JP2008515964A - Substituted N-alkylpyrimidinone - Google Patents

Abstract

The present invention is generally directed to substituted pyrimidinone compounds that generally inhibit p38 kinase, TNF, and / or cyclooxygenase activity. Such substituted pyrimidinones generally have the structure of the following formula I, wherein R ¹ , R ² , R ³ , R ^4A , R ^4B , R ^4C , R ^4D , and R ^4E are defined herein. And the like.] Is included. The present invention also includes compositions of such substituted pyrimidinones (especially pharmaceutical compositions), intermediates for synthesizing such substituted pyrimidinones, methods for producing such substituted pyrimidinones, and p38 kinase activity, TNF activity, And / or methods of treatment (including prevention) of conditions associated with cyclooxygenase 2 activity (usually pathological conditions).
[Chemical 1]

Description

  This application claims priority from US Provisional Application No. 60 / 618,856 filed on Oct. 13, 2004, which claims priority from US Provisional Application No. 60/637949, filed December 21, 2004. Each of these disclosures is hereby incorporated by reference in its entirety.

  The present invention is directed to compounds that inhibit p38 kinase (particularly p38α kinase), TNF (particularly TNF-α), and / or cyclooxygenase (particularly cyclooxygenase 2 or “COX-2”) activity. The present invention relates to compositions of such compounds, methods for the preparation of such compounds, and (prevention of conditions associated with p38 kinase activity, TNF activity, and / or cyclooxygenase 2 activity (usually pathological conditions). Including treatment methods.

  Mitogen activated protein kinases (MAPs) are a family of proline-directed serine / threonine kinases that activate their substrates by double phosphorylation. This kinase is activated by a variety of signals including nutritional and osmotic stress, ultraviolet light, growth factors, endotoxins, and inflammatory cytokines. The p38 MAP kinase group is a MAP family consisting of various isoforms including p38α, p38β, and p38γ. These kinases are responsible for phosphorylation and activation of transcription factors (eg, ATF2, CHOP, and MEF2C) and other kinases (eg, MAPKAP-2 and MAPKAP-3). The p38 isoform is activated by bacterial lipopolysaccharide, physicochemical stress, and pro-inflammatory cytokines including tumor necrosis factor (“TNF”) and interleukin 1 (“IL-1”). The product of p38 phosphorylation mediates the production of inflammatory cytokines including TNF, IL-1, and cyclooxygenase 2.

  p38α kinases are generally associated with, for example, inflammatory outcomes, arthritis, nerve inflammation, pain, fever, lung injury, cardiovascular disease, cardiomyopathy, stroke, ischemia, reperfusion injury, kidney reperfusion injury, cerebral edema, Neurotrauma and head trauma, neurodegenerative disorders, central nervous system disorders, liver and nephritis, gastrointestinal conditions, ulcerative diseases, eye diseases, ophthalmological conditions, glaucoma, acute injury to the eye tissue and eyes Trauma, diabetes, diabetic nephropathy, skin-related conditions, viral and bacterial infections, muscle pain due to infection, influenza, endotoxin shock, toxic shock syndrome, autoimmune disease, bone resorption disease, multiple sclerosis, female Reproductive system disorders; pathological conditions (but not malignant) such as hemangiomas, nasopharyngeal hemangiofibromas, and avascular osteonecrosis; benign and malignant tumors / neoplasia including cancer; leukemia; lymphoma; Ritematodesu (SLE); angiogenesis including neoplasia; cause and metastasis, or are believed can become part because.

  TNF is a cytokine produced primarily by activated monocytes and macrophages. Excess or unregulated production of TNF (especially TNF-α) has been implicated in mediating several diseases. For example, TNF is a consequence of inflammation (eg rheumatoid arthritis and inflammatory bowel disease), asthma, autoimmune disease, graft rejection, multiple sclerosis, fibrotic disease, cancer, fever, psoriasis, cardiovascular disease (eg , Reperfusion injury after ischemia and congestive heart failure), lung disease (eg, alveolar injury due to hyperoxia), bleeding, coagulation, radiation damage, and those seen in infections and sepsis and in shock It is believed that such acute phase responses (eg, infectious and hemodynamic shocks) can be caused and contributed to. Prolonged release of active TNF can cause cachexia and eating disorders. In addition, TNF can be fatal.

  TNF has also been implicated in infectious diseases. These include, for example, malaria, mycobacterial infection, and meningitis. These also include, among others, HIV, influenza virus, and herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV), Virus infections such as Epstein-Barr virus, human herpes virus 6 (HHV-6), human herpes virus 7 (HHV-7), human herpes virus 8 (HHV-8), Aujeszky's disease, and rhinobronchitis Is included.

  IL-8 is another pro-inflammatory cytokine produced by mononuclear cells, fibroblasts, endothelial cells, and keratinocytes. This cytokine is associated with conditions involving inflammation.

  IL-1 is produced by activated monocytes and macrophages and is involved in the inflammatory response. IL-1 plays a role in many pathophysiological responses including rheumatoid arthritis, fever, and reduced bone resorption.

  TNF, IL-1, and IL-8 affect a wide variety of cells and tissues and are important inflammatory mediators of a wide variety of conditions. Suppression of these cytokines by inhibition of p38 kinase is beneficial in controlling, reducing, and alleviating many of these disease states.

  Various substituted pyrimidinones have been described previously.

  US patent application Ser. No. 10 / 808,146 (filed Mar. 24, 2004) refers to certain substituted pyrimidinones.

  Given the importance of substituted pyrimidinones in the treatment of several pathological conditions, particularly those associated with p38 kinase activity, TNF activity, and / or cyclooxygenase 2 activity, an improved safety profile, solubility, There is a continuing need for substituted pyrimidinone compounds that exhibit and / or efficacy. The following disclosure describes substituted pyrimidinone compounds that exhibit one or more such desired properties.

  The present invention is directed to substituted pyrimidinone compounds that inhibit p38 kinase activity, TNF activity, and / or cyclooxygenase 2 activity. The present invention also includes, for example, methods of inhibiting p38 kinase, TNF, and / or cyclooxygenase 2 activity, particularly conditions mediated by p38 kinase activity, TNF activity, and / or cyclooxygenase 2 activity (usually pathological conditions) The subject is a method of treating. Such methods are usually suitable for use in mammals in need of such treatment.

  Briefly, therefore, in part, the present invention generally includes compounds that fall within the scope of the structure of Formula I

またはその薬学的に許容できる塩、鏡像異性体、もしくはラセミ化合物［式中、Ｒ^１は、アルケニル、アルコキシカルボニルアルキルアミノ、アルコキシカルボニルアミノアルコキシ、アルコキシカルボニルアミノヘテロシクロ、アルコキシカルボニルアリール、アルコキシカルボニルアリールアルキルアミノ、アルコキシカルボニルヘテロシクロ、アルキル、アルキルアミノ、アルキルアミノカルボニルアルキル、アルキルアミノカルボニルアルキルアミノ、アルキルアミノカルボニルアミノアルコキシ、アルキルアミノヘテロシクロ、アルキルカルボニルアミノアルコキシ、アルキルカルボニルアミノアルキル、アルキルカルボニルアミノアルキルアミノ、アルキルカルボニルアミノヘテロシクロ、アルキルカルボニルヘテロシクロアミノ、アルキルカルボニルオキシアルキルカルボニルアミノアルコキシ、アルキルカルボニルオキシアルキルカルボニルアミノヘテロシクロ、アルキルスルホニル、アルキルスルホニルアミノアルコキシ、アルキルスルホニルアミノアルキル、アルキルスルホニルアミノアルキルアミノ、アルキルチオ、アミノアルコキシ、アミノアルキル、アミノアルキルアミノ、アミノアルキルカルボニルアミノヘテロシクロ、アミノアルキルカルボニルヘテロシクロ、アミノカルボニルアルコキシ、アミノカルボニルアルキル、アミノカルボニルアルキルアミノ、アミノカルボニルアルキルヘテロシクロ、アミノカルボニルアミノアルコキシ、アミノカルボニルアミノアルキルアミノ、アミノカルボニルアリール、アミノカルボニルジアルキルアミノ、アミノカルボニルヘテロシクロ、アミノヘテロシクロ、アリール、カルボキシアルコキシ、カルボキシアルキル、カルボキシアリール、カルボキシジアルキルアミノ、シクロアルキル、ジアルキルアミノアルキルアミノ、ジヒドロキシアルキルアミノ、ハロ、ハロアルキルスルホニルオキシ、ハロアリールアルキルアミノ、ヘテロアリールアルコキシカルボニルアミノヘテロシクロ、ヘテロシクロカルボニルアルキルアミノ、ヘテロシクロ、水素、ヒドロキシ、ヒドロキシアルコキシ、ヒドロキシアルキル、ヒドロキシアルキルアミノ、ヒドロキシアルキルアミノカルボニルアルコキシ、ヒドロキシアルキルアミノカルボニルアルキル、ヒドロキシアルキルアミノカルボニルアルキルアミノ、ヒドロキシアルキルアミノカルボニルアミノアルコキシ、ヒドロキシアルキルアミノヘテロシクロ、ヒドロキシアルキルカルボニルアミノアルキルアミノ、ヒドロキシアルキルカルボニルアミノヘテロシクロ、ヒドロキシアルキルカルボニルヘテロシクロ、ヒドロキシアルキルヘテロシクロ、およびヒドロキシヘテロシクロからなる群から選択され、Ｒ^２は、アルキル、シクロアルキル、および水素からなる群から選択され、Ｒ^３は、水素、アルキル、アルコキシ、およびハロからなる群から選択され、各アルキルは、どこに存在する場合であっても、それぞれ独立に、アルコキシ、アミノ、カルボキシ、ハロ、およびヒドロキシルで置換されていてもよく、Ｒ^４Ａ、Ｒ^４Ｂ、Ｒ^４Ｃ、Ｒ^４Ｄ、およびＲ^４Ｅはそれぞれ独立に、アルキルアミノカルボニルアミノアルキル、アルキルアリールヘテロアリールアミノカルボニルアミノアルキル、アミノアルキル、アリールシクロアルキルアミノカルボニルジアルキルアミノアルキル、アリールシクロアルキルアミノカルボニルアミノアルキル、シアノ、シクロアルキルアミノカルボニルアミノアルキル、シクロアルキルアミノカルボニルジアルキルアミノアルキル、ハロ、および水素からなる群から選択され、各アリールおよびヘテロアリールは、どこに存在する場合であっても、それぞれ独立に、アルキルで置換されていてもよい］を対象とする。

Or a pharmaceutically acceptable salt, enantiomer or racemic compound thereof, wherein R ¹ is alkenyl, alkoxycarbonylalkylamino, alkoxycarbonylaminoalkoxy, alkoxycarbonylaminoheterocyclo, alkoxycarbonylaryl, alkoxycarbonylarylalkyl Amino, alkoxycarbonylheterocyclo, alkyl, alkylamino, alkylaminocarbonylalkyl, alkylaminocarbonylalkylamino, alkylaminocarbonylaminoalkoxy, alkylaminoheterocyclo, alkylcarbonylaminoalkoxy, alkylcarbonylaminoalkyl, alkylcarbonylaminoalkylamino, Alkylcarbonylaminoheterocyclo, alkylcarbonylheterocycloami Alkylcarbonyloxyalkylcarbonylaminoalkoxy, alkylcarbonyloxyalkylcarbonylamino heterocyclo, alkylsulfonyl, alkylsulfonylaminoalkoxy, alkylsulfonylaminoalkyl, alkylsulfonylaminoalkylamino, alkylthio, aminoalkoxy, aminoalkyl, aminoalkylamino, Aminoalkylcarbonylaminoheterocyclo, aminoalkylcarbonylheterocyclo, aminocarbonylalkoxy, aminocarbonylalkyl, aminocarbonylalkylamino, aminocarbonylalkylheterocyclo, aminocarbonylaminoalkoxy, aminocarbonylaminoalkylamino, aminocarbonylaryl, aminocarbonyldialkyl Amino, a Nocarbonylheterocyclo, aminoheterocyclo, aryl, carboxyalkoxy, carboxyalkyl, carboxyaryl, carboxydialkylamino, cycloalkyl, dialkylaminoalkylamino, dihydroxyalkylamino, halo, haloalkylsulfonyloxy, haloarylalkylamino, heteroarylalkoxy Carbonylaminoheterocyclo, heterocyclocarbonylalkylamino, heterocyclo, hydrogen, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkylamino, hydroxyalkylaminocarbonylalkoxy, hydroxyalkylaminocarbonylalkyl, hydroxyalkylaminocarbonylalkylamino, hydroxyalkylaminocarbonyl Amino Arco Shi, hydroxyalkyl amino heterocycloalkyl, hydroxyalkyl alkylcarbonylamino alkylamino, hydroxyalkyl carbonylamino heterocycloalkyl, hydroxyalkyl carbonyl heterocycloalkyl, selected from hydroxyalkyl heterocycloalkyl, and the group consisting of hydroxy heterocycloalkyl, R ² is alkyl, Selected from the group consisting of cycloalkyl, and hydrogen, and R ³ is selected from the group consisting of hydrogen, alkyl, alkoxy, and halo, and each alkyl, wherever present, is independently alkoxy, amino, carboxy, halo, and hydroxyl may be substituted ^{by, R 4A, R 4B, R} 4C, R 4D, and ^{R 4E} are each independently alkyl aminocarbonylamino alkyl, alkylaryl From heteroheteroaminocarbonylaminoalkyl, aminoalkyl, arylcycloalkylaminocarbonyldialkylaminoalkyl, arylcycloalkylaminocarbonylaminoalkyl, cyano, cycloalkylaminocarbonylaminoalkyl, cycloalkylaminocarbonyldialkylaminoalkyl, halo, and hydrogen Each aryl and heteroaryl is independently substituted with alkyl, wherever present, are selected from the group consisting of].

  The present invention is also directed, in part, to a pharmaceutical composition comprising a therapeutically effective amount of a compound as described above or a pharmaceutically acceptable salt thereof.

  The present invention is also directed, in part, to a method of treating an inflammatory condition in a mammal. This method comprises administering to a mammal a compound as described above or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to treat the condition.

  Other benefits of Applicants' invention will be apparent to those skilled in the art upon reading this specification.

  The detailed description of this embodiment can be best suited to the requirements of a particular use, so that others skilled in the art can adapt and apply the invention in its many forms. It merely informs those skilled in the art of Applicants' invention, its principles, and its practical application. This detailed description and detailed examples thereof, illustrate embodiments of the invention and are for illustrative purposes only. Therefore, the present invention is not limited to the embodiments described in the present specification, and can be variously modified.

Compounds of the Invention According to the present invention, it has been found that certain substituted pyrimidinone compounds are effective in inhibiting the activity (especially pathological activity) of p38 kinase, TNF, and / or cyclooxygenase 2.

  Among its many embodiments, the present invention provides compounds of formula I

またはその薬学的に許容できる塩、鏡像異性体、もしくはラセミ化合物［式中、Ｒ^１は、アルケニル、アルコキシカルボニルアルキルアミノ、アルコキシカルボニルアミノアルコキシ、アルコキシカルボニルアミノヘテロシクロ、アルコキシカルボニルアリール、アルコキシカルボニルアリールアルキルアミノ、アルコキシカルボニルヘテロシクロ、アルキル、アルキルアミノ、アルキルアミノカルボニルアルキル、アルキルアミノカルボニルアルキルアミノ、アルキルアミノカルボニルアミノアルコキシ、アルキルアミノヘテロシクロ、アルキルカルボニルアミノアルコキシ、アルキルカルボニルアミノアルキル、アルキルカルボニルアミノアルキルアミノ、アルキルカルボニルアミノヘテロシクロ、アルキルカルボニルヘテロシクロアミノ、アルキルカルボニルオキシアルキルカルボニルアミノアルコキシ、アルキルカルボニルオキシアルキルカルボニルアミノヘテロシクロ、アルキルスルホニル、アルキルスルホニルアミノアルコキシ、アルキルスルホニルアミノアルキル、アルキルスルホニルアミノアルキルアミノ、アルキルチオ、アミノアルコキシ、アミノアルキル、アミノアルキルアミノ、アミノアルキルカルボニルアミノヘテロシクロ、アミノアルキルカルボニルヘテロシクロ、アミノカルボニルアルコキシ、アミノカルボニルアルキル、アミノカルボニルアルキルアミノ、アミノカルボニルアルキルヘテロシクロ、アミノカルボニルアミノアルコキシ、アミノカルボニルアミノアルキルアミノ、アミノカルボニルアリール、アミノカルボニルジアルキルアミノ、アミノカルボニルヘテロシクロ、アミノヘテロシクロ、アリール、カルボキシアルコキシ、カルボキシアルキル、カルボキシアリール、カルボキシジアルキルアミノ、シクロアルキル、ジアルキルアミノアルキルアミノ、ジヒドロキシアルキルアミノ、ハロ、ハロアルキルスルホニルオキシ、ハロアリールアルキルアミノ、ヘテロアリールアルコキシカルボニルアミノヘテロシクロ、ヘテロシクロカルボニルアルキルアミノ、ヘテロシクロ、水素、ヒドロキシ、ヒドロキシアルコキシ、ヒドロキシアルキル、ヒドロキシアルキルアミノ、ヒドロキシアルキルアミノカルボニルアルコキシ、ヒドロキシアルキルアミノカルボニルアルキル、ヒドロキシアルキルアミノカルボニルアルキルアミノ、ヒドロキシアルキルアミノカルボニルアミノアルコキシ、ヒドロキシアルキルアミノヘテロシクロ、ヒドロキシアルキルカルボニルアミノアルキルアミノ、ヒドロキシアルキルカルボニルアミノヘテロシクロ、ヒドロキシアルキルカルボニルヘテロシクロ、ヒドロキシアルキルヘテロシクロ、およびヒドロキシヘテロシクロからなる群から選択され、Ｒ^２は、アルキル、シクロアルキル、および水素からなる群から選択され、Ｒ^３は、水素、アルキル、アルコキシ、およびハロからなる群から選択され、各アルキルは、どこに存在する場合であっても、それぞれ独立に、アルコキシ、アミノ、カルボキシ、ハロ、およびヒドロキシルで置換されていてもよく、Ｒ^４Ａ、Ｒ^４Ｂ、Ｒ^４Ｃ、Ｒ^４Ｄ、およびＲ^４Ｅはそれぞれ独立に、アルキルアミノカルボニルアミノアルキル、アルキルアリールヘテロアリールアミノカルボニルアミノアルキル、アミノアルキル、アリールシクロアルキルアミノカルボニルジアルキルアミノアルキル、アリールシクロアルキルアミノカルボニルアミノアルキル、シアノ、シクロアルキルアミノカルボニルアミノアルキル、シクロアルキルアミノカルボニルジアルキルアミノアルキル、ハロ、および水素からなる群から選択され、各アリールおよびヘテロアリールは、どこに存在する場合であっても、それぞれ独立に、アルキルで置換されていてもよい］を提供する。

Or a pharmaceutically acceptable salt, enantiomer or racemic compound thereof, wherein R ¹ is alkenyl, alkoxycarbonylalkylamino, alkoxycarbonylaminoalkoxy, alkoxycarbonylaminoheterocyclo, alkoxycarbonylaryl, alkoxycarbonylarylalkyl Amino, alkoxycarbonylheterocyclo, alkyl, alkylamino, alkylaminocarbonylalkyl, alkylaminocarbonylalkylamino, alkylaminocarbonylaminoalkoxy, alkylaminoheterocyclo, alkylcarbonylaminoalkoxy, alkylcarbonylaminoalkyl, alkylcarbonylaminoalkylamino, Alkylcarbonylaminoheterocyclo, alkylcarbonylheterocycloami Alkylcarbonyloxyalkylcarbonylaminoalkoxy, alkylcarbonyloxyalkylcarbonylamino heterocyclo, alkylsulfonyl, alkylsulfonylaminoalkoxy, alkylsulfonylaminoalkyl, alkylsulfonylaminoalkylamino, alkylthio, aminoalkoxy, aminoalkyl, aminoalkylamino, Aminoalkylcarbonylaminoheterocyclo, aminoalkylcarbonylheterocyclo, aminocarbonylalkoxy, aminocarbonylalkyl, aminocarbonylalkylamino, aminocarbonylalkylheterocyclo, aminocarbonylaminoalkoxy, aminocarbonylaminoalkylamino, aminocarbonylaryl, aminocarbonyldialkyl Amino, a Nocarbonylheterocyclo, aminoheterocyclo, aryl, carboxyalkoxy, carboxyalkyl, carboxyaryl, carboxydialkylamino, cycloalkyl, dialkylaminoalkylamino, dihydroxyalkylamino, halo, haloalkylsulfonyloxy, haloarylalkylamino, heteroarylalkoxy Carbonylaminoheterocyclo, heterocyclocarbonylalkylamino, heterocyclo, hydrogen, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkylamino, hydroxyalkylaminocarbonylalkoxy, hydroxyalkylaminocarbonylalkyl, hydroxyalkylaminocarbonylalkylamino, hydroxyalkylaminocarbonyl Amino Arco Shi, hydroxyalkyl amino heterocycloalkyl, hydroxyalkyl alkylcarbonylamino alkylamino, hydroxyalkyl carbonylamino heterocycloalkyl, hydroxyalkyl carbonyl heterocycloalkyl, selected from hydroxyalkyl heterocycloalkyl, and the group consisting of hydroxy heterocycloalkyl, R ² is alkyl, Selected from the group consisting of cycloalkyl, and hydrogen, and R ³ is selected from the group consisting of hydrogen, alkyl, alkoxy, and halo, and each alkyl, wherever present, is independently alkoxy, amino, carboxy, halo, and hydroxyl may be substituted ^{by, R 4A, R 4B, R} 4C, R 4D, and ^{R 4E} are each independently alkyl aminocarbonylamino alkyl, alkylaryl From heteroarylaminocarbonylaminoalkyl, aminoalkyl, arylcycloalkylaminocarbonyldialkylaminoalkyl, arylcycloalkylaminocarbonylaminoalkyl, cyano, cycloalkylaminocarbonylaminoalkyl, cycloalkylaminocarbonyldialkylaminoalkyl, halo, and hydrogen Each aryl and heteroaryl is independently substituted with alkyl, wherever present, are selected from the group consisting of:

In another embodiment, R ¹ is (C ₂ -C ₁₀ ) -alkenyl, (C ₁ -C ₁₀ ) -alkoxycarbonyl- (C ₁ -C ₁₀ ) -alkylamino, (C ₁ -C ₁₀ ) — alkoxycarbonylamino _{- (C} 1 _{~C 10) - alkoxy, (C} 1 _{~C 10)} - alkoxycarbonylamino _{heterocycloalkyl, (C} 1 _{~C 10)} - alkoxycarbonyl _{aryl, (C} 1 _{~C 10)} - alkoxycarbonyl Aryl- (C ₁ -C ₁₀ ) -alkylamino, (C ₁ -C ₁₀ ) -alkoxycarbonylheterocyclo, (C ₁ -C ₁₀ ) -alkyl, (C ₁ -C ₁₀ ) -alkylamino, (C ₁ -C ₁₀₎ - alkylaminocarbonyl _- (C 1 _{-C 10)} - _{alkyl, (C} 1 _{~C 10)} - alkylaminocarbonyl - ( C ₁ ~C ₁₀₎ - _{alkylamino, (C} 1 ~C ₁₀₎ - alkylaminocarbonylamino _{- (C} 1 _{~C 10) - alkoxy, (C} 1 ~C ₁₀₎ - alkylamino heterocycloalkyl, _(C 1 ~ C ₁₀₎ - alkylcarbonylamino _{- (C} 1 _{~C 10) - alkoxy, (C} 1 _{~C 10)} - alkylcarbonylamino _{- (C} 1 _{~C 10) - alkyl, (C} 1 _{~C 10)} - alkylcarbonyl Amino- (C ₁ -C ₁₀ ) -alkylamino, (C ₁ -C ₁₀ ) -alkylcarbonylaminoheterocyclo, (C ₁ -C ₁₀ ) -alkylcarbonylheterocycloamino, (C ₁ -C ₁₀ ) -alkyl carbonyloxy _{- (C} 1 ~C _{10) -} alkylcarbonylamino _{- (C} 1 ~C _{10) - alkoxy, (C 1 ~C} 1 ) - alkylcarbonyloxy _- (C 1 _{-C 10)} - alkylcarbonylamino _{heterocycloalkyl, (C} 1 ~C ₁₀₎ - _{alkylsulfonyl, (C} 1 ~C ₁₀₎ - alkylsulfonylamino _- (C 1 _{-C 10)} - _{alkoxy, (C} 1 _{~C 10)} - alkylsulfonylamino _{- (C} 1 _{~C 10) - alkyl, (C} 1 _{~C 10)} - alkylsulfonylamino _{- (C} 1 _{~C 10) -} alkylamino, (C ₁ -C ₁₀₎ - alkylthio, amino _{- (C} 1 _{~C 10) -} alkoxy, amino _{- (C} 1 _{~C 10) -} alkyl, amino _{- (C} 1 _{~C 10) -} alkylamino, amino - _{(C 1} -C ₁₀₎ - alkylcarbonylamino heterocycloalkyl, amino _{- (C} 1 _{~C 10) -} alkylcarbonyl heterocycloalkyl, Aminoka Boniru _{- (C} 1 _{~C 10) -} alkoxy, aminocarbonyl _{- (C} 1 _{~C 10) -} alkyl, aminocarbonyl _{- (C} 1 _{~C 10) -} alkylamino, aminocarbonyl _{- (C} 1 _{~C 10) -} Alkylheterocyclo, aminocarbonylamino- (C ₁ -C ₁₀ ) -alkoxy, aminocarbonylamino- (C ₁ -C ₁₀ ) -alkylamino, aminocarbonylaryl, aminocarbonyl- (C ₁ -C ₁₀ ) -dialkylamino , aminocarbonyl heterocycloalkyl, amino heterocycloalkyl, aryl, carboxy _{- (C} 1 _{~C 10) -} alkoxy, carboxy _{- (C} 1 _{~C 10) -} alkyl, carboxy aryl, carboxy _{- (C} 1 _{~C 10) -} dialkyl Amino, (C ₁ -C ₁₀ ) -cycloalkyl, (C ₁ -C ₁₀₎ - dialkylamino _{- (C} 1 _{~C 10) -} alkylamino, dihydroxy _{- (C} 1 _{~C 10) -} alkylamino, halo, halo _{- (C} 1 _{~C 10) -} alkylsulfonyloxy, haloaryl - _(C 1 ~C ₁₀₎ - alkylamino, heteroaryl _{- (C} 1 _{~C 10) -} alkoxycarbonylamino heterocycloalkyl, heterocycloalkyl-carbonyl _{- (C} 1 _{~C 10) -} alkylamino, heterocyclo, hydrogen, hydroxy, hydroxy - _(C 1 ~C ₁₀₎ - alkoxy, hydroxy _{- (C} 1 _{~C 10) -} alkylamino, hydroxy _{- (C} 1 _{~C 10) -} alkylaminocarbonyl _{- (C} 1 _{~C 10) -} alkoxy, hydroxy - _(C 1 ~C ₁₀₎ - alkylaminocarbonyl _{- (C} 1 _{~C 10) -} Al Le, hydroxy _{- (C} 1 _{~C 10) -} alkylaminocarbonyl _{- (C} 1 _{~C 10) -} alkylamino, hydroxy _{- (C} 1 _{~C 10) -} alkylaminocarbonylamino _{- (C} 1 _{~C 10) -} Alkoxy, hydroxy- (C ₁ -C ₁₀ ) -alkylaminoheterocyclo, hydroxy- (C ₁ -C ₁₀ ) -alkylcarbonylamino- (C ₁ -C ₁₀ ) -alkylamino, hydroxy- (C ₁ -C ₁₀ ) - alkylcarbonylamino heterocycloalkyl, hydroxy _- (C 1 _{-C 10)} - alkyl carbonyl heterocycloalkyl, hydroxy _- (C 1 _{-C 10)} - are selected from alkyl heterocycloalkyl, and the group consisting of hydroxy heterocycloalkyl, ^{R 2} _{is, (C} 1 _{~C 10)} - _{alkyl, (C} 1 _{~C 10)} - cycloalk Le, and is selected from the group consisting of hydrogen, _{R 3} is _{hydrogen, (C} 1 _{~C 10)} - _{alkyl, (C} 1 _{~C 10)} - is selected from alkoxy, and the group consisting of halo, each alkyl, Wherever present, each independently may be substituted with (C ₁ -C ₁₀ ) -alkoxy, amino, carboxy, halo, and hydroxyl, R ^4A , R ^4B , R ^4C , R ^4D. , And R ^4E are each independently (C ₁ -C ₁₀ ) -alkylaminocarbonylamino- (C ₁ -C ₁₀ ) -alkyl, (C ₁ -C ₁₀ ) -alkylarylheteroarylaminocarbonylamino- (C ₁ -C ₁₀₎ - alkyl, amino _{- (C} 1 _{~C 10) -} alkyl, aryl _{- (C} 1 _{~C 10) -} cycloalkylamino carbonylation - _(C 1 ~C ₁₀₎ - dialkylamino _{- (C} 1 _{~C 10) -} alkyl, aryl _{- (C} 1 _{~C 10) -} cycloalkyl aminocarbonylamino _{- (C} 1 _{~C 10) -} alkyl, cyano, (C ₁ -C ₁₀ ) -Cycloalkylaminocarbonylamino- (C ₁ -C ₁₀ ) -alkyl, (C ₁ -C ₁₀ ) -cycloalkylaminocarbonyl- (C ₁ -C ₁₀ ) -dialkylamino- (C ₁ -C ₁₀ ) -alkyl, halo, and hydrogen, each aryl and heteroaryl independently substituted with (C ₁ -C ₁₀ ) -alkyl, wherever present May be.

In another embodiment, R ¹ is (C ₂ -C ₈ ) -alkenyl, (C ₁ -C ₈ ) -alkoxycarbonyl- (C ₁ -C ₈ ) -alkylamino, (C ₁ -C ₈ ) — Alkoxycarbonylamino- (C ₁ -C ₈ ) -alkoxy, (C ₁ -C ₈ ) -alkoxycarbonylaminoheterocyclo, (C ₁ -C ₈ ) -alkoxycarbonylaryl, (C ₁ -C ₈ ) -alkoxycarbonyl Aryl- (C ₁ -C ₈ ) -alkylamino, (C ₁ -C ₈ ) -alkoxycarbonylheterocyclo, (C ₁ -C ₈ ) -alkyl, (C ₁ -C ₈ ) -alkylamino, (C ₁ -C ₈₎ - alkylaminocarbonyl - _(C 1 ~C ₈₎ - _{alkyl, (C} 1 ~C ₈₎ - alkylaminocarbonyl - _(C 1 ~C ₈₎ - alkylamino , _(C 1 ~C ₈₎ - alkylaminocarbonylamino - _(C 1 -C ₈₎ - _{alkoxy, (C} 1 _{~C 8)} - alkylamino _{heterocycloalkyl, (C} 1 _{~C 8)} - alkylcarbonylamino - ( C ₁ ~C ₈₎ - _{alkoxy, (C} 1 ~C ₈₎ - alkylcarbonylamino - _(C 1 ~C ₈₎ - _{alkyl, (C} 1 ~C ₈₎ - alkylcarbonylamino _{- (C} 1 _~C 8) - _{alkylamino, (C} 1 _{~C 8)} - alkylcarbonylamino _{heterocycloalkyl, (C} 1 _{~C 8)} - alkylcarbonyl heterocycloalkyl _{amino, (C} 1 _{~C 8)} - alkylcarbonyloxy - _(C 1 -C ₈ ) - alkylcarbonylamino - _(C 1 -C ₈₎ - _{alkoxy, (C} 1 _{~C 8)} - alkylcarbonyloxy - _(C 1 -C ₈₎ - Arukiruka Isobornyl amino _{heterocycloalkyl, (C} 1 _{~C 8)} - _{alkylsulfonyl, (C} 1 _{~C 8)} - alkylsulfonylamino - _(C 1 ~C ₈₎ - _{alkoxy, (C} 1 _{~C 8)} - alkylsulfonylamino - (C ₁ -C ₈ ) -alkyl, (C ₁ -C ₈ ) -alkylsulfonylamino- (C ₁ -C ₈ ) -alkylamino, (C ₁ -C ₈ ) -alkylthio, amino- (C ₁ -C ₈₎ - alkoxy, amino - _(C 1 -C ₈₎ - alkyl, amino - _(C 1 -C ₈₎ - alkylamino, amino - _(C 1 -C ₈₎ - alkylcarbonylamino heterocycloalkyl, amino - (C ₁ -C ₈₎ - alkylcarbonyl heterocycloalkyl, aminocarbonyl - _(C 1 ~C ₈₎ - alkoxy, aminocarbonyl - _(C 1 ~C ₈₎ - alkyl, amino Nocarbonyl- (C ₁ -C ₈ ) -alkylamino, aminocarbonyl- (C ₁ -C ₈ ) -alkylheterocyclo, aminocarbonylamino- (C ₁ -C ₈ ) -alkoxy, aminocarbonylamino- (C ₁ -C ₈₎ - alkylamino, aminocarbonyl aryl, aminocarbonyl - _(C 1 ~C ₈₎ - dialkylamino, aminocarbonyl heterocycloalkyl, amino heterocycloalkyl, aryl, carboxy - _(C 1 ~C ₈₎ - alkoxy, carboxy - _(C 1 -C ₈₎ - alkyl, carboxy aryl, carboxy - _(C 1 -C ₈₎ - _{dialkylamino, (C} 1 -C ₈₎ - _{cycloalkyl, (C} 1 -C ₈₎ - dialkylamino - ( C ₁ ~C ₈₎ - alkylamino, dihydroxy - _(C 1 ~C ₈₎ - alkylamino Halo, halo - _(C 1 ~C ₈₎ - alkylsulfonyloxy, haloaryl - _(C 1 ~C ₈₎ - alkylamino, heteroaryl - _(C 1 ~C ₈₎ - alkoxycarbonylamino heterocycloalkyl, heterocycloalkyl-carbonyl - _(C 1 ~C ₈₎ - alkylamino, heterocyclo, hydrogen, hydroxy, hydroxy - _(C 1 ~C ₈₎ - alkoxy, hydroxy - _(C 1 ~C ₈₎ - alkylamino, hydroxy - _(C 1 ~C ₈ ) -Alkylaminocarbonyl- (C ₁ -C ₈ ) -alkoxy, hydroxy- (C ₁ -C ₈ ) -alkylaminocarbonyl- (C ₁ -C ₈ ) -alkyl, hydroxy- (C ₁ -C ₈ )- alkylaminocarbonyl - _(C 1 ~C ₈₎ - alkylamino, hydroxy - _(C 1 ~C ₈₎ - alkylamine Bruno carbonylamino - _(C 1 ~C ₈₎ - alkoxy, hydroxy - _(C 1 ~C ₈₎ - alkylamino heterocycloalkyl, hydroxy - _(C 1 ~C ₈₎ - alkylcarbonylamino _{- (C} 1 _~C 8) - alkylamino, hydroxy - _(C 1 ~C ₈₎ - alkylcarbonylamino heterocycloalkyl, hydroxy - _(C 1 ~C ₈₎ - alkylcarbonyl heterocycloalkyl, hydroxy - _(C 1 ~C ₈₎ - alkyl heterocycloalkyl, and R ² is selected from the group consisting of hydroxyheterocyclo, R ² is selected from the group consisting of (C ₁ -C ₈ ) -alkyl, (C ₁ -C ₈ ) -cycloalkyl, and hydrogen, and R ³ is hydrogen, _(C 1 ~C ₈₎ - _{alkyl, (C} 1 _{~C 8)} - is selected from alkoxy, and the group consisting of halo, each alkyl, Even when present in this, each _{independently, (C} 1 _{~C 8)} - alkoxy, amino, carboxy, halo, and hydroxyl with may be ^{substituted, R 4A, R 4B, R} 4C, R ^4D and R ^4E are each independently (C ₁ -C ₈ ) -alkylaminocarbonylamino- (C ₁ -C ₈ ) -alkyl, (C ₁ -C ₈ ) -alkylarylheteroarylaminocarbonylamino- ( C ₁ -C ₈ ) -alkyl, amino- (C ₁ -C ₈ ) -alkyl, aryl- (C ₁ -C ₈ ) -cycloalkylaminocarbonyl- (C ₁ -C ₈ ) -dialkylamino- (C ₁ -C ₈₎ - alkyl, aryl - _(C 1 ~C ₈₎ - cycloalkyl aminocarbonylamino - _(C 1 ~C ₈₎ - alkyl, cyano, _{(C 1} C ₈₎ - cycloalkyl aminocarbonylamino - _(C 1 ~C ₈₎ - _{alkyl, (C} 1 _{~C 8)} - cycloalkyl amino carbonyl - _(C 1 ~C ₈₎ - dialkylamino - _(C 1 ~C ₈ ) -Alkyl, halo, and hydrogen selected from the group consisting of each aryl and heteroaryl independently of each other, where present and independently substituted with (C ₁ -C ₈ ) -alkyl. Good.

In yet another embodiment _, R ¹ is (C ² -C ⁶ ) -alkenyl, (C ₁ -C ₆ ) -alkoxycarbonyl- (C ₁ -C ₆ ) -alkylamino, (C ₁ -C ₆ ). - alkoxycarbonylamino - _(C 1 ~C ₆₎ - _{alkoxy, (C} 1 _{~C 6)} - alkoxycarbonylamino _{heterocycloalkyl, (C} 1 _{~C 6)} - alkoxycarbonyl _{aryl, (C} 1 _{~C 6)} - alkoxy carbonyl aryl - _(C 1 ~C ₆₎ - _{alkylamino, (C} 1 _{~C 6)} - alkoxycarbonyl _{heterocycloalkyl, (C} 1 _{~C 6)} - _{alkyl, (C} 1 _{~C 6)} - alkylamino, (C ₁ -C ₆₎ - alkylaminocarbonyl - _(C 1 ~C ₆₎ - _{alkyl, (C} 1 ~C ₆₎ - alkylaminocarbonyl - _(C 1 ~C ₆₎ - alkyl _{Amino, (C} 1 _{~C 6)} - alkylaminocarbonylamino - _(C 1 ~C ₆₎ - _{alkoxy, (C} 1 _{~C 6)} - alkylamino _{heterocycloalkyl, (C} 1 _{~C 6)} - alkylcarbonylamino - _(C 1 ~C ₆₎ - _{alkoxy, (C} 1 _{~C 6)} - alkylcarbonylamino - _(C 1 ~C ₆₎ - _{alkyl, (C} 1 _{~C 6)} - alkylcarbonylamino - _(C 1 ~C ₆ ) - _{alkylamino, (C} 1 _{~C 6)} - alkylcarbonylamino _{heterocycloalkyl, (C} 1 _{~C 6)} - alkylcarbonyl heterocycloalkyl _{amino, (C} 1 _{~C 6)} - alkylcarbonyloxy - _(C 1 -C ₆₎ - alkylcarbonylamino - _(C 1 -C ₆₎ - _{alkoxy, (C} 1 -C ₆₎ - alkylcarbonyloxy - _(C 1 -C ₆₎ - Al Le carbonylamino _{heterocycloalkyl, (C} 1 _{~C 6)} - _{alkylsulfonyl, (C} 1 _{~C 6)} - alkylsulfonylamino - _(C 1 ~C ₆₎ - _{alkoxy, (C} 1 _{~C 6)} - alkylsulfonylamino - _(C 1 ~C ₆₎ - _{alkyl, (C} 1 _{~C 6)} - alkylsulfonylamino - _(C 1 ~C ₆₎ - _{alkylamino, (C} 1 _{~C 6)} - alkylthio, amino - _(C 1 ~ C ₆₎ - alkoxy, amino - _(C 1 -C ₆₎ - alkyl, amino - _(C 1 -C ₆₎ - alkylamino, amino - _(C 1 -C ₆₎ - alkylcarbonylamino heterocycloalkyl, amino - ( C ₁ ~C ₆₎ - alkylcarbonyl heterocycloalkyl, aminocarbonyl - _(C 1 ~C ₆₎ - alkoxy, aminocarbonyl - _(C 1 ~C ₆₎ - alkyl , Aminocarbonyl - _(C 1 ~C ₆₎ - alkylamino, aminocarbonyl - _(C 1 ~C ₆₎ - alkyl heterocycloalkyl, aminocarbonylamino - _(C 1 ~C ₆₎ - alkoxy, aminocarbonylamino - (C ₁ -C ₆₎ - alkylamino, aminocarbonyl aryl, aminocarbonyl - _(C 1 ~C ₆₎ - dialkylamino, aminocarbonyl heterocycloalkyl, amino heterocycloalkyl, aryl, carboxy - _(C 1 ~C ₆₎ - alkoxy, Carboxy- (C ₁ -C ₆ ) -alkyl, carboxyaryl, carboxy- (C ₁ -C ₆ ) -dialkylamino, (C ₁ -C ₆ ) -cycloalkyl, (C ₁ -C ₆ ) -dialkylamino- _(C 1 ~C ₆₎ - alkylamino, dihydroxy - _(C 1 ~C ₆₎ - alkyl Amino, halo, halo- (C ₁ -C ₆ ) -alkylsulfonyloxy, haloaryl- (C ₁ -C ₆ ) -alkylamino, heteroaryl- (C ₁ -C ₆ ) -alkoxycarbonylaminoheterocyclo, heterocyclo Carbonyl- (C ₁ -C ₆ ) -alkylamino, heterocyclo, hydrogen, hydroxy, hydroxy- (C ₁ -C ₆ ) -alkoxy, hydroxy- (C ₁ -C ₆ ) -alkylamino, hydroxy- (C _1- C ₆₎ - alkylaminocarbonyl - _(C 1 ~C ₆₎ - alkoxy, hydroxy - _(C 1 ~C ₆₎ - alkylaminocarbonyl - _(C 1 ~C ₆₎ - alkyl, hydroxy - _(C 1 ~C ₆ ) - alkylaminocarbonyl - _(C 1 -C ₆₎ - alkylamino, hydroxy - _(C 1 -C ₆₎ - Al Kilaminocarbonylamino- (C ₁ -C ₆ ) -alkoxy, hydroxy- (C ₁ -C ₆ ) -alkylaminoheterocyclo, hydroxy- (C ₁ -C ₆ ) -alkylcarbonylamino- (C ₁ -C ₆ ) - alkylamino, hydroxy - _(C 1 -C ₆₎ - alkylcarbonylamino heterocycloalkyl, hydroxy - _(C 1 -C ₆₎ - alkylcarbonyl heterocycloalkyl, hydroxy - _(C 1 -C ₆₎ - alkyl heterocycloalkyl, And R ² is selected from the group consisting of (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -cycloalkyl, and hydrogen, and R ³ is hydrogen Each alkyl selected from the group consisting of: (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkoxy, and halo. Wherever present, each independently may be substituted with (C ₁ -C ₆ ) -alkoxy, amino, carboxy, halo, and hydroxyl, and R ^4A , R ^4B , R ^4C. , R ^4D and R ^4E are each independently (C ₁ -C ₆ ) -alkylaminocarbonylamino- (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylarylheteroarylaminocarbonylamino - _(C 1 -C ₆₎ - alkyl, amino - _(C 1 -C ₆₎ - alkyl, aryl - _(C 1 -C ₆₎ - cycloalkyl amino carbonyl - _(C 1 -C ₆₎ - dialkylamino - ( C ₁ ~C ₆₎ - alkyl, aryl - _(C 1 ~C ₆₎ - cycloalkyl aminocarbonylamino - _(C 1 ~C ₆₎ - alkyl, cyano, C ₁ ~C ₆₎ - cycloalkyl aminocarbonylamino - _(C 1 ~C ₆₎ - _{alkyl, (C} 1 ~C ₆₎ - cycloalkyl amino carbonyl - _(C 1 ~C ₆₎ - dialkylamino - _{(C 1} -C 6) _- alkyl, halo, and may be selected from the group consisting of hydrogen, each aryl and heteroaryl, even if there where, independently, _(C 1 _~C 6) _- alkyl May be substituted.

In another embodiment, R ¹ is (C ₂ -C ₆ ) -alkenyl, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylamino, (C ₁ -C ₆ ) -alkyl. aminocarbonyl - _(C 1 ~C ₆₎ - _{alkylamino, (C} 1 _{~C 6)} - alkylamino _{heterocycloalkyl, (C} 1 _{~C 6)} - alkylcarbonylamino - _(C 1 ~C ₆₎ - alkoxy, ( C ₁ ~C ₆₎ - alkylcarbonylamino - _(C 1 ~C ₆₎ - _{alkylamino, (C} 1 ~C ₆₎ - alkylcarbonyl heterocycloalkyl _{amino, (C} 1 ~C ₆₎ - alkylsulfonylamino - (C ₁ -C ₆₎ - _{alkoxy, (C} 1 ~C ₆₎ - alkylsulfonylamino - _(C 1 ~C ₆₎ - _{alkyl, (C} 1 ~C ₆₎ - alkylsulfonylamino - _(C 1 ~C ₆ - _{alkylamino, (C} 1 _{~C 6)} - alkylsulfonylamino - _(C 1 ~C ₆₎ - alkylamino, amino - _(C 1 ~C ₆₎ - alkylamino, amino _{- (C} 1 _~C 6) _- Alkylcarbonylheterocyclo, aminocarbonyl- (C ₁ -C ₆ ) -alkoxy, aminocarbonyl- (C ₁ -C ₆ ) -alkylamino, aminocarbonylamino- (C ₁ -C ₆ ) -alkoxy, aminocarbonylamino- _(C 1 ~C ₆₎ - alkylamino, aminocarbonyl aryl, aminocarbonyl heterocycloalkyl, amino heterocycloalkyl, aryl, dihydroxy - _(C 1 ~C ₆₎ - alkylamino, haloaryl - _(C 1 ~C ₆₎ - alkyl amino, hydrogen, hydroxyl - _(C 1 ~C ₆₎ - alkoxy, hydroxyl - (C ₁ -C ₆₎ - alkyl, hydroxyl - _(C 1 ~C ₆₎ - alkylamino, hydroxyl - _(C 1 ~C ₆₎ - alkylcarbonylamino - _(C 1 ~C ₆₎ - alkylamino, hydroxyl - (C ₁ -C ₆₎ - alkyl heterocycloalkyl, and hydroxyl - _(C 1 ~C ₆₎ - alkylcarbonylamino - _(C 1 ~C ₆₎ - is selected from the group consisting of alkylamino.

In another embodiment, R ² is (C ₁ -C ₆ ) -alkyl.

In another embodiment, R ³ is halo.

In another embodiment, R ^4A , R ^4B , R ^4C , R ^4D , and R ^4E are each independently hydrogen, halo, and (C ₁ -C ₆ ) -alkylaminocarbonylamino- (C ₁ -C ₆ ) -Alkyl.

In another embodiment, R ² is (C ₁ -C ₆ ) -alkyl, R 3 is halo, and R ^4A , R ^4B , R ^4C , R ^4D , and R ^4E are each independently hydrogen, halo , and _(C 1 _{~C 6)} - alkylaminocarbonylamino - _(C 1 ~C ₆₎ - it is selected from the group consisting of alkyl.

In another embodiment, R ¹ is (C ₁ -C ₆ ) -alkylaminoheterocyclo, (C ₁ -C ₆ ) -alkylcarbonylamino- (C ₁ -C ₆ ) -alkylamino, (C _1- C ₆₎ - alkyl sulfonylamino - _(C 1 ~C ₆₎ - _{alkoxy, (C} 1 _{~C 6)} - alkylsulfonylamino - _(C 1 ~C ₆₎ - _{alkylamino, (C} 1 _{~C 6)} - alkyl Sulfonylamino- (C ₁ -C ₆ ) -alkylamino, aminocarbonyl- (C ₁ -C ₆ ) -alkylamino, aminocarbonylamino- (C ₁ -C ₆ ) -alkoxy, aminocarbonylamino- (C _1- C ₆₎ - alkyl, aminocarbonyl heterocycloalkyl, dihydroxy - _(C 1 ~C ₆₎ - alkylamino, hydroxyl - _(C 1 ~C ₆₎ - A Kiruamino, and hydroxy - _(C 1 ~C ₆₎ - alkylcarbonylamino - _(C 1 ~C ₆₎ - is selected from the group consisting of alkylamino.

In another embodiment, R ² is (C ₁ -C ₆ ) -alkyl.

In another embodiment, R ³ is halo.

In another embodiment, R ^4A , R ^4B , R ^4C , R ^4D , and R ^4E are each independently selected from the group consisting of hydrogen and halo.

In another embodiment, R ² is (C ₁ -C ₆ ) -alkyl, R ³ is halo, R ^4A , R ^4B , R ^4C , R ^4D , and R ^4E are each independently hydrogen and It may be selected from the group consisting of halo.

In another embodiment, the compound is:
N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] methanesulfone Amide,
N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] urea,
N ~ 2- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -L-alaninamide,
N- [3-({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] urea,
N- [3-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] methanesulfone Amide,
N- [3-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2 -Hydroxyacetamide,
5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2-[(3R) -3- (methylamino) pyrrolidin-1-yl] pyrimidin-4 (3H) -one,
N-3-3- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -β-alaninamide,
N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] -2 -Hydroxyacetamide,
N- [3-({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] acetamide,
N-3-3- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -β-alaninamide,
N ~ 2- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} glycinamide,
N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] urea,
N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] -2 -Hydroxy-2-methylpropanamide,
4-({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) butanamide,
5-bromo-6-[(2,4-difluorobenzyl) oxy] -2-{[(2S) -2,3-dihydroxypropyl] amino} -3-isopropylpyrimidin-4 (3H) -one,
N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] methanesulfone Amide,
N- [2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] urea,
N- [2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] -2 -Hydroxyacetamide,
N- [2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] methanesulfone Amide,
5-bromo-6-[(2,4-difluorobenzyl) oxy] -2-{[(2R) -2,3-dihydroxypropyl] amino} -3-isopropylpyrimidin-4 (3H) -one,
1- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} prolinamide,
N- [2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] urea,
N- [3-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2 -Hydroxy-2-methylpropanamide,
5-bromo-6-[(2,4-difluorobenzyl) oxy] -2-[(4-fluorobenzyl) amino] -3-isopropylpyrimidin-4 (3H) -one,
N- [2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] acetamide,
N- [2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] methanesulfone Amide,
5-Bromo-6-[(2,4-difluorobenzyl) oxy] -2-[(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] -3-isopropylpyrimidine-4 (3H) -one tri Fluoroacetate,
5-bromo-6-[(2,4-difluorobenzyl) oxy] -2-[(2-hydroxy-2-methylpropyl) amino] -3-isopropylpyrimidin-4 (3H) -one,
1- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} prolinamide,
N- [2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] -2 -Hydroxy-2-methylpropanamide,
N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] acetamide,
5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one,
N-({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} methyl) methanesulfonamide,
2-[(3R) -3-Aminopyrrolidin-1-yl] -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one trifluoroacetate ,
2-[(1-acetylpiperidin-4-yl) amino] -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one,
N ~ 2- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N ~ 1-methyl Glycinamide,
N ~ 2- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} glycinamide,
N- [2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] acetamide,
5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2-phenylpyrimidin-4 (3H) -one,
4- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamide,
1- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} piperidine-3-carboxamide,
N- (2-{[(5-Bromo-1-isopropyl-2-methyl-6-oxo-1,6-dihydropyrimidin-4-yl) oxy] methyl} -5-fluorobenzyl) -N'-ethyl urea,
2- (3-aminopyrrolidin-1-yl) -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one trifluoroacetate salt,
5-bromo-6-[(2,4-difluorobenzyl) oxy] -2-[(3,3-dimethylbutyl) amino] -3-isopropylpyrimidin-4 (3H) -one,
5-chloro-6-[(2,4-difluorobenzyl) oxy] -2- (4-hydroxybutoxy) -3-isopropylpyrimidin-4 (3H) -one,
5-bromo-6-[(2,4-difluorobenzyl) oxy] -2-[(3R) -3- (ethylamino) pyrrolidin-1-yl] -3-isopropylpyrimidin-4 (3H) -one,
4-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) butanamide,
2-[(2-aminoethyl) amino] -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one trifluoroacetate, and 2-but Selected from the group consisting of -3-enyl-5-chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one, or a pharmaceutically acceptable salt thereof. The

In another embodiment, the compound is:
N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] methanesulfone Amide,
N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] urea,
N ~ 2- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -L-alaninamide,
N- [3-({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] urea,
N- [3-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] methanesulfone Amide,
N- [3-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2 -Hydroxyacetamide,
5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2-[(3R) -3- (methylamino) pyrrolidin-1-yl] pyrimidin-4 (3H) -one,
N-3-3- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -β-alaninamide,
N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] -2 -Hydroxyacetamide,
N- [3-({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] acetamide,
N-3-3- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -β-alaninamide,
N ~ 2- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} glycinamide,
N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] urea,
N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] -2 -Hydroxy-2-methylpropanamide,
4-({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) butanamide,
5-bromo-6-[(2,4-difluorobenzyl) oxy] -2-{[(2S) -2,3-dihydroxypropyl] amino} -3-isopropylpyrimidin-4 (3H) -one,
N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] methanesulfone Amide,
N- [2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] urea,
N- [2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] -2 -Hydroxyacetamide,
N- [2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] methanesulfone Amide,
5-bromo-6-[(2,4-difluorobenzyl) oxy] -2-{[(2R) -2,3-dihydroxypropyl] amino} -3-isopropylpyrimidin-4 (3H) -one,
1- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} prolinamide,
N- [2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] urea,
N- [3-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2 -Hydroxy-2-methylpropanamide and 5-bromo-6-[(2,4-difluorobenzyl) oxy] -2-[(4-fluorobenzyl) amino] -3-isopropylpyrimidine-4 (3H)- ON, or selected from the group consisting of these pharmaceutically acceptable salts.

  In one embodiment, a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable excipient.

  In one embodiment, a method for treating or preventing an inflammatory disorder in a subject in need of such treatment or prevention, wherein the subject is in an amount effective to treat or prevent the inflammatory disorder in the subject. Administering a compound of I.

  In one embodiment, the inflammatory disorder is arthritis.

  In one embodiment, the inflammatory disorder is osteoarthritis.

  In one embodiment, the inflammatory disorder is rheumatoid arthritis.

  In one embodiment, the inflammatory disorder is asthma.

  The present invention is also directed to tautomers of such compounds and salts (especially pharmaceutically acceptable salts) of such compounds and tautomers.

  The present invention is also directed, in part, to methods of treating conditions mediated by pathological p38 kinase activity (particularly p38α activity) in a mammal. This method comprises administering to a mammal a compound as described above or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to treat the condition.

  The present invention is also directed, in part, to methods of treating conditions mediated by pathological TNF activity (particularly TNF-α activity) in mammals. This method comprises administering to a mammal a compound as described above or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to treat the condition.

  The present invention is also directed, in part, to methods of treating a condition mediated by pathological cyclooxygenase 2 activity in a mammal. This method comprises administering to a mammal a compound as described above or a pharmaceutically acceptable salt thereof in a therapeutically effective amount to treat the condition.

Compounds of the Invention Having One or More Asymmetric Carbons The present invention also includes compounds of formula I having one or more asymmetric carbons. It is known to those skilled in the art that the compounds of the present invention having asymmetric carbon atoms can exist in diastereoisomers, racemates, or optically active forms. All of these forms are considered within the scope of the present invention. More particularly, the present invention includes enantiomers, diastereoisomers, racemic mixtures, and other mixtures thereof.

Salts of the Compounds of the Invention The compounds of the invention can be used in the form of salts that are derivatives of inorganic or organic acids. Depending on the particular compound, the salt of the compound is advantageous due to one or more of the physical properties of the salt, such as improved pharmaceutical stability at different temperatures and humidity and the desired solubility in water or oil. Can be. In certain instances, the salt of the compound can also be used as an aid in the isolation, purification, and / or resolution of the compound.

  Where a salt is to be administered to a patient (eg, as opposed to being used in an in vitro situation), the salt is preferably pharmaceutically acceptable. Pharmaceutically acceptable salts include those commonly used for the formation of alkali metal salts and the addition salts of free acids or free bases. In general, these salts can be prepared by conventional means, usually against the compound of the invention, for example by reacting the appropriate acid or base with the compound of the invention.

  Pharmaceutically acceptable acid addition salts of the compounds of this invention can be prepared from inorganic or organic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. In general, suitable organic acids include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxyl group-containing, sulfone group-containing classes of organic acids. Specific examples of suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, diglyconate, lactate, malate, Tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilate, mesylate, stearate, salicylate, p -Hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxy Ethanesulfonate, sulfanilate, cyclohexylaminosulfonate, (argenic acid (a generic acid), b-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, bisulfate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecyl sulfate, Glycoheptanoate, glycerophosphate, hemisulfate, heptaneate, hexanoate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectate, persulfate , 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, and undecanoate.

Pharmaceutically acceptable base addition salts of the compounds of this invention include, for example, metal salts and organic acid salts. Preferred metal salts include alkali metal (Group Ia) salts, alkaline earth metal (Group IIa) salts, and other physiologically acceptable metal salts. Such salts may be made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. Preferred organic acid salts are tertiary amine salts and quaternary amines such as tromethamine, diethylamine, N, N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. It can be made from salt. Basic nitrogen-containing groups include halogenated lower alkyl (C ₁ -C ₆ ) (eg, methyl, ethyl, propyl, butyl chloride, bromide butyl, and butyl iodide), dialkyl sulfate (eg, dimethyl, diethyl, dibutyl). , And diamyl sulfate), long chain halides (eg, decyl, lauryl, myristyl, and stearyl chloride, bromide, and iodide), arylalkyl halides (eg, benzyl bromide and phenethyl bromide), And can be quaternized by chemicals such as others.

Treatment of conditions using the compounds of the present invention The present invention is based in part on humans, other primates (eg, monkeys, chimpanzees, etc.), companion animals (eg, dogs, cats, horses, etc.), domestic animals ( Have a condition such as, for example, goats, sheep, pigs, cattle, etc., laboratory animals (eg, mice, rats, etc.), wild and zoo animals (eg, wolves, bears, deer, etc.) It is directed to a method of treating a condition (usually a pathological condition) in a mammal that is prone to having the condition.

  As used herein, the expression “treating a condition” means ameliorating, suppressing, eradicating, reducing the severity, reducing the frequency of occurrence, preventing, reducing the risk, or developing the condition. Means delay.

  Some embodiments of the invention are directed to methods of treating conditions mediated by p38. As used herein, the term “p38-mediated condition” refers to p38 kinases (especially p38α kinase) being regulated by p38 kinase itself, or such as IL-1, IL-6, IL-8, etc. Refers to any condition (especially pathological conditions, ie diseases and disorders) that plays a role by releasing another factor. Thus, for example, a disease state in which IL-1 is a major component and its production or action is exacerbated or secreted in response to p38 should be considered a p38-mediated disorder.

The compounds of the present invention are generally useful for treating pathological conditions, including but not limited to:
(A) inflammation,
(B) arthritis such as rheumatoid arthritis, spondyloarthritis, gouty arthritis, osteoarthritis, systemic lupus erythematosus arthritis, juvenile arthritis, osteoarthritis, and gouty arthritis,
(C) nerve inflammation,
(D) pain such as neuropathic pain (ie use of the compound as an analgesic),
(E) exotherm (ie use of the compound as an antipyretic),
(F) Lung disorders or inflammation, such as adult respiratory stimulation syndrome, pulmonary sarcoidosis, asthma, silicosis, and chronic pulmonary inflammatory disease,
(G) atherosclerosis, myocardial infarction (such as signs after myocardial infarction), thrombosis, congestive heart failure, cardiac reperfusion injury, and complications associated with hypertension and / or heart failure such as vascular organ damage Cardiovascular disease,
(H) cardiomyopathy,
(I) seizures such as ischemic and hemorrhagic seizures;
(J) ischemia, such as cerebral ischemia or ischemia that occurs as a result of heart / coronary artery bypass formation;
(K) reperfusion injury,
(L) kidney reperfusion injury,
(M) cerebral edema,
(N) nerve trauma such as closed head trauma and head trauma,
(O) neurodegenerative disorders,
(P) Central nervous system disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, peripheral neuropathy (these have, for example, inflammatory or apoptotic components Obstacles included),
(Q) liver disease and nephritis;
(R) digestive system conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis,
(S) Ulcerative diseases such as gastric ulcer,
(T) Retinitis, retinopathy (such as diabetic retinopathy), uveitis, photophobia, non-glaucoma optic atrophy, and eyes such as age-related macular degeneration (ARMD) disease,
(U) corneal graft rejection, ocular neovascularization, retinal neovascularization (such as neovascularization following injury or infection), ophthalmic conditions such as posterior lens fibroproliferation,
(V) primary open angle glaucoma (POAG), juvenile-onset primary open angle glaucoma, closed angle glaucoma, pseudoexfoliative glaucoma, anterior ischemic optic neuropathy (AION), ocular hypertension, Leger syndrome, Glaucoma such as normal-tension glaucoma, neovascular glaucoma, eye inflammation, corticosteroid-induced glaucoma,
(W) acute injury and trauma to eye tissues such as post-traumatic glaucoma, traumatic optic neuropathy, central retinal artery occlusion (CRAO),
(X) diabetes,
(Y) diabetic nephropathy,
(Z) skin-related conditions such as psoriasis, eczema, burns, dermatitis, keloid formation, scar tissue formation, and vasogenic disorders;
(Aa) Sepsis, infectious shock, Gram-negative bacterial sepsis, malaria, meningitis, opportunistic infection, secondary cachexia of infection or malignant lesions, secondary cachexia of acquired immune deficiency syndrome (AIDS) Virus and bacterial infections such as AIDS, ARC (AIDS-related complex), pneumonia, and herpes virus,
(Bb) muscle pain due to infection,
(Cc) influenza,
(Dd) endotoxin shock,
(Ee) Toxic shock syndrome,
(Ff) autoimmune diseases such as graft-versus-host reaction and allograft rejection,
(Gg) bone resorption diseases such as osteoporosis,
(Hh) multiple sclerosis,
(Ii) disorders of the female reproductive system, such as endometriosis,
(Jj) a non-malignant but pathological condition such as hemangioma (such as pediatric hemangioma), nasopharyngeal hemangiofibroma, avascular osteonecrosis,
(Kk) colorectal cancer, brain tumor, bone cancer; neoplasia induced by epithelial cells such as basal cell carcinoma (epithelial cancer); adenocarcinoma; Cancer: colorectal cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer; skin cancer such as squamous cell carcinoma and basal cell carcinoma; prostate cancer, renal cell carcinoma, and epithelium throughout the body Benign and malignant tumors / neoplasias, including other known cancers that affect cells,
(Ll) leukemia,
(Mm) lymphoma such as B cell lymphoma,
(Nn) Systemic lupus erythematosus (SLE),
(Oo) Angiogenesis including neoplasia, and (pp) metastasis.

The compounds of the present invention are also generally useful for treating pathological conditions including, but not limited to:
(A) asthma of any type, etiology, or cause, in particular atopic asthma, non-atopic asthma, allergic asthma, lgE-mediated atopic bronchial asthma, bronchial asthma, idiopathic asthma, true asthma, Endogenous asthma caused by pathophysiological disturbances, extrinsic asthma caused by environmental factors, idiopathic asthma of unknown or unknown cause, non-atopic asthma, bronchitis asthma, emphysematous asthma, Exercise-induced asthma, allergen-induced asthma, cold-induced asthma, occupational asthma; infectious asthma caused by bacterial, fungal, protozoan, or viral infections; non-allergic asthma, first asthma, childhood wheezing syndrome Asthma, which is selected from the group consisting of bronchiolitis,
(B) chronic or acute bronchoconstriction, chronic bronchitis, peripheral airway obstruction, and emphysema,
(C) related to any type, etiology, or cause of obstructive or inflammatory airway disease, especially chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD, including chronic bronchitis, COPD Concomitant with or unrelated pulmonary emphysema or dyspnea, COPD characterized by irreversible progressive airway obstruction, adult respiratory tidal syndrome (ARDS), worsening airway hyperresponsiveness resulting from other medications, and pulmonary hypertension Obstructive or inflammatory airway diseases that are selected from the group consisting of airway diseases,
(D) bronchitis of any type, etiology or cause, in particular acute bronchitis, acute laryngotracheobronchitis, arachidic bronchitis, catarrhal bronchitis, croup bronchitis, dry bronchitis, infectious asthma-like Bronchitis, which is selected from the group consisting of bronchitis, wet bronchitis, staphylococcal or streptococcal bronchitis, and alveolar bronchitis,
(E) acute lung injury, and (f) bronchiectasis of any type, etiology, or cause, in particular columnar bronchiectasis, saccular bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cysts Bronchiectasis that is selected from the group consisting of pulmonary bronchiectasis, dry bronchiectasis, and follicular bronchiectasis.

  The compounds of the present invention also generally include any kind, etiology or cause of obstructive or inflammatory airway diseases, in particular chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), chronic bronchitis COPD, pulmonary emphysema or dyspnea with or without COPD, COPD characterized by irreversible progressive airway obstruction, adult respiratory tidal syndrome (ARDS), worsening airway hyperresponsiveness resulting from other medications, And useful in treating obstructive or inflammatory airway diseases that are selected from the group consisting of airway diseases associated with pulmonary hypertension.

  Alternatively (or additionally), some embodiments of the invention are directed to methods of treating a condition mediated by TNF. As used herein, the term “a TNF-mediated condition” refers to TNF being regulated by TNF itself or another monokine such as IL-1, IL-6, and / or IL-8. Refers to any condition (especially any pathological condition, ie disease or disorder) that plays a role by being released. Thus, for example, a disease state in which IL-1 is a major component whose production or action is exacerbated or secreted in response to TNF should be considered a TNF-mediated disorder.

  Examples of conditions mediated by TNF include inflammation (eg rheumatoid arthritis), autoimmune disease, graft rejection, multiple sclerosis, fibrotic disease, cancer, infections (eg malaria, mycobacterial infection, meninges) ), Fever, psoriasis, cardiovascular disease (eg, post-ischemic reperfusion injury and congestive heart failure), lung disease, bleeding, coagulation, hyperalveolar injury due to oxygen, radiation damage, infection and sepsis Acute phase responses (eg, infectious shock, hemodynamic shock, etc.), cachexia, and eating disorders such as those seen and those seen at the time of shock are included. Such conditions include infectious diseases. Such infections include, for example, malaria, mycobacterial infection, and meningitis. Such infections also include, among others, HIV, influenza virus; herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus ( VZV), Epstein Barr virus, human herpesvirus 6 (HHV-6), human herpesvirus 7 (HHV-7), viral infections such as herpesviruses including human herpesvirus 8 (HHV-8), Aujeszky's disease, and Nasal bronchitis is mentioned.

  Since TNF-β is close structurally homologous to TNF-α (also known as cachectin), each induces a similar biological response and binds to the same cellular receptor. Compounds inhibit the synthesis of both TNF-α and TNF-β, and are therefore collectively referred to herein as “TNF” unless otherwise detailed.

  Alternatively (or additionally), some embodiments of the invention are directed to methods of treating a condition mediated by cyclooxygenase 2. As used herein, the term “cyclooxygenase 2 mediated condition” refers to any condition in which cyclooxygenase 2 plays a role by regulation by cyclooxygenase 2 itself or by releasing another factor (especially disease). State, ie disease and disorder). Many cyclooxygenase 2 mediated conditions are known in the art and include, for example, inflammation and other cyclooxygenase mediated disorders listed in Carter et al. US Pat. No. 6,271,253.

  In some particularly important embodiments, the condition treated by the methods of the present invention comprises inflammation.

  In some particularly important embodiments, the condition treated by the methods of the present invention includes arthritis.

  In some particularly important embodiments, the condition treated by the methods of the present invention comprises rheumatoid arthritis.

  In some particularly important embodiments, the condition treated by the methods of the present invention comprises asthma.

  In some embodiments of particular importance, the condition treated by the methods of the present invention comprises a coronary artery condition.

  In some particularly important embodiments, the condition treated by the methods of the present invention comprises bone loss.

  In some embodiments of particular interest, the condition treated by the methods of the present invention comprises B cell lymphoma.

  In some particularly important embodiments, the condition treated by the methods of the present invention comprises COPD.

  The compounds of the present invention may be used in the treatment of TNF-mediated diseases such as smoking-induced airway inflammation, inflammation-enhanced cough, to control myogenesis, to treat mucin overproduction, and / or Alternatively, it can be used to treat mucus hypersecretion.

  In another embodiment of the invention, the compounds of the invention are preferably administered by inhalation.

  In one embodiment, the obstructive or inflammatory airway disease is COPD.

  According to another embodiment of the present invention, the compounds of the present invention are used as a combination with one or more additional therapeutic agents that are co-administered to a patient, including but not limited to (i) bronchoconstriction, Certain particularly desirable such as treatment of pathophysiologically related disease processes including signs and symptoms such as (ii) inflammation, (iii) allergy, (iv) tissue destruction, (v) shortness of breath, cough The end result of treatment can also be obtained. The second and further additional therapeutic agent may be a compound of the invention, or may be one or more p38 and / or TNF inhibitors known in the art. In a more typical example, the second and more therapeutic agents are selected from different classes of therapeutic agents.

As used herein, the terms “co-administration”, “co-administered”, and “in combination” refer to and refer to the following with respect to a compound of the invention and one or more other therapeutic agents: Shall be included.
(A) co-administration of such a combination of a compound of the invention and a therapeutic agent to a patient in need of treatment (its components are formulated together in a single dosage form, the dosage form being administered to said patient) In contrast to the component being released substantially simultaneously),
(B) substantially simultaneous administration of such a combination of a compound of the invention and a therapeutic agent to a patient in need of treatment, the components of which are formulated separately from one another in separate dosage forms A shape is taken by the patient substantially simultaneously, and then the component is released to the patient substantially simultaneously),
(C) Sequential administration of such a combination of a compound of the invention and a therapeutic agent to a patient in need of treatment (the components being formulated separately from one another in separate dosage forms, the dosage form being said patient By subsequent administration with a significant time interval between each administration, after which the component is released to the patient at substantially different times), and (d) to a patient in need of treatment Sequential administration of such combinations of a compound of the present invention and a therapeutic agent (the components are formulated together in a single dosage form that releases the components in a controlled manner, and then these components Are administered in parallel, continuously and / or overlappingly by the patient at the same and / or different times, and each part can be administered by the same or different route).

Suitable examples of other therapeutic agents that can be used in combination with a compound of the present invention, or a pharmaceutically acceptable salt, solvate, or composition thereof include, but are in no way limited to: Is included.
(A) a 5-lipoxygenase (5-LO) inhibitor or a 5-lipoxygenase activating protein (FLAP) antagonist,
(B) a leukotriene antagonist (LTRA) comprising an antagonist of LTB ₄ , LTC ₄ , LTD ₄ , and LTE ₄ ;
(C) a histamine receptor antagonist comprising H1 and H3 antagonists,
(D) an α ₁ -and α ₂ -adrenergic receptor agonist vasoconstrictor sympathomimetic for use as a decongestant;
(E) a muscarinic M3 receptor antagonist or anticholinergic agent,
(F) PDE inhibitors, such as PDE3, PDE4, and PDE5 inhibitors,
(G) theophylline,
(H) sodium cromoglycate,
(I) both non-selective and selective COX inhibitors COX-1 or COX-2 inhibitors (NSAIDs),
(J) oral and inhaled corticosteroids such as DAGR (dissociative agonist of corticoid receptor),
(K) a monoclonal antibody active against endogenous inflammatory entities,
(L) a β2 agonist,
(M) an adhesion molecule inhibitor comprising a VLA-4 antagonist;
(N) Kinin B ₁ and B ₂ receptor antagonists,
(O) an immunosuppressant,
(P) an inhibitor of matrix metalloprotease (MMP),
(Q) tachykinin NK ₁ , NK ₂ , and NK ₃ receptor antagonists,
(R) an elastase inhibitor,
(S) an adenosine A2a receptor agonist,
(T) an inhibitor of urokinase,
(U) a compound acting on a dopamine receptor, such as a D2 agonist,
(V) a modulator of the NFκβ pathway, such as an IKK inhibitor,
(W) modulators of cytokine signaling pathways such as syk kinase or JAK kinase inhibitors;
(X) a drug that can be classified as a mucolytic or antitussive,
(Y) antibiotics,
(Z) an HDAC (histone deacetylase) inhibitor, and (aa) a PI3 kinase inhibitor.

According to one embodiment of the invention, a compound of the invention and
-An H3 antagonist,
A muscarinic M3 receptor antagonist,
-A PDE4 inhibitor,
-Corticosteroids,
An adenosine A2a receptor agonist,
A β2 agonist,
- Modulators of cytokine signaling pathways such as syk kinase, _{or, - LTB 4, LTC 4,} LTD 4, and leukotriene antagonists, including antagonists of LTE ₄ (LTRAs)
A combination of can be used.

According to one embodiment of the invention, a compound of the invention and
-Corticosteroids, especially inhaled corticosteroids with reduced systemic side effects, including prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide, and mometasone furoate. ,
A muscarinic M3 receptor antagonist or anticholinergic agent comprising in particular ipratropium salt, i.e. bromide, tiotropium salt, i.e. bromide, oxitropium salt, i.e. bromide, perenzepine, and telenzepine,
-Or a combination with β2 agonists can be used.

  A wide variety of methods, alone or in combination, can be used to administer the compounds described above. For example, the compounds can be administered orally, intravascularly (IV), intraperitoneally, subcutaneously, intramuscularly (IM), by inhalation spray, rectally, or topically.

  Generally, the compounds described herein are administered in an amount effective to inhibit p38 kinase (particularly p38α kinase), TNF (particularly TNF-α), and / or cyclooxygenase (particularly cyclooxygenase 2). The preferred total daily dose of the compound (administered in one or more divided doses) is usually about 0.01 to about 100 mg / kg, more preferably about 0.1 to about 50 mg / kg, More preferably from about 0.5 to about 30 mg / kg (ie, mg of compound per kg body weight). Dosage unit compositions may comprise such amounts or submultiples thereof to constitute a daily dose. In many cases, administration of the compound is repeated multiple times a day (usually less than 4 times). If desired, multiple daily doses are usually used to increase the total daily dose.

  Factors affecting a preferred dosage regime include: patient type, age, weight, sex, diet, and condition; severity of the morbidity; route of administration; activity, efficacy, pharmacokinetics of the particular compound used, and Pharmacological considerations such as toxicology profiles; whether to utilize a drug delivery system; and whether to administer the compound as part of a drug combination. Thus, the dosage regimes actually used can vary widely and may therefore deviate from the preferred dosage regimes described above.

  The compounds of the present invention can be used in concurrent therapy in steroids, cyclooxygenase 2 inhibitors, non-steroidal anti-inflammatory drugs (“NSAIDs”), disease-modifying anti-rheumatic drugs (“DMARDs”), immunosuppressants, 5-lipoxygenase inhibitors, Can be used in place of other conventional anti-inflammatory drugs, partially or completely, such as with leukotriene B4 ("LTB4") antagonists and leukotriene A4 ("LTA4") hydrolase inhibitors .

Pharmaceutical Compositions Containing Compounds of the Invention The present invention also includes pharmaceutical compositions (or tautomers of compounds, and pharmaceutically acceptable salts of the compounds and tautomers), including the compounds described above (or “Medicaments”), as well as such compounds, in one or more conventional non-toxic pharmaceutically acceptable carriers, diluents, wetting or suspending agents, excipients, and / or adjuvants ( Carriers, diluents, wetting or suspending agents, excipients, and adjuvants are sometimes referred to herein collectively as “carrier materials”); and / or in combination with other active ingredients. The present invention is directed to a method for producing a pharmaceutical composition. The preferred composition will vary depending on the method of administration. Drug formulations are described, for example, in Hoover, John E. et al. "Remington's Pharmaceutical Sciences" (Mack Publishing Co., Easton, Pa., 1975) (incorporated herein by reference). Liberman, H.M. A. Lachman, L .; See also Ed., “Pharmaceutical Dosage Forms” (Marcel Decker, New York, USA, 1980), which is incorporated herein by reference. In many preferred embodiments, the pharmaceutical composition is manufactured in dosage unit form containing a certain amount of active ingredient. Usually, the pharmaceutical composition contains about 0.1 to 1000 mg (more typically 7.0 to 350 mg) of the compound.

  Solid dosage forms for oral administration include, for example, hard or soft capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compound is usually mixed with one or more adjuvants. If administered orally, the compound comprises lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, phosphoric acid and sulfuric acid sodium and calcium salts, It can be mixed with gelatin, gum acacia, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol and then tableted or encapsulated for convenience of administration. Such capsules or tablets may contain sustained-release preparations and can be provided as dispersions of the compounds of the invention in hydroxypropylmethylcellulose. In the case of capsules, tablets, and pills, the dosage forms may contain buffering agents such as sodium citrate or magnesium or calcium carbonate or bicarbonate. Tablets and pills can additionally be prepared with enteric coatings.

  Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (eg, water). Is included. Such compositions may contain adjuvants such as wetting agents, emulsifying agents, suspending agents, bridging agents (eg sweetening agents), and / or flavoring agents.

  “Parenteral administration” includes subcutaneous injections, intravenous injections, intramuscular injections, intrasternal injections, and infusions. Injectable formulations (eg, aqueous or oily sterile injectable suspensions) may be formulated according to known techniques using suitable dispersing, wetting agents, and / or suspending agents. Acceptable carrier materials include, for example, water, 1,3-butanediol, Ringer's solution, isotonic sodium chloride solution, nonirritating fixed oils (eg, synthetic monoglycerides or diglycerides), dextrose, mannitol, fatty acids (Eg oleic acid), dimethylacetamide, surfactants (eg ionic and non-ionic detergents), and / or polyethylene glycol (eg PEG 400).

  Formulations for parenteral administration can be prepared from sterile powders or granules containing one or more of the carrier materials described for use in oral dosage formulations. The compounds 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. The pH can be adjusted with a suitable acid, base, or buffer, if necessary.

  The compounds of the present invention comprise from about 0.075 to about 30% (w / w) (more preferably 0.2 to 20% (w / w), even more, of a pharmaceutical composition used for topical or rectal administration. It is preferable to constitute 0.4 to 15% (w / w)).

  The compounds of the invention are usually in the form of a dry powder from a dry powder inhaler (alone or as a mixture in a dry blend with, for example, lactose or as mixed component particles, for example with a phospholipid such as phosphatidylcholine). Or from a pressurized vessel, pump, spray, atomizer (preferably an atomizer that uses electrohydraulics to produce a fine mist), or a nebulizer, 1,1,1,2-tetrafluoroethane, It can also be administered as an aerosol spray, with or without the use of a suitable propellant such as 1,1,2,3,3,3-heptafluoropropane, intranasally or by inhalation. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

  Pressurized containers, pumps, sprays, atomizers, or nebulizers, for example, ethanol, aqueous ethanol, or another suitable agent to disperse, solubilize or prolong its release, injection as a solvent Solutions or suspensions of the compounds of the invention, including an agent, and an optional surfactant such as sorbitan trioleate, oleic acid, or oligolactic acid.

  Prior to use in a dry powder or suspension formulation, the formulation is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This can be achieved by any suitable comminuting method such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to produce nanoparticles, high pressure homogenization, spray drying and the like.

  Capsules (eg, made from gelatin or hydroxypropylmethylcellulose), blisters, and cartridges for use in an inhaler or insufflator are suitable powder mixtures of the compounds of the invention, such as lactose and starch. And a performance modifier such as l-leucine, mannitol, magnesium stearate. Lactose may be anhydrous or in the form of a monohydrate, preferably the latter. Other suitable pharmaceutical additives include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

  A suitable solution formulation for use in an atomizer that generates a fine mist using electrohydraulic may contain 1 μg to 20 mg of a compound of the invention per run, and a working volume May vary from 1 μl to 100 μl. A typical formulation may comprise a compound of the invention, propylene glycol, sterile water, ethanol and sodium chloride. Other solvents that can be used in place of propylene glycol include glycerin and polyethylene glycol.

  A suitable flavoring agent such as menthol or l-menthol, or a sweetening agent such as saccharin or sodium saccharin may be added to the formulations of the invention intended for inhalation / intranasal administration.

  Inhalation / intranasal formulations can be formulated to be immediate release and / or modified release using, for example, PGLA. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programming release.

  In the case of dry powder inhalers and aerosols, the dosage unit is determined by a valve that delivers a metered amount. In accordance with the present invention, the unit is usually arranged to administer a metered dose or “puff” containing 0.001 mg to 10 mg of the compound of the present invention. The overall daily dose is usually in the range of 0.001 mg to 40 mg and can be administered once or, more usually, in several divided doses throughout the day.

  Suppositories for rectal administration include, for example, a compound of the invention mixed with a suitable nonirritating pharmaceutical additive that is solid at ambient temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. Can be prepared. Suitable pharmaceutical additives include, for example, cocoa butter; synthetic mono-, di-, or triglycerides; fatty acids and / or polyethylene glycol.

  “Topical administration” includes transdermal administration, such as via a transdermal patch or iontophoresis device. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams.

  When formulated into ointments, the compounds of the present invention can be used, for example, with a paraffinic or water-miscible ointment base. When formulated into a cream, the active ingredient can be formulated, for example, with an oil-in-water cream base. If desired, the aqueous phase of the cream base is at least about 30% (w / w), such as, for example, propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerin, polyethylene glycol, mixtures thereof, and the like. Polyhydric alcohols may be included.

  Topical formulations may contain compounds which improve the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration improvers include dimethyl sulfoxide and related analogs.

  When the compounds of the invention are administered by a transdermal device, administration is accomplished using a reservoir and a porous membrane type, or a patch that is a variation of a solid substrate. In either case, the active agent is continuously delivered from the reservoir or microcapsule through the membrane to an adhesive that can be penetrated by the active agent that is in contact with the recipient's skin or mucous membrane. If the active agent is absorbed from the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent also functions as a membrane. Transdermal patches may include an adhesive system such as an acrylic emulsion or a polyester patch, along with a suitable solvent system containing the compound. The oily phase of the emulsion of the present invention may be constituted by methods known from known ingredients. The oil phase may contain only the emulsifier, but may comprise, for example, at least one emulsifier and a mixture of fat or oil or both fat and oil. A hydrophilic emulsifier is preferably included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both oil and fat. Emulsifiers also make so-called emulsifying waxes with or without stabilizers, which together with oils and fats constitute so-called emulsifying ointment bases that become the oily dispersed phase of cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulations of the present invention include, among others, Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate. Given that the solubility of the active compound is very low for most oils likely to be used in pharmaceutical emulsion formulations, the selection of an oil or fat suitable for the formulation is based on achieving the desired cosmetic properties. Thus, the cream should preferably be a non-greasy, non-colored and washable product with an appropriate consistency that avoids leakage from tubes or other containers. For example, linear chains such as blends of diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, branched ester, etc. Linear or branched monobasic or dibasic alkyl esters can be used. These can 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 compound of the invention is dissolved or suspended in a suitable carrier, usually containing an aqueous solvent. The compounds of the present invention may have from about 0.5 to about 20% (w / w) (more preferably from 0.5 to 10% (w / w), often even more preferably from about 1.5% (w / w) ) In such formulations at a concentration of

  Other carrier materials and modes of administration known in the pharmaceutical industry may be used.

Definitions The term “alkyl” (alone or in combination with another term (s)) usually means 1 to about 20 carbon atoms, more typically 1 to about 12 carbon atoms, and even more A linear or branched saturated hydrocarbonyl substituent (i.e. comprising 1 to about 8 carbon atoms in a typical example, and even 1 to about 6 carbon atoms in an even more typical example (i.e. , A substituent containing only carbon and hydrogen). Examples of such substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl, i-amyl, hexyl, and octyl.

  One or more double bonds, and usually 2 to about 20 carbon atoms, more typically 2 to about 12 carbon atoms, and even more typically 2 to about 8 carbon atoms. The term “alkenyl” (alone or in combination with another term (s)), comprising 2 carbon atoms, and even more typically 2 to about 6 carbon atoms, is straight or branched Means a hydrocarbonyl substituent. Examples of such substituents include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, and decenyl. included.

