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Substituted pyrimidinonesRelated Patent Categories: Organic Compounds -- Part Of The Class 532-570 Series, Azo Compounds Containing Formaldehyde Reaction Product As The Coupling Component, Carbohydrates Or Derivatives, Hetero Ring Is Six-membered Having Two Or More Ring Hetero Atoms Of Which At Least One Is Nitrogen (e.g., Selenazines, Etc.), Six-membered Hetero Ring Consists Of Sulfur, Nitrogen, And Carbon, Polycyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos, Thiomorpholines (i.e., Fully Hydrogenated 1,4-thiazines),Substituted pyrimidinones description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070167621, Substituted pyrimidinones. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application claims priority to U.S. Provisional application 60/460,124, filed Apr. 3, 2003. BACKGROUND [0002] 1. Field [0003] This invention relates to substituted pyrimidinones that are useful for treating diseases and conditions caused or exacerbated by unregulated p38 MAP kinase activity. It also relates to Pharmaceutical compositions containing the pyrimidinone compounds, methods of preparing the pyrimidinone compounds and methods of treatment using these compounds. [0004] 2. Description of the Related Art [0005] Numerous cell surface receptors use one or more of the mitogen-activated protein kinase (MAP kinase) cascades during signal transduction. MAP kinases are a family of protein-directed serine/threonine kinases that are activated by dual phosphorylation. One subgroup of the MAP kinases is p38 MAP kinase, which is activated by a variety of signals including proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1), as well as bacterial lipopolysaccharides and environmental stress such as osmotic shock and ultraviolet radiation (Ono, K. and J. Han, Cell Signal. 12: 1, 2000). Within the p38 kinase family, there are four distinct isozymes: p38 alpha, p38 beta, p38 gamma, and p38 delta. The p38 kinase family function downstream of an activating stimulus by phosphorylating and activating transcription factors (e.g. ATF2, CHOP and MEP2C) as well as other kinases (e.g. MAPKAP-2 and MAPKAP-3) (Trends in Cell biology 7, 353-361, 1997;Mol Cell Biology 19, 21-30, 1999; EMBO J 20, 466-479, 2001)Upon activation, the p38 kinase cascade leads to the induction of gene expression of several factors involved in inflammation and immunity including TNF, interleukin-6, granulocyte-macrophage colony stimulating factor (GM-CSF), and HIV long terminal repeat (Paul et al., Cell Signal. 9: 403-410, 1997). The products of the p38 phosphorylation stimulate the production of inflammatory cytokines and other proteins, including TNF and IL-1, and cyclooxygenase-2, and also possibly modulate the effects of these cytokines on their target cells, and thus stimulate inflammation processes (Lee, J. C. et al, Nature, 372: 376, 1994). [0006] P38 MAP kinases have also been shown to promote apoptosis during ischemia in cardiac myocytes, which suggests that p38 MAP kinase inhibitors can be used to treat ischemic heart disease (J. Biol. Chem. 274, 6272, 1999). They are also required for T-cell HIV-1 replication and may be useful targets for AIDS therapy. P38 pathway inhibitors have been used to increase cancer cell sensitivity to cancer therapy also find use in the treatment of asthma (JPET 293, 