- UNSATURATED HETEROCYCLOALKYL AND HETEROAROMATIC ACYL HYDRAZONE LINKERS, METHODS AND USES THEREOF
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The present application is directed to compounds of Formula (I), (II), (III) or (IV) compositions comprising these compounds, methods for their preparation and their uses, for example, as acyl hydrazone linkers, which can link two chemical entities together for further use as medicaments and/or diagnostics.
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Paragraph 00255
(2020/12/30)
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- AMINO-DIHYDROTHIAZINE AND AMINO-DIOXIDO DIHYDROTHIAZINE COMPOUNDS AS BETA-SECRETASE ANTAGONISTS AND METHODS OF USE
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The present invention provides a new class of compounds useful for the modulation of beta-secretase enzyme (BACE) activity. The compounds have a general Formula I: wherein variables A4, A5, A6, A8, R1, R2, R3, R7 and n of Formula I, independently, are defined herein. The invention also provides pharmaceutical compositions comprising the compounds, and corresponding uses of the compounds and compositions for treatment of disorders and/or conditions related to A-beta plaque formation and deposition, resulting from the biological activity of BACE. Such BACE mediated disorders include, for example, Alzheimer's Disease, cognitive deficits, cognitive impairments, schizophrenia and other central nervous system conditions. The invention further provides compounds of Formula II and sub-formula embodiments thereof, intermediates and processes and methods useful for the preparation of compounds of Formulas I-II.
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Page/Page column
(2014/05/07)
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- Structure based design of novel 6,5 heterobicyclic mitogen-activated protein kinase kinase (MEK) inhibitors leading to the discovery of imidazo[1,5-a] pyrazine G-479
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Use of the tools of SBDD including crystallography led to the discovery of novel and potent 6,5 heterobicyclic MEKi's [J. Med. Chem. 2012, 55, 4594]. The core change from a 5,6 heterobicycle to a 6,5 heterobicycle was driven by the desire for increased structural diversity and aided by the co-crystal structure of G-925 [J. Med. Chem. 2012, 55, 4594]. The key design feature was the shift of the attachment of the five-membered heterocyclic ring towards the B ring while maintaining the key hydroxamate and anilino pharamcophoric elements in a remarkably similar position as in G-925. From modelling, changing the connection point of the five membered ring heterocycle placed the H-bond accepting nitrogen within a good distance and angle to the Ser212 [J. Med. Chem. 2012, 55, 4594]. The resulting novel 6,5 benzoisothiazole MEKi G-155 exhibited improved potency versus aza-benzofurans G-925 and G-963 but was a potent inhibitor of cytochrome P450's 2C9 and 2C19. Lowering the log D by switching to the more polar imidazo[1,5-a] pyridine core significantly diminished 2C9/2C19 inhibition while retaining potency. The imidazo[1,5-a] pyridine G-868 exhibited increased potency versus the starting point for this work (aza-benzofuran G-925) leading to deprioritization of the azabenzofurans. The 6,5-imidazo[1,5-a] pyridine scaffold was further diversified by incorporating a nitrogen at the 7 position to give the imidazo[1,5-a] pyrazine scaffold. The introduction of the C7 nitrogen was driven by the desire to improve metabolic stability by blocking metabolism at the C7 and C8 positions (particularly the HLM stability). It was found that improving on G-868 (later renamed GDC-0623) required combining C7 nitrogen with a diol hydroxamate to give G-479. G-479 with polarity distributed throughout the molecule was improved over G-868 in many aspects.
- Robarge, Kirk D.,Lee, Wendy,Eigenbrot, Charles,Ultsch, Mark,Wiesmann, Christian,Heald, Robert,Price, Steve,Hewitt, Joanne,Jackson, Philip,Savy, Pascal,Burton, Brenda,Choo, Edna F.,Pang, Jodie,Boggs, Jason,Yang, April,Yang, Xioaye,Baumgardner, Matthew
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p. 4714 - 4723
(2015/01/09)
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- PERFLUORINATED CYCLOPROPYL FUSED 1,3-OXAZIN-2-AMINE COMPOUNDS AS BETA-SECRETASE INHIBITORS AND METHODS OF USE
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PERFLUORINATED CYCLOPROPYL FUSED 1,3-OXAZIN-2-AMINE COMPOUNDS AS BETA-SECRETASE INHIBITORS AND METHODS OF USE ABSTRACT OF THE DISCLOSURE The present invention provides a new class of compounds useful for the modulation of beta-secretase enzyme (BACE) activity. The compounds have a general Formula I: {INSERT STRUCTURE HERE} I wherein variables A4, A5, A6, A8, each of Ra, Rb, R1, R2, R3 and R7 of Formula I, independently, are defined herein. The invention also provides pharmaceutical compositions comprising the compounds, and uses of the compounds and compositions for treatment of disorders and/or conditions related to A-beta plaque formation and deposition, resulting from the biological activity of BACE. Such BACE mediated disorders include, for example, Alzheimer's Disease, cognitive deficits, cognitive impairments, schizophrenia and other central nervous system conditions. The invention further provides compounds of Formulas II and III, and sub-formula embodiments thereof, intermediates and methods for preparing compounds of the invention.
