preparation of 4- (2,4-difluorobenzyloxy) -1 H-pyridin-2-one

A solution of 4- (2,4-difluorobenzyloxy) pyridine-1-oxide (13.4 g, 57 mmol) in acetic anhydride (30 mL) was stirred under reflux for 4 hours. The solvent was removed under reduced pressure, the residue was diluted with 1: 1 MeOH / water (60 mL) and the mixture was stirred at rt for 1 h. The solvent was removed under reduced pressure. Purification by flash column chromatography (silica, eluent: 9: 1 methylene chloride / methanol from methylene chloride) gave 4- (2,4-difluorobenzyloxy) -1H-pyridin-2-one (4.2 as light brown solid). g, 31%) was prepared: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.43 (q, J = 8 Hz, 1H), 7.23 (d, J = 7 Hz, 1H), 6.91-6.87 (m, 2H), 6.02 (dd, J = 8, 2 Hz, 1H), 5.97 (d, J = 2 Hz, 1H), 5.03 (s, 2H).

Step 3. Preparation of 3-bromo-4- (2,4-difluorobenzyloxy) -1H-pyridin-2-one

To an ice cold solution of 4- (2,4-difluorobenzyloxy) -1H-pyridin-2-one (0.75 g, 3.1 mmol) in AcOH (12 mL) bromine (0.2 mL, 3.5) in AcOH (6 mL) mmol) solution was added and the reaction mixture was stirred for 10 minutes. The solvent was removed under reduced pressure to afford 3-bromo-4- (2,4-difluorobenzyloxy) -1H-pyridin-2-one (1.0 g, 100%) as a white solid: ESI MS m / z 299 [M + H] ⁺ .

Step 4. Preparation of 3-bromo-1- (4-chloromethylbenzyl) -4- (2,4-difluorobenzyloxy) -1H-pyridin-2-one

To a solution of 3-bromo-4- (2,4-difluorobenzyloxy) -1H-pyridin-2-one (0.60 g, 2.5 mmol) in DMF (40 mL), K ₂ CO ₃ (0.70 g, 5.1 mmol) and α, α'-dichloro-p-xylene (0.53 g, 3.0 mmol) were added and the reaction mixture was stirred at 110 ° C. for 2 hours. The reaction mixture was cooled to rt, diluted with brine and extracted with CHCl ₃ (4 × 100 mL). The combined organics were washed with water followed by brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to afford 3-bromo-1- (4-chloromethylbenzyl) -4- (2, 4-difluorobenzyloxy) -1H-pyridin-2-one (0.49 g, 43%) was obtained: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.54 (app q, J = 8 Hz, 1H) , 7.38-7.28 (m, 5H), 6.94 (td, J = 8, 2 Hz, 1H), 6.85 (td, J = 8, 2 Hz, 1H), 6.10 (d, J = 9 Hz, 1H), 5.21 (s, 2H), 5.16 (s, 2H), 4.56 (s, 2H).

Step 5. Preparation of 3-bromo-4- (2,4-difluorobenzyloxy) -1-[(4-dimethylaminomethyl) benzyl] -1 H-pyridin-2-one

In a closed tube containing 3-bromo-1- (4-chloromethylbenzyl) -4- (2,4-difluoro-benzyloxy) -1H-pyridin-2-one (0.49 g, 1.1 mmol) A solution of dimethylamine (5.5 mL, 2.0 M solution in THF, 11 mmol) was added and the reaction mixture was stirred for 15 hours. The solvent was removed under reduced pressure. Purification by flash column chromatography (silica, eluent: methylene chloride from 92: 7.2: 0.8 methylene chloride / methanol / ammonia) gave 3-bromo-4- (2,4-difluorobenzyloxy)-as a light yellow solid. 1- (4-dimethylaminomethylbenzyl) -1H-pyridin-2-one (0.23 g, 46%) was prepared: mp 111 ° C. to 113 ° C .; ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.50-7.49 (m, 1H), 7.26-7.22 (m, 5H), 6.90-6.88 (m, 1H), 6.82-6.78 (m, 1H), 6.04 (d , J = 6 Hz, 1H), 5.16 (s, 2H), 5.11 (s, 2H), 3.37 (s, 2H), 2.19 (s, 6H). ESHRMS m / z 463.0782 (M + H required for C ₂₂ H ₂₂ BrF ₂ N ₂ O ₂ : 463.0827)

Example 75

3-bromo-4- (2,4-difluorobenzyloxy) -1- [3- (isopropylaminomethyl) benzyl] -1 H-pyridin-2-one

The title compound was prepared in a procedure similar to that described in Example 74 (0.06 g, 35%): mp 109 ° C. to 110 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.54 (d, J = 6 Hz, 1H), 7.33-7.20 (m, 5H), 6.94-6.81 (m, 2H), 6.10 (d, J = 6 Hz, 1H), 5.20 (s, 2H), 5.14 (s, 2H), 3.77 (s, 2H), 2.88 (t, J = 6 Hz, 1H), 1.13 (d, J = 6 Hz, 6H). ESHRMS m / z 477.0955 (M + H required for C ₂₃ H ₂₄ BrF ₂ N ₂ O ₂ : 477.0984) Example 76

3-bromo-4- (2,4-difluorobenzyloxy) -1-[(3-dimethylaminomethyl) benzyl] -1 H-pyridin-2-one

The title compound was prepared in a procedure similar to that described in Example 74 (0.06 g, 25%): mp 103 ° C.-107 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.52 (d, J = 8 Hz, 1H), 7.32-7.24 (m, 5H), 6.94 (td, J = 9, 3 Hz, 1H), 6.84 (td, J = 9, 3 Hz, 1H), 6.08 (d, J = 8 Hz, 1H), 5.20 (s, 2H), 5.16 (s, 2H), 3.44 (s, 2H), 2.24 (s, 6H). ESHRMS m / z 463.0801 (M + H required for C ₂₂ H ₂₂ BrF ₂ N ₂ O ₂ : 463.0827).

Example 77

3-bromo-4- (2,4-difluorobenzyloxy) -1-[(3-methylaminomethyl) benzyl] -1 H-pyridin-2-one

The title compound was prepared in a procedure similar to that described in Example 74 (0.05 g, 16%): mp 107 ° C. to 111 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.55 (d, J = 6 Hz, 1H), 7.31-7.19 (m, 5H), 6.94-6.81 (m, 2H), 6.09 (d, J = 6 Hz, 1H), 5.20 (s, 2H), 5.14 (s, 2H), 3.73 (s, 2H), 2.45 (s, 1H). ESHRMS m / z 449.0652 (M + H required for C ₂₁ H ₂₀ BrF ₂ N ₂ O ₂ : 449.0671)

Example 78

{3- [3-bromo-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] benzyl} carbamic acid tert-butyl ester

The title compound was prepared essentially following the procedure described in Example 70. mp 80 ° C. to 84 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.60-7.50 (m, 1H), 7.33-7.21 (m, 5H), 6.97-6.81 (m, 2H), 6.10 (dd, J = 8, 2 Hz , 1H), 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 required for C ₂₅ H ₂₆ BrF ₂ N ₂ O ₄ : 535.1039)

Example 79

1-[(3-aminomethyl) benzyl] -3-bromo-4- (2,4-difluorobenzyloxy) -1H-pyridin-2-one

Step 1. Preparation of 1-[(3-aminomethyl) benzyl] -3-bromo-4- (2,4-difluorobenzyloxy) -1 H-pyridin-2-one

{3- [3-Bromo-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] benzyl} carbamic acid tert in CH ₂ Cl ₂ (2 mL) To an ice cold solution of -butyl ester (Example 78) (0.05 g, 0.1 mmol) was added TFA (2 mL) and the reaction mixture was stirred for 1 h. The solvent was removed under reduced pressure to give 1-[(3-aminomethyl) benzyl] -3-bromo-4- (2,4-difluorobenzyloxy) -1H-pyridin-2-one as a tan solid as a TFA salt. (0.049 g, 100%) was prepared: mp 80 ° C. to 84 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.15 (br s, 3H), 7.97 (d, J = 8 Hz, 1H), 7.79-7.60 (m, 1H), 7.44-7.30 (m, 4H) , 7.20-7.15 (m, 1H), 6.61 (d, J = 6 Hz, 1H), 5.31 (s, 2H), 5.16 (s, 2H), 4.03 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -74.56 (4.8F), -109.63 (1F), -113.61 (1F). ESHRMS m / z 435.0540 (M + H required for C ₂₀ H ₁₈ BrF ₂ N ₂ O ₂ : 435.0515)

Example 80

3-chloro-4- (2,4-difluorobenzyloxy) -1- [4- (isopropylaminomethyl) benzyl] -1H-pyridin-2-one

Step 1. Preparation of 3-chloro-4- (2,4-difluorobenzyloxy) -1H-pyridin-2-one

N-chlorosuccinate was added to a solution of 4-[(4-fluorobenzyl) oxy] pyridin-2 (1H) -one (from step 2 of Example 74) (1.4 g, 5.9 mmol) in AcOH (25 mL). Mid (0.95 g, 7.1 mmol) was added and the reaction mixture was heated at reflux for 2 hours. The solvent was removed under reduced pressure. ¹ H NMR (300 MHz, MeOD) δ 7.63-7.55 (m, 1H), 7.45 (d, J = 8 Hz, 1H), 7.07-7.00 (m, 2H), 6.58 (d, J = 8 Hz, 1H ), 5.31 (d, J = 8 Hz, 1H).

Step 2. Preparation of 3-chloro-1- (4-chloromethylbenzyl) -4- (2,4-difluorobenzyloxy) -1H-pyridin-2-one

3-chloro-1- (4-chloromethylbenzyl) -4- (2,4-difluorobenzyloxy) -1H-pyridin-2-one is 3-bromo-1- (4-chloromethylbenzyl) Prepared as a white solid in a procedure similar to that described in -4- (2,4-difluorobenzyloxy) -1H-pyridin-2-one (step 3) (0.24 g, 34%): ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.53 (app q, J = 9 Hz, 1H), 7.34 (app q, J = 9 Hz, 1H), 7.23 (d, J = 8 Hz, 1H), 6.94 (td, J = 10, 2 Hz, 1H), 6.85 (td, J = 10, 2 Hz, 1H), 6.14 (d, J = 8 Hz, 1H), 5.20 (s, 2H), 5.16 (s, 2H), 4.56 ( s, 2H).

Step 3. Preparation of 3-chloro-4- (2,4-difluorobenzyloxy) -1- [4- (isopropylamino-methyl) benzyl] -1 H-pyridin-2-one

The title compound was prepared in a procedure similar to that described in Example 74 (0.17 g, 69%): mp 146 ° C. to 151 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.52 (app q, J = 9 Hz, 1H), 7.35-7.21 (m, 5H), 6.94 (td, J = 8, 2 Hz, 1H), 6.85 (td , J = 8, 2 Hz, 1H), 6.18 (d, J = 8 Hz, 1H), 5.22 (s, 2H), 5.08 (s, 2H), 3.81 (s, 2H), 2.98 (br s, 1H ), 1.20 (s, 6 H). ESHRMS m / z 433.1481 (M + H required for C ₂₃ H ₂₄ ClF ₂ N ₂ O ₂ : 433.1489)

Example 81

3-chloro-4- (2,4-difluorobenzyloxy) -1-[(3-methanesulfonyl) benzyl] -1 H-pyridin-2-one

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 Et ₂ O / THF (60 mL) add LiAlH ₄ (8.5 mL, 1.0 M solution in THF, 8.5 mmol) 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 (35 mL) in water. The reaction mixture was filtered and then concentrated under reduced pressure and the residue was dissolved in EtOAc. The organic solution was washed with water followed by brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent: 1: 2 to 3: 1 EtOAc / hexanes) gave (3-methanesulfonyl) phenyl methanol (0.56 g, 42%) as a clear oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.93 (s, 1H), 7.83 (d, J = 7 Hz, 1H), 7.64 (d, J = 7 Hz, 1H), 7.53 (t, J = 7 Hz, 1H) , 4.78 (d, J = 6 Hz, 2H), 3.05 (s, 3H), 2.61 (br s, 1H).

Step 2. Preparation of 1-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 rt and the solvent was removed under reduced pressure to give 1-chloromethyl-3-methanesulfonylbenzene (0.23 g, 95%) as a yellow oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.98 (s, 1H), 7.90 (d, J = 8 Hz, 1H), 7.70 (d, J = 8 Hz, 1H), 7.59 (t, J = 8 Hz, 1H), 4.65 (s, 2H), 3.08 (s, 3 H).

Step 3. Preparation of 3-chloro-4- (2,4-difluorobenzyloxy) -1-[(3-methanesulfonyl) -benzyl] -1 H-pyridin-2-one

The title compound was prepared in a procedure similar to that described in Example 80 (0.14 g, 78%): mp 155 ° C.-157 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.88 (d, J = 8 Hz, 1H), 7.83 (m, 1H), 7.67 (d, J = 8 Hz, 1H), 7.58-7.48 (m, 2H) , 7.31 (d, J = 8 Hz, 1H), 6.95-6.83 (m, 2H), 6.22 (d, J = 8 Hz, 1H), 5.22 (s, 4H), 3.08 (s, 3H). ESHRMS m / z 440.0525 (M + H required for C ₂₀ H ₁₇ ClF ₂ NO ₄ S: 440.0529)

Example 82

3-chloro-4- (2,4-difluorobenzyloxy) -1-[(4-methanesulfonyl) benzyl] -1 H-pyridin-2-one

The title compound was prepared in a procedure similar to that described in Example 81 (0.08 g, 73%): mp 223 ° C. to 225 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.91 (d, J = 8 Hz, 2H), 7.53-7.47 (m, 3H), 7.30-7.26 (m, 1H), 6.94-6.86 (m, 2H), 6.22 (d, J = 8 Hz, 1H), 5.23 (s, 4H), 3.03 (s, 3H). ESHRMS m / z 440.0512 (M + H required for C ₂₀ H ₁₇ ClF ₂ NO ₄ S: 440.0529)

Example 83

4- [3-chloro-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] benzamide

Step 1. Preparation of methyl 4- [3-chloro-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] benzoate

Methyl 4- [3-chloro-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] benzoate was prepared by a procedure similar to that described in Example 81 ( 0.14 g, 60%): ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.01 (dd, J = 8, 2 Hz, 1H), 7.52 (app q, J = 8 Hz, 1H), 7.36 (d, J = 9 Hz, 2H), 7.26-7.22 (m, 2H), 6.94 (td, J = 8, 2 Hz, 1H), 6.85 (td, J = 8, 2 Hz, 1H), 6.16 (d, J = 9 Hz, 1H), 5.21 (s, 4H), 3.92 (s, 3H).

Step 2. Preparation of 4- [3-chloro-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] benzamide

4- [3-chloro-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] benzoic acid methyl ester (0.25 g, 0.60 mmol) and NH ₃ (20 mL , A sealed tube containing a 7 N solution in MeOH, 140 mmol) was heated at 75 ° C. for 16 h. The reaction mixture was cooled to rt and the solvent was removed under reduced pressure. Triturated with Et ₂ O / MeOH to yield 4- [3-chloro-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] benzamide (0.14) as a white solid. g, 60%) was obtained: mp 235 ° C. to 238 ° C .; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.93 (d, J = 8 Hz, 2H), 7.79 (d, J = 8 Hz, 2H), 7.60 (app q, J = 8 Hz, 1H), 7.35-7.27 (m, 4H), 7.20-7.10 (m, 1H), 6.61 (d, J = 8 Hz, 1H), 5.28 (s, 2H), 5.14 (s, 2H). ESHRMS m / z 405.0788 (M + H required for C ₂₀ H ₁₆ ClF ₂ N ₂ O ₃ : 405.0812)

Example 84

3-chloro-4- (2,4-difluorobenzyloxy) -1-isoquinolin-5-ylmethyl-1H-pyridin-2-one

Step 1. Preparation of Isoquinoline-5-ylmethanol

To an ice cold solution of isoquinoline-5-carbaldehyde ² (0.68 g, 4.3 mmol) in MeOH (15 mL) was added NaBH ₄ (0.17 g, 4.6 mmol) and the reaction mixture was stirred for 15 minutes. 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 followed by brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give isoquinolin-5-ylmethanol (0.63 g, 93%) as a brown solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.87 (s, 1H), 8.82 (d, J = 6 Hz, 1H), 8.57 (d, J = 6 Hz, 1H), 8.47 (d, J = 9 Hz , 1H), 8.30 (d, J = 6 Hz, 1H), 7.95 (t, J = 9 Hz, 1H), 5.34 (s, 2H).

Step 2. Preparation of 5-bromomethylisoquinoline

To a solution of isoquinoline-5-ylmethanol (0.63 g, 3.9 mmol) in AcOH (3.3 mL) was added HBr (6.6 mL, 30% w / w solution in AcOH, 24 mmol) and the reaction mixture at 75 ° C. Stir for 45 minutes. The reaction mixture was cooled to room temperature and the precipitate was collected to prepare a salt of 5-bromomethylisoquinoline hydrobromic acid (1.1 g, 87%) as a brown solid: ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.22 (s, 1H), 8.58 (d, J = 6 Hz, 1H), 7.95-7.89 (m, 2H), 7.76 (d, J = 9 Hz, 1H), 7.59 (dd, J = 9, 6 Hz, 1H), 5.16 (s, 2H).

Step 3. Preparation of 3-chloro-4- (2,4-difluorobenzyloxy) -1-isoquinolin-5-ylmethyl-1H-pyridin-2-one

The title compound was prepared by a procedure similar to that described in Example 81 as the TFA salt (0.13 g, 33%): mp 235 ° C. to 238 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.55 (s, 1H), 8.66 (d, J = 6 Hz, 1H), 8.29 (d, J = 6 Hz, 1H), 8.22 (d, J = 8 Hz, 1H), 7.91 (d, J = 8 Hz, 1H), 7.77 (t, J = 8 Hz, 1H), 7.65-7.63 (m, 1H), 7.53 (d, J = 7 Hz, 1H) , 7.35-7.25 (m, 1H), 7.20-7.10 (m, 1H), 6.68 (d, J = 8 Hz, 1H), 5.67 (s, 2H), 5.32 (s, 2H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -74.79 (3F), -109.43 (1F), -113.62 (1F). ESHRMS m / z 413.0868 (M + H required for C ₂₂ H ₁₆ ClF ₂ N ₂ O ₃ : 413.0863)

Example 85

3-chloro-4- (2,4-difluorobenzyloxy) -1- (1,2,3,4-tetrahydroisoquinolin-5-ylmethyl) -1H-pyridin-2-one

Step 1. 3-Chloro-4- (2,4-difluorobenzyloxy) -1- (1,2,3,4-tetrahydro-isoquinolin-5-ylmethyl) -1H-pyridine-2- Manufacture of

3-chloro-4- (2,4-difluorobenzyloxy) -1-isoquinolin-5-ylmethyl-1H-pyridin-2-one (Example 84) in AcOH (1.3 mL) (0.14 g, To a solution of 0.34 mmol) was added NaCNBH ₃ (0.09 g, 1.4 mmol) and the reaction mixture was stirred for 2 hours. The reaction mixture was cooled to 0 ° C., diluted with water (10 mL) and 40% aqueous NaOH solution (10 mL), and the aqueous layer was washed with EtOAc (3 × 50 mL). The combined organics were washed with brine, dried (Na ₂ SO ₄ ) filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent: 98: 1.8: 0.2 from 88: 10.8: 1.2 CH ₂ Cl ₂ / MeOH / NH ₃ ) gave 3-chloro-4- (2,4-difluoro as a white solid. -Benzyloxy) -1- (1,2,3,4-tetrahydroisoquinolin-5-ylmethyl) -1H-pyridin-2-one (0.13 g, 92%) was prepared: mp 180 ° C. to 184 ℃; ¹ H NMR (300 MHz, MeOD) δ 7.65-7.55 (m, 2H), 7.16-7.00 (m, 4H), 6.90-6.80 (m, 1H), 6.60 (d, J = 8 Hz, 1H), 5.31 (s, 2H), 5.20 (s, 2H), 4.06 (s, 2H), 3.21 (t, J = 6 Hz, 2H), 2.82 (t, J = 6 Hz, 2H). ESHRMS m / z 417.1173 (M + H required for C ₂₂ H ₂₀ ClF ₂ N ₂ O ₂ : 417.1176)

Example 86

3-chloro-4- (2,4-difluorobenzyloxy) -1- (1H-indol-5-ylmethyl) -1H-pyridin-2-one

Step 1. Preparation of 5- (carboxymethyl) -indole-1-carbamic acid tert-butyl ester

Di-tert-butyl dicarbonate (19 g, in a solution of methyl indole-5-carboxylate (6.9 g, 39 mmol) and Et ₃ N (6.0 mL, 43 mmol) in CH ₂ Cl ₂ (150 mL) 86 mmol) was added and the reaction mixture was stirred for 14 h. The reaction mixture was diluted with CH ₂ Cl ₂ , washed with water then brine, dried (Na ₂ SO ₄ ) and filtered and the solvent was removed under reduced pressure. Purification by flash column chromatography (silica, 3: 7 EtOAc / hexanes) gave 5- (carboxymethyl) -indole-1-carbamic acid tert-butyl ester (11 g, 100%) as a light yellow oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.29 (s, 1H), 8.15 (d, J = 9 Hz, 1H), 7.93 (d, J = 9 Hz, 1H), 7.78 (d, J = 3 Hz, 1H), 6.85 (d, J = 3 Hz, 1H), 3.91 (s, 3H), 1.68 (s, 9H).

Step 2. Preparation of 5-hydroxymethylindole-1-carbamic acid tert-butyl ester

DIBAL (127 mL, 1 M solution in THF, 127 mmol) in a solution of -78 ° C. of 5- (carboxymethyl) -indole-1-carbamic acid tert-butyl ester (10.8 g, 39 mmol) in THF (180 mL) ) Was added and the reaction mixture was stirred for 2.5 h. The reaction was quenched with 1: 1 1 N HCl / MeOH (100 mL) and the reaction mixture was warmed to room temperature, diluted with CH ₂ Cl ₂ (100 mL) and separated. The organic solution was washed with saturated Rochelle salt, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1: 1 EtOAc / hexanes) gave 5-hydroxymethylindole-1-carbamic acid tert-butyl ester (6.5 g, 68%) as a yellow oil: ¹ H NMR ( 300 MHz, CDCl ₃ ) δ 8.07 (d, J = 9 Hz, 1H), 7.59 (d, J = 6 Hz, 1H), 7.54 (s, 1H), 7.28 (d, J = 9 Hz, 1H), 6.58 (d, J = 6 Hz, 1 H), 4.73 (s, 2 H), 1.97 (s, 9 H).

Step 3. Preparation of 5-bromomethylindole-1-carbamic acid tert-butyl ester

PBr ₃ (0.2 mL, 2.2 mmol) in an ice cold solution of 5-hydroxymethylindole-1-carbamic acid tert-butyl ester (0.51 g, 2.1 mmol) in 4: 1 Et ₂ O / CH ₂ Cl ₂ (4 mL). ) Was added and the reaction mixture was stirred for 40 minutes. The reaction mixture is diluted with CH ₂ Cl ₂ , washed with saturated NaHCO ₃ solution (3 × 10 mL), dried (Na ₂ SO ₄ ), filtered and the solvent removed under reduced pressure to afford 5-bromo as a yellow solid. Methyl-indole-1-carbamic acid tert-butyl ester (0.59 g, 93%) was prepared. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.07 (d, J = 9 Hz, 1H), 7.68-7.62 (m, 2H), 7.33 (d, J = 9 Hz, 1H), 6.60 (s, 1H) , 4.68 (s, 2 H), 1.67 (s, 9 H).

Step 4. Preparation of 5- [3-chloro-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] indole-1-carbamic acid tert-butyl ester

5- [3-chloro-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] indole-1-carbamic acid tert-butyl ester is described in Example 81. Prepared as an off-white solid in a procedure similar to that (0.54 g, 67%): ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.10 (d, J = 8 Hz, 1H), 7.60 (d, J = 3 Hz, 2H ), 7.52 (m, 1H), 7.26 (m, 1H), 6.94 (td, J = 9, 2 Hz, 1H), 6.84 (td, J = 9, 2 Hz, 1H) 6.53 (d, J = 2 Hz, 1H), 6.08 (d, J = 8 Hz, 1H), 5.25 (s, 2H), 5.18 (s, 2H), 1.66 (s, 9H).

Step 5. Preparation of 3-chloro-4- (2,4-difluorobenzyloxy) -1- (1H-indol-5-ylmethyl) -1H-pyridin-2-one

5- [3-chloro-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] indole-1-carbamic acid tert-butyl ester (0.48 g, 0.96 mmol ) Flask was heated at 150 ° C. for 4 hours. The reaction mixture is cooled to room temperature and purified HPLC (Phenomenex Luna C18 (2) column, 250 × 21.20 mm, 10 μ

Solvent A: 0.05% TFA in 95: 5 H ₂ O / CH ₃ CN; Solvent B: 0.05% TFA in 95: 5 CH ₃ CN / H ₂ O

Eluent: 30-95% B over 20 minutes; Flow rate of 20.0 mL / min; UV detector: 254 nm; Retention time: 15.6 min), 3-chloro-4- (2,4-difluoro benzyloxy) -1- (1H-indol-5-ylmethyl) -1H-pyridin-2-one as off-white solid (0.14 g, 36%) was prepared: mp 152 ° C. to 153 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.11 (br s, 1H), 7.91 (d, J = 8 Hz, 1H), 7.61 (app q, J = 8 Hz, 1H), 7.51 (s, 1H), 7.36-7.33 (m, 3H), 7.16 (td, J = 8, 2 Hz, 1H), 7.09 (dd, J = 8, 2 Hz, 1H), 6.57 (d, J = 8 Hz, 1H ), 6.40 (br s, 1 H), 5.28 (s, 2 H), 5.16 (s, 2 H). ESHRMS m / z 401.0845 (M + H required for C ₂₁ H ₁₆ ClF ₂ N ₂ O ₂ : 401.0863).

Example 87

1- (1-acetyl-1H-indol-5-ylmethyl) -3-chloro-4- (2,4-difluorobenzyloxy) -1H-pyridin-2-one

₃ -chloro-4- (2,4-difluorobenzyloxy) -1- (1H-indol-5-ylmethyl) -1H-pyridin-2-one in CH ₃ CN (10 mL) (Example 86 To the solution of (Synthesis of Step 5) (0.22 g, 0.57 mmol) was added acetic anhydride (0.06 mL, 0.58 mmol) and Et ₃ N (2 mL) and the reaction mixture was stirred at 86 ° C for 6 h. The reaction mixture was cooled to rt and partitioned between 1 N HCl and EtOAc. The organic solution was separated, washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. ¹ H NMR (300 MHz, MeOD) δ 8.35 (d, J = 9 Hz, 1H), 7.77 (d, J = 9 Hz, 1H), 7.70 (d, J = 3 Hz, 1H), 7.54 (s, 2H), 7.31 (d, J = 9 Hz, 1H), 7.01-6.99 (m, 2H), 6.66 (d, J = 3 Hz, 1H), 6.59 (d, J = 9 Hz, 1H), 5.29 ( s, 4H), 2.63 (s, 3H). ESHRMS m / z 443.0965 (M + H required for C ₂₃ H ₁₈ ClF ₂ N ₂ O ₃ : 443.0969).

Example 88

3-chloro-4- (2,4-difluorobenzyloxy) -1- (2,3-dihydro-1H-indol-5-ylmethyl) -1H-pyridin-2-one

3-chloro-4- (2,4-difluorobenzyloxy) -1- (1H-indol-5-ylmethyl) -1H-pyridin-2-one (Ac 86, step) in AcOH (5 mL) Synthesis of 5) (0.24 g, 0.60 mmol) was added NaCNBH ₃ (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 collected by filtration. Trichloro-4- (2,4-difluorobenzyl-oxy) -1- (2,3-dihydro-1H-indol-5-ylmethyl)-as a white solid by trituration with CH ₂ Cl ₂ . 1H-pyridin-2-one (0.2 g, 81%) was obtained: mp 137 ° C.-139 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.51 (app q, J = 9 Hz, 1H), 7.21 (d, J = 6 Hz, 1H), 7.11 (s, 1H), 6.99-6.80 (m, 3H ), 6.57 (d, J = 9 Hz, 1H), 6.08 (d, J = 9 Hz, 1H), 5.18 (s, 2H), 5.02 (s, 2H), 3.83 (br s, 1H), 3.55 ( t, J = 9 Hz, 2H), 2.99 (t, J = 9 Hz, 2H). ESHRMS m / z 403.1022 (M + H required for C ₂₁ H ₁₈ ClF ₂ N ₂ O ₂ : 403.1019).

The compounds of the following examples were prepared by a procedure similar to that described in Example 74. Yield and analytical data of the title compound are shown below.

Examples 89-101

The compounds of Examples 89-101 were prepared essentially following the procedure described in Example 74 above. Yields (Y), molecular formulas (MF) and analytical data of these compounds are shown below.

%): Mp 179 ° C. to 182 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.58-7.53 (m, 3H), 7.33-7.26 (m, 1H), 7.14-7.02 (m, 2H), 6.96-6.82 (m, 2H), 6.11 (d , J = 9 Hz, 1H), 5.20 (s, 2H), 5.18 (s, 2H). ESHRMS m / z (M + H requirements).

Example 96

3-bromo-4- (2,4-difluorobenzyloxy) -1- (2,4-difluorobenzyl) -1H-pyridin-2-one

Step 1. Preparation of 4- (2,4-difluorobenzyloxy) -1- (2,4-difluorobenzyl) -1 H-pyridin-2-one

To a solution of 2,4-dihydroxypyridine (0.35 g, 3.2 mmol) in DMF (50 mL) K ₂ CO ₃ (2.5 g, 13 mmol) and 2,4-difluorobenzyl bromide (1.0 mL, 7.6 mmol) was added and the reaction mixture was stirred at 110 ° C for 4 h. The reaction mixture was cooled to rt, washed with brine and extracted with CHCl ₃ (4 × 100 mL). The combined organics were washed with water followed by brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.54 (app q, J = 8 Hz, 1H), 7.38-7.28 (m, 5H), 6.94 (td, J = 8, 2 Hz, 1H), 6.85 (td , J = 8, 2 Hz, 1H), 6.10 (d, J = 9 Hz, 1H), 5.21 (s, 2H), 5.16 (s, 2H), 4.56 (s, 2H).

Step 2. Preparation of 3-bromo-4- (2,4-difluorobenzyloxy) -1- (2,4-fluorobenzyl) -1H-pyridin-2-one

Ice-cold solution of 4- (2,4-difluorobenzyloxy) -1- (2,4-difluorobenzyl) -1H-pyridin-2-one (0.72 g, 2.0 mmol) in AcOH (4.0 mL) To a solution of bromine (0.11 mL, 2.2 mmol) in AcOH (7.2 mL) was added and the reaction mixture was stirred for 40 minutes. The solvent was removed under reduced pressure. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.63-7.45 (m, 2H), 7.42 (d, J = 6 Hz, 1H), 6.93-6.77 (m, 4H), 6.12 (d, J = 6 Hz, 1H), 5.20 (s, 2H), 5.12 (s, 2H). ERMS m / z M + H 442.

Example 97

{3- [3-bromo-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] -phenyl} acetonitrile

Step 1. Preparation of Methyl 3-cyanomethylbenzoate

To an ice-cold solution of methyl 3-bromomethylbenzoate (9.1 g, 40 mmol) in CH ₃ CN (108 mL) tetrabutylammonium fluoride (17.3 mL, 60 mmol) and trimethylsilylcyanide (8.0 mL, 60 mmol) ) Was added and the reaction mixture was heated at reflux for 20 h. The reaction mixture was cooled to rt and the solvent was removed under reduced pressure. Purification by flash column chromatography (silica, 1: 1 EtOAc / hexanes) gave methyl 3-cyanomethylbenzoate (3.0 g, 43%) as a clear oil: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.97 (s, 1H), 7.92 (d, J = 8 Hz, 1H), 7.64 (d, J = 8 Hz, 1H), 7.56 (t, J = 8 Hz, 1H), 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) is added LiBH ₄ (8.8 mL, 2 M solution in THF, 18 mmol) and the reaction mixture is refluxed to 4 Heated for hours. The reaction mixture was cooled to rt, the reaction was quenched with 1: 1 water / 1 N HCl, and the aqueous layer was washed with EtOAc (3 × 150 mL). The combined organics were washed with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, 2: 1 EtOAc / hexanes) prepared (3-hydroxymethylphenyl) -acetonitrile (0.97 g, 41%) as a clear oil: ¹ H NMR (300 MHz, MeOD) δ 8.15-8.08 (m, 1H), 7.47-7.34 (m, 1H), 7.27 (s, 1H), 6.97-6.82 (m, 1H), 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) add CBr ₄ (2.5 g, 7.7 mmol) and Ph ₃ P (2.0 g, 7.7 mmol), The reaction mixture was stirred for 3 hours. The reaction mixture was filtered and then concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent: 1: 9 to 1: 4 EtOAc / hexanes) gave (3-bromomethylphenyl) acetonitrile (0.89 g, 58%) as a clear oil: ¹ H NMR ( 300 MHz, MeOD) δ 7.47-7.29 (m, 1H), 7.27 (s, 1H), 6.97-6.82 (m, 1H), 4.87 (s, 2H), 3.91 (s, 2H).

Step 4. Preparation of {3- [3-bromo-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] phenyl} acetonitrile

The title compound was prepared in a procedure similar to that described in Example 74 (0.07 g, 10%): mp 120 ° C. to 121 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.60-7.50 (m, 1H), 7.37-7.27 (m, 5H), 6.96 (td, J = 9, 3 Hz, 1H), 6.82 (td, J = 9 , 3 Hz, 1H), 6.13 (d, J = 8 Hz, 1H), 5.21 (s, 2H), 5.16 (s, 2H). ESHRMS m / z 445.0381 (M + H required for C ₂₁ H ₁₆ BrF ₂ N ₂ O ₂ : 445.0358).

Example 98

2- [3-bromo-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] benzonitrile

The title compound was prepared in a procedure similar to that described in Example 74 (0.13 g, 47%): mp 194 ° C.-197 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.75 (d, J = 9 Hz, 1H), 7.69-7.49 (m, 4H), 7.42 (t, J = 8 Hz, 1H), 6.96-6.73 (m, 2H), 6.18 (d, J = 8 Hz, H), 6.17 (s, 2H), 5.30 (s, 2H). ESHRMS m / z 431.0210 (M + H required for C ₂₀ H ₁₄ BrF ₂ N ₂ O ₂ : 431.0201).

Example 99

1-[(2-aminomethyl) benzyl)]-3-bromo-4- (2,4-difluorobenzyloxy) -1H-pyridin-2-one

2- [3-bromo-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] -benzonitrile (0.11 g, 0.25 mmol in THF (3 mL) ) Was added BH ₃ .DMS (0.25 mL, 2.0 M 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 2 N NaOH and EtOAc. The organic solution was washed with brine, dried (MgSO ₄ ) filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent: methylene chloride 90: 9: 1 methylene chloride / methanol / ammonia) gave 1-[(2-aminomethyl) benzyl] -3-bromo-4- (as a white solid. 2,4-difluorobenzyloxy) -1H-pyridin-2-one (0.15 g, 48%) was prepared: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.55 (app q, J = 8 Hz, 1H), 7.40-7.26 (m, 4H), 7.14 (d, J = 8 Hz, 1H), 6.94 (td, J = 8, 2 Hz, 1H), 6.85 (td, J = 8, 2 Hz, 1H ), 6.08 (d, J = 8 Hz, 1H), 5.31 (s, 2H), 5.21 (s, 2H), 4.03 (s, 2H). ESHRMS m / z 435.0517 (M + H required for C ₂₀ H ₁₈ BrF ₂ N ₂ O ₂ : 435.0514).

Example 100

Methyl 3- [3-bromo-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] benzoate

The title compound was prepared by a procedure similar to that described in Example 74 (0.05 g, 11%): mp 115 ° C. to 117 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.15-7.95 (m, 2H), 7.65-7.50 (m, 2H), 7.45-7.40 (m, 1H), 7.32 (d, J = 6 Hz, 1H), 7.00-6.80 (m, 2H), 6.12 (d, J = 9 Hz, 1H), 5.21 (s, 2H), 5.20 (s, 2H), 3.92 (s, 3H). ESHRMS m / z 464.0292 (M + H required for C ₂₁ H ₁₇ BrF ₂ NO ₄ : 464.0303).

Example 101

Methyl 4- [3-bromo-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl]-benzoate

The title compound was prepared in a procedure similar to that described in Example 74 (0.17 g, 46%): mp 136 ° C. to 139 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.01 (d, J = 8 Hz, 2H), 7.60-7.51 (m, 1H), 7.37 (d, J = 8 Hz, 2H), 7.29-7.26 (m, 1H), 6.93 (td, J = 9, 2 Hz, 1H), 6.84 (td, J = 9, 2 Hz, 1H), 6.13 (d, J = 8 Hz, 1H), 5.23 (s, 4H), 3.91 (s, 3 H). ESHRMS m / z 464.0306 (M + H required for C ₂₁ H ₁₇ BrF ₂ NO ₂ : 464.0304).

Example 102

3- [3-bromo-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] benzamide

Methyl 3- [3-bromo-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] benzoate (0.1 g, 0.21 mmol) and NH ₃ (3 A closed tube containing mL, a 7 N solution in MeOH, 21 mmol) was heated at 75 ° C. for 16 h. The reaction mixture was cooled to rt and the solvent was removed under reduced pressure. Trituration with Et ₂ O / MeOH gave a white solid (0.06 g, 64%): mp 198 ° C. to 201 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.02-8.00 (m, 2H), 7.85-7.75 (m, 2H), 7.70-7.60 (m, 1H), 7.45-7.30 (m, 4H), 7.17 (t, J = 3 Hz, 1H), 6.60 (d, J = 9 Hz, 1H), 5.32 (s, 2H), 5.18 (s, 2H). ESHRMS m / z 449.0295 (M + H required for C ₂₀ H ₁₆ BrF ₂ N ₂ O ₃ : 449.0307).

Example 103

4- [3-bromo-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] benzamide

The title compound was prepared by a procedure analogous to that described in Examples 101-102 (0.04 g, 12%): mp 235-238 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.00 (d, J = 8 Hz, 1H), 7.94 (br s, 1H), 7.78 (d, J = 8 Hz, 1H), 7.64 (app q, J = 8 Hz, 1H), 7.38-7.30 (m, 4H), 7.17 (td, J = 6, 2 Hz, 1H), 6.60 (d, J = 9 Hz, 1H), 5.27 (s, 2H), 5.14 (s, 2 H). ESHRMS m / z 449.0291 (M + H required for C ₂₀ H ₁₆ BrF ₂ N ₂ O ₃ : 449.0307).

Example 104

1- (3-aminomethyl-2-fluorobenzyl) -3-bromo-4- (2,4-difluorobenzyloxy) -1H-pyridin-2-one

Step 1. Preparation of 3-bromo-1- (3-bromomethyl-2-fluorobenzyl) -4- (2,4-difluoro-benzyloxy) -1 H-pyridin-2-one

Solution of 3-bromo-4- (2,4-difluorobenzyloxy) -1H-pyridin-2-one (from step 3 of Example 74) (0.3 g, 0.95 mmol) in DMF (26 mL) To K ₂ CO ₃ (0.26 g, 1.9 mmol) and 2,6-bis (bromomethyl) fluorobenzene (1.6 g, 5.7 mmol) were added and the reaction mixture was stirred at 110 ° C. for 3 hours. The reaction mixture was cooled to rt 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 × 50 mL). The combined organics were washed with water, dried (Na ₂ SO ₄ ) and filtered, then the solvent was removed under reduced pressure. Purification by flash column chromatography (silica, eluent: 99: 1 to 95: 5 methylene chloride / methanol) gave 3-bromo-1- (3-bromomethyl-2-fluorobenzyl) -4- as off-white solid. (2,4-Difluorobenzyloxy) -1 H-pyridin-2-one (0.24 g, 49%) was obtained: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.55-7.40 (m, 3H), 7.35-7.25 (m, 1H), 7.10-7.05 (m, 1H), 7.00-6.80 (m, 2H), 6.14 (d, J = 6 Hz, 1H), 5.22 (s, 2H), 5.19 (s, 2H), 4.50 (s, 2H).

Step 2. Preparation of 1- (3-aminomethyl-2-fluorobenzyl) -3-bromo-4- (2,4-difluoro-benzyloxy) -1H-pyridin-2-one

3-bromo-1- (3-bromomethyl-2-fluorobenzyl) -4- (2,4-difluorobenzyloxy) -1H-pyridin-2-one (0.24 g, 0.45 mmol) and A closed tube containing NH ₃ (24 mL, 7 N solution in MeOH, 168 mmol) was heated at 80 ° C. for 1 h. The reaction mixture was cooled to rt 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) gave a white solid (0.12 g, 60%): mp 160 ° C. to 163 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.46-7.45 (m, 1H), 7.44-7.35 (m, 2H), 7.34-7.26 (m, 1H), 7.15-7.05 (m, 1H), 6.95-6.80 (m, 2H), 6.11 (d, J = 9 Hz, 1H), 5.21 (s, 2H), 5.19 (s, 2H), 3.90 (s, 2H). ESHRMS m / z 453.0442 (M + H required for C ₂₀ H ₁₇ BrF ₃ N ₂ O ₂ : 453.0420).

Example 105

Methyl 3- [3-chloro-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] -2-fluoro-benzoate

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 is cooled, the solvent is removed under reduced pressure and the residue is dissolved in EtOAc. The organic solution was washed with saturated NaHCO ₃ solution followed by brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give methyl 2-fluoro-3-methylbenzoate (3.2 g, 82%) as a yellow oil. ) Was obtained: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.76-7.71 (m, 1H), 7.39-7.34 (m, 1H), 7.08 (t, J = 8 Hz, 1H), 3.98 (s, 3H), 2.31 (d, J = 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). Was added and the mixture was heated at reflux for 16 h. The reaction mixture was cooled down, filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent: 5:95 to 60:40 EtOAc / hexanes) gave methyl 3-bromomethyl-2-fluorobenzoate (0.91 g, 41%) as a light yellow solid. : ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.93-7.88 (m, 1H), 7.61-7.56 (m, 1H), 7.20 (t, J = 8 Hz, 1H), 4.53 (d, J = 3 Hz , 2H), 3.94 (s, 3H).

Step 3. Preparation of Methyl 3- [3-chloro-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] -2-fluorobenzoate

Methyl 3- [3-chloro-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] -2-fluorobenzoate is similar to that described in Example 81 Prepared as a procedure (0.33 g, 69%): mp 171 ° C. to 174 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.89-7.84 (m, 2H), 7.60-7.45 (m, 2H), 7.25-7.15 (m, 1H), 7.00-6.80 (m, 2H), 6.17 (d , J = 6.0 Hz, 1H), 5.21 (s, 2H), 5.19 (s, 2H), 3.93 (s, 3H). ESHRMS m / z 438.0747 (M + H required for C ₂₁ H ₁₆ ClF ₃ NO ₄ : 438.0714).

Example 106

3- [3-chloro-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] -2-fluoro-benzamide

The title compound was prepared in a procedure similar to that described in Example 99 (0.15 g, 62%): mp 252 ° C. to 254 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.04 (d, J = 8 Hz, 1H), 7.92 (br s, 1 H), 7.79-7.65 (m, 3H), 7.49-7.48 (m, 1H) , 7.37-7.31 (m, 3H), 6.80 (d, J = 8 Hz, 1H), 5.46 (s, 2H), 5.33 (s, 2H). ESHRMS m / z 423.0710 (M + H required for C ₂₀ H ₁₅ ClF ₃ N ₂ O ₃ : 423.0718).

Example 107

3-bromo-4- (2,4-difluorobenzyloxy) -1- (3-fluorobenzyl) -1H-pyridin-2-one

Step 1. Preparation of 4-benzyloxy-1- (3-fluorobenzyl) -1H-pyridin-2-one

In a solution of 4-benzyloxy-1H-pyridin-2-one (1.0 g, 5 mmol) and K ₂ CO ₃ (2.0 g, 9.9 mmol) in DMF (30 mL), 3-fluorobenzyl bromide (1.4 g, 7.5 mmol) was added and the reaction mixture was heated to 110 ° C for 3 h. The reaction mixture was cooled to rt and partitioned between EtOAc and water. The organic solution was washed with water followed by brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent: 97: 3 to 93: 7 methylene chloride / methanol) gave 4-benzyloxy-1- (3-fluorobenzyl) -1H-pyridin-2-one (1.04 g, 67%) was obtained: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.45-7.25 (m, 5H), 7.13 (d, J = 8 Hz, 1H), 7.10-6.90 (m, 3H), 6.10- 5.95 (m, 2H), 5.07 (s, 2H), 5.00 (s, 2H).

Step 2. Preparation of 1- (3-fluorobenzyl) -4-hydroxy-1H-pyridin-2-one

To a solution of 4-benzyloxy-1- (3-fluorobenzyl) -1H-pyridin-2-one (1.79 g, 5.8 mmol) in EtOH (50 mL) was added 10% Pd / C (0.4 g) The reaction mixture was stirred for 1.5 h under hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth and concentrated under reduced pressure to give 1- (3-fluorobenzyl) -4-hydroxy-1H-pyridin-2-one (0.92 g, 72%): ¹ H NMR (300 MHz) , CDCl ₃ ) δ 7.55 (d, J = 6 Hz, 1H), 7.40-7.30 (m, 1H), 7.10-6.95 (m, 3H), 6.07 (dd, J = 6, 3 Hz, 1H), 5.85 (d, J = 3 Hz, 1H), 5.11 (s, 2H).

Step 3. Preparation of 3-bromo-1- (3-fluorobenzyl) -4-hydroxy-1H-pyridin-2-one

In an ice cold solution of 1- (3-fluorobenzyl) -4-hydroxy-1H-pyridin-2-one (0.67 g, 3.1 mmol) in AcOH (5.7 mL) bromine (0.52 g, 3.24 mmol) solution was added and the reaction mixture was stirred for 5 minutes. The reaction mixture is allowed to warm to room temperature and concentrated under reduced pressure to afford 3-bromo-1- (3-fluorobenzyl) -4-hydroxy-1H-pyridin-2-one (1.07 g, crude) as a yellow solid. Obtained: ¹ H NMR (500 MHz, MeOD) δ 7.64 (d, J = 8 Hz, 1H), 7.35-7.30 (m, 1H), 7.05-6.90 (m, 3H), 6.20 (d, J = 8 Hz, 1H), 5.18 (s, 2H).

Step 4. Preparation of 3-bromo-4- (2,4-difluorobenzyloxy) -1- (3-fluorobenzyl) -1H-pyridin-2-one

3-bromo-1- (3-fluorobenzyl) -4-hydroxy-1H-pyridin-2-one (0.20 g, 0.67) and K ₂ CO ₃ (0.27 g, 1.34 mmol in acetone (10 mL) 2,4-difluorobenzyl bromide (0.16 g, 0.8 mmol) was added to the solution, and the reaction mixture was heated at reflux for 1 h. The reaction mixture was cooled to rt and concentrated under reduced pressure and the residue was dissolved in EtOAc. The organic solution was washed with water followed by brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.65-7.55 (m, 1H), 7.40-7.25 (m, 2H), 7.15-6.80 (m, 5H), 6.14 (d, J = 8 Hz, 1H), 5.22 (s, 2 H), 5.16 (s, 2 H). ESHRMS m / z 424.0159 (M + H required for C ₁₉ H ₁₄ BrF ₃ NO ₂ : 424.0155).

Example 108

3-bromo-1- (3-fluorobenzyl) -4- (2,3,4-trifluorobenzyloxy) -1H-pyridin-2-one

The title compound was prepared in a procedure similar to that described in Example 107 (0.09 g, 39%): mp 176 ° C. to 178 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.40-7.25 (m, 4H), 7.11-6.98 (m, 4H), 6.11 (d, J = 9 Hz, 1H), 5.23 (s, 2H), 5.16 ( s, 2H). ESHRMS m / z 442.0060 (M + H required for C ₁₉ H ₁₃ BrF ₄ NO ₂ : 442.0061).

Example 109

1- [3- (2-aminoethyl) benzyl] -3-bromo-4- (2,4-difluorobenzyloxy) -1H-pyridin-2-one

The title compound was prepared as a TFA salt from Example 97 in a procedure similar to that described in Example 99 (0.13 g, 33%): mp 70 ° C. to 74 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.21 (br s, 1H), 6.60-6.50 (m, 1H), 7.52 (d, J = 6 Hz, 1H), 7.30-7.10 (m, 3H) , 7.01 (d, J = 9 Hz, 1H), 6.94-6.85 (m, 2H), 6.20 (d, J = 6 Hz, 1H), 5.20 (s, 2H), 5.05 (s, 2H), 3.23 ( br s, 2H), 2.97 (t, J = 8 Hz, 2H), 2.05 (br s, 2H). ESHRMS m / z 449.0698 (M + H required for C ₂₁ H ₂₀ BrF ₂ N ₂ O ₂ : 449.0671).

Example 110

3-chloro-4- (2,4-difluorobenzyloxy) -1- (3-fluorobenzyl) -1H-pyridin-2-one

Step 1. Preparation of 4- (2,4-difluorobenzyloxy) -1- (3-fluorobenzyl) -1 H-pyridin-2-one

1- (3-fluorobenzyl) -4-hydroxy-1H-pyridin-2-one (from step 2 of Example 107) in acetone (62 mL) (0.92 g, 4.2 mmol) and K ₂ CO ₃ ( 1.2 g, 8.4 mmol) was added 2,4-difluorobenzyl bromide (1.3 g, 6.3 mmol) and the reaction mixture was heated at reflux for 3 hours. The reaction mixture was cooled to rt and concentrated under reduced pressure, and the residue was partitioned between water and EtOAc. The organic solution was washed with brine, dried (Na ₂ SO ₄ ) filtered and concentrated under reduced pressure. Purified by flash column chromatography (silica, eluent: 95: 5 methylene chloride / methanol from methylene chloride) to give 4- (2,4-difluorobenzyloxy) -1- (3-fluorobenzyl)-as a white solid. 1 H-pyridin-2-one (1.21 g, 84%) was prepared: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.45-7.20 (m, 2H), 7.14 (d, J = 8 Hz, 1H), 7.05-6.75 (m, 5H), 6.05 (d, J = 3 Hz, 1H), 5.95 (dd, J = 5, 3 Hz, 1H), 5.08 (s, 2H), 5.00 (s, 2H).

Step 2. Preparation of 3-chloro-4- (2,4-difluorobenzyloxy) -1- (3-fluorobenzyl) -1H-pyridin-2-one

N-chloro in a solution of 4- (2,4-difluorobenzyloxy) -1- (3-fluorobenzyl) -1H-pyridin-2-one (0.15 g, 0.4 mmol) in AcOH (3 mL) Succinimide (70 mg, 0.5 mmol) was added and the reaction mixture was heated at reflux for 10 minutes. The reaction mixture was cooled to rt and the solvent was removed under reduced pressure. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.60-7.50 (m, 1H), 7.45-7.20 (m, 2H), 7.10-6.80 (m, 5H), 6.16 (d, J = 8 Hz, 1H), 5.21 (s, 2 H), 5.15 (s, 2 H). ESHRMS m / z 380.0641 (M + H required for C ₁₉ H ₁₄ ClF ₃ NO ₂ : 480.0660).

Examples 111-123

The compounds of the following examples were prepared by a procedure similar to that described in Example 107. Yield and analytical data are described below.

Example 111

3-bromo-4- (3-chlorobenzyloxy) -1- (3-fluorobenzyl) -1H-pyridin-2-one

The title compound was prepared in a procedure similar to that described in Example 107 (0.12 g, 42%): mp 149 ° C. to 153 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.40-7.23 (m, 6H), 7.09 (d, J = 8 Hz, 1H), 7.05-6.95 (m, 2H), 6.05 (d, J = 8 Hz, 1H), 5.19 (s, 2H), 5.14 (s, 2H). ESMS m / z M + H 442.

Example 112

3-bromo-4- (3,4-difluorobenzyloxy) -1- (3-fluorobenzyl) -1H-pyridin-2-one

The title compound was prepared in a procedure similar to that described in Example 107 (0.08 g, 48%): mp 172 ° C. to 174 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.40-6.95 (m, 8H), 6.05 (d, J = 6 Hz, 1H), 5.16 (s, 4H). ESHRMS m / z 424.0111 (M + H required for C ₁₉ H ₁₄ BrF ₃ NO ₂ : 424.0155).

Example 113

3-bromo-1- (3-fluorobenzyl) -4- (4-fluorobenzyloxy) -1H-pyridin-2-one

The title compound was prepared in a procedure similar to that described in Example 107 (0.07 g, 35%): mp 180 ° C.-183 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.50-7.25 (m, 5H), 7.15-7.00 (m, 4H), 6.07 (d, J = 8 Hz, 1H), 5.18 (s, 2H), 5.14 ( s, 2H). ESHRMS m / z 406.0258 (M + H required for C ₁₉ H ₁₅ BrF ₂ NO ₂ : 406.0249).

Example 114

3-bromo-1- (3-fluorobenzyl) -4- (3-fluorobenzyloxy) -1H-pyridin-2-one

AcOH (1 mL) in an ice cold solution of 1- (3-fluorobenzyl) -4- (3-fluorobenzyloxy) -1H-pyridin-2-one (0.14 g, 0.43 mmol) in AcOH (2 mL) A solution of bromine (72 mg, 0.45 mmol) was added and the reaction mixture was stirred for 5 minutes. The reaction mixture is warmed to room temperature and the solvent is removed under reduced pressure. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.45-6.95 (m, 9H), 6.05 (d, J = 8 Hz, 1H), 5.21 (s, 2H), 5.14 (s, 2H). ESHRMS m / z 406.0254 (M + H required for C ₁₉ H ₁₅ BrF ₂ NO ₂ : 406.0249).

Examples 115 to 123

The compounds of Examples 115-123 were prepared essentially according to the procedure described in Example 107 above:

Example 124

3-bromo-1- (3-fluorobenzyl) -4- (2- (hydroxymethylbenzyloxy) -1H-pyridin-2-one

Step 1. Preparation of 3-bromo-1- (3-fluorobenzyl) -4- (2-hydroxymethylbenzyloxy) -1H-pyridin-2-one

Methyl 2- [3-bromo-1- (3-fluorobenzyl) -2-oxo-1,2-dihydro-pyridin-4-yloxymethyl] benzoate (0.12 g, in THF (5 mL), 0.28 mmol) was added LiBH ₄ (0.15 mL, 2.0 M solution in THF, 0.30 mmol) and the reaction mixture was heated at reflux for 5 hours. The reaction mixture is cooled to room temperature, the solvent is removed under reduced pressure and the residue is dissolved in EtOAc. The organic solution was washed with brine, dried (Na ₂ SO ₄ ) filtered and concentrated under reduced pressure. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.98 (d, J = 8 Hz, 1H), 7.46-7.28 (m, 5H), 7.15-7.10 (m, 3H), 6.56 (d, J = 8 Hz, 1H), 5.35 (s, 2H), 5.25 (br s, 1H), 5.14 (s, 2H). ESHRMS m / z 418.0453 (M + H required for C ₂₀ H ₁₈ BrFNO ₃ : 418.0449).

Example 126

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 isochromen-3-one (1.5 g, 10 mmol) in 30% HBr in acetic acid (13 mL) was stirred at room temperature for 2 hours and at 70 ° C. for 1 hour. The reaction mixture was cooled to room temperature and poured into ice water. The precipitate was collected to give (2-bromomethylphenyl) acetic acid (2.15 g, 93%) as off-white solid: ¹ H NMR (300 MHz, DMSO-d ₆ ) 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) is added trimethylsilyldiazomethane (3 mL, 2 M solution in hexanes, 6 mmol) and the reaction mixture is Stir for 14 hours. 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) gave methyl (2-bromomethylphenyl) acetate (0.34 g, 32%) as a light yellow solid: ¹ H NMR (300 MHz, CDCl ₃ ) 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-l-ylmethyl] phenyl} acetate

Methyl {2- [3-bromo-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] -phenyl} acetate was prepared in a procedure similar to that described in Example 74. (0.41 g, 68%): ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.55-6.81 (m, 8H), 6.10 (d, J = 6 Hz, 1H), 5.20 (s, 4H), 3.78 (s, 2 H), 3.60 (s, 3 H).

Step 4. Preparation of 2- {2- [3-bromo-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] phenyl} acetamide

2- {2- [3-Bromo-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] phenyl} -acetamide is similar to that described in Example 102. Prepared in a similar procedure (0.07 g, 72%): mp 178 ° C.-183 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.89 (d, J = 8 Hz, 1H), 7.66 (d, J = 9 Hz, 1H), 7.54 (br s, 1H), 7.35 (br s, 1H), 7.30-7.15 (m, 4H), 6.98 (br s, 1H), 6.85 (d, J = 7 Hz, 1H), 6.60 (d, J = 8 Hz, 1H), 5.32 (s, 2H) , 5.19 (s, 2 H), 3.62 (s, 2 H). ESHRMS m / z 463.0442 (M + H required for C ₂₁ H ₁₈ BrF ₂ N ₂ O ₃ : 463.0463)

Example 127

Ethyl {3- [3-bromo-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-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) is added carbon tetrachloride (45 mL) followed by the addition of benzoyl peroxide (5 mg) The reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to rt, filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent: 5:95 to 2: 3 EtOAc / hexanes) gave ethyl (3-bromomethylphenyl) acetate (0.89 g, 21%) as off-white solid: ¹ H NMR ( 300 MHz, CDCl ₃ ) δ 7.32-7.21 (m, 4H), 4.48 (s, 2H), 4.16 (q, J = 6 Hz, 2H), 3.63 (s, 2H), 1.27 (t, J = 6 Hz , 3H).

Step 2. Preparation of ethyl {3- [3-bromo-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] phenyl} acetate

Ethyl {3- [3-bromo-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] phenyl} -acetate was prepared in a procedure similar to that described in Example 74. (0.27 g, 69%): mp 95 ° C. to 98 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.65-7.55 (m, 1H), 7.40-7.20 (m, 5H), 7.00-6.80 (m, 2H), 6.09 (d, J = 9 Hz, 1H), 5.21 (s, 2H), 5.16 (s, 2H), 4.14 (q, J = 6 Hz, 2H), 3.60 (s, 2H), 1.25 (t, J = 6 Hz, 3H). ESHRMS m / z 492.0655 (M + H required for C ₂₃ H ₂₁ BrF ₂ NO ₄ : 435.0617).

Example 128

2- {3- [3-bromo-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] phenyl} acetamide

The title compound was prepared in a procedure similar to that described in Example 102 (0.07 g, 28%): mp 164 ° C. to 167 ° C .; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.96 (d, J = 9 Hz, 1H), 7.70-7.60 (m, 1H), 7.60 (br s, 1H), 7.50-7.10 (m, 6H) , 6.89 (br s, 1H), 6.58 (d, J = 9 Hz, 1H), 5.31 (s, 2H), 5.12 (s, 2H), 3.32 (s, 2H). ESHRMS m / z 463.0485 (M + H required for C ₂₁ H ₁₈ BrF ₂ N ₂ O ₃ : 463.0464).

Example 129

4- (2,4-difluorobenzyloxy) -1- (3-fluorobenzyl) -3-methyl-1H-pyridin-2-one

Step 1. Preparation of 4- (2,4-difluorobenzyloxy) -1- (3-fluorobenzyl) -3-methyl-1H-pyridin-2-one

3-bromo-4- (2,4-difluorobenzyloxy) -1- (3-fluorobenzyl) -1H-pyridin-2-one (Example 107) (0.14) in dioxane (2 mL) g, 0.32 mmol), K ₂ CO ₃ (88 mg, 0.64 mmol) and Cs ₂ CO ₃ (0.10 g, 0.32 mmol) were added trid, followed by addition of Pd (PPh ₃ ) ₄ (18 mg, 0.12 mmol) to trimethyl Boroxin (40 mg, 0.32 mmol) was added. The reaction mixture was degassed, purged with argon and then heated at reflux for 4 hours. The reaction mixture was cooled to rt and partitioned between water and EtOAc. The organic solution was washed with brine, dried (Na ₂ SO ₄ ) filtered and concentrated under reduced pressure. Purified by flash column chromatography (silica, eluent: methylene chloride from 97: 3 methylene chloride / MeOH) to give 4- (2,4-difluorobenzyloxy) -1- (3-fluorobenzyl)-as a white solid. 3-methyl-1H-pyridin-2-one (0.09 g, 79%) was obtained: mp 127 ° C. to 129 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.50-7.40 (m, 1H), 7.35-7.25 (m, 1H), 7.17 (d, J = 9 Hz, 1H), 7.06 (d, J = 6 Hz, 1H), 7.00-6.80 (m, 4H), 6.12 (d, J = 9 Hz, 1H), 5.12 (s, 4H), 2.07 (s, 3H). ESHRMS m / z 360.1180 (M + H required for C ₂₀ H ₁₆ F ₃ NO ₂ : 360.1206).

Example 130

4- (2,4-difluorobenzyloxy) -1- (3-fluorobenzyl) -3-iodo-1H-pyridin-2-one

Step 1. Preparation of 4- (2,4-difluorobenzyloxy) -1- (3-fluorobenzyl) -1 H-pyridin-2-one

1- (3-fluorobenzyl) -4-hydroxy-1H-pyridin-2-one (from step 1 of Example 110) in acetone (62 mL) (0.92 g, 4.2 mmol) and K ₂ CO ₃ ( 2,4-difluorobenzyl bromide (1.3 g, 6.3 mmol) was added to a mixture of 1.15 g, 8.4 mmol) and the reaction mixture was heated at reflux for 3 hours. The reaction mixture was cooled to rt and concentrated under reduced pressure and the residue was dissolved in EtOAc. The organic solution was washed with water followed by brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purified by flash column chromatography (silica, eluent: 95: 5 methylene chloride / methanol from methylene chloride) to give 4- (2,4-difluorobenzyloxy) -1- (3-fluorobenzyl)-as a white solid. 1 H-pyridin-2-one (1.21 g, 84%) was prepared: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.45-7.20 (m, 2H), 7.14 (d, J = 8 Hz, 1H), 7.05-6.75 (m, 5H), 6.05 (d, J = 3 Hz, 1H), 5.95 (dd, J = 5, 3 Hz, 1H), 5.08 (s, 2H), 5.00 (s, 2H).

Step 2. Preparation of 4- (2,4-difluorobenzyloxy) -1- (3-fluorobenzyl) -3-iodo-1H-pyridin-2-one

4- (2,4-difluorobenzyloxy) -1- (3-fluorobenzyl) -1H-pyridin-2-one (0.15 g, 0.43 mmol) and N-iodine in CH ₃ CN (3 mL) To a mixture of dosuccinimide (0.10 g, 0.46 mmol) was added dichloroacetic acid (13 mg, 0.10 mmol) and the reaction mixture was heated to 60 ° C. for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was dissolved in methylene chloride. The organic solution was washed with saturated NaHCO ₃ solution followed by brine, dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure. Purified by flash column chromatography (silica, eluent: 90:10 methylene chloride / hexane to 99: 1 methylene chloride / methanol) to give 4- (2,4-difluorobenzyloxy) -1- (3- as a white solid. Fluorobenzyl) -3-iodo-1H-pyridin-2-one (0.15 g, 77%) was prepared: mp 164 ° C. to 167 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.65-7.55 (m, 1H), 7.35-7.26 (m, 2H) 7.15-6.80 (m, 5H), 6.05 (d, J = 6 Hz, 1H), 5.22 (s, 2H), 5.16 (s, 2H). ESHRMS m / z 472.0033 (M + H required for C ₁₉ H ₁₄ F ₃ INO ₂ : 472.0018).

Example 131

4- (2,4-difluorobenzyloxy) -1- (3-fluorobenzyl) -2-oxo-1,2-dihydropyridine-3-carbonitrile

Step 1. Preparation of 4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile

A solution of 2- (dimethylaminoethoxymethylene) malononitrile (1.97 g) in concentrated sulfuric acid (7.0 mL) was stirred at room temperature for 6.5 hours. The reaction mixture was poured into water and the precipitate collected by filtration. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.14 (br s, 1H), 7.79 (d, J = 9 Hz, 1H), 6.35 (d, J = 9 Hz, 1H), 3.98 (s, 3H ).

Step 2. Preparation of 1- (3-fluorobenzyl) -4-methoxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile

1- (3-fluorobenzyl) -4-methoxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile was prepared by a procedure similar to that described in Example 74 (0.56 g, 93% ): ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.48 (d, J = 9 Hz, 1H), 7.40-7.27 (m, 1H), 7.00-6.95 (m, 2H), 6.08 (d, J = 9 Hz, 1H), 5.10 (s, 2H), 4.00 (s, 3H).

Step 3. Preparation of 1- (3-fluorobenzyl) -4-hydroxy-2-oxo-1,2-dihydropyridine-3-carbonitrile

To a solution of sodium hydride (92 mg, 60% dispersion in mineral oil, 2.3 mmol) in DMF (7 mL) was added ethanethiol (0.14 g, 2.2 mmol) followed by 1- (3-fluoro in DMF (2 mL). A solution of benzyl) -4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile (0.23 g, 0.89 mmol) was added and the reaction mixture was heated to 100 ° C. The reaction mixture was cooled to rt, acidified with 3N HCl and washed with EtOAc. The organic solution was washed with brine, dried (Na ₂ SO ₄ ) filtered and concentrated under reduced pressure to give 1- (3-fluorobenzyl) -4-hydroxy-2-oxo-1,2- as off-white solid. Dihydro-pyridine-3-carbonitrile (0.20 g, 91%) was obtained: ¹ H NMR (300 MHz, MeOD) δ 8.00 (s, 1H), 7.82 (d, J = 8 Hz, 1H), 7.40- 7.30 (m, 1 H), 7.15-7.00 (m, 2 H), 6.13 (d, J = 8 Hz, 1 H), 5.11 (s, 2H).

Step 4. Preparation of 4- (2,4-difluorobenzyloxy) -1- (3-fluorobenzyl) -2-oxo-1,2-dihydro-pyridine-3-carbonitrile

4- (2,4-difluorobenzyloxy) -1- (3-fluorobenzyl) -2-oxo-1,2-dihydro-pyridine-3-carbonitrile was subjected to a procedure similar to that described in Example 107. (0.09 g, 30%): mp 187 ° C. to 190 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.60-7.45 (m, 2H), 7.40-7.30 (m, 1H), 7.10-6.50 (m, 5H), 6.13 (d, J = 9 Hz, 1H), 5.27 (s, 2 H), 5.10 (s, 2 H).

Example 132

1-cyclohexyl-4- (2,4-difluorobenzyloxy) -3,6-dimethyl-1H-pyridin-2-one

Step 1. Preparation of Methyl 1-cyclohexyl-4-hydroxy-2,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylate

2-methylmalonic acid bis- (2,4,6-trichloro-phenyl) in a solution of 3-cyclohexylaminobut-2-enoic acid methyl ester (1.12 g, 5.72 mmol) in bromobenzene (20 mL) Ester (2.71 g, 5.72 mmol) was added and the reaction mixture was heated at 170 ° C. for 3 hours. The reaction mixture was cooled to rt and concentrated under reduced pressure. Purified by flash column chromatography (silica, eluent: 94: 6 methylene chloride / MeOH from methylene chloride), recrystallized from hot MeOH to give methyl 1-cyclohexyl-4-hydroxy-2,5-dimethyl- as pale yellow crystals. 6-Oxo-1,6-dihydropyridine-3-carboxylate (0.34 g, 21%) was prepared: ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.82 (s, 1H), 4.00- 3.90 (m, 1H), 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, 1H).

Step 2. Preparation of 1-cyclohexyl-4-hydroxy-2,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid

Methyl 1-cyclohexyl-4-hydroxy-2,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylate (0.35 g, 1.25 mmol) in 2N NaOH (5 mL) The solution of was heated at reflux for 3.5 h. The reaction mixture was cooled to rt, acidified to pH 1-2 with 1 N HCl and washed with EtOAc. The organic solution was washed with brine, dried (MgSO ₄ ) filtered and concentrated under reduced pressure to give 1-cyclohexyl-4-hydroxy-2,5-dimethyl-6-oxo-1,6-di as a white solid. Hydropyridine-3-carboxylic acid (0.31 g, 94%) was obtained: ¹ H NMR (300 MHz, MeOD) δ 4.30-4.00 (br s, 1H), 2.76 (br s, 5H), 1.90 (s , 3H), 1.90-1.80 (m, 2H), 1.75-1.60 (m, 3H), 1.50-1.15 (m, 3H).

Step 3. Preparation of 1-cyclohexyl-4-hydroxy-3,6-dimethyl-1H-pyridin-2-one

A solution of 1-cyclohexyl-4-hydroxy-2,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.15 g, 0.57 mmol) in concentrated HCl (5 mL) was added. Heated under reflux for 4 hours. The reaction mixture was cooled to rt, diluted with water and washed with EtOAc. The organic solution was washed with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure to give 1-cyclohexyl-4-hydroxy-3,6-dimethyl-1H-pyridin-2-one (0.2 as a white solid). g, 77%): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.81 (s, 1H), 5.73 (s, 1H), 3.95-3.75 (m, 1H), 2.80-2.55 (m, 2H), 2.25 (s, 3H), 1.85-1.40 (m, 5H), 1.72 (s, 3H), 1.38-1.05 (m, 3H).

Step 4. Preparation of 1-cyclohexyl-4- (2,4-difluorobenzyloxy) -3,6-dimethyl-1H-pyridin-2-one

1-cyclohexyl-4- (2,4-difluorobenzyloxy) -3,6-dimethyl-1H-pyridin-2-one was prepared by a procedure similar to that described in Example 107 (0.05 g, 16% ): mp 118 ° C. to 120 ° C .; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.48-7.41 (m, 1H), 6.95-6.81 (m, 2H), 5.87 (s, 1H), 5.07 (s, 2H), 4.05-3.85 (m, 1H ), 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

3-chloro-4- (2,4-difluorobenzyloxy) -6-methyl-1- (1H-pyrazol-4-ylmethyl) -1H-pyridin-2-one

Step 1. Preparation of 4-methylpyrazole-1-carboxylic acid tert-butyl ester

Di-tert-butyl dicarbonate (2.8 g, 13 mmol) in a solution of 4-methyl-1H-pyrazole (1 g, 12 mmol) and DMAP (0.15 g, 1.2 mmol) in CH ₃ CN (20 mL). Was added and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc. The organic solution was washed with 1 N HCl, water followed by brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure to give 4-methyl-pyrazole-1-carboxylic acid tert-butyl ester as a light yellow oil ( 2.2 g, 100%) was prepared: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.83 (s, 1H), 7.53 (s, 1H), 2.09 (s, 3H), 1.64 (s, 9H).

Step 2. Preparation of 4-bromomethylpyrazole-1-carboxylic acid tert-butyl ester

In a solution of 4-methylpyrazole-1-carboxylic acid tert-butyl ester (1.0 g, 5.5 mmol) in carbon tetrachloride (20 mL), N-bromosuccinimide (1.0 g, 5.6 mmol) and benzoyl peroxide ( 50 mg) was added and the reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to rt, filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1: 4 EtOAc / hexanes) afforded 4-bromomethylpyrazole-1-carboxylic acid tert-butyl ester (0.42 g, 30%) as a light yellow oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.10 (s, 1H), 7.74 (s, 1H), 4.39 (s, 2H), 1.65 (s, 9H).

Step 3. 4- [3-Chloro-4- (2,4-difluorobenzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] pyrazole-1-carboxylic acid tert Preparation of -Butyl Ester

4- [3-Chloro-4- (2,4-difluorobenzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] pyrazole-1-carboxylic acid tert-butyl ester Was prepared by a procedure similar to that described in Example 632: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.09 (s, 1H), 7.72 (s, 1H), 7.53 (app q, J = 6 Hz, 1H) , 6.97-6.82 (m, 2H), 6.00 (s, 1H), 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-1- (1H-pyrazol-4-ylmethyl) -1H-pyridin-2-one

4- [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. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.33 (s, 2H), 7.68 (d, J = 6 Hz, 1H), 7.52 (app q, J = 6 Hz, 1H), 6.93-6.83 (m, 2H ), 6.47 68 (d, J = 9 Hz, 1H), 5.19 (s, 2H), 5.24 (s, 2H), 5.20 (s, 2H).

Example 134

4-{[4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] methyl} benzonitrile

Preparation of 4-{[4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] methyl} benzonitrile

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one (1.0 g, 3.6 mmol) was added N, N-dimethylformamide (5 mL )). α-bromo-p-tolunitrile (0.85 g, 4.3 mmol) was added followed by K ₂ CO ₃ (0.59 g, 4.3 mmol). The resulting mixture was heated to 80 ° C. for 16 hours. The reaction was concentrated to an oil, partitioned between water and ethyl acetate and extracted with ethyl acetate (3 × 100 ml). The organic extracts were combined, washed with brine, dried over Na ₂ S0 ₄ and filtered. The filtrate was concentrated to an oil and purified by chromatography (silica gel, hexane / ethyl acetate) to give a white solid (0.65 g, 46%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.62 (d, J = 8.4 Hz, 2H), 7.41-7.31 (m, 7H), 7.23 (d, J = 7.6 Hz, 1H), 6.11 (d, J = 8.0 Hz, 1H), 5.24 (s, 2H), 5.18 (s, 2H). ES HRMS m / z 395.0404 (M + H required for C ₂₀ H ₁₅ BrN ₂ O ₂ : 395.0390).

Example 135

3-{[4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] methyl} benzonitrile

The title compound was prepared essentially by the procedure described in Example 134. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.62-7.54 (m, 3H), 7.45 (d, J = 7.6 Hz, 1H), 7.43-7.31 (m, 5H), 7.26 (d, J = 1.6 Hz, 1H), 6.12 (d, J = 1.6 Hz, 1H), 5.24 (s, 2H), 5.15 (s, 2H). ES HRMS m / z 395.0420 (M + H required for C ₂₀ H ₁₅ BrN ₂ O ₂ : 395.0390).

Example 136

2-{[4-benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] methyl} benzonitrile

The title compound was prepared essentially by the procedure described in Example 134. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.74 (d, J = 8.4 Hz, 1H); 7.63 (dd, J = 1.2, 8.0 Hz, 1H), 7.57 (dt, J = 1.2, 8.4 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H); 7.43-7.30 (m, 6H), 6.13 (d, J = 8.0 Hz, 1H,), 5.33 (s, 2H), 5.23 (s, 2H). ES HRMS m / z 395.0398 (M + H required for C ₂₀ H ₁₅ BrN ₂ O ₂ : 395.0390).

Example 137

1- [4- (aminomethyl) benzyl] -4- (benzyloxy) -3-bromopyridin-2 (1H) -one

Preparation of 1- [4- (aminomethyl) benzyl] -4- (benzyloxy) -3-bromopyridin-2 (1H) -one

Example 134 (100 mg, 0.25 mmol) was dissolved in tetrahydrofuran (2 mL) under N ₂ . Borane dimethylsulfide complex (0.25 mL, 0.5 mmol, 2 M in tetrahydrofuran) was added. The reaction was then heated to 70 ° C. and shaken overnight. The mixture was cooled down and all solvents were distilled under vacuum. The resulting residue was partitioned between ethyl acetate and 0.2 N NaOH and extracted with ethyl acetate (3 × 10 mL). The organic extracts were combined, washed with brine, dried over Na ₂ S0 ₄ and filtered. The filtrate was concentrated to an oil and triturated with dichloromethane and hexanes to give an off white solid (80 mg, 80%). ¹ H NMR (400 MHz, d ₆ DMSO) δ 7.90 (d, J = 7.6 Hz, 1H); 7.43-7.21 (m, 9H), 6.70 (d, J = 7.6 Hz, 1H), 5.29 (s, 2H), 5.08 (s, 2H), 3.71 (s, 2H). ES HRMS m / z 399.0721 (M + H required for C ₂₀ H ₁₉ BrN ₂ O ₂ : 399.0703).

Example 138

1- [3- (aminomethyl) benzyl] -4- (benzyloxy) -3-bromopyridin-2 (1H) -one

The title compound was prepared essentially by the procedure set forth in Example 137 using the title compound of Example 135 as the starting material. ¹ H NMR (400 MHz, d ₆ DMSO) δ 7.90 (d, J = 7.6 Hz, 1H), 7.44-7.22 (m, 9H), 6.50 (d, J = 7.6 Hz, 1H), 5.30 (s, 2H ), 5.12 (s, 2H), 3.88 (s, 2H). ES HRMS m / z 399.0730 (M + H required for C ₂₀ H ₁₉ BrN ₂ O ₂ : 399.0703).

Example 139

1- [2- (aminomethyl) benzyl] -4- (benzyloxy) -3-bromopyridin-2 (1H) -one

The title compound was prepared essentially by the procedure set forth in Example 137 using the title compound of Example 136 as the starting material. ¹ H NMR (400 MHz, d ₆ DMSO) δ 7.88 (d, J = 8.0 Hz, 1H); 7.45-7.34 (m, 5 H), 7.26-7.21 (m, 3 H); 6.85 (d, J = 7.2 Hz, 1H), 6.53 (d, J = 7.6 Hz, 1H), 5.32 (s, 2H), 5.12 (s, 2H), 3.90 (s, 2H). ES HRMS m / z 399.0699 (M + H required for C ₂₀ H ₁₉ BrN ₂ O ₂ : 399.0703).

Example 140

4-{[4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] methyl} benzamide

Preparation of 4-{[4- (benzyloxy) -3-bromo-2-oxopyridin-1 (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 20 hours. 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 × 20 mL). The organic extracts were combined, dried over Na ₂ S0 ₄ and filtered. The filtrate was concentrated to oil. Trituration with dichloromethane and hexanes gave a solid (11.5 mg, 11%). ¹ H NMR (400 MHz, d ₆ DMSO) δ 7.94 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H); 7.43-7.29 (m, 7H), 6.51 (d, J = 7.6 Hz, 1H), 5.31 (s, 2H), 5.16 (s, 2H). ES HRMS m / z 413.0541 (M + H required for C ₂₀ H ₁₇ BrN ₂ O ₃ : 413.0495).

Example 141

3-{[4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] methyl} benzamide

The title compound was prepared essentially by the procedure set forth in Example 140 using the title compound of Example 135 as the starting material. ¹ H NMR (400 MHz, d ₆ DMSO) δ 7.95 (d, J = 7.6 Hz, 2H), 7.76 (m, 2H); 7.43-7.26 (m, 8H), 6.51 (d, J = 7.6 Hz, 1H), 5.31 (s, 2H), 5.15 (s, 2H). ESHRMS m / z 413.0497 (M + H required for C ₂₀ H ₁₇ BrN ₂ O ₃ : 413.0495).

Example 142

2-{[4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] methyl} benzamide

The title compound was prepared essentially by the procedure set forth in Example 140 using the title compound of Example 136 as the starting material. ¹ H NMR (400 MHz, d ₆ DMSO) δ 7.78 (d, J = 7.6 Hz, 1H), 7.54 (dd, J = 1.6, 7.6 Hz, 1H); 7.45 (d, J = 7.6 Hz, 2H); 7.44-7.32 (m, 5H), 7.15 (d, J = 7.6 Hz, 1H), 6.49 (d, J = 7.6 Hz, 1H), 5.39 (s, 2H), 5.30 (s, 2H). ES HRMS m / z 4413.0506 (M + H required for C ₂₀ H ₁₇ BrN ₂ O ₃ : 413.0495).

Example 143

Methyl 3-{[4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] methyl} benzoate

Preparation of methyl 3-{[4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] methyl} benzoate

Example 134 (100 mg, 0.25 mmol) was suspended in methanol and cooled to 0 ° C. HCl (g) was bubbled through the mixture until saturated (about 30 minutes). The reaction was allowed to warm to room temperature and stirred for 4 hours. HCl and methanol were removed in vacuo to give an oil which was purified by chromatography (silica gel, hexanes / ethyl acetate) to give a white solid (3 mg, 3%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.98 (app d, J = 8.0 Hz, 2H), 7.77 (app d, J = 8.0 Hz, 1H); 7.55 (app d, J = 8.0 Hz, 2H); 7.41-7.35 (m, 5H), 6.52 (d, J = 7.6 Hz, 1H), 5.31 (s, 2H), 5.27 (s, 2H); 3.88 (s, 3 H). API-ES MS m / z 429.0 (M + H required for C ₂₁ H ₁₈ BrNO ₄ : 428.0492).

Example 144

Methyl 4-{[4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] methyl} benzoate

The title compound was prepared essentially by the procedure set forth in Example 143 using the title compound of Example 134 as the starting material. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.94 (app d, J = 8.4 Hz, 2H), 7.76 (app d, J = 7.6 Hz, 1H); 7.46 (app d, J = 8.0 Hz, 2H); 7.39-7.35 (m, 5H), 6.51 (d, J = 7.6 Hz, 1H), 5.31 (s, 2H), 5.26 (s, 2H); 3.88 (s, 3 H). ES HRMS m / z 428.0492 (M + H required for C ₂₁ H ₁₈ BrNO ₄ : 428.0492).

Example 145

4- [4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] benzonitrile

Preparation of 4- [4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] benzonitrile

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one (100 mg, 0.36 mmol) was suspended in dimethylsulfoxide (5 mL) and Cesium carbonate (375 mg, 1.15 mmol) was added and the reaction was shaken for 5 minutes. Then 4-fluorobenzonitrile (52 mg, 0.43 mmol) was added and the reaction heated to 80 ° C. and stirred. The reaction was monitored by LC / MS, heated to 100 ° C. after 4 hours 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 Na ₂ S0 ₄ and filtered. The filtrate was concentrated to an oil and purified by chromatography (silica gel, hexane / ethyl acetate) to give a white solid (40 mg, 29%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.77 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 7.44-7.42 (m, 4H), 7.28 (d, J = 7.6 Hz, 1 H), 7.26 (s, 1 H), 6.24 (d, J = 7.6 Hz, 1 H); 5.31, (s, 2 H). ES HRMS m / z 381.0230 (M + H required for C ₁₉ H ₁₃ BrN ₂ O ₂ : 381.0233).

Example 146

2- [4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] benzonitrile

Preparation of 2- [4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] benzonitrile

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one (100 mg, 0.36 mmol) was suspended in dimethylsulfoxide (5 mL) and Cesium carbonate (375 mg, 1.15 mmol) was added and the reaction was shaken for 5 minutes. Then 4-fluorobenzonitrile (52 mg, 0.43 mmol) was added and the reaction heated to 80 ° C. with stirring. The reaction was monitored by LC / MS, heated to 100 ° C. after 4 hours 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 Na ₂ S0 ₄ and filtered. The filtrate was concentrated to an oil and purified by chromatography (silica gel, hexane / ethyl acetate) to give a white solid (18 mg, 13%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.81 (dd, J = 1.2, 8.4 Hz, 1H), 7.73 (dt, J = 1.2, 8.0 Hz, 1H), 7.57 (dt, J = 0.8, 8.0 Hz, 1H), 7.50-7.36 (m, 6H), 7.27 (d, J = 8.0 Hz, 1H), 6.28 (d, J = 8.0 Hz, 1H); 5.31 (s, 2 H). ES HRMS m / z 381.0249 (M + H required for C ₁₉ H ₁₃ BrN ₂ O ₂ : 381.0233).

Example 147

(4-{[4- (benzyloxy) -3-bromo-2-oxopyridin-1- (2H) -yl] methyl} phenyl) acetic acid

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one (0.5 g, 1.78 mmol) was diluted with N, N-dimethylformamide (5 mL )). 4- (bromomethyl) phenylacetic acid (0.5 g, 2.14 mmol) was added followed by K ₂ CO ₃ (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 further for 16 hours. The reaction mixture was partitioned between water and ethyl acetate and extracted with ethyl acetate (2 x 50 mL). The aqueous layer was acidified with 1 N HCl (pH 2) and extracted with ethyl acetate (3 × 50 ml). The organic extracts were combined, washed with brine, dried over Na ₂ S0 ₄ and filtered. The filtrate was concentrated to an oil, purified by chromatography (silica gel, hexane / ethyl acetate) and then purified by reverse phase chromatography (C ₁₈ , 0.1% aqueous trifluoroacetic acid / acetonitrile) to give a white solid (25 mg, 3% ) Was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40-7.38 (m, 3H), 7.25-7.20 (m, 7H), 6.05 (d, J = 8.0 Hz, 1H), 5.21 (s, 2H); 5.13 (s, 2 H); 3.62 (s, 2 H).

ES HRMS m / z 428.0510 (M + H requirement for C ₂₁ H ₁₈ BrNO ₄ : 428.0492).

Example 148

{4-[(4- (benzyloxy) -3-bromo-2-{[4- (carboxymethyl) benzyl] oxy} -1λ ⁵ -pyridin-1-yl) methyl] phenyl} acetic acid

Preparation of {4-[(4- (benzyloxy) -3-bromo-2-{[4- (carboxymethyl) benzyl] oxy} -lλ ⁵ -pyridin-1-yl) methyl] phenyl} acetic acid

The desired product was isolated by reverse phase chromatography (C ₁₈ , 0.1% aqueous trifluoroacetic acid / acetonitrile) used in the preparation of Example 147 to give a white solid (53 mg, 5%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40-7.38 (m, 3H), 7.27-7.24 (m, 6H), 7.20 (d, J = 7.6 Hz, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.4 Hz, 1H), 6.06 (d, J = 7.6 Hz, 1H), 5.21 (s, 2H); 5.11 (s, 2 H); 5.11 (s, 2 H); 3.63 (s, 2 H); 3.58 (s, 2 H). ES HRMS m / z 576.1009 (M + H requirement for C ₃₀ H ₂₈ BrNO ₆ : 576.1016).

Example 149

2-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzonitrile

Preparation of 2-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzonitrile

3-bromo-4- (2,4-difluorophenoxy) -6-methylpyridin-2 (1H) -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 h. The reaction was filtered through Celite®, the filtrate was concentrated to an oil, 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 MgSO ₄ and filtered. The filtrate was concentrated to an oil and purified by chromatography (silica gel, hexane / ethyl acetate) to give a white solid (25 mg, 37%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.68 (dd, J = 8.0, 1.2 Hz, 1H); 7.58 (app q, J = 8.8 Hz, 1 H); 7.52 (dt, J = 8.0 & 1.2 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H); 7.08 (d, J = 8.8 Hz, 1 H), 7.00-6.93 (m, 1 H); 6.89-6.84 (m, 1 H); 6.05 (s, 1 H), 5.57 (s, 2 H), 5.22 (s, 2 H); 2.28 (s, 3 H). ES HRMS m / z 445.0335 (M + H required for C ₂₁ H ₁₅ BrF ₂ N ₂ O ₂ : 445.0358).

Example 150

3-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzonitrile

The title compound is essentially the example using 3-bromo-4- (2,4-difluorophenoxy) -6-methylpyridin-2 (1H) -one (1 g, 3.0 mmol) as starting material. It was prepared by the procedure described in 149. ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.61-7.55 (m, 2H); 7.45-7. 41 (m, 3 H); 6.98-6.94 (m, 1 H); 6.89-6.84 (m, 1 H); 6.03 (s, 1 H), 5.36 (s, 2 H), 5.22 (s, 2 H); 2.30 (s, 3 H). ES HRMS m / z 445.0349 (M + H required for C ₂₁ H ₁₅ BrF ₂ N ₂ O ₂ : 445.0358)

Example 151

4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzonitrile

The title compound is essentially the example using 3-bromo-4- (2,4-difluorophenoxy) -6-methylpyridin-2 (1H) -one (1 g, 3.0 mmol) as starting material. It was prepared by the procedure described in 149. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.61 (d, J = 8.4 Hz, 2H); 7.62-7.56 (m, 1 H); 7.27 (d, J = 8.8 Hz, 2H); 6.95 (app t, J = 8.4 Hz, 1 H), 6.88-6.83 (m, 1 H); 6.03 (s, 1 H), 5.39 (s, 2 H), 5.21 (s, 2 H); 2.28 (s, 3 H). ES HRMS m / z 445.0359 (M + H required for C ₂₁ H ₁₅ BrF ₂ N ₂ O ₂ : 445.0358).

Example 152

4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzamide

Example 151 (50 mg, 0.11 mmol) was added to a suspension of potassium fluoride (40% on alumina) in t-butyl alcohol. The reaction was heated to 90 ° C. and stirred for 20 hours. 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 × 20 mL). The organic extracts were combined, dried over Na ₂ S0 ₄ and filtered. The filtrate was concentrated to an oil, which was purified by chromatography (silica gel, hexane / ethyl acetate) to give a white solid to give the product (13 mg, 25%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.75 (app d, J = 8.4 Hz, 2H), 7.58 (app q, J = 8.4 Hz, 1H); 7.24 (d, J = 8.4 Hz, 2H); 6.98-6.94 (m, 1 H), 6.89-6.83 (m, 1 H) 6.01 (s, 1 H); 5.40 (s, 2 H), 5.21 (s, 2 H); 2.28 (s, 3 H). ES HRMS m / z 463.0486 (M + H required for C ₂₁ H ₁₇ BrF ₂ N ₂ O ₃ : 463.0463).

Example 153

Methyl 4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzoate

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 (about 30 minutes). The reaction was sealed, warmed to room temperature and stirred for 2 hours. HCl and methanol were removed in vacuo to give an oil which was purified by chromatography (silica gel, hexane / ethyl acetate) to give a white solid (19 mg, 36%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (app d, J = 8.4 Hz, 2H), 7.58 (app q, J = 8.0 Hz, 1H); 7.22 (d, J = 8.4 Hz, 2H); 6.95 (app dt, J = 1.5, 9.6 Hz, 1H), 6.89-6.83 (m, 1H), 6.00 (s, 1H); 5.41 (s, 2 H), 5.21 (s, 2 H); 3.90 (s, 3 H); 2.27 (s, 3 H). ES HRMS m / z 478.0461 (M + H required for C ₂₂ H ₁₈ BrNO ₄ : 478.0460).

Example 154

Methyl 3-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzoate

The title compound was prepared essentially by the procedure set forth in Example 149 using the title compound of Example 150 as the starting material. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.95-7.92 (m, 1H); 7.84 (bs, 1 H); 7.58 (app q, J = 8.0 Hz, 1 H); 7.39-7.37 (m, 2 H); 6.95 (app dt, J = 1.6, 8.4 Hz, 1H), 6.88-6.83 (m, 1H), 6.00 (s, 1H); 5.40 (s, 2 H), 5.21 (s, 2 H); 3.90 (s, 3 H); 2.30 (s, 3 H). ES HRMS m / z 478.0449 (M + H required for C ₂₂ H ₁₈ BrNO ₄ : 478.0460).

Example 155

3-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzamide

The title compound was prepared essentially by the procedure set forth in Example 152 using the title compound of Example 150 as the starting material. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.68-7.66 (m, 2H), 7.57 (app q, J = 8.4 Hz, 1H); 7.42-7.34 (m, 2 H); 6.98-6.92 (m, 1 H), 6.89-6.83 (m, 1 H), 6.01 (s, 1 H); 5.39 (s, 2 H), 5.21 (s, 2 H); 2.28 (s, 3 H). ES HRMS m / z 463.0461 (M + H required for C ₂₁ H ₁₇ BrF ₂ N ₂ O ₃ : 463.0463).

Example 156

2-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzamide

The title compound was prepared essentially by the procedure set forth in Example 152 using the title compound of Example 149 as the starting material. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.68-7.66 (m, 2H), 7.57 (app q, J = 8.4 Hz, 1H); 7.42-7.34 (m, 2 H); 6.98-6.92 (m, 1 H), 6.89-6.83 (m, 1 H), 6.01 (s, 1 H); 5.39 (s, 2 H), 5.21 (s, 2 H); 2.28 (s, 3 H). ES HRMS m / z 463.0461 (M + H required for C ₂₁ H ₁₇ BrF ₂ N ₂ O ₃ : 463.0463). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56-7.55 (m, 2H); 7.32-7.25 (m, 2 H); 7.00-6.94 (m, 1 H), 6.88-6.84 (m, 1 H); 6.81-6.79 (m, 1 H), 6.11 (s, 1 H); 5.51 (s, 2 H), 5.24 (s, 2 H); 2.43 (s, 3 H). ESHRMS m / z 463.0467 (M + H required for C ₂₁ H ₁₇ BrF ₂ N ₂ O ₃ : 463.0463).

Example 157

1- [2- (aminomethyl) benzyl] -3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one

Example 149 (50 mg, 0.11 mmol) was dissolved in tetrahydrofuran (2 mL) under N ₂ . Borane-methyl sulfide complex (0.11 mL, 0.22 mmol, 2 M in tetrahydrofuran) was added. The reaction was then heated to 70 ° C. and shaken overnight. After cooling to room temperature, all solvents were distilled under vacuum. The resulting residue was partitioned between ethyl acetate and 0.2 N NaOH and extracted with ethyl acetate (3 × 20 mL). The organic extracts were combined, washed with brine, dried over Na ₂ S0 ₄ and filtered. The filtrate was concentrated to an oil and purified by chromatography (silica gel, hexane / ethyl acetate) to give a white solid, which gave the product (19 mg, 39%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56-7.55 (m, 2H); 7.32-7.25 (m, 2 H); 7.00-6.94 (m, 1 H), 6.88-6.84 (m, 1 H); 6.81-6.79 (m, 1 H); 6.11 (s, 1 H); 5.44 (s, 2 H), 5.17 (s, 2 H); 4.59 (s, 2 H); 2.18 (s, 3 H). ESHRMS m / z 449.0692 (M + H required for C ₂₁ H ₁₉ BrF ₂ N ₂ O ₂ : 449.0671).

Example 158

3-bromo-1- [3- (bromomethyl) benzyl] -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one

Preparation of 3-bromo-1- [3- (bromomethyl) benzyl] -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one (2 g, 6.06 mmol) was added 1,4-dioxane (250 mL). Suspended in the air. α, α'-dibromo-m-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 h. The reaction was filtered through Celite®, the filtrate was concentrated to an oil, partitioned between water and dichloromethane and extracted with dichloromethane (4 x 250 mL). The organic extracts were combined, washed with brine, dried over Na ₂ S0 ₄ and filtered. The filtrate was concentrated to an oil and purified by chromatography (silica gel, hexane / ethyl acetate) to give a white solid (1.2 g, 38%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57 (app q, J = 7.6 Hz, 1H); 7.28-7.25 (m, 2 H); 7.17 (s, 1 H); 7.08 (m, 1 H); 6.94 (app dt, J = 1.2, 9.6 Hz, 1 H), 6.87-6.82 (m, 1 H); 5.99 (s, 1 H), 5.34 (s, 2 H), 5.20 (s, 2 H); 4.43 (s, 2 H); 2.29 (s, 3 H). ES HRMS m / z 511.9672 (M + H required for C ₂₁ H ₁₇ Br ₂ F ₂ NO ₂ : 511.9667).

Example 159

3-bromo-1- [4- (bromoethyl) benzyl] -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one

The title compound was prepared essentially by the procedure described in Example 158. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.68-7.66 (m, 2H), 7.57 (app q, J = 8.4 Hz, 1H); 7.42-7.34 (m, 2 H); 6.98-6.92 (m, 1 H), 6.89-6.83 (m, 1 H), 6.01 (s, 1 H); 5.39 (s, 2 H), 5.21 (s, 2 H); 2.28 (s, 3 H). ES HRMS m / z 463.0461 (M + H required for C ₂₁ H ₁₇ BrF ₂ N ₂ O ₃ : 463.0463). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56 (app q, J = 7.6 Hz, 1H); 7.32 (d, J = 8.0 Hz, 2H); 7.14 (d, J = 8.0 Hz, 2H); 6.94 (app t, J = 8.4 Hz, 1 H), 6.87-6.82 (m, 1 H); 5.98 (s, 1 H), 5.33 (s, 2 H), 5.19 (s, 2 H); 4.44 (s, 2 H); 2.29 (s, 3 H). ES HRMS m / z 511.9683 (M + H required for C ₂₁ H ₁₇ Br ₂ F ₂ NO ₂ : 511.9667).

Example 160

1- [4- (aminomethyl) benzyl] -3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one

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 and left until it reached room temperature, followed by stirring for 4 hours. The solvent and ammonia were removed from the reaction under vacuum with stirring and the resulting oil was triturated with ether to give a solid (174 mg, 99%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.61 (q, J = 7.6 Hz, 1H); 7.40 (d, J = 8.0 Hz, 2H); 7.20 (d, J = 8.0 Hz, 2H); 7.03 (app t, J = 8.8 Hz, 2H), 6.51 (s, 1H), 5.43 (s, 2H), 5.29 (s, 2H); 4.07 (s, 2 H); 2.36 (s, 3 H). ES HRMS m / z 449.0673 (M + H required for C ₂₁ H ₁₉ BrF ₂ N ₂ O ₂ : 449.0671).

Examples 161-168

The compounds of Examples 161-168 were prepared according to the procedures described in Examples 158-160 above, or using the compounds of Examples 158:

Example 169

3-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzoic acid

Preparation of 3-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzoic acid

Example 154 (150 mg, 0.31 mmol) was dissolved in tetrahydrofuran (5 mL). Calcium trimethylsilanolate (80 mg, 0.62 mmol) was added and the reaction stirred at room temperature for 4 hours. The reaction mixture was concentrated to an oil, partitioned between water and ethyl acetate and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over Na ₂ S0 ₄ and filtered. The filtrate was concentrated to an oil and purified by reverse phase chromatography (C ₁₈ , 0.1% aqueous trifluoroacetic acid / acetonitrile) to give the product (64 mg, 44%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.92 (app d, J = 8.0 Hz, 1H); 7.78 (s, 1 H); 7.62 (app q, J = 8.0 Hz, 1 H); 7.44 (t, J = 7.6 Hz, 1 H); 7.36 (app d, J = 8.0 Hz, 1H); 7.02 (app t, J = 7.6 Hz, 2H); 6.51 (s, 1 H), 5.48 (s, 2 H), 5.30 (s, 2 H); 2.37 (s, 3 H). ES HRMS m / z 464.0328 (M + H required for C ₂₁ H ₁₆ BrF ₂ NO ₄ : 464.0304).

Examples 170-174

The compounds of Examples 170-174 were prepared using the compounds of Examples 159 or 161:

Examples 175-185

The compounds of Examples 175-185 were prepared using the compounds of Examples 159 or 160:

Example 186

4- (4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzoyl) piperazine -1-carboxamide

3-bromo-4- (2,4-difluorophenoxy) -6-methyl-1- [4- (piperazin-1-ylcarbonyl) benzyl] pyridin-2 (1H) -one (300 mg, 0.54 mmol) was dissolved in N, N-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 stirred at room temperature for 1 hour. 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%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.61 (app q, J = 8.0 Hz, 1H); 7.41 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.03 (app t, J = 8.8 Hz, 2H); 6.51 (s, 1H), 5.46 (s, 2H), 5.30 (s, 2H), 3.75-3.35 (m, 8H); 2.37 (s, 3 H). ES HRMS m / z 575.1104 (M + H required for C ₂₆ H ₂₅ BrF ₂ N ₄ O ₄ : 575.1100).

Example 187

N- (4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzyl) -2 -Methoxyacetamide

Polymer bound carbodiimide resin (2.3 g, 1.18 meq / g, 2.7 mmol) was suspended in N, N-dimethylformamide. 1-hydroxybenzotriazole (1 M in N, N-dimethylformamide, 0.165 mL) and N, N-diisopropylethylamine (0.3 mL, after addition of acetoxyacetic acid (120 mg, 1.33 mmol) 2.0 mmol) was added. Example 159 (300 mg, 0.67 mmol) was added and then the reaction was shaken for 1 hour. 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, the mixture was shaken for 72 hours and then filtered and the resulting filtrate was concentrated. Trituration with water then trituration with ether gives a white solid (125 mg, 36%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56 (app q, J = 8.0 Hz, 1H); 7.21 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 6.94 (app t, J = 8.8 Hz, 1H), 6.88-6.81 (m, 1H); 5.97 (s, 1 H), 5.33 (s, 2 H), 5.19 (s, 2 H); 4.43 (d, J = 6.0 Hz, 2H); 3.92 (s, 2 H); 3.39 (s, 3 H); 2.29 (s, 3 H). ES HRMS m / z 521.0882 (M + H required for C ₂₄ H ₂₂ BrF ₂ N ₂ O ₄ : 521.0882).

Examples 188-193

The compound of Examples 188-193 was prepared by following the general preparation of Example 187 and substituting with the appropriate carboxylic acid for acetoxyacetic acid. These compounds were triturated with water and then triturated again with ether and appropriately purified by chromatography (silica gel, hexane / ethyl acetate) to yield an off-white solid. Example 191 was prepared from its Nt-butoxycarbonyl protected intermediate. Deprotection was performed with 4 N HCl in dioxane to give the title compound (86 mg, 24%) in the form of its hydrochloride. Deprotection of the methyl ester from Example 188 was performed with K ₂ CO ₃ in methanol / water to give Example 192 as a white solid. Yield and analytical data is shown below.

Example 194

1- {4-[(4-acetylpiperazin-1-yl) carbonyl] benzyl} -3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridine-2 (1H) -on

3-bromo-4- (2,4-difluorophenoxy) -6-methyl-1- [4- (piperazin-1-ylcarbonyl) benzyl] pyridin-2 (1H) -one (200 mg, 0.36 mmol) was dissolved in N, N-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 at room temperature for 2 hours, concentrated to an oil, triturated with ether and then triturated again with water to give an off-white solid (131 mg, 63%): ¹ H NMR (400 MHz, CD ₃ OD) δ 7.62 (app q, J = 8.0 Hz, 1H); 7.42 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.62-7.02 (m, 1H); 7.02 (app t, J = 8.0 Hz, 1H); 6.52 (s, 1 H), 5.46 (s, 2 H), 5.30 (s, 2 H); 3.80-3.65 (m, 8 H); 2.37 (s, 3 H); 2.11 (s, 3 H). ES HRMS m / z 574.1150 (M + H requirement for C ₂₇ H ₂₆ BrF ₂ N ₃ O ₄ : 574.1148).

Example 195

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (4-{[4- (methylsulfonyl) piperazin-1-yl] carbonyl} benzyl Pyridin-2 (1H) -one

3-bromo-4- (2,4-difluorophenoxy) -6-methyl-1- [4- (piperazin-1-ylcarbonyl) benzyl] pyridin-2 (1H) -one (300 mg, 0.54 mmol) was dissolved in N, N-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 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 h and then filtered, and the resulting filtrate was concentrated to an oil and triturated with water. The resulting white solid was collected, washed with ether and dried (172 mg, 52%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57 (app q, J = 8.2 Hz, 1H); 7.34 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.02 (app dt, J = 1.2, 8.8 Hz, 1H), 6.88-6.82 (m, 1H); 6.02 (s, 1 H), 5.37 (s, 2 H), 5.21 (s, 2 H); 3.80-3.20 (m, 8 H); 2.79 (s, 3 H); 2.30 (s, 3 H). ES HRMS m / z 610.0851 (M + H required for C ₂₆ H ₂₆ BrF ₂ N ₃ O ₅ S: 610.0817).

Example 196

Methyl-4- [4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] benzoate

Step 1. Preparation of 4- [4- (benzyloxy) -2-oxopyridin-1 (2H) -yl] benzonitrile

4-benzyloxy-2 (1H) -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 rt, the reaction was diluted with H ₂ O (150 mL) and the solids were collected by filtration, washing with diethyl ether. Chromatography (silica gel, hexane / ethyl acetate) gave an off-white solid (7.78 g, 65%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.79 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.44-7.41 (m, 5H), 7.22 (d, J = 13.3, 1H), 6.13 (dd, J = 2.6, 7.7 Hz, 1H), 6.06 (d, J = 2.6 Hz, 1H), 5.07 (s, 2H).

