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MX2007004493A - Substituted n-alkylpyrimidinones. - Google Patents

Substituted n-alkylpyrimidinones.

Info

Publication number
MX2007004493A
MX2007004493A MX2007004493A MX2007004493A MX2007004493A MX 2007004493 A MX2007004493 A MX 2007004493A MX 2007004493 A MX2007004493 A MX 2007004493A MX 2007004493 A MX2007004493 A MX 2007004493A MX 2007004493 A MX2007004493 A MX 2007004493A
Authority
MX
Mexico
Prior art keywords
oxy
difluorobenzyl
isopropyl
bromo
oxo
Prior art date
Application number
MX2007004493A
Other languages
Spanish (es)
Inventor
Balekudru Devadas
Terri Lee Boehm
Lance Christopher Christie
Heather Margaret Madsen
Laura Marrufo
Shaun Selness
Original Assignee
Upjohn Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Upjohn Co filed Critical Upjohn Co
Publication of MX2007004493A publication Critical patent/MX2007004493A/en

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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract

This invention is directed generally to substituted pyrimidinone compoundsthat generally inhibit p38 kinase, TNF, and/or cyclooxygenase activity. Suchsubstituted pyrimidinone include compounds generally corresponding in structureto the following formula (I): wherein R1, R2, R3,R4A, R4B, R4C, R4D and R4Eare as defined in this specification. This invention also is directed to compositionsof such substituted pyrimidinones (particularly pharmaceutical compositions),intermediates for the syntheses of such substituted pyrimidinones, methodsfor making such substituted pyrimidinones, and methods for treating (includingpreventing) conditions (typically pathological conditions) associated withp38 kinase activity, TNF activity, and/or cyclooxygenase-2 activity.

Description

N-SUBSTITUTE ALKYL PYRIPYMIDINONES CROSS REFERENCE TO RELATED REQUESTS This application claims priority of the United States Provisional Application Serial Number 60/637949, filed on December 21, 2004, which claims priority to the United States Provisional Application Serial Number 60/618856, filed on October 13, 2004, the discussion of each of which is incorporated in this document by reference in its entirety.
FIELD OF THE INVENTION This invention relates to compounds that inhibit p38 kinase activity (particularly p38a kinase), TNF (particularly TNF-a), and / or cyclooxygenase (particularly cyclooxygenase-2 or "COX-2"). This invention also relates to compositions of such compounds, methods for making such compounds, and methods of treating (including preventing) conditions (typically pathological conditions) associated with p38 kinase activity, TNF activity, and / or cyclooxygenase-2 activity.
BACKGROUND OF THE INVENTION The mitogen-activated protein kinases (MAP) constitute a family of proline-directed serine / threonine kinases that activate their substrates by dual phosphorylation. The kinases are activated by a variety of signals, including nutritional and osmotic stress, UV light, growth factors, endotoxin, and inflammatory cytokines. The p38 MAP kinase group is a MAP family of various isoforms, including p38a, p38β, and p38 ?. These kinases are responsible for phosphorylating and activating transcription factors (e.g., ATF2, CHOP, and MEF2C), as well as other kinases (e.g., MAPKAP-2 and MAPKAP-3). The isoforms of p38 are activated by bacterial lipopolysaccharide, physical and chemical stress, and proinflammatory cytokines, which include tumor necrosis factor ("TNF") and interleukin-1 ("IL-1"). The phosphorylation products with p38 mediate the production of inflammatory cytokines, which include TNF, IL-1, and cyclooxygenase-2. It is believed that p38a kinase can cause or contribute to the effects of, for example, inflammation in general; arthritis; neuroinflammation; pain; fever; lung disorders; cardiovascular diseases; cardiomyopathy; apoplexy; ischemia; reperfusion damage; kidney damage due to reperfusion; cerebral edema; neurotrauma and brain trauma; neurodegenerative disorders; disorders of the central nervous system; liver disease and nephritis; gastrointestinal conditions; ulcerative diseases; ophthalmic diseases; ophthalmological conditions; glaucoma; acute damage to ocular tissue and ocular trauma; diabetes; diabetic nephropathy; skin-related conditions; bacterial and viral infections; myalgia due to infection; flu; endotoxic shock; toxic shock syndrome; autoimmune disease; bone resorption diseases; multiple sclerosis; disorders of the female reproductive system; pathological (but not malignant) conditions, such as hemangiomas, angiofibroma of the nasopharynx, and avascular necrosis of bone; benign and malignant tumors / neoplasm that includes cancer; leukemia; lymphoma; systemic lupus erythematosus (SLE); angiogenesis that includes neoplasia; and metastasis. TNF is a cytokine produced mainly by monocytes and activated macrophages. The production of excessive or unregulated TNF (particularly TNF-a) has been implicated in the mediation of a number of diseases. It is believed, for example, that TNF can cause or contribute to the effects of inflammation (for example, rheumatoid arthritis and inflammatory bowel disease), asthma, autoimmune disease, graft rejection, multiple sclerosis, fibrotic diseases, cancer, fever, psoriasis. , cardiovascular diseases (eg, post-ischemic reperfusion injury and congestive heart failure), lung diseases (e.g., hyperoxic alveolar damage), hemorrhage, coagulation, radiation damage, and acute phase responses such as those seen with infections and sepsis and during the shock (for example, septic shock and hemodynamic shock). The chronic release of active TNF can cause cachexia and anorexia. And TNF can be lethal. TNF has also been implicated in infectious diseases.
These include, for example, malaria, mycobacterial infection and meningitis.
Also included are viral infections, such as HIV, influenza virus, and herpes viruses, which include herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), cytomegalovirus (CMV) , varicella-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and rhinotracheitis, among others. IL-8 is another proinflammatory cytokine, which is produced by mononuclear cells, fibroblasts, endothelial cells, and keratinocytes. This cytokine is associated with conditions that include inflammation. IL-1 is produced by monocytes and activated macrophages, and is involved in inflammatory responses. 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. Inhibition of these cytokines by inhibition of the p38 kinase is beneficial in controlling, reducing, and alleviating many of these disease states. Various substituted pyrimidinones have been previously described: U.S. patent application serial number 10 / 808,146 (filed March 24, 2004) refers to certain substituted pyrimidinones. In view of the importance of substituted pyrimidinones in the treatment of various pathological conditions (particularly those associated with p38 kinase activity, TNF activity, and / or cyclooxygenase-2 activity), there continues to be a need for substituted pyrimidinone compounds that exhibit an improved safety, solubility, and / or power profile. The following description describes substituted pyrimidinone compounds having one or more such desirable qualities.
BRIEF DESCRIPTION OF THE INVENTION This invention relates to substituted pyrimidinone compounds that inhibit p38 kinase activity, TNF activity, and / or cyclooxygenase-2 activity. This invention also relates, for example, to a method for inhibiting p38 kinase activity, TNF activity, and / or cyclooxygenase-2 activity, and particularly to a method for treating a condition (typically a pathological condition) mediated by kinase activity. p38, TNF activity, and / or cyclooxygenase-2 activity. Such a method is typically suitable for use with mammals in need of such treatment.
Briefly, therefore, this invention relates, in part, to compounds that generally fall in the structure of Formula I: or a salt, enantiomer or pharmaceutically racemate acceptable salt thereof, wherein R1 is selected from the group consisting of alkenyl, alkoxycarbonylalkylamino, alcoxicarbonilaminoalcoxi, alcoxicarbonilaminoheterociclo, alkoxycarbonylaryl, alcoxicarbonilarilalquilamino, alcoxicarbonilheterocíclo, alkyl, alkylamino, alkylaminocarbonylalkyl, alquilaminocarbonilalquilamino, alquilaminocarbonilaminoalcoxi, alquilaminoheterociclo, alquilcarbonilaminoalcoxi , alkylcarbonylaminoalkyl, alquilcarbonilaminoalquilamino, alquilcarbonílaminoheterociclo, alquilcarbonilheterocícloamino, alquilcarboniloxialquilcarbonilaminoalcoxi, alquilcarboniloxialquilcarbonilaminoheterociclo, alkylsulfonyl, alquilsulfonilaminoalcoxi, alkylsulfonylaminoalkyl, alquilsulfonilaminoalquilamino, alkylthio, alkylamino, aminoalkyl, aminoalkylamino, aminoalquilcarbonilaminoheterociclo, aminoalquilcarbonilheterocíclo, aminocarbonyl, alkylaminocarbonyl, aminocarbonylalkylamino, aminocarbonyalkylheterocycle, aminocarbonylaminoalkoxy, aminocarbonylaminoalkylamino, aminocarbonylaryl, aminocarbonyldialkylamino, aminocarbonylheterocycle, aminoheterocycle, aryl, carboxyalkoxy, carboxyalkyl, carboxiaryl, carboxydialkylamino, cycloalkyl, Dialkylaminoalkylamino, dihydroxyalkylamino, halo, haloalkylsulfonyloxy, haloarilalquilamino, heteroarílalcoxicarbonilaminoheterocíclo, heterociclocarbonilalquílamino, heterocycle, hydrogen, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkylamino, hidroxialquilaminocarbonilalcoxi, hidroxialquilaminocarbonilalquilo, hidroxialquilaminocarbonilalquilamino, hidroxialquilaminocarbonilaminoalcoxi, hidroxíalquilaminoheterociclo, hidroxialquilcarbonilamínoalquilamino, hidroxialquilcarbonilaminoheterociclo, hidroxialquilcarbonilheterociclo, hidroxialquilheterociclo, and hydroxyheterocycle; R2 is selected from the group consisting of alkyl, cycloalkyl and hydrogen; R3 is selected from the group consisting of hydrogen, alkyl, alkoxy and halo; wherein each alkyl, wherever it occurs, is independently and optionally substituted with alkoxy, amino, carboxy, halo and hydroxyl; and R4A, R4B, R4C, R4D and R4E are independently selected from the group consisting of alkylaminocarbonylaminoalkyl, alkylarylheteroarylaminocarbonylaminoalkyl, aminoalkyl, arylcycloalkylaminocarbonyldyalkylaminoalkyl, arylcycloalkylaminocarbonylaminoalkyl, cyano, cycloalkylaminocarbonylaminoalkyl, cycloalkylaminocarbonyldyalkylaminoalkyl, halo, and hydrogen; wherein each aryl and heteroaryl, wherever they occur, are independently and optionally substituted with alkyl. This invention also relates, in part, to pharmaceutical compositions comprising a therapeutically effective amount of a previously described compound or pharmaceutically acceptable salt thereof. This invention also relates, in part, to a method of treating an inflammatory condition in a mammal. The method comprises administering a compound described above or pharmaceutically acceptable salt thereof, to the mammal in an amount that is therapeutically effective to treat the condition. Additional benefits of the invention of the applicants will be apparent to someone skilled in the art from reading this specification.
DETAILED DESCRIPTION OF THE INVENTION This detailed description of embodiments is intended only to inform others skilled in the art with the applicants' invention, principles, and practical application such that others skilled in the art can adapt and apply the invention in its many forms, as it can be adapted to the requirements of a particular use. This detailed description and its specific examples, while indicating embodiments of this invention, are desired only for purposes of illustration.
This invention, therefore, is not limited to the embodiments described in this specification, and can be modified in various ways.
Compounds of this invention In accordance with this invention, it has been found that certain substituted pyrimidinone compounds are effective to inhibit the activity (particularly pathological activity) of p38, TNF, and / or cyclooxygenase-2 kinase. Among its many embodiments, the present invention provides a compound of Formula I: or a salt, enantiomer or pharmaceutically acceptable racemate thereof, wherein R1 is selected from the group consisting of alkenyl, alkoxycarbonylalkylamino, alcoxicarbonilaminoalcoxi, alcoxicarbonilaminoheterociclo, alkoxycarbonylaryl, alcoxicarbonílarilalquilamino, alcoxícarbonilheterociclo, alkyl, alkylamino, alkylaminocarbonylalkyl, alquilaminocarbonilalquilamino, alquilaminocarbonilaminoalcoxi, alquilaminoheterociclo, alquilcarbonilaminoalcoxi, alkylcarbonylaminoalkyl, alquilcarbonilaminoalquilamíno, alquilcarbonilaminoheterociclo, alquilcarbonilheterocicloamino, alquilcarboniloxialquilcarbonilaminoalcoxi, alquilcarboniloxialquilcarbonilaminoheterociclo, alkylsulfonyl, alquilsulfonilaminoalcoxi, alkylsulfonylaminoalkyl, alquilsulfonilaminoalquilamino, alkylthio, alkylamino, aminoalkyl, aminoalkylamino, aminoalquilcarbonilaminoheterociclo, aminoalquilcarbonilheterociclo, aminocarbonyl, alkylaminocarbonyl, aminocarbonylalkylamino, amin ocarbonilalquilheterociclo, aminocarbonilamínoalcoxi, amínocarbonilaminoalquilamino, aminocarbonylaryl, aminocarbonildialquilamino, aminocarbonilheterociclo, aminoheterocycle, aryl, carboalkoxy, carboxyalkyl, carboxyaryl, carboxidialquilamino, cycloalkyl, dialkylaminoalkylamino, dihydroxyalkylamino, halo, haloalkylsulfonyloxy, haloarilalquilamíno, heteroarilalcoxícarbonilaminoheterociclo, heterocíclocarbonilalquilamino, heterocycle, hydrogen, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkylamino, hydroxylaminocarbonylalkoxy, hydroxyalkylaminocarbonylalkyl, hydroxyalkylaminocarbonylalkylamino, hydroxyalkylaminocarbonylaminoalkoxy, hydroxyalkylaminoheterocycle, hydroxylalkylcarbonylaminoalkylamino, hydroxylalkylcarbonylaminoheterocycle, hydroxyalkylcarbonylheterocycle, hydroxyalkylheterocycle, and hydroxyheterocycle; R2 is selected from the group consisting of alkyl, cycloalkyl and hydrogen; R3 is selected from the group consisting of hydrogen, alkyl, alkoxy and halo; wherein each alkyl, wherever it occurs, is independently and optionally substituted with alkoxy, amino, carboxy, halo and hydroxy; and R4A, RB, R4C, R4D and R4E are each independently selected from the group consisting of alkylaminocarbonylaminoalkyl, alkylarylheteroarylaminocarbonylaminoalkyl, aminoalkyl, arylcycloalkylaminocarbonyldialkylaminoalkyl, arylcycloalkylaminocarbonylaminoalkyl, cyano, cycloalkylaminocarbonylaminoalkyl, cycloalkylaminocarbonyldialkylaminoalkyl, halo, and hydrogen; wherein each aryl and heteroaryl, wherever they occur, are independently and optionally substituted with alkyl. In another embodiment, R1 is selected from the group consisting of alkenyl (C2-C? 0), alkoxycarboni Ci-Cic-alkylamino-CrC-io), alkoxycarbonylamino (CC? O) -alcoxy- (C? -C? O), alkoxycarbonylaminoheterocycle C- iC-io), alkoxycarbonaryl (C -? - C? o), alkoxycarbonaryl (CrC? o) -alkylamino (C -? - C-? o), alkoxycarbonylheterocycle (Cr C10), alkyl (C? -C10), alkylamino (CrC? 0), alkylaminocarbonyl (C? -C10) -alkyl (CC? o), alkylaminocarbonyl (C? -C? o) -alkylamino ( C? -C10), alkylaminocarbonylaminoyC Cio ^ alkoxyCTCo), alkylaminoheterocycle (CrC10), alkylcarbonylamino (CrC? O) -alkoxy (CrC? O), alkylcarbonylamino (C? -C? 0) -alkyl (CrC? O), alkylcarbonyllaminoiCi-CioJ-alkylaminoC-i-Cio), alkylcarbonylaminoheterocycleCyclo), alkylcarbonylheterocycleamino (C? -C10), alkylcarbonyloxy (C? -C? o) -alkylcarbonylamino (C -? - C? o) - alkoxy (C -? - C-? o), alkylcarbonyloxy (C? -C? o) -alkylcarbonylaminoheterocycle (CrC? o), alkylsulfonyl (CrC? o), alkylsulfonylamino (CrC? o) -alkoxy (C? -C10) ), alkylsulfonylamino (CrC? o) -alkyl (CrC10), alkylsulfonylamino (C? -C? 0) -alkylamino (CrC? o), alkylthio (C? -C10), amino-alkoxy (CrC? o), amino-alkyl (Cr C10), amino-alkylamino (CrC10), amino-alkylcarbonylaminoheterocycle (CrC? o), amino-alkylcarbonylheterocycle (CrC? o), aminocarbonyl-alkoxy (CrC? o), aminocarbonyl-alkyl (CrC? o), aminocarbonyl-alkylamino CrC io), aminocarbonyl-alkylheterocycle CrCTo), aminocarbonylamino-(C-? - C? o) alkoxy, aminocarbonylamino-alkylamino (CC? o), aminocarbonylaryl, aminocarbonyl-dialkylamino (CrC? o), aminocarbonylheterocycle, aminoheterocycle, aryl, carboxy-alkoxy (C? -C?), Carboxy-alkyl (C? -C10), carboxyryl, carboxydialkylamino (CrC? O), cycloalkyl (C -? - C10), dialkylamino (C? -C? O) -alkylaminoyCrCio ), dihydroxy-alkylamino (CrC? o), halo, halo-alkylsulfonyloxy (CrC10), haloaryl-alkylamino (CC? o), heteroaryl-alkoxycarbonylaminoheterocycle (C? -C10), heterocyclecarbonyl-alkylamine (C C10), heterocycle, hydrogen, hydroxy, hydroxy-alkoxy (C? -C? 0), hydroxy-alkylamino (CrC? O), hydroxy-alkylaminocarbonyl (C? -C? O) -alkoxy (C? -C? 0), hydroxy-alkylaminocarbonyl (CrC? O) -alkyl (CrC? O), hydroxy-alkylaminocarbonyl (C? -CioJ-alkylaminoicCTCio), hydroxy-alkylaminocarbonylamino (C? -C? O) -alkoxy (C? -C10), hydroxy-alkylaminoheterocycle (CrC? O), hydroxy-alkylcarbonylamino (C C10) -alkylamino (CrC? O), hydroxy-alkylcar bonylaminoheterocycle (C? -C? o), hydroxy-alkylcarbonylheterocycle (C? -C? o), hydroxy-alkylheterocycle (C C? o), and hydroxyheterocyclic; R2 is selected from the group consisting of alkyl (C -? - C? O), cycloalkyl (CrC? O) and hydrogen; R3 is selected from the group consisting of hydrogen, alkyl (C -? - C? O), alkoxy (CrC10) and halo; wherein each alkyl, wherever it occurs, is independently and optionally substituted with (C C 0) alkoxy, amino, carboxy, halo, and hydroxy; and RA, R4B, R4C, RD and R4E are each independently selected from the group consisting of alkylaminocarbonylamino- (CrC? o) -alkyl (C? -C? o), alkylarylheteroarylaminocarbonylamino (CrC? o) -alkyl (CrC? o) , amino-alkyl (CC? o), aryl-cycloalkylaminocarbonyl (CrC? o) -dialkylamino- (CrC? o) -alkyl (CrC10), aryl-cycloalkylaminocarbonylaminoyCrCioJ-alkyl-CrCTo), cyano, cycloalkylaminocarbonylamino- (CrC0) - alkyl- (CrC? o), cycloalkylaminocarbonyl-CrCtoJ-dialkylamino-CrCioy-Alkyl CrCio), halo, and hydrogen; wherein each aryl and heteroaryl, wherever they occur, are independently and optionally substituted by alkyl (C? -C? o). In another embodiment, R1 is selected from the group consisting of (C2-C8) alkenyl, alkoxycarbonyl (CrC8) -alkylamino (C? -8), alkoxycarbonylamino (CrC8) -alkoxy (C? -8), alkoxycarbonylaminoheterocycle ( C C8), alkoxycarbonylaryl (CrC8), alkoxycarbonylaryl (C? -C8) -alkyllamine (C -? - C8), alkoxycarbonylheterocycle (C? -C8), alkyl (C? -C8), alkylamino (CrC8), alkylaminocarbonyl (C? -C8) -alkyl- (C? -C8), alkylaminocarbonyl (C -? - C8) -alkylamino (C8), alkylaminocarbonyllamino (CrC8) - alkoxy- (C? -C8), alkylaminoheterocycle (CrC8), alkylcarbonylamino (C8-C8) -alkoxy (C? -8), alkylcarbonylamino (C8-C8) -alkyl- (CrC8), alkylcarbonylamino (C? -8) - alkylamino (C C8), alkylcarbonylaminoheterocycle (CrC8), alkylcarbonylheterocycloamino (C? -C8), alkylcarbonyloxy (C? -C8) -alkylcarbonyllarnno (C -? - C8) -alcoxy (C ? -C8), alkylcarbonyloxy (C? -C8) -alkylcarbonylaminoheterocycle (C -? - C8), alkylsulfonyl? D-Cß), alkylsulfonylamino (CrC8) -alkoxy (C? -8), alkylsulfonylamino (CrC8) -alkyl (C? -C8), alkylsulfonyl mino (CrC8) -alkylamino (CrC8), alkylthio (C? -C8), amino-alkoxy (CrC8), amino-alkyl (C -? - C8), amino-alkylamine (C8), amino-alkylcarbonylaminoheterocycle (CrC8) , amino-alkylcarbonylheterocycle-Cß), aminocarbonyl-alkoxy (CrC8), aminocarbonyl-alkyl (CrC8), aminocarbonyl-alkylamino (CrC8), aminocarbonyl-alkylheterocycle (CrC8), aminocarbonylamino-alkoxy (C? -8), aminocarbonylamino-alkylamino ( CrC8), aminocarbonylaryl, aminocarbonyl-dialkylamino (C? -8), aminocarbonylheterocycle, aminoheterocycle, aryl, carboxy-alkoxy (CrC8), carboxy-alkyl (C? -8), carboxyryl, carboxy-dialkylamino (C? -8), cycloalkyl (CrC8), dialkylamino (CrC8) -alkylamino (C? -8), dihydroxy-alkylamino (C? -8), halo, halo-alkylsulfonyloxy (CrC8), haloaryl-alkylamino (Cr C8), heteroaryl-alkoxycarbonyl-aminoheterocycle (C? -C8), heterocyclocarbonyl-alkylamino (C8), heterocycle, hydrogen, hydroxy, hydroxy-alkoxy (C? -8), hydroxy-alkylammon (C? -8), hydroxy-alkylaminocarbonyl (CrC8) - alkoxy (C? -C8), hydroxy-alqu ilamcarbonyl (CrC8) -alkyl (CrC8), hydroxy-alkylaminecarbonyl (CrC8) -alkylamino (C? -8), hydroxy-alkylaminocarbonylamino (CrC8) -alkoxy (C? -8), hydroxy-alkylaminoheterocycle (CrC8), hydroxy -alkylcarbonylamino (CrC8) -alkylamino (C? -C8), hydroxy-alkylcarbonyl-laminoheterocycle (CrC8), hydroxy-alkylcarbonylheterocycle (CrC8), hydroxy-alkylheterocycleCrCs), and hydroxyheterocyclic; R2 is selected from the group consisting of alkyl (C? -C8), cycloalkyl (d-C8) and hydrogen; R3 is selected from the group consisting of hydrogen, (C? -C8) alkyl, (C? -C8) alkoxy and halo; wherein each alkyl, wherever it occurs, is independently and optionally substituted with (d-C8) alkoxy, amino, carboxy, halo, and hydroxyloxy; and R4A, R4B, R4C, R4D and R4E are each independently selected from the group consisting of alkylaminocarbonylamino (CrC8) -alkyl (CrC8), alkylarylheteroarylaminocarbonyl amino (CrC8) -alkyl (CrC8), amino-alkyl (C8) , aryl-cycloalkylaminocarbonyl (C? -C8) -dialkylamino (CrC8) -alkyl (CrC8), aryl-cycloalkylaminocarbonylamino (CrC8) -alkyl (CrC8), cyano, cycloalkyl-lanecarbonyl (C -? - C8) -alkyl (CrC8), cycloalkylaminocarboni Ci-CßJ-dialkylaminoyCrCsJ-alkyloC-i-Cß), halo, and hydrogen; wherein each aryl and heteroaryl, wherever it occurs, is independently and optionally substituted with (d-C8) alkyl. In yet another embodiment, R1 is selected from the group consisting of (C2-C6) alkenyl, alkoxycarbonyl (CrC6) -alkylamino (C6-6), alkoxycarbonyl- (C6-C6) alkoxy ( d-C6), alkoxycarbonylaminoethane (C6), alkoxycarbonylamino (C -? - C6), alkoxycarbonylaryl (C? -C6) -alkylamino (C? -C6), alkoxycarbonylheterocycle (C? -C6), alkyl (C -? - C6), alkylaminoyCrCβ), alkylaminocarbonyl (C? -C6) -alkyl- (C? -C6), alkylaminocarbonyl (CrC6) -alkylamino (C? -C6), alkylaminocarbonylamino (d-? C6) -alkoxy- (CrC6), alkylaminoheterocycle (CrC6), alkylcarbonylamino (C? -C6) -alkoxy (C? -C6), alkylcarbonylamino (C? -C6) -alkyl- (C? -C6), alkylcarbonylamino (CrC6) -alkylamino (C? -C6), alkylcarbonylaminoheterocycle (C? -C6), alkylcarbonylheterocycleamino (C? -C6), alkylcarbonyloxy (C6) alkylcarbonyl (C? -C6) -alkoxy (C C6), alkylcarbonyloxy (CrC6) -alkylcarbonylaminoheterocycle (CrC6), alkylsulfonyloid-Cß), alkylsulfonylamino (C? -C6) -alkoxy (C? -C6), alkylsulfonylamine (CrC6) -alkyl (C C6) , alkylsulfonilami no (C? -C6) -alkylamino (C? -C6), alkylthio (C6), amino-alkoxy (Cr6), amino-alkyl (Cr6), amino-alkylamino (C6), amino-alkylcarbonylaminoheterocycle (C6) ), amino-alkylcarbonylheterocycle (d-C6), aminocarbonyl (C6) alkoxy, aminocarbonyl-alkyl (CrC6), aminocarbonyl-alkylamino (CrC6), aminocarbonyl-alkylheterocycle (CrC6), aminocarbonyl-amino-alkoxy ( CrC6), aminocarbonylamino-alkylaminoid-Ce), aminocarbonylaryl, aminocarbonyl-dialkylamino (C? -C6), aminocarbonylheterocycle, aminoheterocycle, aryl, carboxy-alkoxy d-C-), carboxy-alkyl (C? -C6), carboxyryl, carboxy- dialkylamino (C? -C6), cycloalkyl (CrC6), dialkylamino (C? -C6) -alkylamino (CrC6), dihydroxy-alkylamino (d-C6), halo, halo-alkylsulfonyloxy (C? -C6), haloaryl -alkylamino (Cr C6), heteroaryl-alkoxycarbonylaminoheterocycle (CrC6), heterocyclocarbonyl-alkyl-amino (CrC6), heterocyclic, hydrogen, hydroxy, hydroxy-alkoxy (C? -C6), hydroxy-alkylammon (CrC6), hydroxy-alkylaminocarbonyl (C? -C6) -alkoxy (CrC6), hydroxy-alkylamino nocarbon (CrC6) -alkyl (C? -C6), hydroxy-alkylaminocarbonyl (C? -C6) -alkylamino (C6), hydroxy-alkylaminocarbonylamino (C-? - C6) -alcoxy (C-? -C6), hydroxy-alkylaminoheterocycle (CrC6), hydroxy-alkylcarbonylamino (CrC6) -alkylaminoC C), hydroxy-alkylcarbonylaminoheterocycle (C? -C6), hydroxy-alkylcarbonylheterocycle (C? -C6), hydroxy-alkylheterocycle (C6), and hydroxyheterocycle; R2 is selected from the group consisting of alkyl (d-C6), cycloalkyl (C6-6) and hydrogen; R3 is selected from the group consisting of hydrogen, alkyl (C? -C6), alkoxy (C6) and halo; wherein each alkyl, wherever it occurs, is independently and optionally substituted with (C? -C6) alkoxy, amino, carboxy, halo and hydroxyl; and R4A, R4B, R4C, R4D and R4E are independently and optionally each selected from the group consisting of alkylaminocarbonylamino (CrC6) -alkyl (C? -C6), alkyl-1-heteroarylaminocarbonyl (CrC6) -alkyl (d-C6), amino-alkyl (d-Ce), aryl-cycloalkylaminocarboni CrCeJ-dialkylaminoyCrCei-alkylCi-Cß), aryl-cycloalkylaminocarbonylamino (C? -C6) -alkyl (CrC6), cyano, cycloalkylaminocarbonylamino ( C? -C6) -alkyl (C? -C6), cycloalkylaminocarboni CrCei-dialkylaminoyCrCeJ-alkylCyCr?), Halo, and hydrogen; wherein each aryl and heteroaryl, wherever they occur, is independently and optionally substituted with alkyl (d-C6). In another embodiment, R1 is selected from the group consisting of (C2-C6) alkenyl, (CrC6) alkyl, alkylamino (CrC6), alkylaminocarbonyl (C? -C6) -alkylamino (CrC6), alkylaminoheterocycle (C? -C6) , alkylcarbonylammonium (C? -C6) -alkoxy (C? -C6), alkylcarbonylamino (C? -C6) -alkylamino (CrC6), alkylcarbonylheterocycleamino (C? -C6), alkylsulfonylaminoyC CeJ-alkoxyCi-Ce), alkylsulfonylamine no (C? -C6) -alkyl (Cr C6), alkylsulfonylamine CrCeJ-alkylamino CrCe), alkylsulfonyl-lane (d-C6) alkylamino (CrC6), amino-alkylaminoid-Ce), amino-alkylcarbonylheterocycle-C?, aminocarbonyl-alkoxy (C? -C6), aminocarbonyl-alkylamino (CrC6), aminocarbonylamino-alkoxy (CrC6), aminocarbonylamino-alkylamino (CrC6), aminocarbonylaryl, aminocarbonylheterocycle, aminoheterocycle, aryl, dihydroxy-alkylamino (CrC6), haloaryl-alkylamino (d-C6), hydrogen, hydroxylalkoxy (C C6), hydroxyl-alkyl (CrC6), hydroxylalkylamino (d-C6), hydroxyl-alkylcarbonylamino (C? -C6) -alkyl Lamino (CrC6), hydroxyl-alkylheterocycle (C? -C6) and hydroxy? Alkylcarbonyllamino (C? -C6) alkylamine (d-cß). In another embodiment, R2 is alkyl (C C6). In another embodiment, R3 is halo. In another embodiment, R4A, R4B, R4C, R4D and R4E are each independently selected from the group consisting of hydrogen, halo and alkylaminocarbonylamino (CrC6) -alkyl (d-C6). In another embodiment, R2 is alkyl (C C6); R3 is halo; and R4A, R4B, R4C, R D and R4E are each independently selected from the group consisting of hydrogen, halo and alkylaminocarbonylamino (CrC6) -alkyl- (d-C6). In another embodiment, R1 is selected from the group consisting of alkylaminoheterocycle (CrC6), alkylcarbonylamino (C? -C6) -alkylaminoid-C?), Alkylsulfon-lamino (C? -C6) -alkoxy (CrC6), alkylsulfonylaminoid-C? J-alkylaminoyC- i-Ce), alkylsulfonylamino (C? -C6) -alkylamino-CrC?), aminocarbonyl-alkylamino (CrC6), aminocarbonylamino-d-C-alkoxy), aminocarbonylamino-alkylamino (d-C6), aminocarbonylheterocycle, dihydroxy-alkylamino (C? -C6), hydroxylalkylamino (dC6) and hydroxy-alkylcarbonylamino (C6C6) alkylamino (dC6). In another embodiment, R2 is alkyl (d-C6). In another embodiment, R3 is halo. In another embodiment, R4A, R4B, R4C, R4D and R4E are each independently selected from the group consisting of hydrogen and halo. In another embodiment, R2 is alkyl (d-C6); R3 is halo; and R A, R B, R 4 C, R 4 D and R 4 E are each independently and optionally selected from the group consisting of hydrogen and halo. In another embodiment, the compound is selected from the group consisting of N- [2- (. {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1, 6- dihydropyrimidin-2-yl.}. amino) ethyl] methanesulfonamide,? / - [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,? / - [3- (. {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] urea,? / - [3- ( { 5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2 -yl.}. amino) propyl] methane sulfonamide,? / - [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,? / ~ 3 ~ -. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -beta-alaninamide,? / - [2- ( { 5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] -2-hydroxyacetamide,? / - [3- (. {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1, 6- dihydropyrimidin-2-yl.}. amino) propyl] acetamide, N ~ 3 ~ -. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -beta-alaninamide, N ~ 2 ~ -. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} glycinamide,? / - [2- ( { 5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydroxypyridin-2- il.}. amino) etl] urea,? / - [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-dihydropyridin-2-yl.} amino) butanamide, 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -2-. { [(2S) -2,3-dihydroxypropyl] amine} -3-isopropylpyrimidin-4 (3H) -one, / - [2- (. {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1, 6- dihydropyrimidin-2-yl.}. Oxy) ethyl] methanesulfonamide,? / - [2- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo -1,6-dihydropyrimidin-2-yl.}. Amino) ethyl] urea,? / - [2- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1- isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] -2-hydroxyacetamide,? / - [2- (. {5-chloro-4 - [(2,4-difluorobenzyl) ) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] methanesulfonamide, 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,? / - [2- ( { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl.} oxi) etl] urea,? / - [3- ( { 5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-propyl-6-oxo-1,6-dihydropyrim din-2-yl.}. amino) propyl] -2-hydroxy-2-methylpropanamide, 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -2 - [(4-fluorobenzyl) amino] -3 -isopropylpyrimidin-4 (3H) -one,? / - [2- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1, 6-dihydropyrimidin-2-yl} amino) ethyl] acetamide, A / - [2- ( { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl .}. oxy) ethyl] methanesulfonamide, 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -2 - [(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] -3-isopropylpyrimidine trifluoroacetate -4 (3H) -one, 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -2 - [(2-hydroxy-2-methylpropyl) amino] -3-propsopyrimidin-4 (3H) -one , 1 -. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} prolinamide,? / - [2- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. ) ethyl] -2-hydroxy-2-methylpropanamide,? / - [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-iopropylpyrimidin-4 (3H) -one, N- (. { 5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} methyl) methanesulfonamide, trifluoroacetate of 2 - [(3R) -3-aminopyrrolidin-1-yl) -5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one, 2 - [(1-acetylpiperidine- 4-yl) amino] -5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-propsopyrimidin-4 (3H) -one, N ~ 2 ~ -. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N ~ 1 ~ -methylglycinamide,? / ~ 2 ~ -. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} glycineamide, A / - [2- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. oxi) 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'-ethylurea, 2- (3-aminopyrrolidin-1-yl) -5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-isopropyl-pyrimidin-4 trifluoroacetate ( 3H) -one, 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-isopropyl-pyridine-4 (3H) -one, 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -2 - [(3R) -3- (ethylamino) pyrrolidin-1-yl] -3-isopropylpyrimidn-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- trifluoroacetate 6 - [(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one, and 2-but-3-enyl-5-chloro-6 - [(2,4-difluorobenzyl) oxy] - 3-isopropylpyrimidin-4 (3H) -one, or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is selected from the group consisting of N- [2- (. {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1, 6- dihydropyrimidin-2-yl.}. amino) ethyl] methanesulfonamide,? / - [2- (. {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1 , 6-dihydropyrimidin-2-yl.}. Oxi) etl] urea, N ~ 2 ~ -. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -L-alaninamide,? / - [3- (. {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] urea,? / - [3- ( { 5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2 -yl.}. amino) propyl] methane sulfonamide,? / - [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,? / ~ 3 ~ -. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -beta-alaninamide,? / - [2- ( { 5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] -2-hydroxyacetamide,? / - [3- (. {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1, 6-dihydropyrimidin-2-yl.}. Amino) propyl] acetamide, N ~ 3 ~ -. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -beta-alaninamide, N ~ 2 ~ -. { 5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1, 6-dihydropyrimidin-2-yl} glycinamide,? / - [2- ( { 5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl .}. amino) ethyl] urea,? / - [2- (. {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1, 6- dihydropyridin-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,? / - [2- (. {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1 , 6-dihydropyrimidin-2-yl.} Oxy) ethyl] methanesulfonamide,? / - [2- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6 -oxo-1, 6-dihydropyrimidin-2-yl.}. amino) ethyl] urea,? / - [2- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1- isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl.}. amino) ethyl] -2-hydroxyacetamide,? / - [2- (. {5-chloro-4- [ (2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] methanesulfonamide, 5-bromo-6 - [(2,4- difluorobenzyl) oxy] -2-. { [(2R) -2,3-dihydroxypropyl] amino} -3-S-propylpyridin-4 (3H) -one, 1 -. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} prolynamide,? / - [2- ( { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl.} oxi) etl] urea,? / - [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-isopropylpyrimidin-4 (3H) -one, or a pharmaceutically acceptable salt thereof. In one embodiment, a pharmaceutical composition comprises a compound of Formula I and a pharmaceutically acceptable excipient. In one embodiment, a method for the treatment or prevention of an inflammatory disorder in a subject in need of such treatment or prevention, wherein the method comprises administering to the subject an amount of compound of Formula I in which the amount of the compound is effective for the treatment or prevention of inflammatory disorder. 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. This invention also relates to tautomers of such compounds as well as to salts (particularly pharmaceutically acceptable salts) of such compounds and tautomers. This invention also relates, in part, to a method of treating a condition mediated by pathological p38 kinase activity (particularly p38a activity) in a mammal. The method comprises administering a compound described above or pharmaceutically acceptable salt thereof, to the mammal in an amount that is therapeutically effective to treat the condition. This invention also relates, in part, to a method of treating a condition mediated by pathological TNF activity (particularly TNF-α activity) in a mammal. The method comprises administering a compound described above or pharmaceutically acceptable salt thereof, to the mammal in an amount that is therapeutically effective to treat the condition. This invention also relates, in part, to a method of treating a condition mediated by pathological cyclooxygenase-2 activity in a mammal. The method comprises administering a compound described above or pharmaceutically acceptable salt thereof, to the mammal in an amount that is therapeutically effective to treat the condition.
Compounds of This Invention Having One or More Asymmetric Carbons The present invention also comprises compounds of Formulas 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 diastereomeric, racemic, or optically active forms. All these forms are contemplated within the scope of this invention. More specifically, the present invention includes enantiomers, diastereomers, racemic mixtures, and other mixtures thereof.
Salts of the compounds of this invention The compounds of this invention can be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, a salt of the compound may be advantageous due to one or more of the physical properties of the salts, such as improved pharmaceutical stability at different temperatures and humidity, or a desirable solubility in water or oil. In some cases, a salt of a compound can also be used as an aid in the isolation, purification, and / or resolution of the compound. Where a salt is desired to be administered to a patient (as opposed to, for example, being used in an in vitro context), the salt is preferably pharmaceutically acceptable. Pharmaceutically acceptable salts include salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. In general, these salts can typically be prepared by conventional means with a compound of this invention by reacting, for example, the appropriate acid or base with the compound. Pharmaceutically acceptable acid addition salts of the compounds of this invention can be prepared from an inorganic or organic acid. Examples of suitable inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acid. Suitable organic acids generally include, for example, classes of organic acids aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic. Specific examples of suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid , mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, algenic acid, b-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, bisulfate, butyrate, camphorate, camphor sulfonate, cyclopentanepropionate, dodecyl sulfate, glycoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, 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 salts. Preferred metal salts include alkali metal salts (group a), alkaline earth metal salts (group lia), and other physiologically acceptable metal salts. Such salts can be made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. Preferred organic salts can be made from tertiary amines and quaternary amine salts, such as tromethamine, diethylamine, N, N'-dibenzylethylene diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. The basic groups containing nitrogen can be quatemized with agents such as lower alkyl halides (C Ce) (for example, chlorides, bromides, and methyl, ethyl, propyl, and butyl iodides), dialkyl sulfates (eg, sulfates) dimethyl, diethyl, dibutyl, and diamyl), long-chain halides (for example, chlorides, bromides, and decyl, lauryl, myristyl, and stearyl iodides), arylalkyl halides (for example, benzyl and phenethyl bromides), and others.