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Page/Page column 161
(2014/09/29)
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- COMPOUNDS AND METHODS FOR TREATMENT OF CANCER
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Compounds for treating, preventing or managing cancer are disclosed. Also provided are methods for using the compounds in treatment of various cancers. Also provided are methods of treatment using the compounds together with another chemotherapy, radiation therapy, hormonal therapy, biological therapy, or immunotherapy. Pharmaceutical compositions suitable for use in the methods are also disclosed.
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Page/Page column 38
(2011/05/08)
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- PYRAZOLE PYRAZINE AMINE COMPOUNDS AS KINASE INHIBITORS, COMPOSITIONS THEREOF AND METHODS OF TREATMENT THEREWITH
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Provided herein are Pyrazole Pyrazine Amine Compounds having the following structure:Formula (I). Wherein Q and R1-R3 are as defined herein, compositions comprising an effective amount of a Pyrazole Pyrazine Amine Compound and methods for treating or preventing inflammatory conditions, immunological conditions, cancer, neurodegenerative diseases, age-related diseases, cardiovascular diseases and metabolic conditions, or conditions treatable or preventable by inhibition of an IKK, or an IKK pathway, comprising administering an effective amount of a Pyrazole Pyrazine Amine Compound to a patient in need thereof.
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Page/Page column 112
(2009/09/04)
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- 5-ANILINOIMIDAZOPYRIDINES AND METHODS OF USE
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The invention relates to imidazopyridines of formula I with anti-cancer and/or anti-inflammatory activity and more specifically to imidazopyridines which inhibit MEK kinase activity. The invention provides compositions and methods useful for inhibiting abnormal cell growth or treating a hyperproliferative disorder, or treating an inflammatory disease in a mammal. The invention also relates to methods of using the compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, or associated pathological conditions.
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Page/Page column 74-75
(2009/08/14)
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- Cyclic compounds
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1. A cyclic compound of the formula (I) or a pharmacologically acceptable salt thereof, wherein X is ═CH— or ═N—, Y is —NH—, —NR4—, —S—, —O—, —CH═N—, —N═CH—, —N═N—, —CH═CH—, etc., R1 is a lower alkoxy group, an amino group, a heterocyclic ring containing N atom(s), or a hydroxy group substituted by a heterocyclic ring containing N atom(s) (each of which is optionally substituted), R2 is a lower alkylamino group which is optionally substituted by an aryl group, a lower alkoxy group which is optionally substituted by an aryl group, a lower alkoxy group substituted by an aromatic heterocyclic ring containing N atom(s), R3 is an aryl group, a heterocyclic ring containing N atom(s), a lower alkyl group, a lower alkoxy group, a cyclo lower alkoxy group, a hydroxy group substituted by a heterocyclic ring containing N atom(s), or an amino group (each of which is optionally substituted), and R3 and a substituent in Y may be combined to form a lactone ring. The compound of the present invention has excellent selective PDE V inhibitory activity and therefore, is useful as a therapeutic or prophylactic drug for treating various diseases due to functional disorders on cGMP-signaling.
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- Aromatic nitrogen-containing 6-membered cyclic compounds
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An aromatic nitrogen-containing 6-membered cyclic compound of the formula (I): wherein Ring A is a substituted or unsubstituted nitrogen-containing heterocyclic group; R1 is a substituted or unsubstituted lower alkyl group, —NH—Q—R3 (R3 is a substituted or unsubstituted nitrogen containing heterocyclic group, and Q is a lower alkylene group or a single bond), or —NH—R4 (R4 is a substituted or unsubstituted cycloalkyl group); R2 is a substituted or unsubstituted aryl group; one of Y and Z is ═CH—, and the other is ═N—, or a pharmaceutically acceptable salt thereof, these compounds exhibiting excellent selective PDE V inhibitory activities, and hence, being useful in the prophylaxis or treatment of penile erectile dysfunction, etc.
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- NOVEL HETEROCYCLIC CARBOXAMIDE DERIVATIVES
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A nitrogen-containing six-membered heterocyclic compound having substituents -X-A-R3, -N(R1)-(Ph substituted by R2), and -CONH2, or a salt thereof. (The symbols have the following meanings.A: a lower alkylene which may have substituent(s), an arylene which may have substituent(s), a heteroarylene which may have substituent(s), or a cycloalkylene which may have substituent(s);X: NR4, CONR4, NR4CO, O, or S;R1, R4: H, a lower alkyl, -CO-lower alkyl, or -SO2-lower alkyl;R2: H, a lower alkyl, a halogen, a lower alkyl substituted by halogen(s), -O-lower alkyl, -S-lower alkyl, -O-aryl, -O-lower alkylene-aryl, -S-lower alkylene-aryl, nitro, or cyano group;R3: -CO2H, -CO2-lower alkyl, -lower alkylene-CO2H, -lower alylene-CO2-lower alkyl, -CONHOH, -CONHO-lower alkyl, -lower alkylene-CONHOH, -lower alkylene-CONHO-lower alkyl, -NH2, -(NH2 in a prodrug form), -lower alkylene-NH2, or -lower alkylene-(NH2 in a prodrug form))
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