  The term “alkynyl” (alone or in combination with another term (s)) means one or more triple bonds, and usually 2 to about 20 carbon atoms, more typically 2 to about A straight or branched chain containing 12 carbon atoms, even more typically 2 to about 8 carbon atoms, and even more typical 2 to about 6 carbon atoms Means a hydrocarbonyl substituent. Examples of such substituents include ethynyl, 1-propynyl, 2-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl, and 1-pentynyl.

  The term “cycloalkyl” (alone or in combination with another term) means 3 to about 14 carbon ring atoms, more typically 3 to about 12 carbon ring atoms, and even more A typical example refers to a saturated carbocyclyl substituent containing from 3 to about 8 carbon ring atoms. Cycloalkyls can be single carbocycles usually containing 3 to 6 carbon ring atoms. Examples of monocyclic cycloalkyl include cyclopropyl (or “cyclopropanyl”), cyclobutyl (or “cyclobutanyl”), cyclopentyl (or “cyclopentanyl”), and cyclohexyl (or “cyclohexanyl”). included. Alternatively, the cycloalkyl may be one in which two or three carbocycles are fused together, such as decalinyl or norpinanyl.

  The term “cycloalkylalkyl” (alone or in combination with another term (s)) means an alkyl substituted with a cycloalkyl. Examples of such substituents include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.

  The term “aryl” (alone or in combination with another term (s)) means an aromatic carbocyclyl containing 6-14 carbon ring atoms. Examples of aryl include phenyl, naphthalenyl, and indenyl.

In some examples, the number of carbon atoms in a hydrocarbonyl substituent (eg, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, etc.) is designated by the prefix “C _x -C _y- ” where x is , Is the minimum number of carbon atoms in the substituent, and y is the maximum number). Thus, for example, “C ₁ -C ₆ -alkyl” refers to an alkyl substituent containing from 1 to 6 carbon atoms. To further illustrate, C 3 _-C 6 _- Cycloalkyl means a saturated carbocyclyl containing from 3 to 6 carbon ring atoms.

  The term “arylalkyl” (alone or in combination with another term (s)) means an alkyl substituted with an aryl.

  The term “benzyl” (alone or in combination with another term (s)) means phenyl, ie a methyl group substituted with the following structure:

  The term “benzene” means the following structure:

  The term “hydrogen” (alone or in combination with another term (s)) means a hydrogen group, which may also be indicated as —H.

  The term “hydroxy” or “hydroxyl” (alone or in combination with another term (s)) means —OH.

  The term “hydroxyalkyl” (alone or in combination with another term (s)) means an alkyl substituted with one or more hydroxy.

The term “nitro” (alone or in combination with another term (s)) means —NO ₂ .

  The term “cyano” (alone or in combination with another term (s)) means —CN and can be represented as follows:

  The term “keto” (alone or in combination with another term (s)) means an oxo radical, which may also be indicated as ═O.

  The term “carboxy” or “carboxyl” (alone or in combination with another term (s)) means —C (O) —OH, which can also be represented by the following formula:

The term “amino” (alone or in combination with another term (s)) means —NH ₂ . The term “monosubstituted amino” (alone or in combination with another term (s)) means an amino substituent in which one of the hydrogen groups is replaced by a non-hydrogen substituent. The term “disubstituted amino” (alone or in combination with another term (s)) means an amino substituent wherein both hydrogen atoms are replaced by non-hydrogen substituents which may be the same or different.

  The term “halogen” (alone or in combination with another term) refers to a fluorine group (also can be shown as —F), a chlorine group (also can be shown as —Cl), a bromine group (shown as —Br). Or iodine group (which can also be shown as -I). Usually, a fluorine group or a chlorine group is preferred, and a fluorine group is often particularly preferred.

  The prefix “halo” indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen groups. For example, haloalkyl means an alkyl substituent in which at least one hydrogen group is replaced with a halogen group. When a plurality of hydrogens are substituted with halogens, the halogens may be the same or different. Examples of haloalkyl include chloromethyl, dichloromethyl, difluorochloromethyl, dichlorofluoromethyl, trichloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, difluoroethyl, Pentafluoroethyl, difluoropropyl, dichloropropyl, and heptafluoropropyl are included. To illustrate further, “haloalkoxy” refers to an alkoxy substituent in which at least one hydrogen group is replaced by a halogen group. Examples of haloalkoxy substituents include chloromethoxy, 1-bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as “perfluoromethyloxy”), and 1,1,1, -trifluoro Ethoxy is included. It should be appreciated that when a substituent is substituted with multiple halogen groups, the halogen groups may be the same or different (unless otherwise stated).

The prefix “perhalo” indicates that each hydrogen group on the prefixed substituent is substituted with an independently selected halogen group. If all the halogen groups are the same, the prefix can reveal what the halogen group is. Thus, for example, the term “perfluoro” means that all of the hydrogen groups on the prefixed substituent are replaced with fluorine groups. To illustrate, the term “perfluoroalkyl” means an alkyl substituent with a fluorine group at each hydrogen group. Examples of perfluoroalkyl substituents include trifluoromethyl (—CF ₃ ), perfluorobutyl, perfluoroisopropyl, perfluorododecyl, and perfluorodecyl. To further illustrate, the term “perfluoroalkoxy” refers to an alkoxy substituent in which each hydrogen group is replaced with a fluorine group. Examples of perfluoroalkoxy substituents include trifluoromethoxy (—O—CF ₃ ), perfluorobutoxy, perfluoroisopropoxy, perfluorododecoxy, and perfluorodecoxy.

  The term “carbonyl” (alone or in combination with another term (s)) means —C (O) —, which can also be represented by the following formula:

この用語は、水和したカルボニル置換基、すなわち−Ｃ（ＯＨ）_２−も含むものとする。

The term is also intended to include the hydrated carbonyl substituent, i.e., -C (OH) _2- .

The term “aminocarbonyl” (alone or in combination with another term (s)) means —C (O) —NH ₂ and can also be represented by the following formula:

  The term “oxy” (alone or in combination with another term (s)) means an ether substituent and can also be represented as —O—.

The term “alkoxy” (alone or in combination with another term (s)) means an alkyl ether substituent, ie —O-alkyl. Examples of such substituents include methoxy (—O—CH ₃ ), ethoxy, n-propoxy, isopropoxy, n-butoxy, i-butoxy, s-butoxy, and t-butoxy.

The term “alkylthio” (alone or in combination with another term (s)) means —S-alkyl. For example, “methylthio” is —S—CH ₃ . Other examples of alkylthio substituents include ethylthio, propylthio, butylthio, and hexylthio.

  The term “alkylcarbonyl” or “alkanoyl” (alone or in combination with another term (s)) means —C (O) -alkyl. For example, “ethylcarbonyl” can be represented as:

他のしばしば好ましいアルキルカルボニル置換基の例には、メチルカルボニル、プロピルカルボニル、ブチルカルボニル、ペンチルカルボニル、およびヘキシルカルボニルが含まれる。

Examples of other often preferred alkylcarbonyl substituents include methylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcarbonyl, and hexylcarbonyl.

The term “aminoalkylcarbonyl” (alone or in combination with another term (s)) means —C (O) -alkyl-NH ₂ . For example, “aminomethylcarbonyl” can be represented by the following formula:

  The term “alkoxycarbonyl” (alone or in combination with another term (s)) means —C (O) —O-alkyl. For example, “ethoxycarbonyl” can be represented as:

  Examples of other often preferred alkoxycarbonyl substituents include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, and hexyloxycarbonyl.

  The term “carbocyclylcarbonyl” (alone or in combination with another term (s)) means —C (O) -carbocyclyl. For example, “phenylcarbonyl” can be represented as:

同様に、用語「ヘテロシクリルカルボニル」（単独または別の用語との複合語で）とは、−Ｃ（Ｏ）−ヘテロシクリルを意味する。

Similarly, the term “heterocyclylcarbonyl” (alone or in combination with another term (s)) means —C (O) -heterocyclyl.

  The term “carbocyclylalkylcarbonyl” (alone or in combination with another term (s)) means —C (O) -alkyl-carbocyclyl. For example, “phenylethylcarbonyl” can be represented by the following formula:

同様に、用語「ヘテロシクリルアルキルカルボニル」（単独または別の用語との複合語で）とは、−Ｃ（Ｏ）−アルキル−ヘテロシクリルを意味する。

Similarly, the term “heterocyclylalkylcarbonyl” (alone or in combination with another term (s)) means —C (O) -alkyl-heterocyclyl.

  The term “carbocyclyloxycarbonyl” (alone or in combination with another term (s)) means —C (O) —O-carbocyclyl. For example, “phenyloxycarbonyl” can be represented by the following formula:

  The term “carbocyclylalkoxycarbonyl” (alone or in combination with another term (s)) means —C (O) —O-alkyl-carbocyclyl. For example, “phenylethoxycarbonyl” can be represented by the following formula:

  The term “thio” or “thia” (alone or in combination with another term (s)) means a thiaether substituent, ie, an ether substituent with a divalent sulfur atom in place of the ether oxygen atom. Such substituents can also be shown as -S-. For example, “alkyl-thio-alkyl” means alkyl-S-alkyl.

  The term “thiol” (alone or in combination with another term (s)) means a sulfhydryl substituent and can also be represented as —SH.

The term “sulfonyl” (alone or in combination with another term (s)) means —S (O) ₂ —, which can also be represented by the following formula:

すなわち、例えば「アルキル−スルホニル−アルキル」とは、アルキル−Ｓ（Ｏ）_２−アルキルを意味する。典型的に好ましいアルキルスルホニル置換基の例には、メチルスルホニル、エチルスルホニル、およびプロピルスルホニルが含まれる。

Thus, for example, “alkyl-sulfonyl-alkyl” means alkyl-S (O) ₂ -alkyl. Examples of typically preferred alkylsulfonyl substituents include methylsulfonyl, ethylsulfonyl, and propylsulfonyl.

The term “aminosulfonyl” (alone or in combination with another term (s)) means —S (O) ₂ —NH ₂ and can also be represented by the following formula:

  The term “sulfinyl” or “sulfoxide” (alone or in combination with another term (s)) means —S (O) —, which can also be represented by the following formula:

すなわち、例えば「アルキルスルフィニルアルキル」または「アルキルスルホキシドアルキル」とは、アルキル−Ｓ（Ｏ）−アルキルを意味する。典型的に好ましいアルキルスルフィニル基には、メチルスルフィニル、エチルスルフィニル、ブチルスルフィニル、およびヘキシルスルフィニルが含まれる。

Thus, for example, “alkylsulfinylalkyl” or “alkylsulfoxidealkyl” means alkyl-S (O) -alkyl. Typically preferred alkylsulfinyl groups include methylsulfinyl, ethylsulfinyl, butylsulfinyl, and hexylsulfinyl.

  The term “heterocyclyl” (alone or in combination with another term (s)) is a saturated (ie, “heterocycloalkyl”), partially saturated (ie, “heterocyclyl”) containing a total of 3 to 14 ring atoms. Cycloalkenyl ") or a fully unsaturated (ie" heteroaryl ") ring structure. At least one of the ring atoms is a heteroatom (ie, oxygen, nitrogen, or sulfur), and the remaining ring atoms are each independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.

  A heterocyclyl may be a monocyclic ring containing usually 3 to 7 ring atoms, more typically 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms. Examples of monocyclic heterocyclyl include furanyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl (also known as “thiofuranyl”), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl , Imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxadiazolyl 1,2,4-oxadiazolyl (also known as “azoximyl”), 1,2, -Oxadiazolyl (also known as "furazanyl"), or 1,3,4-oxadiazolyl) oxadiazolyl, (1,2,3,4-oxatriazolyl or 1,2,3,5-oxa Oxatriazolyl (including triazolyl), Dioxazolyl (including 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, or 1,3,4-dioxazolyl), oxathiazolyl , Oxathiolyl, oxathiolanyl, pyranyl (including 1,2-pyranyl or 1,4-pyranyl), dihydropyranyl, pyridinyl (also known as “azinyl”), piperidinyl, (pyridazinyl (“1,2-diazinyl ), Pyrimidinyl ("1,3-diazinyl" or "pyri Diazinyl, piperazinyl, (s-triazinyl (also known as “1,3,5-triazinyl”), or pyrazinyl (also known as “1,4-diazinyl”) Known), as-triazinyl (also known as 1,2,4-triazinyl), and v-triazinyl (also known as "1,2,3-triazinyl") triazinyl , (1,2,3-oxazinyl, 1,3,2-oxazinyl, 1,3,6-oxazinyl (also known as “pentoxazolyl”), 1,2,6-oxazinyl, or 1,4- Oxazinyl (including oxazinyl), isoxazinyl (including o-isoxazinyl or p-isoxazinyl), oxazolidinyl, isoxazolidinyl, Oxathiazinyl (including 1,2,5-oxathiazinyl or 1,2,6-oxathiazinyl), oxadiazinyl, morpholinyl, azepinyl (including 1,4,2-oxadiazinyl or 1,3,5,2-oxadiazinyl) , Oxepinyl, thiepinyl, and diazepinyl.

  Alternatively, a heterocyclyl can be two or three rings fused together, and at least one such ring contains a heteroatom (ie, nitrogen, oxygen, or sulfur) as a ring atom. Such substituents include, for example, indolizinyl, pyridinyl, pyranopyrrolyl, 4H-quinolidinyl, purinyl, naphthyridinyl, (pyrido [3,4-b] -pyridinyl, pyrido [3,2-b] -pyridinyl, or pyrido [ Pyridopyridinyl) and pteridinyl (including 4,3-b] -pyridinyl). Other examples of fused ring heterocyclyl are indolyl, isoindolyl (also known as “isobenzoazolyl” or “pseudoisoindolyl”), indoleninyl (also known as “pseudoindolyl”) ), Isoindazolyl (also known as “benzpyrazolyl”), (including quinolinyl (also known as “1-benzoazinyl”) or isoquinolinyl (also known as “2-benzoazinyl”) benzoazinyl , Phthalazinyl, quinoxalinyl, quinazolinyl, (including cinnolinyl (also known as “1,2-benzodiazinyl”) or quinazolinyl (also known as “1,3-benzodiazinyl”)), (“chromanyl” Or “isochromanyl”) Nzopyranyl, benzothiopyranyl (also known as “thiochromanyl”), benzoxazolyl, indoxazinyl (also known as “benzisoxazolyl”), anthranilyl, benzodioxolyl, benzodioxa Nyl, benzooxadiazolyl, benzofuranyl (also known as “coumaronyl”), isobenzofuranyl, benzothienyl (also known as “benzothiophenyl”, “thionaphthenyl”, or “benzothiofuranyl”) ), Isobenzothienyl (also known as “isobenzothiophenyl”, “isothionaphthenyl”, or “isobenzothiofuranyl”), benzothiazolyl, benzothiadiazolyl, benzoimidazolyl, benzotriazolyl, (1,3,2-benzoxa Benzoxazinyl (including 1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl, or 3,1,4-benzoxazinyl), (1,2-benziso) Benzfused heterocyclyls such as benzisoxazinyl (including xazazinyl or 1,4-benzisoxazinyl), tetrahydroisoquinolinyl, carbazolyl, xanthenyl, and acridinyl are included.

  The term “two-fused ring” heterocyclyl (alone or in combination with another term (s)) means a saturated, partially saturated or aryl heterocyclyl containing two fused rings. Examples of 2-fused heterocyclyl include indolizinyl, pyridinyl, pyranopyrrolyl, 4H-quinolidinyl, purinyl, naphthyridinyl, pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzoazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, pyrazolinyl, pyrazolidinyl Benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzooxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzoimidazolyl, benzo Triazolyl, benzoxazinyl, benzisoxazinyl, and tetrahydroisoxy Riniru are included.

  The term “heteroaryl” (alone or in combination with another term (s)) means an aromatic heterocyclyl containing 5 to 14 ring atoms. A heteroaryl may be a single ring or 2 or 3 fused rings. Examples of heteroaryl substituents include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, pyridazinyl; 1,3,5-, 1,2,4-, or 1,2,3-thiazinyl, imidazyl, furanyl 5-membered ring substituents such as thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl, isothiazolyl; 6/5 membered ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, anthranilyl; and 1,2-, 1,4-, 2,3 6-membered such as-and 2,1-benzopyronyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, 1,4-benzoxazinyl It includes a condensed ring.

  The term “heterocyclylalkyl” (alone or in combination with another term (s)) means an alkyl that is substituted with a heterocyclyl.

  The term “heterocycloalkyl” (alone or in combination with another term (s)) means a fully saturated heterocyclyl.

  In the present specification, the terms “substituent” and “group” are used interchangeably.

A prefix attached to a multi-component substituent applies only to the first component. To illustrate, the term “alkylcycloalkyl” includes two components: alkyl and cycloalkyl. _{That, C 1 ~C 6 - C 1} ~C 6 alkyl cycloalkyl - a prefix, means that the alkyl component of the alkylcycloalkyl contains from 1 to 6 carbon _{atoms, C} 1 ~ The C ₆ -prefix does not mention the cycloalkyl component. To further illustrate, the haloalkoxyalkyl prefix “halo” indicates that only the alkoxy component of the alkoxyalkyl substituent is substituted with one or more halogen groups. Alternatively or additionally, if halogen substitution can occur on the alkyl component, the substituent should be described as “halogen-substituted alkoxyalkyl” rather than “haloalkoxyalkyl”. Finally, if halogen substitution can occur only on the alkyl component, the substituent should be described as “alkoxyhaloalkyl” rather than that.

  If substituents are described as “each independently selected” from the group, each substituent is selected independently of the others. Accordingly, each substituent may be the same as or different from other substituents.

  When words are used to describe a substituent, the component described on the rightmost side of the substituent is the component having the usable valence. Illustratively, benzene substituted with methoxyethyl has the following structure:

見てわかるとおり、エチルがベンゼンに結合しており、メトキシは、ベンゼンから最も遠い構成要素である置換基の構成要素である。さらなる説明として、シクロヘキサニルチオブトキシで置換されているベンゼンは、次の構造を有する。

As can be seen, ethyl is attached to benzene and methoxy is the component of the substituent that is the furthest component from benzene. As a further illustration, benzene substituted with cyclohexanylthiobutoxy has the following structure:

  When using words to describe a linking element between two other elements of the indicated chemical structure, the constituent described on the right-most side of the substituent is attached to the left element of the indicated structure. It is a component. To illustrate, when the chemical structure is described as X-L-Y and L is described as methylcyclohexanylethyl, the chemical should be X-ethyl-cyclohexanyl-methyl-Y. .

  When a substituent is described using a chemical formula, the dash on the left side of the formula indicates the portion of the substituent that has a usable valence. Illustratively, benzene substituted with —C (O) —OH has the following structure:

  When a chemical formula is used to describe a linking element between other two elements of the indicated chemical structure, the leftmost dash of the substituent is attached to the left element of the indicated structure. The part of is shown. On the other hand, the rightmost dash indicates the portion of the substituent attached to the right element of the structure shown. To illustrate, if the chemical structure shown is X-L-Y and L is described as -C (O) -N (H)-, the chemical should be of the formula is there.

  The term “pharmaceutically acceptable” is used herein as an adjective, meaning that the modified noun is suitable for use as a medicament or part of a medicament.

  With respect to the use of the words “comprise”, or “comprises”, or “comprising”, this patent (including the claims) claims that, unless the context requires otherwise, these terms To be used with the basic principle and a clear understanding of being interpreted in a non-limiting rather than restrictive manner, and applicants are confident that each of these terms includes the following claims. Particular reference is made to what we believe will be interpreted in the interpretation.

General Synthetic Procedures An outline of a typical procedure for preparing the compounds of the invention is set forth in the following scheme. Starting materials can be purchased or can be prepared using methods known to those skilled in the art. Similarly, the preparation of various intermediates can be accomplished using methods known in the art. As shown by the examples below, the starting materials may vary and additional steps may be used to produce the compounds included in the present invention. Also, the conversion can usually be accomplished using various solvents and reagents. Furthermore, in some situations it may be advantageous to change the order in which the reactions are performed. In some cases, protection of reactive groups may be necessary to achieve the above transformations. In general, the need for protecting groups as well as the conditions necessary to attach and remove such groups will be apparent to those skilled in the art of organic synthesis. When protecting groups are used, deprotection is generally required. Suitable protecting groups and methodologies for protection and deprotection, such as those described in Greene and Wuts' “Protecting Groups in Organic Synthesis” are known and recognized in the art.

  The following scheme is representative of the methods that can be used to prepare these compounds.

  Scheme 1 shows a general method for assembling a C-5 alkylpyrimidinone skeleton. In these procedures, a substituted amine is condensed with potassium thiocyanate in the presence of an acid. The resulting thiourea is then condensed with a substituted malonic acid derivative. The thiol group can then be alkylated with an alkyl halide and the hydroxyl group alkylated using a substituted benzyl halide or subjected to a Mitsunobu reaction with a substituted benzyl alcohol. The sulfide is then oxidized to the sulfone using standard reagents.

  Scheme 2 shows a general method for assembling a C-5 halopyrimidinone skeleton. In these procedures, a substituted amine is condensed with potassium thiocyanate in the presence of an acid. The resulting thiourea is then condensed with a substituted malonic acid derivative. The thiol group can then be alkylated with an alkyl halide and the hydroxyl group alkylated using a substituted benzyl halide or subjected to a Mitsunobu reaction with a substituted benzyl alcohol. C-5 halogen is introduced using N-bromosuccinimide or N-chlorosuccinimide. The sulfide is then oxidized to the sulfone using standard reagents.

  Scheme 3 illustrates a further modification of pyrimidinone sulfone to obtain several C-2 heteroatom substituted derivatives. The sulfone is reacted with a substituted amine, alcohol, or thiol in the presence of a base.

  Scheme 4 shows a further modification of pyrimidinone sulfone to give some C-2 alkyl substituted derivatives. The sulfone is condensed with a functionalized or nonfunctionalized organometallic reagent, which is then further manipulated using standard conditions.

  Scheme 5 shows a further modification of pyrimidinone sulfone by reaction with potassium cyanide. The cyanide functional group can then be manipulated into several derivatives.

  Scheme 6 shows a further modification of pyrimidinone sulfide to obtain C-2 aryl substituted derivatives. The sulfide is reacted with the substituted aryl boronic acid in the presence of a copper and palladium catalyst.

Detailed Preparation Methods The following detailed examples illustrate the preparation of compounds of the present invention. Other compounds of the invention can be prepared using the methods illustrated in these examples, either alone or in combination with techniques generally known in the art. The following examples are illustrative only and do not limit the remainder of this disclosure in any way.

Use the following abbreviations:
g-gram mg-milligram mmol-mmol millidegree C-degree Celsius M-molar concentration ml-milliliter NMR-nuclear magnetic resonance
¹ H-proton MHz-megahertz s-single line dd-double line d-double line t-triple q-quadrute br-broad m-multiple line app-obvious J-coupling constant Hz-hertz LC / MS- liquid chromatograph / mass spectrometer t _r - residence time min- minute nm- nanometer ES-MS- electrospray mass spectrometer m / z-mass-to-charge ratio ES-HRMS- electrospray high resolution mass spectrometry Total calcd-calculated value N-normal L-liter dq-double quadrupole dt-double triplet ddd-double double duplex rt-room temperature h-hour ddt-double duplex triple w / w-weight vs. weight psi-pounds per square inch M + H-exact mass + 1
HPLC-high performance liquid chromatography DCM-dichloromethane TFA-trifluoroacetic acid DMF-dimethylformamide DBU-1,8-diazabicyclo [5.4.0] -undec-7-ene NBS-N-bromosuccinimide NCS-N-chlorosuccinimide ES-HRMS-electrospray high resolution mass spectrometry t-BOC-t-butyloxycarbonyl DMAP-dimethylaminopyridine DCM-dichloromethane EtOAc-ethyl acetate MCPBA-m-chloroperbenzoic acid

Example 1

ステップ１：６−ヒドロキシ−３−イソプロピル−２−（メチルチオ）ピリミジン−４（３Ｈ）−オンの調製
Ｎ−イソプロピルチオ尿素（１２４．０３ｇ、１．０５モル）とマロン酸ジエチル（１６８ｇ、１．０５モル）の混合物を機械で攪拌したものに、周囲温度で市販の（Ａｌｄｒｉｃｈ）メタノール（４６８ｍＬ）中ナトリウムメトキシド（２５％ｗｔ）を一度に加えた。最初に、生成した濃い白色懸濁液を４．５時間かけて６８℃に加熱した（穏やかな還流）。この時点で、反応混合物は、透明（濁りを帯びた）になる。冷却を開始し、５０℃に到達した後、５０℃を維持しながら、安定した流れの中で１０分間かけてヨウ化メチル（１４９ｇ、１．０５モル）を加えた。発熱が認められるので、適度の冷却を適用して、この温度を維持する。（ヨウ化メチルは揮発性であり、したがって還流冷却器はこの時点でも使える状態のままにしておかなければならない。）３０分後、反応液を３５℃に冷却し、十分に攪拌しながら迅速に加えられる１２０ｍＬの氷酢酸で失活させる。温度が４２℃に上昇し、濃い白色懸濁液が生成した。これによって、急な固体の沈殿が妨げられ、滑らかな攪拌が可能になり、均質で急速に濾過される結晶塊が形成される。さらに３０分間攪拌して周囲温度への冷却（水浴）を可能にした後、内容物を濾過し、５００ｍＬの水で４回洗浄した。濾過は急速であり、白色の半結晶固体が得られ、恒量になるまで５０℃かつ２０ｍｍの減圧下で乾燥させた。重量は１９０ｇ（９０％）（純度＞９８％）であった。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ）δ１１．２（ｂｒ ｓ，１Ｈ）、５．０（ｓ，１Ｈ）４．４（ｍ，１Ｈ）、２．４２（ｓ，３Ｈ）、１．４２（ｄ，Ｊ＝６．６Ｈｚ、６Ｈ）。

Step 1: Preparation of 6-hydroxy-3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one N-isopropylthiourea (124.03 g, 1.05 mol) and diethyl malonate (168 g, 1. To a mechanically stirred mixture of (05 mol) sodium methoxide (25% wt) in commercial (Aldrich) methanol (468 mL) was added in one portion at ambient temperature. First, the resulting thick white suspension was heated to 68 ° C. over 4.5 hours (gentle reflux). At this point, the reaction mixture becomes clear (turbid). Cooling was started and after reaching 50 ° C., methyl iodide (149 g, 1.05 mol) was added over 10 minutes in a steady stream while maintaining 50 ° C. Since exotherm is observed, moderate cooling is applied to maintain this temperature. (Methyl iodide is volatile, so the reflux condenser must still be usable at this point.) After 30 minutes, the reaction is cooled to 35 ° C. and rapidly stirred well. Quench with 120 mL of glacial acetic acid added. The temperature rose to 42 ° C and a thick white suspension was formed. This prevents rapid solid precipitation, allows smooth agitation, and forms a homogeneous and rapidly filtered crystal mass. After stirring for an additional 30 minutes to allow cooling to ambient temperature (water bath), the contents were filtered and washed 4 times with 500 mL water. Filtration was rapid and a white semi-crystalline solid was obtained and dried under reduced pressure at 50 ° C. and 20 mm until constant weight. The weight was 190 g (90%) (purity> 98%). ¹ H NMR (400 MHz, DMSO) δ 11.2 (br s, 1H), 5.0 (s, 1H) 4.4 (m, 1H), 2.42 (s, 3H), 1.42 (d, J = 6.6 Hz, 6H).

ステップ２：６−（２，４−ジフルオロベンジルオキシ）−３−イソプロピル−２−（メチルチオ）ピリミジン−４（３Ｈ）−オンの調製
ステップ１からの６−ヒドロキシ−３−イソプロピル−２−（メチルチオ）ピリミジン−４（３Ｈ）−オン（１９０ｇ、０．９５モル）および３２５メッシュの炭酸カリウム（１６０ｇ、１．１５モル）を６００ｍＬのＮメチルピロリジノンに懸濁させた懸濁液を５０℃に温めた。攪拌を容易にし、生成する塩の塊の形成または固化を防ぐために、追加の１００ｍＬの溶媒を加えた。臭化２，４−ジフルオロベンジル（１９７ｇ、０．９６モル）を希釈せずに２０分間かけて加えて、１０℃の発熱を可能にする（最後温度は６０℃）。このとき懸濁液は、約１０分間でより薄くより攪拌しやすくなり、有意な完了が示される。温度を５０℃に低下させ、さらに３時間保持した。少量の分量を抜き取って反応が完了しているか試験した。混合物を周囲温度に冷却し、３Ｌの水を含む大型のフラスコに十分に攪拌しながら注いだ。沈殿した固体を濾別し、６００ｍＬの水で３回洗浄し、５０℃かつ２０ｍｍの減圧下で乾燥させた。ＮＭＲ純度はこの段階で約７５〜８０％であり、重さは約３００ｇであった。粗生成物を２Ｌの酢酸エチルに溶解させ、大型のロータリーエバポレーターによって３５〜４０℃かつ１００ｍｍの減圧下で７５０ｍＬに濃縮した（１２５０ｍＬを蒸留）。晶出が始まったときに加熱および減圧を止めたが、回転は継続し、浴を３０分間かけてゆっくりと１５℃の最終温度に冷却した。懸濁液を濾過し（迅速に行う）、２００ｍＬのヘキサンで２回回洗浄した。微細な白色結晶を５０℃かつ２０ｍｍで乾燥させて、１６０ｇ（５２％）を得た。結晶化またはクロマトグラフィーによって、母液から追加の量の生成物が得られる。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ）δ７．５５（ｍ，１Ｈ）、７．２７（ｍ，１Ｈ）、７．１１（ｍ，１Ｈ）、５．３７（ｓ，１Ｈ）、５．２１（ｓ，２Ｈ）、４．４７−４．３８（ｍ，１Ｈ）、２．４８（ｓ，３Ｈ）、１．４７（ｄ，Ｊ＝６．７Ｈｚ，６Ｈ）。

Step 2: Preparation of 6- (2,4-difluorobenzyloxy) -3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one 6-Hydroxy-3-isopropyl-2- (methylthio from Step 1 ) A suspension of pyrimidin-4 (3H) -one (190 g, 0.95 mol) and 325 mesh potassium carbonate (160 g, 1.15 mol) in 600 mL N-methylpyrrolidinone was warmed to 50 ° C. It was. An additional 100 mL of solvent was added to facilitate stirring and prevent the formation or solidification of the resulting salt lumps. 2,4-Difluorobenzyl bromide (197 g, 0.96 mol) is added undiluted over 20 minutes to allow an exotherm of 10 ° C. (final temperature is 60 ° C.). The suspension then becomes thinner and easier to stir in about 10 minutes, indicating significant completion. The temperature was lowered to 50 ° C. and held for a further 3 hours. A small amount was withdrawn to test whether the reaction was complete. The mixture was cooled to ambient temperature and poured into a large flask containing 3 L of water with good stirring. The precipitated solid was filtered off, washed 3 times with 600 mL of water and dried under reduced pressure at 50 ° C. and 20 mm. The NMR purity at this stage was about 75-80% and the weight was about 300 g. The crude product was dissolved in 2 L of ethyl acetate and concentrated to 750 mL with a large rotary evaporator at 35-40 ° C. and 100 mm vacuum (1250 mL distilled). Heating and vacuum were stopped when crystallization began, but rotation continued and the bath was slowly cooled to a final temperature of 15 ° C. over 30 minutes. The suspension was filtered (done quickly) and washed twice with 200 mL of hexane. Fine white crystals were dried at 50 ° C. and 20 mm to obtain 160 g (52%). Additional amounts of product are obtained from the mother liquor by crystallization or chromatography. ¹ H NMR (400 MHz, DMSO) δ 7.55 (m, 1H), 7.27 (m, 1H), 7.11 (m, 1H), 5.37 (s, 1H), 5.21 (s, 2H), 4.47-4.38 (m, 1H), 2.48 (s, 3H), 1.47 (d, J = 6.7 Hz, 6H).

ステップ３：６−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−３−イソプロピル−２−（メチルチオ）ピリミジン−４（３Ｈ）−オンの調製
基質６−（２，４−ジフルオロベンジルオキシ）−３−イソプロピル−２−（メチルチオ）ピリミジン−４（３Ｈ）−オン（１３７ｇ、０．４２モル）を塩化メチレンに溶解させ、Ｎ−ブロモスクシンイミド（１７８ｇ、０．４２モル）を同量ずつの２回に分けて十分に攪拌しながら周囲温度で加えた。中程度の温度上昇（３〜５℃）が認められた。さらに２時間攪拌した後、ロータリーエバポレーターでほぼ乾燥するまで溶媒を留去した。その後７５０ｍＬの水を加え、１０分間十分に攪拌した。固体を濾別し（迅速に行う）、２００ｍＬの水で３回洗浄した。オフホワイトの固体を５０℃かつ２０ｍｍの減圧下で乾燥させた。生成物の収量は１７０ｇ（１００％）であった。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ）δ７．５５（ｍ，１Ｈ）、７．２７（ｍ，１Ｈ）、７．１５（ｍ，１Ｈ）、５．４７（ｓ，２Ｈ）、４．５１−４．４０（ｍ，１Ｈ）、２．５８（ｓ，３Ｈ）、１．５２（ｄ，Ｊ＝６．７Ｈｚ，６Ｈ）。

Step 3: Preparation of 6- (2,4-difluorobenzyloxy) -5-bromo-3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one Substrate 6- (2,4-difluorobenzyloxy) -3-Isopropyl-2- (methylthio) pyrimidin-4 (3H) -one (137 g, 0.42 mol) was dissolved in methylene chloride, and N-bromosuccinimide (178 g, 0.42 mol) was added in equal portions. Added in two portions at ambient temperature with good stirring. A moderate temperature increase (3-5 ° C.) was observed. After further stirring for 2 hours, the solvent was distilled off until almost dry using a rotary evaporator. Thereafter, 750 mL of water was added and stirred well for 10 minutes. The solid was filtered off (done quickly) and washed 3 times with 200 mL water. The off-white solid was dried at 50 ° C. and a reduced pressure of 20 mm. The yield of product was 170 g (100%). ¹ H NMR (400 MHz, DMSO) δ 7.55 (m, 1H), 7.27 (m, 1H), 7.15 (m, 1H), 5.47 (s, 2H), 4.51-4. 40 (m, 1H), 2.58 (s, 3H), 1.52 (d, J = 6.7 Hz, 6H).

ステップ４：６−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−３−イソプロピル−２−（メチルスルホニル）ピリミジン−４（３Ｈ）−オンの調製
６−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−３−イソプロピル−２−（メチルチオ）ピリミジン−４（３Ｈ）−オン（１７０ｇ、０．４２モル）を３ＬのＴＨＦおよび３００ｍＬの水に溶かした周囲温度に保たれた攪拌溶液に、オキソン（６００ｇ、０．９８モル）を加えた。オキソンは、ＴＨＦ水溶液への溶解性が低かったので、発熱は最小であり（２〜３℃）、反応液は不均一なままであった。混合物をさらに５日間周囲温度で攪拌した。（加熱して反応の速度を上げることは、分解が認められるので勧められない。）反応混合物を濾過し、残渣を５００ｍＬの酢酸エチルで２回洗浄した。濾液を最初の体積の約１／３に濃縮し（２８００ｍＬの留出物）、続いて１Ｌの酢酸エチルを加えた。２００ｍＬの水で３回洗浄した後、有機層を硫酸ナトリウムで乾燥させ、ロータリーエバポレーターで半ペースト状の固体になるまで濃縮した。次いで５００ｍＬのエーテルを加え、十分に攪拌した。結晶性の固体が急速に分離し、これをその後濾過し、１００ｍＬの冷（１０℃）エーテルで１回および１００ｍＬのヘキサンで１回洗浄した。生成物を無色の固体として得、真空オーブンに入れて５０℃かつ２０ｍｍで乾燥させて１００ｇ（５１％）の恒量とした。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ７．４０（ｍ，１Ｈ）、６．９２（ｍ，１Ｈ）、６．８２（ｍ，１Ｈ）、５．４１（ｓ，２Ｈ）、４．２１−４．２８（ｍ，１Ｈ）、３．３８（ｓ，３Ｈ）、１．６０（ｄ，Ｊ＝６．７Ｈｚ，６Ｈ）。

Step 4: Preparation of 6- (2,4-difluorobenzyloxy) -5-bromo-3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one 6- (2,4-difluorobenzyloxy) To a stirred solution maintained at ambient temperature of -5-bromo-3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one (170 g, 0.42 mol) in 3 L THF and 300 mL water. Oxone (600 g, 0.98 mol) was added. Oxone was less soluble in aqueous THF, so the exotherm was minimal (2-3 ° C.) and the reaction remained heterogeneous. The mixture was stirred for an additional 5 days at ambient temperature. (Heating to increase the rate of the reaction is not recommended as decomposition is observed.) The reaction mixture was filtered and the residue was washed twice with 500 mL of ethyl acetate. The filtrate was concentrated to about 1/3 of the original volume (2800 mL of distillate) followed by 1 L of ethyl acetate. After washing three times with 200 mL of water, the organic layer was dried over sodium sulfate and concentrated to a semi-pasty solid with a rotary evaporator. Then 500 mL of ether was added and stirred well. A crystalline solid quickly separated, which was then filtered and washed once with 100 mL cold (10 ° C.) ether and once with 100 mL hexane. The product was obtained as a colorless solid and placed in a vacuum oven and dried at 50 ° C. and 20 mm to a constant weight of 100 g (51%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40 (m, 1H), 6.92 (m, 1H), 6.82 (m, 1H), 5.41 (s, 2H), 4.21-4 .28 (m, 1H), 3.38 (s, 3H), 1.60 (d, J = 6.7 Hz, 6H).

(Example 2)

５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−ピペラジン−１−イルピリミジン−４（３Ｈ）−オントリフルオロ酢酸塩
ステップ１：４−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピペラジン−１−カルボン酸ｔ−ブチルの調製

5-Bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2-piperazin-1-ylpyrimidin-4 (3H) -one trifluoroacetate salt Step 1: 4- {5-Bromo Preparation of tert-butyl-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} piperazine-1-carboxylate

ｔ−ブチル−１−ピペラジンカルボキシラート（１．０ｇ、０．００５４モル）、ステップ３から得た５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（メチルスルホニル）ピリミジン−４（３Ｈ）−オン（１．８ｇ、０．００４モル）、ジイソプロピルエチルアミン（０．７９ｇ、０．００６モル）、およびジメチルアミノピリジン（０．１５ｇ、０．００１２モル）をジオキサン（２０．０ｍＬ）に混ぜた混合物をアルゴン中にて７０℃で１６時間加熱した。真空中で溶媒を除去した後、残渣を５％の冷クエン酸（１０ｍＬ）とジクロロメタン（６０．０ｍＬ）とに分配した。有機抽出物を水で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、濃縮乾燥した。得られる材料を、０．５％のトリフルオロ酢酸を含む１０〜９０％のＣＨ_３ＣＮ／水の勾配（４０分間）を流速８０ｍＬ／分で使用する逆相ＨＰＬＣによって精製した。適切な画分（ＭＨ^＋，ｍ／ｚ＝５４３）を合わせ、小さい体積（約２５ｍＬ）に濃縮し、５％の炭酸水素ナトリウム（５ｍＬ）を加え、ジクロロメタン（２×２０ｍＬ）で抽出し、乾燥させ（Ｎａ_２ＳＯ_４）、減圧下で濃縮乾燥した。合わせた有機抽出物を水で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、および真空中で濃縮乾燥して、表題化合物を非結晶粉末（０．８５ｇ、３６％）として得た。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．５１（ｍ，１Ｈ）、６．９８（ｍ，２Ｈ）、５．４４（ｓ，２Ｈ）、４．６１（ｍ，１Ｈ）、３．５５（ｂｒ，４Ｈ）、３．２４（ｍ，４Ｈ）、１．５７（ｄ，６Ｈ，Ｊ＝６．８Ｈｚ、および１．４６（ｓ，９Ｈ）；ＥＳ−ＨＲＭＳｍ／ｚ５４３．１４４１（Ｃ_２３Ｈ_３０Ｎ_４Ｏ_４Ｆ_２Ｂｒに対するＭ＋Ｈ計算値は５４３．１４１３）。

t-butyl-1-piperazinecarboxylate (1.0 g, 0.0054 mol), 5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (from step 3) Methylsulfonyl) pyrimidin-4 (3H) -one (1.8 g, 0.004 mol), diisopropylethylamine (0.79 g, 0.006 mol), and dimethylaminopyridine (0.15 g, 0.0012 mol). The mixture mixed with dioxane (20.0 mL) was heated at 70 ° C. in argon for 16 hours. After removing the solvent in vacuo, the residue was partitioned between 5% cold citric acid (10 mL) and dichloromethane (60.0 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 gradient of 10-90% of _CH 3 CN / water containing 0.5% trifluoroacetic acid (40 min) at a flow rate of 80 mL / min. Combine the appropriate fractions (MH ⁺ , m / z = 543), concentrate to a small volume (about 25 mL), add 5% sodium bicarbonate (5 mL), extract with dichloromethane (2 × 20 mL), dry (Na ₂ SO ₄ ) and concentrated to dryness under reduced pressure. The combined organic extracts were washed with water, dried (Na ₂ SO ₄ ), and concentrated to dryness in vacuo to give the title compound as an amorphous powder (0.85 g, 36%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.51 (m, 1H), 6.98 (m, 2H), 5.44 (s, 2H), 4.61 (m, 1H), 3.55 ( br, 4H), 3.24 (m , 4H), 1.57 (d, 6H, J = 6.8Hz, and 1.46 (s, 9H); ES -HRMSm / z543.1441 (C 23 H 30 The calculated M + H value for N ₄ O ₄ F ₂ Br is 543.1413).

Step 2: Preparation of the title compound 4- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6 dihydropyrimidin-2-yl obtained from Step 4 } A solution of t-butyl piperazine-1-carboxylate (0.26 g, 4.6 mmol) in a mixture of trifluoroacetic acid (0.3 mL) and dichloromethane (0.3 mL) was stirred at room temperature for 30 minutes, product was isolated by reverse-phase HPLC using a gradient of 10% to 90% of _CH 3 CN / water containing 0.5% trifluoroacetic acid (40 min) at a flow rate of 80 mL / min. Appropriate fractions (MH ⁺ , m / z = 443) were combined and lyophilized to give the title compound as a white powder (0.18 g, 67%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.50 (m, 1H), 6.99 (m, 2H), 5.46 (s, 2H), 4.61 (m, 1H), 3.49 ( m, 4H), 3.39 (m , 4H), 1.58 (d, 6H, J = 6.8Hz); ES-HRMSm / z443.0859 (C 18 H 22 N 4 O 4 F 2 Br for M + H The calculated value is 443.0889).

(Example 3)

５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−２−（４−グリシルピペラジン−１−イル）−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸塩
５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−ピペラジン−１−イルピリミジン−４（３Ｈ）−オントリフルオロ酢酸塩（０．０５５ｇ、０．１ミリモル）のＤＭＦ（０．２５ｍＬ）溶液に、Ｎ−メチルモルホリン（０．０１５ｇ、０．１５ミリモル）およびＢＯＣ−グリシン−Ｎ−ヒドロキシスクシンイミド（０．０４ｇ、０．１５ミリモル）を加え、室温で２時間攪拌した。反応混合物を真空中で濃縮し、残渣をトリフルオロ酢酸（０．１２５ｍＬ）およびジクロロメタン（０，１２５ｍＬ）と共に室温で１５分間攪拌した。溶液をアセトニトリル（３．０ｍＬ）で希釈し、０．５％のトリフルオロ酢酸を含む１０〜９０％のＣＨ_３ＣＮ／水の勾配（４０分）を流速８０ｍＬ／分で使用する逆相ＨＰＬＣによって生成物を単離した。適切な画分（ＭＨ^＋，ｍ／ｚ＝５００）を合わせ、凍結乾燥して、表題化合物を白色粉末（０．０４ｇ）として得た。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．４５（ｍ，１Ｈ）、６．９６（ｍ，２Ｈ）、５．４５（ｓ，２Ｈ）、４．６４（ｍ，１Ｈ）、３．９７（ｓ，２Ｈ）、３．６８（ｂｒ，２Ｈ）、３．５８（ｍ，２Ｈ）、３．３３（ｍ，４Ｈ）、１．５９（ｄ，６Ｈ，Ｊ＝６．８Ｈｚ）；ＥＳ−ＨＲＭＳｍ／ｚ５００．１１１２（Ｃ_２０Ｈ_２５Ｎ_５Ｏ_３Ｆ_２Ｂｒに対するＭ＋Ｈ計算値は５００．１１０３）。

5-Bromo-6-[(2,4-difluorobenzyl) oxy] -2- (4-glycylpiperazin-1-yl) -3-isopropylpyrimidin-4 (3H) -one trifluoroacetate 5-bromo DMF of -6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2-piperazin-1-ylpyrimidin-4 (3H) -one trifluoroacetate (0.055 g, 0.1 mmol) (0.25 mL) solution was added N-methylmorpholine (0.015 g, 0.15 mmol) and BOC-glycine-N-hydroxysuccinimide (0.04 g, 0.15 mmol) and stirred at room temperature for 2 hours. . The reaction mixture was concentrated in vacuo and the residue was stirred with trifluoroacetic acid (0.125 mL) and dichloromethane (0,125 mL) at room temperature for 15 minutes. The solution was diluted with acetonitrile (3.0 mL), by reverse-phase HPLC using a gradient of 10% to 90% of _CH 3 CN / water containing 0.5% trifluoroacetic acid (40 min) at a flow rate of 80 mL / min The product was isolated. Appropriate fractions (MH ⁺ , m / z = 500) were combined and lyophilized to give the title compound as a white powder (0.04 g). ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.45 (m, 1H), 6.96 (m, 2H), 5.45 (s, 2H), 4.64 (m, 1H), 3.97 ( s, 2H), 3.68 (br, 2H), 3.58 (m, 2H), 3.33 (m, 4H), 1.59 (d, 6H, J = 6.8 Hz); ES-HRMSm _{/z500.1112(C 20 H 25 N 5 O 3} F 2 M + H calcd for Br is 500.1103).

Example 4

５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−２−（４−グリコロイルピペラジン−１−イル）−３−イソプロピルピリミジン−４（３Ｈ）−オン
５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−ピペラジン−１−イルピリミジン−４（３Ｈ）−オントリフルオロ酢酸塩（０．１ｇ、０．１８ミリモル）をジクロロメタン（３．０ｍＬ）に溶かした０℃の溶液に、Ｎ−メチルモルホリン（０．０３７ｇ、０．３６ミリモル）およびアセトキシ塩化アセチル（０．０５ｇ、０．３７ミリモル）を加え、０℃で３０分間攪拌した。反応混合物を真空中で濃縮し、０．５％のトリフルオロ酢酸を含む１０〜９０％のＣＨ_３ＣＮ／水の勾配（４０分）を流速８０ｍＬ／分で使用する逆相ＨＰＬＣによって生成物を単離した。適切な画分（ＭＨ^＋，ｍ／ｚ＝５００）を合わせ、凍結乾燥して、０．０６５ｇ（ＭＨ^＋ｍ／ｚ＝５４３）を白色粉末として得た。これを、１．５ＮのＮａＯＨ（０．３ｍＬ）とジオキサン（０．３ｍＬ）の混合物と共に室温で１時間攪拌した。この混合物を水（５．０ｍＬ）で希釈し、トリフルオロ酢酸で酸性化し、生成物を上述のような逆相ＨＰＬＣによって精製して、表題化合物（０．０２５ｇ）を白色粉末として得た。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．５１（ｍ，１Ｈ）、６．９７（ｍ，２Ｈ）、５．４７（ｓ，２Ｈ）、４．６３（ｍ，１Ｈ）、４．２５（ｓ，２Ｈ）、３．６７（ｂｒ，２Ｈ）、３．５９（ｂｒ，２Ｈ）、３．３３（ｍ，４Ｈ）、１．５９（ｄ，６Ｈ，Ｊ＝６．８Ｈｚ）；ＥＳ−ＨＲ ＭＳｍ／ｚ５０１．０９５４（Ｃ_２０Ｈ_２４Ｎ_４Ｏ_４Ｆ_２Ｂｒに対するＭ＋Ｈ計算値は５０１．０９４３）。

5-Bromo-6-[(2,4-difluorobenzyl) oxy] -2- (4-glycoloylpiperazin-1-yl) -3-isopropylpyrimidin-4 (3H) -one 5-bromo-6- [ (2,4-Difluorobenzyl) oxy] -3-isopropyl-2-piperazin-1-ylpyrimidin-4 (3H) -one trifluoroacetate (0.1 g, 0.18 mmol) was added to dichloromethane (3.0 mL). N-methylmorpholine (0.037 g, 0.36 mmol) and acetoxyacetyl chloride (0.05 g, 0.37 mmol) were added to the solution at 0 ° C. dissolved in) and stirred at 0 ° C. for 30 minutes. The reaction mixture was concentrated in vacuo, the product by reverse phase HPLC using a gradient of 10% to 90% of _CH 3 CN / water containing 0.5% trifluoroacetic acid (40 min) at a flow rate of 80 mL / min Isolated. Appropriate fractions (MH ⁺ , m / z = 500) were combined and lyophilized to give 0.065 g (MH ⁺ m / z = 543) as a white powder. This was stirred with a mixture of 1.5 N NaOH (0.3 mL) and dioxane (0.3 mL) at room temperature for 1 hour. The mixture was diluted with water (5.0 mL), acidified with trifluoroacetic acid and the product was purified by reverse phase HPLC as described above to give the title compound (0.025 g) as a white powder. ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.51 (m, 1H), 6.97 (m, 2H), 5.47 (s, 2H), 4.63 (m, 1H), 4.25 ( s, 2H), 3.67 (br, 2H), 3.59 (br, 2H), 3.33 (m, 4H), 1.59 (d, 6H, J = 6.8 Hz); ES-HR _{MSm / z501.0954 (C 20 H 24} N 4 O 4 F 2 M + H calcd for Br is 501.0943).

(Example 5)

５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−［４−（２−メチルアラニル）ピペラジン−１−イル］ピリミジン−４（３Ｈ）−オントリフルオロ酢酸塩
二炭酸ジ−ｔ−ブチル（０．２ｇ、０．８ミリモル）、Ｎ−（ｔ−ブトキシカルボニル）−２−メチルアラニン（０．１５ｇ、０．７４ミリモル）、３−ヒドロキシ−３，４−ジヒドロベンゾトリアジン−４−オン（０．１２ｇ）、およびトリエチルアミン（０．１ｍＬ）をアセトニトリルに混ぜた混合物を室温で１時間攪拌した。次いで、５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−ピペラジン−１−イルピリミジン−４（３Ｈ）−オン（０．２２ｇ、０．５ミリモル）のＤＭＦ（２．０ｍＬ）溶液を加え、得られる混合物をアルゴン中にて室温で３時間攪拌した。真空中で溶媒を除去した後、残渣を５％のクエン酸（５ｍＬ）とジクロロメタン（２０ｍＬ）とに分配した。有機層を洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、濃縮乾燥した。得られる材料を、トリフルオロ酢酸（０．５ｍＬ）とジクロロメタン（０．５ｍＬ）の混合物と共に３０分間攪拌し、生成物を、０．５％のトリフルオロ酢酸を含む１０〜９０％のＣＨ_３ＣＮ／水の勾配（４０分）を流速８０ｍＬ／分で使用する逆相ＨＰＬＣによって精製した。適切な画分（ＭＨ^＋，ｍ／ｚ＝５００）を合わせ、凍結乾燥して、表題化合物（０．１５５ｇ）を白色粉末として得た。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．４５（ｍ，１Ｈ）、６．９５（ｍ，２Ｈ）、５．４３（ｓ，２Ｈ）、４．６２（ｍ，１Ｈ）、３．７９（ｂｒ，４Ｈ）、３．３０（ｍ，４Ｈ）、１．６７（ｓ，６Ｈ）、および１．５９（ｄ，６Ｈ，Ｊ＝６．８Ｈｚ）；ＥＳ−ＨＲＭＳｍ／ｚ５２８．１４３５（Ｃ_２２Ｈ_２９Ｎ_５Ｏ_３Ｆ_２Ｂｒに対するＭ＋Ｈ計算値は５２８．１４１６）。

5-Bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2- [4- (2-methylalanyl) piperazin-1-yl] pyrimidin-4 (3H) -one trifluoroacetate Di-t-butyl dicarbonate (0.2 g, 0.8 mmol), N- (t-butoxycarbonyl) -2-methylalanine (0.15 g, 0.74 mmol), 3-hydroxy-3,4- A mixture of dihydrobenzotriazin-4-one (0.12 g) and triethylamine (0.1 mL) in acetonitrile was stirred at room temperature for 1 hour. Of 5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2-piperazin-1-ylpyrimidin-4 (3H) -one (0.22 g, 0.5 mmol) DMF (2.0 mL) solution was added and the resulting mixture was stirred in argon at room temperature for 3 hours. After removing the solvent in vacuo, the residue was partitioned between 5% citric acid (5 mL) and dichloromethane (20 mL). The organic layer was washed, dried (Na ₂ SO ₄ ) and concentrated to dryness. The resulting material is stirred with a mixture of trifluoroacetic acid (0.5 mL) and dichloromethane (0.5 mL) for 30 minutes and the product is mixed with 10-90% CH ₃ CN containing 0.5% trifluoroacetic acid. A / water gradient (40 min) was purified by reverse phase HPLC using a flow rate of 80 mL / min. Appropriate fractions (MH ⁺ , m / z = 500) were combined and lyophilized to give the title compound (0.155 g) as a white powder. ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.45 (m, 1H), 6.95 (m, 2H), 5.43 (s, 2H), 4.62 (m, 1H), 3.79 ( br, 4H), 3.30 (m , 4H), 1.67 (s, 6H), and 1.59 (d, 6H, J = 6.8Hz); ES-HRMSm / z528.1435 (C 22 H M + H calculated for ₂₉ N ₅ O ₃ F ₂ Br is 528.1416).

(Example 6)

２−（４−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピペラジン−１−イル）アセトアミドトリフルオロ酢酸塩
クロロアセトアミド（０．１ｇ、１．１ミリモル）、５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−ピペラジン−１−イルピリミジン−４（３Ｈ）−オン（０．３０ｇ、０６８ミリモル）、ジイソプロピルエチルアミン（０．０８１ｇ、０．６３ミリモル）、およびＤＭＡＰ（０．０１ｇ）をジオキサン（６．０ｍＬ）に混ぜた混合物を、アルゴン中にて７０℃で１６時間加熱した。減圧下で溶媒を除去した後、残渣を、０．５％のトリフルオロ酢酸を含む１０〜９０％のＣＨ_３ＣＮ／水の勾配（４０分）を流速８０ｍＬ／分で使用するＨＰＬＣによって精製した。適切な画分（ＭＨ^＋，ｍ／ｚ＝５００）を合わせ、凍結乾燥して、表題化合物（０．０８５ｇ）を白色粉末として得た。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．５０（ｍ，１Ｈ）、６．９８（ｍ，２Ｈ）、５．４４（ｓ，２Ｈ）、４．５９（ｍ，１Ｈ）、３．８０（ｂｒ，２Ｈ）、３．５２（ｍ，４Ｈ）、３．２９（ｍ，４Ｈ）、および１．５７（ｄ，６Ｈ，Ｊ＝６．８Ｈｚ）；ＥＳ−ＨＲＭＳｍ／ｚ５００．１０９２（Ｃ_２０Ｈ_２５Ｎ_５Ｏ_３Ｆ_２Ｂｒに対するＭ＋Ｈ計算値は５００．１１０３）。

2- (4- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} piperazin-1-yl) acetamide Trifluoroacetic acid salt chloroacetamide (0.1 g, 1.1 mmol), 5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2-piperazin-1-ylpyrimidine-4 ( 3H) -one (0.30 g, 068 mmol), diisopropylethylamine (0.081 g, 0.63 mmol), and DMAP (0.01 g) mixed with dioxane (6.0 mL) under argon. Heated at 70 ° C. for 16 hours. After removal of the solvent under reduced pressure, the residue was purified by HPLC using a gradient of 10% to 90% of _CH 3 CN / water containing 0.5% trifluoroacetic acid (40 min) at a flow rate of 80 mL / min . Appropriate fractions (MH ⁺ , m / z = 500) were combined and lyophilized to give the title compound (0.085 g) as a white powder. ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.50 (m, 1H), 6.98 (m, 2H), 5.44 (s, 2H), 4.59 (m, 1H), 3.80 ( br, 2H), 3.52 (m , 4H), 3.29 (m, 4H), and 1.57 (d, 6H, J = 6.8Hz); ES-HRMSm / z500.1092 (C 20 H _The calculated M + H for ₂₅ N ₅ O ₃ F ₂ Br is 500.1103).

(Example 7)

２−（２−アミノエトキシ）−５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸塩
ステップ１：２−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチルカルバミン酸ｔ−ブチルの調製

2- (2-Aminoethoxy) -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidine-4 (3H) -one trifluoroacetate salt Step 1: 2-({5 Preparation of t-Butyl-4-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethylcarbamate

５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（メチルスルホニル）−ピリミジン−４（３Ｈ）−オン（０．２５ｇ、０．５７ミリモル）、２−ヒドロキシエチルカルバミン酸ｔ−ブチル（０．１３８ｇ、０．８６ミリモル）、およびＤＢＵ（０．１ｇ、０．６６ミリモル）をＤＭＡＰ（０．０１ｇ）を含むＴＨＦ（５．０ｍＬ）に混ぜた混合物をアルゴン中にて室温で攪拌した。４時間後、混合物を減圧下で濃縮し、残渣をジクロロメタン（１５．０ｍＬ）と５％のクエン酸（５．０ｍＬ）とに分配した。有機層を水で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、濃縮した。得られるシロップをアセトニトリルに溶解させ、水を加えて濁らせると固体が分離した。これらを濾過し、アセトニトリル／水（１：１ｖ／ｖ）で洗浄し、真空中で乾燥させて、表題化合物を白色粉末として得た。ＥＳ−ＨＲＭＳｍ／ｚ５１８．１１３４（Ｃ_２１Ｈ_２７Ｎ_３Ｏ_５Ｆ_２Ｂｒに対するＭ＋Ｈ計算値は５１８．１０９７）。

5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) -pyrimidin-4 (3H) -one (0.25 g, 0.57 mmol), 2- A mixture of t-butyl hydroxyethylcarbamate (0.138 g, 0.86 mmol) and DBU (0.1 g, 0.66 mmol) in THF (5.0 mL) containing DMAP (0.01 g) was added. Stir in argon at room temperature. After 4 hours, the mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane (15.0 mL) and 5% citric acid (5.0 mL). The organic layer was washed with water, dried (Na ₂ SO ₄ ) and concentrated. The obtained syrup was dissolved in acetonitrile and water was added to make it turbid, so that a solid separated. These were filtered, washed with acetonitrile / water (1: 1 v / v) and dried in vacuo to give the title compound as a white powder. _{ES-HRMSm / z518.1134 (C 21} H 27 N 3 O 5 F 2 M + H calcd for Br is 518.1097).

Step 2: Preparation of the title compound 2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) A solution of t-butyl ethylcarbamate (0.1 g, 0.19 mmol) in dichloromethane (0.3 mL) and trifluoroacetic acid (0.2 mL) was stirred at room temperature for 30 minutes. By reverse-phase HPLC using a gradient of 10% to 90% of _CH 3 CN / water containing 0.5% trifluoroacetic acid (40 min) at a flow rate of 80 mL / min, the product was isolated. Appropriate fractions (MH ⁺ , m / z = 418) were combined and lyophilized to give the title compound (0.07 g) as a white powder. ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.51 (m, 1H), 6.98 (m, 2H), 5.45 (s, 2H), 5.21 (br, 1H), 4.68 ( m, 2H), 3.43 (br , 2H), and 1.47 (d, 6H, J = 7.2Hz); for _{ES-HRMSm / z418.0580 (C 16} H 19 N 3 O 3 F 2 Br The calculated M + H value is 418.0572).

(Example 8)

１−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝プロリンアミド
５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（メチルスルホニル）−ピリミジン−４（３Ｈ）−オン（０．４３ｇ、０．９９ミリモル）、Ｓ−プロリンアミド（０．２３ｇ、２．０ミリモル）、ジイソプロピルエチルアミン（０．２５ｇ、１．９５ミリモル）をＤＭＡＰ（０．０１５ｇ）を含むＴＨＦ（５．０ｍＬ）に混ぜた混合物をアルゴン中にて７０℃で１６時間加熱した。反応混合物を減圧下で濃縮し、残渣を５％のクエン酸（１０．０ｍＬ）とジクロロメタン（１５．０ｍＬ）とに分配した。有機層を水で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、減圧下で濃縮乾燥した。得られる材料を、１％のメタノールを含むＥｔＯＡｃを溶離液として使用するシリカゲルフラッシュクロマトグラフィーによって精製した。適切な画分（ＭＨ^＋ｍ／ｚ＝４７１）を合わせ、濃縮乾燥し、残渣を、０．５％のトリフルオロ酢酸を含む１０〜９０％のＣＨ_３ＣＮ／水の勾配（４０分）を流速８０ｍＬ／分で使用する逆相ＨＰＬＣによってさらに精製した。適切な画分（ＭＨ^＋，ｍ／ｚ＝４７１）を合わせ、小さい体積（約２５ｍＬ）に濃縮し、炭酸水素ナトリウム（１．０ｇ）を加え、ジクロロメタン（２×２０ｍＬ）で抽出した。有機抽出物を合わせて水（２×１０ｍＬ）で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、真空中で濃縮乾燥して、表題化合物（０．１３ｇ）を白色粉末として得た。：^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．５０（ｍ，１Ｈ）、６．９７（ｍ，２Ｈ）、５．３８（ｑ，２Ｈ，Ｊ＝１２．８Ｈｚ）、４．５８（ｍ，２Ｈ）、３．８１（ｍ，１Ｈ）、３．６１（ｍ，１Ｈ）、２．３５（ｍ，１Ｈ）、２．１１（ｍ，１Ｈ）、１．８９（ｍ，２Ｈ）、１．７０（ｄ，３Ｈ，Ｊ＝６．８Ｈｚ）、および１．４５（ｄ，３Ｈ，Ｊ＝６．８Ｈｚ）；ＥＳ−ＨＲＭＳｍ／ｚ４７１．０８２０（Ｃ_１９Ｈ_２２Ｎ_４Ｏ_３Ｆ_２Ｂｒに対するＭ＋Ｈ計算値は４７１．０８３８）。

1- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} prolinamide 5-Bromo-6-[( 2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) -pyrimidin-4 (3H) -one (0.43 g, 0.99 mmol), S-prolinamide (0.23 g, 2 0.0 mmol), diisopropylethylamine (0.25 g, 1.95 mmol) in THF (5.0 mL) containing DMAP (0.015 g) was heated in argon at 70 ° C. for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between 5% citric acid (10.0 mL) and dichloromethane (15.0 mL). The organic layer was washed with water, dried (Na ₂ SO ₄ ) and concentrated to dryness under reduced pressure. The resulting material was purified by silica gel flash chromatography using EtOAc with 1% methanol as the eluent. Appropriate fractions (MH ⁺ m / z = 471) were combined, concentrated to dryness and the residue was subjected to a gradient of 10-90% CH ₃ CN / water (40 min) containing 0.5% trifluoroacetic acid. Further purification by reverse phase HPLC using a flow rate of 80 mL / min. Appropriate fractions (MH ⁺ , m / z = 471) were combined, concentrated to a small volume (about 25 mL), sodium bicarbonate (1.0 g) was added and extracted with dichloromethane (2 × 20 mL). The combined organic extracts were washed with water (2 × 10 mL), dried (Na ₂ SO ₄ ) and concentrated to dryness in vacuo to give the title compound (0.13 g) as a white powder. : ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.50 (m, 1H), 6.97 (m, 2H), 5.38 (q, 2H, J = 12.8 Hz), 4.58 (m, 2H), 3.81 (m, 1H), 3.61 (m, 1H), 2.35 (m, 1H), 2.11 (m, 1H), 1.89 (m, 2H), 1. 70 (d, 3H, J = 6.8Hz), and 1.45 (d, 3H, J = 6.8Hz); ES-HRMSm / z471.0820 (C 19 H 22 N 4 O 3 F 2 Br for M + H The calculated value is 471.0838).

Example 9

１−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピペリジン−３−カルボキサミド
５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（メチルスルホニル）−ピリミジン−４（３Ｈ）−オン（０．５０ｇ、１．１５ミリモル）、ニペコトアミド（０．２２ｇ、１．７ミリモル）、ジイソプロピルエチルアミン（０．２２ｇ、１．７ミリモル）をＤＭＡＰ（０．０２ｇ）を含むジオキサン（５．０ｍＬ）に混ぜた混合物を、アルゴン中に７０℃で３時間加熱した。それを減圧下で濃縮し、残渣を５％のクエン酸（１０．０ｍＬ）とジクロロメタン（１５．０ｍＬ）とに分配した。有機層を水で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、減圧下で濃縮乾燥した。得られる材料を、０．５％のトリフルオロ酢酸を含む１０〜９０％のＣＨ_３ＣＮ／水の勾配（４０分）を流速８０ｍＬ／分で使用する逆相ＨＰＬＣによって精製した。適切な画分（ＭＨ^＋，ｍ／ｚ＝４８５）を合わせ、小さい体積に濃縮し、炭酸水素ナトリウム（０．５ｇ）を加え、ジクロロメタン（２×２０ｍＬ）で抽出した。有機抽出物を合わせて水（２×１０ｍＬ）で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、真空中で濃縮乾燥して、表題化合物（０．１３ｇ）を白色粉末として得た。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．４９（ｍ，１Ｈ）、６．９５（ｍ，２Ｈ）、５．４２（ｓ，２Ｈ）、４．５２（ｍ，１Ｈ）、３．５７（ｍ，１Ｈ）、３．４７（ｍ，１Ｈ）、３．１（ｍ １Ｈ）、２．９８（ｍ，１Ｈ）、２．６２（ｍ，１Ｈ）、１．９８（ｍ，１Ｈ）、１．８２（ｍ １Ｈ）、１．６９（ｍ，２Ｈ）、および１．５５（ｍ，６Ｈ）；ＥＳ−ＨＲＭＳｍ／ｚ４８５．１０１６（Ｃ_２０Ｈ_２４Ｎ_４Ｏ_３Ｆ_２Ｂｒに対するＭ＋Ｈ計算値は４８５．０９９４）。

1- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} piperidine-3-carboxamide 5-Bromo-6 -[(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) -pyrimidin-4 (3H) -one (0.50 g, 1.15 mmol), nipecotamide (0.22 g, 1 0.7 mmol), diisopropylethylamine (0.22 g, 1.7 mmol) in dioxane (5.0 mL) containing DMAP (0.02 g) was heated in argon at 70 ° C. for 3 hours. It was concentrated under reduced pressure and the residue was partitioned between 5% citric acid (10.0 mL) and dichloromethane (15.0 mL). The organic layer was washed with water, dried (Na ₂ SO ₄ ) and concentrated to dryness under reduced pressure. The resulting material was purified by reverse phase HPLC using a gradient of 10% to 90% of _CH 3 CN / water containing 0.5% trifluoroacetic acid (40 min) at a flow rate of 80 mL / min. Appropriate fractions (MH ⁺ , m / z = 485) were combined, concentrated to a small volume, sodium bicarbonate (0.5 g) was added and extracted with dichloromethane (2 × 20 mL). The combined organic extracts were washed with water (2 × 10 mL), dried (Na ₂ SO ₄ ) and concentrated to dryness in vacuo to give the title compound (0.13 g) as a white powder. ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.49 (m, 1H), 6.95 (m, 2H), 5.42 (s, 2H), 4.52 (m, 1H), 3.57 ( m, 1H), 3.47 (m, 1H), 3.1 (m 1H), 2.98 (m, 1H), 2.62 (m, 1H), 1.98 (m, 1H), 1 .82 (m 1H), 1.69 (m, 2H), and 1.55 (m, 6H); ES-HRMS m / z 485.016 (M + H calculated for C ₂₀ H ₂₄ N ₄ O ₃ F ₂ Br is 485.0994).

(Example 10)

Ｎ〜２〜−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝グリシンアミド
５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（メチルスルホニル）−ピリミジン−４（３Ｈ）−オン（０．５０ｇ、１．１５ミリモル）、グリシンアミド塩酸塩（０．１９ｇ、１．７２ミリモル）、ジイソプロピルエチルアミン（０．４４ｇ、３．４ミリモル）をＤＭＡＰ（０．０２ｇ）を含むジオキサン（５．０ｍＬ）に混ぜた混合物を、アルゴン中にて７０℃で２時間加熱した。反応混合物を減圧下で濃縮し、残渣を、０．５％のトリフルオロ酢酸を含む１０〜９０％のＣＨ_３ＣＮ／水の勾配（４０分）を流速８０ｍＬ／分で使用する逆相ＨＰＬＣによって精製した。適切な画分（ＭＨ^＋，ｍ／ｚ＝４３１）を合わせ、小さい体積に濃縮し、炭酸水素ナトリウム（０．５ｇ）を加え、ジクロロメタン（２×２０ｍＬ）で抽出した。有機抽出物を合わせて水（２×１０ｍＬ）で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、真空中で濃縮乾燥して、表題化合物（０．１３ｇ）を白色粉末として得た。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．４９（ｍ，１Ｈ）、６．９５（ｍ，２Ｈ）、５．３６（ｓ，２Ｈ）、４．５５（ｂｒ，２Ｈ）、４．００（ｓ，２Ｈ）、および１．５２（ｄ，６Ｈ，Ｊ＝６．８Ｈｚ）；ＥＳ−ＨＲＭＳｍ／ｚ４３１．０５２７（Ｃ_１６Ｈ_１８Ｎ_４Ｏ_３Ｆ_２Ｂｒに対するＭ＋Ｈ計算値は４３１．０５２５）。

N ~ 2- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} glycinamide 5-Bromo-6 -[(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) -pyrimidin-4 (3H) -one (0.50 g, 1.15 mmol), glycinamide hydrochloride (0. 19 g, 1.72 mmol), diisopropylethylamine (0.44 g, 3.4 mmol) in dioxane (5.0 mL) containing DMAP (0.02 g) were mixed in argon at 70 ° C. for 2 hours. Heated. The reaction mixture was concentrated under reduced pressure, the residue by reverse phase HPLC using a gradient of 10% to 90% of _CH 3 CN / water containing 0.5% trifluoroacetic acid (40 min) at a flow rate of 80 mL / min Purified. Appropriate fractions (MH ⁺ , m / z = 431) were combined, concentrated to a small volume, sodium bicarbonate (0.5 g) was added, and extracted with dichloromethane (2 × 20 mL). The combined organic extracts were washed with water (2 × 10 mL), dried (Na ₂ SO ₄ ) and concentrated to dryness in vacuo to give the title compound (0.13 g) as a white powder. ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.49 (m, 1H), 6.95 (m, 2H), 5.36 (s, 2H), 4.55 (br, 2H), 4.00 ( s, 2H), and 1.52 (d, 6H, J = 6.8Hz); ES-HRMSm / z431.0527 (C 16 H 18 N 4 O 3 F 2 M + H calcd for Br is 431.0525).

(Example 11)

２−（３−アミノピロリジン−１−イル）−５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸塩
ステップ１：１−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イルカルバミン酸ｔ−ブチルの調製

2- (3-Aminopyrrolidin-1-yl) -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one trifluoroacetate salt Step 1: 1 Of t-butyl- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidin-3-ylcarbamate Preparation

５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（メチルスルホニル）−ピリミジン−４（３Ｈ）−オン（０．５０ｇ、１．１５ミリモル）をＴＨＦ（５．０ｍＬ）に溶かした溶液、３−ｔ−ブトキシカルボニルアミノピロリジン（０．２７ｇ、１．４５ミリモル）、ＤＢＵ（０．２５ｇ、１．６ｍＬ）、およびＤＭＡＰ（０．０２ｇ）を加えた。得られる混合物を室温で２時間攪拌し、アルゴン中にて減圧下で濃縮した。残渣を５％のクエン酸（２０．０ｍＬ）とジクロロメタン（１５．０ｍＬ）とに分配した。有機層を水で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、減圧下で濃縮乾燥した。得られる材料を、５０％のヘキサン中ＥｔＯＡｃを使用するシリカゲルフラッシュクロマトグラフィーによって精製して、０．４６（ＭＨ^＋ｍ／ｚ＝５４３）を白色粉末として得た。ＥＳ−ＨＲＭＳｍ／ｚ５４３．１４０５（Ｃ_２３Ｈ_３０Ｎ_４Ｏ_４Ｆ_２Ｂｒに対するＭ＋Ｈ計算値は５４３．１４１３）。

5-Bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) -pyrimidin-4 (3H) -one (0.50 g, 1.15 mmol) in THF ( A solution dissolved in 5.0 mL), 3-t-butoxycarbonylaminopyrrolidine (0.27 g, 1.45 mmol), DBU (0.25 g, 1.6 mL), and DMAP (0.02 g) were added. The resulting mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure in argon. The residue was partitioned between 5% citric acid (20.0 mL) and dichloromethane (15.0 mL). The organic layer was washed with water, dried (Na ₂ SO ₄ ) and concentrated to dryness under reduced pressure. The resulting material was purified by silica gel flash chromatography using 50% EtOAc in hexanes to give 0.46 (MH ⁺ m / z = 543) as a white powder. _{ES-HRMSm / z543.1405 (C 23} H 30 N 4 O 4 F 2 M + H calcd for Br is 543.1413).

Step 2: Preparation of the title compound 1- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidine-3 A solution of t-butyl ylcarbamate (0.4 g, 0.74 mmol) in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) was stirred at room temperature for 30 minutes. Product was isolated by reverse-phase HPLC using a gradient of 10% to 90% of _CH 3 CN / water containing 0.5% trifluoroacetic acid (40 min) at a flow rate of 80 mL / min. Appropriate fractions (MH ⁺ , m / z = 443) were combined and lyophilized to give the title compound (0.34 g, 82%) as a white powder. ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.51 (m, 1H), 7.00 (m, 2H), 5.44 (s, 2H), 4.49 (m, 1H), 3.95 ( m, 2H), 3.77 (m, 1H), 3.68 (m, 1H), 3.62 (m, 1H), 2.42 (m, 1H), 2.14 (m, 1H), 1.62 (d, 3H, J = 6.8Hz), and 1.58 (d, 3H, J = 6.8Hz); ES-HR MSm / z443.0882 (C 18 H 22 N 4 O 2 F 2 The calculated M + H value for Br is 443.0889).

Example 12

２−［（３Ｒ）−３−アミノピロリジン−１−イル］−５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸塩
表題化合物は、２−（３−アミノピロリジン−１−イル）−５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸塩について記載したのと同様の手順によって、３−ｔ−ブトキシカルボニルアミノ−ピロリジンの代わりに３Ｒ−３−ｔ−ブトキシカルボニルアミノピロリジンを使用して調製した。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．５０（ｍ，１Ｈ）、６．９６（ｍ，２Ｈ）、５．４１（ｓ，２Ｈ）、４．４５（ｍ，１Ｈ）、３．９５（ｍ，２Ｈ）、３．７４（ｍ，１Ｈ）、３．６８（ｍ，１Ｈ）、３．６０（ｍ，１Ｈ）、２．４１（ｍ，１Ｈ）、２．１５（ｍ，１Ｈ）、１．６０（ｄ，３Ｈ，Ｊ＝６．８Ｈｚ）、および１．５５（ｄ，３Ｈ，Ｊ＝６．８Ｈｚ）；ＥＳ−ＨＲ ＭＳｍ／ｚ４４３．０８３１（Ｃ_１８Ｈ_２２Ｎ_４Ｏ_２Ｆ_２Ｂｒに対するＭ＋Ｈ計算値は４４３．０８８９）。

2-[(3R) -3-Aminopyrrolidin-1-yl] -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one trifluoroacetate The title compound was 2- (3-aminopyrrolidin-1-yl) -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidine-4 (3H) -one trifluoroacetate Prepared by 3R-3-t-butoxycarbonylaminopyrrolidine instead of 3-t-butoxycarbonylamino-pyrrolidine by a similar procedure as described for. ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.50 (m, 1H), 6.96 (m, 2H), 5.41 (s, 2H), 4.45 (m, 1H), 3.95 ( m, 2H), 3.74 (m, 1H), 3.68 (m, 1H), 3.60 (m, 1H), 2.41 (m, 1H), 2.15 (m, 1H), 1.60 (d, 3H, J = 6.8 Hz), and 1.55 (d, 3H, J = 6.8 Hz); ES-HR MSm / z 443.0831 (C ₁₈ H ₂₂ N ₄ O ₂ F ₂ The calculated M + H value for Br is 443.0889).

(Example 13)

２−［（３Ｓ）−３−アミノピロリジン−１−イル］−５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸塩
表題化合物は、２−（３−アミノピロリジン−１−イル）−５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸塩について記載したのと同様の手順によって、３−ｔ−ブトキシカルボニルアミノ−ピロリジンの代わりに３Ｓ−３−ｔ−ブトキシカルボニルアミノピロリジンを使用して調製した。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．５０（ｍ，１Ｈ）、６．９６（ｍ，２Ｈ）、５．４１（ｓ，２Ｈ）、４．４６（ｍ，１Ｈ）、３．９４（ｍ，２Ｈ）、３．７５（ｍ，１Ｈ）、３．６１（ｍ，１Ｈ）、３．６０（ｍ，１Ｈ）、２．４１（ｍ，１Ｈ）、２．１５（ｍ，１Ｈ）、１．５９（ｄ，３Ｈ，Ｊ＝６．８Ｈｚ）、および１．５５（ｄ，３Ｈ，Ｊ＝６．８Ｈｚ）；ＥＳ−ＨＲＭＳｍ／ｚ４４３．０９１４（Ｃ_１８Ｈ_２２Ｎ_４Ｏ_２Ｆ_２Ｂｒに対するＭ＋Ｈ計算値は４４３．０８８９）。

2-[(3S) -3-Aminopyrrolidin-1-yl] -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one trifluoroacetate The title compound was 2- (3-aminopyrrolidin-1-yl) -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidine-4 (3H) -one trifluoroacetate Prepared by a similar procedure as described for, using 3S-3-t-butoxycarbonylaminopyrrolidine instead of 3-t-butoxycarbonylamino-pyrrolidine. ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.50 (m, 1H), 6.96 (m, 2H), 5.41 (s, 2H), 4.46 (m, 1H), 3.94 ( m, 2H), 3.75 (m, 1H), 3.61 (m, 1H), 3.60 (m, 1H), 2.41 (m, 1H), 2.15 (m, 1H), 1.59 (d, 3H, J = 6.8 Hz), and 1.55 (d, 3H, J = 6.8 Hz); ES-HRMS m / z 443.0914 (C ₁₈ H ₂₂ N ₄ O ₂ F ₂ Br M + H calculated for is 443.0889).

(Example 14)

５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−２−［（２Ｓ）−２−（ヒドロキシメチル）ピロリジン−１−イル］−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸塩
５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（メチルスルホニル）−ピリミジン−４（３Ｈ）−オン（０．４３ｇ、０．９９ミリモル）、Ｓ−プロリノール（０．１２ｇ、１．２ミリモル）をＤＭＡＰ（０．０２５ｇ、０．２ミリモル）を含むジオキサン（３．０ｍＬ）に混ぜた混合物を、アルゴン中にて室温で２時間かけて攪拌した。次いで、反応混合物を減圧下で濃縮し、残渣を水（１０．０ｍＬ）とジクロロメタン（１５．０ｍＬ）とに分配した。有機層を水で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、減圧下で濃縮乾燥し、残渣を、５０％のヘキサン中ＥｔＯＡｃを溶離液として使用するシリカゲルフラッシュクロマトグラフィーによって精製した。適切な画分（ＭＨ^＋ｍ／ｚ＝４５８）を合わせ、濃縮し、得られる残渣を、０．５％のトリフルオロ酢酸を含む１０〜９０％のＣＨ_３ＣＮ／水の勾配（４０分）を流速８０ｍＬ／分で使用する逆相ＨＰＬＣによってさらに精製した。適切な画分（ＭＨ^＋，ｍ／ｚ＝４５８）を合わせ、凍結乾燥して、表題化合物（０．０２ｇ）を白色粉末として得た。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．４９（ｍ，１Ｈ）、６．９５（ｍ，２Ｈ）、５．３８（ｑ，２Ｈ，Ｊ＝１０．８Ｈｚ）、４．４８（ｍ，２Ｈ）、３．６１（ｍ，３Ｈ）、３．４５（ｍ，１Ｈ）、２．１８（ｍ，１Ｈ）、２．０１（ｍ，１Ｈ）、１．８５（ｍ，２Ｈ）、１．７３（ｄ，３Ｈ，Ｊ＝６．８Ｈｚ）、および１．３９（ｄ，３Ｈ，Ｊ＝６．８Ｈｚ）；ＥＳ−ＨＲＭＳｍ／ｚ４５８．０８３５（Ｃ_１９Ｈ_２３Ｎ_３Ｏ_３Ｆ_２Ｂｒに対するＭ＋Ｈ計算値は４５８．０８８５）。

5-Bromo-6-[(2,4-difluorobenzyl) oxy] -2-[(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] -3-isopropylpyrimidine-4 (3H) -one tri Fluoroacetate 5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) -pyrimidin-4 (3H) -one (0.43 g, 0.99 mmol) , S-prolinol (0.12 g, 1.2 mmol) in dioxane (3.0 mL) containing DMAP (0.025 g, 0.2 mmol) was stirred in argon at room temperature for 2 hours. And stirred. The reaction mixture was then concentrated under reduced pressure and the residue was partitioned between water (10.0 mL) and dichloromethane (15.0 mL). The organic layer was washed with water, dried (Na ₂ SO ₄ ), concentrated to dryness under reduced pressure, and the residue was purified by silica gel flash chromatography using 50% EtOAc in hexane as eluent. Appropriate fractions (MH ⁺ m / z = 458) were combined and concentrated, and the resulting residue was gradient from 10-90% CH ₃ CN / water containing 40% trifluoroacetic acid (40 min). Was further purified by reverse phase HPLC using a flow rate of 80 mL / min. Appropriate fractions (MH ⁺ , m / z = 458) 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 7.49 (m, 1H), 6.95 (m, 2H), 5.38 (q, 2H, J = 10.8 Hz), 4.48 (m, 2H) ), 3.61 (m, 3H), 3.45 (m, 1H), 2.18 (m, 1H), 2.01 (m, 1H), 1.85 (m, 2H), 1.73 (d, 3H, J = 6.8Hz ), and 1.39 (d, 3H, J = 6.8Hz); M + H calculated for _{ES-HRMSm / z458.0835 (C 19} H 23 N 3 O 3 F 2 Br The value is 458.00885).