Treatment Conditions Using the compounds of this invention This invention relates, in part, to a method of treating a condition (typically a pathological condition) in mammals, such as humans, other primates (e.g., monkeys, chimpanzees, etc.). , companion animals (eg dogs, cats, horses, etc.), farm animals (eg, goats, sheep, pigs, cattle, etc.), laboratory animals (eg, mice, rats, etc.) .), and wild and zoo animals (eg, wolves, bears, deer, etc.) that have or are predisposed to have such a condition. In this specification, the phrase "treating a condition" means improving, suppressing, eradicating, reducing the severity of, decreasing the incidence frequency of, preventing, reducing the risk of, or delaying the onset of the condition. Some embodiments of this invention relate to a method for treating a condition mediated by p38. As used herein, the term "p38-mediated condition" refers to any condition (particularly pathological conditions, i.e., diseases and disorders) in which the p38 kinase (particularly p38a kinase) plays a role, either by p38 kinase control by itself, or by p38 kinase that causes the release of another factor, such as, for example, IL-1, IL-6, or IL-8. A morbid state in which, for example, IL-1 is a major component, and whose production or action was exacerbated or secreted in response to p38, should therefore be considered a p38 mediated disorder. The compounds of this invention are generally useful for treating pathological conditions including, but not limited to: (a) inflammation; (b) arthritis, such as rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, arthritis due to systemic lupus erythematosus, juvenile arthritis, osteoarthritis, and gouty arthritis; (c) neuroinflammation; (d) pain (ie, use of the compounds as analgesics), such as neuropathic pain; (e) fever (ie, use of the compounds as antipyretics); (f) pulmonary disorders or pulmonary inflammation, such as respiratory distress syndrome in adults, pulmonary sarcoidosis, asthma, silicosis, and chronic pulmonary inflammatory disease; (g) cardiovascular diseases, such as atherosclerosis, myocardial infarction (such as indications after myocardial infarction), thrombosis, congestive heart failure, cardiac damage by reperfusion, and complications associated with hypertension and / or cardiac arrest such as organ damage vascular; (h) cardiomyopathy; (i) stroke, such as ischemic and hemorrhagic stroke; (j) ischemia, such as cerebral ischemia and ischemia resulting from cardiac / coronary bypass; (k) reperfusion damage; (I) kidney damage by reperfusion; (m) cerebral edema; (n) neurotrauma and brain trauma, such as closed head injury; (o) neurodegenerative disorders; (p) disorders of the central nervous system (these include, for example, disorders that have an inflammatory or apoptotic component), such as Alzheimer's disease, Parkinson's disease, Huntington, amyotrophic lateral sclerosis, damage to the spinal cord, and peripheral neuropathy; (q) liver disease and nephritis; (r) gastrointestinal conditions, such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, and ulcerative colitis; (s) ulcerative diseases, such as gastric ulcer; (t) ophthalmic diseases, such as retinitis, retinopathies (such as diabetic retinopathy), uveitis, ocular photophobia, non-glaucomatous optic nerve atrophy, and age-related macular degeneration (ARMD) (such as atrophic form of ARMD); (u) ophthalmological conditions, such as rejection of cornea graft, ocular neovascularization, retinal neovascularization (such as neovascularization after wound or infection), and retrolental fibroplasia; (v) glaucoma, such as primary open-angle glaucoma (POAG), primary open angle glaucoma of juvenile onset, angle-closure glaucoma, pseudoexfoliative glaucoma, anterior ischemic optic neuropathy (AION), ocular hypertension, Reiger syndrome, glaucoma of normal tension, neovascular glaucoma, ocular inflammation, and corticosteroid-induced glaucoma; (w) acute damage to ocular tissue and ocular traumatisms, such as posttraumatic glaucoma, optic traumatic neuropathy, and central retinal artery occlusion (CRAO); (x) diabetes; (and) diabetic nephropathy; (z) skin-related conditions, such as psoriasis, eczema, burns, dermatitis, keloid formation, scar tissue formation, and angiogenic disorders; (aa) bacterial and viral infections, such as sepsis, septic shock, gram-negative sepsis, malaria, meningitis, opportunistic infections, cachexia secondary to infection or malignancy, cachexia secondary to acquired immunodeficiency syndrome (AIDS), AIDS, ARC (related complex with AIDS), pneumonia, and herpes virus; (bb) myalgias due to infection; (cc) influenza; (dd) endotoxic shock; (ee) toxic shock syndrome; (ff) autoimmune disease, such as graft versus host reaction and allograft rejections; (gg) bone resorption diseases, such as osteoporosis; (hh) multiple sclerosis; (I) disorders of the female reproductive system, such as endometriosis; (jj) pathological, but not malignant, conditions such as hemangiomas such as infantile hemangiomas), angiofibroma of the nasopharynx, and avascular bone necrosis; (kk) benign and malignant tumors / neoplasm including cancer, such as colorectal cancer, brain cancer, bone cancer, neoplasia derived from epithelial cells (epithelial carcinoma) such as basal cell carcinoma, adenocarcinoma, gastrointestinal cancer such as lip cancer , oral cancer, esophageal cancer, small bowel cancer and stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, skin cancer such as squamous cell cancers and basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that affect epithelial cells throughout the body; (II) leukemia; (mm) lymphoma, such as B-cell lymphoma; (nn) systemic lupus erythematosus (SLE); (oo) angiogenesis that includes neoplasia; and (pp) metastasis. The compounds of this invention are generally also useful for treating pathological conditions including, but not limited to: (a) asthma of any type, etiology, or pathogenesis, in particular asthma which is a member selected from the group consisting of atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, authentic asthma, intrinsic asthma caused by pathophysiological alterations, extrinsic asthma caused by environmental factors, essential asthma of unknown or non-patent cause, non-atopic asthma, bronchitic asthma, emphysematous asthma, exercise-induced asthma, allergen-induced asthma, cold air-induced asthma, occupational asthma, infectious asthma caused by bacterial, fungal, protozoal, or viral infection, non-allergic asthma, incipient asthma, childhood wheezing and bronchiolitis; (b) chronic or acute bronchoconstriction, chronic bronchitis, small airway obstruction, and emphysema; (c) obstructive or inflammatory respiratory diseases of any type, etiology, or pathogenesis, in particular an obstructive or inflammatory airway disease that is a member selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD) ), COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated or not associated with COPD, COPD characterized by irreversible, progressive airway obstruction, adult respiratory distress syndrome (ARDS), exacerbation of airway hyperreactivity consequential to other drug therapy and airway disease that is associated with pulmonary hypertension; (d) bronchitis of any type, etiology, or pathogenesis, in particular bronchitis which is a member selected from the group consisting of acute bronchitis, acute laryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, crupal bronchitis, dry bronchitis, asthmatic infectious bronchitis, productive bronchitis , staphylococcal or streptococcal bronchitis and vesicular bronchitis; (e) acute lung damage; and (f) bronchiectasis of any type, etiology, or pathogenesis, particularly bronchiectasis which is a member selected from the group consisting of cylindrical bronchiectasis, saccular bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis, and follicular bronchiectasis. The compounds of this invention are generally also useful in treating obstructive or inflammatory airway diseases of any type, etiology, or pathogenesis, in particular an obstructive or inflammatory airway disease that is a member selected from the group consisting of eosinophilic pneumonia. chronic, chronic obstructive pulmonary disease (COPD), COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated or not associated with COPD, COPD characterized by irreversible, progressive airway obstruction, progressive adult respiratory distress syndrome (ARDS) , exacerbation of hyperreactivity of the respiratory tract resulting from other drug therapy and respiratory tract disease that is associated with pulmonary hypertension; Some embodiments of this invention are referred alternatively (or optionally) to a method for treating a condition mediated by TNF. As used herein, the term "TNF-mediated condition" refers to any condition (particularly any pathological conditions, i.e., diseases or disorders) in which TNF plays a role, either by controlling TNF by itself, or by TNF which causes another monoquin to be released, such as, for example, IL-1 , IL-6, and / or IL-8. A morbid condition in which, for example, IL-1 is a major component, and whose production or action was exacerbated or secreted in response to TNF, should therefore be considered a disorder mediated by TNF. Examples of TNF-mediated conditions include inflammation (e.g., rheumatoid arthritis), autoimmune disease, graft rejection, multiple sclerosis, a fibrotic disease, cancer, an infectious disease (e.g., malaria, mycobacterial infection, meningitis, etc.), fever, psoriasis, cardiovascular disease (eg, post-ischemic reperfusion injury and congestive heart failure), lung disease, hemorrhage, coagulation, hyperoxic alveolar damage, radiation damage, acute phase responses such as those seen with infections and sepsis and during shock (for example, septic shock, hemodynamic shock, etc.), cachexia, and anorexia. Such conditions also include infectious diseases. Such infectious diseases include, for example, malaria, mycobacterial infection and meningitis. Such infectious diseases also include viral infections, such as HIV, influenza virus, and herpes virus, which includes herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and rhinotracheitis, among others. As TNF-ß has close structural homology with TNF-α (also known as cachectin), and because each induces similar biological responses and binds to the same cell receptor, the synthesis of both TNF-α and TNF-α β is inhibited by the compounds of this invention and is referred to herein as "TNF" unless specifically outlined otherwise. Some embodiments of this invention are referred alternatively (or additionally) to a method for treating a condition mediated by cyclooxygenase-2. As used herein, the term "cyclooxygenase-2 mediated condition" refers to any condition (particularly pathological conditions, i.e., diseases and disorders) in which cyclooxygenase-2 plays a role, either by controlling cyclooxygenase-2 itself, or by cyclo-oxygenase-2 causing another factor to be released. Many conditions mediated by cyclooxygenase-2 are known in the art and include, for example, inflammation and other disorders mediated by cyclooxygenase listed by Carter et al. in U.S. Patent No.:6,271,253. In some embodiments of particular interest, the condition treated by the methods of this invention comprises inflammation. In some embodiments of particular interest, the condition treated by the methods of this invention comprises arthritis. In some embodiments of particular interest, the condition treated by the methods of this invention comprises rheumatoid arthritis. In some embodiments of particular interest, the condition treated by the methods of this invention comprises asthma. In some embodiments of particular interest, the condition treated by the methods of this invention comprises a coronary condition. In some embodiments of particular interest, the condition treated by the methods of this invention comprises bone loss. In some embodiments of particular interest, the condition treated by the methods of this invention comprises B-cell lymphoma. In some embodiments of particular interest, the condition treated by the methods of this invention comprises COPD. The compounds of the invention can also be used in the treatment of a TNF-mediated disease such as airway inflammation induced by smoking, cough enhanced by inflammation, for the control of myogenesis, to treat mucin overproduction, and / or for to treat overgrowth of mucus. 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 invention can also be used as a combination with one or more additional therapeutic agents to co-administer to a patient to obtain some particularly desired therapeutic end result such as the treatment of pathophysiologically morbid processes. relevant including, but not limited to (i) bronchoconstriction, (ii) inflammation, (iii) allergy, (iv) tissue destruction, (v) signs and symptoms such as dyspnea, cough. The second additional therapeutic agent and additional additional therapeutic agents may also be a compound of the invention, or one or more P38 and / or TNF inhibitors known in the art. More typically, the second therapeutic agent and more therapeutic agents will be selected from a different class of therapeutic agents. As used herein, the terms "co-administration", "co-administered" and "in combination with", which refer to the compounds of the invention and one or more other therapeutic agents, are intended to mean, and refer to, include the following: (a) concurrent administration of such combination of compound (s) of the invention and therapeutic agent (s) to a patient in need of treatment, when such components are formulated together within an individual dosage form which releases said components substantially at the same time to said patient, (b) substantially simultaneous administration of such combination of compound (s) of the invention and therapeutic agent (s) to a patient in need of treatment, when such components they are formulated separately from each other within separate dosage forms which are taken substantially at the same time by said patient, after which said components are substantially released at the same time to said patient, (c) sequential administration of such combination compound (s) of the invention and therapeutic agent (s) to a patient in need of treatment, when such components are formulated apart from each other within separate dosage forms which are taken at consecutive times by said patient with a significant time interval between each administration, after which said components are substantially released at different times to said patient; and (d) sequentially administering such combination of compound (s) of the invention and therapeutic agent (s) to a patient in need of treatment, when such components are formulated together within an individual dosage form which releases said components in a controlled form after which they are administered concurrently, consecutively, and / or overlapping at the same time and / or at different times by said patient, where each part can be administered either by the same route or by different routes. Suitable examples of different therapeutic agents which can be used in combination with the compound (s) of the invention, or pharmaceutically acceptable salts, solvates or compositions thereof, include, but are not by any means limited to: (a) ) 5-lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists, (b) leukotriene antagonists (LTRA) including LTB4, LTC4, LTD4, and LTE4 antagonists, (c) antagonists of the histamine receptor including H1 and H3 antagonists, (d) sympathomimetic agents, vasoconstrictors, adrenoceptor agonists a * and adrenoreceptor a 2 for decongestant use, (e) M3 muscarinic receptor antagonists or anticholinergic agents, (f) PDE inhibitors , for example inhibitors of PDE3, PDE4 and PDE5, (g) theophylline, (h) sodium cromoglycate, (i) inhibitors of COX inhibitors of COX-1 or COX-2 both non-selective and selective (NSAID), (j) glucoc Oral and inhaled orthicosteroids, such as DAGR (corticosteroid receptor dissociated agonists) (k) monoclonal antibodies active against endogenous inflammatory entities, (I) β2 agonists (m) inhibitors of adhesion molecules including VLA-4 antagonists, (n) ) antagonists of Bi and B2 receptors of quinines, (or) immunosuppressive agents, (p) inhibitors of matrix metalloproteases (MMP), (q) antagonists of NK-? NK2 and NK3 receptors of tachykinin, (r) elastase inhibitors, adenosine A2a receptor agonists, (t) urokinase inhibitors, (u) compounds that act on dopamine receptors, for example D2 agonists, (v) modulators of the NFi pathway β, for example IKK inhibitors, (w) modulators of cytokine signaling pathways such as inhibitors of syk kinase, or JAK kinase, (x) agents that can be classified as mucolytic or antitussive, (and) antibiotics, (z) ) inhibitors of HDAC (histone deacetylase), and (aa) PI3 kinase inhibitors. According to an embodiment of the present invention, a combination of the compounds of the invention can be used with: - H3 antagonists, - M3 muscarinic receptor antagonists, - PDE4 inhibitors, - glucocorticosteroids, - adenosine A2a receptor agonists , - β2 agonists - modulators of cytokine signaling pathways such as syk kinase, or, - leukotriene antagonists (LTRA) including antagonists of LTB4, LTC4, LTD4, and LTE4. According to an embodiment of the present invention, a combination of the compounds of the invention with: -glucocorticosteroids, in particular inhaled glucocorticosteroids with reduced systemic side effects, including prednisone, prednisolone, flunisolide, triamcinolone acetonide, dipropionate beclomethasone, budesonide, fluticasone propionate, ciclesonide, and mometasone furoate, M3 muscarinic receptor antagonists or anticholinergic agents including, in particular, ipratropium salts, namely bromide, tiotropium salts, namely bromide, oxitropium salts, viz. bromide, perenzepine, and telenzepine, -or p2 agonists. A wide variety of methods can be used alone or in combination 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. Typically, a compound described herein is administered in an amount effective to inhibit p38 kinase (particularly p38a kinase), TNF (particularly TNF-a), and / or cyclooxygenase (particularly cyclooxygenase-2). The preferred total daily dose of the compound (administered in single or divided doses) is typically from about 0.01 to about 100 mg / kg, more preferably from about 0.1 to about 50 mg / kg, and even more preferably from about 0.5 to about 30 mg / kg (ie, mg of compound per kg of body weight). Dosage unit compositions may contain such amounts or submultiples thereof to prepare the daily dose. In many cases, the administration of the compound will be repeated a plurality of times in a day (typically not more than 4 times). Multiple daily doses may typically be used to increase the total daily dose, if desired. Factors that affect the preferred dosage regimen include the type, age, weight, sex, diet, and condition of the patient; the severity of the pathological condition; the route of administration; pharmacological considerations, such as the activity, efficacy, pharmacokinetics, and toxicology profiles of the particular compound employed; if a drug delivery system is used; and if the compound is administered as part of a combination of drugs. Thus, the dosage regimen actually employed may vary widely, and, therefore, may deviate from the preferred dosage regimen set forth above. The present compounds can be used in cotherapies, partially or completely, in place of other conventional anti-inflammatories, such as in conjunction with spheroids, cyclooxygenase-2 inhibitors, non-steroidal anti-inflammatory drugs ("NSAID"), disease modifying antirheumatic drugs ("DMARD "), immunosuppressive agents, 5-lipooxygenase inhibitors, leukotriene B4 (" LTB4") antagonists, and leukotriene A4 hydrolase inhibitors (" LTA4").
Paceutical Compositions Containing the Compounds of this Invention This invention also relates to paceutical compositions (or "medicaments") comprising the compounds described above (which include tautomers of the compounds, and paceutically acceptable salts of the compounds and tautomers), and to for manufacturing paceutical compositions comprising those compounds in combination with one or more carriers, diluents, wetting or suspending agents, vehicles, and / or adjuvants (carriers, diluents, wetting or suspending agents, vehicles, and / or coadjuvants sometimes collectively referred to in this specification as "conveyor materials"); and / or other conventional non-toxic, paceutically acceptable active ingredients. The preferred composition depends on the method of administration. Drug formulation is discussed generally in, for example, Hoover, John E., Remington's Paceutical Sciences (Mack Publishing Co., Easton, PA: 1975) (incorporated by reference within this specification). See also, Liberman, H.A., Lachman, L., eds., Paceutical Dosage Forms (Marcel Decker, New York, N.Y., 1980) (incorporated by reference within this specification). In many preferred embodiments, the paceutical composition is manufactured in the form of a dosage unit containing a particular amount of the active ingredient. Typically, the paceutical composition contains from about 0.1 to 1000 mg (and more typically, from 7.0 to 350 mg) of the compound. Solid dosage forms for oral administration include, for example, or soft capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds are usually combined with one or more adjuvants. If administered orally, the compounds can be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone, and / or poly (vinyl alcohol), and then compressed or encapsulated for convenient administration. Such capsules or tablets may contain a controlled release formulation, as may be provided in a dispersion of the compound of this invention in hydroxypropylmethylcellulose. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents, such as sodium citrate, or magnesium or calcium carbonate or bicarbonate. Tablets and pills can also be prepared with enteric coatings. Liquid dosage forms for oral administration include, for example, paceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art (eg, water). Such compositions may also comprise adjuvants, such as wetting, emulsifying, suspending, flavoring agents (for example, sweeteners), and / or perfuming agents. "Parenteral administration" includes subcutaneous injections, intravenous injections, intramuscular injections, intrasternal injections, and infusion. Injectable preparations (e.g., sterile injectable aqueous or oleaginous suspensions) can be formulated according to the known art using suitable dispersing, wetting, and / or suspending agents. Acceptable carrier materials include, for example, water, 1,3-butanediol, Ringer's solution, isotonic sodium chloride solution, soft fixed oils (for example, synthetic mono or diglycerides), dextrose, mannitol, fatty acids (e.g. , oleic acid), dimethylacetamide, surfactants (for example, ionic and non-ionic detergents), and / or polyethylene glycols (for example, PEG 400). Formulations for parenteral administration can, for example, be prepared from sterile powders or granules having one or more carrier materials mentioned for use in formulations for oral administration. 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, if necessary, with an appropriate acid, base, or buffer. The compounds of this invention preferably comprise from about 0.075 to about 30% (w / w) (more preferably from 0.2 to 20% (w / w), and even more preferably from 0.4 to 15% (w / w)) of a pharmaceutical composition used for rectal or topical administration. The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry mixture with lactose, or as a mixed component particle, for example , mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, sprayer, atomizer (preferably an atomizer that uses electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1, 1, 1, 2-tetrafluoroethane or 1,1,1,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin. The pressurized container, pump, sprayer, atomizer, or nebulizer contains a solution or suspension of the compound (s) of the invention comprising, for example, ethanol, aqueous ethanol, or an alternative agent suitable for dispersing, solubilizing, or extending the release of the active ingredient, a propellant (s) as a solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid. Before use in a dry powder or suspension formulation, the drug product is micronized to a suitable size for administration by inhalation (typically less than 5 microns). This can be achieved by any suitable spraying process, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying. Capsules (made, for example, of gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mixture of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the monohydrate form, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. A solution formulation suitable for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1 μg to 20 mg of the compound of the invention per actuation and the volume of the actuation 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. Alternative solvents which can be used instead of propylene glycol include glycerol and polyethylene glycol. Suitable flavors, such as menthol and levomenthol, or sweeteners, such as saccharin or sodium saccharin, can be added to those formulations of the invention desired for inhaled / intranasal administration. Formulations for inhaled / intranasal administration can be formulated to be released immediately and / or modified using, for example, PGLA. Modified release formulations include delayed, maintained, pulsed, controlled, directed and programmed release. In the case of inhalers and dry powder aerosols, the dosage unit is determined by means of a valve which administers a measured quantity. The units according to the invention are typically arranged to deliver a metered dose or "puff" containing from 0.001 mg to 10 mg of the compound of the invention. The overall daily dose will typically be in the range of 0.001 mg to 40 mg which may be administered in a single dose, or, more usually, as divided doses throughout the day. Suppositories for rectal administration can be prepared, for example, by mixing a compound of this invention with a suitable non-irritating excipient which is solid at ordinary temperatures, but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, such as cocoa butter; mono-, di or synthetic triglycerides; fatty acids; and / or polyethylene glycols. "Topical administration" includes transdermal administration, such as by transdermal patches or iontophoretic devices. Compositions for topical administration also include, for example, gels, sprays, ointments, and topical creams. When formulated in an ointment, the compounds of this invention can be employed with, for example, either a paraffinic ointment base or a water miscible ointment base. When formulated in a cream, the active ingredient (s) can be formulated with, for example, an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least about 30% (w / w) of a polyhydric alcohol, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol, and mixtures thereof. A topical formulation can include a compound which enhances the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethisulfoxide and related analogs. When the compounds of this invention are administered by a transdermal device, administration will be carried out using a patch either of the reservoir and porous membrane type or of a variety of solid matrix. In any case, the active agent is continuously administered from the reservoir or the microcapsules through a membrane inside the adhesive permeable to the active agent, which is in contact with the skin or mucosa of the receptor. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent can also function as the membrane. The transdermal patch can include the compound in a suitable solvent system with an adhesive system, such as an acrylic emulsion, and a polyester patch. The oily phase of the emulsions of this invention can be constituted from known ingredients in a known manner. While the phase may simply comprise an emulsifier, it may comprise, for example, a mixture of at least one emulsifier with a fat or an oil or both a fat and an oil. Preferably, a hydrophilic emulsifier is included in conjunction with a lipophilic emulsifier which acts as a stabilizer. It is also preferable to include both an oil and a fat. Together, the emulsifier (s) with or without stabilizer (s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others. The choice of oils or fats suitable for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most of the oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with adequate consistency to avoid leakage of tubes or other containers. For example, straight or branched chain mono- or dibasic alkyl esters such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate can be used, for example. , 2-ethylhexyl palmitate or a mixture of branched chain esters. 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 in which the compound of this invention is dissolved or suspended in a suitable carrier, typically comprising an aqueous solvent. The compounds of this invention are preferably present in such formulations in a concentration of about 0.5 to about 20% (w / w) (more preferably 0.5 to 10% (w / w), and often even more preferably about 1.5. % (p / p)). Other carrier materials and modes of administration known in the pharmaceutical art can also be used.
Definitions The term "alkyl" (alone or in combination with other term (s)) means a straight or branched chain saturated hydrocarbon substituent (i.e., a substituent containing only carbon and hydrogen) typically containing from 1 to about 20 carbon atoms, more typically from 1 to about 12 carbon atoms, even more typically from 1 to about 8 carbon atoms, and even more typically from 1 to about 6 carbon atoms. Examples of such substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, and octyl. The term "alkenyl" (alone or in combination with other term (s)) means a straight or branched chain hydrocarbon substituent containing one or more double bonds and typically from 2 to about 20 carbon atoms, more typically from 2 to about 12 carbon atoms, even more typically from 2 to about 8 carbon atoms, and even more typically from 2 to about 6 carbon atoms. Examples of such substituents include ethenyl (vinyl); 2-propenyl; 3-propenyl; 1,4-pentadienyl; 1,4-butadienyl; 1 -butenyl; 2-butenyl; 3-butenyl; and decenílo. The term "alkynyl" (alone or in combination with another term (s)) means a straight or branched chain hydrocarbon substituent containing one or more triple bonds and typically from 2 to about 20 carbon atoms, more typically from 2 to about 12 carbon atoms, even more typically from 2 to about 8 carbon atoms, and even more typically from 2 to about 6 carbon atoms. 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 (s)) means a saturated carbocyclic substituent containing from 3 to about 14 carbon ring atoms, more typically from 3 to about 12 ring atoms. carbon, and even more typically from 3 to about 8 carbon ring atoms. A cycloalkyl can be an individual carbon ring, which typically contains from 3 to 6 carbon ring atoms. Examples of individual ring cycloalkyls include cyclopropyl (or "cyclopropanyl"), cyclobutyl (or "cyclobutanyl"), cyclopentyl (or "cyclopentanyl"), and cyclohexyl (or "cyclohexanyl"). A cycloalkyl may alternatively be 2 or 3 carbon rings fused together, such as, for example, decalinyl or norpyranyl. The term "cycloalkylalkyl" (alone or in combination with other term (s)) means alkyl substituted with 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 from 6 to 14 carbon ring atoms. Examples of aryls include phenyl, naphthalenyl, and indenyl. In some cases, the number of carbon atoms in a hydrocarbon substituent (eg, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, etc.) is indicated by the suffix "Cx-Cy-", wherein x is the minimum number e and is the maximum number of carbon atoms in the substituent. Thus, for example, "(d-C6) alkyl" refers to an alkyl substituent containing from 1 to 6 carbon atoms. Further illustrating, (C3-C6) cycloalkyl means a saturated carbocyclyl containing from 3 to 6 carbon ring atoms. The term "arylalkyl" (alone or in combination with other term (s)) means alkyl substituted with aryl. The term "benzyl" (alone or in combination with another term (s)) means a methyl radical substituted with phenyl, that is, the following structure: The term "benzene" means the following structure: The term "hydrogen" (alone or in combination with another term (s)) means a hydrogen radical, and can be represented as -H. The term "hydroxy" or "hydroxyl" (alone or in combination with other term (s)) means -OH. The term "hydroxyalkyl" (alone or in combination with other term (s)) means alkyl substituted with one or more hydroxy. The term "nitro" (alone or in combination with other term (s)) means -NO2. The term "cyano" (alone or in combination with another term (s)) means -CN, which can also be represented: N C 'VUV, The term "keto" (alone or in combination with another term (s)) means an oxo radical, and can be represented as = O. The term "carboxy" or "carboxyl" (alone or in combination with another term (s)) means -C (O) -OH, which may also be represented as: The term "amino" (alone or in combination with another term (s)) means -NH2. The term "monosubstituted amino" (alone or in combination with another term (s)) means an amino substituent in which one of the hydrogen radicals is replaced by a substituent other than hydrogen. The term "disubstituted amino" (alone or in combination with another term (s)) means an amino substituent in which both hydrogen atoms are replaced by substituents other than hydrogen, which may be identical or different. The term "halogen" (alone or in combination with another term (s)) means a fluorine radical (which can be represented as -F), chlorine radical (which can be represented as -Cl) , bromine radical (which can be represented as -Br), or iodine radical (which can be represented as -I). Typically, a fluorine radical or chlorine radical is preferred, a fluorine radical 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 radicals. For example, haloalkyl means an alkyl substituent in which at least one hydrogen radical is replaced by a halogen radical. When there is more than one hydrogen replaced by halogens, the halogens may be identical or different. Examples of haloalkyl include chloromethyl, dichloromethyl, difluorochloromethyl, dichlorofluoromethyl, trichloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-trifluoroethyl, difluoroethyl, pentafluoroethyl, difluoropropyl, dichloropropyl, and heptafluoropropyl. Further illustrating, "haloalkoxy" means an alkoxy substituent in which at least one hydrogen radical is replaced by a halogen radical. Examples of haloalkoxy substituents include chloromethoxy, 1-bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as "perfluoromethyloxy"), and 1,1,1-trifluoroethoxy. It should be recognized that if a substituent is substituted with more than one halogen radical, those halogen radicals may be identical or different (unless otherwise indicated). The prefix "perhalo" indicates that each hydrogen radical in the substituent to which the prefix is attached is replaced by an independently selected halogen radical. If all the halogen radicals are identical, the prefix can identify the halogen radical. Thus, for example, the term "perfluoro" means that each hydrogen radical in the substituent to which the prefix is attached is substituted with a fluoro radical. To illustrate, the term "perfluoroalkyl" means an alkyl substituent in which a fluoro radical is in the place of each hydrogen radical. Examples of perfluoroalkyl substituents include trifluoromethyl (-CF3), polyfluoro butyl, perfluoroisopropyl, perfluorododecyl, and perfluorodecyl. To further illustrate, the term "perfluoroalkoxy" means an alkoxy substituent in which each hydrogen radical is replaced by a fluorine radical.
Examples of perfluoroalkoxy substituents include trifluoromethoxy (-0-CF3), perfluorobutoxy, perfluoroisopropoxy, perfluorododecoxy, and perfluorodecoxy. The term "carbonyl" (alone or in combination with another term (s)) means -C (O) -, which can also be represented as: This term is also intended to encompass a carbonyl substituent hydrate, i.e., -C (OH) 2-. The term "aminocarbonyl" (alone or in combination with another term (s)) means -C (O) -NH2, which may also be represented as: The term "oxy" (alone or in combination with another term (s)) means an ether substituent, and can 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 a substituent include methoxy (-O-CH 3), ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy. The term "alkylthio" (alone or in combination with other term (s)) means -S-alkyl. For example, "methylthio" is -S-CH3. Other examples of alkylthio substituents include ethylthio, propylthio, butylthio, and hexylthio. The term "alkylcarbonyl" or "alkanoyl" (alone or in combination with other term (s)) means -C (O) -alkyl. For example, "ethylcarbonyl" can be represented as: Examples of other preferred alkylcarbonyl substituents often include methylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcarbonyl, and hexylcarbonyl. The term "aminoalkylcarbonyl" (alone or in combination with other term (s)) means -C (O) -alkyl-NH2. For example, "aminomethylcarbonyl" can be represented as: The term "alkoxycarbonyl" (alone or in combination with other term (s)) means -C (O) -O-alkyl. For example, "ethoxycarbonyl" can be represented as: Examples of other preferred alkoxycarbonyl substituents often include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, and hexyloxycarbonyl.
The term "carbocyclylcarbonyl" (alone or in combination with other term (s)) means -C (O) -carbocyclyl. For example, "phenylcarbonyl" can be represented as: Similarly, the term "heterocyclylcarbonyl" (alone or in combination with other term (s)) means -C (O) -heterocyclyl. The term "carbocyclylalkylcarbonyl" (alone or in combination with other term (s)) means -C (O) -alkylcarbocyclyl. For example, "phenylethylcarbonyl" can be represented as: Similarly, the term "heterocyclylalkylcarbonyl" (alone or in combination with other term (s)) means -C (O) -alkyl-heterocyclyl. The term "carbocyclyloxycarbonyl" (alone or in combination with other term (s)) means -C (O) -O-carbocyclyl. For example, "phenyloxycarbonyl" can be represented as: The term "carbocyclylalcoxycarbonyl" (alone or in combination with other term (s)) means -C (O) -O-alkylcarbocyclic. For example, "phenylethoxycarbonyl" can be represented as: The term "thio" or "tia" (alone or in combination with other term (s)) means a thioether substituent, ie, an ether substituent in which a divalent sulfur atom is in the atom's place of ether oxygen. Such a substituent can be represented as -S-. This, for example, "alkylthio-alkyl" means alkyl-S-alkyl. The term "thiol" (alone or in combination with another term (s)) means a sulfhydryl substituent, and may be represented as -SH. The term "sulfonyl" (alone or in combination with another term (s)) means -S (O) 2-, which may also be represented as: 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-NH2, which may also be represented as: The term "sulfinyl" or "sulfoxide" (alone or in combination with another term (s)) means -S (O) -, which may also be represented as: Thus, for example, "alkylsulfinylalkyl" or "alkylsulfoxy-alkyl" means alkyl-S (O) -alkyl. Typically preferred alkylsulfinyl groups include methylisulfinyl, ethylisulfinyl, butylsulfinyl, and hexylulfinyl. The term "heterocyclyl" (alone or in combination with other term (s)) means a saturated (i.e., "heterocycloalkyl"), partially saturated (i.e., "heterocycloalkenyl"), or completely unsaturated ring structure. (ie "heteroaryl") containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being selected independently from the group consisting of carbon, oxygen, nitrogen, and sulfur. A heterocyclyl can be a single ring, which typically contains from 3 to 7 ring atoms, more typically from 3 to 6 ring atoms, and even more typically from 5 to 6 ring atoms. Examples of single ring heterocyclyls include furanyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl (also known as "thiofuranyl"), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, prazrazolinyl, pyrazolidin, triazolyl. , tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazolyl (including 1,3-oxadiazolyl, 1,4-oxadiazolyl (also known as "azoximyl"), 1, 2,5-oxadiazolyl (also known as "furazanyl"), or 1,3,4-oxadiazolyl), oxatriazolyl (including 1, 2,3,4-oxatriazolyl or 1, 2,3 , 5-oxatriazolyl), dioxazolyl (including 1,3-dioxazolyl, 1,4-dioxazolyl, 1,2-dioxazolyl, or 1,3-dioxazolyl), oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl (which includes 1,2-pyranyl or 1,4-pir) anyl), dihydropyranyl, pyridinyl (also known as "azinyl"), piperidinyl, diazinyl (which includes pyridazinyl (also known as "1,2-diazinyl"), pyrimidinyl (also known as "1,3-diazinyl" or "pyrimidyl"). "), or pyrazinyl (also known as" 1,4-diazinyl ")), piperazinyl, triazinyl (which includes s-triazinyl (also known as" 1, 3,5-triazinyl "), as-triazinyl (also known as 1, 2,4-triazinyl), and v-triazinyl (also known as "1, 2,3-triazinyl")), oxazinyl (including 1,3-oxazinyl, 1,2-oxazinyl, 1 , 3,6-oxazinyl (also known as "pentoxazolyl"), 1, 2,6-oxazinyl, or 1,4-oxazinyl), isoxazinyl (including o-isoxazinyl or p-isoxazinyl), oxazolidinyl, isoxazolidinyl, oxathiazinyl ( including 1, 2,5-oxathiazinyl or 1, 2,6-oxathiazinyl), oxadiazinyl (including 1,4,2-oxadiazinyl or 1, 3,5,2-oxadiazinyl), morpholinyl, azepinyl, oxepinyl, thiepinyl and diazepinyl. A heterocyclyl may alternatively be 2 or 3 rings fused together, wherein at least one ring contains a heteroatom as a ring atom (ie, nitrogen, oxygen, or sulfur). Such substituents include, for example, indolizinyl, pyridinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl (including pyrido [3,4-b] -pyridinyl, pyrido [3,2-b] -pyridinyl, or pyrido [ 4,3-b] -pyridinyl), and pteridinyl. Other examples of fused ring heterocyclyls include benzocondensated heterocyclyls, such as indolyl, isoindolyl (also known as "isobenzazolyl" or "pseudoisoindolyl"), indoleninyl (also known as "pseudoindolyl"), isoindazolyl (also known as "benzpyrazolyl"), benzazinyl (which includes quinolinyl (also known as "1-benzazinyl") or isoquinolinyl (also known as "2-benzazinyl")), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (which includes cinnolinyl (also known as "1"), 2-benzodiazinyl ") or quinazolinyl (also known as" 1,3-benzodiazinyl "), benzopyranyl (which includes" chromanyl "or" isochromanyl "), benzothiopyranyl (also known as" thiochromanyl "), benzoxazolyl, indoxazinyl (also known as "benzisoxazolyl"), anthranilyl, benzodioxolyl, benzodioxanil, benzoxadiazoliol, benzofuranyl (also known as "coumaronyl"), iso benzofuran i, benzothienyl (also known as "benzothiophenyl", "thionaphtenyl", or "benzothiofuranyl"), isobenzothienyl (also known as "isobenzothiophenyl", "isothionaphtenyl", or "isobenzothiofuranyl"), benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl (including 1,2-benzoxazinyl, 1,4-benzoxazinyl, 2,3, 1-benzoxazinyl, or 3, 3, 4-benzoxazinyl), benzisoxazinyl (including 1,2-benzisoxazinyl or 1,4-benzisoxazinyl), tetrahydroisoquinolinyl, carbazolyl, xanthenyl, and acridinyl The term heterocyclic of "2 condensed rings" ( alone or in combination with another term (s)) means a saturated, partially saturated, or arylheterocyclyl heterocyclyl which contains 2 fused rings. Examples of fused 2-ring heterocyclics include indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl, and tetrahydroisoquinolinyl. The term "heteroaryl" (alone or in combination with another term (s)) means an aromatic heterocyclyl containing from 5 to 14 ring atoms. A heteroaryl can be a single ring or 2 or 3 fused rings. Examples of heteroaryl substituents include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl.; 5-membered ring substituents such as 1, 3,5-, 1, 2,4- or 1, 2,3-triazinyl, imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1, 2,4-, 1, 2,5-, or 1, 3,4-oxadiazolyl and isothiazolyl; 6/5-membered fused ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6-membered fused rings such as 1, 2-, 1, 4-, 2,3- and 2,1-benzopyryl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1,4-benzoxazinyl. The term "heterocyclylalkyl" (alone or in combination with other term (s)) means alkyl substituted with a heterocyclyl. The term "heterocycloalkyl" (alone or in combination with another term (s)) means a fully saturated heterocyclyl. This specification uses the terms "substituent" and "radical" interchangeably. A suffix attached to a multi-component substituent only applies to the first component of the immediately preceding substituent that can be defined by said suffix. To illustrate, the term "alkylcycloalkyl" contains two components: alkyl and cycloalkyl. Thus, the suffix (d-Cß) in alkyl (CrC 6) -cycloalkyl means that the alkyl component of the alkylcycloalkyl contains from 1 to 6 carbon atoms; the suffix d-C does not describe the cycloalkyl component. To further illustrate, the prefix "halo" in haloalkoxyalkyl indicates that only the alkoxy component of the alkoxyalkyl substituent is substituted with one or more halogen radicals. If the halogen substitution can alternatively or additionally take place in the alkyl component, the substituent should instead be described as "alkoxyalkyl substituted with halogen" instead of "haloalkoxyalkyl." And finally, if the halogen substitution can take place only in the alkyl component, the substituent should instead be described as "alkoxyhaloalkyl." If the substituents are described as being "independently selected" from a group, each substituent is independently selected from the other. Each substituent may therefore be identical to or different from the other / substituent (s). When the words are used to describe a substituent, the component described further to the right of the substituent is the component that has the free valence. To illustrate, benzene substituted with methoxyethyl has the following structure: As can also be seen, ethyl is attached to benzene, and methoxy is the component of the substituent that is the furthest component of benzene. As an additional illustration, benzene substituted with cyclohexanylthiobutoxy has the following structure: When the words are used to describe a joining element between two other elements of a chemical structure represented, the component described further to the right of the substituent is the component that is attached to the left element in the structure described. To illustrate, if the chemical structure is X-L-Y and L is described as methylcyclohexanilethyl, then the chemical should be X-ethyl-cyclohexane-methyl-Y. When a chemical formula is used to describe a substituent, the hyphen on the left side of the formula indicates the part of the substituent that has the free valence. To illustrate, benzene substituted with -C (O) -OH has the following structure: When a chemical formula is used to describe a joining element between two other elements of a chemical structure represented, the leftmost dash of the substituent indicates the part of the substituent that is attached to the left element in the structure depicted. The rightmost script, on the other hand, indicates the part of the substituent that is attached to the right element in the structure represented. To illustrate, if the chemical structure represented is X-L-Y and L is described as -C (O) -N (H) -, then the chemical compound will be: H The term "pharmaceutically acceptable" is used adjectivally in this specification to mean that the modified name is appropriate for use as a pharmaceutical or as part of a pharmaceutical product. With reference to the use of the words "to understand" or "understands" or "comprising" in this patent (including the claims), the applicants emphasize that unless the context requires otherwise, those words are used on the basis and clearly understood to be to be interpreted inclusively, rather than exclusively, and that the applicants desire that each of those words be so interpreted in the interpretation of this patent, including the claims below.
General Synthetic Procedures Representative procedures for the preparation of compounds of the invention are outlined below in the schemes. The starting materials can be purchased or prepared using methods known to those skilled in the art. Similarly, the preparation of the various intermediates can be accomplished using methods known in the art. The starting materials may be varied and additional steps may be employed to produce compounds encompassed by the invention, as demonstrated by the examples below. In addition, different solvents and reagents can typically be used to achieve the above transformations. Furthermore, in certain situations, it may be advantageous to alter the order in which the reactions are carried out. The protection of the reactive groups may also be necessary to achieve the above transformations. In general, the need for protecting groups, as well as the conditions necessary to join and eliminate such groups, will be apparent to those skilled in the art of organic synthesis. When a protecting group is employed, deprotection is generally required. Suitable protecting groups and methodology for protection and deprotection such as those described in Protecting Groups in Organic Synthesis by Greene and Wuts are known and appreciated in the art. The following schemes are representative of the procedures that can be used to prepare these compounds.
SCHEME 1 Scheme 1 represents the general manner by which the alkylpyrimidinone C-5 framework is assembled. In these processes a substituted amine is condensed with potassium thiocyanate in the presence of acid. The generated thiourea is then condensed with a substituted malonate derivative. The thiol group can then be alkylated with an alkyl halide and the hydroxyl group is alkylated using a 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 X = Br or Cl mCPBA or Oxone yx? n Scheme 2 represents the general manner by which the halopyrimidinone C-5 framework is assembled. In these processes a substituted amine is condensed with potassium thiocyanate in the presence of acid. The generated thiourea is then condensed with a substituted malonate derivative. The thiol group can then be alkylated with an alkyl halide and the hydroxy group is alkylated using a substituted benzyl halide or subjected to a Mitsunobu reaction with a substituted benzyl alcohol. The halogen of C-5 is introduced using? / -bromosuccinimide or? / - chlorosuccinimide. The sulfide is then oxidized to the sulfone using standard reagents.
SCHEME 3 X - Cl, Br, alkyl Yn = anything R, Ri = H, alkyl, cycloalkyl, independent of one another Z = 0, N, S R2 = alkyl cycloalkyl, substituted alkyl Scheme 3 represents the manner in which the pyrimidinone sulfone is further elaborated to provide a number of heteroatom substituted derivatives at C-2. The sulfone is reacted with a substituted amine, alcohol or thiol in the presence of a base.
SCHEME 4 X = Cl, Br, alkyl Yn = anything R, Ri = H, alkyl, cycloalkyl, independent of one another R2 = alkyl cycloalkyl, substituted alkyl Scheme 4 represents the manner in which the pyrimidinone sulfone is further elaborated to provide a number of alkyl substituted derivatives at C-2. The sulfone is condensed with a functionalized or non-functionalized organometallic reagent, which can be further elaborated using standard conditions.
SCHEME 5 X = Cl, Br, alkyl Yn = anything R, Ri = H, alkyl, cycloalkyl, independent one from another Scheme 5 represents the manner in which the pyrimidinone sulfone is further elaborated by reaction with potassium cyanide. The cyanide function can then be processed into a number of derivatives.
SCHEME 6 Yn = anything R, Ri = H, alkyl, cycloalkyl, independent of one another Z = aromatic Scheme 6 represents the manner in which the pyrimidinone sulfide is further elaborated to provide aryl-substituted derivatives at C-2. The sulfide is reacted with a substituted arylboric acid in the presence of a copper and palladium catalyst.
Detailed Preparative Procedure The examples detailed below illustrate the preparation of compounds of this invention. Other compounds of this invention can be prepared using the procedures illustrated in these examples, either alone or in combination with techniques generally known in the art. The following examples are merely illustrative, and do not limit the rest of the description in any way. The following abbreviations are used: g - gram mg - milligram mmol - millimole ° C - degrees Celsius M - molar ml - milliliter NMR - nuclear magnetic resonance 1H - proton MHz - megahertz s - singlet dd - doublet of doublets d - doublet t - triplet c - quartet a - width m - multiplet app - apparent J - coupling constant Hz - hertz LC / EM - liquid chromatography / mass spectrometer tr - retention time min - minute nm - nanometers ES - MS - mass spectrometer electrospray m / z - mass ratio versus load ES-HREM - high resolution mass spectrometer by electrospray cale. - calculated N - normal I - liter of - doublet of quartet dt - doublet of triplets ddd - doublet of doublet of doublet ta - room temperature h - hour ddt - doublet of doublet of triplets p / p - proportion in 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-HREM - high-resolution mass spectrometry by electrospray t-BOC - tert-butyloxycarbonyl DMAP - dimethylaminopyridine DCM - dichloromethane EtOAc - ethyl acetate MCPBA - meta-chloroperbenzoic acid EXAMPLE 1 Step 1: Preparation of 6-hydroxy-3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one. To a mechanically stirred mixture of N-isopropylthiourea (124.03 g, 1.05 mol) and diethyl malonate (168 g, 1.05 mol) was added in one portion, sodium methoxide (25% by weight) commercially (Aldrich) in methanol (468). ml) at room temperature. The thick white suspension formed was initially heated to 68 ° C (gentle reflux) for 4.5 hours. At this point, the reaction mixture becomes clear (turbid). Cooling was started and upon reaching 50 ° C, methyl iodide (149 g, 1.05 mol) was added in a stable stream for 10 minutes while maintaining 50 ° C. An exotherm is highlighted and moderate cooling is applied maintaining this temperature (methyl iodide is volatile, thus the reflux condenser has to remain operational at this point as well). After 30 minutes, the reaction is cooled to 35 ° C and deactivated with 120 ml of glacial acetic acid, added quickly with good agitation. The temperature is increased to 42 ° C and a thick white suspension formed. This avoids the sn precipitation of solids, allowing smooth agitation that leads to the formation of a uniform and quickly filterable crystalline mass. After an additional 30 minutes of stirring allowing cooling to room temperature (water bath) the contents were filtered and washed four times with 500 ml of water. The filtrations were rapid and the white semicrystalline solid obtained was dried to constant weight at 50 ° C and at a vacuum of 20 mm (2.66 kPa). The weight was 190 g (90%) (purity > 98%). 1 H NMR (400 MHz, DMSO) d 11.2 (br s, 1 H), 5.0 (s, 1 H) 4.4 (m, 1 H), 2.42 (s, 3H), 1.42 (d, J = 6.6 Hz, 6H).
Step 2: Preparation of 6- (2,4-difluorobenzyloxy) -3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one. A suspension of 6-hydroxy-3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one (190 g, 0.95 mol) from Step 1 and 325 mesh potassium carbonate (160 g, 1.15 mol) in 600 ml of N-methylpyrrolidinone was heated to 50 ° C. 100 ml of additional solvent were added facilitating the agitation and preventing the formation of lumps or the hardening of the salt that is formed. 2,4-difluorobenzyl bromide (197 g, 0.96 mol) was added without dilution for 20 minutes, allowing an exotherm of 10 ° C (the final temperature is 60 ° C). The suspension now becomes thinner and easier to shake in about 10 minutes, indicating significant completion. The temperature dropped to 50 ° C and was maintained for an additional 3 hours. It was checked if the reaction had been completed by removing a small aliquot. The mixture was cooled to room temperature and poured into a large flask containing 3 I of water with good agitation. The precipitated solids were filtered and washed three times with 600 ml of water and dried at 50 ° C and 20 mm vacuum (2.66 kPa). The purity of NMR in this phase was approximately 75-80% and weighed approximately 300 g. The crude product was dissolved in 2 l of ethyl acetate and concentrated to 750 ml (distillation of 1250 ml) in a large rotary evaporator at 35-40 ° C under a vacuum of 100 mm (13.33 kPa). The heat and vacuum were deactivated as the crystallization started but the rotation was continued and the bath cooled slowly for 30 minutes to a final temperature of 15CC. The suspension was filtered (took place quickly) and washed twice with 200 ml of hexanes. The fine white crystals were dried at 50 ° C and 20 mm (2.66 kPa) to obtain 160 g (52%). Additional quantities of product can be obtained from the mother liquor by crystallization or chromatography. 1 H NMR (400 MHz, DMSO) d 7.55 (m, 1 H), 7.27 (m, 1 H), 7.11 (m, 1 H), 5.37 (s, 1 H), 5.21 (s, 2 H), 4.47- 4.38 (m, 1 H), 2.48 (s, 3H), 1.47 (d, J = 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) was dissolved., 0.42 mol) in methylene chloride and N-bromosuccinimide (178 g, 0.42 mol) was added in two equal portions with good stirring at room temperature. It highlights a moderate rise in temperature (3 to 5 ° C). After 2 hours of further stirring, the solvent was distilled to near dryness on a rotary evaporator. 750 ml of water were subsequently added and stirred well for 10 minutes. The solids were filtered (took place quickly) and washed three times with 200 ml of water. The whitish solid was dried at 50 ° C and under vacuum of 20 mm (2.66 kPa). The yield of the product was 170 g (100%). 1 H NMR (400 MHz, DMSO) d 7.55 (m, 1 H), 7.27 (m, 1 H), 7.15 (m, 1 H), 5.47 (s, 2 H), 4.51-4.40 (m, 1 H), 2.58 (s, 3H), 1.52 (d, J = 6.7 Hz, 6H).