Step 2. Preparation of 4- [4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] benzonitrile

4- [4- (benzyloxy) -2-oxopyridin-1 (2H) -yl] benzonitrile (step 1) (2.76 g, 9.13 mmol) is suspended in acetonitrile (50 mL) and cooled in an ice bath. I was. N-bromosuccinimide (1.71 g, 9.54 mmol) was added. After the addition was complete, the cooling bath was removed. After stirring for 45 minutes, the reaction was diluted with acetonitrile and the solid collected by filtration to give a white solid (3.13 g, 90%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.00 (d, J = 8.5 Hz, 2H), 7.84 (d, J = 7.9 Hz, 1H), 7.66 (d, J = 8.5, 2H), 7.50- 7.37 (m, 5H), 6.63 (d, J = 7.9 Hz, 1H), 5.41 (s, 2H).

Step 3. Preparation of Methyl-4- [4- (benzyl) oxy-3-bromo-2-oxopyridin-1 (2H) -yl] benzoate

4- [4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] benzonitrile (step 2) (1.50 g, 3.93 mmol) is suspended in methanol (50 mL), Cool in an ice bath. Thereafter, HCl (g) was bubbled through the mixture for 5 minutes. The reaction was then stirred at rt overnight, then the reaction mixture was concentrated. The residue was suspended in 6 N HCl (60 mL) and heated at reflux for 1.5 h. After cooling to room temperature, the solids were collected by filtration. Chromatography (silica gel, hexane / ethyl acetate) gave an off-white shiny solid (0.540 g, 61%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.04 (d, J = 8.5 Hz, 2H), 7.81 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 8.6 Hz, 2H), 7.47 -7.39 (m, 5H), 6.57 (d, J = 7.9 Hz, 1H), 5.38 (s, 2H), 3.86 (s, 3H). ES-HRMS m / z 416.0355 (M + H calculated for C ₂₀ H ₁₆ BrNO ₄ : 414.0341).

Example 197

4- [4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] benzoic acid

Preparation of 4- [4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] benzoic acid

Example 196 (0.460 g, 1.11 mmol) was dissolved in tetrahydrofuran (5.0 mL). Calcium trimethylsilanolate (0.285 g, 2.22 mmol) was added. The reaction was stirred at rt for 3 h and then H ₂ O (10 mL) was added. The aqueous reaction mixture was acidified (pH-3) with 1 N HCl. Tetrahydrofuran was evaporated, more H ₂ O (50 mL) was added, and the aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and evaporated to give a rust solid (0.444 g, 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.02 (d, J = 8.6 Hz, 2H), 7.80 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 8.6 Hz, 2H), 7.50 -7.34 (m, 5H), 6.57 (d, J = 7.9 Hz, 1H), 5.38 (s, 2H). ES-HRMS m / z 400.0191 (M + H calculated for C ₁₉ H ₁₄ BrNO ₄ : 400.0184).

Example 198

4- [4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] benzamide

Preparation of 4- [4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] benzamide

Step 2 (0.238 g, 0.624 mmol) of Example 196 was suspended in tert-butyl alcohol (3.0 mL). KF (0.453 g, 3.12 mmol) on 40 wt.% Al ₂ O ₃ was added. The reaction mixture was heated at reflux for 5 days. Further KF (0.453 g, 3.12 mmol) on 40 wt.% Al ₂ O ₃ was added and heating was continued under reflux overnight. After cooling to room temperature, chloroform and methanol were added and the solids were collected by filtration. Chromatography (reverse phase, acetonitrile / H ₂ O) produced a tan solid (0.073 g, 30%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.07 (s, 1H), 7.95 (d, J = 8.6 Hz, 2H), 7.79 (d, J = 7.8 Hz, 1H), 7.47-7.34 (m, 7H), 6.56 (d, J = 7.9 Hz, 1H), 5.38 (s, 2H). ES-HRMS m / z 399.0372 (M + H calculated for C ₁₉ H ₁₅ BrN ₂ O ₃ : 399.0344).

Example 199

1- [4- (aminomethyl) phenyl] -4- (benzyloxy) -3-bromopyridin-2 (1H) -one

Preparation of 1- [4- (aminomethyl) phenyl] -4- (benzyloxy) -3-bromopyridin-2 (1H) -one

Step 2 (1.25 g, 3.28 mmol) of Example 196 was dissolved in tetrahydrofuran (15 mL). Borane-dimethylsulfide (3.44 mL, 6.89 mmol, 2.0 M in tetrahydrofuran) was added and the mixture was heated to reflux. After 14.5 hours, the solvent was evaporated. 0.5 M NaOH (50 mL) was added followed by ethyl acetate. The aqueous layer was neutralized with 1 N HCl. Methanol saturated with HCl was added and the mixture was heated at reflux for 5 h. After cooling to room temperature, diethyl ether was added and the solid collected by filtration. The solid was treated with 4 N HCl in dioxane (5 mL) and methanol (1 mL) at room temperature for 1 hour, then diethyl ether was added and the solid collected by filtration to give a tan solid (0.920 g, 67%) Got. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.67 (br s, 2H), 7.76 (d, J = 7.6 Hz, 1H), 7.64 (d, J = 8.3 Hz, 2H), 7.50-7.37 (m , 7H), 6.56 (d, J = 7.6 Hz, 1H), 5.41 (s, 2H), 4.09 (br s, 2H). ESHRMS m / z 385.0555 (M + H calculated for C ₁₉ H ₁₇ BrN ₂ O ₂ : 385.0552).

Example 200

Methyl-4- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxypyridin-1 (2H) -yl] benzoate

Step 1. Preparation of 4- [4- (benzyloxy) -2-oxopyridin-1 (2H) -yl] benzonitrile

4-benzyloxy-2 (1H) -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 rt, the reaction was diluted with H ₂ O (600 mL) and the solids were collected by filtration, washing with diethyl ether. The solid was then washed with hot methanol to give a tan solid (55.6 g, 74%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.79 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.44-7.41 (m, 5H), 7.22 (d, J = 13.3, 1H), 6.13 (dd, J = 2.6, 7.7 Hz, 1H), 6.06 (d, J = 2.6 Hz, 1H), 5.07 (s, 2H).

Step 2. Preparation of 1- [4-nitrilephenyl] -4-hydroxy-2 (1H) -pyridone

4- [4- (benzyloxy) -2-oxopyridin-1 (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 and then the reaction started an exothermic reaction. The reaction was left to cool to room temperature and then filtered through a Celite® pad, washing with methanol. The filtrate was evaporated to give a pale yellow solid (16.2 g, greater than 100%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.46 (s, 1H), 7,95 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 7.7 Hz, 1H), 5.98 (dd, J = 2.6, 7.7 Hz, 1H), 5.54 (d, J = 2.4 Hz, 1H).

Step 3. Preparation of 4- [4-[(2,4-difluorobenzyloxy)]-2-oxopyridin-1 (2H) -yl] benzonitrile

1- [4-nitrilephenyl] -4-hydroxy-2 (1H) -pyridone (step 2) (16.2 g) was dissolved in N, N-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. Further α-bromo-2,4-difluorotoluene (4.25 mL, 33.08 mmol) was added. The resulting mixture was heated to 65 ° C. for 5 hours. Further α-bromo-2,4-difluorotoluene (2.12 mL, 16.54 mmol) was added. After stirring at 65 ° C. overnight, the reaction was left to cool to room temperature. H ₂ O (300 mL) was added and the solid collected by filtration. A portion (8.0 g) of solid was washed with hot methanol to give a pale yellow solid (6.22 g, 78%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.00 (d, J = 8.5 Hz, 2H), 7.72-7.64 (m, 2H), 7.66 (d, J = 8.5 Hz, 2H), 7.40-7.32 (m, 1H), 7.22-7.16 (m, 1H), 6.17-6.11 (m, 2H), 5.17 (s, 2H).

Step 4. Preparation of Methyl-4- [4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] benzoate

4- [4-[(2,4-difluorobenzyloxy)]-2-oxopyridin-1 (2H) -yl] benzonitrile (step 3) (2.00 g, 5.91 mmol) in methanol (20 mL) Suspended in H ₂ O (5 mL) in an ice bath. HCl (g) was bubbled through the mixture until most of the solid was dissolved. The resulting mixture was then heated at reflux for 3 hours. The reaction was then recooled in an ice bath and bubbling HCl through the mixture for 5 minutes. The mixture was heated at reflux for 2 hours and then the methanol was evaporated. More H ₂ 0 (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 Na ₂ SO ₄ , filtered and evaporated. Chromatography (silica gel, hexane / ethyl acetate with 10% methanol) gave an off-white solid (0.630 g, 29%). ¹ H NMR (300 MHz, DMF-d ₆ ) δ 8.15 (d, J = 8.5 Hz, 2H), 7.80 (app q, J = 7.9 Hz, 1H), 7.74-7.67 (m, 1H), 7.68 (d , J = 8.5 Hz, 2H), 7.42-7.34 (app dt, J = 2.4, 9.0 Hz, 1H), 7.28-7.22 (m, 1H), 6.20 (dd, J = 2.6, 7.6 Hz, 1H), 6.15 (d, J = 2.4 Hz, 1H), 5.28 (s, 2H), 3.98 (s, 3H).

Step 5. Preparation of Methyl-4- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxypyridin-1 (2H) -yl] benzoate

Methyl-4- [4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] benzoate (step 4) (0.520 g, 1.40 mmol) was diluted to 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, acetonitrile was further added, and the precipitate was collected by filtration to give an off-white solid (0.331 g, 58%). ¹ H NMR (300 MHz, DMF-d ₆ ) δ 8.34 (d, J = 8.5 Hz, 2H), 8.12 (d, J = 7.9 Hz, 1H), 8.04-7.96 (m, 1H), 7.88 (d, J = 8.5 Hz, 2H), 7.59-7.53 (m, 1H), 7.52-7.41 (m, 1H), 7.05 (d, J = 7.9 Hz, 1H), 5.70 (s, 2H), 4.15 (s, 3H ). ES-HRMS m / z 406.0644 (M + H calculated for C ₂₀ H ₁₄ ClF ₂ NO ₄ : 406.0652).

Example 201

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [3- (hydroxymethyl) phenyl] -6-methylpyridin-2 (1H) -one

Step 1. Preparation of 4-hydroxy-1- [3- (hydroxymethyl) phenyl] 6-methylpyridin-2 (1H) -one

4-hydroxy-6-methyl-2-pyrone (10.0 g, 79.3 mmol) and 3-aminobenzyl alcohol (9. 77 g, 79.3 mmol) were combined in H ₂ O (100 mL) and heated to 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%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.6 (br s, 1H), 7.46-7.35 (m, 2H), 7.09-7.03 (m, 2H), 5.88 (d, J = 1.6 Hz, 1H) , 5.55 (d, J = 2.6 Hz, 1H), 4.54 (d, J = 4.2 Hz, 2H), 1.83 (s, 3H).

Step 2. Preparation of 1- [3- (hydroxymethyl) phenyl] -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one

4-hydroxy-1- [3- (hydroxymethyl) phenyl] 6-methylpyridin-2 (1H) -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 for 2 days at room temperature, the reaction was concentrated. The residue was partitioned between H ₂ O (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 Na ₂ SO ₄ , filtered and concentrated. Chromatography (on silica, hexanes / ethyl acetate with 10% methanol) gave a white solid (0.531 g, 51%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.51-7.39 (m, 3H), 7.82 (s, 1H), 7.16 (d, J = 26.8 Hz, 1H), 7.08-6.86 (m, 2H), 6.00 ( d, J = 2.6 Hz, 1H), 5.92 (d, J = 2.6 Hz, 1H), 5.05 (s, 2H), 4.68 (s, 2H), 1.93 (s, 3H). ES-HRMS m / z 358.1256 (M + H calculated for C ₂₀ H ₁₇ F ₂ NO ₃ : 358.1249).

Step 3. Preparation of 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [3- (hydroxymethyl) phenyl] -6-methylpyridin-2 (1H) -one

1- [3- (hydroxymethyl) phenyl] -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one (step 2) (0.460 g, 1.29 mmol ) Was suspended in acetonitrile (5.0 mL) and cooled in an ice bath. N-bromosuccinimide (0.241 g, 1.35 mmol) was added. After the addition was completed, the cooling bath was removed. After stirring for 1.5 hours, the reaction was diluted with acetonitrile and the solid collected by filtration to give a white solid (0.385 g, 68%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.70 (app q, J = 7.9 Hz, 1H), 7.49-7.32 (M, 3H), 7.24-7.10 (m, 3H), 6.66 (s, 1H) , 5.35 (s, 2H), 4.56 (d, J = 5.6 Hz, 2H), 1.95 (s, 3H). ES-HRMS m / z 436.0384 (M + H calculated for C ₂₀ H ₁₆ BrF ₂ NO ₃ : 436.0354).

Example 202

Methyl-4- [3-bromo-4-[(difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzoate

Step 1.Methyl 4- (4-hydroxy-6-methyl-2-oxypyridin-1 (2H) -yl) benzoate

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 brought to 160 ° C. Cooled rapidly. After 15 minutes at 160 ° C., the reaction was cooled to room temperature. The reaction was diluted with dichloromethane (50 ml) and extracted with saturated Na ₂ CO ₃ (2 × 100 ml). The combined aqueous layers were acidified with concentrated HCl (pH-2). The precipitate was collected by filtration and washed with diethyl ether to give a yellow / orange solid (10.9 g, 25%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.8 (s, 1H), 8.07 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 5.95 (d, J = 2.4 Hz, 1H), 5.61 (d, J = 2.4, 1H), 3.91 (s, 3H), 1.85 (s, 3H).

Step 2. Preparation of Methyl-4- [4-[(difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzoate

Methyl 4- (4-hydroxy-6-methyl-2-oxypyridin-1 (2H) -yl) benzoate (step 1) (10.90 g, 42.04 mmol) was added N, N-dimethylformamide (100 ml). Dissolved in. 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 rt for 3 days and then diluted with H ₂ O (100 ml). The reaction mixture was extracted with ethyl acetate and tetrahydrofuran (2 × 100 ml). The precipitate was collected by filtration and the organic filtrate was washed with brine (50 ml), dried over Na ₂ S0 ₄ , filtered and evaporated. The resulting solid was combined with the precipitate to give a pale pink solid (6.77 g, 42%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.01 (d, J = 8.3 Hz, 2H), 7.67 (q, J = 7.9 Hz, 1H), 7.43 (d, J = 8.3 Hz, 2H), 7.35 (m, 1H), 7.18 (app dt, J = 1.6, 8.5 Hz, 1H), 6.08 (d, J = 1.8 Hz, 1H), 5. 98 (d, J = 2.4 Hz, 1H), 5.14 (s , 2H), 3.91 (s, 3H), 1.87 (s, 3H).

Step 3. Methyl-4- [3-bromo-4-[(difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzoate.

Methyl-4- [4-[(difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzoate suspended in acetonitrile (100 ml) (step 2) g, 17.49 mmol) 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 give the title compound as an off-white solid (6.94 g, 85%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.20 (d, J = 8.7 Hz, 2H), 7.61 (q, J = 7.9 Hz, 1H), 7.30 (d, J = 8.7 Hz, 2H), 7.02- 6.96 (m, 1H), 6.90 (app dt, J = 2.4, 9.5 Hz, 1H), 6.14 (s, 1H), 5.28 (s, 2H), 3.98 (s, 3H), 2.00 (s, 3H). ES-HRMS m / z 464.0304 (M + H calculated for C ₂₁ H ₁₆ BrF ₂ N0 ₄ 464. 0301).

Example 203

4- [3-Bromo-4-[(difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzoic acid.

Example 202 (7.43 g, 16.00 mmol) was dissolved in tetrahydrofuran (40 ml). Potassium trimethylsilanolate (4.10 g, 32.00 mmol) was added and the reaction mixture was stirred at rt for 22 h. Tetrahydrofuran was evaporated and H ₂ O (50 ml) was added. The aqueous reaction mixture was acidified with 1 N HCl and the precipitate was collected by filtration. The solid was washed with boiling methanol to yield an off white solid (5.05 g, 70%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.2 (br s, 1 H), 8.10 (d, J = 8.5 Hz, 2H), 7.72 (q, J = 7.9 Hz, 1H), 7.45 (d, J = 8.3 Hz, 2H), 7.38 (app dt, J = 2.4, 9.9 Hz, 1H), 7.23 (app dt, J = 1.8, 8.5 Hz, 1H), 6.72 (s, 1H), 5.37 (s, 2H ), 1.97 (s, 3 H). ES-HRMS m / z 450.0154 (M + H calculated for C ₂₀ H ₁₄ BrF ₂ NO ₄ 450.0147).

Example 204

4- (benzyloxy) -1- (3-fluorobenzyl) -3- (trifluoromethyl) pyridin-2 (1H) -one.

Starting material (0.250 g, 0.591 mmol) was dissolved in 1-methyl-2-pyrrolidinone (5.0 ml). Trifluoroacetic acid sodium salt (0.322 g, 2.36 mmol) was added followed by copper iodide (0.225 g, 1.18 mmol). The resulting mixture was heated to 180 ° C. for 5 hours and then cooled to room temperature. The reaction was diluted with H ₂ O (50 ml) and brine (50 ml) and then extracted with ethyl acetate (2 × 50 ml). The combined organic layers were washed with brine (50 ml), dried over Na ₂ SO ₄ , filtered and evaporated. Chromatography (reverse phase, acetonitrile / H ₂ O) gave an off white solid (0.050 g, 22%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40-7.27 (m, 8H), 7.06 (d, J = 7.7 Hz, 1H), 6.97 (d, J = 9.0 Hz, 1H), 6.07 (d, J = 7.7 Hz, 1H), 5.20 (s, 2H), 5.06 (s, 2H). ES-HRMS m / z 378.1097 (M + H calculated for C ₂₀ H ₁₅ F ₄ NO ₂ 378.1112).

Example 205

4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzoic acid

Example 153 (50.0 g, 104.54 mmol) was dissolved in methanol (500 ml) and dioxane (100 ml). 1 N NaOH (130 ml, 130 mmol) was added. The resulting mixture was heated to 50 ° C. for 5.5 h. The reaction was partially concentrated and the heterogeneous mixture was acidified with 1N HCl (pH 2). The precipitate was collected by filtration to give an off white solid (49.2 g,> 100%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.94 (d, J = 8.3 Hz, 2H), 7.70 (app q, J = 7.9 Hz, 1H), 7.35 (dt, J = 2.2, 9.9 Hz, 1H ), 7.18 (app d, J = 8.3 Hz, 2H), 7.17-7.12 (m, 1H), 6.64 (s, 1H), 5.41 (s, 2H), 5.33 (s, 2H), 2.32 (s, 3H ). ES-HRMS m / z 464.0327 (M + H calculated for C ₂₁ H ₁₆ BrF ₂ NO ₄ 464.0304).

Example 206

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [4- (hydroxymethyl) benzyl] -6-methylpyridin-2 (1H) -one.

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 added slowly. The resulting mixture was slowly warmed to rt overnight. The mixture was recooled in an ice bath and quenched by addition of a small amount of ice. After the release of the gas stopped, additional ice water was added. The flask was equipped with a distillation apparatus and dimethyl sulfide was removed. After the reaction was cooled to room temperature, H ₂ O (300 ml), ethyl acetate (200 ml) and tetrahydrofuran (300 ml) were added. The precipitate 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 Na ₂ SO ₄ , evaporated and combined with the precipitate to give an off white solid (37.8 g, 97%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47 (app q, J = 7.7 Hz, 1H), 7.23 (d, J = 7.9 Hz, 2H), 7.05 (d, J = 7.9 Hz, 2H), 6.86 (app dt, J = 2. 3, 8.6 Hz, 1H), 6.79 (app dt, J = 2. 4, 8.4 Hz, 1H), 6.00 (s, 1H), 5.28 (s, 2H), 5.16 (s , 2H), 4.57 (s, 2H), 2.25 (s, 3H). ESHRMS m / z 450.0512 (M + H calculated for C ₂₁ H ₁₈ BrF ₂ NO ₃ 450.0511).

Example 207

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [4- (1-hydroxy-1-methylethyl) benzyl] -6-methylpyridin-2 (1H) -one .

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [4- (1-hydroxy-1-methylethyl) benzyl] -6-methylpyridin-2 (1H) -one Manufacture

Example 153 (2.00 g, 4.18 mmol) suspended in tetrahydrofuran (20 ml) was cooled in a dry ice / acetone bath. Methyl magnesium bromide (4.32 ml, 12.96 mmol, 3.0 M in diethyl ether) was added slowly. The resulting mixture was slowly warmed to rt overnight. The mixture was then cooled in an ice bath and quenched by addition of saturated NH ₄ Cl (50 ml). H ₂ O was added and the reaction was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated. The residue was chromatographed (silica gel, hexane / ethyl acetate with 10% methanol) to yield 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 addition was complete, the ice bath was removed. After 2.5 hours at room temperature, the reaction was concentrated. Purification by chromatography (silica gel, hexane / ethyl acetate with 10% methanol) gave a white foam. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56 (app q, J = 7.7 Hz, 1H), 7.39 (d, J = 78.3 Hz, 2H), 7.11 (d, J = 8.2 Hz, 2H), 6.92 (app dt, J = 1.7, 8.4 Hz, 1H), 6.86-6.81 (m, 1H), 5.97 (s, 1H), 5.31 (s, 2H), 5.18 (s, 2H), 2.29 (s, 3H) , 1.52 (s, 6 H). ES-HRMS m / z 478.0811 (M + H calculated 47C824 for C ₂₃ H ₂₂ BrF ₂ NO ₃ ).

Example 208

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- {4-[(methylamino) methyl] benzyl} pyridin-2 (1H) -one.

Step 1. Preparation of 4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzaldehyde

Example 206 (1.30 g, 2.89 mmol) was suspended in acetonitrile (10 ml) and cooled in an ice bath. 1-hydroxy-1,3-dihydro-3,3-bis (trifluoromethyl) -1,2-benziodoxol 1-oxide (0.580 g, 1.44 mmol) is added and the reaction mixture is overnight Stir to room temperature. Diethyl ether was added and the solid collected by filtration to give a white solid (1.14 g, 88%). ¹ H NMR (400 MHz, CDCl ₃ ) δ9.96 (s, 1H), 7.80 (d, J = 8.2 Hz, 2H), 7.56 (app q, J = 7.7 Hz, 1H), 7.30 (d, J = 8.2 Hz, 2H), 6.93 (app dt, J = 1.6, 8.3 Hz, 1H), 6.87-6.82 (m, 1H), 6.02 (s, 1H), 5.41 (s, 2H), 5.20 (s, 2H) , 2.27 (s, 3 H).

Step 2. 3-Bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- {4-[(methylamino) methyl] benzyl} pyridin-2 (1H) -one.

4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzaldehyde (step 1 ) (1.53 g, 3.41 mmol) was dissolved in N, N-dimethylformamide (5.0 ml). After addition of methylamine (3.41 ml, 6.83 mmol, 2.0 M in tetrahydrofuran), NaHB (OAc) ₃ (2.17 g, 10.23 mmol in N, N-dimethylformamide (8.0 ml) and acetic acid (2.0 ml) ) Was added. The reaction was stirred at rt overnight, at which time 1 N NaOH (50 ml) was added, followed by extraction with ethyl acetate (2 × 50 ml). The organic layer was washed with brine (25 ml), dried over Na ₂ S0 ₄ and evaporated. Chromatography (silica gel, ethyl acetate / hexanes with 5% methanolic ammonia) gave a tan solid (0.810 g, 53%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.55 (app q, J = 7.8 Hz, 1H), 7.22 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 8.1 Hz, 2H), 6.92 (app dt, J = 2.4, 8.3 Hz, 1H), 6.90-6.80 (m, 1H), 5.95 (s, 1H), 5.32 (s, 2H), 5.17 (s, 2H), 3.68 (s, 2H) , 2.40 (s, 3 H), 2.27 (s, 3 H). ES-HRMS m / z 463.0838 (M + H calculated for C ₂₂ H ₂₁ BrF ₂ N ₂ O ₄ 463.0827).

Example 209

4-[(2,4-difluorobenzyl) oxy] -1- (4-methoxybenzyl) -6-methylpyridin-2- (1H) -one.

Step 1. Preparation of 1- (4-methoxybenzyl) -4-hydroxy-6-methylpyridin-2 (1H) -one

4-hydroxy-6-methyl-2-pyrone (4.60 g, 36.45 mmol) and 4-methoxy sibenzylamine (5.00 g, 36.45 mmol) in H ₂ O (100 ml) were heated to reflux. After 15 hours at reflux, the reaction was cooled to room temperature. The precipitate was collected by filtration and washed with H ₂ O to give a pale yellow solid (8.00 g, 89%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.2 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8. 7 Hz, 2H), 5.74 (d, J = 2.0 Hz, 1H ), 5.56 (d, J = 2.5 Hz, 1H), 5.08 (s, 2H), 3.68 (s, 3H), 2.14 (s, 3H).

Step 2. Preparation of 4-[(2,4-difluorobenzyl) oxy] -1- (4-methoxybenzyl) -6-methylpyridin-2 (1H) -one

1- (4-methoxybenzyl) -4-hydroxy-6-methylpyridin-2 (1H) -one (step 1) (7.97 g, 32.49 mmol) in N, N-dimethylformamide (60 ml) Dissolved. Potassium carbonate (4.94 g, 35.74 mmol) was added followed by α-bromo-2,4-difluorotoluene (4.38 ml, 34.11 mmol). The reaction was stirred at rt for 20 h, at which time the mixture was filtered through a pad of Celite®, washed with acetonitrile and the filtrate was evaporated. The residue was dissolved in H ₂ O (150 ml) and extracted with ethyl acetate (2 × 100 ml). The organic phase was washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and evaporated. Chromatography (silica gel, hexane / ethyl acetate with 10% methanol) gave an off-white solid (3.64 g, 30%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.42 (app q, J = 7.7 Hz, 1H), 7.13 (d, J = 8.5 Hz, 2H), 6.96-6.84 (m 2H), 6.85 (app d, J = 8.7 Hz, 2H), 6.01 (d, J = 2. 6 Hz, 1H), 5.82 (d, J = 2.8 Hz, 1H), 5.23 (s, 2H), 5.02 (s, 2H), 3.79 ( s, 3H), 2.25 (s, 3H). ES-HRMS m / z 372.1412 (M + H calculated for C ₂₁ H ₁₉ F ₂ NO ₃ 372.1417).

Example 210

3-bromo-4-[(2,4-diflubenzyl) oxy] -1- (4-methoxybenzyl) -6-methylpyridin-2 (1H) -one

Preparation of 3-bromo-4-[(2,4-diflubenzyl) oxy] -1- (4-methoxybenzyl) -6-methylpyridin-2 (1H) -one

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 addition was complete, the ice bath was removed. After 1 hour, the reaction was concentrated. Purification by chromatography (silica gel, hexane / ethyl acetate) gave a white solid (0.240 g, 99%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.59 (app q, J = 7.8 Hz, 1H), 7.16 (d, J = 8.7 Hz, 2H), 6.97 (app dt, J = 2.4, 8.6 Hz, 1H ), 6.91-6.83 (m, 1H), 6.85 (app d, J = 8. 7 Hz, 2H), 5.98 (s, 1H), 5.31 (s, 2H), 5.21 (s, 2H), 3.79 (s , 3H), 2.34 (s, 3H). ES-HRMS m / z 450.0491 (M + H calculated for C ₂₁ H ₁₈ BrF ₂ NO ₃ 450.0511).

Example 211

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (4-hydroxybenzyl) -6-methylpyridin-2 (1H) -one

Preparation of 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (4-hydroxybenzyl) -6-methylpyridin-2 (1H) -one

Example 210 (0.235 g, 0.522 mmol) was suspended in acetonitrile (3 ml). Cerium ammonium nitrate (1.14 g, 2.09 mmol) dissolved in H ₂ O (1 ml) was added. The reaction was stirred at rt for 1 h and then diluted with dichloromethane (25 ml). Then the reaction was washed with H ₂ O (10 ml). The aqueous phase was back extracted with dichloromethane (20 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated. The residue was washed with hot ethyl acetate to give an off white solid (0.134 g, 59%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ7.75 (app q, J = 7.9 Hz, 1H), 7.65 (s, 1H), 7.45-7.36 (m, 1H), 7.36 (d, J = 10 1 Hz, 2H), 7.27-7.20 (m, 1H), 6.49 (d, J = 10.1 Hz, 2H), 5.60 (s, 2H), 5.07 (s, 2H), 2.63 (s, 3H). ES-HRMS m / z 436.0187 (M + H calculated for C ₂₀ H ₁₆ BrF ₂ NO ₃ 436.0354).

Example 212

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1 {4-[(4-hydroxy-4-methylpiperidin-1-yl) carbonyl] benzyl} -6 Methylpyridin-2 (1H) -one.

Step 1. Preparation of 4-hydroxy-4-methylpiperidine hydrochloride

Tert-butyl-4-oxo-1-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 addition of saturated NH ₄ Cl (75 ml). Additional H ₂ O 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 Na ₂ SO ₄ , filtered and concentrated. Chromatography (silica gel, hexane / ethyl acetate) gave 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 for 1 hour at room temperature, the reaction mixture was concentrated to give a pale yellow solid (5.05 g,> 100%).

Step 2. 3-Bromo-4-[(2,4-difluorobenzyl) oxy] -1 {4-[(4-hydroxy-4-methylpiperidin-1-yl) carbonyl] benzyl } -6-Methylpyridin-2 (1H) -one

Acid (0.300 g, 0.646 mmol) was suspended in dichloromethane (6.0 ml). 3- (1-cyclohexylcarbodiimide) propyl functionalized silica gel (2.02 g, 1.29 mmol, loading = 0.64 mmol / g) after addition of 1-hydroxybenzotriazole (0.044 g, 0.323 mmol), 3- (1-morpholine) propyl functionalized silica gel (1.84 g, 1.29 mmol, loading = 0.7 mmol / g) and dichloromethane (2 ml) were added. After stirring for 15 minutes at room temperature, 4-hydroxy-4-methylpiperidine hydrochloride (0.147 g, 0.969 mmol) was added. The resulting mixture was stirred at rt overnight, at which time dimethylamine-3-functionalized silica gel (1.7 g, 2.58 mmol, loading amount = 1.5 mmol / g) was added, followed by isocyanate-3-functionalized silica gel (1.3 g). , 1.62 mmol, loading = 1.22 mmol / g) was added. The resulting mixture was stirred at rt for 3 h. Thereafter, the reaction mixture was filtered and concentrated. Chromatography (silica gel, hexane / ethyl acetate with 10% methanol) gave a white foam (0.200 g, 55%). ¹ H NMR (300 MHz, CDCl ₃ ) 57.58 (app q, J = 7.7 Hz, 1H), 7.33 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 6.96 (app t, J = 8.3 Hz, 1H), 6.87 (app dt, J = 2.0, 9.5 Hz, 1H), 6.06 (s, 1H), 5.38 (s, 2H), 5.22 (s, 2H), 4.27 ( br m, 1H), 3.41 (br m, 3H), 2.30 (s, 3H), 2.06 (s, 1H), 1.60 (br m, 4H), 1.28 (s, 3H). ES-HRMS m / z 561.1173 (M + H calculated for C ₂₇ H ₂₇ BrF ₂ N ₂ O ₄ 561.1195).

Example 213

4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxypyridin-1 (2H) -yl] methyl} -N- (2-hydrate Oxy-2-methylpropyl) benzamide.

The title compound was prepared essentially by the procedure described in Example 212 using 1-amino-2-methyl-2-propanol hydrochloride as starting material.

¹ H NMR (400 MHz, CDCl ₃ ) δ7.70 (d, J = 8.3 Hz, 2H), 7.53 (app q, J = 7.8 Hz, 1H), 7.33 (t, J = 5.8 Hz, 1H), 7.06 (d, J = 8.3 Hz, 2H), 6.95-6.90 (m, 1H), 6.86-6.81 (m, 1H), 6.04 (s, 1H), 5.30 (s, 2H), 5.19 (s, 2H), 3.40 (d, J = 5.9 Hz, 2H), 2.98 (br s, 1H), 2.24 (s, 3H), 1.21 (s, 6H). ES-HRMS m / z 535.1012 (M + H calculated for C ₂₅ H ₂₅ BrF ₂ N ₂ O ₄ 535.1039).

Example 214

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1 {4-[(4-hydroxypiperidin-1-yl) carbonyl] benzyl} -6-methylpyridine- 2 (1H) -on.

The title compound was prepared essentially by the procedure described in Example 212 using 4-hydroxypiperidine as starting material.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.55 (app q, J = 7.7 Hz, 1H), 7.30 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.3 Hz, 2H), 6.94 (app dt, J = 2.4, 8.4 Hz, 1H), 6.84 (app ddd, J = 2.6, 8.9, 10.3 Hz, 1H), 6.01 (s, 1H), 5.36 (s, 2H), 5.19 (s, 2H ), 4.12-4.07 (m, 1H), 3.96-3.90 (m, 1H), 3.60 (br s, 1H), 3.33 (br s, 1H), 3.13 (br s, 1H), 2.27 (s, 3H) , 1.91 (br s, 3 H), 1.77 (br s, 1 H), 1.57 (br s, 1 H), 1.44 (br s, 1 H). ES-HRMS m / z 547.1006 (M + H calculated for C ₂₆ H ₂₅ BrF ₂ N ₂ O ₄ 547.1039).

Example 215

4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N- (2-hydrate Oxyethyl) benzamide.

4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N- (2-hydrate Preparation of oxyethyl) benzamide

Example 205 (0.300 g, 0.646 mmol) was added to the reaction vessel (borosilicate culture tube). A stock solution of 1-hydroxybenzotriazole in N, N-dimethylformamide (3 ml, 0.11 M) is added to the reaction vessel followed by the addition of approximately 1.10 g of polymer-bonded carbodiimide resin (1.8 mmol / g). It was. Then additional N, N-dimethylformamide (2 ml) was added to the reaction vessel. The parallel reactor was then shaken orbited at approximately 200 RPM for 15 minutes at room temperature (Labline Benchtop Orbital Shaker). Thereafter, ethanolamine (0.06 ml, 0.994 mmol) was added to the reaction vessel, and the reaction apparatus was shaken by orbit overnight at room temperature. 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 orbital shaking was carried out. Continue at 200 RPM for 3 hours at room temperature. The reaction vessel was then opened and the solution phase product was separated by filtration from insoluble quenched byproducts and collected in vials. After partial evaporation, the insoluble byproduct was rinsed with additional tetrahydrofuran (2 × 10 ml) and combined with the partially reduced filtrate. The resulting filtrate was concentrated by blowing N ₂ into the vial while heating (60 ° C.) in a reaction block (KEM-Lab parallel reactor) to yield an off-white solid (0.111 g, 34%). ¹ H NMR (400 MHz, DMF-d ₆ ) δ 8.45 (t, J = 5.4 Hz, 1H), 7.94 (d, J = 8.2 Hz, 2H), 7.76 (app q, J = 7.9 Hz, 1H) , 7.33-7.27 (m, 1H), 7.27 (app d, J = 7.9 Hz, 2H), 7.20 (app dt, J = 2.4, 8.6 Hz, 1H), 6.65 (s, 1H), 5.47 (s, 2H ), 5.38 (s, 2H), 4.83 (br s, 1H), 3.64-3.60 (m, 2H), 2.47-3. 42 (m, 2 H), 2.40 (s, 3 H). ES-HRMS m / z 507.0742 (M + H calculated 507.0726 for C ₂₃ H ₂₁ BrF ₂ N ₂ O ₄ ).

Examples 216-231

Preparation of 3-bromo-4- (2,4-difluorophenoxy) -6-methyl-1- [4- (aminocarbonyl) benzyl] pyridin-2 (1H) -one compound

The compounds of Examples 216-231 were prepared by substituting the appropriate amines according to the method of Example 215. Deprotection of the protected intermediate was performed with 4N HCl in dioxane to afford the compound as a hydrochloride salt.

Example 232

4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N- (2-hydroxyethyl Benzamide.

4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N- (2-hydroxyethyl Preparation of Benzamide

Example 203 (0.300 g, 0.666 mmol) was added to the reaction vessel (borosilicate culture tube). A stock solution of 1-hydroxybenzotriazole in N, N-dimethylformamide (3 ml, 0.11 M) is added to the reaction vessel followed by the addition of approximately 1.13 g of polymer-bonded carbodiimide resin (1.8 mmol / g). It was. Then additional N, N-dimethylformamide (2 ml) was added to the reaction vessel. The parallel reactor was then shaken orbited at approximately 200 RPM for 15 minutes at room temperature (Lapline Benchtop Orbital Shaker). Thereafter, ethanolamine (0.06 ml, 0.994 mmol) was added to the reaction vessel, and the reaction apparatus was shaken by orbit overnight at room temperature. 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 orbital shaking was carried out. Continue at 200 RPM for 3 hours at room temperature. The reaction vessel was then opened and the solution phase product was separated by filtration from insoluble quenched byproducts and collected in vials. After partial evaporation, the insoluble byproduct was rinsed with additional tetrahydrofuran (2 × 10 ml) and combined with the partially reduced filtrate. The resulting filtrate was concentrated by blowing N ₂ into the vial while heating (60 ° C.) in a reaction block (KEM-Lab parallel reactor). Purification by chromatography (silica gel) gave an off-white solid (0.155 g, 47%). ¹ H NMR (400 MHz, DMF-d ₆ ) δ8.58 (t, J = 5.5 Hz, 1H), 8.10 (d, J = 8.3 Hz, 2H), 7.79 (app q, J = 7.9 Hz, 1H) , 7.47 (d, J = 8.3 Hz, 2H), 7.36-7.30 (m, 1H), 7.21 (app dt, J = 2.4, 8.5 Hz, 1H), 6.73 (s, 1H), 5.43 (s, 2H) , 3.68 (app t, J = 5.9 Hz, 2H), 3.52-3.49 (m, 2H), 2.03 (s, 3H). ES-HRMS m / z 493.0597 (M + H calculated for C ₂₂ H ₁₉ BrF ₂ N ₂ O ₄ 493.0569).

Examples 233 to 243

The compounds of Examples 233 to 243 were prepared by replacing the appropriate amine with the ethanolamine following the method of Example 232. Deprotection of the protected intermediate was performed with 4N HCl in dioxane to afford the compound as a hydrochloride salt.

Example 244

4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzamide.

Preparation of 4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzamide

Example 203 (0.500 g, 1.11 mmol) was suspended in tetrahydrofuran (5.0 ml). 2-chloro-4,6-dimethoxy-1,3,5-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 rt for 1.5 h, at which time NH ₄ OH (2.5 ml) was added. The resulting mixture was stirred at rt overnight. H ₂ O (25 ml) and tetrahydrofuran (25 ml) were 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), 1N HCl (25 ml), brine (25 ml), dried over Na ₂ SO ₄ , filtered and concentrated to a pale yellow solid (0.500 g, 100%). ) Was obtained. ¹ H NMR (400 MHz, DMF-d ₆ ) δ8.13 (s, 1H), 8.02 (d, J = 8.5 Hz, 2H), 7.70 (app q, J = 7.9 Hz, 1H), 7.40 (d, J = 8.5 Hz, 2H), 7.41-7.34 (m, 1H), 7.22 (app dt, J = 1.8, 8.5 Hz, 1H), 6.71 (s, 1H), 5.37 (s, 2H), 1.97 (s, 3H). ES-HRMS m / z 449.0281 (M + H calculated for C ₂₀ H ₁₅ BrF ₂ N ₂ O ₃ 449.0307).

Example 245

4- (benzyloxy) -3-bromo-1- [4- (morpholin-4-ylcarbonyl) phenyl] pyridin-2 (1H) -one

Preparation of 4- (benzyloxy) -3-bromo-1- [4- (morpholin-4-ylcarbonyl) phenyl] pyridin-2 (1H) -one

To the reaction vessel (borosilicate culture tube), Example 197 (0.100 g, 0.250 mmol) dissolved in N, N-dimethylformamide (2.0 ml) was added. 1-hydroxybenzotriazole (0.017 g, 0.125 mmol) was added to the reaction vessel followed by approximately 0.423 g of polymer-bound carbodiimide resin (1.8 mmol / g). Then additional N, N-dimethylformamide (2 ml) was added to the reaction vessel. The parallel reactor was then shaken orbited at approximately 200 RPM for 15 minutes at room temperature (Lapline Benchtop Orbital Shaker). Then, morpholine (0.033 g, 0.0375 mmol) dissolved in N, N-dimethylformamide (0.5 ml) was added to the reaction vessel, and the reaction apparatus was shaken by orbit overnight at room temperature. At this time the reaction was diluted with N, N-dimethylformamide (2.0 ml) and dichloromethane (4.0 ml) and approximately 0.770 g of polyamine resin (2.63 mmol / g) and approximately 1.0 g of methyl isocyanate functionalized polystyrene (1.10) mmol / g) and orbital shaking was continued at 200 RPM for 3 hours at room temperature. The reaction vessel was then opened and the solution phase product was separated by filtration from insoluble quenched byproducts and collected in vials. After partial evaporation, the insoluble byproduct was rinsed with dichloromethane (2 × 10 ml). The filtrate was evaporated by blowing N ₂ into the vial while heating (60 ° C.) in a reaction block (KEM-Lab parallel reactor) to give an off-white solid (0.092 g, 79%).

¹ H NMR (400 MHz, CDCl ₃ ) δ7.50 (d, J = 8.5 Hz, 2H), 7.48-7.33 (m, 7H), 7.27 (d, J = 7.8 Hz, 1H), 6.19 (d, J = 7.8 Hz, 1H), 5. 29 (s, 2H), 3.76-3.47 (br m, 8H). ES-HRMS m / z 469.0733 (M + H calculated 469. 0757 calculated for C ₂₃ H ₂₁ BrN ₂ O ₄ ).

Example 246

4- (benzyloxy) -3-bromo-1- [4- (piperazin-1-ylcarbonyl) phenyl] pyridin-2 (1H) -one hydrochloride

Preparation of 4- (benzyloxy) -3-bromo-1- [4- (piperazin-1-ylcarbonyl) phenyl] pyridin-2 (1H) -one hydrochloride

The title compound was prepared as Nt-butoxycarbonyl protected compound by replacing morpholine with N-tert-butyl carboxylate piperazine (0.070 g, 0.375 mmol) according to the method of Example 245. Deprotection of the Nt-butoxycarbonyl intermediate was performed with 4N HCl in dioxane to give the title compound as its hydrochloride salt (0.112 g,> 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.55 (br s, 2H), 7.78 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 8.5 Hz, 2H), 7.48-7.33 ( m, 7H), 6.57 (d, J = 7.8 Hz, 1H), 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 calculated for C ₂₃ H ₂₂ BrN ₃ O ₃ 468.0917).

Example 247

4- [4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] -N-hydroxybenzamide.

Preparation of 4- [4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] -N-hydroxybenzamide

The title compound was prepared as tetrahydropyranyl protected compound by replacing morpholine with O- (tetrahydro-2H-pyranyl-2yl) hydroxyamine (0.044 g, 0.375 mmol) according to the method of Example 245. . Deprotection of tetrahydropyranyl intermediate was performed with 4N HCl in dioxane to afford the title compound (0.056 g,> 71%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.03 (br s, 1 H), 7.83 (d, J = 8.6 Hz, 2H), 7.78 (d, J = 7.8 Hz, 1H), 7.48-7.35 ( m, 7H), 6.55 (d, J = 7.8 Hz, 1H), 5.37 (s, 2H). ES-HRMS m / z 415.0278 (M + H calculated 415.0288 for C ₁₉ H ₁₅ BrN ₂ O ₄ ).

Example 248

Methyl-4-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzoate

Step 1. Preparation of 3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -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 h. 1,2-dichloroethane was evaporated and the remaining solid was washed with acetonitrile to give a tan solid (4.97 g, 88%).

Step 2. of methyl-4-([3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzoate Produce

3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one (step 1) suspended in tetrahydrofuran (50 ml) (4.97 g, 17.40 mmol) 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 ice bath was removed and the mixture was heated to 50 ° C. for 19 hours. After cooling to room temperature, saturated NH ₄ Cl (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 Na ₂ SO ₄ , 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%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ7.90 (d, J = 8.5 Hz, 2H), 7.63 (app q, J = 7.9 Hz, 1H), 7.31 (app dt, J = 2.4, 9.9 Hz , 1H), 7.21 (d, J = 8.3 Hz, 2H), 7.17-7.13 (m, 1H), 6.60 (s, 1H), 5.36 (s, 2H), 5.27 (s, 2H), 3.81 ( s, 3H), 2.27 (s, 3H). ES-HRMS m / z 434.0931 (M + H calculated for C ₂₂ H ₁₈ BrF ₂ NO ₄ 434.0965).

Example 249

3-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N-methylbenzamide

Example 169 (0.300 g, 0.646 mmol) was added to the reaction vessel (borosilicate culture tube). A stock solution of 1-hydroxybenzotriazole in N, N-dimethylformamide (3 ml, 0.11 M) is added to the reaction vessel followed by the addition of approximately 1.10 g of polymer-bonded carbodiimide resin (1.8 mmol / g). It was. Then additional N, N-dimethylformamide (2 ml) was added to the reaction vessel. The parallel reactor was then shaken orbited at approximately 200 RPM for 15 minutes at room temperature (Lapline Benchtop Orbital Shaker). M-methylamine (0.50 ml, 0.999 mmol) was then added to the reaction vessel and the reaction apparatus was shaken orbit overnight at room temperature. 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 orbital shaking was carried out. Continue at 200 RPM for 4 hours at room temperature. The reaction vessel was then opened and the solution phase product was separated by filtration from insoluble quenched byproducts and collected in vials. After partial evaporation, the insoluble byproduct was rinsed with additional tetrahydrofuran (2 × 10 ml). The filtrate was evaporated by blowing N ₂ into the vial while heating (60 ° C.) in a reaction block (KEM-Lab parallel reactor). Chromatography (C-18, acetonitrile / H ₂ O with 0.1% trifluoroacetic acid) gave a white solid (0.178 g, 58%). ¹ H NMR (400 MHz, DMF-d ₆ ) δ7.65-7.53 (m, 3H), 7.37-7.28 (m, 2H), 6.97-6.82 (m, 2H), 6.00 (s, 1H), 5.36 ( s, 2H), 5.19 (s, 3H), 2.96 (t, J = 4. 83 Hz, 3H), 2.29 (s, 3H). ES-HRMS m / z 477.0635 (M + H calculated 477.0620 for C ₂₂ H ₁₉ BrF ₂ N ₂ O ₃ ).

Preparation of Examples 250-261

The compounds of Examples 250-261 were prepared by replacing N-methylamine with the appropriate amine according to the method of Example 249. Deprotection of the protected intermediate was performed with 4N HCl in dioxane to afford the compound as a hydrochloride salt.

Example 262

N- (3-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzyl) -2 -Methoxyacetamide

To the reaction vessel (borosilicate culture tube) methoxyacetic acid (0.09 g, 1.00 mmol) was added. Approximately 0.97 g of polymer was added to the reaction vessel after a stock solution of 1-hydroxybenzotriazole (3 ml, 0.16 M) and N-methylmorpholine in N, N-dimethylformamide (3 ml, 0.16 M) was added to the reaction vessel. Binding carbodiimide resin (1.38 mmol / g) was added. Then additional N, N-dimethylformamide (3 ml) was added to the reaction vessel. The parallel reactor was then shaken orbited at approximately 200 RPM for 4 hours at room temperature (Lapline benchtop orbital shaker). 1- [3- (aminomethyl) benzyl] -3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one (Example 161) (0.30 g, 0.668 mmol) was added to the reaction vessel followed by additional N, N-dimethylformamide (5.0 ml) and the reaction apparatus was shaken orbit overnight at room temperature. 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 orbital shaking was carried out. Continue at 200 RPM for 4 hours at room temperature. The reaction vessel was then opened and the solution phase product was separated by filtration from insoluble quenched byproducts and collected in vials. After partial evaporation, the insoluble byproduct was rinsed with additional tetrahydrofuran (2 × 10 ml). The filtrate was evaporated by blowing N ₂ into the vial while heating (60 ° C.) in a reaction block (KEM-Lab parallel reactor) to give a tan solid (0.321 g, 89.4%). ¹ H NMR (400 MHz, DMF-d ₆ ) δ8.33 (br s, 1H), 7.81 (app q, J = 7.85 Hz, 1H), 7.40-7.23 (m, 5H), 7.09 (d, J = 7.25 Hz, 1H), 6.68 (s, 1H), 5.46 (s, 2H), 5.42 (s, 2H), 4.45 (d, J = 6.24 Hz, 2H), 3.93 (s, 2H), 3.39 (s, 3H), 2.44 (s, 3H). ES-HRMS m / z 521.0891 (required 521.0882 calculated for C ₂₄ H ₂₃ BrF ₂ N ₂ O ₄ ).

Preparation of Examples 263-265

The compounds of Examples 263-265 were prepared by replacing methoxyacetic acid with the appropriate acid according to the method of Example 262. Deprotection of the protected intermediate was performed with 4N HCl in dioxane to afford the compound as a hydrochloride salt.

Example 266

N- (3-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzyl) -2 Hydroxy-2-methylpropanamide

1- [3- (aminomethyl) benzyl] -3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -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 1- (3-dimethylaminopropyl) -3-ethylcarb Bodyimide hydrochloride (0.185 g, 0.963 mmol) was dissolved in N, N-dimethylacetamide (3 mL). N-methylmorpholine (0.209 g, 2.064 mmol) was added and the reaction was stirred at rt for 1 h. The reaction was diluted with H ₂ O (50 ml) and the aqueous layer was extracted with ethyl acetate (3 × 25 ml). The combined organics were washed with 1N HCl (25 ml), saturated Na ₂ CO ₃ (25 ml), brine (25 ml), dried over Na ₂ SO ₄ and concentrated to give an off-white solid (0.235 g, 64%). It was. ¹ H NMR (400 MHz, DMF-d ₆ ) δ8.25 (br s, 1H), 7.81 (app q, J = 7.92 Hz, 1H), 7.40-7.21 (m, 5H), 7.09 (d, J = 6.84 Hz, 1H), 6.67 (s, 1H), 5.46 (s, 2H), 5.42 (s, 2H), 4.42 (d, J = 6.24 Hz, 2H), 2.44 (s, 3H), 1.38 (s, 6H). ES-HRMS m / z 535.1024 (M + H calculated for C ₂₅ H ₂₅ BrF ₂ N ₂ O ₄ 535.1039).

Example 267

N- (3-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzyl) -1 Hydroxycyclopropanecarboxamide

The title compound was prepared (0.352 g, 96%) by replacing 1-hydroxyisobutyric acid with 1-hydroxy-1-cyclopropane-carboxylic acid according to the method of Example 266. ¹ H NMR (400 MHz, DMF-d ₆ ) δ8.46 (app t, J = 6.24 Hz, 1H), 7.81 (app q, J = 7.92 Hz, 1H), 7.40-7. 22 (m, 5H), 7.06 (d, J = 7.05 Hz, 1H), 6.67 (s, 1H), 5.45 (s, 2H), 5.42 (s, 2H), 4.46 (d, J = 6.44 Hz, 2H ), 2.45 (s, 3H), 1.17-1.12 (m, 2H), 0.93 (app q, J = 3.82 Hz, 2H). ES-HRMS m / z 533.0861 (M + H calculated for C ₂₅ H ₂₃ BrF ₂ N ₂ O ₄ 533.0882).

Example 267

N '-(3-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzyl)- N, N-dimethylurea

Step 1: 4-nitrophenyl 3-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} Preparation of Benzyl Carbamate

1- [3- (aminomethyl) benzyl] -3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -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 added dropwise again and stirring continued at 40 ° C. overnight. The reaction mixture was concentrated and chromatographed (silica gel, ethyl acetate / hexanes with 10% methanol) to give a yellow solid (1.11 g, 66%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.56 (app t, J = 6.10 Hz, 1H), 8.24-8.21 (m, 2H), 7.62 (app q, J = 7.88 Hz, 1H), 7.40 -7.27 (m, 7H), 6.98 (d, J = 7.52 Hz, 1H), 6.54 (s, 1H), 5.30 (s, 2H), 5.24 (s, 2H), 4.25 (d, J = 6.18 Hz, 2H), 2.30 (s, 3H). ES-HRMS m / z 614.0753 (M + H calculated for C ₂₈ H ₂₂ BrF ₂ N ₃ O ₆ 614.0733).

Step 2: N '-(3-([3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} Preparation of benzyl) -N, N-dimethylurea

In a reaction vessel (borosilicate culture tube), 4-nitrophenyl 3-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6- dissolved in dichloromethane (6.0 ml) Methyl-2-oxopyridin-1 (2H) -yl] methyl} benzylcarbamate (from step 1) (0.350 g, 0.570 mmol) was added. The parallel reactor was then shaken orbited at approximately 200 RPM for 15 minutes at room temperature (Lapline Benchtop Orbital Shaker). Then, a stock solution of N, N-dimethylamine in tetrahydrofuran (0.427 ml, 2.0 M) was added to the reaction vessel, and the reaction apparatus was shaken by orbit overnight at room temperature. The reaction mixture was concentrated and chromatographed (silica gel, ethyl acetate / hexanes with 10% methanol) to give an off white solid (0.226 g, 63.3%). ¹ H NMR (400 MHz, DMF-d ₆ ) δ 7.81 (app q, J = 7.92 Hz, 1H), 7.40-7.19 (m, 5H), 7.06 (d, J = 7.45 Hz, 1H), 6.88 ( app t, J = 5.84 Hz, 1H), 6.68 (s, 1H), 5.45 (s, 2H), 5.42 (s, 1H), 4.35 (d, J = 5.84 Hz, 1H), 2.92 (s, 6H) , 2.44 (s, 3 H). ES-HRMS m / z 520.1065 (M + H calculated 520.1042 for C ₂₄ H ₂₄ BrF ₂ N ₃ O ₃ ).

Preparation of Examples 268-270

The compounds of Examples 268-270 were prepared by replacing N, N-dimethylamine with an appropriate amine according to the method of Example 267. Deprotection of the protected intermediate was performed with 4N HCl in dioxane to afford the compound as a hydrochloride salt.

Example 271

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzoic acid

Step 1: Preparation of Methyl 3- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) benzoate

Methyl 3-aminobenzoate (75.00 g, 496.13 mmol) and 4-hydroxy-6-methyl-2-pyrone (62.57 g, 496.13 mmol) are suspended in 1,2-dichlorobenzene (150 ml) and 165 ° C. Heated for 15 minutes. The reaction was cooled to rt and extracted with 0.54MK ₂ CO ₃ (4 × 250 ml). The aqueous layer was acidified with 4N HCl (pH 2). The precipitate was collected by filtration to give a sulfur-orange solid (20.24 g, 16%). The resulting filtrate was extracted with ethyl acetate (3 × 1 L). The organic layer was washed with brine (500 ml), dried over Na ₂ SO ₄ and evaporated. The resulting solid was washed with hot H ₂ O to give a sulfur-orange solid (3.84 g, 3%). Then the two solids were combined. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.98 (dt, J = 1.31, 7.79 Hz, 1H), 7.69 (app t, J = 1.78 Hz, 1H), 7.62 (t, J = 7.78 Hz, 1H) 7.49 (ddd, J = 1.07, 1.07, 7.85 Hz, 1H), 5.89 (dd, J = 0.87, 2.48 Hz, 1H), 5.55 (app d, J = 0.94 Hz, 1H), 3.83 (s, 3H ), 1.80 (s, 3 H). ES-HRMS m / z 260.0895 (M + H calculated for C ₁₄ H ₁₃ NO ₄ 260.0917).

Step 2: Preparation of methyl 3- [4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzoate

Methyl 3- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) benzoate (from step 1) (24.00 g, 92.57 mmol) and K ₂ CO ₃ (15.35 g, 111.08 mmol ) Was dissolved in N, N-dimethylformamide (220 ml). Then difluorobenzyl bromide (20.12 g, 97.20 mmol) was added and the reaction mixture was stirred at rt for 48 h. The reaction mixture was diluted with H ₂ O (1 L) and the precipitate was collected by filtration to give a white solid (4.08 g, 11%). The resulting oil was purified by chromatography (silica gel, ethyl acetate / hexanes with 10% methanol) to yield an off-white solid (11.88 g, 33%). Two solids were combined. ¹ H NMR (400 MHz, CDCl ₃ ) δ8.11 (dt, J = 1.41, 7.79 Hz, 1H), 7.87 (app t, J = 1. 78 Hz, 1H), 7.58 (app t, J = 7.69 Hz , 1H) 7.45-7.38 (m, 2H), 6.94-6.84 (m, 2H), 5.97 (d, J = 2.68 Hz, 1H), 5.90 (ddd, J = 0.94, 1.74, 1.74 Hz, 1H), 5.97 (s, 1 H), 3.90 (s, 3 H), 1.89 (s, 3 H). ES-HRMS m / z 386.1179 (M + H calculated for C ₂₁ H ₁₇ F ₂ NO ₄ 386.1198).

Step 3: Preparation of methyl 3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzoate

Methyl 3- [4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzoate suspended in acetonitrile (165 ml) (step 2 ) (15.85 g, 41.130 mmol) 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. The reaction was concentrated and chromatographed (silica gel, ethyl acetate / hexanes with 10% methanol) to give an off white solid (17.63 g, 92%). ¹ H NMR (400 MHz, CDCl ₃ ) δ8.17 (dt, J = 1.41, 7.85 Hz, 1H), 7.90 (t, J = 1.81 Hz, 1H), 7.67-7.41 (m, 3H), 7.05-6.88 (m, 2H), 6.13 (s, 1H), 5.30 (s, 2H), 3.95 (s, 1H), 2.01 (s, 3H). ES-HRMS m / z 464.0286 (M + H requirement for C ₂₁ H ₁₆ BrF ₂ NO ₄ 464.0304).

Step 4: Preparation of the title compound.

Methyl 3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzoate (step 3) (10.0 g , 21.539 mmol) was dissolved in methanol (36 ml) and tetrahydrofuran (14 ml). 4 N NaOH (13.5 ml, 53.847 mmol) was added. The resulting mixture was stirred at rt for 1.5 h. The reaction was acidified with 4N HCl (pH 2). The precipitate was collected by filtration to give an off white solid (7.83 g, 81%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.01 (dt, J = 1.41, 7.65 Hz, 1H), 7.76 (app t, J = 1.78 Hz, 1H), 7.76-7.15 (m, 5H), 6.66 (s, 1 H), 5.32 (s, 2 H), 1.92 (s, 3 H). ES-HRMS m / z 450.0134 (M + H requirement for C ₂₀ H ₁₄ BrF ₂ NO ₄ 450.0147).

Example 272

Ethyl 3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzoate

The title compound was prepared (2.66 g, 79%) by replacing methyl 3-aminobenzoate with ethyl 3-aminobenzoate following the method of Example 271. ¹ H NMR (400 MHz, CDCl ₃ ) δ8.13 (dt, J = 1.41, 7.85 Hz, 1H), 7.84 (t, J = 1.88 Hz, 1H), 7.62-7.55 (m, 2H), 7.36 (app dq, J = 1.07, 7.85 Hz, 1H), 6.96 (app dt, J = 2.55, 8.35 Hz, 1H), 6.88-6.84 (m, 1H), 6.08 (s, 1H), 5.25 (s, 2H), 4.42-4.30 (m, 2H), 1.96 (s, 3H), 1.36 (t, J = 7.12 Hz, 3H). ES-HRMS m / z 478.0482 (M + H requirement for C ₂₂ H ₁₈ BrF ₂ NO ₄ 478.0460).

Example 273

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N-methylbenzamide

Example 271 (0.300 g, 0.666 mmol) was added to the reaction vessel (borosilicate culture tube). A stock solution of 1-hydroxybenzotriazole in N, N-dimethylformamide (3 ml, 0.11 M) is added to the reaction vessel followed by the addition of approximately 0.97 g of polymer-bonded carbodiimide resin (1.8 mmol / g). It was. Then additional N, N-dimethylformamide (2 ml) was added to the reaction vessel. The parallel reactor was then shaken orbited at approximately 200 RPM for 15 minutes at room temperature (Lapline Benchtop Orbital Shaker). Thereafter, N-methylamine (0.50 ml, 0.999 mmol) in tetrahydrofuran was added to the reaction vessel, and the reaction apparatus was shaken by orbit overnight at room temperature. 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 orbital shaking was carried out. Continue at 200 RPM for 4 hours at room temperature. The reaction vessel was then opened and the solution phase product was separated by filtration from insoluble quenched byproducts and collected in vials. After partial evaporation, the insoluble byproduct was rinsed with tetrahydrofuran (2 × 10 ml). The filtrate was evaporated by blowing N ₂ into the vial while heating (60 ° C.) in a reaction block (KEM-Lab parallel reactor) to give an off-white solid (0.189 g, 61%). ¹ H NMR (400 MHz, DMF-d ₆ ) δ8.56 (br d, J = 4.16 Hz, 1H), 8.05-7.76 (m, 3H), 7.66 (t, J = 7.79 Hz, 1H), 7.56- 7.19 (m, 3H), 6.74 (s, 1H), 5.43 (s, 2H), 3.46 (s, 3H), 2.03 (s, 3H). ES-HRMS m / z 463.0476 (M + H requirement for C ₂₁ H ₁₇ BrF ₂ N ₂ O ₃ 463.0463).

Preparation of Examples 274 to 289

The compounds of Examples 274-289 were prepared by replacing N-methylamine with the appropriate amine according to the method of Example 273. Deprotection of the protected intermediate was performed with 4N HCl in dioxane to afford the compound as a hydrochloride salt.

Example 290

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzamide

Example 271 (2.00 g, 4.44 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-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 at rt for 1.5 h. NH ₄ OH (10 ml, 148.00 mmol) was added and the reaction stirred at rt for 0.5 h. H ₂ O (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 Na ₂ CO ₃ (50 ml), 1N HCl (50 ml) and brine (50 ml). The organic phase was dried over Na ₂ SO ₄ and evaporated. The resulting solid was washed with diethyl ether to give a white solid (1.86 g, 93%). ¹ H NMR (400 MHz, DMF-d ₆ ) δ8.20 (br s, 1H), 8.10-8. 07 (m, 1H), 7.79 (s, 1H), 7.79 (app q, J = 7.83 Hz, 1H), 7.66 (app t, J = 7.79 Hz, 1H), 7.57-7.54 (m, 1H), 7.46 (br s, 1H), 7.36-7.19 (m, 2H), 6.74 (s, 1H), 5.43 (s, 2H), 2.04 (s, 3H). ES-HRMS m / z 449.0307 (M + H requirement for C ₂₀ H ₁₅ BrF ₂ N ₂ O ₃ 449.0307).

Example 291

3- [3-Chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzoic acid

Step 1: Preparation of Methyl 3- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzoate

The product from Example 271, step 2 (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 at 40 ° C. overnight. The reaction was cooled to room temperature and a precipitate formed. The precipitate was collected by filtration and washed with dichloromethane (3 × 10 ml) to give a white solid (1.75 g, 35%). The filtrate was concentrated and chromatographed (silica gel, ethyl acetate / hexanes with 10% methanol) to yield an off-white solid (1.29 g, 26%). Then the two solids were combined. ¹ H NMR (400 MHz, CDCl ₃ ) δ8.12 (dt, J = 1.38, 7.83 Hz, 1H), 7.85 (t, J = 1.74 Hz, 1H), 7.60-7.52 (m, 2H), 7.37 (dq, J = 0.92, 7.92 Hz, 2H), 6.95 (app dt, J 2. 55,8.32 Hz, 1H), 6.89-6.83 (m, 1H), 6.11 (s, 1H), 5. 24 (s, 2H), 3.90 (s, 3H), 1.96 (s, 3H). ES-HRMS m / z 420.0783 (M + H requirement for C ₂₁ H ₁₆ ClF ₂ NO ₄ 420.0809).

Step 2: Methyl 3- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzoate (from step 1) (2.90 g, 6.91 mmol) was dissolved in methanol (5 ml) and tetrahydrofuran (12 ml). 4 N NaOH (4.3 ml, 17.27 mmol) was added. The resulting mixture was stirred at rt for 1.5 h. The reaction was acidified with 4 N HCl (pH 2). The precipitate was collected by filtration to give an off white solid (2.36 g, 84%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.01 (dt, J = 1.41, 7.65 Hz, 1H), 7.76 (app t, J = 1.68 Hz, 1H), 7.69-7.53 (m, 3H ), 7.36-7.14 (m, 2H), 6.69 (s, 1H), 5.32 (s, 2H), 1.93 (s, 3H). ES-HRMS m / z 406.0662 (M + H requirement for C ₂₀ H ₁₄ ClF ₂ NO ₄ 406.0652).

Example 292

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [3- (hydroxymethyl) phenyl] -6-methylpyridin-2 (1H) -one

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 was heated to 40 ° C. for 9 hours. The reaction was cooled to room temperature to form a precipitate. The precipitate was collected by filtration and washed with dichloromethane (3 × 10 ml) to yield an off white solid (0.286 g, 47%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ7.38 (app q, J = 7.35 Hz, 1H), 7.30-7.24 (m, 2H), 7.00 (br s, 1H), 6.85 (app dt, J = 2.37, 6.24 Hz, 1H), 6.82-6.67 (m, 2H), 6.01 (s, 1H), 5.07 (s, 2H), 4.48 (d, J = 5.24 Hz, 2H), 1.81 (app d, J = 0. 40 Hz, 3H). ES-HRMS m / z 392.0885 (M + H requirement for C ₂₀ H ₁₆ ClF ₂ NO ₃ 392.0860).

Example 293

1- [3- (aminomethyl) phenyl] -3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one

Step 1: Preparation of 1- [3- (chloromethyl) phenyl] -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one

2,4,6-trichloro- [1,3,5] -triazine (3.09 g, 16.78 mmol) was dissolved in N, N-dimethylformamide (45 mL). The reaction mixture was stirred at rt for 1 h and then dichloromethane (90 ml) was added. Then alcohol (5.72 g, 15.99 mmol) was added. The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with dichloromethane (200 ml) and the organic phase was washed with H ₂ O (200 ml), saturated Na ₂ CO ₃ (200 ml), 1 N HCl (200 ml) and brine (200 ml). The organic phase was dried over MgSO ₄ and evaporated to give an orange solid (5.95 g, 99%).

Step 2: Preparation of 1- [3- (aminomethyl) phenyl] -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one

1- [3- (chloromethyl) phenyl] -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one (1.00 g, 2.66 mmol) from step 1 Was suspended in methanol (5 ml). The suspension was then brought to -78 ° C and NH ₃ was bubbled through the reaction mixture for 10 minutes. The reaction was then slowly warmed to room temperature and stirred at room temperature for 4 days. The reaction was concentrated and the residue was dissolved in CH ₂ Cl ₂ and filtered to remove excess salt. The filtrate was concentrated to give a tan solid (0.94 g, 99%).

Step 3: Preparation of the title compound

1- [3- (aminomethyl) phenyl] -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one (3.89 g, 10.93 mmol) from step 3 Was suspended in acetonitrile (42 ml) and 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 at rt for 1.5 h. The reaction was diluted with acetonitrile (100 ml) and the precipitate formed was collected by filtration and washed with acetonitrile (3 × 30 ml) to give an off-white solid (2.74 g, 58%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ7.67-7.59 (m, 3H), 7.34-7.31 (m, 2H), 7.04 (app t, J = 8.72 Hz, 2H), 7.05-6.88 (m , 2H), 6.13 (s, 1H), 5.30 (s, 2H), 3.95 (s, 1H), 2.01 (s, 3H). ES-HRMS m / z 435.0538 (M + H requirement for C ₂₀ H ₁₇ BrF ₂ N ₂ O ₂ 435.0514).

Example 294

N-3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzyl} methanesulfonamide

To the reaction vessel (borosilicate culture tube), Example 293 (0.200 g, 0.459 mmol) and N, N-dimethylformamide (4 ml) were added. After adding a stock solution of 4-methylmorpholine in N, N-dimethylformamide (1.8 ml, 1.0 M) to the reaction vessel, the parallel reactor was shaken by orbit at approximately 200 RPM for 10 minutes at room temperature (wrap Line benchtop orbital shaker). Then, a stock solution of methanesulfonyl chloride (4.50 ml, 0.15 M) in N, N-dimethylformamide was added to the reaction vessel, and the reaction apparatus was shaken by orbit for 2 hours at room temperature. At this time the reaction was diluted with dichloromethane (4 ml), 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 orbital shaking at room temperature. Continued at 200 RPM overnight. The reaction vessel was then opened and the solution phase product was separated by filtration from insoluble quenched byproducts and collected in vials. After partial evaporation, the insoluble byproduct was rinsed with dichloromethane (2 × 10 ml). The filtrate was evaporated by blowing N ₂ into the vial while heating (60 ° C.) in a reaction block (KEM-Lab parallel reactor) to give a yellow solid (0.190 g, 81%). ¹ H NMR (400 MHz, CD ₃ OD) δ7.63 (app q, J = 7.00 Hz, 1H), 7.56-7.50 (m, 2H), 7.25 (m, 1H), 7.16 (dt, J = 1. 94, 7.25 Hz, 1H), 7.04 (app t, J = 8.59 Hz, 2H), 6.58 (s, 1H), 5.34 (s, 2H), 4.30 (s, 2H), 2.87 (s, 3H), 2.03 (s, 3 H). ES-HRMS m / z 513.0313 (M + H requirement 513.0290 for C ₂₁ H ₁₉ BrF ₂ N ₂ O ₄ S).

Preparation of Examples 295 and 296

The compounds of Examples 295 and 296 were prepared by replacing methanesulfonyl chloride with the appropriate acid chloride according to the method of Example 294.

Example 297

N-3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzyl} -2-methoxyacet amides

A stock solution of methoxyacetic acid (8.0 ml, 0.10 M) in N, N-dimethylacetamide was added after the addition of approximately 2.87 g of polymer-bound carbodiimide resin (0.96 mmol / g) to the reaction vessel (borosilicate culture tube). Was added. Stock solutions of 1-hydroxybenzotriazole (3.0 ml, 0.10 M) in N, N-dimethylacetamide and N-methylmorpholine (6.0 ml, 0.10 M) in 1,2-dichloroethane were added to the reaction vessel. . The parallel reactor was then shaken orbited at approximately 200 RPM for 4 hours at room temperature (Lapline benchtop orbital shaker). Thereafter, the stock solution of Example 293 (5.0 ml, 0.10 M) in N, N-dimethylacetamide was added to the reaction vessel, and the reaction apparatus was shaken by orbit overnight at room temperature. 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 methyl isocyanate functionalized polystyrene (1.50 mmol / g), Orbital shaking was continued at 200 RPM for 4 hours at room temperature. The reaction vessel was then opened and the solution phase product was separated by filtration from insoluble quenched byproducts and collected in vials. After partial evaporation, the insoluble byproduct was rinsed with N, N-dimethylacetamide (2 × 5 ml). The filtrate was evaporated by blowing N ₂ into the vial with heating (60 ° C.) in a reaction block (KEM-Lab parallel reactor) and chromatography (silica gel, ethyl acetate / hexanes with 10% methanol) to yield an off-white solid. (0.081 g, 28%). ¹ H NMR (400 MHz, DMF-d ₆ ) δ 7.59 (q, J = 7.65 Hz, 1H), 7.46 (app t, J = 7.55 Hz, 1H), 7.40-7.37 (m, 1H), 7.11- 7.07 (m, 2H), 7.00 (t, J = 8.56 Hz, 2H), 6.54 (s, 1H), 5.30 (s, 2H), 4.43 (s, 2H), 3. 88 (s, 2H), 3.35 (app d, J = 0.80 Hz, 2H), 1.97 (s, 3H). ES-HRMS mlz 507.0699 (M + H requirement for C ₂₃ H ₂₁ BrF ₂ N ₂ O ₄ 507.0726).

Preparation of Examples 298 to 300

The compounds of Examples 298-300 were prepared by replacing methoxyacetic acid with the appropriate acid according to the method. Deprotection of the protected intermediate was performed with 4N HCl in dioxane in methanol or 1M K ₂ CO ₃ in methanol to afford the compound as a hydrochloride salt.

Example 301

N '-{3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzyl} -N, N Dimethylurea

Step 1: 4-nitrophenyl 3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzylcarba Manufacture of mate

1- [3- (aminomethyl) phenyl] -3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -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 added dropwise again and stirring continued at room temperature overnight. The reaction mixture was concentrated and chromatographed (silica gel, ethyl acetate / hexanes with 10% methanol) to give a yellow solid (0.85 g, 57%).

Step 2: Preparation of the title compound

4-nitrophenyl 3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridine-1 (2H) in a reaction vessel (borosilicate culture tube) -Yl] benzylcarbamate (from step 1) (0.150 g, 0.250 mmol) and dichloromethane (2.5 mL) were added. The parallel reactor was then shaken orbited at approximately 200 RPM for 15 minutes at room temperature (Lapline Benchtop Orbital Shaker). Then, a stock solution of N, N-dimethylamine in tetrahydrofuran (0.15 ml, 2.0 M) was added to the reaction vessel, and the reaction apparatus was shaken by orbit overnight at room temperature. The reaction mixture was concentrated and chromatographed (silica gel, ethyl acetate / hexanes with 10% methanol) to give an off white solid (0.065 g, 51%). ¹ H NMR (400 MHz, DMF-d ₆ ) δ 7.58 (app q, J = 7.79 Hz, 1H), 7.42 (app t, J = 7.65 Hz, 1H), 7.37 (app d, J = 7.79 Hz, 1H), 7.08 (s, 1H), 7.03 (app dt, J = 1.58, 5.37 Hz, 1H), 6.96 (app dt, J = 2.55, 8.39 Hz, 1H), 6.88-6.83 (m, 1H), 6.06 (s, 1H), 5.24 (s, 2H), 4.95 (app t, J = 5.57 Hz, 1H), 4.42 (app dddd, J = 5.10, 5.71, 10.20, 15.17 Hz, 2H), 2.90 (s, 6H ), 1.96 (s, 3 H). ES-HRMS m / z 506.0848 (M + H requirement for C ₂₃ H ₂₂ BrF ₂ N ₃ O ₃ 506.0885).

Preparation of Examples 302 and 303

The compounds of Examples 302 and 303 were prepared by replacing N, N-dimethylamine with an appropriate amine following the method of Example 301.

Example 304

N- {3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzyl} urea

To the reaction vessel (borosilicate culture tube), Example 293 (0.200 g, 0.459 mmol) and tetrahydrofuran (4.0 ml) were added. After adding a stock solution of 4-methylmorpholine in tetrahydrofuran (1.8 ml, 1.0 M) to the reaction vessel, the parallel reactor was shaken orbitally at approximately 200 RPM for 10 minutes at room temperature (Lapline benchtop orbital Shaker). Then, a stock solution of trimethylsilyl isocyanate (4.0 ml, 0.2 M) in tetrahydrofuran was added to the reaction vessel, and the reaction apparatus was shaken by orbit for 2 hours at room temperature. At this time the reaction was diluted with tetrahydrofuran (4.0 ml) and the resulting precipitate was collected by filtration. The solid was then washed with tetrahydrofuran (3 × 5 ml) to give a white solid (0.214 g, 97%). ¹ H NMR (400 MHz, CD ₃ OD) δ7.72 (app q, J = 7.83 Hz, 1H), 7.55 (app t, J = 8. 06 Hz, 1H), 7.46 (d, J = 7.52 Hz, 1H), 7.25-7.14 (m, 4H), 6.65 (s, 1H), 5.65 (app t, J = 0.80 Hz, 1H), 5.40 (s, 2H), 4.38 (s, 2H), 2.05 (s, 3H). ES-HRMS m / z 478.0594 (M + H requirement for C ₂₁ H ₁₈ BrF ₂ N ₃ O ₃ 478.0572).

Example 305

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- {3-[(dimethylamino) methyl] phenyl} -6-methylpyridin-2 (1H) -one

Step 1: Preparation of 4-[(2,4-difluorobenzyl) oxy] -1- {3-[(dimethylamino) methyl] phenyl} -6-methylpyridin-2 (1H) -one

1- [3- (chloromethyl) phenyl] -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one (from step 1 of the synthesis of Example 293) (0.500 g, 1.330 mmol) was suspended in a stock solution of N, N-dimethylamine in methanol (2.0 ml, 2.0 M) and stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned between H ₂ O (25 ml) and ethyl acetate (25 ml). The aqueous layer was further extracted with ethyl acetate (2 × 30 ml) and the combined organics washed with brine (30 ml), dried over MgSO ₄ and concentrated to give an off white solid (0.508 g, 99%).

Step 2: Preparation of the title compound

4-[(2,4-difluorobenzyl) oxy] -1- {3-[(dimethylamino) methyl] phenyl} -6-methylpyridin-2 (1H) -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 formed was collected by filtration and washed with acetonitrile (3 × 15 ml) to give a yellow solid (0.160 g, 66%). Chromatography (C-18, acetonitrile / H ₂ O with 0.1% trifluoroacetic acid, followed by silica gel chromatography with ethyl acetate / hexanes containing 10% methanol) gave an off-white solid (0.024). g, 10%). ¹ H NMR (400 MHz, CD ₃ OD) δ7.68 (app q, J = 7.85 Hz, 1H), 7.58 (app t, J = 7.65 Hz, 1H), 7.50 (app d, J = 7.85 Hz, 1H ), 7.25-7.05 (m, 4H), 6.63 (s, 1H), 5.39 (s, 2H), 3.61 (app q, J = 12.08 Hz, 2H), 2.32 (s, 6H), 2.08 (s, 3H ). ES-HRMS m / z 463.0782 (M + H requirement for C ₂₂ H ₂₁ BrF ₂ N ₂ O ₂ 463.0827).

Example 306

N-4- [4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] benzyl} acetamide

In a reaction vessel (borosilicate culture tube), 1- [4- (aminomethyl) phenyl] -4- (benzyloxy) -3-bromopyridin-2 (1H) -one hydrochloride (0.150 g, 0.389 mmol) Was dissolved in N, N-dimethylformamide (3.5 ml). A stock solution of 4-methylmorpholine in N, N-dimethylformamide (1.5 ml, 1.0 M) was added and the reaction stirred at room temperature for 10 minutes. Then, a stock solution of acetyl chloride (3.0 ml, 0.2 M) in N, N-dimethylformamide was added to the reaction vessel, and the reaction apparatus was shaken by orbit for 2 hours at room temperature. At this time the reaction was diluted with dichloromethane (4 ml), 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 orbital shaking at room temperature. Continued at 200 RPM overnight. The reaction vessel was then opened and the solution phase product was separated by filtration from insoluble quenched byproducts and collected in vials. After partial evaporation, the insoluble byproduct was further rinsed with dichloromethane (3 × 5 ml) and combined with the partially concentrated filtrate. The resulting filtrate was concentrated by blowing N ₂ into the vial while heating (60 ° C.) in a reaction block (KEM-Lab parallel reactor) to give an off-white solid (0.083 g, 50%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.59 (d, J = 7.79 Hz, 1H), 7.48-7.29 (m, 9H), 6.55 (d, J = 7.79 Hz, 1H), 5.35 (s, 2H), 4.39 (s, 2H), 1.98 (s, 3H). ES-HRMS m / z 427.0625 (M + H requirement for C ₂₁ H ₁₉ BrN ₂ O ₃ 427.0652).

Example 307

N- {4- [4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] benzyl} -2-hydroxyacetamide

After adding approximately 1.95 g of polymer-bound carbodiimide resin (0.96 mmol / g) to the reaction vessel (borosilicate culture tube), the stock solution of glycolic acid (5.8 ml, 0.10 M) in N, N-dimethylacetamide was added. Added. A stock solution of 1-hydroxybenzotriazole (0.4 ml, 0.10 M) in N, N-dimethylacetamide and N-methylmorpholine (3.9 ml, 0.10 M) in 1,2-dichloroethane was added to the reaction vessel It was. The parallel reactor was then shaken orbited at approximately 200 RPM for 2 hours at room temperature (Lapline benchtop orbital shaker). Then, a stock solution of 1- [4- (aminomethyl) phenyl] -4- (benzyloxy) -3-bromopyridin-2 (1H) -one hydrochloride in N, N-dimethylacetamide (0.05 M, 7.8 ml) was added to the reaction vessel and the reaction apparatus was shaken orbit overnight at room temperature. 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), Orbital shaking was continued at 200 RPM for 4 hours at room temperature. The reaction vessel was then opened and the solution phase product was separated by filtration from insoluble quenched byproducts and collected in vials. After partial evaporation, the insoluble byproduct was rinsed with N, N-dimethylacetamide (2 × 5 ml) and combined with the partially concentrated filtrate. The filtrate was concentrated by blowing N ₂ into the vial while heating (60 ° C.) in a reaction block (KEM-Lab parallel reactor) and chromatography (silica gel, ethyl acetate / hexanes with 10% methanol) gave an off-white solid. (0.081 g, 21%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.55-7.30 (m, 10H), 6.51 (d, J = 7.85 Hz, 1H), 5.37 (s, 2H), 4.52 (s, 2H), 4.08 ( s, 2H). ESHRMS m / z 443.0605 (M + H requirement for C ₂₁ H ₁₉ BrN ₂ O ₄ 443.0601).

Example 308

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (2-morpholin-4-ylethyl) pyridin-2 (1H) -one

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -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) was suspended in acetonitrile (4 ml). The reaction was stirred at 60 ° C. overnight. H ₂ O (25 ml) was added and the resulting precipitate was collected by filtration. The solid was chromatographed (silica gel, ethyl acetate with 10% methanol) to yield an off-white solid (0.040 g, 30%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.55 (app q, J = 7.92 Hz, 1H), 6.93 (app t, J = 8.39 Hz, 1H), 6.84 (app t, J = 9.40 Hz, 1H), 5.95 (s, 1H), 5.18 (s, 2H), 4.16 (app t, J = 6.78 Hz, 2H), 3.68 (s, 4H), 2.65 (app t, J = 6.38 Hz, 2H), 2.54 (s, 4 H), 2.43 (s, 3 H). ES-HRMS m / z 443.0743 (M + H requirement for C ₁₉ H ₂₁ BrF ₂ N ₂ O ₃ 443.0776).

Example 309

Ethyl 3- [4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] propanoate

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one (0.50 g, 1.78 mmol) and cesium fluoride (0.0027 g, 0.178 mmol) Was suspended in tetrahydrofuran (10 ml) and then tetraethylortho silicate (0.37 g, 1.78 mmol) was added dropwise at room temperature. After stirring for 10 minutes at room temperature, ethyl acrylate (0.23 g, 2.32 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 was chromatographed (silica gel, ethyl acetate / hexanes with 10% methanol) to give a white solid (0.62 g, 92%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42 (d, J = 7.79 Hz, 1H), 7.41-7.29 (m, 5H), 6.03 (d, J = 7.65 Hz, 1H), 5.20 (s, 2H ), 4.17 (t, J = 5.98 Hz, 2H), 4.07 (q, J = 7.16 Hz, 2H), 2.83 (t, J = 5. 98 Hz, 2H), 1.19 (t, J = 7.18 Hz, 3H ). ES-HRMS m / z 380.0523 (M + H required for C ₁₇ H ₁₈ BrNO ₄ 380.0492).

Example 310

Methyl 3- [4- (benzyloxy) -3-bromo-2-oxopyridin-1 (2H) -yl] propanoate

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one (5.00 g, 17.85 mmol) and cesium fluoride (0.27 g, 1.78 mmol) Was suspended in tetrahydrofuran (50 ml) and then tetramethylortho silicate (2.70 g, 17.85 mmol) was added dropwise at room temperature. After stirring at room temperature for 10 minutes, 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 was chromatographed (silica gel, ethyl acetate / hexanes with 10% methanol) to give a white solid (6.10 g, 93%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42 (d, J = 7.65 Hz, 1H), 7.41-7.29 (m, 5H), 6.04 (d, J = 7.65 Hz, 1H), 5.20 (s, 2H ), 4.17 (t, J = 5.91 Hz, 2H), 3.63 (s, 3H), 2.85 (t, J = 5.91 Hz, 2H). ES-HRMS m / z 366.0350 (M + H requirement for C ₁₆ H ₁₆ BrNO ₄ 366.0335).

Example 311

N- [3-bromo-1- (3-fluorobenzyl) -2-oxo-1,2-dihydropyridin-4-yl] -2,6-difluorobenzamide

Step 1: Preparation of 3,4-dibromo-1- (3-fluorobenzyl) pyridin-2 (1H) -one

3-bromo-1- (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 N, N-dimethylacetamide (26 ml). Then, the reaction mixture was heated at reflux for 16 hours. The reaction was concentrated and the resulting residue was partitioned between water (50 ml) and ethyl acetate (3 × 50 ml). The combined organics were washed with H ₂ O (2 × 30 ml), brine (50 ml), dried over MgSO ₄ , concentrated and chromatographed (silica gel, ethyl acetate / hexanes with 10% methanol) to give a brown solid Obtained (0.850 g, 51%).

Step 2: Preparation of 4-azido-3-bromo-1- (3-fluorobenzyl) pyridin-2 (1H) -one

Sodium azide (1.08 g, 16.62 mmol) is suspended in N, N-dimethylformamide (10 ml) and 3,4-dibromo-1 in N, N-dimethylformamide (33.0 ml, 0.33 M) -(3-fluorobenzyl) pyridin-2 (1H) -one (from step 1) 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 × 50 ml). The combined organics were washed with H ₂ O (3 × 50 ml), brine (2 × 25 ml), dried over MgSO ₄ , concentrated and chromatographed (silica gel, ethyl acetate / hexanes with 10% methanol) An off-white solid was obtained (3.50 g, 98%).

Step 3: Preparation of 4-amino-3-bromo-1- (3-fluorobenzyl) pyridin-2 (1H) -one hydrochloride

4-azido-3-bromo-1- (3-fluorobenzyl) pyridin-2 (1H) -one (from step 2) (4.00 g, 12.38 mmol) is suspended in ethyl acetate (300 ml) And Fe (2.07 g, 37.14 mmol) was added. A stock solution of NH ₄ Cl in H ₂ O (300 ml, 0.2 M) was added and the reaction mixture was stirred at rt for 36 h. The reaction was filtered through a pad of Celite (R) and concentrated. The resulting solid was dissolved in ethyl acetate (150 ml), washed with water (3 × 50 ml), brine (50 ml), dried over MgSO ₄ and concentrated. ¹ H NMR (400 MHz, CD ₃ OD) δ7.38-7.29 (m, 2H), 7.05 (d, J = 7.79 Hz, 1H), 6.99 (d, J = 8.99 Hz, 2H), 6.03 (d, J = 7.39 Hz 1H), 5.09 (s, 2H). ES-HRMS m / z 297.0023 (M + H requirement for C ₂₀ H ₁₇ BrF ₂ N ₂ O ₂ 297.0033).

Step 4: Preparation of the title compound

4-amino-3-bromo-1- (3-fluorobenzyl) pyridin-2 (1H) -one (from step 3) (0.30 g, 1.01 mmol) and 4-dimethylaminopyridine (0.002 g, 0.01 mmol ) Was suspended in acetonitrile (5 ml) and then triethylamine (0.2 ml, 1.41 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 10 minutes before cooling 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 rt and 1N NaOH (10 ml) was added. The reaction was then stirred at rt for 45 min. The reaction mixture is extracted with ethyl acetate (3 × 25 ml) and the organic layer is washed with 1 N NaOH (2 × 25 ml), H ₂ O (to pH neutral), brine (50 ml), dried over MgSO ₄ and , Concentrated and chromatographed (C-18, acetonitrile / H ₂ O with 0.1% trifluoroacetic acid) to give a white solid (0.19 g, 43%). ¹ H NMR (400 MHz, CDCl ₃ ) δ8.42 (br s, 1H), 7.67 (d, J = 7.65 Hz, 1H), 7.49 (app tt, J = 6.31, 8.60 Hz, 1H), 7.33-28 (m, 2H), 7.10-6.97 (m, 5H), 5.17 (s, 2H). ES-HRMS m / z 437.0083 (M + H requirement for C ₁₉ H ₁₂ BrF ₃ N ₂ O ₂ 437.0107).

Example 312

3-bromo-1- (4-bromo-2,6-difluorophenyl) -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one

Step 1: Preparation of 1- (4-bromo-2,6-difluorophenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one

4-hydroxy-6-methyl-2-pyrone (30.0 g, 238 mmol) and 4-bromo-2,6-difluoroaniline (49.5 g, 238 mmol) were added to the J-Chem thermostat probe, Dean- It was suspended in 50 ml of 1,2-dichlorobenzene in a 250 ml three neck round bottom flask equipped with a stark trap and a heating mantle. The reaction was heated to 165 ° C. for 15 minutes, at which time water and some 1,2-dichlorobenzene were collected in a Dean-Stark trap. The reaction was cooled 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 off, washed three times with toluene and three times with hot water to remove excess pyron and dried under vacuum to give a tan solid (22.1 g, 29%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11. 00 (br s, 1H), 7.71 (d, J = 6.98 Hz, 2H), 5.97 (t, J = 0.88 Hz, 1H), 5.55 (d, J = 2.28 Hz, 1H), 1.91 (s, 3H) . LC / MS, t _r = 1.96 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.). ES-MS m / z 316 (M + H). ES-HRMS m / z 315.9779 (M + H calculated for C ₁₂ H ₈ BrF ₂ NO ₂ 315.9779).

Step 2: Preparation of 1- (4-bromo-2,6-difluorophenyl) -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one

1- (4-Bromo-2,6-difluorophenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one (from step 1) (5.0 g, 15.8 mmol) was diluted with dimethyl at room temperature. Stir vigorously with 2,4-difluorobenzyl bromide (2.23 ml, 17.4 mmol) and K ₂ CO ₃ (3.27 g, 23.7 mmol) in 50 ml of formamide. After stirring overnight, the reaction was poured quickly into 900 ml of cooling water. The resulting precipitate was filtered off and washed with water and hexanes. The product was purified using a Biotage silica chromatography system using 20% ethyl acetate / hexanes to give a beige solid (4.32 g, 62%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41 (app q, J = 6.31 Hz, 1H), 7.25 (dd, J = 8.33, 1.74 Hz, 2H), 6.91 (dt, J = 9.2, 0.8 Hz, 1H), 6.86 (dt, J = 9.2, 0.8 Hz, 1H), 5. 95 (d, J = 2. 56 Hz, 1H), 5.92 (dd, J = 2.56, 0.94 Hz, 1H), 5.01 (s , 2H), 1.98 (s, 3H). LC / MS, t _r = 3.04 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.). ES-MS m / z 442 (M + H). ES-HRMS m / z 442.0057 (M + H calculated for C ₁₉ H ₁₂ BrF ₄ NO ₂ 442.0060).

Step 3: Preparation of the title compound

1- (4-Bromo-2,6-difluorophenyl) -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one (from step 2) (500 mg, 1.13 mmol) was stirred with N-bromosuccinimide (221 mg, 1.24 mmol) in 5 ml of CH ₂ Cl ₂ at room temperature for 1.5 hours. The reaction was evaporated on a rotary evaporator and the resulting solid was washed four times with acetonitrile and dried under vacuum to give a white solid (478 mg, 92%). ¹ H NMR (400 MHz, CDCl ₃ ) δ7.62 (app q, J = 6.64 Hz, 1H), 7.31 (d, J = 6.85 Hz, 2H), 7.01 (app t, J = 8.36 Hz, 1H), 6.96 (dt, J = 9.46, 2.21 Hz, 1 H), 6.19 (s, 1 H), 5.30 (s, 2 H), 2.10 (s, 3 H); LC / MS, t _r = 3.17 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.). ES-MS m / z 520 (M + H). ES-HRMS m / z 521.9134 (M + H calculated 521.9146 calculated for C ₁₉ H ₁₁ Br ₂ F ₄ NO ₂ ).

Example 313

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (2,4,6-trifluorophenyl) pyridin-2 (1H) -one

The title compound was prepared essentially as described in Example 313 using 2,4,6-trifluoroaniline in place of 4-bromo-2,6-difluoroaniline. ¹ H NMR (300 MHz, CDCl ₃ ) δ7.62 (app q, J = 7.79 Hz, 1H), 7.01 (app dt, J = 8.26, 2.01 Hz, 1H), 6.95-6.85 (m, 3H) , 6.19 (s, 1 H), 5.30 (s, 2 H), 2.11 (s, 3 H); LC / MS, t _r = 2.81 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.). ES-MS m / z 460 (M + H). ES-HRMS m / z 459.9954 (M + H calculated for C ₁₉ H ₁₁ BrF ₅ NO ₂ 459.9966).

Example 314

3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (2,4,6-trifluorophenyl) pyridin-2 (1H) -one

4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (2,4,6-trifluorophenyl) pyridin-2 (1H) -one (350 mg, 0.92 mmol) Reflux overnight with N-chlorosuccinimide (147 mg, 1.1 mmol) and dichloroacetic acid (0.038 ml, 0.46 mmol) in 5 ml of CH ₂ Cl ₂ . The reaction was evaporated on a rotary evaporator and the resulting solid washed four times with acetonitrile and dried under vacuum to give a white solid (217 mg, 57%). ¹ H NMR (300 MHz, CDCl ₃ ) δ7.60 (app q, J = 7.75 Hz, 1H), 7.00 (app dt, J = 8.23, 2.05 Hz, 1H), 6.93-6.86 (m, 3H), 6.22 (s, 1 H), 5.30 (s, 2 H), 2.12 (s, 3 H); LC / MS, t _r = 2.78 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 416 (M + H). ES-HRMS m / z 416.0472 (M + H calculated 416.0471 for C ₁₉ H ₁₁ ClF ₅ NO ₂ ).

Example 315

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6- (hydroxymethyl) -1- (2,4,6-trifluorophenyl) pyridine-2 (1H)- On

Step 1: 4-[(2,4-difluorobenzyl) oxy] -6- (hydroxymethyl) -1- (2,4,6-trifluorophenyl) pyridin-2 (1H) -one Produce

4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (2,4,6-trifluorophenyl) pyridin-2 (1H) -one (9.0 g, 23.6 mmol) Heated to 135 ° C. overnight with SeO ₂ (13.1 g, 118 mmol) in 75 ml of 1,4-dioxane in a 350 ml sealed glass pressurized vessel. The reaction mixture was cooled down, placed in a plug of silica gel and washed with 5% methanol in CH ₂ Cl ₂ . The filtrate was evaporated and the resulting solid was washed with diethyl ether and dissolved in hot ethyl acetate. The insoluble Se salt was filtered off and the organic layer was evaporated. 7.01 g (17.6 mmol) of aldehyde to desired alcohol in a 3: 1 ratio were isolated. The mixture was stirred with NaBH ₄ (802 mg, 21.2 mmol) in 30 ml of methanol at room temperature for 1 hour. The reaction was evaporated and the bulk of the solid was dissolved using CH ₂ Cl ₂ and acetonitrile. Residual insoluble solids were filtered off. The organic layer was washed three times with NH ₄ Cl, dried over MgSO ₄ and evaporated. The resulting solid was washed three times with diethyl ether and dried under vacuum to give a pale orange solid (4.35 g, 46%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ7.68 (app q, J = 7.92 Hz, 1H), 7.47 (app t, J = 8.57 Hz, 2H), 7.35 (dt, J = 9.87, 2.42 Hz , 1H), 7.18 (dt, J = 8.31, 1.71 Hz, 1H), 6.21 (d, J = 2.42 Hz, 1H), 6.07 (d, J = 2.62 Hz, 1H), 5.67 (br s, 1H), 5.18 (s, 2 H), 3.98 (s, 2 H); LC / MS, t _r = 2.31 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 398 (M + H).

Step 2: Preparation of the title compound

4-[(2,4-difluorobenzyl) oxy] -6- (hydroxymethyl) -1- (2,4,6-trifluorophenyl) pyridin-2 (1H) -one (from step 1 ) (2.1 g, 5.28 mmol) was stirred with N-bromosuccinimide (1.13 g, 6.34 mmol) in 5 ml of CH ₂ Cl ₂ at room temperature for 2 hours. The reaction was evaporated on a rotary evaporator and the resulting solid was washed four times with acetonitrile and dried under vacuum to give a white solid (1.35 g, 54%). ¹ H NMR (300 MHz, CD ₃ OD) δ 7.69 (app q, J = 6.65 Hz, 1H), 7.20 (app t, J = 8.36 Hz, 2H), 7.09 (app t, J = 8.46 Hz, 2H ), 6.88 (s, 1 H), 5.46 (s, 2 H), 4.21 (s, 2 H); LC / MS, t _r = 2.48 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 476 (M + H). ES-HRMS m / z 475.9907 (M + H calculated for C ₁₉ H ₁₁ BrF ₅ NO ₃ 475.915).

Example 316

3-chloro-4-[(2,4-difluorobenzyl) oxy] -6- (hydroxymethyl) -1- (2,4,6-trifluorophenyl) pyridin-2 (1H) -one

4-[(2,4-difluorobenzyl) oxy] -6- (hydroxymethyl) -1- (2,4,6-trifluorophenyl) pyridin-2 (1H) -one (2.1 g, 5.28 mmol) was refluxed overnight with N-chlorosuccinimide (846 mg, 6.34 mmol) and dichloroacetic acid (0.87 ml, 10.56 mmol) in 5 ml of CH ₂ Cl ₂ . The reaction was evaporated on a rotary evaporator and the resulting oil was triturated with diethyl ether to give a solid. The solid was washed four times with acetonitrile. Chromatography was performed using a Biotage silica gel system with 60% ethyl acetate / hexanes. Poor recovery from the column yielded a white solid (109 mg, 5%). ¹ H NMR (300 MHz, CD ₃ OD) δ7.67 (app q, J = 7.85 Hz, 1H), 7.24-7.06 (m, 4H), 6.90 (s, 1H), 5.45 (s, 2H), 4.22 (s, 2H); LC / MS, t _r = 2.71 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 432 (M + H). ES-HRMS m / z 432.0413 (M + H calculated for C ₁₉ H ₁₁ ClF ₅ NO ₃ 432.0420).

Example 317

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluoro-4-morpholin-4-ylphenyl) -6-methylpyridine-2 ( 1H) -on

Step 1: 4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluoro-4-morpholin-4-ylphenyl) -6-methylpyridine-2 (1H) Manufacture of

4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (2,4,6-trifluorophenyl) pyridin-2 (1H) -one (870 mg, 2.28 mmol) Heated to 100 ° C. for 36 h with K ₂ CO ₃ (630 mg, 4.56 mmol) in 5 ml of morpholine. 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 under vacuum to give a beige solid (738 mg, 72%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41 (app q, J = 7.70 Hz, 1H), 6.93-6.85 (m, 2H), 6.49 (d, J = 10.47 Hz, 2H), 5. 96 ( d, J = 2.41 Hz, 1H), 5.89 (d, J = 1.75 Hz, 1H), 5.00 (s, 2H), 3.83 (t, J = 4.83 Hz, 4H), 3.19 (t, J = 4.84 Hz, 4H), 1.99 (s, 3H); LC / MS, t _r = 3.09 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 449 (M + H). ES-HR / MS m / z 449.1485 (M + H calculated for C ₂₃ H ₂₀ F ₄ N ₂ O ₃ 449.1483).

Step 2: Preparation of the title compound

4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluoro-4-morpholin-4-ylphenyl) -6-methylpyridin-2 (1H) -one ( From step 1) (500 mg, 1.12 mmol) was stirred with N-bromosuccinimide (236 mg, 1.33 mmol) in 5 ml of CH ₂ Cl ₂ at room temperature for 2 hours. The reaction was evaporated on a rotary evaporator and the resulting oil was triturated with diethyl ether to give a solid. The solid was washed four times with acetonitrile and dried under vacuum to give a white solid (171 mg, 29%). ¹ H NMR (400 MHz, CDCl ₃ ) δ7.58 (app q, J = 7.74 Hz, 1H), 6.96 (app t, J = 8.39 Hz, 1H), 6.86 (dt, J = 9.46, 2.28 Hz, 1H ), 6.50 (d, J = 10.74 Hz, 2H), 6.09 (s, 1H), 5.24 (s, 2H), 3.84 (t, J = 4.84 Hz, 4H), 3.20 (t, J = 4.83 Hz, 4H ), 2.07 (s, 3 H); LC / MS, t _r = 3.18 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 527 (M + H). ES-HRMS m / z 527.0570 (M + H calculated for C ₂₃ H ₁₉ BrF ₄ N ₂ O ₃ 527.0588).

Example 318

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [2,6-difluoro-4- (4-methylpiperazin-1-yl) phenyl] -6 -Methylpyridin-2 (1H) -one

The title compound was prepared essentially as described in Example 317 using 1-methylpiperazine instead of morpholine. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57 (app q, J = 7.79 Hz, 1H), 6.96 (dt, J = 8.19, 1.88 Hz, 1H), 6.86 (app dt, J = 9.44, 2.48 Hz , 1H), 6.52 (d, J = 10.61 Hz, 2H), 6.14 (s, 1H), 5.24 (s, 2H), 3.72 (br s, 4H), 3.51 (d, J = 11.27 Hz, 2H), 3.07 (br s, 2 H), 2.85 (d, J = 4.29 Hz, 3 H), 2.06 (s, 3 H); LC / MS, t _r = 2.50 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 540 (M + H). ES-HRMS m / z 540.0930 (M + H calculated for C ₂₄ H ₂₂ BrF ₄ N ₃ O ₂ 540. 0904).

Example 320

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [2,6-difluoro-4- (4-methylpiperazin-1-yl) phenyl] -6-methyl Pyridin-2 (1H) -one

4-[(2,4-difluorobenzyl) oxy] -1- [2,6-difluoro-4- (4-methylpiperazin-1-yl) phenyl] -6-methylpyridine-2 ( 1H) -one (1.3 g, 2.82 mmol) was stirred under reflux overnight with N-chlorosuccinimide (451 mg, 3.38 mmol) and dichloroacetic acid (0.17 ml, 1.41 mmol) in 6 ml CH ₂ Cl ₂ . 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 give a solid. The solid was washed four times with ethyl acetate and diethyl ether and dried under vacuum to give a white solid (606 mg, 43%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ7.66 (br q, J = 7.74 Hz, 1H), 7.33 (br t, J = 9.00 Hz, 1H), 7.16 (br t, J = 7.65 Hz, 1H), 6.96 (d, J = 11.81 Hz, 2H), 6.79 (s, 1H), 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, t _r = 2.45 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 496 (M + H). ES-HRMS m / z 496.1400 (M + H calculated for C ₂₄ H ₂₂ ClF ₄ N ₃ O ₂ 496.1409).

Example 321

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [4- (dimethylamino) -2,6-difluorophenyl] -6-methylpyridine-2 (1H) -On

Dimethylamine instead of morpholine was used to prepare the title compound essentially as described in Example 317. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.59 (q, J = 7.74 Hz, 1H), 6.95 (dt, J = 8.32, 1.61 Hz, 1H), 6.85 (app dt, J = 9.54, 2.41 Hz, 1H), 6.27 (d, J = 11.01 Hz, 2H), 6.08 (s, 1H), 5.23 (s, 2H), 2.98 (s, 3H), 2.07 (s, 3H); LC / MS t _r = 3.35 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 485 (M + H). ES-HRMS m / z 485.0447 (M + H calculated 485.0482 for C ₂₁ H ₁₇ BrF ₄ N ₂ O ₂ ).

Example 322

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- {2,6-difluoro-4-[(2-hydroxyethyl) (methyl) amino] phenyl}- 6-methylpyridin-2 (1H) -one

The title compound was prepared essentially as described in Example 317 using 2- (methylamino) ethanol instead of morpholine.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.58 (q, J = 7.74 Hz, 1H), 6.95 (dt, J = 8.24, 1.66 Hz, 1H), 6.85 (app dt, J = 9.49, 2.37 Hz, 1H), 6.35 (d, J = 11.01 Hz, 2H), 6.10 (s, 1H), 5.23 (s, 2H), 3.77 (t, J = 5.77 Hz, 2H), 3.45 (t, J = 5.78 Hz, 2H), 2.99 (s, 3H), 2.08 (s, 3H); LC / MS t _r = 2.96 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 515 (M + H). ES-HRMS m / z 515.0576 (M + H calculated 515.0588 for C ₂₂ H ₁₉ BrF ₄ N ₂ O ₃ ).

