- HETEROCYCLIC COMPOUNDS AS KINASE INHIBITORS
-
Heterocyclic compounds as CDK4 or CDK6 or other CDK inhibitors are provided. The compounds may find use as therapeutic agents for the treatment of diseases and may find particular use in oncology.
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Paragraph 0414
(2021/01/23)
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- BENZO[B][1,8]NAPHTHYRIDINE ACETIC ACID DERIVATIVES AND METHODS OF USE
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Compounds of Formula I or pharmaceutically acceptable salts or esters thereof capable of binding to and modulating the activity of a stimulator of interferon genes (STING) protein are provided. Methods involving compounds of Formula I as effective modulators of STING are also provided.
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Page/Page column 126
(2020/12/01)
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- 2-AMINO-N-HETEROARYL-NICOTINAMIDES AS NAV1.8 INHIBITORS
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Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are inhibitors of Nav1.8 channel activity and may be useful in the treatment, prevention, management, amelioration, control and suppression of diseases mediated by Nav1.8 channel activity. The compounds of the present invention may be useful in the treatment, prevention or management of pain disorders, cough disorders, acute itch disorders, and chronic itch disorders.
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Page/Page column 103
(2020/05/28)
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- NOVEL NICOTINAMIDE DERIVATIVES OR SALTS THEREOF
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An object of the present invention is to provide to a compound and a pharmaceutical composition, which have excellent Syk-inhibitory activity. Th e present invention provides a nicotinamide derivative represented by the follo wing formula (I) (wherein R 1 represents a halogen atom; R 2 represents a C 1-12 alkyl group, a C 2-12 alkenyl group, a C 2-12 alkynyl group, a C 3-8 cycloalkyl g roup, an aryl group, an ar-C 1-6 alkyl group or a heterocyclic group, each opti onally having at least one substituent; R 3 represents an aryl group or a hetero cyclic group each optionally having at least one substituent; and R 4 and R 5 e ach independently represent a hydrogen atom; and R 2 and R 4 may form a cyc lic amino group optionally having at least one substituent together with the ni trogen atom to which they bind) or a salt thereof, and a pharmaceutical comp osition for use in the treatment of a Syk-related disease which comprises the nicotinamide derivative or a salt thereof.
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Paragraph 0563; 0564; 0697; 0698
(2018/09/08)
-
- A scalable and safe continuous flow procedure for in-line generation of diazomethane and its precursor MNU
-
Diazomethane is a valuable C1-building block for organic synthesis. Due to its intrinsic reactivity and instability, handling of this reagent is associated with serious safety hazards. Herein we present a simple and robust continuous flow process, allowing a safe and on-demand generation of diazomethane with a productivity of 95-117 mmol h-1. The developed two-step process starts from non-hazardous N-methylurea, and generates and consumes N-methyl-N-nitrosourea (MNU) and diazomethane, thus enabling a safe and convenient scale-up to a multi-gram scale in a conventional synthesis laboratory.
- Lehmann
-
supporting information
p. 1449 - 1453
(2017/05/10)
-
- Discovery of a 1-Methyl-3,4-dihydronaphthalene-Based Sphingosine-1-Phosphate (S1P) Receptor Agonist Ceralifimod (ONO-4641). A S1P1 and S1P5 Selective Agonist for the Treatment of Autoimmune Diseases
-
The discovery of 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylic acid 13n (ceralifimod, ONO-4641), a sphingosine-1-phosphate (S1P) receptor agonist selective for S1P1 and S1P5, is described. While it has been revealed that the modulation of the S1P1 receptor is an effective way to treat autoimmune diseases such as relapsing-remitting multiple sclerosis (RRMS), it was also reported that activation of the S1P3 receptor is implicated in some undesirable effects. We carried out a structure-activity relationship (SAR) study of hit compound 6 with an amino acid moiety in the hydrophilic head region. Following identification of a lead compound with a dihydronaphthalene central core by inducing conformational constraint, optimization of the lipophilic tail region led to the discovery of 13n as a clinical candidate that exhibited >30 000-fold selectivity for S1P1 over S1P3 and was potent in a peripheral lymphocyte lowering (PLL) test in mice (ED50 = 0.029 mg/kg, 24 h after oral dosing).