Step 4: Preparation of 6- (2,4-difluorobenzyloxy) -5-bromo-3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one. Oxone (600 g, 0.98 mol) was added to a stirred solution of 6- (2,4-difluorobenzyloxy) -5-bromo-3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one (170 g, 0.42 mol) in 3 I of THF and 300 ml of water maintained at room temperature. The exotherm was minimal (2-3 ° C) and the reaction remained heterogeneous, since the oxone had a low solubility in aqueous THF. The mixture was stirred for an additional 5 days at room temperature (heating is not recommended to accelerate the reaction since decomposition is observed). The reaction mixture was filtered and the residue was washed twice with 500 ml of ethyl acetate. The filtrates were concentrated to approximately 1/3 of the original volume (2800 ml of distillate) followed by the addition of 1 l of ethyl acetate. After washing three times with 200 ml of water, the organic phase was dried over sodium sulfate and concentrated in a rotary evaporator to a semi-paste solid. Then 500 ml of ether were added and stirred well. A crystalline solid was rapidly removed, which was subsequently filtered and washed once with 100 ml of cold ether (10 ° C) and once with 100 ml of hexane. The product was obtained as a colorless solid which was dried in a vacuum oven at 50 ° C and 20 mm (2.66 kPa) at a constant weight of 100 g (51%). 1 H NMR (400 MHz, CDCl 3) d 7.40 (m, 1 H), 6.92 (m, 1 H), 6.82 (m, 1 H), 5.41 (s, 2 H), 4.21-4.28 (m, 1 H), 3.38 (s, 3H), 1.60 (d, J = 6.7 Hz, 6H).
CF3COOH 5-Bromo-6 - [(214-difluorobenzyl) oxp-3-isopropyl-2-piperazin-1-ylpyrimidin-4 (3H) -one trifluoroacetate Stage 1: Preparation of 4-. { 5-Bromo-4-f (2,4-difluorobenzyl) oxyfl-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl) piperazine-1-f-butylcarboxylate.
A mixture of 1-butyl-1-piperazine carboxylate (1.0 g, 0.0054 mol), 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) was heated at 70 ° C. ) pyrimidin-4 (3H) -one (1.8 g, 0.004 mol) obtained from step 3, diisopropylethylamine (0J9 g, 0.006 mol) and dimethylaminopyridine (0.15 g, 0.0012 mol) in dioxane (20.0 ml) for 16 hours under argon . After removal of the solvents in vacuo, the residue was partitioned between cold 5% citric acid (10 ml) and dichloromethane (60.0 ml). The organic extract was washed with water, dried (Na2SO4), and concentrated to dryness. The resulting material was purified by reverse phase HPLC using 10-90% CH3CN / water gradient (40 minutes) containing 0.5% trifluoroacetic acid at a flow rate of 80 ml / minute. The appropriate fractions (MH \ m / z = 543) were combined and concentrated to a small volume (-25 ml), 5% sodium bicarbonate (5 ml) was added and extracted with dichloromethane (2 x 20 ml). dried (Na2SO), and concentrated to dryness under reduced pressure. The combined organic extracts were washed with water, dried (Na2SO), and concentrated to dryness in vacuo to give the title compound as an amorphous powder (0.85 g, 36%): 1 H NMR (CD3OD / 400 MHz) d 7.51 (m , 1 H), 6.98 (m, 2H), 5.44 (s, 2H), 4.61 (m, 1 H), 3.55 (a, 4H), 3.24 (m, 4H), 1.57 (d, 6H, J = 6.8 Hz, and 1.46 (s, 9H); ES-HREM m / z 543.1441 (M + H cale, for C23H30N4O F2Br requires 543.1413).
Step 2: Preparation of the title compound. A solution of 4-. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-0X0-1.6 dihydropyrimidin-2-yl} I-butyl piperazine-1-carboxylate (0.26 g, 4.6 mmol) obtained from step 4 in a mixture of trifluoroacetic acid (0.3 ml) and dichloromethane (0.3 ml) was stirred at room temperature for 30 minutes and the product was isolated by reverse phase HPLC using 10-90% CH3CN / water gradient (40 minutes) containing 0.5% trifluoroacetic acid at a flow rate of 80 ml / minute. The 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 (CD3OD / 400 MHz) d 7.50 (m, 1 H), 6.99 (m, 2H), 5.46 (s, 2H), 4.61 (m, 1 H), 3.49 (m, 4H), 3.39 (m, 4H), 1.58 (d, 6H, J = 6.8 Hz); ES-HREM m / z 443.0859 (M + H cale, for C18H22N4O4F2Br requires 443.0889).
EXAMPLE 3 OR 5-bromo-6-r (2,4-difluorobenzyl) oxy1-2- (4-glycylpiperazin-1-yl) -3- -propylpyrimidin-4 (3H) -one trifluoroacetate To a solution of 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-isopropyl-2-piperazin-1-ylpyrimidin-4 (3H) -one trifluoroacetate (0.055 g, 0.1 mmol) in DMF ( 0.25 ml), N-methylmorpholine (0.015 g, 0.15 mmol) and BOC-glycine-N-hydroxysuccimide (0.04 g, 0.15 mmol) were added 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) and the product was isolated by reverse phase HPLC using 10-90% CH3CN / water gradient (40 minutes) containing 0.5% trifluoroacetic acid at a flow rate of 80 ml /minute. 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) d 7.45 (m, 1 H), 6.96 (m, 2 H), 5.45 (s, 2 H), 4.64 (m, 1 H), 3.97 (s, 2 H), 3.68 (a, 2H), 3.58 (m, 2H), 3.33 (m, 4H), 1.59 (d, 6H, = 6.8 Hz). ES-HREM m / z 500.1112 (M + H cale, for CzoHzsNsOaFzBr requires 500.1103).
EXAMPLE 4 5-bromo-6-r (2,4-difluorobenzyl) oxy1-2- (4-glycolylpiperazin-1-yl) -3 ° isopropylpyrimidin-4 (3H) -one To a solution of 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-isopropyl-2-piperazin-1-ylpyrimidin-4 (3H) -one trifluoroacetate (0.1 g, 0.18 mmol) in dichloromethane (3.0 ml) at 0 ° C, N-methylmorpholine (0.037 g, 0.36 mmol) and acetoxyacetyl chloride (0.05 g, 0.37 mmol) were added and stirred at 0 ° C for 30 minutes. The reaction mixture was concentrated in vacuo and the product was isolated by reverse phase HPLC using 10-90% CH3CN gradient / water (40 minutes) containing 0.5% trifluoroacetic acid at a flow rate of 80 ml / minute. . The appropriate fractions (MH +, m / z = 500) were combined and lyophilized giving 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. This 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) d 7.51 (m, 1 H), 6.97 (m, 2 H), 5.47 (s, 2 H), 4.63 (m, 1 H), 4.25 (s, 2 H), 3.67 (a, 2H), 3.59 (a, 2H), 3.33 (m, 4H), 1.59 (d, 6H, J = 6.8 Hz); ES-HR MS m / z 501.0954 (M + H cale, for C20H24N4O4F2Br requires 501.0943).
EXAMPLE 5 5-bromo-6-y (2,4-difluorobenzyl) oxy-3-isopropyl-2-r4- (2-methylalanyl) piperazin-1-ylpyrimidin-4 (3H) -one trifluoroacetate A mixture of di-t-butyl dicarbonate (0.2 g, 0.8 mmol), N- (tert-butoxycarbonyl) -2-methylalanine (0.15 g, 0.74 mmol) 3-hydroxy-3,4-dihydrobenzotriazine-4-one (0.12 g) ), and triethylamine (0.1 ml) in acetonitrile was stirred at room temperature for 1 hour. A solution of 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-isopropyl-2-piperazin-1-ylpyrimid-4 (3H) -one (0.22 g, 0.5 mmol) in DMF (2.0 ml) was then added and the resulting mixture was stirred at room temperature for 3 hours under argon. After removal of the solvents in vacuo, the residue was partitioned between 5% citric acid (5 ml) and dichloromethane (20 ml). The organic phase was washed and dried (Na2SO), and concentrated to dryness. The resulting material was stirred with a mixture of trifluoroacetic acid (0.5 ml) and dichloromethane (0.5 ml) for 30 minutes and the product was purified by reverse phase HPLC using 10-90% CH 3 CN gradient / water (40 minutes). contained 0.5% trifluoroacetic acid at 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) d 7.45 (m, 1 H), 6.95 (m, 2 H), 5.43 (s, 2H), 4.62 (m, 1 H), 3.79 (a, 4H), 3.30 (m, 4H), 1.67 (s, 6H), and 1.59 (d, 6H, J = 6.8 Hz); ES-HREM m / z 528.1435 (M + H cale, for C 22 H 29 N 5 O 3 F 2 Br requires 528.1416).
EXAMPLE 6 2- (4-. {5-bromo-4-r (2,4-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. Piperazin-1-yl) acetamide trifluoroacetate A mixture of chloroacetamide (0.1 g, 1.1 mmol), 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-isopropyl-2-piperazin-1-pyrimidin-4 (3H) -one ( 0.30 g, 0.68 mmol), diisopropylethylamine (0.081 g, 0.63 mmol) and DMAP (0.01 g) in dioxane (6.0 ml) was heated at 70 ° C under argon for 16 hours. After removal of solvents under reduced pressure the residue was purified by HPLC using 10-90% CH3CN / water gradient (40 minutes) containing 0.5% trifluoroacetic acid at a flow rate of 80 ml / minute. 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) d 7.50 (m, 1 H), 6.98 (m, 2 H), 5.44 (s, 2 H), 4.59 (m, 1 H), 3.80 (a, 2 H), 3.52 (m, 4H), 3.29 (m, 4H), and 1.57 (d, 6H, J = 6.8 Hz) ES-HREM m / z 500.1092 (M + H cale, for C2oH25N5? 3F2Br requires 500.1103).
EXAMPLE 7 2- (2-aminoethoxy) -5-bromo-6-f (2,4-difluorobenzyl) oxy-3-isopropylpyrimidin-4 (3H) -one trifluoroacetate Step 1: Preparation of 2- (. {5-bromo-4-f (2,4-difluorobenzyl) oxyl-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl) oxy) ethylcarbamate of ^ -butyl.
A mixture of 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) -pyrimidin-4 (3H) -one (0.25 g, 0.57 mmol), 2- p-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 stirred at room temperature under argon. 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 phase was washed with water, dried (Na2SO), and concentrated. The resulting syrup was dissolved in acetonitrile and water was added until turbidity when the solids separated. These were filtered, washed with acetonitrile / water (1: 1 v / v) and dried in vacuo yielding the title compound as a white powder ES-HREM m / z 518.1134 (M + H cale, for C21H27N3O5F2Br requires 518.1097) .
Step 2: Preparation of the title compound. A solution of 2- (. {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl was stirred at room temperature. .}. oxy) ethyl f-butyl carbamate (0.1 g, 0.19 mmol) in dichloromethane (0.3 ml) and trifluoroacetic acid (0.2 ml) for 30 minutes. The product was isolated by reverse phase HPLC using 10-90% CH3CN / water gradient (40 minutes) containing 0.5% trifluoroacetic acid at a flow rate of 80 ml / minute. 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) d 7.51 (m, 1 H), 6.98 (m, 2 H), 5.45 (s, 2 H), 5.21 (a, 1 H), 4.68 (m, 2 H), 3.43 (a, 2H), and 1 .47 (d, 6H, J = 7.2 Hz); ES-HREM m / z 418.0580 (M + H cale, for C 16 H 19 N 3 O 3 F 2 Br requires 418.0572).
EXAMPLE 8 1- (5-bromo-4-r (2,4-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. Prolinamide A mixture of 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 mmol), diisopropylethylamine (0.25 g, 1.95 mmol) in THF (5.0 ml) containing DMAP (0.015 g) was heated at 70 ° C for 16 hours under argon. 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 phase was washed with water, dried (Na2SO) and concentrated to dryness under reduced pressure. The resulting material was purified by flash chromatography on silica gel using EtOAc containing 1% methanol as the eluent. Appropriate fractions (MH + m / z = 485) were combined, concentrated to dryness, and the residue was further purified by reverse phase HPLC using 10-90% CH3CN / water gradient (40 minutes) containing trifluoroacetic acid at room temperature. 0.5% at a flow rate of 80 ml / minute. The appropriate fractions (MH +, m / z = 471) were combined, concentrated to a small volume (~25 ml), sodium bicarbonate (1.0 g) was added and extracted with dichloromethane (2 x 20 ml). The combined organic extracts were washed with water (2 x 10 ml), dried (Na2SO4) and concentrated to dryness in vacuo to give the title compound (0.13 g) as a white powder. 1 H NMR (CD3OD / 400 MHz) d 7.50 (m, 1 H), 6.97 (m, 2 H), 5.38 (c, 2 H, J = 12.8 Hz), 4.58 (m, 2 H), 3.81 (m, 1 H) , 3.61 (m, 1 H), 2.35 (m, 1 H), 2.11 (m, 1 H), 1.89 (m, 2H), 1 JO (d, 3H, J = 6.8 Hz), and 1.45 (d, 3H, J = 6.8 Hz); ES-HREM m / z 471.0820 (M + H cale, for C? 9H22N4O3F2Br requires 471.0838).
EXAMPLE 9 1-. { 5-bromo-4-f (214-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} piperidine-3-carboxamide A mixture of 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) -pyrimidin-4 (3H) -one (0.50 g, 1.15 mmol), nipectomide (0.22 g) , 1.7 mmol), diisopropylethylamine (0.22 g, 1.7 mmol) in dioxane (5.0 ml) containing DMAP (0.02 g) was heated at 70 ° C for 3 hours under argon. 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 phase 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 10-90% CH3CN / water gradient (40 minutes) containing 0.5% trifluoroacetic acid at a flow rate of 80 ml / minute. Appropriate fractions (MH \ m / z = 471) were combined, concentrated to a small volume, sodium bicarbonate (0.5 g) was added and extracted with dichloromethane (2 x 20 ml). The combined organic extracts were washed with water (2 x 10 ml), dried (Na2SO4) and concentrated to dryness in vacuo to give the title compound (0.13 g) as a white powder: 1 H NMR (CD3OD / 400 MHz) d 7.49 (m, 1 H), 6.95 (m, 2H), 5.42 (s, 2H), 4.52 (m, 1 H), 3.57 (m, 1 H), 3.47 (m, 1 H), 3.1 (m, 1 H), 2.98 (m, 1 H), 2.62 (m, 1 H), 1.98 (m, 1 H), 1.82 (m, 1 H), 1.69 (m, 2H), and 1.55 (m, 6H); ES-HREM m / z 485.1016 (M + H cale, for C20H24N4O3F2Br requires 485.0994).
EXAMPLE 10 N ~ 2 ~ - (5-bromo-4 - [(2,4-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. Qycinamide A mixture of 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) was heated at 70 ° C for 2 hours under argon. The reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase HPLC using 10-90% CH3CN gradient / water (40 minutes) containing 0.5% trifluoroacetic acid at a flow rate of 80 ml / minute. The 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 x 20 ml). The combined organic extracts were washed with water (2 x 10 ml), dried (Na2SO4) and concentrated to dryness in vacuo to give the title compound (0.13 g) as a white powder: 1 H NMR (CD3OD / 400 MHz) d 7.49 (m, 1 H), 6.95 (m, 2H), 5.36 (s, 2H), 4.55 (a, 2H), 4.00 (s, 2H), and 1.52 (d, 6H, J = 6.8 Hz); ES-HREM m / z 431.0527 (M + H cale, for C? 6H18N4O3F2Br requires 431.0525).
EXAMPLE 11 2- (3-aminopyrrolidin-1-yl) -5-bromo-6-r (2,4-difluorobenzyl) oxyfl-3-isopropylpyrimidin-4 (3H) -one trifluoroacetate Step 1: Preparation of 1- (5-bromo-4-f (2,4-difluorobenzyl) oxyl-1-isopropyl-6-oxo-1,6-dihydropyridin-2-yl. Pyrrolidin- F-butyl 3-carbamate.
To a solution of 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) -pyrimidin-4 (3H) -one (0.50 g, 1.15 mmol) in THF (5.0 ml), 3---butoxycarbonylaminopyrrolodine (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 under argon and concentrated under reduced pressure. The residue was partitioned between 5% citric acid (20.0 ml) and dichloromethane (15.0 ml). The organic phase was washed with water, dried (Na2SO4) and concentrated to dryness under reduced pressure. The resulting material was purified by flash chromatography on silica gel using 50% EtOAc in hexane to give 0.46 (MH + m / z = 543) as a white powder: ES-HREM m / z 543.1405 (M + H cale, for C23H30N4O4F2Br requires 543.1413).
Step 2: Preparation of the title compound. A solution of 1- was stirred at room temperature. { 5-bromo-4- [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1, 6-dihydropyrimidin-2-yl} p-butyl pyrrolidin-3-yl carbamate (0.4 g, 0J4 mmol) in dichloromethane (0.5 ml) and trifluoroacetic acid (0.5 ml) for 30 minutes. The product was isolated by reverse phase HPLC using 10-90% CH3CN / water gradient (40 minutes) containing 0.5% trifluoroacetic acid at a flow rate of 80 ml / minute. Appropriate fractions (MH +, m / z = 443) were combined and lyophilized to provide the title compound (0.34g, 82%) as a white powder: 1 H NMR (CD3OD / 400 MHz) d 7.51 (m, 1 H), 7.00 (m, 2H), 5.44 (s, 2H), 4.49 (m, 1 H), 3.95 (m, 2H), 3.77 (m, 1 H), 3.68 (m, 1 H), 3.62 (m, 1 H), 2.42 (m, 1 H), 2.14 (m, 1 H), 1.62 (d, 3H, J = 6.8 Hz), and 1.58 (d, 3H, J = 6.8 Hz); ES-HR MS m / z 443.0882 (M + H cale, for C18H22N4O2F2Br requires 443.0889).
EXAMPLE 12 2-r (3R) -3-aminopyrrolidin-1-in-5-bromo-6-f (2,4-difluorobenzyl) oxp-3-isopropylpyrimidin-4 (3H) -one trifluoroacetate The title compound was prepared by a similar procedure described for 2- (3-aminopyrrolidin-1-yl) -5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) trifluoroacetate. ) -one using 3 -3-t-butoxycarbonylaminopyrrolidine in place of 3-t-butoxycarbonylamino-pyrrolidine: 1H-NMR (CD3OD / 400 MHz) d 7.50 (m, 1 H), 6.96 (m, 2H), 5.41 (s, 2H), 4.45 (m, 1 H), 3.95 (m, 2H), 3.74 (m, 1H), 3.68 (m, 1 H), 3.60 (m.1 H), 2.41 (m, 1 H), 2.15 (m, 1 H), 1.60 (d, 3H, J = 6.8 Hz), and 1.55 (d, 3H, J = 6.8 Hz); ES-HR MS m / z 443.0831 (M + H cale, for C? 8H22N4O2F2Br requires 443.0889).
EXAMPLE 13 NH2. CF3COOH 2-f (3S) -3-aminopyrrolidin-1-in-5-bromo-6-f (2,4-difluorobenzyl) oxy1-3 ° isopropylpyrimidin-4 (3H) -one trifluoroacetate The title compound was prepared by a similar procedure described for 2- (3-aminopyrrolidin-1-yl) -5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-iso-propylpyrimidin-4 trifluoroacetate. (3 H) -one using 3S-3-t-butoxycarbonylaminopyrrolidine in place of 3-t-butoxycarbonylamino-pyrrolidine: 1 H NMR (CD 3 OD / 400 MHz) d 7.50 (m, 1 H), 6.96 (m, 2 H), 5.41 ( s, 2H), 4.46 (m, 1 H), 3.94 (m, 2H), 3.75 (m, 1 H), 3.61 (m, 1 H), 3.60 (m.1 H), 2.41 (m, 1 H), 2.15 (m, 1 H), 1.59 (d, 3H, J = 6.8 Hz), and 1.55 (d, 3H, J = 6.8 Hz); ES-HR MS m / z 443.0914 (M + H cale, for C18H22N4O2F2Br requires 443.0889).
EXAMPLE 14 CF3COOH 5-bromo-6-r (2,4-d-fluorobenzyl) oxyl-2-r (2S) -2- (hydroxymethyl) pyrrolidin-1-ind 3-isopropylpyrimidin-4 (3H) -one trifluoroacetate A mixture of 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 at room temperature for 2 hours under argon. 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 phase was washed with water, dried (Na2SO4) and concentrated to dryness under reduced pressure and the residue was purified by flash chromatography on silica gel using 50% EtOAc in hexane as the eluent. The appropriate fractions (MH + m / z = 458) were combined and concentrated and the resulting residue was further purified by reverse phase HPLC using 10-90% CH3CN / water gradient (40 minutes) containing 0.5% trifluoroacetic acid. at a flow rate of 80 ml / minute. The appropriate fractions (MH +, m / z = 458) were combined, and lyophilized to provide the title compound (0.02 g) as a white powder: 1 H NMR (CD3OD / 400 MHz) d 7.49 (m, 1 H), 6.95 ( m, 2H), 5.38 (c, 2H, J = 10.8 Hz), 4.48 (m, 2H), 3.61 (m, 3H), 3.45 (m, 1 H), 2.18 (m, 1 H), 2.01 (m , 1 H), 1.85 (m, 2H), 1.73 (d, 3H, J = 6.8 Hz), and 1.39 (d, 3H, J = 6.8 Hz); ES-HREM m / z 458.0835 (M + H cale, for C19H23N3O3F2Br requires 458.0885).
EXAMPLE 15 N ~ 3 ~ -. { 5-bromo-4-r (2,4-difluorobenzyl) ox -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -beta-alaninamide.
A mixture of 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) -pyrimidin-4 (3H) -one (0.50 g, 1.15 mmol), β-hydrochloride alaninamide (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 heated at 65 ° C for 2 hours under argon. 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 phase was washed with water, dried (Na2SO4) and concentrated to dryness under reduced pressure and the residue was purified by flash chromatography on silica gel using EtOAc containing 1% methanol as the eluent. Appropriate fractions (MH + m / z = 445) were combined and 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: 1H NMR (CD3OD) / 400 MHz) d 7.49 (m, 1 H), 6.95 (m, 2H), 5.40 (s, 2H), 4.55 (a, 1 H), 3.67 (t, 2H, J = 6.8 Hz), and 2.51 ( t, 2H, J = 6.8 Hz), and 1.46 (d, 6H, = 6.8 Hz); ES-HR MS m / z 445.0645 (M + H cale, for C17H20N4O3F2Br requires 445.0681).
EXAMPLE 16 N ~ 2 ~ -. { 5-bromo-4-r (2,4-difluorobenzyl) oxyM-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -L-alaninamide A mixture of 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) -pyrimidin-4 (3H) -one (0.50 g, 1.15 mmol), S-hydrochloride alaninamide (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 heated at 65 ° C for 3 hours under argon. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between 5% citric acid (5.0 ml) and dichloromethane (20.0 ml). The organic phase was washed with water, dried (Na2SO4) and concentrated to dryness under reduced pressure and the residue was purified by flash chromatography on silica gel using EtOAc as the eluent. The appropriate fractions (MH + m / z = 445) were combined and concentrated to dryness under reduced pressure. The resulting material was purified by reverse phase HPLC using 10-90% CH3CN / water gradient (40 minutes) containing 0.5% trifluoroacetic acid at a flow rate of 80 ml / minute. The appropriate fractions were combined (MH +, m / z = 445), sodium bicarbonate (0.5 g) was added and it was extracted with dichloromethane (2 x 20 ml). The combined organic extracts were washed with water (2 x 10 ml), dried (Na2SO) and concentrated to dryness under reduced pressure to give the title compound (0.13 g) as a white powder: 1 H NMR (CD3OD / 400 MHz) d 7.49 (m, 1 H), 6.95 (m, 2H), 5.37 (c, 2H, J = 4.0 Hz), 4.46 (m, 1 H), and 1.53 (m, 9H); ES-HREM m / z 445.0672 (M + H cale, during C17H2oN4? 3F2Br requires 445.0681).
EXAMPLE 17 N ~ 1 ~ - (1- { 5-bromo-4 - [(2,4-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidin-3 -yl) glycinamide trifluoroacetate To a solution of 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 at room temperature for 16 hours under argon. The solvents were distilled 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 h. The product was isolated by reverse phase HPLC using 10-90% CH3CN / water gradient (40 minutes) containing 0.5% trifluoroacetic acid at a flow rate of 80 ml / minute. The 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) d 7.48 (m, 1 H), 6.95 (m, 2 H), 5.39 (s, 2 H), 4.44 (m, 2 H), 3.89 (dd, 1 H, J = 6.0 Hz, 11.2 Hz), 3J6 (m, 1 H), 3.62 (m, 3 H), 3.42 (2 d, 1 H, J = 4.0 Hz), 2.21 (m, 1 H), 1.97 (m, 1 H) 1.59 (d , 3H, J = 6.4 Hz), and 1.50 (d, 3H, = 6.4 Hz); ES-HREM m / z 500.1079 (M + H cale, for C2oH25N5O3F2Br requires 500.1103).
EXAMPLE 18 N ~ 2 ~ - (5-bromo-4 - [(2,4-difluorobenzyl) oxyl-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl) -N ~ 1 ~ -methylqlicinamide A mixture of 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) -pyrimidin-4 (3H) -one (0.50 g, 1.15 mmol), N was stirred. methylglycine amide hydrochloride (0.21 g, 1.7 mmol), diisopropylethylamine (0.46 g, 3.6 mmol) in dioxane (5.0 ml) containing DMAP (0.02 g, 0.16 mmol) at room temperature for 2 h under argon. The residue was partitioned between 5% citric acid (5.0 ml) and ethyl acetate (20.0 ml). The organic phase was washed with water, dried (Na2SO4) and concentrated to dryness under reduced pressure and the residue was crystallized from dichloromethane / hexane to give the title compound (0.16 g, 31%) as a white powder: NMR 1H (CD3OD / 400 MHz) d 7.49 (m, 1 H), 6.93 (m, 2H), 5.32 (s, 2H), 3.96 (s, 2H), 2.69 (s, 3H), and 1.53 (d, 6H) , J = 7.2 Hz); ES-HREM m / z 445.0682 (M + H cale, for C? 7H20N4O3F2Br requires 445.0681).
EXAMPLE 19 2- ( {5-bromo-4-f (2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1, 6-dihydropyrimidin-2-yl) oxy) acetamide To a solution of 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), at 10 ° C in dioxane (5.0 ml), sodium hydride (0.04 g, 1.67 mmol) was added and stirred at room temperature under argon. After 30 minutes, DMAP (0.01 g) was added and the mixture was heated to 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 fractionated between 5% citric acid (5.0 ml) and ethyl acetate (20.0 ml). The organic phase was washed with water, dried (Na2SO4), 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 (CD3OD / 400 MHz) d 7.49 (m, 1 H), 6.96 (m, 2 H), 5.39 (s, 2 H), 5.24 (a, 1 H), 4.94 (s, 2 H), and 1.46 (d , 6H, J = 6.8 Hz); ES-HREM m / z 432.0354 (M + H cale, for C16H17N304F2Br requires 432.0365).
EXAMPLE 20 5-bromo-6-r (2,4-difluorobencinoxy1-2-r (3R) -3-hydroxypyrrolidin-1-yn-3-isopropylpyrimidin-4 (3H) -one A mixture of 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) -pyrimidin-4 (3H) -one (0.40 g, 0.92 mmol), (3R) - pyrrolidin-3-ol (0.08 g, 0.93 mmol), and diisopropylethylamine (0.15 g, 1.15 mmol) in dioxane (5.0 mL) containing DMAP (0.02 g, 0.16 mmol) was stirred at room temperature for 1 h under 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 phase was washed with water, dried (Na SO4) and concentrated to dryness under reduced pressure and the residue was purified by flash chromatography on silica gel using ethyl acetate as the eluent to give the title compound (0.27 g, 67%). %) as an amorphous material: 1H-NMR (CD3OD / 400 MHz) d 7.49 (m, 1 H), 6.95 (m, 2H), 5.39 (s, 2H), 4.43 (m, 2H), 3.89 (m, 1 H), 3.79 (m, 1 H), 3.55 (m, 1 H), 3.38 (m, 1 H), 1.98 (m, 2H), 1.65 (d, 3H, J = 7.2 Hz), and 1.43 (d) , 3H, J = 7.2 Hz); ES-HREM m / z 444.0740 (M + H cale, for C18H2? N3O3F2Br requires 444.0729).
EXAMPLE 21 5-bromo-6 - [(2,4-difluorobenzyl) oxyfl-2- (4-hydroxypiperidin-1-yl) -3- isopropylpyrimidin-4 (3H) -one The title compound was prepared by a similar procedure as described for 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -2 - [(3R) -3-hydroxypyrrolidin-1-yl] -3 -sopropylpyrimidin-4 (3H) -one, substituting 4-hydroxypiperidine for (3R) -pyrrolidin-3-ol: 1H-NMR (CD3OD / 400 MHz) d 7.49 (m, 1 H), 6.95 (m, 2H) , 5.42 (s, 2H), 4.53 (m, 1 H), 3.81 (m, 1 H), 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-HREM m / z 458.0842 (M + H cale, for C19H23N3O3F2Br requires 458.0885).
EXAMPLE 22 5-bromo-6-r (2,4-difluorobenzyl) oxy1-2- (i (2S) -2.3-dihydroxypropinamino -3- isopropylpyrimidin-4 (3H) -one A mixture of 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) -pyrimidin-4 (3H) -one (0.50 g, 1.15 mmol), S-1- amine-2-propanol (0.13 g, 1.43 mmol), and diisopropylethylamine (0.22 g, 1.7 mmol) in dioxane (5.0 ml) containing DMAP (0.02 g, 0.16 mmol) was stirred at room temperature for 16 hours under 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 phase was washed with water, dried (Na2SO) and concentrated to dryness under reduced pressure and the residue was purified by flash chromatography on silica gel using ethyl acetate containing 1% methanol as eluent to provide the title compound (0.19 g, 37%) as an amorphous material: 1 H NMR (CD3OD / 400 MHz) d 7.49 (m, 1 H), 6.95 (m, 2 H), 5.40 (s, 2 H), 4.85 (a, 1 H) , 3.86 (m, 1 H), 3.65 (m, 1 H), 3.54 (m, 2H), 3.38 (m, 1 H), and 1.48 (2d, 6H, J = 1.6 Hz); ES-HREM m / z 448.0659 (M + H cale, for d7H2? N3O F2Br requires 448.0678).
EXAMPLE 23 5-bromo-6-r (2,4-difluorobenzyl) oxp-2- (r (2R) -2,3-dihydroxypropylamino.} - 3-isopropylpyrimidin-4 (3H) -one The title compound was prepared by a similar procedure as described for 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -2-. { [(2S) -2.3-dihydroxypropyl] amino} -3-isopropylpyrimidin-4 (3H) -one, substituting for S-1-amino-2-propanol the R-1-amino-2-propanol: 1H NMR (CD3OD / 400 MHz) d 7.49 (m, 1 H) , 6.95 (m, 2H), 5.40 (s, 2H), 3.83 (m, 1 H), 3.62 (m, 1 H), 3.54 (m, 2H), 3.38 (m, 1 H), and 1.48 (2d) , 6H, J = 1.6 Hz); ES-HREM m / z 448.0705 (M + H cale, for C17H21N3O4F2Br requires 448.0678).
EXAMPLE 24 5-bromo-6-r (2,4-difluorobenzyl) oxp-3-isopropyl-2-morpholin-4-ylpyrimidin-4 (3H) -one A mixture of 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) -pyrimidin-4 (3H) -one (0.44 g, 1.0 mmol), morpholine (0.14 g) , 1.6 mmol), and DMAP (0.016 g) in dioxane (5.0 ml) containing diisopropylethylamine (0.13 g, 1.0 mmol) was stirred at room temperature for 16 hours under nitrogen atmosphere. The reaction mixture was diluted with water (15.0 ml) and extracted with dichloromethane (2 x 15 ml). The combined organic extracts were washed with water, dried (Na2SO4), concentrated and the residue was purified by reverse phase HPLC using 10-90% CH3CN / water gradient (45 minutes) containing 0.5% trifluoroacetic acid at a flow rate of 80 ml / minute. The appropriate fractions were combined (MH +, m / z = 444/446), and concentrated to -25 ml, 5% sodium bicarbonate (10 ml) was added and the product was extracted with dichloromethane (2 x 15 ml) . The combined organic extracts were washed with water (2 x 10 ml), dried (Na2SO4) and concentrated to dryness under reduced pressure to give the title compound (0.21 g, 47%) as a pale powder: 1 H NMR (CD3OD / 400 MHz) d 7.48 (m, 1 H), 6.96 (m, 2H), 5.45 (s, 2H), 4.62 (m, 1 H), 3.79 (m, 4H), 3.27 (m, 4H), and 1.57 (d, 6H, J = 6.4 Hz); ES-HREM m / z 444.0744 (M + H cale, for C? 8H21N3O3F2Br requires 444.0729).
EXAMPLE 25 5-bromo-6-r (214-difluorobenzyl) oxy-3-isopropylpyrimidin-4 (3H) -one Step 1: Preparation of 6-f (2,4-difluorobenzyl) oxv1-3-isopropylpyrimidin-4 (3H) -one.
To 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) was added a Raney nickel suspension (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 continued for an additional 2 hours. The catalyst was allowed to settle and the supernatant was removed by pipette. The catalyst was washed with ethanol (2 x 25 ml), the supernatant and organic washings were combined, concentrated, and dried in vacuo. The resulting residue was used without further purification in the next step.
Step 2: Preparation of the title compound. To a cooled (0 ° C) solution of 6 - [(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one (0.34 g, 1.2 mmol) in DCM (3 mL), N was added. -bromosuccinimide (0.19 g, 1.1 mmol). The reaction mixture was allowed to warm to room temperature. After 4 hours the reaction mixture was concentrated and the residue was purified by preparative HPLC using a CH3CN gradient of 10-90% / H2O (30 minutes) containing 0.5% TFA at a flow rate of 80 ml / minute. . The appropriate fractions (M + H m / z = 360) were combined and concentrated to approximately 20 ml under reduced pressure. 5% NaHCO3 (20 ml) was added and extracted with dichloromethane (3 x 15 ml). The combined organic extracts were dried over Na2SO4, 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 (CD3OD / 400 MHz) d 8.33 ( s, 1 H), 7.53 (c, 1 H, J = 8.0 Hz), 6.95 (m, 2H), 5.48 (s, 2H), 4.93 (quintet, 1 H, J = 6.8 Hz), 1.43 (d, 6H, J = 6.8 Hz). ES-HREM m / z 359.0202 (M + H calculated for C14H14BrF2N2O2 requires 359.0201).
EXAMPLE 26 5-bromo-6-f (2,4-difluorobenzyl) oxp-3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one To a cooled (0 ° C) solution of 6 - [(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one (0.20 g, 0.61 mmol) in DCM (2 ml) was added? / - bromosuccinimide (0.11 g, 0.61 mmol). It was stirred at 0 ° C for 30 minutes, at room temperature for 4 h. The crude residue was concentrated and purified by preparative HPLC using 10-90% CH 3 CN gradient / H 2 O (30 minutes) containing 0.5% TFA at a flow rate of 80 ml / minute. The appropriate fractions (M + H m / z = 406) were combined and concentrated to approximately 25 ml under reduced pressure. It was added 5% NaHCO3 (20 ml) and extracted with dichloromethane (3 x 15 ml). The organic extracts were dried over Na2SO, 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) d 7.49 (c, 1 H, J = 8.4 Hz), 6.97 (m, 2 H), 5.51 (s, 2 H), 4.63 (m, 1 H), 2.57 (s, 3 H) , 1.55 (d, 6H, J = 6.8 Hz). ES-HREM m / z 405.0089 (M + H calculated for C15H16BrF2N2O2S requires 405.0078).
EXAMPLE 27 5-bromo-6-f (2,4-difluorobenzyl) oxy1-2-r (3R) -3- (ethylamino) pyrrolidin-1-yl1-3-isopropylpyrimidin-4 (3H) -one Step 1. Preparation of (3R) -1- (5-bromo-4-f (2,4-d-fluorobenzyl) oxyl-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl) pyrrolidin- 3-Tert-butyl ketone D-carbamate.
To a cold solution of (3R) -1-. { 5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} Tert-butyl pyrrolidin-3-ylcarbamate (0.4 g, 0.74 mmol) in anhydrous tetrahydrofuran (4 mL) was added with NaH (0.026 g 1.1 mmol) followed by the addition of iodoethane (0.12 mL, 1.5 mmol). The reaction mixture was stirred at room temperature overnight under nitrogen. Subsequent addition of iodoethane (0.05 ml, 0.5 equiv) was required. The reaction mixture was heated for 3 hours in an oil bath at 69 ° C. It was cooled, diluted with a cold solution of citric acid (5%) and extracted with ethyl acetate. The organic extracts were concentrated, the residue was 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 TFA at room temperature. 0.5% at a flow rate of 80 ml / minute. The appropriate fractions (M + H m / z = 571) were combined and freeze-dried yielding 0.180 g (43%) of (3R) -1-. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} Tert-butyl pyrrolidin-3-yl (ethyl) carbamate as a white solid: 1H NMR (CD3OD, 400 MHz) d 7.51 (c, 1 H, J = 8.4 Hz), 6.96 (m, 2H), 5.43 (m , 2H), 4.43 (m, 2H), 3.60 (m, 4H), 3.27 (m, 1 H), 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-HREM m / z 571.1721 (M + H C 25 H 3 BrF 2 N 4 O 4 requires 571.1726).
Step 2. Preparation of the title compound. To a solution of (3R) -1-. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} tert-butyl pyrrolidin-3-ethyl (ethyl) carbamate (0.162 g, 0.28 mmol) from Step 1 in dichloromethane (3 ml) was added trifluoroacetic acid (0.5 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated by removing the solvent, the residue was 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 / minute. The appropriate fractions (M + H m / z -471) were combined and freeze dried yielding 0.110 g (82%) of 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -2 - [(3R) ) -3- (ethylamino) pyrrolidin-1-yl] -3-isopropyl-pyrimidin-4 (3H) -one as a white solid: 1H-NMR (CD3OD, 400 MHz) d 7.51 (c, 1 H, J = 8.4 Hz) , 6.93 (m, 2H), 5.43 (s, 2H), 4.48 (m, 1 H), 3.96 (m, 2H), 3.69 (m, 3H), 3.17 (m, 2H), 2.43 (m, 1 H) ), 2.19 (m, 1 H), 1.61 (dd, 6H, J = 2.4 Hz), 1.37 (t, 3H, J = 7.2 Hz). ES-HREM m / z 471.1169 (M + H C2oH26BrF2N4O4 requires 471.1202).
EXAMPLE 28 5-bromo-6-f (2,4-d? Fluorobenzyl) oxy-3-isopropyl-2-r (3R) -3- (methylamino) pyrrolidin-1-ylpyrimidin-4 (3H) -one Step 1. Preparation of (3R) -1- (5-bromo-4 - [(2,4-difluorobenzyl) oxyl-1-isopropyl-6-oxo-1,6-dihydropyridin-2-yl) pyrrolidin- 3-yl (methyl) carbamic acid tert-butyl ester.
To a cold solution of (3R) -1-. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyridin-2-yl} Tert-butyl pyrrolidin-3-ylcarbamate (0.4 g, 0.74 mmol) in anhydrous tetrahydrofuran (4 mL) was added with NaH (0.026 g 1.1 mmol) followed by the addition of iodomethane (0.09 mL, 1.5 mmol). The reaction mixture was stirred at room temperature for 3 hours under nitrogen. The subsequent addition of iodomethane (0.06 ml, 1.0 equiv.) And NaH (0.013 g, 0.5 equiv.) Is required. The reaction mixture was stirred at room temperature for 3 h and then cooled, treated with a cold citric acid solution (5%) and extracted with ethyl acetate. The organic extracts were concentrated, the residue was 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 TFA at room temperature. 0.5% at a flow rate of 80 ml / minute. The appropriate fractions (M + H m / z -557) were combined and freeze-dried yielding 0.33 g (80%) of (3R) -1-. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} Tert-butyl pyrrolidin-3-yl (methyl) carbamate as a white solid: 1 H NMR (CD 3 OD, 400 MHz) d 7.51 (c, 1 H, J = 8.4 Hz), 6.97 (m, 2 H), 5.43 (c , 2H), 4.65 (m, 1 H), 4.45 (m, 1 H) 3.61 (m, 4H), 2.83 (s, 3H), 2.10 (m, 2H), 1.65 (d, 3H, = 6.4 Hz) , 1.50 (d, 3H, J = 6.4 Hz), 1.13 (s, 9H). ES-HREM m / z 557.1522 (M + H C 24 H 32 BrF 2 N 4 O 4 requires 557.1570).
Step 2. Preparation of the title compound. To a solution of (3R) -1-. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} tert-butyl pyrrolidin-3-yl (methyl) carbamate (0.30 g, 0.53 mmol) from Step 2 in dichloromethane (3 ml) was added trifluoroacetic acid (1.0 ml). The reaction mixture was stirred at room temperature for 30 minutes. It was concentrated by removing the solvent, the residue was 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 TFA at room temperature. 0.5% at a flow rate of 80 ml / minute. The appropriate fractions (M + H m / z = 457) were combined and freeze dried yielding 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 as a white solid: 1H NMR (CD3OD, 400 MHz) d 7.51 (c, 1 H, J = 8.4 Hz ), 6.99 (m, 2H), 5.43 (s, 2H), 4.48 (m, 1 H), 3.96 (m, 2H), 3.69 (m, 3H), 2.97 (s, 3H), 2.43 (m, 1) H), 2.19 (m, 1 H), 1.62 (d, 3H, J = 6.4 Hz), 1.59 (d, 3H, J = 6.4 Hz). ES-HREM m / z 457.1169 (M + H C19H23BrF2N4O4 requires 457.1202).
EXAMPLE 29 (3R) -1-. { 5-bromo-4-f (2,4-difluorobenzyl) oxyM-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyridin-3-ylmethyl pyrrolidin-3-ylcarbamate To a solution of 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 (0.075 ml, 0.54 mmol). 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) was added. ) oxy] -3-isopropylpyrimidin-4 (3H) -one (0.20 g, 0.45 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was concentrated, the residue was 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 / minute. The appropriate fractions (M + H m / z = 578) were combined and dried by freezing yielding 0.13 g (42%) of (3R) -1 -. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyridin-3-ylmethyl pyrrolidin-3-ylcarbamate as a white solid: H-NMR (CD3OD, 400 MHz) d 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, 1 H, J = 5.6 Hz), 7.51 (c, 1 H, J = 8.4 Hz), 6.96 (m, 2H), 5.40 (s, 2H), 5.25 (s, 2H), 4.43 (m, 1 H), 4.20 (m , 1 H), 3.80 (m, 2H), 3.68 (m, 1 H), 3.44 (m, 1 H), 2.19 (m, 1 H), 2.02 (m, 1 H), 1.61 (d, 3H, J = 6.4 Hz), 1.54 (d, 3H, J = 6.4 Hz). ES-HREM m / z 578.1234 (M + H C25H27BrF2N5O4 requires 578.1209).
EXAMPLE 30 (3R) -1-. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyridin-2-ylmethyl pyrrolidin-3-ylcarbamate The title compound was prepared by a procedure similar to that described for (3R) -1-. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} Pyridin-3-ylmethyl pyrrolidin-3-ylcarbamate which used 2-hydroxymethylpyridine (0.051 mL, 0.62 mmol). After purification with reverse phase HPLC, the appropriate fractions were combined and dried by freezing affording 0.20 g (47%) of (3R) -1-. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyridin-3-ylcarbamate pyridin-2-ylmethyl as a white solid: 1H NMR (CD3OD, 400 MHz) d 8.60 (d, 1 H, J = 5.2 Hz), 8.08 (m, 1 H), 7.67 (d, 1 H, J = 8 Hz), 7.52 (m, 2H), 6.96 (m, 2H), 5.40 (s, 2H), 5.25 (s, 2H), 4.42 (m, 1 H), 4.20 (m, 1 H), 3.80 (m, 2H), 3.68 (m, 1 H), 3.49 (m, 1 H), 2.19 (m, 1 H), 2.02 (m, 1 H), 1.61 (d, 3H, J = 6.8 Hz), 1.54 (d, 3H, J = 6.8 Hz). ES-HREM m / z 578.1234 (M + H C25H27BrF2N5O4 requires 578.1209). EXAMPLE 31 5-bromo-6-r (2,4-difluorobenzyl) oxy1-2 - ((3R) -3-f (2-hydroxyethyl) aminolpyrrolidin-1-yl.} - 3-isopropylpyrimidin-4 (3H) -one Step 1. Preparation of 5-bromo-6-f (2,4-difluorobenzyl) oxp-3-isopropyl-2 - ((3R) -3- { [2- (tetrahydro-2H-pyran-2-yloxy ) ethyleneamino-pyrrolidin-1-yl) pyrimidin-4 (3H) -one.
