- Discovery of SARxxxx92, a pan-PIM kinase inhibitor, efficacious in a KG1 tumor model
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N-substituted azaindoles were discovered as potent pan-PIM inhibitors. Lead optimization, guided by structure and focused on physico-chemical properties allowed us to solve inherent hERG and permeability liabilities, and provided compound 27, which subseq
- Barberis, Claude,Erdman, Paul,Czekaj, Mark,Fire, Luke,Pribish, James,Tserlin, Elina,Maniar, Sachin,Batchelor, Joseph D.,Liu, Jinyu,Patel, Vinod F.,Hebert, Andrew,Levit, Mikhail,Wang, Anlai,Sun, Frank,Huang, Shih-Min A.
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Read Online
- Development of the Convergent, Kilogram-Scale Synthesis of an Antibacterial Clinical Candidate Using Enantioselective Hydrogenation
-
Early chemical development studies into the best way of assembling AZD9742, an antibacterial drug candidate, have involved swapping the order of two reductive aminations. The orthogonally functionalized aminopiperidine partner for these couplings is now enantioselectively synthesized using ruthenium-catalyzed asymmetric hydrogenation. The challenge of controlling defluorination through an appropriate catalyst choice has hitherto prevented this revised sequence from reaching its full potential. However, it is still shown to allow access to the active pharmaceutical ingredient in a stereochemically pure form and has been demonstrated on a multikilogram scale. The reductive aminations in both the original and revised sequences provided different scale-up challenges, and the solutions implemented are described.
- Benson, Helen,Bones, Karen,Churchill, Gwydion,Ford, Gair,Frodsham, Lianne,Janbon, Sophie,Millington, Fiona,Powell, Lyn,Raw, Steven A.,Reid, Julie,Stark, Andrew,Steven, Alan
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p. 588 - 598
(2020/05/19)
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- CERAMIDE GALACTOSYLTRANSFERASE INHIBITORS FOR THE TREATMENT OF DISEASE
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Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or disorders associated with the enzyme ceramide galactosyltransferase (CGT), such as, for example, lysosomal storage diseases. Examples of lysosomal storage diseases include, for example, Krabbe disease and Metachromatic Leukodystrophy.
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Paragraph 001646; 001648
(2018/07/29)
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- FLUOROINDOLE DERIVATIVES AS MUSCARINIC M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS
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The present invention relates to compound of formula (I), or stereoisomers and pharmaceutically acceptable salts as muscarinic M1 receptor positive allosteric modulators. This invention also relates to methods of making such compounds and pharmaceutical compositions comprising such compounds. The compounds of this invention are useful in the treatment of various disorders that are related to muscarinic M1 receptor.(Formula I) (I)
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Page/Page column 28
(2017/03/28)
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- SPIRO[CYCLOBUTANE-1,3'-INDOLIN]-2'-ONE DERIVATIVES AS BROMODOMAIN INHIBITORS
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The present invention provides novel spiro[cyclobutane-1,3'-indolin]-2'- derivatives of formula (I) in which Cy R1, R2, R4, L and 'm' are have the meaning given in the specification, and pharmaceutically acceptable salts thereof. The compounds of formula (I) are useful as bromodomain inhibitors in the treatment or prevention of diseases or disorders where bromodomain inhibition is desired.
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Page/Page column 89
(2017/01/02)
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- COMPOUNDS FOR THE MODULATION OF MYC ACTIVITY
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The present invention provides novel compounds of Formula (I) and Formula (II) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating or preventing proliferative diseases, e.g., cancers (e.g., breast cancer, prostate cancer, lymphoma, lung cancer, pancreatic cancer, ovarian cancer, neuroblastoma, or colorectal cancer), benign neoplasms, angio genesis, inflammatory diseases, fibrosis (e.g., polycystic kidney disease), autoinflammatory diseases, and autoimmune diseases in a subject.