(Example 15)

Ｎ〜３〜−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−β−アラニンアミド
５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（メチルスルホニル）−ピリミジン−４（３Ｈ）−オン（０．５０ｇ、１．１５ミリモル）、β−アラニンアミド塩酸塩（０．１９ｇ、１．７５ミリモル）、ジイソプロピルエチルアミン（０．３３ｇ、２．６ミリモル）をＤＭＡＰ（０．０２５ｇ、０．２ミリモル）を含むジオキサン（５．０ｍＬ）に混ぜた混合物を、アルゴン中にて６５℃で２時間加熱した。反応混合物を減圧下で濃縮し、残渣を５％のクエン酸（１０．０ｍＬ）とジクロロメタン（２０．０ｍＬ）とに分配した。有機層を水で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、減圧下で濃縮乾燥し、残渣を、１％のメタノールを含むＥｔＯＡｃを溶離液として使用するシリカゲルフラッシュクロマトグラフィーによって精製した。適切な画分（ＭＨ^＋ｍ／ｚ＝４４５）を合わせた、減圧下で濃縮乾燥し、得られる固体をＥｔＯＡｃ／ヘキサンから結晶化させて、表題化合物（０．１６ｇ）を白色粉末として得た。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．４９（ｍ，１Ｈ）、６．９５（ｍ，２Ｈ）、５．４０（ｓ，２Ｈ）、４．５５（ｂｒ，１Ｈ）、３．６７（ｔ，２Ｈ，Ｊ＝６．８Ｈｚ）、および２．５１（ｔ，２Ｈ，Ｊ＝６．８Ｈｚ）、および１．４６（ｄ，６Ｈ，Ｊ＝６．８Ｈｚ）；ＥＳ−ＨＲ ＭＳｍ／ｚ４４５．０６４５（Ｃ_１７Ｈ_２０Ｎ_４Ｏ_３Ｆ_２Ｂｒに対するＭ＋Ｈ計算値は４４５．０６８１）。

N-3-3- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -β-alaninamide 5- Bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) -pyrimidin-4 (3H) -one (0.50 g, 1.15 mmol), β-alaninamide A mixture of hydrochloride (0.19 g, 1.75 mmol), diisopropylethylamine (0.33 g, 2.6 mmol) in dioxane (5.0 mL) containing DMAP (0.025 g, 0.2 mmol) was added. And heated in argon at 65 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between 5% citric acid (10.0 mL) and dichloromethane (20.0 mL). The organic layer was washed with water, dried (Na ₂ SO ₄ ), concentrated to dryness under reduced pressure, and the residue was purified by silica gel flash chromatography using EtOAc with 1% methanol as eluent. Appropriate fractions (MH ⁺ m / z = 445) were combined, concentrated to dryness under reduced pressure, and the resulting solid was crystallized from EtOAc / hexane to give the title compound (0.16 g) as a white powder. . ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.49 (m, 1H), 6.95 (m, 2H), 5.40 (s, 2H), 4.55 (br, 1H), 3.67 ( t, 2H, J = 6.8 Hz), and 2.51 (t, 2H, J = 6.8 Hz), and 1.46 (d, 6H, J = 6.8 Hz); ES-HR MSm / z 445. 0645 (M + H calculated for C ₁₇ H ₂₀ N ₄ O ₃ F ₂ Br is 445.0681).

(Example 16)

Ｎ〜２〜−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−Ｌ−アラニンアミド
５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（メチルスルホニル）−ピリミジン−４（３Ｈ）−オン（０．５０ｇ、１．１５ミリモル）、Ｓ−アラニンアミド塩酸塩（０．１８ｇ、１．４４ミリモル）、ジイソプロピルエチルアミン（０．３９ｇ、３．０ミリモル）をＤＭＡＰ（０．０２０ｇ、０．１６ミリモル）を含むジオキサン（５．０ｍＬ）に混ぜた混合物を、アルゴン中にて６５℃で３時間加熱した。次いで、反応混合物を減圧下で濃縮し、残渣を５％のクエン酸（５．０ｍＬ）とジクロロメタン（２０．０ｍＬ）とに分配した。有機層を水で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、減圧下で濃縮乾燥し、残渣を、ＥｔＯＡｃを溶離液として使用するシリカゲルフラッシュクロマトグラフィーによって精製した。適切な画分（ＭＨ^＋ｍ／ｚ＝４４５）を合わせ、減圧下で濃縮乾燥した。得られる物質を、０．５％のトリフルオロ酢酸を含む１０〜９０％のＣＨ_３ＣＮ／水の勾配（４０分）を流速８０ｍＬ／分で使用する逆相ＨＰＬＣによってさらに精製した。適切な画分（ＭＨ^＋，ｍ／ｚ＝４４５）を合わせ、炭酸水素ナトリウム（０．５ｇ）を加え、ジクロロメタン（２×２０ｍＬ）で抽出した。有機抽出物を合わせて水（２×１０ｍＬ）で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、減圧下で濃縮乾燥して、表題化合物（０．１３ｇ）を白色粉末として得た。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．４９（ｍ，１Ｈ）、６．９５（ｍ，２Ｈ）、５．３７（ｑ，２Ｈ，Ｊ＝４．０Ｈｚ）、４．４６（ｍ，１Ｈ）、および１．５３（ｍ，９Ｈ）；ＥＳ−ＨＲＭＳｍ／ｚ４４５．０６７２（Ｃ_１７Ｈ_２０Ｎ_４Ｏ_３Ｆ_２Ｂｒに対するＭ＋Ｈ計算値は４４５．０６８１）。

N-2-2- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -L-alaninamide 5- Bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) -pyrimidin-4 (3H) -one (0.50 g, 1.15 mmol), S-alaninamide A mixture of hydrochloride (0.18 g, 1.44 mmol), diisopropylethylamine (0.39 g, 3.0 mmol) in dioxane (5.0 mL) containing DMAP (0.020 g, 0.16 mmol) was added. And heated in argon at 65 ° C. for 3 hours. The reaction mixture was then concentrated under reduced pressure and the residue was partitioned between 5% citric acid (5.0 mL) and dichloromethane (20.0 mL). The organic layer was washed with water, dried (Na ₂ SO ₄ ), concentrated to dryness under reduced pressure, and the residue was purified by silica gel flash chromatography using EtOAc as the eluent. Appropriate fractions (MH ⁺ m / z = 445) were combined and concentrated to dryness under reduced pressure. The resulting material was further purified by reverse phase HPLC using a gradient of 10% to 90% of _CH 3 CN / water containing 0.5% trifluoroacetic acid (40 min) at a flow rate of 80 mL / min. Appropriate fractions (MH ⁺ , m / z = 445) were combined, sodium bicarbonate (0.5 g) was added and extracted with dichloromethane (2 × 20 mL). The combined organic extracts were washed with water (2 × 10 mL), dried (Na ₂ SO ₄ ) and concentrated to dryness under reduced pressure to give the title compound (0.13 g) as a white powder. ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.49 (m, 1H), 6.95 (m, 2H), 5.37 (q, 2H, J = 4.0 Hz), 4.46 (m, 1H) ), and 1.53 (m, 9H); ES -HRMSm / z445.0672 (C 17 H 20 N 4 O 3 F 2 M + H calcd for Br is 445.0681).

(Example 17)

Ｎ〜１〜−（１−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イル）グリシンアミドトリフルオロ酢酸塩
２−（３−アミノピロリジン−１−イル）−５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸塩（０．１５ｇ、０．２７ミリモル）のＤＭＦ（２．０ｍＬ）溶液、Ｎ−メチルモルホリン（０．０４ｇ、０．４ミリモル）、Ｎ−ｔ−ＢＯＣ−グリシン−Ｎ−スクシンイミドエステル（０．１ｇ、０．３７ミリモル）、およびＤＭＡＰ（０．０５ｇ）を加えた。反応混合物をアルゴン中にて室温で１６時間攪拌した。真空中で溶媒を留去し、残渣をジクロロメタン（０．５ｍＬ）およびトリフルオロ酢酸（０．５ｍＬ）に溶解させ、混合物を室温で１時間攪拌した。０．５％のトリフルオロ酢酸を含む１０〜９０％のＣＨ_３ＣＮ／水の勾配（４０分）を流速８０ｍＬ／分で使用する逆相ＨＰＬＣによって生成物を単離した。適切な画分（ＭＨ^＋，ｍ／ｚ＝５００）を合わせ、凍結乾燥して、表題化合物（０．０９ｇ）を白色粉末として得た。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．４８（ｍ，１Ｈ）、６．９５（ｍ，２Ｈ）、５．３９（ｓ，２Ｈ）、４．４４（ｍ，２Ｈ）、３．８９（ｄｄ，１Ｈ，Ｊ＝６．０Ｈｚ，１１．２Ｈｚ）、３．７６（ｍ，１Ｈ）、３．６２（ｍ，３Ｈ）、３．４２（２ｄ，１Ｈ，Ｊ＝４．０Ｈｚ）、２．２１（ｍ，１Ｈ）、１．９７（ｍ，１Ｈ）１．５９（ｄ，３Ｈ，Ｊ＝６．４Ｈｚ）、および１．５０（ｄ，３Ｈ，Ｊ＝６．４Ｈｚ）；ＥＳ−ＨＲＭＳｍ／ｚ５００．１０７９（Ｃ_２０Ｈ_２５Ｎ_５Ｏ_３Ｆ_２Ｂｒに対するＭ＋Ｈ計算値は５００．１１０３）。

N-1 to-(1- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidine-3- Yl) glycinamide trifluoroacetate 2- (3-aminopyrrolidin-1-yl) -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one Trifluoroacetate (0.15 g, 0.27 mmol) in DMF (2.0 mL), N-methylmorpholine (0.04 g, 0.4 mmol), Nt-BOC-glycine-N-succinimide ester (0.1 g, 0.37 mmol), and DMAP (0.05 g) were added. The reaction mixture was stirred in argon at room temperature for 16 hours. The solvent was removed in vacuo, the residue was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) and the mixture was stirred at room temperature for 1 hour. Product was isolated by reverse-phase HPLC using a gradient of 10% to 90% of _CH 3 CN / water containing 0.5% trifluoroacetic acid (40 min) at a flow rate of 80 mL / min. Appropriate fractions (MH ⁺ , m / z = 500) were combined and lyophilized to give the title compound (0.09 g) as a white powder. ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.48 (m, 1H), 6.95 (m, 2H), 5.39 (s, 2H), 4.44 (m, 2H), 3.89 ( dd, 1H, J = 6.0 Hz, 11.2 Hz), 3.76 (m, 1H), 3.62 (m, 3H), 3.42 (2d, 1H, J = 4.0 Hz), 2. 21 (m, 1H), 1.97 (m, 1H) 1.59 (d, 3H, J = 6.4 Hz), and 1.50 (d, 3H, J = 6.4 Hz); ES-HRMSm / _{z500.1079 (C 20 H 25 N 5} O 3 F 2 M + H calcd for Br is 500.1103).

(Example 18)

Ｎ〜２〜−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−Ｎ〜１〜−メチルグリシンアミド
５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（メチルスルホニル）−ピリミジン−４（３Ｈ）−オン（０．５０ｇ、１．１５ミリモル）、Ｎ−メチルグリシンアミド塩酸塩（０．２１ｇ、１．７ミリモル）、ジイソプロピルエチルアミン（０．４６ｇ、３．６ミリモル）をＤＭＡＰ（０．０２ｇ、０．１６ミリモル）を含むジオキサン（５．０ｍＬ）に混ぜた混合物を、アルゴン中にて室温で２時間攪拌した。残渣を５％のクエン酸（５．０ｍＬ）と酢酸エチル（２０．０ｍＬ）とに分配した。有機層を水で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、減圧下で濃縮乾燥し、残渣をジクロロメタン／ヘキサンから結晶化させて、表題化合物（０．１６ｇ、３１％）を白色粉末として得た。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．４９（ｍ，１Ｈ）、６．９３（ｍ，２Ｈ）、５．３２（ｓ，２Ｈ）、３．９６（ｓ，２Ｈ）、２．６９（ｓ，３Ｈ）、および１．５３（ｄ，６Ｈ，Ｊ＝７．２Ｈｚ）；ＥＳ−ＨＲＭＳｍ／ｚ４４５．０６８２（Ｃ_１７Ｈ_２０Ｎ_４Ｏ_３Ｆ_２Ｂｒに対するＭ＋Ｈ計算値は４４５．０６８１）。

N ~ 2- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N ~ 1-methyl Glycinamide 5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) -pyrimidin-4 (3H) -one (0.50 g, 1.15 mmol), N-methylglycinamide hydrochloride (0.21 g, 1.7 mmol), diisopropylethylamine (0.46 g, 3.6 mmol) and dioxane (5.0 mL) containing DMAP (0.02 g, 0.16 mmol) The mixture mixed with was stirred at room temperature in argon for 2 hours. The residue was partitioned between 5% citric acid (5.0 mL) and ethyl acetate (20.0 mL). The organic layer is washed with water, dried (Na ₂ SO ₄ ), concentrated to dryness under reduced pressure, and the residue is crystallized from dichloromethane / hexane to give the title compound (0.16 g, 31%) as a white powder. It was. ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.49 (m, 1H), 6.93 (m, 2H), 5.32 (s, 2H), 3.96 (s, 2H), 2.69 ( s, 3H), and 1.53 (d, 6H, J = 7.2Hz); ES-HRMSm / z445.0682 (C 17 H 20 N 4 O 3 F 2 M + H calcd for Br is 445.0681).

(Example 19)

２−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）アセトアミド
２−ヒドロキシアセトアミド（０．０８ｇ、１．１ミリモル）および５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（メチルスルホニル）−ピリミジン−４（３Ｈ）−オン（０．３０ｇ、１．６７ミリモル）のジオキサン（５．０ｍＬ）溶液に、１０℃で水素化ナトリウム（０．０４ｇ、１．６７ミリモル）を加え、アルゴン中にて室温で攪拌した。３０分後、ＤＭＡＰ（０．０１ｇ）を加え、混合物を６５℃でさらに３０分間加熱した。反応混合物を冷却し、酢酸（０．１ｍＬ）を加え、減圧下で濃縮した。得られる材料を５％のクエン酸（５．０ｍＬ）と酢酸エチル（２０．０ｍＬ）とに分配した。有機層を水で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、減圧下で濃縮乾燥し、残渣を酢酸エチルから結晶化させて、表題化合物（０．１２ｇ、４０％）を白色粉末として得た。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．４９（ｍ，１Ｈ）、６．９６（ｍ，２Ｈ）、５．３９（ｓ，２Ｈ）、５．２４（ｂｒ，１Ｈ）、４．９４（ｓ，２Ｈ）、および１．４６（ｄ，６Ｈ，Ｊ＝６．８Ｈｚ）；ＥＳ−ＨＲＭＳｍ／ｚ４３２．０３５４（Ｃ_１６Ｈ_１７Ｎ_３Ｏ_４Ｆ_２Ｂｒに対するＭ＋Ｈ計算値は４３２．０３６５）。

2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) acetamide 2-hydroxyacetamide (0 .08 g, 1.1 mmol) and 5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) -pyrimidin-4 (3H) -one (0.30 g) , 1.67 mmol) in dioxane (5.0 mL) was added sodium hydride (0.04 g, 1.67 mmol) at 10 ° C. and stirred at room temperature under argon. After 30 minutes, DMAP (0.01 g) was added and the mixture was heated at 65 ° C. for an additional 30 minutes. The reaction mixture was cooled, acetic acid (0.1 mL) was added and concentrated under reduced pressure. The resulting material was partitioned between 5% citric acid (5.0 mL) and ethyl acetate (20.0 mL). The organic layer was washed with water, dried (Na ₂ SO ₄ ), concentrated to dryness under reduced pressure, and the residue was crystallized from ethyl acetate to give the title compound (0.12 g, 40%) as a white powder. . ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.49 (m, 1H), 6.96 (m, 2H), 5.39 (s, 2H), 5.24 (br, 1H), 4.94 ( s, 2H), and 1.46 (d, 6H, J = 6.8Hz); ES-HRMSm / z432.0354 (C 16 H 17 N 3 O 4 F 2 M + H calcd for Br is 432.0365).

(Example 20)

５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−２−［（３Ｒ）−３−ヒドロキシピロリジン−１−イル］−３−イソプロピルピリミジン−４（３Ｈ）−オン
５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（メチルスルホニル）−ピリミジン−４（３Ｈ）−オン（０．４０ｇ、０．９２ミリモル）、（３Ｒ）−ピロリジン−３−オール（０．０８ｇ、０．９３ミリモル）、およびジイソプロピルエチルアミン（０．１５ｇ、１．１５ミリモル）をＤＭＡＰ（０．０２ｇ、０．１６ミリモル）を含むジオキサン（５．０ｍＬ）に混ぜた混合物を、アルゴン中にて室温で１時間かけて攪拌した。反応混合物を減圧下で濃縮し、残渣を５％のクエン酸（５．０ｍＬ）とジクロロメタン（１５．０ｍＬ）とに分配した。有機層を水で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、および減圧下で濃縮乾燥し、残渣を、酢酸エチルを溶離液として使用するシリカゲルフラッシュクロマトグラフィーによって精製して、表題化合物（０．２７ｇ、６７％）を非結晶材料として得た。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．４９（ｍ，１Ｈ）、６．９５（ｍ，２Ｈ）、５．３９（ｓ，２Ｈ）、４．４３（ｍ，２Ｈ）、３．８９（ｍ，１Ｈ）、３．７９（ｍ，１Ｈ）、３．５５（ｍ，１Ｈ）、３．３８（ｍ，１Ｈ）、１．９８（ｍ，２Ｈ）、１．６５（ｄ，３Ｈ，Ｊ＝７．２Ｈｚ）、および１．４３（ｄ，３Ｈ，Ｊ＝７．２Ｈｚ）；ＥＳ−ＨＲＭＳｍ／ｚ４４４．０７４０（Ｃ_１８Ｈ_２１Ｎ_３Ｏ_３Ｆ_２Ｂｒに対するＭ＋Ｈ計算値は４４４．０７２９）。

5-Bromo-6-[(2,4-difluorobenzyl) oxy] -2-[(3R) -3-hydroxypyrrolidin-1-yl] -3-isopropylpyrimidin-4 (3H) -one 5-bromo- 6-[(2,4-Difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) -pyrimidin-4 (3H) -one (0.40 g, 0.92 mmol), (3R) -pyrrolidine- 3-ol (0.08 g, 0.93 mmol), and diisopropylethylamine (0.15 g, 1.15 mmol) were mixed with dioxane (5.0 mL) containing DMAP (0.02 g, 0.16 mmol). The mixture was stirred for 1 hour at room temperature in argon. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between 5% citric acid (5.0 mL) and dichloromethane (15.0 mL). The organic layer is washed with water, dried (Na ₂ SO ₄ ), and concentrated to dryness under reduced pressure, and the residue is purified by flash chromatography on silica gel using ethyl acetate as the eluent to give the title compound (0. 27 g, 67%) was obtained as an amorphous material. ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.49 (m, 1H), 6.95 (m, 2H), 5.39 (s, 2H), 4.43 (m, 2H), 3.89 ( m, 1H), 3.79 (m, 1H), 3.55 (m, 1H), 3.38 (m, 1H), 1.98 (m, 2H), 1.65 (d, 3H, J = 7.2 Hz), and 1.43 (d, 3H, J = 7.2Hz); ES-HRMSm / z444.0740 (C 18 H 21 N 3 O 3 F 2 M + H calcd for Br is 444.0729) .

(Example 21)

５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−２−（４−ヒドロキシピペリジン−１−イル）−３−イソプロピルピリミジン−４（３Ｈ）−オン
表題化合物は、５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−２−［（３Ｒ）−３−ヒドロキシピロリジン−１−イル］−３−イソプロピルピリミジン−４（３Ｈ）−オンについて記載したのと同様の手順によって、（３Ｒ）−ピロリジン−３−オールの代わりに４−ヒドロキシピペリジンを用いて調製した。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．４９（ｍ，１Ｈ）、６．９５（ｍ，２Ｈ）、５．４２（ｓ，２Ｈ）、４．５３（ｍ，１Ｈ）、３．８１（ｍ，１Ｈ）、３．５２（ｍ，２Ｈ）、３．１２（ｍ，２Ｈ）、１．９６（ｍ，２Ｈ）、１．６１（ｍ，２Ｈ）、および１．５８（ｄ，６Ｈ，Ｊ＝７．２Ｈｚ）；ＥＳ−ＨＲＭＳｍ／ｚ４５８．０８４２（Ｃ_１９Ｈ_２３Ｎ_３Ｏ_３Ｆ_２Ｂｒに対するＭ＋Ｈ計算値は４５８．０８８５）。

5-Bromo-6-[(2,4-difluorobenzyl) oxy] -2- (4-hydroxypiperidin-1-yl) -3-isopropylpyrimidin-4 (3H) -one The title compound is 5-bromo- Procedure similar to that described for 6-[(2,4-difluorobenzyl) oxy] -2-[(3R) -3-hydroxypyrrolidin-1-yl] -3-isopropylpyrimidin-4 (3H) -one Was prepared using 4-hydroxypiperidine instead of (3R) -pyrrolidin-3-ol. ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.49 (m, 1H), 6.95 (m, 2H), 5.42 (s, 2H), 4.53 (m, 1H), 3.81 ( m, 1H), 3.52 (m, 2H), 3.12 (m, 2H), 1.96 (m, 2H), 1.61 (m, 2H), and 1.58 (d, 6H, J = 7.2 Hz); ES-HRMS m / z 458.0842 (calculated M + H for C ₁₉ H ₂₃ N ₃ O ₃ F ₂ Br is 458.0885).

(Example 22)

５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−２−｛［（２Ｓ）−２，３−ジヒドロキシプロピル］アミノ｝−３−イソプロピルピリミジン−４（３Ｈ）−オン
５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（メチルスルホニル）−ピリミジン−４（３Ｈ）−オン（０．５０ｇ、１．１５ミリモル）、Ｓ−１−アミノ−２−プロパノール（０．１３ｇ、１．４３ミリモル）、およびジイソプロピルエチルアミン（０．２２ｇ、１．７ミリモル）をＤＭＡＰ（０．０２ｇ、０．１６ミリモル）を含むジオキサン（５．０ｍＬ）に混ぜた混合物を、アルゴン中にて室温で１６時間攪拌した。反応混合物を減圧下で濃縮し、残渣を５％のクエン酸（５．０ｍＬ）とジクロロメタン（１５．０ｍＬ）とに分配した。有機層を水で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、減圧下で濃縮乾燥し、残渣を、１％のメタノールを含む酢酸エチルを溶離液として使用するシリカゲルフラッシュクロマトグラフィーによって精製して、表題化合物（０．１９ｇ、３７％）を非結晶材料として得た。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．４９（ｍ、１Ｈ）、６．９５（ｍ，２Ｈ）、５．４０（ｓ，２Ｈ）、４．８５（ｂｒ，１Ｈ）、３．８６（ｍ，１Ｈ）、３．６５（ｍ，１Ｈ）、３．５４（ｍ，２Ｈ）、３．３８（ｍ，１Ｈ）、および１．４８（２ｄ，６Ｈ，Ｊ＝１．６Ｈｚ）；ＥＳ−ＨＲＭＳｍ／ｚ４４８．０６５９（Ｃ_１７Ｈ_２１Ｎ_３Ｏ_４Ｆ_２Ｂｒに対するＭ＋Ｈ計算値は４４８．０６７８）。

5-bromo-6-[(2,4-difluorobenzyl) oxy] -2-{[(2S) -2,3-dihydroxypropyl] amino} -3-isopropylpyrimidin-4 (3H) -one 5-bromo -6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) -pyrimidin-4 (3H) -one (0.50 g, 1.15 mmol), S-1-amino 2-Propanol (0.13 g, 1.43 mmol) and diisopropylethylamine (0.22 g, 1.7 mmol) were mixed with dioxane (5.0 mL) containing DMAP (0.02 g, 0.16 mmol). The mixture was stirred in argon at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between 5% citric acid (5.0 mL) and dichloromethane (15.0 mL). The organic layer was washed with water, dried (Na ₂ SO ₄ ), concentrated to dryness under reduced pressure and the residue was purified by silica gel flash chromatography using ethyl acetate containing 1% methanol as eluent. The title compound (0.19 g, 37%) was obtained as an amorphous material. ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.49 (m, 1H), 6.95 (m, 2H), 5.40 (s, 2H), 4.85 (br, 1H), 3.86 ( m, 1H), 3.65 (m, 1H), 3.54 (m, 2H), 3.38 (m, 1H), and 1.48 (2d, 6H, J = 1.6 Hz); ES- _{HRMSm / z448.0659 (C 17 H 21} N 3 O 4 F 2 M + H calcd for Br is 448.0678).

(Example 23)

５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−２−｛［（２Ｒ）−２，３−ジヒドロキシプロピル］アミノ｝−３−イソプロピルピリミジン−４（３Ｈ）−オン
表題化合物は、５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−２−｛［（２Ｓ）−２，３−ジヒドロキシプロピル］アミノ｝−３−イソプロピルピリミジン−４（３Ｈ）−オンについて記載したのと同様の手順によって、Ｒ−１−アミノ−２−プロパノールの代わりにＳ−１−アミノ−２−プロパノールを用いて調製した。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．４９（ｍ，１Ｈ）、６．９５（ｍ，２Ｈ）、５．４０（ｓ，２Ｈ）、３．８３（ｍ，１Ｈ）、３．６２（ｍ，１Ｈ）、３．５４（ｍ，２Ｈ）、３．３８（ｍ，１Ｈ）、および１．４８（２ｄ，６Ｈ，Ｊ＝１．６Ｈｚ）；ＥＳ−ＨＲＭＳｍ／ｚ４４８．０７０５（Ｃ_１７Ｈ_２１Ｎ_３Ｏ_４Ｆ_２Ｂｒに対するＭ＋Ｈ計算値は４４８．０６７８）。

5-Bromo-6-[(2,4-difluorobenzyl) oxy] -2-{[(2R) -2,3-dihydroxypropyl] amino} -3-isopropylpyrimidin-4 (3H) -one The title compound is , 5-bromo-6-[(2,4-difluorobenzyl) oxy] -2-{[(2S) -2,3-dihydroxypropyl] amino} -3-isopropylpyrimidin-4 (3H) -one Prepared following the same procedure as described above, but using S-1-amino-2-propanol instead of R-1-amino-2-propanol. ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.49 (m, 1H), 6.95 (m, 2H), 5.40 (s, 2H), 3.83 (m, 1H), 3.62 ( m, 1H), 3.54 (m , 2H), 3.38 (m, 1H), and 1.48 (2d, 6H, J = 1.6Hz); ES-HRMSm / z448.0705 (C 17 H M + H calculated for ₂₁ N ₃ O ₄ F ₂ Br is 448.0678).

(Example 24)

５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−モルホリン−４−イルピリミジン−４（３Ｈ）−オン
５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（メチルスルホニル）−ピリミジン−４（３Ｈ）−オン（０．４４ｇ、１．０ミリモル）、モルホリン（０．１４ｇ、１．６ミリモル）、およびＤＭＡＰ（０．０１６ｇ）をジイソプロピルエチルアミン（０．１３ｇ、１．０ミリモル）を含むジオキサン（５．０ｍＬ）に混ぜた混合物を、窒素雰囲気中にて室温で１６時間攪拌した。反応混合物を水（１５．０ｍＬ）で希釈し、ジクロロメタン（２×１５ｍＬ）で抽出した。有機抽出物を合わせて水で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、濃縮し、残渣を、０．５％のトリフルオロ酢酸を含む１０〜９０％のＣＨ_３ＣＮ／水勾配（４５分）を流速８０ｍＬ／分で使用する逆相ＨＰＬＣによって精製した。

5-Bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2-morpholin-4-ylpyrimidin-4 (3H) -one 5-bromo-6-[(2,4-difluoro Benzyl) oxy] -3-isopropyl-2- (methylsulfonyl) -pyrimidin-4 (3H) -one (0.44 g, 1.0 mmol), morpholine (0.14 g, 1.6 mmol), and DMAP ( A mixture of 0.016 g) in dioxane (5.0 mL) containing diisopropylethylamine (0.13 g, 1.0 mmol) was stirred at room temperature for 16 hours in a nitrogen atmosphere. The reaction mixture was diluted with water (15.0 mL) and extracted with dichloromethane (2 × 15 mL). The combined organic extracts are washed with water, dried (Na ₂ SO ₄ ), concentrated, and the residue is added to a 10-90% CH ₃ CN / water gradient (45 min with 0.5% trifluoroacetic acid). ) Was purified by reverse phase HPLC using a flow rate of 80 mL / min.

Appropriate fractions (MH ⁺ , m / z = 444/446) were combined, concentrated to approximately 25 mL, 5% sodium bicarbonate (10 mL) was added, and the product was extracted with dichloromethane (2 × 15 mL). The combined organic extracts were washed with water (2 × 10 mL), dried (Na ₂ SO ₄ ) and concentrated to dryness under reduced pressure to give the title compound (0.21 g, 47%) as an off-white powder. It was. : ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.48 (m, 1H), 6.96 (m, 2H), 5.45 (s, 2H), 4.62 (m, 1H), 3.79 (m, 4H), 3.27 ( m, 4H), and 1.57 (d, 6H, J = 6.4Hz); ES-HRMSm / z444.0744 (C 18 H 21 N 3 O 3 F 2 Br The calculated M + H value for is 444.0729).

(Example 25)

５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オン
ステップ１：６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オンの調製

5-Bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one Step 1: 6-[(2,4-Difluorobenzyl) oxy] -3-isopropylpyrimidine Of -4 (3H) -one

６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（メチルチオ）ピリミジン−４（３Ｈ）−オン（０．５３ｇ、１．６２ミリモル）のエタノール（５．０ｍＬ）中混合物に、懸濁液ラネーニッケル（１．０ｍＬ）を加えた。反応混合物を２時間加熱還流した。追加のラネーニッケル（０．５ｍＬ）およびエタノール（２．５ｍＬ）を加え、加熱をさらに２時間続けた。触媒を安定させ、上清をピペットで除去した。触媒をエタノール（２×２５ｍＬ）で洗浄し、上清および有機洗液を合わせ、濃縮し、真空中で乾燥させた。得られる残渣をそれ以上精製せずに次のステップで使用した。

A mixture of 6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one (0.53 g, 1.62 mmol) in ethanol (5.0 mL). To the suspension was added Raney nickel (1.0 mL). The reaction mixture was heated to reflux for 2 hours. Additional Raney nickel (0.5 mL) and ethanol (2.5 mL) were added and heating was continued for another 2 hours. The catalyst was stabilized and the supernatant was removed with a pipette. The catalyst was washed with ethanol (2 × 25 mL) and the supernatant and organic washes were combined, concentrated and dried in vacuo. The resulting residue was used in the next step without further purification.

Step 2: Preparation of the title compound 6-[(2,4-Difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one (0.34 g, 1.2 mmol) was dissolved in DCM (3 mL). To the cooled (0 ° C.) solution, N-bromosuccinimide (0.19 g, 1.1 mmol) was added. The reaction mixture was warmed to ambient temperature. After 4 h, the reaction mixture was concentrated and the residue by preparative HPLC using a 10% to 90% of _{CH 3 CN / H 2 O (} 30 min) gradient containing 0.5% TFA at a flow rate of 80 mL / min Purified. Appropriate fractions (M + Hm / z = 360) were combined and concentrated under reduced pressure to approximately 20 mL. 5% NaHCO ₃ (20 mL) was added and extracted with dichloromethane (3 × 15 mL). The combined organic extracts were dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure and dried in vacuo to give the desired product as a white solid (0.32 g, 55%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 8.33 (s, 1H), 7.53 (q, 1H, J = 8.0 Hz), 6.95 (m, 2H), 5.48 (s, 2H) ), 4.93 (quintet, 1H, J = 6.8 Hz), 1.43 (d, 6H, J = 6.8 Hz). _{ES-HRMSm / z359.0202 (C 14} H 14 BrF 2 N 2 O M + H calcd for ₂ 359.0201).

(Example 26)

５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（メチルチオ）ピリミジン−４（３Ｈ）−オン
６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（メチルチオ）ピリミジン−４（３Ｈ）−オン（０．２０ｇ、０．６１ミリモル）をＤＣＭ（２ｍＬ）に溶かした冷却（０℃）溶液に、Ｎ−ブロモスクシンイミド（０．１１ｇ、０．６１ミリモル）を加えた。０℃で３０分間、周囲温度で４時間攪拌した。濃縮し、未精製の残渣を、０．５％のＴＦＡを含む１０〜９０％のＣＨ_３ＣＮ／Ｈ_２Ｏ（３０分）の勾配を流速８０ｍＬ／分で使用する分取ＨＰＬＣによって精製した。適切な画分（Ｍ＋Ｈｍ／ｚ＝４０６）を合わせ、減圧下で約２５ｍＬに濃縮した。５％ＮａＨＣＯ_３（２０ｍＬ）を加え、ＤＣＭ（３×１５ｍＬ）で抽出した。有機抽出物をＮａ_２ＳＯ_４で乾燥させ、濾過し、減圧下で濃縮し、真空中で乾燥させて、所望の生成物を白色固体（０．１３ｇ、５３％）として得た。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．４９（ｑ，１Ｈ，Ｊ＝８．４Ｈｚ）、６．９７（ｍ，２Ｈ）、５．５１（ｓ，２Ｈ）、４．６３（ｍ，１Ｈ）、２．５７（ｓ，３Ｈ）、１．５５（ｄ，６Ｈ，Ｊ＝６．８Ｈｚ）。ＥＳ−ＨＲＭＳｍ／ｚ４０５．００８９（Ｃ_１５Ｈ_１６ＢｒＦ_２Ｎ_２Ｏ_２Ｓに対するＭ＋Ｈ計算値は４０５．００７８）。

5-Bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one 6-[(2,4-difluorobenzyl) oxy] -3 To a cooled (0 ° C.) solution of isopropyl-2- (methylthio) pyrimidin-4 (3H) -one (0.20 g, 0.61 mmol) in DCM (2 mL) was added N-bromosuccinimide (0.11 g 0.61 mmol). Stir at 0 ° C. for 30 minutes and ambient temperature for 4 hours. Concentrated, The crude residue was purified by preparative HPLC using a gradient of 10% to 90% of _{CH 3 CN / H 2 O (} 30 minutes) containing 0.5% TFA at a flow rate of 80 mL / min. Appropriate fractions (M + Hm / z = 406) were combined and concentrated under reduced pressure to approximately 25 mL. 5% NaHCO ₃ (20 mL) was added and extracted with DCM (3 × 15 mL). The organic extract was dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure and dried in vacuo to give the desired product as a white solid (0.13 g, 53%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.49 (q, 1H, J = 8.4 Hz), 6.97 (m, 2H), 5.51 (s, 2H), 4.63 (m, 1H) ), 2.57 (s, 3H), 1.55 (d, 6H, J = 6.8 Hz). _{ES-HRMSm / z405.0089 (C 15} H 16 BrF 2 N 2 O 2 M + H calcd for S is 405.0078).

(Example 27)

５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−２−［（３Ｒ）−３−（エチルアミノ）ピロリジン−１−イル］−３−イソプロピルピリミジン−４（３Ｈ）−オン
ステップ１．（３Ｒ）−１−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イル（エチル）カルバミン酸ｔ−ブチルの調製

5-Bromo-6-[(2,4-difluorobenzyl) oxy] -2-[(3R) -3- (ethylamino) pyrrolidin-1-yl] -3-isopropylpyrimidin-4 (3H) -one step 1. (3R) -1- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidin-3-yl ( Preparation of t-butyl ethyl) carbamate

（３Ｒ）−１−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イルカルバミン酸ｔ−ブチル（０．４ｇ、０．７４ミリモル）を無水テトラヒドロフラン（４ｍＬ）に溶かした冷溶液に、ＮａＨ（０．０２６ｇ、１．１ミリモル）を加えた後、ヨウ化エタン（０．１２ｍＬ、１．５ミリモル）を加えた。反応混合物を窒素中にて室温で終夜攪拌した。その後ヨードエタン（０．０５ｍＬ、０．５当量）を加える必要があった。反応混合物を６９℃の油浴で３時間加熱した。それを冷却し、クエン酸の冷溶液（５％）で希釈し、酢酸エチルで抽出した。有機抽出物を濃縮し、残渣をアセトニトリル／水（２：１ｖ／ｖ）で処理し、０．５％のＴＦＡを含む１０〜９０％の水中アセトニトリル（３０分）の勾配を流速８０ｍＬ／分で使用する逆相ＨＰＬＣによって精製した。適切な画分（Ｍ＋Ｈｍ／ｚ＝５７１）を合わせ、凍結乾燥して、０．１８０ｇ（４３％）の（３Ｒ）−１−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イル（エチル）カルバミン酸ｔ−ブチルを白色固体として得た。^１Ｈ−ＮＭＲ（ＣＤ_３ＯＤ，４００ＭＨｚ）δ７．５１（ｑ，１Ｈ，Ｊ＝８．４Ｈｚ）、６．９６（ｍ，２Ｈ）、５．４３（ｍ，２Ｈ）、４．４３（ｍ，２Ｈ）、３．６０（ｍ，４Ｈ）、３．２７（ｍ，１Ｈ）、２．１２（ｍ，２Ｈ）、１．６７（ｄ，３Ｈ，Ｊ＝６．８Ｈｚ）、１．４６（ｍ，１２Ｈ）、１．１３（ｔ，３Ｈ，Ｊ＝６．８Ｈｚ）。ＥＳ−ＨＲＭＳｍ／ｚ５７１．１７２１（Ｍ＋Ｈ Ｃ_２５Ｈ_３４ＢｒＦ_２Ｎ_４Ｏ_４は５７１．１７２６）。

(3R) -1- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidin-3-ylcarbamine To a cold solution of t-butyl acid (0.4 g, 0.74 mmol) in anhydrous tetrahydrofuran (4 mL) was added NaH (0.026 g, 1.1 mmol) followed by ethane iodide (0.12 mL). 1.5 mmol) was added. The reaction mixture was stirred overnight at room temperature under nitrogen. It was then necessary to add iodoethane (0.05 mL, 0.5 eq). The reaction mixture was heated in a 69 ° C. oil bath for 3 hours. It was cooled, diluted with a cold solution of citric acid (5%) and extracted with ethyl acetate. The organic extract is concentrated, the residue is treated with acetonitrile / water (2: 1 v / v), and a gradient of 10-90% acetonitrile in water (30 minutes) containing 0.5% TFA at a flow rate of 80 mL / min. Purified by reverse phase HPLC used. Appropriate fractions (M + Hm / z = 571) were combined and lyophilized to give 0.180 g (43%) of (3R) -1- {5-bromo-4-[(2,4-difluorobenzyl) oxy ] 1-Isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidin-3-yl (ethyl) carbamate t-butyl was obtained as a white solid. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.51 (q, 1H, J = 8.4 Hz), 6.96 (m, 2H), 5.43 (m, 2H), 4.43 (m, 2H), 3.60 (m, 4H), 3.27 (m, 1H), 2.12 (m, 2H), 1.67 (d, 3H, J = 6.8 Hz), 1.46 (m , 12H), 1.13 (t, 3H, J = 6.8 Hz). _{ES-HRMSm / z571.1721 (M +} H C 25 H 34 BrF 2 N 4 O 4 is 571.1726).

Step 2. Preparation of the title compound (3R) -1- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidine-2-from Step 1 To a solution of t-butyl yl} pyrrolidin-3-yl (ethyl) carbamate (0.162 g, 0.28 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (0.5 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture is concentrated to remove the solvent, the residue is treated with acetonitrile / water (2: 1 v / v), and a gradient of 10-90% acetonitrile in water (30 min) containing 0.5% TFA is flowed. Purified by reverse phase HPLC using 80 mL / min. Appropriate fractions (M + Hm / z = 471) were combined and lyophilized to give 0.110 g (82%) of 5-bromo-6-[(2,4-difluorobenzyl) oxy] -2-[(3R ) -3- (Ethylamino) pyrrolidin-1-yl] -3-isopropylpyrimidin-4 (3H) -one was obtained as a white solid. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.51 (q, 1H, J = 8.4 Hz), 6.93 (m, 2H), 5.43 (s, 2H), 4.48 (m, 1H), 3.96 (m, 2H), 3.69 (m, 3H), 3.17 (m, 2H), 2.43 (m, 1H), 2.19 (m, 1H), 1. 61 (dd, 6H, J = 2.4 Hz), 1.37 (t, 3H, J = 7.2 Hz). _{ES-HRMSm / z471.1169 (M +} H C 20 H 26 BrF 2 N 4 O 4 is 471.1202).

(Example 28)

５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−［（３Ｒ）−３−（メチルアミノ）ピロリジン−１−イル］ピリミジン−４（３Ｈ）−オン
ステップ１．（３Ｒ）−１−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イル（メチル）カルバミン酸ｔ−ブチルの調製

5-Bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2-[(3R) -3- (methylamino) pyrrolidin-1-yl] pyrimidin-4 (3H) -one step 1. (3R) -1- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidin-3-yl ( Preparation of t-butyl methyl) carbamate

（３Ｒ）−１−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イルカルバミン酸ｔ−ブチル（０．４ｇ、０．７４ミリモル）を無水テトラヒドロフラン（４ｍＬ）に溶かした冷溶液に、ＮａＨ（０．０２６ｇ、１．１ミリモル）を加えた後、ヨードメタン（０．０９ｍＬ、１．５ミリモル）を加えた。反応混合物を窒素中にて室温で３時間攪拌した。その後ヨードメタン（０．０６ｍＬ、１．０当量）およびＮａＨ（０．０１３ｇ、０．５当量）を加える必要があった。反応混合物を室温で３時間攪拌し続け、次いで冷却し、クエン酸の冷溶液（５％）で処理し、酢酸エチルで抽出した。有機抽出物を濃縮し、残渣をアセトニトリル／水（２：１ｖ／ｖ）で処理し、０．５％のＴＦＡを含む１０〜９０％の水中アセトニトリル（３０分）の勾配を流速８０ｍＬ／分で使用する逆相ＨＰＬＣによって精製した。適切な画分（Ｍ＋Ｈｍ／ｚ＝５５７）を合わせ、凍結乾燥して、０．３３ｇ（８０％）の（３Ｒ）−１−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イル（メチル）カルバミン酸ｔ−ブチルを白色固体として得た。^１Ｈ−ＮＭＲ（ＣＤ_３ＯＤ，４００ＭＨｚ）δ７．５１（ｑ，１Ｈ，Ｊ＝８．４Ｈｚ）、６．９７（ｍ，２Ｈ）、５．４３（ｑ，２Ｈ）、４．６５（ｍ，１Ｈ）、４．４５（ｍ，１Ｈ）、３．６１（ｍ，４Ｈ）、２．８３（ｓ，３Ｈ）、２．１０（ｍ，２Ｈ）、１．６５（ｄ，３Ｈ，Ｊ＝６．４Ｈｚ）、１．５０（ｄ，３Ｈ，Ｊ＝６．４Ｈｚ）、１．１３（ｓ，９Ｈ）。ＥＳ−ＨＲＭＳｍ／ｚ５５７．１５２２（Ｍ＋Ｈ Ｃ_２４Ｈ_３２ＢｒＦ_２Ｎ_４Ｏ_４は５５７．１５７０）。

(3R) -1- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidin-3-ylcarbamine To a cold solution of t-butyl acid (0.4 g, 0.74 mmol) in anhydrous tetrahydrofuran (4 mL) was added NaH (0.026 g, 1.1 mmol) followed by iodomethane (0.09 mL, 1 mL). 0.5 mmol) was added. The reaction mixture was stirred at room temperature under nitrogen for 3 hours. It was then necessary to add iodomethane (0.06 mL, 1.0 equiv) and NaH (0.013 g, 0.5 equiv). The reaction mixture was kept stirring at room temperature for 3 hours, then cooled, treated with a cold solution of citric acid (5%) and extracted with ethyl acetate. The organic extract is concentrated, the residue is treated with acetonitrile / water (2: 1 v / v), and a gradient of 10-90% acetonitrile in water (30 minutes) containing 0.5% TFA at a flow rate of 80 mL / min. Purified by reverse phase HPLC used. Appropriate fractions (M + Hm / z = 557) were combined and lyophilized to give 0.33 g (80%) of (3R) -1- {5-bromo-4-[(2,4-difluorobenzyl) oxy ] 1-Isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidin-3-yl (methyl) carbamate t-butyl was obtained as a white solid. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.51 (q, 1H, J = 8.4 Hz), 6.97 (m, 2H), 5.43 (q, 2H), 4.65 (m, 1H), 4.45 (m, 1H), 3.61 (m, 4H), 2.83 (s, 3H), 2.10 (m, 2H), 1.65 (d, 3H, J = 6) .4 Hz), 1.50 (d, 3H, J = 6.4 Hz), 1.13 (s, 9H). _{ES-HRMSm / z557.1522 (M +} H C 24 H 32 BrF 2 N 4 O 4 is 557.1570).

Step 2. Preparation of the title compound (3R) -1- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidine-2-from Step 2 To a dichloromethane solution (3 mL) of t-butyl yl} pyrrolidin-3-yl (methyl) carbamate (0.30 g, 0.53 mmol) was added trifluoroacetic acid (1.0 mL). The reaction mixture was stirred at room temperature for 30 minutes. It is concentrated to remove the solvent, the residue is treated with acetonitrile / water (2: 1 v / v) and a gradient of 10-90% acetonitrile in water (30 min) containing 0.5% TFA is flowed at 80 mL. Purified by reverse phase HPLC using 1 min / min. Appropriate fractions (M + Hm / z = 457) were combined and lyophilized to give 0.20 g (81%) of 5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2. -[(3R) -3- (methylamino) pyrrolidin-1-yl] pyrimidin-4 (3H) -one was obtained as a white solid. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.51 (q, 1H, J = 8.4 Hz), 6.99 (m, 2H), 5.43 (s, 2H), 4.48 (m, 1H), 3.96 (m, 2H), 3.69 (m, 3H), 2.97 (s, 3H), 2.43 (m, 1H), 2.19 (m, 1H), 1. 62 (d, 3H, J = 6.4 Hz), 1.59 (d, 3H, J = 6.4 Hz). _{ES-HRMSm / z457.1169 (M +} H C 19 H 23 BrF 2 N 4 O 4 is 457.1202).

(Example 29)

（３Ｒ）−１−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イルカルバミン酸ピリジン−３−イルメチル
３−ヒドロキシメチルピリジン（０．０４４ｍＬ、０．４５ミリモル）の無水テトラヒドロフラン（３ｍＬ）溶液に、クロロギ酸４−ニトロフェニル（０．１０９ｇ、０．５４ミリモル）およびトリエチルアミン（０．０７５ｍＬ、０．５４ミリモル）を加えた。反応混合物を窒素中にて室温で１時間攪拌し、その時点で２−［（３Ｒ）−３−アミノピロリジン−１−イル］−５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オン（０．２０ｇ、０．４５ミリモル）を加えた。反応混合物を室温で終夜攪拌した。溶媒を濃縮し、残渣をアセトニトリル／水（２：１ｖ／ｖ）で処理し、０．５％のＴＦＡを含む１０〜９０％の水中アセトニトリル（３０分）の勾配を流速８０ｍＬ／分で使用する逆相ＨＰＬＣによって精製した。適切な画分（Ｍ＋Ｈｍ／ｚ＝５７８）を合わせ、凍結乾燥して、０．１３ｇ（４２％）の（３Ｒ）−１−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イルカルバミン酸ピリジン−３−イルメチルを白色固体として得た。^１Ｈ−ＮＭＲ（ＣＤ_３ＯＤ，４００ＭＨｚ）δ８．７６（ｓ，１Ｈ）、８．６８（ｄ，１Ｈ，Ｊ＝５．６Ｈｚ）、８．３４（ｄ，１Ｈ，Ｊ＝８Ｈｚ）、７．８６（ｄｄ，１Ｈ，Ｊ＝５．６Ｈｚ）、７．５１（ｑ，１Ｈ，Ｊ＝８．４Ｈｚ）、６．９６（ｍ，２Ｈ）、５．４０（ｓ，２Ｈ）、５．２５（ｓ，２Ｈ）、４．４３（ｍ，１Ｈ）、４．２０（ｍ，１Ｈ）、３．８０（ｍ，２Ｈ）、３．６８（ｍ，１Ｈ）、３．４４（ｍ，１Ｈ）、２．１９（ｍ，１Ｈ）、２．０２（ｍ，１Ｈ）、１．６１（ｄ，３Ｈ，Ｊ＝６．４Ｈｚ）、１．５４（ｄ，３Ｈ，Ｊ＝６．４Ｈｚ）。ＥＳ−ＨＲＭＳｍ／ｚ５７８．１２３４（Ｍ＋Ｈ Ｃ_２５Ｈ_２７ＢｒＦ_２Ｎ_５Ｏ_４は５７８．１２０９）。

(3R) -1- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidin-3-ylcarbamine Pyridin-3-ylmethyl 3-hydroxymethylpyridine (0.044 mL, 0.45 mmol) in anhydrous tetrahydrofuran (3 mL) was added 4-nitrophenyl chloroformate (0.109 g, 0.54 mmol) and triethylamine (0 0.075 mL, 0.54 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour under nitrogen at which time 2-[(3R) -3-aminopyrrolidin-1-yl] -5-bromo-6-[(2,4-difluorobenzyl) oxy ] -3-Isopropylpyrimidin-4 (3H) -one (0.20 g, 0.45 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solvent is concentrated, the residue is treated with acetonitrile / water (2: 1 v / v), and a gradient of 10-90% acetonitrile in water (30 min) containing 0.5% TFA is used at a flow rate of 80 mL / min. Purified by reverse phase HPLC. Appropriate fractions (M + Hm / z = 578) were combined and lyophilized to give 0.13 g (42%) of (3R) -1- {5-bromo-4-[(2,4-difluorobenzyl) oxy. ] -Isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidin-3-ylcarbamate pyridin-3-ylmethyl was obtained as a white solid. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.76 (s, 1 H), 8.68 (d, 1 H, J = 5.6 Hz), 8.34 (d, 1 H, J = 8 Hz), 7. 86 (dd, 1H, J = 5.6 Hz), 7.51 (q, 1H, J = 8.4 Hz), 6.96 (m, 2H), 5.40 (s, 2H), 5.25 ( s, 2H), 4.43 (m, 1H), 4.20 (m, 1H), 3.80 (m, 2H), 3.68 (m, 1H), 3.44 (m, 1H), 2.19 (m, 1H), 2.02 (m, 1H), 1.61 (d, 3H, J = 6.4 Hz), 1.54 (d, 3H, J = 6.4 Hz). _{ES-HRMSm / z578.1234 (M +} H C 25 H 27 BrF 2 N 5 O 4 is 578.1209).

(Example 30)

（３Ｒ）−１−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イルカルバミン酸ピリジン−２−イルメチル
表題化合物は、（３Ｒ）−１−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イルカルバミン酸ピリジン−３−イルメチルについて記載したものと同様の手順によって、２−ヒドロキシメチルピリジン（０．０５１ｍＬ、０．６２ミリモル）を使用して調製した。逆相ＨＰＬＣ精製の後、適切な画分を合わせ、凍結乾燥して、０．２０ｇ（４７％）の（３Ｒ）−１−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イルカルバミン酸ピリジン−２−イルメチルを白色固体として得た。^１Ｈ−ＮＭＲ（ＣＤ_３ＯＤ，４００ＭＨｚ）δ８．６０（ｄ、１Ｈ，Ｊ＝５．２Ｈｚ）、８．０８（ｍ，１Ｈ）、７．６７（ｄ，１Ｈ，Ｊ＝８Ｈｚ）、７．５２（ｍ，２Ｈ）、６．９６（ｍ，２Ｈ）、５．４０（ｓ，２Ｈ）、５．２５（ｓ，２Ｈ）、４．４２（ｍ，１Ｈ）、４．２０（ｍ，１Ｈ）、３．８０（ｍ，２Ｈ）、３．６８（ｍ，１Ｈ）、３．４９（ｍ，１Ｈ）、２．１９（ｍ，１Ｈ）、２．０２（ｍ，１Ｈ）、１．６１（ｄ，３Ｈ，Ｊ＝６．８Ｈｚ）、１．５４（ｄ，３Ｈ，Ｊ＝６．８Ｈｚ）。ＥＳ−ＨＲＭＳｍ／ｚ５７８．１２３４（Ｍ＋Ｈ Ｃ_２５Ｈ_２７ＢｒＦ_２Ｎ_５Ｏ_４は５７８．１２０９）。

(3R) -1- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidin-3-ylcarbamine Pyridin-2-ylmethyl acid The title compound is (3R) -1- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidine- Prepared using 2-hydroxymethylpyridine (0.051 mL, 0.62 mmol) by a procedure similar to that described for 2-yl} pyrrolidin-3-ylcarbamate pyridin-3-ylmethyl. After reverse phase HPLC purification, the appropriate fractions were combined and lyophilized to give 0.20 g (47%) of (3R) -1- {5-bromo-4-[(2,4-difluorobenzyl) oxy. ] -Isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidin-3-ylcarbamate pyridin-2-ylmethyl was obtained as a white solid. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 8.60 (d, 1H, J = 5.2 Hz), 8.08 (m, 1H), 7.67 (d, 1H, J = 8 Hz), 7. 52 (m, 2H), 6.96 (m, 2H), 5.40 (s, 2H), 5.25 (s, 2H), 4.42 (m, 1H), 4.20 (m, 1H) ), 3.80 (m, 2H), 3.68 (m, 1H), 3.49 (m, 1H), 2.19 (m, 1H), 2.02 (m, 1H), 1.61 (D, 3H, J = 6.8 Hz), 1.54 (d, 3H, J = 6.8 Hz). _{ES-HRMSm / z578.1234 (M +} H C 25 H 27 BrF 2 N 5 O 4 is 578.1209).

(Example 31)

５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−２−｛（３Ｒ）−３−［（２−ヒドロキシエチル）アミノ］ピロリジン−１−イル｝−３−イソプロピルピリミジン−４（３Ｈ）−オン
ステップ１．５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（（３Ｒ）−３−｛［２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エチル］アミノ｝ピロリジン−１−イル）ピリミジン−４（３Ｈ）−オンの調製

5-Bromo-6-[(2,4-difluorobenzyl) oxy] -2-{(3R) -3-[(2-hydroxyethyl) amino] pyrrolidin-1-yl} -3-isopropylpyrimidine-4 ( 3H) -one Step 1.5-Bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2-((3R) -3-{[2- (tetrahydro-2H-pyran-2) Preparation of -yloxy) ethyl] amino} pyrrolidin-1-yl) pyrimidin-4 (3H) -one

（３Ｒ）−１−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イルカルバミン酸ｔ−ブチル（０．７ｇ、１．２９ミリモル）を無水テトラヒドロフラン（７ｍＬ）に溶かした冷溶液に、ＮａＨ（０．０４６ｇ、１．９６ミリモル）を加えた後、２−（２−ブロモエトキシ）テトラヒドロ−２Ｈ−ピラン（０．２９ｍＬ、１．９６ミリモル）を加えた。反応混合物を窒素中にて６９℃の油浴で終夜加熱した。その後、２−（２−ブロモエトキシ）テトラヒドロ−２Ｈ−ピラン（０．１３ｍＬ、０．５当量）およびＮａＨ（０．０２ｇ、０．５当量）を加える必要があった。反応混合物を終夜加熱し続けた。それを冷却し、クエン酸の冷溶液（５％）で希釈し、酢酸エチルで抽出した。有機抽出物を濃縮し、残渣をアセトニトリル／水（２：１ｖ／ｖ）で処理し、０．５％のＴＦＡを含む１０〜９０％の水中アセトニトリル（３０分）の勾配を流速８０ｍＬ／分で使用する逆相ＨＰＬＣによって精製した。適切な画分（Ｍ＋Ｈｍ／ｚ＝６７１）を合わせ、凍結乾燥して、０．２９ｇ（２９％）の５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（（３Ｒ）−３−｛［２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エチル］アミノ｝ピロリジン−１−イル）ピリミジン−４（３Ｈ）−オンを得た。

(3R) -1- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidin-3-ylcarbamine To a cold solution of t-butyl acid (0.7 g, 1.29 mmol) in anhydrous tetrahydrofuran (7 mL) was added NaH (0.046 g, 1.96 mmol) followed by 2- (2-bromoethoxy). ) Tetrahydro-2H-pyran (0.29 mL, 1.96 mmol) was added. The reaction mixture was heated in a 69 ° C. oil bath overnight under nitrogen. Subsequently, 2- (2-bromoethoxy) tetrahydro-2H-pyran (0.13 mL, 0.5 eq) and NaH (0.02 g, 0.5 eq) had to be added. The reaction mixture was kept heating overnight. It was cooled, diluted with a cold solution of citric acid (5%) and extracted with ethyl acetate. The organic extract is concentrated, the residue is treated with acetonitrile / water (2: 1 v / v), and a gradient of 10-90% acetonitrile in water (30 minutes) containing 0.5% TFA at a flow rate of 80 mL / min. Purified by reverse phase HPLC used. Appropriate fractions (M + Hm / z = 671) were combined and lyophilized to give 0.29 g (29%) of 5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2. -((3R) -3-{[2- (Tetrahydro-2H-pyran-2-yloxy) ethyl] amino} pyrrolidin-1-yl) pyrimidin-4 (3H) -one was obtained.

Step 2. Preparation of the title compound 5-Bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2-((3R) -3-{[2- (tetrahydro-2H-pyran- To a dichloromethane solution of 2-yloxy) ethyl] amino} pyrrolidin-1-yl) pyrimidin-4 (3H) -one (0.29 g, 0.43 mmol) was added trifluoroacetic acid (1.0 mL). The reaction mixture was stirred at room temperature for 2.5 hours. It is treated with acetonitrile / water (2: 1 v / v) and purified by reverse-phase HPLC using a gradient of 10-90% acetonitrile in water (30 min) containing 0.5% TFA at a flow rate of 80 mL / min. did. Appropriate fractions (M + Hm / z = 487) were combined and lyophilized to give 0.040 g (19%) of 5-bromo-6-[(2,4-difluorobenzyl) oxy] -2-{(3R ) -3-[(2-hydroxyethyl) amino] pyrrolidin-1-yl} -3-isopropylpyrimidin-4 (3H) -one was obtained as a white solid. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.53 (q, 1H, J = 5.2 Hz), 7.01 (m, 2H), 5.44 (s, 2H), 4.48 (m, 1H), 3.97 (m, 2H), 3.83 (t, 2H, J = 5.2 Hz), 3.74 (m, 3H), 3.25 (m, 2H), 2.45 (m , 1H), 2.19 (m, 1H), 1.61 (d, 3H, J = 6.8 Hz), 1.54 (d, 3H, J = 6.8 Hz). _{ES-HRMSm / z487.1187 (M +} H C 20 H 26 BrF 2 N 4 O 3 is 487.1151).

(Example 32)

Ｎ^２−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−メチル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝グリシンアミド
ステップ１：米国特許第４１５２４２６号（１９７９年）に記載の６−ヒドロキシ−３−メチル−２−（メチルチオ）ピリミジン−４（３Ｈ）−オンの調製

N ^2- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl} glycinamide Step 1: US Pat. No. 4,152,426 Of 6-hydroxy-3-methyl-2- (methylthio) pyrimidin-4 (3H) -one as described in No. (1979)

ステップ２：６−（２，４−ジフルオロベンジルオキシ）−３−メチル−２−（メチルチオ）ピリミジン−４（３Ｈ）−オンの調製

Step 2: Preparation of 6- (2,4-difluorobenzyloxy) -3-methyl-2- (methylthio) pyrimidin-4 (3H) -one

ステップ１からの６−ヒドロキシ−３−メチル−２−（メチルチオ）ピリミジン−４（３Ｈ）−オン（６４ｇ、０．３７１モル）および３２５メッシュの炭酸カリウム（５２ｇ、０．３７２モル）を１７０ｍＬのＮメチルピロリジノンに懸濁させた懸濁液を５０℃に温めて、ペースト状の懸濁液を得た。臭化２，４−ジフルオロベンジル（７７ｇ、０．３７２モル）を希釈せずに２０分間かけて加えて、１０℃の発熱を可能にした（最終温度は５５〜６０℃）。懸濁液は、約１０分でより薄くより攪拌しやすくなり、有意な完了が示される。温度を５０℃に低下させ、さらに２時間保持した。混合物を周囲温度に冷却し、激しく攪拌しながら４００ｍＬの水を加えた。沈殿した固体を濾別し、２５０ｍＬの水で４回洗浄し、５０℃かつ２０ｍｍの減圧下で乾燥させた。粗生成物を、１０％のヘキサン中酢酸エチルを使用するＢｉｏｔａｇｅ７５Ｌカラムでのフラッシュクロマトグラフィーによって精製して、５０ｇ（４６％）の６−（２，４−ジフルオロベンジルオキシ）−３−メチル−２−（メチルチオ）ピリミジン−４（３Ｈ）−オンを得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ７．４０−７．３２（ｍ，１Ｈ）、６．７５−６．９（ｍ，２Ｈ）、７．１１（ｍ，１Ｈ）、５．５７（ｓ，１Ｈ）、５．２９（ｓ，２Ｈ）、３．４２（ｓ，３Ｈ）、２．５３（ｓ，３Ｈ）。

170 mL of 6-hydroxy-3-methyl-2- (methylthio) pyrimidin-4 (3H) -one (64 g, 0.371 mol) and 325 mesh potassium carbonate (52 g, 0.372 mol) from Step 1 The suspension suspended in N methylpyrrolidinone was warmed to 50 ° C. to obtain a paste-like suspension. 2,4-Difluorobenzyl bromide (77 g, 0.372 mol) was added undiluted over 20 minutes to allow an exotherm of 10 ° C. (final temperature 55-60 ° C.). The suspension becomes thinner and easier to stir in about 10 minutes, indicating significant completion. The temperature was lowered to 50 ° C. and held for another 2 hours. The mixture was cooled to ambient temperature and 400 mL of water was added with vigorous stirring. The precipitated solid was filtered off, washed 4 times with 250 mL of water and dried under reduced pressure at 50 ° C. and 20 mm. The crude product was purified by flash chromatography on a Biotage 75L column using 10% ethyl acetate in hexane to give 50 g (46%) of 6- (2,4-difluorobenzyloxy) -3-methyl-2. -(Methylthio) pyrimidin-4 (3H) -one was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40-7.32 (m, 1H), 6.75-6.9 (m, 2H), 7.11 (m, 1H), 5.57 (s, 1H), 5.29 (s, 2H), 3.42 (s, 3H), 2.53 (s, 3H).

  Step 3: Preparation of 6- (2,4-difluorobenzyloxy) -5-bromo-3-methyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one

ステップ２からの６−（２，４−ジフルオロベンジルオキシ）−３−メチル−２−（メチルチオ）ピリミジン−４（３Ｈ）−オン（４９ｇ、０．１６モル）を周囲温度に保たれた４００ｍＬの塩化メチレンに溶かした攪拌溶液に、Ｎ−ブロモスクシンイミド（２９．２ｇ、０．１６モル）を数回に分けて加えた。発熱は最小であり（２〜３℃）、反応液を２時間攪拌した。ＭＣＰＢＡ（ｍ−クロロ過安息香酸）（７３ｇ、７７％アッセイに準じて０．３２モル）を周囲温度で１時間かけて３回で加えた。発熱は依然として穏やかであり、この懸濁液を１２時間勢いよく攪拌した。反応混合物を濾過して還元された副生物の大部分を除去し、濾液を濃縮し、塩化メチレンを溶媒として使用しながら中性アルミナパッド（１５０ｇ）で濾した。乾燥させた後、５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−メチル−２−（メチルスルホニル）ピリミジン−４（３Ｈ）−オン（２９ｇ、５５％）が無色の半結晶固体として得られた。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）δ７．３９−７．４８（ｍ，１Ｈ）、６．７８−６．９２（ｍ，２Ｈ）、５．４２（ｓ，２Ｈ）、３．８３（ｓ，３Ｈ）、３．３９（ｓ，３Ｈ）。

400 mL of 6- (2,4-difluorobenzyloxy) -3-methyl-2- (methylthio) pyrimidin-4 (3H) -one (49 g, 0.16 mol) from Step 2 was kept at ambient temperature. To a stirred solution dissolved in methylene chloride, N-bromosuccinimide (29.2 g, 0.16 mol) was added in several portions. The exotherm was minimal (2-3 ° C.) and the reaction was stirred for 2 hours. MCPBA (m-chloroperbenzoic acid) (73 g, 0.32 mol according to 77% assay) was added 3 times over 1 hour at ambient temperature. The exotherm was still mild and the suspension was stirred vigorously for 12 hours. The reaction mixture was filtered to remove most of the reduced byproducts, the filtrate was concentrated and filtered through a neutral alumina pad (150 g) using methylene chloride as the solvent. After drying, 5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-methyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (29 g, 55%) was colorless. Obtained as a semi-crystalline solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.39-7.48 (m, 1H), 6.78-6.92 (m, 2H), 5.42 (s, 2H), 3.83 (s, 3H), 3.39 (s, 3H).

Step 4: Preparation of the title compound 5-Bromo-6-[(2,4-difluorobenzyl) oxy] -3-methyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (0. 5 g, 1.22 mmol) in anhydrous 1,4-dioxane (5 mL) to diisopropylethylamine (0.43 mL, 2.44 mmol), glycinamide hydrochloride (0.135 g, 1.22 mmol), and DMAP (0.03 g) was added. The reaction mixture was placed in an oil bath in nitrogen and heated at 70 ° C. for 2.5 hours. The reaction mixture was treated with acetonitrile / water (2: 1 v / v) and by reverse phase HPLC using a gradient of 10-90% acetonitrile in water (30 min) containing 0.5% TFA at a flow rate of 80 mL / min. Purified. Appropriate fractions (M + Hm / z = 403) were combined and lyophilized to give 0.066 g (13%) of N ^2- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1 -Methyl-6-oxo-1,6-dihydropyrimidin-2-yl} glycinamide was obtained as a white solid. ¹ H-NMR (CD ₃ OD, 400 MHz) δ 7.53 (q, 1H, J = 5.2 Hz), 6.96 (m, 2H), 5.39 (s, 2H), 4.04 (s, 2H), 3.44 (s, 3H). _{ES-HRMSm / z403.0198 (M +} H C 14 H 14 BrF 2 N 4 O 3 is 403.0212).

(Example 33)

Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］アセトアミド
ステップ１．６−（２，４−ジフルオロベンジルオキシ）−２−（３−アミノプロピルアミノ）−５−ブロモ−３−イソプロピルピリミジン−４（３Ｈ）−オンの調製

N- [3-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] acetamide step Preparation of 1.6- (2,4-difluorobenzyloxy) -2- (3-aminopropylamino) -5-bromo-3-isopropylpyrimidin-4 (3H) -one

６−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−３−イソプロピル−２−（メチルスルホニル）ピリミジン−４（３Ｈ）−オン（３．０ｇ、６．９ミリモル）をジクロロメタン（３０ｍＬ）に溶解させた。プロパン−１，３−ジアミン（０．６５ｍＬ、７．６ミリモル）を加えた後、トリエチルアミン（１．９ｍＬ、１３．８ミリモル）を加えた。反応液を室温で５分間攪拌した。次いで、反応液を濃縮し、残渣を酢酸エチル／水で洗浄した。水層を酢酸エチルに抽出した。有機抽出物を合わせてＭｇＳＯ_４で乾燥させ、濾過し、濃縮した。残渣をメタノールに溶解させて約１．０Ｍとし、トリフルオロ酢酸（０．４ｍＬ、５．５ミリモル）を加えて、白色固体（２．９ｇ、８０％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５２（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）１．９７（ｍ，２Ｈ）２．９４（ｍ，２Ｈ）３．５４（ｔ，Ｊ＝６．７１Ｈｚ，２Ｈ）４．７３（ｍ，１Ｈ）５．４２（ｓ，２Ｈ）６．９９（ｍ，２Ｈ）７．５３（ｍ，１Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝１．９９分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ４３３（Ｍ＋１）。

6- (2,4-Difluorobenzyloxy) -5-bromo-3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (3.0 g, 6.9 mmol) in dichloromethane (30 mL). Dissolved. Propane-1,3-diamine (0.65 mL, 7.6 mmol) was added followed by triethylamine (1.9 mL, 13.8 mmol). The reaction was stirred at room temperature for 5 minutes. The reaction was then concentrated and the residue was washed with ethyl acetate / water. The aqueous layer was extracted into ethyl acetate. The combined organic extracts were dried over MgSO ₄ , filtered and concentrated. The residue was dissolved in methanol to about 1.0 M and trifluoroacetic acid (0.4 mL, 5.5 mmol) was added to give a white solid (2.9 g, 80%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.52 (d, J = 6.98 Hz, 6H) 1.97 (m, 2H) 2.94 (m, 2H) 3.54 (t, J = 6 .71 Hz, 2H) 4.73 (m, 1H) 5.42 (s, 2H) 6.99 (m, 2H) 7.53 (m, 1H). LC / _MS, t r = 1.99 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z433 (M + 1).

Step 2. Of N- [3-({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] acetamide Preparation 6- (2,4-Difluorobenzyloxy) -2- (3-aminopropylamino) -5-bromo-3-isopropylpyrimidin-4 (3H) -one trifluoroacetate (from step 1) (0 .4 g, 0.76 mmol) was dissolved in dichloromethane (4 mL) and cooled in an ice bath. Triethylamine (0.3 mL, 2.3 mmol) was added. To the reaction mixture was added a solution of acetyl chloride (0.07 mL, 0.84 mmol) in dichloromethane (1 mL) precooled in an ice bath. Cooling was removed and the reaction mixture was allowed to warm to room temperature over 1 hour. The reaction was quenched by the addition of a solution of NaHCO ₃ . The aqueous layer was extracted into dichloromethane. The combined organic extracts were dried over MgSO ₄ , filtered and concentrated. The residue was purified by chromatography (silica gel, hexane / ethyl acetate with 10% methanol) to give a white solid (0.092 g, 26%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.53 (d, J = 6.98 Hz, 6H) 1.93 (s, 3H) 3.20 (t, J = 6.71 Hz, 2H) 3.46 (T, J = 6.71 Hz, 2H) 4.76 (m, 1H) 5.42 (s, 2H) 6.98 (m, 2H) 7.49 (m, 1H), ES-HRMS m / z 473. 0986 (M + H calculated for C ₁₉ H ₂₄ BrF ₂ N ₄ O ₃ is 473.0904).

(Example 34)

Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］尿素
Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］尿素の調製。６−（２，４−ジフルオロベンジルオキシ）−２−（３−アミノプロピルアミノ）−５−ブロモ−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸塩（実施例３３ステップ１からのもの）（０．４０ｇ、０．７６ミリモル）をジクロロメタン（４ｍＬ）に溶解させた後、室温でトリエチルアミン（０．３ｍＬ、２．３ミリモル）を加えた。反応混合物に、ジクロロメタン（１ｍＬ）中イソシアン酸トリメチルシリル（０．１ｍＬ、０．８４ミリモル）を加えた。反応混合物を室温で終夜攪拌した。次いで、得られる沈殿を濾過し、エーテルで洗浄し、真空ポンプで乾燥させて、白色固体（０．１７５ｇ、４９％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ−ｄ６）δｐｐｍ １．４３（ｄ，Ｊ＝６．７１Ｈｚ，６Ｈ）１．５７（ｍ，２Ｈ）３．００（ｍ，２Ｈ）３．３５（ｍ，２Ｈ）４．７８（ｍ，１Ｈ）５．３５（ｓ，２Ｈ）７．１２（ｍ，１Ｈ）７．２８（ｍ，１Ｈ）７．５２（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４７４．０９１８（Ｃ_１８Ｈ_２３ＢｒＦ_２Ｎ_５Ｏ_３に対するＭ＋Ｈ計算値は４７４．０９４７）。

N- [3-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] urea N Preparation of-[3-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] urea . 6- (2,4-Difluorobenzyloxy) -2- (3-aminopropylamino) -5-bromo-3-isopropylpyrimidine-4 (3H) -one trifluoroacetate (from Example 33 Step 1) ) (0.40 g, 0.76 mmol) was dissolved in dichloromethane (4 mL) and then triethylamine (0.3 mL, 2.3 mmol) was added at room temperature. To the reaction mixture was added trimethylsilyl isocyanate (0.1 mL, 0.84 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at room temperature overnight. The resulting precipitate was then filtered, washed with ether and dried with a vacuum pump to give a white solid (0.175 g, 49%). ¹ H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (d, J = 6.71 Hz, 6H) 1.57 (m, 2H) 3.00 (m, 2H) 3.35 (m, 2H) 4 .78 (m, 1H) 5.35 (s, 2H) 7.12 (m, 1H) 7.28 (m, 1H) 7.52 (m, 1H), ES-HRMS 474.0918 (C ₁₈ H ₂₃ The calculated M + H for BrF ₂ N ₅ O ₃ is 474.0947).

(Example 35)

Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］メタンスルホンアミド
Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］メタンスルホンアミドの調製
６−（２，４−ジフルオロベンジルオキシ）−２−（３−アミノプロピルアミノ）−５−ブロモ−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸塩（Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］アセトアミド、ステップ１）（０．３９９ｇ、０．７６ミリモル）および塩化メタンスルホニル（０．０６５ｍＬ、０．８３ミリモル）を利用し、Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］アセトアミド（ステップ２）のように調製して、白色固体（０．１２３ｇ、３２％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤ_３ＯＤ）δｐｐｍ １．５１（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）１．８３（ｍ，２Ｈ）２．９１（ｓ，３Ｈ）３．１１（ｔ，Ｊ＝６．７１Ｈｚ，２Ｈ）３．５４（ｔ，Ｊ＝６．７１Ｈｚ，２Ｈ）４．７４（ｍ，１Ｈ）５．４３（ｓ，２Ｈ）６．９８（ｍ，２Ｈ）７．５０（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ５０９．０６５５（Ｃ_１８Ｈ_２４ＢｒＦ_２Ｎ_４Ｏ_４Ｓに対するＭ＋Ｈ計算値は５０９．０６６４）。

N- [3-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] methanesulfone Amido N- [3-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] methane Preparation of Sulfonamide 6- (2,4-Difluorobenzyloxy) -2- (3-aminopropylamino) -5-bromo-3-isopropylpyrimidin-4 (3H) -one trifluoroacetate (N- [3 -({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) Pyll] acetamide, Step 1) (0.399 g, 0.76 mmol) and methanesulfonyl chloride (0.065 mL, 0.83 mmol) were utilized and N- [3-({5-bromo-4-[( 2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] acetamide (Step 2) and prepared as a white solid (0. 123 g, 32%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.51 (d, J = 6.98 Hz, 6H) 1.83 (m, 2H) 2.91 (s, 3H) 3.11 (t, J = 6 .71 Hz, 2H) 3.54 (t, J = 6.71 Hz, 2H) 4.74 (m, 1H) 5.43 (s, 2H) 6.98 (m, 2H) 7.50 (m, 1H) _{), ES-HRMS509.0655 (C 18} H 24 BrF 2 N 4 O 4 M + H calcd for S is 509.0664).

(Example 36)

Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］−２−ヒドロキシ−２−メチルプロパンアミド
ステップ１．酢酸２−（３−（４−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−１，６−ジヒドロ−１−イソプロピル−６−オキソピリミジン−２−イルアミノ）プロピルカルバモイル）プロパン−２−イルアセタートの調製

N- [3-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2 -Hydroxy-2-methylpropanamide Step 1. 2- (3- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) propylcarbamoyl) propan-2-yl acetate Preparation of

６−（２，４−ジフルオロベンジルオキシ）−２−（３−アミノプロピルアミノ）−５−ブロモ−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸塩（Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］アセトアミド、ステップ１）（０．３９９ｇ、０．７６ミリモル）および酢酸２−（クロロカルボニル）プロパン−２−イルアセタート（０．１４ｍＬ、０．８４ミリモル）を利用し、Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］アセトアミド（ステップ２）のように調製して、白色固体（０．２３４ｇ、５５％）を得た。ＬＣ／ＭＳ，ｔ_ｒ＝２．８９分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ５６１（Ｍ＋１）。

6- (2,4-Difluorobenzyloxy) -2- (3-aminopropylamino) -5-bromo-3-isopropylpyrimidine-4 (3H) -one trifluoroacetate (N- [3-({5 -Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] acetamide, step 1) (0.399 g, 0.7-mmol) and 2- (chlorocarbonyl) propan-2-yl acetate (0.14 mL, 0.84 mmol) acetate, and N- [3-({5-bromo-4-[(2,4 -Difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] acetamide (step 2) It was prepared to give a white solid (0.234g, 55%). LC / _MS, t r = 2.89 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z561 (M + 1).

Step 2. N- [3-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2 Preparation of 2-hydroxy-2-methylpropanamide 2- (3- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino ) Propylcarbamoyl) propan-2-yl acetate (from Step 1) (0.234 g, 0.42 mmol) was dissolved in methanol / water (3 mL) and K ₂ CO ₃ (0.087 g, 0.63 mmol) was dissolved. added. The reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was dissolved in ethyl acetate and washed with water.

The aqueous layer was neutralized with 1.0 M HCl (pH 7). The aqueous layer was extracted into ethyl acetate. The combined organic extracts were dried over MgSO ₄ , filtered and concentrated to give an off-white solid (0.193 g, 89%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.35 (s, 6H) 1.53 (d, J = 6.98 Hz, 6H) 1.76 (m, 2H) 3.25 (t, J = 6 .71 Hz, 2H) 3.46 (t, J = 6.58 Hz, 2H) 4.85 (m, 1H) 5.42 (s, 2H) 6.98 (m, 2H) 7.49 (m, 1H) _{), ES-HRMS517.1256 (C 21} H 28 BrF 2 N 4 O M + H calcd for ₄ 517.1256).

(Example 37)

Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］−２−ヒドロキシアセトアミド
ステップ１．（３−（４−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−１，６−ジヒドロ−１−イソプロピル−６−オキソピリミジン−２−イルアミノ）プロピルカルバモイル）メチルアセタートの調製

N- [3-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2 -Hydroxyacetamide Step 1. Preparation of (3- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) propylcarbamoyl) methyl acetate

６−（２，４−ジフルオロベンジルオキシ）−２−（３−アミノプロピルアミノ）−５−ブロモ−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸塩（Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］アセトアミド、ステップ１）（０．４０５ｇ、０．７７ミリモル）および酢酸（クロロカルボニル）メチル（０．０９１ｍＬ、０．８５ミリモル）を利用し、Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］アセトアミド（ステップ２）のように調製して、白色固体（０．１１２ｇ、２７％）を得た。ＬＣ／ＭＳ，ｔ_ｒ＝２．６０分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ５３３（Ｍ＋１）。

6- (2,4-Difluorobenzyloxy) -2- (3-aminopropylamino) -5-bromo-3-isopropylpyrimidine-4 (3H) -one trifluoroacetate (N- [3-({5 -Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] acetamide, step 1) (0.405 g, 0.77 mmol) and (chlorocarbonyl) methyl acetate (0.091 mL, 0.85 mmol) were used to give N- [3-({5-bromo-4-[(2,4-difluorobenzyl) oxy]. Prepared as in -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] acetamide (Step 2) to give a white solid (0 112g, 27%) was obtained. LC / _MS, t r = 2.60 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z533 (M + 1).

Step 2. N- [3-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2 Preparation of 3-hydroxyacetamide (3- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) propylcarbamoyl) methyl acetate (From step 1) (0.112 g, 0.21 mmol) and K ₂ CO ₃ (0.045 g, 0.32 mmol) were used to give N- [3-({5-bromo-4- [ (2,4-Difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2-hydroxy-2 It is prepared as methylpropanamide (step 3) to give a white solid (0.022 g, 21%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.53 (d, J = 6.98 Hz, 6H) 1.77 (m, 2H) 3.30 (t, J = 6.58 Hz, 2H) 3.47 (T, J = 6.58 Hz, 2H) 3.96 (s, 2H) 4.89 (m, 1H) 5.42 (s, 2H) 6.97 (m, 2H) 7.49 (m, 1H _{), ES-HRMS489.0934 (C 19} H 24 BrF 2 N 4 O M + H calcd for ₄ 489.0943).

(Example 38)

６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−フェニルピリミジン−４（３Ｈ）−オン
６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−フェニルピリミジン−４（３Ｈ）−オンの調製。乾いたフラスコに、６−（２，４−ジフルオロベンジルオキシ）−３−イソプロピル−２−（メチルチオ）ピリミジン−４（３Ｈ）−オン（０．１０ｇ、０．３１ミリモル）、ボロン酸フェニル（０．０６３ｇ、０．５２ミリモル）、２−ヒドロキシ−３−メチル安息香酸銅塩（０．１６ｇ、０．６８ミリモル）、およびパラジウム（０）テトラキス（トリフェニルホスフィン）（０．０３６ｇ、０．０３１ミリモル）を加え、排気した後Ｎ_２でパージした。この過程を３回繰り返した。ジオキサン（２ｍＬ）を加え、反応混合物を１５時間かけて８０℃に加熱した。反応混合物を冷却し、残渣を酢酸エチルに溶解させ、ブラインで洗浄した。水層を酢酸エチルに抽出した。有機抽出物を合わせてＭｇＳＯ_４で乾燥させ、濾過し、濃縮した。残渣をクロマトグラフィー（シリカゲル、ヘキサン／酢酸エチル）によって精製して、透明な油状物（０．０９６ｇ、８６％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤ_３ＯＤ）δｐｐｍ １．５１（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）４．３５（ｍ，１Ｈ）５．２７（ｓ，２Ｈ）５．７２（ｓ，１Ｈ）６．９８（ｓ，２Ｈ）７．５３（ｍ，６Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝３．０９分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ３５７（Ｍ＋１）。

6-[(2,4-Difluorobenzyl) oxy] -3-isopropyl-2-phenylpyrimidin-4 (3H) -one 6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2-phenyl Preparation of pyrimidin-4 (3H) -one. A dry flask was charged with 6- (2,4-difluorobenzyloxy) -3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one (0.10 g, 0.31 mmol), phenyl boronate (0 0.063 g, 0.52 mmol), 2-hydroxy-3-methylbenzoic acid copper salt (0.16 g, 0.68 mmol), and palladium (0) tetrakis (triphenylphosphine) (0.036 g, 0.031). mmol) was added and purged with N ₂ after evacuating. This process was repeated three times. Dioxane (2 mL) was added and the reaction mixture was heated to 80 ° C. for 15 hours. The reaction mixture was cooled and the residue was dissolved in ethyl acetate and washed with brine. The aqueous layer was extracted into ethyl acetate. The combined organic extracts were dried over MgSO ₄ , filtered and concentrated. The residue was purified by chromatography (silica gel, hexane / ethyl acetate) to give a clear oil (0.096 g, 86%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.51 (d, J = 6.98 Hz, 6H) 4.35 (m, 1H) 5.27 (s, 2H) 5.72 (s, 1H) 6 .98 (s, 2H) 7.53 (m, 6H). LC / _MS, t r = 3.09 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z357 (M + 1).

(Example 39)

５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−フェニルピリミジン−４（３Ｈ）−オン
５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−フェニルピリミジン−４（３Ｈ）−オンの調製。６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−フェニルピリミジン−４（３Ｈ）−オン（０．０４０ｇ、０．１１２ミリモル）をアセトニトリル（１ｍＬ）に溶解させ、氷浴で冷却した。Ｎ−ブロモスクシンイミド（０．０２２ｇ、０．１２３ミリモル）をゆっくりと加え、反応混合物を冷却しながら１時間攪拌した。反応液を濃縮し、酢酸エチルに溶解させ、次いで水で洗浄した。水層を酢酸エチルに抽出した。有機抽出物を合わせてＭｇＳＯ_４で乾燥させ、濾過し、濃縮した。残渣を３０％の酢酸エチル／ヘキサンに溶解させ、シリカゲルパッドで濾して、黄色の油（０．０４５ｇ、９２％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５３（ｄ，Ｊ＝６．７１Ｈｚ，６Ｈ）４．４０（ｍ，１Ｈ）５．４３（ｓ，２Ｈ）６．９４（ｍ，２Ｈ）７．５５（ｍ，６Ｈ），ＥＳ−ＨＲＭＳ４３５．０５３０（Ｃ_２０Ｈ_１８ＢｒＦ_２Ｎ_２Ｏ_２に対するＭ＋Ｈ計算値は４３５．０５１４）。

5-Bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2-phenylpyrimidin-4 (3H) -one 5-bromo-6-[(2,4-difluorobenzyl) oxy] Preparation of -3-isopropyl-2-phenylpyrimidin-4 (3H) -one. 6-[(2,4-Difluorobenzyl) oxy] -3-isopropyl-2-phenylpyrimidin-4 (3H) -one (0.040 g, 0.112 mmol) was dissolved in acetonitrile (1 mL) and ice bathed. It was cooled with. N-bromosuccinimide (0.022 g, 0.123 mmol) was added slowly and the reaction mixture was stirred for 1 hour with cooling. The reaction was concentrated and dissolved in ethyl acetate and then washed with water. The aqueous layer was extracted into ethyl acetate. The combined organic extracts were dried over MgSO ₄ , filtered and concentrated. The residue was dissolved in 30% ethyl acetate / hexane and filtered through a silica gel pad to give a yellow oil (0.045 g, 92%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.53 (d, J = 6.71 Hz, 6H) 4.40 (m, 1H) 5.43 (s, 2H) 6.94 (m, 2H) 7 .55 (m, 6H), ES -HRMS435.0530 (C 20 H 18 BrF 2 N 2 O 2 for M + H calculated value 435.0514).