To a cold solution of (3R) -1-. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} Tert-butyl pyrrolidin-3-ylcarbamate (OJ g, 1.29 mmol) in anhydrous tetrahydrofuran (7 ml) was added with NaH (0.046 g 1.96 mmol) followed by the addition of 2- (2-bromoethoxy) tetrahydro-2H-pyran ( 0.29 ml, 1.96 mmol). The reaction mixture was heated in an oil bath at 69 ° C overnight under nitrogen. The subsequent addition of 2- (2-bromoethoxy) tetrahydro-2H-pyran (0.13 ml, 0.5 eq.) And NaH (0.02 g, 0.5 eq.) Was necessary. The reaction mixture was continued heating overnight. It was cooled, diluted with a cold solution of citric acid (5%) and extracted with ethyl acetate. The organic extracts were concentrated, the residue was 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 TFA at room temperature. 0.5% at a flow rate of 80 ml / minute. The appropriate fractions (M + H m / z = 671) were combined and freeze dried yielding 0.29 g (29%) of 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-isopropyl-2 - ((3R) -3- { [2- (tetrahydro-2 H -pyran-2-yloxy) ethyl] amino} pyrrolidin-1-yl) pyrimidin-4 (3 H) -one.
Step 2. Preparation of the title compound. Trifluoroacetic acid (1.0 ml) was added to a solution 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 (0.29 g, 0.43 mmol) from Step 1 in dichloromethane. The reaction mixture was stirred at room temperature for 2.5 hours. It was 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 / minute. The appropriate fractions (M + H m / z = 487) were combined and freeze dried yielding 0.040 g of 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -2-. { (3R) -3 - [(2-hydroxyethyl) amino] pyrrolidin-1-yl} -3-isopropylpyrimidin-4 (3H) -one (19%) as a white solid: 1H-NMR (CD3OD, 400 MHz) d 7.53 (c, 1 H, J = 5.2 Hz), 7.01 (m, 2H), 5.44 (s, 2H), 4.48 (m, 1 H), 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, 1 H), 1.61 (d, 3H, J = 6.8 Hz), 1.54 (d, 3H, J = 6.8 Hz). ES-HREM m / z 487.1187 (M + H C20H26BrF2N4O3 requires 487.1151).
EXAMPLE 32 N2-. { 5-bromo-4-r (2,4-difluorobenzyl) oxp-1-methyl-6-oxo-1,6-dihydropyriminedin-2-yl} glycinamide Step 1: Preparation of 6-hydroxy-3-methyl-2- (methylthio) pyrimidin-4 (3H) -one as described in U.S. Patent 4,152,426 (1979).
Step 2: Preparation of 6- (2,4-difluorobenzyl) oxy-3-methyl-2- (methylthio) pyrimidin-4 (3H) -one.
A suspension of 6-hydroxy-3-methyl-2- (methylthio) pyrimidin-4 (3H) -one (64 g, 0.371 mol) from Step 1 and 325 mesh potassium carbonate (52 g, 0.372 mol) in 170 ml of N-methylpyrrolidinone was heated at 50 ° C to obtain a slurry. 2,4-difluorobenzyl bromide (77 g, 0.372 mol) was added without dilution for 20 minutes, allowing an exotherm of 10 ° C (the final temperature is 55-60 ° C). The suspension now becomes thinner and easier to shake in about 10 minutes, indicating significant completion. The temperature was lowered to 50 ° C and maintained for an additional 2 hours. The mixture was cooled to room temperature and 400 ml of water was added with vigorous stirring. The precipitated solids were filtered and washed four times with 250 ml of water and dried at 50 ° C and under vacuum of 20 mm (2.66 kPa). The crude product was purified by flash chromatography on a 75 I Biotage column using 10% ethyl acetate in hexanes to obtain 50 g (46%) of the 6- (2,4-difluorobenzyloxy) -3-methyl-2 - (methylthio) pyrimidin-4 (3H) -one: 1 H NMR (400 MHz, CDCl 3) d 7.40-7.32 (m, 1 H), 6J5-6.9 (m, 2H), 7.11 (m, 1 H), 5.57 (s, 1 H), 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.
N-bromosucinimide (29.2 g, 0.16 mol) was added in portions to a stirred solution of 6- (2,4-difluorobenzyloxy) -3-methyl-2- (methylthio) pyrimidin-4 (3H) -one (49 g, 0.16 mol) of Step 2 in 400 ml of methylene chloride maintained at room temperature. The exotherm was minimal (2-3cC) and the reaction was stirred for two hours. MCPBA (metachloroperbenzoic acid) (73 g, 0.32 mol based on the 77% assay) was added in three portions at room temperature over a period of one hour. The exotherm was smooth as before and this suspension was stirred vigorously for 12 hours. The reaction mixture was filtered off removing most of the reduced side products and the filtrate was concentrated and passed through a bed of neutral alumina (150 g) using methylene chloride as the solvent. 5-Bromo-6 - [(2,4-difluorobenzyl) oxy] -3-methyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (29 g, 55%) was obtained after drying as a semi-crystalline solid. colorless. 1 H NMR (400 MHz, CDCl 3) d 7.39-7.48 (m, 1 H), 6 J8-6.92 (m, 2 H), 5.42 (s, 2 H), 3.83 (s, 3 H), 3.39 (s, 3 H).
Step 4: Preparation of the title compound. To a solution of 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-methyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (0.5 g, 1.22 mmol) from Step 3 in 1.4 anhydrous dioxane (5 ml) was added diisopropylethylamine (0.43 ml, 2.44 mmol), glycine amide hydrochloride (0.135 g, 1.22 mmol) and DMAP (0.03 g). The reaction mixture was heated at 70 ° C in an oil bath for 2.5 h under nitrogen. The reaction mixture was 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 1%. flow rate of 80 ml / minute. The appropriate fractions were combined and freeze-dried (M + H m / z = 403) yielding 0.066 g (13%) of N2-. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl} glycinamide as a white solid: 1H-NMR (CD3OD, 400 MHz) d 7.53 (c, 1 H, J = 5.2 Hz), 6.96 (m, 2H), 5.39 (s, 2H), 4.04 (s, 2H), 3.44 (s, 3H). ES-HREM m / z 403.0198 (M + H C14H14BrF2N4O3 requires 403.0212). ? / - [3- ( { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl ] acetamide Step 1. Preparation of 6- (2,4-difluorobenzyloxy) -2- (3-aminopropylamino) -5-bromo-3-isopropylpyrimidin-4 (3H) -one. 6- (2,4-difluorobenzyloxy) -5-bromo-3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (3.0 g, 6.9 mmol) was dissolved in dichloromethane (30 ml).
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 phase was extracted into ethyl acetate. The combined organics were dried over MgSO 4, filtered, and concentrated. The residue was dissolved in methanol at approximately 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) d ppm 1.52 (d, J = 6.98 Hz, 6 H) 1.97 (m, 2 H) 2.94 (m, 2 H) 3.54 (t, J = 6.71 Hz, 2 H) 4.73 (m, 1 H ) 5.42 (s, 2H) 6.99 (m, 2H) 7.53 (m, 1 H). LC / MS, tr = 1.99 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 433 (M + 1).
Step 2. Preparation of? / - [3- (. {5-bromo-4-f (2,4-difluorobenzyl) oxyl-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl) amino ) propyl acetamide. The trifluoroacetic acid salt of 6- (2,4-difluorobenzyloxy) -2- (3-aminopropylamine) -5-bromo-3-isopropylpyrimidin-4 (3H) -one was dissolved (from step 1) (0.4 g, 0.76 mmol) in dichloromethane (4 ml) and cooled in an ice bath. Triethylamine (0.3 ml, 2.3 mmol) was added. A solution of acetyl chloride (0.07 ml, 0.84 mmol) in dichloromethane (1 ml), pre-cooled in an ice bath, was added to the reaction mixture. The cooling was removed and the reaction mixture was heated at room temperature for 1 hour. The reaction was deactivated by the addition of NaHCO3 solution. The aqueous phase was extracted into dichloromethane. The combined organic extracts were dried over MgSO, filtered, and concentrated. The residue was purified by chromatography (silica gel, hexanes / ethyl acetate with 10% methanol) to give a white solid (0.092 g, 26%). 1 H NMR (400 MHz, CD3OD) d 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, 1 H) 5.42 (s, 2H) 6.98 (m, 2H) 7.49 (m, 1 H), ES-HREM m / z 473.0986 (M + H cale, for C19H24BrF2N4O3 requires 473.0904). ? -r3- ( {5-bromo-4-f (2,4-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyurea Preparation of N- [3- (. {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1- isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] urea. The trifluoroacetic acid salt 6- (2,4-difluorobenzyloxy) -2- (3-aminopropylamino) -5-bromo-3-isopropylpyrimidin-4 (3H) -one (example 33, step 1) (0.40 g) was dissolved. , 0.76 mmol) in dichloromethane (4 ml) followed by the addition of triethylamine (0.3 ml, 2.3 mmol) at room temperature. Trimethylsilyl isocyanate (0.1 ml, 0.84 mmol) in dichloromethane (1 ml) was added to the reaction mixture. The reaction mixture was stirred overnight at room temperature. The resulting precipitate was filtered then washed with ether and dried over a vacuum pump to give a white solid (0.175 g, 49%). 1 H NMR (400 MHz, DMSO-d 6) d ppm 1.43 (d, J = 6.71 Hz, 6H) 1.57 (m, 2H) 3.00 (m, 2H) 3.35 (m, 2H) 4.78 (m, 1 H) 5.35 ( s, 2H) 7.12 (m, 1 H) 7.28 (m, 1 H) 7.52 (m, 1 H), ES-HREM 474.0918 (M + H cale, for C18H23BrF2N5O3 requires 474.0947).
EXAMPLE 35 ? / - r3 - ((5-bromo-4-r (2,4-difluorobenzyl) oxyM-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. amino) propylmethanesulfonamide Preparation of? / - [3- ( { 5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1- Prepared as A / - [3- (. {5-bromo-4- [ (2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] acetamide (step 2) using trifluoroacetic acid salt of 6- (2, 4-difluorobenzyloxy) -2- (3-aminopropylamino) -5-bromo-3-isopropylpyrimidin-4 (3H) -one (? / - [3- (. {5-bromo-4 - [(2,4- difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyridin-2-yl}. amino) propyl] acetamide, step 1) (0.399 g, 0J6 mmol) and methanesulfonyl chloride (0.065 ml 0.83 mmol) to give a white solid (0.123 g, 32%). 1 H NMR (400 MHz, CD3OD) d 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, 1 H) 5.43 (s, 2H) 6.98 (m, 2H) 7.50 (m, 1 H), ES- HREM 509.0655 (M + H cale, for C? 8H24BrF2N4O S requires 509.0664). ? / - r3- ( {5-bromo-4-f (2,4-difluorobenzyl) oxy-1-isopropyl-6-oxo-116-dihydropyrimidin-2-yl} amino) propin -2-hydroxy-2-methylpropanamide Step 1. Preparation of 2- (3- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) propylcarbamoyl) propan-2 acetate -ilo.
Prepared as? / - [3- ( { 5-bromo-4 - [(2,4-d? -fluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2- il.}. amino) propyl] acetamida (step 2) using trifluoroacetic acid salt of 6- (2,4-difluorobenzyloxy) -2- (3-aminopropylamino) -5-bromo-3-isopropylpyrimidin-4 (3H ) -one (N- [3- (. {5-bromo-4- [(2,4-d, fluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] acetamide, step 1) (0.399 g, 0.76 mmol) and 2- (chlorocarbonyl) propan-2-yl acetate (0.14 ml, 0.84 mmol) yielding a white solid (0.234 g, 55%). LC / MS, tr = 2.89 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C). ES-MS m / z 561 (M + 1).
Step 2. Preparation of? / - r3 - ((5-bromo-4-r (2,4-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl) amino) propyl- 2-hydroxy-2-methylpropanamide. 2- (3- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) propylcarbamoyl) propan-2-acetate was dissolved. ilo (from step 1) (0.234 g, 0.42 mmol) in methanol / water (3 ml) and K2CO3 (0.087 g, 0.63 mmol) was 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 phase was neutralized (pH 7) with 1.0 M HCl. The aqueous phase was extracted into ethyl acetate. The combined organics were dried over MgSO, filtered, and concentrated to give an off white solid (0.193 g, 89%). 1 H NMR (400 MHz, CD3OD) d 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, 1 H) 5.42 (s, 2H) 6.98 (m, 2H) 7.49 (m, 1 H), ES-HREM 517.1256 (M + H cale, for C21H28BrF2N4O4 requires 517.1256).
EXAMPLE 37 ? / - f3- ( {5-bromo-4-f (2,4-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl1-2-hydroxyacetamide Step 1. Preparation of (3- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) propylcarbamoyl) methyl acetate.
Prepared as N- [3- (. {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyridin-2-yl}. amino) propyl] acetamide (step 2) using trifluoroacetic acid salt of 6- (2,4-difluorobenzyloxy) -2- (3-aminopropylamino) -5-bromo-3-isopropylpyrimidin-4 (3H) -one (? - [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, 0J7 mmol) and (chlorocarbonyl) methyl acetate (0.091 ml, 0.85 mmol) yielding a white solid (0.112 g, 27%). LC / MS, tr = 2.60 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 533 (M + 1).
Step 2. Preparation of? / - f3 - ((5-bromo-4-f (2,4-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl) amino) propi l1-2-hydroxyacetamide.
Prepared as? / - [3- ( { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. amino) propyl] -2-hydroxy-2-methylpropanamide (step 3) using (3- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl acetate) -6-oxopyrimidin-2-ylamino) propylcarbamoyl) methyl (from step 1) (0.112 g, 0.21 mmol) and K2CO3 (0.045 g, 0.32 mmol) to give a white solid (0.022 g, 21%). 1 H NMR (400 MHz, CD3OD) d 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, 1 H) 5.42 (s, 2H) 6.97 (m, 2H) 7.49 (m, 1 H), ES-HREM 489.0934 (M + H cale, for C? 9H24BrF2N4O requires 489.0943).
EXAMPLE 38 6-f (2,4-difluorobenzyl) oxy-3-isopropyl-2-phenylpyrimidin-4 (3H) -one Preparation of 6 - [(2,4-difluorobenzyl) oxy] -3-isopropyl-2-phenylpyrimidin-4 (3H) -one. 6- (2,4-Difluorobenzyloxy) -3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one (0.10 g) was added., 0.31 mmol), phenylboronic acid (0.063 g, 0.52 mmol), copper salt of 2-hydroxy-3-methylbenzoic acid (0.16 g, 0.68 mmol), and tetrakis (triphenylphosphine) of palladium (O) (0.036 g, 0.031 mmol) was added to a dry flask and evacuated followed by purging with N2. This procedure was repeated three times. Dioxane (2 ml) was added and the reaction mixture was heated at 80 ° C for 15 hours. The reaction mixture was cooled and the residue was dissolved in ethyl acetate, washed with brine. The aqueous phase was extracted into ethyl acetate. The combined organics were dried over MgSO, filtered, and concentrated. The residue was purified by chromatography (silica gel, hexanes / ethyl acetate) to give a clear oil (0.096 g, 86%). 1 H NMR (400 MHz, CD 3 OD) d ppm 1.51 (d, J = 6.98 Hz, 6 H) 4.35 (m, 1 H) 5.27 (s, 2 H) 5 J 2 (s, 1 H) 6.98 (s, 2 H) 7.53 (m , 6H). LC / MS, tr = 3.09 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 357 (M + 1).
EXAMPLE 39 5-bromo-6-f (2,4-difluorobenzyl) oxy-3-isopropyl-2-phenylpyrimidin-4 (3H) -one Preparation of 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -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 cooled in a bath of ice. Slowly? / - bromosuccinimide (0.022 g, 0.123 mmol) was added and the reaction mixture was stirred for 1 hour with cooling. The reaction was concentrated and dissolved in ethyl acetate then washed with water. The aqueous phase was extracted into ethyl acetate. The combined organics were dried over MgSO 4, filtered, and concentrated. The residue was dissolved in 30% ethyl acetate / hexanes and passed through a pad of silica gel to give a yellow oil (0.045 g, 92%). H-NMR (400 MHz, CD3OD) d ppm 1.53 (d, J = 6.71 Hz, 6H) 4.40 (m, 1 H) 5.43 (s, 2H) 6.94 (m, 2H) 7.55 (m, 6H), ES-HREM 435.0530 (M + H cale, for C20H18BrF2N2O2 requires 435. 0514).
EXAMPLE 40 Preparation of 3-. { 4-f (2,4-difluorobenzyl) oxyl-1-isopropyl-6-oxo-1,6,6-dihydropyrimidin-2-yl} methyl benzoate Preparation of 3-. { 4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} methyl benzoate. Prepared as 5-bromo-6 - [(2,4-d-fluorobenzyl) oxy] -3-isopropyl-2-phenylpyrimidin-4 (3H) -one using 3- (methoxycarbonyl) phenylboronic acid (0.936 g , 5.2 mmol) in place of phenylboric acid, giving an off white solid (0.923 g, 72%). 1 H NMR (400 MHz, CD 3 OD) d ppm 1.52 (d, J = 6.71 Hz, 6 H) 4.30 (m, 1 H) 4.84 (s, 3 H) 5.28 (s, 2 H) 5.74 (s, 1 H) 6.94 (m , 2H) 7.49 (m, 1 H) 7.68 (t, J = 8.06 Hz, 1 H) 7.78 (ddd, J = 1.34, 1.48, 7.92 Hz, 1 H) 8.15 (m, 1H) 8.20 (dt, J = 1.48, 7J9 Hz, 1 H), ES-HREM 415.1470 (M + H cale, for C22H21F2N2O4 requires 415.1464).
EXAMPLE 41 4- (4-R (214-difluorobenzyl) oxyM-isopropyl-6-oxo-1,6-dihydropyrimidine-2-iDbenzamide Preparation of 4-. { 4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyridin-2-yl} benzamide. Prepared as 5-bromo-6 - [(2,4-d-fluorobenzyl) oxy] -3-isopropyl-2-phenylpyrimidin-4 (3H) -one using 4-carbamoylphenylboronic acid (0.264 g, 1.6 mmol ) instead of phenylboric acid, giving a light green solid (0.254 g, 69%). 1 H NMR (400 MHz, CD 3 OD) d ppm 1.52 (d, J = 6.71 Hz, 6 H) 4.29 (m, 1 H) 5.28 (s, 2 H) 5.74 (s, 1 H) 6.96 (m, 2 H) 7.49 (m , 1 H) 7.63 (d, J = 8.59 Hz, 2H) 8.03 (d, J = 8.59 Hz, 2H), ES-HREM 400.1480 (M + H cale, for C2? H20F2N3O3 requires 400.1467).
EXAMPLE 42 5-chloro-6-f (2,4-d-fluorobenzyl) oxp-3-isopropyl-2-phenylpyrimidin-4 (3H) -one Preparation of 5-chloro-6 - [(2,4-difluorobenzyl) oxy] -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 cooled in an ice bath . Slowly? / - chlorosuccinimide (0.13 g, 0.98 mmol) was added and the reaction mixture was stirred for 1 hour with cooling. Dichloroacetic acid (cat.) Was added and the reaction mixture was warmed to room temperature overnight. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate then washed with water. The aqueous phase was extracted into ethyl acetate. The combined organics were dried over MgSO, filtered, and concentrated. The residue was purified by chromatography (silica gel, ethyl acetate / hexanes) to give a white solid (0.204 g, 59%). 1 H NMR (400 MHz, CD3OD) d ppm 1.53 (d, J = 6.71 Hz, 6H) 4.40 (m, 1 H) 5.44 (s, 2H) 6.95 (m, 2H) 7.55 (m, 6H), ES-HREM 391.1034 (M + H cale, for C2oH18CIF2N2O2 requires 391.1019).
EXAMPLE 43 4-. { 5-bromo-4-f (2,4-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamide Preparation of 4-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamide. Prepared as 5-chloro-6 - [(2,4-difluorobenzyl) oxy] -3-isopropyl-2-phenylpyrimidin-4 (3H) -one using 4-. { 4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamide (0.102 g, 0.26 mmol) and? / - chlorosuccinimide (0.039 g, 0.29 mmol) to give a white solid (0.051 g, 46%). 1 H NMR (400 MHz, CD 3 OD) d ppm 1.54 (d, J = 6.71 Hz, 6 H) 4.34 (m, 1 H) 5.44 (s, 2 H) 6.94 (m, 2 H) 7.49 (m, 1 H) 7.64 (d , J = 8.86 Hz, 2H) 8.04 (d, J = 8.59 Hz, 2H), ES-HREM 434.1059 (M + H cale, for C21H19CIF2N3O3 requires 434.1078).
EXAMPLE 44 4-. { 5-bromo-4-r (2,4-difluorobenzyl) oxyM-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamide Preparation of 4-. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamide. Prepared as 5-bromo-6 - [(2,4-d-fluorobenzyl) oxy] -3-isopropyl-2-phenylpyrimidin-4 (3H) -one using 4-. { 4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamide (0.076 g, 0.19 mmol) and? / - bromosuccinimide (0.038 g, 0.21 mmol) providing a light brown solid (0.065 g, 74%). 1 H NMR (400 MHz, CD 3 OD) ppm 1.54 (d, J = 6.71 Hz, 6 H) 4.34 (m, 1 H) 5.44 (s, 2 H) 6.96 (m, 2 H) 7.49 (m, 1 H) 7.65 (d, J = 8.59 Hz, 2H) 8.05 (d, J = 8.59 Hz, 2H), ES-HREM 478.0541 (M + H cale, for C21H19BrF2N3O3 requires 478.0572).
Acid 3-. { 4-r (2,4-difluorobenzyl) oxyM-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzoic Preparation of acid 3-. { 4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzoic. It dissolved 3-. { 4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} Methyl benzoate (0.87 g, 2.1 mmol) in tetrahydrofuran (20 ml) and 2.5 N NaOH (8 ml, 20.0 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solvent was removed and the aqueous phase was neutralized (pH 7) with 1.0 M HCl. The aqueous phase was extracted into ethyl acetate. The combined organics 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) d ppm 1.53 (d, J = 6.44 Hz, 6 H) 4.32 (m, 1 H) 5.29 (s, 2 H) 5.73 (s, 1 H) 6.96 (m, 2 H) 7.57 (m , 2H) 7J2 (m, 1 H) 8.14 (m, 2H). LC / MS, tr = 2.60 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 401 (M + 1).
EXAMPLE 46 3-. { 4-f (2,4-difluorobenzyl) oxyM-isopropyl-6-oxo-1,6-dihydropyrimidine-2-iPbenzamide Preparation of 3-. { 4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamida. It dissolved 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. An excess of 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 then washed in water. The aqueous phase was extracted into ethyl acetate. The combined organics were dried over MgSO 4, filtered, and concentrated. The residue was purified by chromatography (silica gel, ethyl acetate with 10% methanol / hexanes) to give a white solid (0.56 g, 67%). 1 H NMR (400 MHz, CDCl 3) d ppm 1.53 (d, J = 6.71 Hz, 6H) 4.26 (m, 1 H) 5.17 (s, 2 H) 5.73 (s, 1 H) 6.82 (m, 2 H) 7.39 (m , 1 H) 7.58 (m, 2H) 7.96 (m, 2H), ES-HREM 400.1444 (M + H cale, for C2? H20F2N3O3 requires 400.1467).
EXAMPLE 47 3-. { 5-bromo-4-f (2,4-difluorobenzyl) oxyM-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamide Preparation of 3-. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamide. Prepared as 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-isopropyl-2-phenylpyrimidin-4 (3H) -one (step 2) using 3-. { 4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamide (0.200 g, 0.50 mmol) and A / -bromosuccinimide (0.098 g, 0.55 mmol) to give a white solid (0.188 g, 79%). 1 H NMR (400 MHz, CD 3 OD) d ppm 1.55 (d, J = 6.98 Hz, 6 H) 4.36 (m, 1 H) 5.44 (s, 2 H) 6.96 (m, 2 H) 7.52 (m, 1 H) 7.67 (m , 1 H) 7.74 (m, 1 H) 8.04 (m, 1H) 8.09 (m, 1 H), ES-HREM 478.0573 (M + H cale, for C2? H19BrF2N3O3 requires 478.0572).
EXAMPLE 48 3-. { 5-Chloro-4-f (2,4-difluorobenzyl) oxyl-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamide Preparation of 3-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamide. Prepared as 5-chloro-6 - [(2,4-difluorobenzyl) oxy] -3-isopropyl-2-phenylpyrimidin-4 (3H) -one using 3-. { 4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzamide (0.200 g, 0.50 mmol) and? / - chlorosuccinimide (0.077 g, 0.55 mmol) to give a white solid (0.133 g, 61%). 1 H NMR (400 MHz, CD 3 OD) d ppm 1.55 (d, J = 6.98 Hz, 6 H) 4.36 (m, 1 H) 5.45 (s, 2 H) 6.96 (m, 2 H) 7.51 (m, 1 H) 7.67 (m , 2H) 8.04 (m, 2H), ES-HREM 434.1081 (M + H cale, for C2 H 9CIF2N3O3 requires 434.1078).
EXAMPLE 49 ? K? ~ -. { 5-bromo-4-r (2,4-difluorobenzyl) oxyl-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -beta-alaninamide Step 1. Preparation of ethyl 3- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylammonyl) propanoate.
Prepared as? / - [3- ( { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. amino) propyl] acetamide (step 1) using ethyl 3-aminopropanoate (0.388 g, 2.52 mmol) in place of propane-1,3-diamine to give a clear oil (0.47 g, 43%). 1 H NMR (400 MHz, CD3OD) d 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) 4.1 1 (c, J = 7.25 Hz, 2H) 4.79 (m, 1 H) 5.42 (s, 2H) 6.97 (m, 2H) 7.50 (m, 1 H). LC / MS, tr = 3.07 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C). ES-MS m / z 474 (M + 1).
Step 2. Preparation of 3- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) propanoic acid.
Prepared as acid 3-. { 4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} benzoic acid using ethyl 3- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) propanoate (from stage 1) (0.47 g, 0.99 mmol) and 2.5 N NaOH (2.0 mL, 4.95 mmol) to give an off white solid (0.13 g, 30%). 1 H NMR (400 MHz, CD3OD) d ppm 1.50 (d, J = 6.98 Hz, 6H) 2.57 (t, J = 6.71 Hz, 2H) 3.69 (t, J = 6J1 Hz, 2H) 4.90 (m, 1 H) 5.43 (s, 2H) 6.97 (m, 2H) 7.51 (m, 1 H). LC / MS, tr = 2.49 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 446 (M + 1).
Stage 3. Preparation of? / ~ 3 ~ -. { 5-Bromo-4-((2,4-d-fluorobenzyl) oxyl-1-isopropyl-6-oxo-1,6-dihydropyridin-2-yl} -beta-alaninamide. 3- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) propanoic acid (from step 2) was dissolved (0.13 g , 0.29 mmol) in tetrahydrofuran (1 ml). 2-Chloro-4,6-dimethoxy-1,3,5-triazine was added (0.062 g, 0.35 mmol) followed by 4-methylmorpholine (0.1 mL, 0.87 mmol). The reaction was stirred at room temperature for 1.5 hours. An excess of 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 then washed in water. The aqueous phase was extracted into ethyl acetate. The combined organics were dried over MgSO 4, filtered, and concentrated. The residue was purified by chromatography (silica gel, ethyl acetate with methanol 10% / hexanes) providing a white solid (0.046 g, 36%). 1 H NMR (400 MHz, CD3OD) d ppm 1.50 (d, J = 6.98 Hz, 6H) 2.54 (t, J = 6.58 Hz, 2H) 3J0 (t, J = 6.58 Hz, 2H) 4.79 (m, 1 H) 5.43 (s, 2H) 6.98 (m, 2H) 7.54 (m, 1 H), ES-HREM 445.0651 (M + H cale, for C? 7H20BrF2N4O3 requires 445.0681).
EXAMPLE 50 4- ( {5-bromo-4-f (2,4-difluorobenzyl) oxp-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) butanamide Step 1. Preparation of ethyl 4- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyridin-2-ylamino) butanoate.
Prepared as? / ~ 3 ~ -. { 5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1, 6-dihydropyrimidin-2-yl} -beta-alaninamide (step 1) using ethyl 4-aminobutanoate (0.436 g, 2.59 mmol) in place of propane-1,3-diamine to provide a clear oil (0.291 g, 25%). 1 H NMR (400 MHz, CD 3 OD) d ppm 1.21 (t, J = 7.12 Hz, 3 H) 1.51 (d, J = 6.98 Hz, 6 H) 1.88 (m, 2 H) 2.35 (t, J = 7.12 Hz, 2 H) 3.46 (t, J = 6.98 Hz, 2H) 4.08 (c, J = 7.25 Hz, 2H) 4.70 (m, 1 H) 5.43 (s, 2H) 6.98 (m, 2H) 7.50 (m, 1 H). LC / MS, tr = 3.15 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 488 (M + 1).
Step 2. Preparation of 4- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) butanoic acid.
Prepared as? / ~ 3 ~ -. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -beta-alaninamide (step 2) using ethyl 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 2.5 N NaOH (2.0 mL, 4.8 mmol) to give a clear oil (0.160 g, 25%). H NMR (400 MHz, CD3OD) d 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, 1 H) 5.43 (s, 2H) 6.97 (m, 2H) 7.49 (m, 1 HOUR). LC / MS, tr = 2.56 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 460 (M + 1).
Step 3. Preparation of 4 - ((5-bromo-4 - [(2,4-difluorobenzyl) oxyH-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) butanamide Prepared as? / ~ 3 ~ - {5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. beta-alaninamide (step 3) using 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 to give a white solid (0.042 g, 26%) 1 H NMR (400 MHz, CD3OD) d 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) 4J2 (m, 1 H) 5.43 (s, 2H) 6.98 (m, 2H) 7.51 (m, 1 H), ES-HREM 459.0841 (M + H cale, for C18H22BrF2N4O3 requires 459.0838).
EXAMPLE 51 2- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxyl-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethylcarbamate tert-butyl Preparation of 2- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. Oxi) tert-butyl ethylcarbamate. T-Butyl 2-hydroxyethylcarbamate (2.2 mL, 14.0 mmol) was dissolved in dioxane (100 mL) and cooled in an ice bath. Sodium hydride (0.770 g, 19.1 mmol) was added portionwise to the reaction mixture. The reaction mixture was warmed to room temperature for 1 hour then re-cooled in an ice bath. A solution of 5-chloro-6 - [(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one was slowly added to the reaction mixture. (5.0 g, 12.8 mmol) in dioxane (30 ml). The reaction mixture was allowed to warm to room temperature overnight. The reaction was quenched by the addition of water and the solvent was removed. The aqueous phase was extracted into ethyl acetate, dried over MgSO, filtered, and concentrated. The residue was dissolved in 50% ethyl acetate / hexanes and passed through a pad of silica gel to provide a white solid (4.92 g, 81%). 1 H NMR (400 MHz, CD3OD) d 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, 1 H ) 5.47 (s, 2H) 6.98 (m, 2H) 7.53 (m, 1 H). LC / MS, tr = 3.30 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 474 (M + 1).
EXAMPLE 52 Acetate 2- (r2- (. {5-Chloro-4-r (2,4-difluorobenzyl) oxyfl-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethylamino} -2-oxoethyl Step 1. Preparation of 6- (2,4-difluorobenzyloxy) -2- (3-aminopropoxy) -5-chloro-3-isopropyl-pyrimidin-4 (3H) -one trifluoroacetic acid. 2- (. {5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. Oxy) ethylcarbamate was dissolved. -butyl (9.4 g, 10.4 mmol) 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 concentrated and the residue was dissolved in ethyl acetate then washed with a solution of NaHCO3. The combined organic extracts were dried over MgSO, filtered and concentrated to give yellow foam (4.58 g, 90%). 1 H NMR (400 MHz, CD3OD) d ppm 1.49 (d, J = 6.98 Hz, 6H) 3.45 (m, 2H) 4.72 (m, 2H) 5.22 (m, 1 H) 5.48 (s, 2H) 7.01 (m, 2H) 7.54 (m, 1 H). LC / MS, tr = 1.94 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 374 (M + 1).
Step 2. Preparation of 2 - ([2- (. {5-Chloro-4-r (2,4-difluorobenzipoxyl-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl) oxy) ) ethylamino > -2-oxoethyl.
Prepared as / - [3- ( { 5-Bromo-4 - [(2,4-difluorobenzyl) ox] -1- isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. ) propyl] -2-hydroxyacetamide (step 2) using 2-. { [2- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] amino} -2-oxoethylacetate and (chlorocarbonyl) methyl acetate (0.121 ml, 1.13 mmol) to give a white solid (0.326 g, 67%). 1 H NMR (400 MHz, CDCl 3) d ppm 1.42 (d, J = 6.98 Hz, 6H) 2.12 (s, 3 H) 3 J 4 (m, 2 H) 4.51 (t, J = 5.50 Hz, 2 H) 4.57 (s, 2 H) 5.36 (m, 1 H) 5.39 (s, 2H) 6.83 (m, 2H) 7.44 (m, 1 H). LC / MS, tr = 2.58 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 474 (M + 1).
EXAMPLE 53 ? / - f2- ( {5-chloro-4-r (2,4-difluorobenzyl) oxyM-isopropyl-6-oxo-1, 6-dihydropyrimidin-2-yl) oxy) etillacetamide Preparation of? / - [2- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. Oxy ) ethyl] acetamide. Prepared as? / - [3- ( {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. ) propyl] acetamide (step 2) using 6- (2,4-difluorobenzyloxy) -2- (3-aminopropoxy) -5-chloro-3-isopropylpyrimidin-4 (3H) -one trifluoroacetic acid (from acetate 2- { [2- ( { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] amino.} -2-oxoethyl, step 1) (0.497 g, 1.02 mmol) and acetyl chloride (0.119 ml, 1.53 mmol) to give a light red solid (0.312 g, 74%). 1 H NMR (400 MHz, CDCl 3) d ppm 1.40 (d, J = 6.98 Hz, 6H) 2.02 (s, 3H) 3.68 (m, 2H) 4.50 (t, J = 5.50 Hz, 2H) 5.32 (m, 1 H ) 5.38 (s, 2H) 6.84 (m, 2H) 7.44 (m, 1 H), ES-HREM 416.1175 (M + H cale, for C? 8H21CIF2N3O requires 416.1183).
EXAMPLE 54 ? / - f2 - ((5-chloro-4-r (2,4-difluorobenzyl) oxyM-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. oxy) ethane-methanesulfonamide Preparation of? / - [2- (. {5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. oxy) ethyl] methanesulfonamide. Prepared as? / - [3- ( { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl.}. Amine ) propyl] acetamide (step 2) using 6- (2,4-difluorobenzyloxy) -2- (3-aminopropoxy) -5-chloro-3-isopropylpyrimidin-4 (3H) -one trifluoroacetic acid (from 2- {[2- ( {5-Chloro-4 - [(2,4-d.fluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-d acetate Glyceryl-2-yl.} Oxy) ethyl] aminoxy] -2-oxoethyl, step 1) (0.510 g, 1.05 mmol) and methanesulfonyl chloride (0.089 ml, 1.16 mmol) providing a white solid (0.369 g, 78%). H-NMR (400 MHz, CDCl 3) d ppm 1.43 (d, J = 6.98 Hz, 6H) 2.97 (s, 3H) 3.54 (m, 2H) 4.54 (t, J = 5.50 Hz, 2H) 5.31 (m, 1 H ) 5.39 (s, 2H) 6.82 (m, 2H) 7.45 (m, 1 H), ES-HREM 452.0846 (M + H cale, for C? 7H21CIF2N3O5S requires 452.0853).
EXAMPLE 55 Acetate 2-. { r2- (. {5-Chloro-4-f (2,4-difluorobenzyl) oxyM-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethylamino} -1.1-dimethyl-2-oxoethyl Preparation of 2- acetate. { [2- ( { {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy} etl ]Not me} -1.1-dimethyl-2-oxoethyl. Prepared as? / - [3- ( {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. ) propyl] -2-hydroxy-2-methylpropanamide (step 2) using 6- (2,4-difluorobenzyloxy) -2- (3-aminopropoxy) -5-chloro-3-isopropylpyrimidin-4 (3H) -one trifluoroacetic acid (from 2- {[2- ( {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropylacetate. R.midin-2-yl.}. Oxy) ethyl] amino.} -2-oxoethyl, step 1) (0.502 g, 1.03 mmol) and 2- (chlorocarbonyl) propan-2-yl acetate (0.185 ml. , 1.13 mmol) to give a white solid (0.364 g, 71%). 1 H NMR (400 MHz, CDCl 3) d ppm 1.42 (d, J = 6.98 Hz, 6H) 1.61 (s, 6H) 2.03 (s, 3H) 3.69 (m, 2H) 4.50 (t, J = 5.37 Hz, 2H) 5.34 (m, 1H) 5.39 (s, 2H) 6.82 (m, 2H) 7.44 (m, 1 HOUR). LC / MS, tr = 2.87 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 502 (M + 1).
EXAMPLE 56 ? / - r2- ( {5-Chloro-4-r (2,4-difluorobenzyl) oxyM-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl) oxy) ethyl-urea Preparation? / - [2- ( {5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] urea. Prepared as? / - [3- ( { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. ) propyl] urea using 6- (2,4-difluorobenzyloxy) -2- (3-aminopropoxy) -5-chloro-3-isopropylpyrimidin-4 (3H) -one trifluoroacetic acid (2- ({. - ( {5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. Oxy) ethyl] amino. -2-oxoethyl, step 1) (0.510 g, 1.05 mmol) and trimethylsilyl isocyanate (0.132 ml, 1.15 mmol) to give a white solid (0.105 g, 24%). 1 H NMR (400 MHz, CD3OD) d ppm 1.46 (d, J = 6.98 Hz, 6H) 3.55 (t, J = 5.37 Hz, 2H) 4.53 (t, J = 5.37 Hz, 2H) 5.29 (m, 1 H) 5.47 (s, 2H) 6.99 (m, 2H) 7.54 (m, 1 H), ES-HREM 417.1145 (M + H cale, for C17H20CIF2N4O4 requires 417.1136). (3S -1- (5-chloro-4-r (2,4-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl.} Pyrrolidin-3-ylcarbamate Preparation of (3S) -1-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidin-3-ylcarbamate. 5-Chloro-6 - [(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (1.0 g, 2.55 mmol) was dissolved in dioxane ( 25 ml). T-butyl (S) -pyrrolidin-3-ylcarbamate (0.57 g, 3.06 mmol) was added followed by triethylamine (OJ ml, 5.1 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction was concentrated and the residue was washed with ethyl acetate / water. The aqueous phase was extracted into ethyl acetate. The combined organics were dried over MgSO 4, filtered, and concentrated. The residue was purified by chromatography (silica gel, ethyl acetate / hexanes) to give an off white solid (0.810 g, 64%). 1 H NMR (300 MHz, CD 3 OD) d ppm 1.44 (m, 9 H) 1.59 (dd, J = 6.65, 12.89 Hz, 6 H) 1.85 (m, 2 H) 3.21 (m, 1 H) 3.41 (m, 1 H) 3.80 ( m, 1 H) 4.12 (m, 2H) 4.44 (m, 1 H) 5.43 (m, 2H) 6.99 (m, 2H) 7.55 (m, 1 H). LC / MS, tr = 3.36 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 499 (M + 1).
EXAMPLE 58 (3 /? H- (5-chloro-4-F (2,4-difluorobenzyl) oxyl-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl.} Pyrrolidin-3-ylcarbamate Preparation of (3f?) - 1-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidin-3-ylcarbamate. Prepared as (3S) -1-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidin-3-ylcarbamate using t-butyl (R) -pyrrolidin-3-ylcarbamate (2.84 g, 15.3 mmol) to give an off-white solid (4.10 g, 64%). 1 H NMR (400 MHz, CD3OD) d 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, 1 H) 3.76 ( m, 2H) 4.14 (m, 1 H) 4.43 (m, 1 H) 5.42 (s, 2H) 6.97 (m, 2H) 7.50 (m, 1 H). LC / MS, tr = 3.36 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 499 (M + 1).
EXAMPLE 59 2-r (3S) -3-aminopyrrolidin-1-yn-5-chloro-6-r (2,4-difluorobenzyl) oxp-3-isopropylpyrimidin-4 (3H) -one Preparation of 2 - [(3S) -3-aminopyrrolidin-1-yl] -5-chloro-6 - [(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one. It was dissolved (3S) -1-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidin-3-carbamate (3.42 g, 6.87 mmol) in dichloromethane (14 ml) and 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 providing a brown solid (3.65 g,> 100%). 1 H NMR (400 MHz, CD3OD) d ppm 1.60 (dd, J = 23.36, 6.71 Hz, 6H) 2.16 (m, 1 H) 2.42 (m, 1 H) 3.66 (m, 2H) 3.92 (m, 3H) 4.50 (m, 1 H) 5.43 (s, 2H) 6.98 (m, 2H) 7.51 (m, 1 H), ES-HREM 399.1390 (M + H cale, for d8H22CIF2N4O2 requires 390.1394).
EXAMPLE 60 2-r (3?) - 3-aminopyrrolidin-1-yn-5-chloro-6-r (2,4-difluorobenzyl) oxi-3-isopropylpyrimidin-4 (3H) -one Preparation of 2 - [(3f?) - 3-aminopyrrolidin-1-yl] -5-chloro-6 - [(2,4-difluorobenzyl) oxy] -3-isopropylpyridimin-4 (3H) - ona Prepared as 2 - [(3S) -3-aminopyrrolidin-1-yl] -5-chloro-6 - [(2,4-d-fluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one using (3ft) -1 -. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} pyrrolidin-3-ylcarbamate (3.87 g, 7.77 mmol) and trifluoroacetic acid (15 ml) to give a red solid (3.82 g, 96%). 1 H NMR (400 MHz, CD3OD) d ppm 1.60 (dd, J = 22.42, 6.58 Hz, 6H) 2.15 (m, 1 H) 2.44 (m, 1 H) 3.67 (m, 2H) 3.82 (m, 1 H) 3.97 (m, 2H) 4.50 (s, 1 H) 5.43 (s, 2H) 6.97 (m, 2H) 7.51 (m, 1 H), ES-HREM 399.1390 (M + H cale, for C? 8H22CIF2N4O2 requires 390.1394) .
EXAMPLE 61 ? / - ((3S -1 - (5-chloro-4-r (2,4-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl.} Pyrrolidin-3-yl) acetamide Preparation of? / - ((3S) -1-. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2- il.}. pyrrolidin-3-yl) acetamide. Prepared as? / - [3- ( { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. ) propyl] acetamide (step 2) using 2 - [(3S) -3-aminopyrrolidin-1-yl] -5-chloro-6 - [(2,4-d-fluorobenzyl) oxy] -3-isopropylpyrimidin-4 ( 3H) -one (0.50 g, 0.98 mmol) and acetyl chloride (0.085 mL, 1.08 mmol) to give a tan / red solid (0.273 g, 63%). 1 H NMR (400 MHz, CD 3 OD) d ppm 1.59 (dd, J = 6.58, 26.45 Hz, 6H) 1.94 (m, 4H) 2.19 (m, 1 H) 3.42 (dd, J = 3.76, 10.74 Hz, 1 H) 3.63 (m, 1 H) 3.75 (m, 1 H) 3.85 (dd, J = 5.91, 11.01 Hz, 1 H) 4.37 (m, 1 H) 4.44 (m, 1 H) 5.42 (s, 2H) 6.96 ( m, 2H) 7.50 (m, 1 H), ES-HREM 441.1475 (M + H cale, for C20H24CIF2N4O3 requires 441. 1500). ? / - ((3?) - 1 - (5-chloro-4-r (2,4-difluorobenzDoxiH-isopropyl-6-oxo-1.6 ° dihydropyrimidin-2-yl) pyrrolidin-3-yl) acetamide Preparation of? / - ((3f?) - 1. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-0 isopropyl-6-oxo-1,6-d! hydropyrimidin-2-yl.}. pyrrolidin-3-yl) acetamide. Prepared as N- [3- (. {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyridin-2-yl}. amine) propyl] acetamide (step 2) using 2 - [(3R) -3-aminopyrrolidin-1-yl] -5-chloro-6 - [(2,4-d-fluorobenzyl) oxy] 3-isopropylpyrimidin-4 (3H) -one (0.50 g, 0.98 mmol) and acetyl chloride (0.085 mL, 1.08 mmol) 5 yielding a tan solid (0.300 g, 70%). 1 H NMR (400 MHz, CD3OD) d ppm 1.59 (dd, J = 6.71, 26.58 Hz, 6H) 1.94 (m, 4H) 2.19 (m, 1 H) 3.42 (dd, J = 3.76, 10.74 Hz, 1 H) 3.63 (m, 1 H) 3.75 (m, 1 H) 3.85 (dd, J = 5.91, 11.01 Hz, 1 H) 4.37 (m, 1 H) 4.43 (m, 1 H) 5.42 (s, 2H) 6.96 ( m, 2H) 7.50 (m, 1 H), 0 ES-HREM 441.1464 (M + H cale, for C20H24CIF2N4O3 requires 441. 1500).