- -
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Paragraph 505; 508-509
(2017/01/31)
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- 7-AZAINDOLE OR 4,7-DIAZAINDOLE DERIVATIVES AS IKK EPSILON AND TBK1 INHIBITOR AND PHARMACEUTICAL COMPOSITION COMPRISING SAME
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Provided are 7-azaindole or 4,7-diazaindole derivatives as an IKKε (I-kappa-B kinase epsilon) and TBK1 (TANK-binding kinase 1) inhibitor. The 7-azaindole or 4,7-diazaindole derivative effectively inhibits IKKε and TBK1, and thus is useful not only as an a
- -
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Paragraph 0654; 0655; 0656
(2016/10/31)
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- Synthesis and evaluation of novel 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives as potent and orally efficacious immunomodulators targeting JAK3
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Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. As a novel class of immunomodulators targeting JAK3, 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives are promising candidates for treating such diseases. In chemical modification of lead compound 2, the substitution of a cycloalkyl ring for an N-cyanopyridylpiperidine in C4-position was effective for increasing JAK3 inhibitory activity. In addition, modulation of physical properties such as molecular lipophilicity and basicity was important for reducing human ether-a-go-go-related gene (hERG) inhibitory activity. Our optimization study gave compound 31, which exhibited potent JAK3 inhibitory activity as well as weak hERG inhibitory activity. In cellular assay, 31 exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation. In a pharmacokinetic study, good metabolic stability and oral bioavailability of 31 were achieved in rats, dogs, and monkeys. Further, 31 prolonged graft survival in an in vivo rat heterotopic cardiac transplant model.
- Nakajima, Yutaka,Inoue, Takayuki,Nakai, Kazuo,Mukoyoshi, Koichiro,Hamaguchi, Hisao,Hatanaka, Keiko,Sasaki, Hiroshi,Tanaka, Akira,Takahashi, Fumie,Kunikawa, Shigeki,Usuda, Hiroyuki,Moritomo, Ayako,Higashi, Yasuyuki,Inami, Masamichi,Shirakami, Shohei
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p. 4871 - 4883
(2015/08/03)
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- COMPOUNDS AND COMPOSITIONS AS INHIBITORS OF MEK
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The present invention relates to compounds of formula I: in which n, R1, R2, R3a, R4 and R5 are defined in the Summary of the Invention; capable of inhibiting the activity of MEK. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of hyperproliferative diseases like cancer.
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Paragraph 0383; 0386; 0387
(2015/02/25)
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- COMPOUNDS AND COMPOSITIONS AS INHIBITORS OF MEK
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The present invention relates to compounds of formula I in which n, R1, R2, R3a, R4 and R5 are defined in the Summary of the Invention; capable of inhibiting the activity of MEK. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of hyperproliferative diseases like cancer.
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Paragraph 002490; 00250
(2015/02/25)
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- GLYCOSIDASE INHIBITORS
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Compounds of formula (I) wherein X1, X2, W, R1 to R5, L and m have the meaning according to the claims, are glucosidase inhibitors, and can be employed, inter alia, for the treatment of Alzheimer's disease.
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Page/Page column 96
(2014/10/15)
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- DIFLUOROETHYL-OXAZOLE SUBSTITUTED BRIDGED SPIRO[2.4]HEPTANE DERIVATIVES AS ALX RECEPTOR AGONISTS
-
The present invention relates to difluoroethyl-oxazole substituted bridged spiro[2.4] heptane derivatives of formula (I), wherein the substituents at the piperidine ring are in trans-arrangement, their preparation and their use as pharmaceutically active compounds.
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Page/Page column 23
(2015/01/16)
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- HEPATITIS B ANTIVIRAL AGENTS
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The present invention includes a method of inhibiting, suppressing or preventing HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of at least one compound of the invention.
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Page/Page column 223
(2013/07/05)
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- GPR 119 MODULATORS
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Compounds that modulate the activity of the G-protein-coupled receptor GPR119 and their uses in the treatment of diseases linked to the modulation of the G-protein- coupled receptor GPR119 in animals are described herein.