Example 323

3-bromo-1- (3,5-dibromo-2,6-difluoro-4-hydroxyphenyl) -4-[(2,4-difluorobenzyl) oxy] -6-methyl Pyridin-2 (1H) -one

Step 1: Preparation of 4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluoro-4-hydroxyphenyl) -6-methylpyridin-2 (1H) -one

4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (2,4,6-trifluorophenyl) pyridin-2 (1H) -one (step 2 above) (10.0 g , 26.2 mmol) was heated to 45 ° C. for 4 days with KOSiMe ₃ (10.08 g, 78.6 mmol) in 50 ml of tetrahydrofuran. The reaction was diluted with 30 ml of ethyl acetate, washed with 1N HCl and water, dried over MgSO ₄ 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 under vacuum to give a white solid (3.79 g, 38%). The filtrate was found to contain a mixture of the desired product and ortho substituted regioisomers. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42 (app q, J = 7.70 Hz, 1H), 6.95-6.83 (m, 2H), 6.34 (d, J = 9.40 Hz, 2H), 6.05 (app s , 2H), 5.06 (s, 2H), 2.01 (s, 3H); LC / MS t _r = 2.80 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 380 (M + H). ES-HRMS m / z 380.0926 (M + H calculated for C ₁₉ H ₁₃ F ₄ NO ₃ 380.0904).

Step 2: Preparation of the title compound

4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluoro-4-hydroxyphenyl) -6-methylpyridin-2 (1H) -one (from step 1) (3.73 g, 8.14 mmol) was stirred with N-bromosuccinimide (1.52 g, 8.55 mmol) in 30 ml of CH ₂ Cl ₂ overnight as a suspension at room temperature. LC-MS showed 60% starting material. The solid was filtered off, dissolved in 30 ml of CH ₂ Cl ₂ / N, N-dimethylformamide and stirred overnight with more N-bromosuccinimide (0.76 g, 4.28 mmol). LC-MS showed the tribromination product as the main product. The reaction was poured into water and extracted with n-butanol. The combined organic layers were evaporated on a rotary evaporator and the resulting solid was washed with diethyl ether and dried under vacuum to give a white solid (873 mg, 17%). ¹ H NMR (400 MHz, CDCl ₃ ) δ7.67 (app q, J = 7.80 Hz, 1H), 7.32 (dt, J = 4.86, 2.11 Hz, 1H), 7.16 (dt, J = 8.48, 1.84 Hz, 1H), 6.79 (s, 1H), 5.35 (s, 2H), 2.08 (s, 3H); LC / MS t _r = 3.26 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 616 (M + H). ES-HRMS m / z 615.8234 (M + H calculated 615.8200 for C ₁₉ H ₁₀ Br ₃ F ₄ NO ₃ ).

Example 324

2- {4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3,5-difluoro Lofenoxy} acetamide

Step 1: 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluoro-4-hydroxyphenyl) -6-methylpyridine-2 (1H ) -On Preparation

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (2,4,6-trifluorophenyl) pyridin-2 (1H) -one (above) (7.5 g, 16.3 mmol) was heated to 45 ° C. for 48 h with KOSiMe ₃ (10.08 g, 78.6 mmol) in 50 ml of tetrahydrofuran. The reaction was diluted with 30 ml of ethyl acetate, washed with 1N HCl and water, dried over MgSO ₄ and evaporated to give a black oil. The oil was dissolved in ethyl acetate. The precipitate formed upon standing was filtered off, washed with ethyl acetate and dried under vacuum to give a white solid (2.80 g, 37%). The filtrate showed the presence of the desired product and the ortho substituted regioisomer. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ7.66 (q, J = 7.92 Hz, 1H), 7.32 (dt, J = 8.77, 2.19 Hz, 1H), 7.15 (m, 1H), 6.73 (s , 1H), 6.67 (d, J = 9.66 Hz, 2H), 5.33 (s, 2H), 2.03 (s, 3H); LC / MS t _r = 2.92 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 458 (M + H). ES-HRMS m / z 457.9995 (M + H calculated for C ₁₉ H ₁₂ BrF ₄ NO ₃ 458.0009).

Step 2: Preparation of the title compound

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluoro-4-hydroxyphenyl) -6-methylpyridin-2 (1H) -one (From step 1) (500 mg, 1.09 mmol) was added 2-bromoacetamide (196 mg, 1.43 mmol) and K ₂ CO ₃ (282 mg, 2.05 mmol) in 5 ml of N, N-dimethylformamide at room temperature. Stir vigorously for 24 hours with. The reaction was poured quickly into cold water and the resulting solid was filtered off, washed with water, acetonitrile and diethyl ether and dried under vacuum to give a white solid (289 mg, 51%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ7.66 (q, J = 7.92 Hz, 1H), 7.61 (br s, 1H), 7.45 (br s, 1H), 7.33 (dt, J = 10.07, 2.15 Hz, 1H), 7.16 (dt, J = 8.53, 1.88 Hz, 1H), 6.99 (d, J = 9.54 Hz, 2H), 6.76 (s, 1H), 5.34 (s, 2H), 2.03 ( s, 3H); LC / MS t _r = 2.70 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 515 (M + H). ES-HRMS m / z 515.0245 (M + H calculated 515.0224 calculated for C ₂₁ H ₁₅ BrF ₄ N ₂ O ₄ ).

Example 325

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [2,6-difluoro-4- (2hydroxyethoxy) phenyl] -6-methylpyridine-2 (1H) -on

The title compound was prepared by a procedure similar to the procedure described for Example 324. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ7.66 (q, J = 7.92 Hz, 1H), 7.33 (dt, J = 10.04, 2.19 Hz, 1H), 7.17 (dt, J = 8.68, 1.84 Hz , 1H), 6.99 (d, J = 9.67 Hz, 2H), 6.75 (s, 1H), 5.34 (s, 2H), 4.92 (t, J = 4.86 Hz, 1H), 4.07 (t, J = 4. 77 Hz, 2H), 3.70 (t, J = 4.83 Hz, 2H), 2.03 (s, 3H); LC / MS t _r = 2.81 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 502 (M + H). ES-HRMS m / z 502.0291 (M + H calculated 502.0272 calculated for C ₂₁ H ₁₆ BrF ₄ NO ₄ ).

Example 326

3-bromo-1- (2,6-difluorophenyl) -4-{[4-fluoro-2- (hydroxymethyl) benzyl] oxy} -6-methylpyridin-2 (1H) -one

Step 1: Preparation of 1- (2,6-difluorophenyl) -4-{[4-fluoro-2- (hydroxymethyl) benzyl] oxy} -6-methylpyridin-2 (1H) -one

Dissolve 1- (2,6-difluorophenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one (step 1) (3.0 g, 12.65 mmol) in N, N-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. 1,2-bis (hydroxymethyl) -4-fluorobenzene (2.57 g, 16.44 mmol) was added and stirred at 0 ° C. for 1 h, then warmed to rt and stirred overnight. LC-MS showed only one product as expected and was not a mixture of regioisomers. The reaction was added to water and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO ₄ and evaporated. Biotage silica column was performed using 60% ethyl acetate / hexane as eluent. The desired product containing substantial impurities was obtained. Another Biotage silica was run with 30% ethyl acetate / hexanes to give the pure product. The resulting oil was triturated with diethyl ether to give a white solid (720 mg, 15%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.51-7.39 (m, 2H), 7.26 (dd, J = 9.62, 2.51 Hz, 1H), 7.13-7.01 (m, 3H), 6.03 (d, J = 2.42 Hz, 1H), 5.96 (d, J = 2.41 Hz, 1H), 5.06 (s, 2H), 4.73 (s, 2H), 2.81 (br s, 1H), 2.02 (s, 3H); LC / MS t _r = 2.37 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 376 (M + H). ES-HR / MS m / z 376.1181 (M + H calculated for C ₂₀ H ₁₆ F ₃ NO ₃ 376.1155). Identification of regioisomers was determined from 2-D NMR experiment hmdc using H to C 2- and 3-bond coupling.

Step 2: Preparation of the title compound

1- (2,6-difluorophenyl) -4-{[4-fluoro-2- (hydroxymethyl) benzyl] oxy} -6-methylpyridin-2 (1H) -one (from step 1) (350 mg, 0.93 mmol) was stirred with N-bromosuccinimide (199 mg, 1.12 mmol) in 1.5 ml of CH ₂ Cl ₂ at room temperature for 1.5 hours. The reaction was evaporated on a rotary evaporator and the resulting solid was washed four times with acetonitrile and dried under vacuum to give a white solid (197 mg, 47%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.53-7.43 (m, 2H), 7.25 (dd, J = 9.46, 2.62 Hz, 1H), 7.11-7.03 (m, 3H), 6.25 (s, 1H) , 5.31 (s, 2H), 4.81 (s, 2H), 2.28 (br s, 1H), 2.10 (s, 3H); LC / MS t _r = 2.38 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 454 (M + H). ES-HRMS m / z 454.0247 (M + H calculated for C ₂₀ H ₁₅ BrF ₃ NO ₃ 454.0260).

Example 327

3-chloro-1- (2,6-difluorophenyl) -4-{[4-fluoro-2- (hydroxymethyl) benzyl] oxy} -6-methylpyridin-2 (1H) -one

1- (2,6-difluorophenyl) -4-{[4-fluoro-2- (hydroxymethyl) benzyl] oxy} -6-methylpyridin-2 (1H) -one (step 1 above) (275 mg, 0.73 mmol) was stirred under reflux overnight with N-chlorosuccinimide (117 mg, 0.88 mmol) and dichloroacetic acid (0.03 ml, 0.36 mmol) in 1.5 ml CH ₂ Cl ₂ . The reaction was evaporated on a rotary evaporator and the resulting solid was washed four times with ethyl acetate and diethyl ether and dried under vacuum to give a white solid (65.5 mg, 22%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.52-7.43 (m, 2H), 7.26 (dd, J = 9.38, 2.52 Hz, 1H), 7.12-7.04 (m, 3H), 6.27 (s, 1H) , 5.32 (s, 2H), 4. 82 (s, 2H), 2.29 (br s, 1H), 2.11 (s, 3H); LC / MS t _r = 2.32 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 410 (M + H). ES-HRMS m / z 410.0755 (M + H calculated 410.0765 for C ₂₀ H ₁₅ ClF ₃ NO ₃ ).

Example 328

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -2-methyl-N- (2- Morpholin-4-ylethyl) benzamide

Step 1: Preparation of Methyl 3- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -2-methylbenzoate

4-hydroxy-6-methyl-2-pyrone (72.6 g, 576 mmol) and methyl-3-amino-2-methylbenzoate (100 g, 605 mmol) were added to the J-Chem thermostat probe, Dean-Stark trap. And suspended in 75 ml of 1,2-dichlorobenzene in a 500 ml three neck round bottom flask equipped with a heating mantle. The reaction was heated to 165 ° C. for 15 minutes, at which time water and some 1,2-dichlorobenzene were collected in a Dean-Stark trap. The reaction was cooled to about 80 ° C. The flask was placed in an ice bath and about 300 ml of toluene was added and stirred. After about 10 minutes, a precipitate formed. The precipitate was filtered off, washed three times with toluene and three times with hot water to remove excess pyron and dried under vacuum to give a tan solid (44.6 g, 28% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.66 (br s, 1H), 7.80 (dd, J = 7.72, 1.28 Hz, 1H), 7.33 (dd, J = 7.78, 1.34 Hz, 1H), 5.91 (dd, J = 2.41, 0.69 Hz, 1H), 5.55 (d, J = 2.42 Hz, 1H), 3.82 (s, 3H), 2.06 (s, 3H), 1.73 (s, 3H); LC / MS t _r = 1.85 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 274 (M + H). ES-HRMS m / z 274.1078 (M + H calculated for C ₁₅ H ₁₅ NO ₄ 274.1074).

Step 2: Preparation of methyl 3- [4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -2-methylbenzoate

Methyl-3- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -2-methylbenzoate (from step 1) (42.0 g, 154 mmol) was added to N, N at room temperature. Stir vigorously with 2-difluorobenzyl bromide (19.7 ml, 154 mmol) and K ₂ CO ₃ (31.8 g, 231 mmol) in 250 ml of dimethylformamide. After stirring overnight, the reaction was poured into 1 L of cooling water. The solution was extracted three times with ethyl acetate and the organic layer was dried over MgSO ₄ and evaporated. The product was transferred to the next step as crude oil (60.4 g, 85%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.96 (dd, J = 7.85, 1.28 Hz, 1H), 7.45-7.34 (m, 2H), 7.27-7.23 (m, 1H), 6.94-6.84 (m, 2H), 5.98 (d, J = 2.68 Hz, 1H), 5.92 (dd, J = 2.69, 0.81 Hz, 1H), 5.01 (s, 2H), 3.88 (s, 3H), 2.28 (s, 3H ), 1.81 (s, 3 H); LC / MS, t _r = 2.96 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 400 (M + H). ES-HRMS m / z 400.1341 (M + H calculated for C ₂₂ H ₁₉ F ₂ NO ₄ 400.1355).

Step 3: Preparation of 3- [4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -2-methylbenzoic acid

Methyl 3- [4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -2-methylbenzoate (from step 2) (60.0 mg , 150 mmol) was stirred overnight at room temperature with 2.5 N NaOH (120 ml, 300 mmol) in 375 ml tetrahydrofuran and 75 ml water. The reaction was acidified with 1 N HCl, 350 ml of water were added, and the solution was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO ₄ , filtered and evaporated. The resulting solid was filtered, washed with ethyl acetate and dried under vacuum to give a white solid (33.8 g, 58%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (dd, J = 7.92, 1.20 Hz, 1H), 7.43 (app q, J = 7.70 Hz, 1H), 7.38 (t, J = 7.72 Hz, 1H) , 7.35 (dd, J = 7.81, 1.21 Hz, 1H), 6.92-6.84 (m, 2H), 6.17 (d, J = 2.56 Hz, 1H), 6.00 (dd, J = 2.55, 0.81 Hz, 1H), 5.05 (s, 2H), 2. 30 (s, 3H), 1.84 (s, 3H); LC / MS, t _r = 2.61 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 386 (M + H). ES-HR / MS m / z 386.1228 (M + H calculated for C ₂₁ H ₁₇ F ₂ NO ₄ 386.1198).

Step 4: Preparation of 3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -2-methylbenzoic acid

3- [4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -2-methylbenzoic acid (from step 3) (23.0 g, 59.7 mmol) was stirred with N-bromosuccinimide (12.74 g, 71.6 mmol) in 120 ml CH ₂ Cl ₂ at room temperature for 2 hours. The reaction was evaporated on a rotary evaporator and the resulting solid was stirred for one hour in acetonitrile, washed seven times with acetonitrile and dried in vacuo to give a white solid (19.14 g, 69%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.87 (dd, J = 7.52, 1.61 Hz, 1H), 7.67 (app q, J = 7.92 Hz, 1H), 7.45-7.37 (m, 2H), 7.33 (dt, J = 9.87, 2.54 Hz, 1H), 7.17 (dt, J = 8.50, 1.67 Hz, 1H), 6.71 (s, 1H), 5.32 (s, 2H), 2.08 (s, 3H), 1.86 (s, 3H); LC / MS, t _r = 2.69 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 464 (M + H). ES-HRMS m / z 464.0284 (M + H calculated for C ₂₁ H ₁₆ BrF ₂ NO ₄ 464.0304).

Step 5: Preparation of the title compound

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 CH ₂ Cl ₂ . 4- (2-aminoethyl) morpholine (170 μl, 1.29 mmol) was added followed by EDCI (247 mg, 1.29 mmol), 1-hydroxybenzotriazole (174 mg, 1.29 mmol) and triethyl in order. Amine (301 μl, 2.16 mmol) was added. The reaction was stirred at rt overnight. The reaction was quenched with NH ₄ Cl and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO ₄ and evaporated. The resulting oil was triturated with diethyl ether / hexanes to give a solid, which was dried under vacuum to give a white solid (472 mg, 76%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ7.64 (app q, J = 7.79 Hz, 1H), 7.47 (dd, J = 7.65, 1.01 Hz, 1H), 7.39 (t, J = 7.75 Hz, 1H), 7.17 (dd, J = 7.65, 0.81 Hz, 1H), 7.01 (dt, J = 8.26, 1.61 Hz, 1H), 6.91 (dt, J = 9.42, 2. 32 Hz, 1H), 6.49 (t, J = 5.04 Hz, 1H), 6.18 (s, 1H), 5.30 (s, 2H), 3.73 (t, J-4.53 Hz, 4H), 3.68-3.47 (m, 2H), 2.59 (t, J = 5.94 Hz, 2H), 2.51 (t, J = 4.33 Hz, 4H), 2.15 (s, 3H), 1.98 (s, 3H); LC / MS, t _r = 2.27 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 576 (M + H). ES-HRMS m / z 576.1313 (M + H calculated for C ₂₇ H ₂₈ BrF ₂ N ₃ O ₄ 576.1304).

Examples 329 to 337

The following compound was prepared essentially following the procedure described in Example 328.

NMR Characterization of the Compounds of Examples 329 to 337

Example 338

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [3- (hydroxymethyl) -2-methylphenyl] -6-methylpyridin-2 (1H) -one

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (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 BH ₃ .THF in tetrahydrofuran was added and stirred overnight to raise the temperature to room temperature. The reaction was cooled back to 0 ° C. and ice cubes were added to quench the reaction. The slurry was extracted three times with an ethyl acetate / tetrahydrofuran mixture. The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and evaporated to give a white solid (1.73 g, 89%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ7.67 (app q, J = 7.92 Hz, 1H), 7.46 (d, J = 7.52 Hz, 1H), 7.32 (dt, J = 10. 74, 2.42 Hz, 1H), 7.30 (t, J = 7.72 Hz, 1H), 7.17 (dt, J = 8.46, 1.88 Hz, 1H), 7.03 (d, J = 7.38 Hz, 1H), 6.68 (s, 1H), 5. 32 (s, 2H), 4.51 (s, 2H), 3. 29 (d, J = 9.40 Hz, 1H), 1. 85 (s, 3H), 1.81 (s, 3H), LC / MS, t _r = 2.64 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 450 (M + H). ES-HRMS m / z 450.0480 (M + H calculated for C ₂₁ H ₁₈ BrF ₂ NO ₃ 450.0511).

Example 339

3- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N- (2-methoxyethyl)- 2-methylbenzamide

Step 1: Preparation of 3- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -2-methylbenzoic acid

3- [4-[(2,4-Difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -2-methylbenzoic acid (step 3 above) (10.0 g, 25.9 mmol) was refluxed overnight with N-chlorosuccinimide (4.15 g, 31.1 mmol) and dichloroacetic acid (1.06 ml, 12.9 mmol) in 50 ml of CH ₂ Cl ₂ . The reaction was evaporated on a rotary evaporator and the resulting solid was stirred for 30 minutes in acetonitrile, washed four times with acetonitrile and dried in vacuo to give a white solid (8.3 g, 78%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ7.93 (dd, J = 7.15, 1.92 Hz, 1H), 7.72 (app q, J = 7.92 Hz, 1H), 7.52-7.35 (m, 3H), 7.22 (dt, J = 8.47, 2.01 Hz, 1 H), 6.80 (s, 1 H), 5.38 (s, 2 H), 2.14 (s, 3 H), 1.93 (s, 3 H); LC / MS, t _r = 2.64 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 420 (M + H). ES-HRMS m / z 420.0806 (M + H calculated for C ₂₁ H ₁₆ ClF ₂ NO ₄ 420.0809).

Step 5: Preparation of the title compound

3- [3-Chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -2-methylbenzoic acid (from step 1 above) (500 mg, 1.19 mmol) was dissolved in 5 ml of CH ₂ Cl ₂ . 2-methoxyethylamine (129 μl, 1.49 mmol) was added, followed by EDCI (286 mg, 1.49 mmol), 1-hydroxybenzotriazole (202 mg, 1.49 mmol) and triethylamine (332 μl , 2.38 mmol) was added. The reaction was stirred at rt overnight. The reaction was quenched with NH ₄ Cl and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO ₄ and evaporated. The resulting solid was dried under vacuum to give a white solid (401 mg, 71%). ¹ H NMR (400 MHz, CDCl ₃ ) 87.56 (app q, J = 7.74 Hz, 1H), 7.47 (d, J = 6.98 Hz, 1H), 7.34 (t, J = 7.72 Hz, 1H), 7.11 (d, J = 7.25 Hz, 1H), 6.95 (dt, J = 8.23, 1.66 Hz, 1H), 6.87 (dt, J = 9.51, 2.46 Hz, 1H), 6.35 (br s, 1H), 6.15 (s , 1H), 5.25 (s, 2H), 3.72-3.63 (m, 1H), 3.58-3.49 (m, 3H), 3.35 (s, 3H), 2.09 (s, 3H), 1.93 (s, 3H); LC / MS, t _r = 2.56 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 477 (M + H). ES-HRMS m / z 477.1363 (M + H calculated for C ₂₄ H ₂₃ ClF ₂ N ₂ O ₄ 477.1387).

Example 340

3- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N, 2-dimethylbenzamide

The title compound was prepared by a procedure similar to the procedure described for Example 337, wherein methylamine was used as the amine and the product was obtained in 73% yield. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.37 (app d, J = 4.64 Hz, 1H), 7.72 (app q, J = 7.92 Hz, 1H), 7.44-7.35 (m, 4H), 7.22 (dt, J = 8.54, 1.61 Hz, 1H), 6.78 (s, 1H), 5.37 (s, 2H), 2.79 (d, J = 4.43 Hz, 3H), 1.95 (s, 3H), 1.94 (s, 3 H); LC / MS, t _r = 2.46 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 433 (M + H). ES-HRMS m / z 433.1163 (M + H calculated for C ₂₂ H ₁₉ ClF ₂ N ₂ O ₃ 433.1125).

Example 341

3- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N- (2-hydroxyethyl)- 2-methylbenzamide

The title compound was prepared by a procedure similar to the procedure described for Example 337, wherein ethanolamine was used as the amine and the product was obtained in 65% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.39 (t, J = 5.51 Hz, 1H), 7.67 (app q, J = 7.88 Hz, 1H), 7.43-7.33 (m, 3H), 7.23 ( d, J = 7.25 Hz, 1H), 7.17 (dt, J = 8.39, 1.66 Hz, 1H), 6.74 (s, 1H), 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, t _r = 2.34 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 463 (M + H). ES-HRMS m / z 463.1220 (M + H calculated for C ₂₃ H ₂₁ ClF ₂ N ₂ O ₄ 463.1231).

Example 342

3- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -2-methylbenzamide

3- [3-Chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -2-methylbenzoic acid (step 1 above) ( 500 mg, 1.19 mmol) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (251 mg, 1.43 mmol) and N-methylmorpholine (392 μl, 3.57 in 5 ml of tetrahydrofuran. mmol) and at room temperature for 2 hours. 2.5 ml NH ₄ 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 NaHCO ₃ , 1N HCl and brine, dried over MgSO ₄ , filtered and evaporated. The resulting solid was dried under vacuum to give a white solid (313 mg, 63%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.87 (br s, 1 H), 7.66 (q, J = 7.83 Hz, 1 H), 7.48-7.30 (m, 3H), 7.23 (d, J = 7.52 Hz, 1H), 7.17 (t, J = 7.65 Hz, 1H), 6.73 (s, 1H), 5.32 (s, 2H), 1.94 (s, 3H), 1.88 (s, 3H); LC / MS, t _r = 2.44 min (5-95% acetonitrile / water over 5 min at 1 ml / min with 254 nm detection at 50 ° C.), ES-MS m / z 419 (M + H). ES-HRMS m / z 419.0963 (M + H calculated 419.0969 for C ₂₁ H ₁₇ ClF ₂ N ₂ O ₃ ).

Example 343

4- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] -3,5-difluorobenzotriazole

Step 1: Preparation of 4-[(2,4-difluorobenzyl) oxy] pyridine 1-oxide

250 g of Cs ₂ CO ₃ (1.1 eq) in 2.5 L of anhydrous dimethylformamide with 2,4-difluorobenzyl alcohol (100 g, 0.694 mol) and 4-nitropyridine N-oxide (98 g, 0.700 mol) Combined and heated to 80 ° C. with stirring. The reaction was subjected to ¹⁹ F-NMR (crude reaction mixture with external D ₂ O reference) and was completed after 40 hours. The mixture was filtered hot and the product crystallized on cooling. 90.21 g (55%) of the white plate was collected by filtration and washed with diethyl ether. The mother liquor was diluted with 2.5 L diethyl ether and stored overnight in a cold motive to yield 68.76 g (41%, combined yield 96%) of the second crop. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.06 (m, 2H), 7.61 (quadrant, J = 8.45 Hz, 1H), 7.30 (t, J = 10.37 Hz, lH), 7.12, ( t, J = 8.45 Hz, 1H), 7.09 (d, J = 5.06 Hz, 2H), 5.14 (s, 2H). ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ-109.43 (quintet, J = 7.78 Hz, 1F), −113.82 (quartet, J = 9.55 Hz, 1F). LC / MS, t _r = 3.90 min (0 to 95% acetonitrile / water, 0.05% trifluoroacetic acid over 1 min at 6 ml with 215 nm detection at 50 ° C.), ES-MS m / z 238 (M + H).

Step 2: Preparation of 4-[(2,4-difluorobenzyl) oxy] -pyridin-2 (1H) -one (7)

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 anhydride (25 g, 0.25 mol) and 10 ml acetic acid were combined in a 250 ml round bottom flask with overhead stirring and heated to 130 ° C. for 4 hours. The mixture was concentrated in vacuo and the solid was dissolved in 95 ml acetonitrile: 5 ml water, filtered through charcoal and poured into 600 ml ice with stirring. After the mixture was allowed to stand overnight at room temperature, 9.62 g (30%) of product was collected by filtration as a medium brown solid (suitable for next step without purification). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 7.59 (quadrant, J = 9.91 Hz, 1H), 7.29 (t, J = 10.36 Hz, 1H), 7.21 (d, J = 8.20 Hz, 1H), 7.11 (t, J = 8.48 Hz, 1H), 5.83 (m, 2H), 5.02 (s, 2H). ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ-109.57 (quintet, J = 7.66 Hz, 1F) −113.88 (quartet, J = 8.93 Hz, 1F). LC / MS, t _r = 4.29 min (0 to 95% acetonitrile / water, 0.05% trifluoroacetic acid over 1 min at 6 ml with 215 nm detection at 50 ° C.), ES-MS m / z 238 (M + H).

Step 3: Preparation of 3-chloro-4-[(2,4-difluorobenzyl) oxy] pyridin-2 (1H) -one

4-[(2,4-difluorobenzyl) oxy] -pyridin-2 (1H) -one (from step 2) (8.60 g, 36.3 mmol) was stirred in 150 ml dimethylformamide and N-chlorosuccine Treated with imide (5.4 g, 39.9 mmol). After 15 hours, the precipitate was collected by filtration (5.11 g, 52%) to give a bright white solid. The mother liquor was diluted to 500 ml with diethyl ether to give 2.47 g (25%) as a second crop. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.87 (s, 1H), 7.60 (quadrant, J = 6.34 Hz, 1H), 7.43 (d, J = 7.58 Hz, 1H), 7.31 (dt, J = 10.08, 2.21 Hz, 1H), 7.14 (dt, J = 8.65, 1.79 Hz, 1H), 6.44 (d, J = 7.49 Hz, 1H), 5.28 (s, 1H). ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ-109.58 (quintet, J = 7.75 Hz, 1F), −113.68 (quartet, J = 8.68 Hz, 1F). LC / MS, t _r = 4.47 min (0 to 95% acetonitrile / water, 0.05% trifluoroacetic acid over 1 min at 6 ml with 254 nm detection at 50 ° C.), ES-MS m / z 272,274 3: 1 (M + H).

Step 4: Preparation of the title compound

3-Chloro-4-[(2,4-difluorobenzyl) oxy] pyridin-2 (1H) -one (from step 3) (3.25 g, 11.9 mmol) was added Cs ₂ CO ₃ in 50 ml dimethylformamide. (3.93 g, 12.1 mmol) and heated to 70 ° C. while 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 three times with hot cyclohexane, dissolved in tetrahydrofuran, treated with MgSO ₄ and charcoal and filtered. The solution was evaporated to give a fine white solid (3.99 g, 82%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.12 (d, J = 7.59 Hz, 2H), 7.92 (d, J = 8.31 Hz, 1H), 7.65 (quadrant, J = 6.77, 1H), 7.34 (dt, J = 9.81, 2.71 Hz, 1H), 7.16 (dt, J = 8.59, 2.50 Hz, 1H), 6.87 (d, J = 8.01 Hz, 1H), 5.39 (s, 2H). ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ-109.17 (quintet, J = 8.97 Hz, 1F), -113.51 (quartet, J = 9.53 Hz, 1F), -116.32 (d, J = 7.69 Hz, 2F). LC / MS, t _r = 5.51 min (0 to 95% acetonitrile / water, 0.05% trifluoroacetic acid over 6 minutes at 1 ml / min with 215 nm detection at 50 ° C.), ES-MS m / z 409 (M + H). ES-HRMS m / z 409.0351 (M + H calculated for C ₁₉ H ₁₀ ClF ₄ N ₂ O ₂ 409.0361).

Example 344

1- [4- (aminomethyl) -2,6-difluorophenyl] -3-chloro-4-[(2,4-difluorobenzyl) oxy] pyridin-2 (1H) -one hydrochloride

Step 1: tert-Butyl 4- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] -3,5-difluorobenzyl Preparation of Carbamate

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 (II) chloride (0.90 g, 6.95 mmol) were combined with 40 ml methanol and 40 ml tetrahydrofuran and stirred in an ice bath. Cool to 0 ° C. Sodium borohydride (1.33 g, 35.2 mmol) was added in small portions over 10 minutes to control foaming and the reaction was stirred for 1 hour. Additional sodium borohydride (0.50 g, 13.2 mmol) was needed to complete the reaction by LC. The change in color from yellow to black was maintained on completion. The mixture was filtered through a charcoal layer deposited on anhydrous MgSO ₄ and evaporated to dryness. Excess di-t-butyl-dicarbonate and by-product t-butanol were removed by repeated heating in vacuo with water to 80 ° C. to give the product as a fine white powder (3.11 g, 87%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.89 (d, J = 8.04 Hz, 1H), 7.65 (quartet, J = 6.73 Hz, 1H), 7.55 (t, J = 6.73 Hz, lH) , 7.34, (dt, J = 10.05, 2.51 Hz, 1H), 7.16 (m, 3H), 6.77 (d, J = 8.18 Hz, 1H), 5.34 (s, 2H), 4.18 (d, J = 5.68 Hz , 2H), 1.34 (s, 9H). ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ-109.26 (quintet, J = 6.91 Hz, 1F), -113.53 (quartet, J = 7.73 Hz, 1F), -120.32 (d, J = 8.91 Hz, 2F). LC / MS, t _r = 5.90 min (0 to 95% acetonitrile / water, 0.05% trifluoroacetic acid over 1 min at 6 ml with 215 nm detection at 50 ° C.), ES-MS m / z 513 (M + H). ES-HRMS m / z 513.1164 (M + H calculated 513.1199 for C ₂₄ H ₂₂ ClF ₄ N ₂ O ₄ ).

Step 2: Preparation of the title compound

tert-butyl 4- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (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 under vacuum to give a fine white solid (1.20 g, 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.54 (m, 2H), 7.86 (d, J = 7.57 Hz, 1H), 7.65 (quadrant, J = 7.62, 1H), 7.50 (d, J = 9.25 Hz, 2H), 7.34 (dt, J = 10.50, 2.45 Hz, 1H), 7.16 (dt, J = 8.38, 2.55 Hz, 1H), 6.78 (d, J = 7.86 Hz, 1H), 5.37 (s , 2H), 4.10 (br s, 2H), 4.97-3.14 (v br s, 3H). ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ-109.21 (quintet, J = 7.77 Hz, 1F), -113.51 (quartet, J = 8.95 Hz, 1F), -119.56 (d, J = 9.44 Hz, 2F). LC / MS, t _r = 4.33 min (0 to 95% acetonitrile / water, 0.05% trifluoroacetic acid over 6 minutes at 1 ml / min with 215 nm detection at 50 ° C.), ES-MS m / z 413 (M + H). ES-HRMS m / z 413.0712 (M + H calculated 413.0674 for C ₁₉ H ₁₄ ClF ₄ N ₂ O ₂ ).

Example 345

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- {2,6-difluoro-4-[(methylamino) methyl] phenyl} pyridin-2 (1H) -one Hydrochloride

Step 1: tert-Butyl 4- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] -3,5-difluorobenzyl Preparation of (methyl) carbamate

tert-butyl 4- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] -3,5-difluorobenzylcarbamate (From step 1) (252 mg, 0.491 mmol) and iodomethane (75 mg, 0.528 mmol) were combined in 8 ml anhydrous dimethylformamide. 60% sodium hydride (30 mg, 0.75 mmol) in mineral oil was added and the mixture was stirred at room temperature under nitrogen for 1 hour. After addition of saturated aqueous NH ₄ Cl (4 ml), 20 ml water are added and the product is extracted with ethyl acetate, washed with brine, dried over MgSO ₄ , filtered and evaporated to white product. Obtained (208 mg, 80%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.87 (d, J = 7.85 Hz, 1H), 7.64 (quadrant, J = 6.66 Hz, 1H), 7.32, (dt, J = 9.39, 3.29 Hz , 1H), 7.13 (m, 3H), 6.77 (d, J = 7.94 Hz, 1), 5.38 (s, 2H), 4.43 (s, 2H), 2.90 (s, 3H), 1.40 (br m, 9H ). ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ 109.25 (quintet, J = 8.93 Hz, 1F), -113.53 (quartet, J = 9.73 Hz, 1F), -119.89 (d, J = 9.35 Hz, 2F). LC / MS, t _r = 6.16 min (0 to 95% acetonitrile / water, 0.05% trifluoroacetic acid over 6 minutes at 1 ml / min with 215 nm detection at 50 ° C., then 95% aceto for 2 minutes) Nitrile), ES-MS m / z 527 (M + H). ES-HRMS m / z 527.1338 (M + H calculated over C ₂₅ H ₂₄ ClF ₄ N ₂ O ₄ , 527.1355).

Step 2: Preparation of the title compound

tert-butyl 4- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] -3,5-difluorobenzyl (methyl) Carbamate (from step 1) (188 mg, 0.357 mmol) was applied to the conditions of step 2 to give a fine white solid (165 mg, 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.30 (br s, 2H), 7.89 (d, J = 7.99 Hz, 1H), 7.65 (quartet, J = 7.64, 1H), 7.55 (d, J = 8.66 Hz, 2H), 7.34 (dt, J = 9.93, 2.57 Hz, 1H), 7.17 (dt, J = 8.49, 2.48 Hz, 1H), 6.81 (d, J = 8.01 Hz, 1H), 5.39 ( s, 2H), 4.21 (s, 2H), 2.56 (s, 3H). ¹⁹ F-NMR (400 MHz, DMSO-d6) δ -109.20 (quintet, J = 7.56 Hz, 1F), -113.52 (quartet, J = 9.67 Hz, 1F), -119.21 (d, J = 8.79 Hz , 2F). LC / MS, t _r = 4.30 min (0 to 95% acetonitrile / water, 0.05% trifluoroacetic acid over 6 minutes at 1 ml / min with 215 nm detection at 50 ° C.), ES-MS m / z 427 (M + H). ES-HRMS m / z 427.0816 (M + H calculated for C ₂₀ H ₁₆ ClF ₄ N ₂ O ₂ 427.0831).

Example 346

3-chloro-1- (4-{[(cyclopropylmethyl) amino] methyl} -2,6-difluorophenyl) -4-[(2,4-difluorobenzyl) oxy] pyridine-2 ( 1H) -one hydrochloride

The title compound was prepared by direct analogy in step 1 where iodomethane was replaced with bromocyclopropylmethane and the reaction time extended to 6 hours.

Step 1:

1 tert-butyl 4- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] -3,5-difluorobenzyl (cyclo Propylmethyl) carbamate

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.89 (d, J = 7.91 Hz, 1H), 7.65 (quartet, J = 6.81 Hz, 1H), 7.33, (dt, J = 9.90, 2.26 Hz , 1H), 7.17 (m, 3H), 6.77 (d, J = 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, 1H), 0.38 (m, 2H), 0.18 (m, 2H). ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ-109.25 (quintet, J = 7.77 Hz, 1F), −113.54 (quartet, J = 9.02 Hz, 1F), −120.24 (m, 2F). LC / MS, t _r = 5.99 min (0 to 95% acetonitrile / water, 0.05% trifluoroacetic acid over 6 minutes at 1 ml / min with 215 nm detection at 50 ° C., then 95% aceto for 2 minutes) Nitrile), ES-MS m / z 567 (M + H). ES-HRMS m / z 567.1653 (M + H calculated 567.1668 for C ₂₈ H ₂₈ ClF ₄ N ₂ O ₄ ).

Step 2: Title Compound

¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.51 (br s, 2H), 7.87 (d, J = 7.96 Hz, 1H), 7.63 (m, 3H), 7.33 (dt, J = 9.93, 2.65 Hz, 1H), 7.16 (dt, J = 8.36,2.32 Hz, 1H), 6.81 (d, J = 7.92 Hz, 1H), 5.38 (s, 2H), 4.22 (br s, 2H), 2.82 (br s , 2H), 1.10 (m, 1H), 0.57 (m, 2H), 0.36 (m, 2H). ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ-109.25 (quintet, J = 7.69 Hz, 1F), -113.54 (quartet, J = 9.35 Hz, 1F), -120.24 (m, 2F). LC / MS, t _r = 4.55 min (0 to 95% acetonitrile / water, 0.05% trifluoroacetic acid over 6 minutes at 1 ml / min with 215 nm detection at 50 ° C.), ES-MS m / z 467 (M + H). ES-HRMS m / z 467.1119 (M + H calculated for C ₂₃ H ₂₀ ClF ₄ N ₂ O ₂ 467.1144).

Example 347

4- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] -3,5-difluoro-N, N-dimethylbenz amides

Step 1: Preparation of 4- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] -3,5-difluorobenzamide

4- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] -3,5-difluorobenzonitrile (540 mg, 1.32 mmol) and 90% (375 mg, 2.63 mmol) of potassium trimethylsilonate were combined in 8 ml anhydrous toluene and heated to reflux with stirring. After 10 minutes, the mixture was cooled and then partitioned between saturated aqueous ammonium chloride and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate and the combined organics were washed with brine, dried over MgSO ₄ and evaporated in vacuo. The crude product was dissolved in tetrahydrofuran, filtered through charcoal deposited on silica gel and the solution was evaporated in vacuo to give the product as a white powder (468 mg, 83%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.22 (br s, 2H), 7.92 (d, J = 7.84 Hz, 1H), 7.78 (d, J = 8.45, 2H), 7.65 (quadrant, J = 8.40 Hz, 1H), 7.34, (dt, J = 10.09, 2.58 Hz, 1H), 7.17 (dt, J = 8.72, 2.30 Hz, 1H), 6.83 (d, J = 7.91 Hz, 1H), 5.39 (s, 2H). ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ-109.21 (quintet, J = 7.43 Hz, 1F), -113.52 (quartet, J = 9.62 Hz, 1F), -118.74 (d, J = 8.88 Hz, 2F). LC / MS, t _r = 4.67 min (0 to 95% acetonitrile / water, 0.05% trifluoroacetic acid over 6 minutes at 1 ml / min with 215 nm detection at 50 ° C., then 95% aceto for 2 minutes) Nitrile), ES-MS m / z 427 (M + H). ES-HRMS m / z 427.0454 (M + H calculated 427.0467 calculated for C ₁₉ H ₁₂ ClF ₄ N ₂ O ₃ ).

Step 2: Preparation of the title compound

4- [3-chloro-4-[(2, except that 2 equivalents of 60% sodium hydride in mineral oil and iodomethane (46 mg, 0.69 mmol and 103 mg, 0.724 mmol, respectively) were used instead of the compound. 4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) yl] -3,5-difluorobenzamide (from step 1) (243 mg, 0.357 mmol) is subjected to the conditions of step 1 I was. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ7.92 (d, J = 7.76 Hz, 1H), 7.66 (quartet, J = 7.33, 1H), 7.44 (d, J = 7.59 Hz, 2H), 7.34 (dt, J = 9.88, 2.63 Hz, 1H), 7.17 (dt, J = 8.35, 2.06 Hz, 1H), 6.83 (d, J = 7.55 Hz, 1H), 5.39 (s, 2H), 2.98 (s , 3H), 2.91 (s, 3H). ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ-109.22 (quintet, J = 8.10 Hz, 1F), -113.53 (quartet, J = 9.18 Hz, IF), -118.88 (d, J = 7.77 Hz, 2F). LC / MS, t _r = 5.13 min (0 to 95% acetonitrile / water, 0.05% trifluoroacetic acid over 6 minutes at 1 ml / min with 215 nm detection at 50 ° C.), ES-MS m / z 455 (M + H). ES-HRMS m / z 455.0791 (M + H calculated for C ₂₁ H ₁₆ ClF ₄ N ₂ O ₃ 455.0780).

Example 348

4- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] -3-fluoro-5-methoxybenzonitrile

Step 1: 4- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] -3-fluoro-5-hydroxybenzonitrile Manufacture

4- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] -3 5-difluorobenzonitrile (522 mg, 1.28 mmol ) And potassium trimethylsilonate 90% (655 mg, 4.60 mmol) were combined in 8 ml anhydrous tetrahydrofuran and stirred at room temperature under nitrogen for 2 hours. The precipitated potassium salt was collected by filtration, washed with a minimum amount of tetrahydrofuran and dried under vacuum. A portion of this salt (275 mg, 0.618 mmol) is dissolved in 5 ml water, the pH is adjusted to less than 6 with concentrated hydrochloric acid, the product is collected by filtration, washed with water and dried aspirated under a blanket of dry nitrogen And further dried under vacuum overnight (251 mg, 100%, 98% total). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.46 (br s, 1H), 7.74 (d, J = 7.81 Hz, 1H), 7.67 (quadrant, J = 6.76 Hz, 1H), 7.52 (d , J = 8.76, 1H), 7.364, (dt, J = 10.18, 2.37 Hz, 1H), 7.24 (br s, 1H), 7.17 (br t, J = 8.75, 1H), 6.74 (d, J = 8.04 Hz, 1H), 5.39 (s, 2H). ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ-109.26 (quintet, J = 8.50 Hz, 1F), -113.52 (quartet, J = 9.29 Hz, 1F), -118.06 (d, J = 9.38 Hz, 1F). LC / MS, t _r = 5.13 min (0-95% acetonitrile / water, 0.05% trifluoroacetic acid over 6 minutes at 1 ml / min with 215 nm detection at 50 ° C., then 95% aceto for 2 minutes) Nitrile), ES-MS m / z 407 (M + H). ES-HRMS m / z 407.0381 (M + H calculated for C ₁₉ H ₁₁ ClF ₃ N ₂ O ₃ 407.0405).

Step 2: Preparation of the title compound

Potassium salt of 4- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (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 hours. The mixture was diluted to 50 ml with ice cold water and the white precipitate collected by filtration. The precipitate was washed three times with water, dried aspirated under a blanket of nitrogen and further dried overnight under vacuum (242 mg, 87%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ7.73 (m, 2H), 7.65 (m, 2H), 7.34 (dt, J = 9.90, 2.39 Hz, 1H), 7.17 (dt, J = 8.75, 2.47 Hz, 1H), 6.75 (d, J = 7.97 Hz, 1H), 5.37 (s, 2H), 3.84 (s, 3H). ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ-109.24 (quintet, J = 7.85 Hz, 1F), -113.54 (quartet, J = 9.83 Hz, 1F), -118.33 (d, J = 7.77 Hz, 1F). LC / MS, t _r = 5.40 min (0 to 95% acetonitrile / water, 0.05% trifluoroacetic acid over 1 min at 6 ml with 215 nm detection at 50 ° C.), ES-MS m / z 421 (M + H). ES-HRMS m / z 421.0522 (M + H calculated for C ₂₀ H ₁₃ ClF ₃ N ₂ O ₃ 421.0561).

Example 349

N- {4- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] -3,5-difluorobenzyl} urea

Step 1: Preparation of the title compound

1- [4- (aminomethyl) -2,6-difluorophenyl] -3-chloro-4-[(2,4-difluorobenzyl) oxy] pyridin-2 (1H) -one hydrochloride ( 162 mg, 0.361 mmol) was dissolved in 4 ml 50% aqueous acetic acid and treated with potassium cyanate (59 mg, 0.72 mmol). After the mixture was stirred for 2 hours, the mixture was diluted to 50 ml with cooling water and the crude product contaminated with acetamide was eluted with silica gel chromatography (first eluted with 20% ethanol in hexanes, then 40% ethanol in hexanes). Purification by 50% fractions were performed by TLC and evaporated to give a fine white powder as product (65 mg, 40%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.87 (d, J = 8.07 Hz, 1H), 7.64 (quadrant, J = 6.53 Hz, 1H), 7.33, (dt, J = 9.47,1.99 Hz , 1H), 7.15 (m, 3H), 6.76 (d, J = 7.97 Hz, 1H), 6.59 (m, 1H), 5.65 (br s, 2H), 5.38 (s, 2H), 4.22 (m, 2H ). ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ- 109.22 (quintet, J = 7.86 Hz, 1F), -113.51 (quartet, J = 9.40 1F), -120.65 (d, J = 8.75 Hz, 2). LC / MS, t _r = 4.85 min (0 to 95% acetonitrile / water, 0.05% trifluoroacetic acid over 1 min at 6 ml with 215 nm detection at 50 ° C.), ES-MS m / z 456 (M + H).

Example 350

2-({4- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] -3,5-difluorobenzyl} amino ) -1,1-dimethyl-2-oxoethyl acetate

Step 1: Preparation of the title compound

1- [4- (aminomethyl) -2,6-difluorophenyl] -3-chloro-4-[(2,4-difluorobenzyl) oxy] pyridin-2 (1H) -one hydrochloride ( 225 mg, 0.501 mmol) was dissolved in a solution of 10 ml of tetrahydrofuran and triethylamine (111 mg, 1.10 mmol). 2-acetoxy-2-methyl-propionyl chloride (85 mg, 0.516 mmol) was added and the mixture was stirred for 30 minutes before partitioning to saturated aqueous ammonium chloride and ethyl acetate. The layers were separated and the aqueous phase extracted twice with ethyl acetate. The combined organics were washed with water and brine, then dried over MgSO ₄ and evaporated in vacuo to give the product as a fine white powder (254 mg, 94%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.47 (t, J = 6.16 Hz, 1H), 7.88 (d, J = 7.71 Hz, 1H), 7.65 (quadrant, J = 7.24 Hz, 1H) , 7.34, (dt, J = 10.04, 2.49 Hz, 1H), 7.16 (m, 3H), 6.77 (d, J = 7.78 Hz, 1H), 5.38 (s, 2H), 4.32 (d, J = 5.93 2H ), 2.02 (s, 3H), 1.48 (s, 6H). ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ-109.26 (5 wire, J = 9.00 Hz, 1F), -113.52 (4 wire, J = 9.52 Hz, 1F), -120.62 (d, J = 9.09 Hz, 2F). LC / MS, t _r = 5.43 min (0 to 95% acetonitrile / water, 0.05% trifluoroacetic acid over 6 minutes at 1 ml / min with 215 nm detection at 50 ° C.), ES-MS m / z 541 (M + H). ES-HRMS m / z 541.1128 (M + H calculated for C ₂₅ H ₂₂ ClF ₄ N ₂ O ₅ 541.1148).

Example 351

N- {4- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] -3,5-difluorobenzyl} acetamide

2-Acetoxy-2-methyl-propionyl chloride (128 mg, 96%) was replaced with acetyl chloride (24 mg, 0.30 mmol) to prepare the compound following the procedure for Example 350. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.48 (br s, 1H), 7.87 (d, J = 7.28 Hz, 1H), 7.64 (quartet, J = 8.01 Hz, 1H), 7.33, (dt, J = 9.87, 2.25 Hz, 1H), 7.17 (m, 3H), 6.76 (d, J = 8.25 Hz, 1H), 5.38 (s, 2H), 4.30 (m, 2H), 1.88 (s, 3H). ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ-109.22 (quintet, J = 8.04 Hz, 1F), -113.52 (quartet, J = 9.91 Hz, 1F), -120.43 (d, J = 8.77 Hz, 2F). LC / MS t _r = 5.04 min (0 to 95% acetonitrile / water, 0.05% trifluoroacetic acid over 6 minutes, 1 ml / min, detection at 215 nm, 50 ° C.) ES-MS m / z 555 (M + H). ES-HRMS m / z 455.0824 (M + H calculated for C ₂₁ H ₁₆ ClF ₄ N ₂ O ₃ : 455.0780).

Example 352

N- {4- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] -3,5-difluorobenzyl} -2 -Methoxyacetamide

Compound was prepared following the procedure for Example 350 by replacing 2-acetoxy-2-methyl-propionyl chloride (124 mg, 78%) with 2-methoxy-acetyl chloride (45 mg, 0.415 mmol). . ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ8.56 (t, J = 6.77 Hz, 1H), 7.90 (d, J = 7.85 Hz, 1H), 7.67 (quartet, J = 7.67 Hz, 1H ), 7.36, (dt, J = 10.03, 2.36 Hz, 1H), 7.20 (m, 3H), 6.79 (d, J = 8.07 Hz, 1H), 5.40 (s, 2H), 4.37 (d, J = 6.28 Hz, 2H), 3.91 (s, 2H), 3.35 (s, 3H). ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ 109.23 (quintet, J = 8.29 Hz, 1F), -113.50 (quartet, J = 9.36 Hz, 1F), -120.43 (d, J = 9.07 Hz, 2F). LC / MS t _r = 5.13 min (0 to 95% acetonitrile / water, 0.05% trifluoroacetic acid, over 6 minutes, 1 ml / min, detection at 215 nm, 50 ° C.) ES-MS m / z 485 (M + H). ES-HRMS m / z 485.0856 (M + H required for C ₂₂ H ₁₈ ClF ₄ N ₂ O ₄ : 485.0886).

Example 353

N- {4- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] -3,5-difluorobenzyl} -2 -Puramide

Compound was prepared following the procedure for Example 350, replacing 2-acetoxy-2-methyl-propionyl chloride with furoyl chloride (62 mg, 0.48 mmol). Yield: 142 mg, 85%. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ9.07 (t, J = 6.14 Hz, 1H), 7.90 (d, J = 7.88 Hz, 1H), 7.87 (dd, J = 1.69, 0.80 Hz, 1H), 7.67 (td, J = 8.46, 6.80 Hz, 1H), 7.35, (dt, J = 10.00, 2.81 Hz, 1H), 7.26 (d, J = 8.78 Hz, 2H), 7.18 (ddt, J = 8.58, 2.30, 1.07 Hz, 1H), 7.16 (dd, J = 3.52, 0.77 Hz, 1H), 6.79 (d, J = 8.07 Hz, 1H), 6.64 (dd, J = 3.16, 1.73 Hz, 1H), 5.40 (s, 2 H), 4.49 (d, J = 6.13 Hz, 2 H). ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ-109.23 (quintet, J = 7.65 Hz, 1F), -113.50 (quartet, J = 9.84 Hz, 1F), -120.29 (d, J = 9.41 Hz, 2F). LC / MS t _r = 5.32 min (0 to 95% acetonitrile / water, 0.05% trifluoroacetic acid over 6 minutes, 1 ml / min, detection at 215 nm, 50 ° C.) ES-MS m / z 507 (M + H). ES-HRMS m / z 507.0716 (M + H calculated for C ₂₄ H ₁₆ ClF ₄ N ₂ O ₄ : 507.0729).

Example 354

N- {4- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] -3,5-difluorobenzyl} -1H Imidazole-4-carboxamide

Step 1: Preparation of the title compound

1- [4- (aminomethyl) -2,6-difluorophenyl] -3-chloro-4-[(2,4-difluorobenzyl) oxy] pyridin-2 (1H) -one hydrochloride ( 150 mg, 0.334 mmol) was dissolved in a solution of 4 ml of tetrahydrofuran and triethylamine (35 mg, 0.35 mmol). 4-imidazole carboxylic acid (62 mg, 0.56 mmol), 1-hydroxybenzotriazole hydrate (90 mg, 0.67 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide Hydrochloride (128 mg, 0.668 mmol) and triethylamine (100 mg, 0.989 mmol) were combined in 5 ml of tetrahydrofuran and stirred under nitrogen. 1- [4- (aminomethyl) -2,6-difluorophenyl] -3-chloro-4-[(2,4-difluorobenzyl) oxy] pyridin-2 (1H) -one hydrochloride Some containing solution was added and rinsed with 2 ml of tetrahydrofuran. After stirring was continued overnight at room temperature, the reaction solution was poured into 90 ml of ice water, the product was collected by filtration and dried under vacuum (254 mg, 94%). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.55 (br s, 1H), 8.73 (t, J = 6.57 Hz, 1H), 7.90 (d, J = 7.87 Hz, 1H), 7.75 (s , 1H), 7.67 (m, 2H), 7.35, (dt, J = 10.04, 2.54 Hz, 1H), 7.21 (m, 3H), 6.78 (d, J = 8.04 Hz, 1H), 5.39 (s, 2H ), 4.47 (m, 2 H). ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ-109.26 (quintet, J = 7.87 Hz, 1F), -113.52 (quartet, J = 9.30 Hz, 1F), -120.59 (d, J = 9.21 Hz, 2F). LC / MS t _r = 4.48 min (0 to 95% acetonitrile / water, 0.05% trifluoroacetic acid over 6 minutes, 1 ml / min, detection at 215 nm, 50 ° C.) ES-MS m / z 507 (M + H). ES-HRMS m / z 507.0818 (M + H calculated for C ₂₃ H ₁₆ ClF ₄ N ₄ O ₃ : 507.0842).

Example 355

N- {4- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] -3,5-difluorobenzyl} -5 Oxoprolineamide

Step 1: Preparation of the title compound

The compound was prepared following the procedure for Example 354, replacing 4-imidazolecarboxylic acid with 2-pyrrolidone-5-carboxylic acid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ8.67 (t, J = 6.08 Hz, 1H), 7.88 (m, 1H), 7.65 (qr, J = 7.57, 1H), 7.34, (dt, J = 9.32, 2.63 Hz, 1H), 7.22 (d, J = 9.36, 2H), 7.17 (dt, J = 8.51, 2.55 Hz, 1H), 6.77 (d, J = 7.66 Hz, 1H), 5.73 (s , 1H), 5.38 (s, 2H), 4.35 (d, J = 5.74, 2H), 4.05 (m, 1H), 2.15 (m, 2H), 1.90 (m, 2H). ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ-109.25 (quintet, J = 7.72 Hz, 1F), -113.52 (quartet, J = 8.94 Hz, 1F), -120.39 (d, J = 9.11 Hz, 2F). LC / MS t _r = 4.81 min (0 to 95% acetonitrile / water, 0.05% trifluoroacetic acid over 6 minutes, 1 ml / min, detection at 215 nm, 50 ° C.) ES-MS m / z 524 (M + H). ES-HRMS m / z 524.0998 (M + H calculated for C ₂₄ H ₁₉ ClF ₄ N ₃ O ₄ : 524.0995).

Example 356

N- {4- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] -3,5-difluorobenzyl} -3 -Hydroxy-3-methylbutanamide

Step 1: Preparation of the title compound

The compound was prepared according to the procedure by replacing 4-imidazolecarboxylic acid with 2-hydroxy-2-methyl butyric acid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.43 (t, J = 6.04 Hz, 1H), 7.88 (d, J = 8.01, 1H), 7.65 (qr, J = 6.84, 1H), 7.34 , (dt, J = 10.13, 2.55 Hz, 1H), 7.22 (d, J = 8.74, 2H), 7.16 (dt, J = 8.57, 2.45 Hz, 1H), 6.77 (d, J = 7.89 Hz, 1H) , 5.38 (s, 2H), 4.75 (s, 0.5H (OH)), 4.35 (d, J = 6.48, 2H), 2.28 (s, 2H), 1.47 (s, 0.5H (OH)), 1.16 ( s, 6H). ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ-109.26 (quintet, J = 7.79 Hz, 1F), -113.53 (quartet, J = 9.23 Hz, 1F), -120.49 (d, J = 9.39 Hz, 2F). LC / MS t _r = 5.08 min (0 to 95% acetonitrile / water, 0.05% trifluoroacetic acid over 6 minutes, 1 ml / min, detection at 215 nm, 50 ° C.) ES-MS m / z 513 (M + H). ES-HRMS m / z 513.1177 (M + H calculated for C ₂₄ H ₂₂ ClF ₄ N ₂ O ₄ : 513.1199).

Example 357

N- {4- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] -3,5-difluorobenzyl} -1 Hydroxycyclopropanecarboxamide

Step 1: Preparation of the title compound

Compounds were prepared according to the procedure by replacing 4-imidazolecarboxylic acid with 1-hydroxy-1-cyclopropanecarboxylic acid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.70 (t, J = 6.26 Hz, 1H), 7.89 (d, J = 6.31, 1H), 7.65 (qr, J = 6.83, 1H), 7.34 (t, J = 10.58 Hz, 1H), 7.19 (m, 3H), 6.77 (d, J = 7.70 Hz, 1H), 5.38 (s, 2H), 4.35 (d, J = 5.66, 2H), 1.14 ( s, 1H), 1.02 (m, 2H), 0.84 (m, 2H). ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ-109.25 (quintet, J = 8.05 Hz, 1F), -113.53 (quartet, J = 8.27 Hz, 1F), -120.59 (d, J = 8.99 Hz, 2F). LC / MS t _r = 5.01 min (0 to 95% acetonitrile / water, 0.05% trifluoroacetic acid over 6 minutes, 1 ml / min, detection at 215 nm, 50 ° C.) ES-MS m / z 497 (M + H). ES-HRMS m / z 497.0873 (M + H calculated for C ₂₃ H ₁₈ ClF ₄ N ₂ O ₄ : 497.0886).

Example 358

N- {4- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] -3,5-difluorobenzyl} -2 Hydroxy-2-methylpropanamide

Step 1: Preparation of the title compound

Compounds were prepared according to the procedure by replacing 4-imidazolecarboxylic acid with 2-hydroxyisobutyric acid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.48 (t, J = 6.41 Hz, 1H), 7.89 (d, J = 7.78, 1H), 7.65 (qr, J = 9.10, 1H), 7.33 (dt, J = 10.12, 2.41 Hz, 1H), 7.17 (m, 3H), 6.77 (d, J = 7.69 Hz, 1H), 5.38 (s, 2H), 4.31 (d, J = 6.50, 2H), 1.41 (s, 1 H), 1.33 (s, 6 H). ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ-109.25 (quintet, J = 7.49 Hz, 1F), -113.53 (quartet, J = 9.64 Hz, 1F), -120.59 (d, J = 8.68 Hz, 2F). LC / MS t _r = 5.05 min (0 to 95% acetonitrile / water, 0.05% trifluoroacetic acid, over 6 minutes, 1 ml / min, detection at 215 nm, 50 ° C.) ES-MS m / z 499 (M + H). ES-HRMS m / z 499.1020 (M + H calculated for C ₂₃ H ₂₀ ClF ₄ N ₂ O ₄ : 499.1042).

Example 359

4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl]-

3,5-difluorobenzonitrile

Step 1: Preparation of 3-bromo-4-[(2,4-difluorobenzyl) oxy] pyridin-2 (1H) -one

N-chlorosuccinimide is replaced with N-bromosuccinimide to give compound 3-chloro-4-[(2,4-difluorobenzyl) oxy] pyridin-2 (1H) -one (step Prepared according to the procedure for 3). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 11.85 (br s, 1 H), 7.61 (m, 1 H), 7.46 (d, J = 7.36 Hz, 1 H), 7.30, (m, 1 H), 7.14 (m, 1 H), 6.40 (d, J = 7.71 Hz, 1 H), 5.26 (s, 2 H). ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ-109.69 (quintet, J = 7.93 Hz, 1F), −113.63 (quartet, J = 9.55 Hz, 1F). LC / MS t _r = 4.48 min (0 to 95% acetonitrile / water, 0.05% trifluoroacetic acid over 6 minutes, 1 ml / min, detection at 215 nm, 50 ° C.) ES-MS m / z 316 (M + H).

Step 2: Preparation of the title compound.

3-chloro-4-[(2,4-difluorobenzyl) oxy] pyridin-2 (1H) -one (, step 3) to 3-bromo-4-[(2,4-difluorobenzyl ) Oxy] pyridin-2 (1H) -one (, step 1) (1.92 g, 6.06 mmol) to replace the compound with 4- [3-chloro-4-[(2,4-difluorobenzyl) oxy ] -2-oxopyridin-1 (2H) -yl] -3,5-difluorobenzonitrile (, step 4). ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ8.13 (d, J = 7.24 Hz, 2H), 7.95 (d, J = 7.76 Hz, 1H), 7.66 (quartet, J = 8.71 Hz, 1H ), 7.34 (dt, J = 9.94, 2.53 Hz, 1H), 7.17 (dt, J = 8.64, 2.33 Hz, 1H), 6.82 (d, J = 7.77 Hz, 1H), 5.39 (s, 2H). ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ-109.28 (quintet, J = 7.98 Hz, 1F), -113.45 (quartet, J = 9.29 Hz, 1F), -116.30 (d, J = 7.44 Hz, 2F). LC / MS t _r = 5.48 min (0 to 95% acetonitrile / water, 0.05% trifluoroacetic acid over 6 minutes, 1 ml / min, detection at 215 nm, 50 ° C.) ES-MS m / z 453 (M + H). ES-HRMS m / z 452.9836 (M + H calculated for C ₁₉ H ₁₀ BrF ₄ N ₂ O ₂ : 452.9856).

Example 360

3-bromo-1- (3-fluorobenzyl) -6-methyl-4- (2-phenylethyl) pyridin-2 (1H) -one

Step 1: Preparation of 1- (3-fluorobenzyl) -4-hydroxy-6-methylpyridin-2 (1H) -one

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 kept under argon atmosphere for 16 hours. Heated to reflux. Butanol was distilled under vacuum, the residue was triturated with EtOAc, cooled and the precipitate was filtered off. It was washed with cold EtOAc and dried to give 0.86 g of the title compound as a pale yellow powder: ¹ H-NMR (CD ₃ OD / 400 MHz) δ7.31 (m, 1H), 7.0-6.85 (m, 2H) , 6.83 (d, 1H, J = 9.6 Hz), 5.96 (d, 1H, J = 2.0 Hz), 5.80 (d, 1H, J = 2.0 Hz), 5.30 (s, 2H), and 2,24 (s , 3H); ESMS m / z = 234 (MH &lt; + &gt;).

Step 2: Preparation of 3-bromo-1- (3-fluorobenzyl) -4-hydroxy-6-methylpyridin-2 (1H) -one

Of 1- (3-fluorobenzyl) -4-hydroxy-6-methylpyridin-2 (1H) -one (0.8 g, 0.0034 mol), NBS (0.64 g, 0.0036 mol) in dichloromethane (15.0 mL) The mixture was stirred at room temperature under argon atmosphere. After 1.5 h, the reaction mixture was diluted with dichloromethane (15.0 mL), cooled and the solid was filtered off. The residue was washed with dichloromethane and dried in vacuo to yield 0.93 g of the title compound as white powder: ¹ H-NMR (CD ₃ OD / 400 MHz) δ 7.33 (m, 1H), 7.2-6.8 ( m, 3H), 6.07 (s, 1 H), 5.34 (s, 2 H), 2.26 (s, 3 H); ES-HRMS m / z 312.0016 (M + H requirement for C ₁₃ H ₁₂ NO ₂ BrF: 312.0035).

Step 3: Preparation of 3-bromo-1- (3-fluorobenzyl) -6-methyl-2-oxo-1,2-dihydropyridin-4-yl trifluoromethanesulfonate

3-bromo-1- (3-fluorobenzyl) -4-hydroxy-6-methylpyridin-2 (1H) -one (0.86 g, 0.0028 mol) in dichloromethane (15.0 mL) cooled to −30 ° C. To a suspension of), triethyl amine (0.5 mL, 0.004 mol) and triflic anhydride (0.7 mL, 0.0042 mol) were added and stirred for 1 hour. The resulting orange solution was poured into cold ice water (25 mL) and extracted with dichloromethane (2 x 25 mL). The combined organic extracts were washed with water, dried over Na ₂ S0 ₄ and concentrated under reduced pressure. The resulting residue is 1: 1 EtOAc / hexane v / v purified by silica gel flash chromatography using to give the 1.0 g (85%) title compound as a light brown _{^{solid: 1 H-NMR (CDCl 3}} /400 MHz ) δ 7.32 (m, 1H), 7.0-6.85 (m, 3H), 6.18 (s, 1H), 5.32 (s, 2H) and 2.34 (s, 3H); ES-HRMS m / z 443.9492 (M + H required for C ₁₄ H ₁₁ NO ₄ BrF ₄ S: 443.9528).

Step 4: Preparation of 3-bromo-1- (3-fluorobenzyl) -6-methyl-4- (phenylethynyl) pyridin-2 (1H) -one

3-bromo-1- (3-fluorobenzyl) -6-methyl-2-oxo-1,2-dihydropyridin-4-yl trifluoromethanesulfonate (1.0 g, in DMF (5.0 mL) 0.0022 mol) and phenylacetylene (0.3 mL, 0.0029 mol) solutions were degassed using house vacuum and purged with argon (3 times).

Then diisopropylethylamine (0.5 mL) was added followed by PdCl ₂ (PPh ₃ ) ₂ (0.36 g). The reaction mixture was heated at 65 ° C. for 1.5 h under argon atmosphere. The solvent was distilled under vacuum and the residue was purified by silica gel flash chromatography using EtOAc / hexanes (2: 3 v / v) to give 0.65 g (70%) of the title compound as a brown amorphous solid: ¹ H-NMR (CD ₃ OD / 400 MHz) δ 7.59 (m, 2H), 7.45-7.3 (m, 4H), 7.05-6.85 (m, 3H), 6.44 (s, 1H), 5.41 (s, 2H ) And 2.31 (s, 3 H); ¹⁹ F-NMR (CD ₃ OD / 400 MHz) δ-116.33 (m); ES-HRMS m / z 396.0373 (M + N requirement for C ₂₁ H ₁₆ NOBrF: 396.0399).

Step 5: Preparation of 3-bromo-1- (3-fluorobenzyl) -6-methyl-4- (2-phenylethyl) pyridin-2 (1H) -one

3-bromo-1- (3-fluorobenzyl) -6-methyl-4- (phenylethynyl) pyridin-2 (1H) -one (0.55 g, in EtOAc (10.0 mL) and EtOH (10.0 mL) 0.0014 mol) was added Pt0 ₂ (0.05 g) to the solution and stirred for 30 minutes at 15 psi under hydrogen gas atmosphere. 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 eluent. Appropriate fractions were combined (exposed under UV) and concentrated to dryness. ¹ H-NMR (CD ₃ OD / 400 MHz) δ7.35 (m, 1H), 7.31-7.16 (m, 5H), 6.99 (m, 1H), 6.91 (m, 1H), 6.81 (m, 1H) , 6.20 (s, 1 H), 5.41 (s, 2 H), 2.94 (m, 4 H) and 2.24 (s, 3 H); ¹⁹ F-NMR (CD ₃ OD / 400 MHz) δ-115.01 (m); ES-HRMS m / z 400.0695 (M + H required for C ₂₁ H ₂₀ NOBrF: 400.0712).

Example 361

3-bromo-1- (3-fluorobenzyl) -4- (1-phenylethoxy) pyridin-2 (1H) -one

3-bromo-1- (3-fluorobenzyl) -4-hydroxypyridin-2 (1H) -one (0.2 g, 0.72 mmol), potassium carbonate (0.1 g, 0.72 mmol) in DMF (3.0 mL) And a mixture of (1-bromoethyl) benzene (0.19 g, 1 mmol) was stirred at rt for 16 h. DMF was distilled under vacuum and the residue was purified by flash chromatography (EtOAc in hexane (1: 3 v / v)) to give a pale yellow syrup. This material was further purified by reverse-phase HPLC using a 10-90% acetonitrile / water gradient (30 minutes) at a flow rate of 100 mL / min. Appropriate fractions were combined, concentrated to small volume (20 mL), EtOAc (25 mL) was added, successively washed with saturated sodium bicarbonate and water and dried over Na ₂ SO ₄ . EtOAc was removed under reduced pressure and the residue was dried under vacuum to afford the title compound (0.15 g, 52%) as amorphous material: ¹ H NMR (CD ₃ OD / 400 MHz) δ7.56 (d, 1H, J = 7.6 Hz), 7.4-7.2 (m, 5H), 7.0 (m, 3H), 6.28 (d, 1H, J = 7.6 Hz), 5.65 (m, 1H), 5.19 (dxd, 2H, J = 14.8 Hz ) And 1.64 (d, 3H, J = 6.4 Hz), ES-HRMS m / z 402.0492 (M + H requirement for C ₂₀ H ₁₈ NO ₂ Br: 402.0499).

Example 362

3-bromo-1- (3-fluorobenzyl) -4-[(E) -2- (4-fluorophenyl) ethenyl] pyridin-2 (1H) -one

3-bromo-1- (3-fluorobenzyl) -2-oxo-1,2-dihydropyridine- in degassed DMF (100 ml) containing diisopropyl ethyl amine (0.37 g, 0.0029 mol) A mixture of 4-yl trifluoromethanesulfonate (1.0 g, 0.0023 mol) and 4-fluorostyrene (0.33 mL, 0.0028 mol) was treated with PdCl ₂ (PPh ₃ ) ₂ (0.32 g, 0.46 mmol), Heated at 65 ° C. under argon atmosphere for 16 h. The DMF was distilled off in vacuo and the residue was purified by flash chromatography (EtOAc / hexane 1: 4 v / v) to give a yellowish material, which was 10-90% acetonitrile / water gradient at a flow rate of 100 mL / min. Further purification by reverse-phase HPLC using (30 min). Appropriate fractions were combined, concentrated to small volume (20 mL), EtOAc (25 mL) was added, successively washed with saturated sodium bicarbonate and water and dried over Na ₂ SO ₄ . EtOAc was removed under reduced pressure and the residue was dried under vacuum to afford the title compound (0.06 g, 6%) as a yellow powder: ¹ H NMR (CD ₃ OD / 400 MHz) δ7.68 (m, 3H), 7.39 (m, 3H), 7.2-7.0 (m, 5H), 6.82 (d, 1H, J = 7.2 Hz) and 5.22 (s, 2H); ¹⁹ F NMR (CD ₃ OD / 400 MHz) δ-113.9 (m) and −115 (m); ES-HRMS m / z 402.0305 (M + H required for C ₂₀ H ₁₅ NOF ₂ Br: 402.0300).

Example 363

4- (benzyloxy) -3-bromo-1-[(6-fluoropyridin-3-yl) methyl] pyridin-2 (1H) -one

4- (benzyloxy) -3-bromopyridin-2 (1H) -one (0.2 g, 0.00076 mol), 5-bromomethyl-2-fluoropyridine (0.25 g, 0.0013 mol in DMF (3.0 ml) ) And potassium carbonate (0.15 g, 0.0011 mol) were stirred under argon atmosphere at room temperature for 16 hours. DMF was distilled under vacuum and the residue was partitioned between water (15 ml) and EtOAc (25 mL). The organic phase was washed with water, dried over Na ₂ SO ₄ and concentrated under reduced pressure. ¹ H NMR (CD ₃ OD / 400 MHz) δ8.22 (m, 1H, 2.4 Hz), 7.92 (m, 1H), 7.82 (d, 1H, J = 7.6 Hz), 7.44-7.31 (m, 5H) , 7.03 (m, 1 H) 6.49 (d, 1 H, J = 7.6 Hz), 5.29 (s, 2H) and 5.20 (s, 2H); ¹⁹ F NMR (CD ₃ OD / 400 MHz) δ-72.30 (d, J = 6.0 Hz) and −115 (m); ES-HRMS m / z 389.0295 (M + H required for C ₁₈ H ₁₅ N ₂ O ₂ FBr: 389.0309).

Example 364

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-dimethylphenyl) -6-methylpyridin-2 (1H) -one

Step 1. Preparation of 1- (2,6-dimethylphenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one

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) was stirred at 140 ° C. for 3 hours. Heated under nitrogen atmosphere. The reaction mixture was cooled down, triturated with acetonitrile, cooled and the solid was filtered off. ¹ H NMR (CD ₃ OD / 400 MHz) δ7.22 (m, 3H), 6.12 (d, 1H, J = 1.6 Hz), 5.83 (d, 1H, J = 1.8 Hz), 2.00 (s, 6H) And 1.82 (s, 3 H); ESMS m / z 229 (M + H).

Step 2. Preparation of 3-bromo-1- (2,6-dimethylphenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one

1- (2,6-dimethylphenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one (0.4 g, 0.00175 mol) and NBS (0.35 g, 0.0019 mol) in dichloromethane (10.0 ml) The mixture was stirred at room temperature under a nitrogen atmosphere. After 1 h, the solid was filtered and washed with dichloromethane to yield 0.42 g (78%) of the title compound as a pale yellow powder: ¹ H NMR (CD ₃ OD / 400 MHz) δ7.22 (m, 3H), 6.21 (s, 1 H), 1.99 (s, 6 H) and 1.82 (s, 3 H); ESMS m / z 308/310 (M + H).

Step 3

3-bromo-1- (2,6-dimethylphenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one (0.15 g, 0.00049 mol), 2,4- in DMF (3.00 mL) A mixture of difluorobenzyl bromide (0.12 g, 0.00058 mol) and potassium carbonate (0.075 g, 0.00054 mol) was stirred at room temperature under argon atmosphere for 2 hours. Then it was heated at 60 ° C. for 30 minutes and concentrated in vacuo. The residue was purified by flash chromatography. ¹ H NMR (CD ₃ OD / 400 MHz) δ7.62 (m, 1H), 7.28 (m, 3H), 7.04 (m, 2H), 6.68 (s, 1H), 5.35 (m, 1H), 1.98 ( s, 6H) and 1.92 (s, 3H); ES-HRMS m / z 434.0574 (M + H required for C ₂₁ H ₁₉ NO ₂ F ₂ Br: 434.0562).

Example 365

3-bromo-1- (2,6-dimethylphenyl) -4-[(4-fluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one

The title compound was prepared by a procedure similar to that described in Example 364. ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.58 (m, 2H), 7.23 (m, 3H), 7.15 (m, 2H), 6.62 (s, 1H), 5.32 (s, 2H), 1.98 ( m, 6H) and 1.91 (s, 3H); ES-HRMS m / z 416.0670. (M + H requirement for C ₂₁ H ₂₀ NO ₂ FBr: 416.0656).

Example 366

3-bromo-1- (2,6-dimethylphenyl) -6-methyl-4-[(2,4,6-trifluorobenzyl) oxy] pyridin-2 (1H) -one

The title compound was prepared by a procedure similar to that described in Example 364. ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.19 (m, 3H), 6.95 (m, 2H), 6.69 (s, 1H), 5.29 (s, 2H), 1.95 (s, 6H) and 1.90 ( s, 3H); ES-HRMS m / z 452.0471. (M + H required for C ₂₁ H ₁₈ NO ₂ F ₃ Br: 452.0468).

Example 367

3-bromo-4-[(2,6-difluorobenzyl) oxy] -1- (2,6-dimethylphenyl) -6-methylpyridin-2 (1H) -one.

The title compound was prepared by a procedure similar to that described in Example 364. ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.46 (m, 1H), 7.24 (m, 3H), 7.08 (m, 2H), 6.74 (s, 1H), 5.38 (s, 2H), 1.99 ( s, 6H) and 1.94 (s, 3H); ES-HRMS m / z 434.0589 (M + H required for C ₂₁ H ₁₉ NO ₂ F ₂ Br: 434.0562).

Example 368

3-bromo-1- (2,6-dichlorophenyl) -4-[(4-fluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one

Step 1. Preparation of 1- (2,6-dichlorophenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one

This compound was prepared by a procedure similar to that described in Step 1 of Example 364. Yield: 28%, ¹ H NMR (CD ₃ OD) δ7.6 (m, 2H), 7.48 (m, 1H), 6.10 (dd, 1H), 5.78 (d, 1H, J = 2.4 Hz), 1.91 ( s, 3H); (ES-MS m / z = 270 (MH ⁺ );

Step 2. Preparation of 3-bromo-1- (2,6-dichlorophenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one

This compound was prepared by a procedure similar to that described in step 2 of Example 364. Yield: 78%, ¹ H NMR (400 MHz) CD ₃ OD δ7.61 (m, 2H), 7.49 (m, 1H), 6.2 (s, 1H) and 1.91 (s, 3H); ES-MS, m / z = 348 (M−H ⁺ ).

Step 3

This compound was prepared by a procedure similar to that described in step 3 of Example 364. Yield: 44%, ¹ H NMR (CD ₃ OD) δ7.62 (d, 2H, J = 8.0 Hz), 7.51 (m, 3H), 7.15 (m, 2H), 6.64 (s, 1H), 5.33 ( s, 2H) and 2.0 (s, 3H); ¹⁹ F NMR (CD ₃ OD) δ-166.21 (m); ES-HRMS m / z 455.9541 (M + H required for C ₁₉ H ₁₄ NO ₂ Cl ₂ BrF: 455.9564).

Example 369

3-bromo-1- (2,6-dichlorophenyl) -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one

This compound was prepared by a procedure similar to that described in Example 368. Yield: 64%, ¹ H NMR (CD ₃ OD / 400 MHz, δ7.62 (m, 3H), 7.48 (m, 1H), 7.05 (m, 2H), 6.70 (s, 1H), 5.36 (s, 2H) and 2.02 (s, 3H), ¹⁹ F NMR (CD ₃ OD) δ-111.43 (m) and -115.89 (m); ES-HRMS m / z 473.9450 (C ₁₉ H ₁₃ NO ₂ Cl ₂ BrF ₂ in M + H requirement for: 473.9469).

Example 370

3-bromo-1- (2,6-dichlorophenyl) -4-[(2,6-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one

This compound was prepared by a procedure similar to that described in Example 368. Yield: 78%, ¹ H NMR (CD ₃ OD / 400 MHz) δ7.62 (d, 2H, J = 8.0 Hz), 7.52 (m, 2H), 7.1 (m, 2H), 6.77 (s, 1H) And 2.04 (s, 3 H); ¹⁹ F NMR (CD ₃ OD) δ-117.04 (m); ES-HRMS m / z 473.9468 (M + H required for C ₁₉ H ₁₃ NO ₂ C1 ₂ BrF ₂ : 473.9469).

Example 371

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2-methoxy-6-methylphenyl) -6-methylpyridin-2 (1H) -one

Step 1. Preparation of 4-hydroxy-1- (2-methoxy-6-methylphenyl) -6-methylpyridin-2 (1H) -one

This compound was prepared by a procedure similar to that described in step 1 of Example 368. Yield: 21%, ¹ H NMR (CD ₃ OD / 400 MHz) δ7.31 (m, 1H), 6.94 (m, 2H), 6.05 (d, 1H, J = 2.4 Hz), 5.78 (d, 1H, 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 required for C ₁₄ H ₁₆ NO ₃ : 246.1123).

Step 2. Preparation of 3-bromo-4-hydroxy-1- (2-methoxy-6-methylphenyl) -6-methylpyridin-2 (1H) -one

This compound was prepared by a procedure similar to that described in step 2 of Example 368. Yield: 58%, ¹ H NMR (CD ₃ OD / 400 MHz) δ7.34 (m, 1H), 6.96 (m, 2H), 6.15 (s, 1H), 3.76 (s, 3H), 1.99 (s, 3H) and 1.83 (s, 3H); ESMS m / z 324 (M + H).

Step 3

This compound was prepared by a procedure similar to that described in Example 368. Yield: 60%, ¹ H NMR (CD ₃ OD / 400 MHz) δ7.63 (m, 1H), 7.36 (m, 1H), 7.01 (m, 4H), 6.61 (s, 1H), 5.33 (s, 2H ), 3.76 (s, 3H), 1.99 (s, 3H) and 1.95 (s, 3H); ¹⁹ F NMR (CD ₃ OD / 400 MHz) δ-111.64 (m) and -116.03 (m); ES-HRMS m / z 450.0532 (M + H required for C ₂₁ H ₁₉ NO ₃ Cl ₂ BrF ₂ : 450.0511).

Example 372

4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3,5-dichlorobenzenesulfonamide

Step 1. Preparation of 3,5-dichloro-4- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) benzenesulfonamide

A mixture of 4-hydroxy-6-methylpyrone (1.2 g, 0.0095 mol) and 2,6-dichlorosulfanylamide (2.4 g, 0.0099 mol) was heated at 170 ° C. under argon for 20 minutes. The resulting dark melt was cooled and the crude material was first purified by flash chromatography (EtOAc) to give a partially purified material containing the desired product. This was further purified by reverse-phase HPLC using 10-90% CH ₃ CN / water (30 min gradient) at a flow rate of 100 mL / min. Appropriate fractions (m / z = 349) were combined and lyophilized to yield 0.19 g of 3,5-dichloro-4- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl as a pale yellow solid. Benzenesulfonamide was obtained: ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.06 (s, 2H), 6.13 (d, 1H, J = 1.6 Hz), 5.78 (d, 1H, J = 1.6 Hz ) And 1.94 (s, 3 H); ES-HRMS m / z 348.9819 (M + H required for C ₁₂ H ₁₁ N ₂ O ₄ SCl ₂ : 348.9811).

Step 2

3,5-dichloro-4- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) benzenesulfonamide in acetic acid (2.0 mL) (0.18 g, 0.0005 mol), N-bro A mixture of mucinsinimide (0.1 g, 0.00056 mol) was stirred at room temperature under argon atmosphere for 1 hour. Acetic acid was removed in vacuo and the residue was dissolved in DMF (2.0 mL) and 2,4-difluorobenzyl bromide (0.128 g, 0.0006 mol) and potassium carbonate (0.1 g, 0.0007 mol) were added. The resulting mixture was stirred at rt for 1 h. The solvent was distilled under vacuum 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% CH ₃ CN / water (30 min gradient) at a flow rate of 100 mL / min. Appropriate fractions (m / z = 553) were combined and lyophilized to yield 0.045 g of pale yellow powder. This was partitioned between EtOAc (25 ml) and 5% sodium bicarbonate. The organic phase was washed with water, dried over Na ₂ SO ₄ and concentrated under reduced pressure. This material was dried under vacuum to give the title compound (0.033 g) as a white amorphous _{^{material: 1 H NMR (CDCl 3/}} 400 MHz) δ7.99 (s, 2H), 7.59 (m, 1H), 6.98 (m , 1H), 6.85 (m, 1H), 6.23 (s, 1H), 5.69 (s, 2H), 5.28 (s, 2H), 1.97 (s, 3H) and 1,76 (br, 2H); ES-HRMS m / z 552.7214 (M + H required for C ₁₉ H ₁₄ BrCl ₂ N ₂ O ₄ S: 552.9197).

Example 373

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-methylpyridin-2 (1H) -one

Step 1. Preparation of 1- (2,6-difluorophenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one

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. for 20 minutes under argon atmosphere. The water formed was removed using a Dean-stark apparatus. The melt was cooled and the dark solid was triturated with EtOAc and filtered. The material was washed thoroughly with EtOAc to give 6.5 g (35%) of 1- (2,6-difluorophenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one as a light brown solid. Obtained: ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.56 (m, 1H), 7.19 (m, 2H), 6.09 (m, 1H), 5.77 (d, 1H, J = 2.4 Hz) and 1.99 (s, 3 H); ES-HRMS m / z 238.0679 (M + H required for C ₁₂ H ₁₀ NO ₂ F ₂ : 238.0674)

Step 2. Preparation of 3-bromo-1- (2,6-difluorophenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one

The title compound was prepared by a procedure similar to that described in step 2 of Example 364. Yield: 79%, ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.58 (m, 1H), 7.21 (m, 2H), 6.19 (d, 1H, J = 0.8 Hz), 1.99 (s, 3H) ; ES-HRMS m / z 315.9811 (M + H required for C ₁₂ H ₉ NO ₂ F ₂ Br: 315.9779).

Step 3

This compound was prepared by a procedure similar to that described in step 3 of Example 364. Yield: 63%, ¹ H NMR (CD ₃ OD) δ 7.58 (m, 2H), 7.23 (m, 2H), 7.06 (m, 2H), 6.68 (s, 1H), 5.36 (s, 2H) and 2.10 (s, 3 H); ¹⁹ F NMR (CD ₃ OD) δ-111.50 (m), -115.96 (m) and -121.93 (m); ES-HRMS m / z 442.0061 (M + H required for C ₁₉ H ₁₃ NO ₂ F ₄ Br: 442.0060).

Example 374

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -5-iodo-6-methylpyridin-2 (1H) -one

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-methylpyridine in dichloroethane containing dichloroacetic acid (0.1 mL) A solution of -2 (1H) -one (0.3 g, 0.00068 mol) and N-iodosuccinimide (0.22 g, 0.00098 mol) was heated to reflux under an argon atmosphere for 6 hours. After removal of solvent under reduced pressure, the residue was partitioned between dichloromethane (20 mL) and 5% sodium sulfite (10 mL). The organic phase was washed with water, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified to give the title compound (0.125 g, 32%) was purified by flash chromatography (25% EtOAc in hexanes) as a pale yellow _{^{powder: 1 H NMR (CDCl 3/}} 400 MHz) δ7.68 (m, 1H) , 7.46 (m, 1H), 7.11 (m, 2H), 6.95 (m, 1H), 6.85 (m, 1H), 5.23 (s, 2H) and 2.38 (s, 3H); ¹⁹ F NMR (CDCl ₃ ) δ-109.15 (m), -112.95 (m), -118.50 (m); ES-HRMS m / z 567.9014 (M + H required for C ₁₉ H ₁₂ NO ₂ F ₄ BrI: 567.9027).

Example 375

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [2- (dimethylamino) -4,6-difluorophenyl] -6-methylpyridine-2 (1H) -On

Step 1. 3,5-Difluoro-N ~ 1 ~, N ~ 1 ~ -dimethylbenzene-1,2-diamine

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 (8.5 mL of 2M solution) in THF and 0 for 45 minutes. Stir at ° C. Thereafter, the mixture was stirred at room temperature for 30 minutes, and then concentrated to dryness. The resulting material was dissolved in EtOH (25 mL), Pd / C (10%, 0.6 g) was added and hydrogenated at 50 psi for 4 hours. The catalyst was removed by filtration and the filtrate was concentrated to dryness under reduced pressure. The residue was partitioned between sodium bicarbonate (10%, 25 mL) and EtOAc (30 mL). The organic phase was washed with water, dried with Na ₂ SO _4, and concentrated to dryness to give the title compound (1.3 g, 50%) as a dark _{^{solid: 1 H NMR (CDCl 3/}} 400 MHz) δ6.52 (m, 2H), 3.64 (br, 2H) and 2.65 (s, 6H); ES-HRMS m / z 172.0772 (M + H required for C ₈ H ₁₀ N ₂ F ₂ : 172.0810).

Step 2. 1- [2- (dimethylamino) -4,6-difluorophenyl] -4-hydroxy-6-methylpyridin-2 (1H) -one

Dense mixture of 4-hydroxy-6-methyl-2-pyrone (1.3 g, 0.0103 mol) and 3,5-difluoro-N, N-dimethylbenzene-1,2-diamine (1.4 g, 0.008 mol) Heated at 160 ° C. under argon for 15 minutes. The dark reaction mixture was cooled, triturated with EtOAc (15 ml) and filtered. The solid was washed with warm EtOAc, then with hexanes and dried to afford the title compound as a pale blue solid (0.4 g, 14%). Analytical pure samples were prepared by reverse-phase HPLC purification using 10-90% CH ₃ CN / water (30 min gradient) at a flow rate of 100 mL / min. Appropriate fractions were combined and lyophilized to afford the title compound: ¹ H NMR (CD ₃ OD / 400 MHz) δ6.61 (m, 2H), 6.08 (d, 1H, J = 2.0 Hz), 6.78 (d, 1H, J = 2.0 Hz), 2.69 (s, 6H) and 1.94 (s, 3H); ES-HRMS m / z 281.1084 (M + H required for C ₁₄ H ₁₅ N ₂ O ₂ F ₂ : 281.1096).

Step 2. Preparation of 3-bromo-1- [2- (dimethylamino) -4,6-difluorophenyl] -4-hydroxy-6-methylpyridin-2 (1H) -one

The title compound was prepared by the method described in step 2 of Example 364. Yield: 71%, ¹ H NMR (CD ₃ OD / 400 MHz) δ6.62 (m, 2H), 6.17 (s, 1H), 2.67 (s, 6H) and 1.94 (s, 3H); ES-HRMS m / z 359.0188 (M + H required for C ₁₄ H ₁₄ N ₂ O ₂ F ₂ Br: 359.0201).

Step 3

This compound was prepared by the method described in step 3 of Example 364. ^{Yield: 34%, 1 H NMR (} CDCl 3/400 MHz) δ7.62 (m, 1H), 6.98 (m, 1H), 6.85 (m, 1H), 6.46 (m, 2H), 6.11 (s, 1H ), 5.24 (s, 2H), 2.66 (s, 6H) and 1.98 (s, 3H); _{^{19 F NMR (CDCl 3/400}} MHz) δ-108.06 (m), -109.60 (m), -115.02 (m) and -116.01 (m); ES-HRMS m / z 485.0451 (M + H required for C ₂₁ H ₁₈ N ₂ O ₂ F ₄ Br: 485.0482).

The title compound was prepared by stirring the suspension of the product of step 3 (0.14 g) with 4N HCl in dioxane (0.7 mL) for 30 minutes at room temperature. The mixture was concentrated to dryness. ¹ H NMR (CD ₃ OD / 400 MHz) δ7.62 (m, 1H), 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

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- {2,4-difluoro-6-[(2-hydroxyethyl) (methyl) amino] phenyl}- 6-methylpyridin-2 (1H) -one

The title compound was prepared in a similar manner as described in Example 375, in which the N, N-dimethyl group was replaced with N-methyl-aminoethanol. _{^{1 H NMR (CDCl 3/400}} MHz) δ7.59 (m, 1H), 6.98 (m, 1H), 6.85 (m, 1H), 6.61 (m, 1H), 6.52 (m, 1H), 6.17 (m , 1H), 5.25 (s, 2H), 3.63 (m, 1H), 3.53 (m, 1H), 3.26 (m, 1H), 3.0 (m, 1H), 2.66 (s, 6H) and 2.09 (s, 3H); ES-HRMS m / z 515.0512 (M + H required for C ₂₂ H ₂₀ N ₂ O ₃ F ₄ Br: 515.0588).

Example 377

2-({[3-bromo-1- (2,6-difluorophenyl) -6-methyl-2-oxo-1,2-dihydropyridin-4-yl] oxy} methyl) -5- Fluorobenzonitrile

Step 1. 2- (Bromomethyl) -5-fluorobenzonitrile

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 carbon tetrachloride (25.0 ml) was added for 6 hours. It was heated to reflux under the atmosphere. The reaction mixture was cooled down and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (5% EtOAc in hexane) to give 2- (bromomethyl) -5-fluorobenzonitrile (1.9 g, 60%) as a colorless liquid. _{^{: 1 H NMR (CDCl 3/}} 400 MHz) δ7.59 (m) 7.58 (m, 1H), 7.38 (m, 1H) and 7.25 (m, 1H).

Step 2

3-bromo-1- (2,6-difluorophenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one (1.0 g, 0.0032 mol) in dimethylacetamide (15.0 ml), A mixture of potassium carbonate (0.65 g, 0.0047 mol) and 2- (bromomethyl) 5-fluorobenzonitrile (0.95 g, 0.0045 mol) was stirred at room temperature under argon atmosphere. After 1 hour, dimethylacetamide was distilled under vacuum and the residue was partitioned between dichloromethane (50 ml) and 5% citric acid (15 mL). The organic phase was washed with water, dried over Na ₂ SO ₄ , concentrated to dryness. Triturated and the resulting material with EtOAc, filtered, washed with EtOAc, and dried to give the title compound (0.86 g, 60%) as a white ^{powder: 1 H NMR (DMSO-d} 6/400 MHz) δ7. 95 (m, 1H), 7.81 (m, 1H), 7.68 (m, 2H), 7.37 (m, 2H), 6.79 (s, 1H), 5.45 (s, 2H) and 2.03 (s, 3H); ¹⁹ F-NMR (DMSO-d ₆ ) δ-111.31 (m), -120.34 (m); ES-HRMS m / z 449.0094 (M + H required for C ₂₀ H ₁₃ N ₂ O ₂ F ₃ Br: 449.0107).

Example 378

4-{[2- (aminomethyl) -4-fluorobenzyl] oxy} -3-bromo-1- (2,6-difluorophenyl) -6-methylpyridin-2 (1H) -one tree Fluoroacetate

2-({[3-bromo-1- (2,6-difluorophenyl) -6-methyl-2-oxo- 1,2-dihydropyridin-4-yl] oxy in THF (3.0 mL) } was added BH ₃ and THF (1.0 mL) to a cold suspension of methyl) -5-fluorobenzonitrile (0.3 g, 0.00066 mol). After stirring for 15 minutes at room temperature, the reaction mixture was heated to reflux for 30 minutes under argon atmosphere. The resulting clear solution was cooled down, MeOH (2.0 mL) was added, concentrated under reduced pressure, and the residue was reversed using 10-90% CH ₃ CN / water (30 min gradient) at a flow rate of 100 mL / min. Purification by phase HPLC purification. Appropriate fractions (m / z = 453 M + H) The layers were combined and lyophilized to give the title compound (0.16 g, 43%) as an acetate salt to its ^{trifluoroacetate: 1 H NMR (DMSO-d} 6/400 MHz) δ 8.19 (br, 3H), 7.65 (m, 2H), 7.37 (m, 4H), 6.78 (s, 1H), 5.42 (s, 2H), 4.21 (br, 2H) and 2.04 (s, 3H) ; _{^{19 F NMR (DMSO-d 6}} /400 MHz) δ-112.96 (m) and -120.41 (m); ES-HRMS m / z 453.0387 (M + H required for C ₂₀ H ₁₇ N ₂ O ₃ F ₃ Br: 453.0420).

Example 379

N- [2-({[3-bromo-1- (2,6-difluorophenyl) -6-methyl-2-oxo-1,2-dihydropyridin-4-yl] oxy} methyl) -5-fluorobenzyl] urea

4-{[2- (aminomethyl) -4-fluorobenzyl] oxy} -3-bromo-1- (2,6-difluorophenyl) -6-methylpyridine-2 in THF (3.0 mL) To a suspension of (1H) -one trifluoroacetate (0.13 g, 0.00023 mol) was added triethyl amine (0.07 mL, 0.0005 mol), followed by trimethylsilyl isocyanate (0.066 mL). The reaction mixture was stirred at rt for 1 h and the desired product was isolated by reverse-phase HPLC purification using 10-90% CH ₃ CN / water (30 min gradient) at a flow rate of 100 mL / min. Appropriate fractions (m / z = 496 M + H) were combined, lyophilized and the residue was partitioned between 5% sodium bicarbonate (20 mL) and dichloromethane (20 mL). The organic phase was washed with water, dried with Na ₂ SO _4, and concentrated to dryness under reduced pressure to give the title compound as a white amorphous powder ^{(0.065 g): 1 H NMR} (DMSO-d 6/400 MHz) δ7.62 ( m, 1H), 7.52 (m, 1H), 7.35 (m, 2H), 7.09 (m, 2H), 6.77 (s, 1H), 6.51 (t, 1H), 5.61 (s, 2H), 5.38 (s , 2H), 4.28 (d, 2H, J = 6.0 Hz) and 2.02 (s, 3H); _{^{19 F NMR (DMSO-d 6}} /400 MHz) δ-114.044 (m) and -120.31 (m); ES-HRMS m / z 496.0460 (M + H required for C ₂₁ H ₁₈ N ₃ O ₃ F ₃ Br: 496.0478).

Example 380

Methyl 2-({[3-bromo-1- (2,6-difluorophenyl) -6-methyl-2-oxo-1,2-dihydropyridin-4-yl] oxy} methyl)- 5-fluorobenzylcarbamate

4-{[2- (aminomethyl) -4-fluorobenzyl] oxy} -3-bromo-1- (2,6-difluorophenyl) -6-methylpyridine in dimethylacetamide (2.0 mL) To a solution of -2 (1H) -on trifluoroacetate (0.12 g, 0.00021 mol) was added triethylamine (0.06 mL, 0.00043 mol) at 0 ° C., followed by methylchloroformate (0.05 mL). The reaction mixture was stirred at room temperature for 30 minutes under argon atmosphere. Dimethylacetamide was distilled under vacuum and the residue was partitioned between dichloromethane (10 mL) and 5% citric acid (10 mL). The organic phase was washed with water, dried over Na ₂ SO ₄ , concentrated to dryness. The resulting residue was purified to give the title compound (0.09 g, 75%) was purified by flash chromatography (60% EtOAc in hexanes) as a white amorphous ^{powder: 1 H NMR (DMSO-d} 6/400 MHz) δ7.68 (m, 1H), 7.62 (m, 1H), 7.59 (m, 1H), 7.38 (m, 2H), 7.115 (m, 2H), 6.78 (s, 1H), 5.38 (s, 2H), 4.31 ( d, 2H, J = 6.0 Hz), 3.53 (s, 3H) and 2.03 (s, 3H); _{^{19 F NMR (DMSO-d 6}} /400 MHz) δ-113.77 (m) and -120.33 (m); ES-HRMS m / z 511.0508 (M + H required for C ₂₂ H ₁₉ N ₂ O ₄ F ₃ Br: 511.0475).

Example 381

N- [2-({[3-bromo-1- (2,6-difluorophenyl) -6-methyl-2-oxo-1,2-dihydropyridin-4-yl] oxy} methyl) -5-fluorobenzyl] -2-hydroxyacetamide

4-{[2- (aminomethyl) -4-fluorobenzyl] oxy} -3-bromo-1- (2,6-difluorophenyl) -6-methylpyridine-2 in THF (2.0 mL) To a suspension of (1H) -one trifluoroacetate (0.12 g, 0.00021 mol) was added triethyl amine (0.036 g, 0.00035 mol) at 5 ° C. followed by the addition of acetoxyacetyl chloride (0.05 mL). The mixture was stirred at rt for 30 min, diluted with cold water (10 mL) and the product extracted with dichloromethane (2 x 10 mL). The combined organic extracts were washed with water, dried over Na ₂ SO ₄ , concentrated to dryness. The residue was dissolved in ethanol (0.5 mL), 1N NaOH (0.5 mL) was added and stirred at rt for 1 h. The resulting solution was diluted with water (15 mL) and extracted with dichloromethane (2 × 10 mL). The combined dichloromethane extracts were washed with water, dried over Na ₂ SO ₄ , concentrated to dryness. The residue was purified by flash chromatography (1% MeOH in EtOAc) to give the title compound (0.032 g, 30%) as a white amorphous powder. _{^{1 H NMR (CDCl 3/400}} MHz) δ7.45 (m, 2H), 7.18 (m, 1H), 7.05 (m, 3H), 6.23 (s, 1H), 5.24 (s, 2H), 4.56 (d , 2H, J = 6.4 Hz), 4.08 (d, 2H, J = 5.2 Hz), 2.79 (t, 1H) and 2.08 (s, 3H); _{^{19 F NMR (CDCl 3/400}} MHz) δ-111.88 (m) and -118.62 (m); ES-HRMS m / z 511.0482 (M + H required for C ₂₂ H ₁₉ N ₂ O ₄ F ₃ Br: 511.0475).

Example 382

Ethyl 2-({[3-chloro-1- (2,6-difluorophenyl) -6-methyl-2-oxo-1,2-dihydropyridin-4-yl] oxy} methyl) -5- Fluorobenzylcarbamate

4-{[2- (aminomethyl) -4-fluorobenzyl] oxy} -3-chloro-1- (2,6-difluorophenyl) -6-methylpyridine- in dimethylacetamide (3.0 mL) N-methylmorpholine (0.064 g, 0.00064 mol) was added to a solution of 2 (1H) -on trifluoroacetate (0.3 g, 0.00057 mol), followed by addition of ethylchloroformate (0.06 mL) and -10 ° C. Stirred for 30 min. The solvent was distilled under vacuum and the residue was purified by reverse-phase HPLC purification using 10-90% CH ₃ CN / water (30 min gradient) at a flow rate of 100 mL / min. Appropriate fractions (m / z = 481 M + H) were combined, lyophilized and the residue was partitioned between 5% sodium carbonate (20 mL) and dichloromethane (20 mL). The organic phase was washed with water, dried over Na ₂ SO ₄ , concentrated under reduced pressure and dried to give the title compound (0.15 g, 55%) as a white amorphous powder: ¹ H NMR (CD ₃ OD / 400 MHz) δ7. 61 (m, 1H), 7.52 (m, 1H), 7.26 (~ t, 2H, J = 8.4 Hz), 7.12 (dd, 1H), 7.05 (3d, 1H, J = 2.4 Hz), 6.74 (s, 1H), 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 required for C ₂₃ H ₂₁ N ₂ O ₄ F ₃ Cl: 481.1136).

Example 383

Isobutyl 2-({[3-chloro-1- (2,6-difluorophenyl) -6-methyl-2-oxo-1,2-dihydropyridin-4-yl] oxy} methyl) -5 Fluorobenzylcarbamate

The title compound was prepared by a procedure similar to that described in Example 382. Yield 57%; ¹ H NMR (CD ₃ OD / 400 MHz) 7.61 (m, 1H), 7.51 (m, 1H), 7.24 (~ t, 2H, J = 8.0 Hz), 7.18 (m, 1H), 7.06 (m, 1H ), 6.74 (s, 1H), 5.40 (s, 2H), 4.21 (s, 2H), 3.79 (d, 2H, J = 6.8 Hz), 2.12 (s, 3H), 1.85 (m, 1H), and 0.91 (d, 6H, J = 6.4 Hz); ES-HRMS m / z 509.1422 (M + H required for C ₂₅ H ₂₅ N ₂ O ₄ F ₃ Cl: 509.1449)

Example 384

Cyclopropylmethyl 2-({[3-chloro-1- (2,6-difluorophenyl) -6-methyl-2-oxo- 1,2-dihydropyridin-4-yl] oxy} methyl)- 5-fluorobenzylcarbamate

The title compound was prepared by a procedure similar to that described in Example 382. Yield 46%; ¹ H NMR (CD ₃ OD / 400 MHz) δ7.61 (m, 1H), 7.55 (m, 1H), 7.24 (~ t, 2H, J = 7.6 Hz), 7.18 (m, 1H), 7.05 (m , 1H), 6.73 (s, 1H), 5.40 (s, 2H), 4.42 (s, 2H), 3.83 (d, 2H, J = 7.2 Hz), 2.12 (s, 3H), 1.1 (br, 1H) , 0.58 (~ d, 2H) and 0.22 (~ d, 2H); ES-HRMS m / z 507.1316 (M + H required for C ₂₅ H ₂₃ N ₂ O ₄ F ₃ Cl: 507.1293).

Example 385

1-[(4-amino-2-methylpyrimidin-5-yl) methyl] -3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridine-2 (1H ) -On trifluoroacetate

Step 1. 1-[(4-Amino-2-methylpyrimidin-5-yl) methyl] -4-hydroxy-6-methylpyridin-2 (1H) -one

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) Heated at 100 ° C. for 1 hour under argon atmosphere. The reaction mixture was cooled down and the yellow precipitate was filtered off. Washing it successively with cold water and ethanol and dried under vacuum to give the title compound (1.01 g, 51%) as a pale yellow ^{powder: 1 H NMR (DMSO-d} 6/400 MHz) δ7.62 (s, 1H ), 7.04 (s, 1H), 5.83 (d, 1H, J = 2.0 Hz), 5.58 (d, 1H, 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 required for C ₁₂ H ₁₄ N ₄ O ₂ Br: 325.0295).