EXAMPLE 63 Acetate 2-f ((3S) -1- (5-chloro-4-f (2,4-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl .}. pyrrolidin-3-yl) amino-1-oxoethyl Preparation of 2 - [((3S) -1-. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-acetate il.}. pyrrolidin-3-yl) amino] -2-oxoethyl. Prepared as? / - [3- ( { 5-bromo-4 - [(2,4-d? Fluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl .}. amino) propyl] -2-hydroxyacetamide (step 2) using 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 (chlorocarbonyl) methyl acetate (0.115 mL, 1.07 mmol) to give a light yellow solid (0.292 g, 60%). 1 H NMR (400 MHz, CD3OD) d ppm 1.59 (dd, J = 6.71, 20.68 Hz, 6H) 2.03 (m, 1 H) 2.11 (s, 3H) 2.21 (m, 1 H) 3.49 (dd, J = 4.16 , 10.88 Hz, 1 H) 3.65 (m, 1 H) 3.75 (m, 1 H) 3.86 (dd, J = 5.91, 11.01 Hz, 1 H) 4.43 (m, 2H) 4.53 (s, 2H) 5.42 (s) , 2H) 6.96 (m, 2H) 7.50 (m, 1 H). LC / MS, tr = 2.63 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 499 (M + 1).
EXAMPLE 64 2 - [((3?) - 1 -. {5-Chloro-4-f (2,4-difluorobenzyl) oxyM-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} acetate. pyrrolidin-3-yl) amino-1-oxoethyl Preparation of 2 - [((3?) - 1. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidine acetate -2-yl.}. Pyrrolidin-3-yl) amino] -2-oxoethyl. Prepared as? / - [3- ( { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. ) propyl] -2-hydroxyacetamide (step 2) using 2 - [(3f?) - 3-aminopyrrolidin-1-yl] -5-chloro-6 - [(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidine- 4 (3H) -one (0.50 g, 0.98 mmol) and (chlorocarbonyl) methyl acetate (0.115 mL, 1.07 mmol) to give a light yellow solid (0.279 g, 57%). 1 H NMR (400 MHz, CD3OD) d ppm 1.59 (dd, J = 6.58, 20.81 Hz, 6H) 2.02 (m, 1 H) 2.11 (s, 3H) 2.21 (m, 1 H) 3.49 (dd, J = 4.16, 10.88 Hz, 1 H) 3.65 (m, 1 H) 3.75 (m, 1 H) 3.86 (dd, J = 5.91, 11.01 Hz, 1 H) 4.44 (m, 2H) 4.53 (s, 2H) 5.42 (s, 2H) 6.96 (m, 2H) 7.50 (m, 1 H).
LC / MS, tr = 2.63 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 499 (M + 1).
EXAMPLE 65 Acetate 2-f ((3S) -1-. {5-chloro-4-f (2,4-difluorobenzyl) oxyl-1-isopropyl-6-oxo-1,6-dihydropyridin-2-yl .}. pyrrolidin-3-yl) amino1-1.1-dimethyl-2-oxoethyl Preparation of 2 - [((3S) -1-. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-acetate il.) pyrrolidin-3-yl) amino] -1,1-dimethyl-2-oxoethyl. Prepared as? / - [3- ( {5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. ) propyl] -2-hydroxy-2-methylpropanamide (step 2) using 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) provided a white solid (0.354 g, 69%). 1 H NMR (400 MHz, CD3OD) d 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, 1 H). LC / MS, tr = 2.87 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 527 (M + 1).
EXAMPLE 66 2-f ((3?) - 1 -. {5-Chloro-4-f (214-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} acetate. pyrrolidin-3-yl) amino1-1.1-dimethyl-2-oxoethyl Preparation of 2 - [((3R) -1-. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropylacetate Rimidin-2-yl.) Pyrrolidin-3-yl) amino] -1,1-dimethyl-2-oxoethyl. Prepared as? / - [3- ( { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. No) propyl] -2-hydroxy-2-methylpropanamide (step 2) using 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) provided a white solid (0.405 g, 79%). 1 H NMR (400 MHz, CD3OD) d 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, 1 H). LC / MS, tr = 2.86 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 527 (M + 1).
EXAMPLE 67 ? / - ((3S) -1- (5-chloro-4-r (2,4-difluorobenzyl-oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl.} Pyrrolidin-3-yl) -2 -hydroxyacetamide Preparation of? / - ((3S) -1-. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2- il.) pyrrolidin-3-yl) -2-hydroxyacetamide. Prepared as? / - [3- ( { 5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyridin-2-yl.} amino) propyl] -2-hydroxyacetamide (step 3) using (0.228 g, 0.46 mmol) and K2CO3 (0.095 g, 0.69 mmol) provided a white solid (0.183 g, 87%). 1 H NMR (300 MHz, CD3OD) d ppm 1.59 (d, J = 6.65 Hz, 6H) 2.10 (m, 2H) 3.69 (m, 4H) 3.99 (d, J = 1.21 Hz, 2H) 4.46 (m, 2H) 5.43 (s, 2H) 6.97 (m, 2H) 7.52 (m, 1 H), ES-HREM 457.1404 (M + H cale, for C20H24CIF2N4O requires 457.1449).
EXAMPLE 68 /V- ((3f?)-1-(5-chloro-4-r(2.4-difluorobenzyl) oxy1-1-isopropyl-6-oxo-1.6- dihydropyrimidin-2-yl) pyrrolidin-3-yl) -2 -hydroxyacetamide Preparation of? / - ((3f?) - 1. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidine- 2-yl.}. Pyrrolidin-3-yl) -2-hydroxyacetamide. Prepared as? / - [3- ( { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. ) propyl] -2-hydroxyacetamide (step 3) using 2 - [((3f?) - 1. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-acetate -oxo-1, 6-dihydropyrimidin-2-yl.} pyrrolidin-3-yl) amino] -2-oxoetyl (0.217 g, 0.44 mmol) and K2CO3 (0.090 g, 0.65 mmol) to give a white solid (0.194 g, 97%). 1 H NMR (300 MHz, CD3OD) d 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, 1 H), ES-HREM 457.1454 (M + H cale, for C20H24CIF2N4O4 requires 457.1449).
EXAMPLE 69 ? / - ((3S) -1- (5-chloro-4-f (2,4-difluorobenzyl) oxyM-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl) pyrrolidin-3-yl) -2-hydroxy-2-methylpropanamide Preparation of A / - ((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. Prepared as? / - [3- ( { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyridin-2-yl}. amine) propyl] -2-hydroxyacetamide (step 3) using 2 - [((3S) -1-. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl- 6-oxo-1,6-dihydropyrimidin-2-yl.} Pyrrolidin-3-yl) amino] -1,1-dimethyl-2-oxoethyl (0.304 g, 0.58 mmol) and K2CO3 (0.120 g, 0.87 mmol) yielding a white solid (0.206 g, 73%). 1 H NMR (300 MHz, CD 3 OD) d ppm 1.35 (s, 3 H) 1.36 (s, 3 H) 1.59 (dd, J = 3.52, 6.54 Hz, 6 H) 2.00 (m, 2 H) 3.69 (m, 4 H) 4.47 (m , 2H) 5.44 (s, 2H) 6.98 (m, 2H) 7.51 (m, 1 H), ES-HREM 485.1723 (M + H cale, for C22H28CIF2N4O requires 485.1762).
EXAMPLE 70 ? / - ((3 /?) - 1- (5-Chloro-4-r (214-difluorobenzyl) oxyl-1-isopropyl-6-oxo-1,6- d, h -dropyrimidin-2-yl.} Pyrrolidine -3-yl) -2-hydroxy-2-methylpropanamide Preparation of? / - ((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. Prepared as? / - [3- ( { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. ) propyl] -2-hydroxyacetamide (step 3) using 2 - [((3R) -1-. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-acetate oxo-1, 6-dihydropyrimidin-2-yl.} pyrrolidin-3-yl) amino] -1,1-dimethyl-2-oxoethyl (0.363 g, 0.69 mmol) and K2CO3 (0.143 g, 1.04 mmol) yielding a white solid (0.313 g, 94%). 1 H NMR (300 MHz, CD 3 OD) d ppm 1.35 (s, 3 H) 1.36 (s, 3 H) 1.59 (dd, J = 3.42, 6.65 Hz, 6 H) 2.00 (m, 2 H) 3.69 (m, 4 H) 4.47 (m , 2H) 5.44 (s, 2H) 6.97 (m, 2H) 7.51 (m, 1 H), ES-HREM 485.1766 (M + H cale, for C22H28CIF2N O requires 485.1762). 5-chloro-6-f (2,4-difluorobenzyl) oxy-3-isopropylpyrimidin-4 (3H) -one Preparation of 5-chloro-6 - [(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one. 5-Chloro-6 - [(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (0.390 g, 1.0 mmol) was dissolved in methanol (3.0 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 and the methanol was removed. The aqueous phase was extracted into ethyl acetate. The combined organics were dried over MgSO 4, filtered, and concentrated. The residue was purified by chromatography (silica gel, ethyl acetate / hexanes) to give white solid (0.140 g, 44%). 1 H NMR (300 MHz, CD 3 OD) d ppm 1.46 (d, J = 6.85 Hz, 6H) 4.96 (m, 1 H) 5.51 (s, 2 H) 6.99 (m, 2 H) 7.55 (m, 1 H) 8.35 (s) , 1H), ES-HREM 315.0696 (M + H cale, for C1 H14CIF2N2O2 requires 315. 0706).
EXAMPLE 72 5-Chloro-6 - [(2,4-d-fluorobenzyl) oxy-3-isopropyl-2-methylpyrimidin-4 (3H) -one Step 1. Preparation of 4- (2,4-difluorobenzyloxy) -5-chloro-1,6-dihydro-1-isopropyl-6-oxopyrimidine-2-carbonitrile. 5-Chloro-6 - [(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (10.0 g, 25.4 mmol) was dissolved in dimethylformamide (56 ml. ). Potassium cyanide (3.31 g) was added50.9 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction was diluted with ethyl acetate (100 ml) and poured into ethyl acetate (100 ml) / ice water (300 ml). The aqueous phase was further extracted into ethyl acetate. The combined organics were dried over MgSO 4, filtered, and concentrated. The residue was purified by chromatography (silica gel, ethyl acetate / hexanes) to give light yellow solid (3.34 g, 39%). 1 H NMR (300 MHz, CDCl 3) d ppm 1.67 (m, 6H) 5.16 (m, 1 H) 5.45 (s, 2 H) 6.88 (m, 2 H) 7.46 (m, 1 H). LC / MS, tr = 3.14 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 340 (M + 1).
Step 2. Preparation of 5-chloro-6-α (2,4-difluorobenzyl) oxyl-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) ) and cooled to -78 ° C. Methylmagnesium bromide (3.0 M in THF, 0.40 ml) was slowly added to the reaction mixture. The reaction was then heated to 0 ° C, deactivated by the addition of water. The aqueous phase was extracted into ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO 4, filtered, and concentrated. The residue was purified by chromatography (silica gel, ethyl acetate / hexanes) to give an off white solid (0.091 g, 56%). 1 H NMR (400 MHz, CDCl 3) d ppm 1.59 (d, J = 6.71 Hz, 6H) 2.52 (s, 3H) 4.49 (m, 1 H) 5.41 (s, 2H) 6.83 (m, 2H) 7.45 (m, 1 H), ES-HREM 329.0898 (M + H cale, for d5H16CIF2N2O2 requires 329.0863). 2-But-3-enyl-5-chloro-6-f (2,4-difluorobenzyl) oxy-3-isopropyl-pyrimidin-4 (3H) -one Preparation of 2-but-3-enyl-5-chloro-6 - [(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) was dissolved in tetrahydrofuran (5 ml) and it was cooled to -78 ° C. But-1-ene-4-magnesium bromide (0.5 M, 0.900 ml) was added slowly. The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was quenched by the addition of a solution of NH 4 Cl, then extracted into ethyl acetate. The combined organics were dried over MgSO, filtered, and concentrated. The crude solid was purified by chromatography (silica gel, ethyl acetate / hexanes) to give a white solid (0.048 g, 52%). 1 H NMR (300 MHz, CD3OD) d ppm 1.58 (d, J = 6.85 Hz, 6H) 2.52 (m, 2H) 2.95 (t, J = 7.45 Hz, 2H) 4.68 (m, 1 H) 5.04 (m, 2H) 5.48 (s, 2H) 5.88 (m, 1 H) 6.96 (m, 2H) 7.50 (m, 1 H), ES-HREM 369.1156 (M + H cale, for C18H20CIF2N2O2 requires 369.1176).
EXAMPLE 74 5-chloro-6-f (2,4-difluorobenzyl) oxy1-2- (4-hydroxybutyl) -3-isopropylpyridin-4 (3H) -one Preparation of 5-chloro-6 - [(2,4-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 dissolved in tetrahydrofuran (3 mL) . Then BH3-THF (1.0 M, 0.53 ml) was added at room temperature. After the evolution of gas 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 organics were dried over MgSO, filtered, and concentrated. The residue was purified by chromatography (silica gel, ethyl acetate / hexanes) to give an off white solid (0.118 g, 36%). 1 H NMR (300 MHz, CD3OD) d 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, 1 H) 5.50 (s, 2H) 6.99 (m, 2H) 7.53 (m, 1 H), ES-HREM 387.1237 (M + H cale, for C? 8H22CIF2N2O3 requires 387.1282).
EXAMPLE 75 4- Acid. { 5-Chloro-4 - [(214-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} butanoic Preparation of acid 4-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} butanoic 5-Chloro-6 - [(2,4-difluorobenzyl) oxy] -2- (4-hydroxybutyl) -3-isopropylpyrimidin-4 (3H) -one (1.32 g, 3.42 mmol) was dissolved in dimethylformamide (17 ml). Pyridinium dichromate (4.5 g, 12.0 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was quenched by the addition of water (125 ml). The aqueous phase was extracted into ethyl acetate. The combined organics were dried over MgSO 4, filtered, and concentrated. The crude solid was washed with small amounts of dichloromethane and filtered to give a tan solid (0.750 g, 55%). 1 H NMR (300 MHz, CD3OD) d 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, 1 H) 5.49 (m, 2H) 6.98 (m, 2H) 7.55 (m, 1 H), ES-HREM 401.1040 (M + H cale, for C18H20CIF2N2O4 requires 401.1074).
EXAMPLE 76 4-. { 5-Chloro-4-f (2,4-difluorobenzyl) oxyl-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl) butanamide Preparation of 4-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} butanamide Prepared as? / ~ 3 ~ -. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -beta-alaninamide (stage 3) using 4-acid. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} butanoic (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 an excess of aqueous ammonium hydroxide afforded a solid cinnamon (0.153 g, 31%). 1 H NMR (300 MHz, CD3OD) d 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, 1 H) 5.50 (s, 2H) 6.98 (m, 2H) 7.54 (m, 1 H), ES-HREM 400.1265 (M + H cale, for C? 8H21CIF2N3O3 requires 400.1234).
EXAMPLE 77 4-. { 5-chloro-4-f (2,4-difluorobenzyl) oxyM-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl) -? / - f (2R) -2-hydroxypropylnbutanamide Preparation of 4-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -? / - [(2R) -2-hydroxypropyl] butanamide. 4-acid was dissolved. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} butanoic (0.210 g, 0.53 mmol) in dioxane (8 ml). ? / - 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 overnight at room temperature. 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, CD3OD) d 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, 1 H) 4.66 (m, 1 H) 5.49 (s, 2H) 6.98 (m, 2H) 7.54 (m, 1 H), ES-HREM 458.1634 (M + H cale, for C21H27CIF2N3O4 requires 458.1653).
EXAMPLE 78 4-. { 5-Chloro-4-f (2,4-difluorobenzyl) oxyl-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -? 2-hydroxyethyl) butanamide Preparation of 4-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -? / - (2-hydroxyethyl) butanamide. Prepared as 4-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -? / - [(2R) -2-hydroxypropyl] butanamide using 4- acid. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} butanoic (0.40 g, 1.0 mmol) and ethanolamine (0.12 ml, 2.0 mmol) yielding an off-white solid (0.244 g, 55%). 1 H NMR (400 MHz, CD3OD) d 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, 1 H) 5.50 (s, 2H) 6.98 (m, 2H) 7.54 (m, 1 H), ES-HREM 444.1488 (M + H cale, for C20H25CIF2N3O requires 444.1496).
EXAMPLE 79 4-. { 5-chloro-4-r (2,4-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl) -? / - methylbutanamide Preparation of 4-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -? / - methylbutanamide. Prepared as 4-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -? / - [(2R) -2-hydroxypropyljbutanamide using 4-acid. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} butanoic (0.40 g, 1.0 mmol) and methylamine (2.0 M in dioxane, 1.0 ml, 2.0 mmol) to give a light brownish red solid (0.239 g, 58%). 1 H NMR (400 MHz, CD3OD) d 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, 1 H) 5.49 (s, 2H) 6.98 (m, 2H) 7.53 (m, 1H), ES-HREM 414.1373 (M + H cale, for C19H23CIF2N3O3 requires 414.1391). 5-chloro-6-f (2,4-difluorobenzyl) oxyl-2-hydroxy-3-isopropylpyrimidin-4 (3H) -one Preparation of 5-chloro-6 - [(2,4-difluorobenzyl) oxy] -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 dissolved in 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, the dioxane was removed and the aqueous phase was made acidic (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) d ppm 1.42 (d, J = 7.05 Hz, 6H) 5.15 (m, 1 H) 5.45 (s, 2 H) 6.91 (m, 2 H) 7.49 (m, 1 H), ES- HREM 331.0622 (M + H cale, for C? 4H14CIF2N2O3 requires 331.0656). 5-Chloro-4 - [(2,4-difluorobenzyl) oxy1-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl trifluoromethanesulfonate Preparation of 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) was 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, with cooling, for 30 minutes. Trifluoromethanesulfonic anhydride (2.1 ml, 12.2 mmol) was added and the reaction was allowed to warm to room temperature for 2.5 hours. The reaction was quenched by the addition of water and extracted into dichloromethane. The combined organics were dried over MgSO, filtered, and concentrated. The residue was purified by chromatography (silica gel, ethyl acetate / hexanes) to give white solid (1.14 g, 41%). 1 H NMR (400 MHz, CD3OD) d ppm 1.51 (d, J = 6.98 Hz, 6H) 5.26 (m, 1 H) 5.43 (s, 2H) 7.01 (m, 2H) 7.54 (m, 1 H). LC / MS, tr = 3.64 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 463 (M + 1).
EXAMPLE 82 2-allyl-5-chloro-6-f (2,4-difluorobenzyl) oxyl-3-isopropylpyrimidin-4 (3H) -one Preparation of 2-allyl-5-chloro-6 - [(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one. Prepared as 2-but-3-enyl-5-chloro-6 - [(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one using prop-1-ene-3-magnesium bromide ( 1.0 M, 3.75 mL, 3.75 mmol) to give a yellow oil (0.620 g, 70%). 1 H NMR (400 MHz, CD3OD) d ppm 1.56 (d, J = 6.98 Hz, 6H) 3.66 (d, J = 5.91 Hz, 2H) 4.61 (m, 1 H) 5.15 (dd, J = 1.34, 17.19 Hz, 1 H) 5.25 (dd, J = 1.34, 10.20 Hz, 1 H) 5.46 (m, 2H) 6.03 (m, 1 H) 6.96 (m, 2H) 7.54 (d, J = 6.44 Hz, 1 H), ES -HREM 355.1019 (M + H cale, for C17H? 8CIF2N2O2 requires 355.1019).
EXAMPLE 83 5-chloro-6-r (2,4-difluorobenzyl) oxyl-2- (3-hydroxypropyl) -3-isopropylpyrimidin-4 (3H) -one Preparation of 5-chloro-6 - [(2,4-difluorobenzyl) oxy] -2- (3-hydroxypropyl) -3-isopropylpyrimidin-4 (3H) -one. Prepared as 5-chloro-6 - [(2,4-d-fluorobenzyl) oxy] -2- (4-hydroxybutyl) -3-isopropylpyrimidin-4 (3H) -one using 2-allyl-5- chloro-6 - [(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one (0.516, 1.46 mmol), BH3-THF (1.0 M in tetrahydrofuran, 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) to give an off-white solid (0.110 g, 20%). 1 H NMR (400 MHz, CD3OD) d ppm 1.58 (d, J = 6.98 Hz, 6H) 1.99 (m, 2H) 2.95 (m, 2H) 3.67 (t, J = 6.18 Hz, 2H) 4.68 (m, 1 H ) 5.47 (s, 2H) 6.95 (m, 2H) 7.51 (m, 1 H), ES-HREM 373.1111 (M + H cale, for C? 7H20CIF2N2O3 requires 373.1125).
EXAMPLE 84 Acid 3-. { 5-Chloro-4-r (214-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} propanoic Preparation of acid 3-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} propanoic Prepared as acid 4-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-ylbutanoic using 5-chloro-6 - [(2,4-difluorobenzyl) oxy] ] -2- (3-hydroxypropyl) -3-isopropylpyrimidin-4 (3H) -one (0.910 g, 2.3 mmol) and pyridinium dichromate (3.03 g, 8.1 mmol) to give an off-white solid (0.410 g, 46%) ). 1 H NMR (400 MHz, CD3OD) d ppm 1.60 (d, J = 6.71 Hz, 6H) 2.82 (m, 2H) 3.17 (m, 2H) 4.74 (m, 1 H) 5.47 (s, 2H) 6.98 (m, 2H) 7.52 (m, 1 H), ES-HREM 387.0897 (M + H cale, for C17H18CIF2N2O requires 387.0918).
EXAMPLE 85 3-. { 5-chloro-4-r (2,4-difluorobenzyl) oxyM -isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl) propanamide Preparation of 3-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} Propanamide Prepared as 4-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} butanamide using 3- acid. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} propanoic (0.180 g, 0.47 mmol) and ammonia (0.5 M in dioxane, 1.86 mL, 0.93 mmol) to give a light yellow solid (0.156 g, 86%). 1 H NMR (400 MHz, CD3OD) d 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, 1 H), ES-HREM 386.1055 (M + H cale, for C17H19CIF2N3O3 requires 386. 1078).
EXAMPLE 86 3-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxyfl-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -? / - methylpropanamide Preparation of 3-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N-methylpropanamide. Prepared as 4-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -? / - methylbutanamide using 3- acid. { 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) to give an off-white solid (0.053 g, 28%). 1 H NMR (400 MHz, CD3OD) d 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, 1 H ) 5.44 (s, 2H) 7.00 (m, 2H) 7.52 (m, 1 H), ES-HREM 400.1232 (M + H cale, for C18H21CIF2N3O3 requires 400. 1234).
EXAMPLE 87 3-. { 5-Chloro-4-f (2,4-difluorobenzyl) oxyM-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N-methylpropanamide Step 1. Preparation of 6- (2,4-difluorobenzyloxy) -2- (4-aminobutyl) -5-chloro-3-isopropylpyrimidin-4 (3H) -one.
To a dry flask of 4-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} butanamide (0.400 g, 1.0 mmol), 1.0 M BH3-THF (1.5 mL, 1.5 mmol) was added and the resulting reaction was refluxed for 1 hour. The reaction mixture was removed after heat and cooled in an ice bath. 1.0 M hydrochloric acid (11 ml) was added slowly and the reaction mixture was warmed to room temperature overnight. The reaction mixture was made alkaline (pH 9) with 2.5 N NaOH then extracted into ethyl acetate. The combined organics were dried over MgSO, 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, CD3OD) d ppm 1.59 (d, J = 6.65 Hz, 6H) 1.83 (m, 4H) 3.00 (m, 4H) 4J4 (m, 1 H) 5.50 (s, 2H) 6.98 (m, 2H) 7.53 (m, 1 H). LC / MS, tr = 3.94 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 413 (M + 1).
Stage 2. Preparation of 3-. { 5-Chloro-4-y (2,4-difluorobenzyl) oxyl-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -? / - methylpropanamide. Prepared as? / - [3- ( { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. ) propyl] acetamide (step 2) using 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) to give a clear oil (0.104 g, 34%). 1 H NMR (300 MHz, CD3OD) d 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, 1 H), ES-HREM 428.1509 (M + H cale, for C20H25CIF2N3O3 requires 428. 1547). 5-bromo-6 - [(2,4-difluorobenzyl) oxp-2- (4-hydroxybutyl) -3-isopropylpyrimidin-4 (3H -one Step 1. Preparation of 6- (2,4-difluorobenzyloxy) -5-bromo-2- (but-3-enyl) -3-yl-propylpyrimidin-4 (3H) -one.
Prepared as 2-but-3-enyl-5-chloro-6 - [(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one using 6- (2,4-difluorobenzyloxy) -5- bromo-3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (5.00 g, 11.4 mmol) and but-1-ene-4-magnesium bromide (0.5 M in tetrahydrofuran, 34.0 mL, 17.2 mmol) providing a light yellow solid (4.18 g, 89%). 1 H NMR (300 MHz, CD3OD) d ppm 1.58 (d, J = 6.65 Hz, 6H) 2.53 (m, 2H) 2.95 (t, J = 7.35 Hz, 2H) 4.68 (m, 1 H) 5.05 (m, 2H) 5.49 (s, 2H) 5.87 (m, 1 H) 6.98 (m, 2H) 7.52 ( m, 1 H). LC / MS, tr = 3.94 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 413 (M + 1).
Step 2. Preparation of 5-bromo-6 - [(2,4-difluorobenzyl) oxyl-2- (4-hydroxybutyl) -3-isopropyl-pyrimidin-4 (3H) -one. Prepared as 5-chloro-6 - [(2,4-difluorobenzyl) oxy] -2- (4-hydroxybutyl) -3-isopropylpyrimidin-4 (3H) -one using 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 BH3-THF (1.0 M in tetrahydrofuran, 5.8 ml, 5.8 mmol), hydrogen peroxide (35%, 9J ml, 3.4 mmol), and 2.5 N NaOH (8.5 ml, 21.3 mmol) to give a white solid (2.34 g, 56%). 1 H NMR (300 MHz, CD3OD) d 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, 1 H) 5.49 (s, 2H) 6.98 (m, 2H) 7.53 (m, 1 H), ES-HREM 431.0756 (M + H cale, for C? 8H22BrF2N2O3 requires 431. 0776).
EXAMPLE 89 4-. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -? / - methylbutanamide Step 1. Preparation of 4- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-yl) butanoic acid.
Prepared as acid 4-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyridin-2-yl} butanoxy using 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -2- (4-hydroxybutyl) -3-isopropylpyrimidin-4 (3H) -one (2.34 g, 5.4 mmol) and pyridinium dichromate (7.11 g, 18.9 mmol) yielding a white solid (1.15 g, 48%). 1 H NMR (300 MHz, CD3OD) d 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, 1 H) 5.49 (s, 2H) 6.98 (m, 2H) 7.54 (m, 1 HOUR). LC / MS, tr = 2.66 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 445 (M + 1).
Stage 2. Preparation of 4-. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxp-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl) -? / - methylbutanamide. Prepared as 4-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-l, 6-dihydropyrimidin-2-yl} -A / -methylbutanamide using 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) to give a white solid (0.068 g, 22%). 1 H NMR (400 MHz, CD3OD) d ppm 1.58 (d, J = 6.71 Hz, 6H) 2.07 (m, 2H) 2.31 (t, J = 7.25 Hz, 2H) 2J0 (s, 3H) 2.88 (t, J = 7.52 Hz, 2H) 4.68 (m, 1 H) 5.49 (s, 2H) 6.97 (m, 2H) 7.53 (m, 1 H), ES-HREM 458.0923 (M + H cale, for C? 9H23BrF2N3O3 requires 458.0885).
EXAMPLE 90 4-. { 5-bromo-4-f (2,4-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl) butanamide Preparation of 4-. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-0x0-1,6-dihydropyrimidin-2-yl} butanamide Prepared as 4-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} butanamide using 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) to give a white solid (0.148 g, 49%). 1 H NMR (400 MHz, CD3OD) d 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, 1 H) 5.49 (s, 2H) 6.98 (m, 2H) 7.55 (m, 1H), ES-HREM 444.0740 (M + H cale, for C18H21BrF2N3O3 requires 444.0729).
EXAMPLE 91 4-. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N- (2-hydroxyethyl) butanamide Preparation of 4-. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -? / - (2-hydroxyethyl) butanamide. Prepared as 4-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -? / - (2-hydroxyethyl) butanamide using 4- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-yl) butanoic acid (stage 1) (0.30 g, 0.68 mmol) and ethanolamine (0.081 ml, 1.35 mmol) to give a white solid (0.131 g, 39%). 1 H NMR (400 MHz, CD3OD) d 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, 1 H) 5.49 (s, 2H) 6.98 (m, 2H) 7.54 (m, 1 H), ES-HREM 488.0976 (M + H cale, for C20H25BrF2N3O4 requires 488. 0991).
EXAMPLE 92 2-f (1-acetylpiperidin-4-yl) aminol-5-bromo-6-f (2,4-difluorobenzyl) oxy] -3- isopropylpyrimidin-4 (3H) -one Step 1. Preparation of 4- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) piperidine-1-tert-butylcarboxylate. 6- (2,4-difluorobenzyloxy) -5-bromo-3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (1.0 g, 2.29 mmol) was dissolved in dichloromethane (10 ml).
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 mixture was quenched by the addition of a NaHCO3 solution, then extracted into ethyl acetate. The combined organics were dried over MgSO, filtered, and concentrated. The residue was purified by chromatography (silica gel, ethyl acetate / hexanes) to give a yellow solid (0.285 g, 22%). 1 H NMR (400 MHz, CD 3 OD) d ppm 1.45 (s, 9 H) 1.51 (d, J = 6.98 Hz, 6 H) 1.85 (m, 2 H) 2.83 (m, 2 H) 4.08 (m, 4 H) 4.57 (m, 1 H) 5.21 (m, 1 H) 5.43 (s, 2H) 7.00 (m, 2H) 7.44 (m, 1 H). LC / MS, tr = 3.52 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 557 (M + 1).
Step 2. Preparation of trifluoroacetic diacid salt of 6- (2,4-difluorobenzyl) -5-bromo-3-isopropyl-2- (piperidin-4-ylamino) pyrimidin-4 (3H) -one Prepared as 2 - [(3S) -3-aminopyrrolidin-1-yl] -5-chloro-6 - [(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one using 4- (4- (2,4-d.fluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) piperidine-1-carboxylic acid t-butyl ester (from step 1) (0.270 g, 0.49 mmol) and trifluoroacetic acid (1 ml) to give a brown solid (0.374 g,> 100%). 1 H NMR (400 MHz, CD 3 OD) d ppm 1.53 (d, J = 6 J 1 Hz, 6 H) 1.80 (m, 2 H) 2.15 (m, 2 H) 3.09 (m, 2 H) 3.45 (m, 2 H) 4.19 (m, 1 H) 4.55 (m, 1 H) 5.44 (s, 2H) 7.00 (m, 2H) 7.49 (m, 1 H). LC / MS, tr = 2.10 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 457 (M + 1).
Step 3. Preparation of 2 - [(1-acetylpiperidin-4-yl) aminol-5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one. Prepared as? / - [3- ( { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. amino) propyl] acetamide (step 2) using trifluoroacetic diacid salt of 6- (2,4-difluorobenzyloxy) -5-bromo-3-isopropyl-2- (piperidin-4-ylamine) pyrimidin-4 (3H) -one (from step 2) (0.374 g, 0.5 mmol) and acetyl chloride (0.043 ml, 0.55 mmol) to give a white solid (0.115 g, 46%). 1 H NMR (300 MHz, CDCl 3) d ppm 1.41 (m, 2 H) 1.45 (d, J = 7.25 Hz, 6 H) 2.11 (m, 2 H) 2.11 (s, 3 H) 2.77 (m, 1 H) 3.19 (m, 1 H) 3.80 (m, 1 H) 4.07 (m, 1 H) 4.51 (m, 1 H) 4.83 (m, 1 H) 5.39 (s, 2 H) 6.85 (m, 2 H) 7.44 (m, 1 H) , ES-HREM 499.1143 (M + H cale, for C21H26BrF2N4O3 requires 499.1151). 4-r (. {5-bromo-4-f (2,4-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) methyl methylbenzoate Preparation of 4 - [(. {5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. amine) methyl] benzoate methyl. 6- (2,4-difluorobenzyloxy) -5-bromo-3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (2.00 g, 4.58 mmol) was dissolved in dichloromethane (23 ml). Triethylamine (1.9 ml, 13.74 mmol) and methyl 4- (aminomethyl) benzoate (1.01 g, 5. 04 mmol) and stirred at room temperature overnight. The reaction was quenched by the addition of a NaHCO3 solution, then extracted into ethyl acetate. The combined organics were dried over MgSO 4, filtered, and concentrated. The residue was purified by chromatography (silica gel, ethyl acetate / hexanes) to give a white solid (0.644 g, 27%). 1 H NMR (400 MHz, CDCl 3) d 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) 5J8 (m, 1 H) 6J0 (m, 1 H) 6.80 (m, 1 H) 7.29 (m, 3H) 7.96 (d, J = 8.32 Hz, 2H), ES-HREM 522.0853 (M + H cale, for C23H23BrF2N3O4 requires 522.0835).
EXAMPLE 94 5-bromo-6 - [(214-difluorobenzyl) oxy1-2 - [(4-fluorobenzyl) amino1-3-isopropylpyrimidin-4 (3H) -one Preparation of 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -2 - [(4-fluorobenzyl) amino] -3-isopropylpyrimidin-4 (3H) -one. Prepared as 4 - [(. {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) methyl ] methyl benzoate using (4-fluorophenyl) methanamine (0.50 g, 1.14 mmol) to give a light pink solid (0.054 g, 11%). H-NMR (300 MHz, CDCl 3) d ppm 1.46 (d, J = 7.25 Hz, 6H) 4.59 (d, J = 5.03 Hz, 2H) 5.33 (s, 2H) 5.33 (m, 1 H) 6.75 (m, 1 H) 6.85 (m, 1 H) 7.02 (m, 2H) 7.22 (m, 2H) 7.37 (m, 1 H), ES-HREM 482.0645 (M + H cale, for C21H20BrF3N3O2 requires 482. 0685).
EXAMPLE 95 5-bromo-6-r (2,4-difluorobenzyl) oxyl-2-r (3,3-dimethylbutyl) amino-3-isopropylpyrimidin-4 (3H) -one Preparation of 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -2 - [(3,3-dimethylbutyl) amino] -3-isopropylpyrimidin-4 (3H) -one. Prepared as 4 - [(. {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) Methyl] benzoate using 3,3-dimethylbutan-1-amine (0.50 g, 1.14 mmol) to give a white solid (0.084 g, 16%). 1 H NMR (400 MHz, CDCl 3) d ppm 0.96 (s, 9 H) 1.47 (d, J = 7.25 Hz, 6H) 1.49 (m, 2H) 3.45 (m, 2H) 4.78 (m, 1 H) 5.42 (s, 2H) 6.80 (m, 1 H) 6.89 (m, 1 H) 7.48 (m, 1 H) , ES-HREM 458.1102 (M + H cale, for C2oH27BrF2N3? 2 requires 458.1255).
N ~ 2 ~ -. { 5-chloro-4-r (214-difluorobenzyl) oxyM-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yi > qylinamide Preparation of N ~ 2 ~ -. { 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 J3 g, 3.9 mmol) was dissolved in dimethylformamide (10 ml) and added slowly to a suspension of triethylamine (1.95 ml, 14.0 mmol) and 2-aminoacetamide hydrochloride salt (1.54 g, 14.0 mmol) in dimethylformamide (20 ml) at room temperature. After 10 minutes, the reaction was quenched by the addition of water then extracted into ethyl acetate. The combined organics were dried over MgSO 4, filtered, and concentrated. The solids were washed with a small amount of ethyl acetate and filtered to give a white solid (0.164 g, 33%). H-NMR (400 MHz, CD3OD) d ppm 1.56 (d, J = 6.98 Hz, 6H) 4.03 (s, 2H) 4.82 (m, 1 H) 5.39 (s, 2H) 6.98 (m, 2H) 7.51 (m, 1 H), ES-HREM 387.0995 (M + H cale, for C16H? 8CIF2N O3 requires 387.1030) .
EXAMPLE 97 ? / ~ 2 ~ -. { 5-bromo-4-f (2,4-difluorobenzyl) oxyfl-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N ~ 1 ~ - (2-hydroxyethyl) glycinamide Step 1. Preparation of ethyl 2- (4- (2,4-difluorobenzyloxy) -5-bromo-1, 6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) ethyl acetate .
Prepared as? / ~ 3 ~ -. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -beta-alaninamide (step 1) using 6- (2,4-difluorobenzyloxy) -5-bromo-3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (1.75 g, 12.6 mmol) and salt of ethyl 2-aminoacetate hydrochloric acid (1.75 g, 12.6 mmol) to give a clear oil (1.8 g, 34%). 1 H NMR (400 MHz, CDCl 3) d ppm 1.31 (t, J = 7.12 Hz, 3 H) 1.51 (d, J = 7.25 Hz, 6H) 4.15 (d, J = 4.57 Hz, 2H) 4.26 (c, J = 7.25 Hz, 2H) 5.36 (s, 2H) 5.67 (m, 1 H) 6.83 (m, 2H) 7.46 (m, 1 H). LC / MS, tr = 2.96 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 460 (M + 1).
Step 2. Preparation of 2- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) acetic acid.
Prepared as A / ~ 3 ~ -. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -beta-alaninamide (stage 2) using 2- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamine) ethyl acetate (from step 1) (1 J3 g, 3.9 mmol ) and 2.5 N NaOH (16.0 ml, 39.0 mmol) to give a white solid (1.19 g, 71%). 1 H NMR (400 MHz, CD3OD) d ppm 1.55 (d, J = 6.98 Hz, 6H) 4.09 (s, 2H) 4.89 (m, 1 H) 5.36 (s, 2H) 6.96 (m, 2H) 7.49 (m, 1 H). LC / MS, tr = 2.57 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 432 (M + 1).
Stage 3. Preparation of? / ~ 2 ~ -. { 5-bromo-4 - [(2,4-difluorobenzyl) oxp-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl) -N ~ 1 - (2-hydroxyetiq-Q-lycinamide. 4- {5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl.} -? / - [(2R) -2-hydroxypropyl] butanamide using 2- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) acetic acid (from step 2) ( 0.39 g, 0.90 mmol) and ethanolamine (0.11 ml, 1.81 mmol) to give a light yellow solid (0.269 g, 63%). H NMR (400 MHz, CD3OD) d ppm 1.56 (d, J = 6.98 Hz, 6H) 3.31 (m, 2H) 3.57 (t, J = 5J7 Hz, 2H) 4.04 (s, 2H) 4.85 (m, 1 H ) 5.35 (s, 2H) 6.98 (m, 2H) 7.50 (m, 1 H), ES-HREM 475.0822 (M + H cale, for C18H22BrF2N4O requires 475.0787). 6- (2,4-difluorobenzyloxy) -2- (2-oxo-2- (pyrrolidin-1-yl) ethylamino) -5-bromo-3-isopropylpyrimidin-4 (3H) -one Preparation of 6- (2,4-difluorobenzyloxy) -2- (2-oxo-2- (pyrroline-1-yl) ethylamine) -5-bromo-3-isopropylpyrimidin-4 (3H) -one. Prepared as 4-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -? / - [(2R) -2-hydroxypropyl] butanamide using 2- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin- 2-ylamino) acetic acid (de? / ~ 2 ~ -. {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl .}. -N ~ 1 ~ - (2-hydroxyethyl) glycinamide from step 2) (0.39 g, 0.9 mmol) and pyrrolidine (0.15 ml, 1.81 mmol) to give a light yellow solid (0.385 g, 89%). 1 H NMR (400 MHz, CD3OD) d 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, 1 H) 5.35 (s, 2H) 6.99 (m, 2H) 7.48 (m, 1 H), ES-HREM 485.0985 (M + H cale, for C20H24BrF2N4O3 requires 485.0994).
EXAMPLE 99 5-chloro-6-f (2,4-difluorobenzyl) oxp-2- (4-hydroxybutoxy) -3-isopropylpyrimidin-4 (3H) -one Preparation of 5-chloro-6 - [(2,4-difluorobenzyl) oxy] -2- (4-hydroxybutoxy) -3-isopropyl-pyridin-4 (3H) -one. Prepared as 2- (. {5-chloro-4- [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. Oxy) ethylcarbamate of tert-butyl using 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) to give a white solid (2.98 g, 58%). 1 H NMR (400 MHz, CD3OD) d ppm 1.45 (d, J = 6.98 Hz, 6H) 1 JO (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, 1 H) 5.48 (s, 2H) 6.98 (m, 2H) 7.52 (m, 1 H), ES-HREM 403.1212 (M + H cale, for C18H22CIF2N2O4 requires 403.1231).
EXAMPLE 100 4- (. {5-Chloro-4-r (2,4-difluorobenzyl) oxyl-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) butanoic acid Preparation of 4- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy} butanoic. Prepared as acid 4-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} butanoic using 5-chloro-6 - [(2,4-difluorobenzyl) oxy] -2- (4-hydroxybutoxy) -3-isopropylpyrimidin-4 (3H) -one (2.98 g, 7.4 mmol) and pyridinium dichromate (9.74) g, 25.9 mmol) yielding a white solid (0.615 g, 20%). 1 H NMR (300 MHz, CD3OD) d 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, 1 H) 5.48 (s, 2H) 7.00 (m, 2H) 7.53 (m, 1 H), ES-HREM 417.1028 (M + H cale, for C18H20CIF2N2O5 requires 417.1023).
EXAMPLE 101 and V-f2- ( {5-chloro-4-f (214-difluorobenzyl) oxy] -1-isopropyl-6"? xo-1,6-dihydropyrimidin-2-yl.} oxy) etill -? / '-methylurea Preparation of? / - [2- ( { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyridin-2-d! l.}. oxy) ethyl] - / V-methylurea. 6- (2,4-difluorobenzyloxy) -2- (3-aminopropoxy) -5-chloro-3-isopropylpyrimidin-4 (3H) -one trifluoroacetic acid (from 2- {2- [ {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1, 6-dihydropyrimidin-2-yl} oxy) ethyl] amino} -2-oxoethyl, 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) was added and 4-nitrophenyl chloroformate (0.310 g, 1.54 mmol) was added and the resulting mixture was stirred with cooling for 10 minutes. Methylamine (2.0 M in tetrahydrofuran, 1.5 ml) was added and the reaction mixture was warmed to room temperature overnight. The reaction was quenched by the addition of water then extracted into ethyl acetate. The combined organics were dried over MgSO, filtered, and concentrated. The residue was purified by chromatography (silica gel, ethyl acetate / hexanes) to give a reddish brown solid (0.093 g, 21%). 1 H NMR (400 MHz, CD3OD) d 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, 1 H) 5.47 (s, 2H) 7.00 (m, 2H) 7.54 (m, 1 H), ES-HREM 431.1297 (M + H cale, for C? 8H22CIF2N4O4 requires 431.1292).
EXAMPLE 102 ? / - f2- ( {5-Chloro-4-r (2,4-d? fluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) et N -? '- (2-hydroxyethyl) urea Preparation of? / - [2- (. {5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1- isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxi) etl] -? / '- (2-hydroxyethyl) urea. Prepared as / - [2- ( { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-iopropyl-6-oxo-1,6-dihydropyrimidin-2-yl. Oxy. ) ethyl] - / V-methylurea using ethanolamine (0.19 ml, 3.09 mmol) yielded a brown solid (0.101 g, 21%). 1 H NMR (400 MHz, CD3OD) d ppm 1.45 (d, J = 6.98 Hz, 6H) 3.22 (t, J = 5.77 Hz, 2H) 3.56 (c, J = 5.64 Hz, 4H) 4.52 (t, J = 5.37 Hz, 2H) 5.28 (m, 1 H) 5.47 (s, 2H) 7.00 (m, 2H) 7.54 (m, 1 H), ES-HREM 461.1428 (M + H cale, for C19H24CIF2N4O5 requires 1398).
EXAMPLE 103 4- ( { 5-Chloro-4-f (2,4-difluorobenzyl) oxyM-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl) oxy) -butanamide Preparation of 4- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl.} Oxy) - butanamide Prepared as? / ~ 3 ~ -. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -beta-alaninamide using 4- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1- isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. oxy) butanoic (0.30 g, 0.72 mmol) and ammonia (0.5 M in dioxane, 2.8 ml, 1.4 mmol) to give a white solid (0.220 g, 74%). 1 H NMR (400 MHz, CD3OD) d 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, 1 H) 5.47 (s, 2H) 6.98 (m, 2H) 7.53 (m, 1 H), ES-HREM 416.1171 (M + H cale, for C18H2? CIF2N3O4 requires 416.1183).
EXAMPLE 104 4 - ((5-Chloro-4-f (2,4-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. Oxy -? / - (2- hydroxyethyl) butanamide Preparation of 4- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. -oxi -? - (2-hydroxyethyl) butanamide, prepared as 4- {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2- il.) -? / - (2-hydroxyethyl) butanamide using 4- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1, 6-dihydropyridin-2-yl.} Oxy] butanoic (0.30 g, 0.72 mmol) and ethanolamine (0.085 mL, 1.4 mmol) to give a light red oil (0.131 g, 40%). 1 H NMR (300 MHz, CD3OD) d 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, 1 H) 5.47 (s, 2H) 6.99 (m, 2H) 7.53 (m, 1 H), ES-HREM 460.1457 (M + H cale, for C2oH25CIF2N3O5 requires 460.1445).