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Page/Page column 23
(2013/03/26)
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- FENTANYL DERIVATIVES AS PH-DEPENDENT OPIOID RECEPTOR AGONISTS
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The invention relates to fluorinated fentanyl derivatives that function as opioid receptor agonists, which activate target opioid receptors in a pH-dependent manner, and are thus selective for the receptors in inflamed (acidic) milieu; uses thereof and ph
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Page/Page column 14-15
(2013/03/26)
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- SUBSTITUTED PIPERIDINYL COMPOUNDS USEFUL AS GPR119 AGONISTS
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Substituted piperidinyl compounds of the formula I: I are disclosed as useful for treating or preventing type 2 diabetes and similar conditions. Pharmaceutically acceptable salts are included as well. The compounds are useful as agonists of the g-protein
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Page/Page column 24
(2013/05/21)
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- Bridged Spiro[2.4]heptane Ester Derivatives
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The invention relates to a method for preparing linear polymers having an amide end or having a star architecture comprising an amide core, by means of a ring opening using lactide and glycolide monomers or a lactide monomer ring in the presence of a cata
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Paragraph 0567
(2013/09/12)
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- Fentanyl derivatives as pH-dependent opioid receptor agonists
-
The invention relates to fluorinated compounds (fentanyl derivates) that function as opioid receptor agonists, which activate target opioid receptors in a pH-dependent manner, uses thereof and pharmaceutical compositions comprising said compounds.
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Paragraph 0049; 0050
(2013/03/26)
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- FLUORINATED BRIDGED SPIRO[2.4]HEPTANE DERIVATIVES AS ALX RECEPTOR AGONISTS
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The present invention relates to fluorinated bridged spiro[2.4]heptane derivatives of formula (I), wherein n and R1 are as defined in the description, their preparation and their pharmaceutically active compounds.
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Page/Page column 31
(2013/12/03)
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- BICYCLIC GPR119 MODULATORS
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The present invention relates to compounds of Formula (I) that are useful for treating, preventing and/or managing the diseases, disorders, syndromes or conditions associated with the modulation of GPR119 receptor activity. The invention also relates to the process for preparation of the compounds, pharmaceutical compositions thereof. The invention further relates to methods o f treating, preventing and/or managing diseases, disorders syndromes or conditions associated with the modulation of GPR119 receptor by using either alone or in combinations of Formula (I)
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Page/Page column 45
(2012/06/15)
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- HETEROCYCLIC-SUBSTITUTED PYRROLOPYRIDINES AND PYRROLOPYRIMIDINES AS JAK INHIBITORS
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The present invention provides heterocyclic-substituted pyrrolopyridines and pyrrolopyrimidines of Formula I: wherein X, Y, Z, L, A, R5, n, m, and r are defined above, as well as their compositions and methods of use, that modulate the activity
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Page/Page column 75
(2012/06/01)
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- 4- (5-CYANO-PYRAZOL-1-YL) -PIPERIDINE DERIVATIVES AS GPR 119 MODULATORS
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Compounds that modulate the activity of the G-protein-coupled receptor GPR119 and their uses in the treatment of diseases linked to the modulation of the G-protein- coupled receptor GPR119 in animals are described herein.
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Page/Page column 81
(2012/06/15)
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- BRIDGED SPIRO[2.4]HEPTANE ESTER DERIVATIVES
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The present invention relates to bridged spiro[2.4]heptane ester derivatives of formula (I) wherein W, Y, R1 and R2 are as defined in the description, their preparation and their use as pharmaceutically active compounds.
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Page/Page column 66
(2012/06/01)
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- 5-HT2B RECEPTOR ANTAGONISTS
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The present invention relates to novel fluorinated piperidine derivatives having antagonistic activity at the 5-HT2B receptor, pharmaceutical compositions comprising these compounds and their use as a medicine in the treatment or prevention of pulmonary arterial hypertension, pulmonary fibrosis or irritable bowel syndrome.