281, 2000). [0007] TNF is a cytokine and a potent proinflammatory mediator implicated in inflammatory conditions such as arthritis, asthma, septic shock, non-insulin dependent diabetes mellitus, multiple sclerosis, asthma, and inflammatory bowel disease. Thus inhibitors of p38 MAP kinases (required for TNF production) may be useful for the treatment of inflammatory conditions resulting from excessive cytokine production such as arthritis. (Boehm, J. C. and J. L. Adams, Exp. Opin. Ther. Patents 10: 25, 2000, and references cited therein). TNF has also been implicated in viral infections, such as HIV, influenza virus, and herpes virus including herpes simplex virus type-1 (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and rhinotracheitis, among others. [0008] Excessive or unregulated TNF production has also been shown to produce elevated levels of IL-1. Inhibition of TNF, therefore, should reduce levels of IL-1 (European Cytokine Netw 6, 225, 1995) and ameliorate disease states caused by unregulated IL-1 synthesis. Such disease states include rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcosis, bone resorption diseases, reperfusion injury, graft versus host reaction, alallograft rejections, fever and myalgias due to infection, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS related complex (ARC), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, and pyresis. [0009] IL-1 has also been shown to mediate a variety of biological activities such as the activation of T-helper cells, induction of fever, stimulation of prostaglandin or collagenase production, neutrophil chemotaxis, and the suppression of plasma iron levels (Rev. Infect. Disease, 6, 51 (1984)). Elevated levels of IL-1 have also been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, inflammatory bowel disease, adult respiratory distress syndrome (ARDS), psoriasis, Crohn's disease, ulcerative colitis, anaphylaxis, muscle degeneration, cachexia, Reiter's syndrome, type I and type II diabetes, bone resorption diseases, ischemia reperfusion injury, arteriosclerosis, brain trauma, multiple sclerosis, sepsis, septic shock, and toxic shock syndrome. Viruses sensitive to TNF inhibition, such as HIV-1, HIV-2, HIV-3, are also affected by IL-1 production. In rheumatoid arthritis, both IL-1 and TNF induce collagenase synthesis and ultimately lead to tissue destruction within arthritic joints (Lymphokine Cytokine Res. (11): 253-256, (1992) and Clin. Exp. Immunol. 989:244-250, (1992)). [0010] IL-6 is another pro-inflammatory cytokine, which is associated with many conditions including inflammation. Consequently, TNF, IL-1 and IL-6 affect a wide variety of cells and tissues and are important inflammatory mediators of a wide variety of disease states and conditions. The inhibition of these cytokines by inhibition or modulation of p38 kinase is of benefit in controlling, reducing and alleviating many of these disease states and conditions. Therefore, the invention concerns finding small molecule inhibitors or modulators of p38 kinase and the p38 kinase pathway. SUMMARY [0011] In a broad aspect, the invention provides compounds of Formula I (Embodiment I): and pharmaceutically acceptable salts thereof, wherein [0012] R.sub.1 is H, halogen, NO.sub.2, alkyl, carboxaldehyde, hydroxyalkyl, dihydroxyalkyl, arylalkoxy, arylalkyl, alkenyl, alkynyl, arylalkynyl, --CN, aryl, alkanoyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, carboxyl, or