EXAMPLE 105 2 - . 2-r (2-aminoethyl) aminol-5-bromo-6-r (2,4-difluorobenzyl) oxy-3-isopropylpi-irimidin-4 (3H) -one trifluoroacetate Step 1. Preparation of Tere-Butyl 2- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) ethylcarbamate. 6- (2,4-difluorobenzyloxy) -5-bromo-3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (1 J7 g, 4.1 mmol) was dissolved in dioxane (40 ml) and added T-butyl 2-aminoethylcarbamate (1.3 ml, 8.2 mmol). After 2 hours, the solvent was removed and then the residue was dissolved in ethyl acetate and washed with water. The aqueous phase was extracted into ethyl acetate. The combined organics were dried over MgSO, filtered, and concentrated. The residue was dissolved in ethyl acetate and passed through a pad of silica gel to provide the desired product (1.95 g, 90%). LC / MS, tr = 3.16 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 517 (M + 1).
Step 2. Preparation of 2-f (2-aminoethyl) arnino] -5-bromo-6-r (2,4-difluorobenzyl) oxyV3-isopropylpyrimidin-4 (3H) -one trifluoroacetate. Prepared as 2- acetate. { [2- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] amino} -2-oxoethyl (step 1) using 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) affording a yellowish solid (1.96 g, 87%). 1 H NMR (400 MHz, CD3OD) d 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, 1 H) 5.43 (s, 2H) 6.98 (m, 2H) 7.51 (m, 1 H), ES-HREM 417.0749 (M + H cale, for C? 6H20BrF2N4O2 requires 417.0732).
EXAMPLE 106 ? -f2- ( {5-bromo-4-r (2,4-difluorobenzyl) oxy-l-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) eti nurea Preparation of? / - [2- ( { 5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyridin-2-yl .}. amino) ethyl] -urea. 2 - [(2-Aminoethyl) amino] -5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-isopropylpyridin-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. To the mixture was added trimethylsilyl isocyanate (0.13 ml, 1.08 mmol) and stirred at room temperature for 45 minutes. The precipitate that formed was collected by filtration, washed with water and ether to give a white solid (0.225 g, 68%). 1 H NMR (400 MHz, CD3OD) d 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, 1 H), ES-HREM m / z 460.0803 (M + H cale, for C17H2? BrF2N5O3 requires 460.0790).
EXAMPLE 107 ? -r2- ( {5-chloro-4-f (2,4-difluorobenzyl) oxyM-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl) amino) etnacetamide Preparation of? / - [2- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] acetamide. Prepared as? / - [3- ( { 5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. amino) propyl] acetamide using 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). The crude solid was purified by chromatography (silica gel, ethyl acetate / hexanes) to give a white solid (0.068 g, 20%). 1 H NMR (400 MHz, CD3OD) d 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, 1 H) 5.44 (s, 2H) 6.98 (m, 2H) 7.51 (m, 1 H), ES-HREM 415.1321 (M + H cale, for C18H22CIF2N4O3 requires 415.1343). After chromatography, LCEM shows mass corresponding to the isotope chloride signal in place of bromide. High resolution MS confirms chloride exchange.
EXAMPLE 108 ? / - [2- ( {5-Chloro-4-r (2,4-difluorobenzyl) oxy1-1-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) etinmethanesulfonamide Preparation of? / - [2- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyridin-2-yl .}. amino) etl] methanesulfonamide. Prepared as? / - [3- ( { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. amino) propyl] methanesulfonamide using 2 - [(2-aminonoyl) 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) to give a light yellow solid (0.094 g, 29%). 1 H NMR (400 MHz, CD3OD) d 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, 1 H ) 5.44 (s, 2H) 6.96 (m, 2H) 7.50 (m, 1 H), ES-HREM 451.0989 (M + H cale, for C17H22CIF2N4O4S requires 451.1013). The same change of bromide by chloride as seen with? / - [2- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1, 6- dihydropyrimidin-2-yl.}. amino) ethyl] acetamide.
EXAMPLE 109 /V-r2-((5-chloro-4-f(2,4-difluorobenzyl) oxyM-isopropyl-6-oxo-1.6- dihydropyrimidin-2-yl.} Amino) etn -2-Hydroxycetamida Step 1. Preparation of (2- (4- (2,4-difluorobenzyloxy) -5-chloro-1,6-dihydro-1-isopropyl-6-oxopyridin-2-ylamino) diethylcarbamoyl acetate) methyl.
Prepared as? / - [3- ( { 5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl.} amino) propyl] -2-hydroxyacetamida (step 1) using 2 - [(2-aminoethyl) amino] -5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidine- 4 (3H) -one trifluoroacetate (0.300 g, 0J2 mmol) and (chlorocarbonyl) methyl acetate (0.118 mL, 1.08 mmol) affording an off white solid (0.181 g, 44%). 1 H NMR (400 MHz, CD3OD) d 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, 1 H) 4.95 (s, 4H) 5.44 (s, 2H) 6.98 (m , 2H) 7.51 (m, 1 H). LC / MS, tr = 2.85 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 573 (M + 1). The same change of bromide by chloride as seen in / - [2- (. {5-Chloro-4 - [(2,4-d-fluorobenzyl) oxy] -1-isopropyl-6-oxo-1 , 6-dihydropyrimidin-2-yl.}. Amino) ethyl] acetamide.
Step 2. Preparation of A / - [2 - ((5-chloro-4-f (2,4-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl) amino) ethyl -2-hydroxyacetamide Prepared as? / - [3- (. {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl .) amino) propyl] -2-hydroxyacetamide (step 2) using (2- (4- (2,4-difluorobenzyloxy) -5-chloro-1,6-dihydro-1- acetate) isopropyl-6-oxopyrimidin-2-ylamino) ethylcarbamoyl) methyl (from step 1) (0.181 g, 0.32 mmol) and K2CO3 (0.065 g, 0.47 mmol) to give an off-white solid (0.100 g, 73%). 1 H NMR (400 MHz, CD3OD) d 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, 1 H) 5.45 (s, 2H) 6.97 (m, J = 8.59 Hz, 2H) 7.51 (m, 1 H), ES-HREM 431.1284 (M + H cale, for C18H22CIF2N4O4 requires 431.1292).
EXAMPLE 110 ? -f2- ( { 5-chloro-4 - [(2,4-difluorobenzyl) oxyM-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl) amino) etn-2-hydroxy- 2-methylpropanamide Step 1. Preparation of 2- (2- (4- (2,4-difluorobenzyloxy) -5-chloro-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) ethylcarbamoyl) propan-2 acetate -ilo.
Prepared as? / - [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) using 2 - [(2-aminoethyl) amino] -5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidine -4 (3H) -one trifluoroacetate (0.307 g, 0.74 mmol) and 2- (chlorocarbonyl) propan-2-yl acetate (0.18 mL, 1.11 mmol) to give an off-white solid (0.127 g, 34%). LC / MS, tr = 2.72 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, a 254 nm, at 50 ° C), ES-MS m / z 501 (M + 1). The same change of bromide by chloride as seen in? / - [2- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1, 6- dihydropyrimidin-2-yl.} amino) etl] acetamide.
Step 2. Preparation of α / - f 2 - ((5-chloro-4-f (2,4-d-fluorobenzyl) oxy-1-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl1-2-hydroxy-2-methylpropanamide Prepared as? / - [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) using (2- (4- (2,4-difluorobenzyloxy) -5-chloroacetate) 1, 6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) etlcarbamoyl) methyl (from step 1) (0.127 g, 0.25 mmol) and K2CO3 (0.053 g, 0.38 mmol) yielding an off-white solid (0.044 g, 38%). 1 H NMR (400 MHz, CD3OD) d 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, 1 H), ES-HREM 459.1593 (M + H cale, for C20H26CIF2N4O4 requires 459. 1603).
EXAMPLE 111 N-f2 - ((5-bromo-4-f (2,4-difluorobenzyl) oxyl-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl-1-methanesulfonamide Preparation of? / - [2- (. {5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. amino) et1] methanesulfonamide. Prepared as / - [3- ( { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. ) propyl] methanesulfonamide using 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) to give a white solid (0.100 g, 35%). 1 H NMR (400 MHz, CD3OD) d 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, 1 H) 5.43 (s, 2H) 6.97 (m, 2H) 7.50 (m, 1 H), ES-HREM 495.0540 (M + H cale, for C? 7H22BrF2N4O4S requires 495.0508).
EXAMPLE 112 / V-r2- (. {5-bromo-4-r (2,4-difluorobenzyl) oxy-1-isopropyl-6-oxo-1-6-dihydropyrimidin-2-yl} amino) ethyl-1 2-hydroxyacetamida Step 1. Preparation of (2- (4- (2,4-difluorobenzyloxy) - bromo-1,6-dhydro-1-isopropyl-6-oxopyrimidin-2-ylamino) ethylcarbamoyl) methyl acetate.
Prepared as? / - [3- ( { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. ) propyl] -2-hydroxyacetamide (step 1) using 2 - [(2-aminoethyl) amino] -5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one trifluoroacetate (0.404 g0.97 mmol) and (chlorocarbonyl) methyl acetate (0.113 mL, 1.06 mmol) to give a white solid (0.292 g, 64%). 1 H NMR (400 MHz, CD3OD) d ppm 1.51 (d, J = 6.98 Hz, 6H) 2.09 (s, 3H) 3.46 (t, J = 5J7 Hz, 2H) 3.56 (t, J = b.ll Hz, 2H ) 4.50 (s, 2H) 4.71 (m, 1 H) 5.43 (s, 2H) 6.97 (m, J = 8.86 Hz, 2H) 7.51 (m, 1 H). LC / MS, tr = 2.48 minutes (5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 517 (M + 1).
Step 2.? / - [2 - ((5-bromo-4-f (2,4-difluorobenzyl) oxyl-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl) amino) ethyl 1-2 -hydroxyacetamide. Prepared as? / - [3- ( { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. amino) propyl] -2-hydroxyacetamide using (2- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-ylamino) etcarbamoyl acetate L) methyl (from step 1) (0.292 g, 0.56 mmol) and K2CO3 (0.116 g, 0.84 mmol) to give a white solid (0.264 g, 100%). 1 H NMR (400 MHz, CD3OD) d ppm 1.51 (d, J = 6.98 Hz, 6H) 3.48 (t, J = 5.11 Hz, 2H) 3.58 (t, J = 5.11 Hz, 2H) 3.95 (s, 2H) 4J3 (m, 1 H) 5.45 (s, 2H) 6.98 (m, 2H) 7.52 (m, 1 H), ES-HREM 475.0795 (M + H cale, for C18H22BrF2N4O4 requires 475.0787).
EXAMPLE 113 / V-f2- ( {5-bromo-4-f (2,4-difluorobenzyl) oxyM-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) etn -2-hydroxy-2-methylpropanamide Step 1. Preparation of 2- (2- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-ylpropyl-6-oxopyrimidin-2-ylamino) ethylcarbamoyl) propan-2-acetate ilo.
Prepared as? / - [3- ( { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyridin-2-yl} amino) propyl] -2-hydroxy-2-methylpropanamide (step 1) using 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) to give a light pink solid (0.335 g, 63 %). 1 H NMR (400 MHz, CD3OD) d 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, 1 H) 5.43 (s, 2H) 6.98 (m, 2H) 7.53 (m, 1 H). LC / MS, tr = 2J7 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 545 (M + 1).
Step 2. Preparation of? / - f2- (. {5-bromo-4-f (2,4-difluorobenzyl) oxp-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethn-2-hydroxy-2-methylpropanamide. Prepared as? / - [3- ( { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. ) propyl] -2-hydroxy-2-methylpropanamide (step 2) using 2- (2- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1- acetate Sodium propyl-6-oxopyrimidin-2-ylamino) ethylcarbamoyl) propan-2-yl (from step 1) (0.335 g, 0.61 mmol) and K2CO3 (0.127 g, 0.92 mmol) yielding a white solid (0.171 g, 56 %). 1 H NMR (400 MHz, CD3OD) d 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 = 5.11 Hz, 2H) 4.75 (m, 1 H) 5.45 (s, 2H) 6.98 (s, 2H) 7.52 (m, 1 H), ES-HREM 503.1071 (M + H cale, for C2oH26BrF2N4O4 requires 503.1100).
EXAMPLE 114 ? -f2- ( {5-chloro-4-f (2,4-difluorobenzyl) oxyM-isopropyl-6-oxo-116-dihydropyrimidin-2-yl} amino) etpurea Preparation of? / - [2- (. {5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. ) ethyl] urea. It was dissolved? / - [2- ( { 5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2- il.}. amino) ethyl] urea (0.283 g, 0.62 mmol) in dioxane (1.5 ml) and tetrabutylammonium chloride (0.690 g, 2.84 mmol) was added. The reaction was heated at 100 ° C for 48 hours. The reaction was concentrated and the residue was dissolved in ethyl acetate and washed with water. The aqueous phase was extracted into ethyl acetate. The combined organics were dried over MgSO 4, filtered, and concentrated. The residue was purified by chromatography (silica gel, ethyl acetate with 10% methanol / hexanes) to give a light yellow solid (0.094 g, 37%). H-NMR (400 MHz, CD3OD) d ppm 1.52 (dd, J = 1.21, 6.85 Hz, 6H) 3.35 (t, J = 5.77 Hz, 2H) 3.49 (t, J = 5.77 Hz, 2H) 4.74 (m, 1 H) 5.44 (s, 2H) 6.97 (m, 2H) 7.51 (m, 1 H), ES-HREM 416.1325 (M + H cale, for C17H21CIF2N5O3 requires 416.1296).
EXAMPLE 115 / V-f2- ( {5-bromo-4 - [(2,4-difluorobenzyl) oxyM-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. Oxi) etpacetamide Step 1. Preparation of tert-butyl 2- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-yloxy) ethylcarbamate.
Prepared as 2- (3-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl.} Oxy] ethylcarbamate. -butyl using 6- (2,4-d.fluorobenzyloxy) -5-bromo-3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (3.0 g, 6.9 mmol) and t-2-hydroxyethylcarbamate. butyl (1.18 mL, 7.6 mmol) to give a white solid (0.440 g, 37%). 1 H NMR (400 MHz, CD3OD) d 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, 1 H) 5.47 (s, 2H) 7.00 (m, 2H) 7.54 (m, 1 H). LC / MS, tr = 3.30 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 518 (M + 1).
Step 2. Preparation of 6- (2,4-difluorobenzyloxy) -2- (2-aminoethoxy) -5-bromo-3-isopropylpyrimidin-4 (3H) -one trifluoroacetic acid.
Prepared as 2- acetate. { [2- ( { {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy} ethyl] am do not} -2-oxoethyl (step 1) using 2- (4- (2,4-difluorobenzyloxy) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-2-yloxy) t-butyl ethylcarbamate (from step 1) (2.36 g, 4.57 mmol) and trifluoroacetic acid (5 ml) to give a light brown oil (0.489 g,> 100%). 1 H NMR (400 MHz, CD3OD) d ppm 1.49 (d, J = 6.98 Hz, 6H) 3.46 (m, 2H) 4.72 (m, 2H) 5.22 (m, 1 H) 5.48 (s, 2H) 7.01 (m, 2H) 7.54 (m, 1 H).
LC / MS, tr = 1.86 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 418 (M + 1).
Step 3. / - [2- ( {5-bromo-4-f (2,4-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl) oxy) ethyl1acetamide Prepared as? / - [3- ( { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. ) propyl] acetamide (step 2) using 6- (2,4-difluorobenzyloxy) -2- (2-aminoethoxy) -5-bromo-3-isopropylpyrimidin-4 (3H) -one trifluoroacetic acid (from stage 1) (0.400 g, 0J5 mmol) and acetyl chloride (0.064 ml, 0.83 mmol) yielding a pink solid (0.200 g, 58%). 1 H NMR (400 MHz, CD3OD) d 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, 1 H) 5.47 (m, 2H) 7.00 (m, 2H) 7.55 (m, 1 H), ES-HREM 460.0697 (M + H cale, for C18H21BrF2N3O4 requires 460.0678).
EXAMPLE 116 V-f2- (. {5-bromo-4-f (2,4-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. Oxy) ethynyl O Prepared as? / - [2- ( { 5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1- isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl. oxy) ethyl] urea. Prepared as? / - [3- ( { 5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. ) propyl] urea using 6- (2,4-difluorobenzyloxy) -2- (2-aminoethoxy) -5-bromo-3-isopropylpyrimidin-4 (3H) -one trifluoroacetic acid (de? / - [2- (. {5-bromo-15 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) to give a white solid (0.146 g, 42%). 1 H NMR (400 MHz, CD3OD) d ppm 1.45 (d, J = 6.98 Hz, 6H) 3.55 20 (t, J = 5.37 Hz, 2H) 4.53 (t, J = 5.37 Hz, 2H) 5.28 (m, 1 H) 5.47 (s, 2H) 6.98 (m, 2H) 7.54 (m, 1 H), ES -HREM 461.0613 (M + H cale, for C? 7H20BrF2N4O requires 461.0630).
EXAMPLE 117 ? - [2- ( {5-bromo-4-f (2,4-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethylethanesulfonamide Preparation of N- [2- (. {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} oxy) ethyl] methanesulfonamide. Prepared as? / - [3- ( { 5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. amino) propyl] methanesulfonamide using 6- (2,4-difluorobenzyloxy) -2- (2-aminoethoxy) -5-bromo-3-isopropylpyrimidin-4 (3H) -one trifluoroacetic acid (de? / - [2- ( {5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-0x0-1,6-dihydropyrimidin-2-yl} oxy) ethyl] acetamide, step 2) (0.489 g, 0.92 mmol) and methanesulfonyl chloride (0.077 mL, 1.0 mmol) to give a yellowish orange solid (0.352 g, 77%). 1 H NMR (400 MHz, CD3OD) d 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, 1 H) 5.47 (s, 2H) 7.00 (m, 2H) 7.54 (m, 1 H), ES-HREM 496.0322 (M + H cale, for C17H21BrF2N3O5S requires 496.0348).
EXAMPLE 118 5-chloro-6-f (2,4-difluorobenzyl) oxyl-3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one Step 1. Preparation of 5-chloro-6-f (2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one. 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 cooled in a bath of ice. Chlorosuccinimide (2.25 g, 16.85 mmol) was added and the reaction was allowed to stir, with heating, for 24 hours. The reaction mixture was then washed with H2O, dried over Na2SO4, filtered and concentrated to give a white solid (5.61 g,> 100%). 1 H NMR (400 MHz, CDCl 3) d 7.43 (c app, J = 1.1 Hz, 1 H), 6.91-6.87 (m, 1 H), 6.84-6.79 (m, 1 H), 5.47 (s, 2 H), 4.58-4.51 (m, 1 H), 2.51 (s, 3H), 1.59 (d, J = 6.7 Hz, 6H). LC / MS, tr = 3.25 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 361 (M + H).
Step 2. Preparation of 5-chloro-6-f (2,4-difluorobenzyl) oxy-3-ylpropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one. 5-Chloro-6 - [(2,4-difluorobenzyl) oxy] -3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one (crude from Step 1) was dissolved (5.61 g, 15.55 mmol) in tetrahydrofuran (50 ml) and H2O (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 by washing the solids with ethyl acetate. The filtrate was diluted with H2O and then extracted with ethyl acetate. The combined organic phases were washed with brine, dried over Na 2 SO 4, filtered, and concentrated. The resulting solids were washed with diethyl ether to give a white solid (4.02 g, 66%). 1 H NMR (400 MHz, CDCl 3) d 7.42 (c app, J = 8.5 Hz, 1 H), 6.93 (dt, J = 8.6, 1.5 Hz, 1 H), 6.84 (dt, J = 9.3, 2.4 Hz, 1 H), 5.40 (s, 2H), 5.23 (septet, J = 6.6 Hz, 1 H), 3.38 (s, 3H), 1.64 (d, J = 6.6 Hz, 6H). LC / MS, tr = 2.60 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 415 (M + Na).
EXAMPLE 119 N ~ 2 ~ -. { 5-Chloro-4-r (2,4-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N ~ 2 ~ -methylqlicinamide Stage 1. Preparation of N-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl) tert-butyl-glycine.
It was suspended in tetrahydrofuran (20 ml) glycine tert-butyl ester hydrochloride (1.71 g, 10.18 mmol). Silica gel-bound dimethylamine (6.79 g, loading = 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) d 7.46 (c app, J = 7.7 Hz, 1 H), 6.88 (dt, J = 8.4, 2.2 Hz, 1 H), 6.82 (m, 1 H), 5.69 (sa, 1 H), 5.48 (ma, 1 H), 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, tr = 3.26 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 444 (M + H).
Stage 2. Preparation of N-. { 5-Chloro-4-f (2,4-difluorobenzyl) oxyl-1-isopropyl-6-oxo-1,6-dihydropyridin-2-yl} -N-tert-butyl methylchlorinate.
N- was suspended. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} Tert-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) 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 replaced and iodomethane (0.151 ml, 2.42 mmol) was added. After stirring, with heating, an additional sodium hydride (60% in mineral oil) was added overnight., 0.026 g, 0.66 mmol) followed by iodomethane (0.068 mL, 1.10 mmol). The resulting mixture was stirred at room temperature for 1.5 hours then deactivated by addition of saturated NH CI and extracted into ethyl acetate. The combined organic phases were washed with brine, dried over Na 2 SO 4, filtered, and concentrated. Chromatography (silica gel, hexanes / ethyl acetate) gave a pale yellow solid (0.920 g, 91%). 1 H NMR (400 MHz, CDCl 3) d 7.45 (c app, J = 7.8 Hz, 1 H), 6.87 (m, 1 H), 6.81 (m, 1 H), 5.34 (s, 2 H), 4.47 (septet, J = 6J Hz, 1 H), 3.83 (s, 2H), 3.01 (s, 3H), 1.63 (d, J = 6JHz, 6H) 1.44 (s, 9H). LC / MS, tr = 3.47 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 458 (M + H).
Stage 3. Preparation of N-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N-methylglycine.
It was N-. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N-Methylglycinate of tert-butyl (Step 2) (0.920 g, 2.01 mmol) with formic acid (4.0 ml) and stirred at room temperature during 24 hours. The reaction mixture was partially concentrated and fractionated between H2O and ethyl acetate. The aqueous phase was further extracted with ethyl acetate. The combined organic phases 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) d 7.42 (c app, J = 7.8 Hz, 1 H), 6.86 (m, 1 H), 6.79 (m, 1 H), 5.32 (s, 2 H), 4.47 (septet, J = 6.8 Hz, 1 H), 3.90 (s, 2H), 3.04 (s, 3H), 1.61 (d, J = 6.7 Hz, 6H). LC / MS, tr = 2.51 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 402 (M + H).
Step 4. Preparation of? / ~ 2 ~ - (5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -N ~ 2 ~ -methylqlicinamide N- {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2 was dissolved. il.) - N -methylglycine (N ~ 2 ~ -. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin- 2-yl.) -N ~ 2 ~ -methylglycinamide, Step 3) (0.300 g, 0.47 mmol) in dioxane (7.0 ml), 1-hydroxybenzotriazole (0.101 g, 0.47 mmol) was added followed by carbodiimide resin attached polymer (1.00 g, loading = 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 the reaction was diluted with dioxane (10 ml) and treated with polyamine resin (1.30 g, loading = 2.87 mmol / g) followed by polystyrene functionalized with methyl isocyanate (2.54 g, arga = 1.47 mmol / g). The resulting reaction was stirred at room temperature for 3 hours and filtered and concentrated to give the title compound as a pale yellow solid (0.220 g, 74%). 1 H NMR (300 MHz, CDCl 3) d 7.40 (c app, J = 7.8 Hz, 1 H), 6.87-6.74 (m, 2H), 6.55 (sa, 1 H), 5.91 (sa, 1 H), 5.33 ( s, 2H), 4.45 (septet, J = 6.6 Hz, 1 H), 3.85 (s, 2H), 2.98 (s, 3H), 1.58 (d, J = 6JHz, 6H). LC / MS, tr = 2.28 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 401 (M + H). ES-HREM m / z 401.1202 (M + H cale for C? 7H20CIF2N4O3 requires 401.1187).
EXAMPLE 120 5-bromo-6-r (2,4-difluorobenzyl) oxyl-2-f (2-hydroxy-2-methylpropyl) amino-3-isopropylpyrimidin-4 (3H) -one Preparation of 5-Bromo-6 - [(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). Carbonate attached to silica gel (3.53 g, loading = 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 filtered and then concentrated. The filtrate was subjected to chromatography (silica gel, hexanes / ethyl acetate) to give an off-white oily solid (0.143 g, 47%). 1 H NMR (400 MHz, CDCl 3) d 7.44 (c app, J = 7.8 Hz, 1 H), 6.93 (t app, J = 8.3 Hz, 1 H), 6.84 (dt, J = 9.1, 2.3 Hz, 1 H ), 5.54 (sa, 1 H), 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, tr = 2J7 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 446 (M + H). ES-HREM m / z 446.0862 (M + H cale, for C18H23BrF2N3O3 requires 446.0885).
EXAMPLE 121 N - ((5-bromo-4-f (2,4-difluorobenzyl) oxyl-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl.} Methyl) methanesulfonamide Step 1. Preparation of 5-bromo-4-α (2,4-difluorobenzyl) oxy-1-isopropyl-6-oxo-1,6-dihydropyrimidine-2-carbonitrile. 6- (2,4-difluorobenzyloxy) -5-bromo-3-isopropyl-2- (methylsulfonyl) pyrimidin-4 (3H) -one (9.85 g, 22.53 mmol) was dissolved in N, N-dimethylacetamide (50 ml) . Potassium cyanide (2.93 g, 45.06 mmol) was added and the resulting mixture was stirred at room temperature for 3 hours. Ethyl acetate (100 ml) was added to the reaction mixture, which was then poured into ice / water (100 ml). The reaction was then extracted into ethyl acetate. The combined organic phases were washed with brine, dried over Na 2 SO 4, filtered, and concentrated. The residue was subjected to chromatography (silica gel, hexanes / ethyl acetate) to give a bright yellow solid (5.05 g, 58%). 1 H NMR (400 MHz, CDCl 3) d 7.45 (c app, J = 7.7 Hz, 1 H), 6.89 (m, 1 H), 6.84 (m, 1 H), 5.44 (s, 2 H), 5.14 (m, 1 H), 1.66 (d, J = 7.0 Hz, 6H). LC / MS, tr = 3.13 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 384 (M + H).
Step 2. Preparation of 2- (aminomethyl) -5-bromo-6-r (2,4-difluorobenzyl) oxy-3-isopropylpyrimidin-4 (3H) -one. 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 and the flask was equipped with a balloon containing H2. The resulting mixture was stirred at room temperature for 1 hour. The reaction was filtered through a pad of Celite® by washing with ethyl acetate. The reaction mixture was made alkaline (pH 10-11) with 2.5 N NaOH. The aqueous phase was removed and the organic phase 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. More? / -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 H2O were added. The reaction was made alkaline (pH 10) with 2.5 N NaOH. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO and concentrated to give an orange / brown foam (1.26 g,> 100%). LC / MS, tr = 1.76 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 388 (M + H).
Step 3. Preparation of? / - (. {5-bromo-4-f (2,4-difluorobenzyl) oxyl-1-isopropyl-6-oxo-1,6-dihydropyridin-2-yl) methyl) methanesulfonamide. 2- (Aminomethyl) -5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one (crude product from Step 2) was dissolved (0.300 g, 0J73 mmol) 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 by the addition of saturated NaHCO3 and extracted into dichloromethane. The combined organic phases were dried over Na 2 SO 4, filtered, and concentrated. Chromatography (silica gel, hexanes / 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) d 7.45 (c app, J = 7.8 Hz, 1 H), 6.88 (t app, J = 8.3 Hz, 1 H), 6.83 (dt, J = 9.5, 2.3 Hz, 1 H ), 5.64 (m, 1 H), 5.44 (s, 2H), 4.35 (d, J = 5.2 Hz, 2H), 2.97 (s, 3H), 1.58 (d, J = 7.3 Hz, 6H). LC / MS, tr = 2.52 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 466 (M + H). ES-HREM m / z 466.0219 (M + H cale, for d6H19BrF2N3O4S requires 446.0242).
EXAMPLE 122 N - ((5-bromo-4 - [(2,4-difluorobenzyl) oxyl-1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl.] Methyl) acetamide Preparation of N- (. {5-bromo-4 - [(2, 4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} methylene) acetamide. 2- (Aminomethyl) -5-bromo-6 - [(2,4-d-fluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one (N- (. {5-bromo-4-) was dissolved [(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, with cooling, for 2 hours. The reaction was quenched by the addition of saturated NaHCO3 and extracted into dichloromethane. The combined organic phases were dried over Na 2 SO, filtered, and concentrated. Chromatography (silica gel, hexanes / ethyl acetate with 10% methanol) afforded the title compound as an off-white solid (0.170 g, 51%). 1 H NMR (400 MHz, CDCl 3) d 7.46 (c app, J = 8.5 Hz, 1 H), 6.88 (t app, J = 7.9 Hz, 1 H), 6.81 (dt, J = 9.5, 2.3 Hz, 1 H ), 6.68 (sa, 1 H), 5.45 (s, 2H), 4.45 (d, J = 4.4 Hz, 2H), 4.35 (m, 1 H), 2.08 (s, 3H), 1.56 (d, J = 6.7 Hz, 6H). LC / MS, tr = 2.34 minutes (from 5 to 95% acetonitrile / water for 5 minutes at 1 ml / minute, at 254 nm, at 50 ° C), ES-MS m / z 430 (M + H). ES-HREM m / z 430.0532 (M + H cale, for C17H19BrF2N3O3 requires 430.0572).
EXAMPLE 123 N- (2-. {F (5-bromo-1-isopropyl-2-methyl-6-oxo-1,6-dihydropyrimidin-4-yl) oxymethyl] -5-fluorobenzyl) -N'-ethylurea Step 1: Preparation of 6-hydroxy-2-methyl-3- (methylethyl) -3-hydropyrimidin-4-one.
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. 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 flash chromatography on silica gel using 1% methanol in dichloromethane as eluent to give 4.65 g (45.5%) of the desired compound as a "beige" solid: 1 H NMR (CD3OD / 400 MHz) d 5.20 ( s, 1 H), 4.60 (a, 1 H), 2.59 (s, 3 H), 1.56 (d, 6 H, = 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.
A mixture of 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 (50 ml) was stirred. at 5 ° C under nitrogen for 1 hour and warmed to room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using 7% methanol in dichloromethane as eluent to give 5.0 g (80%) of the desired product as a solid: 1 H NMR (CD3OD / 400 MHz ) d 4.61 (a, 1 H), 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-1-methyl-5-fluoro-benzenecarbonitrile.
A mixture of 5-bromo-6-hydroxy-2-methyl-3- (methylethyl) -3-hydropyrimidin-4-one (2.55 g, 10.32 mmol), 2-cyano-4-fluorobenzyl bromide (2.32 g) was stirred. , 10.836 mmol) and potassium carbonate (1.71 g, 12.384 mmol) in DMF (30 ml) at room temperature for 18 hours. The resulting mixture was diluted with ethyl acetate (25 ml), washed with water (2 x 100 ml), brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting material was purified by flash chromatography on silica gel using 40% EtOAc in hexanes as eluent to give 2.89 g. (73.8%) of the desired compound as a white powder: 1 H NMR (CD3OD / 400 MHz) d 7.78 (m, 1 H), 7.60 (m, 1 H), 7.44 (m, 1 H), 5.60 (s, 2 H) ), 4.62 (a, 1 H), 2.60 (s, 3H), 1.60 (d, 6H, J = 6.8 Hz); ES-MS m / z 382.07 and 380.10.
Stage 4: Preparation of 6-. { [2- (aminomethyl) -4-fluorophenyl-methoxy} - bromo-2-methyl-3- (methylethyl) -3-hydropyrimidin-4-one.
BH3.THF (1M solution, 11.2 ml, 11.2 mmol) was added dropwise 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 under nitrogen. After stirring at this temperature for 30 minutes, the mixture was allowed to warm to room temperature overnight. 5 ml of methanol was added to the mixture at 0 ° C and its volume was reduced to 10 ml under reduced pressure. The resulting material was purified by flash chromatography on silica gel 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 (CD3OD / 400 MHz) d 7.43 (m, 1 H), 7.20 (m, 1 H), 6.97 (m, 1 H), 5.50 (s, 2H), 4.62 (a, 1 H), 3.86 (s, 2H), 2.60 (s.3H), 1.60 (d, 6H, = 6.8 Hz); ES-MS m / z 386.12, and 384.13.
Step 5: Preparation of N - [(2- {f5-bromo-2-methyl-1- (methylethyl) -6-oxo-pyririmidin-4-yloxy-1-methyl) -5-fluorophenyl) methyl-1 (ethylamino) carboxamide.
Ethyl isocyanate (0.103 ml, 1.3 mmol) was added to a solution of 6-. { [2- (aminomethyl) -4-fluorophenyl] methoxy} -5-bromo-2-methyl-3- (methylethyl) -3-hydropyrimidin-4-one (0.25 g, 0.65 mmol) in dichloromethane (5 ml) at 0 ° C under nitrogen. The reaction mixture was stirred at this temperature for 1.5 h, solvent was removed in vacuo and the residue was purified by column chromatography on silica gel using 10% methanol in dichloromethane as eluent to provide the title compound (0.29 g, 98%). %) as a white solid: mp: 79-80 ° C; 1 H NMR (CD 3 OD / 400 MHz) d 7.75 (m, 1 H), 7.10 (m, 1 H), 6.89 (m, 1 H), 5.80 (s, 2 H), 4 65 (a, 1 H), 4.44 (s, 2H), 3.16 (c, 2H), 2.56 (s, 3H), 1.59 (d, 6H, J = 6.8 Hz), 1061 (t, 3H, J = 6.8 Hz); anal. cale, for C19H2 BrFN4O3: 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 and 455.18.
EXAMPLE 124 N-r (2 - ([5-chloro-2-methyl-1- (methylethyl) -6-oxohydropyrimidin-4-yloxylmethyl] -5-fluorophenyl) methylene (ethylamino) carboxamide Step 1: Preparation of 5-chloro-6-hydroxy-2-methyl-3- (methylethyl) -3-hydropyrimidin-4-one.
A mixture of 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 was stirred (40 g. ml) at 5 ° C under nitrogen for 1 hour and warmed to room temperature overnight. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel using 7% methanol in dichloromethane as eluent to give 4.83 g (97%) of the desired product as a solid: 1 H NMR (CD3OD / 400 MHz) d 4.60 (a, 1 H) , 2.60 (s, 3H), 1.60 (d, 6H, = 6.4 Hz).
Stage 2: Preparation of 2-. { f5-chloro-2-methyl-1- (methylethyl) -6-oxohydropyrimidin-4-yloxylmethyl} -5-fluorobenzenecarbonitrile.
A mixture of 5-chloro-6-hydroxy-2-methyl-3- (methylethyl) -3-hydropyrimidin-4-one (4.65 g, 22.96 mmol), 2-cyano-4-fluorobenzyl bromide (5.41 g, 25.25 mmol) and potassium carbonate (4J5 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 x 100 ml), brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting material was purified by flash chromatography on silica gel using 40% EtOAc in hexanes as eluent to give 5.0 g of the title compound as a white powder (64.9%): H-NMR (CD3OD / 400 MHz) d 7.77 (m, 1 H), 7.60 (m, 1 H), 7.43 (m, 1 H), 5.60 (s, 2H), 4.61 (a, 1 H), 2.60 (s, 3H), 1.60 (d, 6H, J = 6.8 Hz); ES-MS m / z 338.10 and 336.12.
Stage 3: Preparation of 6-. { f2- (aminomethyl) -4-fluorophenyl-1-methoxy) -5-chloro-2-methyl-3- (methylethyl) -3-hydropyrimidin-4-one.
BH3.THF (1 M solution, 25.26 mL, 25.26 mmol) was added dropwise to the solution of 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 under nitrogen. After stirring at this temperature for 30 minutes, the mixture was allowed to warm to room temperature overnight. 10 ml of methanol was added to the mixture at 0 ° C and its volume was reduced to 10 ml in vacuo. The resulting material was purified by flash chromatography on silica gel 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 (CD3OD / 400 MHz) d 7.43 (m, 1 H), 7.20 (m, 1 H), 6.98 (m, 1 H), 5.45 (s, 2H), 4.61 (a, 1H), 3.86 (s, 2H), 2.60 (s, 3H), 1.60 ( d, 6H, J = 6.8 Hz); ES-MS m / z 342.15 and 340.17.
Step 4: Preparation of N - [(2- {[5-chloro-2-methyl-1- (methylethyl) -6-oxohydropyrimidin-4-yloxy-methylene] -5-fluorophenyl) methylene (ethylamino) carboxamide. Ethyl isocyanate (0.119 ml, 1.5 mmol) was added to a solution of 6-. { [2- (aminomethyl) -4-fluorophenyl] methoxy} -5-chloro-2-methyl-3- (methylethyl) -3-hydropyrimidin-4-one (0.255 g, 0J5 mmol) in dichloromethane (5 ml) at 0 ° C under nitrogen. 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 column chromatography using 10% methanol in dichloromethane as eluent to provide the title compound (0.265 g, 86%) as a yellow solid: mp: 160-161 ° C; 1 H NMR (CD 3 OD / 400 MHz) d 7.46 (m, 1 H), 7.08 (m, 1 H), 6.98 (m, 1 H), 5.51 (s, 2 H), 4.63 (a, 1 H), 4.45 ( s, 2H), 3.16 (c, 2H), 2.62 (s, 3H), 1.58 (d, 6H, J = 6.8 Hz), 1.10 (t, 3H, J = 7.6 Hz); anal. cale, for C19H24CIFN4O3: 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 and 411.29.
EXAMPLE 125 N-f (2- { F5-chloro-2-methyl-1- (methylethyl) -6-oxohydropyrimidin-4-yloxymethyl> -5-fluorophenyl) methylene (methylethyl) amino-1-carboxamide Isopropyl isocyanate (0.11 ml, 1125 mmol) was added to a solution of 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 under nitrogen. After stirring for 2 h at room temperature, the reaction mixture was purified by chromatography on silica gel using 10% methanol in dichloromethane to give 0.304 g (95.4%) of the title compound as a yellow solid: mp: 131-132 ° C; 1 H NMR (CD 3 OD / 400 MHz) d 7.46 (m, 1 H), 7.07 (m, 1 H), 6.97 (m, 1 H), 5.50 (s, 2 H), 4.61 (a, 1 H), 4.45 ( s, 2H), 3.79 (m, 1 H), 2.62 (s, 3H), 1.58 (d, 6H, J = 6.8 Hz), 1.12 (d, 6H, J = 6.4 Hz); anal. cale, for C20H26CIFN4O3: 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 and 425.31.
EXAMPLE 126 N-f (2- { F5-bromo-2-methyl-1- (methylethyl) -6-oxo-pyridimidin-4-yloxylmethyl] -5- fluorophenyl) methyl] (cyclohexylamino) carboxamide Cyclohexyl isocyanate (0.124 ml, 0.975 mmol) was added to a solution of 6 { [2- (aminomethyl) -4-fluorophenyl] methoxy} -5-bromo-2-methyl-3- (methylethyl) -3-hydropyrimidin-4-one (0.25 g, 0.65 mmol) in dichloromethane (5 ml) at 0 ° C under nitrogen. After stirring for 2 hours at room temperature, the reaction mixture was purified by chromatography on silica gel using 10% methanol in dichloromethane as the eluent to give 0.325 g (98%) of the title compound as a white solid: mp: 109-110 ° C; 1 NMR (CD3OD / 400 MHz) d 7.46 (m, 1 H), 7.07 (m, 1 H), 6.98 (m, 1 H), 5.49 (s, 2 H), 4.61 (a.1 H), 4.46 (s) , 2H), 3.46 (m, 1 H), 2.61 (s, 3H), 1.58 (d, 6H, J = 4.4 Hz), 1.15-1.89 (m, 11 H); anal. cale, for C23H30BrFN4O3: 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 and 509.30.
EXAMPLE 127 N-1 (2- {f5-chloro-2-methyl-1- (methylethyl) -6-oxohydropyrimidin-4-yloxpmethyl} -5-fluorophenyl) methyl (cyclohexylamino) carboxamide Cyclohexyl isocyanate (0.142 ml, 1125 mmol) was added to a solution of 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 under nitrogen. After stirring for 2 h at room temperature, the product was purified by chromatography on silica gel using 10% methanol in dichloromethane as the eluent to give 0.341 g (98%) of the title compound as a yellow solid: mp: 95-96. ° C; 1 H NMR (CD 3 OD / 400 MHz) d 7.45 (m, 1 H), 7.05 (m, 1 H), 6.96 (m, 1 H), 5.49 (s, 2 H), 4.61 (a.1 H), 4.44 (s) , 2H), 3.45 (m, 1H), 2.61 (s, 3H), 1.57 (d, 6H, J = 4.4 Hz), 1.10-1.88 (m, 11 H); anal. cale, for C23H30BrFN4O3: 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 and 465.30.
EXAMPLE 128 (r3- (tert-butyl) -1- (4-methypheninpyrazol-5-ylamino) -Nr (2- (r5-bromo-2-methyl-1- (methylethyl) -6-oxohydropyridin-4-yloxylmethyl) L.}. -5-fluorophenyl) methylenecarboxamide To a solution of 6-. { [2- (aminomethyl) -4-fluorophenyl] methoxy} -5-bromo-2-methyl-3- (methylethyl) -3-hydropyrimidin-4-one (0.384 g, 1.0 mmol) in dichloromethane (15 ml) and saturated NaHCO3 solution (15 ml), phosgene (20 ml) was added. % in toluene, 1.042 ml, 1.97 mmol). The mixture was stirred during 15 minutes, the organic phase was dried over Na2SO4 and concentrated in vacuo, and the residue was treated with a solution of 3- (tert-butyl) -1- (4-methylphenyl) pyrazol-5-ylamine (0.229 g) in dichloromethane (10 ml). The resulting mixture was stirred for 17 hours at room temperature. After removal of the volatiles in vacuo the residue was purified by flash chromatography using dichloromethane / hexanes / acetone (5: 5: 1) as elution to give the title compound (0.366 g, 57.2%) as a white solid: mp: 133 -135 ° C; H NMR (CD3OD / 400 MHz) d 7.44 (m, 1 H), 7.28 (m.1 H), 6.97 (m, 1 H), 6.29 (s, 1 H), 5.44 (s, 2 H), 4.60 ( a, 1 H), 4.45 (s, 2H), 2.57 (s, 3H), 2.37 (s, 3H), 1.54 (d, 6H, J = 6.8 Hz), 1.30 (s, 9H); anal. cale, for C31H36BrFN6O3: 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 and 639. 39 EXAMPLE 129 (t3- (tert-butyl) -1- (4-methylphenyl) p -razol-5-inamino) -Nr (2- (r5-chloro-2-methyl-1- (methylethyl) -6-oxohydropyridin-4 -yloxylmethyl) -5-fluorophenyl) metincarboxamide To a solution of 3- (tert-butyl) -1- (4-methylphenyl) pyrazol-5-ylamine (0.229 g, 1 mmol) and saturated NaHCO3 solution (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 phase was dried over Na2SO. After removal of the volatiles in vacuo, the residue was treated with a solution of 6-. { [2- (aminomethyl) -4-fluorophenyl] methoxy} -5-chloro-2-methyl-3- (methylethyl) -3-hydropyrimidin-4-one (0.340 g, 1.0 mmol) in dichloromethane (15 ml) and the mixture was stirred for 17 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography using dichloromethane / hexanes / acetone (5: 5: 1) as eluent to give the title compound (0.50 g, 84.0%) as a white solid: mp: 153-155 ° C; 1 H-NMR (CD 3 OD / 400 MHz) d 7.46 (m, 1 H), 7.29 (m, 1 H), 6.98 (m, 1 H), 6.29 (s, 1 H), 5.46 (s, 2 H), 4.60 ( a, 1 H), 4.44 (s, 2H), 2.59 (s, 3H), 2.38 (s, 3H), 1.56 (d, 6H, J = 6.8 Hz), 1.30 (s, 9H); anal. cale, for C3? H36CIFN6O3: 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 and 595.46.
EXAMPLE 130 1- (2 - ((5-chloro-1,6-dihydro-1-isopropyl-2- (methylthio) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzyl) -3-ethylurea Step 1: Preparation of 5-chloro-6-hydroxy-3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one.
To a suspension of 6-hydroxy-3-isopropyl-2- (methylthio) pyrimidin-4-one (5.0 g, 25.0 mmol) in 50 ml of dichloromethane in a three-necked round bottom flask equipped with a magnetic stir bar , N-chlorosuccinimide (4.0 g, 30.0 mmol) was added in portions at 0-5 ° C. The reaction mixture was allowed to warm to room temperature for 48 hours with stirring. It was then poured into brine with vigorous stirring, the solid precipitate was collected by filtration and crystallized from a mixed solvent of acetone / hexane (1: 5), dried under vacuum overnight giving 3.05 g of the title compound as a white powder (52%): 1 H NMR (DMSO-d 6/400 MHz) d 12.08 (s, 1 H), 4.25 (m, 1 H), 2.58 (s, 3 H), 1.43 (d, 6 H); ESI-ES: 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.