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Page/Page column 10
(2012/03/26)
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- SULFONAMIDES AS INHIBITORS OF BCL-2 FAMILY PROTEINS FOR THE TREATMENT OF CANCER
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The present invention includes novel compound and methods of treating a disease or disorder by antagonizing Bcl-2 family proteins, particularly compounds of Formula (I) or pharmaceutically acceptable salt thereof, as well as methods of treating a disease,
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Page/Page column 61
(2011/04/18)
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- GPR 119 MODULATORS
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Compounds of formula (I) that modulate the activity of the G-protein-coupled receptor GPR119 and their uses in the treatment of diseases linked to the modulation of the G-protein-coupled receptor GPR119 in animals are described herein.
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Page/Page column 38
(2011/04/24)
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- IMIDAZO-PYRAZOLES AS GPR119 INHIBITORS
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Compounds of formula (I) wherein: X is (A) or (B); Y is O or a bond; R1 is -C(O)-O-R3 or R2 is hydrogen, cyano, C1-C6 alkyl, or C3-C6 cycloalkyl; R5 is hydrogen, cyano
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Page/Page column 40
(2011/06/19)
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- Enantioselective organocatalytic α-fluorination of cyclic ketones
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The first highly enantioselective α-fluorination of ketones using organocatalysis has been accomplished. The long-standing problem of enantioselective ketone α-fluorination via enamine activation has been overcome via high-throughput evaluation of a new library of amine catalysts. The optimal system, a primary amine functionalized Cinchona alkaloid, allows the direct and asymmetric α-fluorination of a variety of carbo- and heterocyclic substrates. Furthermore, this protocol also provides diastereo-, regio-, and chemoselective catalyst control in fluorinations involving complex carbonyl systems.
- Kwiatkowski, Piotr,Beeson, Teresa D.,Conrad, Jay C.,MacMillan, David W. C.
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supporting information; experimental part
p. 1738 - 1741
(2011/04/17)
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- Exploration of a new series of PAR1 antagonists
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Two series of new PAR1 antagonists have been identified. The first incorporates a cinnamoylpiperidine motif and the second a cinnamoylpyridine pattern. The synthesis, biological activity and structure-activity relationship of these compounds are presented. In each series, one analog showed potent in vivo antithrombotic activity in a rat AV shunt model, with up to 53% inhibition at 1.25 mpk iv for compound 30.
- Planty, Bruno,Pujol, Chantal,Lamothe, Marie,Maraval, Catherine,Horn, Clemens,Grand, Bruno Le,Perez, Michel
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scheme or table
p. 1735 - 1739
(2010/07/08)
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- GPR 119 MODULATORS
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Compounds of Formula (I) that modulate the activity of the G -protein-coupled receptor GPFM 19 and their uses in the treatment of diseases linked to the modulation of the G-protein-coupled receptor GPR119 in animals are described herein.
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Page/Page column 65
(2010/11/18)
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- 2′ Biaryl amides as novel and subtype selective M1 agonists. Part II: Further optimization and profiling
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Further optimization of the biaryl amide series via extensively exploring structure-activity relationships resulted in potent and subtype selective M 1 agonists exemplified by compounds 9a and 9j with good rat PK properties including CNS penetration. Synthesis, structure-activity relationships, subtype selectivity for M1 over M2-5, and DMPK properties of these novel compounds are described.
- Budzik, Brian,Garzya, Vincenzo,Shi, Dongchuan,Walker, Graham,Lauchart, Yann,Lucas, Adam J.,Rivero, Ralph A.,Langmead, Christopher J.,Watson, Jeannette,Wu, Zining,Forbes, Ian T.,Jin, Jian
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supporting information; scheme or table
p. 3545 - 3549
(2010/08/22)
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- 5-Quinoline derivatives having an anti-bacterial activity
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The present invention describes novel anti-bacterial compounds of the formula (I). These compounds are, amongst others, of interest as inhibitors of DNA gyrase and topoisomerases, for example of topoisomerase II and IV.