arylalkanoyl, [0013] wherein the aryl portion of arylalkoxy, arylalkyl, and arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO.sub.2R; [0014] wherein the alkyl portion of the alkyl, hydroxyalkyl, dihydroxyalkyl, arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and arylalkanoyl groups is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkoxycarbonyl, or C.sub.3-C.sub.7 cycloalkyl; [0015] R.sub.2 is H, OH, halogen, --OSO.sub.2--(C.sub.1-C.sub.6) alkyl, --OSO.sub.2-aryl, arylalkoxy, aryloxy, arylthio, arylthioalkoxy, arylalkynyl, alkoxy, aryloxy(C.sub.1-C.sub.6)alkyl, alkyl, alkynyl, --OC(O)NH(CH.sub.2).sub.naryl, --OC(O)N(alkyl)(CH.sub.2).sub.naryl, alkoxyalkoxy, dialkylamino, alkyl, alkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylalkenyl, heterocycloalkyl, heterocycloalkylalkyl, alkoxyalkoxy, NR.sub.8R.sub.9, dialkylamino, or CO.sub.2R, wherein [0016] n is 0, 1, 2, 3, 4, 5 or 6; [0017] each of which groups is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, --(C.sub.1-C.sub.6)alkyl-N(R)--CO.sub.2R.sub.30, haloalkyl, heteroaryl, heteroarylalkyl, --NR.sub.6R.sub.7, R.sub.6R.sub.7N--(C.sub.1-C.sub.6 alkyl)-, --C(O)NR.sub.6R.sub.7, --(C.sub.1-C.sub.4)alkyl-C(O)NR.sub.6R.sub.7, --(C.sub.1-C.sub.4 alkyl)-NRC(O)NR.sub.16R.sub.17, haloalkoxy, alkyl, CN, hydroxyalkyl, dihydroxyalkyl, alkoxy, alkoxycarbonyl, phenyl, --SO.sub.2-phenyl wherein the phenyl and --SO.sub.2-phenyl groups are optionally substituted with 1, 2, or 3 groups that are independently halogen or NO.sub.2, or --OC(O)NR.sub.6R.sub.7, wherein [0018] R.sub.16 and R.sub.17 are independently H or C.sub.1-C.sub.6 alkyl; or [0019] R.sub.16, R.sub.17 and the nitrogen to which they are attached form a morpholinyl ring; [0020] R.sub.6 and R.sub.7 are independently at each occurrence H, alkyl, hydroxyalkyl, dihydroxyalkyl, alkoxy, alkanoyl, arylalkyl, arylalkoxy, alkoxycarbonyl, --SO.sub.2-alkyl, OH, alkoxy, alkoxyalkyl, arylalkoxycarbonyl, --(C.sub.1-C.sub.4)alkyl-CO.sub.2-alkyl, heteroarylalkyl, or arylalkanoyl, wherein each is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, OH, SH, heterocycloalkyl, heterocycloalkylalkyl, C.sub.3-C.sub.7 cycloalkyl, alkoxy, NH.sub.2, NH(alkyl), N(alkyl)(alkyl), --O-alkanoyl, alkyl, haloalkyl, carboxaldehyde, or haloalkoxy; or [0021] R.sub.6, R.sub.7, and the nitrogen to which they are attached form a morpholinyl, pyrrolidinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently C.sub.1-C.sub.4 alkyl, alkoxycarbonyl, C.sub.1-C.sub.4 alkoxy, hydroxyl, hydroxyalkyl, dihydroxyalkyl, or halogen; [0022] R at each occurrence is independently hydrogen or C.sub.1-C.sub.6 alkyl optionally substituted with 1 or 2 groups that are independently OH, SH, halogen, amino, monoalkylamino, dialkylamino or C.sub.3-C.sub.6 cycloalkyl; [0023] R.sub.30 is C.sub.1-C.sub.6 alkyl optionally substituted with 1 or 2 groups that are independently OH, SH, halogen, amino, monoalkylamino, dialkylamino or C.sub.3-C.sub.6 cycloalkyl; [0024] each R.sub.8 is independently hydrogen, alkyl, alkanoyl, arylalkyl and arylalkanoyl, wherein each of the above is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, alkoxy, alkoxycarbonyl, halogen, or haloalkyl; [0025] each R.sub.9 is