(Example 40)

３−｛４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝安息香酸メチル
３−｛４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝安息香酸メチルの調製。ボロン酸フェニルの代わりに３−（メトキシカルボニル）フェニルボロン酸（０．９３６ｇ、５．２ミリモル）を利用し、５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−フェニルピリミジン−４（３Ｈ）−オンのように調製して、オフホワイトの固体（０．９２３ｇ、７２％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５２（ｄ，Ｊ＝６．７１Ｈｚ，６Ｈ）４．３０（ｍ，１Ｈ）４．８４（ｓ，３Ｈ）５．２８（ｓ，２Ｈ）５．７４（ｓ，１Ｈ）６．９４（ｍ，２Ｈ）７．４９（ｍ，１Ｈ）７．６８（ｔ，Ｊ＝８．０６Ｈｚ，１Ｈ）７．７８（ｄｄｄ，Ｊ＝１．３４，１．４８，７．９２Ｈｚ，１Ｈ）８．１５（ｍ，１Ｈ）８．２０（ｄｔ，Ｊ＝１．４８，７．７９Ｈｚ，１Ｈ）、ＥＳ−ＨＲＭＳ４１５．１４７０（Ｃ_２２Ｈ_２１Ｆ_２Ｎ_２Ｏ_４に対するＭ＋Ｈ計算値は４１５．１４６４）。

3- {4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} methyl benzoate 3- {4-[(2,4- Preparation of methyl difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzoate. Using 3- (methoxycarbonyl) phenylboronic acid (0.936 g, 5.2 mmol) instead of phenyl boronate, 5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl Prepared as 2-phenylpyrimidin-4 (3H) -one to give an off-white solid (0.923 g, 72%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.52 (d, J = 6.71 Hz, 6H) 4.30 (m, 1H) 4.84 (s, 3H) 5.28 (s, 2H) 5 .74 (s, 1H) 6.94 (m, 2H) 7.49 (m, 1H) 7.68 (t, J = 8.06 Hz, 1H) 7.78 (ddd, J = 1.34, 1 .48, 7.92 Hz, 1H) 8.15 (m, 1H) 8.20 (dt, J = 1.48, 7.79 Hz, 1H), ES-HRMS 415.1470 (C ₂₂ H ₂₁ F ₂ N ₂ The calculated M + H for O ₄ is 415.1464).

(Example 41)

４−｛４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ベンズアミド
４−｛４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ベンズアミドの調製。ボロン酸フェニルの代わりに４−カルバモイルフェニルボロン酸（０．２６４ｇ、１．６ミリモル）を利用し、５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−フェニルピリミジン−４（３Ｈ）−オンのように調製して、淡緑色の固体（０．２５４ｇ、６９％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５２（ｄ，Ｊ＝６．７１Ｈｚ，６Ｈ）４．２９（ｍ，１Ｈ）５．２８（ｓ，２Ｈ）５．７４（ｓ，１Ｈ）６．９６（ｍ，２Ｈ）７．４９（ｍ，１Ｈ）７．６３（ｄ，Ｊ＝８．５９Ｈｚ，２Ｈ）８．０３（ｄ，Ｊ＝８．５９Ｈｚ，２Ｈ）、ＥＳ−ＨＲＭＳ４００．１４８０（Ｃ_２１Ｈ_２０Ｆ_２Ｎ_３Ｏ_３に対するＭ＋Ｈ計算値は４００．１４６７）。

4- {4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamide 4- {4-[(2,4-difluorobenzyl ) Preparation of oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamide. Using 4-carbamoylphenylboronic acid (0.264 g, 1.6 mmol) instead of phenyl boronate, 5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2- Prepared as phenylpyrimidin-4 (3H) -one to give a pale green solid (0.254 g, 69%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.52 (d, J = 6.71 Hz, 6H) 4.29 (m, 1H) 5.28 (s, 2H) 5.74 (s, 1H) 6 .96 (m, 2H) 7.49 (m, 1H) 7.63 (d, J = 8.59 Hz, 2H) 8.03 (d, J = 8.59 Hz, 2H), ES-HRMS 400.1480 ( M + H calcd for _{C 21 H 20 F 2 N 3} O 3 is 400.1467).

(Example 41)

５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−フェニルピリミジン−４（３Ｈ）−オン
５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−フェニルピリミジン−４（３Ｈ）−オンの調製。６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−フェニルピリミジン−４（３Ｈ）−オン（０．３１８ｇ、０．８９ミリモル）をアセトニトリル（３ｍＬ）に溶解させ、氷浴で冷却した。Ｎ−クロロスクシンイミド（０．１３ｇ、０．９８ミリモル）をゆっくりと加え、反応混合物を冷却しながら１時間攪拌した。ジクロロ酢酸（触媒）を加え、反応混合物を一晩かけて室温に温めた。反応混合物を濃縮し、残渣を酢酸エチルに溶解させ、次いで水で洗浄した。水層を酢酸エチルに抽出した。有機抽出物を合わせてＭｇＳＯ_４で乾燥させ、濾過し、濃縮した。残渣をクロマトグラフィー（シリカゲル、酢酸エチル／ヘキサン）によって精製して、白色固体（０．２０４ｇ、５９％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５３（ｄ，Ｊ＝６．７１Ｈｚ，６Ｈ）４．４０（ｍ，１Ｈ）５．４４（ｓ，２Ｈ）６．９５（ｍ，２Ｈ）７．５５（ｍ，６Ｈ）、ＥＳ−ＨＲＭＳ３９１．１０３４（Ｃ_２０Ｈ_１８ＣｌＦ_２Ｎ_２Ｏ_２に対するＭ＋Ｈ計算値は３９１．１０１９）。

5-chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2-phenylpyrimidin-4 (3H) -one 5-chloro-6-[(2,4-difluorobenzyl) oxy] Preparation of -3-isopropyl-2-phenylpyrimidin-4 (3H) -one. 6-[(2,4-Difluorobenzyl) oxy] -3-isopropyl-2-phenylpyrimidin-4 (3H) -one (0.318 g, 0.89 mmol) was dissolved in acetonitrile (3 mL) and ice bathed. Cooled with. N-chlorosuccinimide (0.13 g, 0.98 mmol) was added slowly and the reaction mixture was stirred for 1 hour with cooling. Dichloroacetic acid (catalyst) was added and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and then washed with water. The aqueous layer was extracted into ethyl acetate. The combined organic extracts were dried over MgSO ₄ , filtered and concentrated. The residue was purified by chromatography (silica gel, ethyl acetate / hexane) to give a white solid (0.204 g, 59%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.53 (d, J = 6.71 Hz, 6H) 4.40 (m, 1H) 5.44 (s, 2H) 6.95 (m, 2H) 7 .55 (m, 6H), ES -HRMS391.1034 (C 20 H 18 ClF 2 N 2 O 2 for M + H calculated value 391.1019).

(Example 42)

４−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ベンズアミド
４−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−ｙｌ｝ベンズアミドの調製。４−｛４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ベンズアミド（０．１０２ｇ、０．２６ミリモル）およびＮ−クロロスクシンイミド（０．０３９ｇ，０．２９ミリモル）を利用し、５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−フェニルピリミジン−４（３Ｈ）−オンのように調製して、白色固体（０．０５１ｇ、４６％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５４（ｄ，Ｊ＝６．７１Ｈｚ，６Ｈ）４．３４（ｍ，１Ｈ）５．４４（ｓ，２Ｈ）６．９４（ｍ，２Ｈ）７．４９（ｍ，１Ｈ）７．６４（ｄ，Ｊ＝８．８６Ｈｚ，２Ｈ）８．０４（ｄ，Ｊ＝８．５９Ｈｚ，２Ｈ）、ＥＳ−ＨＲＭＳ４３４．１０５９（Ｃ_２１Ｈ_１９ＣｌＦ_２Ｎ_３Ｏ_３に対するＭ＋Ｈ計算値は４３４．１０７８）。

4- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamide 4- {5-chloro-4- Preparation of [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidine-2-yl} benzamide. 4- {4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamide (0.102 g, 0.26 mmol) and N- Chlorosuccinimide (0.039 g, 0.29 mmol) was utilized to give 5-chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2-phenylpyrimidin-4 (3H) -one. To give a white solid (0.051 g, 46%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.54 (d, J = 6.71 Hz, 6H) 4.34 (m, 1H) 5.44 (s, 2H) 6.94 (m, 2H) 7 .49 (m, 1H) 7.64 (d, J = 8.86 Hz, 2H) 8.04 (d, J = 8.59 Hz, 2H), ES-HRMS 434.159 (C ₂₁ H ₁₉ ClF ₂ N ₃ The calculated M + H value for O ₃ is 434.1078).

(Example 43)

４−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ベンズアミド
４−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−ｙｌ｝ベンズアミドの調製。４−｛４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ベンズアミド（０．０７６ｇ、０．１９ミリモル）およびＮ−ブロモスクシンイミド（０．０３８ｇ、０．２１ミリモル）を利用し、５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−フェニルピリミジン−４（３Ｈ）−オンのように調製して、淡褐色の固体（０．０６５ｇ、７４％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５４（ｄ，Ｊ＝６．７１Ｈｚ，６Ｈ）４．３４（ｍ，１Ｈ）５．４４（ｓ，２Ｈ）６．９６（ｍ，２Ｈ）７．４９（ｍ，１Ｈ）７．６５（ｄ，Ｊ＝８．５９Ｈｚ，２Ｈ）８．０５（ｄ，Ｊ＝８．５９Ｈｚ，２Ｈ）、ＥＳ−ＨＲＭＳ４７８．０５４１（Ｃ_２１Ｈ_１９ＢｒＦ_２Ｎ_３Ｏ_３に対するＭ＋Ｈ計算値は４７８．０５７２）。

4- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamide 4- {5-Bromo-4- Preparation of [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidine-2-yl} benzamide. 4- {4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamide (0.076 g, 0.19 mmol) and N- Bromosuccinimide (0.038 g, 0.21 mmol) was utilized to give 5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2-phenylpyrimidin-4 (3H) -one. To give a light brown solid (0.065 g, 74%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.54 (d, J = 6.71 Hz, 6H) 4.34 (m, 1H) 5.44 (s, 2H) 6.96 (m, 2H) 7 .49 (m, 1H) 7.65 (d, J = 8.59 Hz, 2H) 8.05 (d, J = 8.59 Hz, 2H), ES-HRMS 478.0541 (C ₂₁ H ₁₉ BrF ₂ N ₃ The calculated M + H value for O ₃ is 478.0572).

(Example 44)

３−｛４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝安息香酸
３−｛４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝安息香酸の調製。３−｛４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝安息香酸メチル（０．８７ｇ、２．１ミリモル）をテトラヒドロフラン（２０ｍＬ）に溶解させ、２．５Ｎ ＮａＯＨ（８ｍＬ、２０．０ミリモル）を加えた。反応混合物を室温で終夜を攪拌した。溶媒を除去し、１．０ＭのＨＣｌで水層を中和した（ｐＨ７）。水層を酢酸エチルに抽出した。有機抽出物を合わせてＭｇＳＯ_４で乾燥させ、濾過し、濃縮して、オフホワイトの固体（０．８４ｇ、１００％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５３（ｄ，Ｊ＝６．４４Ｈｚ，６Ｈ）４．３２（ｍ，１Ｈ）５．２９（ｓ，２Ｈ）５．７３（ｓ，１Ｈ）６．９６（ｍ，２Ｈ）７．５７（ｍ，２Ｈ）７．７２（ｍ，１Ｈ）８．１４（ｍ，２Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝２．６０分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ４０１（Ｍ＋１）。

3- {4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzoic acid 3- {4-[(2,4-difluoro Preparation of (benzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzoic acid. Methyl 3- {4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzoate (0.87 g, 2.1 mmol). Dissolve in tetrahydrofuran (20 mL) and add 2.5 N NaOH (8 mL, 20.0 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed and the aqueous layer was neutralized with 1.0 M HCl (pH 7). The aqueous layer was extracted into ethyl acetate. The combined organic extracts were dried over MgSO ₄ , filtered and concentrated to give an off-white solid (0.84 g, 100%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.53 (d, J = 6.44 Hz, 6H) 4.32 (m, 1H) 5.29 (s, 2H) 5.73 (s, 1H) 6 .96 (m, 2H) 7.57 (m, 2H) 7.72 (m, 1H) 8.14 (m, 2H). LC / _MS, t r = 2.60 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z401 (M + 1).

(Example 45)

３−｛４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ベンズアミド
３−｛４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ベンズアミドの調製。３−｛４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝安息香酸（０．８４０ｇ、２．１ミリモル）をテトラヒドロフラン（７ｍＬ）に溶解させた。２−クロロ−４，６−ジメトキシ−１，３，５−トリアジン（０．４４４ｇ、２．５ミリモル）を加えた後、４−メチルモルホリン（０．７ｍＬ、６．１ミリモル）を加えた。反応液を室温で１．５時間攪拌した。過剰の水酸化アンモニウム水溶液を加え、得られる混合物を室温で終夜攪拌した。反応液を濃縮し、残渣を酢酸エチルに溶解させ、次いで水で洗浄した。水層を酢酸エチルに抽出した。有機抽出物を合わせてＭｇＳＯ_４で乾燥させ、濾過し、濃縮した。残渣をクロマトグラフィー（シリカゲル、１０％のメタノール／ヘキサンを含む酢酸エチル）によって精製して、白色固体（０．５６ｇ、６７％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δｐｐｍ １．５３（ｄ，Ｊ＝６．７１Ｈｚ，６Ｈ）４．２６（ｍ，１Ｈ）５．１７（ｓ，２Ｈ）５．７３（ｓ，１Ｈ）６．８２（ｍ，２Ｈ）７．３９（ｍ，１Ｈ）７．５８（ｍ，２Ｈ）７．９６（ｍ，２Ｈ）、ＥＳ−ＨＲＭＳ４００．１４４４（Ｃ_２１Ｈ_２０Ｆ_２Ｎ_３Ｏ_３に対するＭ＋Ｈ計算値は４００．１４６７）。

3- {4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamide 3- {4-[(2,4-difluorobenzyl ) Preparation of oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamide. 3- {4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzoic acid (0.840 g, 2.1 mmol) in tetrahydrofuran (7 mL). 2-Chloro-4,6-dimethoxy-1,3,5-triazine (0.444 g, 2.5 mmol) was added followed by 4-methylmorpholine (0.7 mL, 6.1 mmol). The reaction was stirred at room temperature for 1.5 hours. Excess aqueous ammonium hydroxide was added and the resulting mixture was stirred at room temperature overnight. The reaction was concentrated and the residue was dissolved in ethyl acetate and then washed with water. The aqueous layer was extracted into ethyl acetate. The combined organic extracts were dried over MgSO ₄ , filtered and concentrated. The residue was purified by chromatography (silica gel, 10% methanol / hexanes in ethyl acetate) to give a white solid (0.56 g, 67%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.53 (d, J = 6.71 Hz, 6H) 4.26 (m, 1H) 5.17 (s, 2H) 5.73 (s, 1H) 82 (m, 2H) 7.39 ( m, 1H) 7.58 (m, 2H) 7.96 (m, 2H), M + H calculated for _{ES-HRMS400.1444 (C 21 H 20} F 2 N 3 O 3 The value is 400.1467).

(Example 46)

３−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ベンズアミド
３−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ベンズアミドの調製。３−｛４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ベンズアミド（０．２００ｇ、０．５０ミリモル）およびＮ−ブロモスクシンイミド（０．０９８ｇ、０．５５ミリモル）を利用し、５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−フェニルピリミジン−４（３Ｈ）−オン（ステップ２）のように調製して、白色固体（０．１８８ｇ、７９％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５５（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）４．３６（ｍ，１Ｈ）５．４４（ｓ，２Ｈ）６．９６（ｍ，２Ｈ）７．５２（ｍ，１Ｈ）７．６７（ｍ，１Ｈ）７．７４（ｍ，１Ｈ）８．０４（ｍ，１Ｈ）８．０９（ｍ，１Ｈ），ＥＳ−ＨＲＭＳ４７８．０５７３（Ｃ_２１Ｈ_１９ＢｒＦ_２Ｎ_３Ｏ_３に対するＭ＋Ｈ計算値は４７８．０５７２）。

3- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamide 3- {5-Bromo-4- Preparation of [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamide. 3- {4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamide (0.200 g, 0.50 mmol) and N- Bromosuccinimide (0.098 g, 0.55 mmol) was utilized and 5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2-phenylpyrimidin-4 (3H) -one ( Prepared as in step 2) to give a white solid (0.188 g, 79%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.55 (d, J = 6.98 Hz, 6H) 4.36 (m, 1H) 5.44 (s, 2H) 6.96 (m, 2H) 7 .52 (m, 1H) 7.67 (m, 1H) 7.74 (m, 1H) 8.04 (m, 1H) 8.09 (m, 1H), ES-HRMS 478.0573 (C ₂₁ H ₁₉ M + H calculated for BrF ₂ N ₃ O ₃ is 478.0572).

(Example 47)

３−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ベンズアミド
３−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ベンズアミドの調製。３−｛４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ベンズアミド（０．２００ｇ、０．５０ミリモル）およびＮ−クロロスクシンイミド（０．０７７ｇ、０．５５ミリモル）を利用し、５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−フェニルピリミジン−４（３Ｈ）−オンのように調製して、白色固体（０．１３３ｇ、６１％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５５（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）４．３６（ｍ，１Ｈ）５．４５（ｓ，２Ｈ）６．９６（ｍ，２Ｈ）７．５１（ｍ，１Ｈ）７．６７（ｍ，２Ｈ）８．０４（ｍ，２Ｈ）、ＥＳ−ＨＲＭＳ４３４．１０８１（Ｃ_２１Ｈ_１９ＣｌＦ_２Ｎ_３Ｏ_３に対するＭ＋Ｈ計算値は４３４．１０７８）。

3- {5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamide 3- {5-Chloro-4- Preparation of [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamide. 3- {4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamide (0.200 g, 0.50 mmol) and N- Chlorosuccinimide (0.077 g, 0.55 mmol) was utilized to give 5-chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2-phenylpyrimidin-4 (3H) -one. To give a white solid (0.133 g, 61%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.55 (d, J = 6.98 Hz, 6H) 4.36 (m, 1H) 5.45 (s, 2H) 6.96 (m, 2H) 7 .51 (m, 1H) 7.67 (m, 2H) 8.04 (m, 2H), ES-HRMS 434.1081 (calculated M + H for C ₂₁ H ₁₉ ClF ₂ N ₃ O ₃ is 434.1078).

(Example 48)

Ｎ〜３〜−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−β−アラニンアミド
ステップ１．３−（４−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−１，６−ジヒドロ−１−イソプロピル−６−オキソピリミジン−２−イルアミノ）プロパン酸エチルの調製

N-3-3- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -β-alaninamide Step 1 Preparation of ethyl 3- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) propanoate

プロパン−１，３−ジアミンの代わりに３−アミノプロパン酸エチル（０．３８８ｇ、２．５２ミリモル）を利用し、Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］アセトアミド（ステップ１）のように調製して、透明な油状物（０．４７ｇ、４３％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．２１（ｔ，Ｊ＝７．１２Ｈｚ，３Ｈ）１．５０（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）２．５９（ｔ，Ｊ＝６．７１Ｈｚ，２Ｈ）３．６９（ｔ，Ｊ＝６．８５Ｈｚ，２Ｈ）４．１１（ｑ，Ｊ＝７．２５Ｈｚ，２Ｈ）４．７９（ｍ，１Ｈ）５．４２（ｓ，２Ｈ）６．９７（ｍ，２Ｈ）７．５０（ｍ，１Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝３．０７分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ４７４（Ｍ＋１）。

Instead of propane-1,3-diamine, ethyl 3-aminopropanoate (0.388 g, 2.52 mmol) was used and N- [3-({5-bromo-4-[(2,4-difluoro Benzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] acetamide (Step 1) and prepared as a clear oil (0.47 g, 43 %). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.21 (t, J = 7.12 Hz, 3H) 1.50 (d, J = 6.98 Hz, 6H) 2.59 (t, J = 6.71 Hz) , 2H) 3.69 (t, J = 6.85 Hz, 2H) 4.11 (q, J = 7.25 Hz, 2H) 4.79 (m, 1H) 5.42 (s, 2H) 6.97 (M, 2H) 7.50 (m, 1H). LC / _MS, t r = 3.07 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z474 (M + 1).

  Step 2. Preparation of 3- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) propanoic acid

３−（４−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−１，６−ジヒドロ−１−イソプロピル−６−オキソピリミジン−２−イルアミノ）プロパン酸エチル（ステップ１から）（０．４７ｇ、０．９９ミリモル）および２．５Ｎ ＮａＯＨ（２．０ｍＬ、４．９５ミリモル）を利用し、３−｛４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝安息香酸のように調製して、オフホワイトの固体（０．１３ｇ、３０％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５０（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）２．５７（ｔ，Ｊ＝６．７１Ｈｚ，２Ｈ）３．６９（ｔ，Ｊ＝６．７１Ｈｚ，２Ｈ）４．９０（ｍ，１Ｈ）５．４３（ｓ，２Ｈ）６．９７（ｍ，２Ｈ）７．５１（ｍ，１Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝２．４９分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ４４６（Ｍ＋１）。

Ethyl 3- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) propanoate (from step 1) (0.47 g , 0.99 mmol) and 2.5N NaOH (2.0 mL, 4.95 mmol) and 3- {4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo- Prepared like 1,6-dihydropyrimidin-2-yl} benzoic acid to give an off-white solid (0.13 g, 30%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.50 (d, J = 6.98 Hz, 6H) 2.57 (t, J = 6.71 Hz, 2H) 3.69 (t, J = 6.71 Hz) , 2H) 4.90 (m, 1H) 5.43 (s, 2H) 6.97 (m, 2H) 7.51 (m, 1H). LC / _MS, t r = 2.49 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z446 (M + 1).

Step 3. Preparation of N ~ 3-{5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidine-2-yl} -β-alaninamide 3- (4- (2,4-Difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) propanoic acid (from step 2) (0. 13 g, 0.29 mmol) was dissolved in tetrahydrofuran (1 mL). 2-Chloro-4,6-dimethoxy-1,3,5-triazine (0.062 g, 0.35 mmol) was added followed by 4-methylmorpholine (0.1 mL, 0.87 mmol). The reaction was stirred at room temperature for 1.5 hours. Excess aqueous ammonium hydroxide was added and the resulting mixture was stirred at room temperature overnight. The reaction was concentrated and the residue was dissolved in ethyl acetate and then washed with water. The aqueous layer was extracted into ethyl acetate. The combined organic extracts were dried over MgSO ₄ , filtered and concentrated. The residue was purified by chromatography (silica gel, 10% methanol / hexanes in hexane) to give a white solid (0.046 g, 36%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.50 (d, J = 6.98 Hz, 6H) 2.54 (t, J = 6.58 Hz, 2H) 3.70 (t, J = 6.58 Hz) , 2H) 4.79 (m, 1H ) 5.43 (s, 2H) 6.98 (m, 2H) 7.54 (m, 1H), ES-HRMS445.0651 (C 17 H 20 BrF 2 N 4 The calculated M + H value for O ₃ is 445.0681).

(Example 49)

４−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）ブタンアミド
ステップ１．４−（４−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−１，６−ジヒドロ−１−イソプロピル−６−オキソピリミジン−２−イルアミノ）ブタン酸エチルの調製

4-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) butanamide Step 1.4- ( Preparation of ethyl 4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) butanoate

プロパン−１，３−ジアミンの代わりに４−アミノブタン酸エチル（０．４３６ｇ、２．５９ミリモル）を利用し、Ｎ〜３〜−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−β−アラニンアミド（ステップ１）のように調製して、透明な油状物（０．２９１ｇ、２５％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．２１（ｔ，Ｊ＝７．１２Ｈｚ，３Ｈ）１．５１（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）１．８８（ｍ，２Ｈ）２．３５（ｔ，Ｊ＝７．１２Ｈｚ，２Ｈ）３．４６（ｔ，Ｊ＝６．９８Ｈｚ，２Ｈ）４．０８（ｑ，Ｊ＝７．２５Ｈｚ，２Ｈ）４．７０（ｍ，１Ｈ）５．４３（ｓ，２Ｈ）６．９８（ｍ，２Ｈ）７．５０（ｍ，１Ｈ）。ＬＣ／ＭＳ、ｔ_ｒ＝３．１５分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ４８８（Ｍ＋１）。

Utilizing ethyl 4-aminobutanoate (0.436 g, 2.59 mmol) instead of propane-1,3-diamine, N-3- {5-bromo-4-[(2,4-difluorobenzyl) Oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -β-alaninamide (Step 1) prepared as a clear oil (0.291 g, 25%) Got. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.21 (t, J = 7.12 Hz, 3H) 1.51 (d, J = 6.98 Hz, 6H) 1.88 (m, 2H) 2.35 (T, J = 7.12 Hz, 2H) 3.46 (t, J = 6.98 Hz, 2H) 4.08 (q, J = 7.25 Hz, 2H) 4.70 (m, 1H) 5.43 (S, 2H) 6.98 (m, 2H) 7.50 (m, 1H). LC / _MS, t r = 3.15 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z488 (M + 1).

  Step 2. Preparation of 4- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) butanoic acid

４−（４−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−１，６−ジヒドロ−１−イソプロピル−６−オキソピリミジン−２−イルアミノ）ブタン酸エチル（ステップ１から）（０．２９１ｇ、０．６０ミリモル）および２．５Ｎ ＮａＯＨ（２．０ｍＬ、４．８ミリモル）を利用し、Ｎ〜３〜−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−β−アラニンアミド（ステップ２）のように調製して、透明な油状物（０．１６０ｇ、２５％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５１（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）１．８８（ｍ，２Ｈ）２．３３（ｔ，Ｊ＝７．１２Ｈｚ，２Ｈ）３．４７（ｔ，Ｊ＝６．９８Ｈｚ，２Ｈ）４．７２（ｍ，１Ｈ）５．４３（ｓ，２Ｈ）６．９７（ｍ，２Ｈ）７．４９（ｍ，１Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝２．５６分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ４６０（Ｍ＋１）。

4- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) butanoate (from step 1) (0.291 g , 0.60 mmol) and 2.5N NaOH (2.0 mL, 4.8 mmol) and N-3— {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1 Preparation as -Isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -β-alaninamide (Step 2) gave a clear oil (0.160 g, 25%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.51 (d, J = 6.98 Hz, 6H) 1.88 (m, 2H) 2.33 (t, J = 7.12 Hz, 2H) 3.47 (T, J = 6.98 Hz, 2H) 4.72 (m, 1H) 5.43 (s, 2H) 6.97 (m, 2H) 7.49 (m, 1H). LC / _MS, t r = 2.56 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z460 (M + 1).

Step 3.4 Preparation of 4-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) butanamide 4 -(4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) butanoic acid (from step 2) (0.160 g 0.35 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.075 g, 0.42 mmol), 4-methylmorpholine (0.115 mL, 1.05 mmol), And an excess of ammonium hydroxide, N to 3-{5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1, Prepared as 6-dihydropyrimidin-2-yl} -β-alaninamide (Step 3) to give a white solid (0.042 g, 26%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.52 (d, J = 6.98 Hz, 6H) 1.90 (m, 2H) 2.27 (t, J = 7.25 Hz, 2H) 3.47 (T, J = 6.85 Hz, 2H) 4.72 (m, 1H) 5.43 (s, 2H) 6.98 (m, 2H) 7.51 (m, 1H), ES-HRMS 459.0841 ( _{C 18 H 22 BrF 2 N 4} O 3 for M + H calculated value 459.0838).

(Example 50)

２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチルカルバミン酸ｔ−ブチル
２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチルカルバミン酸ｔ−ブチルの調製。２−ヒドロキシエチルカルバミン酸ｔ−ブチル（２．２ｍＬ、１４．０ミリモル）をジオキサン（１００ｍＬ）に溶解させ、氷浴で冷却した。反応混合物に水素化ナトリウム（０．７７０ｇ、１９．１ミリモル）を少量ずつ加えた。反応混合物を１時間かけて室温に温め、次いで氷浴で冷却し直した。反応混合物に、５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（メチルスルホニル）ピリミジン−４（３Ｈ）−オン（５．０ｇ、１２．８ミリモル）のジオキサン（３０ｍＬ）溶液をゆっくりと加えた。反応混合物を一晩かけて室温に温めた。水を加えて反応液を失活させ、溶媒を除去した。水層を酢酸エチルに抽出し、ＭｇＳＯ_４で乾燥させ、濾過し、濃縮した。残渣を５０％の酢酸エチル／ヘキサンに溶解させ、シリカゲルパッドで濾して、白色固体（４．９２ｇ、８１％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．４１（ｓ，９Ｈ）１．４５（ｄ，Ｊ＝６．７１Ｈｚ，６Ｈ）３．４９（ｍ，２Ｈ）４．５１（ｔ，Ｊ＝５．１０Ｈｚ，２Ｈ）５．２８（ｍ，１Ｈ）５．４７（ｓ，２Ｈ）６．９８（ｍ，２Ｈ）７．５３（ｍ，１Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝３．３０分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ４７４（Ｍ＋１）。

2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl carbamate t-butyl 2 Preparation of t-butyl-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethylcarbamate . T-Butyl 2-hydroxyethylcarbamate (2.2 mL, 14.0 mmol) was dissolved in dioxane (100 mL) and cooled in an ice bath. To the reaction mixture was added sodium hydride (0.770 g, 19.1 mmol) in small portions. The reaction mixture was allowed to warm to room temperature over 1 hour and then recooled with an ice bath. To the reaction mixture was added 5-chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (5.0 g, 12.8 mmol). Of dioxane (30 mL) was added slowly. The reaction mixture was warmed to room temperature overnight. Water was added to deactivate the reaction solution, and the solvent was removed. The aqueous layer was extracted into ethyl acetate, dried over MgSO ₄ , filtered and concentrated. The residue was dissolved in 50% ethyl acetate / hexane and filtered through a silica gel pad to give a white solid (4.92 g, 81%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.41 (s, 9H) 1.45 (d, J = 6.71 Hz, 6H) 3.49 (m, 2H) 4.51 (t, J = 5 .10 Hz, 2H) 5.28 (m, 1H) 5.47 (s, 2H) 6.98 (m, 2H) 7.53 (m, 1H). LC / _MS, t r = 3.30 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z474 (M + 1).

(Example 51)

２−｛［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチル］アミノ｝−２−オキソエチルアセタート
ステップ１．６−（２，４−ジフルオロベンジルオキシ）−２−（３−アミノプロポキシ）−５−クロロ−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸の調製

2-{[2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] amino } -2-Oxoethyl acetate Step 1.6- (2,4-Difluorobenzyloxy) -2- (3-aminopropoxy) -5-chloro-3-isopropylpyrimidine-4 (3H) -one trifluoroacetic acid Preparation of

２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチルカルバミン酸ｔ−ブチル（９．４ｇ、１０．４ミリモル）をジクロロメタン（１０ｍＬ）に溶解させ、トリフルオロ酢酸（１０ｍＬ）を加えた。反応混合物を室温で１時間攪拌した。次いで反応液を濃縮し、残渣を酢酸エチルに溶解させ、次いでＮａＨＣＯ_３の溶液で洗浄した。有機抽出物を合わせてＭｇＳＯ_４で乾燥させ、濾過し、濃縮して、黄色の泡沫（４．５８ｇ、９０％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．４９（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）３．４５（ｍ，２Ｈ）４．７２（ｍ，２Ｈ）５．２２（ｍ，１Ｈ）５．４８（ｓ，２Ｈ）７．０１（ｍ，２Ｈ）７．５４（ｍ，１Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝１．９４分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ３７４（Ｍ＋１）。

2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl carbamate t-butyl ( 9.4 g, 10.4 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (10 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction was then concentrated and the residue was dissolved in ethyl acetate and then washed with a solution of NaHCO ₃ . The combined organic extracts were dried over MgSO ₄ , filtered and concentrated to give a yellow foam (4.58 g, 90%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.49 (d, J = 6.98 Hz, 6H) 3.45 (m, 2H) 4.72 (m, 2H) 5.22 (m, 1H) 5 .48 (s, 2H) 7.01 (m, 2H) 7.54 (m, 1H). LC / _MS, t r = 1.94 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z374 (M + 1).

Step 2.2-{[2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) Preparation of ethyl] amino} -2-oxoethyl acetate 2-{[2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6 Using -dihydropyrimidin-2-yl} oxy) ethyl] amino} -2-oxoethyl acetate and (chlorocarbonyl) methyl acetate (0.121 mL, 1.13 mmol), N- [3-({5 -Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2-hydroxyacetate Prepared like toamide (Step 2) to give a white solid (0.326 g, 67%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.42 (d, J = 6.98 Hz, 6H) 2.12 (s, 3H) 3.74 (m, 2H) 4.51 (t, J = 5. 50 Hz, 2H) 4.57 (s, 2H) 5.36 (m, 1H) 5.39 (s, 2H) 6.83 (m, 2H) 7.44 (m, 1H). LC / _MS, t r = 2.58 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z474 (M + 1).

(Example 52)

Ｎ−［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチル］アセトアミド
Ｎ−［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチル］アセトアミドの調製。６−（２，４−ジフルオロベンジルオキシ）−２−（３−アミノプロポキシ）−５−クロロ−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸（２−｛［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチル］アミノ｝−２−オキソエチルアセタート、ステップ１からのもの）（０．４９７ｇ、１．０２ミリモル）および塩化アセチル（０．１１９ｍＬ、１．５３ミリモル）を利用し、Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］アセトアミド（ステップ２）のように調製して、淡赤色の固体（０．３１２ｇ、７４％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δｐｐｍ １．４０（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）２．０２（ｓ，３Ｈ）３．６８（ｍ，２Ｈ）４．５０（ｔ，Ｊ＝５．５０Ｈｚ，２Ｈ）５．３２（ｍ，１Ｈ）５．３８（ｓ，２Ｈ）６．８４（ｍ，２Ｈ）７．４４（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４１６．１１７５（Ｃ_１８Ｈ_２１ＣｌＦ_２Ｎ_３Ｏ_４に対するＭ＋Ｈ計算値は４１６．１１８３）。

N- [2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] acetamide N -[2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] acetamide . 6- (2,4-Difluorobenzyloxy) -2- (3-aminopropoxy) -5-chloro-3-isopropylpyrimidine-4 (3H) -one trifluoroacetic acid (2-{[2-({5- Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] amino} -2-oxoethyl acetate, step 1) (0.497 g, 1.02 mmol) and acetyl chloride (0.119 mL, 1.53 mmol) were used and N- [3-({5-bromo-4-[(2,4 -Difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] acetamide (step 2) To give a color solid (0.312g, 74%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.40 (d, J = 6.98 Hz, 6H) 2.02 (s, 3H) 3.68 (m, 2H) 4.50 (t, J = 5. 50Hz, 2H) 5.32 (m, 1H) 5.38 (s, 2H) 6.84 (m, 2H) 7.44 (m, 1H), ES-HRMS416.1175 (C 18 H 21 ClF 2 N _The calculated M + H for ₃ O ₄ is 416.1183).

(Example 53)

Ｎ−［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチル］メタンスルホンアミド
Ｎ−［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−ｙｌ｝オキシ）エチル］メタンスルホンアミドの調製。６−（２，４−ジフルオロベンジルオキシ）−２−（３−アミノプロポキシ）−５−クロロ−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸（２−｛［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチル］アミノ｝−２−オキソエチルアセタート、ステップ１からのもの）（０．５１０ｇ、１．０５ミリモル）および塩化メタンスルホニル（０．０８９ｍＬ、１．１６ミリモル）を利用し、Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］アセトアミド（ステップ２）のように調製して、白色固体（０．３６９ｇ、７８％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δｐｐｍ １．４３（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）２．９７（ｓ，３Ｈ）３．５４（ｍ，２Ｈ）４．５４（ｔ，Ｊ＝５．５０Ｈｚ，２Ｈ）５．３１（ｍ，１Ｈ）５．３９（ｓ，２Ｈ）６．８２（ｍ，２Ｈ）７．４５（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４５２．０８４６（Ｃ_１７Ｈ_２１ＣｌＦ_２Ｎ_３Ｏ_５Ｓに対するＭ＋Ｈ計算値は４５２．０８５３）。

N- [2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] methanesulfone Amido N- [2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidine-2-yl} oxy) ethyl] methane Preparation of sulfonamides. 6- (2,4-Difluorobenzyloxy) -2- (3-aminopropoxy) -5-chloro-3-isopropylpyrimidine-4 (3H) -one trifluoroacetic acid (2-{[2-({5- Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] amino} -2-oxoethyl acetate, step 1) (0.510 g, 1.05 mmol) and methanesulfonyl chloride (0.089 mL, 1.16 mmol) and N- [3-({5-bromo-4-[(2, 4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] acetamide (step 2) Te to give a white solid (0.369g, 78%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.43 (d, J = 6.98 Hz, 6H) 2.97 (s, 3H) 3.54 (m, 2H) 4.54 (t, J = 5. 50Hz, 2H) 5.31 (m, 1H) 5.39 (s, 2H) 6.82 (m, 2H) 7.45 (m, 1H), ES-HRMS452.0846 (C 17 H 21 ClF 2 N _The calculated M + H value for ₃ O ₅ S is 452.0853).

(Example 54)

２−｛［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチル］アミノ｝−１，１−ジメチル−２−オキソエチルアセタート
２−｛［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチル］アミノ｝−１，１−ジメチル−２−オキソエチルアセタートの調製。６−（２，４−ジフルオロベンジルオキシ）−２−（３−アミノプロポキシ）−５−クロロ−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸（２−｛［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチル］アミノ｝−２−オキソエチルアセタート、ステップ１からのもの）（０．５０２ｇ、１．０３ミリモル）および酢酸２−（クロロカルボニル）プロパン−２−イル（０．１８５ｍＬ、１．１３ミリモル）を利用し、Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］−２−ヒドロキシ−２−メチルプロパンアミド（ステップ２）のように調製して、白色固体（０．３６４ｇ、７１％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δｐｐｍ １．４２（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）１．６１（ｓ，６Ｈ）２．０３（ｓ，３Ｈ）３．６９（ｍ，２Ｈ）４．５０（ｔ，Ｊ＝５．３７Ｈｚ，２Ｈ）５．３４（ｍ，１Ｈ）５．３９（ｓ，２Ｈ）６．８２（ｍ，２Ｈ）７．４４（ｍ，１Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝２．８７分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ５０２（Ｍ＋１）。

2-{[2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] amino } -1,1-dimethyl-2-oxoethyl acetate 2-{[2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1, Preparation of 6-dihydropyrimidin-2-yl} oxy) ethyl] amino} -1,1-dimethyl-2-oxoethyl acetate. 6- (2,4-Difluorobenzyloxy) -2- (3-aminopropoxy) -5-chloro-3-isopropylpyrimidine-4 (3H) -one trifluoroacetic acid (2-{[2-({5- Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] amino} -2-oxoethyl acetate, step 1) (0.502 g, 1.03 mmol) and 2- (chlorocarbonyl) propan-2-yl acetate (0.185 mL, 1.13 mmol) and N- [3-({5 -Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2-hydro Be prepared as sheet-2-methylpropanamide (step 2) to give a white solid (0.364 g, 71%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.42 (d, J = 6.98 Hz, 6H) 1.61 (s, 6H) 2.03 (s, 3H) 3.69 (m, 2H) 50 (t, J = 5.37 Hz, 2H) 5.34 (m, 1H) 5.39 (s, 2H) 6.82 (m, 2H) 7.44 (m, 1H). LC / _MS, t r = 2.87 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z502 (M + 1).

(Example 55)

Ｎ−［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチル］尿素
Ｎ−［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチル］尿素の調製。６−（２，４−ジフルオロベンジルオキシ）−２−（３−アミノプロポキシ）−５−クロロ−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸（２−｛［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチル］アミノ｝−２−オキソ酢酸エチル、ステップ１からのもの）（０．５１０ｇ、１．０５ミリモル）およびイソシアン酸トリメチルシリル（０．１３２ｍＬ、１．１５ミリモル）を利用し、Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］尿素のように調製して、白色固体（０．１０５ｇ、２４％）を得た。^１Ｈ ＮＭＲ（４００ ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．４６（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）３．５５（ｔ，Ｊ＝５．３７Ｈｚ，２Ｈ）４．５３（ｔ，Ｊ＝５．３７Ｈｚ，２Ｈ）５．２９（ｍ，１Ｈ）５．４７（ｓ，２Ｈ）６．９９（ｍ，２Ｈ）７．５４（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４１７．１１４５（Ｃ_１７Ｈ_２０ＣｌＦ_２Ｎ_４Ｏ_４に対するＭ＋Ｈ計算値は４１７．１１３６）。

N- [2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] urea N -[2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] urea . 6- (2,4-Difluorobenzyloxy) -2- (3-aminopropoxy) -5-chloro-3-isopropylpyrimidine-4 (3H) -one trifluoroacetic acid (2-{[2-({5- Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] amino} -2-oxoacetate, step 1 (0.510 g, 1.05 mmol) and trimethylsilyl isocyanate (0.132 mL, 1.15 mmol) and N- [3-({5-bromo-4-[(2,4 -Difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] urea and prepared as a white solid (0. 05g, to obtain a 24%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.46 (d, J = 6.98 Hz, 6H) 3.55 (t, J = 5.37 Hz, 2H) 4.53 (t, J = 5. 37Hz, 2H) 5.29 (m, 1H) 5.47 (s, 2H) 6.99 (m, 2H) 7.54 (m, 1H), ES-HRMS417.1145 (C 17 H 20 ClF 2 N _The calculated M + H for ₄ O ₄ is 417.1136).

(Example 56)

（３Ｓ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イルカルバマート
（３Ｓ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イルカルバマートの調製。５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（メチルスルホニル）ピリミジン−４（３Ｈ）−オン（１．０ｇ、２．５５ミリモル）をジオキサン（２５ｍＬ）に溶解させた。（Ｓ）−ピロリジン−３−イルカルバミン酸ｔ−ブチル（０．５７ｇ、３．０６ミリモル）を加えた後、トリエチルアミン（０．７ｍＬ、５．１ミリモル）を加えた。得られる混合物を室温で２時間攪拌した。反応液を濃縮し、残渣を酢酸エチル／水で洗浄した。水層を酢酸エチルに抽出した。有機抽出物を合わせてＭｇＳＯ_４で乾燥させ、濾過し、濃縮した。残渣をクロマトグラフィー（シリカゲル、酢酸エチル／ヘキサン）によって精製して、オフホワイトの固体（０．８１０ｇ、６４％）を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ、ＣＤ_３ＯＤ）δｐｐｍ １．４４（ｍ，９Ｈ）１．５９（ｄｄ，Ｊ＝６．６５，１２．８９Ｈｚ，６Ｈ）１．８５（ｍ，２Ｈ）３．２１（ｍ，１Ｈ）３．４１（ｍ，１Ｈ）３．８０（ｍ，１Ｈ）４．１２（ｍ，２Ｈ）４．４４（ｍ，１Ｈ）５．４３（ｍ，２Ｈ）６．９９（ｍ，２Ｈ）７．５５（ｍ，１Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝３．３６分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ４９９（Ｍ＋１）。

(3S) -1- {5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidin-3-ylcarba Mart (3S) -1- {5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidin-3-yl Preparation of carbamate. 5-Chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (1.0 g, 2.55 mmol) was added to dioxane (25 mL). ). T-Butyl (S) -pyrrolidin-3-ylcarbamate (0.57 g, 3.06 mmol) was added followed by triethylamine (0.7 mL, 5.1 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was washed with ethyl acetate / water. The aqueous layer was extracted into ethyl acetate. The combined organic extracts were dried over MgSO ₄ , filtered and concentrated. The residue was purified by chromatography (silica gel, ethyl acetate / hexane) to give an off-white solid (0.810 g, 64%). ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 1.44 (m, 9H) 1.59 (dd, J = 6.65, 12.89 Hz, 6H) 1.85 (m, 2H) 3.21 (m , 1H) 3.41 (m, 1H) 3.80 (m, 1H) 4.12 (m, 2H) 4.44 (m, 1H) 5.43 (m, 2H) 6.99 (m, 2H) ) 7.55 (m, 1H). LC / _MS, t r = 3.36 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z499 (M + 1).

(Example 57)

（３Ｒ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イルカルバマート
（３Ｒ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イルカルバマートの調製。（Ｒ）−ピロリジン−３−イルカルバミン酸ｔ−ブチル（２．８４ｇ、１５．３ミリモル）を利用し、（３Ｓ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イルカルバマートのように調製して、オフホワイトの固体（４．１０ｇ、６４％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．４４（ｓ，９Ｈ）１．５９（ｄｄ，Ｊ＝６．７１，１７．４５Ｈｚ，６Ｈ）２．１４（ｍ，２Ｈ）３．４２（ｍ，１Ｈ）３．６０（ｍ，１Ｈ）３．７６（ｍ，２Ｈ）４．１４（ｍ，１Ｈ）４．４３（ｍ，１Ｈ）５．４２（ｓ，２Ｈ）６．９７（ｍ，２Ｈ）７．５０（ｍ，１Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝３．３６分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ４９９（Ｍ＋１）。

(3R) -1- {5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidin-3-ylcarba Mart (3R) -1- {5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidin-3-yl Preparation of carbamate. Utilizing t-butyl (R) -pyrrolidin-3-ylcarbamate (2.84 g, 15.3 mmol), (3S) -1- {5-chloro-4-[(2,4-difluorobenzyl) Oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidin-3-ylcarbamate to give an off-white solid (4.10 g, 64%). It was. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.44 (s, 9H) 1.59 (dd, J = 6.71, 17.45 Hz, 6H) 2.14 (m, 2H) 3.42 (m , 1H) 3.60 (m, 1H) 3.76 (m, 2H) 4.14 (m, 1H) 4.43 (m, 1H) 5.42 (s, 2H) 6.97 (m, 2H) ) 7.50 (m, 1H). LC / _MS, t r = 3.36 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z499 (M + 1).

(Example 58)

２−［（３Ｓ）−３−アミノピロリジン−１−イル］−５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オン
２−［（３Ｓ）−３−アミノピロリジン−１−イル］−５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オンの調製。（３Ｓ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イルカルバマート（３．４２ｇ、６．８７ミリモル）をジクロロメタン（１４ｍＬ）に溶解させ、トリフルオロ酢酸（１４ｍＬ）を加え、得られる混合物を室温で１時間攪拌した。次いで、反応液を濃縮し、一晩真空オーブンに入れて、褐色の固体（３．６５ｇ、＞１００％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．６０（ｄｄ，Ｊ＝２３．３６，６．７１Ｈｚ，６Ｈ）２．１６（ｍ，１Ｈ）２．４２（ｍ，１Ｈ）３．６６（ｍ，２Ｈ）３．９２（ｍ，３Ｈ）４．５０（ｍ，１Ｈ）５．４３（ｓ，２Ｈ）６．９８（ｍ，２Ｈ）７．５１（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ３９９．１３９０（Ｃ_１８Ｈ_２２ＣｌＦ_２Ｎ_４Ｏ_２に対するＭ＋Ｈ計算値は３９０．１３９４）。

2-[(3S) -3-Aminopyrrolidin-1-yl] -5-chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one 2-[( Preparation of 3S) -3-Aminopyrrolidin-1-yl] -5-chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one. (3S) -1- {5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidin-3-ylcarba The mart (3.42 g, 6.87 mmol) was dissolved in dichloromethane (14 mL), trifluoroacetic acid (14 mL) was added and the resulting mixture was stirred at room temperature for 1 hour. The reaction was then concentrated and placed in a vacuum oven overnight to give a brown solid (3.65 g,> 100%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.60 (dd, J = 23.36, 6.71 Hz, 6H) 2.16 (m, 1H) 2.42 (m, 1H) 3.66 (m , 2H) 3.92 (m, 3H) 4.50 (m, 1H) 5.43 (s, 2H) 6.98 (m, 2H) 7.51 (m, 1H), ES-HRMS 399.1390 ( _{C 18 H 22 ClF 2 N 4} O 2 for M + H calculated value 390.1394).

(Example 59)

２−［（３Ｒ）−３−アミノピロリジン−１−イル］−５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オン
２−［（３Ｒ）−３−アミノピロリジン−１−イル］−５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オンの調製。（３Ｒ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イルカルバマート（３．８７ｇ、７．７７ミリモル）およびトリフルオロ酢酸（１５ｍＬ）を利用し、２−［（３Ｓ）−３−アミノピロリジン−１−イル］−５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オンのように調製して、赤色の固体（３．８２ｇ、９６％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．６０（ｄｄ，Ｊ＝２２．４２，６．５８Ｈｚ，６Ｈ）２．１５（ｍ，１Ｈ）２．４４（ｍ，１Ｈ）３．６７（ｍ，２Ｈ）３．８２（ｍ，１Ｈ）３．９７（ｍ，２Ｈ）４．５０（ｓ，１Ｈ）５．４３（ｓ，２Ｈ）６．９７（ｍ，２Ｈ）７．５１（ｍ，１Ｈ），ＥＳ−ＨＲＭＳ３９９．１３９０（Ｃ_１８Ｈ_２２ＣｌＦ_２Ｎ_４Ｏ_２に対するＭ＋Ｈ計算値は３９０．１３９４）。

2-[(3R) -3-Aminopyrrolidin-1-yl] -5-chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one 2-[( Preparation of 3R) -3-aminopyrrolidin-1-yl] -5-chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one. (3R) -1- {5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidin-3-ylcarba Utilizing mart (3.87 g, 7.77 mmol) and trifluoroacetic acid (15 mL), 2-[(3S) -3-aminopyrrolidin-1-yl] -5-chloro-6-[(2,4 -Difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one to give a red solid (3.82 g, 96%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.60 (dd, J = 22.42, 6.58 Hz, 6H) 2.15 (m, 1H) 2.44 (m, 1H) 3.67 (m , 2H) 3.82 (m, 1H) 3.97 (m, 2H) 4.50 (s, 1H) 5.43 (s, 2H) 6.97 (m, 2H) 7.51 (m, 1H) _{), ES-HRMS399.1390 (C 18} H 22 ClF 2 N 4 O 2 for M + H calculated value 390.1394).

(Example 60)

Ｎ−（（３Ｓ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イル）アセトアミド
Ｎ−（（３Ｓ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イル）アセトアミドの調製。２−［（３Ｓ）−３−アミノピロリジン−１−イル］−５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オン（０．５０ｇ、０．９８ミリモル）および塩化アセチル（０．０８５ｍＬ、１．０８ミリモル）を利用し、Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］アセトアミド（ステップ２）のように調製して、黄褐色／赤色の固体（０．２７３ｇ、６３％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５９（ｄｄ，Ｊ＝６．５８，２６．４５Ｈｚ，６Ｈ）１．９４（ｍ，４Ｈ）２．１９（ｍ，１Ｈ）３．４２（ｄｄ，Ｊ＝３．７６，１０．７４Ｈｚ，１Ｈ）３．６３（ｍ，１Ｈ）３．７５（ｍ，１Ｈ）３．８５（ｄｄ，Ｊ＝５．９１，１１．０１Ｈｚ，１Ｈ）４．３７（ｍ，１Ｈ）４．４４（ｍ，１Ｈ）５．４２（ｓ，２Ｈ）６．９６（ｍ，２Ｈ）７．５０（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４４１．１４７５（Ｃ_２０Ｈ_２４ＣｌＦ_２Ｎ_４Ｏ_３に対するＭ＋Ｈ計算値は４４１．１５００）。

N-((3S) -1- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidine-3 -Yl) acetamide N-((3S) -1- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl } Preparation of pyrrolidin-3-yl) acetamide. 2-[(3S) -3-Aminopyrrolidin-1-yl] -5-chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one (0.50 g) , 0.98 mmol) and acetyl chloride (0.085 mL, 1.08 mmol) and N- [3-({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1- Prepared as isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] acetamide (Step 2) to give a tan / red solid (0.273 g, 63%). . ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.59 (dd, J = 6.58, 26.45 Hz, 6H) 1.94 (m, 4H) 2.19 (m, 1H) 3.42 (dd , J = 3.76, 10.74 Hz, 1H) 3.63 (m, 1H) 3.75 (m, 1H) 3.85 (dd, J = 5.91, 11.01 Hz, 1H) 4.37 (m, 1H) 4.44 (m , 1H) 5.42 (s, 2H) 6.96 (m, 2H) 7.50 (m, 1H), ES-HRMS441.1475 (C 20 H 24 ClF 2 M + H calculated for N ₄ O ₃ is 441.1500).

(Example 61)

Ｎ−（（３Ｒ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イル）アセトアミド
Ｎ−（（３Ｒ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イル）アセトアミドの調製。２−［（３Ｒ）−３−アミノピロリジン−１−イル］−５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オン（０．５０ｇ、０．９８ミリモル）および塩化アセチル（０．０８５ｍＬ、１．０８ミリモル）を利用し、Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］アセトアミド（ステップ２）のように調製して、黄褐色の固体（０．３００ｇ、７０％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５９（ｄｄ，Ｊ＝６．７１，２６．５８Ｈｚ，６Ｈ）１．９４（ｍ，４Ｈ）２．１９（ｍ，１Ｈ）３．４２（ｄｄ，Ｊ＝３．７６，１０．７４Ｈｚ，１Ｈ）３．６３（ｍ，１Ｈ）３．７５（ｍ，１Ｈ）３．８５（ｄｄ，Ｊ＝５．９１，１１．０１Ｈｚ，１Ｈ）４．３７（ｍ，１Ｈ）４．４３（ｍ，１Ｈ）５．４２（ｓ，２Ｈ）６．９６（ｍ，２Ｈ）７．５０（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４４１．１４６４（Ｃ_２０Ｈ_２４ＣｌＦ_２Ｎ_４Ｏ_３に対するＭ＋Ｈ計算値は４４１．１５００）。

N-((3R) -1- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidine-3 -Yl) acetamide N-((3R) -1- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl } Preparation of pyrrolidin-3-yl) acetamide. 2-[(3R) -3-Aminopyrrolidin-1-yl] -5-chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one (0.50 g) , 0.98 mmol) and acetyl chloride (0.085 mL, 1.08 mmol) to give N- [3-({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1- Prepared as isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] acetamide (Step 2) to give a tan solid (0.300 g, 70%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.59 (dd, J = 6.71, 26.58 Hz, 6H) 1.94 (m, 4H) 2.19 (m, 1H) 3.42 (dd , J = 3.76, 10.74 Hz, 1H) 3.63 (m, 1H) 3.75 (m, 1H) 3.85 (dd, J = 5.91, 11.01 Hz, 1H) 4.37 (m, 1H) 4.43 (m , 1H) 5.42 (s, 2H) 6.96 (m, 2H) 7.50 (m, 1H), ES-HRMS441.1464 (C 20 H 24 ClF 2 M + H calculated for N ₄ O ₃ is 441.1500).

(Example 62)

２−［（（３Ｓ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イル）アミノ］−２−オキソエチルアセタート
２−［（（３Ｓ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イル）アミノ］−２−オキソ酢酸エチルの調製。２−［（３Ｓ）−３−アミノピロリジン−１−イル］−５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オン（０．５０ｇ、０．９８ミリモル）および酢酸（クロロカルボニル）メチル（０．１１５ｍＬ、１．０７ミリモル）を利用し、Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］−２−ヒドロキシアセトアミド（ステップ２）のように調製して、淡黄色の固体（０．２９２ｇ、６０％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５９（ｄｄ，Ｊ＝６．７１，２０．６８Ｈｚ，６Ｈ）２．０３（ｍ，１Ｈ）２．１１（ｓ，３Ｈ）２．２１（ｍ，１Ｈ）３．４９（ｄｄ，Ｊ＝４．１６，１０．８８Ｈｚ，１Ｈ）３．６５（ｍ，１Ｈ）３．７５（ｍ，１Ｈ）３．８６（ｄｄ，Ｊ＝５．９１，１１．０１Ｈｚ，１Ｈ）４．４３（ｍ，２Ｈ）４．５３（ｓ，２Ｈ）５．４２（ｓ，２Ｈ）６．９６（ｍ，２Ｈ）７．５０（ｍ，１Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝２．６３分間（５〜９５％のアセトニトリル／水を１ｍｌ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ４９９（Ｍ＋１）。

2-[((3S) -1- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidine- 3-yl) amino] -2-oxoethyl acetate 2-[((3S) -1- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo- Preparation of ethyl 1,6-dihydropyrimidin-2-yl} pyrrolidin-3-yl) amino] -2-oxoacetate. 2-[(3S) -3-Aminopyrrolidin-1-yl] -5-chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one (0.50 g) , 0.98 mmol) and methyl (chlorocarbonyl) acetate (0.115 mL, 1.07 mmol) and N- [3-({5-bromo-4-[(2,4-difluorobenzyl) oxy] ] -Isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2-hydroxyacetamide (Step 2) to give a pale yellow solid (0.292 g, 60%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.59 (dd, J = 6.71, 20.68 Hz, 6H) 2.03 (m, 1H) 2.11 (s, 3H) 2.21 (m , 1H) 3.49 (dd, J = 4.16, 10.88 Hz, 1H) 3.65 (m, 1H) 3.75 (m, 1H) 3.86 (dd, J = 5.91, 11 .01 Hz, 1H) 4.43 (m, 2H) 4.53 (s, 2H) 5.42 (s, 2H) 6.96 (m, 2H) 7.50 (m, 1H). LC / _MS, t r = 2.63 minutes (5 min 5-95% acetonitrile / water at 1 ml / min, 254nm, 50 ℃), ES -MSm / z499 (M + 1).

(Example 63)

２−［（（３Ｒ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イル）アミノ］−２−オキソエチルアセタート
２−［（（３Ｒ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イル）アミノ］−２−オキソエチルアセタートの調製。２−［（３Ｒ）−３−アミノピロリジン−１−イル］−５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オン（０．５０ｇ、０．９８ミリモル）および酢酸（クロロカルボニル）メチル（０．１１５ｍＬ、１．０７ミリモル）を利用し、Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］−２−ヒドロキシアセトアミド（ステップ２）のように調製して、淡黄色の固体（０．２７９ｇ、５７％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５９（ｄｄ，Ｊ＝６．５８，２０．８１Ｈｚ，６Ｈ）２．０２（ｍ，１Ｈ）２．１１（ｓ，３Ｈ）２．２１（ｍ，１Ｈ）３．４９（ｄｄ，Ｊ＝４．１６，１０．８８Ｈｚ，１Ｈ）３．６５（ｍ，１Ｈ）３．７５（ｍ，１Ｈ）３．８６（ｄｄ，Ｊ＝５．９１，１１．０１Ｈｚ，１Ｈ）４．４４（ｍ，２Ｈ）４．５３（ｓ，２Ｈ）５．４２（ｓ，２Ｈ）６．９６（ｍ，２Ｈ）７．５０（ｍ，１Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝２．６３分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ４９９（Ｍ＋１）。

2-[((3R) -1- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidine- 3-yl) amino] -2-oxoethyl acetate 2-[((3R) -1- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo- Preparation of 1,6-dihydropyrimidin-2-yl} pyrrolidin-3-yl) amino] -2-oxoethyl acetate. 2-[(3R) -3-Aminopyrrolidin-1-yl] -5-chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one (0.50 g) , 0.98 mmol) and methyl (chlorocarbonyl) acetate (0.115 mL, 1.07 mmol) and N- [3-({5-bromo-4-[(2,4-difluorobenzyl) oxy] ] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2-hydroxyacetamide (Step 2) to give a pale yellow solid (0.279 g, 57%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.59 (dd, J = 6.58, 20.81 Hz, 6H) 2.02 (m, 1H) 2.11 (s, 3H) 2.21 (m , 1H) 3.49 (dd, J = 4.16, 10.88 Hz, 1H) 3.65 (m, 1H) 3.75 (m, 1H) 3.86 (dd, J = 5.91, 11 .01 Hz, 1H) 4.44 (m, 2H) 4.53 (s, 2H) 5.42 (s, 2H) 6.96 (m, 2H) 7.50 (m, 1H). LC / _MS, t r = 2.63 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z499 (M + 1).

(Example 64)

２−［（（３Ｓ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イル）アミノ］−１，１−ジメチル−２−オキソエチルアセタート
２−［（（３Ｓ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イル）アミノ］−１，１−ジメチル−２−オキソエチルアセタートの調製。２−［（３Ｓ）−３−アミノピロリジン−１−イル］−５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オン（０．５０ｇ、０．９８ミリモル）および酢酸２−（クロロカルボニル）プロパン−２−イル（０．１８ｍＬ、１．０７ミリモル）を利用し、Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］−２−ヒドロキシ−２−メチルプロパンアミド（ステップ２）のように調製して、白色固体（０．３５４ｇ、６９％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５９（ｄｄ，Ｊ＝６．７１，３０．８８Ｈｚ，６Ｈ）１．６３（ｄ，Ｊ＝６．７１Ｈｚ，３Ｈ）１．９８（ｓ，３Ｈ）２．１０（ｍ，２Ｈ）３．５１（ｍ，２Ｈ）３．７８（ｍ，２Ｈ）４．３８（ｍ，２Ｈ）５．４２（ｓ，２Ｈ）６．９８（ｍ，２Ｈ）７．５１（ｍ，１Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝２．８７分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ５２７（Ｍ＋１）。

2-[((3S) -1- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidine- 3-yl) amino] -1,1-dimethyl-2-oxoethyl acetate 2-[((3S) -1- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1- Preparation of isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidin-3-yl) amino] -1,1-dimethyl-2-oxoethyl acetate. 2-[(3S) -3-Aminopyrrolidin-1-yl] -5-chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one (0.50 g) , 0.98 mmol) and 2- (chlorocarbonyl) propan-2-yl acetate (0.18 mL, 1.07 mmol) using N- [3-({5-bromo-4-[(2, 4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2-hydroxy-2-methylpropanamide (step 2) To give a white solid (0.354 g, 69%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.59 (dd, J = 6.71, 30.88 Hz, 6H) 1.63 (d, J = 6.71 Hz, 3H) 1.98 (s, 3H 2.10 (m, 2H) 3.51 (m, 2H) 3.78 (m, 2H) 4.38 (m, 2H) 5.42 (s, 2H) 6.98 (m, 2H) 7 .51 (m, 1H). LC / _MS, t r = 2.87 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z527 (M + 1).

(Example 65)

２−［（（３Ｒ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イル）アミノ］−１，１−ジメチル−２−オキソエチルアセタート
２−［（（３Ｒ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イル）アミノ］−１，１−ジメチル−２−オキソエチルアセタートの調製。２−［（３Ｒ）−３−アミノピロリジン−１−イル］−５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オン（０．５０ｇ、０．９８ミリモル）および酢酸２−（クロロカルボニル）プロパン−２−イル（０．１８ｍＬ、１．０７ミリモル）を利用し、Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］−２−ヒドロキシ−２−メチルプロパンアミド（ステップ２）のように調製して、白色固体（０．４０５ｇ、７９％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５９（ｄｄ，Ｊ＝６．５８，３１．０２Ｈｚ，６Ｈ）１．６３（ｄ，Ｊ＝６．７１Ｈｚ，３Ｈ）１．９８（ｓ，３Ｈ）２．００（ｍ，２Ｈ）３．５３（ｍ，２Ｈ）３．７７（ｍ，２Ｈ）４．４１（ｍ，２Ｈ）５．４２（ｓ，２Ｈ）６．９７（ｍ，２Ｈ）７．５１（ｍ，１Ｈ）。ＬＣ／ＭＳ、ｔ_ｒ＝２．８６分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ５２７（Ｍ＋１）。

2-[((3R) -1- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidine- 3-yl) amino] -1,1-dimethyl-2-oxoethyl acetate 2-[((3R) -1- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1- Preparation of isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidin-3-yl) amino] -1,1-dimethyl-2-oxoethyl acetate. 2-[(3R) -3-Aminopyrrolidin-1-yl] -5-chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one (0.50 g) , 0.98 mmol) and 2- (chlorocarbonyl) propan-2-yl acetate (0.18 mL, 1.07 mmol) using N- [3-({5-bromo-4-[(2, 4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2-hydroxy-2-methylpropanamide (step 2) To give a white solid (0.405 g, 79%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.59 (dd, J = 6.58, 31.02 Hz, 6H) 1.63 (d, J = 6.71 Hz, 3H) 1.98 (s, 3H ) 2.00 (m, 2H) 3.53 (m, 2H) 3.77 (m, 2H) 4.41 (m, 2H) 5.42 (s, 2H) 6.97 (m, 2H) 7 .51 (m, 1H). LC / _MS, t r = 2.86 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z527 (M + 1).

Example 66

Ｎ−（（３Ｓ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イル）−２−ヒドロキシアセトアミド
Ｎ−（（３Ｓ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イル）−２−ヒドロキシアセトアミドの調製。（０．２２８ｇ、０．４６ミリモル）およびＫ_２ＣＯ_３（０．０９５ｇ、０．６９ミリモル）を利用し、Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］−２−ヒドロキシアセトアミド（ステップ３）のように調製して、白色固体（０．１８３ｇ、８７％）を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５９（ｄ，Ｊ＝６．６５Ｈｚ，６Ｈ）２．１０（ｍ，２Ｈ）３．６９（ｍ，４Ｈ）３．９９（ｄ，Ｊ＝１．２１Ｈｚ，２Ｈ）４．４６（ｍ，２Ｈ）５．４３（ｓ，２Ｈ）６．９７（ｍ，２Ｈ）７．５２（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４５７．１４０４（Ｃ_２０Ｈ_２４ＣｌＦ_２Ｎ_４Ｏ_４に対するＭ＋Ｈ計算値は４５７．１４４９）。

N-((3S) -1- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidine-3 -Yl) -2-hydroxyacetamide N-((3S) -1- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidine Preparation of 2-yl} pyrrolidin-3-yl) -2-hydroxyacetamide. (0.228 g, 0.46 mmol) and _K 2 _CO 3 (0.095g, 0.69 mmol) using, N- [3 - ({5- bromo-4 - [(2,4-difluorobenzyl )] Oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2-hydroxyacetamide (Step 3) to give a white solid (0.183 g, 87%). ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 1.59 (d, J = 6.65 Hz, 6H) 2.10 (m, 2H) 3.69 (m, 4H) 3.99 (d, J = 1) .21Hz, 2H) 4.46 (m, 2H) 5.43 (s, 2H) 6.97 (m, 2H) 7.52 (m, 1H), ES-HRMS457.1404 (C 20 H 24 ClF 2 Calculated M + H for N ₄ O ₄ is 457.1449).

(Example 67)

Ｎ−（（３Ｒ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イル）−２−ヒドロキシアセトアミド
Ｎ−（（３Ｒ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イル）−２−ヒドロキシアセトアミドの調製。２−［（（３Ｒ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イル）アミノ］−２−オキソエチルアセタート（０．２１７ｇ、０．４４ミリモル）およびＫ_２ＣＯ_３（０．０９０ｇ、０．６５ミリモル）を利用し、Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］−２−ヒドロキシアセトアミド（ステップ３）のように調製して、白色固体（０．１９４ｇ、９７％）を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５９（ｄ，Ｊ＝６．６５Ｈｚ，６Ｈ）２．２２（ｓ，２Ｈ）３．７３（ｍ，４Ｈ）３．９８（ｓ，２Ｈ）４．４６（ｍ，２Ｈ）５．４３（ｓ，２Ｈ）６．９８（ｍ，２Ｈ）７．５１（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４５７．１４５４（Ｃ_２０Ｈ_２４ＣｌＦ_２Ｎ_４Ｏ_４に対するＭ＋Ｈ計算値は４５７．１４４９）。

N-((3R) -1- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidine-3 -Yl) -2-hydroxyacetamide N-((3R) -1- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidine Preparation of 2-yl} pyrrolidin-3-yl) -2-hydroxyacetamide. 2-[((3R) -1- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidine- Utilizing 3-yl) amino] -2-oxoethyl acetate (0.217 g, 0.44 mmol) and K ₂ CO ₃ (0.090 g, 0.65 mmol), N- [3-({5 -Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2-hydroxyacetamide (step 3) To give a white solid (0.194 g, 97%). ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 1.59 (d, J = 6.65 Hz, 6H) 2.22 (s, 2H) 3.73 (m, 4H) 3.98 (s, 2H) 4 .46 (m, 2H) 5.43 ( s, 2H) 6.98 (m, 2H) 7.51 (m, 1H), ES-HRMS457.1454 (C 20 H 24 ClF 2 N 4 against _{O 4} M + H The calculated value is 457.1449).

(Example 68)

Ｎ−（（３Ｓ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イル）−２−ヒドロキシ−２−メチルプロパンアミド
Ｎ−（（３Ｓ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イル）−２−ヒドロキシ−２−メチルプロパンアミドの調製。２−［（（３Ｓ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イル）アミノ］−１，１−ジメチル−２−オキソエチルアセタート（０．３０４ｇ、０．５８ミリモル）およびＫ_２ＣＯ_３（０．１２０ｇ、０．８７ミリモル）を利用し、Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］−２−ヒドロキシアセトアミド（ステップ３）のように調製して、白色固体（０．２０６ｇ、７３％）を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．３５（ｓ，３Ｈ）１．３６（ｓ，３Ｈ）１．５９（ｄｄ，Ｊ＝３．５２，６．５４Ｈｚ，６Ｈ）２．００（ｍ，２Ｈ）３．６９（ｍ，４Ｈ）４．４７（ｍ，２Ｈ）５．４４（ｓ，２Ｈ）６．９８（ｍ，２Ｈ）７．５１（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４８５．１７２３（Ｃ_２２Ｈ_２８ＣｌＦ_２Ｎ_４Ｏ_４に対するＭ＋Ｈ計算値は４８５．１７６２）。

N-((3S) -1- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidine-3 -Yl) -2-hydroxy-2-methylpropanamide N-((3S) -1- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1 , 6-Dihydropyrimidin-2-yl} pyrrolidin-3-yl) -2-hydroxy-2-methylpropanamide. 2-[((3S) -1- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidine- 3-yl) amino] -1,1-dimethyl-2-oxoethyl acetate (0.304 g, 0.58 mmol) and K ₂ CO ₃ (0.120 g, 0.87 mmol) were used to give N— [3-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2-hydroxy Prepared as acetamide (step 3) to give a white solid (0.206 g, 73%). ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 1.35 (s, 3H) 1.36 (s, 3H) 1.59 (dd, J = 3.52, 6.54 Hz, 6H) 2.00 (m , 2H) 3.69 (m, 4H) 4.47 (m, 2H) 5.44 (s, 2H) 6.98 (m, 2H) 7.51 (m, 1H), ES-HRMS 485.1723 ( M + H calculated for C ₂₂ H ₂₈ ClF ₂ N ₄ O ₄ is 485.1762).

(Example 69)

Ｎ−（（３Ｒ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イル）−２−ヒドロキシ−２−メチルプロパンアミド
Ｎ−（（３Ｒ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イル）−２−ヒドロキシ−２−メチルプロパンアミドの調製。２−［（（３Ｒ）−１−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ピロリジン−３−イル）アミノ］−１，１−ジメチル−２−オキソエチルアセタート（０．３６３ｇ、０．６９ミリモル）およびＫ_２ＣＯ_３（０．１４３ｇ、１．０４ミリモル）を利用し、Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］−２−ヒドロキシアセトアミド（ステップ３）のように調製して、白色固体（０．３１３ｇ、９４％）を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．３５（ｓ，３Ｈ）１．３６（ｓ，３Ｈ）１．５９（ｄｄ，Ｊ＝３．４２，６．６５Ｈｚ ６Ｈ）２．００（ｍ，２Ｈ）３．６９（ｍ，４Ｈ）４．４７（ｍ，２Ｈ）５．４４（ｓ，２Ｈ）６．９７（ｍ，２Ｈ）７．５１（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４８５．１７６６（Ｃ_２２Ｈ_２８ＣｌＦ_２Ｎ_４Ｏ_４に対するＭ＋Ｈ計算値は４８５．１７６２）。

N-((3R) -1- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidine-3 -Yl) -2-hydroxy-2-methylpropanamide N-((3R) -1- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1 , 6-Dihydropyrimidin-2-yl} pyrrolidin-3-yl) -2-hydroxy-2-methylpropanamide. 2-[((3R) -1- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidine- 3-yl) amino] -1,1-dimethyl-2-oxoethyl acetate (0.363 g, 0.69 mmol) and K ₂ CO ₃ (0.143 g, 1.04 mmol) were used to give N— [3-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2-hydroxy Prepared as acetamide (Step 3) to give a white solid (0.313 g, 94%). ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 1.35 (s, 3H) 1.36 (s, 3H) 1.59 (dd, J = 3.42, 6.65 Hz 6H) 2.00 (m, 2H) 3.69 (m, 4H) 4.47 (m, 2H) 5.44 (s, 2H) 6.97 (m, 2H) 7.51 (m, 1H), ES-HRMS 485.1766 (C _{22 H 28 ClF 2 N 4 O} M + H calcd for ₄ 485.1762).

(Example 70)

５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オン
５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オンの調製。５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（メチルスルホニル）ピリミジン−４（３Ｈ）−オン（０．３９０ｇ、１．０ミリモル）をメタノール（３．０ｍＬ）に溶解させ、氷浴で冷却した。水素化ホウ素ナトリウム（０．０７６ｇ、３．０ミリモル）を加え、反応混合物を一晩かけて室温に温めた。反応を水で失活させ、メタノールを除去した。水層を酢酸エチルに抽出した。有機抽出物を合わせてＭｇＳＯ_４で乾燥させ、濾過し、濃縮した。残渣をクロマトグラフィー（シリカゲル、酢酸エチル／ヘキサン）によって精製して、白色固体（０．１４０ｇ、４４％）を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．４６（ｄ，Ｊ＝６．８５Ｈｚ，６Ｈ）４．９６（ｍ，１Ｈ）５．５１（ｓ，２Ｈ）６．９９（ｍ，２Ｈ）７．５５（ｍ，１Ｈ）８．３５（ｓ，１Ｈ）、ＥＳ−ＨＲＭＳ３１５．０６９６（Ｃ_１４Ｈ_１４ＣｌＦ_２Ｎ_２Ｏ_２に対するＭ＋Ｈ計算値は３１５．０７０６）。

5-chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one 5-chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl Preparation of pyrimidin-4 (3H) -one. 5-Chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (0.390 g, 1.0 mmol) was added to methanol (3 0.0 mL) and cooled in an ice bath. Sodium borohydride (0.076 g, 3.0 mmol) was added and the reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched with water to remove methanol. The aqueous layer was extracted into ethyl acetate. The combined organic extracts were dried over MgSO ₄ , filtered and concentrated. The residue was purified by chromatography (silica gel, ethyl acetate / hexane) to give a white solid (0.140 g, 44%). ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 1.46 (d, J = 6.85 Hz, 6H) 4.96 (m, 1H) 5.51 (s, 2H) 6.99 (m, 2H) 7 .55 (m, 1H) 8.35 ( s, 1H), ES-HRMS315.0696 (M + H calcd for _{C 14 H 14 ClF 2 N 2} O 2 is 315.0706).

(Example 71)

５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−メチルピリミジン−４（３Ｈ）−オン
ステップ１．４−（２，４−ジフルオロベンジルオキシ）−５−クロロ−１，６−ジヒドロ−１−イソプロピル−６−オキソピリミジン−２−カルボニトリルの調製

5-Chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2-methylpyrimidin-4 (3H) -one Step 1.4- (2,4-Difluorobenzyloxy) -5 Preparation of chloro-1,6-dihydro-1-isopropyl-6-oxopyrimidine-2-carbonitrile

５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（メチルスルホニル）ピリミジン−４（３Ｈ）−オン（１０．０ｇ、２５．４ミリモル）をジメチルホルムアミド（５６ｍＬ）に溶解させた。シアン化カリウム（３．３１ｇ、５０．９ミリモル）を加えた。得られる混合物を室温で３時間攪拌した。反応液を酢酸エチル（１００ｍＬ）で希釈し、酢酸エチル（１００ｍＬ）／氷水（３００ｍＬ）中に注いだ。水層をさらに酢酸エチルに抽出した。有機抽出物を合わせてＮａＳＯ_４で乾燥させ、濾過し、濃縮した。残渣をクロマトグラフィー（シリカゲル、酢酸エチル／ヘキサン）によって精製して、淡黄色の固体（３．３４ｇ、３９％）を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δｐｐｍ １．６７（ｍ，６Ｈ）５．１６（ｍ，１Ｈ）５．４５（ｓ，２Ｈ）６．８８（ｍ，２Ｈ）７．４６（ｍ，１Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝３．１４分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ３４０（Ｍ＋１）。

5-Chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (10.0 g, 25.4 mmol) was converted to dimethylformamide ( 56 mL). Potassium cyanide (3.31 g, 50.9 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and poured into ethyl acetate (100 mL) / ice water (300 mL). The aqueous layer was further extracted into ethyl acetate. The combined organic extracts were dried over NaSO ₄ , filtered and concentrated. The residue was purified by chromatography (silica gel, ethyl acetate / hexane) to give a pale yellow solid (3.34 g, 39%). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 1.67 (m, 6H) 5.16 (m, 1H) 5.45 (s, 2H) 6.88 (m, 2H) 7.46 (m, 1H) . LC / _MS, t r = 3.14 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z340 (M + 1).

Step 2.5 Preparation of Chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2-methylpyrimidin-4 (3H) -one 4- (2,4-Difluorobenzyloxy)- 5-chloro-1,6-dihydro-1-isopropyl-6-oxopyrimidine-2-carbonitrile (from step 1) (0.170 g, 0.50 mmol) was dissolved in tetrahydrofuran (17 mL), − Cooled to 78 ° C. To the reaction mixture was added methylmagnesium bromide (3.0 M in THF, 0.40 mL) slowly. Next, the reaction solution was warmed to 0 ° C. and quenched by adding water. The aqueous layer was extracted into ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography (silica gel, ethyl acetate / hexane) to give an off-white solid (0.091 g, 56%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.59 (d, J = 6.71 Hz, 6H) 2.52 (s, 3H) 4.49 (m, 1H) 5.41 (s, 2H) 83 (m, 2H) 7.45 ( m, 1H), ES-HRMS329.0898 (C 15 H 16 ClF 2 N 2 O 2 for M + H calculated value 329.0863).

(Example 72)

２−ブト−３−エニル−５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オン
２−ブト−３−エニル−５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オンの調製。５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（メチルスルホニル）ピリミジン−４（３Ｈ）−オン（０．１００ｇ、０．２５ミリモル）をテトラヒドロフラン（５ｍＬ）に溶解させ、−７８℃に冷却した。臭化ブト−１−エン−４−マグネシウム（０．５Ｍ、０．９００ｍＬ）をゆっくりと加えた。反応混合物を一晩かけて室温に温めた。ＮＨ_４Ｃｌの溶液を加えて反応混合物を失活させ、次いで酢酸エチルに抽出した。有機抽出物を合わせてＭｇＳＯ_４で乾燥させ、濾過し、濃縮した。未精製の固体をクロマトグラフィー（シリカゲル、酢酸エチル／ヘキサン）によって精製して、白色固体（０．０４８ｇ、５２％）を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５８（ｄ，Ｊ＝６．８５Ｈｚ，６Ｈ）２．５２（ｍ，２Ｈ）２．９５（ｔ，Ｊ＝７．４５Ｈｚ，２Ｈ）４．６８（ｍ，１Ｈ）５．０４（ｍ，２Ｈ）５．４８（ｓ，２Ｈ）５．８８（ｍ，１Ｈ）６．９６（ｍ，２Ｈ）７．５０（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ３６９．１１５６（Ｃ_１８Ｈ_２０ＣｌＦ_２Ｎ_２Ｏ_２に対するＭ＋Ｈ計算値は３６９．１１７６）。

2-But-3-enyl-5-chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one 2-but-3-enyl-5-chloro-6 -Preparation of [(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one. 5-Chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (0.100 g, 0.25 mmol) in tetrahydrofuran (5 mL) ) And cooled to -78 ° C. But-1-ene-4-magnesium bromide (0.5M, 0.900 mL) was added slowly. The reaction mixture was warmed to room temperature overnight. The reaction mixture was quenched by adding a solution of NH ₄ Cl and then extracted into ethyl acetate. The combined organic extracts were dried over MgSO ₄ , filtered and concentrated. The crude solid was purified by chromatography (silica gel, ethyl acetate / hexane) to give a white solid (0.048 g, 52%). ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 1.58 (d, J = 6.85 Hz, 6H) 2.52 (m, 2H) 2.95 (t, J = 7.45 Hz, 2H) 4.68 (M, 1H) 5.04 (m, 2H) 5.48 (s, 2H) 5.88 (m, 1H) 6.96 (m, 2H) 7.50 (m, 1H), ES-HRMS369. 1156 (calculated M + H for C ₁₈ H ₂₀ ClF ₂ N ₂ O ₂ is 369.1176).

(Example 73)

５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−２−（４−ヒドロキシブチル）−３−イソプロピルピリミジン−４（３Ｈ）−オン
５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−２−（４−ヒドロキシブチル）−３−イソプロピルピリミジン−４（３Ｈ）−オンの調製。２−ブト−３−エニル−５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オン（０．３１０ｇ、０．８４ミリモル）をテトラヒドロフラン（３ｍＬ）に溶解させた。次いで、ＢＨ_３−ＴＨＦ（１．０Ｍ、０．５３ｍＬ）を室温で加えた。気体の放出が止んだ後、反応混合物に水酸化ナトリウム（２．５Ｎ、１ｍＬ）を加えた後、過酸化水素（３０％、４ｍＬ）を加えた。得られる反応液を終夜攪拌した。次いで、反応混合物を酢酸エチルに抽出し、ブラインで洗浄した。有機抽出物を合わせてＭｇＳＯ_４で乾燥させ、濾過し、濃縮した。残渣をクロマトグラフィー（シリカゲル、酢酸エチル／ヘキサン）によって精製して、オフホワイトの固体（０．１１８ｇ、３６％）を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５９（ｄ，Ｊ＝６．６５Ｈｚ，６Ｈ）１．６４（ｍ，２Ｈ）１．８３（ｍ，２Ｈ）２．８９（ｍ，２Ｈ）３．６１（ｔ，Ｊ＝６．２４Ｈｚ，２Ｈ）４．６７（ｍ，１Ｈ）５．５０（ｓ，２Ｈ）６．９９（ｍ，２Ｈ）７．５３（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ３８７．１２３７（Ｃ_１８Ｈ_２２ＣｌＦ_２Ｎ_２Ｏ_３に対するＭ＋Ｈ計算値は３８７．１２８２）。

5-chloro-6-[(2,4-difluorobenzyl) oxy] -2- (4-hydroxybutyl) -3-isopropylpyrimidin-4 (3H) -one 5-chloro-6-[(2,4- Preparation of (difluorobenzyl) oxy] -2- (4-hydroxybutyl) -3-isopropylpyrimidin-4 (3H) -one. 2-But-3-enyl-5-chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one (0.310 g, 0.84 mmol) was added to tetrahydrofuran ( 3 mL). BH ₃ -THF (1.0 M, 0.53 mL) was then added at room temperature. After gas evolution ceased, sodium hydroxide (2.5 N, 1 mL) was added to the reaction mixture followed by hydrogen peroxide (30%, 4 mL). The resulting reaction was stirred overnight. The reaction mixture was then extracted into ethyl acetate and washed with brine. The combined organic extracts were dried over MgSO ₄ , filtered and concentrated. The residue was purified by chromatography (silica gel, ethyl acetate / hexane) to give an off-white solid (0.118 g, 36%). ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 1.59 (d, J = 6.65 Hz, 6H) 1.64 (m, 2H) 1.83 (m, 2H) 2.89 (m, 2H) 3 .61 (t, J = 6.24 Hz, 2H) 4.67 (m, 1H) 5.50 (s, 2H) 6.99 (m, 2H) 7.53 (m, 1H), ES-HRMS387. 1237 (calculated M + H for C ₁₈ H ₂₂ ClF ₂ N ₂ O ₃ is 387.1282).