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Page/Page column 22
(2010/12/31)
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- THIENOPYRIMIDIENE DERIVATIVES AS PI3K INHIBITORS
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Thienopyrimidines of formula (I) wherein W and R1 to R4 are as defined in the claims, and the pharmaceutically acceptable salts thereof are inhibitors of PI3K and are selective for the p110δ isoform, which is a class Ia PI3 kinase, over both other class Ia and class Ib kinases. The compounds may be used to treat diseases and disorders arising from abnormal cell growth, function or behaviour associated with PI3 kinase such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders.
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Page/Page column 83
(2009/05/28)
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- HEDGEHOG PATHWAY ANTAGONISTS AND THERAPEUTIC APPLICATIONS THEREOF
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Heterocyclic compounds that modulate the hedgehog signaling pathway, pharmaceutical composition thereof and their therapeutic applications.
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Page/Page column 65; 21
(2009/07/17)
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- IMIDAZO[1,2-A]PYRIDINE COMPOUNDS AS RECEPTOR TYROSINE KINASE INHIBITORS
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Compounds of Formula I: in which A, B, R1, R1a, R2, R3, R4, R5 R6, R7 and R8 have the meanings given in the specification, are receptor tyrosine inhibitors useful in the treatment of diseases mediated by class 3 and class 5 receptor tyrosine kinases. Particular compounds of this invention have also been found to be inhibitors of Pim-1.
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Page/Page column 40
(2008/12/04)
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- 2-QUINOLINONE AND 2-QUINOXALINONE- DERIVATIVES AND THEIR USE AS ANTIBACTERIAL AGENTS
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The present invention relates to compounds of Formula (I) : and pharmaceutically acceptable salts thereof, to their use in the treatment of bacterial infections, and to their methods of preparation.
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Page/Page column 96
(2008/12/06)
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- Substituted indole compounds having NOS inhibitory activity
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The present invention features inhibitors of nitric oxide synthase (NOS), particularly those that selectively inhibit neuronal nitric oxide synthase (nNOS) in preference to other NOS isoforms. The NOS inhibitors of the invention, alone or in combination w
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Page/Page column 74; 75
(2010/11/24)
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- 3-Fluoropiperidines and N-methyl-3-fluoropiperidinium salts: The persistence of axial fluorine
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It has previously been shown that the fluorine atom in N-protonated 3-fluoropiperidine salts in water strongly prefers the axial orientation in the six-membered ring chairs. In the present work we examine the proposition that the N-methyl salts are equall
- Sun, Aiming,Lankin, David C.,Hardcastle, Kenneth,Snyder, James P.
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p. 1579 - 1591
(2007/10/03)
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- NOVEL TRICYCLIC SPIROPIPERIDINES OR SPIROPYRROLIDINES
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The invention provides compounds of formula (I) wherein m, R1, n, R2, q, X, Y, Z, R3, R4, R5, R6, R7, R8, t and R9 are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
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- COMPOUNDS
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Piperidine derivatives and pharmaceutically acceptable derivatives thereof useful in methods of treatment of bacterial infections in mammals, particularly in man.