Step 2. 1-[(4-Amino-2-methylpyrimidin-5-yl) methyl] -3-bromo-4-hydroxy-6-methylpyridin-2 (1H) -one

1-[(4-amino-2-methylpyrimidin-5-yl) methyl] -4-hydroxy-6-methylpyridin-2 (1H) -one (0.5 g, 0.002 mol) in glacial acetic acid (5.0 ml) And a mixture of NBS (0.4 g, 0.002 mol) were stirred at room temperature under argon atmosphere for 1 hour. Acetic acid was removed in vacuo and the residue was triturated with EtOAc containing 10% EtOH and filtered. The pale yellow precipitate was washed with EtOAc containing 10% EtOH and dried under vacuum to give the title compound (0.47 g, 725%) as pale yellow powder: ¹ H NMR (CD ₃ OD / 400 MHz) δ7.62 (s , 1H), 6.09 (s, 1H), 5.15 (s, 2H), 2.42 (s, 3H) and 2.33 (s, 3H); ES-HRMS m / z 247.1160 (M + H required for C ₁₂ H ₁₅ N ₄ O ₂ : 247.1190).

Step 3

1-[(4-amino-2-methylpyrimidin-5-yl) methyl] -3-bromo-4-hydroxy-6-methylpyridin-2 (1H) -one in dimethylacetamide (10.0 mL) To a suspension of (1.0 g, 0.0031 mol) and potassium carbonate (0.0 g, 0.004 mol) was added 2,4-difluorobenzyl bromide (0.62 mL, 0.0048 mol) and stirred at room temperature for 2 hours. Dimethylacetamide was distilled under vacuum and the residue was purified by reverse-phase HPLC using 10-90% CH ₃ CN / water (30 min gradient) at a flow rate of 100 mL / min. Appropriate fractions (m / z = 566) were combined and lyophilized to give 0.65 g (37%) of the title compound as its trifluoroacetate salt: ¹ H NMR (CD ₃ OD / 400 MHz) δ7.65 ( s, 1H), 7.58 (m, 1H), 7.05 (m, 2H), 6.61 (s, 1H), 5.31 (s, 2H), 5.18 (s, 2H), 2.51 (s. 3H) and 2.46 (s , 3H); ¹ H NMR (CD ₃ OD / 400 MHz) δ-111.39 (m) and -115.98 (m); ES-HRMS m / z 451.0590 (M + H required for C ₁₉ H ₁₈ N ₄ O ₂ BrF ₂ : 451.0576).

Example 386

1-[(4-amino-2-methylpyrimidin-5-yl) methyl] -3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridine-2 (1H ) -One hydrochloride

Ion exchange (25 g) BioRad AG 2X8 resin (in the form of 200-400 mesh chloride) was washed with 1M HCl (150 mL) and equilibrated for 2.5. This resin was loaded onto a column and a solution of Example 385 (3.3 g, 5.8 mmol) in water / CH ₃ CN (1: 1) was added. The column was eluted slowly over 1 hour, the fractions were collected and lyophilized to give the desired HCl salt (2.2 g, 72%) as a white solid: ¹ H-NMR (CD ₃ OD, 400 MHz) δ7. 60 (m, 2H), 7.21 (m, 2H), 6.62 (s, 1H), 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 requirements for C ₁₉ H ₁₇ N ₄ O ₂ F ₂ Br: 451.0581 / 453.0563).

Example 387

1-[(4-amino-2-methylpyrimidin-5-yl) methyl] -3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridine-2 (1H) -On trifluoroacetate

Step 1. Preparation of 1-[(4-amino-2-methylpyrimidin-5-yl) methyl] -3-chloro-4-hydroxy-6-methylpyridin-2 (1H) -one

¹ H NMR (CD ₃ OD, 400 MHz) δ7.62 (m, 1H), 6.11 (s, 1H), 5.13 (s, 2H), 2.66 (s, 3H), 2.42 (s, 3H); ES-HRMS m / z 281.0793 (M + H required for C ₁₂ H ₁₃ N ₄ O ₂ Cl: 281.0800).

Step 2.

1-[(4-amino-2-methylpyrimidin-5-yl) methyl] -3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridine-2 (1H) Preparation of -on Trifluoroacetate

The title compound was prepared by a procedure similar to that described in step 2 of Example 385. ¹ H NMR (CD ₃ OD, 400 MHz) δ 7.59 (m, 2H), 7.03 (m, 2H), 6.63 (s, 1H), 5.31 (s, 2H), 5.17 (s, 2H), 2.48 ( s, 3H), 2.46 (s, 3H); ES-HRMS m / z 407.1097 (M + H required for C ₁₉ H ₁₇ N ₄ O ₂ ClF ₂ : 407.1081).

Example 388

1-[(4-amino-2-methylpyrimidin-5-yl) methyl] -3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridine-2 (1H) -On hydrochloride

Ion exchange (12.5 g) Biorad AG 2X8 resin (in the form of 200-400 mesh chloride) was washed with 1M HCl (150 mL) and equilibrated for 2.5 h. This resin was loaded on a column and a solution of Example 387 (1.2 g, 2.4 mmol) in water / CH ₃ CN (1: 1) was added. The column was eluted slowly over 1 hour, the fractions were collected and lyophilized to give the desired HCl salt (1.03 g, 97%) as a white solid: ¹ H NMR (CD ₃ OD, 400 MHz) δ7.60 (m, 2H), 7.04 (m, 2H), 6.64 (s, 1H), 5.31 (s, 2H), 5.17 (s, 2H), 2.50 (s, 3H), 2.47 (s, 3H); ES-HRMS m / z 407.1079 (M + H requirement for C ₁₉ H ₁₇ N ₄ 0 ₂ ClF ₂ 407.1081).

Example 389

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (1H-indazol-5-ylmethyl) -6-methylpyridin-2 (1H) -one trifluoro acetate

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one (0.55 g, 0.0017 mol) and 5- (bro) in THF (10.0 mL) NaH (0.045 g, 0.0019 mol) was added to a solution of mother methyl) -1-tetrahydro-2H-pyran-2-yl-1H-indazole (0.5 g, 0.0017 mol) and argon atmosphere at 60 ° C. for 16 hours. Under heating. THF was distilled off under reduced pressure, the residue was suspended with EtOAc, acetic acid (0.5 mL) was added and the product was purified by flash chromatography (80% EtOAc in hexanes). Appropriate fractions were combined and concentrated to give amorphous material (0.31 g). It is stirred with trifluoroacetic acid (0.5 mL) for 30 minutes, the solution is diluted with acetonitrile (5 mL) and the product is 10-90% CH ₃ CN / water (30 minutes at a flow rate of 100 mL / min). Gradient) was isolated by reverse-phase HPLC. Combine the appropriate fractions (m / z = 460), and lyophilized to give the title compound in 0.14 g (52%) as an acetate salt to its _{^{trifluoroacetate: 1 H NMR (CD 3 OD}} / 400 MHz) δ7.97 ( s, 1H), 7.62 (m, 1H), 7.51 (m, 1H), 7.45 (s, 1H), 7.25 (m, 1H), 7.03 (t, 2H), 6.49 (s, 1H), 5.53 (s , 2H), 5.29 (s, 2H) and 2.40 (s, 3H); ¹⁹ F NMR (CD ₃ OD / 400 MHz) δ-111.69 (m), -116.09 (m); ES-HRMS m / z 460.0432 (M + H required for C ₂₁ H ₁₇ N ₃ O ₂ BrF ₂ : 460.0467).

Example 390

N-1 ~-(5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl}- 2-methylpyrimidin-4-yl) glycineamide trifluoroacetate

N-methylmorpholine (0.14 mL, 0.0011 mol) was added to a solution of BOC-Gly-OH (0.19 g, 0.0011 mol) in DMF (2.0 mL), followed by isobutylchloroformate (0.15 mL, 0.0011 mol). Was added and stirred at −10 ° C. for 15 minutes, then 1-[(4-amino-2-methylpyrimidine-5- in DMF (2.0 mL) containing diisopropylethylamine (0.1 g, 0.006 mL). Solution of 1) methyl] -3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one trifluoroacetate (0.125 g, 0.00022 mol) Was added and the resulting mixture was stirred at rt for 16 h. The solvent was distilled under vacuum and the residue was purified by reverse-phase HPLC using 10-90% CH ₃ CN / water (30 min gradient) at a flow rate of 100 mL / min. Appropriate fractions (m / z = 608/610) were combined and lyophilized to yield 0.025 g of white powder. It was stirred with trifluoroacetic acid (0.5 mL) for 1 hour and the product was isolated by reverse-phase HPLC using 10-90% CH ₃ CN / water (30 min gradient) at a flow rate of 100 mL / min. . Appropriate fractions (m / z = 508/510) were combined and lyophilized to give the title compound (0.02 g) as a white powder: ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.18 (s, 1H), 7.61 (m, 1H), 7.02 (m, 2H), 6.59 (s, 1H), 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 required for C ₂₁ H ₂₁ N ₅ O ₃ BrF ₂ : 508.0790).

Example 391

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-{[2- (methylthio) pyrimidin-4-yl] methyl} pyridine-2 (1H) -On

Step 1. 4- (Bromomethyl) -2- (methylthio) pyrimidine

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 an argon atmosphere for 2 hours. Acetic acid was distilled under vacuum and the residue was triturated with dichloromethane (100.0 mL) and poured into saturated sodium bicarbonate solution (200.0 mL). Additional dichloromethane (100.0 ml) was added and stirred for 15 minutes. The organic phase was washed with water (3 x 100 mL), dried over Na ₂ S0 ₄ and concentrated under reduced pressure. The dark residue was purified by flash chromatography (EtOAc / hexane 1: 4 v / v) to give 4- (bromomethyl) -2- (methylthio) pyrimidine (10.9 g, 55%) as dark liquid. _{^{were: 1 H NMR (CDCl 3/}} 400 MHz) δ8.50 (d, 1H, J = 4.8 Hz), 7.09 (d, 1H, J = 4.8 Hz), 4.34 (s, 2H) and 2.56 (s, 3H ); ESMS m / z 219 (M + H).

Step 2

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one (5.0 g, 0.015 mol) and 4- (bro) in THF (50.0 mL) NaH (0.4 g, 0.0017 mol) was added to a mixture of mother methyl) -2- (methylthio) pyrimidine (4.0 g, 0.018 mol) and stirred at 55 ° C. under argon for 16 hours. 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 formed, which was filtered off, washed with water and EtOAc and dried under vacuum to afford the title compound (4.2 g, 59%) as a light brown powder. ¹ H NMR (CD ₃ OD / 400 MHz) δ8.45 (d, 1H, J = 5.2 Hz), 7.6 (m, 1H), 7.06 (d over m, 2H, J = 5.2 Hz), 6.54 (s, 1H), 5.39 (s, 2H), 5.32 (s, 2H), 2.43 (s, 3H), 2.33 (s, 3H); ES-HRMS m / z 468.0173 (M + H required for C ₁₉ H ₁₇ N ₃ O ₂ BrSF ₂ : 468.0187).

Example 392

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-{[2- (methylsulfonyl) pyrimidin-4-yl] methyl} pyridine-2 (1H )-On

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-{[2- (methylthio) pyrimidine in acetonitrile (8.0 ml) and water (2.0 ml) A suspension of -4-yl] methyl} pyridin-2 (1H) -one (0.28 g, 0.0006 mol) and magnesium monoperoxyphthalate hexahydrate (0.6 g, 0.0012 mol) was stirred at rt 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 over Na ₂ SO ₄ and concentrated to give the title compound (0.27 g, 90%) as a pale yellow material: ¹ H NMR (CD ₃ OD / 400 MHz) δ8.91 (d, 1H , J = 5.2 Hz), 7.63 (d over m, 2H, J = 5.2 Hz), 7.03 (m, 2H), 6.58 (s, 1H), 5.54 (s, 2H), 5.33 (s, 2H), 3.28 (s, 3H) and 2.49 (s, 3H); ¹⁹ F NMR (CD ₃ OD / 400 MHz) δ-111.58 (m), -115.98 (m); ES-HRMS m / z 500.0113 (M + H required for C ₁₉ H ₁₇ N ₃ O ₄ BrSF ₂ : 500.0086).

Example 393

4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} pyrimidine-2-carbonitrile Trifluoroacetate

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-{[2- (methylsulfonyl) pyrimidin-4-yl] methyl in DMF (5.0 mL) } A mixture of pyridin-2 (1H) -one (1.0 g, 0.002 mol) and NaCN (0.15 g, 0.0031 mol) was stirred at room temperature under argon atmosphere for 2 hours. DMF was distilled under vacuum, the residue was triturated with acetonitrile (10 mL) and water (10 mL) and the red precipitate was filtered off. It was washed with acetonitrile and dried to give the title compound (0.26 g). The washes and filtrates were combined and purified by reverse-phase HPLC using a 10-90% acetonitrile / water gradient (30 minutes) at a flow rate of 100 mL / min to afford an additional 0.5 g of the title compound: ¹ H NMR (CD ₃ OD / 400 MHz) δ8.83 (d, 1H, J = 5.2 Hz), 7.62 (d over m, 2H, J = 5.2 Hz), 7.00 (m, 2H), 6.58 (s, 1H), 5.46 (s, 2H), 5.33 (s, 2H) and 2.47 (s, 3H); ¹⁹ F NMR (CD ₃ OD / 400 MHz) δ-111.64 (m), -116.03 (m); ES-HRMS m / z 447.0278 (M + H required for C ₁₉ H ₁₄ N ₄ O ₂ BrF ₂ : 447.0263).

Example 394

4-{[2- (aminomethyl) -4-fluorobenzyl] oxy} -3-bromo-1- (2,6-difluorophenyl) -6-methylpyridin-2 (1H) -one tree Fluoroacetate

4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridine-1 in a solvent mixture of EtOAc (15.0 mL) and acetic acid (5.0 mL) To a solution of (2H) -yl] methyl} pyrimidine-2-carbonitrile trifluoroacetate (0.3 g, 0.00066 mol) was added Pd / C (10%, 0.18 g) and 2 hours at 15 psi under hydrogen atmosphere. Was stirred. The catalyst was removed by filtration. The filtrate was concentrated to dryness and the residue was purified by reverse-phase HPLC using a 10-90% acetonitrile / water gradient (30 min) at a flow rate of 100 mL / min. Combine the appropriate fractions (m / z = 451), and lyophilized to give the title compound (0.32 g, 64%) as an acetate salt to its ^{trifluoroacetate: 1 H NMR (DMSO-d} 6/400 MHz) δ8.78 (d, 1H, J = 5.2 Hz), 8.28 (br, 2H), 7.62 (m, 1H), 7.38 (m, 1H), 7.25 (d, 1H, J = 5.2 Hz), 7.18 (m 1H), 6.62 (s, 1H), 5.32 (s, 2H), 5.29 (s, 2H), 4.24 (s, 2H) and 2.46 (s, 3H); _{^{19 F NMR (DMSO-d 6}} /400 MHz) δ-109.59 (m), -113.67 (m); ES-HRMS m / z 451.0530 (M + H required for C ₁₉ H ₁₈ N ₄ O ₂ BrF ₂ : 451.0576).

Example 395

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1-[(2-methoxypyrimidin-4-yl) methyl] -6-methylpyridin-2 (1H) -one Trifluoroacetate

4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} pyridine in MeOH (2.0 mL) A solution of midine-2-carbonitrile trifluoroacetate (0.13 g, 0.00023 mol) was treated with 1N NaOH (0.5 mL). After stirring for 3 hours at room temperature, it was further heated at 60 ° C. for 3 hours and left at room temperature overnight. The resulting solution was diluted with acetonitrile and purified by reverse-phase HPLC using a 10-90% acetonitrile / water gradient (30 minutes) at a flow rate of 100 mL / min. Appropriate fractions (m / z = 452) were combined and lyophilized to afford the title compound (0.015 g) as a white powder: ¹ H NMR (CD ₃ OD) δ 8.84 (d, 1H, J = 5.2 Hz), 7.62 (d, 1H, J = 5.2 Hz), 7.05 (m, 2H), 6.57 (s, 1H), 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 required for C ₁₉ H ₁₇ N ₃ O ₃ BrF ₂ : 452.0416).

Example 396

Methyl 4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] pyrimidine-2-carboxylate Trifluoroacetate

The title compound was converted to 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1-[(2-methoxypyrimidin-4-yl) methyl] -6-methylpyridine-2 (1H Obtained as a secondary product of the formation of) -on trifluoroacetate. ¹ H NMR (CD ₃ OD / 400 MHz) δ8.46 (d, 1H, J = 5.2 Hz), 7.62 (m, 1H), 7.00 (m, 2H), 6.93 (d, 1H, J = 5.2 Hz) , 6.55 (s, 1H), 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 required for C ₂₀ H ₁₇ N ₃ O ₄ BrF ₂ : 480.0365).

Example 397

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1-[(2-hydroxypyrimidin-4-yl) methyl] -6-methylpyridin-2 (1H) -one Trifluoroacetate

4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl in t-butanol (5.0 mL) } A mixture of pyrimidine-2-carbonitrile trifluoroacetate (0.2 g, 0.00035 mol) and potassium fluoride on aluminum oxide (0.25 g) was refluxed under an argon atmosphere for 4 hours. The reaction mixture was cooled down, the precipitate was filtered off and washed with ethanol. The combined filtrates and washes were concentrated to dryness, and the residue was purified by reverse-phase HPLC using a 10-90% acetonitrile / water gradient (30 minutes) at a flow rate of 100 mL / min. Combine the appropriate fractions (m / z = 452), and lyophilized to give the title compound (0.05 g) as a white ^{powder: 1 H NMR (DMSO-d} 6/400 MHz) δ7.85 (d, 1H, J = 6.4 Hz), 7.64 (m, 1H), 7.30 (m, 1H), 7.15 (m, 1H), 6.55 (s, 1H), 6.22 (d, 1H, J = 6.4 Hz), 5.28 (s, 2H) , 5.12 (d, 2H) and 2.29 (s, 3H); ^{19 F-NMR (DMSO-d} 6/400 MHz) δ-109.69 (m) and -113.67 (m); ES-HRMS m / z 438.0228 (M + H required for C ₁₈ H ₁₅ N ₃ O ₃ BrF ₂ : 438.0259).

Example 398

4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} pyrimidine-2-carbox Amide trifluoroacetate

The title compound was obtained by the method described in Example 397. _{^{1 H NMR (DMSO-d 6}} /400 MHz) δ8.82 (d, 1H, J = 5.2 Hz), 8.01 (br, 1H), 7.79 (br 1H), 7.64 (m, 1H), 7.34 (m, 2H), 7.16 (m, 1H), 6.62 (s, 1H), 5.36 (s, 2H), 5.30 (s, 2H) and 2.38 (s, 3H); _{^{19 F NMR (DMSO-d 6}} /400 MHz) δ-109.64 (m) and -113.66 (m); ES-HRMS m / z 465.0385 (M + H required for C ₁₉ H ₁₆ N ₄ O ₃ BrF ₂ : 465.0368).

Example 399

Methyl (4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} pyrimidin-2- (1) methylcarbamate

4-{[2- (aminomethyl) -4-fluorobenzyl] oxy} -3-bromo-1- (2,6-difluorophenyl) -6-methylpyridine in dimethylacetamide (1.0 mL) To a solution of -2 (1H) -on trifluoroacetate (0.13 g, 0.00023 mol) was added triethylamine (0.04 mL, 0.0003 mol) followed by methylchloroformate (0.05 mL) and at 0 ° C. Stir for 30 minutes 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 to dry (Na ₂ SO ₄ ) and concentrated to dryness. The resulting residue was purified by flash chromatography (5% MeOH in EtOAc) to afford the title compound as a pale yellow powder (0.055 g, 37%). _{^{1 H NMR (DMSO-d 6}} /400 MHz) δ8.65 (d, 1H J = 5.6 Hz), 7.63 (1H), 7.5 (m, 1H), 7.28 (m 1H), 7.13 (m, 2H), 6.59 (s, 1 H), 5.28 (s, 4 H), 5.26 (d, 2H, J = 6.0 Hz), and 2.46 (s, 3H); _{^{19 F NMR (DMSO-d 6}} /400 MHz) δ-109.64 (m), and -113.71 (m); ES-HRMS m / z 509.0621 (M + H required for C ₂₁ H ₂₀ N ₄ O ₄ BrF ₂ : 509.0630).

Example 400

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-[(5-methylpyrazin-2-yl) methyl] pyridin-2 (1H) -one

Step 1

4-hydroxy-6-methyl-1-[(5-methylpyrazin-2-yl) methyl] pyridin-2 (1H) -one

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 hour. Heated under argon atmosphere. The reaction mixture was cooled down and the yellow precipitate was filtered off. It was washed with ethanol and dried in vacuo to yield the title compound as a pale yellow powder (5.8 g, 63%). _{^{1 H NMR (DMSO-d 6}} /400 MHz) δ 10.43 (br, 1H), 8.38 (d, 2H, J = 5.2 Hz), 5.77 (d, 1H, J = 2.0 Hz), 5.58 (d, 1H, 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

3-bromo-4-hydroxy-6-methyl-1-[(5-methylpyrazin-2-yl) methyl] pyridin-2 (1H) -one

The title compound was prepared according to the method described in step 2 of Example 385.

Yield: 64%, ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.47 (s, 1H), 8.42 (s, 1H), 6.07 (s, 1H), 5.38 (s, 2H), 2.51 (s, 3H ), And 2.44 (s, 3H), ESMS m / z 310 and 312 (M + H).

Step 3

3-bromo-4-hydroxy-6-methyl-1-[(5-methylpyrazin-2-yl) methyl] pyridin-2 (1H) -one (0.45 g, 0.0015 in dimethylacetamide (5.0 mL) mol) and potassium carbonate (0.25 g, 0.0018 mol) were added 2,4-difluorobenzyl bromide (0.25 mL, 0.0019 mol) and stirred at room temperature under argon for 1 hour. Dimethylacetamide was distilled under vacuum and the residue was partitioned between CH ₂ Cl ₂ (20 mL) and water (20 mL). Dry the organic phase was washed with water (Na ₂ SO ₄₎ and concentrated under reduced pressure. The resulting material was purified by flash chromatography (eluent = EtOAc / hexane 4: 1 v / v). Appropriate fractions (m / z = 451/453) were combined and concentrated under reduced pressure to yield a white solid (0.25 g, 38%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.49 (s, 1H), 8.40 (s, 1H), 7.60 (m, 1H), 6.99 (m, 2H), 6.51 (s, 1H), 5.42 (s , 2H), 5.29 (s, 2H), 2.54 (s, 3H), and 2.50 (s, 3H); ¹⁹ F NMR (CD ₃ OD / 400 MHz) δ-117.70 (m), and -116.09 (m); ES-HRMS m / z 436.0439 (M + H required for C ₁₉ H ₁₇ N ₃ O ₂ BrF ₂ : 436.0467).

Example 401

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (pyrazin-2-ylmethyl) pyridin-2 (1H) -one

Step 1

2-chloromethylpyrazine

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 under an argon atmosphere for 16 hours. It was filtered and the filtrate was concentrated to dryness. The resulting residue was purified by flash chromatography using 30% EtOAc in hexanes to give 2-chloromethylpyrazine as a dark colored liquid (1.7 g, 36%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.75 (d, 1H, J = 1.2 Hz), 8.58 (m, 1H), 8.56 (m, 1H), and 4.75 (s, 2H); ESMS m / z = 129 (M + H).

Step 2

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one (1.8 g, 0.0055 mol) and 2-chloropyrazine (0.8 g, 0.00625) Was suspended in THF (25 mL) before NaH (0.15 g, 0.0062 mol), KI (0.1 g) was added and the mixture was heated at 65 ° C. under an argon atmosphere for 16 h. The reaction mixture was cooled down and acetic acid (0.5 mL) was added and concentrated under reduced pressure until dry. The residue was stirred with a mixture of water (50 mL) and EtoAc (25 mL) and the precipitate was filtered off. It was washed with water and acetonitrile and dried under vacuum to give 1.7 g of a light brown powder. ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.65 (d, 1H), 8.49 (m, 1H), 8.47 (m, 1H), 7.61 (~ q, 1H), 7.02 (m, 2H), 6.52 ( s, 1H), 5.47 (s, 2H), 5.23 (s, 2H), and 2.53 (s, 3H); ¹⁹ F NMR (CD ₃ OD / 400 MHz) δ-111.72 (m), and -116.07 (m); ES-HRMS m / z 422.0283 (M + H required for C ₁₈ H ₁₅ N ₃ O ₂ BrF ₂ : 422.0310).

Example 402

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1-{[5- (hydroxymethyl) pyrazin-2-yl] methyl} -6-methylpyridine-2 (1H) -On

Step 1

Ethyl 5-methylpyrazine-2-carboxylate

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 under an argon atmosphere for 4 hours. The dark solution was cooled and concentrated under reduced pressure by addition of sodium bicarbonate (1.0 g). The residue was partitioned between water (50 mL) and EtOAc (100 mL). The organic layer was washed with water (2 × 25 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to give ethyl 5-methylpyrazine-2-carboxylate as an orange liquid (12.05 g, 67%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 9.1 (d, 1H, J = 1.2 Hz), 8.62 (d, 1H, 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

Ethyl 5- (bromomethyl) pyrazine-2-carboxylate

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 minutes. After acetic acid was removed in vacuo, the residue was partitioned between saturated bicarbonate (100 mL) and EtOAc (3 × 30 mL). The combined EtOAc extracts were washed with water (2 × 25 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The resulting liquid was purified by flash chromatography (20% EtOAc in hexanes), ethyl-to give (5-bromomethyl-pyrazin-2-carboxylate as an orange liquid ^{(7.7 g, 44%) 1} H NMR (CD ₃ OD / 400 MHz) δ 9.18 (d, 1H, J = 1.2 Hz), 8.85 (d, 1H, 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 requirement for C ₈ H ₁₀ N ₂ O ₂ Br: 244.9920).

Step 3

Ethyl 5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} pyrazine-2-carboxyl Rate

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one (6.0 g, 0.018 mol) and ethyl 5- (in THF (50.0 mL) NaH (0.5 g) was added to a mixture of bromomethyl) pyrazine-2-carboxylate (4.9 g, 0.02 mol) and heated at 55 ° C. under an argon atmosphere for 3 hours. The reaction mixture was cooled down and acetic acid (1.2 mL) was added and concentrated under reduced pressure. The residue was triturated with water and the solid was filtered off. It was washed with water, then with ethanol and dried in vacuo to give the title compound as a light brown powder (3.0 g, 78%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 9.10 (d, 1H, J = 1.2 Hz), 8.77 (d, 1H, J = 1.2 Hz), 7.61 (m, 1H), 7.01 (m 2H), 6.54 (s, 1H), 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 ); ¹⁹ F NMR (CD ₃ OD / 400 MHz) δ-111.64 (m), and -116.04 (m); ES-HRMS m / z 494.0482 (M + H required for C ₂₁ H ₁₉ N ₃ 0 ₄ BrF ₂ : 494.0522).

Step 4

ethyl 5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridine in t-butanol (15,0 mL) and THF (5.0 mL) To a suspension of -1 (2H) -yl] methyl} pyrazine-2-carboxylate (2.0 g, 0.004 mol) is added NaBH ₄ (0.18 g, 0.0047 mol) and the mixture is kept under argon atmosphere at room temperature for 16 hours. Stirred. It was cooled and concentrated to dryness by addition of MeOH (5.0 mL) and acetic acid (1.0 mL). 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 give the title compound as a pale yellow powder (0.75 g, 41%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.58 (d, 1H, J = 1.6 Hz), 8.56 (d, 1H, J = 1.6 Hz), 7.6 (m, 1H), 7.01 (m, 2H), 6.52 (s, 1H), 5.46 (s, 2H), 5.29 (s, 2H), 4.71 (s, 2H), and 2.54 (s, 3H); ¹⁹ F NMR (CD ₃ OD / 400 MHz) δ-111.70 (m), and -116.06 (m); ES-HRMS m / z 452.0394 (M + H required for C ₁₉ H ₁₇ N ₃ 0 ₃ BrF ₂ : 452.0416).

Example 403

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1-({5-[(dimethylamino) methyl] pyrazin-2-yl} methyl) -6-methylpyridine-2 ( 1H) -one trifluoroacetate

Step 1

3-bromo-1-{[5- (chloromethyl) pyrazin-2-yl] methyl} -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridine-2 (1H)- On

Cyanurylchloride (0.42 g, 0.0023 mol) was added to DMF (0.52 mL) and stirred at room temperature for 15 minutes. Then 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1-{[5- (hydroxymethyl) pyrazin-2-yl] after addition of dichloromethane (15 mL) Methyl} -6-methylpyridin-2 (1H) -one (1.0 g, 0.0022 mol) was added and the reaction mixture was stirred at room temperature under argon atmosphere. After 1 hour further 1.0 ml of DMF was added and the reaction was allowed to proceed for 1 hour until a clear solution was obtained. The solution was diluted with dichloromethane (20 mL), washed with water to dry (Na ₂ SO ₄ ), and concentrated under reduced pressure until dry. The residue was triturated with EtOAc, filtered, washed with EtOAc and dried to give 0.79 g of the title compound as a pale yellow powder (77%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.66 (s, 2H), 7.73 (m, 1H), 7.05 (m, 2H), 6.56 (s, 1H), 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 required for C ₁₉ H ₁₆ N ₃ O ₂ BrClF ₂ : 470.0077).

Step 2

3-bromo-1-{[5- (chloromethyl) pyrazin-2-yl] methyl} -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridine in THF (1.0 mL) A suspension of -2 (1H) -one (0.25 g, 0.00053 mol) was treated with N, N-dimethylamine (1.0 mL of 2M solution in THF) and stirred at room temperature for 16 hours. The reaction mixture was concentrated and isolated by reverse phase HPLC using 10-90% acetonitrile / water gradient (30 min) at a flow rate of 100 mL / min. Appropriate fractions (m / z = 479) were combined and freeze dried to afford the title compound as a white powder (0.27 g, 87%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.78 (d, 1H, J Hz), 8.56 (d, 1H, J = 1.2 Hz), 7.61 (m 1H), 7.01 (m, 2H), 6.55 (s , 1H), 5.49 (s, 2H), 5.30 (s, 2H), 4.52 (s, 2H), 2.94 (s, 6H) and 2.57 (s, 3H); ¹⁹ F NMR (CD ₃ OD) δ-111.56 (m) and -116.02 (m); ES-HRMS m / z 479.0885 (M + H required for C ₂₁ H ₂₂ N ₄ O ₂ BrF ₂ : 479.0889).

Example 404

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1-[(5-{[(2-hydroxyethyl) (methyl) amino] -methyl} pyrazin-2-yl) Methyl] -6-methylpyridin-2 (1H) -one trifluoroacetate

In the manner described in Example 403, the title compound was prepared by replacing N, N-dimethylamine with N-methylaminoethanol. Yield = 78%. ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.78 (d, 1H, J Hz), 8.59 (d, 1H, J = 1.2 Hz), 7.6 (m, 1H), 7.01 (m, 2H), 6.55 ( s, 1H), 5.49 (s, 2H), 5.30 (s, 2H), 3.89 (~ t, 2H), 2.97 (s, 3H), and 2.57 (s, 3H); ¹⁹ F NMR (CD ₃ OD / 400 MHz) δ-111.56 (m) and -116.04 (m); ES-HRMS m / z 509.0964 (M + H required for C ₂₂ H ₂₄ N ₄ O ₃ BrF ₂ : 509.0994).

Example 405

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-({5-[(4-methylpiperazin-1-yl) carbonyl] pyrazine-2- Methyl) pyridin-2 (1H) -one trifluoroacetate

Step 1

5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} pyrazine-2-carboxylic acid

Ethyl 5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} pyrazine-2-carboxyl The suspension of rate (0.18 g, 0.002 mol) and 1 N NaOH (0.6 mL in 1: 1 v / v EtOH / water) was stirred at room temperature for 1.5 hours. The reaction mixture was acidified with 5% citric acid and the precipitate was filtered off. It was washed with water followed by ethanol and dried in vacuo to give the title compound as a light brown powder (0.14 g, 77%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 9.03 (s. 1H), 8.60 (s, 1H), 7.61 (m. 1H), 7.00 (m, 2H), 6.52 (s, 1H), 5.51 (s , 2H), 5.30 (s. 2H), and 2.52 (s, 3H); ¹⁹ F NMR (CD ₃ OD / 400 MHz) δ-111.75 (m) and -116.06 (m); ES-HRMS m / z 466.0209 (M + H required for C ₁₉ H ₁₅ N ₄ 0 ₃ BrF ₂ : 466.0209).

Step 2

5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} pyrazine in DMF (3.0 mL) Isobutylchloroformate (0.082 g, 0.0006 mol) is added to a -15 ° C solution of 2-carboxylic acid (0.28 g, 0.0006 mol), followed by addition of N-methylmorpholine (0.06 g, 0.00063 mol), And stirred under argon for 15 minutes. To the reaction was then added N-methylpiperazine (0.072 g, 0.00072 mol) in DMF (2.0 mL) and the mixture was stirred at rt for 3 h. After the solvent was removed in vacuo, the residue was purified by reverse phase HPLC using a 10-90% acetonitrile / water gradient (30 min) at a flow rate of 100 mL / min. Appropriate fractions (m / z = 548) were combined and freeze dried to afford the title compound as a white powder (0.32 g, 80%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.89 (d, 1H, J = 1.6 Hz), 8.73 (d, 1H, J = 1.6 Hz), 7.61 (m, 1H), 7.01 (m, 2H), 6.56 (s, 1H), 5.50 (s, 2H), 5.30 (s, 2H), 2.9 (s, 3H), and 2.57 (s, 3H); ¹⁹ F NMR (CD ₃ OD / 400 MHz) δ-109.36 (m) and -114.91 (m); ES-HRMS m / z 548.1090 (M + H required for C ₂₄ H ₂₅ N ₅ 0 ₃ BrF ₂ : 548.1103).

Example 406

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-({5-[(4-methylpiperazin-1-yl) carbonyl] pyrazine-2- Methyl) pyridin-2 (1H) -one

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-({5-[(4-methylpiperazin-1-yl) in 0.1 N NaOH (25 mL) ) Carbonyl] pyrazin-2-yl} methyl) pyridin-2 (1H) -one trifluoroacetate (0.17 g, 0.00026 mol) is stirred at room temperature for 15 minutes and the product is ethyl acetate (2 × 20 Ml). The combined organic extracts were washed with water (2 × 20 mL), dried (Na ₂ SO ₄ ) and concentrated to dryness. The residue was dried in vacuo to give the title product as a white powder (0.09 g, 64%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.69 (d, 1H, J = 1.2 Hz), 8.67 (d, 1H, J = 1.2 Hz), 7.60 (m, 1H), 7.00 (m, 2H), 6.54 (s, 1H), 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); ¹⁹ F NMR (CD ₃ OD / 400 MHz) δ-111.65 (m) and -116.06 (m); ES-HRMS m / z 548.1123 (M + H required for C ₂₄ H ₂₅ N ₅ 0 ₃ BrF ₂ : 548.1103).

Example 407

5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N- (2-hydric Oxyethyl) -N-methylpyrazine-2-carboxamide

In the same manner as described in Example 405, the title compound was prepared by replacing N-methylpiperazine with N-methylethanolamine. Yield = 60%. ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.69 (d, 1H, J = 1.2 Hz), 8.64 (d, 1H, J = 1.2 Hz), 7.61 (m, 1H), 7.00 (m, 2H), 6.54 (s, 1H), 5.49 (s. 2H), 5.30 (s, 2H), 3.81 (~ t, 1H), 3.66 (m, 2H), 3.56 (t, 1H, J = 5.2 Hz), 3.12 ( d, 3H J = 7.6 Hz), 2.56 (s, 3H); ¹⁹ F NMR (CD ₃ OD / 400 MHz) δ-109.64 (m) and -113.66 (m); ES-HRMS m / z 523.0743 (M + H required for C ₂₂ H ₂₂ N ₄ O ₄ BrF ₂ : 523.0797).

Example 408

5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N- (2,3 -Dihydroxypropyl) pyrazine-2-carboxamide

In the same manner as described in Example 405, the title compound was prepared by replacing N-methylpiperazine with 3-amino-1,2-propanediol. Yield = 56%. ¹ H NMR (CD ₃ OD / 400 MHz) δ 9.09 (d, 1H, J = 1.2 Hz), 8.70 (d, 1H, J = 1.2 Hz), 7.60 (m, 1H), 7.00 (m, 2H), 6.54 (s, 1H), 5.53 (s. 2H), 5.30 (s, 2H), 3.80 (m, 1H), 3.61 (dd, 1H), 5.53 (d, 2H), J = 5.2 Hz), 3.42 ( dd, 1 H), and 2.55 (s, 3 H); ¹⁹ F NMR (CD ₃ OD / 400 MHz) δ-109.65 (m), and -113.67 (m); ES-HRMS m / z 539.0703 (M + H required for C ₂₂ H ₂₂ N ₄ O ₄ BrF ₂ : 539.0736).

Example 409

5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N- (2-hydrate Oxyethyl) pyrazine-2-carboxamide

In the same manner as described in Example 405, the title compound was prepared by replacing N-methylpiperazine with 2-aminoethanol. Yield = 46%. ¹ H NMR (CD ₃ OD / 400 Hz) δ 9.08 (d, 1H, J =. 1.2 Hz), 8.70 (d, 1H, J = 1.2 Hz), 7.601 (m, 1H), 7.01 (m, 2H) , 6.54 (s, 1H), 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);); ¹⁹ F NMR (CD ₃ OD / 400 MHz) δ-111.67 (m) and -116.07 (m); ES-HRMS m / z 509.0616 (M + H required for C ₂₁ H ₂₀ N ₄ 0 ₄ BrF ₂ : 509.0630).

Example 410

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1-{[5- (methoxymethyl) pyrazin-2-yl] methyl} -6-methylpyridine-2 (1H) -On

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1-{[5- (hydroxymethyl) pyrazin-2-yl] methyl} -6-methylpyridine-2 in DMF To a 0 ° C. solution of 1H) -one (0.35 g, 0.00078 mol) was added NaH (0.022 g, 0.00092 mol) and stirred for 10 minutes. Iodomethane (0.05 mL) was added to the reaction and the mixture was stirred at 10 ° C. for 3 hours. DMF was distilled under vacuum and the residue was partitioned between 5% citric acid and EtOAc (15.0 mL). The organic phase was washed with water to dry (Na 2 SO 4) and concentrated to dryness. The residue was purified by flash chromatography (EtOAc) and the appropriate fractions combined and concentrated to a pale yellow powder. ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.59 (s), 8.55 (s, 1H), 7.60 (m, 1H), 6.99 (m, 2H), 6.52 (s, 1H), 5.47 (s, 2H ), 5.30 (s, 2H), 4.57 (s, 2H), 3.44 (s, 2H), and 2.54 (s, 3H); ¹⁹ F NMR (CD ₃ OD / 400 MHz) δ-111.69 (m) and -116.09 (m); ES-HRMS m / z 466.0577 (M + H required for C ₂₁ H ₁₉ N ₃ 0 ₃ BrF ₂ : 466.0572).

Example 411

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1-({5-[(2-methoxyethoxy) methyl] pyrazin-2-yl} methyl) -6-methyl Pyridin-2 (1H) -one

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1-{[5- (hydroxymethyl) pyrazin-2-yl] methyl} -6-methylpyridine- in dimethyl acetamide To a 2 (1H) -one (0.25 g, 0.00055 mol) 0 ° C. solution was added NaH (0.016 g, 0.00067 mol) and stirred for 15 minutes. 2-methoxyethyl bromide (0.09 g, 0.00-65 mol) was then added and the mixture was stirred at rt for 6 h. Dimethylacetamide was distilled under vacuum and the product was purified by reverse phase HPLC using a 10-90% acetonitrile / water gradient (30 min) at a flow rate of 100 mL / min. Appropriate fractions (m / z = 510) were combined and lyophilized to afford the title compound as a white powder (0.32 g, 80%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.59 (s. 1H), 8.58 (s, 1H), 7.60 (m, 1H), 7.02 (m, 2H), 6.52 (s, 1H), 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 required for C ₂₀ H ₁₈ N ₄ 0 ₄ BrF ₂ : 510.0835).

Example 412

(5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} pyrazin-2-yl) Methyl carbamate

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1-{[5- (hydroxymethyl) pyrazin-2-yl] in THF (5.0 mL) and DMF (2.0 mL) To a suspension of methyl} -6-methylpyridin-2 (1H) -one (0.21 g, 0.00055 mol) was added 4-nitrophenylchloroformate (0.1 g, 0.0005 mol) and cooled to 0 ° C. Triethylamine (0.052 g, 0.0005 mol) was then added and stirred at room temperature for 1 hour and further stirred at 65 ° C. for 1 hour. It was cooled in an ice bath and 2 M ammonia (1.0 mL) in propanol was added and stirred at room temperature for 2 hours. After removal of solvent under reduced pressure, the residue was partitioned between 5% sodium bicarbonate and EtOAc (25 mL). The organic phase was washed with 5% sodium bicarbonate (3 × 25 mL), water (3 × 25 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The resulting material was purified by isolation by reverse phase HPLC using 10-90% CH ₃ CN / water (30 min gradient) at a flow rate of 100 mL / min. Appropriate fractions (m / z = 495 M + H) were combined and lyophilized and the residue was partitioned between 5% sodium bicarbonate (20 mL) and EtOAc (25 mL). The organic phase was washed with water to dry (Na ₂ SO ₄ ) and concentrated under reduced pressure to dryness to afford the title compound as a white powder (0.065 g). ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.61 (br s, 1H), 8.54 (br s, 1H), 7.60 (m, 1H), 7.02 (m, 2H), 6.52 (s, 1H), 5.47 (s, 2H), 5.29 (s, 2H), 5.15 (s, 2H), and 2.54 (s, 3H): ¹⁹ F NMR (CD ₃ OD) δ-111.70 (m), and -116.09 (m); ES-HRMS m / z 495.0449 (M + H required for C ₂₀ H ₁₈ N ₄ 0 ₄ BrF ₂ : 495.0474)

Example 413

1-benzyl-3-bromo-2-oxo-1,2-dihydropyridin-4-yl methyl (phenyl) carbamate

Step 1: Preparation of 1-benzyl-2-oxo-1,2-dihydropyridin-4-yl methyl (phenyl) carbamate

Triethylamine (0.206 g, 2.04 mmol) was added to a cooled solution of 1-benzyl-4-hydroxypyridin-2 (1H) -one (0.375 g, 1.86 mmol) in anhydrous acetonitrile (10 mL), followed by N -Methyl-N-phenylcarbamoyl chloride (0.379 g, 2.24 mmol) was added. The reaction mixture was stirred at 0 ° C. for 30 minutes under nitrogen atmosphere and then at room temperature for 1 hour. 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 combined organic extracts were washed with water and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure to give a yellow syrup. The residue was purified by flash chromatography (silica gel) using 5% MeOH in CH ₂ Cl ₂ to afford the desired product as a white semisolid (0.382 g, 61%). ¹ H-NMR (d ₆ -DMSO, 400 MHz) δ 7.8 (d, 1H, 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 C ₂₀ H ₁₉ N ₂ 0 ₃ : 335.1418).

Step 2: Preparation of 1-benzyl-3-bromo-2-oxo-1,2-dihydropyridin-4-yl methyl (phenyl) carbamate

N-bromo in a solution of 1-benzyl-2-oxo-1,2-dihydropyridin-4-yl methyl (phenyl) carbamate (0.38 g, 1.13 mmol) in anhydrous CH ₂ Cl ₂ (7 mL). Succinimide (NBS, 0.24 g, 1.34 mmol) was added. The reaction was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was purified by flash chromatography (silica gel) using ethyl acetate / hexanes (1: 1 v / v). Appropriate fractions were collected and concentrated according to ES MS (M + H 413). The dried product was found to be about 14% dibrominated product in analytical HPLC. The compound was separated by reversed phase HPLC using 10-90% acetonitrile (30 min gradient) in water at a flow rate of 100 mL / min to give a salt of the desired compound (after freeze drying). The salt was diluted in ethyl acetate and washed with NaHCO ₃ . The organic extract was dried over anhydrous Na ₂ SO ₄ and concentrated to afford the desired compound as a beige solid (0.271 g, 58%). ¹ H-NMR (d ₆ -DMSO, 400 MHz) δ 7.94 (d, 1H, J = 7.2 Hz), 7.29 (m, 10H), 6.48 (s, 1H), 5.12 (s, 2H), 3.33 (s , 3H); ES-HRMS m / z 413.0495 (M + H calculated for C ₂₀ H ₁₈ 0 ₃ Br: 413.0496).

Example 414

4- (benzyloxy) -3-ethynyl-1- (3-fluorobenzyl) pyridin-2 (1H) -one

Step 1: Preparation of 4- (benzyloxy) -1- (3-fluorobenzyl) -3-iodopyridin-2 (1H) -one

4- (benzyloxy) -1- (3-fluorobenzyl) pyridin-2 (1H) -one (4.83 g, 15.6 mmol) and N-iodosuccinimide (NIS, in anhydrous acetonitrile (55 mL) 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 / hexanes (1: 1 v: v). Appropriate fractions were collected according to ES MS (M + H 436) and washed with Na ₂ SO ₃ to remove colored impurities. Fractions were concentrated under reduced pressure and dried under vacuum to afford the desired product as a light yellow solid (6.15 g, 90%). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.73 (d, 1H, J = 7.6 Hz), 7.47 (d, 2H, J = 7.2 Hz), 7.39 (m, 4H), 7.08 (m, 3H) , 6.39 (d, 1H, J = 8.0 Hz), 5.29 (s, 2H), 5.19 (s, 2H); ES-HRMS m / z 436.0210 (M + H calculated for C ₁₉ H ₁₆ NO ₂ FI: 436.0196).

Step 2: Preparation of 4- (benzyloxy) -1- (3-fluorobenzyl) -3-[(trimethylsilyl) ethynyl] pyridin-2 (1H) -one

A solution of 4- (benzyloxy) -1- (3-fluorobenzyl) -3-iodopyridin-2 (1H) -one (2.01 g, 4.62 mmol) in anhydrous acetonitrile (25 mL) was placed under argon atmosphere. It was degassed. Triethylamine (1.11 g, 11 mmol) was added and degassed rapidly. The reaction mixture was cooled in an ice bath for 15 minutes and then bistriphenylphosphine-palladium chloride (0.34 g, 0.48 mmol) and cuprous iodide (0.2 g) were added. The reaction was stirred at room temperature for 30 minutes and then heated at 60 ° C. under argon atmosphere for 2 hours. The reaction mixture was filtered through a celite bed and the filtrate was concentrated under reduced pressure. Dark brown residue to CH ₂ Cl ₂ (100 mL) and washed with water. The organic extracts were combined, dried over anhydrous Na ₂ SO _{4 and} concentrated under reduced pressure. The dark brown residue was purified by flash chromatography using 30% ethyl acetate in hexanes. Appropriate fractions were combined and concentrated under reduced pressure to give the desired product as a light yellow solid (1.34 g, 72%). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.74 (d, 1H, J = 7.6 Hz), 7.47 (d, 2H, J = 7.6 Hz), 7.35 (m, 4H), 7.09 (m, 3H) , 6.46 (d, 1H, J = 7.6 Hz), 5.26 (s, 2H), 5.13 (s, 2H), 0.18 (s, 9H); ES-HRMS m / z 406.1638 (M + H calculated for C ₂₄ H ₂₅ NO ₂ FSi: 406.1610).

Step 3: Preparation of 4- (benzyloxy) -3-ethynyl-1- (3-fluorobenzyl) pyridin-2 (1H) -one

4- (benzyloxy) -1- (3-fluorobenzyl) -3-[(trimethylsilyl) ethynyl] pyridin-2 (1H) -one (1.31 g, 3.2 mmol) in anhydrous acetonitrile (25 mL) To a 0 ° C. solution of tetrabutylammonium fluoride (0.611 g, 1.93 mmol) was added. The reaction was stirred at 0 ° C. for 15 minutes and then at room temperature for 1 hour. The reaction was concentrated under reduced pressure and the residue was diluted with ethyl acetate and washed with water. The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel) using ethyl acetate in hexanes (1: 1 v / v). Appropriate fractions were combined and concentrated under reduced pressure to afford the desired product as a gold solid (0.779 g, 72%). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.73 (d, 1H, J = 7.6 Hz), 7.43 (d, 2H, J = 7.2 Hz), 7.35 (m, 4H), 7.09 (m, 3H) , 6.45 (d, 1H, J = 7.6 Hz), 5.27 (s, 2H), 5.13 (s, 2H), 3.78 (s, 1H); ES-HRMS m / z 334.1243 (M + H calculated for C ₂₁ H ₁₇ NO ₂ F: 334.1234).

Example 415

4- (benzylamino) -3-bromo-1- (3-fluorobenzyl) pyridin-2 (1H) -one

Step 1: Preparation of 1- (3-fluorobenzyl) -4-hydroxypyridin-2 (1H) -one

A solution of 4- (benzyloxy) -1- (3-fluorobenzyl) pyridin-2 (1H) -one (4.5 g, 14.56 mmol) in anhydrous ethanol (20 mL) was added in a Fischer-Porter bottle. After washing with nitrogen, a palladium catalyst (1.05 g, 10% Pd / C) was added. The bottle was sealed and the system evacuated. 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 washed with nitrogen. The reaction was filtered and the catalyst was carefully washed with fresh ethanol. The filtrate was concentrated under reduced pressure. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.54 (d, 1H, J = 7.6 Hz), 7.32 (m, 1H), 7.06 (d, 1H, J = 7.6 Hz), 6.99 (m, 2H) , 6.05 (dd, 1H, J = 2.4 Hz, 2.8 Hz), 5.83 (d, 1H, J = 2.4 Hz), 5.09 (s, 2H); ES-HRMS m / z 220.0774 (M + H calculated for C ₁₂ H ₁₁ NO ₂ F: 220.0787).

Step 2: Preparation of 4- (benzylamino) -1- (3-fluorobenzyl) pyridin-2 (1H) -one

A mixture of 1- (3-fluorobenzyl) -4-hydroxypyridin-2 (1H) -one (1.005 g, 4.5 mmol) in benzylamine (15 mL) was heated to reflux for 24 hours under nitrogen atmosphere (185 ° C.) ) The reaction was monitored by ES-MS (MH + 309). The solvent was removed by vacuum distillation to yield a yellow residue. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.31 (m, 7H), 7.03 (m, 3H), 5.98 (d, 1H, J = 7.2 Hz), 5.45 (s, 1H), 5.00 (s, 2H), 4.30 (s, 2H); ES-HRMS m / z 309.1403 (M + H calculated for C ₁₉ H ₁₈ N ₂ 0F: 309.1375).

Step 3: Preparation of 4- (benzylamino) -3-bromo-1- (3fluorobenzyl) pyridin-2 (1H) -one

Anhydrous CH ₂ Cl ₂ N-bromosuccinimide (NBS, 0.30) in a solution of 4- (benzylamino) -1- (3-fluorobenzyl) pyridin-2 (1H) -one (0.50 g, 1.62 mmol) in (10 mL) g, 1.7 mmol) was added. The reaction was stirred at room temperature under nitrogen atmosphere for 3 hours. The reaction mixture was purified by flash chromatography (silica gel) using ethyl acetate in hexanes (1: 1 v / v). Appropriate fractions were combined and concentrated. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.41 (d, 1H, J = 7.6 Hz), 7.31 (m, 6H), 7.04 (m, 3H), 5.99 (d, 1H, J = 7.6 Hz) , 5.08 (s, 2 H), 4.53 (s, 2 H); ES-HRMS m / z 387.0508 (M + H calculated for C ₁₉ H ₁₇ N ₂ OBrF: 387.0504).

Example 416

4- (benzyloxy) -1- (3-fluorobenzyl) -3-methylpyridin-2 (1H) -one

Step 1: Preparation of 4- (benzyloxy) -1- (3-fluorobenzyl) -3-iodopyridin-2 (1H) -one

4- (benzyloxy) -1- (3-fluorobenzyl) pyridin-2 (1H) -one (4.83 g, 15.6 mmol) and N-iodosuccinimide (NIS, in anhydrous acetonitrile (55 mL) 3.86 g, 17.1 mmol) was heated at 65 ° C. for 4 hours under a 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). Appropriate fractions were collected according to ES MS (M + H 436) and washed with Na ₂ SO ₃ to remove colored impurities. Fractions were concentrated under reduced pressure and dried under vacuum to afford the desired product as a light yellow solid (6.15 g, 90%). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.73 (d, 1H, J = 7.6 Hz), 7.36 (m, 6H), 7.08 (m, 3H), 6.39 (d, 1H, J = 8.0 Hz) , 5.28 (s, 2 H), 5.19 (s, 2 H); ES-HRMS m / z 436.0196 (M + H calculated for C ₁₉ H ₁₆ NO ₂ FI: 436.0210).

Step 2: Preparation of 4- (benzyloxy) -1- (3-fluorobenzyl) -3-methylpyridin-2 (1H) -one

Degassed solution of 4- (benzyloxy) -1- (3-fluorobenzyl) -3-iodopyridin-2 (1H) -one (1.03 g, 2.36 mmol) in anhydrous DMF (15 mL) under argon atmosphere To this was added triethylamine (1.11 g, 11 mmol). The reaction mixture was cooled in an ice bath for 15 minutes and then tetramethyl tin (2.10 g, 11.75 mmol) was added followed by bistriphenylphosphine-palladium chloride (0.166 g, 0.24 mmol). The reaction was stirred at room temperature for 30 minutes and then heated at 95 ° C. under an argon atmosphere for 3 hours. The reaction mixture was filtered through a celite bed and the filtrate was concentrated under reduced pressure. The dark brown residue was diluted with ethyl acetate (100 mL) and washed with water. The combined organic extracts were dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The dark brown residue was purified by flash chromatography (30% ethyl acetate in hexanes). Appropriate fractions were combined and concentrated under reduced pressure to afford the desired product as a light yellow solid (0.1758 g, 22%). The product was further purified by reversed phase HPLC using 10-90% acetonitrile / water (30 min gradient) at a flow rate of 100 mL / min to give a purer product as a light yellow solid (0.0975 g, 8%). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.58 (d, 1H, J = 7.6 Hz), 7.35 (m, 6H), 6.98 (m, 3H), 6.46 (d, 1H, 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 ₂₀ H ₁₉ NO ₂ F: 324.1394).

Example 417

1- (3-fluorobenzyl) -4-[(4-fluorobenzyl) oxy] -3-iodopyridin-2 (1H) -one

Step 1: Preparation of 1- (3-fluorobenzyl) -4-hydroxy-3-iodopyridin-2 (1H) -one

N-iodosuccinimide (1.1 g, in a mixture of 1- (3-fluorobenzyl) -4-hydroxypyridin-2 (1H) -one (1.1 g, 5 mmol) in acetonitrile (15 mL) 5.5 mmol) and a catalytic amount of dichloroacetic acid (0.1 mL) were added. The reaction mixture was stirred under nitrogen for 1 hour at room temperature. The mixture was cooled in an ice bath and filtered with fresh MeCl ₂ in the cooled state. The beige solid was dried to give the desired iodide intermediate (1.21 g, 69%). ES-LRMS m / z 346.

Step 2: Preparation of 1- (3-fluorobenzyl) -4-[(4-fluorobenzyl) oxy] -3-iodopyridin-2 (1H) -one

K ₂ CO ₃ (0.199 g) to a mixture of 1- (3-fluorobenzyl) -4-hydroxy-3-iodopyridin-2 (1H) -one (0.5 g, 1.44 mmol) in DMF (5 mL) , 1.44 mmol) was added followed by 4-fluorobenzyl bromide (0.189 mL, 1.51 mmol). The reaction mixture was stirred at rt for 30 min. The mixture was diluted with ethyl acetate (50 mL) and washed with water. The organic extract was dried over anhydrous Na ₂ SO ₄ and concentrated to dryness. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.75 (d, 1H, J = 7.6 Hz), 7.49 (q, 2H), 7.34 (q, 1H), 7.11 (m, 5H), 6.40 (d, 1H, J = 7.6 Hz), 5.26 (s, 2H), 5.19 (s, 2H); ES-HRMS m / z 454.0098 (M + H calculated for C ₁₉ H ₁₅ NO ₂ F ₂ I: 454.0110).

Example 418

1- (3-fluorobenzyl) -4-[(4-fluorobenzyl) oxy] -3-methylpyridin-2 (1H) -one

1- (3-fluorobenzyl) -4-[(4-fluorobenzyl) oxy] -3-iodopyridin-2 (1H) -one in DMF (10 mL) and LiCl (0.25 g, 5.9 mmol) Tetramethyl tin (0.49 mL, 3.54 mmol) was added to (0.804 g, 1.7 mmol) degassed solution followed by the bistriphenylphosphine-palladium chloride catalyst (0.124 g, 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 extract was dried over anhydrous Na ₂ SO ₄ and concentrated to dryness. The residue was purified by flash column chromatography (20% ethyl acetate in hexanes). The appropriate fractions were concentrated. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.59 (d, 1H, J = 7.6 Hz), 7.46 (m, 2H), 7.34 (m, 1H), 7.10 (m, 4H), 6.46 (d, 1H, J = 7.6 Hz), 5.17 (s, 2H), 5.15 (s, 2H), 1.99 (s, 3H); ES-HRMS m / z 342.1314 (M + H calculated for C ₂₀ H ₁₈ NO ₂ F ₂ : 342.1300).

Example 419

1-benzyl-3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one

DEAD (0.44 mL, 2.75 mmol) was added to a degassed cold solution of DMF (10 mL) and PPh ₃ (resin, 0.93 g, 2.75 mmol). The reaction mixture was stirred at −10 ° C. for 20 minutes under nitrogen. To the resin suspension was added 1-benzyl-3-bromo-4-hydroxy-6-methylpyridin-2 (1H) -one (0.62 g, 2.1 mmol) and 2,4-difluoro in DMF (10 mL). A solution of benzyl alcohol (0.283 mL, 2.5 mmol) was added. The reaction mixture was stirred at −10 ° C. for 30 minutes and then at room temperature for 1 hour. The resin was filtered off, 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. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.62 (m, 1H), 7.31 (m, 3H), 7.1 (d, 2H, J = 7.2 Hz), 7.02 (t, 2H, J = 8.6 Hz) , 6.48 (s, 1 H), 5.42 (s, 2 H), 5.28 (s, 2 H), 2.34 (s, 3 H); ES-HRMS m / z 420.0399 / 422.0380 (M + H calculated for C ₂₀ H ₁₇ NO ₂ F ₂ Br: 420.0405 / 422.0387).

Example 420

N- [3-bromo-1- (3-fluorobenzyl) -2-oxo-1,2-dihydropyridin-4-yl] -4-fluorobenzamide

Step 1: Preparation of 4-amino-1- (3-fluorobenzyl) pyridin-2 (1H) -one

In Fischer-Porter's disease, a solution of 4- (benzylamino) -1- (3-fluorobenzyl) pyridin-2 (1H) -one (2.5 g, 8.11 mmol) in glacial acetic acid (20 mL) was added. After the solution was washed with nitrogen, a catalyst (10% Pd / C, 2.0 g) was added. The vessel was sealed and evacuated and purged with hydrogen gas. The system was charged with hydrogen gas (50 psi) and the mixture was stirred at room temperature for 4 hours. The system was evacuated and flushed with nitrogen. The reaction mixture was filtered through a celite bed 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. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.32 (q, 1H), 7.02 (m, 3H), 5.93 (dd, 1H, J = 2.4 Hz, 2.8 Hz), 5.58 (d, 1H, J = 2.4 Hz); ES-HRMS m / z 219.0966 (M + H calculated for C ₁₂ H ₁₂ N ₂ OF: 219.0928).

Step 2: Preparation of 4-fluoro-N- [1- (3-fluorobenzyl) -2-oxo-1,2-dihydropyridin-4-yl] benzamide

To a solution of 4-amino-1- (3-fluorobenzyl) pyridin-2 (1H) -one (0.263 g, 1.2 mmol) in acetonitrile (7 mL), DMAP (catalyst amount), triethylamine (0.25 mL, 1.8 mmol) and 4-fluorobenzoyl chloride (0.213 mL, 1.8 mmol) were added. The reaction mixture was stirred at 0 ° C. for 25 minutes and then filtered. After drying the solid by washing with 10% citric acid and water, the desired compound was obtained (0.326 g, 79%). ¹ H-NMR (d ₆ -DMSO, 400 MHz) δ 7.98 (m, 2H), 7.71 (d, 1H, J = 7.6 Hz), 7.35 (m, 3H), 7.08 (m, 3H), 6.98 (d , 1H, J = 2.4 Hz), 6.61 (dd, 1H, J = 2.4 Hz, 2.4 Hz), 5.03 (s, 2H); ESLRMS m / z 341.1.

Step 3: Preparation of N- [3-bromo-1- (3-fluorobenzyl) -2-oxo-1,2-dihydropyridin-4-yl] -4-fluorobenzamide

4-fluoro-N- [1- (3-fluorobenzyl) -2-oxo-1,2-dihydropyridin-4-yl] benzamide (0.305 g, 0.89 mmol) in acetonitrile (7 mL) To the mixture was added NBS (0.159 g, 0.89 mmol). The reaction mixture was stirred at rt for 1.5 h. The filtrate was removed under reduced pressure and the residue was purified by flash column chromatography (ethyl acetate / hexane 1: 1 v / v). Fractions were concentrated. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.03 (m, 2H), 7.79 (d, 1H, J = 7.6 Hz), 7.47 (d, 1H, J = 8.0 Hz), 7.28 (m, 3H) , 7.12 (m, 3 H), 5.23 (s, 2 H); ES-HRMS m / z 419.0202 / 421.0191 (M + H calculated for C ₁₉ H ₁₄ N ₂ 0 ₂ F ₂ Br: 419.0201 / 421.0183).

Example 421

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-methylpyridin-2 (1H) -one

Step 1: Preparation of 3-chloro-1- (2,6-difluorophenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one

NCS (2.52 g) to a mixture of 1- (2,6-difluorophenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one (0.30 g, 1.26 mmol) in dichloromethane (5 mL) , 1.90 mmol) was added. The reaction mixture was stirred at room temperature under nitrogen for 4.5 hours. The suspension was cooled in an ice bath, filtered and the solid was rinsed with fresh dichloromethane to afford the desired product as a white solid (0.271 g, 79%). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.58 (m, 1H), 7.22 (m, 2H), 6.20 (s 1H), 2.00 (s, 3H); ES-HRMS m / z 272.0287 (M + H calculated for C ₁₂ H ₉ NO ₂ F ₂ Cl: 272.0290).

Step 2: Preparation of 3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-methylpyridin-2 (1H) -one

K in a solution of 3-chloro-1- (2,6-difluorophenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one (0.27 g, 1.00 mmol) in DMA (5 mL) After addition of ₂ CO ₃ , 2,4-difluorobenzyl bromide (0.128 mL, 1 mmol) was added. The reaction mixture was stirred at rt for 2 h and then diluted in water. The reaction mixture was extracted with ethyl acetate and the organic extracts were dried over Na ₂ S0 ₄ and the filtrate was concentrated. The resulting residue was purified by flash column chromatography (ethyl acetate / hexane 3: 4 v / v) to afford the desired product. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.60 (m, 2H), 7.25 (m, 2H), 7.04 (m, 2H), 6.71 (s, 1H), 5.36 (s, 2H), 2.11 ( s, 3H); ES-HRMS m / z 398.0551 (M + H calculated for C ₁₉ H ₁₃ NO ₂ F ₄ Cl: 398.0571).

Example 422

3-bromo-1- (4-fluorobenzyl) -4-[(4-fluorobenzyl) amino] -6-methylpyridin-2 (1H) -one

Step 1: Preparation of 1- (4-fluorobenzyl) -4-[(4-fluorobenzyl) amino] -6-methylpyridin-2 (1H) -one

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 under an argon atmosphere for 24 hours. . The resulting solution was concentrated under reduced pressure until dry. The residue was triturated with ethyl acetate and filtered. It was washed thoroughly with ethyl acetate and dried to give the title compound as a pale yellow powder (4.1 g. 30%). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.33 (q, 2H), 7.04 (m, 5H), 5.85 (d, 1H, J = 2.0 Hz), 5.44 (d, 2H, J = 2.4 Hz) , 5.20 (s, 1 H), 4.29 (s, 2 H), 2.17 (s, 3 H); ES-HRMS m / z 341.1488 (M + H calculated for C ₂₀ H ₁₉ N ₂ OF ₂ : 341.1460).

Step 2: Preparation of 3-bromo-1- (4-fluorobenzyl) -4-[(4-fluorobenzyl) amino] -6-methylpyridin-2 (1H) -one

MeCl ₂ of 1- (4-fluorobenzyl) -4 - [(4-fluoro-benzyl) amino] -6-methyl-pyridin -2 (1H) - NBS (0.156 To a solution of the whole (0.2857 g, 0.84 mmol) g, 0.88 mmol) was added. The reaction was stirred at room temperature under nitrogen for 45 minutes. The reaction mixture was diluted with MeCl ₂ and washed with NaHCO ₃ . The organic extract was washed with water, dried over Na ₂ SO ₄ and concentrated to give the desired product as a yellow solid (0.3242 g, 92%). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.32 (q, 2H), 7.04 (m, 6H), 5.91 (s, 1H), 5.28 (s, 2H), 4.50 (s, 2H), 2.17 ( s, 3H); ES-HRMS m / z 419.0549 / 421.0537 (M + H calculated for C ₂₀ H ₁₈ N ₂ OBrF ₂ : 419.0565 / 421.0547).

Example 423

3-bromo-1- (cyclopropylmethyl) -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one

3-bromo-1- (cyclopropylmethyl) -4-hydroxy-6-methylpyridin-2 (1H) -one (0.276 g, 1.07 mmol) and K ₂ CO ₃ (0.148 g) in DMA (4 mL) , 1.07 mmol) was added 2,4-difluorobenzyl bromide (0.14 mL, 1.07 mmol). The mixture was stirred at rt for 1.5 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was dried over Na ₂ S0 ₄ and concentrated. The residue was purified by flash column chromatography (ethyl acetate / hexane 1: 1 v / v). Appropriate fractions were combined and concentrated. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.60 (q, 1H), 7.04 (m, 2H), 6.42 (s, 1H), 5.26 (s, 2H), 4.06 (s, 1H), 4.04 ( s, 1H), 2.50 (s, 3H), 0.53 (m, 2H), 0.43 (m, 2H); ES-HRMS m / z 384.0392 (M + H calculated for C ₁₇ H ₁₇ N ₂ OBrF ₂ : 384.0405).

Example 424

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (pyridin-4-ylmethyl) pyridin-2 (1H) -one

Step 1: Preparation of 3-bromo-4-hydroxy-6-methyl-1- (pyridin-4-ylmethyl) pyridin-2 (1H) -one

Commercially available 4-hydroxy-6-methyl pyrone (10 g, 79.3 mmol) was condensed in commercial 4- (aminomethyl) pyridine (8 mL, 79.3 mmol) and water (50 mL). The mixture was heated to reflux under nitrogen in an oil bath for 1 hour. The solvent was evaporated. MS and ¹ H-NMR were consistent with the desired debrominated structure. ¹ H-NMR (CD ₃ OD, 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, 1H, J = 2.0 Hz ), 5.80 (d, 1H, J = 2.4 Hz), 5.34 (s, 2H), 2.23 (s, 3H); ES-LRMS (M + H) m / z 217.

To a suspension of the compound (0.801 g, 3.7 mmol) in MeCl ₂ (10 mL) was added NBS (0.725 g, 4.07 mmol). The reaction mixture was stirred at rt for 30 min under nitrogen. The suspension was filtered by cooling in an ice bath. The solid was washed with fresh MeCl ₂ and dried, after drying a beige solid was obtained (0.9663 g, 88%). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.47 (d, 2H, J = 5.2 Hz), 7.16 (d, 2H, J = 6.0 Hz), 6.09 (s, 1H), 5.40 (s, 2H) , 2.24 (s, 3 H); ES-LRMS (M + H) m / z 295/297.

Step 2: Preparation of 3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (pyridin-4-ylmethyl) pyridin-2 (1H) -one

To a cold solution of 2,4-difluorobenzyl alcohol (0.569 mL, 5.1 mmol) in THF (5 mL) was added PPh ₃ (resin, 2.55 g, 7.65 mmol) followed by DIAD (1.48 mL, 7.65 mmol). Added. The reaction mixture was stirred at −10 ° C. for 15 minutes under nitrogen. To the resin suspension was added 3-bromo-4-hydroxy-6-methyl-1- (pyridin-4-ylmethyl) pyridin-2 (1H) -one (1.0 g, 3.4 mmol) in DMF (10 mL). The solution was added. The reaction mixture was stirred at 0 ° C. for 1.5 h and then at rt overnight. The resin was filtered off, 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. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.47 (d, 2H, J = 5.6 Hz), 7.63 (q, 1H), 7.15 (d, 1H, J = 5.6 Hz), 7.05 (m, 2H) , 6.55 (s, 1 H), 5.45 (s, 2 H), 5.31 (s, 2 H), 2.35 (s, 3 H); ES-HRMS m / z 421.0366 / 423.0355 (M + H calculated for C ₁₉ H ₁₆ N ₂ 0 ₂ F ₂ Br: 421.0358 / 423.0339).

Example 428

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one

Step 1: Preparation of 3-bromo-4-hydroxy-6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one

Commercially available 4-hydroxy-6-methyl pyrone (15 g, 119.0 mmol) was condensed in commercial 3- (aminomethyl) pyridine (12.10 mL, 119.0 mmol) and water (75 mL). The mixture was heated to reflux under nitrogen in an oil bath for 1 hour. The solvent was evaporated. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.43 (d, 1H, J = 4.8 Hz), 8.38 (s, 1H), 7.60 (d, 1H, J = 8.0 Hz), 7.39 (dd, 1H, J = 4.8 Hz, 4.8 Hz), 5.97 (d, 1H, J = 2.0 Hz), 5.79 (d, 1H, J = 2.4 Hz), 5.33 (s, 2H), 2.28 (s, 3H); ES-LRMS (M + H) m / z 217.

To a suspension of the compound (5.01 g, 23.1 mmol) in MeCl ₂ (50 mL) was added NBS (4.53 g, 25.4 mmol). The reaction mixture was stirred at rt for 30 min under nitrogen. The suspension was filtered by cooling in an ice bath. The solid was washed with fresh MeCl ₂ and dried and a beige solid was obtained after drying (7.89 g, 114%). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.44 (d, 1H, J = 4.4 Hz), 8.39 (s, 1H), 7.62 (d, 1H, J = 7.6 Hz), 7.39 (dd, 1H, J = 5.2 Hz, 4.4 Hz), 6.07 (s, 1 H), 5.39 (s, 2 H), 2.29 (s, 3 H); ES-LRMS (M + H) m / z 295/297.

Step 2: Preparation of 3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one

The compound was prepared essentially as described in step 2 of 424 using 3-bromo-4-hydroxy-6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one. . ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.45 (d, 1H, J = 4.4 Hz), 8.41 (s, 1H), 7.63 (m, 2H), 7.41 (dd, 1H, J = 5.2 Hz, 4.8 Hz), 7.02 (m, 2H), 6.52 (s, 1H), 5.44 (s, 2H), 5.29 (s, 2H), 2.40 (s, 3H); ES-HRMS m / z 421.0355 / 423.0358 (M + H calculated for C ₁₉ H ₁₆ N ₂ 0 ₂ F ₂ Br: 421.0358 / 423.0339).

Example 435

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (pyridin-2-ylmethyl) pyridin-2 (1H) -one

Step 1: Preparation of 3-bromo-4-hydroxy-6-methyl-1- (pyridin-2-ylmethyl) pyridin-2 (1H) -one

Commercially available 4-hydroxy-6-methyl pyrone (5 g, 39.6 mmol) was condensed in commercial 2- (aminomethyl) pyridine (4.03 mL, 39.6 mmol) and water (25 mL). The mixture was heated to reflux under nitrogen in an oil bath for 1.5 h. The solvent was evaporated. MS and ¹ H-NMR were consistent with the desired debrominated structure. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.47 (d, 1H, J = 4.8 Hz), 7.75 (ddd, 1H, J = 2.0 Hz, 1.6 Hz, 1.6 Hz), 7.28 (dd, 1H, J = 4.8 Hz, 4.8 Hz), 7.11 (d, 1H, J = 7.6 Hz), 5.98 (d, 1H, J = 2.4 Hz), 5.77 (d, 1H, J = 2.4 Hz), 5.35 (s, 2H) , 2.28 (s, 3 H); ES-LRMS (M + H) m / z 217.

To a suspension of the compound (3.0 g, 13.8 mmol) in MeCl ₂ (30 mL) was added NBS (2.71 g, 15.18 mmol). The reaction mixture was stirred at rt for 2.5 h under nitrogen. The suspension was filtered by cooling in an ice bath. The solid was washed with fresh MeCl ₂ and dried, giving a beige solid after drying (3.18 g, 77%). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.46 (d, 1H, J = 4.8 Hz), 7.76 (ddd, 1H, J = 2.0 Hz, 1.6 Hz, 1.6 Hz), 7.29 (dd, 1H, J = 5.2 Hz, 5.2 Hz), 7.17 (d, 1H, J = 8.0 Hz), 6.07 (s, 1H), 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-1- (pyridin-2-ylmethyl) pyridin-2 (1H) -one

The compound was prepared essentially as described in step 2 of 424 using 3-bromo-4-hydroxy-6-methyl-1- (pyridin-2-ylmethyl) pyridin-2 (1H) -one. . ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.45 (d, 1H, J = 4.4 Hz), 7.76 (ddd, 1H, J = 2.0 Hz, 2.0 Hz, 1.6 Hz), 7.62 (q, 1H), 7.29 (dd, 1H, J = 5.2 Hz, 5.6 Hz), 7.21 (d, 1H, J = 8.0 Hz), 7.04 (m, 2H), 6.51 (s, 1H), 5.45 (s, 2H), 5.29 ( s, 2H), 2.42 (s, 3H); ES-HRMS m / z 421.0354 / 423.0332 (M + H calculated for C ₁₉ H ₁₆ N ₂ 0 ₂ F ₂ Br: 421.0358 / 423.0339).

Examples 425-427, 429-435, 436-437

The following compounds were prepared essentially according to the method set forth in Example 424 using the product obtained in step 1 of Example 424, 428 or 435.

NMR analysis of the compounds of Examples 425-427, 429-435, 436-437

Example 439

3-bromo-4- [2- (4-fluorophenyl) ethyl] -6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one

Step 1: Preparation of 3-bromo-6-methyl-2-oxo-1- (pyridin-3-ylmethyl) -1,2-dihydropyridin-4-yl trifluoromethanesulfonate

Cooled suspension of 3-bromo-4-hydroxy-6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one (0.481 g, 1.63 mmol) in dichloromethane (6 mL) To (-30 ° C.) triethylamine (0.28 mL, 2.04 mmol) was added followed by a solution of trifluoromethanesulfonic anhydride (0.4 mL, 2.44 mmol) in dichloromethane (3 mL). The reaction mixture was stirred at −30 ° C. under nitrogen for 1 hour. The reaction mixture was diluted with dichloromethane and washed with cold NaHCO ₃ / water. The organic extract was dried over Na ₂ SO ₄ and the filtrate was concentrated to dryness under reduced pressure, then the desired compound was obtained as a yellow semisolid (0.6675 g, 95%). ES-LRMS (M + H) m / z 427.1 / 429.1.

Step 2: Preparation of 3-bromo-4-[(4-fluorophenyl) ethynyl] -6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one

3-bromo-6-methyl-2-oxo-1- (pyridin-3-ylmethyl) -1,2-dihydropyridin-4-yl trifluoromethanesulfonate (0.6675 in DMF (9 mL) g, 1.56 mmol) was added DIEA (0.35 mL, 2.03 mmol), 4-fluorophenylacetylene (0.235 mL, 1.95 mmol) and PdCl ₂ (PPh ₃ ) ₂ (0.11 g). The reaction mixture was stirred for 1 hour under nitrogen at room temperature and then heated under nitrogen in an oil bath (65 ° C.) overnight. The solvent was distilled under vacuum and the residue was purified by flash column chromatography (5% methanol in ethyl acetate). After the extract was concentrated to dryness, the desired compound was obtained (0.432 g, 69%). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.45 (s, 2H), 7.96 (s, 1H), 7.64 (m, 3H), 7.41 (dd, 1H, J = 4.8 Hz, 4.8 Hz), 7.18 (t, 2H, J = 8.8 Hz), 6.46 (s, 1H), 5.45 (s, 2H), 2.37 (s, 3H); ES-HRMS m / z 397.0361 / 399.0310 (M + H calculated for C ₂₀ H ₁₅ N ₂ OFBr: 397.0346 / 399.0328).

Step 3: Preparation of 3-bromo-4- [2- (4-fluorophenyl) ethyl] -6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one

3-bromo-4-[(4-fluorophenyl) ethynyl] -6-methyl-1- (pyridine- in ethyl acetate (5 mL) and EtOH (5 mL) containing PtO ₂ (0.015 g) A suspension of 3-ylmethyl) pyridin-2 (1H) -one (0.430 g, 1.01 mmol) was stirred in a Fischer-Porter bottle under hydrogen atmosphere (15 psi) 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). After the appropriate fractions were combined, concentrated to dryness under reduced pressure, the desired product was obtained as a viscous semisolid (0.0943 g, 22%). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.46 (d, 2H, J = 26.4 Hz), 7.60 (d, 1H, J = 8.0 Hz), 7.41 (dd, 1H, J = 4.8 Hz, 4.8 Hz ), 7.21 (m, 2H), 6.97 (t, 2H, J = 8.8 Hz), 6.24 (s, 1H), 5.43 (s, 2H), 2.93 (m, 4H), 2.31 (s, 3H); ES-HRMS m / z 401.0645 / 403.0603 (M + H calculated for C ₂₀ H ₁₉ N ₂ OFBr: 401.0659 / 403.0641).

Example 440

3-bromo-4- [2- (4-fluorophenyl) ethyl] -6-methyl-1- (pyridin-4-ylmethyl) pyridin-2 (1H) -one

The title compound was prepared by a method similar to that described in steps 1 to 3 (0.374 g, 25%). MS and ¹ H-NMR of step 1 were consistent with the desired structure. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.80 (d, 2H, J = 6.8 Hz), 7.89 (d, 2H, J = 6.8 Hz), 6.61 (s, 1H), 5.66 (s, 2H) , 2.45 (s, 3 H); ES-HRMS m / z 427.9645 / 429.9625 (M + H calculated for C ₁₃ H ₁₁ N ₂ 0 ₄ SF ₃ Br: 427.9599 / 429.9578).

MS and ¹ H-NMR of step 3 were consistent with the desired structure. ¹ H-NMR (CD ₃ OD, 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, 1 H), 5.43 (s, 2 H), 2.95 (m, 4 H), 2.25 (s, 3 H); ES-HRMS m / z 401.0682 / 403.0636 (M + H calculated for C ₂₀ H ₁₉ N ₂ 0FBr: 401.0659 / 403.0641).

Example 441

3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one

Step 1: Preparation of 3-chloro-4-hydroxy-6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one

NCS (1.21 g, 1.78) in a suspension of 4-hydroxy-6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one (1.016 g, 4.7 mmol) in MeCl ₂ (10 mL). mmol) was added. The reaction mixture was stirred at rt for 24 h under nitrogen. The suspension was filtered by cooling in an ice bath. The solid was washed with fresh MeCl ₂ and dried, giving a yellow solid after drying (1.00 g, 85%). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.54 (m, 2H), 7.85 (d, 1H, J = 1.6 Hz), 7.61 (m, 1H), 6.10 (s, 1H), 5.41 (s, 2H), 2.33 (s, 3 H); ES-LRMS (M + H) m / z 251/253.

Step 2: Preparation of 3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one

To a degassed cold solution of DMF (10 mL) and PPh ₃ (resin, 2.2 g, 6.6 mmol) was added DEAD (1.038 mL, 6.6 mmol). The reaction mixture was stirred at −10 ° C. for 20 minutes under nitrogen. To the resin suspension was added 3-chloro-4-hydroxy-6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one (1.00 g, 4.0 mmol) and 2 in DMF (10 mL). A solution of, 4-difluorobenzyl alcohol (0.66 mL, 6.0 mmol) was added. The reaction mixture was stirred at −10 ° C. for 30 minutes and then at room temperature for 1 hour. The resin was filtered off, rinsed with fresh MeOH and the filtrate was concentrated. The residue was dissolved in ethyl acetate and purified by flash column chromatography (5% methanol in ethyl acetate). The appropriate fractions were concentrated. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.45 (ddd, 2H, J = 1.6 Hz, 1.6 Hz, 1.6 Hz), 7.61 (m, 2H), 7.41 (dd, 1H, J = 4.4 Hz, 4.8 Hz), 7.02 (m, 2H), 6.55 (s, 1H), 5.43 (s, 2H), 5.29 (s, 2H), 2.41 (s, 3H); ES-HRMS m / z 377.0882 / 379.0840 (M + H calculated for C ₁₉ H ₁₆ N ₂ O ₂ F ₂ Cl: 377.0863 / 379.0840).

Example 442

1-[(4-amino-2-methylpyrimidin-5-yl) methyl] -3-bromo-6-methyl-4-[(2,4,6-trifluorobenzyl) oxy] pyridine-2 (1H) -one trifluoroacetate

The title compound was prepared in a similar manner as described in step 2 of Example 385 (0.142 g, 9%). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.64 (s, 1H), 7.00 (m, 2H), 6.66 (s, 1H), 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 C ₁₉ H ₁₇ N ₄ O ₂ F ₃ Br: 469.0481 / 471.0463).

Example 443

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-{[2-methyl-4- (methylamino) pyrimidin-5-yl] methyl} pyridine- 2 (1H) -one trifluoroacetate

1-[(4-amino-2-methylpyrimidin-5-yl) methyl] -3-bromo-4-[(2,4-difluorobenzyl) oxy] -6- in DMF (3 mL) To a solution of methylpyridin-2 (1H) -one hydrochloride (0.15 g, 0.3 mmol) 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 was stirred at room temperature under nitrogen for 2 hours. The reaction was purified by reverse phase HPLC using 10-90% CH ₃ CN / water (30 min gradient) at a flow rate of 100 mL / min. Appropriate fractions (m / z = 465 M + H) were combined and freeze dried to afford the desired product as a white powder (0.036 g, 25%). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.72 (s, 1H), 7.60 (m, 1H), 7.03 (m, 2H), 6.62 (s, 1H), 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 C ₂₀ H ₂₀ N ₄ 0 ₂ F ₂ Br: 465.0732 / 467.0714).

Example 444

Ethyl N- (5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -2- Methylpyrimidin-4-yl) glycinate trifluoroacetate

The title compound was prepared similar to that described in Example 442, but the reaction mixture was heated at oil bath temperature 70 ° C. for 2 days (0.1384 g, 51%). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.78 (s, 1H), 7.61 (m, 1H), 7.03 (m, 2H), 6.61 (s, 1H), 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 C ₂₃ H ₂₄ N ₄ 0 ₄ F ₂ Br: 537.0943 / 539.0926).

Example 445

N- (5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -2-methylpyri Midin-4-yl) -2-hydroxyacetamide trifluoroacetate

1-[(4-amino-2-methylpyrimidin-5-yl) methyl] -3-chloro-4-[(2,4-difluorobenzyl) oxy] in catalytic amount of DMAP and DMF (20 mL) To a cooled solution of -6-methylpyridin-2 (1H) -one trifluoroacetate (0.200 g, 0.38 mmol) was added triethylamine (0.064 mL, 0.38 mmol). The reaction was stirred at -20 ° C and acetoxyacetyl chloride (0.082 mL, 0.76 mmol) was added. The reaction was kept cold and stirred for 15 minutes before warming to room temperature for 3 hours. The reaction was monitored by LR-ESMS (m / z = 466). After 3 hours, the reaction was incomplete. Acetoxyacetyl chloride (0.05 mL, 0.466 mmol) and triethylamine (0.2 mL, 1.43 mmol) were added to the reaction mixture and stirring continued overnight at room temperature. The next morning the reaction was heated at 65 ° C. for 3 hours. The solvent was removed in vacuo and 1 N 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 using 10-90% CH ₃ CN / water (30 min gradient) at a flow rate of 50 mL / min. The appropriate fractions were freeze dried to afford the desired product (0.020 g, 9%). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.04 (s, 1H), 7.6 (m, 1H), 7.02 (m, 1H), 6.59 (s, 1H), 5.30 (s, 2H), 5.24 ( s, 2H), 4.26 (s, 1H), 2.60 (s, 3H), 2.43 (s, 3H); ES-HRMS m / z 465.1161 (M + H calculated for C ₂₁ H ₂₀ N ₄ 0 ₄ F ₂ Cl: 465.1136).

Example 446

3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-[(5-methylpyrazin-2-yl) methyl] pyridin-2 (1H) -one

Step 1: Preparation of 3-chloro-4-hydroxy-6-methyl-1-[(5-methylpyrazin-2-yl) methyl] pyridin-2 (1H) -one

To a solution of 4-hydroxy-6-methyl-1-[(5-methylpyrazin-2-yl) methyl] pyridin-2 (1H) -one (1.00 g, 4.3 mmol) in glacial acetic acid (10 mL) NCS ( 0.79 g, 5.94 mmol) was added. The reaction mixture was 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%). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.47 (s, 1H), 8.42 (s, 1H), 6.08 (s, 1H), 5.36 (s, 2H), 2.50 (s, 3H), 2.43 ( s, 3H); ES-HRMS m / z 266.0691 (M + H calculated for C ₁₂ H ₁₃ N ₃ 0 ₂ Cl: 266.0691).

Step 2: 3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-[(5-methylpyrazin-2-yl) methyl] pyridin-2 (1H) -one Manufacture

Of 3-chloro-4-hydroxy-6-methyl-1-[(5-methylpyrazin-2-yl) methyl] pyridin-2 (1H) -one (2.48 g, 9.3 mmol) in DMA (7 mL) To the solution was added K ₂ CO ₃ (1.54 g, 11.0 mmol) followed by 2,4-difluorobenzyl bromide (1.2 mL, 9.3 mmol). The reaction mixture was stirred at room temperature under nitrogen for 1.5 hours. The solvent was distilled off under vacuum. The resulting residue was diluted in dichloromethane and washed with water. The organic extract was concentrated and the resulting residue was purified by flash column chromatography (ethyl acetate). Appropriate fractions were combined and concentrated. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.49 (d, 1H, J = 1.2 Hz), 8.40 (s, 1H), 7.59 (m, 1H), 7.04 (m, 2H), 6.54 (s, 1H), 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 C ₁₉ H ₁₇ N ₃ O ₂ ClF ₂ : 392.0972).

Example 447

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-({5-[(methylamino) methyl] pyrazin-2-yl} methyl) pyridine-2 ( 1H) -one trifluoroacetate

3-bromo-1-{[5- (chloromethyl) pyrazin-2-yl] methyl} -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridine-2 (1H in THF To a suspension of) -one (0.25 g, 0.53 mmol) was added methylamine (1 mL, 2.1 mmol). The reaction was sealed and stirred overnight at room temperature. The reaction mixture was diluted in water: acetonitrile (1: 1) and purified by reverse phase HPLC using 10-90% CH ₃ CN / water (30 min gradient) at a flow rate of 70 mL / min. Appropriate fractions were combined and lyophilized to afford the desired product as an amorphous solid (0.22 g, 71%). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.73 (s, 1H), 8.55 (s, 1H), 7.6 (m, 2H), 7.02 (m, 1H), 6.54 (s, 1H), 5.47 ( s, 2H), 5.29 (s, 2H), 4.37 (s, 2H), 2.78 (s, 3H), 2.56 (s, 3H). ES-HRMS m / z 465.0732 / 467.0709 (M + H calculated for C ₂₀ H ₂₀ N ₄ O ₂ BrF ₂ : 465.0732 / 467.0714).

Example 448

Ethyl 5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} pyrazine-2-carboxylate

3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one (0.59 g, 2.07 mmol) and ethyl 5- (bro) in THF (15 mL) To the mixture of momethyl) pyrazine-2-carboxylate (0.62 g, 2.4 mmol) was added NaH (0.06 g, 2.4 mmol). The reaction was stirred at 60 ° C. for 3.5 h. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane and citric acid (5%). The organic extract was washed with water and dried over Na ₂ SO ₄ (anhydrous). The organic extract was concentrated and the residue was purified by flash column chromatography (100% ethyl acetate). Appropriate fractions were combined and concentrated under reduced pressure to remove solvent. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 9.11 (d, 1H, J = 1.6 Hz), 8.77 (s, 1H), 7.52 (m, 1H), 7.02 (m, 2H), 6.57 (s, 1H), 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 C ₂₁ H ₁₉ N ₃ O ₄ ClF ₂ : 450.01027).

Example 449

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[5- (hydroxymethyl) pyrazin-2-yl] methyl} -6-methylpyridine-2 (1H)- On

THF: t-butanol (1: 1) (10 mL) ethyl 5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridine-1 To a suspension of (2H) -yl] methyl} pyrazine-2-carboxylate (4.0 g, 8.9 mmol) was added NaBH ₄ (0.46 g, 12.4 mmol). The reaction was stirred at room temperature overnight under argon. 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). Appropriate fractions were combined and concentrated under reduced pressure to afford the desired compound as a white solid (1.58 g, 44%). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.59 (s, 1H), 8.56 (s, 1H), 7.52 (m, 1H), 7.01 (m, 2H), 6.55 (m, 1H), 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 C ₁₉ H ₁₇ N ₃ O ₃ ClF ₂ : 408.0921).

Example 450

5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N, N-dimethylpyrazine 2-carboxamide

5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl in DMF (5 mL, -10 ° C.) ] To a cold solution of methyl} pyrazine-2-carboxylic acid (0.175 g, 0.37 mmol) was added IBCF (0.046 mL, 0.35 mmol) followed by NMM (0.041 mL 0.37 mmol). The reaction was activated at −15 ° C. for 20 minutes before dimethylamine (0.375 mL, 0.74 mmol) was added. The reaction was stirred at −10 ° C. for room temperature for 45 minutes. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC using 10-90% CH ₃ CN / water (30 min gradient) at a flow rate of 70 mL / min. Appropriate fractions were combined and lyophilized to afford the desired product as a white solid (0.140 g, 75%). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.68 (s, 1H), 8.67 (s, 1H), 7.52 (m, 1H), 7.02 (m, 2H), 6.54 (s, 1H), 5.50 ( s, 2H), 5.30 (s, 2H), 3.11 (s, 3H), 3.07 (s, 3H), 2.55 (s, 3H); ES-HRMS m / z 493.0680 / 495.0657 (M + H calculated for C ₂₁ H ₂₀ N ₄ O ₃ BrF ₂ : 493.0680 / 495.0657).

Example 451

5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N-methylpyrazine-2 Carboxamide

Essentially as in Example 450, the title compound was prepared by replacing dimethylamine with methylamine. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 9.07 (s, 1H), 8.68 (s, 1H), 7.54 (m, 1H), 7.02 (m, 2H), 6.54 (s, 1H), 5.52 ( s, 2H), 5.30 (s, 2H), 2.94 (s, 3H), 2.54 (s, 3H); ES-HRMS m / z 479.0542 / 481.0518 (M + H calculated for C ₂₀ H ₁₈ N ₄ O ₃ BrF ₂ : 479.0525, 481.0507).

Example 452

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1-{[5- (1-hydroxy-1-methylethyl) pyrazin-2-yl] methyl} -6-methyl Pyridin-2 (1H) -one

In a cold flask containing MeMgBr (1.59 mL, 1.0 mmol) in ethyl 5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl- in THF (20 mL) 2-oxopyridin-1 (2H) -yl] methyl} pyrazine-2-carboxylate (0.5 g, 1.0 mmol) was added. The reaction was stirred at 0 ° C. for 1.5 h and then at rt overnight. The reaction was quenched with cold citric acid (25 mL, 5%) and extracted with ethyl acetate (2 x 100 mL). The organic extract was washed with fresh water. The organic extract was concentrated and purified by reverse phase HPLC using 10-90% CH ₃ CN / water (30 min gradient) at a flow rate of 70 mL / min. Appropriate fractions were combined and lyophilized to afford the desired product (29.9 mg, 6%). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.76 (d, 1H, J = 1.6 Hz), 8.54 (d, 1H, J = 1.2 Hz), 7.52 (m, 1H), 7.02 (m, 2H) , 6.52 (s, 1H), 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 C ₂₁ H ₂₁ N ₃ O ₃ BrF ₂ : 480.0729 / 482.0711).

Example 453

5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N- (2-meth Methoxyethyl) pyrazine-2-carboxamide

Essentially as in Example 450, the title compound was prepared by replacing dimethylamine with 2-methoxyethylamine. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 9.08 (d, 1H, J = 1.2 Hz), 8.70 (d, 1H, J = 1.2 Hz), 7.61 (m, 1H), 7.04 (m, 2H) , 6.54 (s, 1H), 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 C ₂₂ H ₂₂ N ₄ O ₄ BrF ₂ : 523.0787 / 525.0770).

Example 454

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-{[5- (morpholin-4-ylcarbonyl) pyrazin-2-yl] methyl} pyridine -2 (1H) -on

Essentially as in Example 450, the title compound was prepared by replacing dimethylamine with morpholine. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.77 (d, 1H, J = 1.6 Hz), 8.67 (s, 1H), 7.54 (m, 1H), 7.02 (m, 2H), 6.54 (s, 1H), 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 C ₂₃ H ₂₂ N ₄ O ₄ BrF ₂ : 535.0787 / 537.0770).

Example 455

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-({5-[(4-hydroxypiperidin-1-yl) carbonyl] parazin-2-yl} Methyl) -6-methylpyridin-2 (1H) -one

Step 1: 5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} pyrazine-2-car Preparation of Acids

Ethyl 5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl- in 1 N NaOH (3.4 mL, 3.45 mmol, EtOH / water 1: 1 v / v) A mixture of 2-oxopyridin-1 (2H) -yl] methyl} pyrazine-2-carboxylate (1.03 g, 2.3 mmol) was 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 give the desired product as a white solid (1.011 g, 100%). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 9.02 (s, 1H), 8.60 (s, 1H), 7.60 (m, 1H), 7.04 (m, 2H), 6.55 (s, 1H), 5.50 ( s, 2H), 5.30 (s, 2H), 2.52 (s, 3H); ES-HRMS m / z 422.0732 (M + H calculated for C ₁₉ H ₁₅ N ₃ O ₄ ClF ₂ : 422.0714).

Step 2: 3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-({5-[(4-hydroxypiperidin-1-yl) carbonyl] pyrazine-2- Preparation of methyl) -6-methylpyridin-2 (1H) -one

The title compound was prepared in a similar manner as described in Example 453 (0.1396 g, 47%). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.67 (s, 2H), 7.59 (m, 1H), 7.02 (m, 2H), 6.57 (s, 1H), 5.49 (s, 2H), 5.30 ( s, 2H), 4.16 (m, 1H), 3.89 (septet, 1H), 3.72 (m, 1H), 3.38 (m, 2H), 2.56 (s, 3H), 1.93 (m, 1H), 1.83 (m , 1H), 1.45 (m, 2H); ES-HRMS m / z 505.1485 (M + H calculated for C ₂₄ H ₂₄ N ₄ 0 ₄ ClF ₂ : 505.1449).

Example 456

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N- (3-hydroxy -2,2-dimethylpropyl) pyrazine-2-carboxamide

The title compound was prepared in a similar manner as described in Example 455 (0.215 g, 71%). ¹ H-NMR (CD ₃ OD, 400 MHz) δ 9.08 (d, 1H, J = 1.2 Hz), 8.71 (d, 1H, J = 1.6 Hz), 7.58 (m, 1H), 7.02 (m, 2H) , 6.57 (s, 1H), 5.52 (s, 1H), 5.30 (s, 1H), 3.31 (s, 4H), 2.55 (s, 3H), 0.912 (s, 6H); ES-HRMS m / z 507.1630 (M + H calculated for C ₂₄ H ₂₆ N ₄ O ₄ ClF ₂ : 507.1605).

Example 457

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N- (2,2, 2-trifluoroethyl) pyrazine-2-carboxamide

The title compound was prepared (0.2176 g, 73%) in a similar manner as described in Example 455 except that no purification step was needed and only a NaHC0 ₃ / ethyl acetate extraction step was required. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 9.11 (d, 1H, J = 1.6 Hz), 8.73 (d, 1H, J = 1.3 Hz), 7.59 (m, 1H), 7.02 (m, 2H) , 6.57 (s, 1H), 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 C ₂₁ H ₁₇ N ₄ 0 ₃ ClF ₅ : 503.0904).

Example 458

1-allyl-3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one

Step 1: 1-allyl-4-hydroxy-6-methylpyridin-2 (1H) -one. 4-hydroxy-6-methyl-2-pyrone (2 g, 16 mmol) was stirred in water (25 mL). To the reaction was added allylamine (1.2 mL, 16 mmol). The reaction was then heated to 100 ° C. at which temperature the reaction became homogeneous. The reaction was stirred at 100 ° C. for 2 hours. Then, after cooling the reaction to room temperature, a white precipitate formed. The precipitate was isolated via suction filtration. After further washing with water, 1.8 g of an off-white solid was obtained (69%).

Step 2: 1-allyl-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one. To the stirred solution of pyrone (4.0 g, 24 mmol) in DMF (75 mL) was added 2,4-difluorobenzyl bromide (3.4 mmol, 26.4 mmol) after addition of Cs ₂ CO ₃ (7.8 g, 24 mmol). ) Was added. The resulting mixture was stirred at rt for 2 h. Additional Cs ₂ CO ₃ (1 g) and bromide (1 mL) were added and the reaction was further stirred for an additional 2 hours. Cs ₂ CO ₃ was removed by suction filtration. DMF was removed in vacuo and crude was purified by flash chromatography. Elution with ethyl acetate-hexane (2: 1 to 1: 1) gave 1.5 g of the target compound (21%).

Step 3: 1-allyl-3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one. To the stirred suspension of pyridinone (1 g, 3.4 mmol) in CH ₃ CN (10 mL) was added n-bromosuccinimide (670 mg, 3.8 mmol). The reaction mixture was stirred at rt for 3 h. The reaction mixture was filtered and the solid was washed with diethyl ether to give the product. ^{1 H-NMR (DMSO-d} 6/400 MHz) δ 7.62 (app q, J = 8.8 Hz, 1H), 7.31 (ddd, J = 12.0, 9.6, 2.8 Hz, 1H); 7.15 (app dtd, J = 8.4, 2.4, 0.8 Hz, 1H); 6.50 (s, 1 H); 5.87 (ddt, J = 12.4, 10.4, 5.6 Hz, 1H), 5.30 (s, 2H), 5.10 (dd, J = 10, 1.6 Hz, 1H), 4.87 (dd, J = 17.6, 1.6 Hz, 1H) , 4.64 (m, 2 H), 2.34 (s, 3 H); ¹⁹ F-NMR (DMSO-d ₆ /282.2 MHz) -109.68 (quin, J = 1H), -113.66 (quar, J = 1H); HRMS m / z 370.0255 (M + H = 370.0246 calculated for C ₁₆ H ₁₅ BrF ₂ NO ₂ ).

Example 459

1-allyl-3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one

Step 1: 1-allyl-3-chloro-4-hydroxy-6-methylpyridin-2 (1H) -one. N-bromosuccinimide (440 mg) in a stirred solution of 1-allyl-4-hydroxy-6-methylpyridin-2 (1H) -one (500 mg, 3.0 mmol) in CH ₃ CN (10 mL) , 3.3 mmol) and dichloroacetic acid (546 μl, 6.62 mmol) were added in sequence at room temperature. The resulting mixture was stirred for 2 hours. The heterogeneous mixture was filtered and the solid was washed with additional CH ₃ CN to give 350 mg of the desired product as a tan solid (59%). ^{1 H-NMR (DMSO-d} 6/300 MHz) δ 11.16 (s, 1H), 5.98-5.86 (m, 2H), 5.12 (dd, J = 10.5, 1.5 Hz, 1H), 4.89 (dd, J = 17.1, 1.5 Hz, 1H), 4.63-4.61 (m, 2H), 2.29 (s, 3H). ES-HRMS m / z 200.050 (M + H calculated for C ₉ H ₁₁ ClNO ₂ = 200.0470)

Step 2: 1-allyl-3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one. The title compound was prepared according to the method outlined in the synthesis method of step 3 of Example 458. ^{1 H-NMR (DMSO-d} 6/300 MHz) δ 7.67 (app q, J = 8.4 Hz, 1H), 7.36 (app dt, J = 10.2, 2.7 Hz, 1H); 7.15 (m, 1 H); 6.58 (s, 1 H); 5.93 (ddt, J = 15.3, 9.6, 4.8 Hz, 1H), 5.30 (s, 2H) 5.15 (dd, J = 10.2, 1.2 Hz, 1H), 4.92 (dd, J = 17.4, 1.2 Hz, 1H), 4.69-4.67 (m, 2 H), 2.41 (s, 3 H). ES-HRMS m / z 326.0760 (M + H = 326.0790 calculated for C ₁₆ H ₁₅ ClF ₂ N0 ₂ ).

Example 460

Methyl (2E) -4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] but-2-eno Eight

A stirred suspension of NaH (277 mg, 11 mmol) in anhydrous THF (30 mL) was cooled to 0 ° C. and 3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl Pyridin-2 (1H) -one (3.3 g, 10 mmol) was added slowly. The slurry was stirred for 15 minutes before methyl 4-bromocrotonate (1.4 mL, 12 mmol) was added to the reaction. The ice bath was removed and the reaction heated to reflux for 16 hours. The reaction was quenched by addition of 1 N NH ₄ C. The layers were separated and the aqueous layer was extracted (5 ×) with CH ₂ Cl ₂ . The combined organics were dried and concentrated in vacuo. The yellowish crude was then triturated with Et ₂ O, filtered and dried to give 1.8 g of a white solid (43%). ^{1 H-NMR (DMSO-d} 6/300 MHz) δ 7.65 (app q, J = 8.7 Hz, 1H), 7.36 (app dt, J = 12.0, 3.0 Hz, 1H); 7.17 (dt, J = 8.4, 1.8 Hz, 1H); 6.94 (dt, J = 15.9, 4.5 Hz, 1H); 6.57 (s, 1H), 5.52 (d, J = 15.9 Hz, 1H), 5.29 (s, 2H), 4.84 (m, 2H), 3.63 (s, 3H), 2.33 (s, 3H). ES-HRMS m / z 428.0301 (M + H = 428.0310 calculated for C ₁₈ H ₁₇ BrF ₂ NO ₄ ).

Example 461

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-prop-2-ynylpyridin-2 (1H) -one

Step 1: 4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-prop-2-ynylpyridin-2 (1H) -one. 4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one (2.5 g, 10 mmol) with propargyl bromide (1.3 mL, 11.0 mmol) as described above ) Was alkylated to give the title compound, giving 1.3 g (44%) of the desired product. ^{1 H-NMR (DMSO-d} 6/300 MHz) δ 7.60 (app q, J = 8.4 Hz, 1H), 7.35-7.27 (m, 1H); 7.16-7.10 (m, 1 H); 5.94 (d, J = 2.1 Hz, 1H), 5.88 (d, J = 3.0 Hz, 1H), 5.03 (s, 2H), 4.76 (d, J = 2.4, Hz, 2H), 3,31 (s, 3H), 3.24 (t, J = 2.4 Hz, 1H), 2.39 (s, 3H); ES-HRMS m / z 290.0994 (M + H = 290.0993 calculated for C ₁₆ H ₁₄ F ₂ NO ₂ ).