(Example 74)

４−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ブタン酸
４−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ブタン酸の調製。５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−２−（４−ヒドロキシブチル）−３−イソプロピルピリミジン−４（３Ｈ）−オン（１．３２ｇ、３．４２ミリモル）をジメチルホルムアミド（１７ｍＬ）に溶解させた。二クロム酸ピリジニウム（４．５ｇ、１２．０ミリモル）を加え、反応液を室温で終夜攪拌した。水（１２５ｍＬ）を加えて反応を失活させた。水層を酢酸エチルに抽出した。有機の抽出物を合わせてＭｇＳＯ_４で乾燥させ、濾過し、濃縮した。未精製の固体を少量のジクロロメタンで洗浄し、濾過して、黄褐色の固体（０．７５０ｇ、５５％）を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５９（ｄ，Ｊ＝６．６５Ｈｚ，６Ｈ）２．０６（ｍ，２Ｈ）２．４５（ｔ，Ｊ＝７．０５Ｈｚ，２Ｈ）２．９２（ｔ，Ｊ＝７．３５Ｈｚ，２Ｈ）４．７０（ｍ，１Ｈ）５．４９（ｍ，２Ｈ）６．９８（ｍ，２Ｈ）７．５５（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４０１．１０４０（Ｃ_１８Ｈ_２０ＣｌＦ_２Ｎ_２Ｏ_４に対するＭ＋Ｈ計算値は４０１．１０７４）。

4- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} butanoic acid 4- {5-chloro-4 -Preparation of [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} butanoic acid. 5-Chloro-6-[(2,4-difluorobenzyl) oxy] -2- (4-hydroxybutyl) -3-isopropylpyrimidin-4 (3H) -one (1.32 g, 3.42 mmol) in dimethyl Dissolved in formamide (17 mL). Pyridinium dichromate (4.5 g, 12.0 mmol) was added and the reaction was stirred at room temperature overnight. Water (125 mL) was added to quench the reaction. The aqueous layer was extracted into ethyl acetate. The combined organic extracts were dried over MgSO ₄ , filtered and concentrated. The crude solid was washed with a small amount of dichloromethane and filtered to give a tan solid (0.750 g, 55%). ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 1.59 (d, J = 6.65 Hz, 6H) 2.06 (m, 2H) 2.45 (t, J = 7.05 Hz, 2H) 2.92 (T, J = 7.35 Hz, 2H) 4.70 (m, 1H) 5.49 (m, 2H) 6.98 (m, 2H) 7.55 (m, 1H), ES-HRMS 401.1040 ( M + H calculated for C ₁₈ H ₂₀ ClF ₂ N ₂ O ₄ is 401.1074).

(Example 75)

４−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ブタンアミド
４−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ブタンアミドの調製。４−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ブタン酸（０．５０ｇ、１．２５ミリモル）、２−クロロ−４，６−ジメトキシ−１，３，５−トリアジン（０．３３ｇ、１．８８ミリモル）、４−メチルモルホリン（０．４１ｍＬ、３．７５ミリモル）、および過剰の水酸化アンモニウム水溶液を利用し、Ｎ〜３〜−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−β−アラニンアミド（ステップ３）のように調製して、黄褐色の固体（０．１５３ｇ、３１％）を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５９（ｄ，Ｊ＝６．８５Ｈｚ，６Ｈ）２．０７（ｍ，２Ｈ）２．３５（ｔ，Ｊ＝７．１５Ｈｚ，２Ｈ）２．９０（ｔ，Ｊ＝７．４５Ｈｚ，２Ｈ）４．６９（ｍ，１Ｈ）５．５０（ｓ，２Ｈ）６．９８（ｍ，２Ｈ）７．５４（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４００．１２６５（Ｃ_１８Ｈ_２１ＣｌＦ_２Ｎ_３Ｏ_３に対するＭ＋Ｈ計算値は４００．１２３４）。

4- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} butanamide 4- {5-chloro-4- Preparation of [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} butanamide. 4- {5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} butanoic acid (0.50 g, 1.25 Mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.33 g, 1.88 mmol), 4-methylmorpholine (0.41 mL, 3.75 mmol), and excess water Using an aqueous ammonium oxide solution, N to 3-{5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} Prepared as -β-alaninamide (Step 3) to give a tan solid (0.153 g, 31%). ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 1.59 (d, J = 6.85 Hz, 6H) 2.07 (m, 2H) 2.35 (t, J = 7.15 Hz, 2H) 2.90 (T, J = 7.45 Hz, 2H) 4.69 (m, 1H) 5.50 (s, 2H) 6.98 (m, 2H) 7.54 (m, 1H), ES-HRMS 400.1265 ( M + H calculated for C ₁₈ H ₂₁ ClF ₂ N ₃ O ₃ is 400.1234).

(Example 76)

４−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−Ｎ−［（２Ｒ）−２−ヒドロキシプロピル］ブタンアミド
４−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−Ｎ−［（２Ｒ）−２−ヒドロキシプロピル］ブタンアミドの調製。４−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ブタン酸（０．２１０ｇ、０．５３ミリモル）をジオキサン（８ｍＬ）に溶解させた。Ｎ−ヒドロキシベンゾトリアゾール（０．０７２ｇ、０．５３ミリモル）およびカルボジイミド樹脂（１．３１ミリモル／ｇ、１．３９ｇ）を加え、反応液を１５分間攪拌した。（Ｒ）−１−アミノプロパン−２−オール（０．０８０ｇ、１．０６ミリモル）を加え、得られる反応混合物を室温で終夜攪拌した。ジオキサン（２０ｍＬ）、ポリアミン樹脂（２．８７ミリモル／ｇ、１．４４ｇ）、およびＰＳ−イソシアン酸樹脂（１．４７ミリモル／ｇ、２．６７ｇ）を加え、反応混合物を４時間攪拌した。反応混合物を濾過し、濃縮して、透明な油状物（０．１４５ｇ、６０％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．１３（ｄ，Ｊ＝６．４４Ｈｚ，３Ｈ）１．５９（ｄ，Ｊ＝６．７１Ｈｚ，６Ｈ）２．０８（ｍ，２Ｈ）２．３６（ｔ，Ｊ＝７．１２Ｈｚ，２Ｈ）２．８９（ｔ，Ｊ＝７．３８Ｈｚ，２Ｈ）３．１９（ｍ，２Ｈ）３．８１（ｍ，１Ｈ）４．６６（ｍ，１Ｈ）５．４９（ｓ，２Ｈ）６．９８（ｍ，２Ｈ）７．５４（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４５８．１６３４（Ｍ＋Ｈ Ｃ_２１Ｈ_２７ＣｌＦ_２Ｎ_３Ｏ_４に対する計算値は４５８．１６５３）。

4- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N-[(2R) -2- Hydroxypropyl] butanamide 4- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N-[(2R ) -2-Hydroxypropyl] butanamide. 4- {5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} butanoic acid (0.210 g, 0.53 Mmol) was dissolved in dioxane (8 mL). N-hydroxybenzotriazole (0.072 g, 0.53 mmol) and carbodiimide resin (1.31 mmol / g, 1.39 g) were added and the reaction was stirred for 15 minutes. (R) -1-Aminopropan-2-ol (0.080 g, 1.06 mmol) was added and the resulting reaction mixture was stirred at room temperature overnight. Dioxane (20 mL), polyamine resin (2.87 mmol / g, 1.44 g), and PS-isocyanate resin (1.47 mmol / g, 2.67 g) were added and the reaction mixture was stirred for 4 hours. The reaction mixture was filtered and concentrated to give a clear oil (0.145 g, 60%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.13 (d, J = 6.44 Hz, 3H) 1.59 (d, J = 6.71 Hz, 6H) 2.08 (m, 2H) 2.36 (T, J = 7.12 Hz, 2H) 2.89 (t, J = 7.38 Hz, 2H) 3.19 (m, 2H) 3.81 (m, 1H) 4.66 (m, 1H) 5 .49 (s, 2H) 6.98 ( m, 2H) 7.54 (m, 1H), ES-HRMS458.1634 ( calcd for _{M + H C 21 H 27 ClF} 2 N 3 O 4 is 458.1653).

(Example 77)

４−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−Ｎ−（２−ヒドロキシエチル）ブタンアミド
４−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−Ｎ−（２−ヒドロキシエチル）ブタンアミドの調製。４−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ブタン酸（０．４０ｇ、１．０ミリモル）およびエタノールアミン（０．１２ｍＬ、２．０ミリモル）を利用し、４−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−Ｎ−［（２Ｒ）−２−ヒドロキシプロピル］ブタンアミドのように調製して、オフホワイトの固体（０．２４４ｇ、５５％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５９（ｄ，Ｊ＝６．７１Ｈｚ，６Ｈ）２．０８（ｍ，２Ｈ）２．３５（ｔ，Ｊ＝７．１２Ｈｚ，２Ｈ）２．８９（ｔ，Ｊ＝７．５２Ｈｚ，２Ｈ）３．３０（ｍ，２Ｈ）３．５８（ｔ，Ｊ＝５．７７Ｈｚ，２Ｈ）４．６７（ｍ，１Ｈ）５．５０（ｓ，２Ｈ）６．９８（ｍ，２Ｈ）７．５４（ｍ，１Ｈ），ＥＳ−ＨＲＭＳ４４４．１４８８（Ｃ_２０Ｈ_２５ＣｌＦ_２Ｎ_３Ｏ_４に対するＭ＋Ｈ計算値は４４４．１４９６）。

4- {5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N- (2-hydroxyethyl) butanamide 4- {5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N- (2-hydroxyethyl) butanamide Preparation. 4- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} butanoic acid (0.40 g, 1.0 Mmol) and ethanolamine (0.12 mL, 2.0 mmol) and 4- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1, Prepared as 6-dihydropyrimidin-2-yl} -N-[(2R) -2-hydroxypropyl] butanamide to give an off-white solid (0.244 g, 55%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.59 (d, J = 6.71 Hz, 6H) 2.08 (m, 2H) 2.35 (t, J = 7.12 Hz, 2H) 2.89 (T, J = 7.52 Hz, 2H) 3.30 (m, 2H) 3.58 (t, J = 5.77 Hz, 2H) 4.67 (m, 1H) 5.50 (s, 2H) 6 .98 (m, 2H) 7.54 ( m, 1H), ES-HRMS444.1488 (M + H calcd for _{C 20 H 25 ClF 2 N 3} O 4 is 444.1496).

(Example 78)

４−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−Ｎメチルブタンアミド
４−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−Ｎメチルブタンアミドの調製。４−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ブタン酸（０．４０ｇ、１．０ミリモル）およびメチルアミン（ジオキサン中２．０Ｍ、１．０ｍＬ、２．０ミリモル）を利用し、４−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−Ｎ−［（２Ｒ）−２−ヒドロキシプロピル］ブタンアミドのように調製して、淡褐色−赤色の固体（０．２３９ｇ、５８％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５９（ｄ，Ｊ＝６．７１Ｈｚ，６Ｈ）２．０６（ｍ，２Ｈ）２．３１（ｔ，Ｊ＝７．２５Ｈｚ，２Ｈ）２．７１（ｓ，３Ｈ）２．８８（ｔ，Ｊ＝７．３８Ｈｚ，２Ｈ）４．６７（ｍ，１Ｈ）５．４９（ｓ，２Ｈ）６．９８（ｍ，２Ｈ）７．５３（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４１４．１３７３（Ｃ_１９Ｈ_２３ＣｌＦ_２Ｎ_３Ｏ_３に対するＭ＋Ｈ計算値は４１４．１３９１）。

4- {5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N methylbutanamide 4- {5- Preparation of chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N methylbutanamide. 4- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} butanoic acid (0.40 g, 1.0 Mmol) and methylamine (2.0 M in dioxane, 1.0 mL, 2.0 mmol) and 4- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl- Prepared as 6-oxo-1,6-dihydropyrimidin-2-yl} -N-[(2R) -2-hydroxypropyl] butanamide, a light brown-red solid (0.239 g, 58%) Got. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.59 (d, J = 6.71 Hz, 6H) 2.06 (m, 2H) 2.31 (t, J = 7.25 Hz, 2H) 2.71 (S, 3H) 2.88 (t, J = 7.38 Hz, 2H) 4.67 (m, 1H) 5.49 (s, 2H) 6.98 (m, 2H) 7.53 (m, 1H _{), ES-HRMS414.1373 (C 19} H 23 ClF 2 N 3 O M + H calcd for ₃ 414.1391).

(Example 79)

５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−２−ヒドロキシ−３−イソプロピルピリミジン−４（３Ｈ）−オン
５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−２−ヒドロキシ−３−イソプロピルピリミジン−４（３Ｈ）−オンの調製。５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（メチルスルホニル）ピリミジン−４（３Ｈ）−オン（５．００ｇ、１２．７ミリモル）をジオキサン（１３０ｍＬ）に溶解させ、反応混合物に室温で２．５Ｎ ＮａＯＨ（２５．５ｍＬ、６３．７ミリモル）を加えた。１５分後、ジオキサンを除去し、水層を１．０ＭのＨＣｌで酸性（ｐＨ４．５）にした。沈殿を濾過によって収集し、エーテルで洗浄して、白色固体（３．９９ｇ、９５％）を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δｐｐｍ １．４２（ｄ，Ｊ＝７．０５Ｈｚ，６Ｈ）５．１５（ｍ，１Ｈ）５．４５（ｓ，２Ｈ）６．９１（ｍ，２Ｈ）７．４９（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ３３１．０６２２（Ｃ_１４Ｈ_１４ＣｌＦ_２Ｎ_２Ｏ_３に対するＭ＋Ｈ計算値は３３１．０６５６）。

5-chloro-6-[(2,4-difluorobenzyl) oxy] -2-hydroxy-3-isopropylpyrimidin-4 (3H) -one 5-chloro-6-[(2,4-difluorobenzyl) oxy] Preparation of 2-hydroxy-3-isopropylpyrimidin-4 (3H) -one. 5-Chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (5.00 g, 12.7 mmol) was added to dioxane (130 mL). And 2.5 N NaOH (25.5 mL, 63.7 mmol) was added to the reaction mixture at room temperature. After 15 minutes, dioxane was removed and the aqueous layer was acidified (pH 4.5) with 1.0 M HCl. The precipitate was collected by filtration and washed with ether to give a white solid (3.99 g, 95%). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 1.42 (d, J = 7.05 Hz, 6H) 5.15 (m, 1H) 5.45 (s, 2H) 6.91 (m, 2H) 49 (m, 1H), ES -HRMS331.0622 (C 14 H 14 ClF 2 N 2 O M + H calcd for ₃ 331.0656).

(Example 80)

トリフルオロメタンスルホン酸５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル
５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イルトリフルオロメタンスルホナートの調製。５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−２−ヒドロキシ−３−イソプロピルピリミジン−４（３Ｈ）−オン（２．００ｇ、６．１ミリモル）をジクロロメタン（２０ｍＬ）に溶解させ、氷浴で冷却した。ピリジン（１．５ｍＬ、１８．３ミリモル）を加え、反応液を冷却しながら３０分間攪拌した。無水トリフルオロメタンスルホン酸（２．１ｍＬ、１２．２ミリモル）を加え、反応液を２．５時間かけて室温に温めた。水を加えて反応を失活させ、ジクロロメタンに抽出した。有機抽出物を合わせてＭｇＳＯ_４で乾燥させ、濾過し、濃縮した。残渣をクロマトグラフィー（シリカゲル、酢酸エチル／ヘキサン）によって精製して、白色固体（１．１４ｇ、４１％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５１（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）５．２６（ｍ，１Ｈ）５．４３（ｓ，２Ｈ）７．０１（ｍ，２Ｈ）７．５４（ｍ，１Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝３．６４分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ４６３（Ｍ＋１）。

Trichloromethanesulfonic acid 5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl 5-chloro-4-[(2, 4-Difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl trifluoromethanesulfonate. 5-Chloro-6-[(2,4-difluorobenzyl) oxy] -2-hydroxy-3-isopropylpyrimidin-4 (3H) -one (2.00 g, 6.1 mmol) is dissolved in dichloromethane (20 mL). And cooled in an ice bath. Pyridine (1.5 mL, 18.3 mmol) was added and the reaction was stirred for 30 minutes while cooling. Trifluoromethanesulfonic anhydride (2.1 mL, 12.2 mmol) was added and the reaction was allowed to warm to room temperature over 2.5 hours. The reaction was quenched by adding water and extracted into dichloromethane. The combined organic extracts were dried over MgSO ₄ , filtered and concentrated. The residue was purified by chromatography (silica gel, ethyl acetate / hexane) to give a white solid (1.14 g, 41%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.51 (d, J = 6.98 Hz, 6H) 5.26 (m, 1H) 5.43 (s, 2H) 7.01 (m, 2H) 7 .54 (m, 1H). LC / _MS, t r = 3.64 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z463 (M + 1).

(Example 81)

２−アリル−５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オン
２−アリル−５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オンの調製。臭化プロパ−１−エン−３−マグネシウム（１．０Ｍ、３．７５ｍＬ、３．７５ミリモル）を利用し、２−ブト−３−エニル−５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オンのように調製して、黄色の油状物（０．６２０ｇ、７０％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５６（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）３．６６（ｄ，Ｊ＝５．９１Ｈｚ，２Ｈ）４．６１（ｍ，１Ｈ）５．１５（ｄｄ，Ｊ１．３４，１７．１９Ｈｚ，１Ｈ）５．２５（ｄｄ，Ｊ＝１．３４，１０．２０Ｈｚ，１Ｈ）５．４６（ｍ，２Ｈ）６．０３（ｍ，１Ｈ）６．９６（ｍ，２Ｈ）７．５４（ｄ，Ｊ＝６．４４Ｈｚ，１Ｈ）、ＥＳ−ＨＲＭＳ３５５．１０１９（Ｃ_１７Ｈ_１８ＣｌＦ_２Ｎ_２Ｏ_２に対するＭ＋Ｈ計算値は３５５．１０１９）。

2-allyl-5-chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one 2-allyl-5-chloro-6-[(2,4-difluoro Preparation of (benzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one. Using prop-1-ene-3-magnesium bromide (1.0 M, 3.75 mL, 3.75 mmol), 2-but-3-enyl-5-chloro-6-[(2,4-difluoro (Benzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one to give a yellow oil (0.620 g, 70%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.56 (d, J = 6.98 Hz, 6H) 3.66 (d, J = 5.91 Hz, 2H) 4.61 (m, 1H) 5.15 (Dd, J1.34, 17.19 Hz, 1H) 5.25 (dd, J = 1.34, 10.20 Hz, 1H) 5.46 (m, 2H) 6.03 (m, 1H) 6.96 (M, 2H) 7.54 (d, J = 6.44 Hz, 1H), ES-HRMS 355.10.19 (calculated M + H for C ₁₇ H ₁₈ ClF ₂ N ₂ O ₂ is 355.1019).

(Example 82)

５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−２−（３−ヒドロキシプロピル）−３−イソプロピルピリミジン−４（３Ｈ）−オン
５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−２−（３−ヒドロキシプロピル）−３−イソプロピルピリミジン−４（３Ｈ）−オンの調製。２−アリル−５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オン（０．５１６、１．４６ミリモル）、ＢＨ_３−ＴＨＦ（テトラヒドロフラン中１．０Ｍ、０．９ｍＬ、０．９２ミリモル）、過酸化水素（３０％、１．７ｍＬ、０．５１ミリモル）、および２．５Ｎ ＮａＯＨ（０．２５ｍＬ、０．０９ミリモル）を利用し、５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−２−（４−ヒドロキシブチル）−３−イソプロピルピリミジン−４（３Ｈ）−オンのように調製して、オフホワイトの固体（０．１１０ｇ、２０％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５８（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）１．９９（ｍ，２Ｈ）２．９５（ｍ，２Ｈ）３．６７（ｔ，Ｊ＝６．１８Ｈｚ，２Ｈ）４．６８（ｍ，１Ｈ）５．４７（ｓ，２Ｈ）６．９５（ｍ，２Ｈ）７．５１（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ３７３．１１１１（Ｃ_１７Ｈ_２０ＣｌＦ_２Ｎ_２Ｏ_３に対するＭ＋Ｈ計算値は３７３．１１２５）。

5-chloro-6-[(2,4-difluorobenzyl) oxy] -2- (3-hydroxypropyl) -3-isopropylpyrimidin-4 (3H) -one 5-chloro-6-[(2,4- Preparation of (difluorobenzyl) oxy] -2- (3-hydroxypropyl) -3-isopropylpyrimidin-4 (3H) -one. 2-allyl-5-chloro-6 - [(2,4-difluorobenzyl) oxy] -3-isopropyl-pyrimidin -4 (3H) - one (0.516,1.46 _mmol), BH 3-THF (tetrahydrofuran 1.0M, 0.9 mL, 0.92 mmol), hydrogen peroxide (30%, 1.7 mL, 0.51 mmol), and 2.5 N NaOH (0.25 mL, 0.09 mmol). , 5-chloro-6-[(2,4-difluorobenzyl) oxy] -2- (4-hydroxybutyl) -3-isopropylpyrimidin-4 (3H) -one, an off-white solid (0.110 g, 20%) was obtained. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.58 (d, J = 6.98 Hz, 6H) 1.99 (m, 2H) 2.95 (m, 2H) 3.67 (t, J = 6 .18Hz, 2H) 4.68 (m, 1H) 5.47 (s, 2H) 6.95 (m, 2H) 7.51 (m, 1H), ES-HRMS373.1111 (C 17 H 20 ClF 2 Calculated M + H for N ₂ O ₃ is 373.1125).

(Example 83)

３−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝プロパン酸
３−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝プロパン酸の調製。５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−２−（３−ヒドロキシプロピル）−３−イソプロピルピリミジン−４（３Ｈ）−オン（０．９１０ｇ、２．３ミリモル）および二クロム酸ピリジニウム（３．０３ｇ、８．１ミリモル）を利用し、４−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ブタン酸のように調製して、オフホワイトの固体（０．４１０ｇ、４６％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．６０（ｄ，Ｊ＝６．７１Ｈｚ，６Ｈ）２．８２（ｍ，２Ｈ）３．１７（ｍ，２Ｈ）４．７４（ｍ，１Ｈ）５．４７（ｓ，２Ｈ）６．９８（ｍ，２Ｈ）７．５２（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ３８７．０８９７（Ｃ_１７Ｈ_１８ＣｌＦ_２Ｎ_２Ｏ_４に対するＭ＋Ｈ計算値は３８７．０９１８）。

3- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} propanoic acid 3- {5-chloro-4 -Preparation of [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} propanoic acid. 5-Chloro-6-[(2,4-difluorobenzyl) oxy] -2- (3-hydroxypropyl) -3-isopropylpyrimidin-4 (3H) -one (0.910 g, 2.3 mmol) and 2 Utilizing pyridinium chromate (3.03 g, 8.1 mmol), 4- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6- Prepared like dihydropyrimidin-2-yl} butanoic acid to give an off-white solid (0.410 g, 46%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.60 (d, J = 6.71 Hz, 6H) 2.82 (m, 2H) 3.17 (m, 2H) 4.74 (m, 1H) 5 .47 (s, 2H) 6.98 ( m, 2H) 7.52 (m, 1H), ES-HRMS387.0897 (M + H calcd for _{C 17 H 18 ClF 2 N 2} O 4 is 387.0918).

(Example 84)

３−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝プロパンアミド
３−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝プロパンアミドの調製。３−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝プロパン酸（０．１８０ｇ、０．４７ミリモル）およびアンモニア（ジオキサン中０．５Ｍ、１．８６ｍＬ、０．９３ミリモル）を利用し、４−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ブタンアミドのように調製して、淡黄色の固体（０．１５６ｇ、８６％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．６１（ｄ，Ｊ＝６．７１Ｈｚ，６Ｈ）２．７７（ｔ，Ｊ＝６．３１Ｈｚ，２Ｈ）３．１７（ｔ，Ｊ＝６．４４Ｈｚ，２Ｈ）４．７５（ｍ，１Ｈ）５．４９（ｓ，２Ｈ）６．９９（ｍ，２Ｈ）７．５３（ｍ，１Ｈ），ＥＳ−ＨＲＭＳ３８６．１０５５（Ｃ_１７Ｈ_１９ＣｌＦ_２Ｎ_３Ｏ_３に対するＭ＋Ｈ計算値は３８６．１０７８）。

3- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} propanamide 3- {5-chloro-4 -Preparation of [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} propanamide. 3- {5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} propanoic acid (0.180 g, 0.47 Mmol) and ammonia (0.5 M in dioxane, 1.86 mL, 0.93 mmol) and 4- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6 Prepared like -oxo-1,6-dihydropyrimidin-2-yl} butanamide to give a pale yellow solid (0.156 g, 86%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.61 (d, J = 6.71 Hz, 6H) 2.77 (t, J = 6.31 Hz, 2H) 3.17 (t, J = 6.44 Hz) , 2H) 4.75 (m, 1H ) 5.49 (s, 2H) 6.99 (m, 2H) 7.53 (m, 1H), ES-HRMS386.1055 (C 17 H 19 ClF 2 N 3 The calculated M + H for O ₃ is 386.1078).

(Example 85)

３−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−Ｎ−メチルプロパンアミド
３−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−Ｎ−メチルプロパンアミドの調製。３−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝プロパン酸（０．１８０ｇ、０．４７ミリモル）およびメチルアミン（ジオキサン中２．０Ｍ、１．０ｍＬ、２．０ミリモル）を利用し、４−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−Ｎ−メチルブタンアミドのように調製して、オフホワイトの固体（０．０５３ｇ、２８％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．６１（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）２．７０（ｓ，３Ｈ）２．７１（ｍ，２Ｈ）３．１８（ｔ，Ｊ＝６．３１Ｈｚ，２Ｈ）４．７５（ｍ，１Ｈ）５．４４（ｓ，２Ｈ）７．００（ｍ，２Ｈ）７．５２（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４００．１２３２（Ｃ_１８Ｈ_２１ＣｌＦ_２Ｎ_３Ｏ_３に対するＭ＋Ｈ計算値は４００．１２３４）。

3- {5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N-methylpropanamide 3- {5 Preparation of -Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N-methylpropanamide. 3- {5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} propanoic acid (0.180 g, 0.47 Mmol) and methylamine (2.0 M in dioxane, 1.0 mL, 2.0 mmol) and 4- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl- Prepared as 6-oxo-1,6-dihydropyrimidin-2-yl} -N-methylbutanamide to give an off-white solid (0.053 g, 28%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.61 (d, J = 6.98 Hz, 6H) 2.70 (s, 3H) 2.71 (m, 2H) 3.18 (t, J = 6 .31 Hz, 2H) 4.75 (m, 1H) 5.44 (s, 2H) 7.00 (m, 2H) 7.52 (m, 1H), ES-HRMS 400.1232 (C ₁₈ H ₂₁ ClF ₂ The calculated M + H for N ₃ O ₃ is 400.1234).

(Example 86)

３−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−Ｎ−メチルプロパンアミド
ステップ１．６−（２，４−ジフルオロベンジルオキシ）−２−（４−アミノブチル）−５−クロロ−３−イソプロピルピリミジン−４（３Ｈ）−オンの調製

3- {5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N-methylpropanamide Step 1.6 Preparation of-(2,4-difluorobenzyloxy) -2- (4-aminobutyl) -5-chloro-3-isopropylpyrimidin-4 (3H) -one

４−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ブタンアミド（０．４００ｇ、１．０ミリモル）の乾いたフラスコに、１．０ＭのＢＨ_３−ＴＨＦ（１．５ｍＬ、１．５ミリモル）を加え、得られる反応液を１時間かけて還流させた。反応混合物を加熱装置から取り出し、氷浴で冷却した。１．０Ｍの塩化水素酸（１１ｍＬ）をゆっくりと加え、反応混合物を一晩かけて室温に温めた。反応混合物を２．５Ｎ ＮａＯＨでアルカリ性（ｐＨ９）にし、酢酸エチルに抽出した。有機抽出物を合わせてＭｇＳＯ_４で乾燥させ、濾過し、濃縮した。残渣をメタノールに溶解させ、１．０Ｍの塩酸（１ｍＬ）を加えた。残渣を濃縮して、白色固体（０．３００ｇ、７１％）を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５９（ｄ，Ｊ＝６．６５Ｈｚ，６Ｈ）１．８３（ｍ，４Ｈ）３．００（ｍ，４Ｈ）４．７４（ｍ，１Ｈ）５．５０（ｓ，２Ｈ）６．９８（ｍ，２Ｈ）７．５３（ｍ，１Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝３．９４分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ４１３（Ｍ＋１）。

4- {5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} butanamide (0.400 g, 1.0 mmol) in dry flask), _BH 3-THF (1.5 mL of 1.0 M, 1.5 mmol) was added and refluxed for 1 hour and the reaction liquid obtained. The reaction mixture was removed from the heating apparatus and cooled with an ice bath. 1.0 M Hydrochloric acid (11 mL) was added slowly and the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was made alkaline (pH 9) with 2.5N NaOH and extracted into ethyl acetate. The combined organic extracts were dried over MgSO ₄ , filtered and concentrated. The residue was dissolved in methanol and 1.0 M hydrochloric acid (1 mL) was added. The residue was concentrated to give a white solid (0.300 g, 71%). ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 1.59 (d, J = 6.65 Hz, 6H) 1.83 (m, 4H) 3.00 (m, 4H) 4.74 (m, 1H) 5 .50 (s, 2H) 6.98 (m, 2H) 7.53 (m, 1H). LC / _MS, t r = 3.94 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z413 (M + 1).

Step 2. 3- {5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N-methylpropanamide Preparation 6- (2,4-Difluorobenzyloxy) -2- (4-aminobutyl) -5-chloro-3-isopropylpyrimidin-4 (3H) -one (from Step 1) (0.300 g, 0 .71 mmol) and acetyl chloride (0.060 mL, 0.85 mmol) and N- [3-({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl- Prepared as 6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] acetamide (Step 2) to give a clear oil (0.104 g, 34%). . ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 1.58 (d, J = 6.85 Hz, 6H) 1.60 (m, 2H) 1.79 (m, 2H) 1.91 (s, 3H) 2 .88 (t, J = 7.45 Hz, 2H) 3.21 (m, 2H) 4.66 (m, 1H) 5.49 (s, 2H) 6.99 (m, 2H) 7.52 (m _{, 1H), ES-HRMS428.1509 (} C 20 H 25 ClF 2 N 3 O M + H calcd for ₃ 428.1547).

(Example 87)

５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−２−（４−ヒドロキシブチル）−３−イソプロピルピリミジン−４（３Ｈ）−オン
ステップ１．６−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−２−（ブト−３−エニル）−３−イソプロピルピリミジン−４（３Ｈ）−オンの調製

5-Bromo-6-[(2,4-difluorobenzyl) oxy] -2- (4-hydroxybutyl) -3-isopropylpyrimidin-4 (3H) -one Step 1.6- (2,4-Difluorobenzyl Preparation of Oxy) -5-bromo-2- (but-3-enyl) -3-isopropylpyrimidin-4 (3H) -one

６−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−３−イソプロピル−２−（メチルスルホニル）ピリミジン−４（３Ｈ）−オン（５．００ｇ、１１．４ミリモル）および臭化ブト−１−エン−４−マグネシウム（テトラヒドロフラン中０．５Ｍ、３４．０ｍＬ、１７．２ミリモル）を利用し、２−ブト−３−エニル−５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オンのように調製して、淡黄色の固体（４．１８ｇ、８９％）を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ１．５８（ｄ，Ｊ＝６．６５Ｈｚ，６Ｈ）２．５３（ｍ，２Ｈ）２．９５（ｔ，Ｊ＝７．３５Ｈｚ，２Ｈ）４．６８（ｍ，１Ｈ）５．０５（ｍ，２Ｈ）５．４９（ｓ，２Ｈ）５．８７（ｍ，１Ｈ）６．９８（ｍ，２Ｈ）７．５２（ｍ，１Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝３．９４分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ４１３（Ｍ＋１）。

6- (2,4-Difluorobenzyloxy) -5-bromo-3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (5.00 g, 11.4 mmol) and but-1 bromide 2-Ben-3-enyl-5-chloro-6-[(2,4-difluorobenzyl) oxy was utilized using -ene-4-magnesium (0.5M in tetrahydrofuran, 34.0 mL, 17.2 mmol). ] -3-isopropylpyrimidin-4 (3H) -one to give a pale yellow solid (4.18 g, 89%). ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 1.58 (d, J = 6.65 Hz, 6H) 2.53 (m, 2H) 2.95 (t, J = 7.35 Hz, 2H) 4.68 ( m, 1H) 5.05 (m, 2H) 5.49 (s, 2H) 5.87 (m, 1H) 6.98 (m, 2H) 7.52 (m, 1H). LC / _MS, t r = 3.94 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z413 (M + 1).

Step 2.5 Preparation of Bromo-6-[(2,4-difluorobenzyl) oxy] -2- (4-hydroxybutyl) -3-isopropylpyrimidin-4 (3H) -one 6- (2,4- Difluorobenzyloxy) -5-bromo-2- (but-3-enyl) -3-isopropylpyrimidin-4 (3H) -one (from Step 1) (4.00 g, 9.7 mmol) and BH ₃ -THF (1.0 M in tetrahydrofuran, 5.8 mL, 5.8 mmol), hydrogen peroxide (35%, 9.7 mL, 3.4 mmol), and 2.5 N NaOH (8.5 mL, 21.3 mmol) ), Such as 5-chloro-6-[(2,4-difluorobenzyl) oxy] -2- (4-hydroxybutyl) -3-isopropylpyrimidin-4 (3H) -one Prepared to give a white solid (2.34 g, 56%). ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 1.58 (d, J = 6.85 Hz, 6H) 1.63 (m, 2H) 1.84 (m, 2H) 2.89 (m, 2H) 3 .61 (t, J = 6.24 Hz, 2H) 4.68 (m, 1H) 5.49 (s, 2H) 6.98 (m, 2H) 7.53 (m, 1H), ES-HRMS431. 0756 (M + H calculated for C ₁₈ H ₂₂ BrF ₂ N ₂ O ₃ is 431.0776).

(Example 88)

４−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−Ｎ−メチルブタンアミド
ステップ１．４−（４−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−１，６−ジヒドロ−１−イソプロピル−６−オキソピリミジン−２−イル）ブタン酸の調製

4- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N-methylbutanamide Step 1.4 Preparation of-(4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-yl) butanoic acid

５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−２−（４−ヒドロキシブチル）−３−イソプロピルピリミジン−４（３Ｈ）−オン（２．３４ｇ、５．４ミリモル）および二クロム酸ピリジニウム（７．１１ｇ、１８．９ミリモル）を利用し、４−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ブタン酸のように調製して、白色固体（１．１５ｇ、４８％）を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５８（ｄ，Ｊ＝６．８５Ｈｚ，６Ｈ）２．０４（ｍ，２Ｈ）２．４５（ｔ，Ｊ＝６．９５Ｈｚ，２Ｈ）２．９２（ｔ，Ｊ＝７．３５Ｈｚ，２Ｈ）４．７１（ｍ，１Ｈ）５．４９（ｓ，２Ｈ）６．９８（ｍ，２Ｈ）７．５４（ｍ，１Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝２．６６分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ４４５（Ｍ＋１）。

5-Bromo-6-[(2,4-difluorobenzyl) oxy] -2- (4-hydroxybutyl) -3-isopropylpyrimidin-4 (3H) -one (2.34 g, 5.4 mmol) and two Utilizing pyridinium chromate (7.11 g, 18.9 mmol), 4- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6- Prepared as dihydropyrimidin-2-yl} butanoic acid to give a white solid (1.15 g, 48%). ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 1.58 (d, J = 6.85 Hz, 6H) 2.04 (m, 2H) 2.45 (t, J = 6.95 Hz, 2H) 2.92 (T, J = 7.35 Hz, 2H) 4.71 (m, 1H) 5.49 (s, 2H) 6.98 (m, 2H) 7.54 (m, 1H). LC / _MS, t r = 2.66 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z445 (M + 1).

Step 2. 4- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N-methylbutanamide Preparation 4- (4- (2,4-Difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-yl) butanoic acid (from step 1) (0 .30 g, 0.68 mmol) and methylamine (2.0 M in dioxane, 0.68 mL, 1.35 mmol) were used to give 4- {5-chloro-4-[(2,4-difluorobenzyl) oxy ] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N-methylbutanamide to give a white solid (0.068 g, 22%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.58 (d, J = 6.71 Hz, 6H) 2.07 (m, 2H) 2.31 (t, J = 7.25 Hz, 2H) 2.70 (S, 3H) 2.88 (t, J = 7.52 Hz, 2H) 4.68 (m, 1H) 5.49 (s, 2H) 6.97 (m, 2H) 7.53 (m, 1H _{), ES-HRMS458.0923 (C 19} H 23 BrF 2 N 3 O M + H calcd for ₃ 458.0885).

Example 89

４−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ブタンアミド
４−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ブタンアミドの調製。４−（４−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−１，６−ジヒドロ−１−イソプロピル−６−オキソピリミジン−２−イル）ブタン酸（ステップ１）（０．３０ｇ、０．６８ミリモル）およびアンモニア（ジオキサン中０．５Ｍ、２．７ｍＬ、１．３５ミリモル）を利用し、４−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ブタンアミドのように調製して、白色固体（０．１４８ｇ、４９％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５８（ｄ，Ｊ＝６．７１Ｈｚ，６Ｈ）２．０６（ｍ，２Ｈ）２．３５（ｔ，Ｊ＝７．１２Ｈｚ，２Ｈ）２．８９（ｔ，Ｊ＝７．３８Ｈｚ，２Ｈ）４．６８（ｍ，１Ｈ）５．４９（ｓ，２Ｈ）６．９８（ｍ，２Ｈ）７．５５（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４４４．０７４０（Ｃ_１８Ｈ_２１ＢｒＦ_２Ｎ_３Ｏ_３に対するＭ＋Ｈ計算値は４４４．０７２９）。

4- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} butanamide 4- {5-Bromo-4- Preparation of [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} butanamide. 4- (4- (2,4-Difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-yl) butanoic acid (Step 1) (0.30 g, 0 .68 mmol) and ammonia (0.5 M in dioxane, 2.7 mL, 1.35 mmol) and 4- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl Prepared as -6-oxo-1,6-dihydropyrimidin-2-yl} butanamide to give a white solid (0.148 g, 49%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.58 (d, J = 6.71 Hz, 6H) 2.06 (m, 2H) 2.35 (t, J = 7.12 Hz, 2H) 2.89 (T, J = 7.38 Hz, 2H) 4.68 (m, 1H) 5.49 (s, 2H) 6.98 (m, 2H) 7.55 (m, 1H), ES-HRMS 444.0740 ( _{C 18 H 21 BrF 2 N 3} O 3 for M + H calculated value 444.0729).

(Example 90)

４−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−Ｎ−（２−ヒドロキシエチル）ブタンアミド
４−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−Ｎ−（２−ヒドロキシエチル）ブタンアミドの調製。４−（４−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−１，６−ジヒドロ−１−イソプロピル−６−オキソピリミジン−２−イル）ブタン酸（ステップ１）（０．３０ｇ、０．６８ミリモル）およびエタノールアミン（０．０８１ｍＬ、１．３５ミリモル）を利用し、４−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−Ｎ−（２−ヒドロキシエチル）ブタンアミドのように調製して、白色固体（０．１３１ｇ、３９％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５９（ｄ，Ｊ＝６．７１Ｈｚ，６Ｈ）２．０８（ｍ，２Ｈ）２．３６（ｔ，Ｊ＝７．２５Ｈｚ，２Ｈ）２．８９（ｔ，Ｊ＝７．５２Ｈｚ，２Ｈ）３．３０（ｍ，２Ｈ）３．５９（ｔ，Ｊ＝５．７７Ｈｚ，２Ｈ）４．６９（ｍ，１Ｈ）５．４９（ｓ，２Ｈ）６．９８（ｍ，２Ｈ）７．５４（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４８８．０９７６（Ｃ_２０Ｈ_２５ＢｒＦ_２Ｎ_３Ｏ_４に対するＭ＋Ｈ計算値は４８８．０９９１）。

4- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N- (2-hydroxyethyl) butanamide 4- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N- (2-hydroxyethyl) butanamide Preparation. 4- (4- (2,4-Difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-yl) butanoic acid (Step 1) (0.30 g, 0 .68 mmol) and ethanolamine (0.081 mL, 1.35 mmol) and 4- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo- Prepared like 1,6-dihydropyrimidin-2-yl} -N- (2-hydroxyethyl) butanamide to give a white solid (0.131 g, 39%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.59 (d, J = 6.71 Hz, 6H) 2.08 (m, 2H) 2.36 (t, J = 7.25 Hz, 2H) 2.89 (T, J = 7.52 Hz, 2H) 3.30 (m, 2H) 3.59 (t, J = 5.77 Hz, 2H) 4.69 (m, 1H) 5.49 (s, 2H) 6 .98 (m, 2H) 7.54 ( m, 1H), ES-HRMS488.0976 (M + H calcd for _{C 20 H 25 BrF 2 N 3} O 4 is 488.0991).

(Example 91)

２−［（１−アセチルピペリジン−４−イル）アミノ］−５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オン
ステップ１．４−（４−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−１，６−ジヒドロ−１−イソプロピル−６−オキソピリミジン−２−イルアミノ）ピペリジン−１−カルボン酸ｔ−ブチルの調製

2-[(1-Acetylpiperidin-4-yl) amino] -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one Step 1.4- Preparation of t-butyl (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) piperidine-1-carboxylate

６−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−３−イソプロピル−２−（メチルスルホニル）ピリミジン−４（３Ｈ）−オン（１．０ｇ、２．２９ミリモル）をジクロロメタン（１０ｍＬ）に溶解させた。トリエチルアミン（０．６４ｍＬ、２．０ミリモル）および４−アミノピペリジン−１−カルボン酸ｔ−ブチル（０．５０４ｇ、２．５２ミリモル）を加え、反応混合物を室温で終夜攪拌した。ＮａＨＣＯ_３の溶液を加えて反応を失活させ、次いで酢酸エチルに抽出した。有機抽出物を合わせてＭｇＳＯ_４で乾燥させ、濾過し、および濃縮した。残渣をクロマトグラフィー（シリカゲル、酢酸エチル／ヘキサン）によって精製して、黄色の固体（０．２８５ｇ、２２％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．４５（ｓ，９Ｈ）１．５１（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）１．８５（ｍ，２Ｈ）２．８３（ｍ，２Ｈ）４．０８（ｍ，４Ｈ）４．５７（ｍ，１Ｈ）５．２１（ｍ，１Ｈ）５．４３（ｓ，２Ｈ）７．００（ｍ，２Ｈ）７．４４（ｍ，１Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝３．５２分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ５５７（Ｍ＋１）。

6- (2,4-Difluorobenzyloxy) -5-bromo-3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (1.0 g, 2.29 mmol) in dichloromethane (10 mL). Dissolved. Triethylamine (0.64 mL, 2.0 mmol) and t-butyl 4-aminopiperidine-1-carboxylate (0.504 g, 2.52 mmol) were added and the reaction mixture was stirred at room temperature overnight. The reaction was quenched by the addition of a solution of NaHCO ₃ and then extracted into ethyl acetate. The organic extracts were combined, dried over MgSO ₄ , filtered, and concentrated. The residue was purified by chromatography (silica gel, ethyl acetate / hexane) to give a yellow solid (0.285 g, 22%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.45 (s, 9H) 1.51 (d, J = 6.98 Hz, 6H) 1.85 (m, 2H) 2.83 (m, 2H) 4 .08 (m, 4H) 4.57 (m, 1H) 5.21 (m, 1H) 5.43 (s, 2H) 7.00 (m, 2H) 7.44 (m, 1H). LC / _MS, t r = 3.52 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z557 (M + 1).

  Step 2. Preparation of 6- (2,4-difluorobenzyloxy) -5-bromo-3-isopropyl-2- (piperidin-4-ylamino) pyrimidin-4 (3H) -one ditrifluoroacetate

４−（４−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−１，６−ジヒドロ−１−イソプロピル−６−オキソピリミジン−２−イルアミノ）ピペリジン−１−カルボン酸ｔ−ブチル（ステップ１からのもの）（０．２７０ｇ、０．４９ミリモル）およびトリフルオロ酢酸（１ｍＬ）を利用し、２−［（３Ｓ）−３−アミノピロリジン−１−イル］−５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オンのように調製して、褐色の固体（０．３７４ｇ、＞１００％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５３（ｄ，Ｊ＝６．７１Ｈｚ，６Ｈ）１．８０（ｍ，２Ｈ）２．１５（ｍ，２Ｈ）３．０９（ｍ，２Ｈ）３．４５（ｍ，２Ｈ）４．１９（ｍ，１Ｈ）４．５５（ｍ，１Ｈ）５．４４（ｓ，２Ｈ）７．００（ｍ，２Ｈ）７．４９（ｍ，１Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝２．１０分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ４５７（Ｍ＋１）。

4- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) piperidine-1-carboxylate (step 1) 2) (0.270 g, 0.49 mmol) and trifluoroacetic acid (1 mL) and 2-[(3S) -3-aminopyrrolidin-1-yl] -5-chloro-6-[( Prepared as 2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one to give a brown solid (0.374 g,> 100%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.53 (d, J = 6.71 Hz, 6H) 1.80 (m, 2H) 2.15 (m, 2H) 3.09 (m, 2H) 3 .45 (m, 2H) 4.19 (m, 1H) 4.55 (m, 1H) 5.44 (s, 2H) 7.00 (m, 2H) 7.49 (m, 1H). LC / _MS, t r = 2.10 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z457 (M + 1).

Step 3. Preparation of 2-[(1-acetylpiperidin-4-yl) amino] -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one 6- (2,4-Difluorobenzyloxy) -5-bromo-3-isopropyl-2- (piperidin-4-ylamino) pyrimidin-4 (3H) -one di-trifluoroacetate (from step 2) ( 0.374 g, 0.5 mmol) and acetyl chloride (0.043 mL, 0.55 mmol) were used and N- [3-({5-bromo-4-[(2,4-difluorobenzyl) oxy] Prepared as in -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] acetamide (Step 2) to give a white solid (0.1 15 g, 46%). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 1.41 (m, 2H) 1.45 (d, J = 7.25 Hz, 6H) 2.11 (m, 2H) 2.11 (s, 3H) 77 (m, 1H) 3.19 (m, 1H) 3.80 (m, 1H) 4.07 (m, 1H) 4.51 (m, 1H) 4.83 (m, 1H) 5.39 ( s, 2H) 6.85 (m, 2H) 7.44 (m, 1H), ES-HRMS499.1143 (C 21 H 26 BrF 2 N 4 O 3 for M + H calculated value 499.1151).

(Example 92)

４−［（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）メチル］安息香酸メチル
４−［（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−ｙｌ｝アミノ）メチル］安息香酸メチルの調製。６−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−３−イソプロピル−２−（メチルスルホニル）ピリミジン−４（３Ｈ）−オン（２．００ｇ、４．５８ミリモル）をジクロロメタン（２３ｍＬ）に溶解させた。トリエチルアミン（１．９ｍＬ、１３．７４ミリモル）および４−（アミノメチル）安息香酸メチル（１．０１ｇ、５．０４ミリモル）を加え、室温で終夜攪拌した。反応液を失活させ、ＮａＨＣＯ_３の溶液を加え、次いで酢酸エチルに抽出した。有機抽出物を合わせてＭｇＳＯ_４で乾燥させ、濾過し、濃縮した。残渣をクロマトグラフィー（シリカゲル、酢酸エチル／ヘキサン）によって精製して、白色固体（０．６４４ｇ、２７％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δｐｐｍ １．４９（ｄ，Ｊ＝７．２５Ｈｚ，６Ｈ）３．９０（ｓ，３Ｈ）４．６８（ｄ，Ｊ＝５．１０Ｈｚ，２Ｈ）５．２５（ｓ，２Ｈ）５．７８（ｍ，１Ｈ）６．７０（ｍ，１Ｈ）６．８０（ｍ，１Ｈ）７．２９（ｍ，３Ｈ）７．９６（ｄ，Ｊ＝８．３２Ｈｚ，２Ｈ）、ＥＳ−ＨＲＭＳ５２２．０８５３（Ｃ_２３Ｈ_２３ＢｒＦ_２Ｎ_３Ｏ_４に対するＭ＋Ｈ計算値は５２２．０８３５）。

4-[({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) methyl] methyl benzoate 4 Preparation of methyl [-[({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidine-2-yl} amino) methyl] benzoate . 6- (2,4-Difluorobenzyloxy) -5-bromo-3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (2.00 g, 4.58 mmol) in dichloromethane (23 mL). Dissolved. Triethylamine (1.9 mL, 13.74 mmol) and methyl 4- (aminomethyl) benzoate (1.01 g, 5.04 mmol) were added and stirred at room temperature overnight. The reaction was quenched and a solution of NaHCO ₃ was added and then extracted into ethyl acetate. The combined organic extracts were dried over MgSO ₄ , filtered and concentrated. The residue was purified by chromatography (silica gel, ethyl acetate / hexane) to give a white solid (0.644 g, 27%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.49 (d, J = 7.25 Hz, 6H) 3.90 (s, 3H) 4.68 (d, J = 5.10 Hz, 2H) 5.25 ( s, 2H) 5.78 (m, 1H) 6.70 (m, 1H) 6.80 (m, 1H) 7.29 (m, 3H) 7.96 (d, J = 8.32 Hz, 2H) _{, ES-HRMS522.0853 (C 23 H} 23 BrF 2 N 3 O M + H calcd for ₄ 522.0835).

(Example 93)

５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−２−［（４−フルオロベンジル）アミノ］−３−イソプロピルピリミジン−４（３Ｈ）−オン
５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−２−［（４−フルオロベンジル）アミノ］−３−イソプロピルピリミジン−４（３Ｈ）−オンの調製。（４−フルオロフェニル）メタンアミン（０．５０ｇ、１．１４ミリモル）を利用し、４−［（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）メチル］安息香酸メチルのように調製して、淡いピンク色の固体（０．０５４ｇ、１１％）を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δｐｐｍ １．４６（ｄ，Ｊ＝７．２５Ｈｚ，６Ｈ）４．５９（ｄ，Ｊ＝５．０３Ｈｚ，２Ｈ）５．３３（ｓ，２Ｈ）５．３３（ｍ，１Ｈ）６．７５（ｍ，１Ｈ）６．８５（ｍ，１Ｈ）７．０２（ｍ，２Ｈ）７．２２（ｍ，２Ｈ）７．３７（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４８２．０６４５（Ｃ_２１Ｈ_２０ＢｒＦ_３Ｎ_３Ｏ_２に対するＭ＋Ｈ計算値は４８２．０６８５）。

5-Bromo-6-[(2,4-difluorobenzyl) oxy] -2-[(4-fluorobenzyl) amino] -3-isopropylpyrimidin-4 (3H) -one 5-bromo-6-[(2 , 4-Difluorobenzyl) oxy] -2-[(4-fluorobenzyl) amino] -3-isopropylpyrimidin-4 (3H) -one. Utilizing (4-fluorophenyl) methanamine (0.50 g, 1.14 mmol), 4-[({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6- Preparation like methyl oxo-1,6-dihydropyrimidin-2-yl} amino) methyl] benzoate gave a pale pink solid (0.054 g, 11%). ¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 1.46 (d, J = 7.25 Hz, 6H) 4.59 (d, J = 5.03 Hz, 2H) 5.33 (s, 2H) 5.33 ( m, 1H) 6.75 (m, 1H) 6.85 (m, 1H) 7.02 (m, 2H) 7.22 (m, 2H) 7.37 (m, 1H), ES-HRMS 482.0645 (M + H calculated for C ₂₁ H ₂₀ BrF ₃ N ₃ O ₂ is 482.0685).

(Example 94)

５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−２−［（３，３−ジメチルブチル）アミノ］−３−イソプロピルピリミジン−４（３Ｈ）−オン
５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−２−［（３，３−ジメチルブチル）アミノ］−３−イソプロピルピリミジン−４（３Ｈ）−オンの調製。３，３−ジメチルブタン−１−アミン（０．５０ｇ、１．１４ミリモル）を利用し、４−［（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）メチル］安息香酸メチルのように調製して、白色固体（０．０８４ｇ、１６％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δｐｐｍ ０．９６（ｓ，９Ｈ）１．４７（ｄ，Ｊ＝７．２５Ｈｚ，６Ｈ）１．４９（ｍ，２Ｈ）３．４５（ｍ，２Ｈ）４．７８（ｍ，１Ｈ）５．４２（ｓ，２Ｈ）６．８０（ｍ，１Ｈ）６．８９（ｍ，１Ｈ）７．４８（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４５８．１１０２（Ｃ_２０Ｈ_２７ＢｒＦ_２Ｎ_３Ｏ_２に対するＭ＋Ｈ計算値は４５８．１２５５）。

5-Bromo-6-[(2,4-difluorobenzyl) oxy] -2-[(3,3-dimethylbutyl) amino] -3-isopropylpyrimidin-4 (3H) -one 5-Bromo-6- [ Preparation of (2,4-difluorobenzyl) oxy] -2-[(3,3-dimethylbutyl) amino] -3-isopropylpyrimidin-4 (3H) -one. Utilizing 3,3-dimethylbutan-1-amine (0.50 g, 1.14 mmol), 4-[({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl. Prepared as methyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) methyl] benzoate to give a white solid (0.084 g, 16%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.96 (s, 9H) 1.47 (d, J = 7.25 Hz, 6H) 1.49 (m, 2H) 3.45 (m, 2H) 78 (m, 1H) 5.42 ( s, 2H) 6.80 (m, 1H) 6.89 (m, 1H) 7.48 (m, 1H), ES-HRMS458.1102 (C 20 H 27 BrF ₂ N ₃ O ₂ for M + H calculated value 458.1255).

(Example 95)

Ｎ〜２〜−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝グリシンアミド
Ｎ〜２〜−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝グリシンアミドの調製。５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（メチルスルホニル）ピリミジン−４（３Ｈ）−オン（１．７３ｇ、３．９ミリモル）をジメチルホルムアミド（１０ｍＬ）に溶解させ、トリエチルアミン（１．９５ｍＬ、１４．０ミリモル）および２−アミノアセトアミド塩酸塩（１．５４ｇ、１４．０ミリモル）をジメチルホルムアミド（２０ｍＬ）に懸濁させた懸濁液に室温でゆっくりと加えた。１０分後、水を加えて反応を失活させ、次いで酢酸エチルに抽出した。有機抽出物を合わせてＭｇＳＯ_４で乾燥させ、濾過し、濃縮した。固体を少量の酢酸エチルで洗浄し、濾過して、白色固体（０．１６４ｇ、３３％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５６（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）４．０３（ｓ，２Ｈ）４．８２（ｍ，１Ｈ）５．３９（ｓ，２Ｈ）６．９８（ｍ，２Ｈ）７．５１（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ３８７．０９９５（Ｃ_１６Ｈ_１８ＣｌＦ_２Ｎ_４Ｏ_３に対するＭ＋Ｈ計算値は３８７．１０３０）。

N ~ 2- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} glycinamide N ~ 2- Preparation of {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} glycinamide. 5-Chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (1.73 g, 3.9 mmol) was converted to dimethylformamide ( In a suspension of triethylamine (1.95 mL, 14.0 mmol) and 2-aminoacetamide hydrochloride (1.54 g, 14.0 mmol) in dimethylformamide (20 mL) at room temperature. Slowly added. After 10 minutes, water was added to quench the reaction and then extracted into ethyl acetate. The combined organic extracts were dried over MgSO ₄ , filtered and concentrated. The solid was washed with a small amount of ethyl acetate and filtered to give a white solid (0.164 g, 33%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.56 (d, J = 6.98 Hz, 6H) 4.03 (s, 2H) 4.82 (m, 1H) 5.39 (s, 2H) 6 .98 (m, 2H) 7.51 ( m, 1H), ES-HRMS387.0995 (M + H calcd for _{C 16 H 18 ClF 2 N 4} O 3 is 387.1030).

Example 96

Ｎ〜２〜−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−Ｎ〜１〜−（２−ヒドロキシエチル）グリシンアミド
ステップ１．２−（４−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−１，６−ジヒドロ−１−イソプロピル−６−オキソピリミジン−２−イルアミノ）酢酸エチルの調製

N ~ 2- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N ~ 1- ( 2-Hydroxyethyl) glycinamide Step 1.2- (4- (2,4-Difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) ethyl acetate Preparation of

６−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−３−イソプロピル−２−（メチルスルホニル）ピリミジン−４（３Ｈ）−オン（１．７５ｇ、１２．６ミリモル）および２−アミノ酢酸エチル塩酸塩（１．７５ｇ、１２．６ミリモル）を利用し、Ｎ〜３〜−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−β−アラニンアミド（ステップ１）のように調製して、透明な油状物（１．８ｇ、３４％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δｐｐｍ １．３１（ｔ，Ｊ＝７．１２Ｈｚ，３Ｈ）１．５１（ｄ，Ｊ＝７．２５Ｈｚ，６Ｈ）４．１５（ｄ，Ｊ＝４．５７Ｈｚ，２Ｈ）４．２６（ｑ，Ｊ＝７．２５Ｈｚ，２Ｈ）５．３６（ｓ，２Ｈ）５．６７（ｍ，１Ｈ）６．８３（ｍ，２Ｈ）７．４６（ｍ，１Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝２．９６分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ４６０（Ｍ＋１）。

6- (2,4-Difluorobenzyloxy) -5-bromo-3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (1.75 g, 12.6 mmol) and ethyl 2-aminoacetate Hydrochloric acid salt (1.75 g, 12.6 mmol) was utilized and N-3-3- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1, Prepared as 6-dihydropyrimidin-2-yl} -β-alaninamide (Step 1) to give a clear oil (1.8 g, 34%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.31 (t, J = 7.12 Hz, 3H) 1.51 (d, J = 7.25 Hz, 6H) 4.15 (d, J = 4.57 Hz, 2H) 4.26 (q, J = 7.25 Hz, 2H) 5.36 (s, 2H) 5.67 (m, 1H) 6.83 (m, 2H) 7.46 (m, 1H). LC / _MS, t r = 2.96 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z460 (M + 1).

  Step 2.2-Preparation of (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) acetic acid

２−（４−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−１，６−ジヒドロ−１−イソプロピル−６−オキソピリミジン−２−イルアミノ）酢酸エチル（ステップ１からのもの）（１．７３ｇ、３．９ミリモル）および２．５Ｎ ＮａＯＨ（１６．０ｍＬ、３９．０ミリモル）を利用し、Ｎ〜３〜−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−β−アラニンアミド（ステップ２）のように調製して、白色固体（１．１９ｇ、７１％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５５（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）４．０９（ｓ，２Ｈ）４．８９（ｍ，１Ｈ）５．３６（ｓ，２Ｈ）６．９６（ｍ，２Ｈ）７．４９（ｍ，１Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝２．５７分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ４３２（Ｍ＋１）。

2- (4- (2,4-Difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) ethyl acetate (from step 1) (1. 73 g, 3.9 mmol) and 2.5 N NaOH (16.0 mL, 39.0 mmol) were utilized to obtain N-3-{5-bromo-4-[(2,4-difluorobenzyl) oxy]- Prepared as 1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -β-alaninamide (Step 2) to give a white solid (1.19 g, 71%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.55 (d, J = 6.98 Hz, 6H) 4.09 (s, 2H) 4.89 (m, 1H) 5.36 (s, 2H) 6 .96 (m, 2H) 7.49 (m, 1H). LC / _MS, t r = 2.57 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z432 (M + 1).

Step 3. N ~ 2- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidine-2-yl} -N ~ 1- ( Preparation of 2-hydroxyethyl) glycinamide 2- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) acetic acid (step 2) (0.39 g, 0.90 mmol) and ethanolamine (0.11 mL, 1.81 mmol) were used to give 4- {5-chloro-4-[(2,4-difluorobenzyl) Oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N-[(2R) -2-hydroxypropyl] butanamide A solid (0.269 g, 63%) is obtained. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.56 (d, J = 6.98 Hz, 6H) 3.31 (m, 2H) 3.57 (t, J = 5.77 Hz, 2H) 4.04 (s, 2H) 4.85 (m , 1H) 5.35 (s, 2H) 6.98 (m, 2H) 7.50 (m, 1H), ES-HRMS475.0822 (C 18 H 22 BrF 2 The calculated M + H value for N ₄ O ₄ is 475.0787).

(Example 97)

６−（２，４−ジフルオロベンジルオキシ）−２−（２−オキソ−２−（ピロリジン−１−イル）エチルアミノ）−５−ブロモ−３−イソプロピルピリミジン−４（３Ｈ）−オン
６−（２，４−ジフルオロベンジルオキシ）−２−（２−オキソ−２−（ピロリジン−１−ｙｌ）エチルアミノ）−５−ブロモ−３−イソプロピルピリミジン−４（３Ｈ）−オンの調製。２−（４−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−１，６−ジヒドロ−１−イソプロピル−６−オキソピリミジン−２−イルアミノ）酢酸（Ｎ〜２〜−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−Ｎ〜１〜−（２−ヒドロキシエチル）グリシンアミド ステップ２からのもの）（０．３９ｇ、０．９ミリモル）およびピロリジン（０．１５ｍＬ、１．８１ミリモル）を利用し、４−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−Ｎ−［（２Ｒ）−２−ヒドロキシプロピル］ブタンアミドのように調製して、淡黄色の固体（０．３８５ｇ、８９％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５６（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）１．８６（ｍ，２Ｈ）２．００（ｍ，２Ｈ）３．４２（ｔ，Ｊ＝６．９８Ｈｚ，２Ｈ）３．５３（ｔ，Ｊ＝６．７１Ｈｚ，２Ｈ）４．１５（ｓ，２Ｈ）５．００（ｍ，１Ｈ）５．３５（ｓ，２Ｈ）６．９９（ｍ，２Ｈ）７．４８（ｍ，１Ｈ），ＥＳ−ＨＲＭＳ４８５．０９８５（Ｃ_２０Ｈ_２４ＢｒＦ_２Ｎ_４Ｏ_３に対するＭ＋Ｈ計算値は４８５．０９９４）。

6- (2,4-Difluorobenzyloxy) -2- (2-oxo-2- (pyrrolidin-1-yl) ethylamino) -5-bromo-3-isopropylpyrimidin-4 (3H) -one 6- ( Preparation of 2,4-difluorobenzyloxy) -2- (2-oxo-2- (pyrrolidin-1-yl) ethylamino) -5-bromo-3-isopropylpyrimidin-4 (3H) -one. 2- (4- (2,4-Difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) acetic acid (N-2-{5-bromo- 4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N to 1- (2-hydroxyethyl) glycinamide from step 2 ) (0.39 g, 0.9 mmol) and pyrrolidine (0.15 mL, 1.81 mmol) to give 4- {5-chloro-4-[(2,4-difluorobenzyl) oxy]- Prepared like 1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N-[(2R) -2-hydroxypropyl] butanamide and prepared as a pale yellow solid (0.38 5 g, 89%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.56 (d, J = 6.98 Hz, 6H) 1.86 (m, 2H) 2.00 (m, 2H) 3.42 (t, J = 6 .98 Hz, 2H) 3.53 (t, J = 6.71 Hz, 2H) 4.15 (s, 2H) 5.00 (m, 1H) 5.35 (s, 2H) 6.99 (m, 2H) ) 7.48 (m, 1H), ES-HRMS485.0985 (C 20 H 24 BrF 2 N 4 O 3 for M + H calculated value 485.0994).

(Example 98)

５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−２−（４−ヒドロキシブトキシ）−３−イソプロピルピリミジン−４（３Ｈ）−オン
５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−２−（４−ヒドロキシブトキシ）−３−イソプロピルピリミジン−４（３Ｈ）−オンの調製。５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（メチルスルホニル）ピリミジン−４（３Ｈ）−オン（５．０ｇ、１２．８ミリモル）およびブタン−１，４−ジオール（１．２４ｍＬ、１４．０ミリモル）を利用し、２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチルカルバミン酸ｔ−ブチルのように調製して、白色固体（２．９８ｇ、５８％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．４５（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）１．７０（ｍ，２Ｈ）１．８８（ｍ，２Ｈ）３．６２（ｔ，Ｊ＝６．４４Ｈｚ，２Ｈ）４．５２（ｔ，Ｊ＝６．５８Ｈｚ，２Ｈ）５．３０（ｍ，１Ｈ）５．４８（ｓ，２Ｈ）６．９８（ｍ，２Ｈ）７．５２（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４０３．１２１２（Ｃ_１８Ｈ_２２ＣｌＦ_２Ｎ_２Ｏ_４に対するＭ＋Ｈ計算値は４０３．１２３１）。

5-chloro-6-[(2,4-difluorobenzyl) oxy] -2- (4-hydroxybutoxy) -3-isopropylpyrimidin-4 (3H) -one 5-chloro-6-[(2,4- Preparation of difluorobenzyl) oxy] -2- (4-hydroxybutoxy) -3-isopropylpyrimidin-4 (3H) -one. 5-chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (5.0 g, 12.8 mmol) and butane-1 , 4-diol (1.24 mL, 14.0 mmol) and 2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1, Prepared as t-butyl 6-dihydropyrimidin-2-yl} oxy) ethylcarbamate to give a white solid (2.98 g, 58%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.45 (d, J = 6.98 Hz, 6H) 1.70 (m, 2H) 1.88 (m, 2H) 3.62 (t, J = 6 .44 Hz, 2H) 4.52 (t, J = 6.58 Hz, 2H) 5.30 (m, 1H) 5.48 (s, 2H) 6.98 (m, 2H) 7.52 (m, 1H) _{), ES-HRMS403.1212 (C 18} H 22 ClF 2 N 2 O M + H calcd for ₄ 403.1231).

Example 99

４−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）ブタン酸
４−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）ブタン酸の調製。５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−２−（４−ヒドロキシブトキシ）−３−イソプロピルピリミジン−４（３Ｈ）−オン（２．９８ｇ、７．４ミリモル）および二クロム酸ピリジニウム（９．７４ｇ、２５．９ミリモル）を利用し、４−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝ブタン酸のように調製して、白色固体（０．６１５ｇ、２０％）を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．４５（ｄ，Ｊ＝７．０５Ｈｚ，６Ｈ）２．１２（ｍ，２Ｈ）２．４８（ｔ，Ｊ＝７．１５Ｈｚ，２Ｈ）４．５４（ｔ，Ｊ＝６．４４Ｈｚ，２Ｈ）５．２８（ｍ，１Ｈ）５．４８（ｓ，２Ｈ）７．００（ｍ，２Ｈ）７．５３（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４１７．１０２８（Ｃ_１８Ｈ_２０ＣｌＦ_２Ｎ_２Ｏ_５に対するＭ＋Ｈ計算値は４１７．１０２３）。

4-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) butanoic acid 4-({5 Preparation of -chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) butanoic acid. 5-Chloro-6-[(2,4-difluorobenzyl) oxy] -2- (4-hydroxybutoxy) -3-isopropylpyrimidin-4 (3H) -one (2.98 g, 7.4 mmol) and two Utilizing pyridinium chromate (9.74 g, 25.9 mmol), 4- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6- Prepared like dihydropyrimidin-2-yl} butanoic acid to give a white solid (0.615 g, 20%). ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 1.45 (d, J = 7.05 Hz, 6H) 2.12 (m, 2H) 2.48 (t, J = 7.15 Hz, 2H) 4.54 (T, J = 6.44 Hz, 2H) 5.28 (m, 1H) 5.48 (s, 2H) 7.00 (m, 2H) 7.53 (m, 1H), ES-HRMS 417.1028 ( _{C 18 H 20 ClF 2 N 2} O M + H calcd for ₅ 417.1023).

(Example 100)

Ｎ−［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチル］−Ｎ’−メチル尿素
Ｎ−［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチル］−Ｎ’−メチル尿素の調製。６−（２，４−ジフルオロベンジルオキシ）−２−（３−アミノプロポキシ）−５−クロロ−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸（２−｛［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチル］アミノ｝−２−オキソエチルアセタート、ステップ１からのもの）（０．５０ｇ、１．０３ミリモル）をジメチルアセトアミド（１５ｍＬ）に溶解させ、氷浴で冷却した。ジイソプロピルエチルアミン（０．４８０ｍＬ、２．７ミリモル）およびクロロギ酸４−ニトロフェニル（０．３１０ｇ、１．５４ミリモル）を加え、得られる混合物を冷却しながら１０分間攪拌した。メチルアミン（テトラヒドロフラン中２．０Ｍ、１．５ｍＬ）を加え、反応混合物を一晩かけて室温に温めた。水を加えて反応を失活させ、次いで酢酸エチルに抽出した。有機抽出物を合わせてＭｇＳＯ_４で乾燥させ、濾過し、濃縮した。残渣をクロマトグラフィー（シリカゲル、酢酸エチル／ヘキサン）によって精製して、赤褐色の固体（０．０９３ｇ、２１％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．４５（ｄ，Ｊ＝６．７１Ｈｚ，６Ｈ）２．６７（ｓ，３Ｈ）３．５６（ｔ，Ｊ＝４．９７Ｈｚ，２Ｈ）４．５２（ｔ，Ｊ＝５．１０Ｈｚ，２Ｈ）５．２８（ｍ，１Ｈ）５．４７（ｓ，２Ｈ）７．００（ｍ，２Ｈ）７．５４（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４３１．１２９７（Ｃ_１８Ｈ_２２ＣｌＦ_２Ｎ_４Ｏ_４に対するＭ＋Ｈ計算値は４３１．１２９２）。

N- [2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] -N '-Methylurea N- [2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) Preparation of [ethyl] -N'-methylurea. 6- (2,4-Difluorobenzyloxy) -2- (3-aminopropoxy) -5-chloro-3-isopropylpyrimidine-4 (3H) -one trifluoroacetic acid (2-{[2-({5- Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] amino} -2-oxoethyl acetate, step 1) (0.50 g, 1.03 mmol) was dissolved in dimethylacetamide (15 mL) and cooled in an ice bath. Diisopropylethylamine (0.480 mL, 2.7 mmol) and 4-nitrophenyl chloroformate (0.310 g, 1.54 mmol) were added and the resulting mixture was stirred for 10 minutes with cooling. Methylamine (2.0 M in tetrahydrofuran, 1.5 mL) was added and the reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched by adding water and then extracted into ethyl acetate. The combined organic extracts were dried over MgSO ₄ , filtered and concentrated. The residue was purified by chromatography (silica gel, ethyl acetate / hexane) to give a reddish brown solid (0.093 g, 21%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.45 (d, J = 6.71 Hz, 6H) 2.67 (s, 3H) 3.56 (t, J = 4.97 Hz, 2H) 4.52 (T, J = 5.10 Hz, 2H) 5.28 (m, 1H) 5.47 (s, 2H) 7.00 (m, 2H) 7.54 (m, 1H), ES-HRMS 431.1297 ( _{C 18 H 22 ClF 2 N 4} O M + H calculated for ₄ 431.1292).

(Example 101)

Ｎ−［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチル］−Ｎ’−（２−ヒドロキシエチル）尿素
Ｎ−［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチル］−Ｎ’−（２−ヒドロキシエチル）尿素の調製。エタノールアミン（０．１９ｍＬ、３．０９ミリモル）を利用し、Ｎ−［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチル］−Ｎ’−メチル尿素のように調製して、褐色の固体（０．１０１ｇ、２１％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．４５（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）３．２２（ｔ，Ｊ＝５．７７Ｈｚ，２Ｈ）３．５６（ｑ，Ｊ＝５．６４Ｈｚ，４Ｈ）４．５２（ｔ，Ｊ＝５．３７Ｈｚ，２Ｈ）５．２８（ｍ，１Ｈ）５．４７（ｓ，２Ｈ）７．００（ｍ，２Ｈ）７．５４（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４６１．１４２８（Ｃ_１９Ｈ_２４ＣｌＦ_２Ｎ_４Ｏ_５に対するＭ＋Ｈ計算値は１３９８）。

N- [2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] -N '-(2-hydroxyethyl) urea N- [2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidine-2 Preparation of -yl} oxy) ethyl] -N '-(2-hydroxyethyl) urea. Ethanolamine (0.19 mL, 3.09 mmol) was utilized and N- [2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1 , 6-Dihydropyrimidin-2-yl} oxy) ethyl] -N′-methylurea to give a brown solid (0.101 g, 21%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.45 (d, J = 6.98 Hz, 6H) 3.22 (t, J = 5.77 Hz, 2H) 3.56 (q, J = 5.64 Hz) , 4H) 4.52 (t, J = 5.37 Hz, 2H) 5.28 (m, 1H) 5.47 (s, 2H) 7.00 (m, 2H) 7.54 (m, 1H), _{ES-HRMS461.1428 (C 19 H 24} ClF 2 N 4 O M + H calcd for ₅ 1398).

(Example 102)

４−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）ブタンアミド
４−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）ブタンアミドの調製。４−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）ブタン酸（０．３０ｇ、０．７２ミリモル）およびアンモニア（ジオキサン中０．５Ｍ、２．８ｍＬ、１．４ミリモル）を利用し、Ｎ〜３〜−｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−β−アラニンアミドのように調製して、白色固体（０．２２０ｇ、７４％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．４６（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）２．１３（ｍ，２Ｈ）２．３９（ｔ，Ｊ＝７．３８Ｈｚ，２Ｈ）４．５３（ｔ，Ｊ＝６．４４Ｈｚ，２Ｈ）５．２８（ｍ，１Ｈ）５．４７（ｓ，２Ｈ）６．９８（ｍ，２Ｈ）７．５３（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４１６．１１７１（Ｃ_１８Ｈ_２１ＣｌＦ_２Ｎ_３Ｏ_４に対するＭ＋Ｈ計算値は４１６．１１８３）。

4-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) butanamide 4-({5- Preparation of chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) butanamide. 4-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) butanoic acid (0.30 g, 0.72 mmol) and ammonia (0.5 M in dioxane, 2.8 mL, 1.4 mmol), and N-3-3- {5-bromo-4-[(2,4-difluorobenzyl) oxy] Prepared as -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -β-alaninamide to give a white solid (0.220 g, 74%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.46 (d, J = 6.98 Hz, 6H) 2.13 (m, 2H) 2.39 (t, J = 7.38 Hz, 2H) 4.53 (T, J = 6.44 Hz, 2H) 5.28 (m, 1H) 5.47 (s, 2H) 6.98 (m, 2H) 7.53 (m, 1H), ES-HRMS 416.1171 ( M + H calculated for C ₁₈ H ₂₁ ClF ₂ N ₃ O ₄ is 416.1183).

(Example 103)

４−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）−Ｎ−（２−ヒドロキシエチル）ブタンアミド
４−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）−Ｎ−（２−ヒドロキシエチル）ブタンアミドの調製。４−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）ブタン酸（０．３０ｇ、０．７２ミリモル）およびエタノールアミン（０．０８５ｍＬ、１．４ミリモル）を利用し、４−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−Ｎ−（２−ヒドロキシエチル）ブタンアミドのように調製して、明るい赤色の油（０．１３１ｇ、４０％）を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．４６（ｄ，Ｊ＝７．０５Ｈｚ，６Ｈ）２．１３（ｍ，２Ｈ）２．３９（ｔ，Ｊ＝７．３５Ｈｚ，２Ｈ）３．３０（ｍ，２Ｈ）３．５８（ｔ，Ｊ＝５．７４Ｈｚ，２Ｈ）４．５２（ｔ，Ｊ＝６．４４Ｈｚ，２Ｈ）５．２９（ｍ，１Ｈ）５．４７（ｓ，２Ｈ）６．９９（ｍ，２Ｈ）７．５３（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４６０．１４５７（Ｃ_２０Ｈ_２５ＣｌＦ_２Ｎ_３Ｏ_５に対するＭ＋Ｈ計算値は４６０．１４４５）。

4-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) -N- (2-hydroxy Ethyl) butanamide 4-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) -N- ( Preparation of 2-hydroxyethyl) butanamide. 4-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) butanoic acid (0.30 g, 0.72 mmol) and ethanolamine (0.085 mL, 1.4 mmol) were used and 4- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo Prepared like -1,6-dihydropyrimidin-2-yl} -N- (2-hydroxyethyl) butanamide to give a bright red oil (0.131 g, 40%). ¹ H NMR (300 MHz, CD ₃ OD) δ ppm 1.46 (d, J = 7.05 Hz, 6H) 2.13 (m, 2H) 2.39 (t, J = 7.35 Hz, 2H) 3.30 (M, 2H) 3.58 (t, J = 5.74 Hz, 2H) 4.52 (t, J = 6.44 Hz, 2H) 5.29 (m, 1H) 5.47 (s, 2H) 6 .99 (m, 2H) 7.53 ( m, 1H), ES-HRMS460.1457 (M + H calcd for _{C 20 H 25 ClF 2 N 3} O 5 is 460.1445).

(Example 104)

２−［（２−アミノエチル）アミノ］−５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸塩
ステップ１．２−（４−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−１，６−ジヒドロ−１−イソプロピル−６−オキソピリミジン−２−イルアミノ）エチルカルバミン酸ｔ−ブチルの調製

2-[(2-Aminoethyl) amino] -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one trifluoroacetate salt Step 1.2- Preparation of t-butyl (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) ethylcarbamate

６−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−３−イソプロピル−２−（メチルスルホニル）ピリミジン−４（３Ｈ）−オン（１．７７ｇ、４．１ミリモル）をジオキサン（４０ｍＬ）に溶解させ、２−アミノエチルカルバミン酸ｔ−ブチル（１．３ｍＬ、８．２ミリモル）を加えた。２時間後、溶媒を除去し、次いで残渣を酢酸エチルに溶解させ、水で洗浄した。水層を酢酸エチル抽出した。有機抽出物を合わせてＭｇＳＯ_４で乾燥させ、濾過し、濃縮した。残渣を酢酸エチルに溶解させ、シリカゲルパッドで濾して、所望の生成物（１．９５ｇ、９０％）を得た。ＬＣ／ＭＳ，ｔ_ｒ＝３．１６分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ５１７（Ｍ＋１）。

6- (2,4-Difluorobenzyloxy) -5-bromo-3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (1.77 g, 4.1 mmol) in dioxane (40 mL). Dissolve and add t-butyl 2-aminoethylcarbamate (1.3 mL, 8.2 mmol). After 2 hours, the solvent was removed, then the residue was dissolved in ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over MgSO ₄ , filtered and concentrated. The residue was dissolved in ethyl acetate and filtered through a silica gel pad to give the desired product (1.95 g, 90%). LC / _MS, t r = 3.16 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z517 (M + 1).

Step 2.2-Preparation of [(2-aminoethyl) amino] -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one trifluoroacetate T-Butyl 2- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) ethylcarbamate (from step 1) ) (1.95 g, 3.8 mmol) and trifluoroacetic acid (1 mL) to give 2-{[2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1- Prepared like isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] amino} -2-oxoethyl acetate (Step 1) Yielded solid (1.96 g, 87%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.51 (d, J = 6.71 Hz, 6H) 3.20 (t, J = 5.91 Hz, 2H) 3.74 (t, J = 6.04 Hz) , 2H) 4.61 (m, 1H) 5.43 (s, 2H) 6.98 (m, 2H) 7.51 (m, 1H), ES-HRMS 417.0749 (C ₁₆ H ₂₀ BrF ₂ N ₄ M + H calculated for O ₂ is 417.0732).

(Example 105)

Ｎ−［２−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）エチル］尿素
Ｎ−［２−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）エチル］尿素の調製。２−［（２−アミノエチル）アミノ］−５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸塩（０．３ｇ、０．７ミリモル）をジクロロメタン（４ｍＬ）に溶解させ、トリエチルアミン（０．２ｍＬ、１．４４ミリモル）を加えた。混合物にイソシアン酸トリメチルシリル（０．１３ｍＬ、１．０８ミリモル）を加え、室温で４５分間攪拌した。生成した沈殿を濾過によって収集し、水およびエーテルで洗浄して、白色固体（０．２２５ｇ、６８％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５３（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）３．３５（ｔ，Ｊ＝５．７７Ｈｚ，２Ｈ）３．４９（ｔ，Ｊ＝５．７７Ｈｚ，２Ｈ）４．７４（ｍ，１Ｈ）５．４３（ｓ，２Ｈ）６．９８（ｍ，２Ｈ）７．５１（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳｍ／ｚ４６０．０８０３（Ｃ_１７Ｈ_２１ＢｒＦ_２Ｎ_５Ｏ_３に対する計算値は４６０．０７９０）。

N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] urea N Preparation of-[2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] urea . 2-[(2-aminoethyl) amino] -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one trifluoroacetate (0.3 g, 0.7 mmol) was dissolved in dichloromethane (4 mL) and triethylamine (0.2 mL, 1.44 mmol) was added. Trimethylsilyl isocyanate (0.13 mL, 1.08 mmol) was added to the mixture and stirred at room temperature for 45 minutes. The resulting precipitate was collected by filtration and washed with water and ether to give a white solid (0.225 g, 68%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.53 (d, J = 6.98 Hz, 6H) 3.35 (t, J = 5.77 Hz, 2H) 3.49 (t, J = 5.77 Hz) , 2H) 4.74 (m, 1H ) 5.43 (s, 2H) 6.98 (m, 2H) 7.51 (m, 1H), ES-HRMSm / z460.0803 (C 17 H 21 BrF 2 calcd for N ₅ O ₃ is 460.0790).

(Example 106)

Ｎ−［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）エチル］アセトアミド
Ｎ−［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）エチル］アセトアミドの調製。２−［（２−アミノエチル）アミノ］−５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸塩（０．３０１ｇ、０．７２ミリモル）および塩化アセチル（０．０９０ｍＬ、１．０８ミリモル）を利用して、Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］アセトアミドのように調製した。未精製の残渣をクロマトグラフィー（シリカゲル、酢酸エチル／ヘキサン）によって精製して、白色固体（０．０６８ｇ、２０％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５２（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）１．９３（ｓ，３Ｈ）３．３９（ｔ，Ｊ＝５．９１Ｈｚ，２Ｈ）３．５２（ｔ，Ｊ＝５．９１Ｈｚ，２Ｈ）４．７４（ｍ，１Ｈ）５．４４（ｓ，２Ｈ）６．９８（ｍ，２Ｈ）７．５１（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４１５．１３２１（Ｃ_１８Ｈ_２２ＣｌＦ_２Ｎ_４Ｏ_３に対するＭ＋Ｈ計算値は４１５．１３４３）。クロマトグラフィーの後、ＬＣＭＳでは、臭化物の代わりに塩化物同位体のサインに相当する質量が示される。高分解能ＭＳによって塩化物への交換が確認される。

N- [2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] acetamide N -[2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] acetamide . 2-[(2-aminoethyl) amino] -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one trifluoroacetate (0.301 g, 0.72-mmol) and acetyl chloride (0.090 mL, 1.08 mmol) to give N- [3-({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1- Isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] acetamide. The crude residue was purified by chromatography (silica gel, ethyl acetate / hexane) to give a white solid (0.068 g, 20%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.52 (d, J = 6.98 Hz, 6H) 1.93 (s, 3H) 3.39 (t, J = 5.91 Hz, 2H) 3.52 (T, J = 5.91 Hz, 2H) 4.74 (m, 1H) 5.44 (s, 2H) 6.98 (m, 2H) 7.51 (m, 1H), ES-HRMS 415.1321 ( _{C 18 H 22 ClF 2 N 4} O 3 for M + H calculated value 415.1343). After chromatography, LCMS shows the mass corresponding to the chloride isotope signature instead of bromide. High resolution MS confirms exchange for chloride.