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), potassium carbonate (2.1) was added. g, 19.18 mmol) and the mixture was stirred for 15 minutes, after which 2-cyano-4-fluorobenzyl bromide (3.1 g, 14.07 mmol) was added in portions. The resulting mixture was stirred at room temperature overnight and then brine was added at 0-5 ° C with vigorous stirring. A light yellow precipitate was collected by filtration, washed with water, dried in vacuo to give 3.15 g (71%) of pink powder: 1 H NMR (CDCl 3, 400 MHz) d 7.63 (m, 1 H), 7.39 (m, 2H), 5.62 (s, 2H), 4.46 (m, 1 H), 2.58 (s, 3H), 1.61 (d, 6H); ESI ES: m / z 368 (M + H).
Step 3: Preparation of 6- (2- (aminomethyl) -4-fluorobenzyloxy-5-chloro-3-isopropyl-2- (methylthio) -pyrimidin-4 (3H) -one.
To a solution of 2 - ((5-chloro-1,6-dihydro-1-isopropyl-2- (methylthio) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzonitrile (22 g, 59.86 mmol) in Dry THF (250 ml) was added BH3.THF (1 M, 120 ml) dropwise at -10 ° C. The resulting mixture was stirred at -10 ° C for 3 hours, and then allowed to warm to room temperature 16 h. The mixture was cooled to -0 ° C and methanol (20 ml) was added slowly removing excess BH3. After removing the solvent in vacuo the crude syrup was purified by silica gel column chromatography eluting with hexane / DCM / CH3OH (3: 6: 1) to give 12.1 g (55%) of the title compound as a syrup. colorless: 1 H NMR (CDCl 3, 400 MHz) d 7.38 (m, 1 H), 1.17 (m, 1 H), 6.95 (m, 1 H), 5.46 (s, 2 H), 4.52 (m, 1 H), 4.51 (s, 2H), 2.58 (s, 3H), 2.16 (sa, 2H), 1.61 (d, 6H); ESI-ES: m / z 372 (M + H).
Step 4: Preparation of the title compound. To a solution of 6- (2- (aminomethyl) -4-fluorobenzyloxy) -5-chloro-3-isopropyl-2- (methylthio) -pyrimidin-4 (3H) -one (0.35 g, 0.943 mmol ) in dry dichloromethane (5 ml) was added ethyl isocyanate (0.1 ml, 1886 mmol) dropwise at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 8 hours. After removal of solvent in vacuo, the crude product was purified by chromatography on silica gel using hexane / DCM (1: 5) as the eluent to give 0.087 g of the title compound (21%): 1H NMR (CDCl3, 400 MHz) d 7.36 (m, 1 H), 7.22 (m, 1 H), 6.95 (m, 1 H), 5.42 (s, 2H), 4.48 (m, 1 H), 4.30 (s, 2H), 3.19 (c, 2H), 2.62 (s, 3H), 1.61 (d, 6H), 1.08 (t, 3H); ESI-ES: m / z 443 (M + H). Anal. cale, for C19H24CIFN4O3S: C, 51.52; H, 5.46; N, 12.65. Found: C, 51.73; H, 5.53; N, 12.75.
EXAMPLE 131 1- (2 - ((5-chloro-1,6-dihydro-1-isopropyl-2- (methylthio) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzyl) -3-isopropylurea To a solution of 6- (2- (aminomethyl) -4-fluorobenzyloxy) -5-chloro-3-isopropyl-2- (methylthio) -pyrimidin-4 (3H) -one (0.5 g, 1.346 mmol) in dry dichloromethane (5 ml) was added isopropyl isocyanate (0.41 g)4.037 mmol) dropwise at room temperature under nitrogen. The resulting mixture was stirred at room temperature overnight. After removal of solvent in vacuo, the crude product was purified by chromatography on silica gel 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) d 7.38 (m, 1 H), 7.21 (m, 1 H), 6.90 (m, 1 H), 5.45 (s, 2 H), 4.58 (m, 1 H), 4.43 ( s, 2H), 3.85 (m, 1 H), 2.61 (s, 3H), 1.61 (d, 6H), 1.15 (d, 6H); ESI ES: m / z 457 (M + H). Anal. cale, for C20H26CIFN4O3S: C, 52.57; H, 5J3; N, 12.26. Found: C, 52.45; H, 5.80; N, 11.87.
EXAMPLE 132 1- (2 - ((5-bromo-1,6-dihydro-1-isopropyl-2- (methylthio) -6-oxopyrimidin-4-yloxy) methyl) -5-f! Uorobenzyl) -3-ethylurea Step 1: Preparation of 5-bromo-6-hydroxy-3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one.
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 , added N-bromosuccinimide (25.0 g, 140.0 mmol) in portions and was stirred at 0-5 ° C under nitrogen. The reaction mixture was allowed to warm to room temperature over a period of 48 hours. The mixture was poured into brine with vigorous stirring, the solid precipitate was collected by filtration, crystallized from a mixed solvent of acetone / DCM (6: 1), and dried under vacuum overnight providing 28.1 g of the compound of the title as a white powder (81.0%): 1H-NMR (DMSO-d6 / 400 MHz) d 12.08 (s, 1 H), 4.57 (m, 1 H), 2.58 (s, 3H), 1.43 (d, 6H) ); EM-ESI: m / z 280 (M + H cale, for 280).
Step 2: Preparation of 2 - ((5-bromo-1,6-dihydro-1-isopropyl-2- (methyltio) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzonitrile.
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), potassium carbonate (1 g) was added. J0 g, 12.15 mmol) and the mixture was stirred for 15 minutes, then 2-cyano-4-fluorobenzyl bromide (1.90 g, 8.907 mmol) was added in portions. The resulting mixture was stirred at room temperature overnight and then poured into brine at 0-5 ° C with vigorous stirring. A light pink precipitate was collected by filtration, washed with water, dried in vacuo to give 3.01 g (91%) of the title compound: 1 H NMR (DMSO-d 6, 400 MHz) d 7.98 (dd, 1 H), 7.70 (m, 2H), 5.62 (s, 2H), 4.53 (m, 1 H), 2.59 (s, 3H), 1.53 (d, 6H); ESI ES: m / z 412 (M + H).
Step 3: Preparation of 6- (2- (aminomethyl) -4-fluorobenzyloxy) -5-bromo-3-isopropyl-2- (methylthio) pyrimidin-4 (3H) -one.
To a solution of 2 - ((5-bromo-1,6-dihydro-1-isopropyl-2- (methylthio) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzonitrile (1.0 g, 2.427 mmol) in dry THF (250 ml) was added BH3.THF (1 M, 5.0 ml) dropwise at -10 ° C. The resulting mixture was stirred at -10 ° C at 0 ° C for 3 hours, then allowed to warm to room temperature overnight. It was refluxed for 30 minutes, cooled to 0 ° C and 3N NaOH solution was added at pH 12. The organic phase was isolated, washed with brine, dried over Na 2 SO, filtered, and concentrated to dryness. The resulting syrup was purified by column chromatography on silica gel, 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) d 7.36 (m, 1 H), 1.16 (m, 1 H), 6.93 (m, 1 H), 5.36 (s, 2 H), 4.41 (m, 1 H), 4.38 (s, 2 H), 2.58 (s, 3H), 2.35 (sa, 2H), 1.60 (d, 6H); ESI ES: m / z 417 (M + H).
Step 4: Preparation of the title compound. To a solution of 6- (2- (aminomethyl) -4-fluorobenzyloxy) -5-bromo-3-isopropyl-2- (methylthio) -pyrimidin-4 (3H) -one (0.25 g, 0.602 mmol) in dry dichloromethane (5 ml) was added ethyl isocyanate (0.065 g, 0.903 mmol) dropwise at room temperature and stirred under nitrogen for 16 h. After removal of the solvent in vacuo the crude product was purified by chromatography on silica gel using hexane / dichloromethane (1: 5) to give 0.175 g (60%) of the title compound as a white powder: 1H-NMR (CDCl3, 400 MHz) d 7.38 (m, 1 H), 7.22 (m, 1 H), 6.97 (m, 1 H), 5.43 (s, 2 H), 4.58 (m, 1 H), 4.45 (s, 2 H), 3.21 (c, 2H), 2.62 (s, 3H), 1.63 (d, 6H), 1.11 (t, 3H); ESI ES: m / z 488 (M + H). Anal. cale, for C2oH27BrFN4O5S: C, 46.82%; H, 4.96%; N, 11.50%. Found: C, 47.18%; H, 4.83%; N, 11.27%.
EXAMPLE 133 1- (2 - ((5-bromo-1,6-dihydro-1-isopropyl-2- (methylthio) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzyl) -3-isopropylurea To a solution of 6- (2- (aminomethyl) -4-fluorobenzyloxy) -5-bromo-3-isopropyl-2- (methylthio) -pyrimidin-4 (3H) -one (0.5 g, 1202 mmol) in dry dichloromethane (8 ml) was added isopropyl isocyanate (0.2 ml, 1.715 mmol) dropwise at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 16 h, concentrated in vacuo, and the residue was purified by chromatography on silica gel eluting with hexane / dichloromethane (1: 5 v / v) to provide 0.38 g (63%) of the compound of the title as a white powder: 1 H NMR (CDCl 3, 400 MHz) d 7.36 (m, 1 H), 7.19 (m, 1 H), 6.97 (m, 1 H), 5.45 (s, 2 H), 4.55 (m , 1 H), 4.43 (s, 2H), 3.85 (m, 1 H), 2.62 (s, 3H), 1.62 (d, 6H), 1.12 (d, 6H); ESI ES: m / z 501 (M +). Anal. cale, for C20H26BrFN4O3S: C, 47.91%; H, 5.23%; N, 1 1.17%.
Found: C, 47.89%; H, 5.58%; N, 10.74%.
EXAMPLE 134 2-f5-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.
To a solution of 2 - ((5-bromo-1,6-dihydro-1-isopropyl-2- (methylthio) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzonitrile (10.0 g, 24.272 mmol) in THF (200 ml) containing deionized water (40 ml) added oxone (37.3 g, 60,679 mmol) in small portions. The resulting mixture was stirred at room temperature for 5 days. The reaction mixture was poured into ice-cold brine with vigorous stirring and the white precipitate was collected by filtration, washed with water, and dried in the air to give 10.6 g (98.9%) of the title compound as a white powder: 1 H NMR (CDCl 3, 400 MHz) d 7.69 (m, 1 H), 7.45 (m, 2H), 5.59 (s, 2H), 5.28 (m, 1 H), 3.46 (S, 3H), 1.68 (d, 6H); ESI ES: m / z 444.03 (M +).
Step 2: Preparation of the title compound. To a solution of 2 - ((5-bromo-1,6-dihydro-1-isopropyl-2- (methylsulfonyl) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzonitrile (0.5 g, 1.126 mmol ) in dry DMF (5 ml) was added pyridine (0.445 g, 5.631 mmol), followed by the addition of 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 solid which precipitated was collected by filtration, washed with water, 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) d 7.95 (m, 1 H), 7.68 (m, 2 H), 7.40 (sa, 1 H), 5.48 (s, 2H), 4.70 (t, 2H), 3.51 (m, 2H), 3.38 (m, 2H), 1.42 (d, 6H); ESI-MS: m / z 426 (M + H). Anal. cale, for C17H18BrFN4O3: C, 48.02%; H, 4.27%; N, 13.17%. Found: 47.85%; H, 4.35%; N, 12.94%.
EXAMPLE 135 1- (2 - ((5-bromo-1,6-dihydro-1-isopropyl-2- (methylsulfonyl) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzyl) -3-isopropylurea To a solution of 1- (2 - ((5-bromo-1,6-dihydro-1-isopropyl-2- (methylthio) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzyl) -3 -isopropylurea (04-003-137a, 0.92 g, 1836 mmol) in THF (10 ml) containing deionized water (1 ml), oxone (2.26 g, 3673 mmol) was added. The resulting mixture was stirred at room temperature for 50 hours. The reaction was cooled to -10 ° C, brine (50 ml) was added, and vigorously stirred. The solid precipitate was collected by filtration, washed with water, dried in vacuo to give 0.88 g (90%) of the title compound as a light yellow powder: 1 H NMR (CDCl 3, 400 MHz) d 7.39 (m, 1 H) , 7.15 (m, 1 H), 7.02 (m, 1 H), 5.42 (s, 2H), 5.28 (m, 1H), 4.43 (s, 2H), 3.83 (m, 1 H), 3.55 (s, 3H), 1.68 (d, 6H), 1.12 (d, 6H); ESI ES: m / z 533.24 (M +). Anal. cale, for C20H28BrFN4O6S.H2O: C, 43.55%; H, 5.08%; N, 10.16%.
Found: C, 43.25%; H, 4.63%; N, 9.68%.
EXAMPLE 136 1- (2 - ((2- (2-hydroxyethylamino) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzyl) -3 -isopropylurea To a solution of 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 dry DMF (3 mL), potassium carbonate (0.065 g, 0.469 mmol) and ethanolamine (0.039 mL, 0.516 mmol) were 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 afford 0.136 g (58%) of the title compound as a white powder: 1H-NMR (DMSO-d6, 400 MHz) d 7.42 (m, 1H ), 7.38 (m, 1 H), 7.06 (m, 2H), 6.23 (t, 1 H), 5.85 (d, 1 H), 5.38 (s, 2H), 4.78 (t, 1 H), 4.35 (d, 2H), 3.65 (m, 1 H) ), 3.55 (m, 2H), 3.42 (m, 2H), 1.42 (d, 6H), 1.05 (d, 6H); ESI ES: m / z 514.25 (M +). Anal. cale, for C21H29BrFN504: C, 49.03%; H, 5.68%; N, 13.05%. Found: C, 49.11%; H, 5.89%; N, 12.71%.
EXAMPLE 137 1- (2 - ((2- (2- (dimethylamino) ethylamino) -5-bromo-1,6-dihydro-1-isopropyl-6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzyl) -3- isopropylurea To a solution of 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 dry DMF (2 ml), pyridine (0.076 ml, 0.938 mmol) and? /,? / - dimethylethylenediamine (0.057 ml, 0.515 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours, cooled to -10 ° C and poured into brine (30 ml). The solid that precipitated 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: 1H-NMR (DMSO-d6, 400 MHz) d 7.42 (m, 1 H), 7.29 (m, 1 H), 7.08 (m, 2H), 6.23 (t, 1H), 5.85 (d, 1 H), 5.39 (s, 2H), 4.25 (d, 2H), 3.66 ( m, 1 H), 3.45 (m, 2H), 2.42 (t, 2H), 2.18 (s, 6H), 1.41 (d, 6H), 1.03 (d, 6H); EM-ESI: m / z 539.37 (M-2H) Anal. cale, for C23H34BrFN6O3: C, 50.69%; H, 6.34%; N, 15.41%. Found: C, 50.68%; H, 6.29%; N, 14.92%.
EXAMPLE 138 1- (2 - ((5-chloro-1,6-dihydro-1-isopropyl-2- (methylthio) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzyl) -3-cyclohexylurea To a solution of 1- (2 - ((5-chloro-1,6-dihydro-1-isopropyl-2- (methylthio) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzyl) -3-cyclohexylurea (0.76 g, 1.53 mmol) in THF (6 mL) and H2O (0.6 mL), oxone (1.88 g, 3061 mmol) was added and stirred at room temperature for 16 hours. The reaction was quenched by the addition of brine (30 ml) and stirred at 0 ° C. The solid that precipitated was collected by filtration, washed with water and dried in vacuo to afford 0.73 g (91%) of the title compound as a yellow powder: 1 H-NMR (CDCl 3, 400 MHz) d 7.38 (m, 1 H), 7.17 (m, 1 H), 7.05 (m, 1 H), 5.41 (s, 2 H), 5.26 (m, 1 H), 4.43 ( s, 2H), 3.75 (m, 1 H), 3.53 (s, 3H), 3.43 (m, 1 H), 1.85 (m, 3H), 1.68 (d, 6H), 1.60 (m, 1 H), 1.30 (m, 2H), 1.05 (m, 2H); ESI ES: m / z 529.31 (M +). Anal. cale, for C23H30CIFN4O3S: C, 55.58%; H, 6.08%; N, 11. 27% Found: C, 55.47%; H, 6.21%; N, 11.18%.
EXAMPLE 139 1- (2 - ((5-chloro-1,6-dihydro-1-isopropyl-2- (methylthio) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzyl) -3-cyclohexylurea To a solution of 1- (2 - ((5-chloro-1,6-dihydro-1-isopropyl-2- (methylthio) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzyl) -3-cyclohexylurea (0.76 g, 1531 mmol) in THF (10 mL) containing deionized water (1 mL), oxone (1.88 g, 3061 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The mixture was cooled to -10 ° C, brine (50 ml) was added with vigorous stirring. The solid precipitate was collected by filtration, washed with water, dried in vacuo affording 0J3 g (90%) of the title compound as a light yellow powder: 1 H NMR (CDCl 3, 400 MHz) d 7.39 (m, 1 H) , 7.15 (m, 1 H), 7.02 (m, 1 H), 5.42 (s, 2H), 5.28 (m, 1 H), 4.43 (s, 2H), 3.83 (m, 1 H), 3.55 (s) , 3H), 1.68 (d, 6H), 1.12 (d, 6H); ESI ES: m / z 533.24 (M +). Anal. cale, for C23H30CIFN4O5S: C, 52.22%; H, 5.72%; N, 10. 59% Found: C, 51.88%; H, 5.88%; N, 9.83%.
EXAMPLE 140 1 - . 1 - (2 - ((5-chloro-1,6-dihydro-1-isopropyl-2- (methylthio) -6-oxopyrimidin-4-yloxy) methyl) -5-fluorobenzyl) -3- (3-tert- butyl-1-p-tolyl-1H-pyrazol-5-yl) urea To a solution of 6- (2- (aminomethyl) -4-fluorobenzyloxy) -5-chloro-3-isopropyl-2- (methylthio) -pyrimidin-4 (3H) -one (0.4 g, 1.076 mmol) in dichloromethane ( 12 ml) was added a saturated solution of NaHCO3 (12 ml). The mixture was cooled to 5 ° C, and a solution of phosgene in toluene (20%, 1.14 mL, 2154 mmol) was added dropwise with vigorous stirring. The resulting mixture was stirred at 5 ° C for 30 minutes, the organic phase was separated, dried over Na 2 SO 4, filtered, concentrated to 6 ml and 1- (4-methyl) phenyl-3-t-butyl- pyrazolyl-5-amine (0.493 g, 2.152 mmol). The resulting mixture was stirred at room temperature under nitrogen for 48 hours and the product was purified by chromatography on silica gel eluting with hexane / dichloromethane / acetone (5: 5: 1) to give 186 mg (30%) of the title compound as a light yellowish powder: 1 H NMR (CDCl 3, 400 MHz) d 7.30 (m, 3 H), 7.20 (d, 2 H), 7.05 (dd, 1 H), 6.95 (m, 1 H), 6.35 (s, 1 H), 6.31 (sa, 1 H), 5.55 (sa, 1 H), 5.40 (s, 2H), 4.45 (d, 2H), 2.60 (s, 3H), 2.36 (s, 3H), 1.58 (d) , 6H), 1.15 (s, 9H); ESI ES: m / z 627.37 (M +). Anal. cale, for C31H36CIFN6O2S: C, 59.37%; H, 5.79%; N, 13.40%. Found: C, 59.10%; H, 6.00%; N, 12.67%. 6-f (214-difluorophenyl) methoxy-1-3-cyclopropyl-2-methylthio-3-hydropyrimidin-4-one Stage 1: Preparation of cyclopropylisothiocyanate.
NCS To a stirred solution of cyclopropylamine (8.03 g, 0.141 mol) and triethylamine (15.65 g, 0.155 mol) in THF (100 ml), carbon disulfide (32.12 g, 0.422 mol) was added at 0-10 ° C. Stirring was continued for 0.5 hours, a solution of hydrogen peroxide (30% by weight, 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 phase was washed with brine, dried over Na2SO, and evaporated under reduced pressure. The resulting residue was distilled giving 8.50 g (61.0%) of the desired product as a colorless oil: m.p. : 125-130 ° C; 1 H NMR (CDCl 3/200 MHz) d 2.94-2.82 (m, 1 H), 0.96-0.82 (m, 4H).
Stage 2: Preparation of cyclopropyl thiourea.
To a solution of cyclopropyl isothiocyanate (8,140 g, 82.2 mmol) in methanol (10 ml) at 0 ° C was added a methanolic solution of ammonia (7 N, 23.5 ml). The resulting mixture was then stirred at room temperature for 5 h, cooled to -10 ° C and the white precipitate filtered, washed with ether and dried to give 10,251 g (100%) of the title product as a white crystalline solid. 1 H NMR (DMSO-d6 / 400 MHz) d 7.95 (a, 1 H), 7.62 (a, 1 H), 7.15 (a, 1 H), 2.20 (a, 1 H), 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.
A vigorously stirred mixture of cyclopropyl thiourea (10191 g, 87.8 mmol), diethylmalonate (14.060 g, 87.8 mmol), sodium methoxide (25-30% in methanol, 35.1 mL) was heated under reflux under nitrogen. After 4.5 h, the reaction mixture was cooled, and iodomethane (12952 g, 91.3 mmol) was added while the temperature was maintained at 50 ° C. The mixture was stirred for 30 minutes, then cooled to 10 ° C, and treated with acetic acid (21.1 ml). The product which precipitated was diluted with water (50 ml), filtered, washed with water, and dried in air to yield 13853 g (79.7%) of the desired product: 1 H NMR (DMSO-d6 / 400 MHz) d 5.10 ( s, 2H), 2.68-2.62 (m, 1 H), 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-α- (2,4-difluorophenyl) methoxy-1-3-cyclopropyl-2-methylthio-3-hiropyrimidin-4-one.
A mixture of 3-cyclopropyl-6-hydroxy-2-methylthio-3-hydropyrimidin-4-one (13853 g, 66.9 mmol), 2,4-difluorobenzylbromide (14.760 g, 71.3 mol) was stirred at 0 ° C under nitrogen. and potassium carbonate (17.390 g, 125 mmol) in DMF (80 ml). After 30 minutes, it was stirred at room temperature for an additional 30 minutes and filtered and the filtrate was concentrated in vacuo. The residue was partitioned between dichloromethane (50 ml) and 5% hydrochloric acid (20 ml). The organic phase was washed with water, dried (Na 2 SO 4) and concentrated to dryness under reduced pressure. The resulting material was purified by flash chromatography on silica gel using 33% EtOAc in hexane as elution to give 11144 g of the title compound as a white powder: mp: 106.1-106.8 ° C; 1 H NMR (CDCl 3/400 MHz) d 7.41-7.39 (m, 1 H), 6.91-6.81 (m, 2 H), 5.56 (s, 1 H), 5.30 (s, 2 H), 2.70-2.51 (m, 1 H), 2.51 (s, 3H), 1.29-1.24 (m, 2H), 1.02-0.98 (m, 2H); anal. cale, for d5H? 4N2O2SF2: 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 142 6 - [(2,4-d.fluorophenyl) methoxy1-2-. { f2- (dimethylamino) ethyleneamino} -5-bromo-3 ° cyclopropyl-3-hydropyrimidin-4-one Step 1: Preparation of 6-α (2,4-difluorophenyl) methoxy-5-bromo-3-cyclopropyl-2-methylthio-3-hydropyrimidin-4-one.
A mixture of 6 - [(2,4-difluorophenyl) methoxy] -3-cyclopropyl-2-methylthio-3-hydropyrimidin-4-one (1600 g, 4.93 mmol), N was stirred at room temperature under nitrogen for 1 hour. -bromosuccinimide (0.922 g, 5.18 mmol) in dichloromethane (15 ml). The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel using 33% ethyl acetate in hexanes as elution to give 1544 g (11.1%) of the title compound as a white powder: mp: 121.0-122.4 ° C. 1 H NMR (CDCl 3/400 MHz) d 7.52-7.44 (m, 1 H), 6.98-6.78 (m, 2 H), 5.52 (s, 2 H), 2.80-2.72 (m, 1 H), 2.52 (s, 3 H) ), 1.32-1.24 (m, 2H), 1.08-1.02 (m, 2H); ES-MS m / z 403.05 and 405.04.
Step 2: Preparation of 6-f (2,4-difluorophenyl) methoxy-1-5-bromo-3-cyclopropyl-2- (methylsulfonyl) -3-hydropyrimidin-4-one.
A mixture of 6 - [(2,4-difluorophenyl) methoxy] -5-bromo-3-cyclopropyl-2-methylthio-3-hydropyrimidin-4-one (0.758 g, 1.88 mmol), acid was stirred at room temperature. -chloroperbenzoic acid (60%, 1352 g, 4J0 mmol) in dichloromethane (40 ml) for 16 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel using 33% ethyl acetate in hexanes as elution to give 0.695 g (84.9%) of product as a white powder . P.f. 159.6-160.5 ° C; 1 H NMR (CDCl 3/400 MHz) d 7.48-7.41 (m, 1 H), 6.98-6.84 (m, 2 H), 5.42 (s, 2 H), 3.38-2.72 (m, 1 H), 2.52 (s, 3 H) ), 1.32-1.24 (m, 2H), 1.08-1.02 (m, 2H); ES-MS m / z 434.97 and 436.97.
Step 3: Preparation of 6 - [(2,4-difluorophenyl) methoxy1-2-. { [2- (dimethylamino) ethylammonium} -5-bromo-3-cyclopropyl-3-hydropyrimidin-4-one. A mixture 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) was stirred at room temperature for 12 hours. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using 13% methanol in dichloromethane as elution to give 0.154 g (40.2%) of the title compound as a white powder: m.p. 125.8-127.2 ° C; 1 H NMR (400 MHz CDCl 3) d 7.52-7.46 (m, 1 H), 6.92-6J8 (m, 2 H), 6.58 (a, 1 H), 5.41 (s, 2 H), 3.48-3.44 (m, 2 H) , 2.64-2.55 (m, 3H), 2.31 (s, 6H), 1.28-1.24 (m, 2H), 0.92-0.88 (m, 2H); anal. cale, for C18H2? N4O2BrF2: C, 48.77; H, 4.77; N, 12.64. Found: C, 48.58; H, 4.68; N, 12.35; ES-MS m / z 443. 6 - [(2,4-difluorophenyl) methoxy1-2-. { [2- (dimethylamino) etinamino} -5-chloro-3-cyclopropyl-3-hydropyrimidin-4-one Step 1: Preparation of 6 - [(2,4-difluorophenyl) methoxy-1-3-cyclopropyl-2- (methylsulfonyl) -3-hydropyrimidin-4-one.
A mixture of 6 - [(2,4-difluorophenyl) methoxy] -3-cyclopropyl-2-methylthio-3-hydropyrimidin-4-one (5,000 g, 15.4 mmol), m-chloroperbenzoic acid (60 g) was stirred at room temperature. %, 13306 g, 46.3 mmol) in dichloromethane (200 ml) for 12 hours. The reaction mixture was filtered, the filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using 50% ethyl acetate in hexanes as elution to give 4.266 g (77.6%) of the title compound as a powder White. P.f .: 113.5-114.2 ° C; 1 H-NMR (CDCl 3/400 MHz) d 7.46-7.35 (m, 1 H), 6.98-6.84 (m, 2 H), 5.82 (s, 1 H), 5.24 (s, 2 H), 3.35 (s, 3 H), 3.24-3.16 (m, 1 H), 1.35-1.32 (m, 2H), 1.18-1.12 (m, 2H); ES-MS m / z 357.10.
Step 2: Preparation of 6 - [(2,4-difluorophenyl) methoxy1-2-. { [2- (dimethylamino) ethylamino} -3-cyclopropyl-3-hydropyrimidin-4-one.
A mixture of 6 - [(2,4-difluorophenyl) methoxy] -3-cyclopropyl-2- (methylsulfonyl) -3-hydropyrimidin-4-one (1,000 g, 2.81 mmol), N, N-dimethylethylenediamine (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 in vacuo and the residue was purified by flash chromatography on silica gel using 9% methanol in dichloromethane as elution to give 0.951 g (92.2%) of white powder as product: mp: 103.5-104.0 ° C; 1 H NMR (CDCl 3/400 MHz) d 7.46-7.38 (m, 1 H), 6.92-6.68 (m, 2 H), 6.52 (a, 1 H), 5.24 (s, 2 H), 5.22 (s, 1 H) , 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-MS m / z 365.27 (M + H).
Step 3: Preparation of 6 - [(2,4-difluorophenyl) methoxfl-2-. { f2- (dimethylamino) -etin-amino-5-chloro-3-cyclopropyl-3-hydropyrimidin-4-one. A mixture 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 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel using 10% methanol in dichloromethane as elution to give 0.329 g (60.2%) of the title compound as a white powder: mp: 127.6- 128.4 ° C; 1 H NMR (CDCl 3/400 MHz) d 7.51-7.47 (m, 1 H), 6.91-6.78 (m, 2 H), 5.41 (s, 2 H), 3.46-3.45 (m, 2 H), 2.63-2.56 (m, 3H), 2.31 (s, 6H), 1.28-1.24 (m, 2H), 0.93-0.90 (m, 2H); anal. cale, for C? 8H2? N4? 2CIF2: 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 144 6-f (2,4-D-fluoro-phenyl) -methoxy-1-5-chloro-3- (2-methyl-propyl) -2-methylthio-3 ° hydropyrimidin-4-one Stage 1: Preparation of isobutylthiourea. S N NH, H 2 A methanolic solution of ammonia (7 N, 29.8 ml) was added to a solution of isobutyl isothiocyanate (12,000 g, 104 mmol) in methanol (15 ml) at 0 ° C. The resulting mixture was then stirred at room temperature, solid that separated 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 (400 MHz DMSO) d 7.68 (a, 1 H) , 7.58 (a, 1 H), 6.88 (s, 1 H), 3.18 (a, 1 H), 1.80-1.76 (m, 1 H), 0.88 (a, 6H); ES-MS m / z 133.10 (M + H).
Step 2: Preparation of 6-hydroxy-3- (2-methylpropyl) -2-methylthio-3-hydropyrimidin-4-one.
A vigorously stirred mixture of isobutylthiourea (11.468 g, 86.9 mmol), diethyl malonate (13.900 g, 86.7 mmol), sodium methoxide (25-30% in methanol, 34J mL) was heated under reflux under nitrogen. After 4.5 h, the reaction mixture was cooled, and iodomethane (12803 g, 90.2 mmol) was added while the temperature was maintained 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 product which precipitated was diluted with water (100 ml), filtered, washed with water, and dried in the air to give 17,010 g (91.6%) of the desired product: 1 H NMR (DMSO-de / 400 MHz) d 5.20 ( s, 1 H), 3J6 (d, 1 H, J = 7.4 Hz), 3.56 (s, 3H), 2.18-2.10 (m, 1 H), 0.85 (d, 6H, J = 6.6 Hz); ES-MS m / z 215.14 (M + H).
Step 3: Preparation of 6 - [(2,4-difluorophenyl) methoxyl-3- (2-methylpropyl) -2-methylthio-3-hydropyridin-4-one.
A mixture of 6-hydroxy-3- (2-methylpropyl) -2-methylthio-3-hydropyrimidin-4-one (16,800 g, 78.4 mmol), 2,4-difluorobenzylbromide (21,098 g, 102 mol) was stirred at 0 ° C under nitrogen. ) and potassium carbonate (16,253 g, 118 mmol) in DMF (100 ml). After 30 minutes, it was stirred at room temperature for an additional 30 minutes and filtered. The filtrate was concentrated in vacuo and the residue was partitioned between dichloromethane and 5% hydrochloric acid (20 ml). The organic phase was washed with water, dried (Na 2 SO 4) and concentrated to dryness under reduced pressure. The resulting material was purified by flash chromatography on silica gel using 20% ethyl acetate in hexanes as elution to give 15,680 g (58.8%) of the desired product as a white powder: mp: 89.8-90.2 ° C; 1 H NMR (CDCl a OO MHz) d 7.44-7.38 (m, 1 H), 6.92-6J8 (m, 2 H), 5.58 (s, 1 H), 5.30 (s, 2 H), 3.88 (d, 2 H, J = 7.8 Hz), 2.56 (s, 3H), 2.32-2.24 (m, 1 H), 0.96 (d, 6H, = 6.3 Hz); anal. cale, for C6H17N2O2SCIF2: 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-α (2,4-difluorophenyl) methoxyfl-5-chloro-3- (2-methyl-propyl) -2-methylthio-3-hydropyrimidin-4-one. At room temperature for 5 hours a mixture of 6 - [(2,4-difluorophenyl] methoxy] -3- (2-methylpropyl) -2-methylthio-3-h -dropyrimidin-4-one (1400 g, 4.11 mmol),? / -chlorosuccinimide (0.577 g, 4.32 mmol) in dichloromethane (15 ml). The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel. silica using 20% ethyl acetate in hexanes as elution to give 1.457 g (94.6%) of the title compound as a white powder: p.f .: 58.0-58.8 ° C; 1 H NMR (CDCl 3/400 MHz) d 7.48-7.44 (m, 1 H), 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, 1 H), 0.95 (d, J = 6.4 Hz, 6H); anal. cale, for C 16 H 17 N 2 O 2 SCIF 2: 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 145 O Br = v YtfXA -F) = N F S 6-f (2,4-difluorophenyl) methoxy-1-5-bromo-3- (2-methyl-propyl) -2-methylthio-3-hydropyrimidin-4-one A mixture of 6 - [(2,4-d-fluorophenyl) methoxy] -3- (2-methylpropyl) -2-methylthio-3-hydopyridine-4-one was stirred at room temperature for 5 hours. (1400 g, 4.11 mmol),? / - bromosuccinimide (0.769 g, 4.32 mmol) in dichloromethane (15 ml). The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel using 20% ethyl acetate in hexanes as elution to give 1672 g (97.0%) of the title compound as a white powder: mp: 70.1-70.8 ° C; H NMR (CDCl 3/400 MHz) d 7.51-7.45 (m, 1 H), 6.94-6.81 (m, 2 H), 5.50 (s, 2 H), 3.91 (d, J = 7.2 Hz, 2 H), 2.55 (s) , 3H), 2.32-2.28 (m, 1 H), 0.95 (d, J = 6.8 Hz, 6H); anal. cale, for C16H17N2O2SBrF2: 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 146 6-r (2,4-difluorophenyl) methoxp-3- (2-methylpropih-2- (methylsulfonih-3-hydropyrimidin-4-one) A mixture of 6 - [(2,4-difluorophenyl) methoxy] -3- (2-methylpropyl) -2-methylthio-3-hydroxypyrimidin-4-one (3,000 g, 8.88 mmol), was stirred at room temperature. m-chloroperbenzoic (60%, 6.338 g, 22.0 mmol) in dichloromethane (150 ml) for 16 hours. The reaction mixture was filtered, the filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using 20% ethyl acetate in hexanes as elution to give 2.093 g (63.8%) of the title compound as a powder White. P.f .: 110.5-110.9 ° C; 1 H NMR (CDCl 3/400 MHz) d 7.44-7.38 (m, 1 H), 6.96-6.85 (m, 2 H), 5.88 (s, 1 H), 5.23 (s, 2 H), 4.24 (d, J = 7.6 Hz, 2H), 3.40 (s, 3H), 2.41 -2.37 (m, 1 H), 0.95 (d, J = 6.8 Hz, 6H); anal. cale, 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 (molecular mass: 372).
EXAMPLE 147 6-r (2,4-difluorophenyl) methoxy1-2- (r2- (dimethylamine) ethylamino.} - 3 - (2-methylpropyl) -3-hydropyrimidin-4-one A mixture of 6 - [(2,4-difluorophenyl) methoxy] -3- (2-methylpropyl) -2- (methylsulfonyl) -3-hydropyrimidin-4-one (1.49 g, 4.00 mmol), N, N-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 was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using 10% methanol in dichloromethane as elution to give 1156 g (76.0%) of the title compound as a colorless liquid oil: 1 H NMR (CDCl 3 / 400 MHz) d 7.46-7.40 (m, 1 H), 6.90-6.79 (m, 2H), 5.94 (a, 1 H), 5.28 (s, 1 H), 5.22 (s, 2H), 3J2 (a , 2H), 3.45-3.41 (m, 2H), 2.55-2.52 (m, 2H), 2.29 (s, 6H), 2.07-2.03 (m, 1 H), 0.97 (d, J = 6.4 Hz, 6H); anal. cale, for C19H26N4O2F2: 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 148 6-f (2,4-difluorophenyl) methoxp-2- (r 2 - (dimethylamino) ethynamino) -5-bromo-3- (2-methylpropyl) -3-hydropyrimidin-4-one A mixture of 6 - [(2,4-difluorophenyl) methoxy] -2-. { [2- (dimethylamino) 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 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using 9% methanol in dichloromethane as elution to give 0.410 g (85.1%) of the title compound as a white powder: mp: 133.8-135.6 ° C; 1 H NMR (CDCl 3/400 MHz) d 7.54-7.48 (m, 1 H), 6.92-6.79 (m, H), 5.99 (a, 1 H), 5.42 (s, 2 H), 3.76 (a, 2 H), 3.43-3.39 (m, 2H), 2.56-2.53 (m, H), 2.29 (s, 6H), 2.07-2.04 (m, 1 H), 0.97 (d, J = 6.8 Hz, 6H); anal. cale, for C? 9H25N4O2BrF2: 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 149 6-r (2,4-difluorophenyl) methoxy-3- (2,2-dimethylpropyl) -2-methylthio-3-hydropyrimidin-4-one Step 1: Preparation of 2,2-dimethylpropylamine.
To a suspension of lithium aluminum hydride (10956 g, 0.289 mol) in diethyl ether (50 ml) was added trimethylacetonitrile (20.00 g, 0.241 mol) in ether (100 ml) at 0 ° C. 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 over sodium sulfate. The resulting solution was used directly in the next step.
Step 2: Preparation of 2,2-dimethylpropanisothiocyanate.
To a stirred solution of 2,2-dimethylpropylamine (8.03 g, 0.141 mol) was added triethylamine (26.228 g, 0.259 mol), and carbon disulfide (49.339 g, 0.648 mol) at 0-10 ° C. Stirring was continued for 0.5 hours, followed by dropwise addition of hydrogen peroxide (30% by weight, 73.46 g, 0.0648 mol) at room temperature. After 1 hour, the reaction mixture was neutralized with dilute hydrochloric acid (1: 1) until neutral. The organic phase was washed with brine, dried over Na2SO4. The resulting solution was used directly in the next step.
Step 3: Preparation of amino [(2,2-dimethylpropyl) amino] methane-1-thione.
A methanolic solution of ammonia (7 N, 55.0 ml) was added to a solution of 2,2-dimethylpropanisothiocyanate in ether 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 hexanes, and dried to provide 18,889 g (53.7% overall in 3 steps) of white solid as the desired product: 1 H NMR (CDCl 3/400 MHz ) d 6.24 (a, 1 H), 5.80 (a, 2H), 2.92 (a, 2H), 0.98 (s, 9H).
Step 4: Preparation of 3- (2,2-dimethylpropyl) -6-hydroxy-2-methylthio-3-hiropyrimidin-4-one.
A vigorously stirred mixture of amine [(2,2-dimethylpropyl) amino] methane-1-thione (8.00 g, 54.7 mmol), diethylmalonate (8J67 g, 54J mmol), sodium methoxide (25-30% in methanol, 21.9 ml) was added. heated to reflux under nitrogen. After 5 h, the reaction mixture was cooled and iodomethane (8.076 g, 56.9 mmol) was added while the temperature was maintained 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 product that precipitated was diluted with water. The solid was filtered, washed with water, and air dried to yield 11.057 g (88.5%) of the desired product: 1 H NMR (DMSO-d6 / 400 MHz) d 5.22 (s, 1 H), 3.83 (a, 2H ), 2.48 (s, 3H), 0.98 (s, 9H); ES-MS m / z 229.14 (M + H).
Step 5: Preparation of 6 - [(2,4-difluorophenyl) methoxyl-3- (2,2-dimethylpropyl) -2-methylthio-3-hydropyrimidin-4-one.
A mixture of 3- (2,2-dimethylpropyl) -6-hydroxy-2-methylthio-3-hydropyrimidin-4-one (11.057 g, 48.4 mmol), 2,4-difluorobenzylbromide (15.040 g) was stirred at 0 ° C under nitrogen. , 72.6 mmol) and potassium carbonate (12,049 g, 87.2 mmol) in DMF (80 mL). After 30 minutes, it was stirred at room temperature for an additional 30 minutes and filtered. The filtrate was concentrated in vacuo and the residue was partitioned between dichloromethane and 5% hydrochloric acid. The organic phase was washed with water, dried (Na 2 SO 4) and concentrated to dryness under reduced pressure. The resulting material was purified by flash chromatography on silica gel using 20% EtOAc in hexane as elution to give 9.366 g (54.6%) of the title compound as a white powder: 1 H NMR (CDCIa OO MHz) d 7.42-7.39 (m , 1 H), 6.90-6.81 (m, 2H), 5.56 (s, 1 H), 5.31 (s, 2H), 3.95 (a, 2H), 2.51 (s, 3H), 1.04 (s, 9H); anal. cale, for C17H2oN2O2SF2: C, 57.61; H, 5.69; N, 7.90. Found: C, 57.83; H, 5.81; N, 7.97; ES-MS m / z 355 (Molecular mass: 354).
Biological Evaluation P38 kinase assay Cloning of human p38a: The coding region of the human p38a cDNA was obtained by PCR amplification of RNA isolated from the human monocyte cell line THP.1. The first strand of cDNA was synthesized from the total RNA as follows: 2 μg of RNA was fused to 100 ng of random hexamer primers in 10 μl of reaction by heating at 70 ° C for 10 minutes followed by 2 minutes on ice. CDNA was synthesized after adding 1 μl of RNAip (Promega, Madison Wis.), 2 μl of 50 mM dNTP, 4 μl of 5X buffer, 2 μl of 100 mM DTT and 1 μl (200 U) of AMV Superscript II reverse transcriptase ™. Reagents random primer, dNTP and Superscript II ™ were all purchased from Life-Technologies, Gaithersburg, Mass. The reaction was incubated at 42 ° C for 1 hour. The amplification of p38 cDNA was carried out by taking aliquots of 5 μl of the reverse transcriptase reaction in 100 μl of a PCR reaction containing the following: 80 μl of dH2O, 2 μl of 50 mM dNTP, 1 μl of each one of forward and reverse primers (50 pmol / μl), 10 μl of 10X buffer and 1 μl of Expand ™ polymerase (Boehringer Mannheim). PCR primers incorporated Bam Hl sites on the 5 'and 3' end of the amplified fragment, and were purchased from Genosys. The sequences of the forward and reverse primers were 5'- GATCGAGGATTCATGTCTCAGGAGAGGCCCA-3 'and 5'GATCGAGGATTCTCAGGACTCCATCTCTTC-3"respectively.The amplification by PCR was carried out in a DNA thermal cycler (Perkin Elmer) repeating 30 cycles of 94 ° C during 1 minute, 60 ° C for 1 minute and 68 ° C for 2 minutes. After amplification, the excess primers and unincorporated dNTP were removed from the amplified fragment with a prep. of PCR Wizard ™ (Promega) and digested with Bam Hl (New England Biolabs). The fragment digested with Bam Hl was ligated into DNA of plasmid pGEX 2T digested with BamHI (PharmaciaBiotech) using T-4 DNA ligase (New England Biolabs) as described by T. Maniatis, Molecular Cloning: A Laboratory Manual, 2nd ed. (1989). The binding reaction was transformed into chemically competent E. coli DH10B cells purchased from Life-Technologies following the manufacturer's instructions. The plasmid DNA was isolated from the resulting bacterial colonies using a miniprep kit. of Promega Wizard ™. Plasmids containing the appropriate Bam Hl fragment were sequenced in a DNA thermal cycler (Perkin Elmer) with Prism ™ (Applied Biosystems Inc.). We identified cDNA clones that encoded both isoforms of human p38a (Lee et al., Nature 372, 739). One of the clones containing the cDNA for p38a-2 (CSB-2) inserted in the cloning site of PGEX 2T, 3 'with respect to the coding region of GST was designated pMON 35802. The sequence obtained for this clone is a coincidence of the cDNA clone reported by Lee et al. This expression plasmid allows the production of a GST-p38aa fusion protein.
Expression of human p38a The GST / p38a fusion protein was expressed from plasmid pMON 35802 in E. coli, strain DH10B (Life Technologies, Gibco-BRL). Cultures were grown overnight in Luria Broth (LB) containing ampicillin at 100 mg / ml. The next day, 500 ml of freshly prepared LB were inoculated with 10 ml of culture overnight, and cultured in a 2 liter flask at 37 ° C with constant agitation until the culture reached an absorbance of 0.8 to 600 nm . Expression of the fusion protein was induced by the addition of isopropyl-b-D-thiogalactosidase (IPTG) to a final concentration of 0.05 mM. The cultures were shaken for three hours at room temperature, and the cells were collected by centrifugation. The cell pellets were stored frozen until protein purification.