Step 2: 4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-prop-2-ynylpyridine-2 (1H with NBS (300 mg, 1.67 mmol) in the manner described above Bromination of) -one (500 mg, 1.67 mmol) was carried out to give 350 mg of the target compound (57%). ^{1 H-NMR (DMSO-d} 6/300 MHz) δ 7.67 (app q, J = 9.0 Hz, 1H), 7.36 (app dt, J = 10.5, 2.4 Hz, 1H); 7.23-7.16 (m, 1 H); 6.60 (s, 1H), 5.29 (s, 2H), 4.90 (d, J = 2.4, Hz, 1H), 3.35 (s, 3H), 3.32 (s, 1H), 2.53 (s, 3H); ES-HRMS m / z 368.0107 (M + H = 368.0098 calculated for C ₁₆ H ₁₃ BrF ₂ NO ₂ ).

Example 462

4-[(2,4-difluorobenzyl) oxy] -6- (hydroxymethyl) -1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one

Step 1: (4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one) in dioxane (10 mL) To a suspension of (710 mg, 2 mmol) was added selenium dioxide (1.1 g, 10 mmol). The resulting mixture was heated to 160 ° C. for 1 hour in a sealed 125 ml tube. The reaction was filtered through a fritted funnel. The filtrate was washed with CH ₂ Cl ₂ -MeOH (10: 1). The organics were combined and concentrated in vacuo. The crude material was purified by flash chromatography. Elution with hexane (50: 50 → 0: 100) gave 450 mg of aldehyde (63%). ^{1 H-NMR (DMSO-d} 6/400 MHz) δ 9.48 (s, 1H, 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 NaBH ₄ (28 mg, 1 mmol) all at once. After 30 minutes, additional NaBH ₄ (20 mg) was added to the reaction. MeOH was then removed under vacuum. The residue was extracted with CH ₂ Cl ₂ (4 ×) after the addition of 1 N NH ₄ Cl. The organics were combined, dried and concentrated in vacuo. The yellowish crude product was then dissolved in CH ₂ Cl ₂ -Et ₂ O (1: 1). After standing for a period of time a white precipitate formed. After filtration, washing with additional Et ₂ O and drying, 250 mg (55%) of the desired alcohol were obtained. ^{1 H-NMR (DMSO-d} 6/400 MHz) δ 8.42 (dd, J = 4.4, 1.6 Hz, 1H) 8.37 (d, J = 1.6 Hz, 1H), 7.61 (app q, J = 8.0 Hz, 1H ), 7.45 (d, J = 8.0 Hz, 1H), 7.32-7.27 (M, 2H), 7.12 (dt, J = 8.4, 1.6 Hz, 1H), 6.07 (d, J = 2.8 Hz, 1H), 5.99 (d, J = 12.8 Hz, 1H), 5.63 (br s, 1H), 5.18 (s, 2H), 5.09 (s, 2H), 4.29 (s, 2H). LC / MS, t _r = 1.19 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 359.1 (M + H)

Example 463

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6- (hydroxymethyl) -1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one

The title compound was prepared via bromination as described above in 60% yield. ^{1 H-NMR (DMSO-d} 6/300 MHz) δ 7.93 (d, J = 7.8 Hz, 1H), 7.73-7.65 (m, 3H), 7.38 (dt, J = 10.2, 2.4 Hz, 1H), 7.21 (app t, J = 8.7 Hz, 2H), 6.74 (s, 1 H), 5.38-5.36 (m, 4H), 4.50 (s, 2H); ES-HRMS m / z 437.0311 (M + H calculated for C ₁₉ H ₁₆ BrF ₂ N ₂ O ₂ = 437.0313).

Example 464

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-[(dimethylamino) methyl] -1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-[(dimethylamino) -methyl] pyridine-2 (1H) In a similar manner to the method summarized below for -one, the title compound was prepared using a 2.0 N THF solution of aldehyde (300 mg, 0.85 mmol) and dimethylamine (500 μl, 1 mmol) as described above, to be colorless. 110 mg (34%) of oil were obtained. The oil was then dissolved in MeOH (1 mL) and stirred with fumaric acid (25 mg) for 1 hour. The resulting precipitate was filtered off, washed with diethyl ether and dried to afford the pure product as fumarate. ^{1 H-NMR (DMSO-d} 6/400 MHz) δ 8.43-8.41 (m, 1H), 8.35 (s, 1H), 7.67-7.61 (m, 1H), 7.44-7.40 (m, 1H), 7.35- 7.29 (m, 2H), 7.17-7.12 (m, 1H), 6.62 (s, 1H), 6.60 (s, 1H), 5.41 (s, 2H), 5.32 (s, 2H), 3.13 (s, 2H) , 2.12 (s, 6 H). LC / MS, t _r = 1.55 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 464 (M + H).

Example 465

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6- (hydroxymethyl) pyridin-2 (1H) -one

Step 1: 4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-oxo-1,6-dihydropyridine-2-carbaldehyde

Dissolved in 1,4-dioxane (90 mL) in a 300 mL high pressure glass reaction vessel (16.3 g, 45 mmol). The reaction vessel was sealed and placed in an oil bath preheated to 170 ° C. The reaction was heated at 170 ° C. (165-170 ° C.) for 1.5 hours and then cooled to room temperature. The reaction mixture was worked up by filtering through a plug of celite and silica gel. The plug was then washed with 500 mL of methanol-CH ₂ Cl ₂ mixture (1: 5). The filtrate was evaporated to yield 14.2 g of the desired crude aldehyde.

Step 2: Preparation of 4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6- (hydroxymethyl) pyridin-2 (1H) -one

4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-oxo-1,6- in a 500 ml three neck round bottom flask equipped with a stir bar Dihydropyridine-2-carbaldehyde (14.2 g, 37.7 mmol) was dissolved in methanol (200 mL). The reaction mixture was cooled to 0 ° C., and sodium borohydride (2.13 g, 56.30 mmol) was added slowly in portions. The reaction was stirred at 0 ° C for 2 h. Excess sodium borohydride was added to complete the reaction. After stirring for about 2.5 hours, the reaction was allowed to warm to room temperature and then concentrated to dryness. The residue was dissolved in ethyl acetate (100 mL) and washed with dilute HCl (the pH of the aqueous layer was about 4). The organic extract was washed with brine (1 x 50 mL), dried over MgSO ₄ and concentrated in vacuo. The crude product was recrystallized from ethyl acetate and hexanes to give 7.56 g of the desired alcohol (44% yield, starting from step 1).

Step 3: Preparation of the title compound

4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6- (hydroxymethyl) pyridine-2 obtained from step 2 in a 100 ml round bottom flask. (1H) -one (2.49 g, 6.56 mmol) was dissolved in acetonitrile (35 mL). The reaction mixture was cooled to 0 ° C. in an ice bath for 10 minutes and then charged with N-bromosuccinamide (1.17 g, 6.6 mmol). The mixture was stirred at 0 ° C. under a nitrogen atmosphere for 2 hours. Acetonitrile was removed under vacuum to work up the reaction. The resulting residue was then filtered, washing with a small amount of acetonitrile to give a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.695-7.588 (m, 2H), 7.368-7.314 (m, 3H), 7.175 (dt, J = 8.5, 2.5, Hz, 1H), 6.760 (s, 1H), 5.712 (t, J = 5.674 Hz, 1H), 5.384 (s, 2H), 4.004-3.990 (m, 2H); ES-HRMS m / z 458.0013 (M + H calculated for C ₁₉ H ₁₃ BrF ₄ NO ₃ : 458.0013).

Example 466

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6- (hydroxymethyl) pyridin-2 (1H) -one

4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6- (hydroxymethyl) pyridin-2 (1H) -one (1.5 g, 3.9 mmol ) Was dissolved in acetonitrile (15 mL), and N-chlorosuccinimide (580 mg, 4.3 mmol) was added thereto to prepare the title compound. After the reaction was stirred at room temperature for 3 hours, a small amount of additional N-chlorosuccinimide (50 mg, 0.4 mmol) was added to the reaction. Stirring was continued for 1 hour. The reaction mixture was filtered through a fritted funnel to give crude material. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.69-7.61 (m, 2H), 7.37-7.31 (m, 3H), 7.17 (dt, J = 8.8, 2.0 Hz, 1H), 6.80 (s, 1H ), 5.70 (t, J = 6.0 Hz, 1H), 5.38 (s, 2H), 4.01 (d, J = 6.0 Hz, 2H); ES-HRMS m / z 414.0515 (M + H calculated for C ₁₉ H ₁₃ ClF ₄ NO ₃ : 414.0520).

Example 467

5-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-oxo-1,6-dihydropyridine-2-carb Aldehyde

Preparation of the title compound: 4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-oxo-1,6- in a 50 mL one-neck round bottom flask Dihydropyridine-2-carbaldehyde (0.36 g, 0.95 mmol) was dissolved in acetonitrile (5 mL). The reaction mixture was cooled to 0 ° C. in an ice bath and charged with N-bromosuccinamide (0.17 g, 0.95 mmol). The mixture was stirred at 0 ° C. for 2 hours under nitrogen atmosphere. After 2 hours, the solvent was evaporated in vacuo. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.53 (s, 1H), 7.73-7.67 (m, 2H), 7.62-7.54 (m, 1H), 7.35 (dt, J = 10.40, 2.56 Hz, 1H ), 7.27 (t, J = 8.35 Hz, 2H), 7.19 (dt, J = 8.60, 2.44 Hz, 1H), 5.72 (s, 1H), 5.50 (s, 2H); ES-MS m / z 455.9836 (M + H calculated for C ₁₉ H ₁₁ BrF ₄ NO ₃ : 455.9859).

Example 468

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-[(dimethylamino) methyl] pyridine-2 (1H)- On

5-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-oxo-1,6-dihydro in a 50 ml round bottom flask Pyridine-2-carbaldehyde (0.456 g, 1.0 mmol) was stirred in dichloromethane (5 mL). To this mixture was added a 2 M THF solution of dimethylamine (1.25 mL, 2.5 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. To this mixture was then added sodium triacetoxy borohydride (0.37 g, 1.75 mmol) followed by 2-3 drops of acetic acid. The mixture was then stirred at rt overnight. The solvent was then removed by evaporation and the residue was dissolved in ethyl acetate (30 mL) and washed with aqueous sodium bicarbonate and brine. The combined organics were then dried over MgSO ₄ 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 afford 0.14 g (30% yield) of the desired product. ¹ H NMR (300 MHz, DMSO-d ₆ ) 7.73-7.58 (m, 2H), 7.42-7.30 (m, 3H), 7.22 (dt, J = 8.73, 2.60 Hz, 1H), 6.81 (s, 1H) , 5.44 (s, 2H), 3.04 (s, 2H), 1.96 (s, 6H); ES-MS mlz 485.0 (M + H). ES-HRMS m / z 485.0457 (M + H calculated for C ₂₁ H ₁₈ BrF ₄ N ₂ 0 ₂ : 485.0489).

Example 469

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6- (morpholin-4-ylmethyl) pyridine-2 (1H )-On

5-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-oxo-1 using a method similar to that described in Example 468 , 6-Dihydropyridine-2-carbaldehyde (0.456 g, 1 mmol) was added morpholine (0.13 mL, 1.5 mmol) and triacetoxy sodium borohydride (0.42 g, 2.0 mmol) in dichloromethane (7 mL). Reaction with to give the title compound. The crude product was purified by flash column chromatography. Elution with (50: 50 → 0: 100) hexane-ethyl acetate gave 0.15 g (29% yield) of the desired product. ¹ H NMR (300 MHz, DMSO-d ₆ ) 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, 1H ), 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 calculated for C ₂₃ H ₂₀ BrF ₄ N ₂ 0 ₃ : 527.0594).

Example 470

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-{[(2-methoxyethyl) amino] methyl} pyridine -2 (1H) -on

5-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-oxo-1 using a method similar to that described in Example 468 , 6-dihydropyridine-2-carbaldehyde (0.319 g, 0.7 mmol) was added 2-methoxy ethylamine (0.086 mL, 1.0 mmol) and diacetoxy sodium borohydride (0.42) in dichloromethane (4 mL). g, 2.0 mmol) to give the title compound. The crude product was purified by flash column chromatography. Elution with (50: 50 → 0: 100) hexane-ethyl acetate gave 0.13 g of the desired product. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.54 (q, J = 6.89 Hz, 1H), 7.41-7.33 (m, 1H), 7.19 (s, 1H), 6.99 (t, J = 7.90 Hz, 2H) , 6.90 (dt, J = 7.90, 2.78, Hz, 1H), 6.80 (dt, J = 10.60, 2.34 Hz, 1H), 6.51 (s, 1H), 5.24 (s, 2H), 3.33 (t, J = 4.69 Hz, 1H), 3.30 (s, 3H), 2.57 (t, J = 4.86 Hz, 2H), 1.53 (s, 2H); ES-HRMS m / z 515.0548 (M + H calculated for C ₂₂ H ₂₀ BrF ₄ N ₂ 0 ₃ : 515.0594).

Example 471

5-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-oxo-1,6-dihydropyridine-2-carboxyl mountain

In a 100 ml round bottom flask, 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6 (hydroxymethyl) pyridine-2 (1H) -one (1.70 g, 3.7 mmol) was dissolved in acetone (10 mL) and cooled to 0 ° C. in an ice bath. To the reaction was added Jones's 1 M acetone solution (5 mL, excess). Additional Jones reagent was added until the reaction was complete (for about 6 hours). The reaction was then concentrated to dryness. The residue was then dissolved in ethyl acetate (10 mL) and washed with brine. The dark yellow to brown crude product was purified by dissolving in 1 N aqueous NaOH. The remaining organic impurities were removed by extraction with diethyl ether. The organic layer was discarded and the aqueous layer acidified with dilute HCl (until about pH 1) to precipitate pure acid, which was then filtered and triturated with ether to give 1.17 g of the desired product (65%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.66 (q, J = 9.41 Hz, 1H), 7.57-7.50 (m, 1H), 7.34 (dt, J = 10.11, 2.78 Hz, 1H), 7.28- 7.23 (m, 3 H), 7.18 (dt, 8.90, 2.42 Hz, 1 H), 5.47 (s, 2 H). ES-HRMS m / z 471.9814 (M + H calculated for C ₁₉ H ₁₁ BrF ₄ NO ₄ : 471.9808)

Example 472

Methyl 4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-l (2H) -yl] -3-methylbenzoate

Step 1: Preparation of Methyl 4- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -3-methylbenzoate

In a 50 ml one-neck round bottom flask equipped with a stir bar, Dean-Stark trap and condenser, 4-amino-2-methyl-methylbenzoate (1.19 g, 11.63 mmol) and 4-hydroxy-6-methyl- 2H-pyran-2-one (1.611 g, 12.78 mmol) was mixed together and dissolved in 1,2-dichlorobenzene (5 mL). The mixture was stirred vigorously and then placed in an oil bath preheated to 165 0 ° C. The reaction was maintained at 165 0 ° C. for 1.5 hours and then 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 formed. The crude product was isolated via filtration and then triturated with ether. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.64 (s, 1H), 7.93 (s, 1H), 7.85 (dd, 8.46 Hz, 1H), 7.26 (d, J = 8.12 Hz, 1H), 5.91 (d, J = 2.32 Hz, 1H), 5.54 (d, J = 2.32 Hz, 1H), 3.84 (s, 3H), 1.99 (s, 3H), 1.73 (s, 3H). ES-HRMS m / z 272.0880 (MH calculated for C ₁₅ H ₁₄ NO ₄ : 272.1001).

Step 3: Preparation of Methyl 4- (3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -3-methylbenzoate

N-methyl 4- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -3-methylbenzoate was added to N in acetonitrile according to a method analogous to that described in step 3 of Example 465. -Methyl 4- (3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -3-methylbenzoate was reacted with bromosuccinamide. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.95 (s, 1H), 7.87 (dd, J = 7.76, 2.02 Hz, 1H), 7.31 (d, J = 8.54, 1H), 6.09 (s, 1H ), 3.85 (s, 3H), 1.99 (s, 3H), 1.74 (s, 1H). ES-HRMS m / z 352.0195 (M + H calculated for C ₁₅ H ₁₄ BrNO ₄ : 352.0185)

Step 4: Take methyl 4- (3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -3-methylbenzoate (0.92 g, 2.61 mmol) and dry DMF Dissolve in (5 mL) to give the title compound. Then potassium carbonate (0.432 g, 3.13 mmol) and 2,4 difluorobenzyl bromide (0.335 mL, 2.61 mmol) were added. The mixture was stirred at rt for 2 h. The reaction was then poured into 100 ml of ice water and worked up, which resulted in the formation of a precipitate which was isolated by filtration in a fritted funnel. The crude product was washed with ether and dried in vacuo to yield 0.85 g (76.20%) of pure product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.98 (d, J = 1.6 Hz, 1H), 7.88 (dd, J = 8.04, 2.0 Hz, 1H), 7.69 (q, J = 8.6 Hz, 1H) , 7.36-7.30 (m, 2H), 7.17 (dt, J = 8.7, 2.3 Hz, 1H), 6.71 (s, 1H), 5.32 (s, 2H), 3.86 (s, 3H), 2.00 (s, 3H ), 1.86 (s, 3 H). ES-HRMS m / z 478.0459 (M + H calculated for C ₂₂ H ₁₉ BrF ₂ NO ₄ : 478.0466).

Examples 473-476

The compounds of Examples 473-476 were prepared by derivatization of the compounds of Examples 472.

NMR Analysis of the Compounds of Examples 473-476

Example 477

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (2-methyl-4-vinylphenyl) pyridin-2 (1H) -one

Step 1: Preparation of -1- (4-bromo-2-methylphenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one

The title compound was prepared in a similar manner to the method outlined in 4- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -3-methylbenzoate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.61 (s, 1H), 7.59 (d, J = 2.84 Hz, 1H), 7.45 (dd, J = 8.39, 2.44 Hz, 1H), 7.06 (d, J = 7.44, 1H), 5.89 (d, J = 2.73 Hz, 1H), 5.53 (d, J = 2.30, 1H), 1.91 (s, 3H), 1.75 (s, 3H). ES-HRMS m / z 294.0127 (M + H calculated for C ₁₃ H ₁₃ BrNO ₃ : 294.0130).

Step 2: Preparation of -1- (4-Bromo-2-methylphenyl) -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one

1- (4-Bromo-2-methylphenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one (7.35 g, 25.0 mmol) is dissolved in DMF (15 mL) and potassium carbonate (4.14 g, 30.0 mmol) and 2,4-difluorobenzyl bromide (3.21 mL, 25.0 mmol) were stirred at room temperature for 2 hours. The reaction was poured into 300 ml of continuously stirred ice water and worked up. The white precipitate was isolated by filtration, triturated with ether and further purified to give 3.06 g (29%) of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.65-7.59 (m, 2H), 7.49 (dd, J = 8.45, 2.22 Hz, 1H), 7.31 (dt, J = 9.79, 2.22 Hz, 1H), 7.16-7.08 (m, 2H), 6.05 (d, J = 2.58 Hz, 1H), 5.93 (d, J = 2.66 Hz, 1H), 5.08 (s, 2H), 1.93 (s, 3H), 1.77 (s , 3H). ES-HRMS m / z 420.0390 (M + H calculated for C ₂₀ H ₁₇ BrF ₂ NO ₂ : 420.0411).

Step 3: Preparation of 4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (2-methyl-4-vinylphenyl) pyridin-2 (1H) -one

1- (4-bromo-2-methylphenyl) -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridine-2 (1H in a 50 ml round bottom flask pre-vented with nitrogen ) -One (0.420 g, 1.0 mmol) was dissolved in dry THF (10 mL). Pd (PPh ₃ ) ₄ (0.173 g, 0.15 mmol) was added to this mixture. The reaction flask was sealed with a rubber septum to evacuate and filled with nitrogen. Under nitrogen atmosphere, tributyl (vinyl) tin (0.35 mL, 1.2 mmol) was added to the sealed reaction mixture and stirred at 50 ° C. overnight. The reaction was worked up by quenching with water and the product extracted with ethyl acetate. The crude product was purified by column chromatography. Elution with ethyl acetate-hexane (50: 50 → 0: 100) gave 0.32 g (69%) of the desired product.

Step 4: 4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (2-methyl-4-vinylphenyl, using a method similar to that described in step 3 of Example 465 ) Pyridin-2 (1H) -one (0.64 g, 1.74 mmol) was reacted with N-bromosuccinamide (0.325 g, 1.83 mmol) in acetonitrile (9 mL) at 0 ° C. to prepare the title compound, Compound was obtained (0.423 g, 54.5% after recrystallization). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.67 (app q, J = 7.59 Hz, 1H), 7.48 (s, 1H), 7.42 (dd, J = 8.21, 1.98 Hz, 1H), 7.33 (dt , J = 10.00, 2.27 Hz, 1H), 7.17 (dt, J = 8.51, 2.44 Hz, 1H), 7.13 (d, J = 7.88 Hz, 1H) 6.74 (dd, J = 11.29, 6.34 Hz, 1H), 6.67 (s, 1 H), 5.88 (d, J = 17.85, 1 H), 5.32-5.30 (m, 2H), 1.92 (s, 3H), 1.88 (s, 3H). ES-HRMS m / z 446.0579 (M + H calculated for C ₂₂ H ₁₉ BrF ₂ NO ₂ : 446.0568).

Example 478

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [4- (1,2-dihydroxyethyl) -2-methylphenyl] -6-methylpyridine-2 (1H )-On

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (2-methyl-4-vinylphenyl) pyridin-2 (1H) -one (0.126 g, 0.28 mmol) was dissolved in a mixture of acetone (3 mL) and water (1 mL). To this, 4-methylmorpholine N-oxide (0.032 g, 0.28 mmol) and a catalytic amount (about 5 mg) of osmium tetraoxide were added and stirred under a nitrogen atmosphere. After about 2 hours, the reaction was worked up with acetone evaporation. The product was extracted with ethyl acetate and concentrated to give a dark solid, which was further purified by column chromatography to give 0.049 g (37% yield) of charcoal solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.67 (q, J = 8.24 Hz, 1H), 7.37-7.23 (m, 3H), 7.17 (dt, J = 8.62, 2.62 Hz, 1H), 7.07 ( dd, J = 9.36, 2.24 Hz, 1H), 6.65 (s, 1H), 5.30 (s, 2H), 4.74 (t, J = 6.16 Hz, 1H), 4.57-4.50 (m, 1H), 3.45 (app t, J = 6.12 Hz, 2H), 3.41-3.37 (m, 1H), 1.91 (s, 3H), 1.85 (s, 3H). ES-HRMS m / z 480.0625 (M + H calculated for C ₂₂ H ₂₁ BrF ₂ NO ₄ : 480.0623).

Example 479

Methyl 3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-chlorobenzoate

Step 1: Preparation of Methyl 4-chloro-3- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) benzoate

Condensation reaction of methyl 3-amino-4-chlorobenzoate (14.5 g, 78.2 mmol) with 4-hydroxy-6-methyl pyranone under reaction conditions similar to those described in step 3 of Example 465 yielded 12.32 ( 53.8%) was obtained.

Step 3: Preparation of Methyl-4-chloro-3- [4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzoate

Methyl 4-chloro-3- (4-hydroxy-6-methyl-2-oxopyridine-1 (2H)-from step 1 in a 250 ml round bottom flask using a method similar to step 3 of Example 472 Yl) benzoate (5.28 g, 18.0 mmol) was reacted with 2,4-difluoro-benzylbromide (3.72 g, 18.0 mmol) in DMF. After aqueous workup and chromatography purification, 2.3 g (30%) of pure product were obtained.

Step 4: Methyl-4-chloro-3- [4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxo using a method similar to that described in step 3 of Example 465 Pyridin-1 (2H) -yl] benzoate (2.3 g, 5.47 mmol) was reacted with N-bromosuccinamide (0.97 g, 5.47 mmol) in acetonitrile (10 mL) at 0 ° C. to methyl 3- [3 -Bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-chlorobenzoate to make 1.80 g of the desired product (66.2%) was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.06-8.03 (m, 2H), 7.86 (d, J = 9.70 Hz, 1H), 7.68 (q, J = 7.62, 1H), 7.34 (dt, J = 10.07, 2.46 Hz, 1H), 7.17 (dt, J = 8.72, 2.90 Hz, 1H), 6.73 (s, 1H), 5.33 (s, 2H), 3.85 (s, 3H), 1.91 (s, 3H) . ES-MS m / z 495.9757 (MH calculated for C ₂₁ H ₁₄ BrClF ₂ NO ₄ : 495.9795).

Example 480

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-chlorobenzoic acid

Methyl-4-chloro-3- [4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzoate in a 50 ml round bottom flask ( 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 rt overnight. THF was evaporated and the residue acidified with dilute HCl. A white precipitate was obtained. The product was filtered off, washed with water and dried in vacuo to yield 0.375 g (86% yield) of the desired product. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.89 (dd, J = 7.78, 1.73 Hz, 1H), 7.71-7.65 (m, 2H), 7.53 (d, J = 9.08 Hz, 1H), 7.33 ( dt, J = 9.95, 2.59 Hz, 1H), 7.17 (dt, J = 8.22, 2.59 Hz, 1H), 6.68 (s, 1H), 5.32 (s, 2H), 1.89 (s, 3H). ES-MS m / z 481.9585 (MH calculated for C ₂₀ H ₁₂ BrClF ₂ NO ₄ : 481.9601).

Example 481

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [5- (hydroxymethyl) -2-methylphenyl] -6-methylpyridin-2 (1H) -one

Step 1: Preparation of 4-hydroxy-1- [5- (hydroxymethyl) -2-methylphenyl] -6-methyl pyridin-2 (1H) -one

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 dissolved 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 thermostat probe and a heating mantle. In 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 pyron solution was poured into a flask containing aniline and the reaction stirred at 165 ° C. for 20 minutes. The reaction was cooled to room temperature. The reaction contents were washed with saturated aqueous NaHCO ₃ . The organic layer and the aqueous layer were separated. Acidified by dropwise addition of concentrated HCl to the aqueous layer. The product was extracted with n-BuOH from acidic aqueous layer. N-BuOH was removed under vacuum to give a reddish brown oil (8.5 g, 19%). The contents were used for the next reaction without further purification. ¹ H NMR (300 MHz, CD ₃ OD) δ 7.35 (m, 2H), 7.08 (s, 1H), 6.08 (br s, 1H), 5.81 (br s, 1H), 4.60 (s, 2H), 2.01 (s, 3 H), 1.87 (s, 3 H). LC / MS, t _r = 1.42 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS mlz 246.1131 (M + H). ES-HRMS m / z 246.1107 (M + H calculated for C ₁₄ H ₁₆ NO ₃ : 246.1125).

Step 2: 4-[(2,4-difluorobenzyl) oxy] -1- [5- (hydroxymethyl) -2-methylphenyl] -6-methyl-pyridin-2 (1H) -one

4-hydroxy-1- [5- (hydroxymethyl) -2-methylphenyl] -6-methyl pyridin-2 (1H) -one (prepared in step 1) (8.0 g, 32.6 mmol) was dimethyl at room temperature. Stir vigorously with 2,4-difluorobenzyl bromide (4.2 mL, 32.6 mmol) and K ₂ CO ₃ (4.5 g, 32.6 mmol) in 50 mL formamide. After stirring for 8 hours, H ₂ 0 (100 mL) was added to the reaction mixture. The product was extracted with ethyl acetate. The ethyl acetate layer was separated and dried over Na ₂ SO ₄ . Ethyl acetate was removed in vacuo. A yellow oil was obtained. The oil was first passed through a plug of silica gel, eluting with 500 ml of ethyl acetate / hexanes (1: 1). This eluate was left to stand. Ethyl acetate (100%) was then passed through the plug until the desired product was thoroughly washed from silica (3 L). The solvent was removed in vacuo. A light yellow oil was obtained (7.5 g, 62%). ¹ H NMR (300 MHz, CD ₃ OD) δ 7.60 (app q, J = 6.44 Hz, 1H), 7.42 (d, J = .81 Hz, 2H), 7.15 (s, 1H), 7.06 (m, 2H ), 6.21 (dd, J = 1.61, 1.00 Hz, 1H), 6.12 (d, J = 2.62 Hz, 1H), 5.16 (s, 2H), 4.65 (s, 2H), 2.07 (s, 3H), 1.93 (s, 3H); LC / MS, t _r = 2.38 min (detecting at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 372 (M + H).

Step 3: Preparation of the title compound. 4-[(2,4-difluorobenzyl) oxy] -1- [5- (hydroxymethyl) -2-methylphenyl] -6-methyl-pyridin-2 (1H) -one (prepared in step 2) ) (4.0 g, 10.8 mmol) was stirred with N-bromosuccinimide (2.1 g, 11.9 mmol) in 100 mL CH ₂ Cl ₂ at RT for 2.0 h. The reaction was evaporated in a rotary evaporator and the resulting solid was washed with acetonitrile and precursord in vacuo to give a white solid (3.9 g, 80%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.67 (app q, J = 6.24 Hz, 1H), 7.35 (d, J = 1.01 Hz, 2H), 7.10 (s, 1H), 7.04 (m, 1H), 6.91 (ddd, J = 11.08, 8.66, 2.42 Hz, 1H), 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 calculated for C ₂₁ H ₁₉ BrF ₂ NO ₃ : 450.0511).

Example 482

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [5- (hydroxymethyl) -2-methylphenyl] -6-methylpyridin-2 (1H) -one

The title compound was prepared in a similar manner as described in Example 481 except that the product of Step 2 of Example 481 was chlorinated instead of brominated. The method was as follows: 4-[(2,4-difluorobenzyl) oxy] -1- [5- (hydroxymethyl) -2-methylphenyl] -6-methyl-pyridin-2 (1H) -one (Obtained in step 2 of Example 481 above) (7.0 g, 18.8 mmol) was refluxed overnight in 50 mL of CH ₂ Cl ₂ with N-chlorosuccinimide (2.5 g, 18.8 mmol). The reaction was evaporated in a rotary evaporator and the resulting solid was stirred in MeOH. The precipitate was collected on a filter pad, washed with MeOH and dried under vacuum to give a white solid (1.6 g, 21%). ¹ H NMR (300 MHz, DMF-d ₇ ) δ 7.85 (app q, J = 6.44 Hz, 1H), 7.43 (d, J = 0.81, 1H), 7.42-7.23 (m, 3H), 6.84 (s, 1H), 5.48 (s, 2H), 4.67 (s, 2H), 2.05 (s, 3H), 2.03 (s, 3H); ES-MS m / z 406 (M + H). ES-HRMS m / z 406.1033 (M + H calculated for C ₂₁ H ₁₆ ClF ₂ NO ₄ : 406.1016).

Example 483

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [5- (hydroxymethyl) -2-methylphenyl] -6-methylpyridin-2 (1H) -one

Step 1: Preparation of 3-amino-4-chloro-benzyl alcohol

3-nitro-4-chloro-benzyl alcohol (23.0 g, 122.6 mmol) was dissolved in isopropyl alcohol (175 mL) and water (35 mL). Iron powder (<10 microns) (68.0 g, 1.2 mol) and NH ₄ Cl (66.0 g, 1.2 mol) were added. The suspension was stirred at 70 ° C. in a three necked round bottom flask equipped with a heating mantle and a J-Kem thermostat probe. After 4 hours, isopropyl alcohol was removed under vacuum. Water (100 mL) and concentrated HCl (10 mL) were added to the mixture. The contents were transferred to a separatory funnel and the aqueous layer of impurities was extracted using ethyl acetate. The aqueous layer was then basified with 50% aqueous NaOH. The product was extracted with ethyl acetate from the basic aqueous layer. The ethyl acetate layer was dried over Na ₂ SO _{4 and} then removed in vacuo. The remaining residue was dissolved in 50% ethyl acetate / hexanes and the precipitate was collected on a filter pad. The precipitate was washed with 50% ethyl acetate / hexanes to give a downy brown solid (8.4 g, 44%). ¹ H NMR (300 MHz, CD ₃ OD) δ 7.17 (d, J = 8.26 Hz, 1H), 6.86 (d, J = 2.01 Hz ,, 1H), 6.66 (dd, J = 2.01, 0.61 Hz, 1H) , 4.51 (s, 2 H); LC / MS, t _r = 0.32 min (detecting at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min); ES-MS m / z 158 (M + H).

Step 2: 1- [2-Chloro-5- (hydroxymethyl) phenyl] -4-hydroxy-6-methylpyridin-2 (1H) -one

3-amino-4-chloro-benzyl alcohol (8.0 g, 51.0 mmol) and 4-hydroxy-6-methyl-2-pyrone (6.4 g, 51.0 mmol) were dissolved in 1,2-dichlorobenzene (50 mL). I was. The mixture was placed in an 165 ° C. oil bath and stirred for 20 minutes. The reaction was cooled to room temperature, the reaction washed with saturated aqueous NaHCO ₃ and the impurities were extracted with ethyl acetate. The product remained in the aqueous layer. The basic aqueous layer was acidified with concentrated HCl. The product was extracted with ethyl acetate from the acidic aqueous layer. Ethyl acetate layer with Na ₂ SO ₄ Dry over, and remove solvent under vacuum. The product was obtained in 26% yield as a yellow oil and used in the next step without further purification. ¹ H NMR (300 MHz, CD ₃ OD) δ 7.62 (d, J = 8.26 Hz, 2H), 7.51 (dd, J = 8.46, 2.22 Hz, 1H), 7.36 (d, J = 2.01 Hz, 1H), 6.13 (br s, 1 H), 5.84 (d, J = 2.42 Hz, 1 H), 4.68 (s, 2 H), 1.97 (s, 3 H); LC / MS, t _r = 0.25 min and 1.41 min (tautomer), (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 266 (M + H).

Step 3: 1- [2-Chloro-5- (hydroxymethyl) phenyl] -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one.

1- [2-chloro-5- (hydroxymethyl) phenyl] -4-hydroxy-6-methylpyridin-2 (1H) -one (prepared in step 2) (3.5 g, 13.2 mmol) was added DMF ( 10 ml) and cooled to 0 ° C. 2,4-difluorobenzyl bromide (1.7 mL, 13.2 mmol) and K ₂ CO ₃ (1.8 g, 13.2 mmol) were added and the reaction stirred for 6 hours. Saturated aqueous NaHCO ₃ was added to the reaction, followed by extraction with ethyl acetate. The ethyl acetate extract was washed with water and the aqueous layer was extracted with ethyl acetate. Combined Organic Layers Na ₂ SO ₄ Dry over, filter and remove solvent in vacuo. The product was obtained in 83% crude yield and used as the next step as a brown oil. LC / MS, t _r = 2.48 min (detecting at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 392 (M + H). ES-HRMS m / z 392.0853 (M + H calculated for C ₂₀ H ₁₇ ClF ₂ NO ₃ : 392.0860).

Step 4: The title compound was purified by 1- [2-chloro-5- (hydroxymethyl) phenyl] -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one (Prepared from step 3) (1.8 g, 4.6 mmol) and N-bromosuccinimide (0.82 g, 4.6 mmol) were CH ₂ Cl ₂ (10 mL) and prepared by stirring at room temperature for 2 hours. The solvent was removed in vacuo and the residue dissolved in CH ₃ CN. The precipitate was collected on a filter pad and rinsed with CH ₃ CN to give a white solid (370 mg, 17%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.65 (app q, J = 6.24 Hz, 1H), 7.52 (d, J = 8.26 Hz, 1H), 7.40 (dd, J = 8.26, 2.01 Hz 1H), 7.26 (d, J = 0.81 Hz, 1H), 7.03 (m, 1H), 6.91 (ddd, J = 11.08, 8.66, 2.42 Hz, 1H), 6.17 (d, J = 0.81 1H), 5.29 (s, 2H) , 4.63 (s, 2 H), 2.02 (s, 3 H); ES-MS m / z 471 (M + H). ES-HRMS m / z 471.9953 (M + H calculated for C ₂₀ H ₁₆ BrClF ₂ N0 ₃ : 471.9944).

Example 484

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1- [5- (hydroxymethyl) -2-methylphenyl] -6-methylpyridin-2 (1H) -one

The title compound was diluted to 1- [2-chloro-5- (hydroxymethyl) phenyl] -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridine in 65 ° C. dichloroethane (20 mL). Prepared from -2 (1H) -one (2.4 g, 6.1 mmol) and NCS (815.0 mg, 6.1 mmol). A catalytic amount of dichloroacetic acid (2 drops) was added. After 2 h the solvent was removed in vacuo and the residue was dissolved in diethyl ether. The precipitate was collected on a filter pad and then dissolved in 50% ethyl acetate / hexanes to remove residual succinimide. The precipitate was collected on a filter pad and then dried in vacuo to yield a white powder (180 mg, 6.9%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.61 (app q, J = 6.44 Hz, 1H), 7.52 (d, J = 8.26 Hz, 1H), 7.40 (dd, J = 8.26, 2.01 Hz, 1H), 7.27 (d, J = 2.01 Hz, 1H), 7.00 (m, 1H), 6.91 (m, 1H), 6.20 (s, 1H), 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 calculated for C ₂₀ H ₁₆ Cl ₂ F ₂ NO ₃ : 426.0470).

Example 485

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- {5-[(dimethylamino) methyl] -2-methylphenyl} -6-methylpyridin-2 (1H) -one Hydrochloride

Step 1: Preparation of 3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methylbenzaldehyde

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [5- (hydroxymethyl) -2-methylphenyl] -6-methylpyridin-2 (1H) -one (1.5 g, 3.33 mmol) was dissolved in 75% CH ₃ CN / CH ₂ Cl ₂ (20 mL) and cooled to 0 ° C. Dess-Martin Periodinane (2.8 g, 6.66 mmol) was added and the reaction stirred for 4 hours. At this point, the reaction was quenched with 5% aqueous sodium bisulfite. The product was extracted with ethyl acetate. The combined organic extracts were then washed with saturated aqueous NaHCO ₃ . The aqueous layer was extracted with ethyl acetate. Combined organic extracts with Na ₂ SO ₄ Dried over, filtered and concentrated. The resulting residue was dissolved in diethyl ether and the precipitate collected on a filter pad and washed with additional diethyl ether to give a white solid (1.35 g, 91%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 10.00 (s, 1H), 7.91 (dd, J = 7.65, 1.61 Hz, 1H), 7.65 (m, 2H), 7.57 (d, J = 7.85 Hz, 1H) , 7.03 (m, 1H), 6.95 (ddd, J = 12.69, 8.86, 2.62 Hz, 1H), 6.19 (s, 1H), 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 calculated for C ₂₁ H ₁₇ BrF ₂ N0 ₃ : 448.0354).

Step 2: Preparation of the title compound. 3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methylbenzaldehyde (prepared in step 1 (0.50 g, 1.11 mmol) in CH ₂ Cl ₂ (10 mL). N, N-dimethylamine (2.0 M in THF) (1.11 mL, 2.22 mmol) was added. This mixture was stirred at rt for 12 h. Next, sodium triacetoxy borohydride (0.47 g, 2.22 mmol) was added and the reaction stirred for an additional 2 hours. The reaction was washed with aqueous 1 N NaOH and then extracted with CH ₂ Cl ₂ . The combined organic extracts were washed with water. The aqueous layer was separated and extracted with CH ₂ Cl ₂ . Combined Organic Extract Na ₂ SO ₄ Dry over, filter and concentrate in vacuo. The resulting residue was dissolved in diethyl ether. 1 M HCl (5 mL) in diethyl ether was added and the precipitate was collected on a filter pad. This precipitate was hygroscopic. The hygroscopic solid was then dissolved in hot ethyl acetate. Hexane was added until a precipitate formed. The precipitate was collected on a filter pad to give a white solid (150 mg, 26%). ¹ H NMR (400 MHz, D ₂ O) δ 7.42 (m, 3H), 7.17 (s, 1H), 6.86 (m, 2H), 6.53 (s, 1H), 5.20 (s, 2H), 4.18 (s , 1H), 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 calculated for C ₂₃ H ₂₄ BrF ₂ N ₂ O ₂ : 477.0984).

Example 486

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- {5-[(isopropylamino) methyl] -2-methylphenyl} -6-methylpyridine-2 (1H)- Hydrochloride

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridine-1 (2H according to the method described in Example 485 (step 2) above) ) -Yl] -4-methylbenzaldehyde (prepared in step 1) (0.50 g, 1.11 mmol) is subjected to reductive amination with isopropyl amine (0.13 g, 2.22) to give the title compound, which is the desired compound (0.49 g , 84%) was obtained. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.64 (app quartet, J = 6.58 Hz, 1H), 7.53 (m, 2H), 7.29 (br s, 1H), 7.03 (m, 1H), 6.68 (s , 1H), 5.36 (s, 2H), 4.22 (s, 2H), 3.46 (m, 1H), 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 calculated for C ₂₄ H ₂₆ BrF ₂ N ₂ 0 ₂ : 491.1140).

Example 487

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N- (2-hydroxyethyl) -4-methylbenzamide

Step 1: Preparation of Methyl 3- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -4-methylbenzoate

4-hydroxy-6-methyl-2-pyrone (22.9 g, 181.6 mmol) and methyl-3- in a 250 ml three neck round bottom flask equipped with a J-Kem thermostat probe, Dean-Stark trap and heating mantle Amino-2-methylbenzoate (25 g, 151.3 mmol) was suspended in 50 ml of 1,2-dichlorobenzene. The reaction was heated to 165 ° C. for 15 minutes during which time water and some 1,2-dichlorobenzene were collected in a Dean-Stark trap. The reaction was cooled to about 110 ° C. At this point, 200 ml of toluene was added. The flask was placed in an 0 ° C. ice bath and stirred. "Oiling out" has occurred. Too much toluene may have been added, so some of the solvent was removed under vacuum. The oil was returned to solution and a light brown precipitate remained. The toluene mixture was stirred at rt for 72 h. The precipitate was collected on a filter pad. The precipitate was filtered off, washed three times with toluene and three times with water at 50 ° C. to remove excess pyron and dried under vacuum to give a tan solid (16.5 g, 40% yield). ¹ H NMR (300 MHz, CD ₃ OD) δ 8.06 (dd, J = 8.06, 1.61 Hz, 1H), 7.80 (d, J = 1.61 Hz, 1H), 7.56 (d, J = 8.6, Hz, 1H) , 6.15 (dd, J = 2.42, 0.81 Hz, 1H), 5.86 (d, J = 2.42 1H), 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 calculated for C ₁₅ H ₁₆ NO ₄ : 274.1074).

Step 2: Preparation of methyl 3- [4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methylbenzoate

Methyl 3- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -4-methylbenzoate (prepared in step 1) (16.5 g, 60.4 mmol) and 2,4- Difluorobenzyl bromide (7.8 mL, 60.4 mmol) was dissolved in 250 mL N, N-dimethylformamide and the mixture was cooled to 0 ° C. K ₂ CO ₃ (8.3 g, 60.4 mmol) was added and the reaction stirred for 12 hours, during which the reaction was allowed to warm to room temperature. LC / MS indicated that starting material was present after 12 hours. Excess K ₂ CO ₃ was added with 0.50 ml of 2,4-difluorobenzyl bromide at room temperature. The reaction was further stirred for 2 hours. Saturated aqueous NaHC0 ₃ was poured into the reaction vessel. The solution was extracted with ethyl acetate and the organic layers combined and washed with water. The organic layer was separated and the aqueous layer was washed with ethyl acetate. Organic layers combined and Na ₂ SO ₄ Dry over phase and evaporate. The product was used for next step as crude oil (24.1 g, quantitative yield). ¹ H NMR (300 MHz, CDC1 ₃ ) δ 8.06 (dd, J = 7.85, 1.61 Hz, 1H), 7.82 (d, J = 1.61, 1H), 7.52-7.44 (m, 2H), 7.01-6.88 (m , 2H), 6.05 (d, J = 2.62 Hz, 1H), 5.97 (dd, J = 2.62, 0.81 Hz, 1H), 5.08 (s, 2H), 3.93 (s, 3H), 2.20 (s, 3H) , 1.89 (s, 3 H); ES-MS m / z 400 (M + H). ES-HRMS m / z 400.1374 (M + H calculated for C ₂₂ H ₂₀ F ₂ NO ₄ : 400.1355).

Step 3: Preparation of 3- [4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methylbenzoic acid

Methyl 3- [4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methylbenzoate (14 g, 35.0 mmol) ( Prepared in Step 2) was dissolved in THF (25 mL) and H ₂ O. Aqueous 2.5 N NaOH was added and the reaction stirred at rt for 30 min. The reaction was acidified by addition of concentrated HCl. The product was extracted with ethyl acetate. The ethyl acetate extract was dried over Na ₂ S0 _4, filtered and the solvent removed in vacuo. After vacuum removal of the solvent, the product was produced from ethyl acetate. This precipitate was collected on a filter pad and washed with 50% ethyl acetate / hexanes to give a white powder (9 g, 7%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.01 (dd, J =, 1.61 Hz, 1H), 7.84 (d, J = 1.61 Hz, 1H), 7.52-7.47 (app q, J = 8.26, 1H), 7.43 (d, J = 8.06 Hz, 1H), 7.00-6.88 (m, 2H), 6.19 (d, J = 2.62 Hz, 1H), 6.05 (dd, J = 2.62, 1.81 Hz, 1H), 5.17 (s , 2H), 2.19 (s, 3H), 1.90 (s, 3H); ES-HR / MS m / z 386.12 (M + H calculated for C ₂₁ H ₁₈ F ₂ NO ₄ : 386.1198).

Step 4: Preparation of 3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methylbenzoic acid

3- [4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methylbenzic acid (5.9 g, 15.2 mmol) (above Prepared in step 3) was dissolved in dichloromethane (25 mL). N-bromosuccinimide was added and the reaction stirred for 14 hours. Dichloromethane was removed in vacuo and the residue dissolved in acetonitrile. The precipitate was collected on a filter pad and rinsed with acetonitrile to afford the desired product as a white solid (5.2 g, 74%). ¹ H NMR (300 MHz, CD ₃ OD) δ 7.87 (dd, J = 7.85, 1.61, Hz, 1H), 7.82 (d, J = 1.81 Hz, 1H), 7.69 (app q, J = 8.06 Hz 1H) , 7.57 (d, J = 8.06 Hz, 1H), 7.09 (dt, J = 8.66, 2.22 Hz, 1H), 6.70 (s, 1H), 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 calculated for C ₂₁ H ₁₇ BrF ₂ NO ₄ : 464.0304).

Step 5: Preparation of the title compound. 3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methylbenzoic acid (from step 4 above) (1.9 g, 4.10 mmol) was dissolved in 20 mL of CH ₂ Cl ₂ . Ethanolamine (297 μl, 4.92 mmol) was added followed by EDCI (0.764 g, 4.92 mmol), 1-hydroxybenzotriazole (0.665 g, 4.92 mmol) and triethylamine (1.14 mL, 8.20 mmol) in this order. Added. The reaction was stirred at rt overnight. The reaction was quenched with NH ₄ Cl and extracted three times with ethyl acetate. The combined organic layers were then washed with saturated aqueous NaHCO ₃ and extracted three times with ethyl acetate. The organic layers were combined, washed with H ₂ O and extracted three times with ethyl acetate. Organic layers were combined, dried over Na ₂ SO ₄ and evaporated. The resulting residue was triturated with diethyl ether / hexanes to give a solid, which was dried under vacuum to give a white solid (1.5 g, 72%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.93 (dd, J = 7.85, 1.61 Hz, 1H), 7.65 (d, J = 1.61 Hz, 1H), 7.62 (app q, J = 8.26 Hz, 1H), 7.40 (d, J = 8.06 Hz, 1H), 7.39-7.30 (m, 1H), 7.03-6.97 (m, 1H), 6.88-6.81 (m, 1H), 6.25 (s, 1H), 5.20 (s, 2H), 3.70-3.52 (m, 1H), 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 calculated for C ₂₃ H ₂₂ BrF ₂ N ₂ 0 ₄ : 507.0726).

Examples 488-491

The compounds of Examples 488-491-476 were prepared essentially according to the method set forth in Example 487.

Example 492

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [5- (1-hydroxy-1-methylethyl) -2-methylphenyl] -6-methylpyridine-2 ( 1H) -on

Step 1: Methyl 3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methylbenzoate Manufacture

Methyl 3- [4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methylbenzoate (prepared above) (1.8) g, 4.51 mmol) in CH ₂ Cl ₂ (10 mL). N-bromosuccinimide (0.80 g, 4.51 mmol) was added and the mixture was stirred at rt for 2 h. CH ₂ Cl ₂ was removed under vacuum and the residue was dissolved in CH ₃ CN. The resulting precipitate was collected on a filter pad and washed with CH ₃ CN to give a white solid (0.30 g, 14%, first crop). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.06 (dd, J = 8.06, 1.61 Hz, 1H), 7.80 (d, J = 1.61 Hz, 2H), 7.65 (app q, J = 8.46 Hz, 1H), 7.48 (d, J = 8.06, 1H), 7.05-6.99 (m, 1H), 6.96-6.89 (m, 1H), 6.16 (s, 1H), 5.31 (s, 2H), 3.93 (s, 3H), 2.17 (s, 3 H), 1.96 (s, 3 H). ES-HRMS m / z 478.0476 (M + H calculated for C ₂₂ H ₁₉ BrF ₂ NO ₄ : 478.0476).

Step 2: Preparation of the title compound. 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 dissolved in THF and cooled to 0 ° C. MeMgCl (3.0 M in THF) (0.73 mL, 2.2 mmol) was added slowly to the 0 ° C. solution. The reaction proceeded without maintaining a bath temperature of 0 ° C. The reaction was completed within 2 hours. At this point, the mixture was quenched with saturated aqueous NH ₄ Cl and extracted with ethyl acetate. The organic layers were combined, washed with H ₂ O and extracted with ethyl acetate. The organic layers were combined, dried over Na ₂ SO _4, filtered and evaporated. The residue was dissolved in 50% ethyl acetate / hexanes. The precipitate was collected on a filter pad and washed with 50% ethyl acetate / hexanes to give a white solid (0.10 g, 45%). ¹ H NMR (300 MHz, CD ₃ OD) δ 7.70 (app q, J = 8.26, Hz, 1H), 7.54 (dd, J = 8.06, 2.01 Hz, 1H), 7.40 (d, J = 1.81 Hz, 1H ), 7.12-7.06 (m, 2H), 6.68 (s, 1H), 5.40 (s, 2H), 2.05 (s, 3H), 2.02 (s, 3H), 1.57 (s, 6H). ES-HRMS m / z 478.0785 (M + H calculated for C ₂₃ H ₂₃ BrF ₂ NO ₃ : 478.0824).

Example 493

Methyl 3- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methylbenzoate

Methyl 3- [4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methylbenzoate (1.46 g, 3.66 mmol) Dissolve in dichloroethane (25 mL), N-chlorosuccinimide (0.49 g, 3.66 mmol), dichloroacetic acid (catalyst) were added and heated at 50 ° C. for 6 hours to prepare the title compound. At this point, the solvent was removed in vacuo and the residue was dissolved in diethyl ether. The precipitate was collected on a filter pad. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.07 (dd, J = 7.85, 1.61 Hz, 1H), 7.80 (d, J = 1.81 Hz, 2H), 7.62 (app q, J = 8.46 Hz, 1H), 7.48 (d, J = 7.85, 1H), 7.05-6.95 (m, 1H), 6.93-6.89 (m, 1H), 6.19 (s, 1H), 5.30 (s, 2H), 3.93 (s, 3H), 2.17 (s, 3 H), 1.97 (s, 3 H). ES-HRMS m / z 434.0932 (M + H calculated for C ₂₂ H ₁₉ ClF ₂ NO ₄ : 434.0965).

Example 494

Methyl 4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3-chlorobenzoate

Step 1: Preparation of methyl 3-chloro-4- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) benzoate.

4-hydroxy-6-methyl-2-pyrone (24.5 g, 193.9 mmol) and methyl-3- in a 250 ml three neck round bottom flask equipped with J-Kem thermostat probe, Dean-Stark trap and heating mantle Amino-2-chlorobenzoate (30 g, 161.6 mmol) was suspended in 75 mL of 1,2-dichlorobenzene. The reaction was heated to 175 ° C. for 20 minutes during which time water and some 1,2-dichlorobenzene were collected in a Dean-Streck trap. The reaction was cooled to about 110 ° C. At this point, 200 ml of toluene was added. The toluene mixture was stirred at rt for 72 h. The precipitate was collected on a filter pad. The precipitate was filtered off, washed three times with toluene and three times with 50 ° C. water to remove excess pyrone and dried under vacuum to give a tan solid (13.0 g, 27% yield). ¹ H NMR (300 MHz, CD ₃ OD) δ 8.26 (d, J = 1.81 Hz, 1H), 8.14 (dd, J = 8.26, 1.81 Hz, 1H), 7.54 (d, J = 8.26, Hz, 1H ), 6.14 (dd, J = 2.42, 1.0 Hz, 1H), 5.83 (d, J = 2.42 1H), 4.00 (s, 3H), 1.96 (s, 3H); LC / MS, t _r = 1.81 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 294 (M + H).

Step 2: Preparation of methyl 3-chloro-4- [4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzoate.

Methyl 3-chloro-4- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) benzoate (prepared from step 1) (2.4 g, 8.17 mmol) was added DMF (10 mL). )). 2,4-difluorobenzylbromide (1.05 mL, 8.17 mmol) and K ₂ CO ₃ (1.13 g, 8.17 mmol) were added. The reaction was stirred at rt for 6 h. At this point, the reaction was poured into water (200 mL) and extracted with ethyl acetate. The ethyl acetate layer was dried over Na ₂ S0 ₄ , filtered and the solvent removed in vacuo to give an amber oil (2.62 g, 77% crude yield). LC / MS, t _r = 2.79 min (detecting at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 294 (M + H).

Step 3: Preparation of the title compound. Methyl 3-chloro-4- [4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzoate (prepared from step 2) ( 2.60 g, 6.21 mmol) was dissolved in CH ₂ Cl ₂ (20 mL). N-bromosuccinimide (1.11 g, 6.21 mmol) was added and the mixture was stirred at rt for 4 h. CH ₂ Cl ₂ was removed under vacuum and the residue was dissolved in CH ₃ CN. The resulting precipitate was collected on a filter pad and washed with CH ₃ CN to give a white solid (0.75 g, 24%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.22 (d, J = 1.88 Hz, 1H), 8.06 (dd, J = 8.19, 1.75 Hz, 1H), 7.59 (app q, J = 8.46 Hz, 1H), 7.33 (d, J = 8.19, 1H), 6.96 (dt, J = 8.06, 1.21 Hz, 1H), 6.89-6.84 (m, 1H), 6.13 (s, 1H), 5.26 (s, 2H), 3.95 ( s, 3H), 1.95 (s, 3H). ES-HRMS m / z 497.9892 (M + H calculated for C ₂₂ H ₁₆ BrClF ₂ NO ₄ : 497.9914).

Example 495

3-bromo-4-[(2,4-difluorobenzyl) amino] -1- (3-fluorobenzyl) pyridin-2 (1H) -one

Step 1

Preparation of 4- (benzyloxy) -1- (3-fluorobenzyl) pyridin-2 (1H) one

A 100 mL round bottom flask equipped with a stir bar and nitrogen inlet was charged with 4-benzyloxy-2 (1H) -pyridinone (20 g, 99.6 mmol) and N, N-dimethyl formamide (50 mL). K ₂ CO ₃ (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 at 80 ° C. for 18 hours. The reaction mixture was concentrated in vacuo and treated with hot ethyl acetate. The solid was filtered off and the filtrate was poured into water and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was dissolved in hot ethyl acetate and precipitated with hexanes to give the title compound (10 g, 33%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.57 (d, J = 8.4 Hz, 1H), 7.37 (m, 5H), 7.07 (d, J = 8.4 Hz, 1H), 7.01 (app d, J = 8.4 Hz, 2H), 6.17 (d, J = 2.68 and 7.6 Hz, 1H), 6.04 (d, J = 2.68 Hz, 1H), 5.10 (s, 2H), 5.08 (s, 2H) ppm. ¹⁹ F NMR (400 MHz, CD ₃ OD) δ −114.88 (1 F) ppm. ES-HRMS m / z 310.1271 (M + H calculated for C ₁₉ H ₁₇ FNO ₂ : 310.1238).

Step 2

Preparation of 1- (3-fluorobenzyl) -4-hydroxypyridin-2 (1H) -one

A small Parr bottle was charged with SC-82484 (10 g, 32.3 mmol), ethanol (175 mL) and 10% Pd / C (0.5 g). The system was washed twice with both nitrogen and hydrogen. The reaction mixture was hydrogenated at 30 psi until no starting material was seen in LC-MS. The reaction mixture was slurried with celite and then filtered through a pad of celite. The filtrate and subsequent ethanol washes were concentrated in vacuo to yield a beige solid. ¹ H MMR (400 MHz, CD ₃ OD) δ 7.53 (d, J = 7.67 Hz, 1H), 7.32 (m, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.05 (dd, J = 2.58 and 7.67 Hz, 1H), 5.83 (d, J = 2.0 Hz, 2H), 5.10 (s, 2H) ppm. ¹⁹ F NMR (400 MHz, CD ₃ OD) δ −115.33 (1 F) ppm. ES-HRMS m / z 218.0641 (M + H calculated for C ₁₂ H ₁₁ FNO ₂ : 218.0612).

Step 3

Preparation of 4-[(2,4-difluorobenzyl) amino] -1- (3-fluorobenzyl) pyridin-2 (1H) -one

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 culture tube washed with nitrogen. The tube was blocked and heated at 180 ° C. for 24 hours. Excess amine was distilled under vacuum and the residue was chromatographed on silica gel (95: 5 ethyl acetate: methanol). The final compound was isolated as a light yellow solid (0.16 g, 36%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.33 (m, 3H), 7.03 (d, J = 8 Hz, 1H), 6.96 (m, 3H), 6.95 (m, 1H), 5.97 (dd, J = 3.2 and 8.0 Hz, 1 H), 5.48 (d, J = 2.56 Hz, 1H), 5.02 (s, 2H), 4.33 (s, 2H) ppm. ¹⁹ F NMR (400 MHz, CD ₃ OD) δ -113.88 (1 F), -115.33 (1F), -116.78 (1F) ppm. ES-HRMS m / z 345.1221 (M + H calculated for C ₁₉ H ₁₇ F ₃ N ₂ O: 345.1209).

Step 4 Preparation of 3-bromo-4-[(2,4-difluorobenzyl) amino] -1- (3-fluorobenzyl) pyridin-2 (1H) -one

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). The reaction was complete after stirring at 25 ° C. for 1 hour (LC-MS). The reaction mixture was poured into saturated aqueous NaHCO ₃ . The aqueous mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO ₄ and concentrated in vacuo. ¹ H NMR (400 MHz, CDCl ₃ ) 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, 1H), 5.30 (br s, 1H), 5.08 (s, 2H), 4.46 (d, J = 6 Hz, 2H) ppm. ¹⁹ F NMR (400 MHz, CDCl ₃ ) δ -110.64 (1 F), -112.75 (1F), -114.79 (1F) ppm. ES-HRMS m / z 423.0275 (M + H calculated for C ₁₉ H ₁₅ BrF ₃ N ₂ O: 423.0314).

Example 496

3-bromo-1- (3-fluorobenzyl) -4-{[3- (trifluoromethyl) benzyl] amino} pyridin-2 (1H) -one

The title compound was prepared essentially as in Example 495. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.54 (m, 2H), 7.48 (m, 2H), 7.27 (q, J = 3.1, 9.0 Hz, 1H), 6.96 (app t, J = 8.8 Hz, 2H ), 5.71 (d, J = 7.6 Hz, 1H), 5.4 (br m, 1H), 5.08 (s, 2H), 4.52 (d, J = 5.6 Hz, 2H) ppm. ¹⁹ F NMR (400 MHz, CDCl ₃ ) δ −63 (3 F), −112 (1 F) ppm. ES-HRMS m / z 455.0388 (M + H calculated for C ₂₀ H ₁₆ BrF ₄ N ₂ 0: 455.0377).

Example 497

3-bromo-1- (3-fluorobenzyl) -4-{[4-fluoro-2- (trifluoromethyl) benzyl] amino} pyridin-2 (1H) -one

The title compound was prepared essentially as in Example 495. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43 (m, 2H), 7.27 (m, 3H), 7.07 (m, 2H), 6.99 (m, 2H), 5.65 (d, J = 10 Hz, 1H) , 5.46 (br s, 1 H), 5.09 (s, 2 H), 4.64 (s, 2 H) ppm. ¹⁹ F NMR (400 MHz, CDCl ₃ ) δ -61.31 (3 F), -112.69 (1 F), 112.97 (1F) ppm. ES-HRMS m / z 473.0246 (M + H calculated for C ₂₀ H ₁₅ BrF ₅ N ₂ 0: 473.0282).

Example 498

Preparation of -bromo-4-[(4-chloro-2-fluorobenzyl) amino] -1- (3-fluorobenzyl) pyridin-2 (1H) -one

The title compound was prepared essentially as in Example 495. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.27 (m, 1H), 7.19 (app t, J = 8.8 Hz, 1H), 7.10 (m, 4H), 6.95 (app t, J = 8.8 Hz, 2H) , 5.74 (d, J = 8 Hz, 1H), 5.40 (br s, 1H), 5.08 (s, 2H), 4.47 (d J = 6 Hz, 2H) ppm. ¹⁹ F NMR (400 MHz, CDCl ₃ ) δ −112.67 (1 F), −116.39 (1 F) ppm. ES-HRMS m / z 439.0047 (M + H calculated for C ₁₉ H ₁₅ ClBrF ₂ N ₂ O: 439.0019).

Example 499

The title compound was prepared essentially as in Example 495. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.35-7.2 (m, 1H), 7.27 (dd, J = 2.5 and 8 Hz, 1H), 7.05 (app d, J = 7.2 Hz, 3H), 6.97 (m , 4H), 5.72 (d, J = 7.6 Hz, 1H), 5.41 (br s, 1H), 5.08 (s, 2H), 4.46 (d, J = 6.4 Hz, 2H) ppm. ¹⁹ F NMR (400 MHz, CDCl ₃ ) δ −112.5 (1 F), −113 (1 F) ppm. ES-HRMS m / z 405.0431 (M + H calculated for C ₁₉ H ₁₆ BrF ₂ N ₂ O: 405.0409).

Example 500

Preparation of 3-bromo-4-[(2,4-difluorobenzyl) amino] -6-methyl-1- (pyridin-4-ylmethyl) pyridin-2 (1H) -one

Step 1 Preparation of 4-[(2,4-difluorobenzyl) amino] -6-methyl-1- (pyridin-4-ylmethyl) pyridin-2 (1H) -one

(0.3 g, 1.39 mmol) and 2,4-difluoro benzylamine (1 mL, 8.4 mmol) were combined in a culture tube washed with nitrogen. The tube was blocked and heated at 180 ° C. for 24 hours. Excess amine was distilled off under vacuum. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.44 (dd, J = 1.7 and 4.8 Hz, 2H), 7.38 (q, J = 10 and 15 Hz, 1H), 7.14 (d, J = 4.8 Hz, 2H ), 6.95 (m, 2H), 5.90 (dd, J = 1 and 2.5 Hz, 1H), 5.47 (d, J = 2,1H), 5.28 (s, 2H), 4.33 (s, 2H), 2.27 ( s, 3H) ppm. ¹⁹ F NMR (400 MHz, CD ₃ OD) δ −113.73 (1 F), −116.66 (1 F) ppm. ES-HRMS m / z 342.1422 (M + H calculated for C ₁₉ H ₁₈ F ₂ N ₃ 0: 342.1418).

Step 2 Preparation of 3-bromo-4-[(2,4-difluorobenzyl) amino] -6-methyl-1- (pyridin-4-ylmethyl) pyridin-2 (1H) -one

N-bromo succinimide (77 mg, 0.43 mmol) was added to a solution of the product from step 1 (0.14 g, 0.41 mmol) in methylene chloride (10 mL). The reaction was complete after stirring at 25 ° C. for 1 hour (LC-MS). The reaction mixture was poured into saturated aqueous NaHCO ₃ . The aqueous mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was triturated with hexanes to give the title compound as a yellow solid (81 mg, 47%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.47 (dd, J = 1.6 and 4.8 Hz, 2H), 7.24 (q, J = 6.4 and 13.6 Hz, 1H), 7.01 (d, J = 6.4 Hz, 2H) , 6.83 (m, 2H), 5.68 (s, 1H), 5.25 (s, 2H), 4.45 (d, J = 6.4 Hz, 2H), 2.12 (s, 3H) ppm. ¹⁹ F NMR (400 MHz, CDCl ₃ ) δ −110.51 (m, 1 F), −114.66 (m, 1 F) ppm. ES-HRMS m / z 420.0524 (M + H calculated for C ₁₉ H ₁₇ BrF ₂ N ₃ 0: 420.0523).

Example 501

Preparation of 3-bromo-4-[(2,4-difluorobenzyl) amino] -6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one

The title compound was prepared essentially as in Example 500.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.45 (d, J = 4.8 Hz, 2H), 7.55 (app t, J = 6 Hz, 1H), 7.21 (m, 2H), 6.83 (m, 2H), 5.65 (s, 1H), 5.34 (d, J = 5.2 Hz, 1H), 5.27 (s, 2H), 4.45 (s, 2H), 2.10 (d, J = 4.8 Hz, 3H) ppm. ¹⁹ F NMR (400 MHz, CDCl ₃ ) δ −110.74 (1 F), −114.86 (1 F) ppm. ES-HRMS m / z 420.0533 (M + H calculated for C ₁₉ H ₁₇ BrF ₂ N ₃ 0: 420.0523).

Example 502

Preparation of 3-bromo-4-[(2,4-difluorobenzyl) amino] -1- (2,6-difluorophenyl) -6-methylpyridin-2 (1H) -one

Step 1 Preparation of 4-[(2,4-difluorobenzyl) amino] -1- (2,6-difluorophenyl) -6-methylpyridin-2 (1H) -one

1- (2,6-difluorophenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one (0.3 g, 1.26 mmol) and 2,4-difluoro benzylamine (1 mL, 8.4 mmol) were combined in a culture tube washed with nitrogen. The tube was blocked and heated at 180 ° C. for 24 hours. Excess amine was distilled under vacuum and the residue was chromatographed on silica (1: 1 hexanes: ethyl acetate). The purity of the compound was about 50% and used without further purification (0.633 g). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.53 (m, 1H), 7.41 (m, 1H), 7.16 (t, J = 8.8 Hz, 2H), 6.93 (m, 2H), 6.00 (s, 1H ), 5.42 (s, 1H), 5.42 (s, 1H), 4.37 (s, 2H), 1.93 (s, 3H) ppm. LC / MS, t _r = 4.65 min (detecting at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 8 min). ES-MS m / z 363 (M + H).

Step 2 Preparation of 3-bromo-4-[(2,4-difluorobenzyl) amino] -1- (2,6-difluorophenyl) -6-methylpyridin-2 (1H) -one

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 hour the reaction was complete 50% (LC-MS). Additional N-bromo succinimide (150 mg) was added and the reaction stirred at 25 ° C. for 12 hours. The reaction mixture was poured into saturated aqueous NaHCO ₃ . The aqueous mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated 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 TFA salt (0.161 g, 23%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.53 (m, 1H), 7.35 (q, J = 8, 15.6 Hz, 1H), 7.16 (t, J = 8 Hz, 2H), 6.96 (app q, J = 8, 16.4 Hz, 2H), 6.12 (s, 1H), 4.86 (s, 2H), 1.94 (s, 3H) ppm. ¹⁹ F NMR (400 MHz, CD ₃ OD) δ -77.33 (1 F), -113.60 (1 F), -116.63 (1F), -121.50 (1F) ppm. ES-HRMS m / z 441.0231 (M + H calculated for C ₁₉ H ₁₄ BrF ₄ N ₂ O: 441.0220).

Example 503

Preparation of 3-chloro-4-[(2,4-difluorobenzyl) amino] -1- (2,6-difluorophenyl) -6-methylpyridin-2 (1H) -one

1- (2,6-difluorophenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one (0.3 g, 1.26 mmol) and 2,4-difluoro benzylamine (l mL, 84 mmol) were combined in a culture tube washed with nitrogen. The tube was blocked and heated at 180 ° C. for 24 hours. Excess amine was distilled off under vacuum 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 hour, the reaction mixture is poured into saturated aqueous NaHCO ₃ . The aqueous mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was chromatographed on silica (25:75 hexanes: ethyl acetate) to give the title compound (32 mg, 6%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.55 (m, 1H), 7.36 (q, J = 9.2 and 15.2 Hz, 1H), 7.18 (t, J = 7.6 Hz, 2H), 6.98 (m, 2H ), 6.15 (s, 1H), 4.62 (s, 2H), 1.96 (s, 3H) ppm. ¹⁹ F NMR (400 MHz, CD ₃ OD) δ -113.78 (1 F), -116.72 (1 F), -121.57 (1 F) ppm. ES-HRMS m / z 397.0752 (M + H calculated for C ₁₉ H ₁₄ ClF ₄ N ₂ 0: 397.0725).

Example 504

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

3-phthalimidomethyl-benzonitrile is described in Bookser, B. C .; Bruice, T.C. J. Am. Chem. Soc. 1991, 113, 4208-18.

Step 2 Preparation of 3- (aminomethyl) benzonitrile

3- (aminomethyl) benzonitrile is described in 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

To a Pyrex reaction tube washed with nitrogen, 3- (aminomethyl) benzonitrile (1 g, 7.9 mmol), 4-hydroxy-6-methyl-2-pyrone (1 g, 7.9 mmol) and water (20 mL) Charged. The tube was blocked and heated to reflux. After 1.5 hours the product precipitated out of solution. The reaction mixture was cooled to rt, filtered and washed with water. The product was used without further purification (1.67 g, 88%). ¹ H NMR (400 MHz, dmso-d ₆ ) δ 10.53 (s, 1H), 7.61 (d, J = 8 Hz, 1H), 7.52 (t, J = 8 Hz, 2H), 7.38 (d, J = 8 Hz, 1H), 5.79 (dd, J = 1 and 2.5 Hz, 1H), 5.56 (d, J = 2.7 Hz, 1H), 5.18 (s, 2H), 2.14 (s, 3H) ppm. ES-HRMS m / z 241.0968 (M + H calculated for C ₁₄ H ₁₃ N ₂ 0 ₂ : 241.0972).

Step 5 Preparation of 3-{[4-[(2,4-difluorobenzyl) amino] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzonitrile

The product from step 4 (0.5 g, 2.08 mmol) and 2,4-difluoro benzylamine (2 mL, 16.8 mmol) were combined in a culture tube washed with nitrogen. The tube was blocked and heated at 180 ° C. for 24 hours. Excess amine was distilled under vacuum and the residue was triturated with ethyl acetate / hexanes to precipitate starting material. The residue was chromatographed in reverse phase (1: 1 water: acetonitrile with 0.05% trifluoroacetic acid). The product of step 5 was isolated as white semisolid (0.125 g, 15%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.61 (d, J = 8 Hz, 1H), 7.49 (t, J = 8 Hz, 1H), 7.41 (m, 3H), 6.94 (m, 2H), 5.89 (dd, J = 0.8 and 2.7 Hz, 1H), 5.47 (d, J = 2.8 Hz, 1H), 5.27 (s, 2H), 4.34 (s, 2H), 2.18 (s, 3H) ppm. LC / MS, t _r = 4.87 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 8 min). ES-MS m / z 366 (M + H).

Step 6 Preparation of 3-{[3-chloro-4-[(2,4-difluorobenzyl) amino] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzonitrile

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). The reaction was complete after stirring at 25 ° C. for 2 hours (LC-MS). The reaction mixture was poured into saturated aqueous NaHCO ₃ . The aqueous mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was triturated with acetonitrile to afford the title compound as a tan solid (20 mg, 13%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.61 (d, J = 8.4 Hz, 1H), 7.49 (m, 2H), 7.40 (d, J = 8.4 Hz, 1H), 7.33 (q, J = 8.4 And 14.8 Hz, 1H), 6.94 (m, 2H), 6.00 (s, 1H), 5.34 (s, 2H), 4.56 (s, 2H), 2.21 (s, 3H) ppm. ¹⁹ F NMR (400 MHz, CD ₃ OD) δ −114.00 (1 F), −116.89 (1 F) ppm. LC / MS, t _r = 5.49 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 8 min). ESMS m / z 400 (M + H).

Example 505

Preparation of 4-{[3-chloro-4-[(2,4-difluorobenzyl) amino] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzonitrile

The title compound was prepared essentially as in Example 504. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.66 (d, J = 8 Hz, 2H), 7.33 (q, J = 8 and 15.2 Hz, 1H), 7.25 (d, J = 8 Hz, 2H), 6.94 (m, 2H), 6.01 (s, 1H), 5.36 (s, 2H), 4.55 (s, 2H), 2.19 (s, 3H) ppm. ¹⁹ F NMR (400 MHz, CD ₃ OD) δ -77.52 (1 F), -113.89 (1 F), -116.71 (1 F) ppm. LC / MS, t _r = 5.49 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 8 min). ES-MS m / z 400 (M + H).

Example 506

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [2-fluoro-5- (hydroxymethyl) phenyl] -6-methylpyridin-2 (lH) -one Manufacture

Step 1 Preparation of (3-amino-4-fluorophenyl) methanol

A flask equipped with an overhead stirrer was charged with 200 mL of 4-fluoro-3-nitrobenzyl alcohol (20 g, 0.117 mol) and 5: 1 isopropanol: water. Ammonium chloride (62 g, 1.17 mol) was added followed by iron filings (65 g, 1.17 mol). The mixture was stirred at 70 ° C. for 1.5 h, at which point the reaction appeared to be complete (LC-MS). The liquid was decanted off and the solid was washed with additional isopropanol: water. Isopropanol was removed and the residue was diluted with 0.5 N HCl and extracted with ethyl acetate. The aqueous layer was brought to pH 12-14 with 2.5 N NaOH and extracted with ethyl acetate. The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. 3-amino-4-fluorophenyl methanol was isolated as a brown solid (4.5 g, 27%) and used without further purification. LC / MS, t _r = 2.40 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 8 min). ES-MS m / z 142 (M + H). ES-HRMS m / z 142.0692 (M + H calculated for C ₇ H ₈ FNO: 142.0663).

Step 2 Preparation of 1- [2-fluoro-5- (hydroxymethyl) phenyl] -4-hydroxy-6-methylpyridin-2 (1H) -one

(3-amino-4-fluorophenyl) methanol (4.5 g, 31.9 mmol), 4-hydroxy-6-methyl-2 in a 100 ml round bottom flask equipped with a stir bar, Dean-Stark trap and reflux condenser Charged pyron (4 g, 31.9 mmol) and o-dichlorobenzene (5 mL). The system was soaked in a 170 ° C. oil bath for 10 minutes. The solvent was removed in vacuo and the residue was chromatographed in reverse phase (75:25 water: acetonitrile with 0.05% TFA). After purification the product contained some starting material and was used without further purification (1.27 g, 15%). ¹ H NMR (400 MHz, dmso-d ₆ ) δ 7.39 (m, 1H), 7.20 (dd, J = 2.2 and 7.6 Hz, 1H), 6.74 (dd, J = 2.7 and 9.6 Hz, 1H), 5.93 ( dd, J = 1.2 and 2.2 Hz, 1H), 5.22 (dd, J = 0.4 and 2.2 Hz, 1H), 2.12 (s, 3H) ppm. ES-HRMS m / z 250.0862 (M + H calculated for C ₁₃ H ₁₃ FN0 ₃ : 250.0874).

Step 3 Preparation of 4-[(2,4-difluorobenzyl) oxy] -1- [2-fluoro-5- (hydroxymethyl) phenyl] -6-methylpyridin-2 (1H) -one

In a 100 mL round bottom flask (purged with nitrogen) 1- [2-fluoro-5- (hydroxymethyl) phenyl] -4-hydroxy-6-methylpyridin-2 (1H) -one (1.2 g , 4.82 mmol) and N, N-dimethyl formamide (10 mL) were charged. Potassium carbonate (0.6 g, 4.4 mmol) and 2,4-difluorobenzyl bromide (0.56 mL, 4.4 mmol) were added and the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with saturated aqueous NaHCO ₃ and extracted with ethyl acetate. The organic layer was concentrated in vacuo and the residue was chromatographed on silica (9: 1 methylene chloride: ethanol). Impure oil (0.3 g, 17%) was used without further purification. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.54 (m, 2H), 7.30 (m, 2H), 7.02 (m, 2H), 6.17 (dd, J = 1 and 2.8 Hz, 1H), 6.03 (d , J = 2.8 Hz, 1H), 5.14 (s, 2H), 4.62 (s, 2H), 2.14 (s, 3H) ppm. ¹⁹ F NMR (400 MHz, CD ₃ OD) δ -111.35 (1 F), -115.97 (1 F), -127.31 (1 F) ppm. LC / MS, t _r = 5.05 min (5-95% acetonitrile / water for 8 min, flow rate: 1 ml / min, detection: 254 nm, 50 ° C.). ES-MS m / z 375 (M + H).

Step 4 3-Bromo-4-[(2,4-difluorobenzyl) oxy] -1- [2-fluoro-5- (hydroxymethyl) phenyl] -6-methylpyridine-2 (1H) Manufacture of

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 for 2 hours at 25 ° C., trifluoroacetic acid (50 μl) was added. After 1 hour additional N-bromo succinimide (30 mg) was added. After 1 hour the reaction was complete (LC-MS). The reaction mixture was poured into brine and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was chromatographed in reverse phase (95: 5 methylene chloride: ethanol). The title compound was isolated as TFA salt (38 mg, 260%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.64 (q, J = 7.6 and 14.8 Hz, 1H), 7.51 (m, 1H), 7.31 (app t, J = 8.4 Hz, 1H), 7.04 (t, J = 8.4 Hz, 2H), 6.63 (s, 1H), 5.34 (s, 2H), 4.62 (s, 2H), 2.06 (s, 3H) ppm. ¹⁹ F NMR (400 MHz, CD ₃ OD) δ -111.48 (1 F), -115.92 (1 F), -127.23 (1 F) ppm. ES-HRMS m / z 454.0228 (M + H calculated for C ₂₀ H ₁₆ BrF ₃ NO ₃ : 454.0260).

Example 507

Preparation of 3- [3-Chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4 -fluorobenzoic acid

Step 1 Preparation of Methyl 4-fluoro-3-nitrobenzoate

A 4-liter 3-neck round bottom flask equipped with a nitrogen inlet, stir bar, 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 chloride (27 mL, 0.37 mol) was added dropwise. The system was warmed to room temperature and the addition funnel was replaced with a reflux condenser and heated to reflux for 1.5 hours. The reaction mixture was cooled to rt, quenched with saturated aqueous NaHCO ₃ and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo to afford methyl 4-fluoro-3-nitrobenzoate as an orange solid (40.6 g, 75%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.67 (dd, J = 2.2 and 6.8 Hz, 1H), 8.34 (dddd, J = 2.2, 4.4, 6.4 and 8.8 Hz, 1H), 7.55 (dd, J = 8.8 and 10.8 Hz, 1H), 3.94 (s, 3H) ppm. ES-HRMS m / z 200.02446 (M + H calculated for C ₈ H ₇ FNO ₄ : 200.0354).

Step 2 Preparation of Methyl 3-amino-4-fluorobenzoate

The Parr bottle was charged with the product of step 1 (40 g, 0.2 mol), ethanol (400 mL) and 100% Pd / C (1 g). The system was washed twice with nitrogen and hydrogen. The reaction mixture was hydrogenated at 40 psi until no starting material was seen in LC-MS. The reaction mixture was slurried with celite and then filtered through a pad of celite. The filtrate and subsequent ethanol were concentrated in vacuo to afford methyl 3-amino-4-fluorobenzoate as an orange solid (30.6 g, 91%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.54 (d, J = 8.7 Hz, 1H), 7.35 (m, 1H), 7.06 (t, J = 8.7 Hz, 1H), 3.09 (s, 3H) ppm . ¹⁹ F NMR (400 MHz, CD ₃ OD) δ −131.02 (1F) ppm. ES-HRMS m / z 199.0281 (M + H calculated for C ₈ H ₇ FN0 ₄ : 199.02).

Step 3 Preparation of Methyl 4-fluoro-3- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) benzoate

In a 250 ml round bottom flask equipped with a stir bar, Dean-Stark trap and reflux condenser, 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 soaked in a 170 ° C. oil bath for 30 minutes and then cooled to room temperature. The reaction mixture was washed with aqueous Na ₂ CO ₃ (38 g, 0.36 mol, 300 mL water). The aqueous layer was washed with ethyl acetate and then acidified to pH 1-2 with concentrated HCl. It was extracted with ethyl acetate, which was dried over MgSO ₄ and concentrated in vacuo. A viscous orange oil was used without further purification (14.4 g, 28%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.18 (dddd, J = 2.3, 5.2, 7.2 and 8.8 Hz, 1H), 7.97 (dd, J = 2 and 7.2 Hz, 1H), 7.44 (t, J = 8.8 Hz, 1H), 6.09 (d, J = 1.8 Hz, 1H), 5.78 (d, J = 2.4 Hz, 1H), 3.9 (s, 3H), 2.14 (s, 3H) ppm. ¹⁹ F NMR (400 MHz, CD ₃ OD) δ −117.29 (1F) ppm. ES-HRMS m / z 278.0796 (M + H calculated for C ₁₄ H ₁₃ FNO ₄ : 278.0823).

Step 4 Preparation of Methyl 3- [4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-fluorobenzoate

A 100 mL round bottom flask equipped with a stir bar and nitrogen inlet was charged with the product of step 3 (14.4 g, 51.9 mmol) and N, N-dimethyl formamide (40 mL). 1,8-diazobicyclo [5.4.0] undes-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 and then poured into saturated aqueous NaHCO ₃ and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo to afford the title product as an orange oil (21.5 g), which was used for the next reaction without further purification. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.20 (dddd, J = 2.2, 4.8, 7.2 and 8.8 Hz, 1H), 8.00 (dd, J = 2.2 and 7.2 Hz, 1H), 7.56 (td, J = 2.4, 6.4 and 9.2 Hz, 1H), 7.46 (t, J = 9.2 Hz, 1H), 7.02 (m, 2H), 6.18 (dd, J = 0.8 and 2.6 Hz, 1H), 6.04 (d, J = 2.7 Hz, 1H), 5.14 (s, 2H), 3.90 (s, 3H), 1.98 (s, 3H) ppm. ¹⁹ F NMR (400 MHz, CD ₃ OD) δ −111.34 (1 F), −116.00 (1 F), −117.35 (1 F) ppm. ES-HRMS m / z 404.1104 (M + H calculated for C ₂₁ H ₁₇ F ₃ NO ₄ : 404.1104).

Step 5 of Methyl 3- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-fluorobenzoate Produce

A 250 mL round bottom flask equipped with a stir bar 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 stirred at 65 ° C. for 2 hours. The mixture was then cooled to rt, poured into saturated aqueous NaHCO ₃ and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was triturated with diethyl ether and filtered to give the title compound as white powder (5.9 g, 25%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.22 (dddd, J = 2, 4.8, 6.8 and 8.8 Hz, 1H), 8.03 (dd, J = 2 and 7.2 Hz, 1H), 7.62 (q, J = 8.4 and 14.8 Hz, 1H), 7.48 (t, J = 14 Hz, 1H), 7.04 (m, 2H), 6.69 (s, 1H), 5.36 (s, 2H), 3.91 (s, 3H), 2.08 ( s, 3H) ppm. ¹⁹ F NMR (400 MHz, CD ₃ OD) δ -111.38 (1 F), -115.97 (1 F), -117.43 (1 F) ppm. ES-HRMS m / z 438.0723 (M + H calculated for C ₂₁ H ₁₆ ClF ₃ NO ₄ : 438.0714).

Step 6 Preparation of 3- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-fluorobenzoic acid

A 100 mL round bottom 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). 2.5 N NaOH (4.6 mL, 11.4 mmol) was added to this slurry. The reaction mixture became clear after 5 minutes and the reaction was complete after 35 minutes (LC-MS). The organics were removed on a rotary evaporator and the residual solution was acidified to pH 3 with 6 N HCl. Diethyl ether was added to precipitate the desired product, which was then filtered. The title compound was isolated as a white powder (2.5 g, 98%). ¹ H NMR (400 MHz, dmso-d ₆ ) δ 8.10 (dddd, J = 2.1, 4.8, 7.2 and 8.4 Hz, 1H), 8.00 (dd, J = 2.1 and 7.6 Hz, 1H), 7.66 (q, J = 9.2 and 15.6 Hz, 1H), 7.57 (t, J = 8.8 Hz, 1H), 7.34 (td, J = 2.4 and 10.4 Hz, 1H), 7.17 (tdd, J = 1, 2.7 and 8.4 Hz, 1H) , 6.76 (s, 1 H), 5.33 (s, 2 H), 1.98 (s, 3 H) ppm. ¹⁹ F NMR (400 MHz, dmso-d ₆ ) δ -109.32 (1F), -113.64 (1 F), -117.22 (1 F) ppm. ES-HRMS m / z 424.0575 (M + H calculated for C ₂₀ H ₁₄ ClF ₃ NO ₄ : 424.0558).

Example 508

3- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-fluoro-N-methylbenzamide Manufacture

3- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4 in a reaction vessel (borosilicate culture tube) -Fluorobenzoic acid (0.300 g, 0.708 mmol) and 1-hydroxybenzotriazole (0.048 g, 0.45 mmol) were added. N, N-dimethylformamide (3 mL) was added to the reaction vessel followed by about 1.2 g of polymer bound carbodiimide resin (1.38 mmol / g). Then additional N, N-dimethylformamide (2 mL) was added to the reaction vessel. The parallel reactor was then shaken for 15 minutes at room temperature at about 200 rpm (Labline Benchtop Orbital Shaker). N-methyl amine (1 mL, 2 mmol) was then added to the reaction vessel and the reaction apparatus was rotated shaken at room temperature overnight. At this point, the reaction was diluted with tetrahydrofuran (20 mL), treated with about 2.17 g of polyamine resin (2.63 mmol / g) and about 2.8 g of methylisocyanate functionalized polystyrene (1.5 mmol / g), and rotary shake Continue at room temperature for 200 hours at 200 rpm. The reaction vessel was then opened and the solution phase product was separated by filtration from the quenched insoluble byproduct and collected into a vial. Insoluble byproducts were partially evaporated and then rinsed with tetrahydrofuran (2 × 10 mL). The filtrate was evaporated by blowing N ₂ over the vial and the resulting solid was triturated with diethyl ether to give an off-white solid (0.168 g, 59%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.02 (dddd, J = 2, 4.4, 7.2 and 8.4 Hz, 1H), 7.80 (dd, J = 2 and 6.8 Hz, 1H), 7.62 (q, J = 8 and 14.4 Hz, 1H), 7.34 (t, J = 8.8 Hz, 1H), 7.04 (m, 2H), 6.69 (s, 1H), 5.36 (s, 2H), 3.29 (s, 3H), 1.98 ( s, 3H) ppm. ¹⁹ F NMR (400 MHz, CD ₃ OD) δ -108.94 (1 F), -113.55 (1 F), -117.76 (1 F) ppm. ES-HRMS m / z 437.0861 (M + H calculated for C ₂₁ H ₁₇ ClF ₃ N ₂ O ₃ : 437.0874).

Examples 509-518

The compounds of Examples 509-518 were prepared by following the method of Example 508, replacing N-methylamine with an appropriate amine.

Example 519

Preparation of 3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-fluorobenzoic acid

Step 1 Methyl 3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-fluorobenzoate Manufacture

Methyl 3- [4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] in a 100 ml round bottom flask equipped with a stir bar and nitrogen inlet 4-Fluorobenzoate (7.3 g, 18 mmol) and N-methyl-2-pyrrolidine (20 mL) were charged. N-bromo succinimide (3.5 g, 19.8 mmol) was added and the reaction mixture was stirred at rt for 30 min. The mixture was poured into saturated aqueous NaHCO ₃ and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ SO ₄ 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). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.16 (qd, J = 3, 6.8 and 15.6 Hz, 1H), 7.84 (d, J = 2.12 Hz, 1H), 7.64 (q, J = 8.4 and 14.8 Hz , 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.04 (m, 2H), 6.60 (s, 1H), 5.34 (s, 2H), 3.87 (s, 3H), 2.00 (s, 3H) ppm. ¹⁹ F NMR (400 MHz, CD ₃ OD) δ -111.51 (1F), -115.98 (1F), -117.43 (1F) ppm. ES-HRMS m / z 494.0387 (M + H calculated for C ₂₂ H ₁₉ BrF ₂ NO ₅ : 494.0409).

Step 2 Preparation of 3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-fluorobenzoic acid

A 100 mL round bottom flask was charged with the product of step 2 (3.4 g, 7.05 mmol), tetrahydrofuran (40 mL), methanol (10 mL) and water (10 mL). 2.5 N NaOH (5.6 mL, 14.1 mmol) was added to this slurry. The reaction mixture became clear after 5 minutes and the reaction was complete after 1 hour (LC-MS). The organics were removed on a rotary evaporator and the residual solution was acidified to pH 1-2 with 6 N HCl. Water and diethyl ether were added to precipitate the desired product and filtered. The title compound was isolated as a white powder (2.64 g, 80%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.21 (dddd, J = 2.4, 5.2, 7.2 and 9.2 Hz, 1H), 8.00 (dd, J = 2.0 and 7.2 Hz, 1H), 7.65 (q, J = 8.4 and 14.8 Hz, 1H), 7.45 (t, J = 8.4 Hz, 1H), 7.04 (appt, J = 9.6 Hz, 1H), 6.65 (s, 1H), 5.36 (s, 2H), 2.07 (s, 3H) ppm. ¹⁹ F NMR (400 MHz, CD ₃ OD) δ −111.40 (1 F), −116.00 (1 F), −118.36 (1 F) ppm. ES-HRMS m / z 480.0259 (M + H calculated for C ₂₁ H ₁₇ BrF ₂ NO ₅ : 480.0253).

Example 520

Preparation of 3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methoxybenzoic acid

Step 1 Preparation of Methyl 3-amino-4-methoxybenzoate

A 1 L three necked round bottom flask equipped with a nitrogen inlet, stir bar, 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 chloride (30 mL, 0.42 mol) was added dropwise. The system was warmed to room temperature, the addition funnel was replaced with a reflux condenser and heated to reflux for 1.5 hours. The reaction mixture was cooled to rt, quenched with saturated aqueous NaHCO ₃ and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo to afford methyl 3-amino-4-methoxybenzoate as a dark solid (47.9 g, 88%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.40 (t, J = 2 68 Hz, 1H), 7.37 (t, J = 2.0 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 3.98 (s, 3H), 3.81 (s, 3H) ppm. ES-HRMS m / z 182.0826 (M + H calculated for C ₉ H ₁₂ ClNO ₃ : 182.0812).

Step 2 Preparation of Methyl 3- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -4-methoxybenzoate

In a 250 ml round bottom flask equipped with a stir bar, Dean-Stark trap and reflux condenser, 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) were charged. The system was soaked in a 170 ° C. oil bath for 2 hours and then cooled to room temperature. The reaction mixture was washed with aqueous Na ₂ CO ₃ (28 g, 0.26 mol, 500 mL water). The aqueous layer was washed with ethyl acetate and then acidified to pH 1-2 with concentrated sulfuric acid. It was extracted with ethyl acetate, dried over Na ₂ SO ₄ and concentrated in vacuo. The viscous oil was triturated with MeOH to afford the title compound as a yellow solid (1.61 g, 4%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.14 (dd, J = 2.2 and 8.8 Hz, 1H), 7.79 (d, J = 2.2 Hz, 1H), 7.27 (d, J = 8.8 Hz, 1H), 6.05 (d, J = 2.3 Hz, 1H), 5.77 (d, J = 2.3 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 1.90 (s, 3H) ppm. ES-HRMS m / z 290.0997 (M + H calculated for C ₁₅ H ₁₆ NO ₅ : 290.1023).

Step 3 Preparation of Methyl 3- [4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methoxybenzoate

A 100 mL round bottom flask equipped with a stir bar and nitrogen inlet was charged with the product of step 2 (1.6 g, 5.5 mmol) and N, N-dimethyl formamide (10 mL). 1,8-diazobicyclo [5.4.0] undes-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, poured into saturated aqueous NaHCO ₃ and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo to afford the title compound as an orange foam (2.13 g, 93%), which was used in the reaction without further purification. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.17 (dd, J = 2.64 and 11.6 Hz, 1H), 7.82 (td, J = 2.7 and 6.8 Hz, 1H), 7.57 (m, 1H), 7.29 (d , J = 11.6 Hz, 1H), 7.02 (m, 2H), 6.16 (m, 1H), 6.03 (d, J = 3.5 Hz, 1H), 5.14 (s, 2H), 3.89 (s, 6H), 1.93 (s, 3H) ppm. ¹⁹ F NMR (400 MHz, CD ₃ OD) δ −111.43 (1 F), −116.04 (1 F) ppm. ES-HRMS m / z 416.1310 (M + H calculated for C ₂₂ H ₂₀ F ₂ NO ₅ : 416.1304).

Step 4 Methyl 3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methoxybenzoate Manufacture

A 100 mL round bottom flask equipped with a stir bar and nitrogen inlet was charged with the product of step 2 (2.1 g, 5.06 mmol) and N-methyl-2-pyrrolidine (10 mL). N-bromo succinimide (1 g, 5.56 mmol) was added and the reaction mixture was stirred at rt for 1 h. The mixture was poured into saturated aqueous NaHCO ₃ and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was chromatographed on silica (1: 1 hexanes: ethyl acetate) to give the title compound as a long colored oil (0.77 g, 31%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.16 (app qd, J = 2.5 and 7.2 Hz, 1H), 7.84 (d, J = 2.6 Hz, 1H), 7.64 (m, 1H), 7.30 (d, J = 9.2 Hz, 1H), 7.04 (appt, J = 8.4 Hz, 2H), 6.60 (s, 1H), 5.33 (s, 2H), 3.80 (s, 6H), 1.99 (s, 3H) ppm. ¹⁹ F NMR (400 MHz, CD ₃ OD) δ −111.56 (1 F), −116.00 (1 F) ppm. ES-HRMS m / z 494.0398 (M + H calculated for C ₂₂ H ₁₉ BrF ₂ NO ₅ : 494.0409).

Step 5 Preparation of 3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methoxybenzoic acid

A 100 mL round bottom 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). 2.5 N NaOH (1.2 mL, 3.1 mmol) was added to this slurry. The reaction mixture became clear after 30 minutes and the reaction was complete after 1 hour (LC-MS). The organics were removed on a rotary evaporator and the residual solution was acidified to pH 2-3 with 6 N HCl. Water and diethyl ether were added to precipitate the desired compound followed by filtration. The title compound was isolated as a white powder (0.60 g, 81%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.17 (dd, J = 2.2 and 8.8 Hz, 1H), 7.82 (d, J = 2.2 Hz, 1H), 7.64 (q, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.34 (t, J = 8.8 Hz, 2H), 6.60 (s, 1H), 5.34 (s, 2H), 3.87 (s, 3H), 2.01 (s, 3H) ppm. ES-HRMS m / z 480.0259 (M + H calculated for C ₂₁ H ₁₇ BrF ₂ NO ₅ : 480.0253).

Example 521

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methoxy-N-methylbenz Preparation of Amides

Step 1

Example 520 (0.300 g, 0.624 mmol) and 1-hydroxybenzotriazole (0.042 g, 0.31 mmol) were added to the reaction vessel (borosilicate culture tube). N, N-dimethylformamide (3 mL) was added to the reaction vessel followed by about 1.06 g of the polymer-bound carbodiimide resin (1.38 mmol / g). Then additional N, N-dimethylformamide (2 mL) was added to the reaction vessel. The parallel reactor was then shaken for 15 minutes at 200 rpm at room temperature (Lapline Benchtop Orbital Shaker). N-methyl amine (2 mL, 4 mmol) was then added to the reaction vessel and the reaction apparatus was rotary shaken at room temperature overnight. At this point, the reaction was diluted with tetrahydrofuran (20 mL), treated with about 2 g of polyamine resin (2.63 mmol / g) and about 2.5 g of methylisocyanate functionalized polystyrene (1.5 mmol / g), and rotary shake Continue at room temperature for 200 hours at 200 rpm. The reaction vessel was then opened and the solution phase product was separated by filtration from insoluble quenched byproducts and collected into vials. Insoluble byproducts were partially evaporated and then rinsed with tetrahydrofuran (2 × 10 mL). The filtrate was evaporated by blowing N ₂ over the vial and the resulting solid was triturated with diethyl ether to afford the desired product as an off-white solid (0.094 g, 31%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.98 (dd, J = 2.2 and 8.8 Hz, 1H), 7.64 (m, 2H), 7.28 (d, J = 9.2 Hz, 1H), 7.04 (t, J = 9.2 Hz, 2H), 6.60 (s, 1H), 5.34 (s, 2H), 3.86 (s, 3H), 2.88 (s, 3H), 2.01 (s, 3H) ppm. ¹⁹ F NMR (400 MHz, CD ₃ OD) δ −111.59 (1 F), −116.01 (1 F) ppm. ES-HRMS m / z 493.0593 (M + H calculated for C ₂₂ H ₂₀ BrF ₂ N ₂ 0 ₄ : 493.0569).

Example 522

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methoxy-N, N- Preparation of Dimethylbenzamide

The title compound was prepared essentially as in Example 521. ¹ H NMR (400 MHz, CD ₃ OD) δ 7.64 (m, 1H), 7.61 (dd, J = 2 and 8.8 Hz, 1H), 7.33 (d, J = 2.2 Hz, 1H), 7.27 (d, J = 8 Hz, 1H), 7.04 (t, J = 8 Hz, 2H), 6.59 (s, 1H), 5.33 (s, 2H), 3.85 (s, 3H), 3.07 (s, 6H), 2.02 (s , 3H) ppm. ¹⁹ F NMR (400 MHz, CD ₃ OD) δ −111.60 (1 F), −116.01 (1 F) ppm. ES-HRMS m / z 507.0716 (M + H calculated for C ₂₃ H ₂₂ BrF ₂ N ₂ 0 ₄ : 507.0726).

Example 523

1- [5- (aminomethyl) -2-fluorophenyl] -3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one hydrochloride

Step 1

Preparation of 3- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-fluorobenzamide

3- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridine-1 (2H) in a 250 ml round bottom flask equipped with a stir bar and nitrogen inlet -Yl] -4-fluorobenzoic acid (2.58 g, 6.1 mmol), 4-methylmorpholine (2.0 mL, 18.3 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine ( 1.28 g, 7.3 mmol) and tetrahydrofuran (30 mL) were charged. The mixture was stirred at 25 ° C. for 30 minutes before NH ₄ 0H (15.0 mL) was added. The mixture was stirred for 30 minutes and diluted with water. The product precipitated out of solution. The precipitate was filtered off and washed with water and diethyl ether to give the title compound as a white solid (2.55 g, 78%). ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 8.10 (m, 1H), 7.9 (dd, J = 2.1 and 5.2 Hz, 1H), 7.65 (q, 6.7 and 8.5 Hz, 1H), 7.56 ( t, J = 9.1 Hz, 1H), 7.35 (td, J = 2.4 and 8.2 Hz, 1H), 7.17 (td, J = 2 and 6.6 Hz, 1H), 6.78 (s, 1H), 5.36 (s, 2H ), 2 (s, 3H) ppm. ES-HRMS m / z 423.0719 (M + H calculated for C ₂₀ H ₁₅ ClF ₃ N ₂ 0 ₃ : 423.0718).

Step 2

1- [5- (aminomethyl) -2-fluorophenyl] -3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one hydrochloride Manufacture

A 100 mL round bottom flask equipped with a stir bar and nitrogen inlet was charged with the product from step 1 (1.5 g, 3.5 mmol), BH ₃ .THF complex (7.4 mL, 7.4 mmol) and tetrahydrofuran (15 mL). . The mixture was refluxed for 6 hours, cooled to room temperature and quenched with 6N HCl. The organics were evaporated and the remaining aqueous solution saturated with NaOH 2.5 N and extracted with dichloromethane. The organic phase was dried over Na ₂ S0 ₄ and concentrated in vacuo. 6 N HCl was added and concentrated in vacuo. ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 8.2 (m, 1H), 7.6 (m, 1H), 7.5 (m, 1H), 7.3 (t, J = 9.8 Hz, 1H), 7.16 ( t, J = 8.6 Hz, 1H), 6.78 (s, 1H), 5.36 (s, 2H), 4.05 (d, J = 5.8 Hz, 2H), 2 (s, 3H) ppm. ES-HRMS m / z 409.0940 (M + H calculated for C ₂₀ H ₁₇ ClF ₃ N ₂ O ₂ : 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

3- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-fluoro-N- [2- Preparation of hydroxy-1- (hydroxymethyl) ethyl] benzamide

The title compound was prepared essentially as in Example 521. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.1 (m, 1H), 7.8 (dd, J = 2.3 and 5.1 Hz, 1H), 7.6 (q, J = 7.4 and 7.0 Hz, 1H), 7.41 (t , J = 8.9 Hz, 1H), 7.04 (m, 2H), 6.7 (s, 1H), 5.36 (s, 2H), 4.1 (t, J = 5.8 Hz, 1H), 3.7 (d, J = 5.1 Hz , 4H), 2.1 (s, 3H) ppm. ES-HRMS m / z 497.1045 (M + H calculated for C ₂₃ H ₂₁ ClF ₃ N ₂ 0 ₅ : 497.1086).

Examples 525-528

The compounds of Examples 525-528 were prepared by the derivatization of Example 523. Analytical data is shown below.

NMR Analysis of the Compounds of Examples 525-528

Example 529

2-({[3-chloro-1- (2,6-difluorophenyl) -6-methyl-2-oxo-1,2-dihydropyridin-4-yl] oxy} methyl) -5-fluor Robenzonitrile

2- (bromomethyl) -5-fluorobenzonitrile (3.47 g, 16.2 mmol), 3-chloro-1- (2,6-difluorophenyl) -4-hydroxy-6-methylpyridine-2 (1H) -one (3.15 g, 11.6 mmol), K ₂ CO ₃ (2.56 g, 18.6 mmol) and 18-crown-6 (0.15 g) were dissolved in N, N-dimethylacetamide (25 mL). The reaction mixture was stirred in a 60 ° C. oil bath for 4 hours. The solvent was distilled off. The reaction was neutralized with 5% citric acid. The solid product was washed with hexane followed by 30% EtOAc / hexanes. Filtration gave a brown solid (5.2 g, 79% yield). ¹ H NMR (CD ₃ 0D / 400 MHz) δ 7.82 (m, 2H), 7.61 (m, 4H), 6.75 (s, 1H), 5.49 (s, 2H), 2.13 (s, 3H). ES-HRMS m / z 405.0616 (M + H required for C ₂₀ H ₁₃ ClF ₃ N ₂ 0 ₂ : 405.0612).

Example 530

4-{[2- (aminomethyl) -4-fluorobenzyl] oxy} -3-chloro-1- (2,6-difluorophenyl) -6-methylpyridin-2 (1H) -one trifluor Loacetate

BH ₃ THF (17.8 mL, 17.8 mmol) was added 2-({[3-chloro-1- (2,6-difluorophenyl) -6-methyl-2 in chilled (0 ° C.) THF (30 mL). -Oxo-1,2-dihydropyridin-4-yl] oxy} methyl) -5-fluorobenzonitrile (3.61 g, 8.92 mmol) was added dropwise. After addition the reaction was heated at 60 ° C. for 1.5 h. The reaction was quenched with MeOH, the solvent was evaporated and the crude product was purified by preparative HPLC. The product was lyophilized and the solvent was isolated by evaporation to give a white solid (1.52 g, 32.6%). ¹ H NMR (CD ₃ 0D / 400MHz) δ 7.62 (m, 2H), 7.32 (m, 1H), 7.25 (tr, 2H, J = 8.00 Hz), 7.18 (m, 1H), 6.78 (s, 1H) , 5.43 (s, 1 H), 4.22 (s, 1 H), 2.14 (s, 3 H). ES-HRMS m / z 409.0900 (M + H required for C ₂₀ H ₁₇ N ₂ O ₂ F ₃ Cl: 409.0925).