(Example 107)

Ｎ−［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）エチル］メタンスルホンアミド
Ｎ−［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）エチル］メタンスルホンアミドの調製。２−［（２−アミノエチル）アミノ］−５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸塩（０．２９９ｇ、０．７２ミリモル）および塩化メタンスルホニル（０．０９０、１．０８ミリモル）を利用し、Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］メタンスルホンアミドのように調製して、淡黄色の固体（０．０９４ｇ、２９％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５３（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）２．９０（ｓ，３Ｈ）３．２６（ｔ，Ｊ＝６．１８Ｈｚ，２Ｈ）３．５５（ｍ，２Ｈ）４．７４（ｍ，１Ｈ）５．４４（ｓ，２Ｈ）６．９６（ｍ，２Ｈ）７．５０（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４５１．０９８９（Ｃ_１７Ｈ_２２ＣｌＦ_２Ｎ_４Ｏ_４Ｓに対するＭ＋Ｈ計算値は４５１．１０１３）。Ｎ−［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）エチル］アセトアミドで見られたのと同じ臭化物→塩化物交換。

N- [2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] methanesulfone Amido N- [2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] methane Preparation of sulfonamides. 2-[(2-aminoethyl) amino] -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one trifluoroacetate (0.299 g, 0.72 mmol) and methanesulfonyl chloride (0.090, 1.08 mmol) and N- [3-({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1- Preparation like isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] methanesulfonamide gave a pale yellow solid (0.094 g, 29%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.53 (d, J = 6.98 Hz, 6H) 2.90 (s, 3H) 3.26 (t, J = 6.18 Hz, 2H) 3.55 (m, 2H) 4.74 (m , 1H) 5.44 (s, 2H) 6.96 (m, 2H) 7.50 (m, 1H), ES-HRMS451.0989 (C 17 H 22 ClF 2 The calculated M + H for N ₄ O ₄ S is 451.1013). With N- [2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] acetamide Same bromide → chloride exchange as seen.

(Example 108)

Ｎ−［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）エチル］−２−ヒドロキシアセトアミド
ステップ１．（２−（４−（２，４−ジフルオロベンジルオキシ）−５−クロロ−１，６−ジヒドロ−１−イソプロピル−６−オキソピリミジン−２−イルアミノ）ジエチルカルバモイル）メチルアセタートの調製

N- [2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] -2 -Hydroxyacetamide Step 1. Preparation of (2- (4- (2,4-difluorobenzyloxy) -5-chloro-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) diethylcarbamoyl) methyl acetate

２−［（２−アミノエチル）アミノ］−５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸塩（０．３００ｇ、０．７２ミリモル）および酢酸（クロロカルボニル）メチル（０．１１８ｍＬ、１．０８ミリモル）を利用し、Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］−２−ヒドロキシアセトアミド（ステップ１）のように調製して、オフホワイトの固体（０．１８１ｇ、４４％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５１（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）２．０７（ｓ，６Ｈ）３．６９（ｔ，Ｊ＝６．０４Ｈｚ，２Ｈ）３．９１（ｔ，Ｊ＝５．９１Ｈｚ，２Ｈ）４．６２（ｍ，１Ｈ）４．９５（ｓ，４Ｈ）５．４４（ｓ，２Ｈ）６．９８（ｍ，２Ｈ）７．５１（ｍ，１Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝２．８５分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ５７３（Ｍ＋１）。Ｎ−［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）エチル］アセトアミドで見られるのと同じ臭化物→塩化物交換。

2-[(2-aminoethyl) amino] -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one trifluoroacetate (0.300 g, 0.72-mmol) and (chlorocarbonyl) methyl acetate (0.118 mL, 1.08 mmol) were used to give N- [3-({5-bromo-4-[(2,4-difluorobenzyl) oxy] Prepared as in -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2-hydroxyacetamide (Step 1) to give an off-white solid (0.181 g, 44 %). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.51 (d, J = 6.98 Hz, 6H) 2.07 (s, 6H) 3.69 (t, J = 6.04 Hz, 2H) 3.91 (T, J = 5.91 Hz, 2H) 4.62 (m, 1H) 4.95 (s, 4H) 5.44 (s, 2H) 6.98 (m, 2H) 7.51 (m, 1H ). LC / _MS, t r = 2.85 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z573 (M + 1). With N- [2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] acetamide The same bromide → chloride exchange seen.

Step 2. N- [2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] -2 Preparation of 2-hydroxyacetamide (2- (4- (2,4-difluorobenzyloxy) -5-chloro-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) ethylcarbamoyl) methyl acetate (From step 1) (0.181 g, 0.32 mmol) and K ₂ CO ₃ (0.065 g, 0.47 mmol) were used to give N- [3-({5-bromo-4- [ (2,4-Difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2-hydroxyacetoa De was prepared as (Step 2) to give an off-white solid (0.100 g, 73%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.51 (d, J = 6.71 Hz, 6H) 3.48 (t, J = 6.58 Hz, 2H) 3.57 (t, J = 5.64 Hz) , 2H) 3.95 (s, 2H) 4.74 (m, 1H) 5.45 (s, 2H) 6.97 (m, J = 8.59 Hz, 2H) 7.51 (m, 1H), _{ES-HRMS431.1284 (C 18 H 22} ClF 2 N 4 O M + H calcd for ₄ 431.1292).

(Example 109)

Ｎ−［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）エチル］−２−ヒドロキシ−２−メチルプロパンアミド
ステップ１．２−（２−（４−（２，４−ジフルオロベンジルオキシ）−５−クロロ−１，６−ジヒドロ−１−イソプロピル−６−オキソピリミジン−２−イルアミノ）エチルカルバモイル）プロパン−２−イルアセタートの調製

N- [2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] -2 -Hydroxy-2-methylpropanamide Step 1.2- (2- (4- (2,4-difluorobenzyloxy) -5-chloro-1,6-dihydro-1-isopropyl-6-oxopyrimidine-2- Preparation of (Ilamino) ethylcarbamoyl) propan-2-yl acetate

２−［（２−アミノエチル）アミノ］−５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸塩（０．３０７ｇ、０．７４ミリモル）および酢酸２−（クロロカルボニル）プロパン−２−イル（０．１８ｍＬ、１．１１ミリモル）を利用し、Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］−２−ヒドロキシ−２−メチルプロパンアミド（ステップ１）のように調製して、オフホワイトの固体（０．１２７ｇ、３４％）を得た。ＬＣ／ＭＳ，ｔ_ｒ＝２．７２分間（５〜９５％のアセトニトリル／水を１ｍｌ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ５０１（Ｍ＋１）。Ｎ−［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）エチル］アセトアミドで見られたのと同じ臭化物→塩化物交換。

2-[(2-aminoethyl) amino] -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one trifluoroacetate (0.307 g, 0.7-mmol) and 2- (chlorocarbonyl) propan-2-yl acetate (0.18 mL, 1.11 mmol) were used and N- [3-({5-bromo-4-[(2,4 -Difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2-hydroxy-2-methylpropanamide (step 1) An off-white solid (0.127 g, 34%) was obtained. LC / _MS, t r = 2.72 minutes (5 min 5-95% acetonitrile / water at 1 ml / min, 254nm, 50 ℃), ES -MSm / z501 (M + 1). With N- [2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] acetamide Same bromide → chloride exchange as seen.

Step 2. N- [2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] -2 Preparation of 2-hydroxy-2-methylpropanamide (2- (4- (2,4-difluorobenzyloxy) -5-chloro-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) ethyl Carbamoyl) methyl acetate (from Step 1) (0.127 g, 0.25 mmol) and K ₂ CO ₃ (0.053 g, 0.38 mmol) were utilized to give N- [3-({5- Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2-hydride It is prepared as carboxymethyl-2-methyl propanamide (Step 2) to give an off-white solid (0.044 g, 38%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.31 (s, 6H) 1.52 (d, J = 6.98 Hz, 6H) 3.45 (m, 2H) 3.57 (m, 2H) 4 .75 (m, 1H) 5.46 ( s, 2H) 6.98 (m, 2H) 7.52 (m, 1H), ES-HRMS459.1593 (C 20 H 26 ClF 2 N 4 against _{O 4} M + H The calculated value is 459.1603).

(Example 110)

Ｎ−［２−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）エチル］メタンスルホンアミド
Ｎ−［２−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）エチル］メタンスルホンアミドの調製。２−［（２−アミノエチル）アミノ］−５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸塩（０．３０３ｇ、０．５７ミリモル）および塩化メタンスルホニル（０．０５０ｍＬ、０．６３ミリモル）を利用し、Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］メタンスルホンアミドのように調製して、白色固体（０．１００ｇ、３５％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５２（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）２．９０（ｓ，３Ｈ）３．２６（ｔ，Ｊ＝６．１８Ｈｚ，２Ｈ）３．５５（ｔ，Ｊ＝６．０４Ｈｚ，２Ｈ）４．７４（ｍ，１Ｈ）５．４３（ｓ，２Ｈ）６．９７（ｍ，２Ｈ）７．５０（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４９５．０５４０（Ｃ_１７Ｈ_２２ＢｒＦ_２Ｎ_４Ｏ_４Ｓに対するＭ＋Ｈ計算値は４９５．０５０８）。

N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] methanesulfone Amido N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] methane Preparation of sulfonamides. 2-[(2-aminoethyl) amino] -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one trifluoroacetate (0.303 g, 0.57 mmol) and methanesulfonyl chloride (0.050 mL, 0.63 mmol) were used to give N- [3-({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1- Prepared as isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] methanesulfonamide to give a white solid (0.100 g, 35%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.52 (d, J = 6.98 Hz, 6H) 2.90 (s, 3H) 3.26 (t, J = 6.18 Hz, 2H) 3.55 (T, J = 6.04 Hz, 2H) 4.74 (m, 1H) 5.43 (s, 2H) 6.97 (m, 2H) 7.50 (m, 1H), ES-HRMS 495.0540 ( _{C 17 H 22 BrF 2 N 4} O 4 M + H calcd for S is 495.0508).

(Example 111)

Ｎ−［２−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）エチル］−２−ヒドロキシアセトアミド
ステップ１．（２−（４−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−１，６−ジヒドロ−１−イソプロピル−６−オキソピリミジン−２−イルアミノ）エチルカルバモイル）メチルアセタートの調製

N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] -2 -Hydroxyacetamide Step 1. Preparation of (2- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) ethylcarbamoyl) methyl acetate

２−［（２−アミノエチル）アミノ］−５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸塩（０．４０４ｇ、０．９７ミリモル）および酢酸（クロロカルボニル）メチル（０．１１３ｍＬ、１．０６ミリモル）を利用し、Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］−２−ヒドロキシアセトアミド（ステップ１）のように調製して、白色固体（０．２９２ｇ、６４％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５１（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）２．０９（ｓ，３Ｈ）３．４６（ｔ，Ｊ＝５．７７Ｈｚ，２Ｈ）３．５６（ｔ，Ｊ＝５．７７Ｈｚ，２Ｈ）４．５０（ｓ，２Ｈ）４．７１（ｍ，１Ｈ）５．４３（ｓ，２Ｈ）６．９７（ｍ，Ｊ＝８．８６Ｈｚ，２Ｈ）７．５１（ｍ，１Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝２．４８分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ５１７（Ｍ＋１）。

2-[(2-aminoethyl) amino] -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one trifluoroacetate (0.404 g, 0.97 mmol) and (chlorocarbonyl) methyl acetate (0.113 mL, 1.06 mmol) and N- [3-({5-bromo-4-[(2,4-difluorobenzyl) oxy] Prepared as in -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2-hydroxyacetamide (Step 1), white solid (0.292 g, 64%) Got. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.51 (d, J = 6.98 Hz, 6H) 2.09 (s, 3H) 3.46 (t, J = 5.77 Hz, 2H) 3.56 (T, J = 5.77 Hz, 2H) 4.50 (s, 2H) 4.71 (m, 1H) 5.43 (s, 2H) 6.97 (m, J = 8.86 Hz, 2H) 7 .51 (m, 1H). LC / _MS, t r = 2.48 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z517 (M + 1).

Step 2. N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] -2 Preparation of 2-hydroxyacetamide (2- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) ethylcarbamoyl) methyl acetate (those from step 1) (0.292 g, 0.56 mmol) and _K 2 _CO 3 (0.116g, 0.84 mmol) using, N- [3 - ({5- bromo-4- [ (2,4-Difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2-hydroxyacetoa It is prepared as de, to give a white solid (0.264g, 100%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.51 (d, J = 6.98 Hz, 6H) 3.48 (t, J = 5.77 Hz, 2H) 3.58 (t, J = 5.77 Hz) , 2H) 3.95 (s, 2H) 4.73 (m, 1H) 5.45 (s, 2H) 6.98 (m, 2H) 7.52 (m, 1H), ES-HRMS 475.0795 ( _{C 18 H 22 BrF 2 N 4} O M + H calcd for ₄ 475.0787).

(Example 112)

Ｎ−［２−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）エチル］−２−ヒドロキシ−２−メチルプロパンアミド
ステップ１．２−（２−（４−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−１，６−ジヒドロ−１−イソプロピル−６−オキソピリミジン−２−イルアミノ）エチルカルバモイル）プロパン−２−イルアセタートの調製

N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] -2 -Hydroxy-2-methylpropanamide Step 1.2- (2- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidine-2- Preparation of (Ilamino) ethylcarbamoyl) propan-2-yl acetate

２−［（２−アミノエチル）アミノ］−５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸塩（０．４０３ｇ、０．９７ミリモル）および酢酸２−（クロロカルボニル）プロパン−２−イル（０．１７ｍＬ、１．０６ミリモル）を利用し、Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］−２−ヒドロキシ−２−メチルプロパンアミド（ステップ１）のように調製して、淡いピンク色の固体（０．３３５ｇ、６３％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５１（ｓ，６Ｈ）１．５２（ｍ，６Ｈ）２．０２（ｓ，３Ｈ）３．４５（ｔ，Ｊ＝５．３７Ｈｚ，２Ｈ）３．５５（ｔ，Ｊ＝５．６４Ｈｚ，２Ｈ）４．６８（ｍ，１Ｈ）５．４３（ｓ，２Ｈ）６．９８（ｍ，２Ｈ）７．５３（ｍ，１Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝２．７７分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ５４５（Ｍ＋１）。

2-[(2-aminoethyl) amino] -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one trifluoroacetate (0.403 g, 0.97 mmol) and 2- (chlorocarbonyl) propan-2-yl acetate (0.17 mL, 1.06 mmol) were used and N- [3-({5-bromo-4-[(2,4 -Difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2-hydroxy-2-methylpropanamide (step 1) A pale pink solid (0.335 g, 63%) was obtained. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.51 (s, 6H) 1.52 (m, 6H) 2.02 (s, 3H) 3.45 (t, J = 5.37 Hz, 2H) 3 .55 (t, J = 5.64 Hz, 2H) 4.68 (m, 1H) 5.43 (s, 2H) 6.98 (m, 2H) 7.53 (m, 1H). LC / _MS, t r = 2.77 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z545 (M + 1).

Step 2. N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] -2 Preparation of 2-hydroxy-2-methylpropanamide 2- (2- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino ) Ethylcarbamoyl) propan-2-yl acetate (from Step 1) (0.335 g, 0.61 mmol) and K ₂ CO ₃ (0.127 g, 0.92 mmol) were used to obtain N- [3- ({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) pro ] -2- hydroxy-2-methylpropanamide was prepared as (Step 2) to give a white solid (0.171 g, 56%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.31 (s, 6H) 1.51 (d, J = 6.71 Hz, 6H) 3.45 (t, J = 5.77 Hz, 2H) 3.57 (T, J = 5.77 Hz, 2H) 4.75 (m, 1H) 5.45 (s, 2H) 6.98 (s, 2H) 7.52 (m, 1H), ES-HRMS 503.1071 ( _{C 20 H 26 BrF 2 N 4} O M + H calcd for ₄ 503.1100).

(Example 113)

Ｎ−［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）エチル］尿素
Ｎ−［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）エチル］尿素の調製。Ｎ−［２−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）エチル］尿素（０．２８３ｇ、０．６２ミリモル）をジオキサン（１．５ｍＬ）に溶解させ、塩化テトラブチルアンモニウム（０．６９０ｇ、２．８４ミリモル）を加えた。反応液を４８時間かけて１００℃に加熱した。反応液を濃縮し、残渣を酢酸エチルに溶解させ、水で洗浄した。水層を酢酸エチルに抽出した。有機抽出物を合わせてＭｇＳＯ_４で乾燥させ、濾過し、濃縮した。残渣をクロマトグラフィー（シリカゲル、１０％のメタノール／ヘキサンを含む酢酸エチル）によって精製して、淡黄色の固体（０．０９４ｇ、３７％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．５２（ｄｄ，Ｊ＝１．２１，６．８５Ｈｚ，６Ｈ）３．３５（ｔ，Ｊ＝５．７７Ｈｚ，２Ｈ）３．４９（ｔ，Ｊ＝５．７７Ｈｚ，２Ｈ）４．７４（ｍ，１Ｈ）５．４４（ｓ，２Ｈ）６．９７（ｍ，２Ｈ）７．５１（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４１６．１３２５（Ｃ_１７Ｈ_２１ＣｌＦ_２Ｎ_５Ｏ_３に対するＭ＋Ｈ計算値は４１６．１２９６）。

N- [2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] urea N -[2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] urea . N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] urea ( 0.283 g, 0.62 mmol) was dissolved in dioxane (1.5 mL) and tetrabutylammonium chloride (0.690 g, 2.84 mmol) was added. The reaction was heated to 100 ° C. over 48 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and washed with water. The aqueous layer was extracted into ethyl acetate. The combined organic extracts were dried over MgSO ₄ , filtered and concentrated. The residue was purified by chromatography (silica gel, 10% methanol / hexanes in ethyl acetate) to give a pale yellow solid (0.094 g, 37%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.52 (dd, J = 1.21, 6.85 Hz, 6H) 3.35 (t, J = 5.77 Hz, 2H) 3.49 (t, J = 5.77Hz, 2H) 4.74 (m , 1H) 5.44 (s, 2H) 6.97 (m, 2H) 7.51 (m, 1H), ES-HRMS416.1325 (C 17 H 21 M + H calculated for ClF ₂ N ₅ O ₃ is 416.1296).

(Example 114)

Ｎ−［２−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチル］アセトアミド
ステップ１．２−（４−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−１，６−ジヒドロ−１−イソプロピル−６−オキソピリミジン−２−イルオキシ）エチルカルバミン酸ｔ−ブチルの調製

N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] acetamide step Preparation of t-butyl 1.2- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-yloxy) ethylcarbamate

６−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−３−イソプロピル−２−（メチルスルホニル）ピリミジン−４（３Ｈ）−オン（３．０ｇ、６．９ミリモル）および２−ヒドロキシエチルカルバミン酸ｔ−ブチル（１．１８ｍＬ、７．６ミリモル）を利用し、２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチルカルバミン酸ｔ−ブチルのように調製して、白色固体（０．４４０ｇ、３７％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．４１（ｓ，９Ｈ）１．４５（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）３．４９（ｔ，Ｊ＝５．２４Ｈｚ，２Ｈ）４．５１（ｔ，Ｊ＝５．２４Ｈｚ，２Ｈ）５．３１（ｍ，１Ｈ）５．４７（ｓ，２Ｈ）７．００（ｍ，２Ｈ）７．５４（ｍ，１Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝３．３０分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ５１８（Ｍ＋１）。

6- (2,4-Difluorobenzyloxy) -5-bromo-3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (3.0 g, 6.9 mmol) and 2-hydroxyethylcarbamine Utilizing t-butyl acid (1.18 mL, 7.6 mmol), 2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1, Prepared as t-butyl 6-dihydropyrimidin-2-yl} oxy) ethylcarbamate to give a white solid (0.440 g, 37%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.41 (s, 9H) 1.45 (d, J = 6.98 Hz, 6H) 3.49 (t, J = 5.24 Hz, 2H) 4.51 (T, J = 5.24 Hz, 2H) 5.31 (m, 1H) 5.47 (s, 2H) 7.00 (m, 2H) 7.54 (m, 1H). LC / _MS, t r = 3.30 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z518 (M + 1).

  Step 2. Preparation of 6- (2,4-difluorobenzyloxy) -2- (2-aminoethoxy) -5-bromo-3-isopropylpyrimidine-4 (3H) -one trifluoroacetic acid

２−（４−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−１，６−ジヒドロ−１−イソプロピル−６−オキソピリミジン−２−イルオキシ）エチルカルバミン酸ｔ−ブチル（ステップ１からのもの）（２．３６ｇ、４．５７ミリモル）およびトリフルオロ酢酸（５ｍＬ）を利用し、２−｛［２−（｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチル］アミノ｝−２−オキソエチルアセタート（ステップ１）のように調製して、淡褐色の油（０．４８９ｇ、＞１００％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．４９（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）３．４６（ｍ，２Ｈ）４．７２（ｍ，２Ｈ）５．２２（ｍ，１Ｈ）５．４８（ｓ，２Ｈ）７．０１（ｍ，２Ｈ）７．５４（ｍ，１Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝１．８６分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ_、５０℃）、ＥＳ−ＭＳｍ／ｚ４１８（Ｍ＋１）。

T-Butyl 2- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-yloxy) ethylcarbamate (from step 1) ) (2.36 g, 4.57 mmol) and trifluoroacetic acid (5 mL) and 2-{[2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1- Prepared as isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] amino} -2-oxoethyl acetate (Step 1) to give a pale brown oil (0.489 g, > 100%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.49 (d, J = 6.98 Hz, 6H) 3.46 (m, 2H) 4.72 (m, 2H) 5.22 (m, 1H) 5 .48 (s, 2H) 7.01 (m, 2H) 7.54 (m, 1H). LC / _MS, t r = 1.86 minutes (5 min 5-95% acetonitrile / water with 1 mL / _{min, 254nm, 50 ℃), ES} -MSm / z418 (M + 1).

Step 3. Of N- [2-({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] acetamide Preparation 6- (2,4-Difluorobenzyloxy) -2- (2-aminoethoxy) -5-bromo-3-isopropylpyrimidin-4 (3H) -one trifluoroacetic acid (from step 1) (0. 400 g, 0.75 mmol) and acetyl chloride (0.064 mL, 0.83 mmol) and N- [3-({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1 -Isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] acetamide (Step 2) and prepared as a pink solid (0.200 g, 58%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.44 (d, J = 6.98 Hz, 6H) 1.94 (s, 3H) 3.61 (t, J = 5.37 Hz, 2H) 4.54 (T, J = 5.37 Hz, 2H) 5.28 (m, 1H) 5.47 (m, 2H) 7.00 (m, 2H) 7.55 (m, 1H), ES-HRMS 460.0697 ( _{C 18 H 21 BrF 2 N 3} O M + H calcd for ₄ 460.0678).

(Example 115)

Ｎ−［２−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチル］尿素
Ｎ−［２−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチル］尿素の調製。６−（２，４−ジフルオロベンジルオキシ）−２−（２−アミノエトキシ）−５−ブロモ−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸（Ｎ−［２−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチル］アセトアミド ステップ２からのもの）（０．４０６ｇ、０．７６ミリモル）およびイソシアン酸トリメチルシリル（０．９６ｍＬ、０．８４ミリモル）を利用し、Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］尿素のように調製して、白色固体（０．１４６ｇ、４２％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．４５（ｄ，Ｊ＝６．９８Ｈｚ，６Ｈ）３．５５（ｔ，Ｊ＝５．３７Ｈｚ，２Ｈ）４．５３（ｔ，Ｊ＝５．３７Ｈｚ，２Ｈ）５．２８（ｍ，１Ｈ）５．４７（ｓ，２Ｈ）６．９８（ｍ，２Ｈ）７．５４（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４６１．０６１３（Ｃ_１７Ｈ_２０ＢｒＦ_２Ｎ_４Ｏ_４に対するＭ＋Ｈ計算値は０６３０）。

N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] urea N Preparation of — [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] urea . 6- (2,4-Difluorobenzyloxy) -2- (2-aminoethoxy) -5-bromo-3-isopropylpyrimidin-4 (3H) -one trifluoroacetic acid (N- [2-({5-bromo -4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] acetamide (from Step 2) (0.406 g, 0.76 mmol) and trimethylsilyl isocyanate (0.96 mL, 0.84 mmol) were used to give N- [3-({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1- Isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] urea to give a white solid (0.146 g, 42%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.45 (d, J = 6.98 Hz, 6H) 3.55 (t, J = 5.37 Hz, 2H) 4.53 (t, J = 5.37 Hz) , 2H) 5.28 (m, 1H ) 5.47 (s, 2H) 6.98 (m, 2H) 7.54 (m, 1H), ES-HRMS461.0613 (C 17 H 20 BrF 2 N 4 M + H calculated for O ₄ is 0630).

(Example 116)

Ｎ−［２−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチル］メタンスルホンアミド
Ｎ−［２−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチル］メタンスルホンアミドの調製。６−（２，４−ジフルオロベンジルオキシ）−２−（２−アミノエトキシ）−５−ブロモ−３−イソプロピルピリミジン−４（３Ｈ）−オントリフルオロ酢酸（Ｎ−［２−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝オキシ）エチル］アセトアミド、ステップ２からのもの）（０．４８９ｇ、０．９２ミリモル）および塩化メタンスルホニル（０．０７７ｍＬ、１．０ミリモル）を利用し、Ｎ−［３−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝アミノ）プロピル］メタンスルホンアミドのように調製して、黄色〜橙色の固体（０．３５２ｇ、７７％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤ_３ＯＤ）δｐｐｍ １．４７（ｄ，Ｊ＝６．７１Ｈｚ，６Ｈ）２．９５（ｓ，３Ｈ）３．４９（ｔ，Ｊ＝５．３７Ｈｚ，２Ｈ）４．５７（ｔ，Ｊ＝５．５０Ｈｚ，２Ｈ）５．３０（ｍ，１Ｈ）５．４７（ｓ，２Ｈ）７．００（ｍ，２Ｈ）７．５４（ｍ，１Ｈ）、ＥＳ−ＨＲＭＳ４９６．０３２２（Ｃ_１７Ｈ_２１ＢｒＦ_２Ｎ_３Ｏ_５Ｓに対するＭ＋Ｈ計算値は４９６．０３４８）。

N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] methanesulfone Amido N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] methane Preparation of sulfonamides. 6- (2,4-Difluorobenzyloxy) -2- (2-aminoethoxy) -5-bromo-3-isopropylpyrimidin-4 (3H) -one trifluoroacetic acid (N- [2-({5-bromo -4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] acetamide, from Step 2) (0.489 g , 0.92 mmol) and methanesulfonyl chloride (0.077 mL, 1.0 mmol) to give N- [3-({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1 -Isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] methanesulfonamide prepared as a yellow-orange solid (0.352 g 77%) was obtained. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.47 (d, J = 6.71 Hz, 6H) 2.95 (s, 3H) 3.49 (t, J = 5.37 Hz, 2H) 4.57 (T, J = 5.50 Hz, 2H) 5.30 (m, 1H) 5.47 (s, 2H) 7.00 (m, 2H) 7.54 (m, 1H), ES-HRMS 496.0322 ( M + H calculated for C ₁₇ H ₂₁ BrF ₂ N ₃ O ₅ S is 496.0348).

(Example 117)

５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（メチルスルホニル）ピリミジン−４（３Ｈ）−オン
ステップ１．５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（メチルチオ）ピリミジン−４（３Ｈ）−オンの調製

5-chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one Step 1.5-Chloro-6-[(2,4 -Difluorobenzyl) oxy] -3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one

６−（２，４−ジフルオロベンジルオキシ）−３−イソプロピル−２−（メチルチオ）ピリミジン−４（３Ｈ）−オン（５．００ｇ、１５．３２ミリモル）をジクロロメタン（５０ｍＬ）に溶解させ、氷浴で冷却した。Ｎ−クロロスクシンイミド（２．２５ｇ、１６．８５ミリモル）を加え、反応液を温めながら２４時間攪拌した。次いで、反応混合物をＨ_２Ｏで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮して、白色固体（５．６１ｇ、＞１００％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ７．４３（ａｐｐ ｑ，Ｊ＝７．７Ｈｚ，１Ｈ）、６．９１−６．８７（ｍ，１Ｈ）、６．８４−６．７９（ｍ，１Ｈ）、５．４７（ｓ，２Ｈ）、４．５８−４．５１（ｍ，１Ｈ）、２．５１（ｓ，３Ｈ）、１．５９（ｄ，Ｊ＝６．７Ｈｚ，６Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝３．２５分間（５〜９５％のアセトニトリル／水を１ｍＬ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ３６１（Ｍ＋Ｈ）。

6- (2,4-Difluorobenzyloxy) -3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one (5.00 g, 15.32 mmol) was dissolved in dichloromethane (50 mL) and ice bathed. It was cooled with. N-chlorosuccinimide (2.25 g, 16.85 mmol) was added and stirred for 24 hours while warming the reaction. The reaction mixture was then washed with H ₂ O, dried over Na ₂ SO ₄ , filtered and concentrated to give a white solid (5.61 g,> 100%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43 (app q, J = 7.7 Hz, 1H), 6.91-6.87 (m, 1H), 6.84-6.79 (m, 1H) 5.47 (s, 2H), 4.58-4.51 (m, 1H), 2.51 (s, 3H), 1.59 (d, J = 6.7 Hz, 6H). LC / _MS, t r = 3.25 minutes (5 min 5-95% acetonitrile / water with 1 mL / min, 254nm, 50 ℃), ES -MSm / z361 (M + H).

Step 2.5 Preparation of Chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one 5-Chloro-6-[(2 , 4-Difluorobenzyl) oxy] -3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one (unpurified from Step 1) (5.61 g, 15.55 mmol) was added to tetrahydrofuran (50 mL). ) And H ₂ O (5 mL). Oxone (38.3 g, 62.2 mmol) was added and the resulting mixture was stirred at room temperature for 4 days. The reaction mixture was then filtered while washing the solid with ethyl acetate. The filtrate was diluted with H ₂ O and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The resulting solid was washed with diethyl ether to give a white solid (4.02 g, 66%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42 (app q, J = 8.5 Hz, 1H), 6.93 (dt, J = 8.6, 1.5 Hz, 1H), 6.84 (dt, J = 9.3, 2.4 Hz, 1H), 5.40 (s, 2H), 5.23 (Sevent, J = 6.6 Hz, 1H), 3.38 (s, 3H), 1.64 (D, J = 6.6 Hz, 6H). LC / _MS, t r = 2.60 minutes (5 min 5-95% acetonitrile / water at 1 ml / min, 254nm, 50 ℃), ES -MSm / z415 (M + Na).

(Example 118)

Ｎ〜２〜−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−Ｎ〜２〜−メチルグリシンアミド
ステップ１．Ｎ−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝グリシン酸ｔ−ブチルの調製

N ~ 2- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N ~ 2-methyl Glycinamide Step 1. Preparation of t-butyl N- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} glycinate

グリシンｔ−ブチルエステル塩酸塩（１．７１ｇ、１０．１８ミリモル）をテトラヒドロフラン（２０ｍＬ）に懸濁させた。シリカゲル結合型ジメチルアミン（６．７９ｇ、使用量＝１．５０ミリモル／ｇ）を加え、得られる混合物を室温で３０分間攪拌した。５−クロロ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピル−２−（メチルスルホニル）ピリミジン−４（３Ｈ）−オン（２．００ｇ、５．０９ミリモル）を加え、混合物を室温で２日間攪拌した。反応混合物を濾過し、濃縮した。残渣をメタノールで処理し、沈殿を濾過によって収集して、白色固体（０．７９ｇ、３５％）を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ７．４６（ａｐｐ ｑ，Ｊ＝７．７Ｈｚ，１Ｈ）、６．８８（ｄｔ，Ｊ＝８．４，２．２Ｈｚ，１Ｈ）、６．８２（ｍ，１Ｈ）、５．６９（ｂｒ ｓ，１Ｈ）、５．４８（ｂｒ ｍ １Ｈ）、５．３８（ｓ，２Ｈ）、４．０５（ｄ，Ｊ＝４．２Ｈｚ，２Ｈ）、１．５２（ｄ，Ｊ＝７．３Ｈｚ，６Ｈ）１．５０（ｓ，９Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝３．２６分間（５〜９５％のアセトニトリル／水を１ｍｌ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ４４４（Ｍ＋Ｈ）。

Glycine t-butyl ester hydrochloride (1.71 g, 10.18 mmol) was suspended in tetrahydrofuran (20 mL). Silica gel-bound dimethylamine (6.79 g, used amount = 1.50 mmol / g) was added, and the resulting mixture was stirred at room temperature for 30 minutes. 5-Chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (2.00 g, 5.09 mmol) was added and the mixture Was stirred at room temperature for 2 days. The reaction mixture was filtered and concentrated. The residue was treated with methanol and the precipitate was collected by filtration to give a white solid (0.79 g, 35%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.46 (app q, J = 7.7 Hz, 1H), 6.88 (dt, J = 8.4, 2.2 Hz, 1H), 6.82 (m, 1H), 5.69 (br s, 1H), 5.48 (br m 1H), 5.38 (s, 2H), 4.05 (d, J = 4.2 Hz, 2H), 1.52 ( d, J = 7.3 Hz, 6H) 1.50 (s, 9H). LC / _MS, t r = 3.26 minutes (5 min 5-95% acetonitrile / water at 1 ml / min, 254nm, 50 ℃), ES -MSm / z444 (M + H).

  Step 2. Of t-butyl N- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N-methylglycinate Preparation

Ｎ−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝グリシン酸ｔ−ブチル（Ｎ〜２〜−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−Ｎ〜２〜−メチルグリシンアミド、ステップ１）をテトラヒドロフラン（１０ｍＬ）に懸濁させ、氷浴で冷却した。水素化ナトリウム（鉱油中６０％、０．１０６ｇ、２．６４ミリモル）を加え、氷浴を取り外した。３０分後、氷浴を戻し、ヨードメタン（０．１５１ｍＬ、２．４２ミリモル）を加えた。温めながら終夜攪拌した後、追加の水素化ナトリウム（鉱油中６０％、０．０２６ｇ、０．６６ミリモル）を加え、続いてヨードメタン（０．０６８ｍＬ、１．１０ミリモルを加えた）。得られる混合物を室温で１．５時間攪拌し、次いで飽和ＮＨ_４Ｃｌを加えて失活させ、酢酸エチル抽出した。有機層を合わせてブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮した。クロマトグラフィー（シリカゲル、ヘキサン／酢酸エチル）にかけると、淡黄色の固体（０．９２０ｇ、９１％）が得られた。^１Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ_３）δ７．４５（ａｐｐ ｑ，Ｊ＝７．８Ｈｚ，１Ｈ）、６．８７（ｍ，１Ｈ）、６．８１（ｍ，１Ｈ）、５．３４（ｓ，２Ｈ）、４．４７（七重線，Ｊ＝６．７Ｈｚ，１Ｈ）、３．８３（ｓ，２Ｈ）、３．０１（ｓ，３Ｈ）、１．６３（ｄ，Ｊ＝６．７Ｈｚ，６Ｈ）１．４４（ｓ，９Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝３．４７分間（５〜９５％のアセトニトリル／水を１ｍｌ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ４５８（Ｍ＋Ｈ）。

N- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} t-butyl glycinate (N˜2 -{5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N ~ 2-methylglycinamide, step 1) was suspended in tetrahydrofuran (10 mL) and cooled in an ice bath. Sodium hydride (60% in mineral oil, 0.106 g, 2.64 mmol) was added and the ice bath was removed. After 30 minutes, the ice bath was returned and iodomethane (0.151 mL, 2.42 mmol) was added. After stirring overnight while warming, additional sodium hydride (60% in mineral oil, 0.026 g, 0.66 mmol) was added followed by iodomethane (0.068 mL, 1.10 mmol was added). The resulting mixture was stirred at room temperature for 1.5 hours, then quenched by addition of saturated NH ₄ Cl and extracted with ethyl acetate. 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 pale yellow solid (0.920 g, 91%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45 (app q, J = 7.8 Hz, 1H), 6.87 (m, 1H), 6.81 (m, 1H), 5.34 (s, 2H ), 4.47 (Sevent, J = 6.7 Hz, 1H), 3.83 (s, 2H), 3.01 (s, 3H), 1.63 (d, J = 6.7 Hz, 6H) 1.44 (s, 9H). LC / _MS, t r = 3.47 minutes (5 min 5-95% acetonitrile / water at 1 ml / min, 254nm, 50 ℃), ES -MSm / z458 (M + H).

  Step 3. Preparation of N- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N-methylglycine

Ｎ−｛５−クロロ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝−Ｎ−メチルグリシン酸ｔ−ブチル（ステップ２）（０．９２０ｇ、２．０１ミリモル）をギ酸（４．０ｍＬ）で処理し、室温で２４時間攪拌した。反応混合物を部分的に濃縮し、Ｈ_２Ｏと酢酸エチルとに分配した。水層をさらに酢酸エチルで抽出した。有機層を合わせてブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮して、淡黄色の固体（０．６９０ｇ、８５％）を得た。^１Ｈ ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ_３）δ７．４２（ａｐｐ ｑ，Ｊ＝７．８Ｈｚ，１Ｈ）、６．８６（ｍ，１Ｈ）、６．７９（ｍ，１Ｈ）、５．３２（ｓ，２Ｈ）、４．４７（七重線，Ｊ＝６．８Ｈｚ，１Ｈ）、３．９０（ｓ，２Ｈ）、３．０４（ｓ，３Ｈ）、１．６１（ｄ，Ｊ＝６．７Ｈｚ，６Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝２．５１分間（５〜９５％のアセトニトリル／水を１ｍｌ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ４０２（Ｍ＋Ｈ）。

N- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N-methylglycinate t-butyl ( Step 2) (0.920 g, 2.01 mmol) was treated with formic acid (4.0 mL) and stirred at room temperature for 24 hours. The reaction mixture was partially concentrated and partitioned between H ₂ O and ethyl acetate. 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 a pale yellow solid (0.690 g, 85%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.42 (app q, J = 7.8 Hz, 1H), 6.86 (m, 1H), 6.79 (m, 1H), 5.32 (s, 2H ), 4.47 (Sevent, J = 6.8 Hz, 1H), 3.90 (s, 2H), 3.04 (s, 3H), 1.61 (d, J = 6.7 Hz, 6H) . LC / _MS, t r = 2.51 minutes (5 min 5-95% acetonitrile / water at 1 ml / min, 254nm, 50 ℃), ES -MSm / z402 (M + H).

Step 4. N ~ 2- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N ~ 2-methyl Preparation of Glycinamide N- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N methylglycine (N ˜2-{5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N˜2-methylglycine Amide, step 3) (0.300 g, 0.747 mmol) was dissolved in dioxane (7.0 mL). 1-Hydroxybenzotriazole (0.101 g, 0.747 mmol) was added, followed by polymer-bonded carbodiimide resin (1.00 g, amount used = 1.8 mmol / g). The mixture was then stirred at room temperature for 15 minutes. Ammonia in dioxane (2.62 mL, 1.31 mmol, 0.5 M) was added and the reaction mixture was stirred at room temperature overnight. At this point, the reaction solution was diluted with dioxane (10 mL), treated with a polyamine resin (1.30 g, used amount = 2.87 mmol / g), and then functionalized with methyl isocyanate (2 .54 g, amount used = 1.47 mmol / g). The resulting reaction was stirred at room temperature for 3 hours, filtered and concentrated to give the title compound as a pale yellow solid (0.220 g, 74%). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.40 (app q, J = 7.8 Hz, 1H), 6.87-6.74 (m, 2H), 6.55 (br s, 1H), 5. 91 (br s, 1H), 5.33 (s, 2H), 4.45 (sevent, J = 6.6 Hz, 1H), 3.85 (s, 2H), 2.98 (s, 3H) 1.58 (d, J = 6.7 Hz, 6H). LC / _MS, t r = 2.28 minutes (5 min 5-95% acetonitrile / water at 1 ml / min, 254nm, 50 ℃), ES -MSm / z401 (M + H). _{ES-HRMSm / z401.1202 (C 17} H 20 ClF 2 N 4 O 3 for M + H calculated value 401.1187).

(Example 119)

５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−２−［（２−ヒドロキシ−２−メチルプロピル）アミノ］−３−イソプロピルピリミジン−４（３Ｈ）−オン
５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−２−［（２−ヒドロキシ−２−メチルプロピル）アミノ］−３−イソプロピルピリミジン−４（３Ｈ）−オンの調製。１−アミノ−２−メチル−２−プロパノール塩酸塩（０．１５ｇ、１．１９ミリモル）をジオキサン（１０ｍＬ）に溶解させた。シリカゲルに結合した炭酸（３．５３ｇ、使用量＝０．７ミリモル／ｇ）を加え、混合物を室温で５分間攪拌した。６−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−３−イソプロピル−２−（メチルスルホニル）ピリミジン−４（３Ｈ）−オン（０．３００ｇ、０．６８６ミリモル）を加え、得られる混合物を室温で１８時間攪拌した。次いで、反応混合物を濾過し、濃縮した。濾液をクロマトグラフィー（シリカゲル、ヘキサン／酢酸エチル）にかけて、オフホワイトの油状固体（０．１４３ｇ、４７％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ７．４４（ａｐｐ ｑ，Ｊ＝７．８Ｈｚ，１Ｈ）、６．９３（ａｐｐ ｔ，Ｊ＝８．３Ｈｚ，１Ｈ）、６．８４（ｄｔ，Ｊ＝９．１，２．３Ｈｚ，１Ｈ）、５．５４（ｂｒ ｓ，１Ｈ）、５．３６（ｓ，２Ｈ）、３．４２（ｄ，Ｊ＝５．０Ｈｚ，２Ｈ）、１．４６（ｄ，Ｊ＝７．３Ｈｚ，６Ｈ）１．２６（ｓ，６Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝２．７７分間（５〜９５％のアセトニトリル／水を１ｍｌ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ４４６（Ｍ＋Ｈ）。ＥＳ−ＨＲＭＳｍ／ｚ４４６．０８６２（Ｃ_１８Ｈ_２３ＢｒＦ_２Ｎ_３Ｏ_３に対するＭ＋Ｈ計算値は４４６．０８８５）。

5-Bromo-6-[(2,4-difluorobenzyl) oxy] -2-[(2-hydroxy-2-methylpropyl) amino] -3-isopropylpyrimidin-4 (3H) -one 5-Bromo-6 -Preparation of [(2,4-difluorobenzyl) oxy] -2-[(2-hydroxy-2-methylpropyl) amino] -3-isopropylpyrimidin-4 (3H) -one. 1-Amino-2-methyl-2-propanol hydrochloride (0.15 g, 1.19 mmol) was dissolved in dioxane (10 mL). Carbonic acid bound to silica gel (3.53 g, usage = 0.7 mmol / g) was added and the mixture was stirred at room temperature for 5 minutes. 6- (2,4-Difluorobenzyloxy) -5-bromo-3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (0.300 g, 0.686 mmol) was added and the resulting mixture Was stirred at room temperature for 18 hours. The reaction mixture was then filtered and concentrated. The filtrate was chromatographed (silica gel, hexane / ethyl acetate) to give an off-white oily solid (0.143 g, 47%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44 (app q, J = 7.8 Hz, 1H), 6.93 (app t, J = 8.3 Hz, 1H), 6.84 (dt, J = 9 .1, 2.3 Hz, 1H), 5.54 (br s, 1H), 5.36 (s, 2H), 3.42 (d, J = 5.0 Hz, 2H), 1.46 (d, J = 7.3 Hz, 6H) 1.26 (s, 6H). LC / _MS, t r = 2.77 minutes (5 min 5-95% acetonitrile / water at 1 ml / min, 254nm, 50 ℃), ES -MSm / z446 (M + H). _{ES-HRMSm / z446.0862 (C 18} H 23 BrF 2 N 3 O M + H calculated for ₃ 446.0885).

(Example 120)

Ｎ−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝メチル）メタンスルホンアミド
ステップ１．５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−カルボニトリルの調製

N-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} methyl) methanesulfonamide Step 1.5 -Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidine-2-carbonitrile

６−（２，４−ジフルオロベンジルオキシ）−５−ブロモ−３−イソプロピル−２−（メチルスルホニル）ピリミジン−４（３Ｈ）−オン（９．８５ｇ、２２．５３ミリモル）をＮ，Ｎ−ジメチルアセトアミド（５０ｍＬ）に溶解させた。シアン化カリウム（２．９３ｇ、４５．０６ミリモル）を加え、得られる混合物を室温で３時間攪拌した。反応混合物に酢酸エチル（１００ｍＬ）を加え、次いで氷／水（１００ｍＬ）中に注いだ。次いで、反応液を酢酸エチルに抽出した。有機層を合わせてブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮した。残渣をクロマトグラフィー（シリカゲル、ヘキサン／酢酸エチル）にかけて、鮮やかな黄色の固体（５．０５ｇ、５８％）を得た。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ７．４５（ａｐｐ ｑ，Ｊ＝７．７Ｈｚ，１Ｈ）、６．８９（ｍ，１Ｈ）、６．８４（ｍ，１Ｈ）、５．４４（ｓ，２Ｈ）、５．１４（ｍ，１Ｈ）、１．６６（ｄ，Ｊ＝７．０Ｈｚ，６Ｈ）。ＬＣ／ＭＳ，ｔ_ｒ＝３．１３分間（５〜９５％のアセトニトリル／水を１ｍｌ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ３８４（Ｍ＋Ｈ）。

6- (2,4-Difluorobenzyloxy) -5-bromo-3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (9.85 g, 22.53 mmol) was converted to N, N-dimethyl. Dissolved in acetamide (50 mL). Potassium cyanide (2.93 g, 45.06 mmol) was added and the resulting mixture was stirred at room temperature for 3 hours. To the reaction mixture was added ethyl acetate (100 mL) and then poured into ice / water (100 mL). The reaction solution was then extracted into ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was chromatographed (silica gel, hexane / ethyl acetate) to give a bright yellow solid (5.05 g, 58%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45 (app q, J = 7.7 Hz, 1H), 6.89 (m, 1H), 6.84 (m, 1H), 5.44 (s, 2H ), 5.14 (m, 1H), 1.66 (d, J = 7.0 Hz, 6H). LC / _MS, t r = 3.13 minutes (5 min 5-95% acetonitrile / water at 1 ml / min, 254nm, 50 ℃), ES -MSm / z384 (M + H).

  Step 2.2 Preparation of 2- (Aminomethyl) -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one

５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−カルボニトリル（ステップ１）（１．３０ｇ、３．３８ミリモル）を酢酸エチル（４．０ｍＬ）および酢酸（４．０ｍＬ）に溶解させた。１０％のＰｄ／Ｃ（０．６７６ｇ）を加え、フラスコにＨ_２を含む風船を装着した。得られる混合物を室温で１時間攪拌した。反応液を、酢酸エチルで洗浄しながらＣｅｌｉｔｅ（登録商標）パッドで濾過した。反応混合物を２．５Ｎ ＮａＯＨでアルカリ性にした（ｐＨ１０〜１１）。水層を除去し、有機層をブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濾過し、濃縮した。残渣をジクロロメタン（１０ｍＬ）に溶解させた。Ｎ−ブロモスクシンイミド（０．１４１ｇ、０．７９２ミリモル）を加え、混合物を室温で４時間攪拌した。追加のＮ−ブロモスクシンイミド（０．０２８ｇ、０．１５９ミリモル）を加え、得られる混合物を室温で終夜攪拌した。反応液を濃縮し、次いで酢酸エチルおよびＨ_２Ｏを加えた。反応液を２．５Ｎ ＮａＯＨでアルカリ性にした（ｐＨ１０）。水層を酢酸エチルで抽出した。有機層を合わせてブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮して、橙色／褐色の泡沫（１．２６ｇ、＞１００％）を得た。ＬＣ／ＭＳ，ｔ_ｒ＝１．７６分間（５〜９５％のアセトニトリル／水を１ｍｌ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ３８８（Ｍ＋Ｈ）。

5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidine-2-carbonitrile (Step 1) (1.30 g, 3.38 mmol) ) Was dissolved in ethyl acetate (4.0 mL) and acetic acid (4.0 mL). 10% Pd / C (0.676 g) was added, was fitted with a balloon containing _{H 2} to flask. The resulting mixture was stirred at room temperature for 1 hour. The reaction was filtered through a Celite® pad with washing with ethyl acetate. The reaction mixture was made alkaline with 2.5N NaOH (pH 10-11). The aqueous layer was removed and the organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was dissolved in dichloromethane (10 mL). N-bromosuccinimide (0.141 g, 0.792 mmol) was added and the mixture was stirred at room temperature for 4 hours. Additional N-bromosuccinimide (0.028 g, 0.159 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction was concentrated and then ethyl acetate and H ₂ O were added. The reaction was made alkaline with 2.5N NaOH (pH 10). The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated to give an orange / brown foam (1.26 g,> 100%). LC / _MS, t r = 1.76 minutes (5 min 5-95% acetonitrile / water at 1 ml / min, 254nm, 50 ℃), ES -MSm / z388 (M + H).

Step 3. Preparation of N-({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} methyl) methanesulfonamide 2- (Aminomethyl) -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one (unpurified from Step 2) (0.300 g, 0 .773 mmol) was dissolved in dichloromethane (2.0 mL) and cooled in an ice bath. Triethylamine (0.162 mL, 1.16 mmol) was added followed by methanesulfonyl chloride (0.066 mL, 0.850 mmol). The resulting mixture was stirred for 1.5 hours with cooling. The reaction was quenched with saturated NaHCO ₃ and extracted with dichloromethane. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. Chromatography (silica gel, hexane / ethyl acetate with 10% methanol) gave the title compound as a pale pink solid (0.250 g, 69%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45 (app q, J = 7.8 Hz, 1H), 6.88 (app t, J = 8.3 Hz, 1H), 6.83 (dt, J = 9 .5, 2.3 Hz, 1H), 5.64 (m, 1H), 5.44 (s, 2H), 4.35 (d, J = 5.2 Hz, 2H), 2.97 (s, 3H) ), 1.58 (d, J = 7.3Hz, 6H), LC / MS, 5 min t r = 2.52 minutes (5% to 95% acetonitrile / water at 1 ml / min, 254nm, 50 ℃) ES-MS m / z 466 (M + H). _{ES-HRMSm / z466.0219 (C 16} H 19 BrF 2 N 3 O 4 M + H calcd for S is 446.0242).

(Example 121)

Ｎ−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝メチル）アセトアミド
Ｎ−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝メチル）アセトアミドの調製。２−（アミノメチル）−５−ブロモ−６−［（２，４−ジフルオロベンジル）オキシ］−３−イソプロピルピリミジン−４（３Ｈ）−オン（Ｎ−（｛５−ブロモ−４−［（２，４−ジフルオロベンジル）オキシ］−１−イソプロピル−６−オキソ−１，６−ジヒドロピリミジン−２−イル｝メチル）メタンスルホンアミド、ステップ２）（０．３００ｇ、０．７７３ミリモル）をジクロロメタン（２．０ｍＬ）に溶解させ、氷浴で冷却した。トリエチルアミン（０．１６２ｍＬ、１．１６ミリモル）を加えた後、塩化アセチル（０．０６０ｍＬ、０．８５０ミリモル）を加えた。得られる混合物を冷却しながら２時間攪拌した。飽和ＮａＨＣＯ_３を加えて反応液を失活させ、ジクロロメタンで抽出した。有機層を合わせてＮａ_２ＳＯ_４で乾燥させ、濾過し、濃縮した。クロマトグラフィー（シリカゲル、１０％のメタノールを含むヘキサン／酢酸エチル）にかけると、表題化合物がオフホワイトの固体（０．１７０ｇ、５１％）として得られた。^１Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ７．４６（ａｐｐ ｑ，Ｊ＝８．５Ｈｚ，１Ｈ）、６．８８（ａｐｐ ｔ，Ｊ＝７．９Ｈｚ，１Ｈ）、６．８１（ｄｔ，Ｊ＝９．５，２．３Ｈｚ，１Ｈ）、６．６８（ｂｒ ｓ，１Ｈ）、５．４５（ｓ，２Ｈ）、４．４５（ｄ，Ｊ＝４．４Ｈｚ，２Ｈ）、４．３５（ｍ，１Ｈ）、２．０８（ｓ，３Ｈ）、１．５６（ｄ，Ｊ＝６．７Ｈｚ，６Ｈ）、ＬＣ／ＭＳ，ｔ_ｒ＝２．３４分間（５〜９５％のアセトニトリル／水を１ｍｌ／分で５分間、２５４ｎｍ、５０℃）、ＥＳ−ＭＳｍ／ｚ４３０（Ｍ＋Ｈ）。ＥＳ−ＨＲＭＳｍ／ｚ４３０．０５３２（Ｃ_１７Ｈ_１９ＢｒＦ_２Ｎ_３Ｏ_３に対するＭ＋Ｈ計算値は４３０．０５７２）。

N-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} methyl) acetamide N-({5- Preparation of bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} methyl) acetamide. 2- (Aminomethyl) -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one (N-({5-bromo-4-[(2 , 4-Difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} methyl) methanesulfonamide, Step 2) (0.300 g, 0.773 mmol) in dichloromethane ( 2.0 mL) and cooled in an ice bath. Triethylamine (0.162 mL, 1.16 mmol) was added followed by acetyl chloride (0.060 mL, 0.850 mmol). The resulting mixture was stirred for 2 hours with cooling. Saturated NaHCO ₃ was added to quench the reaction and extracted with dichloromethane. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. Chromatography (silica gel, hexane / ethyl acetate with 10% methanol) gave the title compound as an off-white solid (0.170 g, 51%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46 (app q, J = 8.5 Hz, 1H), 6.88 (app t, J = 7.9 Hz, 1H), 6.81 (dt, J = 9 .5, 2.3 Hz, 1 H), 6.68 (br s, 1 H), 5.45 (s, 2 H), 4.45 (d, J = 4.4 Hz, 2 H), 4.35 (m, 1H), 2.08 (s, 3H ), 1.56 (d, J = 6.7Hz, 6H), LC / MS, t r = 2.34 minutes (5% to 95% acetonitrile / water 1 ml / Min, 5 min, 254 nm, 50 ° C.), ES-MS m / z 430 (M + H). _{ES-HRMSm / z430.0532 (C 17} H 19 BrF 2 N 3 O M + H calcd for ₃ 430.0572).

(Example 122)

Ｎ−（２−｛［（５−ブロモ−１−イソプロピル−２−メチル−６−オキソ−１，６−ジヒドロピリミジン−４−イル）オキシ］メチル｝−５−フルオロベンジル）−Ｎ’−エチル尿素
ステップ１：６−ヒドロキシ−２−メチル−３−（メチルエチル）−３−ヒドロピリミジン−４−オンの調製

N- (2-{[(5-Bromo-1-isopropyl-2-methyl-6-oxo-1,6-dihydropyrimidin-4-yl) oxy] methyl} -5-fluorobenzyl) -N'-ethyl Urea Step 1: Preparation of 6-hydroxy-2-methyl-3- (methylethyl) -3-hydropyrimidin-4-one

（イミノエチル）（メチルエチル）アミン（６．０８ｇ、６０．８ミリモル）とナトリウムメトキシド（メタノール中２５％、２６．３ｍＬ）の混合物を室温で１５分間攪拌し、油浴で加熱してメタノールを除去した。マロン酸ジエチル（９．６９ｍｌ、６３．８４ミリモル）を加え、混合物を攪拌しながら１５分間かけて１１０℃に加熱した。得られる黄色の固体を、７％のジクロロメタン中メタノールを溶離液として使用するシリカゲルフラッシュクロマトグラフィーによって精製して、４．６５ｇ（４５．５％）の所望の化合物をベージュ色の固体として得た。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ５．２０（ｓ，１Ｈ）、４．６０（ｂｒ，１Ｈ）、２．５９（ｓ，３Ｈ）、１．５６（ｄ，６Ｈ，Ｊ＝６．６Ｈｚ）；ＥＳ−ＭＳｍ／ｚ＝１６９．０９。

A mixture of (iminoethyl) (methylethyl) amine (6.08 g, 60.8 mmol) and sodium methoxide (25% in methanol, 26.3 mL) was stirred at room temperature for 15 minutes and heated in an oil bath to remove methanol. Removed. Diethyl malonate (9.69 ml, 63.84 mmol) was added and the mixture was heated to 110 ° C. with stirring for 15 minutes. The resulting yellow solid was purified by silica gel flash chromatography using 7% methanol in dichloromethane as eluent to give 4.65 g (45.5%) of the desired compound as a beige solid. ¹ H NMR (CD ₃ OD / 400 MHz) δ 5.20 (s, 1H), 4.60 (br, 1H), 2.59 (s, 3H), 1.56 (d, 6H, J = 6.6 Hz) ); ES-MS m / z = 169.09.

  Step 2: Preparation of 5-bromo-6-hydroxy-2-methyl-3- (methylethyl) -3-hydropyrimidin-4-one

６−ヒドロキシ−２−メチル−３−（メチルエチル）−３−ヒドロピリミジン−４−オン（４．３ｇ、２５．６ミリモル）、Ｎ−ブロモスクシンイミド（５．１ｇ、２８．６７ミリモル）のジクロロメタン（５０ｍＬ）中混合物を窒素中にて５℃で１時間攪拌し、一晩かけて室温に温めた。反応混合物を減圧下で濃縮し、残渣を、７％のジクロロメタン中メタノールを溶離液として使用するシリカゲルフラッシュクロマトグラフィーによって精製して、５．０ｇ（８０％）の所望の生成物を固体として得た。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ４．６１（ｂｒ，１Ｈ）、２．６０（ｓ，３Ｈ）、１．６０（ｄ，６Ｈ，Ｊ＝６．４Ｈｚ）。

6-Hydroxy-2-methyl-3- (methylethyl) -3-hydropyrimidin-4-one (4.3 g, 25.6 mmol), N-bromosuccinimide (5.1 g, 28.67 mmol) in dichloromethane The mixture in (50 mL) was stirred in nitrogen at 5 ° C. for 1 hour and allowed to warm to room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography using 7% methanol in dichloromethane as eluent to give 5.0 g (80%) of the desired product as a solid. . ¹ H NMR (CD ₃ OD / 400 MHz) δ 4.61 (br, 1H), 2.60 (s, 3H), 1.60 (d, 6H, J = 6.4 Hz).

  Step 3: Preparation of 2-{[5-Bromo-2-methyl-1- (methylethyl) -6-oxohydropyrimidin-4-yloxy] methyl} -5-fluorobenzenecarbonitrile

５−ブロモ−６−ヒドロキシ−２−メチル−３−（メチルエチル）−３−ヒドロピリミジン−４−オン（２．５５ｇ、１０．３２ミリモル）、臭化２−シアノ−４−フルオロベンジル（２．３２ｇ、１０．８３６ミリモル）、および炭酸カリウム（１．７１ｇ、１２．３８４ミリモル）をＤＭＦ（３０ｍＬ）に混ぜた混合物を室温で１８時間攪拌した。得られる混合物を酢酸エチル（２５ｍｌ）で希釈し、水（２×１００ｍＬ）、ブラインで洗浄し、硫酸ナトリウムで乾燥させ、減圧下で濃縮した。得られる材料を、４０％のヘキサン中ＥｔＯＡｃを溶離液として使用するシリカゲルフラッシュクロマトグラフィーによって精製して、２．８９ｇ（７３．８％）の所望の化合物を白色粉末として得た。^１Ｈ ＮＭＲＣＤ_３ＯＤ／４００ＭＨｚ）δ７．７８（ｍ，１Ｈ）、７．６０（ｍ，１Ｈ），７．４４（ｍ，１Ｈ）、５．６０（ｓ，２Ｈ）、４．６２（ｂｒ，１Ｈ）、２．６０（ｓ，３Ｈ）、１．６０（ｄ，６Ｈ，Ｊ＝６．８Ｈｚ）；ＥＳ−ＭＳｍ／ｚ３８２．０７＆３８０．１０。

5-Bromo-6-hydroxy-2-methyl-3- (methylethyl) -3-hydropyrimidin-4-one (2.55 g, 10.32 mmol), 2-cyano-4-fluorobenzyl bromide (2 A mixture of .32 g, 10.836 mmol) and potassium carbonate (1.71 g, 12.384 mmol) in DMF (30 mL) was stirred at room temperature for 18 hours. The resulting mixture was diluted with ethyl acetate (25 ml), washed with water (2 × 100 mL), brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting material was purified by silica gel flash chromatography using 40% EtOAc in hexane as eluent to give 2.89 g (73.8%) of the desired compound as a white powder. ¹ H NMRCD ₃ OD / 400 MHz) δ 7.78 (m, 1H), 7.60 (m, 1H), 7.44 (m, 1H), 5.60 (s, 2H), 4.62 (br, 1H), 2.60 (s, 3H), 1.60 (d, 6H, J = 6.8 Hz); ES-MS m / z 382.07 & 380.10.

  Step 4: Preparation of 6-{[2- (aminomethyl) -4-fluorophenyl] methoxy} -5-bromo-2-methyl-3- (methylethyl) -3-hydropyrimidin-4-one

窒素で、２−｛［５−ブロモ−２−メチル−１−（メチルエチル）−６−オキソヒドロピリミジン−４−イルオキシ］メチル｝−５−フルオロベンゼンカルボニトリルのＴＨＦ（１８ｍＬ）溶液に０℃でＢＨ_３。ＴＨＦ（１Ｍ溶液、１１．２ｍｌ、１１．２ミリモル）を滴下した。この温度で３０分間攪拌した後、混合物を一晩かけて室温に温めた。混合物に０℃で５ｍＬのメタノールを加え、減圧下でその体積を１０ｍＬに縮小した。得られる材料を、１０％のジクロロメタン中メタノールを溶離液として使用するシリカゲルフラッシュクロマトグラフィーによって精製して、１．２４ｇ（５７．５％）の表題化合物を白色固体として得た。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．４３（ｍ，１Ｈ）、７．２０（ｍ，１Ｈ）、６．９７（ｍ，１Ｈ）、５．５０（ｓ，２Ｈ）、４．６２（ｂｒ，１Ｈ）、３．８６（ｓ，２Ｈ）、２．６０（ｓ，３Ｈ）、１．６０（ｄ，６Ｈ，Ｊ＝６．８Ｈｚ）；ＥＳ−ＭＳｍ／ｚ３８６．１２＆３８４．１３。

To a solution of 2-{[5-bromo-2-methyl-1- (methylethyl) -6-oxohydropyrimidin-4-yloxy] methyl} -5-fluorobenzenecarbonitrile in THF (18 mL) at 0 ° C. with nitrogen. And BH ₃ . THF (1M solution, 11.2 ml, 11.2 mmol) was added dropwise. After stirring at this temperature for 30 minutes, the mixture was allowed to warm to room temperature overnight. To the mixture was added 5 mL of methanol at 0 ° C. and the volume was reduced to 10 mL under reduced pressure. The resulting material was purified by silica gel flash chromatography using 10% methanol in dichloromethane as eluent to give 1.24 g (57.5%) of the title compound as a white solid. ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.43 (m, 1H), 7.20 (m, 1H), 6.97 (m, 1H), 5.50 (s, 2H), 4.62 ( br, 1H), 3.86 (s, 2H), 2.60 (s, 3H), 1.60 (d, 6H, J = 6.8 Hz); ES-MS m / z 386.12 & 384.13.

Step 5: N-[(2-{[5-Bromo-2-methyl-1- (methylethyl) -6-oxohydropyrimidin-4-yloxy] methyl} -5-fluorophenyl) methyl] (ethylamino) Preparation of carboxamide In nitrogen, 6-{[2- (aminomethyl) -4-fluorophenyl] methoxy} -5-bromo-2-methyl-3- (methylethyl) -3-hydropyrimidin-4-one ( Ethyl isocyanate (0.103 ml, 1.3 mmol) was added to a solution of 0.25 g, 0.65 mmol) in dichloromethane (5 mL) at 0 ° C. The reaction mixture is stirred at this temperature for 1.5 hours, the solvent is removed in vacuo, and the residue is purified by chromatography on a silica column using 10% methanol in dichloromethane as eluent to give the title compound ( 0.29 g, 98%) was obtained as a white solid. Melting point 79-80 ° C .; ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.75 (m, 1H), 7.10 (m, 1H), 6.89 (m, 1H), 5.80 (s, 2H ), 4.65 (br, 1H), 4.44 (s, 2H), 3.16 (q, 2H), 2.56 (s, 3H), 1.59 (d, 6H, J = 6. 8 Hz), 1.061 (t, 3H, J = 6.8 Hz); elemental analysis: calculated for C ₁₉ H ₂₄ BrFN ₄ O ₃ : C, 50.12; H, 5.31; N, 12.30 . Found: C, 49.50; H, 5.37; N, 11.75; ES-MS m / z 457.17 & 455.18.

(Example 123)

Ｎ−［（２−｛［５−クロロ−２−メチル−１−（メチルエチル）−６−オキソヒドロピリミジン−４−イルオキシ］メチル｝−５−フルオロフェニル）メチル］（エチルアミノ）カルボキサミド
ステップ１：５−クロロ−６−ヒドロキシ−２−メチル−３−（メチルエチル）−３−ヒドロピリミジン−４−オンの調製

N-[(2-{[5-Chloro-2-methyl-1- (methylethyl) -6-oxohydropyrimidin-4-yloxy] methyl} -5-fluorophenyl) methyl] (ethylamino) carboxamide Step 1 Preparation of 5-chloro-6-hydroxy-2-methyl-3- (methylethyl) -3-hydropyrimidin-4-one

６−ヒドロキシ−２−メチル−３−（メチルエチル）−３−ヒドロピリミジン−４−オン（４．１３ｇ、２４．５８ミリモル）、Ｎ−クロロスクシンイミド（３．６８ｇ、２７．５６ミリモル）をジクロロメタン（４０ｍＬ）に混ぜた混合物を窒素中にて５℃で１時間攪拌し、一晩かけて室温に温めた。反応混合物を減圧下で濃縮した。残渣を、７％のジクロロメタン中メタノールを溶離液として使用するシリカゲルフラッシュクロマトグラフィーによって精製して、４．８３ｇ（９７％）の所望の生成物を固体として得た。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ４．６０（ｂｒ，１Ｈ）、２．６０（ｓ，３Ｈ）、１．６０（ｄ，６Ｈ，Ｊ＝６．４Ｈｚ）。

6-Hydroxy-2-methyl-3- (methylethyl) -3-hydropyrimidin-4-one (4.13 g, 24.58 mmol), N-chlorosuccinimide (3.68 g, 27.56 mmol) in dichloromethane (40 mL) was stirred in nitrogen at 5 ° C. for 1 hour and allowed to warm to room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using 7% methanol in dichloromethane as eluent to give 4.83 g (97%) of the desired product as a solid. ¹ H NMR (CD ₃ OD / 400 MHz) δ 4.60 (br, 1H), 2.60 (s, 3H), 1.60 (d, 6H, J = 6.4 Hz).

  Step 2: Preparation of 2-{[5-chloro-2-methyl-1- (methylethyl) -6-oxohydropyrimidin-4-yloxy] methyl} -5-fluorobenzenecarbonitrile

５−クロロ−６−ヒドロキシ−２−メチル−３−（メチルエチル）−３−ヒドロピリミジン−４−オン（４．６５ｇ、２２．９６ミリモル）、２−シアノ−４−フルオロ臭化ベンジル（５．４１ｇ、２５．２５ミリモル）、および炭酸カリウム（４．７５ｇ、３４．４４ミリモル）をＤＭＦ（５０ｍＬ）に混ぜた混合物を室温で１８時間攪拌した。得られる混合物を酢酸エチル（２５ｍＬ）で希釈し、水（２×１００ｍＬ）、ブラインで洗浄し、硫酸ナトリウムで乾燥させ、減圧下で濃縮した。得られる材料を、４０％のヘキサン中ＥｔＯＡｃを溶離液として使用するシリカゲルフラッシュクロマトグラフィーによって精製して、５．０ｇの表題化合物を白色粉末（６４．９％）として得た。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．７７（ｍ，１Ｈ）、７．６０（ｍ，１Ｈ）、７．４３（ｍ，１Ｈ）、５．６０（ｓ，２Ｈ）、４．６１（ｂｒ，１Ｈ）、２．６０（ｓ，３Ｈ）、１．６０（ｄ，６Ｈ，Ｊ＝６．８Ｈｚ）；ＥＳ−ＭＳｍ／ｚ３３８．１０＆３３６．１２。

5-chloro-6-hydroxy-2-methyl-3- (methylethyl) -3-hydropyrimidin-4-one (4.65 g, 22.96 mmol), 2-cyano-4-fluorobenzyl bromide (5 A mixture of .41 g, 25.25 mmol) and potassium carbonate (4.75 g, 34.44 mmol) in DMF (50 mL) was stirred at room temperature for 18 hours. The resulting mixture was diluted with ethyl acetate (25 mL), washed with water (2 × 100 mL), brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting material was purified by silica gel flash chromatography using 40% EtOAc in hexane as eluent to give 5.0 g of the title compound as a white powder (64.9%). ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.77 (m, 1H), 7.60 (m, 1H), 7.43 (m, 1H), 5.60 (s, 2H), 4.61 ( br, 1H), 2.60 (s, 3H), 1.60 (d, 6H, J = 6.8 Hz); ES-MS m / z 338.10 & 336.12.

  Step 3: Preparation of 6-{[2- (aminomethyl) -4-fluorophenyl] methoxy} -5-chloro-2-methyl-3- (methylethyl) -3-hydropyrimidin-4-one

窒素中で、２−｛［５−クロロ−２−メチル−１−（メチルエチル）−６−オキソヒドロピリミジン−４−イルオキシ］メチル｝−５−フルオロベンゼンカルボニトリル（４．２４ｇ、１２．６２ミリモル）のＴＨＦ（４０ｍＬ）溶液に、０℃でＢＨ_３。ＴＨＦ（１Ｍ溶液、２５．２６ｍＬ、２５．２６ミリモル）を滴下した。この温度で３０分間攪拌した後、混合物を一晩かけて室温に温めた。混合物に０℃で１０ｍＬのメタノールを加え、真空中でその体積を１０ｍＬに縮小した。得られる材料を、１０％のジクロロメタン中メタノールを溶離液として使用するシリカゲルフラッシュクロマトグラフィーによって精製して、２．６５ｇ（６１．８％）の表題化合物を黄色の固体として得た。^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．４３（ｍ，１Ｈ）、７．２０（ｍ，１Ｈ）、６．９８（ｍ，１Ｈ）、５．４５（ｓ，２Ｈ）、４．６１（ｂｒ，１Ｈ）、３．８６（ｓ，２Ｈ）、２．６０（ｓ，３Ｈ）、１．６０（ｄ，６Ｈ，Ｊ＝６．８Ｈｚ）；ＥＳ−ＭＳｍ／ｚ３４２．１５＆３４０．１７。

In nitrogen, 2-{[5-chloro-2-methyl-1- (methylethyl) -6-oxohydropyrimidin-4-yloxy] methyl} -5-fluorobenzenecarbonitrile (4.24 g, 12.62). Mmol) in THF (40 mL) at 0 ° C. with BH ₃ . THF (1M solution, 25.26 mL, 25.26 mmol) was added dropwise. After stirring at this temperature for 30 minutes, the mixture was allowed to warm to room temperature overnight. To the mixture was added 10 mL of methanol at 0 ° C. and the volume was reduced to 10 mL in vacuo. The resulting material was purified by silica gel flash chromatography using 10% methanol in dichloromethane as eluent to give 2.65 g (61.8%) of the title compound as a yellow solid. ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.43 (m, 1H), 7.20 (m, 1H), 6.98 (m, 1H), 5.45 (s, 2H), 4.61 ( br, 1H), 3.86 (s, 2H), 2.60 (s, 3H), 1.60 (d, 6H, J = 6.8 Hz); ES-MS m / z 342.15 & 340.17.

Step 4: N-[(2-{[5-Chloro-2-methyl-1- (methylethyl) -6-oxohydropyrimidin-4-yloxy] methyl} -5-fluorophenyl) methyl] (ethylamino) Preparation of carboxamide In nitrogen, 6-{[2- (aminomethyl) -4-fluorophenyl] methoxy} -5-chloro-2-methyl-3- (methylethyl) -3-hydropyrimidin-4-one ( Ethyl isocyanate (0.119 mL, 1.5 mmol) was added to a solution of 0.255 g (0.75 mmol) in dichloromethane (5 mL) at 0 ° C. The reaction mixture was stirred at this temperature for 1.5 hours, the solvent was removed in vacuo, and the residue was purified by silica gel chromatography column using 10% methanol in dichloromethane as eluent to give the title compound (0. 265 g, 86%) was obtained as a yellow solid. ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.46 (m, 1H), 7.08 (m, 1H), 6.98 (m, 1H), 5.51 (s, 2H) ), 4.63 (br, 1H), 4.45 (s, 2H), 3.16 (q, 2H), 2.62 (s, 3H), 1.58 (d, 6H, J = 6. 8 Hz), 1.10 (t, 3H, J = 7.6 Hz); elemental analysis: calculated for C19H24ClFN4O3: C, 55.54; H, 5.89; N, 13.64. Found: C, 55.41; H, 6.12; N, 13.10. ES-MS m / z 413.28 & 411.29.

(Example 124)

Ｎ−［（２−｛［５−クロロ−２−メチル−１−（メチルエチル）−６−オキソヒドロピリミジン−４−イルオキシ］メチル｝−５−フルオロフェニル）メチル］［（メチルエチル）アミノ］カルボキサミド
窒素中で、６−｛［２−（アミノメチル）−４−フルオロフェニル］メトキシ｝−５−クロロ−２−メチル−３−（メチルエチル）−３−ヒドロピリミジン−４−オン（０．２５５ｇ、０．７５ミリモル）のジクロロメタン溶液（５ｍＬ）に０℃でイソシアン酸イソプロピル（０．１１ｍＬ、１．１２５ミリモル）を加えた。室温で２時間攪拌した後、反応混合物を、１０％のジクロロメタン中メタノールを使用するシリカゲルクロマトグラフィーによって精製して、０．３０４ｇ（９５．４％）の表題化合物を黄色の固体として得た。融点１３１〜１３２℃；^１ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．４６（ｍ，１Ｈ）、７．０７（ｍ，１Ｈ）、６．９７（ｍ，１Ｈ）、５．５０（ｓ，２Ｈ）、４．６１（ｂｒ，１Ｈ）、４．４５（ｓ，２Ｈ）、３．７９（ｍ，１Ｈ）、２．６２（ｓ，３Ｈ）、１．５８（ｄ，６Ｈ，Ｊ＝６．８Ｈｚ）、１．１２（ｄ，６Ｈ，Ｊ＝６．４Ｈｚ）；元素分析：Ｃ２０Ｈ２６ＣｌＦＮ４Ｏ３に対する計算値：Ｃ，５６．５４；Ｈ，６．１７；Ｎ，１３．１９。実測値：Ｃ，５６．３９；Ｈ，６．４１；Ｎ，１２．８２。ＥＳ−ＭＳｍ／ｚ４２７．３１＆４２５．３１。

N-[(2-{[5-chloro-2-methyl-1- (methylethyl) -6-oxohydropyrimidin-4-yloxy] methyl} -5-fluorophenyl) methyl] [(methylethyl) amino] Carboxamide In nitrogen, 6-{[2- (aminomethyl) -4-fluorophenyl] methoxy} -5-chloro-2-methyl-3- (methylethyl) -3-hydropyrimidin-4-one (0. To a solution of 255 g, 0.75 mmol) in dichloromethane (5 mL) was added isopropyl isocyanate (0.11 mL, 1.125 mmol) at 0 ° C. After stirring at room temperature for 2 hours, the reaction mixture was purified by silica gel chromatography using 10% methanol in dichloromethane to give 0.304 g (95.4%) of the title compound as a yellow solid. ¹ NMR (CD ₃ OD / 400 MHz) δ 7.46 (m, 1H), 7.07 (m, 1H), 6.97 (m, 1H), 5.50 (s, 2H) 4.61 (br, 1H), 4.45 (s, 2H), 3.79 (m, 1H), 2.62 (s, 3H), 1.58 (d, 6H, J = 6.8 Hz) ), 1.12 (d, 6H, J = 6.4 Hz); elemental analysis: calculated for C20H26ClFN4O3: C, 56.54; H, 6.17; N, 13.19. Found: C, 56.39; H, 6.41; N, 12.82. ES-MS m / z 427.31 & 425.31.

(Example 125)

Ｎ−［（２−｛［５−ブロモ−２−メチル−１−（メチルエチル）−６−オキソヒドロピリミジン−４−イルオキシ］メチル｝−５−フルオロフェニル）メチル］（シクロヘキシルアミノ）カルボキサミド
窒素中で、６｛［２−（アミノメチル）−４−フルオロフェニル］メトキシ｝−５−ブロモ−２−メチル−３−（メチルエチル）−３−ヒドロピリミジン−４−オン（０．２５ｇ、０．６５ミリモル）のジクロロメタン（５ｍＬ）溶液に０℃でイソシアン酸シクロヘキシル（０．１２４ｍＬ、０．９７５ミリモル）を加えた。室温で２時間攪拌した後、反応混合物を、１０％のジクロロメタン中メタノールを溶離液として使用するシリカゲルクロマトグラフィーによって精製して、０．３２５ｇ（９８％）の表題化合物を白色固体として得た。融点１０９〜１１０℃；^１ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．４６（ｍ，１Ｈ）、７．０７（ｍ，１Ｈ）、６．９８（ｍ，１Ｈ）、５．４９（ｓ，２Ｈ）、４．６１（ｂｒ，１Ｈ）、４．４６（ｓ，２Ｈ）、３．４６（ｍ，１Ｈ）、２．６１（ｓ，３Ｈ）、１．５８（ｄ，６Ｈ，Ｊ＝４．４Ｈｚ）、１．１５−１．８９（ｍ，１１Ｈ）；元素分析：Ｃ_２３Ｈ_３０ＢｒＦＮ_４Ｏ_３に対する計算値：Ｃ，５４．２３；Ｈ，５．９４；Ｎ，１１．００。実測値：Ｃ，５４．４３；Ｈ，６．００；Ｎ，１０．７４。ＥＳ−ＭＳｍ／ｚ５１１．２９＆５０９．３０。

N-[(2-{[5-Bromo-2-methyl-1- (methylethyl) -6-oxohydropyrimidin-4-yloxy] methyl} -5-fluorophenyl) methyl] (cyclohexylamino) carboxamide in nitrogen 6 {[2- (aminomethyl) -4-fluorophenyl] methoxy} -5-bromo-2-methyl-3- (methylethyl) -3-hydropyrimidin-4-one (0.25 g,. Cyclohexyl isocyanate (0.124 mL, 0.975 mmol) was added to a solution of 65 mmol) in dichloromethane (5 mL) at 0 ° C. After stirring at room temperature for 2 hours, the reaction mixture was purified by silica gel chromatography using 10% methanol in dichloromethane as eluent to give 0.325 g (98%) of the title compound as a white solid. Melting point 109-110 ° C .; ¹ NMR (CD ₃ OD / 400 MHz) δ 7.46 (m, 1H), 7.07 (m, 1H), 6.98 (m, 1H), 5.49 (s, 2H) 4.61 (br, 1H), 4.46 (s, 2H), 3.46 (m, 1H), 2.61 (s, 3H), 1.58 (d, 6H, J = 4.4 Hz) ), 1.15-1.89 (m, 11H) ; elemental _analysis: calcd for _{C 23 H 30 BrFN 4 O 3} : C, 54.23; H, 5.94; N, 11.00. Found: C, 54.43; H, 6.00; N, 10.74. ES-MS m / z 511.29 & 509.30.

(Example 126)

Ｎ−［（２−｛［５−クロロ−２−メチル−１−（メチルエチル）−６−オキソヒドロピリミジン−４−イルオキシ］メチル｝−５−フルオロフェニル）メチル］（シクロヘキシルアミノ）カルボキサミド
窒素中で、６−｛［２−（アミノメチル）−４−フルオロフェニル］メトキシ｝−５−クロロ−２−メチル−３−（メチルエチル）−３−ヒドロピリミジン−４−オン（０．２５５ｇ、０．７５ミリモル）のジクロロメタン（５ｍＬ）溶液に０℃でイソシアン酸シクロヘキシル（０．１４２ｍＬ、１．１２５ミリモル）を加えた。室温で２時間攪拌した後、生成物を、１０％のジクロロメタン中メタノールを溶離液として使用するシリカゲルクロマトグラフィーによって精製して、０．３４１ｇ（９８％）の表題化合物を黄色の固体として得た。融点９５〜９６℃；^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．４５（ｍ，１Ｈ）、７．０５（ｍ，１Ｈ）、６．９６（ｍ，１Ｈ）、５．４９（ｓ，２Ｈ）、４．６１（ｂｒ，１Ｈ）、４．４４（ｓ，２Ｈ）、３．４５（ｍ，１Ｈ）、２．６１（ｓ，３Ｈ）、１．５７（ｄ，６Ｈ，Ｊ＝４．４Ｈｚ）、１．１０−１．８８（ｍ，１１Ｈ）；元素分析：Ｃ_２３Ｈ_３０ＢｒＦＮ_４Ｏ_３に対する計算値：Ｃ，５９．４１；Ｈ，６．５０；Ｎ，１２．０５。実測値：Ｃ，５９．１１；Ｈ，６．６２；Ｎ，１１．３１。ＥＳ−ＭＳｍ／ｚ４６７．２８＆４６５．３０。

N-[(2-{[5-Chloro-2-methyl-1- (methylethyl) -6-oxohydropyrimidin-4-yloxy] methyl} -5-fluorophenyl) methyl] (cyclohexylamino) carboxamide in nitrogen 6-{[2- (aminomethyl) -4-fluorophenyl] methoxy} -5-chloro-2-methyl-3- (methylethyl) -3-hydropyrimidin-4-one (0.255 g, 0 .75 mmol) in dichloromethane (5 mL) at 0 ° C. was added cyclohexyl isocyanate (0.142 mL, 1.125 mmol). After stirring at room temperature for 2 hours, the product was purified by silica gel chromatography using 10% methanol in dichloromethane as eluent to give 0.341 g (98%) of the title compound as a yellow solid. ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.45 (m, 1H), 7.05 (m, 1H), 6.96 (m, 1H), 5.49 (s, 2H) ), 4.61 (br, 1H), 4.44 (s, 2H), 3.45 (m, 1H), 2.61 (s, 3H), 1.57 (d, 6H, J = 4. 4Hz), 1.10-1.88 (m, 11H ); elemental _analysis: calcd for _{C 23 H 30 BrFN 4 O 3} : C, 59.41; H, 6.50; N, 12.05. Found: C, 59.11; H, 6.62; N, 11.31. ES-MS m / z 467.28 & 465.30.