hydrogen, alkyl, alkanoyl, arylalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, heteroaryl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, arylalkanoyl, --SO.sub.2-phenyl, and aryl wherein each of the above is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, alkoxy, alkoxycarbonyl, halogen, or haloalkyl; [0026] R.sub.4 is hydrogen or R.sub.4 is alkyl unsubstituted or substituted with one or two groups that are independently CO.sub.2R, --CO.sub.2--(C.sub.1-C.sub.6)alkyl, --C(O)NR.sub.6R.sub.7, --C(O)R.sub.6, --N(R.sub.30)C(O)NR.sub.16R.sub.17, --N(R.sub.30)C(O)--(C.sub.1-C.sub.6)alkoxy, or --NR.sub.6R.sub.7, arylalkoxy, arylalkyl, heteroaryl, heteroarylalkyl, hydroxyalkyl, dihydroxyalkyl, haloalkyl, R.sub.6R.sub.7N--(C.sub.1-C.sub.6 alkyl)-, --NR.sub.6R.sub.7, alkoxy, hydroxyalkoxy-, (R.sub.6R.sub.7N)-alkoxy-, R.sub.6R.sub.7NC(O)-alkoxy-, R.sub.6C(O)N(R.sub.7)alkoxy-, carboxaldehyde, --C(O)NR.sub.6R.sub.7, CO.sub.2R, alkoxyalkyl, or alkoxyalkoxy, wherein the heteroaryl or aryl portions of is the above are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, hydroxy, alkoxy, alkyl, --CO.sub.2--(C.sub.1-C.sub.6)alkyl, --CONR.sub.6R.sub.7, --NR.sub.6R.sub.7, R.sub.6R.sub.7N--(C.sub.1-C.sub.6)alkyl-, nitro, haloalkyl, or haloalkoxy; and [0027] R.sub.5 is H, aryl, arylalkyl, arylthioalkyl, alkyl optionally substituted with 1, 2, or 3 groups that are independently arylalkoxycarbonyl, --NR.sub.8R.sub.9, halogen, --C(O)NR.sub.8R.sub.9, alkoxycarbonyl, C.sub.3-C.sub.7 cycloalkyl, or alkanoyl, alkoxy, alkoxyalkyl optionally substituted with one trimethylsilyl group, amino, alkoxycarbonyl, hydroxyalkyl, dihydroxyalkyl, alkynyl, --SO.sub.2-alkyl, alkoxy optionally substituted with one trimethylsilyl group, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl, -alkyl-S-aryl, -alkyl-SO.sub.2-aryl, heteroarylalkyl, heterocycloalkyl, heteroaryl, or alkenyl optionally substituted with alkoxycarbonyl, wherein [0028] each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, alkoxy, hydroxyalkyl, dihydroxyalkyl, arylalkoxy, thioalkoxy, alkoxycarbonyl, arylalkoxycarbonyl, CO.sub.2R, CN, OH, hydroxyalkyl, dihydroxyalkyl, amidinooxime, --NR.sub.6R.sub.7, --NR.sub.8R.sub.9, R.sub.6R.sub.7N--(C.sub.1-C.sub.6 alkyl)-, carboxaldehyde, SO.sub.2alkyl, --SO.sub.2H, --SO.sub.2NR.sub.6R.sub.7, alkanoyl wherein the alkyl portion is optionally substituted with OH, halogen or alkoxy, --C(O)NR.sub.6R.sub.7, --(C.sub.1-C.sub.4 alkyl)-C(O)NR.sub.6R.sub.7, amidino, haloalkyl, --(C.sub.1-C.sub.4 alkyl)-NR.sub.15C(O)NR.sub.16R.sub.17, --(C.sub.1-C.sub.4 alkyl)-NR.sub.15C(O)R.sub.18, --O--CH.sub.2--O, --O--CH.sub.2CH.sub.2--O--, or haloalkoxy; wherein [0029] R.sub.15 is H or C.sub.1-C.sub.6 alkyl; and [0030] R.sub.18 is C.sub.1-C.sub.6 alkyl optionally substituted with --O--(C.sub.2-C.sub.6 alkanoyl, C.sub.1-C.sub.6 hydroxyalkyl, C.sub.1-C.sub.6 dihydroxyalkyl-C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkoxy C.sub.1-C.sub.6 alkyl; amino C.sub.1-C.sub.6 alkyl, mono or dialkylamino C.sub.1-C.sub.6 alkyl. [0031] The invention also includes intermediates that are useful in making the compounds of the invention. [0032] The compounds and salts of the invention bind and/or interact with p38 kinase and/or TNF. Preferably, they inhibit the activity of p38 kinase and/or TNF. They are therefore used in treating p38 map kinase or TNF mediated disorders. Preferably they are used in treating p38 alpha or TNF