Examples 531 to 551

The compounds of Examples 531 to 551 were prepared by the derivatization of Example 530. Analytical data is shown below.

NMR Analysis of the Compounds of Examples 531-551

¹ H NMR (CD ₃ OD / 400 MHz) δ 7.58 (m, 2H), 7.26 (m, 3H), 7.10 (m, 1H), 6.74 (s, 1H), 5.45 (s, 2H), 4.39 (s, 2H), 3.06 (q, 2H, J = 7.60 Hz), 2.11 (s, 3H), 1.31 (t, 3H, J = 7.2 Hz) ¹ H NMR (CD ₃ OD / 300 MHz) δ 7.63 (m, 1H) , 7.54 (m, 1H), 7.26 (t, 2H, J = 8.7 Hz), 7.15 (m, 1H), 7.05 (m, 1H), 6.75 (s, 1H), 5.42 (s, 2H), 4.47 ( s, 2H), 2.70 (s, 3H), 2.14 (s, 3H). ES-HRMS m / z 466.1141 (M + H required for C ₂₂ H ₂₀ ClF ₃ N ₃ 0 ₃ : 466.1140).

Example 552

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1-{[5- (1-hydroxy-1-methylethyl) pyridin-2-yl] methyl} -6-methyl Pyridin-2 (1H) -one

Step 1: Preparation of Methyl 6-methylnicotinate 1-oxide

Methyl 6-methylnicotinate (6.0 g, 39.7 mmol) was added to dichloromethane (100 mL) in a round bottom flask under nitrogen. 3-chloroperoxybenzoic acid (10.0 g, 57.9 mmol) was then added to the flask and stirred for 5 hours. Saturated sodium bicarbonate solution (100 mL) was added to the reaction and the mixture was transferred to a separatory funnel. Additional 200 ml of dichloromethane was added to the funnel to give an organic layer. The organic layer was washed with water (150 mL) and dried over anhydrous magnesium sulfate. The resulting solution was evaporated to give a white solid (6 g, 90%). LC / MS, t _r = 0.33 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 168 (M + H). ES-HRMS m / z 168.0628 (M + H calculated for C ₈ H ₁₀ N0 ₃ : 168.0655).

Step 2: Preparation of Methyl 6- (chloromethyl) nicotinate.

Methyl 6-methylnicotinate 1-oxide (prepared from step 1) (6.0 g, 35.9 mmol) was added to 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 to the reaction and the mixture was transferred to a separatory funnel. The compound was extracted with ethyl acetate (300 mL × 2) and the combined ethyl acetate solution was dried over magnesium sulfate and evaporated to give a black solid (5.2 g, 78%). LC / MS, t _r = 1.52 min (detecting at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 186 (M + H). ES-HRMS m / z 186.0314 (M + H calculated for C ₈ H ₉ ClNO ₂ : 186.0316).

Step 3: Preparation of Methyl 6-{[4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} nicotinate

Methyl 6- (chloromethyl) nicotinate (prepared from step 2) (2 g, 10.8 mmol) was added 4-[(2,4-difluorobenzyl) oxy] -6-methyl in 20 ml of dimethyl formamide. Cesium carbonate (5 g, 15.3 mmol) was added after adding to pyridin-2 (1H) -one. The mixture was heated at 100 ° C. for 20 hours. It was cooled to room temperature and 400 ml of water was added. Brown precipitate formed from the solution. It was filtered, rinsed with water (200 mL × 3) and dried to give 4 g of solid. The product was purified by Gilson reverse phase preparative chromatography to give a white solid (1.4 g, 32%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.09 (d, J = 1.48 Hz, 1H), 8.19 (dd, J = 6.04, 2.15 Hz, 1H), 7.37 (app q, J = 8.32 Hz, 1H), 7.25 (d, J = 8.33 Hz, 1H), 6.84 (m, 2H), 5.94 (d, J = 2.82 Hz, 1H), 5.83 (d, J = 2.15 Hz, 1H), 5.36 (s, 2H), 4.97 (s, 2H), 3.90 (s, 3H), 2.27 (s, 3H); LC / MS, t _r = 2.30 min (detecting at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 401 (M + H). ES-HRMS m / z 401.1307 (M + H calculated for C ₂₁ H ₁₉ F ₂ N ₂ 0 ₄ : 401.1307).

Step 4: Preparation of the title compound.

A 3 M solution of methyl magnesium bromide in ether (5 ml, 15 mmol) was added to 5 ml of anhydrous tetrahydrofuran in a round bottom flask under nitrogen. The mixture was cooled to 0 ° C. Methyl 6-{[4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} nicotinate (prepared from step 3) ( 300 mg, 0.75 mmol) was dissolved in 5 mL of anhydrous tetrahydrofuran in a dropping funnel and the solution was slowly added to a cold methyl magnesium bromide solution in a round bottom flask. After addition the mixture was continued stirring at 0 ° C. for 30 min and cold saturated ammonium chloride solution (100 mL) was added slowly to the reaction mixture. The mixture was transferred to a separatory funnel and the product was extracted with ethyl acetate (200 mL × 2). The combined ethyl acetate solution was dried over anhydrous magnesium sulfate and evaporated to dryness. The resulting residue (220 mg) was added to 10 ml of dichloromethane followed by the addition of N-bromo succinimide (100 mg, 0.56 mmol). The solution was stirred at rt for 3 h. Saturated sodium bicarbonate solution (100 mL) was added to the reaction mixture, which was transferred to a separatory funnel. The product was extracted with ethyl acetate (200 mL × 2). The combined ethyl acetate solution was dried over anhydrous magnesium sulfate and evaporated to dryness. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.61 (d, J = 1.88 Hz, 1H), 7.73 (dd, J = 5.77, 2.42 Hz, 1H), 7.55 (app q, J = 6.31 Hz, 1H), 7.30 (d, J = 8.19b Hz, 1H), 6.93 (m, 1H), 6.84 (m, 1H), 6.00 (s, 1H), 5.37 (s, 2H), 5.19 (s, 2H), 2.48 ( s, 3 H), 1.56 (s, 6 H); LC / MS, t _r = 2.29 min (detecting at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 479 (M + H). ES-HRMS m / z 479.0791 (M + H calculated for C ₂₂ H ₂₂ BrF ₂ N ₂ 0 ₃ : 479.0776).

Example 553

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1-{[5- (hydroxymethyl) pyridin-2-yl] methyl} -6-methylpyridine-2 (1H) -On

Step 1: 4-[(2,4-difluorobenzyl) oxy] -1-{[5- (hydroxymethyl) pyridin-2-yl] methyl} -6-methylpyridin-2 (1H) -one Manufacture

Methyl 6-{[4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} nicotinate (prepared from step 3) ( 350 mg, 0.87 mmol) was added to anhydrous tetrahydrofuran (15 mL) and the solution was cooled to -78 ° C. To the cold solution was added lithium aluminum hydride (100 mg, 2.6 mmol). After addition the reaction mixture was warmed to 0 ° C. and stirring continued for an additional hour. Potassium hydrogen sulfate (IN solution, 150 mL) was added slowly to the reaction mixture to quench the reaction. The resulting mixture was transferred to a separatory funnel and the product was extracted with ethyl acetate (200 mL × 2). The combined ethyl acetate solution was dried over anhydrous magnesium sulfate and evaporated to dryness. LC / MS, t _r = 1.88 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 373 (M + H)

Step 2: Preparation of the title compound

4-[(2,4-difluorobenzyl) oxy] -1-{[5- (hydroxymethyl) pyridin-2-yl] methyl} -6-methylpyridin-2 (1H) -one (step 1 (230 mg, 0.62 mmol) was added to 10 ml of dichloromethane followed by the addition of N-bromo succinimide (110 mg, 0.62 mmol). The solution was stirred at rt for 3 h. Saturated sodium bicarbonate solution (100 mL) was added to the reaction mixture, which was transferred to a separatory funnel. The product was extracted with ethyl acetate (200 mL × 2). The combined ethyl acetate solution was dried over anhydrous magnesium sulfate and evaporated to dryness. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.47 (app s, 1H), 7.64 (dd, J = 5.77, 2.29 Hz, 1H), 7.55 (app q, J = 6.45 Hz, 1H), 7.33 (d, J = 6.05 Hz, 1H), 6.93 (m, 1H), 6.84 (m, 1H), 6.00 (s, 1H), 5.39 (s, 2H), 5.19 (s, 2H), 4.68 (s, 2H), 2.46 (s, 3 H); LC / MS, t _r = 2.01 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 451 (M + H)

Example 554

6-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N- (2-hydrate Oxyethyl) -N-methylnicotinamide

Step 1: Methyl 6-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} nicotinate Manufacture

Methyl 6-{[4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} nicotinate (350 mg, 0.87 mmol) ( 1.0 g, 2.5 mmol) was added to 150 mL of dichloromethane followed by N-bromo succinimide (500 mg, 2.8 mmol). The solution was stirred at rt for 3 h. Saturated sodium bicarbonate solution (300 mL) was added to the reaction mixture, which was transferred to a separatory funnel. The product was extracted with ethyl acetate (500 mL x 2). The combined ethyl acetate solution was dried over anhydrous magnesium sulfate and evaporated to dryness. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.08 (app d, J = 2.15 Hz, 1H), 8.21 (dd, J = 6.04, 2.15 Hz, 1H), 7.55 (app qt, J = 6.31 Hz, 1H) , 7.41 (d, J = 6.31 Hz, 1H), 6.91 (m, 1H), 6.84 (m, 1H), 6.02 (s, 1H), 5.42 (s, 2H), 5.19 (s, 2H), 3.91 ( s, 3H), 2.45 (s, 3H); LC / MS, t _r = 2.85 min (detecting at 254 nm, 50 ° C. using 5 to 95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 479 (M + H). ES-HRMS m / z 479.0415 (M + H calculated for C ₂₁ H ₁₈ BrF ₂ N ₂ 0 ₄ : 479.0413).

Step 2: Preparation of 6-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} nicotinic acid

Methyl 6-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-l (2H) -yl] methyl} nicotinate (step 1 (1.0 g, 2.1 mmol) was added to a mixture of 100 mL tetrahydrofuran and 10 mL methanol followed by 2.5 N sodium hydroxide (0.85 mL, 2.1 mmol). The solution was heated to 50 ° C. for 2 hours. The solution was cooled to room temperature and evaporated to dry the residue completely. The residue was added to 50 N tetrahydrofuran and 4 N HCl in 1,4-dioxane (0.52 mL, 2.1 mmol) and the mixture was stirred for 30 minutes. The mixture was evaporated to dryness. The residue was added to 20 mL of water and neutralized to pH 7 accurately by dropwise addition of saturated sodium bicarbonate solution to the aqueous solution. The resulting heterogeneous mixture was left for 20 hours. Filter, rinse with water (30 mL × 3) and dry in a high vacuum oven to give a white solid (950 mg, 97%). ¹ H NMR (400 MHz, CDCl ₃ and CD ₃ OD) δ 8.98 (app br s, 1H), 8.15 (dd, J = 6.17, 2.02 Hz, 1H), 7.45 (app q, J = 6.58 Hz, 1H) , 7.21 (d, J = 8.19 Hz, 1H), 6.84 (m, 1H), 6.76 (m, 1H), 6.04 (s, 1H), 5.35 (s, 2H), 5.12 (s, 2H), 2.32 ( s, 3H); LC / MS, t _r = 2.48 min (detecting at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 465 (M + H). ES-HRMS m / z 465.0254 (M + H calculated for C ₂₀ H ₁₆ BrF ₂ N ₂ 0 ₄ : 465.0256).

Step 3: Preparation of the title compound

6-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} nicotinic acid (prepared from step 2 ) (230 mg, 0.5 mmol) was added to 1-hydroxybenzotriazole (101 mg, 0.75 mmol) in 5 mL N, N-dimethylformamide. 4-methyl morpholine (0.16 mL, 1.5 mmol) was added to the mixture followed by 1- (3- (dimethylamino) propyl-3-ethylcarbodiimide hydrochloride (143 mg, 0.75 mmol). Stirring for 30 minutes gave a homogeneous solution, to which was added 2- (methylamino) ethanol (0.06 mL, 0.75 mmol) and the mixture was stirred for 20 minutes Water (150 mL) was added to the reaction mixture. And the product was extracted with ethyl acetate (400 mL × 2) The combined ethyl acetate solution was dried over anhydrous magnesium sulfate and evaporated to dryness ¹ H NMR (400 MHz, dmso-d ₆ ) δ 8.47 (app br s, 1H), 7.80 (br d, J = 7.92 Hz, 1H), 7.64 (app q, J = 6.58 Hz, 1H), 7.30 (m, 2H), 7.15 (m, 1H), 6.56 (s, 1H), 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, t _r = 2.29 min (using 5-95% acetonitrile / water at 1 mL / min over 5 min) High 254 nm, detected at 50 ° C. ES-HRMS m / z 522.0850 (M + H calculated for C ₂₃ H ₂₃ BrF ₂ N ₃ 0 ₄ : 522.0835).

Example 555

6-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N- (2-hydrate Oxyethyl) nicotinamide

Follow Example 554 (step 3), but replace the ethanolamine with 2- (methylamino) ethanol to afford the title compound as a white solid (79% yield). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.93 (d, J = 2.01 Hz, 1H), 8.21 (dd, J = 6.04, 2.21 Hz, 1H), 7.67 (app q, J = 6.44 Hz, 1H) , 7.39 (d, J = 8.06 Hz, 1H), 7.08 (m, 2H), 6.58 (s, 1H), 5.55 (s, 2H), 5.35 (s, 2H), 3.74 (app t, J = 5.73 Hz , 2H), 3.53 (app t, J = 5.73 Hz, 2H0, 2.49 (s, 3H); LC / MS, t _r = 2.26 min (5-95% acetonitrile / water at 1 mL / min over 5 min) Detected at 254 nm 50 ° C.) ES-HRMS m / z 508.0673 (M + H calculated for C ₂₂ H ₂₁ BrF ₂ N ₃ O ₄ : 508.0678).

Example 556

6-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N, N-dimethylnicotin amides

Following the method of Example 554 (step 3), ethanolamine was replaced with dimethylamine to afford the title compound as a white solid (75% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.55 (d, J = 1.62 Hz, 1H), 7.68 (dd, J = 5.77, 2.15 Hz, 1H), 7.55 (app q, J = 6.45 Hz, 1H), 7.37 (d, J = 8.06 Hz, 1H), 6.93 (m, 1H), 6.84 (m, 1H), 6.02 (s, 1H), 5.40 (s, 2H), 5.20 (s, 2H), 3.09 (s , 3H), 2.97 (s, 3H), 2.45 (s, 3H); LC / MS, t _r = 2.45 min (detecting at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-HRMS m / z 492.0710 (M + H calculated for C ₂₂ H ₂₁ BrF ₂ N ₃ 0 ₃ : 492.0729).

Example 557

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [2- (trifluoromethyl) phenyl] pyridin-2 (1H) -one

Step 1: Preparation of 4-hydroxy-6-methyl-1- [2- (trifluoromethyl) phenyl] pyridin-2 (1H) -one

4-hydroxy-6-methyl-2-pyrone (10 g, 79.3 mmol) was added to 2- (trifluoromethyl) aniline (14 mL, 111.3 mmol) in 10 mL of 1,2-dichlorobenzene in a round bottom flask. Added. The mixture was then placed in an oil bath preheated to 165 ° C. After heating for 30 minutes the mixture was cooled to room temperature and 250 ml of saturated sodium bicarbonate solution was added. The mixture was stirred at rt for 15 min and transferred to a separatory funnel. Ethyl acetate (300 mL) was added to a separatory funnel and the layers were partitioned. An aqueous layer was obtained, and 200 ml of saturated sodium bicarbonate solution was added to the organic layer. The aqueous layer was obtained again and the combined aqueous solutions were neutralized with HCl solution. After neutralization a white solid precipitated out of solution. The solid was filtered, rinsed with water (100 mL × 5) and dried in a high vacuum oven to give a white solid (7.5 g, 35.5%). LC / MS, t _r = 1.77 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 270 (M + H).

Step 2: Preparation of 4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [2- (trifluoromethyl) phenyl] pyridin-2 (1H) -one

60 mL of 4-hydroxy-6-methyl-1- [2- (trifluoromethyl) phenyl] pyridin-2 (lH) -one (prepared from step 1) (7.3 g, 27.1 mmol) in dimethyl formamide To 3,4-difluorobenzyl bromide (5.5 g, 26.5 mmol). The mixture was cooled to 0 ° C. and cesium carbonate (20 g, 61.3 mmol) was added to the mixture. After addition the mixture was allowed to warm to room temperature and stirred for 4 hours. Water (500 mL) was added to the reaction mixture. A yellow solid was produced from the solution. Filter and rinse with water (200 mL × 2) to give a yellow solid. The solid was dissolved in ethyl acetate (500 mL) and water (300 mL) and transferred to a separatory funnel to give an organic layer. The organic layer was washed again with water (200 mL) and dried over anhydrous magnesium sulfate. The organic solution was evaporated to dryness. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.82 (d, J = 7.65 Hz, 1H), 7.7 (t, J = 7.52 Hz, 1H), 7.58 (t, J = 7.65 Hz, 1H), 7.42 (q, J = 6.45 Hz, 1H), 7.27 (d, J = 7.78 Hz, 2H), 6.89 (m, 2H), 5.95 (app d, J = 2.42 Hz, 1H), 5.90 (app d, J = 2.42 Hz, 1H), 5.01 (app d, J = 2.94 Hz, 2H), 1.86 (s, 3H); LC / MS, t _r = 2.74 min (detecting at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 396 (M + H)

Step 3: Preparation of the title compound

N-bromosuccinimide (0.24 g, 1.36 mmol) was added 4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- [2- (trifluoromethyl) in 20 ml of dichloromethane. ) Phenyl] pyridin-2 (1H) -one (0.54 g, 1.36 mmol). The mixture was stirred at rt for 2 h. Saturated sodium bicarbonate solution (150 mL) was added to the reaction mixture and the combined solutions were transferred to a separatory funnel. The product was extracted with ethyl acetate (250 mL). The ethyl acetate solution was dried over anhydrous magnesium sulfate and evaporated to dryness. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.82 (d, J = 7.25 Hz, 1H), 7.7 (app t, J = 7.66 Hz, 1H), 7.60 (m, 2H), 7.26 (s, 1H), 6.97 (m, 1 H), 6.87 (m, 1 H), 6.09 (s, 1 H), 5.25 (app d, J = 3.35 Hz, 2H), 1.94 (s, 3H); LC / MS, t _r = 2.84 min (detecting at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-HRMS m / z 474.0113 (M + H calculated for C ₂₀ H ₁₄ BrF ₅ N0 ₂ : 474.0123).

Example 558

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-methyl-5-vinylpyridin-2 (1H) -one

Step 1: 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -5-iodo-6 in anhydrous THF (12 mL) To a room temperature solution of -methylpyridin-2 (1H) -one (1.00 g, 1.76 mmol), tributyl (vinyl) tin (1.21 g, 3.81 mmol) and tetrakis (triphenylphosphine) palladium (236 mg, 0.204) mmol) was added in order under the argon stream. The reflux condenser was then equipped with a reaction vessel and the reaction system was purged with argon airflow. The resulting yellow solution was heated to 68 ° C. and stirred for 12.0 h under constant pressure argon until the starting material disappeared completely in LCMS analysis. The reaction mixture was concentrated in vacuo and the resulting dark residue was SiO ₂ chromatographed with ethyl acetate / hexanes (3: 7) to give a red solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.62 (app q, J = 7.8 Hz, 1H), 7.45 (app tt, J = 8.4, 6.2, 1H), 7.09 (app t, J = 8.8 Hz, 2H) , 6.90 (app t, J = 8.0 Hz, 1H), 6.83 (app dt, J = 6.8, 2.5 Hz, 1H), 6.51 (dd, J = 17.7, 11.4 Hz, 1H), 5.53 (dd, J = 11.4 , 1.5 Hz, 1H), 5.41 (dd, J = 17.8, 1.5 Hz, 1H), 5.09 (br s, 2H), 2.09 (s, 3H); LC / MS C-18 column, t _r = 3.20 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 468 (M + H). ES-HRMS m / z 468.0210 (M + H calculated for C ₂₁ H ₁₅ BrF ₄ NO ₂ : 468.0217).

Example 560

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -5- (1,2-dihydroxyethyl) -6-methyl Pyridin-2 (1H) -one

Step 1: 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6- in water / acetone 1: 3 (8.7 mL) Osmium tetraoxide (0.110 g, 0.433 mmol) and N-methyl morpholine oxide (1.32 g, 11.2 mmol) were added to a room temperature solution of methyl-5-vinylpyridin-2 (1H) -one (0.970 g, 2.07 mmol). As added. The resulting solution was stirred for 1 h until the starting material was completely consumed in LCMS analysis and the reaction was concentrated in vacuo. The resulting residue was subjected to SiO ₂ chromatography with ethyl acetate / hexanes (3: 7) to give a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.59 (app q, J = 8.2 Hz, 1H), 7.45 (ddd, J = 14.7, 8.5, 6.8 Hz, 1H), 7.08 (app t, J = 8.5 Hz, 2H), 6.94 (app t, J = 8.2 Hz, 1H), 6.88 (app t, J = 8.5 Hz, 1H), 5.31 (AB-q, J = 10.6 Hz, Δ = 38.3 Hz, 2H), 5.07 ( dd, J = 9.1, 3.8 Hz, 1H), 3.83 (t, J = 10.8 Hz, 1H), 3.60 (dd, J = 11.4, 3.9 Hz, 1H), 2.94 (br s, 1H), 2.16 (s, 3H); LC / MS C-18 column, t _r = 2.26 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 502 (M + H). ES-HRMS m / z 502.0276 (M + H calculated for C ₂₁ H ₁₇ BrF ₄ NO ₄ : 502.0272).

Example 561

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -5- (hydroxymethyl) -6-methylpyridine-2 (1H )-On

Step 1: 5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -2-methyl-6-oxo in methanol (10 mL) Solid sodium borohydride (3.6 g, 96 mmol) was added to a -20 ° C solution of -1,6-dihydropyridine-3-carbaldehyde (0.659 g, 1.40 mmol) for 1 hour. Add portions in portions until consumed. The reaction mixture was then diluted with 500 mL of ethyl acetate and washed with water (3 x 200 mL). The resulting organic extract was dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo to a volume of about 100 ml. The resulting liquid was diluted with hexane (100 mL) to give an amorphous solid which was collected and dried under 1 mm Hg vacuum to give the desired product (620 mg, 94%). ¹ H NMR (400 MHz, d ₄ -MeOH) δ 7.70 (app q, J = 8.3 Hz, 1H), 7.62 (app tt, J = 10.4, 6.3 Hz, 1H), 7.25 (app t, J = 8.6 Hz , 2H), 7.03 (app t, J = 8.6 Hz, 1H), 6.88 (app t, J = 8.5 Hz, 1H), 5.31 (s, 2H), 4.58 (s, 2H), 2.17 (s, 3H) ; LC / MS C-18 column, t _r = 2.49 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 472 (M + H). ES-HRMS m / z 472.0152 (M + H calculated for C ₂₀ H ₁₅ BrF ₄ NO ₃ : 472.0166).

Example 562

4- (benzyloxy) -3-bromo-1- (2,6-difluorophenyl) -6-methylpyridin-2 (1H) -one

Step 1: Preparation of 4- (benzyloxy) -1- (2,6-difluorophenyl) -6-methylpyridin-2 (1H) -one

Of vigorously stirred, 1- (2,6-difluorophenyl) -4-hydroxy-6-methylpyridin-2 (1H) -one (1.43 g, 6.03 mmol) in dimethylformamide (4.6 mL) To the room temperature solution was added K ₂ CO ₃ (2.01 g, 14.5 mmol) and benzyl bromide (2.40 mL, 20.2 mmol) in order. The resulting suspension was stirred for 6.5 hours until the starting material was consumed completely in LCMS analysis. The reaction was then diluted with ethyl acetate (200 mL) and washed with brine (3 × 200 mL). The resulting organic extract was dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo to a volume of about 100 ml. The resulting mother liquor was quickly precipitated to give an amorphous solid which was collected and dried under 1 mm Hg vacuum to give a solid (1.62 g, 82%). ¹ H NMR (300 MHz, d ₄ -MeOH) δ 7.62 (app tt, J = 8.6, 6.4 Hz, 1H), 7.52-7.32 (m, 4H), 7.30-7.12 (m, 3H), 6.27 (d, J = 1.6 Hz, 1H), 6.04 (d, J = 2.6 Hz, 1H), 5.18 (s, 2H), 2.06 (s, 3H). LC / MS C-18 column, t _r = 2.51 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 328 (M + H). ES-HRMS m / z 328.1179 (M + H calculated for C ₁₉ H ₁₆ F ₂ NO ₂ : 328.1144).

Step 2: room temperature of 4- (benzyloxy) -1- (2,6-difluorophenyl) -6-methylpyridin-2 (1H) -one (1.52 g, 4.64 mmol) in methylene chloride (15 mL) N-bromosuccinimide (2.01 g, 11.3 mmol) was added to the solution and the resulting reddish solution was stirred for 4.0 h. At this point, 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 extract was dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo to a volume of about 60 mL. The resulting mother liquor was rapidly precipitated to give an amorphous solid which was collected and dried under 1 mm Hg vacuum to give a solid (1.70 g, 91%). ¹ H NMR (300 MHz, d ₄ -MeOH) δ 7.64 (app tt, J = 8.6, 6.4 Hz, 1H), 7.57 (br d, J = 7.1 Hz, 1H), 7.50-7.34 (m, 4H), 7.27 (app t, J = 8.0 Hz, 1 H), 7.26-7.21 (m, 1 H), 6.66 (s, 1 H), 5.40 (s, 2 H), 2.12 (s, 3 H); LC / MS C-18 column, t _r = 2.63 min (detecting at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 406 (M + H). ES-HRMS m / z 406.0228 (M + H calculated for C ₁₉ H ₁₅ BrF ₂ NO ₂ : 406.0249).

Example 563

5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -2-methyl-6-oxo-1,6-dihydropyridine- 3-yl] methyl carbamate

Step 1: 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -5- (hydroxymethyl in methylene chloride (0.4 mL) To a room temperature solution of) -6-methylpyridin-2 (1H) -one (76.2 mg, 0.161 mmol) was added a solution of trichloroacetyl isocyanate (toluene, 0.60 M, 0.5 mL, 0.30 mmol). The resulting solution was stirred for 1 hour until the starting material was consumed completely in LCMS analysis. The reaction mixture was then directly added to Al ₂ O ₃ (0.5 g Broeckman-activity type I) and the slurry was aged for 3 hours. At this point, the Al ₂ 0 ₃ plug was washed with ethyl acetate / methanol (95: 5), the resulting mother liquor was concentrated and the residue was Si0 ₂ chromatographed with ethyl acetate / hexanes (1: 1) to give a white solid. Was obtained (71.0 mg, 85%). ¹ H NMR (400 MHz, d ₄ -MeOH) 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, t _r = 2.35 min (detecting at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 515 (M + H). ES-HRMS m / z 515.0188 (M + H calculated for C ₂₁ H ₁₆ BrF ₄ N ₂ 0 ₄ : 515.0224).

Example 564

5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -2-methyl-6-oxo-1,6-dihydropyridine- 3-carbaldehyde

Step 1: 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -5- (1,2- in toluene (10.0 mL) To a room temperature solution of dihydroxyethyl) -6-methylpyridin-2 (1H) -one (550 mg, 1.10 mmol) was added lead (IV) acetate (810 mg, 1.82 mmol). The resulting dark brown solution was stirred for 2 hours until complete consumption of starting material in LCMS analysis. The reaction mixture was then diluted with ethyl acetate (400 mL), washed with water (3 x 100 mL) and brine (3 x 300 mL). The resulting organic extract was separated, dried over Na ₂ SO ₄ and concentrated. The resulting dark colored residue was SiO ₂ chromatographed with ethyl acetate / hexanes (1: 1) to give a light yellow solid (321 mg, 62%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.08 (s, 1H), 7.56-7.48 (m, 2H), 7.12 (app t, J = 7.3 Hz, 2H), 6.94 (app t, J = 8.5 Hz, 1H), 6.88 (appt, J = 8.7 Hz, 1H), 5.33 (s, 2H), 2.45 (s, 3H); LC / MS C-18 column, t _r = 2.94 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 470 (M + H). ES-HRMS m / z 469.9996 (M + H calculated for C ₂₀ H ₁₃ BrF ₄ NO ₃ : 470.0009).

Example 565

5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -2-methyl-6-oxo-1,6-dihydropyridine- 3-carbaldehyde oxime

Step 1: 5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -2-methyl-6-oxo in methanol (10.0 mL) Solid NH ₂ OH.H ₂ O (300.0 mg, 4.32 mmol) and sodium acetate (480.0 mg, 5.85 mmol) in a room temperature solution of -1,6-dihydropyridine-3-carbaldehyde (316.5 mg, 0.673 mmol) Was added. The resulting suspension was stirred for 1.5 hours until the starting material was consumed completely in LCMS analysis. The reaction mixture was then concentrated in vacuo and the resulting residue was diluted with methylene chloride (300 mL) and washed with water (2 × 100 mL). The resulting organic extract was separated, dried over Na ₂ SO ₄ and concentrated to give a light yellow solid (390 mg, 99%). ¹ H NMR (400 MHz, d ₄ -MeOH, CDCl ₃ ) δ 8.06 (s, 1H), 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, 1H), 6.83 (app dt, J = 9.2, 2.4 Hz, 1H), 5.13 (s, 2H), 2.76 (s, 3H); LC / MS C-18 column, t _r = 2.61 min (detecting at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 485 (M + H). ES-HRMS m / z 485.0093 (M + H calculated for C ₂₀ H ₁₄ BrF ₄ N ₂ 0 ₃ : 485.0118).

Example 566

5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -2-methyl-6-oxo-1,6-dihydropyridine- 3-carbonitrile

Step 1: 5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -2-methyl-6- in methylene chloride (8.0 mL) To a room temperature solution of oxo-1,6-dihydropyridine-3-carbaldehyde oxime (340.0 mg, 0.701 mmol) solid 1,1 'carbonyl diimidazole (290.0 mg, 1.79 mmol) and sodium acetate (480.0 mg) , 5.85 mmol) was added. The resulting solution was stirred for 1.5 h until the starting material was consumed completely in LCMS analysis. The reaction mixture was then concentrated in vacuo and the resulting residue was directly SiO ₂ chromatographed with ethyl acetate / hexanes (3: 7) to give a white solid (262 mg, 90%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.61 (app q, J = 7.4 Hz, 1H), 7.52 (app tt, J = 8.4, 6.3 Hz, 1H), 7.14 (app dd, J = 8.6, 7.4 Hz , 2H), 6.94 (app dt, J = 8.5, 2.5 Hz, 1H), 6.88 (app dt, J = 8.5, 2.4 Hz, 1H), 5.43 (s, 2H), 2.32 (s, 3H); LC / MS C-18 column, t _r = 2.95 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). IR (solvent free) 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 calculated for C ₂₀ H ₁₂ BrF ₄ N ₂ 0 ₂ : 467.0013).

Example 567

4- (benzyloxy) -3-bromo-1- (2,6-difluorophenyl) -5-iodo-6-methylpyridin-2 (1H) -one

Step 1: 4- (benzyloxy) -3-bromo-1- (2,6-difluorophenyl) -6-methylpyridin-2 (1H) -one in 1,2-dichloroethane (18 mL) (1.42 g, 3.50 mmol) 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 stirred and heated at 50 ° C. for 2.5 hours until complete consumption of the starting material in LCMS. At this point, 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 extract was dried over Na ₂ S0 ₄ , filtered and concentrated to about 30 mL volume under vacuum. The resulting mother liquor quickly precipitated to give an amorphous solid which was collected and dried under 1 mm Hg vacuum to give a solid (1.49 g, 82%). ¹ H NMR (400 MHz, CDCl ₃ ) 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, t _r = 3.28 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 532 (M + H). ES-HRMS m / z 531.9196 (M + H calculated for C ₁₉ H ₁₄ BrF ₂ INO ₂ : 531.9215).

Example 568

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-methyl-5-oxirane-2-ylpyridine-2 ( 1H) -on

Step 1: 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-methyl-5-vinylpyridine-2 (1H) A sample of -one (10.0 mg, 0.0214 mmol) was treated with a solution of dimethyl dioxirane in acetone (about 0.1 M, 5 mL, 0.5 mmol). The reaction vessel was sealed, sealed and the resulting solution was stirred for 6.0 hours. At this point, the reaction was concentrated in vacuo and the resulting residue was subjected to SiO ₂ chromatography with ethyl acetate / hexanes (4: 6) to give a semisolid (5.0 mg, 48%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.57 (app q, J = 7.4 Hz, 1H), 7.46 (app tt, J = 8.5, 6.2, 1H), 7.11 (app t, J = 8.0 Hz, 2H) , 6.94 (app t, J = 8.2 Hz, 1H), 6.83 (app t, J = 9.2 Hz, 1H), 5.31 (AB-q, J = 10.9 Hz, Δ = 29.0 Hz, 2H), 3.63 (app t , J = 3.5 Hz, 1H), 3.03 (dd, J = 9.4, 5.0, 1H), 2.85 (dd, J = 5.2, 2.7, 1H), 2.14 (s, 3H); LC / MS C-18 column, t _r = 2.26 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 484 (M + H) and 502 (M + H ₃ 0). ES-HRMS m / z 502.0273 (M + H ₃ 0 calculated for C ₂₁ H ₁₇ BrF ₄ NO ₄ : 502.0272).

Example 569

4- (benzylamino) -3-bromo-1- (2,6-difluorophenyl) -5-iodo-6-methylpyridin-2 (1H) -one

Step 1: 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -5-iodo-6-methylpyridine-2 (1H The slurry of) -one (80.0 mg, 0.141 mmol) and benzyl amine (300 mg, 2.80 mmol) was heated to 63 ° C. and stirred for 1.0 h until the starting material disappeared completely in LCMS analysis. The reaction mixture was then diluted with ethyl acetate (300 mL) and washed with brine (3 x 200 mL). The resulting organic extract was dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo, and the residue was then chromatographed SiO ₂ with ethyl acetate / hexanes (3: 7) to give a brown solid (60.0 mg, 81 %). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43-7.22 (m, 6H), 7.04 (app t, J = 8.4 Hz, 2H), 5.02 (br t, J = 1.6 Hz, 1H), 4.86 (d, J = 5.5 Hz, 2H), 2.37 (s, 3H); LC / MS C-18 column, t _r = 3.02 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 531 (M + H). ES-HRMS m / z 530.9344 (M + H calculated for C ₁₉ H ₁₅ BrF ₂ IN ₂ 0: 530.9375).

Example 570

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-methyl-5-[(E) -2-phenylethenyl ] Pyridin-2 (1H) -one

Step 1: To a −78 ° C. anhydrous solution of β-bromostyrene (1.80 g, 10.0 mmol) in ether (18 mL) was added zinc chloride solution (10.0 mL, 1.0 M ether, 10.0 mmol) for 1.0 min followed by tert -Butylnium solution (15.0 mL, 1.6 M pentane, 24.0 mmol) was added for 8.0 minutes. The resulting solution was cloudy and the reaction mixture was allowed to warm to room temperature by itself (for 30 minutes). After an additional 1.0 hour the suspension was dispensed by syringe with 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) in dry THF (4 mL). In a separate vessel containing a solution of -5-iodo-6-methylpyridin-2 (1H) -one (1.50 g, 2.64 mmol) and tetrakis (triphenylphosphine) palladium (294 mg, 0.254 mmol) I transferred it myself. The resulting suspension was heated at 55 ° C. for 40 minutes, cooled to room temperature and stirred for an additional 4.0 hours under constant pressure argon until the starting material disappeared completely in LCMS analysis. The reaction suspension was then treated with NaHC0 ₃ and brine (100 and 200 mL respectively). The resulting emulsion was extracted with ethyl acetate (3 × 300 mL), the organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo, and the residue was then purified by SiO ₂ chromatography with ethyl acetate / hexanes (3: 7). The chromatography gave a red solid (1.25 g, 86%). ¹ H NMR (400 MHz, CDCl ₃ ) 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 , 1H), 6.82-6.75 (m, 1H), 6.74-6.68 (m, 1H), 6.69 (d, J = 17.2, 1H), 5.11 (br s, 2H), 2.15 (s, 3H); LC / MS C-18 column, t _r = 3.74 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 544 (M + H). ES-HRMS m / z 544.0565 (M + H calculated for C ₂₇ H ₁₉ BrF ₄ NO ₂ : 544.0530).

Example 574

4- (allylamino) -3-bromo-1- (2,6-difluorophenyl) -5-iodo-6-methylpyridin-2 (1H) -one

Step 1: 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -5-iodo-6-methylpyridine-2 (1H The slurry of) -one (1.40 g, 2.46 mmol) and allyl amine (1.98 mg, 34.6 mmol) was heated to 50 ° C. and stirred for 1.0 h until the starting material disappeared completely in LCMS analysis. The reaction mixture was then concentrated in vacuo (1.0 mm Hg) at 50 ° C. for 2 days to give a brown solid (1.18 g, 99%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.43 (app tt, J = 8.4, 6.2, 1H), 7.09 (app t, J = 8.45 Hz, 2H), 6.02 (app dq, J = 11.0, 6.2 Hz, 1H), 5.39 (dd, J = 16.9, 1.8 Hz, 1H), 5.30 (dd, J = 11.0, 1.8 Hz, 1H), 4.84 (br s, 2H), 2.42 (s, 3H); LC / MS C-18 column, t _r = 2.71 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 481 (M + H). ES-HRMS m / z 480.9261 (M + H calculated for C ₁₅ H ₁₃ BrF ₂ IN ₂ O: 480.9219).

Example 575

4- (allylamino) -1- (2,6-difluorophenyl) -5-iodo-6-methylpyridin-2 (lH) -one

Step 1: 4- (allylamino) -3-bromo-1- (2,6-difluorophenyl) -5-iodo-6-methylpyridine-2 (in anhydrous THF (10 mL) under argon stream) 1H) -one (1.00 g, 2.07 mmol) and tetrakis (triphenylphosphine) palladium (420 mg, 0.363 mmol) solution were treated at 64 ° C. for 12 hours until the starting material disappeared completely in LCMS analysis. Stirred. The reaction suspension was then treated with brine (600 mL). The resulting emulsion was extracted with ethyl acetate (3 × 400 mL), the organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo and the residue was purified by SiO with ethyl acetate / hexanes (gradient 3: 7). ₂ chromatography gave a solid (376 mg, 45%). ¹ H NMR (400 MHz, d ₄ -MeOH) δ 7.55 (app tt, J = 8.7, 6.3, 1H), 7.18 (app t, J = 7.6 Hz, 2H), 5.89 (app ddd, J = 15.4, 10.3 , 5.1 Hz, 1H), 5.01 (app d, J = 17.0, Hz, 1H), 5.50 (s, 1H), 5.22 (app d, J = 11.0 Hz, 1H), 4.35 (app d, J = 5.0 Hz , 2H), 2.36 (s, 3H); LC / MS C-18 column, t _r = 2.33 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 403 (M + H). ES-HRMS m / z 403.0133 (M + H calculated for C ₁₅ H ₁₄ F ₂ IN ₂ O: 403.0113).

Example 576

4- (allylamino) -1- (2,6-difluorophenyl) -5-iodo-6-methylpyridin-2 (1H) -one

Step 1: 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-methylpyridine-2 (in THF (6.0 mL) A solution of 1H) -one (197 mg, 0.445 mmol) and allyl amine (1.32 mg, 23.1 mmol) was heated to 68 ° C. and heated for 74.0 hours. The reaction mixture was concentrated in vacuo (30 mm Hg) and the residue was chromatographed SiO ₂ with ethyl acetate / hexanes (3: 7) to give a solid (36.0 mg, 23%). ¹ H NMR (400 MHz, d ₄ -MeOH) δ 7.55 (app tt, J = 8.5, 6.5, 1H), 7.18 (app t, J = 8.5 Hz, 2H), 6.14 (s, 1H), 5.91 (app dq, J = 11.5, 6.4 Hz, 1H), 5.23 (dd, J = 17.0, 1.5 Hz, 1H), 5.19 (dd, J = 11.0, 1.6 Hz, 1H), 4.00 (app d, J = 4.7 Hz, 2H), 1.98 (s, 3H); LC / MS C-18 column, t _r = 2.24 min (detecting at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 355 (M + H). ES-HRMS m / z 355.0257 (M + H calculated for C ₁₅ H ₁₄ F ₂ BrF ₂ N ₂ 0: 355.0252).

Example 577

Ethyl 3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxo-2H-1,2'-bipyridine-5'-carboxylate

Step 1: 3-Bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one in 1-methyl-2-pyrrolidinone (3.0 mL) ( To a room temperature suspension of 500.0 mg, 1.51 mmol) and Cs ₂ CO ₃ (1.50 g, 4.60 mmol) was added ethyl 6-chloronicotinate (900 mg, 4.85 mmol). The resulting suspension was stirred and heated at 106 ° C. for 36 hours until complete consumption of starting material in LCMS analysis. The reaction mixture was then diluted with ethyl acetate (400 mL) and washed with water (3 x 200 mL). The resulting organic extract was separated, dried over Na ₂ S0 ₄ and concentrated. The resulting dark residue was subjected to SiO ₂ chromatography with ethyl acetate / hexanes (3: 7) to give a solid. ¹ H NMR (400 MHz, d ₄ -MeOH) δ 8.68 (app d, J = 2.5 Hz, 1H), 8.39 (dd, J = 8.7, 2.3 Hz, 1H), 7.62 (app q, J = 8.2 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 7.08 (s, 1H), 7.08-6.99 (m, 2H), 5.31 (s, 2H), 4.37 (q, J = 7.1 Hz, 2H), 2.43 (s, 3 H), 1.37 (t, J = 7.1 Hz, 3 H); LC / MS C-18 column, t _r = 3.44 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 479 (M + H). ES-HRMS m / z 479.0401 (M + H calculated for C ₂₁ H ₁₈ BrF ₂ N ₂ 0 ₄ : 479.0431).

Example 578

3-bromo-4-[(2,4-difluorobenzyl) oxy] -5 '-(1-hydroxy-1-methylethyl) -6-methyl-2H-1,2'-bipyridine- 2-on

Step 1: A 0 ° C. solution of methyl magnesium bromide (3.0 M, 3.5 mL, 10.5 mmol) was added with ethyl 3-bromo-4-[(2,4-difluorobenzyl) oxy] -6 in THF (4.0 mL). A solution of -methyl-2-oxo-2H-1,2'-bipyridine-5'-carboxylate (500.0 mg, 1.05 mmol) was added dropwise over 15 minutes. The internal temperature of the reaction never exceeded 0 ° C. The resulting solution was maintained for 30 minutes until the starting material was consumed completely in LCMS analysis. Next, ammonium chloride solution (saturated aqueous solution, 160 mL) was added. The reaction mixture is extracted with ethyl acetate (3 × 100 mL), the resulting organic extracts are separated, dried over Na ₂ SO ₄ , concentrated in vacuo and the residue is ethyl acetate / hexanes (gradient 3: 7 to 6) SiO ₂ chromatography with: 4) gave a solid (386 mg, 79%). ¹ H NMR (400 MHz, d ₄ -MeOH) δ 8.23 (app d, J = 2.8 Hz, 1H), 7.97 (dd, J = 8.6, 2.3 Hz, 1H), 7.61 (app q, J = 8.2 Hz, 1H), 7.06-7.00 (m, 3H), 7.00 (s, 1H), 5.30 (s, 2H), 2.38 (s, 3H), 1.54 (s, 6H); LC / MS C-18 column, t _r = 2.75 min (detecting at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 465 (M + H). ES-HRMS m / z 465.0615 (M + H calculated for C ₂₁ H ₂₀ BrF ₂ N ₂ 0 ₃ : 465.0620). IR (solvent-free) 3366, 3030, 2974, 1600, 1507, 1362, 1232 cm ^-1 . ¹³ C NMR (400 MHz, d ₄ -MeOH, peak appearing in the presence of carbon fluorine coupling) 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

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2-furylmethyl) -6-methylpyridin-2 (1H) -one

Step 1: Preparation of the title compound. 3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one (330.0 mg, 1.00 mmol) and NaH (48.0 mg) in THF (3.0 mL) , 2.0 mmol) was added 2- (chloromethyl) furan (461 mg, 3.97 mmol). The resulting suspension was stirred and heated at 68 ° C. for 9 hours until complete consumption of starting material in LCMS analysis. The reaction mixture was then diluted with ethyl acetate (400 mL) and washed with water (3 x 200 mL). The resulting organic extract was separated, dried over Na ₂ SO ₄ and concentrated. The resulting dark residue was SiO ₂ chromatographed with ethyl acetate / hexanes (4: 6) to give a solid. ¹ H NMR (300 MHz, d ₄ -MeOH) δ 7.62 (app q, J = 8.4 Hz, 1H), 7.46 (s, 1H), 7.06 (app t, J = 8.7 Hz, 2H), 6.51 (s, 1H), 6.41-6.37 (m, 2H), 5.37 (s, 2H), 5.32 (s, 2H), 2.61 (s, 3H); LC / MS C-18 column, t _r = 2.63 min (detecting at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 410 (M + H). ES-HRMS m / z 410.0177 (M + H calculated for C ₁₈ H ₁₅ BrF ₂ NO ₃ : 410.0198).

Example 580

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (thien-2-ylmethyl) pyridin-2 (1H) -one

Step 1: 3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one (330.0 mg, 1.00 mmol) and NaH in THF (3.0 mL) To (48.0 mg, 2.0 mmol) at room temperature suspension was added 2- (chloromethyl) thiophene (461 mg, 3.97 mmol). The resulting suspension was stirred and heated at 68 ° C. for 12 hours until complete consumption of starting material in LCMS analysis. The reaction mixture was then diluted with ethyl acetate (400 mL) and washed with water (3 x 200 mL). The resulting organic extract was separated, dried over Na ₂ SO ₄ and concentrated. The resulting dark residue was SiO ₂ chromatographed with ethyl acetate / hexanes (4: 6) to give a solid. ¹ H NMR (400 MHz, d ₄ -MeOH) δ 7.58 (app q, J = 8.2 Hz, 1H), 7.30 (app dd, J = 5.1, 1.2 Hz, 1H), 7.05 (d, J = 2.6 Hz, 1H), 7.01 (app t, J = 8.1 Hz, 2H), 6.93 (dd, J = 5.1,3.4 Hz, 1H), 6.43 (s, 1H), 5.49 (s, 2H), 5.25 (s, 2H) , 2.51 (s, 3 H); LC / MS C-18 column, t _r = 2.74 min (detecting at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 426 (M + H). ES-HRMS m / z 425.9936 (M + H calculated for C ₁₈ H ₁₅ BrF ₂ NO ₂ S: 425.9969).

Example 581

3-bromo-1- (2,6-difluorophenyl) -4- (2-furylmethoxy) -6-methylpyridin-2 (1H) -one

Step 1: 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-methylpyridine-2 (in THF (2.5 mL) To a suspension of 1H) -one (250 mg, 0.445 mmol) and furfuryl alcohol (198 mg, 2.0 mmol) was added solid NaH (46.0 mg, 1.92 mmol). After evaporation of the gas the resulting suspension was heated to 60 ° C. and stirred for 3.5 h until the starting material was consumed completely in LCMS analysis. The reaction mixture was then diluted with ammonium chloride (saturated aqueous solution, 100 mL) and extracted with ethyl acetate (3 x 100 mL). The resulting organic extract was separated, dried over Na ₂ SO ₄ and the residue was chromatographed SiO ₂ with ethyl acetate / hexanes (3: 7) to give a solid (110.0 mg, 49%). ¹ H NMR (400 MHz, d ₄ -MeOH) δ 7.63 (app tt, J = 8.5, 6.2, 1H), 7.62-7.61 (m, 1H), 7.28 (appt, J = 8.5 Hz, 2H), 6.77 (s, 1H), 6.68 (d, J = 4.1 Hz, 1H), 6.51 (dd, J = 4.2, 3.9 Hz, 1H), 5.34 (s, 2H), 2.15 (s, 3H); LC / MS C-18 column, t _r = 2.43 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 396 (M + H). ES-HRMS m / z 396.0044 (M + H calculated for C ₁₇ H ₁₃ BrF ₂ NO ₃ : 396.0041).

Example 582

3-bromo-1- [2-fluoro-6- (3-furylmethoxy) phenyl] -4- (3-furylmethoxy) -6-methylpyridin-2 (1H) -one

Follow the process for preparing 3-bromo-1- (2,6-difluorophenyl) -4- (2-furylmethoxy) -6-methylpyridin-2 (1H) -one (Example 581), Purfuryl alcohol was replaced with 3-furylmethanol to give the title compound in a chemical yield of 55%. ¹ H NMR (400 MHz, d ₄ -MeOH) δ 7.64 (s, 1H), 7.55-7.42 (m, 3H), 7.40 (app t, J = 1.4 Hz, 1H), 7.12 (d, J = 9.0 Hz , 1H), 6.92 (app t, J = 8.4 Hz, 1H), 6.58 (s, 2H), 6.34 (br s, 1H), 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, t _r = 2.67 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 474 (M + H). ES-HRMS m / z 474.0346 (M + H calculated for C ₂₂ H ₁₈ BrFNO ₅ : 474.0347).

Example 583

3-bromo-1- [2-fluoro-6- (thien-3-ylmethoxy) phenyl] -6-methyl-4- (thien-3-ylmethoxy) pyridin-2 (1H) -one

Follow the process for preparing 3-bromo-1- (2,6-difluorophenyl) -4- (2-furylmethoxy) -6-methylpyridin-2 (1H) -one (Example 581), Furfuryl alcohol was replaced with thien-3-ylmethanol to afford the title compound in a chemical yield of 38%. ¹ H NMR (400 MHz, d ₄ -MeOH) δ 7.50-7.42 (m, 3H), 7.33 (dd, J = 5.0, 3.0 Hz, 1H), 7.26 (br d, J = 2.0 Hz, 1H), 7.19 (dd, J = 5.0, 1.2 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H), 6.98 (dd, J = 14.9, 1.3 Hz, 1H), 6.93 (dt, J = 8.7, 1.0 Hz, 1H), 6.53 (br s, 1H), 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, t _r = 2.93 min (detecting at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 506 (M + H). ES-HRMS m / z 505.9881 (M + H calculated for C ₂₂ H ₁₈ BrFNO ₃ S ₂ : 505.9890).

Example 584

Methyl 2- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-[(methylamino) car Carbonyl] benzoate

Step 1: Preparation of 3- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -4- (methoxycarbonyl) benzoic acid

4-hydroxy-6-methyl-2-pyrone (75.0 g, 595 mmol) and 3-amino- in a 500 ml three necked round bottom flask equipped with J-Kem thermostat probe, Dean-Stark trap and heating mantle 4- (methoxycarbonyl) benzoic acid (40.0 g, 0.205 mmol) was suspended in 56 ml of 1,2-dichlorobenzene. The reaction was heated at 180 ° C. for 26 minutes during which all solids dissolved. The reaction was held at this temperature for an additional 25.0 minutes after the internal temperature reached 180 ° C. during which water evolved from the reaction mixture. Next, the heating device was removed and the reaction was allowed to cool to about 100 ° C by itself. The reaction was then diluted with 160 mL of toluene and stirred. After about 10 minutes the reaction reached room temperature and a gummy solid formed. The precipitate was filtered off, washed with EtOAc (400 mL) and water (200 mL, 55 ° C.) and dried under vacuum to give a tan solid (30.5 g, 49%). ¹ H NMR (400 MHz, d ₄ -MeOH) δ 8.20-8.09 (m, 2H), 7.84 (2, 1H), 6.08 (app d, J = 1.0 Hz, 1H), 5.76 (app d, J = 2.3 Hz, 1H), 3.76 (s, 3H). LC / MS, C-18 column, t _r = 1.96 min (detecting at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 304 (M + H). ES-HRMS m / z 304.0803 (M + H calculated for C ₁₅ H ₁₄ NO ₆ : 304.0816).

Step 2: Preparation of Methyl 2- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -4-[(methylamino) carbonyl] benzoate

3- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -4- (methoxycarbonyl) benzoic acid in dimethylformamide (10 mL) and THF (10 mL) Prepared from 1) (1.00 g, 3.30 mmol) in a solution of cyclohexylcarbodiimide-derivatized silica gel (Silicycle chemical division, Quebec, Canada) 0.60 mmol / g (15.2 g, 9.73 mmol). After stirring for 30 minutes, methylamine solution (2.0 M, THF, 2.9 mL, 5.8 mmol) was added followed by 1-hydroxy-benzotriazole (20.0 mg, 0.15 mmol). The reaction suspension was stirred for 24 hours until the starting material disappeared completely in LCMS analysis. The silica suspension was filtered and washed with 300 ml of ethyl acetate / methanol (9: 1) and 300 ml of ethyl acetate / methanol (1: 1). The resulting mother liquor was concentrated to give a brown semisolid (898 mg, 86%). ¹ H NMR (300 MHz, d ₄ -MeOH) δ 8.22 (d, J = 8.0 Hz, 1H), 8.04 (dd, J = 8.3, 1.9 Hz, 1H), 7.73 (d, J = 1.6 Hz, 1H) , 6.13 (d, J = 1.5, Hz, 1H), 5.80 (d, J = 2.2 Hz, 1H), 3.80 (s, 3H), 3.03 (s, 3H), 1.97 (s, 3H). LC / MS, C-18 column, t _r = 1.31 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 317 (M + H). ES-HRMS m / z 317.1142 (M + H calculated for C ₁₆ H ₁₇ N ₂ 0 ₅ : 317.1132).

Step 3: Preparation of methyl 2- (3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -4-[(methylamino) carbonyl] benzoate.

CH₂Cl₂ Methyl 2- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -4-[(methylamino) carbonyl] benzoate in (8 mL) prepared from step 2 Solid N-bromosuccinimide (251 mg, 1.41 mmol) was added to a room temperature suspension of) (406.0 mg, 1.28 mmol) and stirred for 10 minutes until complete consumption of starting material in LCMS analysis. Next, the reactant is CH₂Cl₂ (5 mL), ethyl acetate (5 mL) and hexane (1 mL). After about 30 minutes the resulting white precipitate was filtered and washed with ethyl acetate (5 mL) to give a solid (298 mg, 62%).^OneH NMR (400 MHz, d₄-MeOH) δ 8.20 (d, J = 8.2 Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.69 (s, 1H), 6.18 (s 1H), 3.75 (s, 3H), 2.91 ( s, 3H), 1.91 (s, 3H); LC / MS, t_r = 1.27 min (detecting at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 ml / min over 5 min). ES-MS m / z 395 (M + H). ES-HRMS m / z 395.0237 (C₁₆H₁₆BrN₂0₅M + H calculated for: 395.0237).

Step 4: Preparation of the title compound

Methyl 2- (3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -4-[(methylamino) carbonyl] benzo in dimethylformamide (0.5 mL) To a solution of eight (prepared from step 3) (241 mg, 0.610 mmol) was added K ₂ CO ₃ (240 mg, 1.73 mmol) and 2,4 difluorobenzyl bromide (0.085 mL, 0.66 mmol) in that order. . The resulting wilt was stirred for 6.5 hours until the starting material was consumed completely in LCMS analysis. The reaction was then diluted with ethyl acetate (200 mL) and washed with brine (3 × 200 mL). The resulting organic extract was dried over Na ₂ SO ₄ , filtered and concentrated to about 5 mL volume under vacuum. The resulting mother liquor was rapidly precipitated to give an amorphous solid which was collected. ¹ H NMR (400 MHz, d ₄ -MeOH) δ 8.22 (d, J = 8.2 Hz, 1H), 8.03 (dd, J = 8.2, 1.7 Hz, 1H), 7.71 (d, J = 1.8 Hz, 1H) , 7.67 (app q, J = 8.3 Hz, 1H), 7.05 (app t, J = 8.6 Hz, 2H), 6.64 (s, 1H), 5.37 (s, 2H), 3.74 (s, 3H), 2.90 ( s, 3H), 2.01 (s, 3H). LC / MS C-18 column, t _r = 2.87 min (detecting at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 521 (M + H). ES-HRMS m / z 521.0491 (M + H calculated for C ₂₃ H ₂₀ BrF ₂ N ₂ 0 ₅ : 521.0518).

Example 585

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4- (1-hydroxy-1 -Methylethyl) -N-methylbenzamide

Step 1: A -10 ° C solution of methyl magnesium bromide (3.0 M, 0.60 mL, 1.8 mmol) in methyl 2- [3-bromo-4-[(2,4-difluorobenzyl) in THF (1.0 mL) A solution of oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-[(methylamino) carbonyl] benzoate (85.0 mg, 0.163 mmol) was added dropwise over 10 minutes. The internal temperature of the reactants never exceeded 0 ° C. The resulting solution was kept for 10 hours. Next, ammonium chloride solution (saturated aqueous solution, 100 ml) was added. The reaction mixture is removed from the bath, the resulting emulsion is extracted with ethyl acetate (3 × 100 mL), the resulting organic extract is separated, dried over Na ₂ SO ₄ , concentrated in vacuo and the residue is ethyl acetate SiO ₂ chromatography with / hexanes (gradient 3: 7 to 6: 4) gave a solid (16 mg, 19%). ¹ H NMR (400 MHz, d ₄ -MeOH) δ 7.89 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.61 (app q, J = 8.2 Hz, 1H), 7.41 (s, 1H), 7.03-6.99 (m, 2H), 6.57 (s, 1H), 5.30 (s, 2H), 2.83 (s, 3H), 2.05 (s, 3H), 1.51 (s, 3H) , 1.39 (s, 3 H); LC / MS C-18 column, t _r = 2.28 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 521 (M + H). ES-HRMS m / z 521.0860 (M + H calculated for C ₂₄ H ₂₄ BrF ₂ N ₂ 0 ₄ : 521.0882).

Example 586

3-bromo-1- [2-fluoro-6- (thien-3-ylmethoxy) phenyl] -6-methyl-4- (thien-3-ylmethoxy) pyridin-2 (1H) -one

Follow the process for preparing 3-bromo-1- (2,6-difluorophenyl) -4- (2-furylmethoxy) -6-methylpyridin-2 (lH) -one (Example 581), 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluorophenyl) -6-methylpyridin-2 (1H) -one 4-{[ 3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzamide, replacing the title compound by 76% It was prepared in the chemical yield of. ¹ H NMR (400 MHz, d ₄ -MeOH) δ 7.83 (d, J = 8.1 Hz, 2H), 7.54 (app d, J = 1.1 Hz, 1H), 7.19 (d, J = 8.1 Hz, 2H), 6.57 (d, J = 3.2 Hz, 1H), 6.53 (s, 1H), 6.43 (dd, J = 3.1, 1.8 Hz, 1H), 5.45 (br s, 2H), 5.22 (s, 2H), 2.34 ( s, 3H); LC / MS C-18 column, t _r = 1.98 min (detecting at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 417 (M + H). ES-HRMS m / z 417.0469 (M + H calculated for C ₁₉ H ₁₈ BrN ₂ 0 ₄ : 417.0444).

Example 587

(-)-3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N, 4-dimethyl Benzamide

Example 489 (1.78 g, 4.36 mmol) was eluted with 100% ethanol (isosolvent, 20 mL / min) using a Chiral Technologies Chiralpak AD column (21 mm × 250 mm, 20 mL) 10 mg per injection was loaded for separation. The rapidly eluting atropisomers were collected and concentrated in vacuo to afford the title compound (718 mg, 80%). Analytical chiral LC (chiralpak AD, 4.6 mm × 50 mm, 10 μm particle size, 0.5 mL / min ethanol) Retention time: 1.70 minutes, ee 94%. [a] _D = -23.8 ° (5 mg / ml DMSO, 22 ° C). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.42 (br qr, J = 4.51 Hz, 1H), 7.82 (dd, J = 7.92, 1.70 Hz, 1H), 7.68 (dt, J = 8.24, 6.58 Hz , 1H), 7.58 (d, J = 1.59 Hz, 1H), 7.48 (d, J = 7.98 Hz, 1H), 7.34 (dt, J = 9.90, 2.50 Hz, 1H), 7.18 (dt, J = 8.53, 2.57 Hz, 1H), 6.71 (s, 1H), 5.33 (s, 2H), 2.74 (s, 3H), 1.98 (s, 3H), 1.88 (s, 3H). ¹⁹ F-NMR (400 MHz, dmso-d ₆ ) δ −109.58 (quintet, J = 7.49 Hz, 1F), −113.65 (quartet, J = 9.11 Hz, 1F). ES-HRMS m / z 477.0612 (M + H calculated for C ₂₂ H ₂₀ BrF ₂ N ₂ 0 ₃ : 477.0620).

Example 588

(+)-3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N, 4-dimethyl Benzamide

The title compound was prepared as in Example 587, incorporating the late eluting isomers (722 mg, 81%). Analytical chiral LC (chiralpak AD, 4.6 mm × 50 mm, 10 μm particle size, 0.5 mL / min ethanol) Retention time: 2.00 min, ee 98%. [a] _D = +28.2 (5 mg / ml DMSO, 22 ° C). ¹ H NMR (400 MHz, dmso-d ₆ ) δ 8.42 (br qr, J = 4.51 Hz, 1H), 7.82 (dd, J = 7.92, 1.70 Hz, 1H), 7.68 (dt, J = 8.24, 6.58 Hz , 1H), 7.58 (d, J = 1.59 Hz, 1H), 7.48 (d, J = 7.98 Hz, 1H), 7.34 (dt, J = 9.90, 2.50 Hz, 1H), 7.18 (dt, J = 8.53, 2.57 Hz, 1H), 6.71 (s, 1H), 5.33 (s, 2H), 2.74 (s, 3H), 1.98 (s, 3H), 1.88 (s, 3H). ¹⁹ F-NMR (400 MHz, DMSO-d ₆ ) δ −109.58 (quintet, J = 7.49 Hz, 1F), −113.65 (quartet, J = 9.11 Hz, 1F). ES-HRMS m / z 477.0614 (M + H calculated for C ₂₂ H ₂₀ BrF ₂ N ₂ 0 ₃ : 477.0620).

Example 589

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-1 (2H) -yl) benzoate

4-hydroxy-6-methyl-2-pyrone (24.5 g, 193.9 mmol) and methyl-3- in a 250 ml three neck round bottom flask equipped with J-Kem thermostat probe, Dean-Stark trap and heating mantle Amino-2-chlorobenzoate (30 g, 161.6 mmol) was suspended in 75 mL of 1,2-dichlorobenzene. The reaction was heated at 175 ° C. for 20 minutes during which time water and some 1,2-dichlorobenzene were collected in a Dean-Stark trap. The reaction was cooled to about 110 ° C. At this point, 200 ml of toluene was added. The toluene mixture was stirred for 72 hours at room temperature. The precipitate was collected on a filter pad. The precipitate was filtered off and washed three times with toluene and three times with water at 50 ° C. to remove excess pyrone and dried under vacuum to give a tan solid (13.0 g, 27% yield). ¹ H NMR (300 MHz, CD ₃ OD) δ 8.26 (d, J = 1.81 Hz, 1H), 8.14 (dd, J = 8.26, 1.81 Hz, 1H), 7.54 (d, J = 8.26, Hz, 1H) , 6.14 (dd, J = 2.42, 1.0 Hz, 1H), 5.83 (d, J = 2.42 1H), 4.00 (s, 3H), 1.96 (s, 3H); LC / MS, t _r = 1.81 min (detected at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 294 (M + H).

Step 2: Preparation of methyl 3-chloro-4- [4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzoate

Methyl 3-chloro-4- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) benzoate (prepared from step 1) (2.4 g, 8.17 mmol) was added DMF (10 mL). )). 2,4-Difluorobenzylbromide (1.05 mL, 8.17 mmol) and K ₂ CO ₃ (1.13 g, 8.17 mmol) were added. The reaction was stirred for 6 hours at room temperature. At this point, the reaction was poured into water (200 mL) and extracted with ethyl acetate. The ethyl acetate layer was dried over Na ₂ S0 ₄ , filtered and the solvent removed to give an amber oil (2.62 g, 77% crude yield). LC / MS, t _r = 2.79 min (detecting at 254 nm, 50 ° C. using 5-95% acetonitrile / water at 1 mL / min over 5 min). ES-MS m / z 294 (M + H).

Step 3: Methyl 4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3-chlorobenzoate Manufacture

Methyl 3-chloro-4- [4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzoate (prepared from step 2) ( 2.60 g, 6.21 mmol) was replaced with CH ₂ Cl ₂ (20 mL). N-bromosuccinimide (1.11 g, 6.21 mmol) was added and the mixture was stirred at rt for 4 h. CH ₂ Cl ₂ was removed under vacuum and the residue was dissolved in CH ₃ CN. The resulting precipitate was collected on a filter pad and washed with CH ₃ CN to give a white solid (0.75 g, 24%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.22 (d, J = 1.88 Hz, 1H), 8.06 (dd, J = 8.19, 1.75 Hz, 1H), 7.59 (app q, J = 8.46 Hz, 1H), 7.33 (d, J = 8.19, 1H), 6.96 (dt, J = 8.06, 1.21 Hz, 1H), 6.89-6.84 (m, 1H), 6.13 (s, 1H), 5.26 (s, 2H), 3.95 ( s, 3H), 1.95 (s, 3H); ES-MS m / z 478 (M + H). ES-HRMS m / z 497.9892 (M + H calculated for C ₂₂ H ₁₆ BrClF ₂ NO ₄ : 497.9914).

Step 4: Preparation of 4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3-chlorobenzoic acid

Methyl-4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3-chlorobenzoate (2.30 g, 4.61 mmol) was dissolved in THF (20 mL) and H ₂ 0 (4 mL). 2.5 N NaOH (9.2 mL) was added to the vessel and stirred overnight to complete the reaction. Concentrated HCl was added dropwise until the reaction became acidic (pH = 1). H ₂ O (100 mL) and THF (100 mL) were added to the mixture. The contents were poured into a separatory funnel and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over Na ₂ SO ₄ , the solvent was removed in vacuo, and the residue was dissolved in 50% ethyl acetate / hexane mixture. The precipitate was collected on a filter pad to give a white powder (1.5 g, 67%). ¹ H NMR (300 MHz, DMSO) δ 13.59 (1H), 8.16 (d, J = 1.81 Hz, 1H), 8.06 (dd, J = 6.24, 1.81 Hz, 1H), 7.73 (app q, J = 8.46, 1H), 7.68 (d, J = 8.26 Hz, 1H), 7.38 (dt, J = 9.48, 2.62 Hz, 1H), 7.26-7.18 (m, 1H), 6.80 (s, 1H), 5.39 (s, 2H ), 3.93 (s, 3 H), 1.96 (s, 3 H); ES-MS m / z 483 (M + H). ES-HRMS m / z 483.9749 (M + H calculated for C ₂₀ H ₁₄ BrClF ₂ NO ₄ : 483.9757).

Step 5: 4- [3-Bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3-chlorobenzoic acid (0.5 g, 1.03 mmol) was dissolved in THF (10 mL). 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.22 g, 1.24 mmol) and N-methyl morpholine (0.34 mL, 3.09 mmol) were added. The mixture was stirred at rt for 1 h. At this point, NH ₄ 0H (2.5 mL) was added and the reaction stirred further for 1 h at room temperature. Additional THF (50 mL) and water (200 mL) were added to the reaction mixture. The mixture was extracted with ethyl acetate. The ethyl acetate extracts were washed with saturated brine solution. The brine layer was extracted with ethyl acetate. The organic layers were combined, dried over Na ₂ SO ₄ , filtered and the solvent removed in vacuo. The residue was dissolved in ethyl acetate and the resulting precipitate was collected on a filter pad to give a white powder (0.38 g, 76%). ¹ H NMR (300 MHz, CD ₃ OD) δ 8.18 (d, J = 1.81 Hz, 1H), 8.02 (dd, J = 8.26, 2.01 Hz, 1H), 7.69 (app q, J = 8.26 Hz, 1H) , 7.55 (d, J = 8.06 Hz, 1H) 7.12-7.06 (m, 2H), 6.71 (s, 1H), 5.40 (s, 2H), 2.07 (s, 3H). ES-MS m / z 482 (M + H). ES-HRMS m / z 482.9919 (M + H required: 482.9917 calculated for C ₂₀ H ₁₅ BrClF ₂ N ₂ 0 ₃ ).

Example 590

3- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (H) -yl] -4-methylbenzamide

Step 1: Preparation of 3- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methylbenzoic acid

3- [4-[(2,4-Difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methylbenzoic acid (from above) (7.5 g, 19.4 mmol ) And NCS (2.6 g, 19.4 mmol) were dissolved in 65 ° C. dichloroethane (100 ml). A catalytic amount of dichloroacetic acid (2 drops) was added. After 2 hours the solvent was removed in vacuo and the residue was dissolved in diethyl ether. The precipitate was collected on a filter pad and then dissolved in 50% ethyl acetate / hexanes to remove residual succinimide. The precipitate was collected on a filter pad and then dried under vacuum to give a white powder (4.2 g, 52%). ¹ H NMR (300 MHz, CD ₃ OD) δ 8.10 (dd, J = 7.85, 1.81 Hz, 1H), 7.83 (d, J = 8.26, 1.81 Hz, 1H), 7.40 (app q, J = 8.26 Hz, 1H), 7.58 (d, J = 7.85 Hz, 1H), 7.13-7.06 (m, 2H), 6.74 (s, 1H), 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 calculated for C ₂₁ H ₁₇ ClF ₂ NO ₄ : 420.0809).

Step 2: 3- [3-Chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methylbenzoic acid (1.5 g , 3.57 mmol) was dissolved in THF (30 ml). 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.75 g, 4.28 mmol) and N-methyl morpholine (1.18 ml, 10.72 mmol) were added. The mixture was stirred at rt for 1 h. At this time, NH ₄ OH (7.5 ml) was added, and the reaction was stirred at room temperature for 1 hour or more. Additional THF (100 ml) and water (150 ml) were added to the reaction mixture. The mixture was extracted with ethyl acetate. The ethyl acetate extracts were washed with saturated brine solution. The brine layer was extracted with ethyl acetate. The organic layers were combined, dried over Na ₂ SO ₄ , filtered and the solvent removed in vacuo. The residue was taken up in ethyl acetate and the resulting precipitate was collected on a filter pad to give a white powder (1.32 g, 88%). ¹ H NMR (300 MHz, CD ₃ OD) δ 7.96 (dd, J = 7.85, 1.81 Hz, 1H), 7.71 (d, J = 1.81 Hz, 1H), 7.67 (app q, J = 8.06 Hz, 1H) , 7.56 (d, J = 8.06 Hz, 1H), 7.12-7.06 (m, 2H), 6.74 (s, 1H), 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 calculated for C ₂₁ H ₁₈ ClF ₂ N ₂ O ₃ : 419.0969).

Example 591

3- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N, 4-dimethylbenzamide

3- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methyl in dichloromethane (35 ml) The title compound was prepared from benzoic acid (from step 1 above) (1.5 g, 3.57 mmol). To this mixture is added 2.0M methyl amine in THF (3.6 ml, 7.14 mmol), followed by EDCI (0.67 g, 4.28 mmol), 1-hydroxybenzotriazole (0.58 g, 4.28 mmol) and triethylamine ( 0.99 ml, 7.14 mmol) was added sequentially. The reaction was stirred at rt overnight. The reaction was quenched with NH ₄ Cl and extracted three times with ethyl acetate. The combined organic layers were then washed with saturated NaHCO ₃ (aq) and extracted three times with ethyl acetate. The organic layers were combined, washed with H ₂ O and extracted three times with ethyl acetate. Organic layers were combined, dried over Na ₂ SO ₄ and evaporated. The resulting residue was triturated with diethyl ether / hexanes to give a solid, which was dried under vacuum to give a white solid (1.5 g, 72%). ¹ H NMR (300 MHz, CD ₃ OD) δ 7.90 (dd, J = 8.06, 1.81 Hz, 1H), 7.67 (app q, J = 6.44 Hz, 1H), 7.55 (d, J = 8.06 Hz, 1H) , 7.13-7.06 (m, 2H), 6.74 (s, 1H), 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 calculated for C ₂₂ H ₂₀ ClF ₂ N ₂ O ₃ : 433.1125).

Example 592

N- {3- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-fluorobenzyl} propane amides

1- [5- (aminomethyl) -2-fluorophenyl] -3-chloro-4-[(2,4-difluorobenzyl) oxy] in a 10 ml round bottom flask equipped with a stir bar and nitrogen inlet -6-methylpyridin-2 (1H) -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 stirring at 25 ° C. for 5 minutes, the reaction was completed by LC-MS. The reaction mixture was poured into saturated aqueous NH ₄ Cl solution. The aqueous mixture was extracted with ethyl acetate. The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo to afford a yellow solid (240 mg, 91%). ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 8.3 (t, J = 5.8 Hz, 1H), 7.6 (q, J = 8.7 and 6.58 Hz, 1H), 7.38 (d, J = 7.78 Hz, 1H), 7.3 (dd, J = 2.6 and 7.6 Hz, 1H), 7.22 (d, J = 7.51 Hz, 1H), 7.12 (td, J = 2.0 and 6.5 Hz, 1H), 6.65 (s, 1H), 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 calculated for C ₂₃ H ₂₁ ClF ₃ N ₂ O ₃ : 465.1187).

Example 593

N- {3- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-fluorobenzyl} dimethyl Urea

1- [5- (aminomethyl) -2-fluorophenyl] -3-chloro-4-[(2,4-difluorobenzyl) oxy] in a 10 ml round bottom flask equipped with a stir bar and nitrogen inlet -6-methylpyridin-2 (1H) -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) was added. After stirring at 25 ° C. for 5 minutes, the reaction was completed by LC-MS. The reaction mixture was poured into saturated aqueous NH ₄ Cl solution. The aqueous mixture was extracted with ethyl acetate. The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo to afford the desired product as a white solid (245 mg, 86%). ¹ H NMR (400 MHz, (CD ₃ OD) δ 7.61 (q, J = 7.9 and 6.7 Hz, 1H), 7.4 (m, 1H), 7.3 (d, J = 9.3 Hz, 1H), 7.21 (m, 1H), 7.1 (m, 2H), 6.65 (s, 1H), 5.35 (s, 2H), 4.38 (s, 2H), 2.9 (s, 6H), 2.1 (s, 3H) ppm.ES-HRMS m / z 480.1269 (M + H calculated for C ₂₃ H ₂₂ ClF ₃ N ₃ O ₃ : 480.1296).

Example 594

N- {3- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-fluorobenzyl}- 2-hydroxyacetamide

1- [5- (aminomethyl) -2-fluorophenyl] -3-chloro-4-[(2,4-difluorobenzyl) oxy] in a 10 ml round bottom flask equipped with a stir bar and nitrogen inlet -6-methylpyridin-2 (1H) -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) was added. After stirring at 25 ° C. for 5 minutes, the reaction was completed by LC-MS. NaOH (2.5M, 2.24 mmol, 1.0 ml) and MeOH (2.0 ml) were added and stirred for 10 minutes to afford the title compound. The reaction mixture was acidified with concentrated HCl and extracted with ethyl. The organic phase was dried over Na ₂ S0 ₄ and concentrated in vacuo to afford the desired product as a yellow solid (217 mg, 78%). ¹ H NMR (400 MHz, (CD ₃ OD) δ 7.6 (q, J = 7.6 and 6.9 Hz, 1H), 7.44 (m, 1H), 7.34 (m, 2H), 7.22 (m, 2H), 6.63 ( s, 1H), 5.35 (s, 2H), 4.41 (s, 2H), 4.0 (s, 2H), 2.05 (s, 3H) ppm.ES-HRMS m / z 467.0957 (C ₂₂ H ₁₉ ClF ₃ N ₂ M + H calculated for O ₄ : 467.0980).

Example 595

N- {3- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-fluorobenzyl}- 2-hydroxy-2-methylpropanamide

The title compound was prepared essentially as described in Example 594 using 1-chlorocarbonyl-1-methylethyl acetate substituted acetoxyacetyl chloride. ¹ H NMR (400 MHz, (CDCl ₃ ) δ 9.9 (q, J = 8.2 and 6.5 Hz, 1H), 9.7 (t, J = 2.6 Hz, 1H), 9.5 (t, J = 8.9 Hz, 2H), 9.3 (m, 1H), 9.2 (m, 1H), 8.6 (s, 1H) 7.6 (s, 2H), 6.8 (d, J = 15 Hz, 1H), 6.63 (d, J = 15 Hz, 1H) , 4.42 (d, J = 3.2 Hz, 6H), 3.99 (s, 3H) ppm.ES-HRMS m / z 495.1271 (M + H calculated for C ₂₄ H ₂₃ ClF ₃ N ₂ O ₄ : 495.1293) .

Example 596

N ^1- {3- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-fluorobenzyl} Glycineamide Hydrochloride

In a 25 ml round bottom flask equipped with a stir bar and nitrogen inlet was placed boc-glycine (105 mg, 0.6 mmol) and 8 ml of DMF. The mixture was cooled to 0 ° C., isobutylchloroformate (77.5 μl, 0.6 mmol) was added and stirred for 20 minutes. 1- [5- (aminomethyl) -2-fluorophenyl] -3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one hydrochloride (250 mg, 0.6 mmol) was added and stirred for 3 hours. After the reaction was completed by LC-MS, boc groups were removed by addition of concentrated HCl (2 ml) and 2 ml of methanol. The reaction was stirred for 24 hours, neutralized with 2M NaOH and extracted with ethyl acetate. The organic phase was dried over Na ₂ S0 ₄ and concentrated in vacuo to afford the desired product as an HCl salt (196 mg, 66%). ¹ H NMR (400 MHz, (CD ₃ OD) δ 7.6 (q, J = 8 and 6.5 Hz, 1H), 7.5 (m, 1H), 7.3 (m, 2H), 7.0 (m, 2H), 6.63 ( s, 1H), 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 (C M + H calculated for ₂₂ H ₂₀ ClF ₃ N ₃ O ₃ 466.1140).

Example 597

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-fluorobenzamide

In a 250 ml round bottom flask equipped with a stir bar and nitrogen inlet, 3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridine-1 (2H ) -Yl] -4-fluorobenzoic acid (3.65 g, 7.8 mmol), 4-methylmorpholine (2.6 ml, 23.4 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (1.64 g, 9.36 mmol) and tetrahydrofuran (40 ml) were added. After the mixture was stirred at 25 ° C. for 30 minutes, NH ₄ OH (20.0 ml) was added. The mixture was stirred for 30 minutes and diluted with water. The product precipitated out of solution. The precipitate was filtered off and washed with water and diethyl ether to give the title compound as a white solid (2.37 g, 65%). ¹ H NMR (400 MHz, (CD ₃ ) ₂ SO) δ 7.9 (d, J = 7.3 Hz, 1H), 7.61 (q, J = 8.6 and 6.7 Hz, 1H), 7.5 (m, 2H), 7.3 ( t, J = 9.6 Hz, 1H), 7.15 (t, J = 8.7 Hz, 1H), 6.7 (s, 1H), 5.36 (s, 2H), 2 (s, 3H) ppm. ES-HRMS m / z 469.0172 (M + H calculated for C ₂₀ H ₁₅ BrF ₃ N ₂ O ₃ : 469.0195).

Example 598

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-fluoro-N-methylbenz amides

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridine-1 (2H)-in N, N-dimethylformamide (20 ml) A solution of il] -4-fluorobenzoic acid (1 g, 2.1 mmol) 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 20 min stirring at -10 ° C, a solution of N-methyl amine (2.1 ml, 4.2 mmol, 2M in THF) was added and the reaction mixture was stirred for 18 h to warm to room temperature. The reaction mixture was concentrated in vacuo, suspended in water, filtered and washed with water, ethyl acetate and diethyl ether. ¹ H NMR (400 MHz, CD ₃ OD) δ 8.03 (dddd, J = 3.0, 6.4, 9.2 and 11.6 Hz, 1H), 7.81 (dd, J = 3.0 and (.2 Hz, 1H), 7.66 (q, J = 10.4 Hz, 1H), 7.47 (t, J = 12 Hz, 1H), 7.06 (t, J = 12 Hz, 2H), 6.67 (s, 1H), 5.38 (s, 2H), 2.91 (s, 3H), 2.10 (s, 3H) ppm; ¹⁹ F NMR (400 MHz, CD ₃ OD) δ-111.50 (1F), -115.97 (1F), -120.16 ppm.ES-HRMS m / z 481.0346 (C ₂₁ H M + H calculated for ₁₇ BrF ₃ N ₂ O ₃ : 481.0369).

Example 599

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-fluoro-N, N- Dimethylbenzamide

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridine-1 (2H)-in N, N-dimethylformamide (20 ml) A solution of il] -4-fluorobenzoic acid (1 g, 2.1 mmol) 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 20 min stirring at -10 ° C, a solution of N-methyl amine (2.1 ml, 4.2 mmol, 2M in THF) was added and the reaction mixture was stirred for 18 h to warm to room temperature. 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 afford the desired product as a white powder (0.31 g, 30%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.64 (m, 1H), 7.50 (dd, J = 2.4 and 7.2 Hz, 1H), 7.45 (t, J = 9.6 Hz, 1H), 7.04 (t, J = 9.2 Hz, 2H), 6.65 (s, 1H), 5.36 (s, 2H), 3.09 (s, 3H), 3.05 (s, 3H), 2.10 (s, 3H) ppm; ¹⁹ F NMR (400 MHz, CD ₃ OD) δ-111.51 (1F), -115.88 (1F), -121.90 (1F) ppm. ES-HRMS m / z 495.0508 (M + H calculated for C ₂₂ H ₁₉ BrF ₃ N ₂ O ₃ : 495.0526).

Example 600

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- {2-fluoro-5-[(4-methylpiperazin-1-yl) carbonyl] phenyl} -6 -Methylpyridin-2 (1H) -one

Step 1: 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- {2-fluoro-5-[(4-methylpiperazin-1-yl) carbonyl] phenyl } -6-Methylpyridin-2 (1H) -one

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl]-in a reaction vessel (borosilicate culture tube)- 4-fluorobenzoic acid (0.300 g, 0.623 mmol) and 1-hydroxybenzotriazole (0.042 g, 0.45 mmol) were added. N, N-dimethylformamide (3 ml) was added to the reaction vessel followed by approximately 1.1 g of polymer-bonded carbodiimide resin (1.38 mmol / g). Then additional N, N-dimethylformamide (2 ml) was added to the reaction vessel. The parallel reactor was then shaken at approximately 200 RPM for 15 minutes at room temperature (Labline Benchtop Orbital Shaker). N-methyl amine (1 ml, 2 mmol) was then added to the reaction vessel and the reaction apparatus was rotated 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 2.5 g of methylisocyanate functionalized polystyrene (1.5 mmol / g) and room temperature Rotation was continued shaking at 200 RPM for 3 hours. The reaction vessel was then opened and the solution phase product was separated from the insoluble quenched by-product by filtration and collected in vials. After partial evaporation, the insoluble byproducts were washed with tetrahydrofuran (2 × 10 ml). The filtrate was evaporated by blowing N ₂ over the vial and the resulting solid was triturated with diethyl ether to give an off-white solid (0.14 g, 41%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.63 (m, 1H), 7.51 (dd, J = 2.2 and 7.2 Hz, 1H), 7.45 (t, J = 8.4 Hz, 1H), 7.03 (m, 2H ), 6.65 (s, 1H), 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, CD ₃ OD) δ-111.31 (1F), -115.72 (1F), -121.41 (1F) ppm. ES-HRMS m / z 550.0946 (M + H calculated for C ₂₅ H ₂₄ ClF ₃ N ₃ O ₃ : 550.0948).

Example 601-603

The compound of Examples 601-603 was prepared according to the method of Example 600 and using an appropriate amine instead of N-methylamine.

Compound number R ₁ R ₂ % Yield MF M + H requirement ES-HRMS m / z Example 601 CH ₂ CH ₂ O- CH ₂ CH _2- 98 C ₂₄ H ₂₁ BrF ₃ N ₂ O ₄ 537.0631 537.0620 Example 602 CH ₃ CH ₂ CH ₂ OH 43 C ₂₃ H ₂₁ BrF ₃ N ₂ O ₄ 525.0631 525.0618 Example 603 H CH ₂ C (CH ₃ ) ₂ OH 65 C ₂₄ H ₂₃ BrF ₃ N ₂ O ₄ 539.0783 539.0788

Example 604

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

3-fluoro-4-aminobenzoic acid is described by Schmelkes, F.C; Rubin, M.J. Am. Chem. Soc 1944, 66, 1631-2).

Step 2: Preparation of Methyl 4-amino-3-fluorobenzoate

4-amino-3-fluorobenzoic acid (11.8 g, 76 mol) and methanol (100 ml) were placed in a 250 ml three-necked round bottom flask equipped with a nitrogen inlet, stir bar, addition funnel and thermoelectric. The system was cooled to 0 ° C. and acetyl chloride (7.6 ml, 107 mol) was added dropwise. The system was warmed to room temperature, the addition funnel was replaced with a reflux condenser and heated to reflux for 6 hours. The reaction mixture was cooled to rt, quenched with saturated aqueous NaHCO ₃ and extracted with ethyl acetate. The organic extract was washed with brine and concentrated in vacuo to afford methyl 4-amino-3-fluorobenzoate as a tan solid (8.2 g, 64%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.56 (dd, J = 1.6 and 8.0 Hz, 1H), 7.52 (dd, J = 1.9 and 12 Hz, 1H), 6.76 (t, J = 8.4 Hz, 1H ), 3.81 (s, 3 H) ppm; ¹⁹ F NMR (400 MHz, CD ₃ OD) δ-139.05 (1F) ppm. ES-HRMS m / z 170.0565 (M + H calculated for C ₈ H ₉ FNO ₂ : 170.0612).

Step 3: Preparation of Methyl 3-fluoro-4- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) benzoate

In a 250 ml round bottom flask equipped with a stir bar, Dean-Stark trap and reflux condenser, 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-pyrrolidone (8 ml) were added. The system was soaked in a 150 ° C. oil bath for 2 hours and then cooled to room temperature. The reaction mixture was washed with aqueous K ₂ CO ₃ (8.5 g, 200 ml water). The aqueous layer was washed with ethyl acetate and then acidified to pH 4-5 with glacial acetic acid. It was extracted with ethyl acetate and then concentrated in vacuo. The viscous oil was triturated with acetonitrile and filtered to give the title compound as a tan solid (2.3 g, 17%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.98 (dd, J = 1.8 and 8.0 Hz, 1H), 7.91 (dd, J = 1.7 and 10 Hz, 1H), 7.46 (t, J = 8 Hz, 1H ), 6.09 (dd, J = 0.9 and 2.4 Hz, 1H), 5.77 (d, J = 2.7 Hz, 1H), 3.94 (s, 3H), 1.97 (s, 3H) ppm; ¹⁹ F NMR (400 MHz, CD ₃ OD) δ-123.00 (1F) ppm. ES-HRMS m / z 278.0781 (M + H calculated for C ₁₄ H ₁₃ FNO ₄ : 278.0823).

Step 4: Preparation of methyl 4- [4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3-fluorobenzoate

In a 100 ml round bottom flask equipped with a stir bar and nitrogen inlet was placed the product of step 4 (2.3 g, 8.3 mmol) and N, N-dimethyl formamide (20 ml). 1,8-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 stirred at 60 ° C. for 3 h, poured into saturated aqueous NaHCO ₃ and extracted 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%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.99 (dd, J = 1.7 and 8.4 Hz, 1H), 7.93 (dd, J = 1.8 and 10.4 Hz, 1H), 7.55 (m, 1H), 7.48 (t , J = 6.8 Hz, 1H), 7.02 (m, 2H), 6.18 (dd, J = 1.3 and 2.76 Hz, 1H), 6.02 (d, J = 2.7 Hz, 1H), 5.14 (s, 2H), 3.94 (s, 3H), 1.98 (s, 3H) ppm; ¹⁹ F NMR (400 MHz, CD ₃ OD) δ-111.34 (1F), -115.97 (1F), -122.98 (1F) ppm. ES-HRMS m / z 404.1133 (M + H calculated for C ₂₁ H ₁₇ F ₃ NO ₄ : 404.1104).

Step 5: Methyl 4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3-fluorobenzo Manufacture of Eight

In a 100 ml round bottom flask equipped with a stir bar and nitrogen inlet was placed the product of step 4 (2.15 g, 5.3 mmol) and N-methyl-2-pyrrolidone (15 ml). After cooling to 0 ° C., a solution of N-bromo succinimide (1.03 g, 5.8 mmol) in 10 ml of N-methyl-2-pyrrolidone was added over 15 minutes. After an additional 15 minutes, the reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was then poured into saturated aqueous NaHCO ₃ 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%). ¹ H NMR (400 MHz, CD ₃ OD) δ 8.00 (dd, J = 2.0 and 8.4 Hz, 1H), 7.95 (dd, J = 1.7 and 10 Hz, 1H), 7.64 (q, J = 8.8 and 14.4 Hz , 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.04 (t, J = 8.4 Hz, 2H), 6.66 (s, 1H), 5.36 (s, 2H), 3.95 (s, 3H), 2.01 (s, 3H) ppm; ¹⁹ F NMR (400 MHz, CD ₃ OD) δ-111. 50 (1F), -115.97 (1F), -123.01 (1F) ppm. ES-HRMS m / z 484.0169 (M + H calculated for C ₂₁ H ₁₆ BrF ₃ NO ₄ : 484.0192).

Example 605

4-{[3-Chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzoic acid

Preparation of 4-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzoic acid

Methyl-4-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (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 h. The reaction was partially concentrated and the hybrid mixture was acidified with 1N HCl (pH 2). The precipitate was collected by filtration and washed with H ₂ O and diethyl ether to give a white solid (29.2 g, 99%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.88 (d, J = 8.3 Hz, 2H), 7.63 (app q, J = 7.9 Hz, 1H), 7.31 (dt, J = 2.4, 9.9 Hz, 1H ), 7.18 (app d, J = 8.3 Hz, 2H), 7.17-7.12 (m, 1H), 6.60 (s, 1H), 5.35 (s, 2H), 5.27 (s, 2H), 2.28 (s, 3H ). ES-HRMS m / z 420.0821 (M + H calculated for C ₂₁ H ₁₇ ClF ₂ NO ₄ : 420.0809).

Example 606

4-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (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-1 (2H) -yl] methyl} benzoic acid (12.0 g, 28.58 mmol) Was suspended in tetrahydrofuran (100 ml). 2-chloro-4,6-dimethoxy-1,3,5-triazine (6.02 g, 34.3 mmol) was added followed by 4-methylmorpholine (9.43 ml, 85.74 mmol). The resulting mixture was stirred at rt for 1.5 h, at which time NH ₄ OH (50.0 ml) was added. The resulting mixture was stirred at rt for 1 h and then partially concentrated. The precipitate was collected by filtration and washed with H ₂ O and diethyl ether to give an off-white solid (12.11 g,> 100%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.91 (br s, 1 H), 7.80 (d, J = 8.3 Hz, 2H), 7.63 (app q, J = 7.9 Hz, 1H), 7.31 (dt, J = 2.6, 10.5 Hz, 1H), 7.17-7.12 (m, 1H), 7.13 (app d, J = 8.3 Hz, 2H), 6.59 (s, 1H), 5.32 (s, 2H), 5.27 (s, 2H), 2.28 (s, 3H). ES-HRMS m / z 419.0968 (M + H calculated for C ₂₁ H ₁₈ ClF ₂ N ₂ O ₃ : 419.0969).

Example 607

4-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N, N-dimethylbenzamide

4-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N, N-dimethylbenzamide Manufacture

4-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (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 (1.57 ml, 14.28 mmol) and dimethylamine (7.14 ml, 2.0M in tetrahydrofuran, 14.28 mmol) 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (1.28 g, 6.66 mmol) was added. The resulting mixture was stirred at rt for 3 h, at which time the reaction was diluted with H ₂ O (75 ml). The reaction mixture was then extracted with ethyl acetate. The combined organic extracts were washed with saturated NaHCO ₃ and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The resulting solid was washed with ethyl acetate to give the title compound as a white solid (1.67 g, 78%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.53 (app q, J = 7.8 Hz, 1H), 7.33 (d, J = 8.3 Hz, 2H), 7.16 (d, J = 8.3 Hz, 2H), 6.95- 6.90 (m, 1H), 6.84 (app dt, J = 2.5, 9.4 Hz, 1H), 6.02 (s, 1H), 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 calculated for C ₂₃ H ₂₂ ClF ₂ N ₂ O ₃ : 447.1282).

Example 608

4-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N- (2-hydroxy -2-methylpropyl) benzamide

4-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N- (2-hydroxy Preparation of 2-methylpropyl) benzamide

4-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzoic acid (2.00 g, 4.76 mmol) Was suspended in N, N-dimethylformamide (10 ml). After addition of 1-hydroxybenzotriazole (0.772 g, 5.71 mmol), 4-methylmorpholine (1.57 ml, 14.28 mmol) and 1-amino-2-methyl-2-propanol hydrochloride (1.49 g, 11.90 mmol) followed by 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (1.28 g, 6.66 mmol). The resulting mixture was stirred at rt for 2 days, at which time the reaction was diluted with H ₂ O (50 ml). The reaction mixture was then extracted with ethyl acetate. The combined organic extracts were washed with saturated NaHCO ₃ and brine, dried over Na ₂ SO ₄ , filtered and concentrated. The resulting solid was washed with diethyl ether to give the title compound as a tan solid (2.08 g, 89%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.72 (d, J = 8.2 Hz, 2H), 7.51 (app q, J = 7.7 Hz, 1H), 7.25-7.21 (m, 1H), 7.10 (d, J = 8.2 Hz, 2H), 6.93 (app dt, J = 1.6, 8.3, 9.4 Hz, 1H), 6.87-6.82 (m, 1H), 6.01 (s, 1H), 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 calculated for C ₂₅ H ₂₆ ClF ₂ N ₂ O ₄ : 491.1544).

Example 609

N- {4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzyl} -2-hydroxy Acetamide.

Step 1: Preparation of 1- [4- (aminomethyl) phenyl] -3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one

The compound of 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 tetrahydrofuran, 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 addition of 6.0N HCl (5.0 ml) and then washed with ethyl acetate. The aqueous layer was made alkaline with 2.5N NaOH and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give an off white solid (0.180 g, 74%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.58 (app q, J = 7.8 Hz, 1H), 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, 1H), 6.88-6.83 (m, 1H), 6.06 (s, 1H), 5.24 (s, 2H), 3.93 (s, 2H), 1.96 (s, 3H) .

Step 2: 2-((4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzyl} amino Preparation of 2-oxoethyl

Acetoxyacetic acid (0.037 g, 0.310 mmol) was dissolved in dichloromethane (2.0 ml). 3- (1-cyclohexylcarbodiimide) propyl-functionalized silica gel (1.00 g, 0.620 mmol, loading rate = 0.64 mmol / g) after addition of 1-hydroxybenzotriazole (0.021 g, 0.155 mmol) ) Was added. After 15 min stirring at room temperature, 1- [4- (aminomethyl) phenyl] -3-bromo-4-[(2,4-difluorobenzyl) oxy] -6 in dichloromethane (2.0 ml) -Methylpyridin-2 (1H) -one (step 1) (0.180 g, 0.310 mmol) was added. The resulting mixture was stirred at rt overnight, at which time the reaction mixture was filtered and concentrated. This was chromatographed (silica gel, hexane / ethyl acetate with 10% methanol) to give a white solid (0.130 g, 78%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.58 (app q, J = 7.8 Hz, 1H), 7.33 (d, J = 8.3 Hz, 2H), 7.05 (app d, J = 8.3 Hz, 2H), 6.97 -6.92 (m, 1H), 6.88-6.83 (m, 1H), 6.08 (s, 1H), 5.24 (s, 2H), 4.58 (s, 2H), 4.44 (d, J = 6.0 Hz, 2H), 2.13 (s, 3 H), 1.95 (s, 3 H).

Step 3: N- {4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzyl} -2 Preparation of Hydroxyacetamide

2-({4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzyl} amino) -2 Oxoethyl (step 2) (0.130 g, 0.243 mmol) was dissolved in methanol (5 ml) and H ₂ O (1 ml). K ₂ CO ₃ (0.055 g, 0.398 mmol) was added and the resulting mixture was stirred at rt for 2 h. The mixture was then concentrated and the residue was partitioned between H ₂ O and ethyl acetate. The organic layer was removed and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give an off white solid (0.100 g, 84%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56 (app q, J = 7.7 Hz, 1H), 7.43 (t, J = 5.8 Hz, 1H), 7.33 (d, J = 8.2 Hz, 2H), 7.04 ( app d, J = 8.3 Hz, 2H), 6.98-6.93 (m, 1H), 6.88-6.83 (m, 1H), 6.11 (s, 1H), 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 ( C 22 H 2O BrF 2 N 2 O 4 calculated M + H for the required value: 493.0569).

Example 610

3- [3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzamide

The compound of Example 291 (2.00 g, 4.93 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (1.04 g, 5.91 mmol) were suspended in tetrahydrofuran (20 ml). . 4-methylmorpholine (1.6 ml, 14.79 mmol) was added. The resulting mixture was stirred at rt for 1.5 h. NH ₄ OH (10 ml, 148.00 mmol) was added and the reaction stirred at rt for 0.5 h. H ₂ O (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 Na ₂ CO ₃ (50 ml), 1N HCl (50 ml) and brine (50 ml). The organic phase was dried over Na ₂ S0 ₄ and evaporated. The resulting solid was washed with diethyl ether to give a white solid (1.96 g, 98%). ¹ H NMR (400 MHz, DMF-d ₆ ) δ 8.24 (br s, 1H), 8.10 (dt, J = 1.21, 7.79 Hz, 1H), 7.90 (t, J = 1.88 Hz, 1H), 7.79 (app dt, J = 6.58, 8.59 Hz, 1H), 7.66 (t, J = 7.79 Hz, 1H), 7.57-7.55 (m, 1H), 7.46 (br s, 1H), 7.33 (ddd, J = 2.55, 9.26 , 11.82 Hz, 1H), 7.24-7.19 (m, 1H), 6.78 (s, 1H), 5.44 (s, 2H), 2.04 (s, 3H). ES-HRMS m / z 405.0835 (M + H calculated for C ₂₀ H ₁₆ BrF ₂ N ₂ O ₃ : 405.0812).

Example 611

1- (4-aminobenzyl) -3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one

Step 1: 1-tert-butyl-4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] Preparation of Methyl} phenylcarbamate

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 h. The reaction mixture was cooled to rt, concentrated and chromatographed (silica, ethyl acetate with 10% methanol / hexanes) to give 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-1 (2H) -yl] Methyl} phenylcarbamate (step 1) (6.14 g, 11.47 mmol) was suspended in 4N HCl (5.74 ml, 22.94 mmol) in dioxane. The reaction mixture was stirred at rt for 1 h and then diluted with diethyl ether. The precipitate was collected by filtration and washed with diethyl ether (3 × 30 ml) to give a tan solid (3.45 g, 69%). ¹ H NMR (400 MHz, DMF-d ₆ ) δ 7.64 (app dt, J = 6.58, 8.59 Hz, 1H), 7.31 (ddd, J = 2.55, 9.53, 10.61 Hz, 1H) 7.29-7.12 (m, 5H ), 6.56 (s, 1H), 5.28 (s, 2H), 5.27 (s, 2H), 2.28 (s, 3H). ES-HRMS m / z 435.0516 (M + H calculated for C ₂₀ H ₁₈ BrF ₂ N ₂ O ₂ : 435.0514).

Example 612

1- (3-aminobenzyl) -3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one

Following the method of Example 611, 3-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl } Title using 4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) yl] methyl} benzoic acid instead of benzoic acid Compound was prepared (2.65 g, 67%). ¹ H NMR (400 MHz, DMF-d ₆ ) δ 7.64 (app dt, J = 6.58, 8.59 Hz, 1H), 7.39 (t, J = 7.79 Hz, 1H), 7.32 (ddd, J = 2.55, 9.53, 10.61 Hz, 1H), 7.18-7.08 (m, 3H), 6.96 (s, 1H), 6.58 (s, 1H), 5.30 (s, 2H), 5.27 (s, 2H), 2.29 (s, 3H). ES-HRMS m / z 435.0513 (M + H calculated for C ₂₀ H ₁₈ BrF ₂ N ₂ O ₂ : 435.0514).

Example 613

N- (4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} phenyl) acetamide

To the reaction vessel (borosilicate culture tube) was added the compound of Example 611 (0.300 g, 0.689 mmol) and dichloromethane (3.0 ml). After addition of the stock solution of N-methylmorpholine (0.30M, 3.0 ml), the parallel reaction apparatus was shaken at approximately 200 RPM for 10 minutes at room temperature (Lapline benchtop orbital shaker). Acetyl chloride (0.074 ml, 1.033 mmol) was then added to the reaction vessel, and the reaction apparatus was rotary 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 at room temperature Rotational shaking continued at 200 RPM overnight. The reaction vessel was then opened and the solution phase product was separated from the insoluble quenched by-product by filtration and collected in vials. After partial evaporation, the insoluble byproducts were washed with dichloromethane (2 × 10 ml). The filtrate was evaporated by blowing N ₂ over the vial to give a white solid (0.135 g, 41%). ¹ H NMR (400 MHz, DMF-d ₆ ) δ 7.75 (app dt, J = 6.58, 8.59 Hz, 1H), 7.63 (d, J = 8.59 Hz, 1H), 7.30 (ddd, J = 2.55, 9.53, 10.61 Hz, 1H), 7.22-7.14 (m, 3H), 6.60 (s, 1H), 5.37 (s, 4H), 2.40 (s, 3H), 2.06 (s, 3H). ES-HRMS m / z 477.0600 (M + H calculated for C ₂₂ H ₂₁ BrF ₂ N ₂ O ₃ : 477.0620).

Example 614-616 Preparation of Compound

Following the method of Example 613, the compounds of Examples 614-616 were prepared using the appropriate acid chloride or sulfamoyl chloride instead of acetyl chloride. The protected intermediate was deprotected with 1M K ₂ CO ₃ in methanol to afford the title compound.

Compound number R % Yield MF M + H requirement ES-HRMS m / z Example 614 CH ₂ OH 65 C ₂₂ H ₂₀ BrF ₂ N ₂ O ₄ 493.0569 493.0593 Example 615 CH ₂ OCOCH ₃ 43 C ₂₄ H ₂₂ BrF ₂ N ₂ O ₅ 535.0675 535.0702 Example 616 SO ₂ N (CH ₃ ) ₂ 43 C ₂₂ H ₂₃ BrF ₂ N ₃ O ₄ S 542.0555 542.0572

Example 617

N- (3-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} phenyl) acetamide

To the reaction vessel (borosilicate culture tube) was added the compound of Example 612 (0.300 g, 0.689 mmol) and dichloromethane (3.0 ml). A stock solution of N-methylmorpholine (0.30M, 3.0 ml) was added and the parallel reaction apparatus was shaken at approximately 200 RPM for 10 minutes at room temperature (Lapline benchtop orbital shaker). Acetyl chloride (0.074 ml, 1.033 mmol) was then added to the reaction vessel, and the reaction apparatus was rotary 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 at room temperature Rotational shaking continued at 200 RPM overnight. The reaction vessel was then opened and the solution phase product was separated from the insoluble quenched by-product by filtration and collected in vials. After partial evaporation, the insoluble byproduct was diluted with dichloromethane (2 × 10 ml). The filtrate was evaporated by blowing N ₂ over the vial to give a white solid (0.167 g, 51%). ¹ H NMR (400 MHz, DMF-d ₆ ) δ 7.77 (app dt, J = 6.58, 8.59 Hz, 1H), 7.69 (d, J = 8.32 Hz, 1H), 7.41 (br s, 1H), 7.34- 7.17 (m, 3H), 6.88 (d, J = 7.65 Hz, 1H), 6.63 (s, 1H), 5.39 (s, 3H), 5.38 (s, 2H), 2.40 (s, 3H), 2.06 (s , 3H). ES-HRMS m / z 477.0620 (M + H calculated for C ₂₂ H ₂₁ BrF ₂ N ₂ O ₃ : 477.0620).