(Example 127)

｛［３−（ｔ−ブチル）−１−（４−メチルフェニル）ピラゾール−５−イル］アミノ｝−Ｎ−［（２−｛［５−ブロモ−２−メチル−１−（メチルエチル）−６−オキソヒドロピリジン−４−イルオキシ］メチル｝−５−フルオロフェニル）メチル］カルボキサミド
６−｛［２−（アミノメチル）−４−フルオロフェニル］メトキシ｝−５−ブロモ−２−メチル−３−（メチルエチル）−３−ヒドロピリミジン−４−オン（０．３８４ｇ、１．０ミリモル）をジクロロメタン（１５ｍＬ）およびＮａＨＣＯ_３の飽和溶液（１５ｍＬ）に溶かした溶液に、ホスゲン（トルエン中２０％、１．０４２ｍＬ、１．９７ミリモル）を加えた。混合物を１５分間攪拌し、有機層をＮａ_２ＳＯ_４で乾燥させ、真空中で濃縮し、残渣を３−（ｔ−ブチル）−１−（４−メチルフェニル）ピラゾール−５−イルアミン（０．２２９ｇ）のジクロロメタン（１０ｍＬ）溶液で処理した。得られる混合物を室温で１７時間攪拌した。揮発性物質を真空中で除去した後、残渣を、ジクロロメタン／ヘキサン／アセトン（５：５：１）を溶離として使用するフラッシュクロマトグラフィーによって精製して、表題化合物（０．３６６ｇ、５７．２％）を白色固体として得た。融点１３３〜１３５℃；^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．４４（ｍ，１Ｈ）、７．２８（ｍ，１Ｈ）、６．９７（ｍ，１Ｈ）、６．２９（ｓ，１Ｈ）、５．４４（ｓ，２Ｈ）、４．６０（ｂｒ，１Ｈ）、４．４５（ｓ，２Ｈ）、２．５７（ｓ，３Ｈ）、２．３７（ｓ，３Ｈ）、１．５４（ｄ，６Ｈ，Ｊ＝６．８Ｈｚ）、１．３０（ｓ，９Ｈ）；元素分析：Ｃ_３１Ｈ_３６ＢｒＦＮ_６Ｏ_３に対する計算値：Ｃ，５８．２２；Ｈ，５．６７；Ｎ，１３．１４。実測値：Ｃ，５７．７２；Ｈ，５．２４；Ｎ，１２．７６。ＥＳ−ＭＳｍ／ｚ６４１．３９＆６３９．３９。

{[3- (t-butyl) -1- (4-methylphenyl) pyrazol-5-yl] amino} -N-[(2-{[5-bromo-2-methyl-1- (methylethyl)- 6-oxohydropyridin-4-yloxy] methyl} -5-fluorophenyl) methyl] carboxamide 6-{[2- (aminomethyl) -4-fluorophenyl] methoxy} -5-bromo-2-methyl-3- To a solution of (methylethyl) -3-hydropyrimidin-4-one (0.384 g, 1.0 mmol) in dichloromethane (15 mL) and a saturated solution of NaHCO ₃ (15 mL) was added phosgene (20% in toluene, 1.042 mL, 1.97 mmol) was added. The mixture was stirred for 15 minutes, the organic layer was dried over Na ₂ SO ₄ , concentrated in vacuo, and the residue was 3- (t-butyl) -1- (4-methylphenyl) pyrazol-5-ylamine (0. 229 g) in dichloromethane (10 mL). The resulting mixture was stirred at room temperature for 17 hours. After removing the volatiles in vacuo, the residue was purified by flash chromatography using dichloromethane / hexane / acetone (5: 5: 1) as eluent to give the title compound (0.366 g, 57.2%). ) Was obtained as a white solid. ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.44 (m, 1H), 7.28 (m, 1H), 6.97 (m, 1H), 6.29 (s, 1H) ), 5.44 (s, 2H), 4.60 (br, 1H), 4.45 (s, 2H), 2.57 (s, 3H), 2.37 (s, 3H), 1.54 (d, 6H, J = 6.8Hz ), 1.30 (s, 9H); elemental _analysis: calcd for _{C 31 H 36 BrFN 6 O 3} : C, 58.22; H, 5.67; N, 13.14. Found: C, 57.72; H, 5.24; N, 12.76. ES-MS m / z 641.39 & 639.39.

(Example 128)

｛［３−（ｔ−ブチル）−１−（４−メチルフェニル）ピラゾール−５−イル］アミノ｝−Ｎ−［（２−｛［５−クロロ−２−メチル−１−（メチルエチル）−６−オキソヒドロピリジン−４−イルオキシ］メチル｝−５−フルオロフェニル）メチル］カルボキサミド
３−（ｔ−ブチル）−１−（４−メチルフェニル）ピラゾール−５−イルアミン（０．２２９ｇ、１ミリモル）およびＮａＨＣＯ_３の飽和溶液（１５ｍＬ）をジクロロメタン（１０ｍＬ）に溶かした溶液に、ホスゲン（トルエン中２０％、１．０４２ｍＬ、１．９７ミリモル）を加えた。混合物を１５分間攪拌し、有機層をＮａ_２ＳＯ_４で乾燥させた。真空中で揮発性物質を除去した後、残渣を６−｛［２−（アミノメチル）−４−フルオロフェニル］メトキシ｝−５−クロロ−２−メチル−３−（メチルエチル）−３−ヒドロピリミジン−４−オン（０．３４０ｇ、１．０ミリモル）のジクロロメタン（１５ｍＬ）溶液で処理し、混合物を室温で１７時間攪拌した。反応混合物を真空中で濃縮し、残渣を、ジクロロメタン／ヘキサン／アセトン（５：５：１）を溶離液として使用するフラッシュクロマトグラフィーによって精製して、表題化合物（０．５０ｇ、８４．０％）を白色固体として得た。融点１５３〜１５５℃；^１Ｈ ＮＭＲ（ＣＤ_３ＯＤ／４００ＭＨｚ）δ７．４６（ｍ，１Ｈ）、７．２９（ｍ，１Ｈ）、６．９８（ｍ，１Ｈ）、６．２９（ｓ，１Ｈ）、５．４６（ｓ，２Ｈ）、４．６０（ｂｒ，１Ｈ）、４．４４（ｓ，２Ｈ）、２．５９（ｓ，３Ｈ）、２．３８（ｓ，３Ｈ）、１．５６（ｄ，６Ｈ，Ｊ＝６．８Ｈｚ）、１．３０（ｓ，９Ｈ）；元素分析：Ｃ_３１Ｈ_３６ＣｌＦＮ_６Ｏ_３に対する計算値：Ｃ，６２．５７；Ｈ，６．１０；Ｎ，１４．１２。実測値：Ｃ，６２．９８；Ｈ，６．５６；Ｎ，１３．６１。ＥＳ−ＭＳｍ／ｚ５９７．４５＆５９５．４６。

{[3- (t-butyl) -1- (4-methylphenyl) pyrazol-5-yl] amino} -N-[(2-{[5-chloro-2-methyl-1- (methylethyl)- 6-oxohydropyridin-4-yloxy] methyl} -5-fluorophenyl) methyl] carboxamide 3- (t-butyl) -1- (4-methylphenyl) pyrazol-5-ylamine (0.229 g, 1 mmol) And to a solution of a saturated solution of NaHCO ₃ (15 mL) in dichloromethane (10 mL) was added phosgene (20% in toluene, 1.042 mL, 1.97 mmol). The mixture was stirred for 15 minutes and the organic layer was dried over Na ₂ SO ₄ . After removal of volatiles in vacuo, the residue is taken up with 6-{[2- (aminomethyl) -4-fluorophenyl] methoxy} -5-chloro-2-methyl-3- (methylethyl) -3-hydro. Treated with a solution of pyrimidin-4-one (0.340 g, 1.0 mmol) in dichloromethane (15 mL) and the mixture was stirred at room temperature for 17 hours. The reaction mixture is concentrated in vacuo and the residue is purified by flash chromatography using dichloromethane / hexane / acetone (5: 5: 1) as eluent to give the title compound (0.50 g, 84.0%). Was obtained as a white solid. ¹ H NMR (CD ₃ OD / 400 MHz) δ 7.46 (m, 1H), 7.29 (m, 1H), 6.98 (m, 1H), 6.29 (s, 1H) ), 5.46 (s, 2H), 4.60 (br, 1H), 4.44 (s, 2H), 2.59 (s, 3H), 2.38 (s, 3H), 1.56 (d, 6H, J = 6.8Hz ), 1.30 (s, 9H); elemental _analysis: calcd for _{C 31 H 36 ClFN 6 O 3} : C, 62.57; H, 6.10; N, 14.12. Found: C, 62.98; H, 6.56; N, 13.61. ES-MS m / z 597.45 & 595.46.

(Example 129)

１−（２−（（５−クロロ−１，６−ジヒドロ−１−イソプロピル−２−（メチルチオ）−６−オキソピリミジン−４−イルオキシ）メチル）−５−フルオロベンジル）−３−エチル尿素
ステップ１：５−クロロ−６−ヒドロキシ−３−イソプロピル−２−（メチルチオ）ピリミジン−４（３Ｈ）−オンの調製

1- (2-((5-chloro-1,6-dihydro-1-isopropyl-2- (methylthio) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzyl) -3-ethylurea step Preparation of 1: 5-chloro-6-hydroxy-3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one

磁気攪拌子を備え付けた三ツ口丸底フラスコに入った、６−ヒドロキシ−３−イソプロピル−２−（メチルチオ）ピリミジン−４−オン（５．０ｇ、２５．０ミリモル）を５０ｍＬのジクロロメタンに懸濁させた懸濁液に、０〜５℃でＮ−クロロスクシンイミド（４．０ｇ、３０．０ミリモル）を数回に分けて加えた。反応混合物を攪拌しながら４８時間かけて室温に温めた。次いで、それを激しく攪拌しながらブライン中に注ぎ、固体の沈殿を濾過によって収集し、アセトン／ヘキサン（１：５）の混合溶媒から結晶化させ、真空中で一晩乾燥させて、３．０５ｇの表題化合物を白色粉末（５２％）として得た。^１Ｈ ＮＭＲ（ＤＭＳＯ−ｄ６／４００ＭＨｚ）δ１２．０８（ｓ，１Ｈ）、４．２５（ｍ，１Ｈ）、２．５８（ｓ，３Ｈ）、１．４３（ｄ，６Ｈ）；ＭＳ−ＥＳＩ：ｍ／ｚ２３５（Ｍ＋Ｈ）。

6-Hydroxy-3-isopropyl-2- (methylthio) pyrimidin-4-one (5.0 g, 25.0 mmol) in a three-necked round bottom flask equipped with a magnetic stir bar was suspended in 50 mL of dichloromethane. To the suspension was added N-chlorosuccinimide (4.0 g, 30.0 mmol) in several portions at 0-5 ° C. The reaction mixture was allowed to warm to room temperature over 48 hours with stirring. It is then poured into brine with vigorous stirring and the solid precipitate is collected by filtration, crystallized from a mixed solvent of acetone / hexane (1: 5), dried in vacuo overnight, 3.05 g Of the title compound as a white powder (52%). ¹ H NMR (DMSO-d6 / 400 MHz) δ 12.08 (s, 1H), 4.25 (m, 1H), 2.58 (s, 3H), 1.43 (d, 6H); MS-ESI: m / z 235 (M + H).

  Step 2: Preparation of 2-((5-chloro-1,6-dihydro-1-isopropyl-2- (methylthio) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzonitrile

５−クロロ−６−ヒドロキシ−３−イソプロピル−２−（メチルチオ）ピリミジン−４（３Ｈ）−オン（３．０ｇ、１２．７９ミリモル）のＤＭＦ（２５ｍＬ）溶液に炭酸カリウム（２．７ｇ、１９．１８ミリモル）を加え、混合物を１５分間攪拌し、その後臭化２−シアノ−４−フルオロベンジル（３．１ｇ、１４．０７ミリモル）を数回に分けて加えた。得られる混合物を室温で終夜攪拌し、次いで０〜５℃で激しく攪拌しながらブラインを加えた。淡黄色の沈殿を濾過によって収集し、水で洗浄し、真空中で乾燥させて、３．１５ｇ（７１％）のピンク色の粉末を得た。^１Ｈ ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）δ７．６３（ｍ，１Ｈ）、７．３９（ｍ，２Ｈ）、５．６２（ｓ，２Ｈ）、４．４６（ｍ，１Ｈ）、２．５８（ｓ，３Ｈ）、１．６１（ｄ，６Ｈ）；ＭＳ−ＥＳＩ：ｍ／ｚ３６８（Ｍ＋Ｈ）。

To a solution of 5-chloro-6-hydroxy-3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one (3.0 g, 12.79 mmol) in DMF (25 mL) was added potassium carbonate (2.7 g, 19 .18 mmol) was added and the mixture was stirred for 15 minutes, after which 2-cyano-4-fluorobenzyl bromide (3.1 g, 14.07 mmol) was added in several portions. The resulting mixture was stirred at room temperature overnight and then brine was added with vigorous stirring at 0-5 ° C. The pale yellow precipitate was collected by filtration, washed with water and dried in vacuo to give 3.15 g (71%) of a pink powder. ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.63 (m, 1H), 7.39 (m, 2H), 5.62 (s, 2H), 4.46 (m, 1H), 2.58 (s , 3H), 1.61 (d, 6H); MS-ESI: m / z 368 (M + H).

  Step 3: Preparation of 6- (2- (aminomethyl) -4-fluorobenzyloxy) -5-chloro-3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one

２−（（５−クロロ−１，６−ジヒドロ−１−イソプロピル−２−（メチルチオ）−６−オキソピリミジン−４−イルオキシ）メチル）−５−フルオロベンゾニトリル（２２ｇ、５９．８６ミリモル）の無水ＴＨＦ（２５０ｍＬ）溶液に、−１０℃でＢＨ_３。ＴＨＦ（１Ｍ、１２０ｍＬ）を滴下した。得られる混合物を−１０℃で３時間攪拌し、次いで１６時間かけて室温に温めた。混合物を−０℃に冷却し、メタノール（２０ｍＬ）をゆっくりと加えて過剰のＢＨ_３を除去した。真空中で溶媒を除去した後、未精製のシロップを、ヘキサン／ＤＣＭ／ＣＨ_３ＯＨ（３：６：１）を溶離液とするシリカゲルカラムクロマトグラフィーによって精製して、１２．１ｇ（５５％）の表題化合物を無色のシロップとして得た。^１Ｈ ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）δ７．３８（ｍ，１Ｈ）、１．１７（ｍ，１Ｈ）、６．９５（ｍ，１Ｈ）、５．４６（ｓ，２Ｈ）、４．５２（ｍ，１Ｈ）、４．５１（ｓ，２Ｈ）、２．５８（ｓ，３Ｈ）、２．１６（ｂｓ，２Ｈ）、１．６１（ｄ，６Ｈ）；ＭＳ−ＥＳＩ：ｍ／ｚ３７２（Ｍ＋Ｈ）。

Of 2-((5-chloro-1,6-dihydro-1-isopropyl-2- (methylthio) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzonitrile (22 g, 59.86 mmol) in anhydrous THF (250 mL) solution, _BH 3 at -10 ° C.. THF (1M, 120 mL) was added dropwise. The resulting mixture was stirred at −10 ° C. for 3 hours and then warmed to room temperature over 16 hours. The mixture was cooled to −0 ° C. and methanol (20 mL) was added slowly to remove excess BH ₃ . After removing the solvent in vacuo, the crude syrup was purified by silica gel column chromatography eluting with hexane / DCM / CH ₃ OH (3: 6: 1) to give 12.1 g (55%). The title compound was obtained as a colorless syrup. ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.38 (m, 1H), 1.17 (m, 1H), 6.95 (m, 1H), 5.46 (s, 2H), 4.52 (m , 1H), 4.51 (s, 2H), 2.58 (s, 3H), 2.16 (bs, 2H), 1.61 (d, 6H); MS-ESI: m / z 372 (M + H) .

Step 4: Preparation of the title compound In nitrogen, 6- (2- (aminomethyl) -4-fluorobenzyloxy) -5-chloro-3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one ( To a solution of 0.35 g, 0.943 mmol) in anhydrous dichloromethane (5 mL) was added ethyl isocyanate (0.1 mL, 1.886 mmol) dropwise at room temperature. The resulting mixture was stirred at room temperature for 8 hours. After removing the solvent in vacuo, the crude product was purified by silica gel chromatography using hexane / DCM (1: 5) as the eluent to give 0.087 g of the title compound (21%). ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.36 (m, 1H), 7.22 (m, 1H), 6.95 (m, 1H), 5.42 (s, 2H), 4.48 (m , 1H), 4.30 (s, 2H), 3.19 (q, 2H), 2.62 (s, 3H), 1.61 (d, 6H), 1.08 (t, 3H); MS -ESI: m / z 443 (M + H). Elemental _{analysis: C 19 H 24 ClFN 4 O} 3 Calcd for S: C, 51.52; H, 5.46; N, 12.65. Found: C, 51.73; H, 5.53; N, 12.75.

(Example 130)

１−（２−（（５−クロロ−１，６−ジヒドロ−１−イソプロピル−２−（メチルチオ）−６−オキソピリミジン−４−イルオキシ）メチル）−５−フルオロベンジル）−３−イソプロピル尿素
窒素中で、６−（２−（アミノメチル）−４−フルオロベンジルオキシ）−５−クロロ−３−イソプロピル−２−（メチルチオ）ピリミジン−４（３Ｈ）−オン（０．５ｇ、１．３４６ミリモル）の無水ジクロロメタン（５ｍＬ）溶液に、室温でイソシアン酸イソプロピル（０．４１ｇ、４．０３７ミリモル）を滴下した。得られる混合物を室温で終夜攪拌した。真空中で溶媒を除去した後、粗生成物を、ヘキサン／ジクロロメタン（１：５ｖ／ｖ）を溶離液とするシリカゲルクロマトグラフィーによって精製して、０．２０４ｇの表題化合物を白色粉末（３５．０％）として得た。^１Ｈ ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）δ７．３８（ｍ，１Ｈ）、７．２１（ｍ，１Ｈ）、６．９０（ｍ，１Ｈ）、５．４５（ｓ，２Ｈ）、４．５８（ｍ，１Ｈ）、４．４３（ｓ，２Ｈ）、３．８５（ｍ，１Ｈ）、２．６１（ｓ，３Ｈ）、１．６１（ｄ，６Ｈ）、１．１５（ｄ，６Ｈ）；ＭＳ−ＥＳＩ：ｍ／ｚ４５７（Ｍ＋Ｈ）。元素分析：Ｃ_２０Ｈ_２６ＣｌＦＮ_４Ｏ_３Ｓに対する計算値：Ｃ，５２．５７；Ｈ，５．７３；Ｎ，１２．２６。実測値：Ｃ，５２．４５；Ｈ，５．８０；Ｎ，１１．８７。

1- (2-((5-chloro-1,6-dihydro-1-isopropyl-2- (methylthio) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzyl) -3-isopropylurea nitrogen 6- (2- (aminomethyl) -4-fluorobenzyloxy) -5-chloro-3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one (0.5 g, 1.346 mmol) ) In anhydrous dichloromethane (5 mL) was added dropwise isopropyl isocyanate (0.41 g, 4.037 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. After removal of the solvent in vacuo, the crude product was purified by silica gel chromatography eluting with hexane / dichloromethane (1: 5 v / v) to give 0.204 g of the title compound as a white powder (35.0 %). ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.38 (m, 1H), 7.21 (m, 1H), 6.90 (m, 1H), 5.45 (s, 2H), 4.58 (m , 1H), 4.43 (s, 2H), 3.85 (m, 1H), 2.61 (s, 3H), 1.61 (d, 6H), 1.15 (d, 6H); MS -ESI: m / z 457 (M + H). Elemental _{analysis: C 20 H 26 ClFN 4 O} 3 Calcd for S: C, 52.57; H, 5.73; N, 12.26. Found: C, 52.45; H, 5.80; N, 11.87.

(Example 131)

１−（２−（（５−ブロモ−１，６−ジヒドロ−１−イソプロピル−２−（メチルチオ）−６−オキソピリミジン−４−イルオキシ）メチル）−５−フルオロベンジル）−３−エチル尿素
ステップ１：５−ブロモ−６−ヒドロキシ−３−イソプロピル−２−（メチルチオ）ピリミジン−４（３Ｈ）−オンの調製

1- (2-((5-bromo-1,6-dihydro-1-isopropyl-2- (methylthio) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzyl) -3-ethylurea step Preparation of 1: 5-bromo-6-hydroxy-3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one

磁気攪拌子を備え付けた三ツ口丸底フラスコに入った６−ヒドロキシ−３−イソプロピル−２−（メチルチオ）ピリミジン−４−オン（２５．０ｇ、１２５．０ミリモル）のジクロロメタン（２５０ｍＬ）懸濁液に、Ｎ−ブロモスクシンイミド（２５．０ｇ、１４０．０ミリモル）を数回に分けて加え、窒素中にて０〜５℃で攪拌した。次いで、反応混合物を４８時間かけて室温に温めた。混合物を激しく攪拌しながらブライン中に注ぎ、固体の沈殿を濾過によって収集し、アセトン／ＤＣＭ（６：１）の混合溶媒から結晶化させ、真空中で一晩乾燥させて、２８．１ｇの表題化合物を白色粉末（８１．０％）として得た。^１Ｈ ＮＭＲ（ＤＭＳＯ−ｄ_６／４００ＭＨｚ）δ１２．０８（ｓ，１Ｈ）、４．５７（ｍ，１Ｈ）、２．５８（ｓ，３Ｈ）、１．４３（ｄ，６Ｈ）；ＭＳ−ＥＳＩ：ｍ／ｚ２８０（Ｃ_８Ｈ_１１ＢｒＮ_２Ｏ_２Ｓに対するＭ＋Ｈ計算値は２８０）。

To a suspension of 6-hydroxy-3-isopropyl-2- (methylthio) pyrimidin-4-one (25.0 g, 125.0 mmol) in dichloromethane (250 mL) in a three-necked round bottom flask equipped with a magnetic stir bar. N-bromosuccinimide (25.0 g, 140.0 mmol) was added in several portions and stirred at 0-5 ° C. in nitrogen. The reaction mixture was then warmed to room temperature over 48 hours. The mixture is poured into brine with vigorous stirring and the solid precipitate is collected by filtration, crystallized from a mixed solvent of acetone / DCM (6: 1) and dried in vacuo overnight to yield 28.1 g of the title. The compound was obtained as a white powder (81.0%). _{^{1 H NMR (DMSO-d 6}} /400MHz)δ12.08(s,1H),4.57(m,1H),2.58(s,3H),1.43(d,6H);MS-ESI : M / z 280 (M + H calculated value for C ₈ H ₁₁ BrN ₂ O ₂ S is 280).

  Step 2: Preparation of 2-((5-bromo-1,6-dihydro-1-isopropyl-2- (methylthio) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzonitrile

５−ブロモ−６−ヒドロキシ−３−イソプロピル−２−（メチルチオ）ピリミジン−４（３Ｈ）−オン（２．０ｇ、８．０９７ミリモル）のＤＭＦ（２５ｍＬ）溶液に、炭酸カリウム（１．７０ｇ、１２．１５ミリモル）を加え、混合物を１５分間攪拌し、次いで臭化２−シアノ−４−フルオロベンジル（１．９０ｇ、８．９０７ミリモル）を数回に分けて加えた。得られる混合物を室温で終夜攪拌し、０〜５℃で激しく攪拌しながらブライン中に注いだ。淡いピンク色の沈殿を濾過によって収集し、水で洗浄し、真空中で乾燥させて、３．０１ｇ（９１％）の表題化合物を得た。^１Ｈ ＮＭＲ（ＤＭＳＯ−ｄ_６，４００ＭＨｚ）δ７．９８（ｄｄ，１Ｈ）、７．７０（ｍ，２Ｈ）、５．６２（ｓ，２Ｈ）、４．５３（ｍ，１Ｈ）、２．５９（ｓ，３Ｈ）、１．５３（ｄ，６Ｈ）；ＭＳ−ＥＳＩ：ｍ／ｚ４１２（Ｍ＋Ｈ）。

To a solution of 5-bromo-6-hydroxy-3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one (2.0 g, 8.097 mmol) in DMF (25 mL) was added potassium carbonate (1.70 g, 12.15 mmol) was added and the mixture was stirred for 15 minutes, then 2-cyano-4-fluorobenzyl bromide (1.90 g, 8.907 mmol) was added in several portions. The resulting mixture was stirred at room temperature overnight and poured into brine with vigorous stirring at 0-5 ° C. The pale pink precipitate was collected by filtration, washed with water and dried in vacuo to give 3.01 g (91%) of the title compound. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 7.98 (dd, 1H), 7.70 (m, 2H), 5.62 (s, 2H), 4.53 (m, 1H), 2.59 (S, 3H), 1.53 (d, 6H); MS-ESI: m / z 412 (M + H).

  Step 3: Preparation of 6- (2- (aminomethyl) -4-fluorobenzyloxy) -5-bromo-3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one

２−（（５−ブロモ−１，６−ジヒドロ−１−イソプロピル−２−（メチルチオ）−６−オキソピリミジン−４−イルオキシ）メチル）−５−フルオロベンゾニトリル（１．０ｇ、２．４２７ミリモル）の無水ＴＨＦ（２５０ｍＬ）溶液に、−１０℃でＢＨ_３。ＴＨＦ（１Ｍ、５．０ｍＬ）を滴下した。得られる混合物を−１０℃〜０℃で３時間攪拌し、次いで一晩かけて室温に温めた。それを３０分間加熱還流し、０℃に冷却し、３Ｎ ＮａＯＨ溶液を加えてｐＨ１２にした。有機層を単離し、ブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ_、濾過し、濃縮乾燥した。得られるシロップを、ヘキサン／ＤＣＭ／ＣＨ_３ＯＨ（３：６：１）を溶離液とするシリカゲルカラムクロマトグラフィーによって精製して、８３０ｍｇ（８２％）の表題化合物を無色のシロップとして得た。^１Ｈ ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）δ７．３６（ｍ，１Ｈ）、１．１６（ｍ，１Ｈ）、６．９３（ｍ，１Ｈ）、５．３６（ｓ，２Ｈ）、４．４１（ｍ，１Ｈ）、４．３８（ｓ，２Ｈ）、２．５８（ｓ，３Ｈ）、２．３５（ｂｓ，２Ｈ）、１．６０（ｄ，６Ｈ）；ＭＳ−ＥＳＩ：ｍ／ｚ４１７（Ｍ＋Ｈ）。

2-((5-Bromo-1,6-dihydro-1-isopropyl-2- (methylthio) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzonitrile (1.0 g, 2.427 mmol) ) In anhydrous THF (250 mL) at −10 ° C. with BH ₃ . THF (1M, 5.0 mL) was added dropwise. The resulting mixture was stirred at −10 ° C. to 0 ° C. for 3 hours and then allowed to warm to room temperature overnight. It was heated to reflux for 30 minutes, cooled to 0 ° C., and brought to pH 12 with the addition of 3N NaOH solution. The organic layer was isolated, washed with brine, dried over Na ₂ SO _{4 ,} filtered and concentrated to dryness. The resulting syrup was purified by silica gel column chromatography eluting with hexane / DCM / CH ₃ OH (3: 6: 1) to give 830 mg (82%) of the title compound as a colorless syrup. ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.36 (m, 1H), 1.16 (m, 1H), 6.93 (m, 1H), 5.36 (s, 2H), 4.41 (m , 1H), 4.38 (s, 2H), 2.58 (s, 3H), 2.35 (bs, 2H), 1.60 (d, 6H); MS-ESI: m / z 417 (M + H) .

Step 4: Preparation of the title compound 6- (2- (aminomethyl) -4-fluorobenzyloxy) -5-bromo-3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one (0.25 g, To a solution of 0.602 mmol) in anhydrous dichloromethane (5 mL), ethyl isocyanate (0.065 g, 0.903 mmol) was added dropwise at room temperature, and the mixture was stirred in nitrogen for 16 hours. After removal of the solvent in vacuo, the crude product was purified by silica gel chromatography using hexane / dichloromethane (1: 5) to give 0.175 g (60%) of the title compound as a white powder. ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.38 (m, 1H), 7.22 (m, 1H), 6.97 (m, 1H), 5.43 (s, 2H), 4.58 (m , 1H), 4.45 (s, 2H), 3.21 (q, 2H), 2.62 (s, 3H), 1.63 (d, 6H), 1.11 (t, 3H); MS -ESI: m / z 488 (M + H). Elemental _{analysis: C 20 H 27 BrFN 4 O} 5 Calcd for S: C, 46.82%; H , 4.96%; N, 11.50%. Found: C, 47.18%; H, 4.83%; N, 11.27%.

(Example 132)

１−（２−（（５−ブロモ−１，６−ジヒドロ−１−イソプロピル−２−（メチルチオ）−６−オキソピリミジン−４−イルオキシ）メチル）−５−フルオロベンジル）−３−イソプロピル尿素
窒素中で、６−（２−（アミノメチル）−４−フルオロベンジルオキシ）−５−ブロモ−３−イソプロピル−２−（メチルチオ）ピリミジン−４（３Ｈ）−オン（０．５０ｇ、１．２０２ミリモル）の無水ジクロロメタン（８ｍＬ）溶液に、イソシアン酸イソプロピル（０．２ｍＬ、１．７１５ミリモル）を室温で滴下した。得られる混合物を室温で１６時間攪拌し、真空中で濃縮し、残渣を、ヘキサン／ジクロロメタン（１：５ｖ／ｖ）を溶離液とするシリカゲルクロマトグラフィーによって精製して、０．３８ｇ（６３％）の表題化合物を白色粉末として得た。^１Ｈ ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）δ７．３６（ｍ，１Ｈ）、７．１９（ｍ，１Ｈ）、６．９７（ｍ，１Ｈ）、５．４５（ｓ，２Ｈ）、４．５５（ｍ，１Ｈ）、４．４３（ｓ，２Ｈ）、３．８５（ｍ，１Ｈ）、２．６２（ｓ，３Ｈ）、１．６２（ｄ，６Ｈ）、１．１２（ｄ，６Ｈ）；ＭＳ−ＥＳＩ：ｍ／ｚ５０１（Ｍ^＋）。元素分析：Ｃ_２０Ｈ_２６ＢｒＦＮ_４Ｏ_３Ｓに対する計算値：Ｃ，４７．９１％；Ｈ，５．２３％；Ｎ，１１．１７％。実測値：Ｃ，４７．８９％；Ｈ，５．５８％；Ｎ，１０．７４％。

1- (2-((5-bromo-1,6-dihydro-1-isopropyl-2- (methylthio) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzyl) -3-isopropylurea nitrogen 6- (2- (aminomethyl) -4-fluorobenzyloxy) -5-bromo-3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one (0.50 g, 1.202 mmol) ) In anhydrous dichloromethane (8 mL) was added dropwise isopropyl isocyanate (0.2 mL, 1.715 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours, concentrated in vacuo, and the residue was purified by silica gel chromatography eluting with hexane / dichloromethane (1: 5 v / v) to give 0.38 g (63%). Of the title compound as a white powder. ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.36 (m, 1H), 7.19 (m, 1H), 6.97 (m, 1H), 5.45 (s, 2H), 4.55 (m , 1H), 4.43 (s, 2H), 3.85 (m, 1H), 2.62 (s, 3H), 1.62 (d, 6H), 1.12 (d, 6H); MS -ESI: m / z 501 (M ^<+> ). Elemental _{analysis: C 20 H 26 BrFN 4 O} 3 Calcd for S: C, 47.91%; H , 5.23%; N, 11.17%. Found: C, 47.89%; H, 5.58%; N, 10.74%.

(Example 133)

２−［５−ブロモ−２−（２−ヒドロキシ−エチルアミノ）−１−イソプロピル−６−オキソ−１，６−ジヒドロ−ピリミジン−４−イルオキシメチル］−５−フルオロ−ベンゾニトリル
ステップ１：２−（（５−ブロモ−１，６−ジヒドロ−１−イソプロピル−２−（メチルスルホニル）−６−オキソピリミジン−４−イルオキシ）メチル）−５−フルオロベンゾニトリルの調製

2- [5-Bromo-2- (2-hydroxy-ethylamino) -1-isopropyl-6-oxo-1,6-dihydro-pyrimidin-4-yloxymethyl] -5-fluoro-benzonitrile Step 1: Preparation of 2-((5-bromo-1,6-dihydro-1-isopropyl-2- (methylsulfonyl) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzonitrile

２−（（５−ブロモ−１，６−ジヒドロ−１−イソプロピル−２−（メチルチオ）−６−オキソピリミジン−４−イルオキシ）メチル）−５−フルオロベンゾニトリル（１０．０ｇ、２４．２７２ミリモル）をＴＨＦ（２００ｍＬ）に溶かした、脱イオン水（４０ｍＬ）を含む溶液に、オキソン（３７．３ｇ、６０．６７９ミリモル）を少量ずつ加えた。得られる混合物を室温で５日間攪拌した。反応混合物を激しく攪拌しながら氷−ブライン中に注ぎ、白色沈殿を濾過によって収集し、水で洗浄し、風乾して、１０．６ｇ（９８．９％）の表題化合物を白色粉末として得した。^１Ｈ ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）δ７．６９（ｍ，１Ｈ）、７．４５（ｍ，２Ｈ）、５．５９（ｓ，２Ｈ）、５．２８（ｍ，１Ｈ）、３．４６（Ｓ，３Ｈ）、１．６８（ｄ，６Ｈ）；ＭＳ−ＥＳＩ：ｍ／ｚ４４４．０３（Ｍ＋）。

2-((5-Bromo-1,6-dihydro-1-isopropyl-2- (methylthio) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzonitrile (10.0 g, 24.272 mmol) Oxone (37.3 g, 60.679 mmol) was added in small portions to a solution of deionized water (40 mL) dissolved in THF (200 mL). The resulting mixture was stirred at room temperature for 5 days. The reaction mixture was poured into ice-brine with vigorous stirring and the white precipitate was collected by filtration, washed with water and air dried to give 10.6 g (98.9%) of the title compound as a white powder. ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.69 (m, 1H), 7.45 (m, 2H), 5.59 (s, 2H), 5.28 (m, 1H), 3.46 (S , 3H), 1.68 (d, 6H); MS-ESI: m / z 444.03 (M +).

Step 2: Preparation of the title compound 2-((5-Bromo-1,6-dihydro-1-isopropyl-2- (methylsulfonyl) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzonitrile ( To a solution of 0.5 g, 1.126 mmol) in anhydrous DMF (5 mL) was added pyridine (0.445 g, 5.631 mmol) followed by ethanolamine (0.138 g, 2.252 mmol). The resulting mixture was stirred at room temperature for 2 hours, cooled to −10 ° C., brine (30 mL) was added, and the pH was adjusted to 3 with 0.5 N HCl. The precipitated solid was collected by filtration, washed with water and dried in vacuo to give 0.36 g (76%) of the title compound as a white powder. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 7.95 (m, 1H), 7.68 (m, 2H), 7.40 (bs, 1H), 5.48 (s, 2H), 4.70 (T, 2H), 3.51 (m, 2H), 3.38 (m, 2H), 1.42 (d, 6H); MS-ESI: m / z 426 (M + H). Elemental _analysis: calculated for _{C 17 H 18 BrFN 4 O 3} : C, 48.02%; H, 4.27%; N, 13.17%. Found: 47.85%; H, 4.35%; N, 12.94%.

(Example 134)

１−（２−（（５−ブロモ−１，６−ジヒドロ−１−イソプロピル−２−（メチルスルホニル）−６−オキソピリミジン−４−イルオキシ）メチル）−５−フルオロベンジル）−３−イソプロピル尿素
１−（２−（（５−ブロモ−１，６−ジヒドロ−１−イソプロピル−２−（メチルチオ）−６−オキソピリミジン−４−イルオキシ）メチル）−５−フルオロベンジル）−３−イソプロピル尿素（０４−００３−１３７ａ、０．９２ｇ、１．８３６ミリモル）をＴＨＦ（１０ｍＬ）に溶かした、脱イオン水（１ｍＬ）を含む溶液に、オキソン（２．２６ｇ、３．６７３ミリモル）を加えた。得られる混合物を室温で５０時間攪拌した。反応液を−１０℃に冷却し、ブライン（５０ｍＬ）を加え、激しく攪拌した。生成した固体沈殿を濾過によって収集し、水で洗浄し、真空中で乾燥させて、０．８８ｇ（９０％）の表題化合物を淡黄色の粉末として得た。^１Ｈ ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）δ７．３９（ｍ，１Ｈ）、７．１５（ｍ，１Ｈ）、７．０２（ｍ，１Ｈ）、５．４２（ｓ，２Ｈ）、５．２８（ｍ，１Ｈ）、４．４３（ｓ，２Ｈ）、３．８３（ｍ，１Ｈ）、３．５５（ｓ，３Ｈ）、１．６８（ｄ，６Ｈ）、１．１２（ｄ，６Ｈ）；ＭＳ−ＥＳＩ：ｍ／ｚ５３３．２４（Ｍ＋）。Ｃ_２０Ｈ_２８ＢｒＦＮ_４Ｏ_６Ｓ．Ｈ_２Ｏに対する計算値：Ｃ，４３．５５％；Ｈ，５．０８％；Ｎ，１０．１６％。実測値：Ｃ，４３．２５％；Ｈ，４．６３％；Ｎ，９．６８％。

1- (2-((5-Bromo-1,6-dihydro-1-isopropyl-2- (methylsulfonyl) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzyl) -3-isopropylurea 1- (2-((5-Bromo-1,6-dihydro-1-isopropyl-2- (methylthio) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzyl) -3-isopropylurea ( Oxone (2.26 g, 3.673 mmol) was added to a solution of deionized water (1 mL) in THF (10 mL) dissolved in 04-003-137a, 0.92 g, 1.836 mmol). The resulting mixture was stirred at room temperature for 50 hours. The reaction was cooled to −10 ° C., brine (50 mL) was added and stirred vigorously. The resulting solid precipitate was collected by filtration, washed with water and dried in vacuo to give 0.88 g (90%) of the title compound as a pale yellow powder. ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.39 (m, 1H), 7.15 (m, 1H), 7.02 (m, 1H), 5.42 (s, 2H), 5.28 (m , 1H), 4.43 (s, 2H), 3.83 (m, 1H), 3.55 (s, 3H), 1.68 (d, 6H), 1.12 (d, 6H); MS -ESI: m / z 533.24 (M +). _{C 20 H 28 BrFN 4 O 6} S. Calcd for _{H 2 O: C, 43.55%} ; H, 5.08%; N, 10.16%. Found: C, 43.25%; H, 4.63%; N, 9.68%.

(Example 135)

１−（２−（（２−（２−ヒドロキシエチルアミノ）−５−ブロモ−１，６−ジヒドロ−１−イソプロピル−６−オキソピリミジン−４−イルオキシ）メチル）−５−フルオロベンジル）−３−イソプロピル尿素
１−（２−（（５−ブロモ−１，６−ジヒドロ−１−イソプロピル−２−（メチルスルホニル）−６−オキソピリミジン−４−イルオキシ）メチル）−５−フルオロベンジル）−３−イソプロピル尿素（０４−００３−１６５ａ、０．２５ｇ、０．４６９ミリモル）の無水ＤＭＦ（３ｍＬ）溶液に、炭酸カリウム（０．０６５ｇ、０．４６９ミリモル）およびエタノールアミン（０．０３９ｍＬ、０．５１６ミリモル）を加えた。得られる混合物を室温で２時間攪拌し、次いで−１０℃に冷却し、ブライン（３０ｍＬ）を加えた。固体沈殿を濾過によって収集し、水で洗浄し、真空中で乾燥させて、０．１３６ｇ（５８％）の表題化合物を白色粉末として得た。^１Ｈ ＮＭＲ（ＤＭＳＯ−ｄ_６，４００ＭＨｚ）δ７．４２（ｍ，１Ｈ）、７．３８（ｍ，１Ｈ）、７．０６（ｍ，２Ｈ）、６．２３（ｔ，１Ｈ）、５．８５（ｄ，１Ｈ）、５．３８（ｓ，２Ｈ）、４．７８（ｔ，１Ｈ）、４．３５（ｄ，２Ｈ）、３．６５（ｍ，１Ｈ）、３．５５（ｍ，２）、３．４２（ｍ，２Ｈ）、１．４２（ｄ，６Ｈ）、１．０５（ｄ，６Ｈ）；ＭＳ−ＥＳＩ：ｍ／ｚ５１４．２５（Ｍ^＋）。元素分析：Ｃ_２１Ｈ_２９ＢｒＦＮ_５Ｏ_４に対する計算値：Ｃ，４９．０３％；Ｈ，５．６８％；Ｎ，１３．０５％。実測値：Ｃ，４９．１１％；Ｈ，５．８９％；Ｎ，１２．７１％。

1- (2-((2- (2-hydroxyethylamino) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzyl) -3 -Isopropylurea 1- (2-((5-bromo-1,6-dihydro-1-isopropyl-2- (methylsulfonyl) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzyl) -3 -Isopropylurea (04-003-165a, 0.25 g, 0.469 mmol) in anhydrous DMF (3 mL) to potassium carbonate (0.065 g, 0.469 mmol) and ethanolamine (0.039 mL, .0. 516 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours, then cooled to −10 ° C. and brine (30 mL) was added. The solid precipitate was collected by filtration, washed with water and dried in vacuo to give 0.136 g (58%) of the title compound as a white powder. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 7.42 (m, 1H), 7.38 (m, 1H), 7.06 (m, 2H), 6.23 (t, 1H), 5.85 (D, 1H), 5.38 (s, 2H), 4.78 (t, 1H), 4.35 (d, 2H), 3.65 (m, 1H), 3.55 (m, 2) 3.42 (m, 2H), 1.42 (d, 6H), 1.05 (d, 6H); MS-ESI: m / z 514.25 (M ^<+> ). Elemental _analysis: calculated for _{C 21 H 29 BrFN 5 O 4} : C, 49.03%; H, 5.68%; N, 13.05%. Found: C, 49.11%; H, 5.89%; N, 12.71%.

(Example 136)

１−（２−（（２−（２−（ジメチルアミノ）エチルアミノ）−５−ブロモ−１，６−ジヒドロ−１−イソプロピル−６−オキソピリミジン−４−イルオキシ）メチル）−５−フルオロベンジル）−３−イソプロピル尿素
１−（２−（（５−ブロモ−１，６−ジヒドロ−１−イソプロピル−２−（メチルスルホニル）−６−オキソピリミジン−４−イルオキシ）メチル）−５−フルオロベンジル）−３−イソプロピル尿素（０．２５ｇ、０．４６９ミリモル）の無水ＤＭＦ（２ｍＬ）溶液に、ピリジン（０．０７６ｍＬ、０．９３８ミリモル）およびＮ，Ｎ−ジメチルエチレンジアミン（０．０５７ｍＬ、０．５１５ミリモル）を加えた。混合物を室温で２時間攪拌し、−１０℃に冷却し、ブライン（３０ｍＬ）中に注いだ。沈殿した固体を濾過によって収集し、水で洗浄し、真空中で乾燥させて、０．１９６ｇ（７８％）の表題化合物を白色粉末として得た。^１Ｈ ＮＭＲ（ＤＭＳＯ−ｄ_６，４００ＭＨｚ）δ７．４２（ｍ，１Ｈ）、７．２９（ｍ，１Ｈ）、７．０８（ｍ，２Ｈ）、６．２３（ｔ，１Ｈ）、５．８５（ｄ，１Ｈ）、５．３９（ｓ，２Ｈ）、４．２５（ｄ，２Ｈ）、３．６６（ｍ，１Ｈ）、３．４５（ｍ，２Ｈ）、２．４２（ｔ，２Ｈ）、２．１８（ｓ，６Ｈ）、１．４１（ｄ，６Ｈ）、１．０３（ｄ，６Ｈ）；ＭＳ−ＥＳＩ：ｍ／ｚ５３９．３７（Ｍ−２Ｈ）。元素分析：Ｃ_２３Ｈ_３４ＢｒＦＮ_６Ｏ_３に対する計算値：Ｃ，５０．６９％；Ｈ，６．３４％；Ｎ，１５．４１％。実測値：Ｃ，５０．６８％；Ｈ，６．２９％；Ｎ，１４．９２％。

1- (2-((2- (2- (dimethylamino) ethylamino) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzyl ) -3-Isopropylurea 1- (2-((5-bromo-1,6-dihydro-1-isopropyl-2- (methylsulfonyl) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzyl ) -3-Isopropylurea (0.25 g, 0.469 mmol) in anhydrous DMF (2 mL) was added to pyridine (0.076 mL, 0.938 mmol) and N, N-dimethylethylenediamine (0.057 mL, .0. 515 mmol) was added. The mixture was stirred at room temperature for 2 hours, cooled to −10 ° C. and poured into brine (30 mL). The precipitated solid was collected by filtration, washed with water and dried in vacuo to give 0.196 g (78%) of the title compound as a white powder. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 7.42 (m, 1H), 7.29 (m, 1H), 7.08 (m, 2H), 6.23 (t, 1H), 5.85 (D, 1H), 5.39 (s, 2H), 4.25 (d, 2H), 3.66 (m, 1H), 3.45 (m, 2H), 2.42 (t, 2H) 2.18 (s, 6H), 1.41 (d, 6H), 1.03 (d, 6H); MS-ESI: m / z 539.37 (M-2H). Elemental _analysis: calculated for _{C 23 H 34 BrFN 6 O 3} : C, 50.69%; H, 6.34%; N, 15.41%. Found: C, 50.68%; H, 6.29%; N, 14.92%.

(Example 137)

１−（２−（（５−クロロ−１，６−ジヒドロ−１−イソプロピル−２−（メチルチオ）−６−オキソピリミジン−４−イルオキシ）メチル）−５−フルオロベンジル）−３−シクロヘキシル尿素
１−（２−（（５−クロロ−１，６−ジヒドロ−１−イソプロピル−２−（メチルチオ）−６−オキソピリミジン−４−イルオキシ）メチル）−５−フルオロベンジル）−３−シクロヘキシル尿素（０．７６ｇ、１．５３ミリモル）をＴＨＦ（６ｍＬ）およびＨ_２Ｏ（０．６ｍＬ）に溶かした溶液に、オキソン（１．８８ｇ、３．０６１ミリモル）を加え、室温で１６時間攪拌した。ブライン（３０ｍＬ）を加えて反応液を失活させ、０℃で攪拌した。沈殿した固体を濾過によって収集し、水で洗浄し、真空中で乾燥させて、０．７３ｇ（９１％）の表題化合物を黄色の粉末として得た。^１Ｈ ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）δ７．３８（ｍ，１Ｈ）、７．１７（ｍ，１Ｈ）、７．０５（ｍ，１Ｈ）、５．４１（ｓ，２Ｈ）、５．２６（ｍ，１Ｈ）、４．４３（ｓ，２Ｈ）、３．７５（ｍ，１Ｈ）、３．５３（ｓ，３Ｈ）、３．４３（ｍ，１Ｈ）、１．８５（ｍ，３Ｈ）、１．６８（ｄ，６Ｈ）、１．６０（ｍ，１Ｈ）、１．３０（ｍ，２Ｈ）、１．０５（ｍ，２Ｈ）；ＭＳ−ＥＳＩ：ｍ／ｚ５２９．３１（Ｍ^＋）。元素分析：Ｃ_２３Ｈ_３０ＣｌＦＮ_４Ｏ_３Ｓに対する計算値：Ｃ，５５．５８％；Ｈ，６．０８％；Ｎ，１１．２７％。実測値：Ｃ，５５．４７％；Ｈ，６．２１％；Ｎ，１１．１８％。

1- (2-((5-chloro-1,6-dihydro-1-isopropyl-2- (methylthio) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzyl) -3-cyclohexylurea 1 -(2-((5-chloro-1,6-dihydro-1-isopropyl-2- (methylthio) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzyl) -3-cyclohexylurea (0 Oxone (1.88 g, 3.061 mmol) was added to a solution of .76 g, 1.53 mmol) in THF (6 mL) and H ₂ O (0.6 mL) and stirred at room temperature for 16 hours. Brine (30 mL) was added to quench the reaction and stirred at 0 ° C. The precipitated solid was collected by filtration, washed with water and dried in vacuo to give 0.73 g (91%) of the title compound as a yellow powder. ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.38 (m, 1H), 7.17 (m, 1H), 7.05 (m, 1H), 5.41 (s, 2H), 5.26 (m , 1H), 4.43 (s, 2H), 3.75 (m, 1H), 3.53 (s, 3H), 3.43 (m, 1H), 1.85 (m, 3H), 1 .68 (d, 6H), 1.60 (m, 1H), 1.30 (m, 2H), 1.05 (m, 2H); MS-ESI: m / z 529.31 (M ⁺ ). Elemental _{analysis: C 23 H 30 ClFN 4 O} 3 Calcd for S: C, 55.58%; H , 6.08%; N, 11.27%. Found: C, 55.47%; H, 6.21%; N, 11.18%.

(Example 138)

１−（２−（（５−クロロ−１，６−ジヒドロ−１−イソプロピル−２−（メチルチオ）−６−オキソピリミジン−４−イルオキシ）メチル）−５−フルオロベンジル）−３−シクロヘキシル尿素
１−（２−（（５−クロロ−１，６−ジヒドロ−１−イソプロピル−２−（メチルチオ）−６−オキソピリミジン−４−イルオキシ）メチル）−５−フルオロベンジル）−３−シクロヘキシル尿素（０．７６ｇ、１．５３１ミリモル）をＴＨＦ（１０ｍＬ）に溶かした脱イオン水（１ｍＬ）を含む溶液に、オキソン（１．８８ｇ、３．０６１ミリモル）を加えた。得られる混合物を室温で１６時間攪拌した。混合物を−１０℃に冷却し、激しく攪拌しながらブライン（５０ｍＬ）を加えた。分離した固体を濾過によって収集し、水で洗浄し、真空中で乾燥させて、０．７３ｇ（９０％）の表題化合物を淡黄色の粉末として得た。^１Ｈ ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）δ７．３９（ｍ，１Ｈ）、７．１５（ｍ，１Ｈ）、７．０２（ｍ，１Ｈ）、５．４２（ｓ，２Ｈ）、５．２８（ｍ，１Ｈ）、４．４３（ｓ，２Ｈ）、３．８３（ｍ，１Ｈ）、３．５５（ｓ，３Ｈ）、１．６８（ｄ，６Ｈ）、１．１２（ｄ，６Ｈ）；ＭＳ−ＥＳＩ：ｍ／ｚ５３３．２４（Ｍ＋）。元素分析：Ｃ_２３Ｈ_３０ＣｌＦＮ_４Ｏ_５Ｓに対する計算値：Ｃ，５２．２２％；Ｈ，５．７２％；Ｎ，１０．５９％。実測値：Ｃ，５１．８８％；Ｈ，５．８８％；Ｎ，９．８３％。

1- (2-((5-chloro-1,6-dihydro-1-isopropyl-2- (methylthio) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzyl) -3-cyclohexylurea 1 -(2-((5-chloro-1,6-dihydro-1-isopropyl-2- (methylthio) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzyl) -3-cyclohexylurea (0 Oxone (1.88 g, 3.061 mmol) was added to a solution containing deionized water (1 mL) dissolved in THF (10 mL) in .76 g, 1.531 mmol). The resulting mixture was stirred at room temperature for 16 hours. The mixture was cooled to −10 ° C. and brine (50 mL) was added with vigorous stirring. The separated solid was collected by filtration, washed with water and dried in vacuo to give 0.73 g (90%) of the title compound as a pale yellow powder. ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.39 (m, 1H), 7.15 (m, 1H), 7.02 (m, 1H), 5.42 (s, 2H), 5.28 (m , 1H), 4.43 (s, 2H), 3.83 (m, 1H), 3.55 (s, 3H), 1.68 (d, 6H), 1.12 (d, 6H); MS -ESI: m / z 533.24 (M +). Elemental _{analysis: C 23 H 30 ClFN 4 O} 5 Calcd for S: C, 52.22%; H , 5.72%; N, 10.59%. Found: C, 51.88%; H, 5.88%; N, 9.83%.

(Example 139)

１−（２−（（５−クロロ−１，６−ジヒドロ−１−イソプロピル−２−（メチルチオ）−６−オキソピリミジン−４−イルオキシ）メチル）−５−フルオロベンジル）−３−（３−ｔ−ブチル−１−ｐ−トリル−１Ｈ−ピラゾール−５−イル）尿素
６−（２−（アミノメチル）−４−フルオロベンジルオキシ）−５−クロロ−３−イソプロピル−２−（メチルチオ）ピリミジン−４（３Ｈ）−オン（０．４ｇ、１．０７６ミリモル）のジクロロメタン（１２ｍＬ）溶液に、ＮａＨＣＯ_３の飽和溶液（１２ｍＬ）を加えた。混合物を５℃に冷却し、激しく攪拌しながら、ホスゲンのトルエン溶液（２０％、１．１４ｍＬ、２．１５４ミリモル）を滴下した。得られる混合物を５℃で３０分間攪拌し、有機層を分離し、Ｎａ_２ＳＯ_４で乾燥させ、濾過し、６ｍＬに濃縮し、１−（４−メチル）フェニル−３−ｔ−ブチル−ピラゾリル−５−アミン（０．４９３ｇ、２．１５２ミリモル）を加えた。得られる混合物を窒素中にて室温で４８時間攪拌し、生成物を、ヘキサン／ジクロロメタン／アセトン（５：５：１）を溶離液とするシリカゲルクロマトグラフィーによって精製して、１８６ｍｇ（３０％）の表題化合物を淡い黄色がかった粉末として得た。^１Ｈ ＮＭＲ（ＣＤＣｌ_３，４００ＭＨｚ）δ７．３０（ｍ，３Ｈ）、７．２０（ｄ，２Ｈ）、７．０５（ｄｄ，１Ｈ）、６．９５（ｍ，１Ｈ）、６．３５（ｓ，１Ｈ）、６．３１（ｂｓ，１Ｈ）、５．５５（ｂｓ，１Ｈ）、５．４０（ｓ，２Ｈ）、４．４５（ｄ，２Ｈ）、２．６０（ｓ，３Ｈ）、２．３６（ｓ，３Ｈ）、１．５８（ｄ，６Ｈ）、１．１５（ｓ，９Ｈ）；ＭＳ−ＥＳＩ：ｍ／ｚ６２７．３７（Ｍ^＋）。元素分析：Ｃ_３１Ｈ_３６ＣｌＦＮ_６Ｏ_２Ｓに対する計算値：Ｃ，５９．３７％；Ｈ，５．７９％；Ｎ，１３．４０％。実測値：Ｃ，５９．１０％；Ｈ，６．００％；Ｎ，１２．６７％。

1- (2-((5-chloro-1,6-dihydro-1-isopropyl-2- (methylthio) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzyl) -3- (3- t-butyl-1-p-tolyl-1H-pyrazol-5-yl) urea 6- (2- (aminomethyl) -4-fluorobenzyloxy) -5-chloro-3-isopropyl-2- (methylthio) pyrimidine -4 (3H) - on (0.4 g, 1.076 mmol) in dichloromethane (12 mL) solution of was added a saturated solution of NaHCO ₃ (12 mL). The mixture was cooled to 5 ° C. and a solution of phosgene in toluene (20%, 1.14 mL, 2.154 mmol) was added dropwise with vigorous stirring. The resulting mixture is stirred at 5 ° C. for 30 min, the organic layer is separated, dried over Na ₂ SO ₄ , filtered, concentrated to 6 mL, and 1- (4-methyl) phenyl-3-tert-butyl-pyrazolyl. -5-amine (0.493 g, 2.152 mmol) was added. The resulting mixture was stirred at room temperature for 48 hours under nitrogen and the product was purified by silica gel chromatography eluting with hexane / dichloromethane / acetone (5: 5: 1) to give 186 mg (30%) of The title compound was obtained as a pale yellowish powder. ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.30 (m, 3H), 7.20 (d, 2H), 7.05 (dd, 1H), 6.95 (m, 1H), 6.35 (s) , 1H), 6.31 (bs, 1H), 5.55 (bs, 1H), 5.40 (s, 2H), 4.45 (d, 2H), 2.60 (s, 3H), 2 .36 (s, 3H), 1.58 (d, 6H), 1.15 (s, 9H); MS-ESI: m / z 627.37 (M ^<+> ). Elemental _{analysis: C 31 H 36 ClFN 6 O} 2 Calculated for S: C, 59.37%; H , 5.79%; N, 13.40%. Found: C, 59.10%; H, 6.00%; N, 12.67%.

(Example 140)

６−［（２，４−ジフルオロフェニル）メトキシ］−３−シクロプロピル−２−メチルチオ−３−ヒドロピリミジン−４−オン
ステップ１：イソチオシアン酸シクロプロピルの調製

6-[(2,4-Difluorophenyl) methoxy] -3-cyclopropyl-2-methylthio-3-hydropyrimidin-4-one Step 1: Preparation of cyclopropyl isothiocyanate

シクロプロピルアミン（８．０３ｇ、０．１４１モル）およびトリエチルアミン（１５．６５ｇ、０．１５５モル）をＴＨＦ（１００ｍＬ）に溶かした攪拌溶液に、０〜１０℃で二硫化炭素（３２．１２ｇ、０．４２２モル）を加えた。攪拌を０．５時間継続し、室温で過酸化水素の溶液（３０ｗｔ％、４７．８２ｇ、０．４２２モル）を滴下した。１時間後、反応混合物を希塩酸（１：１）で中和して中性のｐＨにし、エーテル（５０ｍＬ）で希釈した。有機層をブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、減圧下で蒸発にかけた。得られる残渣を蒸留して８．５０ｇ（６１．０％）の所望の生成物を無色の油状物として得た。融点１２５〜１３０℃；^１Ｈ ＮＭＲ（ＣＤＣｌ_３／２００ＭＨｚ）δ２．９４−２．８２（ｍ，１Ｈ）、０．９６−０．８２（ｍ，４Ｈ）。

To a stirred solution of cyclopropylamine (8.03 g, 0.141 mol) and triethylamine (15.65 g, 0.155 mol) in THF (100 mL) was added carbon disulfide (32.12 g, 0.422 mol) was added. Stirring was continued for 0.5 hour, and a hydrogen peroxide solution (30 wt%, 47.82 g, 0.422 mol) was added dropwise at room temperature. After 1 hour, the reaction mixture was neutralized with dilute hydrochloric acid (1: 1) to neutral pH and diluted with ether (50 mL). The organic layer was washed with brine, dried over Na ₂ SO ₄ and evaporated under reduced pressure. The resulting residue was distilled to give 8.50 g (61.0%) of the desired product as a colorless oil. Mp _{^{125~130 ℃; 1 H NMR (CDCl}} 3 /200MHz)δ2.94-2.82(m,1H),0.96-0.82(m,4H).

  Step 2: Preparation of cyclopropylthiourea

イソチオシアン酸シクロプロピル（８．１４０ｇ、８２．２ミリモル）のメタノール（１０ｍＬ）溶液に、０℃でアンモニアのメタノール溶液（７Ｎ、２３．５ｍＬ）を加えた。次いで、得られる混合物を室温で５時間攪拌し、−１０℃に冷却し、白色沈殿を濾別し、それをエーテルで洗浄し、乾燥させて、１０．２５１ｇ（１００％）の表題生成物を白色の結晶性固体として得た。^１Ｈ ＮＭＲ（ＤＭＳＯ−ｄ_６／４００ＭＨｚ）δ７．９５（ｂｒ，１Ｈ）、７．６２（ｂｒ，１Ｈ）、７．１５（ｂｒ，１Ｈ）、２．２０（ｂｒ，１Ｈ）。０．６８−０．６２（ｍ，２Ｈ）、０．５０−０．４２（ｍ，２Ｈ）；ＥＳ−ＭＳｍ／ｚ１１７．０７（Ｍ＋Ｈ）。

To a solution of cyclopropyl isothiocyanate (8.140 g, 82.2 mmol) in methanol (10 mL) was added a methanol solution of ammonia (7N, 23.5 mL) at 0 ° C. The resulting mixture was then stirred at room temperature for 5 hours, cooled to −10 ° C., the white precipitate was filtered off, washed with ether and dried to yield 10.251 g (100%) of the title product. Obtained as a white crystalline solid. _{^{1 H NMR (DMSO-d 6}} /400MHz)δ7.95(br,1H),7.62(br,1H),7.15(br,1H),2.20(br,1H). 0.68-0.62 (m, 2H), 0.50-0.42 (m, 2H); ES-MS m / z 117.07 (M + H).

  Step 3: Preparation of 3-cyclopropyl-6-hydroxy-2-methylthio-3-hydropyrimidin-4-one

シクロプロピルチオ尿素（１０．１９１ｇ、８７．８ミリモル）、ジエチルマロン酸（１４．０６０ｇ、８７．８ミリモル）、ナトリウムメトキシド（メタノール中２５−３０％、３５．１ｍＬ）からなる激しく攪拌した混合物を窒素中で加熱還流した。４．５時間後、反応混合物を冷却し、ヨードメタン（１２．９５２ｇ、９１．３ミリモル）を加え、その間温度は５０℃に保った。混合物を３０分間攪拌し、次いで１０℃に冷却し、酢酸（２１．１ｍＬ）で処理した。沈殿した生成物を水（５０ｍＬ）で希釈し、濾過し、水で洗浄し、風乾して、１３．８５３ｇ（７９．７％）の所望の生成物を得た。^１Ｈ ＮＭＲ（ＤＭＳＯ−ｄ_６／４００ＭＨｚ）δ５．１０（ｓ，２Ｈ）、２．６８−２．６２（ｍ，１Ｈ）、２．５０（ｓ，３Ｈ）、１．１８−１．０６（ｍ，２Ｈ）、０．８８−０．８２（ｍ，２Ｈ）；ＥＳ−ＭＳｍ／ｚ１９８．０９（Ｍ^＋）。

A vigorously stirred mixture consisting of cyclopropylthiourea (10.191 g, 87.8 mmol), diethylmalonic acid (14.060 g, 87.8 mmol), sodium methoxide (25-30% in methanol, 35.1 mL). Was heated to reflux in nitrogen. After 4.5 hours, the reaction mixture was cooled and iodomethane (12.952 g, 91.3 mmol) was added while maintaining the temperature at 50 ° C. The mixture was stirred for 30 minutes, then cooled to 10 ° C. and treated with acetic acid (21.1 mL). The precipitated product was diluted with water (50 mL), filtered, washed with water and air dried to give 13.853 g (79.7%) of the desired product. _{^{1 H NMR (DMSO-d 6}} / 400MHz) δ5.10 (s, 2H), 2.68-2.62 (m, 1H), 2.50 (s, 3H), 1.18-1.06 ( m, 2H), 0.88-0.82 (m, 2H); ES-MS m / z 198.09 (M ^<+> ).

  Step 4: Preparation of 6-[(2,4-difluorophenyl) methoxy] -3-cyclopropyl-2-methylthio-3-hydropyrimidin-4-one

３−シクロプロピル−６−ヒドロキシ−２−メチルチオ−３−ヒドロピリミジン−４−オン（１３．８５３ｇ、６６．９ミリモル）、臭化２，４−ジフルオロベンジル（１４．７６０ｇ、７１．３モル）、および炭酸カリウム（１７．３９０ｇ、１２５ミリモル）をＤＭＦ（８０ｍＬ）に混ぜた混合物を窒素中にて０℃で攪拌した。３０分後、それを室温でさらに３０分間攪拌し、濾過し、濾液を減圧下で濃縮した。残渣をジクロロメタン（５０ｍＬ）と５％の塩酸（２０ｍＬ）とに分配した。有機層を水で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、減圧下で濃縮乾燥した。得られる材料を、３３％のヘキサン中ＥｔＯＡｃを溶離として使用するシリカゲルフラッシュクロマトグラフィーによって精製して、１１．１４４ｇの表題化合物を白色粉末として得た。融点１０６．１〜１０６．８℃；^１Ｈ ＮＭＲ（ＣＤＣｌ_３／４００ＭＨｚ）δ７．４１−７．３９（ｍ，１Ｈ）、６．９１−６．８１（ｍ，２Ｈ）、５．５６（ｓ，１Ｈ）、５．３０（ｓ，２Ｈ）、２．７０−２．５１（ｍ，１Ｈ）、２．５１（ｓ，３Ｈ）、１．２９−１．２４（ｍ，２Ｈ）、１．０２−０．９８（ｍ，２Ｈ）；元素分析：Ｃ_１５Ｈ_１４Ｎ_２Ｏ_２ＳＦ_２に対する計算値：Ｃ，５５．５５；Ｈ，４．３８；Ｎ，８．６４。実測値：Ｃ，５５．６８；Ｈ，４．４４；Ｎ，８．５９；ＥＳ−ＭＳｍ／ｚ３２５。

3-Cyclopropyl-6-hydroxy-2-methylthio-3-hydropyrimidin-4-one (13.853 g, 66.9 mmol), 2,4-difluorobenzyl bromide (14.760 g, 71.3 mol) , And potassium carbonate (17.390 g, 125 mmol) in DMF (80 mL) was stirred at 0 ° C. under nitrogen. After 30 minutes, it was stirred at room temperature for an additional 30 minutes, filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between dichloromethane (50 mL) and 5% hydrochloric acid (20 mL). The organic layer was washed with water, dried (Na ₂ SO ₄ ) and concentrated to dryness under reduced pressure. The resulting material was purified by silica gel flash chromatography eluting with 33% EtOAc in hexanes to give 11.144 g of the title compound as a white powder. Mp _{^{106.1~106.8 ℃; 1 H NMR (CDCl}} 3 /400MHz)δ7.41-7.39(m,1H),6.91-6.81(m,2H),5.56(s , 1H), 5.30 (s, 2H), 2.70-2.51 (m, 1H), 2.51 (s, 3H), 1.29-1.24 (m, 2H), 02-0.98 (m, 2H); elemental _{analysis: C 15 H 14 N 2 O} 2 SF 2 calculated for: C, 55.55; H, 4.38 ; N, 8.64. Found: C, 55.68; H, 4.44; N, 8.59; ES-MS m / z 325.

(Example 141)

６−［（２，４−ジフルオロフェニル）メトキシ］−２−｛［２−（ジメチル−アミノ）エチル］アミノ｝−５−ブロモ−３−シクロプロピル−３−ヒドロピリミジン−４−オン
ステップ１：６−［（２，４−ジフルオロフェニル）メトキシ］−５−ブロモ−３−シクロプロピル−２−メチルチオ−３−ヒドロピリミジン−４−オンの調製

6-[(2,4-Difluorophenyl) methoxy] -2-{[2- (dimethyl-amino) ethyl] amino} -5-bromo-3-cyclopropyl-3-hydropyrimidin-4-one Step 1: Preparation of 6-[(2,4-difluorophenyl) methoxy] -5-bromo-3-cyclopropyl-2-methylthio-3-hydropyrimidin-4-one

６−［（２，４−ジフルオロフェニル）メトキシ］−３−シクロプロピル−２−メチルチオ−３−ヒドロピリミジン−４−オン（１．６００ｇ、４．９３ミリモル）、Ｎ−ブロモスクシンイミド（０．９２２ｇ、５．１８ミリモル）をジクロロメタン（１５ｍＬ）に混ぜた混合物を窒素中にて室温で１時間攪拌した。反応混合物を減圧下で濃縮し、残渣を、３３％のヘキサン中酢酸エチルを溶離として使用するシリカゲルフラッシュクロマトグラフィーによって精製して、１．５４４ｇ（７７．７％）の表題化合物を白色粉末として得た。融点１２１．０〜１２２．４℃。^１Ｈ ＮＭＲ（ＣＤＣｌ_３／４００ＭＨｚ）δ７．５２−７．４４（ｍ，１Ｈ）、６．９８−６．７８（ｍ，２Ｈ），５．５２（ｓ，２Ｈ）、２．８０−２．７２（ｍ，１Ｈ）、２．５２（ｓ，３Ｈ）、１．３２−１．２４（ｍ，２Ｈ）、１．０８−１．０２（ｍ，２Ｈ）；ＥＳ−ＭＳｍ／ｚ４０３．０５＆４０５．０４。

6-[(2,4-Difluorophenyl) methoxy] -3-cyclopropyl-2-methylthio-3-hydropyrimidin-4-one (1.600 g, 4.93 mmol), N-bromosuccinimide (0.922 g) A mixture of 5.18 mmol) in dichloromethane (15 mL) was stirred in nitrogen at room temperature for 1 hour. The reaction mixture is concentrated under reduced pressure and the residue is purified by silica gel flash chromatography eluting with 33% ethyl acetate in hexanes to give 1.544 g (77.7%) of the title compound as a white powder. It was. Melting point 121.0-122.4 ° C. ¹ H NMR _(CDCl 3 ^{/400MHz)δ7.52-7.44(m,1H),6.98-6.78(m,2H),5.52(s,2H),2.80-2.} 72 (m, 1H), 2.52 (s, 3H), 1.32-1.24 (m, 2H), 1.08-1.02 (m, 2H); ES-MS m / z 403.05 & 405. 04.

  Step 2: Preparation of 6-[(2,4-difluorophenyl) methoxy] -5-bromo-3-cyclopropyl-2- (methylsulfonyl) -3-hydropyrimidin-4-one

６−［（２，４−ジフルオロフェニル）メトキシ］−５−ブロモ−３−シクロプロピル−２−メチルチオ−３−ヒドロピリミジン−４−オン（０．７５８ｇ、１．８８ミリモル）、ｍ−クロロ過安息香酸（６０％、１．３５２ｇ、４．７０ミリモル）をジクロロメタン（４０ｍＬ）に混ぜた混合物を室温で１６時間攪拌した。反応混合物を濾過し、減圧下で濾液を濃縮し、残渣を、３３％のヘキサン中酢酸エチルを溶離として使用するシリカゲルフラッシュクロマトグラフィーによって精製して、０．６９５ｇ（８４．９％）の生成物を白色粉末として得た。融点１５９．６〜１６０．５℃；^１Ｈ ＮＭＲ（ＣＤＣｌ_３／４００ＭＨｚ）δ７．４８−７．４１（ｍ，１Ｈ）、６．９８−６．８４（ｍ，２Ｈ）、５．４２（ｓ，２Ｈ）、３．３８−２．７２（ｍ，１Ｈ）、２．５２（ｓ，３Ｈ）、１．３２−１．２４（ｍ，２Ｈ）、１．０８−１．０２（ｍ，２Ｈ）；ＥＳ−ＭＳｍ／ｚ４３４．９７＆４３６．９７。

6-[(2,4-Difluorophenyl) methoxy] -5-bromo-3-cyclopropyl-2-methylthio-3-hydropyrimidin-4-one (0.758 g, 1.88 mmol), m-chloroperoxide A mixture of benzoic acid (60%, 1.352 g, 4.70 mmol) in dichloromethane (40 mL) was stirred at room temperature for 16 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography using 33% ethyl acetate in hexane as eluent to give 0.695 g (84.9%) of product. Was obtained as a white powder. Mp _{^{159.6~160.5 ℃; 1 H NMR (CDCl}} 3 /400MHz)δ7.48-7.41(m,1H),6.98-6.84(m,2H),5.42(s , 2H), 3.38-2.72 (m, 1H), 2.52 (s, 3H), 1.32-1.24 (m, 2H), 1.08-1.02 (m, 2H) ); ES-MS m / z 434.97 & 436.97.

Step 3: 6-[(2,4-Difluorophenyl) methoxy] -2-{[2- (dimethyl-amino) ethyl] amino} -5-bromo-3-cyclopropyl-3-hydropyrimidin-4-one Preparation of 6-[(2,4-difluorophenyl) methoxy] -5-bromo-3-cyclopropyl-2- (methylsulfonyl) -3-hydropyrimidin-4-one (0.378 g, 0.868 mmol) , N, N-dimethylethylenediamine (0.230 g, 2.60 mmol), and potassium carbonate (0.144 g, 1.04 mmol) in DMF (4 mL) were stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography using 13% methanol in dichloromethane as eluent to give 0.154 g (40.2%) of the title compound as a white powder. . Mp _{^{125.8~127.2 ℃; 1 H NMR (CDCl}} 3 /400MHz)δ7.52-7.46(m,1H),6.92-6.78(m,2H),6.58(br , 1H), 5.41 (s, 2H), 3.48-3.44 (m, 2H), 2.64-2.55 (m, 3H), 2.31 (s, 6H), 28-1.24 (m, 2H), 0.92-0.88 (m, 2H); elemental _{analysis: C 18 H 21 N 4 O} 2 BrF 2 calculated for: C, 48.77; H, 4 .77; N, 12.64. Found: C, 48.58; H, 4.68; N, 12.35; ES-MS m / z 443.

(Example 142)

６−［（２，４−ジフルオロフェニル）メトキシ］−２−｛［２−（ジメチル−アミノ）エチル］アミノ｝−５−クロロ−３−シクロプロピル−３−ヒドロピリミジン−４−オン
ステップ１：６−［（２，４−ジフルオロフェニル）メトキシ］−３−シクロプロピル−２−（メチルスルホニル）−３−ヒドロピリミジン−４−オンの調製

6-[(2,4-Difluorophenyl) methoxy] -2-{[2- (dimethyl-amino) ethyl] amino} -5-chloro-3-cyclopropyl-3-hydropyrimidin-4-one Step 1: Preparation of 6-[(2,4-difluorophenyl) methoxy] -3-cyclopropyl-2- (methylsulfonyl) -3-hydropyrimidin-4-one

６−［（２，４−ジフルオロフェニル）メトキシ］−３−シクロプロピル−２−メチルチオ−３−ヒドロピリミジン−４−オン（５．０００ｇ、１５．４ミリモル）、ｍ−クロロ過安息香酸（６０％、１３．３０６ｇ、４６．３ミリモル）をジクロロメタン（２００ｍＬ）に混ぜた混合物を室温で１２時間攪拌した。反応混合物を濾過し、濾液を減圧下で濃縮し、残渣を、５０％のヘキサン中酢酸エチルを溶離として使用するシリカゲルフラッシュクロマトグラフィーによって精製して、４．２６６ｇ（７７．６％）の表題化合物を白色粉末として得た。融点１１３．５〜１１４．２℃；^１Ｈ ＮＭＲ（ＣＤＣｌ_３／４００ＭＨｚ）δ７．４６−７．３５（ｍ，１Ｈ）、６．９８−６．８４（ｍ，２Ｈ）、５．８２（ｓ，１Ｈ）、５．２４（ｓ，２Ｈ）、３．３５（ｓ，３Ｈ）、３．２４−３．１６（ｍ，１Ｈ）、１．３５−１．３２（ｍ，２Ｈ）、１．１８−１．１２（ｍ，２Ｈ）；ＥＳ−ＭＳｍ／ｚ３５７．１０。

6-[(2,4-Difluorophenyl) methoxy] -3-cyclopropyl-2-methylthio-3-hydropyrimidin-4-one (5.000 g, 15.4 mmol), m-chloroperbenzoic acid (60 %, 13.306 g, 46.3 mmol) in dichloromethane (200 mL) was stirred at room temperature for 12 hours. The reaction mixture is filtered, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel flash chromatography, eluting with 50% ethyl acetate in hexane, to give 4.266 g (77.6%) of the title compound. Was obtained as a white powder. Mp _{^{113.5~114.2 ℃; 1 H NMR (CDCl}} 3 /400MHz)δ7.46-7.35(m,1H),6.98-6.84(m,2H),5.82(s , 1H), 5.24 (s, 2H), 3.35 (s, 3H), 3.24-3.16 (m, 1H), 1.35-1.32 (m, 2H), 18-1.12 (m, 2H); ES-MS m / z 357.10.

  Step 2: Preparation of 6-[(2,4-difluorophenyl) methoxy] -2-{[2- (dimethylamino) ethyl] amino} -3-cyclopropyl-3-hydropyrimidin-4-one

６−［（２，４−ジフルオロフェニル）メトキシ］−３−シクロプロピル−２−（メチルスルホニル）−３−ヒドロピリミジン−４−オン（１．０００ｇ、２．８１ミリモル）、Ｎ，Ｎ−ジメチルエチレンジアミン（０．３４８ｇ、３．９３ミリモル）、および炭酸カリウム（０．４６５ｇ、３．３７ミリモル）をＴＨＦ（１０ｍＬ）に混ぜた混合物を室温で６時間攪拌した。反応混合物を減圧下で濃縮し、残渣を、９％のジクロロメタン中メタノールを溶離として使用するシリカゲルフラッシュクロマトグラフィーによって精製して、０．９５１ｇ（９２．２％）の白色粉末を生成物として得た。融点１０３．５〜１０４．０℃；^１Ｈ ＮＭＲ（ＣＤＣｌ_３／４００ＭＨｚ）δ７．４６−７．３８（ｍ，１Ｈ）、６．９２−６．６８（ｍ，２Ｈ）、６．５２（ｂｒ，１Ｈ）、５．２４（ｓ，２Ｈ）、５．２２（ｓ，１Ｈ）、３．５２−３．４２（ｍ，２Ｈ）、２．５８−２．５２（ｍ，３Ｈ）、２．５２（ｓ，３Ｈ）、１．２８−１．２２（ｍ，２Ｈ）、０．９０−０．８４（ｍ，２Ｈ）；ＥＳ−ＭＳｍ／ｚ３６５．２７（Ｍ＋Ｈ）。

6-[(2,4-Difluorophenyl) methoxy] -3-cyclopropyl-2- (methylsulfonyl) -3-hydropyrimidin-4-one (1.000 g, 2.81 mmol), N, N-dimethyl A mixture of ethylenediamine (0.348 g, 3.93 mmol) and potassium carbonate (0.465 g, 3.37 mmol) in THF (10 mL) was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography using 9% methanol in dichloromethane as eluent to give 0.951 g (92.2%) of white powder as product. . Mp _{^{103.5~104.0 ℃; 1 H NMR (CDCl}} 3 /400MHz)δ7.46-7.38(m,1H),6.92-6.68(m,2H),6.52(br , 1H), 5.24 (s, 2H), 5.22 (s, 1H), 3.52-3.42 (m, 2H), 2.58-2.52 (m, 3H), 52 (s, 3H), 1.28-1.22 (m, 2H), 0.90-0.84 (m, 2H); ES-MS m / z 365.27 (M + H).

Step 3: 6-[(2,4-Difluorophenyl) methoxy] -2-{[2- (dimethylamino) ethyl] -amino} -5-chloro-3-cyclopropyl-3-hydropyrimidin-4-one Preparation of 6-[(2,4-difluorophenyl) methoxy] -2-{[2- (dimethylamino) ethyl] amino} -3-cyclopropyl-3-hydropyrimidin-4-one (0.500 g, 1 .37 mmol), N-chlorosuccinimide (0.192 g, 1.44 mmol) in dichloromethane (10 mL) was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography using 10% methanol in dichloromethane as eluent to give 0.329 g (60.2%) of the title compound as a white powder. . Mp _{^{127.6~128.4 ℃; 1 H NMR (CDCl}} 3 /400MHz)δ7.51-7.47(m,1H),6.91-6.78(m,2H),5.41(s , 2H), 3.46-3.45 (m, 2H), 2.63-2.56 (m, 3H), 2.31 (s, 6H), 1.28-1.24 (m, 2H) ), 0.93-0.90 (m, 2H) ; elemental _{analysis: C 18 H 21 N 4 O} 2 ClF 2 calculated for: C, 54.23; H, 5.31 ; N, 14.05. Found: C, 53.80; H, 5.23; N, 13.69; ES-MS m / z 399 (M + H).

(Example 143)

６−［（２，４−ジフルオロフェニル）メトキシ］−５−クロロ−３−（２−メチル−プロピル）−２−メチルチオ−３−ヒドロピリミジン−４−オン
ステップ１：イソブチルチオ尿素の調製

6-[(2,4-Difluorophenyl) methoxy] -5-chloro-3- (2-methyl-propyl) -2-methylthio-3-hydropyrimidin-4-one Step 1: Preparation of isobutylthiourea

イソチオシアン酸イソブチル（１２．０００ｇ、１０４ミリモル）のメタノール（１５ｍＬ）溶液に、０℃でアンモニアのメタノール溶液（７Ｎ、２９．８ｍＬ）を加えた。次いで、得られる混合物を室温で攪拌し、分離した固体を濾過によって収集し、エーテルで洗浄し、乾燥させて、１２．９５０ｇ（９４．２％）の表題化合物を白色の結晶性材料として得た。^１Ｈ ＮＭＲ（ＤＭＳＯ−ｄ_６／４００ＭＨｚ）δ７．６８（ｂｒ，１Ｈ）、７．５８（ｂｒ，１Ｈ）、６．８８（ｓ，１Ｈ）、３．１８（ｂｒ，１Ｈ）、１．８０−１．７６（ｍ，１Ｈ）、０．８８（ｂｒ，６Ｈ）；ＥＳ−ＭＳｍ／ｚ１３３．１０（Ｍ＋Ｈ）。

To a solution of isobutyl isothiocyanate (12.000 g, 104 mmol) in methanol (15 mL) was added ammonia solution in methanol (7N, 29.8 mL) at 0 ° C. The resulting mixture was then stirred at room temperature and the separated solid was collected by filtration, washed with ether and dried to give 12.950 g (94.2%) of the title compound as a white crystalline material. . _{^{1 H NMR (DMSO-d 6}} /400MHz)δ7.68(br,1H),7.58(br,1H),6.88(s,1H),3.18(br,1H),1.80 -1.76 (m, 1H), 0.88 (br, 6H); ES-MS m / z 133.10 (M + H).

  Step 2: Preparation of 6-hydroxy-3- (2-methylpropyl) -2-methylthio-3-hydropyrimidin-4-one

イソブチルチオ尿素（１１．４６８ｇ、８６．９ミリモル）、マロン酸ジエチル（１３．９００ｇ、８６．７ミリモル）、ナトリウムメトキシド（メタノール中２５〜３０％、３４．７ｍＬ）からなる、激しく攪拌した混合物を窒素中で加熱還流した。４．５時間後、反応混合物を冷却し、ヨードメタン（１２．８０３ｇ、９０．２ミリモル）を加え、その間温度は５０℃に保った。混合物を５０℃で１時間攪拌し、次いで０℃に冷却し、酢酸（９．０ｍＬ）で処理した。沈殿した生成物を水（１００ｍＬ）で希釈し、濾過し、水で洗浄し、風乾して、１７．０１０ｇ（９１．６％）の所望の生成物を得た。^１Ｈ ＮＭＲ（ＤＭＳＯ−ｄ_６／４００ＭＨｚ）δ５．２０（ｓ，１Ｈ）、３．７６（ｄ，１Ｈ，Ｊ＝７．４Ｈｚ）、３．５６（ｓ，３Ｈ）、２．１８−２．１０（ｍ，１Ｈ）、０．８５（ｄ，６Ｈ，Ｊ＝６．６Ｈｚ）；ＥＳ−ＭＳｍ／ｚ２１５．１４（Ｍ＋Ｈ）。

A vigorously stirred mixture consisting of isobutylthiourea (11.468 g, 86.9 mmol), diethyl malonate (13.900 g, 86.7 mmol), sodium methoxide (25-30% in methanol, 34.7 mL) Was heated to reflux in nitrogen. After 4.5 hours, the reaction mixture was cooled and iodomethane (12.803 g, 90.2 mmol) was added while maintaining the temperature at 50 ° C. The mixture was stirred at 50 ° C. for 1 hour, then cooled to 0 ° C. and treated with acetic acid (9.0 mL). The precipitated product was diluted with water (100 mL), filtered, washed with water and air dried to give 17.010 g (91.6%) of the desired product. _{^{1 H NMR (DMSO-d 6}} /400MHz)δ5.20(s,1H),3.76(d,1H,J=7.4Hz),3.56(s,3H),2.18-2. 10 (m, 1H), 0.85 (d, 6H, J = 6.6 Hz); ES-MS m / z 215.14 (M + H).