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Page/Page column 27
(2008/06/13)
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- CHEMICAL COMPOUNDS
-
The present invention relates to cyclic amine derivatives of formula(I) (I)whereinR represents halogen, C1-4 alkyl, cyano, C1-4 alkoxy, trifluoromethyl or trifluoromethoxy;R1 represents hydrogen, halogen, C3-7cycloalkyl, hydroxy, nitro, cyano or C1-4 alkyl optionally substituted by halogen, cyano or C1-4 alkoxy;R2 represents hydrogen or C1-4 alkyl;R3 and R4 independently represent hydrogen, cyano, C1-4 alkyl or R3 together with R4 represents C3-7 cycloalkyl;R5 represents trifluoromethyl, S(O)t C 1-4 alkyl, C1-4 alkyl, C1-4 alkoxy, trifluoromethoxy, halogen or cyano;R6 represents hydrogen or (CH2)rR7;R7 represents hydrogen, C3-7 cycloalkyl, NH(C1-4alkylOC1-4alkoxy), NH(C1-4alkyl), N(C1-4alkyl)2, OC(O)NR9R8, NR8C(O)R9 or C(O)NR9R8;R9 and R8 independently represent hydrogen, C1-4 alkyl or C3-7 cycloalkyl; m represents zero or an integer from 1 to 4;n represents 1 or 2;p is zero or an integer from 1 to 3;q is an integer from 1 to 3;r is an integer from 1 to 4;t is 0, 1 or 2;provided that when m is 0, p is 2, q, r and n represent 1, R1, R2,R3, R4, R5 and R7 are hydrogen and R is chlorine, R5 is not iodine; and pharmaceutically acceptable salts and solvates thereof; process for their preparation and their use in the treatment of conditions mediated by tackykinins and/or by selective inhibition of serotonin reuptake transporter protein.
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- Synthesis and in vitro biological evaluation of fluoro-substituted-4- phenyl-1,2,3,6-tetrahydropyridines as monoamine oxidase B substrates
-
The substrate properties of three β-fluoro-4-phenyl-1,2,3,6- tetrahydropyridines related to the proneurotoxin 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine have been examined in an effort to evaluate the contribution of electronic parameters to the MAO-B
- Beeler, Aaron B.,Gadepalli, Rama Sarma V. S.,Steyn, Salome,Castagnoli Jr., Neal,Rimoldi, John M.
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p. 5229 - 5223
(2007/10/03)
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- Fluorination of 3-(3-(piperidin-1-yl)propyl)indoles and 3-(3-(piperazin- 1-yl)propyl)indoles gives selective human 5-HT(1D) receptor ligands with improved pharmacokinetic profiles
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It has previously been reported that a 3-(3-(piperazin-1- yl)propyl)indole series of 5-HT(1D) receptor ligands have pharmacokinetic advantages over the corresponding 3-(3-(piperidin-1-yl)propyl)indole series and that the reduced pK(a) of the piperazines compared to the piperidines may be one possible explanation for these differences. To investigate this proposal we have developed versatile synthetic strategies for the incorporation of fluorine into these ligands, producing novel series of 4- fluoropiperidines, 3-fluoro-4-aminopiperidines, and both piperazine and piperidine derivatives with one or two fluorines in the propyl linker. Ligands were identified which maintained high affinity and selectivity for the 5-HT(1D) receptor and showed agonist efficacy in vitro. The incorporation of fluorine was found to significantly reduce the pK(a) of the compounds, and this reduction of basicity was shown to have a dramatic, beneficial influence on oral absorption, although the effect on oral bioavailability could not always be accurately predicted.
- Van Niel, Monique B.,Collins, Ian,Beer, Margaret S.,Broughton, Howard B.,Cheng, Susan K. F.,Goodacre, Simon C.,Heald, Anne,Locker, Karen L.,MacLeod, Angus M.,Morrison, Denise,Moyes, Christopher R.,O'Connor, Desmond,Pike, Andrew,Rowley, Michael,Russell, Michael G. N.,Sohal, Baibinder,Stanton, Josephine A.,Thomas, Steven,Verrier, Hugh,Watt, Alan P.,Castro, José L.
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p. 2087 - 2104
(2007/10/03)
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- 3-fluoro-4-aminopiperidine derivatives as 5-HT receptor agonists
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A class of substituted 3-fluoro-4-aminopiperidine derivatives are selective agonists of 5-HT 1 -like receptors, being potent agonists of the human 5-HT 1D α receptor subtype whilst possessing at least a 10-fold selective affinity for the 5-HT 1D α recepto
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