Example 618-620 Preparation of Compound

Following the method of Example 617, the compounds of Examples 618-620 were prepared using the appropriate acid chloride or sulfamoyl chloride instead of acetyl chloride. The protected intermediate was deprotected with 1M K ₂ CO ₃ in methanol to afford the title compound.

Compound number R % Yield MF M + H requirement ES-HRMS m / z Example 618 CH ₂ OH 72 C ₂₂ H ₂₀ BrF ₂ N ₂ O ₄ 493.0569 493.0604 Example 619 CH ₂ OCOCH ₃ 53 C ₂₄ H ₂₂ BrF ₂ N ₂ O ₅ 535.0675 535.0692 Example 620 SO ₂ N (CH ₃ ) ₂ 21 C ₂₂ H ₂₃ BrF ₂ N ₃ O ₄ S 542.0555 542.0567

Example 621

N- (4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzyl) -N '-Methylurea

(4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzyl) -N'- Preparation of Methylurea

The compound of Example 159 (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 stirred 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 room temperature and stirred for 1 hour. 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 at room temperature for 16 hours, filtered and the resulting filtrate was concentrated to give an oil which was triturated with ether. The resulting white solid was collected, washed with ether and dried (87 mg, 52%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.61 (app q, J = 8.4 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 7.02 (app t, J = 8.4 Hz, 2H), 6.47 (s, 1H), 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 calculated for C ₂₃ H ₂₃ BrF ₂ N ₃ O ₃ : 506.0885).

Example 622

N- (4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzyl) -N '-(2-hydroxy-2-methylpropyl) urea

N- (4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzyl) -N Preparation of '-(2-hydroxy-2-methylpropyl) urea

The compound of Example 159 (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 stirred 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 room temperature and stirred for 3 hours. 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 at room temperature for 16 hours, filtered and the resulting filtrate was concentrated to give an oil which was triturated with ether. The resulting white solid was purified by chromatography (silica gel, hexanes / ethyl acetate / methanol) followed by reverse phase chromatography (C ₁₈ , 0.1% aqueous trifluoroacetic acid / acetonitrile) to give an off-white solid (43 mg, 11%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56 (app q, J = 8.0 Hz, 1H), 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, 1H), 6.06 (s, 1H), 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 calculated for C ₂₆ H ₂₉ BrF ₂ N ₃ O ₄ : 564.1304).

Example 623

N- (4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzyl) piperi Dean-1-carboxamide

Following the general method for example 622, the title compound is prepared using 3-amino-2methyl-2-propanol instead of piperidine (170 mg, 2.0 mmol) and chromatographed (silica gel, hexane / ethyl acetate / Methanol) to give an oil, which was triturated with ether to give a white solid (107 mg, 28%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56 (app q, J = 8.0 Hz, 1H), 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, 1H), 5.97 (s, 1H), 5.32 (s, 2H), 5.19 (s, 2H), 4.37 (s, 2H), 3.34- 3.28 (m, 4 H), 2.29 (s, 3 H), 1.68-1.50 (m, 6 H). ES-HRMS m / z 560.1365 (M + H calculated for C ₂₇ H ₂₉ BrF ₂ N ₃ O ₃ : 560.1355).

Example 624

N- (4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzyl) morpholine -4-carboxamide

Following the general method for example 622, the title compound was prepared using 3-amino-2-methyl-2-propanol instead of morpholine (175 mg, 2.0 mmol) and chromatographed (silica gel, hexane / ethyl acetate / Methanol) followed by reverse phase chromatography (C ₁₈ , 0.1% aqueous trifluoroacetic acid / acetonitrile) yielded an off-white solid (51 mg, 13%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.55 (app q, J = 8.0 Hz, 1H), 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, 1H), 6.02 (s, 1H), 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 calculated for C ₂₆ H ₂₇ BrF ₂ N ₃ O ₄ : 562.1148).

Example 625

N- (4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzyl) piperazine -1-carboxamide hydrochloride

Following the general method for example 622, using 3-amino-2-methyl-2-propanol instead of 1-Boc-piperazine (372 mg, 2.0 mmol) gave the title compound its Nt-butoxycarbonyl protected Prepared from the intermediate, which was purified by chromatography (silica gel, hexane / ethyl acetate / methanol). This was deprotected with 4N HCl in dioxane to give the title compound as its hydrochloride salt (78 mg, 19%). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.61 (app q, J = 7.6 Hz, 1H), 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, 1H), 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 calculated for C ₂₆ H ₂₈ BrF ₂ N ₄ O ₃ : 561.1307).

Example 626

N- (4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzyl) -N '-(2-hydroxyethyl) urea

Following the general method for example 622, the title compound is prepared using 3-amino-2-methyl-2-propanol instead of ethanolamine (121 mg, 2.0 mmol), which is chromatographed (silica gel, hexane / ethyl) Purification by acetate / methanol) gave an off-white solid (130 mg, 36%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.54 (app q, J = 7.6 Hz, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.0 Hz, 2H), 6.96- 6.92 (m, 1H), 6.83-6.88 (m, 1H), 6.09 (s, 1H), 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 calculated for C ₂₄ H ₂₅ BrF ₂ N ₃ O ₄ : 536.0991).

Example 627

N '-(4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzyl)- N, N-dimethylurea

Following the general method for example 622, the title compound is prepared using 3-amino-2-methyl-2-propanol instead of N, N-dimethylamine (1.0 ml, 2.0 mmol, 2M in tetrahydrofuran), It was purified by chromatography (silica gel, hexane / ethyl acetate / methanol) to give an oil, which was triturated with ether to give a white solid (65 mg, 19%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56 (app q, J = 8.0 Hz, 1H), 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, 1H), 6.87-6.81 (m, 1H), 5.97 (s, 1H), 5.31 (s, 2H), 5.19 (s, 2H), 4.36 (s, 2H), 2.89 (s, 6 H), 2.28 (s, 3 H). ES-HRMS m / z 520.1072 (M + H calculated for C ₂₄ H ₂₅ BrF ₂ N ₃ O ₃ : 520.1042).

Example 628

N- (4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzyl) -4 Hydroxypiperidine-1-carboxamide

Following the general method for example 622, the title compound was prepared using 3-amino-2-methyl-2-propanol instead of 4-hydroxypiperidine (202 mg, 2.0 mmol) and chromatographed (silica gel , Hexane / ethyl acetate / methanol) to give an oil, which was triturated with ether to give a white solid (41 mg, 11%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56 (app q, J = 8.0 Hz, 1H), 7.20 (d, J = 7.6 Hz, 2H), 7.06 (d, J = 8.0 Hz, 2H), 6.94 ( app t, J = 8.0 Hz, 1H), 6.84 (app t, J = 8.0 Hz, 1H), 5.99 (s, 1H), 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 calculated for C ₂₇ H ₂₉ BrF ₂ N ₃ O ₄ : 576.1304).

Example 629

4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N, N-dimethylbenzene Sulfonamide

Step 1: Preparation of 4-bromomethyl-N, N-dimethylbenzenesulfonamide

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 tetrahydrofuran) and N, N-diisopropylethylamine (3.5 ml, 20.1 mmol) were added and the reaction was allowed to stir at room temperature for 2 hours. . The reaction was concentrated to give an oil, which was partitioned between water and ethyl acetate and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over Na ₂ S0 ₄ and filtered. The resulting filtrate was concentrated to give an oil, which precipitated into a needle which was a mixture of the title compound and 4-chloromethyl N, N-dimethylbenzenesulfonamide. The resulting needle was collected and dried (2.3 g, 44%). ES-MS m / z 534 (M + H) and 578 (M + H).

Step 2: 4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N, N Preparation of -dimethylbenzenesulfonamide

3-bromo-4- (2,4-difluorophenoxy) -6-methylpyridin-2 (1H) -one (300 mg, 0.91 mmol) is suspended in 1,4-dioxane (50 ml). I was. 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 inorganic oil). It was. The reaction was heated to 80 ° C., stirred for 16 h, then additional sodium hydride (45 mg, 1.09 mmol, 60% in inorganic oil) and sodium iodide (150 mg, 1.0 mmol) were added. The reaction was allowed to stir at 80 ° C. for 4 more hours. The reaction was then filtered through Celite® and the filtrate was concentrated to give an oil, which was followed by chromatography (silica gel, hexanes / ethyl acetate) followed by reverse phase chromatography (C ₁₈ , 0.1% aqueous trifluoro). Purification by roacetic acid / acetonitrile) gave an off-white solid (41 mg, 8%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.71 (d, J = 8.4 Hz, 2H), 7.57 (app q, J = 7.6 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 6.95 ( app dt, J = 2.0, 8.0 Hz, 1H), 6.88-6.83 (m, 1H), 6.05 (s, 1H), 5.42 (s, 2H), 5.22 (s, 2H), 2.69 (s, 6H), 2.29 (s, 3 H). ES-HRMS m / z 527.0439 (M + H calculated for C ₂₂ H ₂₂ Br ₂ F ₂ N ₂ O ₄ S: 527.0446).

Example 630

4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N- (2-hydrate Oxyethyl) benzenesulfonamide

Step 1: Preparation of 4-bromomethyl-N- (2-hydroxyethyl) benzenesulfonamide

4- (bromomethyl) benzenesulfonyl chloride (5.0 g, 18.6 mmol) was dissolved in tetrahydrofuran. Ethanolamine (1.1 ml, 18.6 mmol) and N, N-diisopropylethylamine (3.9 ml, 22.3 mmol) were added and the reaction was allowed to stir at room temperature for 30 minutes. The reaction was concentrated to give an oil, which was partitioned between water and ethyl acetate and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over Na ₂ S0 ₄ and filtered. The resulting filtrate was concentrated to give an oil which was a mixture of the title compound and 4-chloromethyl N- (2-hydroxyethyl) benzenesulfonamide. The resulting oil was dried under vacuum (3.7 g, 68%). ES-MS m / z 250 (M + H) and 294 (M + H).

Step 2: 4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N- ( Preparation of 2-hydroxyethyl) benzenesulfonamide

The title compound was prepared essentially according to the method described in step 2 of Example 629 using 4-bromomethyl-N- (2-hydroxyethyl) benzenesulfonamide (from step 1). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.81 (d, J = 8.4 Hz, 2H), 7.61 (app q ,, J = 7.6 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 6.95 (app t, J = 8.4 Hz, 2H), 6.53 (s, 1H), 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 calculated for C ₂₂ H ₂₂ Br ₂ F ₂ N ₂ O ₅ S: 543.0395).

Example 631

4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N- (2-hydrate Roxy-2-methylpropyl) benzenesulfonamide

Step 1: Preparation of 4-bromomethyl-N- (2-hydroxy-2-methylpropyl) benzenesulfonamide

4- (bromomethyl) benzenesulfonyl chloride (2.0 g, 7.3 mmol) was dissolved in tetrahydrofuran. 3-amino-2-methyl-2-propanol (1.0 g, 8 mmol) and N, N-diisopropylethylamine (1.5 ml, 8.8 mmol) were added and the reaction was allowed to stir at room temperature for 30 minutes. The reaction was concentrated to give an oil, which was partitioned between water and ethyl acetate and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over Na ₂ S0 ₄ and filtered. The resulting filtrate was concentrated to give an oil which was a mixture of the title compound and 4-chloromethyl-N- (2-hydroxy-2-methylpropyl) benzenesulfonamide. The resulting oil was dried under vacuum (1.9 g, 81%).

Step 2: 4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N- ( Preparation of 2-hydroxy-2-methylpropyl) benzenesulfonamide

The title compound was prepared essentially according to the method described in step 2 of Example 629, using 4-bromomethyl-N- (2-hydroxy-2-methylpropyl) benzenesulfonamide (from step 1). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.78 (d, J = 8.4 Hz, 2H), 7.56 (app q, J = 7.6 Hz, 1H), 7.26 (d, J = 8.4 Hz), 6.95 (app t , J = 8.4 Hz, 1H), 6.86-6.83 (m, 1H), 6.07 (s, 1H), 5.41 (s, 2H), 5.22 (s, 2H), 4.98 (t, J = 6.4 Hz, 1H) , 2.84 (d, J = 6.4 Hz, 2H), 2.29 (s, 3H), 1.21 (s, 6H). ES-HRMS m / z 571.0684 (M + H calculated for C ₂₄ H ₂₆ Br ₂ F ₂ N ₂ O ₅ S: 571.0708).

Example 632

3-chloro-4- (2,4-difluorobenzyloxy) -6-methyl-1- (1H-pyrazol-3-ylmethyl) -1H-pyridin-2-one

Step 1: Preparation of 4-hydroxy-6-methyl-1H-pyridin-2-one

4-hydroxy-6-methyl-pyran-2-one (25.8 g, 0.2 mol) was dissolved in 180 ml of concentrated ammonium hydroxide. The reaction was heated at reflux for 4 hours. The reaction was cooled to room temperature and evaporated on a rotary evaporator until it became 1/4 of its original volume. The resulting solid was filtered, washed with cold water and hexanes and dried overnight in a vacuum oven to give a white solid (25 g, 98%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.94 (br s, 1H), 10.34 (s, 1H), 5.59 (d, J = 1.4 Hz, 1H), 5.32 (d, J = 2.0 Hz, 1H ), 2.07 (s, 3 H).

Step 2: Preparation of 3-chloro-4-hydroxy-6-methyl-1H-pyridin-2-one

4-hydroxy-6-methyl-1H-pyridin-2-one (25 g, 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 rt and the solid was filtered off and washed with acetic acid and hexanes. The solid was dried overnight in a vacuum oven to give a white solid (19.2 g, 60%). ¹ H NMR (300 MHz, DMSO-d 6) δ 11.46 (br s, 1H), 11.04 (s, 1H), 5.79 (s, 1H), 2.09 (s, 3H).

Step 3: Preparation of 3-chloro-4- (2,4-difluorobenzyloxy) -6-methyl-1H-pyridin-2-one

3-Chloro-4-hydroxy-6-methyl-1H-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 heated at 80 ° C. for 6 hours. The reaction was cooled to rt and the solid was filtered off and washed with NMP and hexanes. The solid was dried overnight in a vacuum oven to give a white solid (4.4 g, 13%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.88 (br s, 1H), 7.63 (app q, J = 9 Hz, 1H), 7.33 (app t, J = 10 Hz, 1H), 7.16 (app t, J = 9 Hz, 1H), 6.37 (s, 1H), 5.24 (s, 2H), 2.20 (s, 3H).

Step 4: Preparation of 3-methylpyrazole-1-carboxylic acid tert-butyl ester

3-methyl-1H-pyrazole (5.3 g, 65 mmol), DMAP (0.79 g, 6.5 mmol) and di-tert-butyl dicarbonate (2.8 g, 13 mmol) were added to 1 ml in 90 ml of CH ₃ CN at room temperature. It was left for hours. The reaction was evaporated on a rotary evaporator and the resulting solid was dissolved in EtOAc, washed with 1N HCl, water and brine, dried (MgSO ₄ ), filtered and evaporated on a rotary evaporator to give a light yellow oil (11.4). g, 96%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.96 (d, J = 2.7 Hz, 1H), 6.17 (d, J = 2.7 Hz, 1H), 2.32 (s, 3H), 1.63 (s, 9H).

Step 5: Preparation of 3-bromomethylpyrazole-1-carboxylic acid tert-butyl ester

3-methylpyrazole-1-carboxylic acid tert-butyl ester (6.0 g, 33 mmol), N-bromosuccinimide (1.0 g, 5.6 mmol) and benzoyl peroxide (50 mg) were added to 20 ml of carbon tetrachloride. Dissolved. The reaction was heated at reflux for 16 h. The reaction was cooled to rt, 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%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.03 (d, J = 2.6 Hz, 1H), 6.47 (d, J = 2.6 Hz, 1H), 4.48 (s, 2H), 1.64 (s, 9H).

Step 6: 3- [3-chloro-4- (2,4-difluorobenzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] pyrazole-1-carboxylic acid tert Preparation of -Butyl Ester

3- [3-Chloro-4- (2,4-difluorobenzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] pyrazole-1-carboxylic acid tert-butyl ester Was prepared by a method analogous to that described in Example 401 to give a yellow solid (1.4 g, 39%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.53-7.49 (m, 2H), 6.97-6.81 (m, 2H), 6.35 (d, J = 2.0 Hz, 1H), 6.01 (s, 1H), 5.32 ( s, 2H), 5.26 (s, 2H), 2.52 (s, 3H), 1.62 (s, 9H).

Step 7: Example 632 Preparation of the title compound.

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 gave an off-white solid (1.0 g, 91%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.67 (br s, 1H), 7.67-7.60 (m, 2H), 7.34 (dt, J = 10.5, 2.5 Hz, 1H), 7.17 (dt, J = 8.5, 1.6 Hz, 1H), 6.52 (s, 1H), 6.10 (d, J = 1.9 Hz, 1H), 5.27 (s, 2H), 5.20 (s, 2H), 2.48 (s, 2H).

Example 633

3-chloro-4- (2,4-difluorobenzyloxy) -6-methyl-1- (2,3-dihydro-1H-indol-5-ylmethyl) -1H-pyridin-2-one

Step 1: 5- [3-Chloro-4- (2,4-difluorobenzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] indole-1-carbamic acid tert-butyl Preparation of ester

5- [3-Chloro-4- (2,4-difluorobenzyloxy) -2-oxo-2H-pyridin-1-ylmethyl] indole-1-car by methods analogous to those described in Example 632 Chest acid tert-butyl ester was prepared as an off-white solid (2.5 g, 61%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.00 (d, J = 8.5 Hz, 1H), 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, 1H), 6.66 (s, 1H), 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-1- (1H-indol-5-ylmethyl) -1H-pyridin-2-one

5- [3-chloro-4- (2,4-difluorobenzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] indole-1-carbamic acid dissolved in 40 ml of DMSO tert-butyl ester (1.08 g, 2.1 mmol) was stirred at 120 ° C. for 20 h. The reaction was cooled to rt, diluted with water and washed five times with ethyl acetate. The combined organics were washed once with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.1 (br s, 1H), 7.67 (d, J = 6.7 Hz, 1H), 7.36-7.32 (m, 2H), 7.23 (s, 1H), 7.18 (d, J = 2.3 Hz, 1H), 6.93 (dd, J = 8.4, 1.2 Hz, 1H), 6.57 (s, 1H), 6.38 (s, 1H), 5.37 (s, 2H), 5.29 (s, 2H), 2.35 (s, 3H).

Step 3: 3-chloro-4- (2,4-difluorobenzyloxy) -6-methyl-1- (1H-indol-5-ylmethyl) -1H-pyridin-2-one (from step 2) (1.7 g, 4.1 mmol) was stirred in 26 ml of acetic acid and NaCNBH ₃ (0.27 g, 4.3 mmol) was added in several portions. The reaction was stirred for 1 hour. The reaction was diluted with water and washed five times with ethyl acetate. The combined organics were washed once with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, 100% EtOAc) gave a white solid (1.2 g, 71%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.64 (app q, J = 8.5 Hz, 1H), 7.34 (dt, J = 9.5, 2.6 Hz, 1H), 7.17 (app t, J = 8.5, 1H ), 6.82 (s, 1H), 6.72 (d, J = 8.0 Hz, 1H), 6.53 (s, 1H), 6.42 (d, J = 8.0 Hz, 1H), 5.48 (br s, 1H), 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

5- [3-chloro-4- (2,4-difluorobenzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] -1, 3-dihydro-indole-2- On

Step 1: 5- [3-Chloro-4- (2,4-difluorobenzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] -3,3-dibromo- Preparation of 1H-indole-2-one

3-chloro-4- (2,4-difluorobenzyloxy) -6-methyl-1- (1H-indol-5-ylmethyl) -1H-pyridin-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 in several portions. The reaction was stirred for 16 hours. The reaction was diluted with water and washed four times with ethyl acetate. The combined organics were washed once with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Trituration with methylene chloride gave an off white solid (0.25 g, 39%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.26 (br s, 1H), 7.66 (app q, J = 8.6 Hz, 1H), 7.48 (s, 1H), 7.35 (dt, J = 10.5, 2.5 Hz, 1H), 7.18 (dt, J = 8.7, 1.9 Hz, 1H), 7.05 (dd, J = 8.2, 1.5 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.61 (s, 1H ), 5.29 (s, 4H), 2.36 (s, 3H).

Step 2: 5- [3-Chloro-4- (2,4-difluorobenzyloxy) -6-methyl-2-oxo-2H-pyridin-1-ylmethyl] -3,3-dibromo- 1H-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 stirred for 48 hours. The reaction was diluted with water and washed twice with ethyl acetate. The combined organics were washed once with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, 100% EtOAc) gave a white solid (0.12 g, 82%). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.37 (br s, 1H), 7.65 (app q, J = 6.9 Hz, 1H), 7.34 (dt, J = 8.2, 2.5 Hz, 1H), 7.18 ( dt, J = 7.1, 1.9 Hz, 1H), 6.98 (br s, 2H), 6.77 (d, J = 8.4 Hz, 1H), 6.57 (s, 1H), 5.28 (s, 2H), 5.23 (s, 2H), 3.44 (s, 2H), 2.34 (s, 3H).

Example 635

N-[(5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} pyrazine-2 -Yl) methyl] -N-methylmethanesulfonamide

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-({5-[(methylamino) methyl] pyrazin-2-yl} methyl) pyridine in acetonitrile To a suspension of -2 (1H) -one (0.16 g, 0.34 mmol) was added triethylamine (0.043 g, 0.42 mmol) at 0 ° C., followed by methane sulfonylchloride (0.047 g, 0.41 mmol), Stir under argon atmosphere for 1 hour at room temperature. The solvent was removed in vacuo and the residue was triturated with water and filtered. It was washed with water and acetonitrile and dried in vacuo to yield 0.11 g of material. ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.62 (s, 1H), 8.55 (s, 1H), 7.61 (m, 1H), 7.0 (m, 2H), 6.53 (s, 1H), 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); ¹⁹ F NMR CD ₃ OD / 400 MHz) -111.70 (m) and -116.07 (m). ES-HRMS m / z 543.0515 (M + H calculated for C ₂₁ H ₂₂ BrF ₂ N ₄ O ₄ S: 543.0508).

Example 636

Methyl (5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} pyrazin-2-yl Methyl (methyl) carbamate

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-({5-[(methylamino) methyl] pyrazin-2-yl} in DMF (2.0 ml) To a chilled (5 ° C.) solution of methyl) pyridin-2 (1H) -one (0.20 g, 0.4 mmol) was added methylchloroformate (0.049 g, 0.52 mmol) followed by triethylamine (0.072 g, 0.71 mmol ) Was added. The mixture was stirred at 5 ° C. for 30 minutes, at room temperature for another 30 minutes, 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 (Na ₂ SO ₄ ) and concentrated to dryness. The resulting material was purified by reverse phase HPLC using a 10-90% CH ₃ CN / water gradient (60 minutes) at a flow rate of 70 ml / min. Appropriate fractions (m / z = 523 M + H) were combined and lyophilized to give a white powder. It was partitioned between 5% NaHCO ₃ (10 ml) and EtOAc (15 ml). The organic layer was washed with water, dried (Na ₂ SO ₄ ) and concentrated to dryness to afford the title compound as a white powder (0.12 g, 53%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.59 (s, 1H), 8.41 (m, 1H), 7.60 (m, 1H), 7.05 (m, 2H), 6.52 (s, 1H), 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); ¹⁹ F NMR (CD ₃ OD / 400 MHz) -111.69 (m) and -116.09 (m). ES-HRMS m / z 523.0775 (M + H calculated for C ₂₂ H ₂₂ BrF ₂ N ₄ O ₄ : 523.0787).

Example 637

N-[(5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} pyrazine-2 -Yl) methyl] -2-hydroxy-N, 2-dimethylpropanamide

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-({5-[(methylamino) methyl] pyrazin-2-yl} in DMF (2.0 ml) To a cooled (5 ° C.) solution of methyl) pyridin-2 (1H) -one (0.24 g, 0.52 mmol) was added 2-acetoxyisobutyryl chloride (0.093 g, 0.56 mmol), followed by triethylamine (0.072 g, 0.71 mmol) was added. The mixture was stirred at rt for a further 2 h and concentrated in vacuo. The residue was partitioned between water (5.0 ml) and EtOAc (15.0 ml). EtOAc extracts were washed with water, dried (Na ₂ SO ₄ ) and concentrated to dryness. The resulting material (0.2 g) was stirred with 1M LiOH (0.5 ml, MeOH / water 1: 1 volume / volume) at room temperature for 3 hours, cooled, acidified with trifluoroacetic acid and the product 70 ml / Purification by reverse phase HPLC using a 10-90% CH ₃ CN / water gradient (60 minutes) at a flow rate of minutes. Appropriate fractions (m / z = 551 M + H) were combined and lyophilized to give a white powder. It was partitioned between 5% NaHCO ₃ (10 ml) and EtOAc (15 ml). The organic layer was washed with water, dried (Na ₂ SO ₄ ) and concentrated to dryness to afford the title compound as a white powder (0.075 g). ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.59 (s, 1H), 8.41 (br, 1H), 7.60 (m, 2H), 7.01 (m, 2H), 6.52 (s, 1H), 5.45 (s , 2H), 5.29 (s, 2H).

Example 638

5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N- (2-hydrate Roxy-2-methylpropyl) pyrazine-2-carboxamide

5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} pyrazine in DMF (3.0 ml) Isobutylchloroformate (0.126 g, 0.13 mmol) is added to a solution of 2-carboxylic acid (0.42 g, 0.9 mmol), then N-methylmorpholine (0.11 g, 1.1 mmol) is added- It stirred at 10 degreeC under argon atmosphere. After 20 minutes, a solution of 1,1-dimethyl-2-aminoethanol hydrochloride (0.135 g, 1.1 mmol) in DMF (2.0 ml) containing N-methylmorpholine (0.11 g, 1.1 mmol) was added. The mixture was stirred at rt for 1 h and concentrated to dryness in vacuo. The resulting residue was purified by reverse phase HPLC using a 10-90% CH ₃ CN / water gradient (60 minutes) at a flow rate of 70 ml / min. Appropriate fractions (m / z = 537 M + H) were combined and lyophilized to give a white powder. It was partitioned between 5% NaHCO ₃ (10 ml) and EtOAc (15 ml). The organic layer was washed with water, dried (Na ₂ SO ₄ ) and concentrated to dryness to afford the title compound (0.35 g, 75%) as a white powder. ¹ H NMR (CD ₃ OD / 400 MHz) δ9.1 (d, 1H, J = 1.6 Hz), 8.71 (d, 1H, J = 1.6 Hz), 7.61 (m 1H), 7.02 (m, 2H), 6.54 (s, 1H), 5.54 (s, 2H), 5.30 (s, 2H), 3.30 (s, 2H), 2.55 (s, 3H) and 1.21 (s, 6H); ¹⁹ F NMR (CD ₃ OD / 400 MHz) -111.67 (m) and -116.05 (m). ES-HRMS m / z 537.0948 (M + H calculated for C ₂₃ H ₂₄ BrF ₂ N ₄ O ₄ : 537.0943).

Example 639

1-[(5-aminopyrazin-2-yl) methyl] -3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one trifluor Loacetate

5-{[3-bromo-4-[(2,4-difluoro) in dimethylacetamide (15.0 ml) and t-butanol (5.0 ml) containing triethylamine (0.18 g, 1.8 mmol) Benzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} pyrazine-2-carboxylic acid (0.70 g, 1.5 mmol) and diphenylphosphoryl azide (0.51 g, 1.8 mmol ) Was heated at 90 ° C. for 6 h under argon atmosphere. The reaction mixture was cooled down and the precipitate was filtered off. It was washed with acetonitrile and dried to give 0.22 g of nonreactive acid. The combined filtrates and washes were concentrated in vacuo and the resulting material was purified by reverse phase HPLC using a 10-90% CH ₃ CN / water gradient (60 minutes) at a flow rate of 70 ml / min. Appropriate fractions (m / z = 437 M + H) were combined and lyophilized to afford the title compound as a white powder (0.21 g, 37%). _{^{1 H NMR (DMSO-d 6}} /400 MHz) δ7.88 (d, 1H, J = 1.2 Hz), 7.75 (d, 1H, J = 1.2 Hz), 7.61 (m 1H), 7.34 (m, 1H) , 7.18 (m, lH), 6.49 (s, 1H), 5.25 (s, 2H), 5.10 (s, 2H) and 2.49 (s, 3H); ¹⁹ F NMR (CD ₃ OD / 400 MHz) −111.72 (m) and −116.11 (m). ES-HRMS m / z 437.0402 (M + H calculated for C ₁₈ H ₁₆ BrF ₂ N ₄ O ₂ : 437.0419).

Example 640

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-[(3-methyl-1,2,4-triazin-6-yl) methyl] pyridine- 2 (1H) -one trifluoroacetate

Step 1: Preparation of (2-methylpyrimidin-5-yl) methanol trifluoroacetate

To a solution of methyl 2-methylpyrimidinecarboxylate (2.6 g, 17.1 mmol) in THF was added dropwise diisobutylaluminum hydride (39.5 ml, 1M solution in THF) dropwise at -20 ° C. for 1.5 h under argon atmosphere. Stir and stir for 2 hours at room temperature. Sodium sulfate decahydrate powder (25 g) was added to quench the reaction, THF (25 ml) was added and stirred at room temperature for 1 hour. This mixture was kept in the refrigerator overnight and filtered through a pad of celite. Precipitate completely with warm THF (100 ml) containing 10% ethanol. The combined washes and filtrates were concentrated to give a yellow syrup, which was purified by reverse phase HPLC using a 10-90% CH ₃ CN / water gradient (60 minutes) at a flow rate of 70 ml / min. Appropriate fractions (m / z = 125 M + H) were combined and lyophilized to afford the title compound as its trifluoroacetate salt (0.67 g, 32%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.65 (s, 2H), 4.62 (s, 2H) and 2.66 (s, 3H). ES-HRMS m / z 125.0678 (M + H calculated for C ₆ H ₉ N ₂ O: 125.0709).

Step 2: 3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-[(3-methyl-1,2,4-triazin-6-yl) methyl ] Preparation of Pyridine-2 (1H) -one trifluoroacetate

To a solution of (2-methylpyrimidin-5-yl) methanol trifluoroacetate (0.9 g, 3.76 mmol) in dichloromethane (10 ml) was added triethylamine (0.95 g, 9.41 mmol) at 0 ° C. , Methanesulfonyl chloride (0.59 g, 5.17 mmol) was added and stirred at 0 ° C. for 1 h. After stirring for 1 hour at room temperature, additional triethylamine (0.22 g) and methanesulfonyl chloride (0.15 g) were added and the mixture was stirred at room temperature under an argon atmosphere for an additional hour. Cold water (15 ml) was added to quench the reaction and stirred for 15 minutes. The organic layer was washed with water, then washed with 5% sodium bicarbonate (2 × 15 ml) and water and dried (Na ₂ SO ₄ ). After removing the solvent under reduced pressure, the residue was dried in a drier under vacuum for 4 hours. This material is suspended in THF (10 ml) and DMF (5.0 ml) and 3-bromo-4- (2,4-difluorophenoxy) -6-methylpyridin-2 (1H) -one (0.5) g, 1.52 mmol) and NaH (0.04 g) were added. The resulting mixture was heated at 65 ° C. for 16 h under argon atmosphere. The solvent was distilled under vacuum and the residue was purified by reverse phase HPLC using a 10-90% CH ₃ CN / water gradient (60 minutes) at a flow rate of 70 ml / min. Appropriate fractions (m / z = 436 M + H) were combined and lyophilized to afford the title compound as its trifluoroacetate salt (0.045 g). ¹ H NMR (CD ₃ OD / 400 MHz) δ8.58 (s, 2H), 7.61 (m, 1H), 7.01 (m, 2H), 6.53 (s, 1H), 5.37 (s, 2H), 5.29 ( s, 2H), 2.65 (s, 3H) and 2.46 (s, 3H); ¹⁹ F NMR (CD ₃ OD / 400 MHz) −111.62 (m) and −116.08 (m). ES-HRMS m / z 436.0433 (M + H calculated for C ₁₉ H ₁₇ BrF ₂ N ₃ O ₂ : 436.0467).

Example 641

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (1H-indazol-5-yl) -6-methylpyridin-2 (1H) -one

Step 1: Preparation of 4-hydroxy-1- (1H-indazol-5-yl) -6-methylpyridin-2 (1H) -one

A mixture of 4-hydroxy-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 hour. It was. The mixture was cooled, the supernatant was removed, the residue was triturated with ethanol, cooled and the solid was filtered off. It was washed with cold ethanol and dried. ¹ H NMR (CD ₃ OD / 400 MHz) δ8.11 (s, 1H), 7.64 (m, 2H), 7.18 (d, 1H, J = 2.0 Hz), 7.16 (d, 1H, J = 2.0 Hz) , 6.07 (m, 1 H), 5.81 (d, 1 H, J = 2.8 Hz) and 1.94 (s, 3H). ES-HRMS m / z 242.0962 (M + H calculated for C ₁₃ H ₁₂ N ₃ O ₂ : 242.0924).

Step 2:

4-hydroxy-1- (1H-indazol-5-yl) -6-methylpyridin-2 (1H) -one (0.2 g, 0.83 mmol) in dichloromethane (4.0 ml) and acetic acid (1.0 ml), A mixture of N-bromosuccinimide (0.15 g, 0.84 mmol) was stirred at room temperature for 2.5 hours under argon atmosphere. After removal of the solvent, the residue was dried in a dryer for 4 hours under vacuum. It was suspended in DMF (3.0 ml), potassium carbonate (0.1 g) and 2,4-difluorobenzyl bromide were added and the mixture was stirred at rt for 3 h. DMF was distilled under vacuum and the residue was purified by reverse phase HPLC using a 10-90% CH ₃ CN / water gradient (60 minutes) at a flow rate of 70 ml / min. Appropriate fractions (m / z = 537 M + H) were combined and lyophilized to give a white powder. It was partitioned between 5% NaHCO ₃ (10 ml) and EtOAc (15 ml). The organic layer was washed with water, dried (Na ₂ SO ₄ ) and concentrated to dryness to afford the title compound as a white powder (0.075 g). ¹ H NMR (CD ₃ OD / 400 MHz) δ8.13 (s, 1H), 7.68 (m, 3H), 7.20 (2d, 1H, J = 1.2 Hz), 7.05 (m, 2H), 6.61 (s, 1H), 5.35 (s, 2H) and 2.05 (s, 3H); ¹⁹ F NMR (CD ₃ OD / 400 MHz) -111.62 (m) and -116.02 (m). ES-HRMS m / z 446.0305 (M + H calculated for C ₂₀ H ₁₅ BrF ₂ N ₃ O ₂ : 446.0310).

Example 642

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (1H-indazol-6-yl) -6-methylpyridin-2 (1H) -one

Step 1: Preparation of 4-hydroxy-1- (1H-indazol-6-yl) -6-methylpyridin-2 (1H) -one

The title compound was prepared in a similar manner as described for 4-hydroxy-1- (1H-indazol-5-yl) -6-methylpyridin-2 (1H) -one. Yield = 12%. ¹ H NMR (CD ₃ OD / 400 MHz) δ8.12 (s, 1H), 7.90 (d, 1H, J = 8.0 Hz), 7.42 (s, 1H), 6.94 (d, 1H, J = 8.8 Hz) , 6.08 (br s, 1 H), 5.81 (d, 1 H, J = 2.4 Hz) and 1.96 (s, 3H). ES-HRMS m / z 242.0946 (M + H calculated for C ₁₃ H ₁₂ N ₃ O ₂ : 242.0924).

Step 2:

With the method described for 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (1H-indazol-5-yl) -6-methylpyridin-2 (1H) -one The title compound was prepared in a similar manner. ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.14 (s, 1H), 7.93 (d, 1H, J = 8.4 Hz), 7.61 (m 1H), 7.46 (s, 1H), 7.04 (m, 2H) , 6.98 (m, 1 H), 6.62 (s, 1 H), 5.36 (s, 2H) and 2.06 (s, 3H); ¹⁹ F NMR (CD ₃ OD / 400 MHz) −111.62 (m) and −116.03 (m). ES-HRMS m / z 446.0302 ( C 13 H 12 N 3 O 2 calculated M + H for the required value: 446.0310).

Example 643

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

2- (bromomethyl) -5-fluorobenzonitrile (4.31 g, 20.1 mmol) and methyl 3- (4-hydroxy-6-methyl-2-oxopyridine-1 (2H) in DMF (20 ml) To a cooled solution (0 ° C.) of -yl) -4-methylbenzoate (5.00 g, 18.3 mmol) was added K ₂ CO ₃ (3.00 g, 22.0 mmol). The reaction was allowed to warm to room temperature and stirred overnight. Additional 2- (bromomethyl) -5-fluorobenzonitrile (0.39 g, 1.83 mmol) and K ₂ CO ₃ (0.25 g, 1.83 mmol) were added and the reaction heated at 60 ° C. for 2 hours. The solvent was removed by distillation. The reaction was neutralized with 5% citric acid (50 ml). The organic product was extracted with DCM (3 × 25 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give a viscous dark brown oil. Purification by silica gel flash column chromatography using EtOAc as eluent gave the product as a brown solid, which was dried under vacuum (6.18 g, 76%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.03 (m, 1H), 7.76 (m, 2H), 7.66 (m, 1H), 7.52 (m, 2H), 6.24 (s, 1H), 6.09 ( s, 1H), 5.27 (s, 2H), 3.89 (s, 3H), 2.12 (s, 3H), 1.90 (s, 3H). ES-HRMS m / z 407.1408 (M + H calculated for C ₂₃ H ₂₀ FN ₂ O ₄ : 407.1402).

Step 2: Methyl 3- [4-{[2- (aminomethyl) -4-fluorobenzyl] oxy} -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methylbenzoate tri Preparation of Fluoroacetate

Methyl 3- [4-[(2-cyano-4-fluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methylbenzoate in THF (5 ml) BH ₃ THF (2.51 ml, 2.51 mmol) was added dropwise (from step 1) (0.510 g, 1.25 mmol) to a cooled solution (0 ° C.). The reaction was then stirred at rt for 2.5 h. The reaction was cooled (0 ° C.), quenched by the slow addition of MeOH, concentrated and purified by preparative HPLC. The product was isolated by freeze-drying and the solvent was evaporated to give a white solid, which was dried under vacuum (0.39 g, 76%). ¹ H NMR (CD ₃ OD / 40O MHz) δ 8.04 (m, 1H), 7.75 (s, 1H), 7.63 (m, 1H), 7.55 (d, 1H, J = 8.4 Hz), 7.32 (m, 1H), 7.24 (m, 1H), 6.25 (s, 1H), 6.12 (s, 1H), 5.23 (s, 2H), 4.25 (s, 2H), 3.90 (s, 3H), 2.11 (s, 3H ), 1.90 (s, 3 H). ES-HRMS m / z 411.1691 (M + H calculated for C ₂₃ H ₂₄ FN ₂ O ₄ : 411.1715).

Step 3: Methyl 3- [4-[(4-fluoro-2-{[(methoxycarbonyl) amino] methyl} benzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl ] -4-Methylbenzoate Preparation

Methyl 3- [4-{[2- (aminomethyl) -4-fluorobenzyl] oxy} -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methyl in DMA (4 ml) To a cooled solution of benzoate trifluoroacetate (from step 2) (0.50 g, 0.95 mmol) (0 ° C.) 4-methylmorpholine (0.21 ml, 1.9 mmol) and methyl chloroformate (0.08 ml, 1.0 mmol ) Was added. The reaction was stirred at rt for 1 h. The solvent was removed by distillation. The crude product was purified by preparative HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHCO ₃ (30 ml) and extracted with DCM (3 × 25 ml). The organic extract was dried over Na ₂ S0 ₄ , filtered and concentrated to give a white solid, which was dried under vacuum (0.36 g, 81%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.03 (m, 1H), 7.77 (s, 1H), 7.53 (d, 1H, J = 7.6 Hz), 7.47 (m, 1H), 7.12 (m, 1H), 7.03 (m, 1H), 6.21 (s, 1H), 6.08 (s, 1H), 5.18 (s, 2H), 4.38 (s, 2H), 3.89 (s, 3H), 3.65 (s, 3H ), 2.12 (s, 3H), 1.89 (s, 3H). ES-HRMS m / z 469.1767 (M + H calculated for C ₂₅ H ₂₆ FN ₂ O ₆ : 469.1769).

Step 4: 3- [4-[(4-fluoro-2-{[(methoxycarbonyl) amino] methyl} benzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] Preparation of 4-methylbenzoic acid

Methyl 3- [4-[(4-fluoro-2-{[(methoxycarbonyl) amino] methyl} benzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4 To methylbenzoate (from step 3) (0.17 g, 0.36 mmol) was added a 1.5N NaOH solution in 1: 1 MeOH: water (0.39 ml, 0.59 mmol). The reaction mixture was stirred at 60 ° C. for 2.5 h. The solution was cooled (0 ° C.), neutralized by the slow addition of 5% citric acid and the organic product was extracted with DCM. The white solid suspended in the organic layer was filtered, washed with DCM and water and dried in vacuo to afford the desired product (0.090 g, 55%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.03 (m, 1H), 7.75 (s, 1H), 7.52 (d, 1H, J = 8.0 Hz), 7.47 (m, 1H), 7.12 (m, 1H), 7.03 (m, 1H), 6.21 (s, 1H), 6.08 (s, 1H), 5.18 (s, 2H), 4.38 (s, 2H), 3.65 (s, 3H), 2.12 (s, 3H ), 1.90 (s, 3 H). ES-HRMS m / z 455.1632 (M + H calculated for C ₂₄ H ₂₄ FN ₂ O ₆ : 455.1613).

Step 5: 3- [3-Bromo-4-[(4-fluoro-2-{[(methoxycarbonyl) amino] methyl} benzyl) oxy] -6-methyl-2-oxopyridine-1 ( Preparation of 2H) -yl] -4-methylbenzoic acid

3- [4-[(4-fluoro-2-{[(methoxycarbonyl) amino] methyl} benzyl) oxy] -6-methyl-2-oxopyridine-1 (2H) in DCM (45 ml) To a solution of -yl] -4-methylbenzoic acid (from step 4) (1.75 g, 3.85 mmol) was added NBS (0.69 g, 3.85 mmol). After 1.5 h, the solvent was removed on a rotary evaporator. The solid was dissolved in EtOAc and hexane was added to give a solid precipitate. This solid was filtered off. The solid was then dissolved in DCM and washed with water. The organic layer was dried over Na ₂ S0 ₄ , filtered and concentrated. The pale yellow solid was dried under vacuum (1.47 g, 72%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.04 (m, 1H), 7.77 (s, 1H), 7.54 (m, 2H), 7.13 (m, 1H), 7.05 (m, 1H), 6.68 (s , 1H), 5.40 (s, 2H), 4.44 (s, 2H), 3.64 (s, 3H), 2.09 (s, 3H), 1.99 (s, 3H). ES-HRMS m / z 533.0700 and 535.0677 (M + H calculated for C ₂₄ H ₂₃ BrFN ₂ O ₆ : 533.0718 and 535.0701).

Step 6: Preparation of the title compound

3- [3-bromo-4-[(4-fluoro-2-{[(methoxycarbonyl) amino] methyl} benzyl) oxy] -6-methyl-2-oxopyridine in DMF (2.0 ml) In a cooled solution (-10 ° C) of -1 (2H) -yl] -4-methylbenzoic acid (0.07 g, 0.13 mmol) isobutyl chloroformate (0.02 ml, 0.16 mmol) and 4-methylmorpholine (0.02 ml, 0.16 mmol) was added. After 15 minutes, 2.0 M methylamine (0.01 ml, 0.20 mmol) in THF was added. After 30 minutes the solvent was removed by distillation. The crude product was purified by preparative HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHCO ₃ (30 ml) and extracted with DCM (3 × 25 ml). The organic extract was dried over Na ₂ S0 ₄ , filtered, concentrated and dried in vacuo to give a white foam (0.061 g, 86%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.85 (m, 1H), 7.54 (m, 3H), 7.14 (m, 1H), 7.05 (m, 1H), 6.68 (s, 1H), 5.40 ( s, 2H), 4.43 (s, 2H), 3.64 (s, 3H), 2.89 (s, 3H), 2.08 (s, 3H), 1.99 (s, 3H). ES-HRMS m / z 546.0987 and 548.1018 (M + H calculated for C ₂₅ H ₂₆ BrFN ₃ O ₅ : 546.1034 and 548.1018).

Example 644

Methyl 2-({[3-bromo-1- (5-{[(2-hydroxyethyl) amino] carbonyl} -2-methylphenyl) -6-methyl-2-oxo-1,2-dihydro Pyridin-4-yl] oxy} methyl) -5-fluorobenzylcarbamate

The title compound was prepared using a method analogous to the method used for preparing Example 643. ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.88 (m, 1H), 7.61 (s, 1H), 7.53 (m, 2H), 7.13 (m, 1H), 7.04 (m, 1H), 6.68 ( s, 1H), 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 = 5.6 Hz), 2.08 (s, 3 H), 2.00 (s, 3 H). ES-HRMS m / z 576.1101 and 578.1072 (M + H calculated for C ₂₆ H ₂₈ BrFN ₃ O ₆ : 576.1140 and 578.1124).

Example 645

Methyl 2-({[3-bromo-1- (5-{[(2-hydroxy-2-methylpropyl) 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 for the preparation of Example 643. ¹ H NMR (CD ₃ OD / 400MHz) δ 7.89 (m, 1H), 7.63 (s, 1H), 7.54 (m, 2H), 7.13 (m, 1H), 7.04 (m, 1H), 6.69 (s , 1H), 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, 3 H). ESHRMS m / z 604.1412 and 606.1418 (M + H calculated for C ₂₈ H ₃₂ BrFN ₃ O ₆ : 604.1453 and 606.1438).

Example 646

Methyl 2-({[3-bromo-1- (5-{[(2-methoxyethyl) amino] carbonyl} -2-methylphenyl) -6-methyl-2-oxo-1,2-dihydro Pyridin-4-yl] oxy} methyl) -5-fluorobenzylcarbamate

The title compound was prepared using a procedure similar to that used for the preparation of Example 643. ¹ H NMR (CD ₃ OD / 400MHz) δ 7.87 (m, 1H), 7.59 (s, 1H), 7.53 (m, 2H), 7.14 (m, 1H), 7.05 (m, 1H), 6.68 (s , 1H), 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 C ₂₇ H ₃₀ BrFN ₃ O ₆ : 590.1297 and 592.1281).

Example 647

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 for the preparation of Example 643. ¹ H NMR (CD ₃ OD / 400 MHz) δ7.91 (m, 1H), 7.64 (s, 1H), 7.54 (m, 2H), 7.14 (m, 1H), 7.05 (m, 1H), 6.68 (s , 1H), 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 C ₂₄ H ₂₄ BrFN ₃ O ₅ : 532.0878 and 534.0861).

Example 648

N- [2-({[3-chloro-1- (2,6-difluorophenyl) -6-methyl-2-oxo-1,2-dihydropyridin-4-yl] oxy} methyl)- 5-fluorobenzyl] -N'-phenylurea

4-{[2- (aminomethyl) -4-fluorobenzyl] oxy} -3-chloro-1- (2,6-difluorophenyl) -6-methylpyridine-2 in DMA (2.0 mL) To a cooled (0 ° C.) solution of 1H) -on trifluoroacetate (0.25 g, 0.48 mmol) was added 4-methylmorpholine (0.06 mL, 0.53 mmol) and phenyl isocyanate (0.06 mL, 0.53 mmol). The reaction was stirred at rt for 1.5 h. The solvent was distilled off and the crude product was purified by preparative HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHCO ₃ (30 mL) and extracted with DCM (3 × 25 mL). The organic extract was dried over Na ₂ S0 ₄ , filtered, concentrated and dried under vacuum to give a white solid (0.18 g, 71%). ¹ H NMR (CD ₃ OD / 400 MHz) δ7.60 (m, 1H), 7.54 (m, 1H), 7.33 (d, 2H, J = 7.6 Hz), 7.22 (m, 5H), 7.06 (m, 1H ), 6.95 (t, 1H, J = 7.2 Hz), 6.73 (s, 1H), 5.44 (s, 2H), 4.53 (s, 2H), 2.07 (s, 3H). ESHRMS m / z 528.1304 (M + H calculated for C ₂₇ H ₂₂ ClF ₃ N ₃ O ₃ : 528.1296).

Example 649

Thien-3-ylmethyl 2-({[3-chloro-1- (2,6-difluorophenyl) -6-methyl-2-oxo-1,2-dihydropyridin-4-yl] oxy} Methyl) -5-fluorobenzylcarbamate

4-{[2- (aminomethyl) -4-fluorobenzyl] oxy} -3-chloro-1- (2,6-difluorophenyl) -6-methylpyridine-2 in DMA (2.0 mL) 4-methylmorpholine (0.06 mL, in a cooled (0 ° C) solution of 1H) -one trifluoroacetate (0.26 g, 0.50 mmol) and 1,1-carbonyldiimidazole (0.10 g, 0.60 mmol) 0.55 mmol) was added. After 1 h at rt, 3-thiophenmethanol (0.09 mL, 0.99 mmol) was added. After 2 hours at room temperature no product was observed. NaH (0.01 g, 0.50 mmol) was added and the reaction stirred at 60 ° C. The reaction was complete after 20 minutes. The reaction mixture was cooled to 0 ° C. and acetic acid was added to quench the reaction. The solvent was removed by distillation. The crude product was purified by preparative HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHCO ₃ (30 mL) and extracted with DCM (3 × 25 mL). The organic extract was dried over Na ₂ SO ₄ , filtered, concentrated and dried under vacuum to give a white foam (0.20 g, 73%). ¹ H NMR (CD ₃ OD / 400 MHz) δ7.61 (m, 1H), 7.52 (m, 1H), 7.34 (s, 2H), 7.23 (t, 3H, J = 8.4 Hz), 7.10 (m, 2H ), 6.71 (s, 1H), 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 C ₂₆ H ₂₁ ClF ₃ N ₂ O ₄ S: 549.0857).

Example 650

Ethyl 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: Methyl 3- [4-[(2-{[(ethoxycarbonyl) amino] methyl} -4-fluorobenzyl) oxy] -6-methyl-2-oxopyridine-1 (2H)- Preparation of Japanese] -4-methylbenzoate

Methyl 3- [4-[(4-fluoro-2-{[(methoxycarbonyl) amino] methyl} benzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4 Prepared using a procedure similar to that used for the preparation of methylbenzoate. ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.03 (m, 1H), 7.76 (s, 1H), 7.53 (d, 1H, J = 8.0 Hz), 7.47 (m, 1H), 7.12 (m, 1H ), 7.03 (m, 1H), 6.21 (s, 1H), 6.08 (s, 1H), 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 C ₂₆ H ₂₈ FN ₂ O ₆ : 483.1926).

Step 2: 3- [4-[(2-{[(ethoxycarbonyl) amino] methyl} -4-fluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] Preparation of 4-methylbenzoic acid

3- [4-[(4-fluoro-2-{[(methoxycarbonyl) amino] methyl} benzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4- Prepared using a procedure similar to that used for the preparation of methylbenzoic acid. ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.03 (m, 1H), 7.74 (s, 1H), 7.48 (m, 2H), 7.11 (m, 1H), 7.03 (m, 1H), 6.21 (s , 1H), 6.08 (s, 1H), 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 C ₂₅ H ₂₆ FN ₂ O ₆ : 469.1769).

Step 3: 3- [3-bromo-4-[(2-{[(ethoxycarbonyl) amino] methyl} -4-fluorobenzyl) oxy] -6-methyl-2-oxopyridine-1 ( Preparation of 2H) -yl] -4-methylbenzoic acid

Prepared using a procedure similar to that used in step 5 of the synthesis of Example 643. ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.04 (m, 1H), 7.76 (s, 1H), 7.55 (m, 2H), 7.13 (m, 1H), 7.05 (m, 1H), 6.68 (s , 1H), 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 C ₂₅ H ₂₅ BrFN ₂ O ₆ : 547.0875 and 549.0858).

Step 4:

Prepared using a procedure similar to that used for the preparation of Example 643. ¹ H NMR (CD ₃ OD / 400MHz) δ 7.85 (m, 1H), 7.54 (m, 3H), 7.13 (m, 1H), 7.04 (m, 1H), 6.68 (s, 1H), 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 C ₂₆ H ₂₈ BrFN ₃ O ₅ : 560.1191 and 562.1175).

Example 651

3- [3-bromo-4-{[2-({[(cyclopropylamino) carbonyl] amino} methyl) -4-fluorobenzyl] oxy} -6-methyl-2-oxopyridine-1 ( 2H) -yl] -N, 4-dimethylbenzamide

Step 1: Methyl 3- [4-{[2-({[(cyclopropylamino) carbonyl] amino} methyl) -4-fluorobenzyl] oxy} -6-methyl-2-oxopyridine-1 (2H ) -Yl] -4-methylbenzoate

Methyl 3- [4-{[2- (aminomethyl) -4-fluorobenzyl] oxy} -6-methyl-2-oxopyridin-1 (2H) -yl] -4-methyl in DMA (8.0 mL) 4-Methylmorpholine (0.36 mL, 3.2 mmol) in a cooled (0 ° C) solution of benzoate trifluoroacetate (1.13 g, 2.16 mmol) and 1,1-carbonyldiimidazole (0.42 g, 2.59 mmol) ) Was added. The reaction was stirred at rt for 2 h. DMA was removed by distillation. The crude product was purified by preparative HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHCO ₃ (30 mL) and extracted with DCM (3 × 25 mL). The organic extract was dried over Na ₂ S0 ₄ , filtered, concentrated and dried in vacuo (0.78 g, 73%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.03 (m, 1H), 7.76 (s, 1H), 7.53 (d, 1H, J = 8.0 Hz), 7.46 (m, 1H), 7.12 (m, 1H ), 7.01 (m, 1H), 6.22 (s, 1H), 6.08 (s, 1H), 5.19 (s, 2H), 4.44 (s, 2H), 3.89 (s, 3H), 2.48 (m, 1H) , 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 C ₂₇ H ₂₉ FN ₃ O ₅ : 494.2086).

Step 2: 3- [4-{[2-({[(cyclopropylamino) carbonyl] amino} methyl) -4-fluorobenzyl] oxy} -6-methyl-2-oxopyridine-1 (2H) -Yl] -4-methylbenzoic acid

3- [4-[(4-fluoro-2-{[(methoxycarbonyl) amino] methyl} benzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4- Prepared using a procedure similar to that used for the preparation of methylbenzoic acid. ¹ H NMR (CD ₃ OD / 400MHz) δ8.02 (m, 1H), 7.74 (s, 1H), 7.48 (m, 2H), 7.12 (m, 1H), 7.01 (m, 1H), 6.22 (s , 1H), 6.08 (s, 1H), 5.19 (s, 2H), 4.44 (s, 2H), 2.48 (m, 1H), 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 C ₂₆ H ₂₇ FN ₃ O ₅ : 480.1929).

Step 3: 3- [3-bromo-4-{[2-({[(cyclopropylamino) carbonyl] amino} methyl) -4-fluorobenzyl] oxy} -6-methyl-2-oxopyridine Preparation of -1 (2H) -yl] -4-methylbenzoic acid

Prepared using a procedure similar to that used in step 5 of the synthesis of Example 643. _{^{1 H NMR (DMSO-d 6}} / 400MHz) δ7.92 (m, 1H), 7.67 (s, 1H), 7.54 (m, 2H), 7.12 (m, 2H), 6.71 (s, 1H), 5.37 ( s, 2H), 4.31 (d, 2H, J = 6.4 Hz), 2.40 (m, 1H), 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 C ₂₆ H ₂₆ BrFN ₃ O ₅ : 558.1034 and 560.1018).

Step 4:

Prepared using a procedure similar to that used for the preparation of Example 643. ¹ H NMR (CD ₃ OD / 400MHz) δ 7.85 (m, 1H), 7.54 (m, 3H), 7.14 (m, 1H), 7.03 (m, 1H), 6.69 (s, 1H), 5.41 (s , 2H), 4.48 (s, 2H), 2.89 (s, 3H), 2.48 (m, 1H), 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 C ₂₇ H ₂₉ BrFN ₄ 0 ₄ : 571.1351 and 573.1335).

Example 652

3- [3-bromo-4-{[2-({[(cyclopropylamino) carbonyl] amino} methyl) -4-fluorobenzyl] oxy} -6-methyl-2-oxopyridine-1 ( 2H) -yl] -4-methylbenzoic acid

Step 1: Preparation of ethyl (5-fluoro-2-methylphenoxy) acetate

To a solution of 5-fluoro-2-methylphenol (1.00 g, 7.93 mmol) and ethyl bromoacetate (1.59 g, 9.51 mmol) in DMF (15 mL) was added K ₂ CO ₃ (1.10 g, 7.93 mmol). It was. After 30 minutes at room temperature, the DMF was removed by distillation. The crude product was washed with 5% citric acid (30 mL) and water (30 mL), extracted with DCM (3 × 20 mL), dried over Na ₂ SO ₄ , filtered, concentrated and dried in vacuo. The desired product was obtained as a yellow oil (1.30 g, 77%). ¹ H NMR (CD ₃ OD / 400MHz) δ7.09 (t, 1H, J = 8.8 Hz), 6.58 (m, 1H), 6.56 (m, 1H), 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 C ₁₁ H ₁₃ FO ₃ : 212.0849).

Step 2: Preparation of ethyl [2- (bromomethyl) -5-fluorophenoxy] acetate

Ethyl (5-fluoro-2-methylphenoxy) acetate (prepared from step 1) (0.65 g, 3.06 mmol), NBS (0.65 g, 3.68 mmol) and benzoyl peroxide (0.05) in CCl ₄ (7.0 mL) g, 0.21 mmol) was refluxed at 90 ° C. for 2.5 hours. Additional NBS (0.16 g, 0.92 mmol) was added and reaction continued overnight. The solid was filtered off and the filtrate was concentrated on silica gel. Purification by flash column chromatography using hexane and 2.5% EtOAc / hexane as eluent. The product was obtained as a yellow liquid (0.27 g, 30%). ¹ H NMR (CD ₃ OD / 400 MHz) δ7.37 (m, 1H), 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: ethyl [2-({[3-bromo-1- (2,6-difluorophenyl) -6-methyl-2-oxo-1,2-dihydropyridin-4-yl] oxy} Preparation of Methyl) -5-fluorophenoxy] acetate

Ethyl [2- (bromomethyl) -5-fluorophenoxy] acetate (prepared from step 2) in DMF (3.0 mL) (0.59 g, 2.03 mmol) and 3-bromo-1- (2,6 To a solution of -difluorophenyl) -4-hydroxy-6-methylpyridin-2 (1H))-one (0.61 g, 1.93 mmol) was added K ₂ CO ₃ (0.34 g, 2.43 mmol). After 2 hours at room temperature, the DMF was removed by distillation. The crude product was washed with 5% citric acid, extracted with DCM, dried over Na ₂ SO ₄ , filtered and concentrated on silica gel. Purification by flash column chromatography using 50% EtOAc / hexanes as eluent. The product was obtained as a pale yellow solid (0.45 g, 42%). ¹ H NMR (CD ₃ OD / 400 MHz) δ7.21 (q, 3H, J = 8.4 Hz), 6.80 (m, 2H), 6.69 (s, 1H), 6.15 (s, 1H), 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 C ₂₃ H ₂₀ BrF ₃ NO ₅ : 526.0471 and 528.0454).

Step 4: [2-({[3-bromo-1- (2,6-difluorophenyl) -6-methyl-2-oxo-1,2-dihydropyridin-4-yl] oxy} methyl ) -5-fluorophenoxy] acetic acid

Ethyl [2-({[3-bromo-1- (2,6-difluorophenyl) -6-methyl-2-oxo-1,2-dihydropyridin-4-yl] oxy} methyl)- 5-fluorophenoxy] acetate (prepared from step 3) (0.62 g, 1.18 mmol), a solution of 1.5 N NaOH solution (1.2 mL, 1.77 mmol), and THF (1.2 mL) in 1: 1 MeOH: water. Was refluxed at 60 ° C. for 1 h. The solution was concentrated on a rotary evaporator, cooled and 5% citric acid was added. The solid precipitate was filtered off and dried under vacuum. The product was obtained as a pale yellow solid (0.35 g, 60%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.59 (m, 1H), 7.49 (m, 1H), 7.22 (m, 2H), 6.75 (m, 2H), 6.72 (s, 1H), 5.43 (s , 2H), 4.66 (s, 2H), 2.07 (s, 3H). ESHRMS m / z 498.0143 and 500.0186 (M + H calculated for C ₂₁ H ₁₆ BrF ₃ NO ₅ : 498.0158 and 500.0141).

Step 5: 2- [2-({[3-bromo-1- (2,6-difluorophenyl) -6-methyl-2-oxo-1,2-dihydropyridin-4-yl] oxy } Methyl) -5-fluorophenoxy] -N-ethylacetamide

[2-({[3-bromo-1- (2,6-difluorophenyl) -6-methyl-2-oxo-1,2-dihydropyridin-4-yl] in DMA (2.0 mL) In a cooled (-10 ° C) solution of oxy} methyl) -5-fluorophenoxy] acetic acid (prepared from step 4) (0.15 g, 0.30 mmol), 4-methylmorpholine (0.04 mL, 0.36 mmol) and Isobutyl chloroformate (0.05 mL, 0.36 mmol) was added. After 20 minutes ethylamine (0.04 mL, 0.45 mmol) was added. After 1 hour DMF was removed by distillation. The crude product was purified by preparative HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHCO ₃ (30 mL) and extracted with DCM (3 × 25 mL). The organic extract was dried over Na ₂ SO ₄ , filtered, concentrated and dried under vacuum to give a white solid (0.080 g, 51%). ¹ H NMR (CD ₃ OD / 400 MHz) δ7.60 (m, 1H), 7.53 (t, 1H, J = 8.0 Hz), 7.23 (t, 2H, J = 8.4 Hz), 6.82 (m, 2H), 6.71 (s, 1H), 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 C ₂₃ H ₂₁ BrF ₃ N ₂ O ₄ : 525.0631 and 527.0614).

Example 653

Methyl 3- [6-[(acetyloxy) methyl] -3-bromo-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] -4- Methylbenzoate

Step 1: Preparation of 3- (2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl) -2-oxopropyl acetate

A solution of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (20 g, 141 mmol) in dry THF (400 mL) was cooled to -78 ° C. LiHMDS (1M-THF, 160 mL, 160 mmol) was slowly added to this solution. The resulting solution was kept at −78 ° C. for 30 minutes with stirring. Acetoxy acetylchloride (17 mL, 160 mmol) was added to the reaction mixture and the resulting mixture was kept at -78 ° C for 1 hour. The reaction was then slowly warmed to room temperature and stirred for an additional 1 hour. Thereafter, a 1N solution of ammonium chloride was added to quench the reaction. The layers were separated and the aqueous layer was extracted five times with ethyl acetate. The organic layers were combined, dried and concentrated in vacuo. The crude product was purified using a medium pressure liquid chromatography biotage system. Elution with hexane-ethyl acetate (3: 1) gave 13.1 g (38%) of reddish brown oil. The product appeared transparent by NMR. ¹ H NMR (300 MHz, CDCl ₃ ) δ5.42 (s, 1H), 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-oxopyridin-1 (2H) -yl] -4-methylbenzoate

To 100 mL RBF containing methyl 3-amino, 4-methylbenzoate (1.65 g, 10 mmol) was added Enone (2.6 g, 10.7 mmol) prepared from step 1. The mixture was then dissolved in toluene (40 mL), fitted with a reflux condenser and placed in an oil bath preset at 115 ° C. The mixture was heated at reflux for 1.5 h. 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 at reflux for an additional 2 hours. The reaction was then cooled to 0 ° C. The toluene was then removed under vacuum to give a dark brown residue. The residue was then dissolved in acetonitrile (10-15 mL) and left to stand. After 20-30 minutes, a precipitate formed which was filtered off and washed with diethyl ether. After drying, an off-white solid (1.9 g, 57% yield) was obtained. ¹ H NMR (300 MHz, DMSO _{- d6} ) δ7.94 (dd, J = 7.8, 1.5 Hz, 1H), 7.73 (s, 1H), 7.54 (d, J = 8.1 Hz, 1H), 6.19 (s, 1H), 5.73-5.71 (m, 1H), 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 calculated for C ₁₇ H ₁₈ NO ₆ : 332.1129).

Step 3: Preparation of Methyl 3- [6-[(acetyloxy) methyl] -3-bromo-4-hydroxy-2-oxopyridin-1 (2H) -yl] -4-methylbenzoate

To a slurry of phenol (2.5 g, 7.5 mmol) in dry acetonitrile (50 mL) at room temperature was added n-bromosuccinimide (1.33 g, 7.5 mmol). The resulting homogeneous mixture was stirred at room temperature for 3 hours. The resulting precipitate was filtered off and washed successively with acetonitrile and diethyl ether. The product was dried in a vacuum oven to give an off white solid (2.5 g, 81%). ¹ H NMR (300 MHz, DMSO _{- d6} ) δ 11.82 (s, 1H), 7.97 (dd, J = 7.8, 1.5 Hz, 1H), 7.80 (d, J = 1.5 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 6.38 (s, 1H), 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 calculated for C ₁₇ H ₁₇ NBrO ₆ : 410.0234).

Step 4: Preparation of the title compound

To a solution of the phenol (2.5 g, 6.0 mmol) in dry DMF (25 mL) was added solid potassium carbonate (804 mg, 6.0 mmol). Then 2,4-difluorobenzyl bromide (783 μL, 6.0 mmol) was added to the mixture via syringe. The resulting mixture was stirred at rt overnight. Thereafter, the reaction was poured into ice water and stirred vigorously. The resulting precipitate was filtered off and washed successively with water and diethyl ether. The solid was dried in a vacuum oven to give an off white solid (3.3 g, 99%). ¹ H NMR (400 MHz, DMSO _{- d6} ) δ 7.97 (dd, J = 7.6, 1.2 Hz, 1H), 7.83 (d, J = 1.6 Hz, 1H), 7.71 (q, J = 8.8 Hz, 1H) , 7.57 (d, J = 8.0 Hz, 1H), 7.37 (dt, J = 10.4, 2.4 Hz, 1H), 7.21 (dt, J = 8.4, 2.0 Hz, 1H), 6.90 (s, 1H), 5.40 ( s, 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 calculated for C ₂₄ H ₂₁ NF ₂ BrO ₆ : 536.0515).

Example 654

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6- (hydroxymethyl) -2-oxopyridin-1 (2H) -yl] -4-methylbenzoic acid

To a stirred room temperature suspension of Example 643 (2.0 g, 3.7 mmol) in THF (10 mL) was added a solution of 2.5N NaOH (3 mL, 7.5 mmol). The resulting homogeneous solution was stirred for 2 hours. Judging the completion of the reaction, 1N HCl was added dropwise until approximately pH 4 was reached. Then the reaction was diluted with CH ₂ Cl ₂ (10 mL). The resulting precipitate was filtered off and washed further with CH ₂ Cl ₂ . The solid was dried in a vacuum oven to give a pure white solid (1.8 g, 99%). ¹ H NMR (300 MHz, DMSO _{- d6} ) δ 7.95 (dd, J = 7.8, 1.8 Hz, 1H), 7.74-7.66 (m, 2H), 7.54 (d, J = 8.1 Hz, 1H), 7.37 ( dq, J = 7.8, 2.7 Hz, 1H), 7.24-7.17 (m, 1H), 6.72 (s, 1H), 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 calculated for C ₂₁ H ₁₇ NF ₂ BrO ₅ : 480.0253).

Example 655

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6- (hydroxymethyl) -2-oxopyridin-l (2H) -yl] -N- (2- Hydroxyethyl) -4-methylbenzamide

To a slurry of Example 654 (500 mg, 1.04 mmol) in anhydrous CH ₂ Cl ₂ was added Et ₃ N (218 μl, 1.56 mmol) and the resulting homogeneous mixture was stirred at room temperature. Then ethanolamine (70 μl, 1.14 mmol) was added to the mixture via syringe. Then HOBt (155 mg, 1.14 mmol) was added followed by EDC (217 mg, 1.14 mmol). The reaction was stirred at rt overnight. The reaction was quenched by adding a solution of 1N NH ₄ Cl. The biphasic mixture was separated and the aqueous layer was extracted four times with CH ₂ Cl ₂ . The organic layers were combined, dried and concentrated in vacuo. The resulting residue was purified by flash chromatography on a 16 g Michel-Miller column. Elution with CH ₂ Cl ₂ -MeOH (10: 1 → 12: 1) afforded the desired product as a viscous oil. The oil was then dissolved in the CH ₃ CN-Et ₂ O combination. After 5-10 minutes, a precipitate formed which was filtered and dried to give a pure white solid (210 mg, 40%). ¹ H NMR (300 MHz, DMSO _{- d6} ) δ8.46 (t, J = 5.2 Hz, 1H), 7.88 (dd, J = 8.0, 2.0 Hz, 1H), 7.72-7.65 (m, 2H), 7.50 ( d, J = 8.4 Hz, 1H), 7.37 (dq, J = 9.6, 2.4 Hz, 1H), 7.20 (dq, J = 7.6, 1.6 Hz, 1H), 6.71 (s, 1H), 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, 1H), 3.70 (dd, J = 16.4, 5.6 Hz, 1H), 3.52-3.48 (m, 2H), 3.39-3.25 (m, 2H), 2.00 (s, 3H). ES-HRMS m / z 523.0674 (M + H calculated for C ₂₃ H ₂₂ N ₂ F ₂ BrO ₅ : 523.0675).

Example 656

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6- (hydroxymethyl) -2-oxopyridin-1 (2H) -yl] -N, 4-dimethyl Benzamide

The title compound was purified from the acid (550 mg, 1.07 mmol) of Example 654 by EDC (245 mg, 1.28 mmol), HOBt (171 μL, 1.28 mmol), Et ₃ N (225 mL, 1.6) in a similar manner to the amide described above. mmol) and 2.0 M MeNH ₂ -THF (1.2 μl, 2.48 mmol). After workup with 1N NH ₄ Cl and diluted with additional CH ₂ Cl ₂ , the product was precipitated from the biphasic mixture to give a white solid (250 mg, 51% yield). ¹ H NMR (300 MHz, DMSO _{- d6} ) δ 8.48 (quar, J = 4.5 Hz, 1H), 7.88 (dd, J = 8.1, 1.8 Hz, 1H), 7.72 (app quar, J = 6.6 Hz, 1H ), 7.63 (d, J = 1.8 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.37 (dt, J = 10.2, 2.4 Hz, 1H), 7.20 (app dt, J = 8.4, 1.8 Hz, 1H), 6.74 (s, 1H), 5.71 (t, J = 5.4 Hz, 1H), 5.42 (s, 2H), 4.03 (dd, J = 13.8, 5.1 Hz, 1H), 3.72 (dd, J = 16.4, 5.1 Hz, 1H), 2.78 (d, J = 4.5 Hz, 3H), 2.02 (s, 3H). ES-HRMS m / z 493.0575 (M + H calculated for C ₂₂ H ₂₀ N ₂ F ₂ BrO ₄ : 493.0569).

Example 657

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6- (hydroxymethyl) -2-oxopyridin-1 (2H) -yl] -4-methylbenzamide

To a stirred room temperature suspension of carboxylic acid (400 mg, 0.80 mmol) of Example 654 in anhydrous THF (4 mL) was added 4-methylmorpholine (274 μl, 2.5 mmol). Thereafter, 2-chloro-4,6-dimethyltriazine (170 mg, 1.0 mmol) was added to the resulting heterogeneous solution, and the mixture was stirred at room temperature for 1 hour. Ammonium hydroxide solution (28-32%, 2 mL) was then added to the reaction and stirred overnight at room temperature. The reaction was then diluted with H ₂ O (2 to 3 mL), worked up and vigorously stirred. The resulting precipitate was filtered off and washed with H ₂ O followed by diethyl ether. After drying in a vacuum oven, an off-white solid (140 mg, 32%) was obtained. ¹ H 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, 1H), 7.43-7.36 (m, 2H), 7.20 (dt, J = 8.7, 1.8 Hz, IH), 6.74 (s, 1H), 5.41 (s, 2H), 4.02 -3.62 (m, 2 H), 2.03 (s, 3 H). ES-HRMS m / z 479.0411 (M + H calculated for C ₂₁ H ₁₈ N ₂ F ₂ BrO ₄ : 479.0413).

Example 658

(5-bromo-4-[(2,4-difluorobenzyl) oxy] -1- {2-methyl-5-[(methylamino) carbonyl] phenyl} -6-oxo-1,6- Dihydropyridin-2-yl) methyl acetate

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6- (hydroxymethyl) -2-oxopyridin-1 (2H) -yl stirred in CH ₂ Cl ₂ To a solution of] -N, 4-dimethylbenzamide (225 mg, 0.50 mmol) was added pyridine (55 μl, 0.69 mmol). Thereafter, acetic anhydride (47 μl, 0.51 mmol) was added to the resulting homogeneous solution. The mixture was stirred at rt for 3 h. Then additional pyridine (150 μl, 1.8 mmol) and acetic anhydride (100 μl, 1.05 mmol) were added and the reaction was stirred at rt overnight. The reaction was then quenched with 1N NHCl ₄ and diluted with CH ₂ Cl ₂ . The layers were separated and then the organic layer was extracted three times with CH ₂ Cl ₂ . Then the organic layers were combined and concentrated in vacuo. The residue was then triturated with Et ₂ O and filtered to yield an off white solid (150 mg, 61%). ¹ H NMR (300 MHz, DMSO _{- d6} ) δ8.48 (br s, 1H), 7.87 (app d, J = 7.8 Hz, 1H), 7.74-7.69 (m, 2H), 7.52 (d, J = 7.5 Hz, 1H), 7.40 (app t, J = 8.1 Hz, 1H), 7.28-7.19 (m, 1H), 6.91 (s, 1H), 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 calculated for C ₂₄ H ₂₂ N ₂ F ₂ BrO ₅ : 535.0675).

Example 659

(2E) -4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N-methylbut- 2-enamide

Step 1: (2E) -4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] but-2 Ensan

A carboxylic acid composition was prepared by stirring the ester (900 mg, 2.1 mmol) in THF (10 mL). 1N NaOH (1 mL) was added to the solution and the resulting mixture was stirred at room temperature. After 2 hours, additional NaOH (1 mL) was added to the reaction and then stirred overnight at room temperature. Thereafter, THF was concentrated in vacuo. The remaining aqueous layer was then acidified to approximately pH 4, resulting in a white precipitate. Filtration and drying in vacuo gave a white solid (900 mg) which was used as such in the next step.

The title compound was prepared by stirring the acid (480 mg, 1.16 mmol) in CH ₂ Cl ₂ at room temperature. To the mixture was added Et ₃ N (244 μl), HOBt (188 mg, 1.4 mmol), MeNH ₂ (2.0M-THF, 700 mL, 1.4 mmol) and finally EDC (266 mg, 1.4 mmol) in succession. The homogeneous mixture was then stirred overnight at room temperature. The reaction was quenched with 1N HCl. The layers were separated and the aqueous layer was extracted four times with CH ₂ Cl ₂ . The organic layers were combined, dried and concentrated in vacuo. The crude residue was triturated with a CH ₃ CN-Et ₂ O combination and filtered to give a pure white solid (330 mg, 67%). _{^{1 H-NMR (DMSO -d6 /}} 300 MHz) δ8.20-7.90 (m, 1H), 7.68 (q, J = 8.4 hz, 1H); 7.37 (dt, J = 10.2, 2.4 Hz, 1H); 7.20 (dt, J = 15.6, 4.2 Hz, 1H); 6.60 (s, 1H), 5.63 (d, J = 15.6 Hz, 1H), 5.31 (s, 2H), 4.81 (d, J = 2.7 Hz, 2H), 3.33 (d, J = 6.9 Hz, 1H), 2.61 (d, J = 4.8 Hz, 3H), 2.37 (s, 3H). ES-HRMS m / z 427.0493 (M + H = 427.0463, calculated for C ₁₈ H ₁₈ BrF ₂ N ₂ O ₃ ).

Example 660

Methyl 5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-l (2H) -yl] methyl} -2-furoate

Step 1: 3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one (330.1 mg, 1.00 mmol) and NaH in THF (1.6 mL) To a room temperature suspension of (48.0 mg, 2.0 mmol) was added methyl-5-chloromethyl-2-furoate (400 mg, 2.30 mmol). The resulting suspension was stirred and heated to 68 ° C. for 8 hours until complete consumption of the starting material by LCMS analysis. Then the reaction mixture was diluted with ammonium chloride (saturated aqueous solution, 10 mL) and water (100 mL). The resulting emulsion was then extracted with ethyl acetate (3 x 300 mL). The resulting organic extract was separated, dried over Na ₂ SO ₄ and concentrated. SiO ₂ chromatography using ethyl acetate / hexanes (3: 7) on the resulting dark residue gave a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.53 (app q, J = 8.2 Hz, 1H), 7.07 (d, J = 3.5 Hz, 1H), 6.93 (app dt, J = 8.4, 1.5 Hz, 1H ), 6.84 (app ddd, J = 10.2, 8.7, 2.4 Hz, 1H), 6.53 (d, J = 3.4 Hz, 1H), 6.00 (s, 1H), 5.27 (s, 2H), 5.18 (s, 2H ), 3.85 (s, 3 H), 2.54 (s, 3 H); LC / MS C-18 column, t _r = 2.64 min (detect at 254 nm using 5-95% acetonitrile / water at 1 ml / min over 5 min at 50 ° C.). ES-MS m / z 468 (M + H). ES-HRMS m / z 468.0276 (M + H calculated for C ₂₀ H ₁₇ BrF ₂ NO ₅ : 468.0253).

Example 661

3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4- (hydroxymethyl) -N Methylbenzamide

Step 1: 2- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-[(methylamino ) Carbonyl] benzoic acid

Methyl 2- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4- in THF (10.0 mL) To a room temperature solution of [(methylamino) carbonyl] benzoate (1.05 g, 2.02 mmol) 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 aqueous hydrochloric acid solution (2.0 N, 5.0 mL, 10 mmol). The resulting biphasic solution was separated and the resulting aqueous layer was further extracted with ethyl acetate (2 × 200 mL). The resulting combined organic extracts were dried over Na ₂ SO ₄ , 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 stirred until the precipitate formation stopped (approximately 1.0 hour). The precipitate was collected and dried in vacuo (1.0 mm Hg) to give a solid acid (806 mg, 78%) as an intermediate. ¹ H NMR (400 MHz, d ₇ -DMF) δ 13.19 (s, 1 H), 8.63 (app d, J = 4.5 Hz, 1 H), 8.09 (d, J = 8.0 Hz, 1 H), 8.00 (dd, J = 8.0, 1.6 Hz, 1H), 7.71-7.67 (m, 2H), 7.34 (app dt, J = 9.6, 1.6 Hz, 1H), 7.16 (app dt, J = 8.7, 1.8 Hz, 1H), 6.66 (s, 1 H), 5.33 (s, 2 H), 3.29 (s, 3 H), 1.92 (s, 3 H); LC / MS C-18 column, t _r = 2.15 min (detected at 254 nm using 5 to 95% acetonitrile / water at 1 ml / min over 5 min at 50 ° C.). ES-MS m / z 507 (M + H). ES-HRMS m / z 507.0344 (M + H calculated for C ₂₂ H ₁₈ BrF ₂ N ₂ O ₅ : 507.0362).

Step 2: Preparation of the title compound.

2- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4- [in THF (6.8 mL) To a 0 ° C. solution of (methylamino) carbonyl] benzoic acid (500 mg, 0.986 mmol) was added dropwise a solution of borane-dimethyl sulfide complex (THF solution, 2.0 M, 2.0 mL, 4.0 mmol). The internal temperature of the reaction never exceeded 0 ° C. The resulting solution was maintained for 4.0 hours, at which time the cooling bath was removed and the reaction was held for an additional 2 hours at room temperature. Then ammonium chloride solution (saturated aqueous, 300 mL) was added. The resulting emulsion was extracted with ethyl acetate (3 × 300 mL) and the resulting organic extracts were separated, dried over Na ₂ SO ₄ and concentrated in vacuo to give a residue, ethyl acetate / to the residue. SiO ₂ chromatography with hexanes (6: 4) was performed to give a solid (392 mg, 81%). ¹ H NMR (400 MHz, d ₄ -MeOH) δ 7.96 (dd, J = 8.0, 1.9 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.65 (app q, J = 8.0 Hz, 1H), 7.58 (d, J = 1.7 Hz, 1H), 7.05 (app t, J = 8.5 Hz, 2H), 6.64 (s, 1H), 5.36 (s, 2H), 4.35 (AB-q, J = 14.1 Hz, A = 60.8 Hz, 2H), 2.90 (s, 3H), 2.03 (s, 3H); LC / MS C-18 column, t _r = 2.16 min (detected at 254 nm using 5-95% acetonitrile / water at 1 ml / min over 5 min at 50 ° C.). ES-MS m / z 493 (M + H). ES-HRMS m / z 493.0590 (M + H calculated for C ₂₂ H ₂₀ BrF ₂ N ₂ O ₄ : 493.0596).

Example 662

2- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N, N'-dimethylterephthalamide

Step 1: 2- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl]-in DMF (5.0 mL) 1- (3-dimethylaminopropyl) -ethylcarbodiimide hydrochloride (EDC-HCl, 350.0 mg, 1.83 mmol) in a room temperature solution of 4-[(methylamino) carbonyl] benzoic acid (500 mg, 0.986 mmol) and 1-hydroxy-benzotriazole (HOBT, 100.0 mg, 0.74 mmol) was added sequentially. Then, to the resulting suspension was added a solution of methylamine (2.0 M THF, 1.0 mL, 2.0 mmol). The reaction was stirred for 16.0 hours, at which time the reaction was diluted with ethyl acetate (600 mL). The mixture was washed with water (3 x 200 mL), the organic extracts were saturated, dried over Na ₂ S0 ₄ and concentrated in vacuo to a volume of approximately 60 mL. At this point, a solid precipitate formed which was collected to yield 289 mg (56%). ¹ H NMR (300 MHz, d ₄ -MeOH) δ 8.06 (br d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.73 (s, 1H), 7.70 (app q , J = 7.4 Hz, 1H), 7.09 (app t, J = 8.0 Hz, 2H), 6.65 (s, 1H), 5.39 (s, 2H), 2.96 (s, 3H), 2.79 (s, 3H), 2.13 (s, 3 H); LC / MS C-18 column, t _r = 2.13 min (detect at 254 nm using 5-95% acetonitrile / water at 1 ml / min over 5 min at 50 ° C.). ES-MS m / z 520 (M + H). ES-HRMS m / z 520.0700 (M + H calculated for C ₂₃ H ₂₁ BrF ₂ N ₃ O ₄ : 520.0678).

Example 663

2- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N-4-methylterephthalamide

Step 1: 2- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl]-in THF (1.8 mL)- 2-chloro-4,6-dimethoxy-1,3,5-triazine (140.5 mg, 0.800 mmol) and N in a room temperature suspension of 4-[(methylamino) carbonyl] benzoic acid (302 mg, 0.595 mmol) -Methyl morpholine (NMM, 184 mg, 1.824 mmol) was added continuously. The resulting solution was allowed to mature for 2 hours and then saturated aqueous ammonium hydroxide solution (0.60 mL) was added. The reaction was continued for another hour, at which time a precipitate formed, which was collected, washed with 20 mL of diethyl ether and dried under vacuum to give a solid (201 mg, 66%). ¹ H NMR (400 MHz, d ₆ -DMSO) δ8.59 (br d, J = 8.0, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.83 (s, 1H), 7.72 (d, J = 9.0, 1H), 7.69-7.64 (m, 2H), 7.39-7.31 (m, 1H), 7.19 (app t, J = 8.0 Hz, 1H), 6.60 (s, 1H), 5.31 (s, 2H) , 3.85 (s, 1 H), 2.78 (br d, J = 8.0 Hz, 3H), 1.96 (s, 3H); LC / MS C-18 column, t _r = 2.20 min (detected at 254 nm using 5-95% acetonitrile / water at 1 ml / min over 5 min at 50 ° C.). ES-MS m / z 506 (M + H). ES-HRMS m / z 506.0550 (M + H calculated for C ₂₂ H ₁₉ BrF ₂ N ₃ O ₄ : 506.0522).

Example 664

Methyl 4- (aminocarbonyl) -2- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzo Eight

Step 1: 3- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -4- (methoxycarbonyl) benzoic acid (3.01 g, 9.93 mmol) in DMF (20 mL) To a room temperature solution of 1- (3-dimethylaminopropyl) -ethylcarbodiimide hydrochloride (EDC-HCl, 2.00 g, 10.4 mmol) and 1-hydroxy-benzotriazole (HOBT, 50.0 mg, 0.367 mmol) It was added in turn. 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 stirred for 16.0 hours until LCMS analysis showed complete consumption of starting material. At this time, the reaction vessel was placed on a rotary evaporator under 30 mm Hg vacuum and held at 30 ° C. for 30 minutes to remove any residual ammonia from the reaction mixture. The reaction vessel was removed from the rotary evaporator, then charged with solid N-bromosuccinimide (1.790 g, 10.06 mmol) and the resulting reddish solution stirred for 3.0 hours. At this time, the reaction was charged with K ₂ CO ₃ (3.00 g, 21.7 mmol) and 2,4-difluorobenzyl bromide (1.95 mL, 15.2 mmol). The resulting suspension was stirred for 16.0 hours. At this time, the reaction suspension was diluted with water (400 mL) and extracted with ethyl acetate (3 X 300 mL). The organic extract was separated, dried over Na ₂ SO ₄ and concentrated to give a residue, which was subjected to SiO ₂ chromatography using ethyl acetate / hexanes / methanol (6: 3.5: 0.5) as an off-white solid (1.09 g, 21%). Obtained. ¹ H NMR (400 MHz, d ₄ -MeOH) δ 8.21 (dd, J = 8.5, 1.5 Hz, 1H), 8.09 (dd, J = 7.6, 2.0 Hz, 1H), 7.78 (br s, 1H), 7.65 (app q, J = 7.9 Hz, 1H), 7.03 (app t, J = 8.0 Hz, 2H), 6.63 (s, 1H), 5.37 (s, 2H), 3.75 (s, 3H), 2.02 (s, 3H); LC / MS C-18 column, t _r = 2.28 min (5-95% acetonitrile / water over 5 min, 1 ml / min, detection at 254 nm, 50 ° C.). ES-MS m / z 507 (M + H). ES-HRMS m / z 507.0385 (M + H calculated for C ₂₂ H ₁₈ BrF ₂ N ₂ O ₅ : 507.0362).

Example 665

2- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -N ¹ , N ¹ , N ^4- Trimethylterephthalamide

Step 1: 2- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl]-in DMF (1.8 mL)- 1- (3-dimethylaminopropyl) ethylcarbodiimide hydrochloride (EDC-HCl, 190.0 mg, 1.0 mmol) and 1 in a room temperature solution of 4-[(methylamino) carbonyl] benzoic acid (300 mg, 0.591 mmol) and 1 -Hydroxy-benzotriazole (HOBT, 26.0 mg, 0.191 mmol) was added sequentially. Then to this resulting suspension was added a solution of dimethylamine (2.0 M THF, 0.50 mL, 1.0 mmol). The reaction was stirred for 16.0 hours and the reaction mixture was directly applied to SiO ₂ chromatography with ethyl acetate / hexanes (6: 4) to give a solid (206 mg, 65%). ¹ H NMR (400 MHz, d ₄ -MeOH) δ 8.01 (dd, J = 8.2, 1.5 Hz, 1H), 7.73 (app d, J = 8.1 Hz, 1H), 7.61 (app q, J = 7.2 Hz, 1H), 7.60 (app d, J = 9.5 Hz, 1H), 7.04 (app t, J = 8.0 Hz, 2H), 6.65 (s, 1H), 5.32 (s, 2H), 3.64 (s, 3H), 2.92 (s, 6 H), 2.13 (s, 3 H); LC / MS C-18 column, t _r = 2.20 min (5-95% acetonitrile / water over 5 min, 1 ml / min, detection at 254 nm, 50 ° C.). ES-MS m / z 534 (M + H). ES-HRMS m / z 534.0820 (M + H calculated for C ₂₄ H ₂₃ BrF ₂ N ₃ O ₄ : 534.0835).

Example 666

2- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-[(methylamino) carbonyl ] Benzyl Carbamate

Step 1: 3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] in methylene chloride (5.0 mL) To a room temperature solution of -4- (hydroxymethyl) -N-methylbenzamide (493 mg, 1.00 mmol) was added a solution of trichloroacetyl isocyanate (toluene, 0.53 M, 1.9 mL, 1.0 mmol). The resulting solution was stirred for 1 hour until the starting material was consumed completely by LCMS analysis. Thereafter, the reaction mixture was directly applied to Al ₂ O ₃ (0.5 g of active form I), and the slurry was aged for 3 hours. At this time, the Al ₂ O ₃ plug was washed with ethyl acetate / methanol (95: 5), and the resulting mother liquor was concentrated to give a residue, which was obtained using ethyl acetate / hexane / methanol (6: 3.5: 0.5). Si0 ₂ chromatography gave a white solid (396 mg, 74%). ¹ H NMR (300 MHz, d ₄ -MeOH) δ 8.00 (dd, J = 8.0, 1.7 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.72-7.64 (m, 2H), 7.09 ( app t, J = 8.5 Hz, 2H), 6.69 (s, 1H), 5.40 (s, 2H), 4.85 (m, 2H), 2.90 (s, 3H), 2.10 (s, 3H); LC / MS C-18 column, t _r = 2.15 min (5-95% acetonitrile / water over 5 min, 1 ml / min, detection at 254 nm, 50 ° C.). ES-MS m / z 536 (M + H). ES-HRMS m / z 536.0617 (M + H calculated for C ₂₃ H ₂₁ BrF ₂ N ₃ O ₅ : 536.0627).

Example 667

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluoro-4-vinylphenyl) -6-methylpyridin-2 (1H) -one

Step 1: Preparation of 4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluoro-4-vinylphenyl) -6-methylpyridin-2 (1H) -one

1- (4-bromo-2,6-difluorophenyl) -4-[(2,4-difluorobenzyl) oxy] -6-methylpyridine-2 (1H) in anhydrous THF (30 mL) To a room temperature solution of -one (4.01 g, 9.06 mmol) tributyl (vinyl) tin (5.00 g, 15.7 mmol) and tetrakis (triphenylphosphine) palladium (1.00 g, 0.865 mmol) were added sequentially under an argon stream. . The reaction vessel was then equipped with a reflux condenser and the reaction system was purged with argon flow. The resulting yellow solution was heated to 68 ° C. and stirred for 12.0 h under positive pressure of argon until the starting material disappeared completely by LCMS analysis. The reaction mixture was diluted with 300 mL of brine and extracted with ethyl acetate (3 X 300 mL). The organic extract was separated, dried over Na ₂ SO ₄ , concentrated in vacuo and the resulting dark residue was chromatographed with SiO ₂ using ethyl acetate / hexanes (1: 1) to give a yellowish solid (3.18 g, 90 %) Was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41 (app q, J = 8.0 Hz, 1H), 7.08 (app d, J = 8.3 Hz, 2H), 6.90 (app t, J = 7.2 Hz, 1H), 6.85 (app t, J = 7.4 Hz, 1H), 6.63 (dd, J = 17.5, 10.9 Hz, 1H), 5.96 (app d, 15.8 Hz, 1H), 5.94 (app d, J = 15.8 Hz, 1H) , 5.79 (d, J = 17.4 Hz, 1H), 5.43 (d, J = 10.9 Hz, 1H), 5.01 (br s, 2H), 1.99 (s, 3H); LC / MS C-18 column, t _r = 2.93 min (5-95% acetonitrile / water over 5 min, 1 ml / min, detection at 254 nm, 50 ° C.). ES-MS m / z 390 (M + H). ES-HRMS m / z 390.1095 (M + H calculated for C ₂₁ H ₁₆ F ₄ NO ₂ : 390.1112).

Step 2: 4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluoro-4-vinylphenyl) -6-methylpyridine-2 (in methylene chloride (10 mL) To a strongly stirred room temperature solution of 1H) -one (721 mg, 1.85 mmol) was added solid N-bromosuccinimide (330 mg, 1.86 mmol) and the resulting reddish solution was stirred for 10 minutes. At this time, the reaction was diluted with ethyl acetate (100 mL) and washed with sodium sulfite (5% aqueous solution, 50 mL). The resulting organic extract was dried over Na ₂ S0 ₄ , filtered and concentrated in vacuo to a volume of about 50 mL. The resulting mother liquor precipitated rapidly and the collected amorphous solid was obtained and dried under 1 mm Hg vacuum to give a solid (610 mg, 70%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.59 (app q, J = 8.0 Hz, 1H), 7.09 (app d, J = 8.3 Hz, 2H), 6.95 (app t, J = 7.2 Hz, 1H), 6.87 (app t, J = 7.4 Hz, 1H), 6.62 (dd, J = 17.5, 10.9 Hz, 1H), 6.12 (s, 1H), 5.81 (d, J = 17.4 Hz, 1H), 5.43 (d, J = 10.9 Hz, 1H), 5.25 (br s, 2H), 2.07 (s, 3H); LC / MS C-18 column, t _r = 3.17 min (5-95% acetonitrile / water over 5 min, 1 ml / min, detection at 254 nm, 50 ° C.). ES-MS m / z 468 (M + H). ES-HRMS m / z 468.0249 (M + H calculated for C ₂₁ H ₁₅ BrF ₄ NO ₂ : 468.0217).

Example 668

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [4- (1,2-dihydroxyethyl) -2,6-difluorophenyl] -6-methyl Pyridin-2 (1H) -one

Step 1: Preparation of the title compound

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2,6-difluoro-4-vinylphenyl) -6 in water / acetone 1: 3 (8.0 mL) N-methyl morpholine oxide (268.0 mg, 2.29 mmol) and osmium tetraoxide (4% aqueous solution, 0.25 mL or about 10) in turn to a room temperature solution of -methylpyridin-2 (1H) -one (408.0 mg, 0.871 mmol) mg, 0.039 mmol) was added. The resulting solution was stirred for 8 h until complete consumption of the starting material by LCMS analysis, and the reaction was concentrated in vacuo to 1/4 the original volume. The resulting solution was diluted with ethyl acetate (300 mL) and washed with water (2 × 100 mL). The organic extract was separated, dried over Na ₂ SO ₄ , concentrated in vacuo and the resulting dark residue was purified by SiO ₂ chromatography with ethyl acetate / hexanes / methanol (6: 3.5: 0.5) to give a solid (389 mg). , 88%) was obtained. ¹ H NMR (400 MHz, d ₄ -MeOH) δ 7.62 (app q, J = 8.0 Hz, 1H), 7.26 (dd, J = 9.6, 4.5 Hz, 2H), 7.04 (app t, J = 8.6 Hz, 2H), 6.67 (s, 1H), 5.36 (s, 2H), 4.75 (app t, J = 5.6 Hz, 1H), 3.68-3.61 (m, 2H), 2.11 (s, 3H); LC / MS C-18 column, t _r = 2.26 min (5-95% acetonitrile / water over 5 min, 1 ml / min, detection at 254 nm, 50 ° C.). ES-MS m / z 502 (M + H). ES-HRMS m / z 502.0247 (M + H calculated for C ₂₁ H ₁₇ BrF ₄ NO ₄ : 502.0272).

Example 669

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

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [4- (1,2-dihydroxyethyl) -2,6-difluoro in toluene (3.0 mL) To a room temperature solution of phenyl] -6-methylpyridin-2 (1H) -one (310 mg, 0.615 mmol) was added lead (IV) (443 mg, 1.63 mmol). The resulting dark brown solution was stirred for 1 hour until the starting material was consumed completely by LCMS analysis. Then, the reaction mixture was diluted with ethyl acetate (100 mL), washed with water (3 X 100 mL), and brine (3 X 30 mL). The resulting organic extract was separated, dried over Na ₂ SO ₄ and concentrated. The resulting dark residue was SiO ₂ chromatographed with ethyl acetate / hexanes (1: 1) to give a light yellow solid (269 mg, 93%). Note that the product is easily air oxidized. ¹ H NMR (300 MHz, d ₄ -MeOH) δ 10.05 (s, 1H), 7.68 (app q, J = 7.2 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.05 (app t, J = 8.2 Hz, 2H), 6.73 (s, 1H), 5.40 (s, 2H), 2.15 (s, 3H); LC / MS C-18 column, t _r = 2.72 min (5-95% acetonitrile / water over 5 min, 1 ml / min, detection at 254 nm, 50 ° C.). ES-MS m / z 470 (M + H). ES-HRMS m / z 470.0049 (M + H calculated for C ₂₀ H ₁₃ BrF ₄ NO ₃ : 470.0009).

Example 670

4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3,5-difluorobenzyl carbox Barmate

Step 1: 4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl]-in methanol (10 mL) To a room temperature solution of 3,5-difluorobenzaldehyde (220 mg, 0.468 mmol) was added solid sodium borohydride (60.0 mg, 1.58 mmol). The resulting solution was evacuated for about 0.5 minutes and stirred for an additional 10 minutes until the starting material was consumed completely by LCMS analysis. The reaction was then diluted with saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (4 X 50 mL). The organic extract was separated, dried over Na ₂ SO ₄ and concentrated to give 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 stirred for 1 hour until the starting material was consumed completely by LCMS analysis. The reaction mixture was then applied directly to Al ₂ O ₃ (0.5 g of active form I) and the slurry was aged for 3 hours. At this time, Al ₂ 0 ₃ The plug was washed with ethyl acetate / methanol (95: 5) and the resulting mother liquor was concentrated to give a residue, which was subjected to SiO ₂ chromatography with ethyl acetate / hexanes / methanol (6: 3.8: 0.2) to give a white solid. (181 mg, 75%) was obtained. ¹ H NMR (400 MHz, d ₄ -MeOH) δ 7.63 (app q, J = 8.0 Hz, 1H), 7.43 (d, J = 8.2 Hz, 2H), 7.04 (app t, J = 8.1 Hz, 2H) , 6.68 (s, 1H), 5.37 (s, 2H), 5.12 (m, 2H), 2.11 (s, 3H); LC / MS C-18 column, t _r = 2.54 min (5-95% acetonitrile / water over 5 min, 1 ml / min, detection at 254 nm, 50 ° C.). ES-MS m / z 515 (M + H). ES-HRMS m / z 515.0232 (M + H calculated for C ₂₁ H ₁₆ BrF ₄ N ₂ O ₄ : 515.0234).

Examples 671-687

The following compounds are prepared mainly following the schemes and methods outlined in the above examples.

Example 701

N- (4-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzyl) -2- Hydroxyacetamide

Step 1. Preparation of 1- [4- (aminomethyl) benzyl] -3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one

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 mL, 2.0 M in tetrahydrofuran, 11.7 mmol) was added. The resulting mixture was heated to reflux overnight and cooled to room temperature. The flask was placed in 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 cooled in an ice bath. The reaction was quenched by addition of 1.0 N HCl (75.0 mL) and then partially concentrated. The aqueous layer was made alkaline with 2.5 N NaOH and a precipitate formed. The solid was collected by filtration and washed with diethyl ether to give a pale purple solid (3.00 g, 32%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.64 (app q, J = 7.9 Hz, 1H), 7.44 (d, J = 7.9 Hz, 2H), 7.32 (app dt, J = 2.4, 9.9 Hz, 1H), 7.14 (app dt, J = 1.9, 8.5 Hz, 1H), 7.13 (d, J = 7.9 Hz, 2H), 6.61 (s, 1H), 5.27 (s, 4H), 3.90 (s, 2H) , 2.29 (s, 3 H).

Step 2. N- (4-{[3-Chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzyl) Preparation of 2-hydroxyacetamide

Acetoxyacetic acid (1.46 g, 12.35 mmol) is dissolved in N, N-dimethylformamide (30 mL) and 1-hydroxybenzotriazole (1.84 g, 13.59 mmol) is added, followed by 4-methylmorpholine (2.04 mL, 18.53 mmol), 1- [4- (aminomethyl) benzyl] -3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridine-2 (1H)- Warm (compound from step 1) (2.50 g, 6.18 mmol) was then added 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (2.84 g, 14.83 mmol). The resulting mixture was stirred at rt for 1 h and the reaction diluted with H ₂ O (100 mL). Then the reaction mixture was extracted with ethyl acetate. The combined organic extracts are washed with saturated NaHCO ₃ , brine, Na ₂ SO ₄ Dried over, filtered and concentrated. Chromatography (silica gel, hexane / ethyl acetate with 10% methanol) gave a white foam. The resulting foam was dissolved in 10% aqueous methanol (20 mL). K ₂ CO ₃ (0.653 g, 4.73 mmol) was added and the mixture was stirred at rt for 2 h. The reaction mixture was concentrated and H ₂ O (50 mL) was added. The resulting precipitate was collected by filtration and washed with diethyl ether to give an off white solid (1.34 g, 47%). ¹ H NMR (400 MHz, CDC1 ₃ ) δ 7.50 (app q, J = 7.7 Hz, 1H), 7.27 (app t, J = 5.8 Hz, 1H), 7.12 (d, J = 8.1 Hz, 2H), 6.97 (d, J = 8.1 Hz, 2H), 6.94-6.89 (m, 1H), 6.86-6.81 (m, 1H), 6.09 (s, 2H), 5.23 (s, 2H), 5.18 (s, 2H), 4.53 (t, J = 5.8 Hz, 1H), 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 calculated for C ₂₃ H ₂₂ ClF ₂ N ₂ O ₄ : 463.1231).

Example 702

N- (4-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzyl) -1- Hydroxycyclopropanecarboxamide

N- (4-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} benzyl) -1- Preparation of hydroxycyclopropanecarboxamide

1-hydroxy-1-cyclopropane-carboxylic acid (1.26 g, 12.35 mmol) was dissolved in N, N-dimethylformamide (30 mL). 4-methylmorpholine (2.04 mL, 18.53 mmol), 1- [4- (aminomethyl) benzyl] -3-chloro-4- after addition of 1-hydroxybenzotriazole (1.84 g, 13.59 mmol) [(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one (Example 701, step 1) (2.50 g, 6.18 mmol) was then added 1- [3- ( Dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (2.84 g, 14.83 mmol) was added. The resulting mixture was stirred at rt for 24 h and the reaction diluted with H ₂ O (100 mL). Then the reaction mixture was extracted with ethyl acetate. The combined organic extracts were washed with saturated NaHCO ₃ , brine, dried over Na ₂ SO ₄ , filtered and concentrated. Chromatography (silica gel, hexane / ethyl acetate with 10% methanol) gave a white foam. The resulting foam was dissolved in 10% aqueous methanol (20 mL) to give a white foam (1.45 g, 48%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.52-7.46 (m, 1H), 7.34 (t, J = 5.9 Hz, 1H), 7.08 (d, J = 8.2 Hz, 2H), 6.92 (app d, J = 8.2 Hz, 2H), 6.92-6.89 (m, 1H), 6.86-6.81 (m, 1H), 6.11 (s, 1H), 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 calculated for C ₂₅ H ₂₄ ClF ₂ N ₂ O ₄ : 489.1387).