Purification of P38 kinase-alpha All chemicals were from Sigma Chemical Co. unless noted. Twenty grams of E. coli cell pellet from five flask fermentations with 1 L shake were collected and resuspended in a volume of PBS (140 mM NaCl, 2.1 mM KCl, 10 mM Na 2 HPO 4, 1.8 mM KH 2 PO 4, pH 7.3) until 200 ml. The cell suspension was adjusted to 5 mM DTT with 2 M DTT and then divided equally into five 50 ml Falcon conical tubes. Cells were sonicated (Ultrasonics model W375) with 1 cm probe 3 times for 1 minute on ice (pulsed). The lysate cell material was removed by centrifugation (12,000 x g, 15 minutes) and the clarified supernatant was applied to glutathione-sepharose resin (Pharmacia).
Glutathione-Sepharose Affinity Chromatography Twelve milliliters of a PBS suspension of 50% glutathione-sepharose was added to 200 ml of clarified supernatant and batch-batch incubated for 30 minutes at room temperature. The resin was collected by centrifugation (at 600 x g, 5 minutes) and washed with 150 ml of PBS / 1% Triton X-100 2 times, followed by 40 ml of PBS 4 times. To cleave the p38 kinase from the GST-p38 fusion protein, the glutathione-sepharose resin was resuspended in 6 ml of PBS containing 250 units of thrombin protease (Pharmacia, specific activity> 7500 units / mg) and mixed gently for 4 hours at room temperature. The glutathione-sepharose resin was removed by centrifugation (600 x g, 5 minutes) and washed twice with 6 ml of PBS. Washing fractions with PBS and digestion supernatant containing p38 protein kinase were mixed and adjusted to 0.3 mM PMSF.
Mono Q anion exchange chromatography The p38 kinase cleaved by thrombin was further purified by anion exchange chromatography-FPLC. The thrombin-cleaved sample was diluted twice with buffer A (25 mM HEPES, pH 7.5, 25 mM beta-glycerophosphate, 2 mM DTT, 5% glycerol) and injected onto an Mono Q HR 10 / anion exchange column. 10 (Pharmacia) equilibrated with buffer A. The column was eluted with a gradient of 0.1-0.6 M NaCl / buffer A of 160 ml (flow rate of 2 ml / minute). The p38 kinase peak eluting at 200 mM NaCl was collected and concentrated to 3-4 ml with a Filtron 10 concentrator (Filtron Corp.).
Sephacryl S100 Gel Filtration Chromatography The purified sample of concentrated p38 MonoQ-kinase kinase was purified by gel filtration chromatography (column of Pharmacia HiPrep 26/60 Sephacryl S100 equilibrated with Buffer B (50 mM HEPES, pH 7.5, 50 mM NaCl , 2 mM DTT, 5% glycerol)). The protein was eluted from the column with Buffer B at a flow rate of 0.5 ml / minute and the protein was detected by absorbance at 280 nm. Fractions containing p38 kinase (detected by polyacrylamide gel electrophoresis-SDS) were combined and frozen at -80 ° C. The yields of purified protein typical of flask fermentations with 5 I E. coli shake were 35 mg p38 kinase.
In Vitro Assay The ability of the compounds to inhibit human p38 alpha kinase was evaluated using two in vitro assay procedures. In the first procedure, activated human p38 alpha kinase phosphorylates a biotinylated substrate, PHAS-I (heat-stable and stable phosphorylated protein in acid-inducible insulin medium), in the presence of gamma 32P-ATP (32P-ATP). PHAS-I was biotinylated before the assay and provided a means of capturing the substrate, which was phosphorylated during the assay. The p38 kinase was activated by MKK6. The compounds were tested in 10-fold serial dilutions throughout the range of 100 μM to 0.001 μM using 1% DMSO. Each concentration of inhibitor was tested in triplicate. All reactions were carried out in 96-well polypropylene plates. Each reaction well contained 25 mM HEPES at pH 7.5, 10 mM magnesium acetate and 50 μM unlabeled ATP. Activation of p38 is required to achieve sufficient signal in the assay. Biotinylated PHAS-I was used at 1-2 μg per 50 μl reaction volume, with a final concentration of 1.5 μM. Human activated p38 alpha kinase was used at 1 μg per 50 μl reaction volume representing a final concentration of 0.3 μM. Gamma 32P-ATP was used to follow phosphorylation of PHAS-1. 32 P-ATP has a specific activity of 3000 Ci / mmol and was used at 1.2 μCi per 50 μl of reaction volume. The reaction was carried out for 1 hour or overnight at 30 ° C. After incubation, 20 μl of reaction mixture was transferred to a high-capacity 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 capture of biotinylated PHAS-I with incorporated 32 P, each well was washed to remove 32 P-ATP not incorporated three times with 2 M NaCl, three washes of 2 M NaCl with 1% phosphoric, three washes of distilled water and finally one only washing of 95% ethanol. The filter plates were air-dried and 20 μl of scintillation liquid was added. The plates were sealed and counted. A second assay format was also employed which is based on the phosphorylation induced by p38 alpha kinase of EGFRP (epidermal growth factor receptor peptide, 21 -mer) in the presence of 33P-ATP. The compounds were tested in 10-fold serial dilutions throughout the range of 100 μM to 0.001 μM in 1% DMSO. Each concentration of inhibitor was tested in triplicate. Compounds were evaluated in reaction volumes of 50 μl in the presence of 25 mM Hepes at pH 7.5, 10 mM magnesium acetate, 4% glycerol, 0.4% bovine serum albumin, 0.4 mM DTT, 50 μM unlabeled ATP, EGFRP 25 μg (200 μM), and 33P-ATP of 0.05 μCi. Reactions were initiated by addition of 0.09 μg of purified, activated human p38 alpha GST kinase. Activation was carried out using GST-MKK6 (5: 1, p38: MKK6) for one hour at 30 ° C in the presence of 50 μM ATP. After incubation for 60 minutes at room temperature, the reaction was stopped by addition of 150 μl of AG 1x8 resin in 900 mM sodium formate buffer, pH 3.0 (1 volume of resin at 2 volumes of buffer). The mixture was mixed three times with pipetting and the resin allowed to settle. A total of 50 μl head volume of the clarified solution was transferred from the reaction wells to the Microlite-2 plates. 150 μl of Microscint 40 was then added to each well of the Microlite plate, and the plate was sealed, mixed, and counted. The above protocol assays were used to determine the Cl50 values for compounds in the previous examples. The results are shown in Table 1.
TABLE 1 fifteen 20 10 fifteen 20 TNF Cellular Assays Isolation Procedure of Human Peripheral Blood Mononuclear Cells: Whole human blood was collected in Vacutainer tubes containing EDTA as an anticoagulant. A blood sample (7 ml) was carefully stratified on 5 ml of PMN Cell Insulation Media (Robbins Scientific) in a 15 ml round bottom centrifuge tube. The sample was centrifuged at 450-500 x g for 30-35 minutes in a tilting rotor at room temperature. After centrifugation, the upper band of cells was removed and washed three times with PBS without calcium or magnesium. The cells were centrifuged at 400 x g for 10 minutes at room temperature. The cells were resuspended in Macrophage Serum Free Medium (Gibco BRL) at a concentration of 2 million cells / ml. Stimulation with LPS of human PBM PBM cells (0.1 ml, 2 million / ml) were co-incubated with 0.1 ml of compound (10-0.41 μM, final concentration) for 1 hour in 96 well flat bottom microtiter plates. The compounds were initially dissolved in DMSO and diluted in TCM to a final concentration of 0.1% DMSO. LPS (Calbiochem, 20 ng / ml, final concentration) was then added at a volume of 0.010 ml. The cultures were incubated overnight at 37 ° C. The supernatants were then removed and tested by ELISA for TNF-a and IL1-b. Viability was analyzed using MTS. After 0.1 ml of supernatant was collected, 0.020 ml of MTS was added to the 0.1 ml of remaining cells. The cells were incubated at 37 ° C for 2-4 hours, then the D.O. it was measured at 490-650 nM.
Maintenance and Differentiation of the U937 Human Histiocytic Lymphoma Cell Line U937 cells (ATCC) were propagated in RPMI 1640 containing 10% fetal bovine serum, 100 IU / ml penicillin, 100 μg / ml streptomycin, and 2 mM glutamine. (Gibco) Differentiation of fifty million cells in 100 ml of medium was induced by incubation for 24 hours with 12-myristate 13-phorbol acetate (Sigma) at 20 ng / ml. The cells were washed by centrifugation (200 x g for 5 minutes) and resuspended in 100 ml of fresh medium. After 24-48 hours, the cells were harvested, centrifuged and resuspended in culture medium at 2 million cells / ml.
Stimulation by LPS of TNF production by U937 cells U937 cells (0.1 ml, 2 million / ml) were incubated with 0.1 ml of compound (0.004-50 μM, final concentration) for 1 hour in 96-well microtiter plates. The compounds were prepared as 10 mM stock solutions in DMSO and diluted in culture medium to provide a final DMSO concentration of 0.1% in the cell assay. LPS (E.coli, 100 ng / ml, final concentration) was then added to a volume of 0.02 ml. After an incubation of 4 hours at 37 ° C, the amount of TNF-alpha released in the culture medium was quantified by ELISA. The inhibitory potency was expressed as IC 50 (μM).
Rat Assay The efficacy of novel compounds in blocking TNF production was also evaluated using a model based on rats exposed to LPS. Male Harlen Lewis rats [Sprague Dawley Co.] were used in this model. Each rat weighed approximately 300 g and were fasted for a whole night before the test. Compound administration was typically by oral gavage (although intraperitoneal, subcutaneous, and intravenous administration were also used in a few cases) 1 to 24 hours before exposure to LPS. The rats were administered 30 μg / kg of LPS [Salmonella typhosa, Sigma Co.] intravenously by means of the tail vein. Blood was collected by cardiac puncture 1 hour after exposure to LPS. Serum samples were stored at -20 ° C until quantitative analysis of TNF-alpha by Enzyme Linked Immunosorbent Assay ("ELISA") [Biosource]. Additional details of the assay are set forth in Perretti, M., et al., Br. J. Pharmacol. (1993), 110, 868-874, which are incorporated by reference in this application.
Test in Mice Mouse Model of TNF-alpha Production Induced by LPS TNF-alpha was induced in female BALB / c mice 10-12 weeks of age by injection into the vein of the tail with 100 ng of lipopolysaccharide (from S. typhosa) in 0.2 ml of saline. One hour later, blood was taken from the mice from the retroorbital sinus and the concentrations of TNF in serum were quantified by ELISA from coagulated blood. Typically, serum TNF peak levels ranged from 2-6 ng / ml one hour after LPS injection. The tested compounds were administered to mice on an empty stomach by oral gavage as a suspension in 0.2 ml of 0.5% methylcellulose and 0.025% Tween 20 in water 1 hour or 6 hours before the injection of LPS. The 1 hour protocol allowed the evaluation of the compound's potency at Cmax plasma levels while the 6-hour protocol allowed estimation of the compound's duration of action. Efficacy was determined at each time point as percentage of inhibition of serum TNF levels relative to mice injected with LPS that They received only vehicle.
Induction and Evaluation of Collagen-induced Arthritis in Mice Arthritis was induced in mice according to the procedure set forth in J. M. Stuart, Collagen Autoimmune Arthritis, Annual Rev. Immunol. 2: 199 (1984), which is incorporated herein by reference. Specifically, arthritis was induced in DBA / 1 male mice of 8-12 weeks of age by injection of 50 μg of chicken type II collagen (CM) (provided by Dr. Marie Griffiths, Univ. Of Utah, Salt Lake City , Utah) in Freund's complete adjuvant (Sigma) on day 0 at the base of the tail. The injection volume was 100 μl. The animals were given a booster dose on day 21 with 50 μg of CU in incomplete Freund's adjuvant (volume of 100 μl). The animals were evaluated several times a week for signs of arthritis. Any animal with redness or swelling of the paw was counted as arthritic. The valuation of the arthritic claws was carried out according to the procedure set forth in Wooley et al., Genetic Control of Type II Collagen Induced Arthritis in Mice: Factors Influencing Disease Suspectibility and Evidence for Multiple MHC Associated Gene Control., Trans. Proc., 15: 180 (1983). Gravity assessment was carried out using a score of 1-3 for each claw (maximum score of 12 / mouse). Animals that presented any redness or swelling of fingers or paw were evaluated as 1. The thick swelling of the entire paw or deformity was assessed as 2. The ankylosis of joints was assessed as 3. The animals were evaluated for 8 weeks. 8-10 animals were used per group. The above detailed description of embodiments is intended only to inform others skilled in the art with the invention, its principles, and its practical application in such a way that others skilled in the art can adapt and apply the invention in its many forms, as it can be better adapted to the requirements of a particular use. This invention, therefore, is not limited by the above embodiments, and can be modified in various ways.

Claims (22)

NOVELTY OF THE INVENTION CLAIMS
1. A compound of formula I or a salt, enantiomer or pharmaceutically acceptable racemate thereof, wherein R is selected from the group consisting of alkenyl, alkoxycarbonylalkylamino, alcoxicarbonilaminoalcoxi, alcoxicarbonilaminoheterociclo, alkoxycarbonylaryl, alcoxicarbonilarilalquilamino, alcoxicarbonilheterociclo, alkyl, alkylamino, alkylaminocarbonylalkyl, alquilamínocarbonilalquilamino, alquilaminocarbonilaminoalcoxi, alquílaminoheterocíclo, alquilcarbonilaminoalcoxi, alkylcarbonylaminoalkyl, alquilcarbonilaminoalquilamino, alquilcarbonilaminoheterociclo, alquilcarbonilheterocicloamino, alquilcarboniloxialquilcarbonilaminoalcoxi, alquilcarboniloxialquilcarbonilaminoheterociclo, alkylsulfonyl, alquilsulfonilaminoalcoxí, alkylsulfonylaminoalkyl, alquilsulfonilaminoalquilamino, alkylthio, alkylamino, aminoalkyl, aminoalkylamino, aminoalquilcarbonilamínoheterociclo, aminoalquilcarbonilheterociclo, aminocarbonyl, alkylaminocarbonyl, aminocarbonylalkylamino, aminocarbo nilalquilheterociclo, aminocarbonilaminoalcoxi, aminocarbonilaminoalquilamino, aminocarbonylaryl, aminocarbonildialquilamino, aminocarbonilheterociclo, aminoheterocycle, aryl, carboalkoxy, carboxyalkyl, carboxyaryl, carboxídialquilamino, cycloalkyl, dialkylaminoalkylamino, dihydroxyalkylamino, halo, haloalkylsulfonyloxy, haloarilalquilamino, heteroarilalcoxicarbonilaminoheterocíclo, heterociclocarbonilalquilamíno, heterocycle, hydrogen, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkylamino, hydroxyalkylaminocarbonylalkoxy, hydroxyalkylaminocarbonylalkyl, hydroxyalkylaminocarbonylalkylamino, hydroxyalkylaminocarbonylaminoalkoxy, hydroxyalkylaminoheterocycle, hydroxyalkylcarbonylaminoalkylamino, hydroxyalkylcarbonylaminoheterocycle, hydroxyalkylcarbonylheterocycle, hydroxyalkylheterocycle, and hydroxyheterocycle; R2 is selected from the group consisting of alkyl, cycloalkyl and hydrogen; R3 is selected from the group consisting of hydrogen, alkyl, alkoxy and halo; wherein each alkyl, wherever it occurs, is independently and optionally substituted with alkoxy, amine, carboxy, halo, and hydroxyl; and R4A, R4B, R4C, R4D and R E are each independently selected from the group consisting of alkylaminocarbonylaminoalkyl, alkylarylheteroarylaminocarbonylaminoalkyl, aminoalkyl, arylcycloalkylaminocarbonyldyalkylaminoalkyl, arylcycloalkylaminocarbonylaminoalkyl, cyano, cycloalkylaminocarbonylaminoalkyl, cycloalkylaminocarbonyldialkylaminoalkyl, halo, and hydrogen; wherein each aryl and heteroaryl, wherever they occur, are independently and optionally substituted with alkyl.
2. The compound according to claim 1, further characterized in that R1 is selected from the group consisting of alkenyl (C2-C-? 0), alkoxycarbonyl (C? -C? O) -alkylamino (C? -C10), alkoxycarbonylamino CrC -ioí-alkoxy Ci-C-io), alkoxycarbonylaminoheterocycle (Cr C10), alkoxycarbonylamino (C? -C? o), alkoxycarbonylaryl (CrC? o) -alkylamino (C? -C? o), alkoxycarbonylheterocycle (CrC? o), alkyl (CrC-? o), alkylamino (C? -C-? o), alkylamcarbonyl (CrC? o) -alkyl (C -? - C? o), alkylaminocarbonylid- C ^) - alkylamino (C? -C? O), alkylaminocarbonylamino (CrC? 0) -alkoxy (C? -C? O), alkylaminoheterocycle (CrC10), alkylcarbonylamino (CrC? O) -alkoxy (C? -C? 0), alkylcarbonylaminoyCT-Cio ^ alkyl-Ci-Cio), alkylcarbonylamino (C? -C10) -alkylamino (C? -C? O), alkylcarbonylaminoheterocycle (C? -C? O), alkylcarbonylheterocycleamino (CrC? o), alkylcarbonyloxy (C? -C? o) -alkylcarbonylaminoyCTCoí-alkoxyC Cio), alkylcarbonyloxy (C? -C? o) -alkylcarbonylaminoheterocycle (CrC? o), alkylsulfonyl (C? -C 0), alkylsulf onylamino (CrC10) -alkoxy (C? -C? o), alkylsulfonylamino (C? -C10) -alkyl (C -? - C? o), alkylsulfonylamino (CrC? o) -alkylamino (CrC? o), alkylthio ( Cr C10), aminoalkoxy (C -? - C? O), aminoalkyl (CrC? O), aminoalkylamino- (C? -C10), amino-alkylcarbonylaminoheterocycle (C? -C10), amino-alkylcarbonylheterocycle (CrC? or), aminocarbonyl-alkoxy (C -? - C? o), aminocarbonyl-alkyl (CC? o), aminocarbonyl-alkylamino (CrC10), aminocarbonyl-alkyheterocycle (C? -C10), aminocarbonylamino-alkoxy (C? -C?), Aminocarbonylamino-alkylamino (CC? O), aminocarbonylaryl, aminocarbonyl-dyalkylamino (CrC? O), aminocarbonylheterocycle, aminoheterocycle, aryl, carboxy-alkoxy (CrC? O), carboxy-alkyl (CrC? ), carboxyryl, carboxy-dialkylamino (C? -C?), cycloalkyl (CrC? o), dialkylamino (C? -C10) -alkylamino (CC? o), dihydroxy-alkylamino (CrC? o), halo, halo -alkylsulfonyloxy (CrC? o), haloaryl-alkylamino (CrC? o), heteroaryl-alkoxycarbonylaminoheterocycle (CrC10), heterocyclocarbonyl-alkylaminoCCr C10), heterocycle, hydrogen, hydroxy, hydroxy-alkoxy (CrC? o), hydroxyalkylamine (CrC? ), hydroxy-alkylaminocarbonyl (C? -C? o) -alkoxy (C? -C10), hydroxy-alkylaminocarbonyl (C? -C? o) -alkyl (C? -C? o), hydroxy-alkylaminecarbonyl (Cr C) o) -alkylamino (C -? - C? 0), hydroxy-alkylaminocarbonylamino (CrC? o) -alkoxy (Cr C10), hydroxy-alkylaminohe tercycle (CC? o), hydroxy-alkylcarbonylamino (Cr C? 0) -alkylamino (C? -C? o), hydroxy-alkylcarbonylaminoheterocycle (C? -C? o), hydroxy-alkylcarbonylheterocycle (C? -C? o) , hydroxy-alkylheterocycle (CrC? o), and hydroxyheterocycle; R 2 is selected from the group consisting of alkyl (C? -C10), cycloalkyl (C C? O) and hydrogen; R3 is selected from the group consisting of hydrogen, alkyl (C? -C? O), alkoxy (C? -C? O) and halo; wherein each alkyl, wherever it occurs, is independently and optionally substituted with (C 10) alkoxy, amino, carboxy, halo, and hydroxy; and R4A, R4B, RC, R4D and R4E are each independently selected from the group consisting of alkylaminocarbonylamino (CrC? o) -alkyl (CrC? o), alkylarylheteroarylaminocarbonylaminoiCi-CioJ-alkyloCiClio), aminoalkyl (C-? -C? o), aryl-cycloalkylaminocarbonyl (C? -C? o) -d -alkyllamine (C -? - C? o) -alkyl (CC? o), aryl-cycloalkylaminocarbonylamino (CrC? ) -alkyl (C? -C? o), cyano, cycloalkylaminocarbonylamino (CrC? o) -alkyl (C? -C? o), cycloalkylaminocarbonyl (CrC? o) -dialkylamino (CrC? o) -alkyl (C? - C? O), halo, and hydrogen; wherein each aryl and heteroaryl wherever given are independently and optionally substituted with (C? -C10) alkyl.
3. The compound according to claim 2, further characterized in that R1 is selected from the group consisting of (C2-C8) alkenyl, alkoxycarbonyl (CrC8) -alkylamino (C? -8), alkoxycarbonylamino (C? -8) -alkoxy (CrC8), alkoxycarbonylaminoheterocycle (Cr C8), alkoxycarbonylaryl (CrC8), alkoxycarbarylaryl (C? -C8) -alkylamino (C-? -8), alkoxycarbonylheterocycle (CrC8), alkyl (C8), alkylam No (C -? - C8), alkylaminocarbonyl (C? -C8) -alkyl (CrC8), alkylaminocarbonyl (C? -C8) -alkylamino (C8), alkylaminocarbonyl-amino (C? -8) -alkoxy (C? -C8), alkylaminoheterocycle (C8), alkylcarbonylamino (CrC8) -alkoxy (C? -C8), alkylcarbonylamino (CrC8) -alkyl (C? -8), alkylcarbonylamino (C? -8) -alkylamino (C C8), alkylcarbonylaminoheterocycle (C? -C8), alkylcarbonylheterocycleamino (CrC8), alkylcarbonyloxy (C? -C8) -alkylcarbonylamino (CrC8) -alkoxy (C? -8), alkylcarbonyloxy (C? C8) -alkylcarbonylaminoheterocycle-Cs), alkylsulfonyl (C? -C8), alkylsulfonylamino (C? -8) -alkoxy (CrC8), alkyls ulphonylamino (CrC8) -alkyl (C? -8), alkylsulfonylaminoyCrCJ-alkylaminoCCrCs), alkylthio (C8), amino-alkoxy (C8), amino-alkyl (C? -8), amine-alkylamine CrC?), amino-alkylcarbonylaminoheterocycle (CrC8), amino-alkylcarbonylheterocycleCrCs), aminocarbonyl-(C8) alkoxy, aminocarbonyl-alkyl (CrC8), aminocarbonyl-alkylamino (CrC8), aminocarbonyl-alkylheterocycle (C? -8), aminocarbonylamino-alkoxy (CrC8), aminocarbonylamino- alkylamino (C -? - C8), aminocarbonylaryl, aminocarbonyl-dialkylamino (C? -8), aminocarbonylheterocycle, aminoheterocycle, aryl, carboxy-alkoxy (C -? - C8), carboxy- (C8) alkyl, carboxyryl, carboxy- dyalkyl (C -? - C8), cycloalkyl (CrC8), dialkylamino (CrC8) -alkylamino (C? -8), dihydroxy-alkylamino (CrC8), halo, haloalkylsulfonylloxy (C ? -C8), haloaryl-alkylamino (Cr C8), heteroaryl-alkoxycarbonylaminoheterocycle (CrC8), heterocyclocarbonyl-alkylaminoCCrC?), Heterocycle, hydrogen, hydroxy, hydroxy-(C-? - C8) alkoxy, hydroxy-alkylamino (C? C8), hydro xi-alkylaminocarbonyl (C? -C8) -alkoxy (C? -C8), hydroxy-alkylaminocarbonyl (CrC8) -alkyl (CrC8), hydroxy-alkylamcarbonyl (C? -8) -alkylamino ( C -? - C8), hydroxy-alkylaminocarbonylamino (CrC8) -alkoxy (C -? - C8), hydroxy-alkylaminoheterocycle (CrC8), hydroxy-alkylcarbonylamino (C? -8) -alkylamino (C8), hydroxy- alkylcarbonylaminoheterocycle (CrC8), hydroxy-alkylcarbonylheterocycle (CrC8), hydroxy-alkylheterocycle (C? -8), and hydroxyheterocycle; R2 is selected from the group consisting of alkyl (C? -C8), cycloalkyl (CrC8) and hydrogen; R3 is selected from the group consisting of hydrogen, (C? -C8) alkyl, (C-? - C8) alkoxy and halo; wherein each alkyl, wherever it occurs, is independently and optionally substituted with (C 8) alkoxy, amino, carboxy, halo and hydroxyl; and R4A, R4B, RC, R4D and R4E are each independently selected from the group consisting of alkylaminocarbonylamino (CrC8) -alkyl (C? -8), alkylaryl-heteroarylaminocarbonylamino (CrC8) -alkyl (C? -8), amino-alkyl (Cr C8), aryl-cycloalkylaminocarbonyl-CrCsJ-dialkylaminoyCi-Csy-alkylCTCβ), ary-cycloalkylaminocarbonylamino (C? -8) -alkyl (CrC8), cyano, cycloalkylaminocarbonylamino (CrC8) -alkyl (CrC8), cycloalkylaminocarbonyl (C? C8) -dialkylamino (CrC8) -alkyl (C? -8), halo, and hydrogen; wherein each aryl and heteroaryl wherever they occur are independently and optionally substituted with alkyl (CrC8).
4. The compound according to claim 3, further characterized in that R1 is selected from the group consisting of (C2-C6) alkenyl, alkoxycarbonyl (CrC6) -alkylamino (C? -C6), alkoxycarbonylamino (CrC6) -alkoxy ( CrC6), alkoxycarbonylaminoheterocycle (Cr C6), alkoxycarbonarylar (C? -C6), alkoxycarbonylaryl (CrC6) -alkylamino- (C? -C6), alkoxycarbonylheterocycle (C6C), alkyl (CrC6), alkylamino (C? -C6 ), alkylaminocarbonyl (CrC6) -alkyl (C? -C6), alkylaminocarbonyl (C? -C6) -alkylamino (CrC6), alkylaminocarbonylaminoyCrCeJ-alkoxy Ci-Ce), alkylaminoheterocycle (CrC6), alkylcarbonyllamine (C? - C6) -alcoxy (C? -C6), alkylcarbonylamino (CrC6) -alkyl (CrC6), alkylcarbonylamino (C? -C6) -alkylamino (CrC6), alkylcarbonylaminoheterocycle (C? -C6), alkylcarbonylheterocycleamino (C C6), alkylcarbonyloxy (CtC6) -alkylcarbonylamino (C C6) -alkoxy (CrC6), alkylcarbonyloxy (C? -C6) -alkylcarbonylaminoheterocycle CrC?), Alkylsulfonyl (C? -C6), alkylsulfonylamino (CrC6) -alkoxy (C? -C6), alkylsulfonyl no (C? -C6) -alkyl (C? -C6), alkylsulfonylamino (CrC6) -alkylamino (CrC6), alkylthio (C? -C6), amino-alkoxy (CrC6), amino-alkyl (CrC6), amino-alkylamino (C? -C6), amino-alkylcarbonylaminoheterocycle (C? -C6), aminoalkylcarbonylheterocycleCTCe), aminocarbonyl-alkoxy (C?? C6), aminocarbonyl-alkyl (CrC6), aminocarbonyl-alkylamino ( CrC6), aminocarbonyl-alkylheterocycle (C?-C6), aminocarbonylamino-(C?-C6) alkoxy, aminocarbonylamino-alkylamino (C?-C6), aminocarbonylaryl, aminocarbonyl-dialkylamino (C?-C6), aminocarbonylheterocycle, aminoheterocycle , aryl, carboxy-alkoxy (C? -C6), carboxy-alkyl (CrC6), carboxaryl, carboxy-dialkylamino (C? -C6), cycloalkyl (C? -C6), dialkylamino (C? -C6) -alkylamine no- (CrC6), dihydroxy-alkylamino (C? -C6), halo, haloalkylsulfonyloxy (CrC6), haloaryl-alkylamino (C6), heteroaryl-alkoxycarbonylaminoheterocycle (Cr6), heterocyclocarbonyl-alkylamino (C6-6), heterocycle, hydrogen, hydroxy, hydroxy-alkoxy (C? -C6), hydroxy-alkylamino (CrC6), hydroxy-alkylamino ocarbonyl (CrC6) -alcoxy (C? -C6), hydroxy-alkylaminocarbonyl (C? -C6) -alkyl (C? -C6), hydroxy-alkylaminocarbonyl (C? -C6) -alkylamino (C? - C6), hydroxy-alkylaminocarbonylamino (CrC6) -alkoxy (CrC6), hydroxy-alkylaminoheterocycle (C6), hydroxy-alkylcarbonylamino (C6-6) -alkylamino (C6-6), hydroxy-alkylcarbonylaminoheterocycle (Cr6 ), hydroxy-alkylcarbonylheterocycle (C? -C6), hydroxy-alkylheterocycle (CrC6), and hydroxyheterocycle; R2 is selected from the group consisting of alkyl (C? -C6), cycloalkyl (C? -C6) and hydrogen; R3 is selected from the group consisting of hydrogen, (C -? - C6) alkyl, (C -? - C6) alkoxy and halo; wherein each alkyl, wherever it occurs, is independently and optionally substituted with alkoxy (CrC6), amine, carboxy, halo and hydroxyl; and R4A, R4B, R4C, R4D and R4E are each independently and optionally selected from the group consisting of alkylaminocarbonylamino (CrC6) -alkyl (C? -C6), alkylarylheteroarylaminocarbonylamino (C? -C6) -alkyl (C? -C6) ), amino-alkyl (Cr C6), aryl-cycloalkylaminocarbonyl (CrC6) -dialkylamino (CrC6) -alkyl (C? -C6), aryl-cycloalkylaminocarbonylamino (CrC6) -alkyl (C? -C6), cyano, cycloalkylaminocarbonylamino (C? -C6) -alkyl (C? -C6), cycloalkylaminocarbonyl? CrC? I-dialkylaminoiCi-CeJ-alkyloCrCe), halo, and hydrogen; wherein each aryl and heteroaryl, wherever they occur, are independently and optionally substituted with (C C6) alkyl.
5. The compound according to claim 4, further characterized in that R1 is selected from the group consisting of (C2-C6) alkenyl, (C? -C6) alkyl, alkylammonium (C? -C6), alkylaminocarbonyl (C? -C6) -alkylamino (C? -C6), alkylaminoheterocycle (C? -C6), alkylcarbonylamino (CrC6) -alkoxy (CrC6), alkylcarbonylamino (C -? - C6) -alkylamino ( C -? - C6), alkylcarbonylheterocycleamino (CrC6), alkylsulfonylamino (CrC6) -alkoxy (C? -C6), alkylsulfonylamino (CrC6) -alkyl (C? -C6), alkylsulfonylamino (C? -C6) -alkylamino (CrC6), alkylsulfonylamino (C? -C6) alkylamino (CrC6), amino-alkylaminoCCrC?), amino-alkylcarbonylheterocycleC-i-C?), aminocarbonyl-alkoxy (CrC6), aminocarbonyl-alkylamino (C? -C6), aminocarbonylamino-alkoxy (C C6) ), aminocarbonylamino-alkylamino (C? -C6), aminocarbonylaryl, aminocarbonylheterocycle, aminoheterocycle, aryl, dihydroxy-alkylamino (C? -C6), haloaryl-alkylamino (CrC6), hydrogen, hydroxyl-alkoxy (CrC6), hydroxyl-alkyl ( CrC6), hydroxyalkylamino (C? -C6), hydroxyl-alkylcarbonylamino (C? -C6) -alkylamino (CrC6), hydroxyl-alkylheterocycle (C? -C6) and hydroxyl-alkylcarbonylamino (CrC6) -alkylamino (CrC6).
6. The compound according to claim 5, further characterized in that R2 is alkyl (C -? - C6).
7. The compound according to claim 5, further characterized in that R3 is halo.
8. The compound according to claim 5, further characterized in that R4A, R4B, R4C, R4D and R4E are each independently selected from the group consisting of hydrogen, halo and alkylaminocarbonylamino (CrC6) -alkyl (C? C6).
9. The compound according to claim 5, further characterized in that R2 is alkyl (CrC6); R3 is halo; and R4A, R B, R4C, R D and R4E are each independently selected from the group consisting of hydrogen, halo, and alkylaminocarbonylamino (C? -C6) -alkyl- (C? -C6).
10. The compound according to claim 5, further characterized in that R1 is selected from the group consisting of alkylaminoheterocycle (C? -C6), alkylcarbonylamino (CrC6) -alkylamino (C? -C6), alkylsulfonylamino (C? -C6) ) -alkoxy (C? -C6), alkylsulfonylamino (C? -C6) -alkylamino (C -? - C6), alkylsulfonylamino (CrC6) -alkylamino (C? -C6), aminocarbonyl-alkylamino (CrC6), aminocarbonylamino-alkoxy (C? -C6), aminocarbonylamino-alkylamino (C?? C6), aminocarbonylheterocycle, dihydroxy-alkylamino (CrC6), hydroxyalkylamino (CrC6) and hydroxy-alkylcarbonylamino (CrC6) -alkylamino (C? - C6).
11. The compound according to claim 10, further characterized in that R2 is alkyl (CrC6).
12. The compound according to claim 10, further characterized in that R3 is halo.
13. The compound according to claim 10, further characterized in that R4A, R4B, R4C, R4D and R4E are each independently selected from the group consisting of hydrogen and halo.
14. The compound according to claim 10, further characterized in that R2 is alkyl (CrC6); R3 is halo; and R4A, R4B, R4C, R4D and R4E are independently and optionally each selected from the group consisting of hydrogen and halo.
15. The compound according to claim 1, further characterized in that it is selected from the group consisting of N- [2- (. {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl- 6-oxo-1, 6-dihydropyrimidin-2-yl} amino) ethyl] methanesulfonamide,? / - [2- (. {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1 -isopropyl-6-oxo-1,6-dihydropyridin-2-yl}. oxy) ethyl] urea, N ~ 2 ~ -. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyridin-2-yl} -L-alaninamide,? / - [3- ( { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidine- 2-yl.}. Amino) propyl] urea,? / - [3- (. {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1, 6 -dihydropyrimidin-2-yl.}. amino) propyl] methane sulfonamide,? / - [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,? / ~ 3 ~ -. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -beta-alaninamide,? / - [2- ( { 5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] -2-hydroxyacetamide,? / - [3- (. {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1, 6- dihydropyridin-2-yl.}. amino) propyl] acetamide, N ~ 3 ~ -. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -beta-alaninamide, N ~ 2 ~ -. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} glycinamide,? / - [2- (. {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. ) ethyl] urea, A / - [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,? / - [2- (. {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1, 6 -dihydropyrimidin-2-yl.}. oxy) ethyl] methanesulfonamide,? / - [2- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo- 1,6-dihydropyrimidin-2-yl.} Amino) ethyl] urea,? / - [2- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6 -oxo-1, 6-dih -dropyrimidin-2-yl.}. amino) ethyl] -2-hydroxyacetamide,? / - [2- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. amino) ethyl] methanesulfonamide, 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,? / - [2- ( { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. Oxy) ethyl] urea,? / - [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,? / - [2- ( { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. amino) ethyl] acetamide,? / - [2- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl .}. oxy) ethyl] methanesulfonamide, 5-bromo-6 - [(2,4-difluorobenzyl) oxy] -2 - [(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] -3-isopropylpyrimidin-4 (3H) -one trifluoroacetate, 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,? / - [2- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] -2-hydroxy-2-methylpropanamide,? / - [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-lyl] -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 - methylglycinamide, N ~ 2 ~ -. { 5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} glycinamide,? / - [2- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-propso-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} benzamida, 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'-ethylurea, 2- (3-aminopyrrolidin-1-yl) -5-bromo-6 - [(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one trifluoroacetate, 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-isopropyl-pyrimidin-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-isopropylpyrimidine -4 (3H) -one trifluoroacetate, and 2-but-3-enyl-5-chloro-6 - [(2,4-difluorobenzyl) oxy] -3-isopropylpyrimidin-4 (3H) -one, or a pharmaceutically salt acceptable of it.
16. The compound according to claim 1, further characterized in that it is selected from the group consisting of N- [2- (. {5-bromo-4 - [(2,4-d.fluorobenzyl) oxy] -1- isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl.} amino) ethyl] methanesulfonamide,? / - [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,? / - [3- (. {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) propyl] urea,? / - [3- ( { 5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2 -yl.}. amino) propyl] methane sulfonamide,? / - [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) No) pyrrolidin-1-yl] pyrimidin-4 (3H) -one,? / ~ 3 ~ -. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -beta-alaninamide,? / - [2- ( { 5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) ethyl] -2-hydroxyacetamide,? / - [3- (. {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2- il.}. amino) propyl] acetamide, N ~ 3 ~ -. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} -beta-alaninamide, N ~ 2 ~ -. { 5-Bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} glycinamide,? / - [2- ( {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-propso-propyl-6-oxo-1,6-dihydropyrimidin-2-yl}. ) ethyl] urea,? / - [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,? / - [2- (. {5-bromo-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1, 6 -dihydropyrimidin-2-yl.}. oxy) ethyl] methanesulfonamide,? / - [2- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1- isopropyl-6- oxo-1, 6-dihydropyrimidin-2-yl} amino) ethyl] urea,? / - [2- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl -6-oxo-1, 6-dihydropyrimidin-2-yl.}. Amino) ethyl] -2-hydroxyacetamide,? / - [2- (. {5-chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl} amino) etl] methanesulfonamide, 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,? / - [2- ( {5-Chloro-4 - [(2,4-difluorobenzyl) oxy] -1-isopropyl-6-oxo-1,6-dihydropyrimidin-2-yl}. oxy ) ethyl] urea,? / - [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-isopropylpyrimidin-4 ( 3H) -one, or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, enantiomer or racemate thereof, wherein R1 is selected from the group consisting of alkenyl, alkoxycarbonylalkylamino, alkoxycarbonylaminoalkoxy, alkoxycarbonylaminoheterocycle, alkoxycarbonylaryl, alkoxycarbonylarylalkylamino, alkoxycarbonylheterocycle, alkyl, alkylamino, alkylaminocarbonylalkyl, alkylaminocarbonylalkylamino, alkylaminocarbonylaminoalkoxy, alkylaminoheterocycle, alkylcarbonylaminoalkoxy, alkylcarbonylaminoalkyl, alquilcarbonilaminoalquilamino, alquilcarbonilaminoheterociclo, alquilcarbonilheterocicloamino, alquilcarboniloxialquilcarbonilaminoalcoxi, alquilcarboniloxialquilcarbonilaminoheterociclo, alkylsulfonyl, alquilsulfonilaminoalcoxi, alkylsulfonylaminoalkyl, alquilsulfonílaminoalquilamino, alkylthio, alkylamino, aminoalkyl, aminoalkylamino, aminoalquilcarbonilaminoheterociclo, aminoalquilcarbonilheterociclo, aminocarbonyl, alkylaminocarbonyl, aminocarbonylalkylamino, aminocarboni lalquilheterociclo, aminocarbonilaminoalcoxi, aminocarbonílaminoalquilamino, aminocarbonylaryl, aminocarbonildialquilamino, aminocarbonilheterociclo, aminoheterocycle, aryl, carboalkoxy, carboxyalkyl, carboxyaryl, carboxidialquilamino, cycloalkyl, dialkylaminoalkylamino, dihydroxyalkylamino, halo, haloalkylsulfonyloxy, ino haloarilalquila, heteroarilalcoxicarbonilaminoheterociclo, heterociclocarbonilalquilamino, heterocycle, hydrogen, hydroxy, hydroxyalkoxy, hydroxyalkyl , hydroxyalkylamino, hydroxyalkylaminocarbonylalkoxy, hydroxyalkylaminocarbonylalkyl, hydroxyalkylaminocarbonylalkylamino, hydroxyalkylaminocarbonylaminoalkoxy, hydroxyalkylaminoheterocycle, hydroxyalkylcarbonylaminoalkylamino, hydroxyalkylcarbonylaminoheterocycle, hydroxyalkylcarbonylheterocycle, hydroxyalkylheterocycle, and hydroxyheterocycle; R2 is selected from the group consisting of alkyl, cycloalkyl and hydrogen; R3 is selected from the group consisting of hydrogen, alkyl, alkoxy and halo; wherein each alkyl, wherever it occurs, is independently and optionally substituted with alkoxy, amino, carboxy, halo and hydroxyl; R4A, R4B, R4C, R4D and R are each independently selected to form the group consisting of alkylaminocarbonylaminoalkyl, alkylarylheteroarylaminocarbonylaminoalkyl, aminoalkyl, arylcycloalkylaminocarbonyldialkylaminoalkyl, arylcycloalkylaminocarbonylaminoalkyl, cyano, cycloalkylaminocarbonylaminoalkyl, cycloalkylaminocarbonyldialkylaminoalkyl, halo, and hydrogen; wherein each aryl and heteroaryl, wherever they occur, are independently and optionally substituted with alkyl; and a pharmaceutically acceptable excipient.
18. The use of compound of Formula I or a pharmaceutically acceptable salt, enantiomer or racemate thereof, wherein R1 is selected from the group consisting of alkenyl, alkoxycarbonylalkylamino, alkoxycarbonylaminoalkoxy, alkoxycarbonylaminoheterocycle, alkoxycarbonylaryl, alkoxycarbonylarylalkylamino, alkoxycarbonylheterocycle, alkyl, alkylamino, alkylaminocarbonylalkyl, alkylaminocarbonylalkylamino, alkylaminocarbonylaminoalkoxy, alkylaminoheterocycle, alkylcarbonylaminoalkoxy, alkylcarbonylaminoalkyl, alquilcarbonilaminoalquilamino, alquilcarbonilaminoheterociclo, alquilcarbonilheterocicloamino, alquilcarboniloxialquilcarbonilaminoalcoxi, alkylsulfonyl alquilcarboniloxialquilcarbonilaminoheterociclo, alquilsulfonilaminoalcoxi, alkylsulfonylaminoalkyl, alquilsulfonilaminoalquilamino, alkylthio, alkylamino, aminoalkyl, aminoalkylamino, aminoalquilcarbonílaminoheterociclo, aminoalquilcarbonilheterociclo, aminocarbonyl, alkylaminocarbonyl, aminocarbonylalkylamino, aminocarbonyl alkylheterocycle, aminocarbonylaminoalkoxy, aminocarbonylaminoalkylamino, aminocarbonylaryl, aminocarbonyldialkylamino, aminocarbonylheterocycle, aminoheterocycle, aryl, carboxyalkoxy, carboxyalkyl, carboxiaryl, carboxydialkylamino, cycloalkyl, Dialkylaminoalkylamino, dihydroxyalkylamino, halo, haloalkylsulfonyloxy, haloarilalquilamino, heteroarilalcoxicarbonilaminoheterociclo, heterociclocarbonilalquilamino, heterocycle, hydrogen, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkylamino, hidroxialquilaminocarbonilalcoxi, hidroxialquilaminocarbonílalquilo, hidroxialquilaminocarbonilalquilamino, hidroxialquilaminocarbonilaminoalcoxi, hidroxialquilaminoheterociclo, hidroxialquilcarbonilaminoalquilamino, hidroxialquilcarbonilaminoheterociclo, hidroxialquilcarbonilheterociclo, hidroxialquilheterociclo, and hydroxyheterocycle; R2 is selected from the group consisting of alkyl, cycloalkyl and hydrogen; R3 is selected from the group consisting of hydrogen, alkyl, alkoxy and halo; wherein each alkyl, wherever it occurs, is independently and optionally substituted with alkoxy, amino, carboxy, halo and hydroxyl; and R A, R 4 B, R 4 C, R 4 D and R E are each independently selected from the group consisting of alkylaminocarbonylaminoalkyl, alkylarylheteroarylaminocarbonylaminoalkyl, aminoalkyl, arylcycloalkylaminocarbonyldialkylaminoalkyl, arylcycloalkylaminocarbonylaminoalkyl, cyano, cycloalkylaminocarbonylaminoalkyl, cycloalkylaminocarbonyldialkylaminoalkyl, halo, and hydrogen; wherein each aryl and heteroaryl, wherever they occur, are independently and optionally substituted with alkyl; in the preparation of a medicament useful for the treatment or prevention of an inflammatory disorder in a subject.
19. The use claimed in claim 18, wherein the inflammatory disorder is arthritis.
20. The use claimed in claim 18, wherein the inflammatory disorder is osteoarthritis.
21. The use claimed in claim 18, wherein the inflammatory disorder is rheumatoid arthritis.
22. The use claimed in claim 18, wherein the inflammatory disorder is asthma.
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