mediated disorders. [0033] The invention also includes pharmaceutical compositions comprising at least one compound or salt of formula I and at least one pharmaceutically acceptable carrier, solvent, adjuvant or excipient. [0034] The invention also includes methods of treating a TNF mediated disorder, a p38 kinase mediated disorder, inflammation and/or arthritis in a subject, the method comprising treating a subject having or susceptible to such disorder or condition with a therapeutically-effective amount of a compound or salt of Formula I. DETAILED DESCRIPTION [0035] In a preferred aspect, the invention provides compounds of formula I wherein: [0036] no more than two of R.sub.1, R.sub.2, R.sub.4, and R.sub.5 are simultaneously hydrogen; [0037] R.sub.6 and R.sub.7 are not simultaneously OH; [0038] when R.sub.2 is OH, R.sub.4 is methyl and R.sub.5 is phenyl, R.sub.1 is not acetyl; and [0039] R.sub.4 and R.sub.5 are not simultaneously hydrogen. [0040] In other aspects and embodiments, the invention provides: [0041] Embodiment 2. Compounds of the formula: and the pharmaceutically acceptable salts thereof, wherein [0042] R.sub.1 is H, halogen, alkyl, carboxaldehyde, hydroxyalkyl, dihydroxyalkyl, arylalkoxy, arylalkyl, alkenyl, alkynyl, arylalkynyl, CN, alkanoyl, alkoxy, alkoxyalkyl, haloalkyl, carboxyl, or arylalkanoyl, [0043] wherein the aryl portion of arylalkoxy, arylalkyl, and arylalkanoyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, nitro, CN, haloalkyl, haloalkoxy or CO.sub.2R; [0044] wherein the alkyl portion of the alkyl, hydroxyalkyl, dihydroxyalkyl, arylalkoxy, arylalkyl, alkanoyl, alkoxy, alkoxyalkyl and arylalkanoyl groups is unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkoxycarbonyl, or cyclopropyl; [0045] R.sub.2 is H, OH, halogen, --OSO.sub.2--(C.sub.1-C.sub.6)alkyl, --OSO.sub.2-aryl, arylalkoxy, aryloxy, arylthioalkoxy, arylalkynyl, alkoxy, phenyloxy(C.sub.1-C.sub.6)alkyl, --OC(O)NH(CH.sub.2).sub.naryl, --OC(O)N(alkyl)(CH.sub.2).sub.naryl, alkyl, alkynyl, alkoxyalkoxy, dialkylamino, heteroaryl, heterocycloalkyl, aryloxyalkyl, or CO.sub.2R, wherein [0046] each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, --NR.sub.6R.sub.7, haloalkyl, haloalkoxy, alkyl, heteroaryl, heteroarylalkyl, --(C.sub.1-C.sub.4)alkyl-C(O)NR.sub.6R.sub.7, R.sub.6R.sub.7N--(C.sub.1-C.sub.6 alkyl)-, --C(O)NR.sub.6R.sub.7, --(C.sub.1-C.sub.4 alkyl)-NRC(O)NR.sub.16R.sub.17, CN, hydroxyalkyl, dihydroxyalkyl, --OC(O)NR.sub.6R.sub.7, or --(C.sub.1-C.sub.6)alkyl-N(R)--CO.sub.2R.sub.30, wherein [0047] R.sub.16 and R.sub.17 are independently H or C.sub.1-C.sub.6 alkyl; or [0048] R.sub.16, R.sub.17 and the nitrogen to which they are attached form a morpholinyl ring; [0049] R.sub.6 and R.sub.7 are independently at each occurrence H, alkyl, hydroxyalkyl, dihydroxyalkyl, alkoxy, alkoxyalkyl, alkanoyl, arylalkyl, arylalkoxy, arylalkoxycarbonyl, or arylalkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, alkoxy, alkyl, OH, SH, carboxaldehyde, haloalkyl, or haloalkoxy; or [0050] R.sub.6, R.sub.7, and the nitrogen to which they are attached form a morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently C.sub.1-C.sub.4 alkyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, dihydroxyalkyl, or halogen; [0051] n is 0, 1, 2, 3, 4, 5 or 6; [0052] R at each occurrence is independently H or C.sub.1-C.sub.6 alkyl optionally