Example 703

4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (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

The compound of Example 206 (0.868 g, 1.93 mmol) was dissolved in dichloromethane (7.0 mL). Trichloroacetyl isocyanate (4.00 mL, 0.53 M in toluene, 2.12 mmol) was added. The resulting mixture was stirred at rt for 3 h, then diluted with tetrahydrofuran (50 mL), Al ₂ O ₃ (5.0 g) was added and the mixture was stirred at rt overnight. The reaction mixture was filtered through a pad of Celite® and washed with methanol. The filtrate was then concentrated and the residue was redissolved in tetrahydrofuran (30 mL). Al ₂ O ₃ (5.0 g) was added and the mixture was heated to 40 ° C. for 3 hours. After cooling to room temperature, the reaction was filtered through a pad of Celite® and washed 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%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.54 (app q, J = 7.7 Hz, 1H), 7.25 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 8.2 Hz, 2H), 6.25 ( app dt, J = 2.0, 8.3 Hz, 1H), 6.86-6.30 (m, 1H), 5.97 (s, 1H), 5.32 (s, 2H), 5.18 (s, 2H), 5.02 (s, 2H), 4.81 (br s, 2 H), 2.25 (s, 3 H). ES-HRMS m / z 493.0580 (M + H calculated for C ₂₂ H ₂₀ BrF ₂ N ₂ O ₄ : 493.0569).

Example 704

2-[(4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-l (2H) -yl] methyl} phenyl) amino ] -1-methyl-2-oxoethyl acetate

To the reaction vessel (borosilicate culture tube) was added the compound of Example 611 (0.300 g, 0.69 mmol) and dichloromethane (3.0 mL). After addition of the stock solution of N-methylmorpholine (0.30 M, 3.0 mL), the parallel reactor was shaken by running at room temperature at about 200 RPM for 10 minutes (Labline Benchtop Orbital Shaker). . Thereafter, (S)-(-)-2-acetoxypropionyl chloride (0.131 mL, 1.04 mmol) was added to the reaction vessel, and the reaction apparatus was rotary shaken at room temperature for 1.5 hours. At this time, the reaction was diluted with dichloromethane (20 mL), treated with about 2.1 g of polyamine resin (2.63 mmol / g) and about 3.8 g of methylisocyanate functionalized polystyrene (1.10 mmol / g), and continued at room temperature overnight. Rotational shaking at 200 RPM. The reaction vessel was then opened and the solution phase product was separated from the insoluble quenched by-product by filtration and collection into vials. The insoluble byproduct was partially evaporated and then rinsed with dichloromethane (2 x 10 mL). The filtrate was evaporated by blowing N ₂ onto the vial to yield an off white solid (0.375 g, 99%). ¹ H NMR (400 MHz, DMF-d ₆ ) δ 10.14 (s, 1H), 7.75 (app dt, J = 6.98, 8.59 Hz, 1H), 7.67-7.64 (m, 2H), 7.30 (ddd, J = 2.55, 9.26, 11.81 Hz, 1H), 7.21-7.17 (m, 3H), 6.61 (s, 1H), 5.37 (s, 4H), 5.11 (q, J = 6. 85 Hz, 1H), 2.40 (s , 3H), 2.10 (s, 3H), 1.46 (d, J = 6.85 Hz, 3H). ES-HRMS m / z 549.0790 (M + H calculated for C ₂₅ H ₂₃ BrF ₂ N ₂ O ₅ : 549.0831).

Example 705

2-[(4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} phenyl) amino ] -1,1-dimethyl-2-oxoethyl acetate

The title compound was prepared by the method of Example 704 and by replacing (S)-(-)-2-acetoxypropionyl chloride with 2-acetoxy-2-methylpropionyl chloride (0.380 g, 98 %). ¹ H NMR (400 MHz, DMF-d ₆ ) δ 9.68 (s, 1H), 7.75 (app dt, J = 6.72, 8.60 Hz, 1H), 7.71-7.68 (m, 2H), 7.30 (ddd, J = 2.55, 9.40, 11.95 Hz, 1H), 7.21-7.15 (m, 3H), 6.61 (s, 1H), 5.37 (s, 4H), 2.41 (s, 3H), 2.04 (s, 3H), 1.59 (s , 6H). ES-HRMS m / z 563.1027 (M + H calculated for C ₂₆ H ₂₅ BrF ₂ N ₂ O ₅ : 563.0988).

Example 706

{1- [3- (aminocarbonyl) phenyl] -5-chloro-4-[(2,4-difluorobenzyl) oxy] -6-oxo-1,6-dihydropyridin-2-yl} Methyl acetate

Step 1: Preparation of {1- [3- (aminocarbonyl) phenyl] -4-hydroxy-6-oxo-1,6-dihydropyridin-2-yl} methyl acetate

3- (2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl) -2-oxopropyl acetate (4.00 g, 16.52 mmol) was added 1,4-dioxane (160 mL) In water and 3-aminobenzamide (1.73 g, 12.71 mmol) was added. The reaction was heated to reflux for 1 hour and then cooled to 70 ° C. Methanesulfonic acid (1.22 g, 12.71 mmol) was added and the reaction was again heated to reflux for 1 hour. The reaction was cooled to rt, concentrated and used as crude product for the next step.

Step 2: {1- [3- (aminocarbonyl) phenyl] -4-[(2,4-difluorobenzyl) oxy] -6-oxo-1,6-dihydropyridin-2-yl} methyl Preparation of Acetate

{1- [3- (aminocarbonyl) phenyl] -4-hydroxy-6-oxo-1,6-dihydropyridin-2-yl} methyl acetate (prepared from step 1) (3.61 g, 11.94 mmol ) Was dissolved in N, N-dimethylformamide (40 mL). K ₂ CO ₃ (3.80 g, 27.46 mmol) was added followed by 2,4-difluorobenzyl bromide (5.44 g, 26.27 mmol). The reaction mixture was stirred for 48 hours at room temperature. The reaction mixture is then partially concentrated and the residue is dissolved in dichloromethane / tetrahydrofuran 1: 1 and filtered. The filtrate was collected, concentrated and the residue triturated with dichloromethane to give a tan solid (1.64 g, 32%). ¹ H NMR (400 MHz, DMF-d ₆ ) δ 8.19 (br s, 1H), 8.07 (app dt, J = 1.35, 7.66 Hz, 1H), 7.91 (app t, J = 1.81 Hz, 1H), 7.76 (app dt, J = 6.58, 8.59 Hz, 1H) 7.62 (t, J = 7.79 Hz, 1H), 7.55 (ddd, J = 1.21, 2.01, 7.79 Hz, 1H), 7.46 (br s, 1H), 7.34 (ddd, J = 2.55, 9.40, 10.47 Hz, 1H), 7.23- 7.18 (m, 1H), 6.26 (d, J = 2.55 Hz, 1H), 6.11 (d, J = 2.69 Hz, 1H), 5.23 ( s, 2H), 4.62 (AB q, J _AB = 14.97 Hz, 2H), 1.96 (s, 3H). ES-HRMS m / z 429.1280 (M + H calculated for C ₂₂ H ₁₈ F ₂ N ₂ O ₅ : 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 (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 stirred at 40 ° C. for 1.5 h. The reaction was cooled to room temperature and a precipitate formed. The reaction mixture was diluted with diethyl ether and the precipitate collected by filtration and washed with diethyl ether (3 x 15 mL) to give a tan solid (0.940 g, 85%). ¹ H NMR (400 MHz, DMF-d ₆ ) δ 8.21 (br s, 1H), 8.11 (app dt, J = 1.48, 7.52 Hz, 1H), 7.95 (app t, J = 1. 61 Hz, 1H) , 7.80 (app dt, J = 6.72, 8.59 Hz, 1H) 7.69-7.60 (m, 2H), 7.48 (br s, 1H), 7.35 (ddd, J = 2.55, 9.53, 10.61 Hz, 1H), 7.24- 7.19 (m, 1 H), 6.97 (s, 1 H), 5.49 (s, 2 H), 4.71 (AB q, J _AB = 15.04 Hz, 2H), 1.98 (s, 3H). ES-HRMS m / z 463.0883 (M + H calculated for C ₂₂ H ₁₇ ClF ₂ N ₂ O ₅ : 463.0867).

Example 707

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-{[2- (methylthio) pyrimidin-5-yl] methyl} pyridine-2 (1H) -On

Step 1. Preparation of Methyl 2- (methylthio) pyrimidine-5-carboxylate

Sodium salt of 3,3-dimethoxy-2-methoxycarbonylpropen-1-ol (5.0 g, 25 mmol) in anhydrous methanol (25 mL), 2-methyl-2-thioshudorea sulfate (3.5 g, 25 mmol) was refluxed under anhydrous conditions for 3 hours. The reaction mixture was cooled down and diluted with ethyl acetate. The reaction mixture is filtered and the residue is washed with ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography (silica gel) using 25% ethyl acetate in hexanes to give the desired product (3.5 g, 75%) as a white powder. ¹ H-NMR (d ₆ -DMSO, 400 MHz) δ 9.0 (s, 2H), 3.92 (s, 3H), 2.58 (s, 3H); ES-HRMS m / z 185.041 (M + H required for C ₇ H ₈ N ₂ O ₂ S: 185.0379).

Step 2. Preparation of [2- (methylthio) pyrimidin-5-yl] methanol

To a cold suspension of methyl 2- (methylthio) pyrimidine-5-carboxylate (1.74 g, 9.4 mmol) in dichloromethane (20 mL, -70 ° C.) add DIBAL (20.8 mL, 20 mmol) via a funnel Added dropwise. The mixture was stirred 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 (10 g) in water (50 mL). The slurry was filtered through celite and the filtrate was concentrated. The residue was purified by flash chromatography (100 silica gel) using 100% ethyl acetate to afford the desired compound (0.7813 g, 39%) as a yellow solid. ¹ H-NMR ((CD ₃ OD, 400 MHz) δ 8.53 (s, 2H), 4.56 (s, 2H), 2.54 (s, 3H); ES-HRMS m / z 157.0409 (C ₆ H ₈ N ₂ OS M + H requirement for: 157.0430).

Step 3. Preparation of 5- (chloromethyl) -2- (methylthio) pyrimidine

To a cold solution of [2- (methylthio) pyrimidin-5-yl] methanol (0.7813 g, 5.0 mmol) in anhydrous dichloromethane (10 mL, 0 ° C.) was added triethylamine (0.836 mL, 8.2 mmol). Then methanesulfonyl chloride (0.465 mL, 6.0 mmol) was added. The reaction mixture was stirred at 0 ° C. under nitrogen 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 extract was concentrated and the residue was purified by flash chromatography (silica gel) using 15% ethyl acetate in hexanes to give the desired compound (0.720 g, 82%) as a white solid. ¹ H-NMR ((CD ₃ OD, 400 MHz) δ 8.60 (s, 2H), 4.64 (s, 2H), 2.54 (s, 3H); ES-HRMS m / z 175.0106 (C ₆ H ₇ N M + H requirement for ₂ ClS: 175.0091).

Step 4. 3-Bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-{[2- (methylthio) pyrimidin-5-yl] methyl} pyridine- Preparation of 2 (1H) -one

To a solution of 5- (chloromethyl) -2- (methylthio) pyrimidine (0.62 g, 3.56 mmol) in anhydrous DMF (10 mL) was added KBr (0.424, 3.56 mmol). The suspension was stirred at rt for 30 min, then 3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one (1.05 g, 3.19 mmol) After addition, NaH (0.102 g, 4.25 mmol) was added. The reaction mixture was stirred at 70 ° C. under nitrogen atmosphere for 3.5 h. The solvent was distilled off and the residue was washed with water and extracted with ethyl acetate. The organic extract was concentrated and the residue was purified by reverse phase HPLC using 10-90% acetonitrile / water (30 min gradient) at 70 mL / min flow rate to give the desired TFA salt (0.32 g, 15%) as a white powder. Obtained. The TFA compound was washed with sodium bicarbonate (5%) and extracted with dichloromethane. The organic extract was concentrated to give the desired compound (0.295 g, 18%) as a yellow solid. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.47 (s, 2H), 7.62 (q, 1H, J = 8 Hz), 7.03 (m, 2H), 6.51 (s, 1H), 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 required for C ₁₉ H ₁₆ N ₃ O ₂ F ₂ BrS: 468.0187 / 470.0168).

Example 708

3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-{[2- (methylsulfonyl) pyrimidin-5-yl] methyl} pyridine-2 (1H )-On

Acetonitrile: 3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-{[2- (methylthio) in water (4: 1 v / v, 10 mL) To a solution of pyrimidin-5-yl] methyl} pyridin-2 (1H) -one (Example 707) (0.26 g, 0.55 mmol) was added MMPP (0.549 g, 1.1 mmol). The reaction was stirred at rt 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 10-90% acetonitrile / water (30 min gradient) at 70 mL / min flow rate to give the desired TFA salt of the title compound (0.13 g, 38%) as white. Obtained as a powder. ¹ H-NMR ((CD ₃ OD, 400MHz) δ 8.86 (s, 2H), 7.62 (q, 1H, J = 8Hz), 7.02 (m, 2H), 6.56 (s, 1H), 5.48 (s, 2H ), 5.31 (s, 2H), 3.34 (s, 3H), 2.49 (s, 2H); M-H requirements for ES-HRMS m / z 500.0109 / 502.0066 (C ₁₉ H ₁₆ N ₃ O ₄ F ₂ BrS) : 500.0086 / 502.0067).

Example 709

Ethyl 2-({[3-bromo-1- (5-{[(2-hydroxyethyl) amino] carbonyl} -2-methylphenyl) -6-methyl-2-oxo-1,2-dihydro Pyridin-4-yl] oxy} methyl) -5-fluorobenzylcarbamate

3- [3-bromo-4-[(2-{[(ethoxycarbonyl) amino] methyl} -4-fluorobenzyl) oxy] -6-methyl-2-oxopyridine-1 (2H in DMF Isobutyl chloroformate (0.07 mL, 0.55 mmol) in a cooled (-10 ° C.) solution of) -yl] -4-methylbenzoic acid (0.25 g, 0.46 mmol) and 4-methylmorpholine (0.06 mL, 0.55 mmol) ) Was added. The colorless solution gradually turned dark brown. After 30 minutes, ethanolamine (0.04 mL, 0.69 mmol) was added and the solution was allowed to warm to room temperature. After 1 hour, the solvent was removed and the crude product was purified by preparative HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHCO ₃ (20 mL) and extracted in DCM (3 × 15 mL). The organic extract was dried over Na ₂ S0 ₄ , filtered and concentrated to give a white solid and dried under vacuum (0.09 g, 33%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.88 (m, 1H), 7.61 (s, 1H), 7.53 (m, 2H), 7.13 (m, 1H), 7.05 (m, 1H), 6.68 (s , 1H), 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 590.1266 and 592.1254 (M + H calculated for C ₂₇ H ₃ OBrFN ₃ O ₆ : 590.1297 and 592.1281).

Example 710

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [5- (1H-imidazol-2-yl) -2-methylphenyl] -6-methylpyridine-2 (1H) -one trifluoroacetate

Oven dried flasks were alternately evacuated and washed with argon. Toluene (2.18 mL) and trimethyl aluminum (1.25 mL, 2.51 mmol) were added sequentially and the solution was 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-1 (2H) -yl] -4-methylbenzoate (0.75 g , 1.57 mmol) was added in portions to the cooled solution. The reaction mixture was then refluxed at 110 ° C. for 4 hours. The solution was cooled and water (0.7 mL), DCM (2.2 mL), and MeOH (2.2 mL) were added. After this addition, the solution was refluxed for 15 minutes, then dried over Na ₂ S0 ₄ , filtered and concentrated. The residue is dissolved in EtOAc (20 mL), refluxed for 15 minutes, Na ₂ SO ₄ Dried over, filtered and concentrated. The crude product was purified by preparative HPLC. The product was isolated by freeze drying and the solvent was evaporated to give a white solid which was dried under vacuum (0.30 g, 31%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.88 (m, 1H), 7.71 (d, 1H, J = 8.0 Hz), 7.64 (m, 2H), 7.05 (m, 2H), 6.70 (s, 1H) , 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 C ₂₃ H ₂₁ BrF ₂ N ₃ O ₂ : 488.0780 and 490.0762).

Example 711

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [5- (5-hydroxy-1H-pyrazol-3-yl) -2-methylphenyl] -6-methyl Pyridin-2 (1H) -one

Step 1: ethyl 3- {3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4- Preparation of Methylphenyl} -3-oxopropanoate

In an oven dried round bottom flask, 3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (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 dissolution. Stir overnight at room temperature. Solvent was removed and the crude acid chloride was co-evaporated with DCM (3-5 mL × 3) and dried in vacuo to give an orange solid. In a separate oven dried flask, a solution of monoethyl malonate (0.38 mL, 3.23 mmol) in THF (3.00 mL) was cooled to -78 ° C under argon atmosphere. Isopropyl magnesium chloride (3.23 mL, 6.46 mmol) was added dropwise. The solution was stirred for 30 min at -78 ° C. The acid chloride prepared as described above was added dropwise as a solution in THF. The reaction was warmed to room temperature. After 30 minutes, the reaction was cooled (0 ° C.) and 10% citric acid (5.0 mL) was added. The crude product was extracted in EtOAc, washed with 5% NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated to give a brown crude oil. Recrystallized from DCM and hexanes. The beige solid was filtered off and dried under vacuum (0.41 g, 47%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.02 (m, 1H), 7.79 (s, 1H), 7.65 (m, 2H), 7.05 (t, 2H, J = 9.2 Hz), 6.66 (s, 1H ), 5.36 (s, 2H), 4.16 (q, 2H, 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 C ₂₅ H ₂₃ BrF ₂ NO ₅ : 534.0722 and 536.0706).

Step 2: Preparation of the title compound

Ethyl 3- {3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] in EtOH (5.00 mL) To a mixture of -4-methylphenyl} -3-oxopropanoate (from step 1) (0.20 g, 0.37 mmol) was added hydrated hydrazine (0.01 mL, 0.41 mmol). The reaction mixture was heated at 60 ° C. with a condenser. After 1 hour, additional hydration hydrazine (0.01 mL) was added. After 2 hours acetic acid (2 drops) was added. After 4 hours, additional hydrazine was added (0.1 mL). After 5 hours, the reaction appeared to be complete. It was left in the refrigerator overnight. The precipitate was filtered off, washed with hexane and the product white solid (0.10 g, 54%) was obtained. ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.66 (m, 2H), 7.45 (m, 2H), 7.05 (t, 2H, J = 9.6 Hz), 6.65 (s, 1H), 5.36 (s, 2H ), 2.04 (s, 3H), 2.02 (s, 3H). ESHRMS m / z 502.0552 and 504.0569 (M + H calculated for C ₂₃ H ₁₉ BrF ₂ N ₃ O ₃ : 502.0572 and 504.0555).

Example 712

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [5- (5-hydroxyisoxazol-3-yl) -2-methylphenyl] -6-methylpyridine-2 (1H) -on

Ethyl 3- {3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] in EtOH (3.00 mL) A solution of -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) at 60 ° C. Heated with condenser overnight. Additional triethylamine (0.06 mL) and hydroxylamine hydrochloride (0.03 g) were added. After 2.5 hours, the addition of triethylamine and hydroxylamine hydrochloride was repeated. After 1 hour, the reaction was concentrated and purified by preparative HPLC. The product was isolated by lyophilization and the solvent was evaporated to give a white solid. The solid was dissolved in DCM. 5% NaHCO ₃ was added and the solution became a milky emulsion. Additional DCM and some brine were added. The organic extract was dried over Na ₂ SO ₄ , filtered and concentrated to give a pink solid and dried under vacuum (120 mg, 64%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.66 (m, 2H), 7.44 (m, 2H), 7.04 (t, 2H, J = 8.8 Hz), 6.64 (s, 1H), 5.36 (s, 2H ), 2.04 (s, 3H), 2.01 (s, 3H). ESHRMS m / z 503.0415 and 505.0402 (M + H calculated for C ₂₃ H ₁₈ BrF ₂ N ₂ O ₄ : 503.0413 and 505.0395).

Example 713

3- [4-{[2-({[(cyclopropylamino) carbonyl] amino} methyl) -4-fluorobenzyl] oxy} -6-methyl-2-oxopyridin-1 (2H) -yl] -N, 4-dimethylbenzamide

3- [4-{[2-({[(cyclopropylamino) carbonyl] amino} methyl) -4-fluorobenzyl] oxy} -6-methyl-2-oxopyridine-1 in DMF (3.00 mL) 4-methyl in a cooled (-15 ° C.) solution of (2H) -yl] -4-methylbenzoic acid (see Example 651) (0.30 g, 0.63 mmol) and isobutyl chloroformate (0.10 mL, 0.75 mmol) Morpholine (0.08 mL, 0.75 mmol) was added. The solution immediately turned yellow and became dark brown in minutes. After 20 minutes, methylamine (0.47 mL of 2.0 M solution in THF, 0.94 mmol) was added. The reaction was carried out at room temperature. After 2.5 hours, catalytic amount of DMAP and additional methylamine (0.47 mL, 0.94 mmol) were added. After an additional 2.5 hours, the reaction was concentrated to give a dark red oil. The crude product was purified by preparative HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHCO ₃ (20 mL) and extracted in DCM (3 × 15 mL). The organic extract was dried over Na ₂ S0 ₄ , filtered and concentrated to give an off-white solid and dried under vacuum (0.06 g, 19%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.85 (m, 1H), 7.58 (s, 1H), 7.48 (m, 2H), 7.14 (m, 1H), 7.02 (m, 1H), 6.23 (s , 1H), 6.09 (s, 1H), 5.20 (s, 2H), 4.45 (s, 2H), 2.90 (s, 3H), 2.49 (m, 1H), 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 C ₂₇ H ₃₀ N ₄ O ₄ F: 493.2246).

Example 714

Methyl 4-{[4-[(2,4-difluorobenzyl) oxy] -2-oxoquinolin-1 (2H) -yl] methyl} benzoate

Step 1: Preparation of 3-bromo-4-[(2,4-difluorobenzyl) oxy] quinolin-2 (1H) -one.

CH ₂ Cl ₂ To a room temperature solution of 4-hydroxy-1,2-dihydroquinolin-2-one (500 mg, 3.10 mmol) in (10.0 mL) was added solid N-bromosuccinimide (551.5 mg, 3.10 mmol) in portions. Add in portions. After the reaction was stirred vigorously for 1.0 h, K ₂ CO ₃ (540 mg, 3.90 mmol), DMF (4.0 mL) and 2,4-difluorobenzyl bromide (0.430 mL, 3.30 mmol) were added successively. . The resulting suspension was stirred for 4.5 hours until complete formation of the desired product was shown by LCMS analysis. The reaction was then diluted with ethyl acetate (400 mL) and washed with brine (3 X 200 mL). The resulting organic extract was dried over Na ₂ S0 ₄ , filtered, concentrated in vacuo and the residue was Si0 ₂ chromatographed with ethyl acetate / hexanes / methanol (60: 35: 5) to give a solid (529 mg). , 47%). ¹ H NMR (300 MHz, d ₆ -DMSO) δ 12.23 (s, 1H), 7.68 (app q, J = 7.5 Hz, 1H), 7.64 (app q, J = 8.5 Hz, 1H), 7.54 (app q , J = 8.3 Hz, 1H), 7.38-7.27 (m, 2H), 7.20 (app t, J = 7.4 Hz, 1H), 7.13 (app dt, J = 8.4, 2.6 Hz, 1H), 5.25 (s, 2H); LC / MS C-18 column, t _r = 2.64 min (5-95% acetonitrile / water over 5 min, 1 ml / min, detection wavelength 254 nm, 50 ° C.). ES-MS m / z 366 (M + H). ES-HRMS m / z 365.9967 (M + H calculated for C ₁₆ H ₁₁ BrF ₂ NO ₂ : 365.9936).

Step 2: Preparation of methyl 4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -2-oxoquinolin-1 (2H) -yl] methyl} benzoate.

Solid sodium hydride (95) in a room temperature solution of 3-bromo-4-[(2,4-difluorobenzyl) oxy] quinolin-2 (1H) -one (400 mg, 1.09 mmol) in THF (4.5 mL). % Oil free, 60.0 mg, 2.49 mmol) was added in portions. The reaction was stirred vigorously for 30 minutes before methyl-4- (bromomethyl) -benzoate (400 mg, 1.75 mmol) was added. 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 extracted with ethyl acetate (3 × 300 mL). The resulting organic extracts were dried over Na ₂ S0 ₄ , filtered, concentrated in vacuo and the residue was chromatographed with SiO ₂ chromatography with ethyl acetate / hexanes (60:40) to give a solid (396 mg, 71%). . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (app d, J = 8.0 Hz, 2H), 7.87 (d, J = 7.5 Hz, 1H), 7.60 (app q, J = 8.4 Hz, 1H), 7.49 -7.42 (m, 1H), 7.30-7.15 (m, 4H), 6.94 (app t, J = 6.3 Hz, 1H), 6.88 (app t, J = 9.4 Hz, 1H), 5.64 (s, 2H), 5.33 (s, 2 H), 3.88 (s, 3 H); LC / MS C-18 column, t _r = 3.46 min (5 to 95% acetonitrile / water over 5 min, 1 ml / min, detection wavelength 254 nm, 50 ° C.). ES-MS m / z 514 (M + H). ES-HRMS m / z 514.0451 (M + H calculated for C ₂₅ H ₁₉ BrF ₂ NO ₄ : 514.0460).

Step 3: Preparation of the title compound.

In a 25 mL round bottom flask, methyl 4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -2-oxoquinoline-1 (2H)-in MeOH (3.0 mL) at room temperature A solution of il] methyl} benzoate (step 2) (120 mg, 0.233 mmol) was added. Next, a combination of Pd on carbon (10% Pd, weight by 50% water, 100 mg, 0.047 mmol) and Pd (OAc) ₂ (15 mg, 0.067 mmol) was purged with argon and fixed with septum To the reaction vessel. The vessel was then equipped with a 2.0 L hydrogen balloon (about 20 psi). The resulting suspension was stirred for 12.0 hours and then directly added to SiO ₂ chromatography using ethyl acetate / hexanes (3: 7) to afford the title compound (52 mg, 51%) as a solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.05-7.98 (m, 3H), 7.55 (app q, J = 8.3 Hz, 1H), 7.48 (app t, J = 7.5 Hz, 1H), 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, 1H), 5.60 (s, 2H), 5.26 (s, 2H), 3.91 (s, 3H); LC / MS C-18 column, t _r = 3.71 min (5-95% acetonitrile / water over 5 min, 1 ml / min, detection wavelength 254 nm, 50 ° C.). ES-MS m / z 436 (M + H). ES-HRMS m / z 436.1371 (M + H calculated for C ₂₅ H ₂₀ BrF ₂ N0 ₄ : 436.1355).

Example 715

5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -2-furamide

Step 1: 5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -2-furo Preparation of the acid.

Methyl 5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} in THF (8.0 mL) To a room temperature solution of -2-furoate (Example 660) (608 g, 1.30 mmol) was added dropwise an aqueous sodium hydroxide solution (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 aqueous hydrochloric acid solution (1.0 N, 1.5 mL, 10 mmol). The resulting biphasic solution was then concentrated in vacuo to a volume of 50 mL. At this point a white solid began to form and the resulting solid suspension was allowed to stand until the precipitation stopped (about 1.0 hour). The precipitate was collected and dried under vacuum (1.0 mm Hg) to give a solid acid as an intermediate (500 mg, 85%). ¹ H NMR (300 MHz, d ₄ -MeOH) δ 7.64 (app q, J = 8.3 Hz, 1H), 7.18 (d, J = 3.4 Hz, 1H), 7.10-7.02 (m, 2H), 6.54 (s , 1H), 6.50 (d, J = 3.5 Hz, 1H), 5.42 (s, 2H), 5.37 (s, 2H), 2.64 (s, 3H); LC / MS C-18 column, t _r = 2.38 min (5-95% acetonitrile / water over 5 min, 1 ml / min, detection wavelength 254 nm, 50 ° C.). ES-MS m / z 454 (M + H). ES-HRMS m / z 454.0070 (M + H calculated for C ₁₉ H ₁₅ BrF ₂ NO ₅ : 454.0096).

Step 2: Preparation of the title compound.

5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl}-in THF (6.0 mL) 2-chloro-4,6-dimethoxy-1,3,5-triazine (307 mg, 1.75 mmol) and N-methyl morpholine (NMM, in a room temperature solution of 2-furoic acid (500 mg, 1.10 mmol) 184 mg, 1.82 mmol) was added continuously. The resulting solution was aged for 2 hours, then saturated aqueous solution of ammonium hydroxide (0.70 mL) was added. The resulting suspension was continued for an additional hour. The reaction mixture was diluted with 400 mL brine and extracted with ethyl acetate (3 X 400 mL). The organic extract was separated, dried over Na ₂ SO ₄ , concentrated in vacuo, and the resulting residue was subjected to Si0 ₂ chromatography with ethyl acetate / hexanes / methanol (57: 38: 5) to give the title compound (370 g, 74%). ¹ H NMR (300 MHz, d ₄ -MeOH) δ 7.64 (app q, J = 8.1 Hz, 1H), 7.10-7.00 (m, 3H), 6.53 (s, 1H), 6.52 (d, J = 3.4 Hz , 1H), 5.43 (s, 2H), 5.32 (s, 2H), 2.61 (s, 3H); LC / MS C-18 column, t _r = 2.15 min (5-95% acetonitrile / water over 5 min, 1 ml / min, detection wavelength 254 nm, 50 ° C.). ES-MS m / z 453 (M + H). ES-HRMS m / z 453.0249 (M + H calculated for C ₁₉ H ₁₆ BrF ₂ N ₂ 0 ₄ : 453.0256).

Example 716

5- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -2-furamide

Step 1: Preparation of methyl 5- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -2-furoate.

5- (1-hydroxy-3-oxobutylidene) -2, in a room temperature solution of methyl-2-amino-5-furoate (4.85 g, 34.4 mmol) in 1,4-dioxane (28.0 mL), 2-dimethyl-1,3-dioxane-4,6-dione (8.16 g, 44.3 mmol) was added. The reaction was stirred vigorously and heated rapidly (within 8 minutes) to bring the internal temperature to 98 ° C. When this temperature was reached, the reaction was allowed to stand for 1.0 hour. At this time, the reaction was rapidly cooled to room temperature 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 about 100 ° C. After 1.0 hour the reaction was diluted with 10 mL of toluene and allowed to spontaneously cool to room temperature. After 3.0 hours a solid formed which was collected and then recrystallized from methanol / ethyl acetate (1: 1). Allow developmental crystals to form and allow to stand for 12.0 hours before collecting to give the desired product as a solid (3.78 g, 44%). ¹ H NMR (400 MHz, d ₇ -DMF) δ 11.34 (s, 1H), 7.43 (app d, J = 3.6 Hz, 1H), 6.79 (app d, J = 3.6 Hz, 1H), 6.01 (s, 1H), 5.63 (d, J = 2.0 Hz, 1H), 3.87 (s, 3H), 2.02 (s, 3H); LC / MS C-18 column, t _r = 1.47 min (5-95% acetonitrile / water over 5 min, 1 ml / min, detection wavelength 254 nm, 50 ° C.). ES-MS m / z 250 (M + H). ES-HRMS m / z 250.0696 (M + H calculated for C ₁₂ H ₁₂ NO ₅ : 250.0710).

Step 2: of methyl 5- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -2-furoate Produce.

Room temperature solution of methyl 5- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) -2-furoate (step 1) (3.19 g, 12.8 mmol) in DMF (14 mL) To the solid N-bromosuccinimide (2.29 g, 12.9 mmol) was added in portions. After the reaction was stirred vigorously for 1.0 hour, K ₂ CO ₃ (1.88 g, 13.6 mmol), DMF (4.0 mL) and 2,4-difluorobenzyl bromide (2.00 mL, 15.55 mmol) were added sequentially. . The resulting suspension was stirred for 9.0 hours until complete formation of the desired product was shown by LCMS analysis. The reaction was then diluted with saturated brine (300 mL) and extracted with ethyl acetate (3 X 300 mL). The resulting organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the resulting residue by Si0 ₂ chromatography with a gradient elution using ethyl acetate / hexanes (40:60 to 60:40) to give a solid. Obtained (3.20 mg, 55%). ¹ H NMR (400 MHz, d ₇ -DMF) δ 7.78 (app q, J = 8.6 Hz, 1H), 7.48 (app d, J = 3.6 Hz, 1H), 7.33 (app dt, J = 10.0, 2.4 Hz , 1H), 7.21 (app dt, J = 8.5, 1.8 Hz, 1H), 6.92 (d, J = 3.6 Hz, 1H), 6.81 (s, 1H), 5.47 (s, 2H), 3.88 (s, 3H ), 2.15 (s, 3 H); LC / MS C-18 column, t _r = 3.11 min (5-95% acetonitrile / water over 5 min, 1 ml / min, detection wavelength 254 nm, 50 ° C.). ES-MS m / z 454 (M + H). ES-HRMS m / z 454.0117 (M + H calculated for C ₁₉ H ₁₅ BrF ₂ N ₂ 0 ₅ : 454.0096).

Step 3: Preparation of 5- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -2-furoic acid .

Methyl 5- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -2- in THF (20 mL) To a room temperature solution of furoate (step 2) (3.00 g, 6.61 mmol) was added dropwise an aqueous sodium hydroxide solution (3.0 M, 4.00 mL, 12.0 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 aqueous hydrochloric acid solution (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 point a white solid began to form and the resulting solid suspension was allowed to stand (about 1.0 hour) until precipitation stopped. The precipitate was collected and dried under vacuum (1.0 mm Hg) to give a solid acid as an intermediate (2.27 g, 78%). ¹ H NMR (400 MHz, d ₇ -DMF) δ 7.79 (app q, J = 8.0 Hz, 1H), 7.32 (t, J = 9.2 Hz, 1H), 7.20 (app t, J = 7.4 Hz, 1H) , 6.88 (app d, J = 2.5 Hz, 1H), 6.74 (s, 1H), 6.51 (d, J = 2.5 Hz, 1H), 5.44 (s, 2H), 2.10 (s, 3H); LC / MS C-18 column, t _r = 2.77 min (5-95% acetonitrile / water over 5 min, 1 ml / min, detection wavelength 254 nm, 50 ° C.). ES-MS m / z 440 (M + H). ES-HRMS m / z 439.9959 (M + H calculated for C ₁₈ H ₁₃ BrF ₂ NO ₅ : 439.9940).

Step 4: Preparation of the title compound.

5- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -2-furo in THF (8.0 mL) In a room temperature solution of acid (1.00 g, 2.27 mmol) 2-chloro-4,6-dimethoxy-1,3,5-triazine (610 mg, 3.47 mmol) and N-methyl morpholine (NMM, 368 mg, 3.62 mmol) was added continuously. The resulting solution was aged for 2 hours and then saturated aqueous ammonium hydroxide solution (1.5 mL) was added. The resulting suspension was continued for an additional hour. The reaction mixture was diluted with 800 mL brine and extracted with ethyl acetate (3 X 600 mL). The organic extract was separated, dried over Na ₂ SO ₄ , concentrated in vacuo and the resulting residue was subjected to Si0 ₂ chromatography with ethyl acetate / hexanes / methanol (57: 38: 5) to afford the title compound (710 mg, 71%). ¹ H NMR (400 MHz, d ₇ -DMF) δ 8.07 (s, 1H), 7.79 (app q, J = 8.6 Hz, 1H), 7.50 (br s, 1H), 7.32 (app dt, J = 10.1, 2.2 Hz, 1H), 7.30 (app dd, J = 8.0, 3.3 Hz, 1H), 7.20 (app dt, J = 8.6, 2.0 Hz, 1H), 6.81 (s, 1H), 6.79 (d, J = 3.4 Hz, 1H), 5.47 (s, 2H), 2.14 (s, 3H); LC / MS C-18 column, t _r = 2.60 min (5-95% acetonitrile / water, over 5 min, 1 ml / min, detection wavelength 254 nm, 50 ° C.). ES-MS m / z 439 (M + H). ES-HRMS m / z 439.0088 (M + H calculated for C ₁₈ H ₁₄ BrF ₂ N ₂ 0 ₄ : 439.0010).

Example 717

1- [3,5-bis (hydroxymethyl) phenyl] -3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one

Step 1: Preparation of Dimethyl 5- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) isophthalate

Dimethyl 5-aminoisophthalate (24.45 g, 117 mmol) was dissolved in 500 ml of toluene and heated to reflux. 5- (1-hydroxy-3-oxobutylidene) -2,2-dimethyl-1,3-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-toluenesulfonic acid (22.25 g, 117 mmol) were added and refluxed for 1 hour. The reaction was cooled to room temperature and left overnight. The resulting precipitate was filtered, washed three times with 250 ml of water and 250 ml of acetonitrile and dried under vacuum to give a tan solid (18.85 g, 51% yield). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.70 (br s, 1H), 8.47 (t, J = 1.54 Hz, 1H), 7.99 (d, J = 1.47 Hz, 2H), 5.90 (d, J = 1.61 Hz, 1H), 5.55 (d, J = 2.42 Hz, 1H), 3.87 (s, 6H), 1.82 (s, 3H); LC / MS, t _r = 1.79 min (5-95% acetonitrile / water over 5 min, 254 nm at 1 ml / min, 50 ° C.), ES-MS m / z 318 (M + H). ES-HRMS m / z 318.0994 (M + H calculated for C ₁₆ H ₁₆ NO ₆ : 318.0972).

Step 2: Preparation of Dimethyl 5- (3-Bromo-4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) isophthalate

Dimethyl 5- (4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) isophthalate (prepared from step 1) (18.0 g, 56.7 mmol) was added N, N-dimethyl at room temperature. Stir with N-bromosuccinimide (10.6 g, 59.6 mmol) in 35 ml of formamide and 180 ml of methylene chloride. After stirring for 1 hour, a white precipitate formed. The precipitate was filtered off, washed with acetonitrile and concentrated in vacuo to give a white solid (11.55 g, 51%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.49 (br s, 1H), 8.49 (t, J = 1.24 Hz, 1H), 8.06 (d, J = 1.47 Hz, 2H), 6.07 (s, 1H ), 3.88 (s, 6 H), 1.82 (s, 3 H); LC / MS, t _r = 1.81 min (5-95% acetonitrile / water over 5 min, 254 nm at 1 ml / min, 50 ° C.), ES-MS m / z 396 (M + H). ES-HRMS m / z 396.0102 (M + H calculated for C ₁₆ H ₁₅ BrNO ₆ : 396.0077).

Step 3: Preparation of Dimethyl 5- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] isophthalate.

Dimethyl 5- (3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1 (2H) -yl) isophthalate (prepared from step 2) (11.3 g, 28.5 mmol) was added N, Stir vigorously for 3 hours at room temperature with 2,4-difluorobenzylbromide (3.66 ml, 28.5 mmol) and K ₂ CO ₃ (5.91 g, 42.8 mmol) in 50 ml of N-dimethylformamide. The reaction was then poured into 1 L of cold water and the resulting precipitate was filtered off, washed with water and diethyl ether and dried under vacuum to give a white solid (13.8 g, 93%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.51 (t, J = 1.60 Hz, 1H), 8.12, (d, J = 1.60 Hz, 2H), 7.67 (app q, J = 7.92 Hz, 1H) , 7.34 (app dt, J = 9.94, 2.19 Hz, 1H), 7.17 (dt, J = 8.53, 2.11 Hz, 1H), 6.68 (s, 1H), 5.33 (s, 2H), 3.88 (s, 6H) , 1.93 (s, 3 H); LC / MS, t _r = 2.77 min (5-95% acetonitrile / water over 5 min, 254 nm at 1 ml / min, 50 ° C.), ES-MS m / z 522 (M + H). ES-HR / MS m / z 522.0335 (M + H calculated for C ₂₃ H ₁₉ BrF ₂ NO ₆ : 522.0358).

Step 4: Preparation of 5- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] isophthalic acid.

Dimethyl 5- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] isophthalate (prepared from step 3) (5.0 g, 9.57 mmol) was stirred with 2.5 N NaOH (15.3 ml, 38.3 mmol) in 30 ml of 5: 1 THF / water at room temperature for 1 hour. The reaction was then acidified with 1 N HCl and the resulting precipitate was filtered off, washed with water and dried under vacuum to give a white solid (4.48 g, 95%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.50 (br s, 2H), 8.51 (t, J = 1.41 Hz, 1H), 8.02, (d, J = 1.48 Hz, 2H), 7.67 (app q , J = 7.88 Hz, 1H), 7.32 (dt, J = 9.94, 2.19 Hz, 1H), 7.16 (dt, J = 8.52, 1.99 Hz, 1H), 6.68 (s, 1H), 5.32 (s, 2H) , 1.94 (s, 3 H); LC / MS, t _r = 2.27 min (5-95% acetonitrile / water over 5 min, 254 nm at 1 ml / min, 50 ° C.), ES-MS m / z 494 (M + H). ES-HRMS m / z 494.0054 (M + H calculated for C ₂₁ H ₁₅ BrF ₂ NO ₆ : 494.0045).

Step 5: Preparation of the title compound.

5- [3-Bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] isophthalic acid (prepared from step 4 above) (500 mg, 1.01 mmol) was added to a solution (9.0 ml, 9.00 mmol) of the 1 M borane-dimethylsulfide complex in tetrahydrofuran in 2.5 ml tetrahydrofuran at 0 ° C. The reaction was allowed to warm to room temperature while stirring. After stirring overnight, more 1 M borane-dimethylsulfide complex (0.60 ml, 0.60 mmol) in tetrahydrofuran was added and stirred at room temperature. After 4 hours, the ice was added to quench the reaction. The reaction was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over MgSO ₄ and evaporated. The resulting solid was washed with acetonitrile and diethyl ether and dried under vacuum to give a white solid (281 mg, 60%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.66 (app q, J = 7.92 Hz, 1H), 7.35 (s, 1H), 7.33 (dt, J = 9.40, 2.24 Hz, 1H), 7.16 (dt , J = 8.52, 1.88 Hz, 1H), 6.99 (s, 2H), 6.62 (s, 1H), 5.31 (s, 2H), 5.27 (br s, 2H), 4.51 (s, 4H), 1.93 (s , 3H); LC / MS, t _r = 2.19 min (5-95% acetonitrile / water over 5 min, 254 nm at 1 ml / min, 50 ° C.), ES-MS m / z 466 (M + H). ES-HRMS m / z 466.0454 (M + H calculated for C ₂₁ H ₁₉ BrF ₂ NO ₄ : 4660.0460).

Example 718

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-1 (2H) -yl] isophthalic acid (Example 717, step 4) (500 mg, 1.01 mmol) was dissolved in 4 ml of tetrahydrofuran. After addition of 0.5 M ammonia in 1,4-dioxane (12.12 ml, 6.06 mmol), EDCI (494 mg, 2.53 mmol), 1-hydroxybenzotriazole (342 mg, 2.53 mmol) and triethylamine ( 563 μl, 4.04 mmol) were added sequentially. The reaction was stirred overnight at room temperature. The reaction was evaporated and the product was triturated with water. The resulting solid was filtered, washed with water, acetonitrile, ethyl acetate and diethyl ether and dried under vacuum to give a white solid (202 mg, 41%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.45 (s, 1H), 8.08 (br s, 2H), 7.86, (d, J = 1.34 Hz, 2H), 7.67 (app q, J = 7.92 Hz , 1H), 7.55 (br s, 2H), 7.33 (dt, J = 9.94, 2.18 Hz, 1H), 7.17 (dt, J = 8.59, 1.92 Hz, 1H), 6.70 (s, 1H), 5.34 (s , 2H), 1.96 (s, 3H); LC / MS, t _r = 2.10 min (5-95% acetonitrile / water over 5 min, 254 nm at 1 ml / min, 50 ° C.), ES-MS m / z 492 (M + H). ES-HRMS m / z 492.0381 (M + H calculated for C ₂₁ H ₁₇ BrF ₂ N ₃ 0 ₄ : 492.0365).

Example 719

1- [3,5-bis (1-hydroxy-1-methylethyl) phenyl] -3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridine-2 ( 1H) -on

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 dropwise to a solution of 3M MeMgBr (1.6 ml, 4.79 mmol) in diethyl ether in 15 ml of tetrahydrofuran at −5 ° C. and stirred at −5 ° C. The reaction turned red. After 2.5 hours, the reaction was quenched with saturated NH ₄ Cl solution and extracted twice with ethyl acetate. The combined organic layers were washed with NaHCO ₃ solution and brine, dried over MgSO ₄ and evaporated. The resulting solid was washed with diethyl ether and dried under vacuum to give a white solid (329 mg, 66%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.69-7.63 (m, 2H), 7.33 (dt, J = 9.87, 2.41 Hz, 1H), 7.16 (dt, J = 8.46, 1.75 Hz, 1H), 7.07 (d, J = 1.48 Hz, 2H), 6.61 (s, 1H), 5.32 (s, 2H), 5.06 (s, 2H), 1.89 (s, 3H), 1.41 (s, 12H); LC / MS, t _r = 2.45 min (5-95% acetonitrile / water over 5 min, 254 nm at 1 ml / min, 50 ° C.), ES-MS m / z 522 (M + H). ES-HRMS m / z 522.1098 (M + H calculated for C ₂₅ H ₂₇ BrF ₂ NO ₄ : 522.1086).

Example 720

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [4- (hydroxymethyl) phenyl] -6-methylpyridin-2 (1H) -one

4- [3-Bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzoic acid (Example 203) (500 mg, 1.11 mmol) was added to a solution (3.33 ml, 6.66 mmol) of the 2 M borane-dimethylsulfide complex in tetrahydrofuran in 2.5 ml tetrahydrofuran at 0 ° C. The reaction was allowed to warm to room temperature while stirring. After 2.5 hours, the ice was added to quench the reaction. The resulting precipitate was filtered off, washed with diethyl ether and dried under vacuum to give a white solid (160 mg, 33%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.66 (app q, J = 7.88 Hz, 1H), 7.42 (d, J = 8.19 Hz, 2H), 7.33 (dt, J = 9.87, 2.06 Hz, 1H ), 7.19-7.14 (m, 3H), 6.62 (s, 1H), 5.31 (s, 2H), 5.30 (s, 1H), 4.54 (d, J = 5.24, 2H), 1.92 (s, 3H); LC / MS, t _r = 2.36 min (5-95% acetonitrile / water over 5 min, 254 nm at 1 ml / min, 50 ° C.), ES-MS m / z 436 (M + H). ES-HRMS m / z 436.0374 (M + H calculated for C ₂₀ H ₁₇ BrF ₂ NO ₃ : 436.0354).

Example 721

3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- [4- (1-hydroxy-1-methylethyl) phenyl] -6-methylpyridine-2 (1H)- On

Methyl-4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] benzoate (Example 202) ( 500 mg, 1.08 mmol) was added dropwise to a solution of 3M MeMgBr (0.90 ml, 2.69 mmol) in diethyl ether in 15 ml of tetrahydrofuran at −5 ° C. and stirred at −5 ° C. After 2.75 h, further 3M MeMgBr (0.45 ml, 1.35 mmol) in diethyl ether was added and stirred at -5 ° C. After 4 hours, the reaction was quenched with saturated NH ₄ Cl solution and extracted twice with ethyl acetate. The combined organic layers were washed with NaHCO ₃ solution and brine, dried over MgSO ₄ and evaporated. The resulting solid was washed with diethyl ether and dried under vacuum to give a white solid (268 mg, 53%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.66 (app q, J = 7.92 Hz, 1H), 7.57 (d, J = 8.46 Hz, 2H), 7.33 (dt, J = 9.87, 2.11 Hz, 1H ), 7.16 (dt, J = 8.59, 2.24 Hz, 1H), 7.14 (d, J = 8.63 Hz, 2H), 6.62 (s, 1H), 5.31 (s, 2H), 5.12 (s, 1H), 1.91 (s, 3 H), 1.44 (s, 6 H); LC / MS, t _r = 2.54 min (5-95% acetonitrile / water over 5 min, 254 nm at 1 ml / min, 50 ° C.), ES-MS m / z 464 (M + H). ES-HRMS m / z 464.0604 (M + H calculated for C ₂₂ H ₂₁ BrF ₂ N0 ₃ : 464.0667).

Example 722

1- (5-amino-2-fluorophenyl) -3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one hydrochloride

Step 1: tert-Butyl 3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-fluoro Preparation of rophenylcarbamate

A solution of the compound of Example 519 (4.3 g, 9.2 mmol) in tert-butanol (50 mL) was washed with nitrogen. 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 hours, the reaction mixture was concentrated in vacuo. The residue was diluted with methylene chloride and washed successively with aqueous ammonium chloride and aqueous NaHCO ₃ . The organic layer was concentrated in vacuo and the resulting solid was suspended in acetonitrile and filtered to give the title compound (2.9 g, 58%). ¹ H NMR (400 MHz, CD ₃ 0D) δ 7.64 (q, J = 7.2 and 14.4 Hz, 1H), 7.49 (m, 1H), 7.43 (m, 1H), 7.24 (t, J = 9.6 Hz, 1H ), 7.04 (t, J = 8.4 Hz, 2H), 6.62 (s, 1H), 5.35 (s, 2H), 2.09 (s, 3H), 1.49 (s, 9H) ppm. ¹⁹ F NMR (300 MHz, CD ₃ 0D) δ −111.53 (1 F), −115.93 (1 F), —132.58 ppm. ES-HRMS m / z 540.0822 (M + H calculated for C ₂₄ H ₂₃ BrF ₃ N ₂ 0 ₄ : 540.0820).

Step 2: 1- (5-Amino-2-fluorophenyl) -3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one hydro Preparation of Chloride

The product of step 1 (2.9 g, 5.3 mmol) was dissolved in tetrahydrofuran (75 mL) and 6 N HCl (10 mL). The reaction mixture was heated to 60 ° C. for 18 h and concentrated in vacuo to afford the final product (1.89 g, 75%). ¹ H NMR (400 MHz, CD ₃ 0D) δ 7.64 (q, J = 8.4 and 15.2 Hz, 1H), 7.56 (m, 2H), 7.46 (m, 1H), 7.05 (m, 2H), 6.69 (s , 1H), 5.37 (s, 2H), 2.10 (s, 3H) ppm. ¹⁹ F NMR (400 MHz, CD ₃ 0D) δ −111.37 (1 F), −115.86 (1 F), −123.16 ppm. ES-HRMS m / z 440.0334 (M + H calculated for C ₁₉ H ₁₅ BrF ₃ N ₂ O ₂ : 440.0295).

Example 723

N- {3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-fluorophenyl} 2-hydroxyacetamide

Step 1: 2-({3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4- Preparation of fluorophenyl} amino) -2-oxoethyl acetate

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 for 2 hours at room temperature, the reaction was complete. The reaction mixture was poured into saturated aqueous ammonium chloride. The solid was filtered off and washed with water and diethyl ether. The title product was isolated as a white solid (0.32 g, 58%). ¹ H NMR (400 MHz, CD ₃ 0D) δ 7.65 (m, 3H), 7.32 (t, J = 8.4 Hz, 1H), 7.04 (t, J = 8.4 Hz, 2H), 6.64 (s, 1H), 5.35 (s, 2H), 4.68 (s, 2H), 2.15 (s, 3H), 2.10 (s, 3H) ppm. ¹⁹ F NMR (400 MHz, CD ₃ 0D) δ -111.56 (1F), -115.99 (1 F), -129.48 (1F) ppm. LC / MS, t _r = 5.35 min (1 ml / min over 8 min with 5-95% acetonitrile / water, using detection wavelength 254 nm, 50 ° C.). ES-MS m / z 540 (M + H).

Step 2: N- {3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-fluoro Preparation of Rophenyl} -2-hydroxyacetamide

The product of step 1 (0.1 g, 0.18 mmol) was suspended in tetrahydrofuran (10 mL), methanol (2 mL) and 2.5 N NaOH (1 mL). After stirring for 1 hour at room temperature, the reaction is complete and the organics are removed in vacuo. The aqueous layer was acidified to pH 1 with 6 N HCl and the solid was suspended in water, filtered and washed with diethyl ether. The title compound was obtained as a white powder (56.2 mg, 61%). ¹ H NMR (400 MHz, CD ₃ 0D) δ 7.75 (dq, J = 2.9, 4.8 and 9.2 Hz, 1H), 7.71 (dd, J = 2.4 and 6.8 Hz, 1H), 7.64 (q, J = 8 and 14.8 Hz, 1H), 7.32 (t, J = 9.6 Hz, 1H), 7.04 (t, J = 8.8 Hz, 2H), 6.64 (s, 1H), 5.36 (s, 2H), 4.10 (s, 2H) , 2.10 (s, 3H) ppm. ¹⁹ F NMR (400 MHz, CD ₃ 0D) δ -111.54 (1F), -115.99 (1 F), -129.71 (1F) ppm. LC / MS, t _r = 5.04 min (1 ml / min over 8 min with 5-95% acetonitrile / water, using detection wavelength 254 nm, 50 ° C.). ES-MS m / z 498 (M + H).

Example 724

N- {3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-fluorophenyl} -2-hydroxy-2-methylpropanamide

Step 1: 2-({3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4- Preparation of Fluorophenyl} amino) -1,1-dimethyl-2-oxoethyl acetate

A solution of the compound of Example 722 (0.5 g, 1.05 mmol) in tetrahydrofuran (20 mL) was diluted with triethyl amine (0.3 mL, 2.1 mmol) and 1-chlorocarbonyl-1-methylethyl acetate (0.16 mL). , 1.15 mmol). After stirring for 2 hours at room temperature, the reaction was complete. The reaction mixture was poured into saturated aqueous ammonium chloride. The solid was filtered off and washed with water and diethyl ether. The compound of step 1 was isolated as a white solid (0.23 g, 39%). ¹ H NMR (400 MHz, CD ₃ 0D) δ 7.64 (m, 2H), 7.54 (dd, J = 2.8 and 6.8 Hz, 1H), 7.30 (t, J = 9.2 Hz, 1H), 7.04 (t, J = 9.2 Hz, 2H), 6.64 (s, 1H), 5.35 (s, 2H), 2.11 (s, 3H), 2.08 (s, 3H), 1.61 (s, 6H) ppm. ¹⁹ F NMR (400 MHz, CD ₃ 0D) δ −111.57 (1F), −116.00 (1 F), —129.56 (1F) ppm. LC / MS, t _r = 5.65 min (1 ml / min over 8 min with 5-95% acetonitrile / water, using detection wavelength 254 nm, 50 ° C.). ES-MS m / z 568 (M + H).

Step 2: N- {3- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -4-fluoro Preparation of Rophenyl} -2-hydroxy-2-methylpropanamide

The product of step 1 (0.1 g, 0.17 mmol) was suspended in tetrahydrofuran (10 mL), methanol (2 mL) and 2.5 N NaOH (1 mL). After stirring for 1 hour at room temperature, the reaction is complete and the organics are removed in vacuo. The aqueous layer was acidified to pH 1 with 6N HCl and the solid was suspended in water, filtered and washed with diethyl ether. The title compound was obtained as a white powder (56 mg, 61%). ¹ H NMR (400 MHz, CD ₃ 0D) δ 7.75 (dq, J = 2.8, 4.4 and 9.2 Hz, 1H), 7.69 (dd, J = 2.8 and 6.8 Hz, 1H), 7.64 (q, J = 8 and 14.8 Hz, 1H), 7.31 (t, J = 9.2 Hz, 1H), 7.04 (t, J = 8.4 Hz, 2H), 6.64 (s, 1H), 5.35 (s, 2H), 2.10 (s, 3H) , 1.43 (s, 6H) ppm. ¹⁹ F NMR (400 MHz, CD ₃ 0D) δ -111.55 (1F), -115.95 (1F), -129.80 (1F) ppm. LC / MS, t _r = 5.34 min (1 ml / min over 8 min with 5-95% acetonitrile / water, using detection wavelength 254 nm, 50 ° C.). ES-MS m / z 526 (M + H).

Example 725

4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3-fluoro-N, N- Dimethylbenzamide

Step 1: of 4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3-fluorobenzoic acid Produce

The compound of Example 604 (4.1 g, 8.5 mmol) was suspended in tetrahydrofuran (30 mL), methanol (15 mL), water (15 mL) and 2.5 N NaOH (6.8 mL, 17 mmol). After stirring for 2 hours at room temperature, the reaction was complete and the organics were removed. The aqueous layer was acidified to pH 1 with 3 N HCl, the solid was suspended in water, filtered and washed with diethyl ether. The title compound was obtained as a white powder (4.4 g) and used without further purification. ¹ H NMR (400 MHz, CD ₃ 0D) δ 8.00 (dd, J = 1.8 and 8.8 Hz, 1H), 7.93 (dd, J = 1.48 and 10 Hz, 1H), 7.64 (q, J = 8 and 14.8 Hz , 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.05 (t, J = 10 Hz, 2H), 6.66 (s, 1H), 5.36 (s, 2H), 2.08 (s, 3H) ppm. ¹⁹ F NMR (400 MHz, CD ₃ 0D) δ -111.48 (1F), -115.96 (1F), -123.35 (1F) ppm. ES-HRMS m / z 468.9987 (M + H calculated for C ₂₀ H ₁₄ BrF ₃ N0 ₄ : 469.0086).

Step 2: 4- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -3-fluoro-N , N-dimethylbenzamide

The solution of the product of step 1 (0.5 g, 1.07 mmol) in N, N-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, N, N-dimethylamine (2.0 M, 1.1 mL, 2.14 mmol) was added and the reaction mixture was allowed to warm to room temperature over 18 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous NaHCO ₃ . The organics were washed with brine and concentrated in vacuo. The resulting semisolid was treated with ethyl acetate and acetone to precipitate the title compound (90 mg, 17%). ¹ H NMR (400 MHz, dmso-d ₆ ) δ 7.67 (q, J = 8 and 14.8 Hz, 1H), 7.52 (m, 2H), 7.35 (m, 2H), 7.18 (td, J = 2.8 and 8.8 Hz, 1H), 6.73 (s, 1H), 5.34 (s, 2H), 2.98 (s, 3H), 2.91 (s, 3H), 2.00 (s, 3H) ppm. ¹⁹ F NMR (400 MHz, dmso-d ₆ ) δ -109.50 (1F), -113.63 (1F), -122.09 (1F) ppm. ES-HRMS m / z 496.0570 (M + H calculated for C ₂₂ H ₁₉ BrF ₃ N ₂ 0 ₃ : 496.0558).

Example 726

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-[(1-glycoloil-2,3-dihydro-1H-indol-5-yl) methyl] -6-methyl Pyridin-2 (1H) -one

In a 10 mL round bottom flask equipped with a stir bar and nitrogen inlet, the compound of Example 633 (180 mg, 0.43 mmol), acetoxyacetyl chloride (51 μL, 0.47 mmol), triethylamine (119 μL, 0.86 mmol) and Tetrahydrofuran (3.0 mL) was charged. After stirring at 25 ° C. for 20 minutes, the reaction was completed by LC-MS. NaOH (2.5 M, 2.24 mmol, 1.0 mL) and MeOH (2.O mL) were added and stirred for 20 minutes to afford the title compound. The compound precipitated out of solution. The precipitate was filtered off and washed with water and diethyl ether to give the title compound as a white solid (130 mg, 64%). ¹ H NMR (400 MHz, (DMSO) δ 7.9 (d, J = 8.2, 1H), 7.6 (q, J = 8.5 and 6.9 Hz, 1H), 7.3 (t, J = 8.7 Hz, 1H), 7.1 ( t, J = 7.9 Hz, 1H), 6.9 (s, 2H), 6.5 (s, 1H), 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, 1H), 3.35 (t, J = 4.8 Hz, 1H), 3.2 (t, J = 8.5 Hz, 2H), 2.3 (s, 3H) ppm.ES -HRMS m / z 475.1220 (M + H calculated for C ₂₄ H ₂₂ ClF ₂ N ₂ 0 ₄ : 475.1231).

Example 727

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[1- (2-hydroxy-2-methylpropaneoyl) -2,3-dihydro-1H-indole- 5-yl] methyl} -6-methylpyridin-2 (1H) -one

In a 10 mL round bottom flask equipped with a stir bar and nitrogen inlet, the compound of Example 633 (200 mg, 0.48 mmol), 1-chlorocarbonyl-1-methylethyl acetate (104.3 μL, 0.72 mmol), triethylamine ( 133 μL, 0.96 mmol) and tetrahydrofuran (4.0 mL) were charged. After stirring at 25 ° C. for 20 minutes, the reaction was completed by LC-MS. NaOH (2.5 M, 2.24 mmol, 1.5 mL) and MeOH (2.O mL) were added and stirred for 20 minutes to afford the title compound. The compound precipitated out of solution. The precipitate was filtered off and washed with water and diethyl ether to give a white solid (240 mg, 99%). ¹ H NMR (400 MHz, (DMSO) δ 8.0 (d, J = 8.3, 1H), 7.6 (q, J = 8.6 and 6.9 Hz, 1H), 7.3 (td, J = 2.5 and 7.8 Hz, 1H), 7.1 (td, J = 1.75 and 6.7 Hz, 1H), 6.95 (s, 1H), 6.89 (d, J = 8.5 Hz, 1H), 6.58 (s, 1H), 5.25 (s, 2H), 4.3 (t , J = 8.3 Hz, 2H), 3.42 (t, J = 5.4 Hz, 1H), 3.35 (t, J = 5.2 Hz, 1H), 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 calculated for C ₂₆ H ₂₆ ClF ₂ N ₂ 0 ₄ : 503.1544).

Example 728

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[1- (methoxyacetyl) -2,3-dihydro-1H-indol-5-yl] methyl}- 6-methylpyridin-2 (1H) -one

In a 10 mL round bottom flask equipped with a stir bar and nitrogen inlet, the 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) was charged. After stirring at 25 ° C. for 20 minutes, the reaction was completed by LC-MS. The compound precipitated out of solution. The precipitate was filtered off and washed with water and diethyl ether to give a white solid (195 mg, 83%). ¹ H NMR (400 MHz, (DMSO) δ 8.0 (d, J = 8.0, 1H), 7.6 (q, J = 8.6 and 6.7 Hz, 1H), 7.3 (td, J = 2.4 and 6.7 Hz, 1H), 7.1 (td, J = 1.88 and 6.6 Hz, 1H), 6.9 (s, 2H), 6.58 (s, 1H), 5.25 (s, 2H), 4.15 (s, 2H), 3.9 (t, J = 8.3 Hz , 2H), 3.45 (m, 1H), 3.4 (m, 1H), 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 calculated for C ₂₅ H ₂₄ ClF ₂ N ₂ 0 ₄ : 489.1387).

Example 729

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N, N-dimethylindolin -1-carboxamide

In a 10 mL round bottom flask equipped with a stir bar and nitrogen inlet, the 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) was charged. After stirring at 25 ° C. for 5 minutes, the reaction was complete by LC-MS. The compound precipitated out of solution. The precipitate was filtered off and washed with water and diethyl ether to give a white solid (198 mg, 85%). ¹ H NMR (400 MHz, (DMSO) δ 7.6 (q, J = 7.4 Hz, 1H), 7.3 (t, J = 8.9 Hz, 1H), 7.1 (t, J = 8.5 Hz, 2H), 6.93 (s , 1H), 6.86 (s, 1H), 6.58 (s, 1H), 5.25 (s, 2H), 3.9 (t, J = 8.2 Hz, 2H), 3.45 (m, 1H), 3.4 (m, 1H) , 2.9 (t, J = 8.3 Hz, 2H), 2.8 (s, 6H), 2.3 (s, 3H) ppm.ES-HRMS m / z 488.1548 (calculated for C ₂₅ H ₂₄ ClF ₂ N ₂ 0 ₄ M + H required: 488.1547).

Example 730

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-[(1-glycoloil-2,3-dihydro-1H-indol-5-yl) methyl] pyridine-2 ( 1H) -on

In a 10 mL round bottom flask equipped with a stir bar and nitrogen inlet, the compound of Example 88 (200 mg, 0.5 mmol), acetoxyacetyl chloride (59 μL, 0.55 mmol), triethylamine (140 μL, 1.0 mmol) and Tetrahydrofuran (3.0 mL) was charged. After stirring at 25 ° C. for 20 minutes, the reaction was completed by LC-MS. NaOH (2.5 M, 2.24 mmol, 1.0 mL) and MeOH (2.O mL) were added and stirred for 20 minutes to afford the title compound. The compound precipitated out of solution. The precipitate was filtered off and washed with water and diethyl ether to give the title compound as a white solid (200 mg, 83%). ¹ H NMR (400 MHz, (DMSO) δ 7.98 (d, J = 8.1, 1H), 7.9 (d, J = 7.8 Hz, 1H), 7.6 (q, J = 8.6 and 6.6 Hz, 1H), 7.3 ( dt, J = 2.4 and 7.2 Hz, 1H), 7.1 (m, 2H), 6.56 (d, J = 7.8 Hz, 1H), 5.25 (s, 2H), 5.1 (s, 2H), 4.8 (t, J = 5.8 Hz, 1H), 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 calculated for C ₂₃ H ₂₀ ClF ₂ N ₂ 0 ₄ : 461.1074).

Example 731

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-[(1-glycoloil-2,3-dihydro-1H-indol-5-yl) methyl] pyridine-2 ( Preparation of 1H) -one

In a 10 mL round bottom flask equipped with a stir bar and nitrogen inlet was added the compound of Example 88 (200 mg, 0.50 mmol), 1-chlorocarbonyl-1-methylethyl acetate (80 μL, 0.55 mmol), triethylamine ( 140 μL, 1.0 mmol) and tetrahydrofuran (4.0 mL) were charged. After stirring at 25 ° C. for 20 minutes, the reaction was completed by LC-MS. NaOH (2.5 M, 2.24 mmol, 1.5 mL) and MeOH (2.O mL) were added and stirred for 20 minutes to afford the title compound. The compound precipitated out of solution. The precipitate was filtered off and washed with water and diethyl ether to give the title compound as a white solid (136 mg, 55%). ¹ H NMR (400 MHz, (DMSO) δ 7.98 (d, J = 8.1, 1H), 7.9 (d, J = 7.8 Hz, 1H), 7.6 (q, J = 8.6 and 6.6 Hz, 1H), 7.3 ( m, 1H), 7.1 (m, 2H), 6.56 (d, J = 7.8 Hz, 1H), 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 calculated for C ₂₅ H ₂₄ ClF ₂ N ₂ 0 ₄ : 489.1387).

Example 732

3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[1- (methoxyacetyl) -2,3-dihydro-1H-indol-5-yl] methyl} pyridine -2 (1H) -on

In a 10 mL round bottom flask equipped with a stir bar and nitrogen inlet, 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 minutes, the reaction was completed by LC-MS. The compound precipitated out of solution. The precipitate was filtered off and washed with water and diethyl ether to give a white solid (195 mg, 83%). ¹ H NMR (400 MHz, (DMSO) δ 7.98 (d, J = 8.2, 1H), 7.9 (d, J = 7.7 Hz, 1H), 7.6 (d, J = 8.5 Hz, 1H), 7.3 (t, J = 9.6 Hz, 1H), 7.1 (m, 3H), 6.56 (d, J = 7.8 Hz, 1H), 5.25 (s, 2H), 5.1 (s, 2H), 4.1 (s, 2H), 3.98 ( t, J = 7.9 Hz, 2H), 3.33 (s, 3H), 3.0 (t, J = 7.9 Hz, 2H) ppm.For ES-HRMS m / z 461.1088 (C ₂₃ H ₂₀ ClF ₂ N ₂ 0 ₄ Calculated M + H requirement 461.1074).

Example 733

5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -2-oxopyridin-1 (2H) -yl] methyl} -N, N-dimethylindolin-1-car Voxamide

In a 10 mL round bottom flask equipped with a stir bar and nitrogen inlet, the compound of Example 88 (200 mg, 0.5 mmol), dimethylcarbamyl chloride (69 μl, 0.75 mmol), triethylamine (139 μl, 1.0 mmol) And tetrahydrofuran (4.0 mL). After stirring at 25 ° C. for 20 minutes, the reaction was completed by LC-MS. The compound precipitated out of solution. The precipitate was filtered off and washed with water and diethyl ether to give a white solid (188 mg, 58%). ¹ H NMR (400 MHz, (DMSO) δ 7.9 (d, J = 8.1, 1H), 7.6 (q, J = 8.6 and 6.6 Hz, 1H), 7.3 (t, J = 9.3 Hz, 1H), 7.1 ( m, 3H), 6.8 (d, J = 8.0 Hz, 1H), 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.M + H calculated for ES-HRMS m / z 474.1387 (C ₂₄ H ₂₃ ClF ₂ N ₃ 0 ₃ Requirement 474.1391).

Biological Evaluation

p38 kinase assay

Cloning of human p38a:

RNA isolated from human monocyte cell line THP1 was PCR-amplified to obtain the coding region of human p38a cDNA. The first strand cDNA was synthesized from total RNA as follows: 2 μg of RNA was heated to 100 ng of random hexamer primer in 10 μl reaction for 10 minutes at 70 ° C. followed by annealing on ice for 2 minutes. 1 μl RNAsin (Promega, Madison, WI), 2 μl 50 mM dNTP, 4 μl 5X buffer, 2 μl 100 mM DTT and 1 μl (200 U) Superscript ) II (tradename) cDNA was synthesized by addition of AMV reverse transcriptase. Random primers, dNTPs, and SuperScript II ™ reagents were all purchased from Life-Technologies, Gatorsburg, Massachusetts. The reaction was incubated at 42 ° C. for 1 hour. 80 μl dH ₂ O, 2 μl 50 mM dNTP, 1 μl forward and reverse primer (50 pmol / μl), 10 μl 10 × buffer and 1 μl Expand (trade name) polymerase (Bollinger Mannheim) P38 cDNA was amplified by aliquoting 5 μl of the reverse transcriptase reactant into 100 μl PCR reaction. PCR primers were incorporated into the Bam HI site at the 5 'and 3' ends of the fragments to be amplified, purchased from Genosys. The sequences of the forward and reverse primers were 5'-GATCGAGGATTCATGTCTCAGGAGAGGCCCA-3 'and 5'-GATCGAGGATTCTCAGGACTCCATCTCTTC-3', respectively. PCR amplification was performed by repeating 30 cycles of 1 minute at 94 ° C, 1 minute at 60 ° C, and 2 minutes at 68 ° C in a DNA Thermal Cycler (Perkin Elmer). After amplification, excess primers and unincorporated dNTPs were removed from the amplified fragments using Wizard® PCR prep (promega) and Bam HI (New England Biolabs). Digestion). Bam HI digested fragments using T-4 DNA ligase (New England Biolabs) were described in BamHI digested pGEX 2T plasmid DNA (PharmaciaBiotech). Maniatis, Molecular Cloning: A Laboratory Manual, 2nd ed. (1989). According to the manufacturer's instructions, a chemically qualified E. coli obtained from Life-Technologies. Transformed into E. coli DH10B cells. Plasmid DNA was isolated from the resulting bacterial colonies using the Promega Wizard Miniprep Kit. Prism (Applied Biosystems Inc.) was used to sequence plasmids containing the appropriate Bam HI fragments in a DNA summer cycler (Perkin Elmer). cDNA clones have been identified that encode both human p38a isotypes (Lee et al. Nature 372, 739). One of the clones containing cDNA for p38a-2 (CSB-2) was inserted into the cloning site of PGEX 2T and 3 ′ of the GST coding region represented pMON 35802. The sequences obtained for these clones exactly match the cDNA clones reported by Lee et al. The expression plasmid produces the GST-p38a fusion protein.

Expression of human p38a

The GST / p38a fusion protein is Lee. E. coli strain DH10B (Life Technologies, Gibco-BRL) was expressed from plasmid pMON 35802. Cultures were grown overnight in Luria Broth (LB) containing 100 mg / ml ampicillin. The following day, 10 ml of overnight culture was inoculated into 500 ml of fresh LB and grown with constant shaking in a 2 liter flask at 37 ° C. until the absorbance of the culture reached 0.8 at 600 nm. Expression of the fusion protein was induced by adding isopropyl b-D-thiogalactosidase (IPTG) to a final concentration of 0.05 mM. The culture was shaken for 3 hours at room temperature and cells were collected by centrifugation. Cell pellets were stored frozen until protein was purified.

Purification of P38 Kinase-alpha

Unless otherwise indicated, all chemicals are Sigma Chemical Co. It was purchased from Sigma Chemical Co. E. coli collected from a 1 L shake flask fermenter. 20 grams of E. coli pellets were resuspended in volumes up to 200 ml PBS (140 mM NaCl, 2.7 mM KCl, 10 mM Na ₂ HPO ₄ , 1.8 mM KH ₂ PO ₄ , pH 7.3). The 2 M DTT was adjusted to 5 mM DTT in the cell suspension, and then the cell suspension was divided equally into five 50 ml Falcon conical tubes. Cells were sonicated on ice for 3 x 1 min (pulse) using a 1 cm probe (Ultrasonics Model W375). Lysed cell material was removed by centrifugation (12,000 xg, 15 minutes) and the cleared supernatant was applied to glutathione-sepharose resin (Pharmacia).

Glutathione-Sepharose Affinity Chromatography

20 ml of 50% glutathione Sepharose-PBS suspension was added to 200 ml of cleared supernatant and incubated in batch for 30 minutes at room temperature. The resin was collected by centrifugation (600 × g, 5 min) and washed 2 × 150 ml with PBS / 1% Triton X-100 and then 4 × 40 ml with PBS. To cleave p38 kinase from GST-p38 fusion protein, glutathione-sepharose resin was resuspended in 6 ml of PBS containing 250 units of thrombin protease (Pharmacia, High Activity> 7500 units / mg) and 4 hours at room temperature. Mixed gently. Glutathione-Sepharose resin was removed by centrifugation (600 × g, 5 min) and washed with PBS (2 × 6 ml). Digestive supernatants and pBS wash fractions containing p38 kinase protein were pooled and adjusted to 0.3 mM PMSF.

Mono Q Anion Exchange Chromatography

Thrombin-cleaved p38 kinase was further purified by FPLC-anion exchange chromatography. Thrombin-cleaved samples are diluted 2-fold with Buffer A (25 mM HEPES, pH 7.5, 25 mM beta-glycerophosphate, 2 mM DTT, 5% glycerol) and a mono Q HR 10/10 (Pharmacia) anion exchange column Phase was in equilibrium with Buffer A. The column was eluted with 160 ml of 0.1 M to 0.6 M NaCl / buffer A gradient (flow rate: 2 ml / min). The p38 kinase peak eluting at 200 mM NaCl was collected and concentrated to 3-4 ml using a Filtron 10 concentrator (Filtron Corp.).

Sephacryl S100 Gel Filtration Chromatography

Concentrated mono Q-p38 kinase purified sample was purified by gel filtration chromatography (Pharmacia Hyprep) equilibrated with buffer B (50 mM HEPES, pH 7.5, 50 mM NaCl, 2 mM DTT, 5% glycerol) 26 / 60 Sephacryl S100 column). Protein was eluted from the column using buffer B at a flow rate of 0.5 ml / min and the protein was detected by absorbance at 280 nm. p38 kinase containing fractions (detected by SDS-polyacrylamide gel electrophoresis) were pooled and frozen at -80 ° C. 5 L this. A typical purified protein obtained from E. coli shake flask fermenter was 35 mg of p38 kinase.

In vitro test

The ability of compounds to inhibit human p38 kinase alpha was assessed using two in vitro assays. In a first method, PHAS-I (phosphorescent heat and acid stable attractant protein-insulin), which is biotinylated by activated human p38 kinase alpha, is phosphorylated in the presence of gamma ³² P-ATP ( ³² P-ATP). . Biotinylation of PHAS-I prior to testing provides a means to capture substrates that are phosphorylated during the testing. p38 kinase is activated by MKK6. Compounds were tested at 10-fold serial dilutions over a range of 100 μM to 0.001 μM using 1% DMSO. Triple test for each concentration of inhibitor.

All reactions were performed 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 test. Biotinylated PHAS-I was used at 1-2 μg per 50 μl reaction volume to a final concentration of 1.5 μM. Activated human p38 kinase alpha was used at 1 μg per 50 μl reaction volume to give a final concentration of 0.3 μM. Gamma ³² P-ATP was used to phosphorylate PHAS-I. ³² P-ATP had a specific activity of 3000 Ci / mmol and was used at 1.2 μCi per 50 μl of reaction volume. The reaction was allowed to proceed at 30 ° C. for 1 hour or overnight.

After incubation, 20 μl of the reaction mixture was transferred to a high performance streptavidin coated filter plate (SAM-streptavidin-matrix, promega) prewet with phosphate buffered saline. The transferred reaction mix was contacted with the streptavidin membrane, a promega plate, for 1-2 minutes. After capturing the biotinylated PHAS-I incorporating ³² P, each well was three times with 2M NaCl, three times with 2M NaCl containing 1% phosphoric acid, three times with distilled water and finally with 95% ethanol. Washing removes unincorporated ³² P-ATP. The filter plate was air-dried and 20 μl of scintillant was added. Plates were sealed and counted.

In addition, a second test format based on p38 kinase alpha induced phosphorylation of EGFRP (epidermal growth factor receptor peptide, 21 mer) in the presence of ³³ P-ATP was used. Compounds were tested at 10-fold serial dilutions over a range of 100 μM to 0.001 μM in 1% DMSO. Each concentration of inhibitor was tested in triplicate. 25 mM Hepes pH 7.5, 10 mM magnesium acetate, 4% glycerol, 0.4% bovine serum albumin, 0.4 mM DTT, 50 μM unlabeled ATP, 25 μg EGFRP (200 μM), and 0.05 μCi of ³³ P-ATP 50 μl of the reaction volume was evaluated. The reaction was initiated by adding 0.09 μg of activated and purified human GST-p38 kinase alpha. Activation was performed for 1 hour at 30 ° C. in the presence of 50 μM ATP using GST-MKK6 (5: 1, p38: MKK6). After incubation at room temperature for 60 minutes, the reaction was stopped by adding 150 μl AG 1 × 8 resin (1 volume resin to 2 volume buffer) in 900 mM sodium formate buffer, pH 3.0. The mixture was mixed three times by pipetting and the resin was allowed to settle. A total of 50 μl of clear solution head volume was transferred from the reaction wells to Microlite-2 plates. 150 μl of Microscint 40 was then added to each well of the microlite plate, the plate was sealed, mixed and counted.

Representative compounds with IC ₅₀ values _ranging from 1 to 25 μM (p38 alpha kinase assay) can be found in Example numbers 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 and 576.

Representative compounds having IC ₅₀ values _ranging from 25 to 100 μM (p38 alpha kinase assay) include Example Nos. 1, 25, 33, 35, 37, 42, 45, 47, 49, 119, 204, 308, 558, 560, 564, 565, 566, 568 and 577.

Representative compounds with IC ₅₀ values of less than 1 μM (p38 alpha kinase assay) are shown in 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, 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 And 643.

Representative compounds with IC ₅₀ 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 Cytometry

Isolation Methods of Human Peripheral Blood Mononuclear Cells:

Human whole blood was collected in Vacutainer tubes containing EDTA as anticoagulant. Blood samples (7 ml) were carefully stacked on 5 ml PMN cell isolation medium (Robbins Scientific) in a 15 ml round bottom centrifuge tube. The samples were centrifuged for 30-35 minutes at 450-500 × g at room temperature swing out rotor. After centrifugation, the top band of cells was harvested and washed three times with PBS without calcium or magnesium. Cells were centrifuged at 400 x g for 10 minutes at room temperature. The cells were resuspended in a macrophage serum free medium (Gibco BRL) at a concentration of 2 million cells / ml.

LPS Stimulation of Human PBM

PBM cells (0.1 ml, 2 million / ml) were co-incubated with 0.1 ml of compound (10 to 0.41 μM, final concentration) for 1 hour in flat bottom 96 well microtiter plates. The compound was first dissolved in DMSO and diluted in TCM so that the final concentration of DMSO was 0.1%. LPS (Calbiochem, 20 ng / ml, final concentration) was then added in a volume of 0.010 ml. Cultures were incubated overnight at 37 ° C. The supernatants were then harvested and tested by ELISA for TNF-a and IL1-b. Survival was analyzed using MTS. After collecting 0.1 ml of supernatant, 0.020 ml of MTS was added to the remaining 0.1 ml of cells. After incubating these cells at 37 ° C. for 2-4 hours, O.D. was measured at 490-650 nM.

Maintenance and Differentiation of U937 Human Tissue Lymphoma Cell Line

U937 cells (ATCC) were grown in RPMI 1640 containing 10% fetal bovine serum, 100 IU / ml penicillin, 100 μg / ml streptomycin and 2 mM glutamine (Gibco). Five million cells in 100 ml medium induced termination of monocyte differentiation by 24 hour incubation with 20 ng / ml phorbol 12-myristate 13-acetate (Sigma). Cells were washed by centrifugation (200 × g, 5 min) and resuspended in 100 ml fresh medium. After 24 to 48 hours, cells were collected, centrifuged and resuspended at 2 million cells / ml in culture medium.

LPS Stimulation of TNF Production by U937 Cells

U937 cells (0.1 ml, 2 million / ml) were incubated with 0.1 ml of compound (0.004-50 μM, final concentration) in 96 well microtiter plates for 1 hour. Compounds were prepared as 10 mM stocks in DMSO and diluted in culture medium to give 0.1% final DMSO concentration on cytology. LPS (E. coli, 100 ng / ml final concentration) was then added in a volume of 0.02 ml. After 4 hours incubation at 37 ° C., the amount of TNF-alpha released in the culture medium was quantified by ELISA. Inhibitory efficacy is expressed as IC ₅₀ (μM).

Rat Test

In addition, a model based on rats challenged with LPS was used to assess the efficacy of the novel compounds in blocking TNF production. Male Harlen Lewis rats (Sprague Dawley Co.) were used in this model. Each rat weighed approximately 300 g and fasted overnight before testing. Typically, compounds were administered by oral nutrition (peritoneal, subcutaneous and intravenous administration may be used in some instances) 1 to 24 hours prior to LPS challenge. 30 μg / kg of LPS (salmonella typhosa, Sigma Company) was administered intravenously to rats via the tail vein. Blood was collected via cardiac puncture one hour after LPS challenge. Serum samples were stored at −20 ° C. until TNF-alpha was quantified with Enzyme Linked-Immuno Sorbent Assay (“ELISA”) (Biosource). Further details of this assay can be found in Perretti, M., et al., Br. J. Pharmacol. (1993), 110, 868-874, which is incorporated herein by reference.

Mouse test

LPS-induced TNF Alpha-generated Mouse Model

TNF alpha was induced by injecting 100 ng of lipopolysaccharide (obtained from S. Typhosa) in 0.2 ml of saline into the tail vein of 10-12 week old BALB / c female mice. After 1 hour, bleeding occurred in the orbital region of mice, and TNF concentration in serum from coagulated blood was quantified by ELISA. Typically, the peak level of serum TNF was 2-6 ng / ml 1 hour after LPS injection.

Mice fasted at 1 or 6 hours prior to LPS injection were administered orally by suspension as a suspension of 0.2 ml of 0.5% methylcellulose and 0.025% Tween 20 in water. The duration of application of the compound was estimated by the 6 hour protocol, while the efficacy of the compound at Cmax plasma levels was assessed by the 1 hour protocol. Efficacy was measured as a percentage inhibition of serum TNF levels for mice administered with vehicle only at each time point and LPS injected.

Induction and Evaluation of Collagen-Induced Arthritis in Mice

J., incorporated herein by reference. M. Stuart, Collagen Autoimmune Arthritis, Annual Rev. Immunol. 2: 199 (1984)] induced arthritis in mice. Specifically, on day 0, 50 μg of chicken type II collagen (CII) (provided by Dr. Marie Griffiths, University of Utah, Salt Lake City, Utah) in full-round adjuvant (Sigma) was injected. Arthritis was induced in 8-12 week old DBA / 1 male mice. Injection volume was 100 μl. On day 21 50 μg of CII in incomplete Freund's adjuvant (100 μl volume) was added to the animals. Animals were evaluated several times per week for arthritis signals. Any animal with redness or boil on the foot was counted as arthritis. Woolley 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), scores were calculated for feet with arthritis. Severity scores were calculated using scores of 1 to 3 (maximum score per mouse is 12) for each foot. Animals showing any redness or boil on their toes or feet were scored as 1. Large boils or deformations of the entire foot were calculated with a score of 2. Joint stiffness was calculated with a score of 3. Animals were evaluated for 8 weeks. 8 to 10 animals per group were used.

The present invention and its means and methods of making and using the same are described herein in complete, obvious, concise and accurate terms, so that any person skilled in the art to which they are included may make and use the same. It is understood that the foregoing describes preferred embodiments of the invention and that modifications may be made without departing from the spirit and scope of the invention as described in the claims. In particular, in order to point out and explicitly claim the subject matter related to the present invention, the following claims are completed herein.

In accordance with the present invention, a compound that acts as a P38 MAP kinase modulator can be provided to treat TNF mediated disorders, p38 kinase mediated disorders, inflammation and / or arthritis.

Claims (18)

A compound of formula (1a) or a pharmaceutically acceptable salt thereof. <Formula 1a>

In the above formula, L is -O-; M is -CH _2- ; X ₁ and X ₂ are independently selected from hydroxy (C ₁ -C ₄ ) alkyl, H, halogen, C ₁ -C ₆ alkyl, and R ₆ R ₇ N- (C ₁ -C ₆ alkyl)- ; R ₅ is heteroaryl or heteroaryl (C ₁ -C ₆ ) alkyl, wherein the heteroaryl and heteroaryl (C ₁ -C ₆ ) alkyl groups are independently —C (O) NR ₆ R ₇ , -NR ₆ R ₇ , Hydroxy (C ₁ -C ₄ ) alkyl, H, OH, halogen, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkyl, R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-or- Substituted or unsubstituted with 1, 2, 3 or 4 groups which are CO _2- (C ₁ -C ₆ ) alkyl, heteroaryl being 5 to 10 containing one or more heteroatoms selected from N, O and S A ring aromatic ring system; R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycarbonyl, OH, C ₁ -C ₆ hydroxide Oxyalkyl or C ₁ -C ₆ alkanoyl, each of which is independently substituted or unsubstituted with 1, 2 or 3 groups which are OH or C ₁ -C ₄ alkyl; Y, Y ₁ , Y ₂ , Y ₃ and Y ₄ are independently selected from H, halogen and C ₁ -C ₆ alkyl. The method of claim 1, R ₅ is a heteroaryl or heteroaryl (C ₁ -C ₆ ) alkyl group, each heteroaryl is pyrazolyl, imidazolyl, furanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl , Imidazolyl, dihydroindolyl, dihydroisoindolyl, indolon-2-yl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, dihydroisoquinolinyl or indolyl, these Each independently represents -C (O) NR ₆ R ₇ , -NR ₆ R ₇ , hydroxy (C ₁ -C ₄ ) alkyl, hydrogen, hydroxy, halogen, C ₁ -C ₄ haloalkyl, C ₁ -C Substituted or unsubstituted with 1, 2, 3 or 4 groups which are ₄ alkyl, R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-or —CO _2- (C ₁ -C ₆ ) alkyl; R ₆ and R ₇ are independently at each occurrence H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycarbonyl, OH, C ₁ -C ₆ hydroxide Or oxyalkyl or C ₁ -C ₆ alkanoyl, each of which is independently substituted or unsubstituted with 1, 2 or 3 groups which are independently OH or C ₁ -C ₄ alkyl. The compound or pharmaceutically acceptable salt thereof according to claim ₂ , wherein Y ₂ , Y ₄ and Y are independently halogen and Y ₁ and Y ₃ are both hydrogen. The compound or pharmaceutically acceptable compound of claim 3, wherein X ₁ and X ₂ are independently H, methyl, R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-or hydroxy (C ₁ -C ₄ ) alkyl. His salt. The compound of claim 4, wherein R ₅ is pyridyl C ₁ -C ₆ alkyl, pyrimidinyl C ₁ -C ₆ alkyl or pyrazinyl C ₁ -C ₆ alkyl, each of which is independently hydroxy (C ₁ -C) ₄ ) ₁ , _{2 which} is alkyl, OH, halogen, C ₁ -C ₄ alkyl, -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-or -C (O) NR ₆ R ₇ Or a compound or a pharmaceutically acceptable salt thereof, which is unsubstituted or substituted with three groups. The method of claim 5, R ₅ is a chemical formula

ego; Wherein Z ₅ is hydroxy (C ₁ -C ₄ ) alkyl, OH, halogen, C ₁ -C ₄ alkyl, -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-or- C (O) NR ₆ R ₇ and R ₆ and R ₇ in each occurrence are independently H or C ₁ -C ₆ alkyl unsubstituted or substituted with OH or a pharmaceutically acceptable salt thereof. The method of claim 5, R ₅ is a chemical formula

ego; Wherein Z ₅ is hydroxy (C ₁ -C ₄ ) alkyl, OH, halogen, C ₁ -C ₄ alkyl, -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-or- C (O) NR ₆ R ₇ and R ₆ and R ₇ in each occurrence are independently H or C ₁ -C ₆ alkyl unsubstituted or substituted with OH or a pharmaceutically acceptable salt thereof. The method of claim 5, R ₅ is a chemical formula

ego; Wherein Z ₁₀ is H or methyl and Z ₂₀ is hydroxy (C ₁ -C ₄ ) alkyl, OH, halogen, C ₁ -C ₄ alkyl, -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-or -C (O) NR ₆ R ₇ and R ₆ and R ₇ in each occurrence are independently H or C ₁ -C ₆ alkyl unsubstituted or substituted with OH or a pharmaceutical Its acceptable salts. The method of claim 5, R ₅ is a chemical formula

ego; Wherein Z ₁₀ is H or methyl and Z ₂₀ is hydroxy (C ₁ -C ₄ ) alkyl, OH, halogen, C ₁ -C ₄ alkyl, -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-or -C (O) NR ₆ R ₇ and R ₆ and R ₇ in each occurrence are independently H or C ₁ -C ₆ alkyl unsubstituted or substituted with OH or a pharmaceutical Its acceptable salts. The method of claim 5, R ₅ is a chemical formula

ego; Wherein Z ₁₀ is H or methyl and Z ₂₀ is hydroxy (C ₁ -C ₄ ) alkyl, OH, halogen, C ₁ -C ₄ alkyl, -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-or -C (O) NR ₆ R ₇ and R ₆ and R ₇ in each occurrence are independently H or C ₁ -C ₆ alkyl unsubstituted or substituted with OH or a pharmaceutical Its acceptable salts. The method of claim 5, R ₅ is a chemical formula

ego; Wherein Z ₁₀ is H or methyl and Z ₂₀ is hydroxy (C ₁ -C ₄ ) alkyl, OH, halogen, C ₁ -C ₄ alkyl, -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-or -C (O) NR ₆ R ₇ and R ₆ and R ₇ in each occurrence are independently H or C ₁ -C ₆ alkyl unsubstituted or substituted with OH or a pharmaceutical Its acceptable salts. The method of claim 5, R ₅ is a chemical formula

ego; Wherein Z ₁₀ is H or methyl and Z ₂₀ is hydroxy (C ₁ -C ₄ ) alkyl, OH, halogen, C ₁ -C ₄ alkyl, -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-or -C (O) NR ₆ R ₇ and R ₆ and R ₇ in each occurrence are independently H or C ₁ -C ₆ alkyl unsubstituted or substituted with OH or a pharmaceutical Its acceptable salts. The method of claim 5, R ₅ is a chemical formula

ego; Wherein Z ₁₀ is H or methyl and Z ₂₀ is hydroxy (C ₁ -C ₄ ) alkyl, OH, halogen, C ₁ -C ₄ alkyl, -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-or -C (O) NR ₆ R ₇ and R ₆ and R ₇ in each occurrence are independently H or C ₁ -C ₆ alkyl unsubstituted or substituted with OH or a pharmaceutical Its acceptable salts. The method of claim 5, R ₅ is a chemical formula

ego; Wherein Z ₁₀ is H or methyl and Z ₂₀ is hydroxy (C ₁ -C ₄ ) alkyl, OH, halogen, (C ₁ -C ₄ ) alkyl, -NR ₆ R ₇ , R ₆ R ₇ N- ( C ₁ -C ₆ alkyl)-or -C (O) NR ₆ R ₇ and R ₆ and R ₇ in each occurrence are independently H or C ₁ -C ₆ alkyl unsubstituted or substituted with OH Or a pharmaceutically acceptable salt thereof. The method of claim 5, R ₅ is a chemical formula

ego; Wherein Z ₁₀ is H or methyl and Z ₂₀ is hydroxy (C ₁ -C ₄ ) alkyl, OH, halogen, C ₁ -C ₄ alkyl, -NR ₆ R ₇ , R ₆ R ₇ N- (C ₁ -C ₆ alkyl)-or -C (O) NR ₆ R ₇ and R ₆ and R ₇ in each occurrence are independently H or C ₁ -C ₆ alkyl unsubstituted or substituted with OH or a pharmaceutical Its acceptable salts. delete A pharmaceutical composition for treating inflammation, pain, or lung disorders comprising the compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof. 4- (4-fluorobenzyloxy) -3-bromo-1- (pyridin-4-ylmethyl) pyridin-2 (1H) -one; 4- (4-fluorobenzyloxy) -3-bromo-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one; 3-chloro-4- (2,4-difluorobenzyloxy) -1-isoquinolin-5-ylmethyl-1H-pyridin-2-one; 3-chloro-4- (2,4-difluorobenzyloxy) -1- (1,2,3,4-tetrahydroisoquinolin-5-ylmethyl) -1H-pyridin-2-one; 3-chloro-4- (2,4-difluorobenzyloxy) -1- (1H-indol-5-ylmethyl) -1H-pyridin-2-one; 3-chloro-4- (2,4-difluorobenzyloxy) -1- (2,3-dihydro-1H-indol-5-ylmethyl) -1H-pyridin-2-one; 4- (2,4-difluorobenzyloxy) -3-bromo-1- (pyridin-4-ylmethyl) pyridin-2 (1H) -one; 4- (2,4-difluorobenzyloxy) -3-bromo-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one; 4- (2,4-difluorobenzyloxy) -3-bromo-1- (pyridin-2-ylmethyl) pyridin-2 (1H) -one; 3-chloro-4- (2,4-difluorobenzyloxy) -6-methyl-1- (1H-pyrazol-4-ylmethyl) -1H-pyridin-2-one; 4- (benzyloxy) -3-bromo-1-[(6-fluoropyridin-3-yl) methyl] pyridin-2 (1H) -one; 1-[(4-amino-2-methylpyrimidin-5-yl) methyl] -3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridine-2 (1H ) -On trifluoroacetate; 1-[(4-amino-2-methylpyrimidin-5-yl) methyl] -3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridine-2 (1H ) -One hydrochloride; 1-[(4-amino-2-methylpyrimidin-5-yl) methyl] -3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridine-2 (1H) -On trifluoroacetate; 1-[(4-amino-2-methylpyrimidin-5-yl) methyl] -3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridine-2 (1H) -One hydrochloride; 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (1H-indazol-5-ylmethyl) -6-methylpyridin-2 (1H) -one trifluoroacetate ; 4-{[2- (aminomethyl) -4-fluorobenzyl] oxy} -3-bromo-1- (2,6-difluorophenyl) -6-methylpyridin-2 (1H) -one tree Fluoroacetates; Methyl 4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} pyrimidin-2-car Carboxylate trifluoroacetate; 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1-[(2-hydroxypyrimidin-4-yl) methyl] -6-methylpyridin-2 (1H) -one Trifluoroacetate; 4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} pyrimidine-2-carbox Amide trifluoroacetate; Methyl (4-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} pyrimidin-2- (1) methylcarbamate; 3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-[(5-methylpyrazin-2-yl) methyl] pyridin-2 (1H) -one; 3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (pyrazin-2-ylmethyl) pyridin-2 (1H) -one; 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1-{[5- (hydroxymethyl) pyrazin-2-yl] methyl} -6-methylpyridine-2 (1H) -On; 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1-({5-[(dimethylamino) methyl] pyrazin-2-yl} methyl) -6-methylpyridine-2 ( 1H) -one trifluoroacetate; 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1-[(5-{[(2-hydroxyethyl) (methyl) amino] -methyl} pyrazin-2-yl) Methyl] -6-methylpyridin-2 (1H) -one trifluoroacetate; 5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N- (2-hydrate Oxyethyl) -N-methylpyrazine-2-carboxamide; 5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N- (2,3 -Dihydroxypropyl) pyrazine-2-carboxamide; 5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N- (2-hydrate Oxyethyl) pyrazine-2-carboxamide; 3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (pyridin-4-ylmethyl) pyridin-2 (1H) -one; 3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one; 3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (pyridin-2-ylmethyl) pyridin-2 (1H) -one; 4- (4-fluorobenzyloxy) -3-bromo-6-methyl-1- (pyridin-4-ylmethyl) pyridin-2 (1H) -one; 4- (2,6-difluorobenzyloxy) -3-bromo-6-methyl-1- (pyridin-4-ylmethyl) pyridin-2 (1H) -one; 4- (2,4,6-trifluorobenzyloxy) -3-bromo-6-methyl-1- (pyridin-4-ylmethyl) pyridin-2 (1H) -one; 4- (4-fluorobenzyloxy) -3-bromo-6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one; 4- (2,4,6-trifluorobenzyloxy) -3-bromo-6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one; 4- (2-fluorobenzyloxy) -3-bromo-6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one; 4- (2,4,5-trifluorobenzyloxy) -3-bromo-6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one; 4- (4-chloro-2-fluorobenzyloxy) -3-bromo-6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one; 4- (2-chloro-4-fluorobenzyloxy) -3-bromo-6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one; 4- (2-chloro-4-fluorobenzyloxy) -3-bromo-6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one; 4- (4-fluorobenzyloxy) -3-bromo-6-methyl-1- (pyridin-2-ylmethyl) pyridin-2 (1H) -one; 4- (2,4,6-trifluorobenzyloxy) -3-bromo-6-methyl-1- (pyridin-2-ylmethyl) pyridin-2 (1H) -one; 4- (2,4,5-trifluorobenzyloxy) -3-bromo-6-methyl-1- (pyridin-2-ylmethyl) pyridin-2 (1H) -one; 3-bromo-4- [2- (4-fluorophenyl) ethyl] -6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one; 3-bromo-4- [2- (4-fluorophenyl) ethyl] -6-methyl-1- (pyridin-4-ylmethyl) pyridin-2 (1H) -one; 3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one; 1-[(4-amino-2-methylpyrimidin-5-yl) methyl] -3-bromo-6-methyl-4-[(2,4,6-trifluorobenzyl) oxy] pyridine-2 (1H) -one trifluoroacetate; 3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-{[2-methyl-4- (methylamino) pyrimidin-5-yl] methyl} pyridine- 2 (1H) -one trifluoroacetate; 3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-[(5-methylpyrazin-2-yl) methyl] pyridin-2 (1H) -one; 3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-({5-[(methylamino) methyl] pyrazin-2-yl} methyl) pyridine-2 ( 1H) -one trifluoroacetate; Ethyl 5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} pyrazine-2-carboxylate ; 3-chloro-4-[(2,4-difluorobenzyl) oxy] -1-{[5- (hydroxymethyl) pyrazin-2-yl] methyl} -6-methylpyridine-2 (1H)- On; 5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N, N-dimethylpyrazine -2-carboxamide; 5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N-methylpyrazine-2 Carboxamides; 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1-{[5- (1-hydroxy-1-methylethyl) pyrazin-2-yl] methyl} -6-methyl Pyridin-2 (1H) -one; 5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N- (2-meth Oxyethyl) pyrazine-2-carboxamide; 5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N- (2,2, 2-trifluoroethyl) pyrazine-2-carboxamide; 4-[(2,4-difluorobenzyl) oxy] -6- (hydroxymethyl) -1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one; 3-bromo-4-[(2,4-difluorobenzyl) oxy] -6- (hydroxymethyl) -1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one; 3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-[(dimethylamino) methyl] -1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one; 3-bromo-4-[(2,4-difluorobenzyl) amino] -6-methyl-1- (pyridin-4-ylmethyl) pyridin-2 (1H) -one; 3-bromo-4-[(2,4-difluorobenzyl) amino] -6-methyl-1- (pyridin-3-ylmethyl) pyridin-2 (1H) -one; 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1-{[5- (1-hydroxy-1-methylethyl) pyridin-2-yl] methyl} -6-methyl Pyridin-2 (1H) -one; 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1-{[5- (hydroxymethyl) pyridin-2-yl] methyl} -6-methylpyridine-2 (1H) -On; 6-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N- (2-hydrate Oxyethyl) -N-methylnicotinamide; 6-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N- (2-hydrate Oxyethyl) nicotinamide; 6-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N, N-dimethylnicotin amides; Ethyl 3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxo-2H-1,2'-bipyridine-5'-carboxylate; 3-bromo-4-[(2,4-difluorobenzyl) oxy] -5 '-(1-hydroxy-1-methylethyl) -6-methyl-2H-1,2'-bipyridine- 2-one; 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (2-furylmethyl) -6-methylpyridin-2 (1H) -one; 3-chloro-4- (2,4-difluorobenzyloxy) -6-methyl-1- (1H-pyrazol-3-ylmethyl) -1H-pyridin-2-one; 3-chloro-4- (2,4-difluorobenzyloxy) -6-methyl-1- (2,3-dihydro-1H-indol-5-ylmethyl) -1H-pyridin-2-one; Methyl (5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} pyrazin-2-yl ) Methyl (methyl) carbamate; N-[(5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} pyrazine-2 -Yl) methyl] -2-hydroxy-N, 2-dimethylpropanamide; 5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N- (2-hydrate Oxy-2-methylpropyl) pyrazine-2-carboxamide; 1-[(5-aminopyrazin-2-yl) methyl] -3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methylpyridin-2 (1H) -one trifluor Low acetate; 3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-1-[(3-methyl-1,2,4-triazin-6-yl) methyl] pyridine- 2 (1H) -one trifluoroacetate; 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (1H-indazol-5-yl) -6-methylpyridin-2 (1H) -one; 3-bromo-4-[(2,4-difluorobenzyl) oxy] -1- (1H-indazol-6-yl) -6-methylpyridin-2 (1H) -one; Methyl 5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -2-furoate; 4- (2,4-difluorobenzyloxy) -3-chloro-6-methyl-1-((5-methylpyrazin-2-yl) methyl) pyridin-2 (1H) -one; 4- (2,4-difluorobenzyloxy) -3-chloro-1-((5- (hydroxymethyl) pyrazin-2-yl) methyl) -6-methylpyridin-2 (1H) -one; 4- (2,4-difluorobenzyloxy) -3-bromo-1- (indolin-5-ylmethyl) -6-methylpyridin-2 (1H) -one; 1-((1H-pyrazol-3-yl) methyl) -4- (4-fluoro-2-methylbenzyloxy) -3-bromo-6-methylpyridin-2 (1H) -one; 4- (2,4-difluorobenzyloxy) -1-((2- (aminomethyl) -4-methylpyrimidin-5-yl) methyl) -3-bromo-6-methylpyridine-2 ( 1H) -one; 4- (2,4-difluorobenzyloxy) -3-bromo-1-((2-((dimethylamino) methyl) -4-methylpyrimidin-5-yl) methyl) -6-methylpyridine -2 (1H) -one; 5-((4- (2,4-difluorobenzyloxy) -3-bromo-6-methyl-2-oxopyridin-1 (2H) -yl) methyl) -4-methylpyrimidine-2- Carboxamides; 5-((4- (2,4-difluorobenzyloxy) -3-bromo-6-methyl-2-oxopyridin-1 (2H) -yl) methyl) -N, 4-dimethylpyrimidine- 2-carboxamide; 5-{[3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -2-puramide; 5- [3-bromo-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] -2-puramide; 5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] -6-methyl-2-oxopyridin-1 (2H) -yl] methyl} -N, N-dimethylindolin -1-carboxamide; And 5-{[3-chloro-4-[(2,4-difluorobenzyl) oxy] 2-oxopyridin-1 (2H) -yl] methyl} -N, N-dimethylindolin-1-carbox amides Or a pharmaceutically acceptable salt thereof.