  Step 3: Preparation of 6-[(2,4-difluorophenyl) methoxy] -3- (2-methylpropyl) -2-methylthio-3-hydropyrimidin-4-one

６−ヒドロキシ−３−（２−メチルプロピル）−２−メチルチオ−３−ヒドロピリミジン−４−オン（１６．８００ｇ、７８．４ミリモル）、臭化２，４−ジフルオロベンジル（２１．０９８ｇ、１０２モル）、および炭酸カリウム（１６．２５３ｇ、１１８ミリモル）をＤＭＦ（１００ｍＬ）に混ぜた混合物を窒素中にて０℃で攪拌した。３０分後、それを室温でさらに３０分間攪拌し、濾過した。濾液を減圧下で濃縮し、残渣をジクロロメタンと５％塩酸（２０ｍＬ）とに分配した。有機層を水で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、減圧下で濃縮乾燥した。得られる材料を、２０％のヘキサン中酢酸エチルを溶離として使用するシリカゲルフラッシュクロマトグラフィーによって精製して、１５．６８０ｇ（５８．８％）の所望の生成物を白色粉末として得た。融点８９．８〜９０．２℃；^１Ｈ ＮＭＲ（ＣＤＣｌ_３／４００ＭＨｚ）δ７．４４−７．３８（ｍ，１Ｈ）、６．９２−６．７８（ｍ，２Ｈ）、５．５８（ｓ，１Ｈ）、５．３０（ｓ，２Ｈ）、３．８８（ｄ，２Ｈ，Ｊ＝７．８Ｈｚ）、２．５６（ｓ，３Ｈ）、２．３２−２．２４（ｍ，１Ｈ）、０．９６（ｄ，６Ｈ，Ｊ＝６．３Ｈｚ）；元素分析：Ｃ_１６Ｈ_１７Ｎ_２Ｏ_２ＳＣｌＦ_２に対する計算値：Ｃ，５１．２７；Ｈ，４．５７；Ｎ，７．４２。実測値：Ｃ，５１．２２；Ｈ，４．６５；Ｎ，７．３８；ＥＳ−ＭＳｍ／ｚ３４１．２０（Ｍ＋Ｈ）。

6-Hydroxy-3- (2-methylpropyl) -2-methylthio-3-hydropyrimidin-4-one (16.800 g, 78.4 mmol), 2,4-difluorobenzyl bromide (21.098 g, 102 Mol), and potassium carbonate (16.253 g, 118 mmol) in DMF (100 mL) was stirred at 0 ° C. under nitrogen. After 30 minutes, it was stirred for an additional 30 minutes at room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was partitioned between dichloromethane and 5% hydrochloric acid (20 mL). The organic layer was washed with water, dried (Na ₂ SO ₄ ) and concentrated to dryness under reduced pressure. The resulting material was purified by silica gel flash chromatography using 20% ethyl acetate in hexane as eluent to give 15.680 g (58.8%) of the desired product as a white powder. Mp _{^{89.8~90.2 ℃; 1 H NMR (CDCl}} 3 /400MHz)δ7.44-7.38(m,1H),6.92-6.78(m,2H),5.58(s , 1H), 5.30 (s, 2H), 3.88 (d, 2H, J = 7.8 Hz), 2.56 (s, 3H), 2.32-2.24 (m, 1H), 0.96 (d, 6H, J = 6.3Hz); elemental _{analysis: C 16 H 17 N 2 O} 2 SClF 2 calculated for: C, 51.27; H, 4.57 ; N, 7.42. Found: C, 51.22; H, 4.65; N, 7.38; ES-MS m / z 341.20 (M + H).

Step 4: Preparation of 6-[(2,4-difluorophenyl) methoxy] -5-chloro-3- (2-methyl-propyl) -2-methylthio-3-hydropyrimidin-4-one 6-[(2 , 4-difluorophenyl) methoxy] -3- (2-methylpropyl) -2-methylthio-3-hydropyrimidin-4-one (1.400 g, 4.11 mmol), N-chlorosuccinimide (0.577 g, A mixture of 4.32 mmol) in dichloromethane (15 mL) was stirred at room temperature for 5 hours. The reaction mixture is concentrated under reduced pressure and the residue is purified by silica gel flash chromatography using 20% ethyl acetate in hexane as eluent to give 1.457 g (94.6%) of the title compound as a white powder. It was. Mp _{^{58.0~58.8 ℃; 1 H NMR (CDCl}} 3 /400MHz)δ7.48-7.44(m,1H),6.92-6.82(m,2H),5.51(s , 2H), 3.90 (d, J = 7.6 Hz, 2H), 2.55 (s, 3H), 2.30-2.27 (m, 1H), 0.95 (d, J = 6). .4Hz, 6H); elemental _{analysis: C 16 H 17 N 2 O} 2 SClF 2 calculated for: C, 51.27; H, 4.57 ; N, 7.42. Found: C, 51.22; H, 4.65; N, 7.38; ES-MS m / z 375 (M + H).

(Example 144)

６−［（２，４−ジフルオロフェニル）メトキシ］−５−ブロモ−３−（２−メチル−プロピル）−２−メチルチオ−３−ヒドロピリミジン−４−オン
６−［（２，４−ジフルオロフェニル）メトキシ］−３−（２−メチルプロピル）−２−メチルチオ−３−ヒドロピリミジン−４−オン（１．４００ｇ、４．１１ミリモル）、Ｎ−ブロモスクシンイミド（０．７６９ｇ、４．３２ミリモル）をジクロロメタン（１５ｍＬ）に混ぜた混合物を室温で５時間攪拌した。反応混合物を減圧下で濃縮し、残渣を、２０％のヘキサン中酢酸エチルを溶離として使用するシリカゲルフラッシュクロマトグラフィーによって精製して、１．６７２ｇ（９７．０％）の表題化合物を白色粉末として得た。融点７０．１〜７０．８℃；^１Ｈ ＮＭＲ（ＣＤＣｌ_３／４００ＭＨｚ）δ７．５１−７．４５（ｍ，１Ｈ）、６．９４−６．８１（ｍ，２Ｈ）、５．５０（ｓ，２Ｈ）、３．９１（ｄ，Ｊ＝７．２Ｈｚ，２Ｈ）、２．５５（ｓ，３Ｈ）、２．３２−２．２８（ｍ，１Ｈ）、０．９５（ｄ，Ｊ＝６．８Ｈｚ，６Ｈ）、元素分析：Ｃ_１６Ｈ_１７Ｎ_２Ｏ_２ＳＢｒＦ_２に対する計算値：Ｃ，４５．８３；Ｈ，４．０９；Ｎ，６．６８。実測値：Ｃ，４６．０７；Ｈ，４．２０；Ｎ，６．６３；ＥＳ−ＭＳｍ／ｚ４１９（Ｍ＋Ｈ）。

6-[(2,4-Difluorophenyl) methoxy] -5-bromo-3- (2-methyl-propyl) -2-methylthio-3-hydropyrimidin-4-one 6-[(2,4-difluorophenyl) ) Methoxy] -3- (2-methylpropyl) -2-methylthio-3-hydropyrimidin-4-one (1.400 g, 4.11 mmol), N-bromosuccinimide (0.769 g, 4.32 mmol) Was mixed with dichloromethane (15 mL) and stirred at room temperature for 5 hours. The reaction mixture is concentrated under reduced pressure and the residue is purified by silica gel flash chromatography eluting with 20% ethyl acetate in hexanes to give 1.672 g (97.0%) of the title compound as a white powder. It was. Mp _{^{70.1~70.8 ℃; 1 H NMR (CDCl}} 3 /400MHz)δ7.51-7.45(m,1H),6.94-6.81(m,2H),5.50(s , 2H), 3.91 (d, J = 7.2 Hz, 2H), 2.55 (s, 3H), 2.32-2.28 (m, 1H), 0.95 (d, J = 6). .8Hz, 6H), elemental _{analysis: C 16 H 17 N 2 O} 2 SBrF 2 calculated for: C, 45.83; H, 4.09 ; N, 6.68. Found: C, 46.07; H, 4.20; N, 6.63; ES-MS m / z 419 (M + H).

(Example 145)

６−［（２，４−ジフルオロフェニル）メトキシ］−３−（２−メチルプロピル）−２−（メチルスルホニル）−３−ヒドロピリミジン−４−オン
６−［（２，４−ジフルオロフェニル）メトキシ］−３−（２−メチルプロピル）−２−メチルチオ−３−ヒドロピリミジン−４−オン（３．０００ｇ、８．８８ミリモル）、ｍ−クロロ過安息香酸（６０％、６．３３８ｇ、２２．０ミリモル）をジクロロメタン（１５０ｍＬ）に混ぜた混合物を室温で１６時間攪拌した。反応混合物を濾過し、濾液を減圧下で濃縮し、残渣を、２０％のヘキサン中酢酸エチルを溶離として使用するシリカゲルフラッシュクロマトグラフィーによって精製して、２．０９３ｇ（６３．８％）の表題化合物を白色粉末として得た。
融点１１０．５〜１１０．９℃；^１Ｈ ＮＭＲ（ＣＤＣｌ_３／４００ＭＨｚ）δ７．４４−７．３８（ｍ，１Ｈ）、６．９６−６．８５（ｍ，２Ｈ）、５．８８（ｓ，１Ｈ）、５．２３（ｓ，２Ｈ）、４．２４（ｄ，Ｊ＝７．６Ｈｚ，２Ｈ）、３．４０（ｓ，３Ｈ）、２．４１−２．３７（ｍ，１Ｈ）、０．９５（ｄ，Ｊ＝６．８Ｈｚ，６Ｈ）；元素分析：Ｃ_１６Ｈ_１８Ｎ_２Ｏ_４ＳＦ_２に対する計算値：Ｃ，５１．６１；Ｈ，４．８７；Ｎ，７．５２。実測値：Ｃ，５１．７１；Ｈ，４．９８；Ｎ，７．３３；ＥＳ−ＭＳｍ／ｚ３７３（ＭＷ：３７２）。

6-[(2,4-Difluorophenyl) methoxy] -3- (2-methylpropyl) -2- (methylsulfonyl) -3-hydropyrimidin-4-one 6-[(2,4-difluorophenyl) methoxy ] -3- (2-methylpropyl) -2-methylthio-3-hydropyrimidin-4-one (3.000 g, 8.88 mmol), m-chloroperbenzoic acid (60%, 6.338 g, 22. 0 mmol) in dichloromethane (150 mL) was stirred at room temperature for 16 hours. The reaction mixture is filtered, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel flash chromatography using 20% ethyl acetate in hexane as eluent to give 2.093 g (63.8%) of the title compound. Was obtained as a white powder.
Mp _{^{110.5~110.9 ℃; 1 H NMR (CDCl}} 3 /400MHz)δ7.44-7.38(m,1H),6.96-6.85(m,2H),5.88(s , 1H), 5.23 (s, 2H), 4.24 (d, J = 7.6 Hz, 2H), 3.40 (s, 3H), 2.41-2.37 (m, 1H), 0.95 (d, J = 6.8Hz, 6H); elemental _analysis: calcd for _{C 16 H 18 N 2 O 4} SF 2: C, 51.61; H, 4.87; N, 7.52. Found: C, 51.71; H, 4.98; N, 7.33; ES-MS m / z 373 (MW: 372).

(Example 146)

６−［（２，４−ジフルオロフェニル）メトキシ］−２−｛［２−（ジメチル−アミノ）エチル］アミノ｝−３−（２−メチルプロピル）−３−ヒドロピリミジン−４−オン
６−［（２，４−ジフルオロフェニル）メトキシ］−３−（２−メチルプロピル）−２−（メチルスルホニル）−３−ヒドロピリミジン−４−オン（１．４９ｇ、４．００ミリモル）、Ｎ，Ｎ−ジメチルエチレンジアミン（０．５２９ｇ、６．００ミリモル）、および炭酸カリウム（０．７４４ｇ、５．６０ミリモル）をＤＭＦ（１０ｍＬ）に混ぜた混合物を室温で５時間攪拌した。反応混合物を減圧下で濃縮し、残渣を、１０％のジクロロメタン中メタノールを溶離として使用するシリカゲルフラッシュクロマトグラフィーによって精製して、１．１５６ｇ（７６．０％）の表題化合物を無色の液状油状物として得た。^１Ｈ ＮＭＲ（ＣＤＣｌ_３／４００ＭＨｚ）δ７．４６−７．４０（ｍ，１Ｈ）、６．９０−６．７９（ｍ，２Ｈ）、５．９４（ｂｒ，１Ｈ）、５．２８（ｓ，１Ｈ）、５．２２（ｓ，２Ｈ）、３．７２（ｂｒ，２Ｈ）、３．４５−３．４１（ｍ，２Ｈ）、２．５５−２．５２（ｍ，２Ｈ）、２．２９（ｓ，６Ｈ）、２．０７−２．０３（ｍ，１Ｈ）、０．９７（ｄ，Ｊ＝６．４Ｈｚ，６Ｈ）；元素分析：Ｃ_１９Ｈ_２６Ｎ_４Ｏ_２Ｆ_２に対する計算値：Ｃ，５９．９９；Ｈ，６．８９；Ｎ，１４．７３。実測値：Ｃ，５９．６４；Ｈ，６．９３；Ｎ，１４．８２；ＥＳ−ＭＳｍ／ｚ３８１（Ｍ＋Ｈ）。

6-[(2,4-Difluorophenyl) methoxy] -2-{[2- (dimethyl-amino) ethyl] amino} -3- (2-methylpropyl) -3-hydropyrimidin-4-one 6- [ (2,4-Difluorophenyl) methoxy] -3- (2-methylpropyl) -2- (methylsulfonyl) -3-hydropyrimidin-4-one (1.49 g, 4.00 mmol), N, N- A mixture of dimethylethylenediamine (0.529 g, 6.00 mmol) and potassium carbonate (0.744 g, 5.60 mmol) in DMF (10 mL) was stirred at room temperature for 5 hours. The reaction mixture is concentrated under reduced pressure and the residue is purified by silica gel flash chromatography using 10% methanol in dichloromethane as eluent to give 1.156 g (76.0%) of the title compound as a colorless liquid oil. Got as. ¹ H NMR _(CDCl 3 ^{/400MHz)δ7.46-7.40(m,1H),6.90-6.79(m,2H),5.94(br,1H),5.28(s,} 1H), 5.22 (s, 2H), 3.72 (br, 2H), 3.45-3.41 (m, 2H), 2.55-2.52 (m, 2H), 2.29 (s, 6H), 2.07-2.03 ( m, 1H), 0.97 (d, J = 6.4Hz, 6H); elemental _analysis: calcd for _{C 19 H 26 N 4 O 2} F 2 : C, 59.99; H, 6.89; N, 14.73. Found: C, 59.64; H, 6.93; N, 14.82; ES-MS m / z 381 (M + H).

(Example 147)

６−［（２，４−ジフルオロフェニル）メトキシ］−２−｛［２−（ジメチル−アミノ）エチル］アミノ｝−５−ブロモ−３−（２−メチルプロピル）−３−ヒドロピリミジン−４−オン
６−［（２，４−ジフルオロフェニル）メトキシ］−２−｛［２−（ジメチル−アミノ）エチル］アミノ｝−３−（２−メチルプロピル）−３−ヒドロピリミジン−４−オン（０．４００ｇ、１．０５ミリモル）、Ｎ−ブロモスクシンイミド（０．１９７ｇ、１．１０ミリモル）をジクロロメタン（１０ｍＬ）に混ぜた混合物を室温で５時間攪拌した。反応混合物を減圧下で濃縮し、残渣を、９％のジクロロメタン中メタノールを溶離として使用するシリカゲルフラッシュクロマトグラフィーによって精製して、０．４１０ｇ（８５．１％）の表題化合物を白色粉末として得た。融点１３３．８〜１３５．６℃；^１Ｈ ＮＭＲ（ＣＤＣｌ_３／４００ＭＨｚ）δ７．５４−７．４８（ｍ，１Ｈ）、６．９２−６．７９（ｍ，２Ｈ）、５．９９（ｂｒ，１Ｈ）、５．４２（ｓ，２Ｈ）、３．７６（ｂｒ，２Ｈ）、３．４３−３．３９（ｍ，２Ｈ）、２．５６−２．５３（ｍ，２Ｈ）、２．２９（ｓ，６Ｈ）、２．０７−２．０４（ｍ，１Ｈ）、０．９７（ｄ，Ｊ＝６．８Ｈｚ，６Ｈ）；元素分析：Ｃ_１９Ｈ_２５Ｎ_４Ｏ_２ＢｒＦ_２に対する計算値：Ｃ，４９．６８；Ｈ，５．４８；Ｎ，１２．２０。実測値：Ｃ，４９．９３；Ｈ，５．５５；Ｎ，１２．２２；ＥＳ−ＭＳｍ／ｚ４５９（Ｍ＋Ｈ）。

6-[(2,4-Difluorophenyl) methoxy] -2-{[2- (dimethyl-amino) ethyl] amino} -5-bromo-3- (2-methylpropyl) -3-hydropyrimidine-4- ON 6-[(2,4-Difluorophenyl) methoxy] -2-{[2- (dimethyl-amino) ethyl] amino} -3- (2-methylpropyl) -3-hydropyrimidin-4-one (0 .400 g, 1.05 mmol), N-bromosuccinimide (0.197 g, 1.10 mmol) in dichloromethane (10 mL) was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel flash chromatography using 9% methanol in dichloromethane as eluent to give 0.410 g (85.1%) of the title compound as a white powder. . Mp _{^{133.8~135.6 ℃; 1 H NMR (CDCl}} 3 /400MHz)δ7.54-7.48(m,1H),6.92-6.79(m,2H),5.99(br , 1H), 5.42 (s, 2H), 3.76 (br, 2H), 3.43-3.39 (m, 2H), 2.56-2.53 (m, 2H), 2. 29 (s, 6H), 2.07-2.04 (m, 1H), 0.97 (d, J = 6.8Hz, 6H); elemental _analysis: calculated for _{C 19 H 25 N 4 O 2} BrF 2 Value: C, 49.68; H, 5.48; N, 12.20. Found: C, 49.93; H, 5.55; N, 12.22; ES-MS m / z 459 (M + H).

(Example 148)

６−［（２，４−ジフルオロフェニル）メトキシ］−３−（２，２−ジメチルプロピル）−２−メチルチオ−３−ヒドロピリミジン−４−オン
ステップ１：２，２−ジメチルプロピルアミンの調製

6-[(2,4-Difluorophenyl) methoxy] -3- (2,2-dimethylpropyl) -2-methylthio-3-hydropyrimidin-4-one Step 1: Preparation of 2,2-dimethylpropylamine

水素化リチウムアルミニウム（１０．９５６ｇ、０．２８９モル）のジエチルエーテル（５０ｍＬ）懸濁液に、０℃で、トリメチルアセトニトリル（２０．００ｇ、０．２４１モル）の入ったエーテル（１００ｍＬ）を加えた。得られる混合物を室温で２時間攪拌した。次いで、反応混合物に、５％の水酸化ナトリウム溶液をガスが放出されなくなるまで加えた。混合物を濾過した。濾液を硫酸ナトリウムで乾燥させた。得られる溶液を次のステップでそのまま使用した。

To a suspension of lithium aluminum hydride (10.956 g, 0.289 mol) in diethyl ether (50 mL) at 0 ° C. was added ether (100 mL) containing trimethylacetonitrile (20.00 g, 0.241 mol). It was. The resulting mixture was stirred at room temperature for 2 hours. Then, 5% sodium hydroxide solution was added to the reaction mixture until no gas was released. The mixture was filtered. The filtrate was dried with sodium sulfate. The resulting solution was used as such in the next step.

  Step 2: Preparation of 2,2-dimethylpropane isothiocyanate

２，２−ジメチルプロピルアミン（８．０３ｇ、０．１４１モル）の攪拌溶液に、０〜１０℃でトリエチルアミン（２６．２２８ｇ、０．２５９モル）および二硫化炭素（４９．３３９ｇ、０．６４８モル）を加えた。攪拌を０．５時間継続した後、室温で過酸化水素（３０ｗｔ％、７３．４６ｇ、０．０．６４８モル）を滴下した。１時間後、反応混合物を希塩酸（１：１）で中和して中性にした。有機層をブラインで洗浄し、Ｎａ_２ＳＯ_４で乾燥させた。得られる溶液を次のステップでそのまま使用した。

To a stirred solution of 2,2-dimethylpropylamine (8.03 g, 0.141 mol) at 0-10 ° C. triethylamine (26.228 g, 0.259 mol) and carbon disulfide (49.339 g, 0.648). Mol) was added. After stirring was continued for 0.5 hour, hydrogen peroxide (30 wt%, 73.46 g, 0.0.648 mol) was added dropwise at room temperature. After 1 hour, the reaction mixture was neutralized with dilute hydrochloric acid (1: 1). The organic layer was washed with brine and dried over Na ₂ SO ₄ . The resulting solution was used as such in the next step.

  Step 3: Preparation of amino [(2,2-dimethylpropyl) amino] methane-1-thione

イソチオシアン酸２，２−ジメチルプロパンのエーテル溶液に、０℃でアンモニアのメタノール溶液（７Ｎ、５５．０ｍｌ）を加えた。次いで、得られる混合物を室温で４時間攪拌した。濃縮した後、黄色がかった残渣を濾過によって収集し、３０％のヘキサン中エーテルで洗浄し、乾燥させて、１８．８８９ｇ（３ステップ全体で５３．７％）の白色固体を所望の生成物として得た。^１Ｈ ＮＭＲ（ＣＤＣｌ_３／４００ＭＨｚ）δ６．２４（ｂｒ，１Ｈ）、５．８０（ｂｒ，２Ｈ）、２．９２（ｂｒ，２Ｈ）、０．９８（ｓ，９Ｈ）。

To a ether solution of 2,2-dimethylpropane isothiocyanate, a methanol solution of ammonia (7N, 55.0 ml) was added at 0 ° C. The resulting mixture was then stirred at room temperature for 4 hours. After concentration, the yellowish residue was collected by filtration, washed with 30% ether in hexane and dried to give 18.889 g (53.7% over 3 steps) of white solid as the desired product. Obtained. _{^{1 H NMR (CDCl 3 /400MHz)δ6.24(br,1H),5.80(br,2H),2.92(br,2H),0.98(s,9H)}} .

  Step 4: Preparation of 3- (2,2-dimethylpropyl) -6-hydroxy-2-methylthio-3-hydropyrimidin-4-one

アミノ［（２，２−ジメチルプロピル）アミノ］メタン−１−チオン（８．００ｇ、５４．７ミリモル）、マロン酸ジエチル（８．７６７ｇ、５４．７ミリモル）、ナトリウムメトキシド（メタノール中２５〜３０％、２１．９ｍＬ）からなる、激しく攪拌した混合物を窒素中で加熱還流した。５時間後、反応混合物を冷却し、ヨードメタン（８．０７６ｇ、５６．９ミリモル）を加え、温度を５０℃に保った。混合物を５０℃で１時間攪拌し、次いで１０℃に冷却し、酢酸（６．３ｍＬ）で処理した。沈殿した生成物を水で希釈した。固体を濾過し、水で洗浄し、風乾して、１１．０５７ｇ（８８．５％）の所望の生成物を得た。^１Ｈ ＮＭＲ（ＤＭＳＯ−ｄ_６／４００ＭＨｚ）δ５．２２（ｓ，１Ｈ）、３．８３（ｂｒ，２Ｈ）、２．４８（ｓ，３Ｈ）、０．９８（ｓ，９Ｈ）；ＥＳ−ＭＳｍ／ｚ２２９．１４（Ｍ＋Ｈ）。

Amino [(2,2-dimethylpropyl) amino] methane-1-thione (8.00 g, 54.7 mmol), diethyl malonate (8.767 g, 54.7 mmol), sodium methoxide (25-25 in methanol) A vigorously stirred mixture consisting of 30%, 21.9 mL) was heated to reflux in nitrogen. After 5 hours, the reaction mixture was cooled and iodomethane (8.076 g, 56.9 mmol) was added to keep the temperature at 50 ° C. The mixture was stirred at 50 ° C. for 1 hour, then cooled to 10 ° C. and treated with acetic acid (6.3 mL). The precipitated product was diluted with water. The solid was filtered, washed with water and air dried to give 11.057 g (88.5%) of the desired product. _{^{1 H NMR (DMSO-d 6}} /400MHz)δ5.22(s,1H),3.83(br,2H),2.48(s,3H),0.98(s,9H);ES-MSm / Z 229.14 (M + H).

  Step 5: Preparation of 6-[(2,4-difluorophenyl) methoxy] -3- (2,2-dimethylpropyl) -2-methylthio-3-hydropyrimidin-4-one

３−（２，２−ジメチルプロピル）−６−ヒドロキシ−２−メチルチオ−３−ヒドロピリミジン−４−オン（１１．０５７ｇ、４８．４ミリモル）、臭化２，４−ジフルオロベンジル（１５．０４０ｇ、７２．６ミリモル）、および炭酸カリウム（１２．０４９ｇ、８７．２ミリモル）をＤＭＦ（８０ｍＬ）に混ぜた混合物を窒素中にて０℃で攪拌した。３０分後、それを室温でさらに３０分間攪拌し、濾別した。濾液を減圧下で濃縮し、残渣をジクロロメタンと５％塩酸とに分配した。有機層を水で洗浄し、乾燥させ（Ｎａ_２ＳＯ_４）、減圧下で濃縮乾燥した。得られる材料を、２０％のヘキサン中ＥｔＯＡｃを溶離として使用するシリカゲルフラッシュクロマトグラフィーによって精製して、９．３６６ｇ（５４．６％）の表題化合物を白色粉末として得た。^１Ｈ ＮＭＲ（ＣＤＣｌ_３／４００ＭＨｚ）δ７．４２−７．３９（ｍ，１Ｈ）、６．９０−６．８１（ｍ，２Ｈ）、５．５６（ｓ，１Ｈ）、５．３１（ｓ，２Ｈ）、３．９５（ｂｒ，２Ｈ）、２．５１（ｓ，３Ｈ）、１．０４（ｓ，９Ｈ）；元素分析：Ｃ_１７Ｈ_２０Ｎ_２Ｏ_２ＳＦ_２に対する計算値：Ｃ，５７．６１；Ｈ，５．６９；Ｎ，７．９０。実測値：Ｃ，５７．８３；Ｈ，５．８１；Ｎ，７．９７；ＥＳ−ＭＳｍ／ｚ３５５（ＭＷ：３５４）。

3- (2,2-dimethylpropyl) -6-hydroxy-2-methylthio-3-hydropyrimidin-4-one (11.057 g, 48.4 mmol), 2,4-difluorobenzyl bromide (15.040 g) , 72.6 mmol), and potassium carbonate (12.049 g, 87.2 mmol) in DMF (80 mL) was stirred at 0 ° C. under nitrogen. After 30 minutes it was stirred at room temperature for a further 30 minutes and filtered off. The filtrate was concentrated under reduced pressure and the residue was partitioned between dichloromethane and 5% hydrochloric acid. The organic layer was washed with water, dried (Na ₂ SO ₄ ) and concentrated to dryness under reduced pressure. The resulting material was purified by silica gel flash chromatography using 20% EtOAc in hexanes as eluent to give 9.366 g (54.6%) of the title compound as a white powder. ¹ H NMR _(CDCl 3 ^{/400MHz)δ7.42-7.39(m,1H),6.90-6.81(m,2H),5.56(s,1H),5.31(s,} 2H), 3.95 (br, 2H ), 2.51 (s, 3H), 1.04 (s, 9H); elemental _{analysis: C 17 H 20 N 2 O} 2 SF 2 calculated for: C, 57 .61; H, 5.69; N, 7.90. Found: C, 57.83; H, 5.81; N, 7.97; ES-MS m / z 355 (MW: 354).

Biological evaluation p38 kinase assay Cloning of human p38a:
Human monocytic cell line THP. The coding region of human p38a cDNA was obtained from RNA isolated from 1 by PCR-amplification. The first strand cDNA was synthesized from total RNA as follows. That is, after heating at 70 ° C. for 10 minutes, 2 μg of RNA was annealed to 100 ng of random hexamer primer in 10 μl of reaction solution by placing on ice for 2 minutes. Then add 1 μl RNAsin (Promega, Madison, Wis.), 2 μl 50 mM dNTPs, 4 μl 5 × buffer, 2 μl 100 mM DTT, and 1 μl (200 U) Superscript II ™ AMV reverse transcriptase and add cDNA Was synthesized. Random primers, dNTPs, and Superscript II ™ reagent were all purchased from Life-Technologies, Gaithersburg, MA. The reaction was incubated at 42 ° C. for 1 hour. Amplification of p38 cDNA consists of 5 μl reverse transcriptase reaction, 80 μl dH ₂ O, 2 μl 50 mM dNTP, 1 μl forward and reverse primers (50 pmol / μl), 10 μl 10 × buffer, and 1 μl This was carried out by dispensing into 100 μl of a PCR reaction solution containing the Expand ™ polymerase (Boehringer, Mannheim, Germany). PCR primers were purchased from Genosys with BamHI sites incorporated at the 5 'and 3' ends of the amplified fragment. The forward and reverse primer sequences were 5'-GATCGAGGATTCATGTTCTCAGGAGAGGCCCA-3 'and 5'GATCGAGGATTTCCAGGACTCCATCTCTTC-3', respectively. PCR amplification was performed in a DNA Thermal Cycler (Perkin Elmer) by repeating 30 cycles of 94 ° C. for 1 minute, 60 ° C. for 1 minute, and 68 ° C. for 2 minutes. After amplification, excess primers and unincorporated dNTPs were removed from the amplified fragment using Wizard ™ PCR prep (Promega) and digested with BamHI (New England Biolabs). T.A. PGEX was obtained by digesting a BamHI digested fragment with BamHI digested using T-4 DNA ligase (New England Biolabs) as described in Maniatis, “Molecular Cloning: A Laboratory Manual”, 2nd edition (1989). Ligated to 2T plasmid DNA (Pharmacia Biotech). The ligation reaction was transformed into chemically competent E. coli DH10B cells purchased from Life-Technologies according to the manufacturer's instructions. Plasmid DNA was isolated from the resulting bacterial colonies using the Promega Wizard ™ miniprep kit. The plasmid containing the appropriate BamHI fragment was sequenced on a DNA Thermal Cycler (Perkin Elmer) using Prism ™ (Applied Biosystems Inc.). A cDNA clone encoding both human p38a isoforms was identified (Lee et al., Nature 372, 739). One of the clones containing the cDNA for p38a-2 (CSB-2) inserted at the 3 ′ side of the PGEX2T cloning site, ie, the GST coding region, was named pMON35802. The sequence obtained for this clone is an exact copy of the cDNA clone reported by Lee et al. This expression plasmid allows the production of a GST-p38a fusion protein.

Expression of human p38a The GST / p38a fusion protein was expressed from plasmid pMON35802 in the E. coli DH10B strain (Life Technologies, Gibco-BRL). The culture was grown overnight in Luria Broth (LB) containing 100 mg / ml ampicillin. The next day, 500 ml of fresh LB was seeded with 10 ml of overnight culture and grown at 37 ° C. with constant shaking in a 2 liter flask until the culture reached an absorbance of 0.8 at 600 nm. Isopropyl bD-thiogalactosidase (IPTG) was added to a final concentration of 0.05 mM to induce expression of the fusion protein. The culture was shaken for 3 hours at room temperature and the cells were collected by centrifugation. Cell pellets were stored frozen until protein purification.

Purification of p38 kinase-α Unless otherwise noted, all chemicals are available from Sigma Chemical Co. Was from. A 20 gram E. coli cell pellet collected from five 1 L shake flask fermentations was added to PBS (140 mM NaCl, 2.7 mM KCl, 10 mM Na ₂ HPO ₄ , 1.8 mM KH ₂ PO ₄ , pH 7.3). To a volume of 200 ml. The cell suspension was adjusted with 2M DTT to a DTT of 5 mM and then aliquoted into five 50 ml Falcon conical tubes. Cells were sonicated on ice for 3 × 1 min (pulse) with a 1 cm probe (Ultrasonics W375 model). Lysed cell material was removed by centrifugation (12,000 × g, 15 min) and the clear supernatant was applied to glutathione-Sepharose resin (Pharmacia).

Glutathione-Sepharose Affinity Chromatography 12 ml of 50% glutathione Sepharose-PBS suspension was added to 200 ml of clear supernatant and incubated in batch format for 30 minutes at room temperature. The resin was collected by centrifugation (600 × g, 5 minutes) and washed with 2 × 150 ml PBS / 1% Triton X-100 followed by 4 × 40 ml PBS. To cleave p38 kinase from the GST-p38 fusion protein, glutathione-sepharose resin was resuspended in 6 ml PBS containing 250 units of thrombin protease (Pharmacia, specific activity> 7500 units / mg) for 4 hours at room temperature. Mix gently. Glutathione-Sepharose resin was removed by centrifugation (600 × g, 5 minutes) and washed with PBS (2 × 6 ml). PBS wash fractions containing p38 kinase protein and digest supernatant were pooled and adjusted to a PMSF of 0.3 mM.

MonoQ anion exchange chromatography p38 kinase cleaved by thrombin was further purified by FPLC-anion exchange chromatography. Samples cleaved by thrombin were diluted 2-fold with buffer A (25 mM HEPES, pH 7.5, 25 mM β-glycerophosphate, 2 mM DTT, 5% glycerin) and equilibrated with buffer A MonoQHR10 / 10 (Pharmacia) anion exchange column was injected. 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 with 200 mM NaCl was collected and concentrated to 3-4 ml with a Filtron 10 concentrator (Filtron Corp.).

Sephacryl S100 Gel Filtration Chromatography A concentrated MonoQ-p38 kinase purified sample was equilibrated with Gel Filtration Chromatography (Buffer B (50 mM HEPES, pH 7.5, 50 mM NaCl, 2 mM DTT, 5% glycerin) from Pharmacia). Purified by HiPrep 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 light absorption at 280 nm. Fractions containing p38 kinase (detected by SDS polyacrylamide gel electrophoresis) were pooled and frozen at -80 ° C. A typical purified protein yield from a 5 L E. coli shake flask fermentation was 35 mg of p38 kinase.

In Vitro Assay The ability of compounds to inhibit human p38 kinase alpha was evaluated using two in vitro test methods. In the first method, activated human p38 kinase α is a biotinylated substrate PHAS-I (phosphorylated, heat and acid stable, protein, in the presence of γ ³² P-ATP ( ³² P-ATP). -Phosphorylate insulin-induced). Since PHAS-I is biotin-labeled prior to the assay, it provides a means for capturing a substrate that is phosphorylated during the assay. p38 kinase was activated by MKK6. Compounds were tested at 10-fold serial dilutions ranging from 100 μM to 0.001 μM using 1% DMSO. Each concentration of inhibitor was tested in triplicate.

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. This assay required activation of p38 to achieve sufficient signal. Biotin-labeled PHAS-I was used at 1-2 μg per 50 μl reaction volume with a final concentration of 1.5 μM. Activated human p38 kinase α was used at 1 μg per 50 μl reaction volume, resulting in a final concentration of 0.3 μM. γ ³² P-ATP was used to follow PHAS-I phosphorylation. ³² P-ATP had a specific activity of 3000 Ci / mmol and was used at 1.2 μCi per 50 μl reaction volume. The reaction was allowed to proceed for 1 hour or overnight at 30 ° C.

After incubation, 20 μl of the reaction mixture was transferred to a high throughput streptavidin-coated filter plate (SAM-streptavidin-matrix, Promega) pre-wetted with phosphate buffered saline. The transferred reaction mixture was allowed to contact the streptavidin membrane of the Promega plate for 1-2 minutes. After capturing biotin labeled PHAS-I incorporating ³² P, each well was washed 3 times with 2 M NaCl, 3 times with 2 M NaCl containing 1% phosphoric acid, 3 times with distilled water, and finally Was washed once with 95% ethanol to remove unincorporated ³² P-ATP. The filter plate was air dried and 20 μl scintillant was added. Plates were sealed and counted.

^A second assay format based on phosphorylation of EGFRP (epidermal growth factor receptor peptide, 21-mer) induced by p38 kinase α in the presence of ³³ P-ATP was also used. Compounds were tested at 10-fold serial dilutions ranging from 100 μM to 0.001 μM in 1% DMSO. Each concentration of inhibitor was tested in triplicate. The compound consists of 25 mM Hepes pH 7.5, 10 mM magnesium acetate, 4% glycerin, 0.4% bovine serum albumin, 0.4 mM DTT, 50 μM unlabeled ATP, 25 μg EGFRP (200 μM), and 0 Evaluated in a reaction volume of 50 μl in the presence of 0.05 μCi ³³ P-ATP. The reaction was initiated by adding 0.09 μg of activated purified human GST-p38 kinase α. Activation was performed for 1 hour at 30 ° C. using GST-MKK6 (5: 1, p38: MKK6) in the presence of 50 μM ATP. After incubation for 60 minutes at room temperature, the reaction was stopped by adding 900 mM sodium formate buffer, pH 3.0 (2 volumes of buffer for 1 volume of resin) containing 150 μl of AG1 × 8 resin. The mixture was mixed three times by pipetting to stabilize the resin. A total of 50 μl of clear solution supernatant was transferred from the reaction wells to a Microlite-2 plate. Then 150 μl of Microscint 40 was added to each well of the Microlite plate, the plate was sealed, mixed and counted.

The above protocol assay was used to determine IC ₅₀ values for the compounds of the above examples. The results are shown in Table 1.

TNF cell assay Method for isolating human peripheral blood mononuclear cells:
Human whole blood was collected in a Vacutainer tube containing EDTA as an anticoagulant. A blood sample (7 ml) was carefully layered on 5 ml of PMN cell separation medium (Robbins Scientific) in a 15 ml round bottom centrifuge tube. This sample was placed in a swing-out rotor and centrifuged at 450-500 × g for 30-35 minutes at room temperature. After centrifugation, the upper band of cells was removed and washed 3 times with PBS w / o calcium or magnesium. Cells were centrifuged at 400 xg for 10 minutes at room temperature. Cells were resuspended in 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 incubated for 1 hour with 0.1 ml compound (10-0.41 μM, final concentration) in flat bottom 96 well microtiter plates. The compound was first dissolved in DMSO and diluted with TCM to a final concentration of 0.1% DMSO. LPS (Calbiochem, final concentration 20 ng / ml) was then added in a volume of 0.010 ml. The culture was incubated at 37 ° C. overnight. The supernatant was then removed and tested by ELISA against TNF-a and IL1-b. Viability was analyzed using MTS. After collecting 0.1 ml supernatant, 0.020 ml MTS was added to the remaining 0.1 ml cells. Cells are incubated at 37 ° C. for 2-4 hours and then OD at 490-650 nM. D. Was measured.

Maintenance and differentiation of U937 human histiocytic lymphoma cell line U937 cells (ATCC) are grown in RPMI 1640 with 10% fetal bovine serum, 100 IU / ml penicillin, 100 μg / ml streptomycin, and 2 mM glutamine (Gibco). I let you. 50 million cells in 100 ml medium were incubated with 20 ng / ml phorbol 13-acetate 12-myristate 12-myristate (Sigma) for 24 hours to induce the end of monocyte differentiation. Cells were washed by centrifugation (200 × g for 5 minutes) and resuspended in 100 ml fresh medium. After 24-48 hours, cells were harvested, centrifuged, and resuspended in medium at 2 million cells / ml.

LPS stimulation of TNF production by U937 cells U937 cells (0.1 ml, 2 million / ml) were incubated for 1 hour with 0.1 ml compound (0.004-50 μM, final concentration) in 96-well microtiter plates. . Compounds were prepared as 10 mM stock solutions in DMSO and diluted with media to a final DMSO concentration of 0.1% in the cell assay. LPS (E. coli, final concentration 100 ng / ml) was then added in a volume of 0.02 ml. After incubation at 37 ° C. for 4 hours, the amount of TNFα released into the medium was quantified by ELISA. Inhibitory activity is shown as IC50 (μM).

Rat Assay Using a model based on rats inoculated with LPS, the efficacy of the novel compounds was also evaluated in blocking TNF production. Male Harlen Lewis rats [Sprague Dawley Co. ] Was used in this model. Each rat weighed approximately 300 g and was fasted overnight prior to testing. The compounds were usually administered by oral gavage 1-24 hours prior to LPS administration (although intraperitoneal, subcutaneous, and intravenous administration were also used in a few cases). Rats were treated with 30 μg / kg LPS [S. typhi, Sigma Co. Was administered intravenously from the tail vein. One hour after LPS administration, blood was collected by cardiac puncture. Serum samples were stored at −20 ° C. until quantitative analysis of TNF-α by enzyme-linked immunosorbent assay (“ELISA”) [Biosource]. Other details of the assay can be found in Perretti, M .; Et al., Br. J. et al. Pharmacol. (1993), 110, 868-874, which is incorporated herein by reference.

Mouse assay Mouse model of TNFα production by LPS Induction of TNFα by tail vein injection of 0.2 ml saline containing 100 ng lipopolysaccharide (derived from Salmonella typhi) in 10-12 week old female BALB / c mice did. One hour later, mouse blood was collected from the retroorbital sinus and serum TNF concentration from clotted blood was quantified by ELISA. Usually, peak levels of serum TNF ranged from 2 to 6 ng / ml 1 hour after LPS injection.

  One or six hours prior to LPS injection, the compounds tested were orally administered by gavage to fasted mice as a suspension of water containing 0.2 ml of 0.5% methylcellulose and 0.025% Tween20. Administered. The 1 hour protocol allowed assessment of compound potency at Cmax plasma levels, while the 6 hour protocol allowed estimation of the duration of action of the compound. Efficacy was determined at each time point as percent inhibition of serum TNF levels on LPS injected mice given vehicle alone.

Induction and Evaluation of Collagen-Induced Arthritis in Mice J. et al., Incorporated herein by reference. M.M. Stuart, “Collagen Autoimmune Arthritis”, Annual Rev. Immunol. The arthritis of mice was induced according to the procedure described in Volume 2: 199 (1984). Specifically, Freund containing 50 μg chicken type II collagen (CII) (provided by Dr. Marie Griffiths, University of Utah, Salt Lake City, Utah) in 8-12 week old male DBA / 1 mice. Complete adjuvant (Sigma) was injected from the base of the tail on day 0 to induce arthritis. The injection volume was 100 μl. On day 21, animals were boosted with incomplete Freund's adjuvant (100 μl volume) containing 50 μg CII. Animals were evaluated several times each week for signs of arthritis. Any animal with redness or swelling in the paw was considered arthritis. The scoring of arthritic feet can be found in Wooley et al., “Genetic Control of Type II Collagen Induced Artificience Censitivity and Efficacy of HC. Proc. 15: 180 (1983). Severity scoring was performed using a score of 1-3 for each paw (maximum score 12 / mouse). Animals showing any redness or swelling of the toes or paws were scored as 1. A severe swelling or deformity of the entire foot was given a score of 2. The joint stiffness was given a score of 3. Animals were evaluated over 8 weeks. 8-10 animals were used per group.

  The detailed description of the above embodiments can be best suited to the requirements of a particular use so that others skilled in the art can adapt and apply the invention in its many forms. And merely inform others skilled in the art of the invention, its principles, and its practical application. Therefore, the present invention is not limited to the above embodiment, and can be variously changed.

Claims (22)

Compound of formula I

Or a pharmaceutically acceptable salt, enantiomer or racemate thereof [wherein
R ¹ is alkenyl, alkoxycarbonylalkylamino, alkoxycarbonylaminoalkoxy, alkoxycarbonylaminoheterocyclo, alkoxycarbonylaryl, alkoxycarbonylarylalkylamino, alkoxycarbonylheterocyclo, alkyl, alkylamino, alkylaminocarbonylalkyl, alkylaminocarbonyl Alkylamino, alkylaminocarbonylaminoalkoxy, alkylaminoheterocyclo, alkylcarbonylaminoalkoxy, alkylcarbonylaminoalkyl, alkylcarbonylaminoalkylamino, alkylcarbonylaminoheterocyclo, alkylcarbonylheterocycloamino, alkylcarbonyloxyalkylcarbonylaminoalkoxy, Alkyl Carbonyloxyalkylcarbonylaminoheterocyclo, alkylsulfonyl, alkylsulfonylaminoalkoxy, alkylsulfonylaminoalkyl, alkylsulfonylaminoalkylamino, alkylthio, aminoalkoxy, aminoalkyl, aminoalkylamino, aminoalkylcarbonylaminoheterocyclo, aminoalkylcarbonylhetero Cyclo, aminocarbonylalkoxy, aminocarbonylalkyl, aminocarbonylalkylamino, aminocarbonylalkylheterocyclo, aminocarbonylaminoalkoxy, aminocarbonylaminoalkylamino, aminocarbonylaryl, aminocarbonyldialkylamino, aminocarbonylheterocyclo, aminoheterocyclo, Aryl, carboxyal Xy, carboxyalkyl, carboxyaryl, carboxydialkylamino, cycloalkyl, dialkylaminoalkylamino, dihydroxyalkylamino, halo, haloalkylsulfonyloxy, haloarylalkylamino, heteroarylalkoxycarbonylaminoheterocyclo, heterocyclocarbonylalkylamino, heterocyclo , Hydrogen, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkylamino, hydroxyalkylaminocarbonylalkoxy, hydroxyalkylaminocarbonylalkyl, hydroxyalkylaminocarbonylalkylamino, hydroxyalkylaminocarbonylaminoalkoxy, hydroxyalkylaminoheterocyclo, hydroxyalkylcarbonyl Aminoalkyl amino, hydroxy alkylcarbonylamino heterocycloalkyl, selected hydroxyalkylcarbonyl heterocycloalkyl, hydroxyalkyl heterocycloalkyl, and from the group consisting of hydroxy heterocycloalkyl,
R ² is selected from the group consisting of alkyl, cycloalkyl, and hydrogen;
R ³ is selected from the group consisting of hydrogen, alkyl, alkoxy, and halo, where each alkyl is independently substituted with alkoxy, amino, carboxy, halo, and hydroxyl, wherever present. You can,
R ^4A , R ^4B , R ^4C , R ^4D , and R ^4E are each independently alkylaminocarbonylaminoalkyl, alkylarylheteroarylaminocarbonylaminoalkyl, aminoalkyl, arylcycloalkylaminocarbonyldialkylaminoalkyl, arylcycloalkyl Selected from the group consisting of aminocarbonylaminoalkyl, cyano, cycloalkylaminocarbonylaminoalkyl, cycloalkylaminocarbonyldialkylaminoalkyl, halo, and hydrogen, each aryl and heteroaryl, wherever present, Independently, it may be substituted with alkyl. R ¹ is (C ₂ -C ₁₀ ) -alkenyl, (C ₁ -C ₁₀ ) -alkoxycarbonyl- (C ₁ -C ₁₀ ) -alkylamino, (C ₁ -C ₁₀ ) -alkoxycarbonylamino- (C ₁ -C ₁₀₎ - _{alkoxy, (C} 1 ~C ₁₀₎ - alkoxycarbonylamino _{heterocycloalkyl, (C} 1 ~C ₁₀₎ - alkoxycarbonyl _{aryl, (C} 1 ~C ₁₀₎ - alkoxycarbonyl aryl - _(C 1 ~ C ₁₀₎ - _{alkylamino, (C} 1 _{~C 10)} - alkoxycarbonyl _{heterocycloalkyl, (C} 1 _{~C 10)} - _{alkyl, (C} 1 _{~C 10)} - _{alkylamino, (C} 1 _{~C 10)} - alkyl aminocarbonyl _{- (C} 1 _{~C 10) - alkyl, (C} 1 ~C ₁₀₎ - alkylaminocarbonyl _{- (C} 1 _{~C 10) Alkylamino, (C} 1 _{~C 10)} - alkylaminocarbonylamino _{- (C} 1 _{~C 10) - alkoxy, (C} 1 _{~C 10)} - alkylamino _{heterocycloalkyl, (C} 1 _{~C 10)} - alkylcarbonylamino - _(C 1 ~C ₁₀₎ - _{alkoxy, (C} 1 ~C ₁₀₎ - alkylcarbonylamino _{- (C} 1 _{~C 10) - alkyl, (C} 1 ~C ₁₀₎ - alkylcarbonylamino - _(C 1 -C ₁₀₎ - _alkylamino, (C 1 _{-C 10)} - alkylcarbonylamino _{heterocycloalkyl,} (C 1 _{-C 10)} - alkyl carbonyl heterocycloalkyl _amino, (C 1 _{-C 10)} - alkylcarbonyloxy - _(C 1 ~ C ₁₀₎ - alkylcarbonylamino _{- (C} 1 _{~C 10) - alkoxy, (C} 1 _{~C 10)} - alkyl Cal Bonyloxy- (C ₁ -C ₁₀ ) -alkylcarbonylaminoheterocyclo, (C ₁ -C ₁₀ ) -alkylsulfonyl, (C ₁ -C ₁₀ ) -alkylsulfonylamino- (C ₁ -C ₁₀ ) -alkoxy, ( C ₁ ~C ₁₀₎ - alkylsulfonylamino _{- (C} 1 _{~C 10) - alkyl, (C} 1 _{~C 10)} - alkylsulfonylamino _{- (C} 1 _{~C 10) - alkylamino, (C} 1 _{~C 10} ) -Alkylthio, amino- (C ₁ -C ₁₀ ) -alkoxy, amino- (C ₁ -C ₁₀ ) -alkyl, amino- (C ₁ -C ₁₀ ) -alkylamino, amino- (C ₁ -C ₁₀ ) - alkylcarbonylamino heterocycloalkyl, amino _{- (C} 1 _{~C 10) -} alkylcarbonyl heterocycloalkyl, aminocarbonyl - _(C 1 ~ C ₁₀₎ - alkoxy, aminocarbonyl _{- (C} 1 _{~C 10) -} alkyl, aminocarbonyl _{- (C} 1 _{~C 10) -} alkylamino, aminocarbonyl _{- (C} 1 _{~C 10) -} alkyl heterocycloalkyl, aminocarbonyl Amino- (C ₁ -C ₁₀ ) -alkoxy, aminocarbonylamino- (C ₁ -C ₁₀ ) -alkylamino, aminocarbonylaryl, aminocarbonyl- (C ₁ -C ₁₀ ) -dialkylamino, aminocarbonylheterocyclo, amino heterocycloalkyl, aryl, carboxy _{- (C} 1 _{~C 10) -} alkoxy, carboxy _{- (C} 1 _{~C 10) -} alkyl, carboxy aryl, carboxy _{- (C} 1 _{~C 10) -} dialkylamino, _(C 1 ~ C ₁₀₎ - _{cycloalkyl, (C} 1 _{~C 10)} - Zia Alkylamino _{- (C} 1 _{~C 10) -} alkylamino, dihydroxy _{- (C} 1 _{~C 10) -} alkylamino, halo, halo _{- (C} 1 _{~C 10) -} alkylsulfonyloxy, haloaryl _{- (C} 1 _{~C 10} ) -Alkylamino, heteroaryl- (C ₁ -C ₁₀ ) -alkoxycarbonylaminoheterocyclo, heterocyclocarbonyl- (C ₁ -C ₁₀ ) -alkylamino, heterocyclo, hydrogen, hydroxy, hydroxy- (C ₁ -C ₁₀₎ - alkoxy, hydroxy _- (C 1 _{-C 10)} - alkylamino, hydroxy _- (C 1 _{-C 10)} - alkylaminocarbonyl _- (C 1 _{-C 10)} - alkoxy, hydroxy _- (C 1 _{-C 10} ) - alkylaminocarbonyl _- (C 1 _{-C 10)} - alkyl, hydroxy - C ₁ -C ₁₀₎ - alkylaminocarbonyl _- (C 1 _{-C 10)} - alkylamino, hydroxy _- (C 1 _{-C 10)} - alkyl aminocarbonylamino _- (C 1 _{-C 10)} - alkoxy, hydroxy - ( C ₁ ~C ₁₀₎ - alkylamino heterocycloalkyl, hydroxy _{- (C} 1 _{~C 10) -} alkylcarbonylamino _{- (C} 1 _{~C 10) -} alkylamino, hydroxy _{- (C} 1 _{~C 10) -} alkylcarbonylamino Selected from the group consisting of heterocyclo, hydroxy- (C ₁ -C ₁₀ ) -alkylcarbonylheterocyclo, hydroxy- (C ₁ -C ₁₀ ) -alkylheterocyclo, and hydroxyheterocyclo;
R ² is selected from the group consisting of (C ₁ -C ₁₀ ) -alkyl, (C ₁ -C ₁₀ ) -cycloalkyl, and hydrogen;
R ³ is selected from the group consisting of hydrogen, (C ₁ -C ₁₀ ) -alkyl, (C ₁ -C ₁₀ ) -alkoxy, and halo, wherein each alkyl is independently wherever present Optionally substituted with (C ₁ -C ₁₀ ) -alkoxy, amino, carboxy, halo, and hydroxyl,
R ^4A , R ^4B , R ^4C , R ^4D , and R ^4E are each independently (C ₁ -C ₁₀ ) -alkylaminocarbonylamino- (C ₁ -C ₁₀ ) -alkyl, (C ₁ -C ₁₀ ) - alkylaryl heteroaryl aminocarbonylamino _{- (C} 1 _{~C 10) -} alkyl, amino _{- (C} 1 _{~C 10) -} alkyl, aryl _{- (C} 1 _{~C 10) -} cycloalkylaminocarbonyl - _(C 1 ~ C ₁₀₎ - dialkylamino _{- (C} 1 ~C _{10) -} alkyl, aryl _{- (C} 1 ~C _{10) -} cycloalkyl aminocarbonylamino _{- (C} 1 ~C _{10) -} alkyl, _{cyano, (C} 1 -C ₁₀₎ - cycloalkyl aminocarbonylamino _- (C 1 _{-C 10)} - _alkyl, (C 1 _{-C 10)} - cycloalkyl aminocapronitrile Rubonyl- (C ₁ -C ₁₀ ) -dialkylamino- (C ₁ -C ₁₀ ) -alkyl, halo, and hydrogen, each aryl and heteroaryl, wherever present, The compound of claim 1, each independently substituted with (C ₁ -C ₁₀ ) -alkyl. R ¹ is (C ₂ -C ₈ ) -alkenyl, (C ₁ -C ₈ ) -alkoxycarbonyl- (C ₁ -C ₈ ) -alkylamino, (C ₁ -C ₈ ) -alkoxycarbonylamino- (C ₁ -C ₈₎ - _{alkoxy, (C} 1 ~C ₈₎ - alkoxycarbonylamino _{heterocycloalkyl, (C} 1 ~C ₈₎ - alkoxycarbonyl _{aryl, (C} 1 ~C ₈₎ - alkoxycarbonyl aryl - _(C 1 ~ C ₈₎ - _{alkylamino, (C} 1 _{~C 8)} - alkoxycarbonyl _{heterocycloalkyl, (C} 1 _{~C 8)} - _{alkyl, (C} 1 _{~C 8)} - _{alkylamino, (C} 1 _{~C 8)} - alkyl aminocarbonyl - _(C 1 _{~C 8)} - _{alkyl, (C} 1 _{~C 8)} - alkylaminocarbonyl - _(C 1 _{~C 8)} - _{alkylamino, (C} 1 _{~C 8} - alkylaminocarbonylamino - _(C 1 ~C ₈₎ - _{alkoxy, (C} 1 _{~C 8)} - alkylamino _{heterocycloalkyl, (C} 1 _{~C 8)} - alkylcarbonylamino - _(C 1 ~C ₈₎ - alkoxy , (C ₁ -C ₈ ) -alkylcarbonylamino- (C ₁ -C ₈ ) -alkyl, (C ₁ -C ₈ ) -alkylcarbonylamino- (C ₁ -C ₈ ) -alkylamino, (C _1- C ₈₎ - alkylcarbonylamino _{heterocycloalkyl, (C} 1 _{~C 8)} - alkylcarbonyl heterocycloalkyl _{amino, (C} 1 _{~C 8)} - alkylcarbonyloxy - _(C 1 ~C ₈₎ - alkylcarbonylamino - (C ₁ -C ₈₎ - _{alkoxy, (C} 1 ~C ₈₎ - alkylcarbonyloxy - _(C 1 ~C ₈₎ - alkylcarbonylamino het _{Cycloalkyl, (C} 1 _{~C 8)} - _{alkylsulfonyl, (C} 1 _{~C 8)} - alkylsulfonylamino - _(C 1 ~C ₈₎ - _{alkoxy, (C} 1 _{~C 8)} - alkylsulfonylamino - _{(C 1} -C ₈₎ - _{alkyl, (C} 1 ~C ₈₎ - alkylsulfonylamino - _(C 1 ~C ₈₎ - _{alkylamino, (C} 1 ~C ₈₎ - alkylthio, amino _{- (C} 1 _~C 8) _- Alkoxy, amino- (C ₁ -C ₈ ) -alkyl, amino- (C ₁ -C ₈ ) -alkylamino, amino- (C ₁ -C ₈ ) -alkylcarbonylaminoheterocyclo, amino- (C ₁ -C ₈₎ - alkylcarbonyl heterocycloalkyl, aminocarbonyl - _(C 1 -C ₈₎ - alkoxy, aminocarbonyl - _(C 1 -C ₈₎ - alkyl, aminocarbonyl - (C ₁ -C ₈₎ - alkylamino, aminocarbonyl - _(C 1 ~C ₈₎ - alkyl heterocycloalkyl, aminocarbonylamino - _(C 1 ~C ₈₎ - alkoxy, aminocarbonylamino _{- (C} 1 _~C 8) _- alkylamino, aminocarbonyl aryl, aminocarbonyl - _(C 1 ~C ₈₎ - dialkylamino, aminocarbonyl heterocycloalkyl, amino heterocycloalkyl, aryl, carboxy - _(C 1 ~C ₈₎ - alkoxy, carboxy - _(C 1 ~ C ₈₎ - alkyl, carboxy aryl, carboxy - _(C 1 ~C ₈₎ - _{dialkylamino, (C} 1 _{~C 8)} - _{cycloalkyl, (C} 1 _{~C 8)} - dialkylamino - _(C 1 ~C ₈ ) -Alkylamino, dihydroxy- (C ₁ -C ₈ ) -alkylamino, halo, halo- (C ₁ -C ₈₎ - alkyl sulfonyloxy, haloaryl - _(C 1 ~C ₈₎ - alkylamino, heteroaryl - _(C 1 ~C ₈₎ - alkoxycarbonylamino heterocycloalkyl, heterocycloalkyl-carbonyl - _(C 1 ~C ₈ ) - alkylamino, heterocyclo, hydrogen, hydroxy, hydroxy - _(C 1 -C ₈₎ - alkoxy, hydroxy - _(C 1 -C ₈₎ - alkylamino, hydroxy - _(C 1 -C ₈₎ - alkylaminocarbonyl - _(C 1 ~C ₈₎ - alkoxy, hydroxy - _(C 1 ~C ₈₎ - alkylaminocarbonyl - _(C 1 ~C ₈₎ - alkyl, hydroxy - _(C 1 ~C ₈₎ - alkylaminocarbonyl - (C ₁ -C ₈₎ - alkylamino hydroxy - _(C 1 ~C ₈₎ - alkylaminocarbonyl amino - _(C 1 ~C ₈₎ - alkoxy, hydroxy - _(C 1 ~C ₈₎ - alkylamino heterocycloalkyl, hydroxy - _(C 1 ~C ₈₎ - alkylcarbonylamino - _(C 1 ~C ₈₎ - alkylamino , hydroxy - _(C 1 ~C ₈₎ - alkylcarbonylamino heterocycloalkyl, hydroxy - _(C 1 ~C ₈₎ - alkylcarbonyl heterocycloalkyl, hydroxy - _(C 1 ~C ₈₎ - alkyl heterocycloalkyl, and hydroxy heterocycloalkyl Selected from the group consisting of
R ² is selected from the group consisting of (C ₁ -C ₈ ) -alkyl, (C ₁ -C ₈ ) -cycloalkyl, and hydrogen;
R ³ is selected from the group consisting of hydrogen, (C ₁ -C ₈ ) -alkyl, (C ₁ -C ₈ ) -alkoxy, and halo, wherein each alkyl is independently wherever present _{to, (C} 1 _{~C 8)} - alkoxy, amino, carboxy, halo, and hydroxyl may be substituted with,
R ^4A , R ^4B , R ^4C , R ^4D , and R ^4E are each independently (C ₁ -C ₈ ) -alkylaminocarbonylamino- (C ₁ -C ₈ ) -alkyl, (C ₁ -C ₈ ) - alkylaryl heteroaryl aminocarbonylamino - _(C 1 ~C ₈₎ - alkyl, amino - _(C 1 ~C ₈₎ - alkyl, aryl - _(C 1 ~C ₈₎ - cycloalkyl amino carbonyl - _(C 1 ~ C ₈₎ - dialkylamino - _(C 1 _{~C 8)} - alkyl, aryl - _(C 1 _{~C 8)} - cycloalkyl aminocarbonylamino - _(C 1 _{~C 8)} - alkyl, _{cyano, (C} 1 -C ₈₎ - cycloalkyl aminocarbonylamino - _(C 1 -C ₈₎ - _{alkyl, (C} 1 -C ₈₎ - cycloalkyl amino carbonyl - _(C 1 -C ₈ - dialkylamino _{- (C} 1 ~C 8) - alkyl, halo, and is selected from the group consisting of hydrogen, each aryl and heteroaryl, even if there where, independently, (C ₁ -C ₈ ) A compound according to claim 2, optionally substituted with -alkyl. R ¹ is (C ₂ -C ₆ ) -alkenyl, (C ₁ -C ₆ ) -alkoxycarbonyl- (C ₁ -C ₆ ) -alkylamino, (C ₁ -C ₆ ) -alkoxycarbonylamino- (C ₁ -C ₆₎ - _{alkoxy, (C} 1 ~C ₆₎ - alkoxycarbonylamino _{heterocycloalkyl, (C} 1 ~C ₆₎ - alkoxycarbonyl _{aryl, (C} 1 ~C ₆₎ - alkoxycarbonyl aryl - _(C 1 ~ C ₆₎ - _{alkylamino, (C} 1 _{~C 6)} - alkoxycarbonyl _{heterocycloalkyl, (C} 1 _{~C 6)} - _{alkyl, (C} 1 _{~C 6)} - _{alkylamino, (C} 1 _{~C 6)} - alkyl aminocarbonyl - _(C 1 _{~C 6)} - _{alkyl, (C} 1 _{~C 6)} - alkylaminocarbonyl - _(C 1 _{~C 6)} - _{alkylamino, (C} 1 _{~C 6} - alkylaminocarbonylamino - _(C 1 ~C ₆₎ - _{alkoxy, (C} 1 _{~C 6)} - alkylamino _{heterocycloalkyl, (C} 1 _{~C 6)} - alkylcarbonylamino - _(C 1 ~C ₆₎ - alkoxy , (C ₁ -C ₆ ) -alkylcarbonylamino- (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylcarbonylamino- (C ₁ -C ₆ ) -alkylamino, (C _1- C ₆₎ - alkylcarbonylamino _{heterocycloalkyl, (C} 1 _{~C 6)} - alkylcarbonyl heterocycloalkyl _{amino, (C} 1 _{~C 6)} - alkylcarbonyloxy - _(C 1 ~C ₆₎ - alkylcarbonylamino - (C ₁ -C ₆₎ - _{alkoxy, (C} 1 ~C ₆₎ - alkylcarbonyloxy - _(C 1 ~C ₆₎ - alkylcarbonylamino het _{Cycloalkyl, (C} 1 _{~C 6)} - _{alkylsulfonyl, (C} 1 _{~C 6)} - alkylsulfonylamino - _(C 1 ~C ₆₎ - _{alkoxy, (C} 1 _{~C 6)} - alkylsulfonylamino - _{(C 1} -C ₆₎ - _{alkyl, (C} 1 ~C ₆₎ - alkylsulfonylamino - _(C 1 ~C ₆₎ - _{alkylamino, (C} 1 ~C ₆₎ - alkylthio, amino _{- (C} 1 _~C 6) _- Alkoxy, amino- (C ₁ -C ₆ ) -alkyl, amino- (C ₁ -C ₆ ) -alkylamino, amino- (C ₁ -C ₆ ) -alkylcarbonylaminoheterocyclo, amino- (C ₁ -C ₆₎ - alkylcarbonyl heterocycloalkyl, aminocarbonyl - _(C 1 -C ₆₎ - alkoxy, aminocarbonyl - _(C 1 -C ₆₎ - alkyl, aminocarbonyl - (C ₁ -C ₆₎ - alkylamino, aminocarbonyl - _(C 1 ~C ₆₎ - alkyl heterocycloalkyl, aminocarbonylamino - _(C 1 ~C ₆₎ - alkoxy, aminocarbonylamino _{- (C} 1 _~C 6) _- alkylamino, aminocarbonyl aryl, aminocarbonyl - _(C 1 ~C ₆₎ - dialkylamino, aminocarbonyl heterocycloalkyl, amino heterocycloalkyl, aryl, carboxy - _(C 1 ~C ₆₎ - alkoxy, carboxy - _(C 1 ~ C ₆₎ - alkyl, carboxy aryl, carboxy - _(C 1 ~C ₆₎ - _{dialkylamino, (C} 1 _{~C 6)} - _{cycloalkyl, (C} 1 _{~C 6)} - dialkylamino - _(C 1 ~C ₆ ) -Alkylamino, dihydroxy- (C ₁ -C ₆ ) -alkylamino, halo, halo- (C ₁ -C ₆₎ - alkyl sulfonyloxy, haloaryl - _(C 1 ~C ₆₎ - alkylamino, heteroaryl - _(C 1 ~C ₆₎ - alkoxycarbonylamino heterocycloalkyl, heterocycloalkyl-carbonyl - _(C 1 ~C ₆ ) - alkylamino, heterocyclo, hydrogen, hydroxy, hydroxy - _(C 1 -C ₆₎ - alkoxy, hydroxy - _(C 1 -C ₆₎ - alkylamino, hydroxy - _(C 1 -C ₆₎ - alkylaminocarbonyl - (C ₁ -C ₆ ) -alkoxy, hydroxy- (C ₁ -C ₆ ) -alkylaminocarbonyl- (C ₁ -C ₆ ) -alkyl, hydroxy- (C ₁ -C ₆ ) -alkylaminocarbonyl- (C ₁ -C ₆₎ - alkylamino, hydroxy - _(C 1 ~C ₆₎ - alkylaminocarbonyl amino - _(C 1 ~C ₆₎ - alkoxy, hydroxy - _(C 1 ~C ₆₎ - alkylamino heterocycloalkyl, hydroxy - _(C 1 ~C ₆₎ - alkylcarbonylamino - _(C 1 ~C ₆₎ - alkylamino , hydroxy - _(C 1 ~C ₆₎ - alkylcarbonylamino heterocycloalkyl, hydroxy - _(C 1 ~C ₆₎ - alkylcarbonyl heterocycloalkyl, hydroxy - _(C 1 ~C ₆₎ - alkyl heterocycloalkyl, and hydroxy heterocycloalkyl Selected from the group consisting of
R ² is selected from the group consisting of (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -cycloalkyl, and hydrogen;
R ³ is selected from the group consisting of hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkoxy, and halo, wherein each alkyl is independently wherever it is present Optionally substituted with (C ₁ -C ₆ ) -alkoxy, amino, carboxy, halo, and hydroxyl,
R ^4A , R ^4B , R ^4C , R ^4D , and R ^4E are each independently (C ₁ -C ₆ ) -alkylaminocarbonylamino- (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) - alkylaryl heteroaryl aminocarbonylamino - _(C 1 ~C ₆₎ - alkyl, amino - _(C 1 ~C ₆₎ - alkyl, aryl - _(C 1 ~C ₆₎ - cycloalkyl amino carbonyl - _(C 1 ~ C ₆₎ - dialkylamino - _(C 1 _{~C 6)} - alkyl, aryl - _(C 1 _{~C 6)} - cycloalkyl aminocarbonylamino - _(C 1 _{~C 6)} - alkyl, _{cyano, (C} 1 -C ₆₎ - cycloalkyl aminocarbonylamino - _(C 1 -C ₆₎ - _{alkyl, (C} 1 -C ₆₎ - cycloalkyl amino carbonyl - _(C 1 -C ₆ - dialkylamino _{- (C} 1 ~C 6) - alkyl, halo, and may be selected from the group consisting of hydrogen, each aryl and heteroaryl, even if there where, independently, (C ₁ -C 6) _- alkyl which may be substituted, the compounds according to claim 3. R ¹ is (C ₂ -C ₆ ) -alkenyl, (C ₁ -C ₆ ) -alkyl, (C ₁ -C ₆ ) -alkylamino, (C ₁ -C ₆ ) -alkylaminocarbonyl- (C ₁ -C ₆₎ - _{alkylamino, (C} 1 ~C ₆₎ - alkylamino _{heterocycloalkyl, (C} 1 ~C ₆₎ - alkylcarbonylamino - _(C 1 ~C ₆₎ - _{alkoxy, (C} 1 _~C 6) - alkylcarbonylamino - _(C 1 ~C ₆₎ - _{alkylamino, (C} 1 _{~C 6)} - alkylcarbonyl heterocycloalkyl _{amino, (C} 1 _{~C 6)} - alkylsulfonylamino _{- (C} 1 _~C 6) _{- alkoxy, (C} 1 _{~C 6)} - alkylsulfonylamino - _(C 1 ~C ₆₎ - _{alkyl, (C} 1 _{~C 6)} - alkylsulfonylamino - _(C 1 ~C ₆₎ - alkylamino _(C 1 ~C ₆₎ - alkylsulfonylamino - _(C 1 ~C ₆₎ - alkylamino, amino - _(C 1 ~C ₆₎ - alkylamino, amino - _(C 1 ~C ₆₎ - alkylcarbonyl heterocycloalkyl Aminocarbonyl- (C ₁ -C ₆ ) -alkoxy, aminocarbonyl- (C ₁ -C ₆ ) -alkylamino, aminocarbonylamino- (C ₁ -C ₆ ) -alkoxy, aminocarbonylamino- (C _1- C ₆₎ - alkyl, aminocarbonyl aryl, aminocarbonyl heterocycloalkyl, amino heterocycloalkyl, aryl, dihydroxy - _(C 1 ~C ₆₎ - alkylamino, haloaryl - _(C 1 ~C ₆₎ - alkylamino, hydrogen, hydroxyl - _(C 1 ~C ₆₎ - alkoxy, hydroxyl - _(C 1 ~C ₆₎ - A Kill, hydroxyl - _(C 1 ~C ₆₎ - alkylamino, hydroxyl - _(C 1 ~C ₆₎ - alkylcarbonylamino - _(C 1 ~C ₆₎ - alkylamino, hydroxyl _{- (C} 1 _~C 6) _- alkyl heterocycloalkyl, and hydroxyl - _(C 1 ~C ₆₎ - alkylcarbonylamino - _(C 1 ~C ₆₎ - is selected from the group consisting of alkylamino the compound according to claim 4. R ² is _(C 1 _{~C 6)} - alkyl, A compound according to claim 5. R ³ is halo, A compound according to claim 5. R ^4A , R ^4B , R ^4C , R ^4D , and R ^4E are each independently hydrogen, halo, and (C ₁ -C ₆ ) -alkylaminocarbonylamino- (C ₁ -C ₆ ) -alkyl. 6. A compound according to claim 5 selected from. R ² is (C ₁ -C ₆ ) -alkyl, R ³ is halo, R ^4A , R ^4B , R ^4C , R ^4D , and R ^4E are each independently hydrogen, halo, and (C ₁ -C ₆₎ - alkyl aminocarbonylamino - _(C 1 ~C ₆₎ - is selected from the group consisting of alkyl, a compound according to claim 5. R ¹ is (C ₁ -C ₆ ) -alkylaminoheterocyclo, (C ₁ -C ₆ ) -alkylcarbonylamino- (C ₁ -C ₆ ) -alkylamino, (C ₁ -C ₆ ) -alkylsulfonyl Amino- (C ₁ -C ₆ ) -alkoxy, (C ₁ -C ₆ ) -alkylsulfonylamino- (C ₁ -C ₆ ) -alkylamino, (C ₁ -C ₆ ) -alkylsulfonylamino- (C ₁ -C ₆₎ - alkylamino, aminocarbonyl - _(C 1 ~C ₆₎ - alkylamino, aminocarbonylamino - _(C 1 ~C ₆₎ - alkoxy, aminocarbonylamino - _(C 1 ~C ₆₎ - alkylamino , aminocarbonyl heterocycloalkyl, dihydroxy - _(C 1 ~C ₆₎ - alkylamino, hydroxyl - _(C 1 ~C ₆₎ - alkylamino, Oyo Hydroxy - _(C 1 ~C ₆₎ - alkylcarbonylamino - _(C 1 ~C ₆₎ - it is selected from the group consisting of alkylamino The compound according to claim 5. R ² is _(C 1 _{~C 6)} - alkyl, A compound according to claim 10. R ³ is halo, A compound according to claim 10. ^{R 4A, R 4B, R 4C} , R 4D, and ^{R 4E} are each independently selected from the group consisting of hydrogen and halo, A compound according to claim 10. R ² is (C ₁ -C ₆ ) -alkyl, R ³ is halo, and R ^4A , R ^4B , R ^4C , R ^4D , and R ^4E are each independently selected from the group consisting of hydrogen and halo 11. The compound of claim 10, which may be N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] methanesulfone Amide,
N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] urea,
N ~ 2- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -L-alaninamide,
N- [3-({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] urea,
N- [3-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] methanesulfone Amide,
N- [3-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2 -Hydroxyacetamide,
5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2-[(3R) -3- (methylamino) pyrrolidin-1-yl] pyrimidin-4 (3H) -one,
N-3-3- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -β-alaninamide,
N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] -2 -Hydroxyacetamide,
N- [3-({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] acetamide,
N-3-3- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -β-alaninamide,
N ~ 2- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} glycinamide,
N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] urea,
N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] -2 -Hydroxy-2-methylpropanamide,
4-({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) butanamide,
5-bromo-6-[(2,4-difluorobenzyl) oxy] -2-{[(2S) -2,3-dihydroxypropyl] amino} -3-isopropylpyrimidin-4 (3H) -one,
N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] methanesulfone Amide,
N- [2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] urea,
N- [2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] -2 -Hydroxyacetamide,
N- [2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] methanesulfone Amide,
5-bromo-6-[(2,4-difluorobenzyl) oxy] -2-{[(2R) -2,3-dihydroxypropyl] amino} -3-isopropylpyrimidin-4 (3H) -one,
1- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} prolinamide,
N- [2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] urea,
N- [3-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2 -Hydroxy-2-methylpropanamide,
5-bromo-6-[(2,4-difluorobenzyl) oxy] -2-[(4-fluorobenzyl) amino] -3-isopropylpyrimidin-4 (3H) -one,
N- [2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] acetamide,
N- [2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] methanesulfone Amide,
5-Bromo-6-[(2,4-difluorobenzyl) oxy] -2-[(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] -3-isopropylpyrimidine-4 (3H) -one tri Fluoroacetate,
5-bromo-6-[(2,4-difluorobenzyl) oxy] -2-[(2-hydroxy-2-methylpropyl) amino] -3-isopropylpyrimidin-4 (3H) -one,
1- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} prolinamide,
N- [2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] -2 -Hydroxy-2-methylpropanamide,
N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] acetamide,
5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one,
N-({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} methyl) methanesulfonamide,
2-[(3R) -3-Aminopyrrolidin-1-yl] -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one trifluoroacetate ,
2-[(1-acetylpiperidin-4-yl) amino] -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one,
N ~ 2- {5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N ~ 1-methyl Glycinamide,
N ~ 2- {5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} glycinamide,
N- [2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] acetamide,
5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2-phenylpyrimidin-4 (3H) -one,
4- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamide,
1- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} piperidine-3-carboxamide,
N- (2-{[(5-Bromo-1-isopropyl-2-methyl-6-oxo-1,6-dihydropyrimidin-4-yl) oxy] methyl} -5-fluorobenzyl) -N'-ethyl urea,
2- (3-aminopyrrolidin-1-yl) -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one trifluoroacetate salt,
5-bromo-6-[(2,4-difluorobenzyl) oxy] -2-[(3,3-dimethylbutyl) amino] -3-isopropylpyrimidin-4 (3H) -one,
5-chloro-6-[(2,4-difluorobenzyl) oxy] -2- (4-hydroxybutoxy) -3-isopropylpyrimidin-4 (3H) -one,
5-bromo-6-[(2,4-difluorobenzyl) oxy] -2-[(3R) -3- (ethylamino) pyrrolidin-1-yl] -3-isopropylpyrimidin-4 (3H) -one,
4-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) butanamide,
2-[(2-aminoethyl) amino] -5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one trifluoroacetate, and 2-but -3-enyl-5-chloro-6-[(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one,
Or the compound of claim 1 selected from the group consisting of pharmaceutically acceptable salts thereof. N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] methanesulfone Amide,
N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] urea,
N ~ 2- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -L-alaninamide,
N- [3-({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] urea,
N- [3-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] methanesulfone Amide,
N- [3-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2 -Hydroxyacetamide,
5-bromo-6-[(2,4-difluorobenzyl) oxy] -3-isopropyl-2-[(3R) -3- (methylamino) pyrrolidin-1-yl] pyrimidin-4 (3H) -one,
N-3-3- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -β-alaninamide,
N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] -2 -Hydroxyacetamide,
N- [3-({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] acetamide,
N-3-3- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -β-alaninamide,
N ~ 2- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} glycinamide,
N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] urea,
N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] -2 -Hydroxy-2-methylpropanamide,
4-({5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) butanamide,
5-bromo-6-[(2,4-difluorobenzyl) oxy] -2-{[(2S) -2,3-dihydroxypropyl] amino} -3-isopropylpyrimidin-4 (3H) -one,
N- [2-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] methanesulfone Amide,
N- [2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] urea,
N- [2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] -2 -Hydroxyacetamide,
N- [2-({5-Chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] methanesulfone Amide,
5-bromo-6-[(2,4-difluorobenzyl) oxy] -2-{[(2R) -2,3-dihydroxypropyl] amino} -3-isopropylpyrimidin-4 (3H) -one,
1- {5-bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} prolinamide,
N- [2-({5-chloro-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] urea,
N- [3-({5-Bromo-4-[(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] -2 -Hydroxy-2-methylpropanamide and 5-bromo-6-[(2,4-difluorobenzyl) oxy] -2-[(4-fluorobenzyl) amino] -3-isopropylpyrimidine-4 (3H)- on,
Or the compound of claim 1 selected from the group consisting of pharmaceutically acceptable salts thereof. Compound of formula I

Or a pharmaceutically acceptable salt, enantiomer or racemate thereof [wherein
R ¹ is alkenyl, alkoxycarbonylalkylamino, alkoxycarbonylaminoalkoxy, alkoxycarbonylaminoheterocyclo, alkoxycarbonylaryl, alkoxycarbonylarylalkylamino, alkoxycarbonylheterocyclo, alkyl, alkylamino, alkylaminocarbonylalkyl, alkylaminocarbonyl Alkylamino, alkylaminocarbonylaminoalkoxy, alkylaminoheterocyclo, alkylcarbonylaminoalkoxy, alkylcarbonylaminoalkyl, alkylcarbonylaminoalkylamino, alkylcarbonylaminoheterocyclo, alkylcarbonylheterocycloamino, alkylcarbonyloxyalkylcarbonylaminoalkoxy, Alkyl Carbonyloxyalkylcarbonylaminoheterocyclo, alkylsulfonyl, alkylsulfonylaminoalkoxy, alkylsulfonylaminoalkyl, alkylsulfonylaminoalkylamino, alkylthio, aminoalkoxy, aminoalkyl, aminoalkylamino, aminoalkylcarbonylaminoheterocyclo, aminoalkylcarbonylhetero Cyclo, aminocarbonylalkoxy, aminocarbonylalkyl, aminocarbonylalkylamino, aminocarbonylalkylheterocyclo, aminocarbonylaminoalkoxy, aminocarbonylaminoalkylamino, aminocarbonylaryl, aminocarbonyldialkylamino, aminocarbonylheterocyclo, aminoheterocyclo, Aryl, carboxyal Xy, carboxyalkyl, carboxyaryl, carboxydialkylamino, cycloalkyl, dialkylaminoalkylamino, dihydroxyalkylamino, halo, haloalkylsulfonyloxy, haloarylalkylamino, heteroarylalkoxycarbonylaminoheterocyclo, heterocyclocarbonylalkylamino, heterocyclo , Hydrogen, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkylamino, hydroxyalkylaminocarbonylalkoxy, hydroxyalkylaminocarbonylalkyl, hydroxyalkylaminocarbonylalkylamino, hydroxyalkylaminocarbonylaminoalkoxy, hydroxyalkylaminoheterocyclo, hydroxyalkylcarbonyl Aminoalkyl amino, hydroxy alkylcarbonylamino heterocycloalkyl, selected hydroxyalkylcarbonyl heterocycloalkyl, hydroxyalkyl heterocycloalkyl, and from the group consisting of hydroxy heterocycloalkyl,
R ² is selected from the group consisting of alkyl, cycloalkyl, and hydrogen;
R ³ is selected from the group consisting of hydrogen, alkyl, alkoxy, and halo, where each alkyl is independently substituted with alkoxy, amino, carboxy, halo, and hydroxyl, wherever present. You can,
R ^4A , R ^4B , R ^4C , R ^4D , and R ^4E are each independently alkylaminocarbonylaminoalkyl, alkylarylheteroarylaminocarbonylaminoalkyl, aminoalkyl, arylcycloalkylaminocarbonyldialkylaminoalkyl, arylcycloalkyl Selected from the group consisting of aminocarbonylaminoalkyl, cyano, cycloalkylaminocarbonylaminoalkyl, cycloalkylaminocarbonyldialkylaminoalkyl, halo, and hydrogen, each aryl and heteroaryl, wherever present, Independently, which may be substituted with alkyl] and a pharmaceutically acceptable excipient. A method of treating or preventing an inflammatory disorder in a subject in need thereof, comprising an amount of a compound of the following formula I effective in treating or preventing the inflammatory disorder in the subject

Or a pharmaceutically acceptable salt, enantiomer or racemate thereof [wherein
R ¹ is alkenyl, alkoxycarbonylalkylamino, alkoxycarbonylaminoalkoxy, alkoxycarbonylaminoheterocyclo, alkoxycarbonylaryl, alkoxycarbonylarylalkylamino, alkoxycarbonylheterocyclo, alkyl, alkylamino, alkylaminocarbonylalkyl, alkylaminocarbonyl Alkylamino, alkylaminocarbonylaminoalkoxy, alkylaminoheterocyclo, alkylcarbonylaminoalkoxy, alkylcarbonylaminoalkyl, alkylcarbonylaminoalkylamino, alkylcarbonylaminoheterocyclo, alkylcarbonylheterocycloamino, alkylcarbonyloxyalkylcarbonylaminoalkoxy, Alkyl Carbonyloxyalkylcarbonylaminoheterocyclo, alkylsulfonyl, alkylsulfonylaminoalkoxy, alkylsulfonylaminoalkyl, alkylsulfonylaminoalkylamino, alkylthio, aminoalkoxy, aminoalkyl, aminoalkylamino, aminoalkylcarbonylaminoheterocyclo, aminoalkylcarbonylhetero Cyclo, aminocarbonylalkoxy, aminocarbonylalkyl, aminocarbonylalkylamino, aminocarbonylalkylheterocyclo, aminocarbonylaminoalkoxy, aminocarbonylaminoalkylamino, aminocarbonylaryl, aminocarbonyldialkylamino, aminocarbonylheterocyclo, aminoheterocyclo, Aryl, carboxyal Xy, carboxyalkyl, carboxyaryl, carboxydialkylamino, cycloalkyl, dialkylaminoalkylamino, dihydroxyalkylamino, halo, haloalkylsulfonyloxy, haloarylalkylamino, heteroarylalkoxycarbonylaminoheterocyclo, heterocyclocarbonylalkylamino, heterocyclo , Hydrogen, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkylamino, hydroxyalkylaminocarbonylalkoxy, hydroxyalkylaminocarbonylalkyl, hydroxyalkylaminocarbonylalkylamino, hydroxyalkylaminocarbonylaminoalkoxy, hydroxyalkylaminoheterocyclo, hydroxyalkylcarbonyl Aminoalkyl amino, hydroxy alkylcarbonylamino heterocycloalkyl, selected hydroxyalkylcarbonyl heterocycloalkyl, hydroxyalkyl heterocycloalkyl, and from the group consisting of hydroxy heterocycloalkyl,
R ² is selected from the group consisting of alkyl, cycloalkyl, and hydrogen;
R ³ is selected from the group consisting of hydrogen, alkyl, alkoxy, and halo, where each alkyl is independently substituted with alkoxy, amino, carboxy, halo, and hydroxyl, wherever present. You can,
R ^4A , R ^4B , R ^4C , R ^4D , and R ^4E are each independently alkylaminocarbonylaminoalkyl, alkylarylheteroarylaminocarbonylaminoalkyl, aminoalkyl, arylcycloalkylaminocarbonyldialkylaminoalkyl, arylcycloalkyl Selected from the group consisting of aminocarbonylaminoalkyl, cyano, cycloalkylaminocarbonylaminoalkyl, cycloalkylaminocarbonyldialkylaminoalkyl, halo, and hydrogen, each aryl and heteroaryl, wherever present, Independently, optionally substituted with alkyl].   The method of claim 18, wherein the inflammatory disorder is arthritis.   The method of claim 18, wherein the inflammatory disorder is osteoarthritis.   The method of claim 18, wherein the inflammatory disorder is rheumatoid arthritis.   The method of claim 18, wherein the inflammatory disorder is asthma.