substituted with 1 or 2 groups that are independently OH, SH, halogen, amino, monoalkylamino, dialkylamino or C.sub.3-C.sub.6 cycloalkyl; [0053] R.sub.30 is C.sub.1-C.sub.6 alkyl optionally substituted with 1 or 2 groups that are independently OH, SH, halogen, amino, monoalkylamino, dialkylamino or C.sub.3-C.sub.6 cycloalkyl; [0054] R.sub.4 is H, alkyl optionally substituted with one or two groups that are independently CO.sub.2R, --CO.sub.2alkyl, --C(O)NR.sub.6R.sub.7, --C(O)R.sub.6, --N(R.sub.30)C(O)NR.sub.16R.sub.17, --N(R.sub.30)C(O)--(C.sub.1-C.sub.6)alkoxy, or --NR.sub.6R.sub.7, arylalkoxy, heteroaryl, arylalkyl, hydroxyalkyl, dihydroxyalkyl, haloalkyl, --NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, alkoxy, hydroxyalkoxy-, (R.sub.6R.sub.7N)-alkoxy-, R.sub.6R.sub.7NC(O)-alkoxy-, R.sub.6C(O)N(R.sub.7)alkoxy-, alkoxyalkyl, or alkoxyalkoxy, wherein [0055] the heteroaryl or aryl portions of the above are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, hydroxy, alkoxy, alkyl, --CO.sub.2--(C.sub.1-C.sub.6)alkyl, --CONR.sub.6R.sub.7, --NR.sub.6R.sub.7, R.sub.6R.sub.7N--(C.sub.1-C.sub.6)alkyl-, nitro, haloalkyl, or haloalkoxy; and [0056] R.sub.5 is H, arylalkyl, alkyl optionally substituted with 1, 2, or 3 groups that are independently arylalkoxycarbonyl, --NR.sub.8R.sub.9, halogen, --C(O)NR.sub.8R.sub.9, alkoxycarbonyl, or alkanoyl, alkoxyalkyl optionally substituted with one trimethylsilyl group, alkoxycarbonyl, amino, hydroxyalkyl, dihydroxyalkyl, alkenyl optionally substituted with alkoxycarbonyl, alkynyl, --SO.sub.2-alkyl, aryl, alkoxy optionally substituted with one trimethylsilyl group, heterocycloalkylalkyl, heteroarylalkyl, heterocycloalkyl, or heteroaryl, wherein [0057] each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently alkyl, halogen, alkoxy, arylalkoxy, hydroxyalkyl, dihydroxyalkyl, thioalkoxy, --SO.sub.2alkyl, alkoxycarbonyl, arylalkoxycarbonyl, CO.sub.2R, CN, OH, amidinooxime, NR.sub.8R.sub.9, R.sub.6R.sub.7N--(C.sub.1-C.sub.6 alkyl)-, --C(O)NR.sub.6R.sub.7, amidino, hydroxyalkyl, dihydroxyalkyl, carboxaldehyde, --NR.sub.6R.sub.7, haloalkyl, --(C.sub.1-C.sub.4 alkyl)-C(O)NR.sub.6R.sub.7, --(C.sub.1-C.sub.4 alkyl)-CO.sub.2R, --(C.sub.1-C.sub.4 alkyl)-C.sub.1-C.sub.6 alkoxycarbonyl, --(C.sub.1-C.sub.4 alkyl)-CN, --(C.sub.1-C.sub.4 alkyl)-NR.sub.15C(O)R.sub.18, --O--CH.sub.2--O--, --O--CH.sub.2CH.sub.2--O--, phenyl or haloalkoxy; [0058] R.sub.8 is hydrogen, alkyl, alkanoyl, arylalkyl and arylalkanoyl; [0059] R.sub.9 is alkyl, alkanoyl, arylalkyl, heteroaryl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, and arylalkanoyl. [0060] Embodiment 3. Compounds according to embodiment 2 wherein [0061] R.sub.1 is H, halogen, alkyl optionally substituted with C.sub.1-C.sub.4 alkoxycarbonyl, carboxaldehyde, hydroxyalkyl, dihydroxyalkyl, phenyl(C.sub.1-C.sub.6)alkoxy, phenyl(C.sub.1-C.sub.6)alkyl, CN, alkanoyl, alkoxy, C.sub.2-C.sub.4 alkynyl, C.sub.2-C.sub.6 alkenyl optionally substituted with C.sub.1-C.sub.4 alkoxycarbonyl, alkoxyalkyl, haloalkyl, or phenyl(C.sub.1-C.sub.6)alkanoyl, [0062] wherein the phenyl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, nitro, CN, CF.sub.3, OCF.sub.3 or CO.sub.2R; [0063] wherein the alkyl groups are unsubstituted or substituted with 1, 2, or 3 groups that are independently halogen, methoxy, or ethoxy; [0064] R.sub.2 is OH, phenyl(C.sub.1-C.sub.6)alkoxy, phenyloxy, phenyloxy(C.sub.1-C.sub.6)alkyl, phenyl (C.sub.1-C.sub.4) thioalkoxy, C.sub.1-C.sub.8 alkoxy, alkoxyalkoxy, --O--SO.sub.2phenyl, alkynyl, phenyl (C.sub.2-C.sub.4) alkynyl, alkyl, --OC(O)NH(CH.sub.2).sub.nphenyl, --OC(O)N(alkyl)(CH.sub.2).sub.nphenyl, dialkylamino, pyridyl, pyrimidyl, pyridazyl, pyrazolyl, imidazolyl, pyrrolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrazolyl, pyrazinyl, benzimidazolyl, triazinyl, tetrahydrofuryl, piperidinyl, hexahydropyrimidinyl, thiazolyl, thienyl, or CO.sub.2R, wherein [0065] n is 0, 1, 2, 3, 4, 5 or 6; [0066] each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, NR.sub.6R.sub.7, haloalkyl, haloalkoxy, hydroxyalkyl, dihydroxyalkyl, alkyl, phenyl, pyridyl, piperidinyl, piperazinyl, --(C.sub.1-C.sub.6)alkyl-N(R)--CO.sub.2R.sub.30, R.sub.6R.sub.7N--(C.sub.1-C.sub.6 alkyl)-, --C(O)NR.sub.6R.sub.7, --(C.sub.1-C.sub.4)alkyl-C(O)NR.sub.6R.sub.7, --(C.sub.1-C.sub.4 alkyl)-NRC(O)NR.sub.16R.sub.17, or --OC(O)NR.sub.6R.sub.7, wherein [0067] R.sub.6 and R.sub.7 are independently at each occurrence H, alkyl, (C.sub.1-C.sub.4) hydroxyalkyl, (C.sub.1-C.sub.4) dihydroxyalkyl, (C.sub.1-C.sub.4) alkoxy, (C.sub.1-C.sub.4) alkoxy (C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkanoyl, phenyl (C.sub.1-C.sub.4) alkyl, phenyl (C.sub.1-C.sub.4) alkoxy, phenyl (C.sub.1-C.sub.4) alkoxycarbonyl, or phenyl (C.sub.1-C.sub.4) alkanoyl, wherein each of the above is unsubstituted or substituted with 1, 2, or 3 groups that are independently, halogen, OH, SH, C.sub.3-C.sub.6 cycloalkyl, (C.sub.1-C.sub.4) alkoxy, (C.sub.1-C.sub.4) alkyl, CF.sub.3, carboxaldehyde, NH.sub.2, NH(C.sub.1-C.sub.6)alkyl, N(C.sub.1-C.sub.6)alkyl (C.sub.1-C.sub.6)alkyl, OCF.sub.3; or [0068] R.sub.6, R.sub.7, and the nitrogen to which they are attached form a morpholinyl, thiomorpholinyl; piperidinyl, pyrrolidinyl, or piperazinyl ring which is optionally substituted with 1 or 2 groups that are independently C.sub.1-C.sub.4 alkyl, hydroxy, hydroxy C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 dihydroxyalkyl, C.sub.1-C.sub.4 alkoxycarbonyl, or halogen; and [0069] R.sub.4 is H, alkyl optionally substituted with one or two groups that are independently CO.sub.2R, --CO.sub.2alkyl, --C(O)NR.sub.6R.sub.7, --C(O)R.sub.6, --N(R.sub.30)C(O)NR.sub.16R.sub.17, --N(R.sub.30)C(O)--(C.sub.1-C.sub.6)alkoxy, or --NR.sub.6R.sub.7, arylalkoxy, heteroaryl, arylalkyl, hydroxyalkyl, dihydroxyalkyl, haloalkyl, --NR.sub.6R.sub.7, --C(O)NR.sub.6R.sub.7, alkoxy, hydroxyalkoxy-, (R.sub.6R.sub.7N)-alkoxy-, R.sub.6R.sub.7NC(O)-alkoxy-, R.sub.6C(O)N(R.sub.7)alkoxy-, alkoxyalkyl, or alkoxyalkoxy, wherein [0070] the heteroaryl or aryl portions of the above are unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, hydroxy, alkoxy, alkyl, --CO.sub.2--(C.sub.1-C.sub.6)alkyl, --CONR.sub.6R.sub.7, --NR.sub.6R.sub.7, R.sub.6R.sub.7N--(C.sub.1-C.sub.6)alkyl-, nitro, haloalkyl, or haloalkoxy; and [0071] R.sub.5 is phenyl(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkyl optionally substituted with 1, 2, 3, 4, or 5 groups that are independently phenyl C.sub.1-C.sub.4 alkoxycarbonyl, --NR.sub.8R.sub.9, halogen, --C(O)NR.sub.8R.sub.9, alkoxycarbonyl, or alkanoyl, phenyl, alkoxy, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 alkenyl optionally substituted with alkoxycarbonyl, indolyl, quinolinyl, isoquinolinyl, isoindolyl, dihydroindolyl, pyrazolyl, imidazolyl, dihydroisoindolyl, indolon-2-yl, indazolyl, benzimidazolyl, pyridyl, imidazolidine dione, pyrazolyl(C.sub.1-C.sub.6 alkyl), imidazolyl(C.sub.1-C.sub.6 alkyl), piperidinyl(C.sub.1-C.sub.6)alkyl, pyrrolidinyl(C.sub.1-C.sub.6)alkyl, imidazolidinyl(C.sub.1-C.sub.6)alkyl, tetrahydroisoquinolinyl(C.sub.1-C.sub.6)alkyl, 1H-indazolyl(C.sub.1-C.sub.6)alkyl, dihydroindolon-2-yl(C.sub.1-C.sub.6 alkyl), indolinyl(C.sub.1-C.sub.6 alkyl), dihydrobenzimidazolyl(C.sub.1-C.sub.6 alkyl), or dihydrobenzoimidazolonyl(C.sub.1-C.sub.6 alkyl), pyridyl (C.sub.1-C.sub.6) alkyl, pyridazinyl (C.sub.1-C.sub.6) alkyl, pyrimidinyl (C.sub.1-C.sub.6) alkyl, pyrazinyl (C.sub.1-C.sub.6) alkyl, tetrahydrofuryl(C.sub.1-C.sub.6)alkyl, naphthyl(C.sub.1-C.sub.6)alkyl, morpholinyl (C.sub.1-C.sub.6) alkyl, tetrahydrofuryl (C.sub.1-C.sub.6) alkyl, thienyl (C.sub.1-C.sub.6) alkyl, piperazinyl (C.sub.1-C.sub.6) alkyl, indolyl (C.sub.1-C.sub.6) alkyl, quinolinyl(C.sub.1-C.sub.6) alkyl, isoquinolinyl(C.sub.1-C.sub.6) alkyl, isoindolyl(C.sub.1-C.sub.6) alkyl, dihydroindolyl(C.sub.1-C.sub.6) alkyl, pyrazolyl(C.sub.1-C.sub.4) alkyl, imidazolyl(C.sub.1-C.sub.4) alkyl, dihydroisoindolyl(C.sub.1-C.sub.6) alkyl, indoon-2-yl(C.sub.1-C.sub.6) alkyl, indolon-2-yl(C.sub.1-C.sub.6) alkyl, or morpholinyl C.sub.1-C.sub.6 alkyl, wherein [0072] each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently C.sub.1-C.sub.6 alkyl, halogen, C.sub.1-C.sub.6 alkoxy, phenyl C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 thioalkoxy, C.sub.1-C.sub.6 alkoxycarbonyl, CO.sub.2R, CN, --SO.sub.2(C.sub.1-C.sub.6)alkyl, amidinooxime, NR.sub.8R.sub.9, --NR.sub.6R.sub.7, NR.sub.6R.sub.7 C.sub.1-C.sub.6 alkyl, --C(O)NR.sub.6R.sub.7, --(C.sub.1-C.sub.4)alkyl-C(O)NR.sub.6R.sub.7, amidino, C.sub.1-C.sub.4 haloalkyl, hydroxy C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 dihydroxyalkyl, or C.sub.1-C.sub.4 haloalkoxy; wherein [0073] R.sub.8 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkanoyl, phenyl C.sub.1-C.sub.6 alkyl and phenyl C.sub.1-C.sub.6 alkanoyl; and [0074] R.sub.9 is aminoalkyl, mono C.sub.1-C.sub.6 alkylamino C.sub.1-C.sub.6 alkyl, di C.sub.1-C.sub.6 alkylamino C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkanoyl, phenyl C.sub.1-C.sub.6 alkyl, indazolyl, and phenyl C.sub.1-C.sub.6 alkanoyl. [0075] Embodiment 4. Compounds according to embodiment 3, wherein [0076] R.sub.1 is H, halogen, C.sub.1-C.sub.4 alkyl optionally substituted with C.sub.1-C.sub.4 alkoxycarbonyl, C.sub.2-C.sub.4 alkenyl optionally substituted with C.sub.1-C.sub.4 alkoxycarbonyl, C.sub.2-C.sub.4 alkynyl, or carboxaldehyde; [0077] R.sub.2 is benzyloxy, OH, phenyloxy, phenyloxy(C.sub.1-C.sub.6)alkyl, phenyl (C.sub.1-C.sub.4) thioalkoxy, or pyridyl; wherein each of the above is optionally substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, --(C.sub.1-C.sub.6)alkyl-N(R)--CO.sub.2R.sub.30, NR.sub.6R.sub.7, --(C.sub.1-C.sub.4)alkyl-C(O)NR.sub.6R.sub.7, (C.sub.1-C.sub.4) haloalkyl, --C(O)NR.sub.6R.sub.7, --(C.sub.1-C.sub.4 alkyl)-NRC(O)NR.sub.16R.sub.17, (C.sub.1-C.sub.4) haloalkoxy, hydroxyalkyl, C.sub.1-C.sub.6 dihydroxyalkyl, (C.sub.1-C.sub.6) alkyl, pyridyl, or R.sub.6R.sub.7N--(C.sub.1-C.sub.6 alkyl)-. [0078] Embodiment 4a. Compounds according to embodiment 4, wherein R.sub.1 is H. 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