- Kurata, Haruto,Kusumi, Kensuke,Otsuki, Kazuhiro,Suzuki, Ryo,Kurono, Masakuni,Komiya, Takaki,Hagiya, Hiroshi,Mizuno, Hirotaka,Shioya, Hiroki,Ono, Takeji,Takada, Yuka,Maeda, Tatsuo,Matsunaga, Norikazu,Kondo, Tetsu,Tominaga, Sachiko,Nunoya, Ken-Ici,Kiyoshi, Hidekazu,Komeno, Masaharu,Nakade, Shinji,Habashita, Hiromu
-
p. 9508 - 9530
(2017/12/26)
-
- Structure-Guided Optimization of HIV Integrase Strand Transfer Inhibitors
-
Integrase mutations can reduce the effectiveness of the first-generation FDA-approved integrase strand transfer inhibitors (INSTIs), raltegravir (RAL) and elvitegravir (EVG). The second-generation agent, dolutegravir (DTG), has enjoyed considerable clinical success; however, resistance-causing mutations that diminish the efficacy of DTG have appeared. Our current findings support and extend the substrate envelope concept that broadly effective INSTIs can be designed by filling the envelope defined by the DNA substrates. Previously, we explored 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides as an INSTI scaffold, making a limited set of derivatives, and concluded that broadly effective INSTIs can be developed using this scaffold. Herein, we report an extended investigation of 6-substituents as well the first examples of 7-substituted analogues of this scaffold. While 7-substituents are not well-tolerated, we have identified novel substituents at the 6-position that are highly effective, with the best compound (6p) retaining better efficacy against a broad panel of known INSTI resistant mutants than any analogues we have previously described.
- Zhao, Xue Zhi,Smith, Steven J.,Maskell, Daniel P.,Métifiot, Mathieu,Pye, Valerie E.,Fesen, Katherine,Marchand, Christophe,Pommier, Yves,Cherepanov, Peter,Hughes, Stephen H.,Burke, Terrence R.
-
p. 7315 - 7332
(2017/09/22)
-
- TrkA KINASE INHIBITORS, COMPOSITIONS AND METHODS THEREOF
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The present invention is directed to substituted indole compounds of formula (I) which are tropomyosin-related kinase (Trk) family protein kinase inhibitors, and hence are useful in the treatment of pain, inflammation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, adisease, disorder, injury, or malfunction relating to dysmyelination or demyelination or a disease or disorder associated with abnormal activities of nerve growth factor (NGF) receptor TrkA.
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Page/Page column 76
(2016/05/02)
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- Effects of the pyridine 3-substituent on regioselectivity in the nucleophilic aromatic substitution reaction of 3-substituted 2,6-dichloropyridines with 1-methylpiperazine studied by a chemical design strategy
-
A chemical design strategy has been used to select 3-substituted 2,6-dichloropyridines for the nucleophilic aromatic substitution reaction with 1-methylpiperazine. The aim was to study the dependency of the regioselectivity in these reactions on the character of the pyridine 3-substituent expressed by their lipophilicity (PI), size (MR), and inductive effect (Ip). Interestingly, the regioselectivity did not correlate with any of these parameters, but in a statistically significant manner with the Verloop steric parameter B1, as indicated by the p value of 0.006 (R2 = 0.45). This implies that bulky 3-substituents close to the pyridine ring induce regioselectivity towards the 6-position. Useful in practical synthesis is the different regioselectivity obtained with a carboxylic acid 3-substituent and precursors or derivatives thereof. Thus, in acetonitrile as solvent, 3-carboxylate and 3-amide substituents were preferred to obtain the 2-isomer (9:1 ratio of the 6-isomer), whereas the 3-cyano and 3-trifluoromethyl substitutents were preferred to obtain the 6-isomer (9:1 ratio of the 2-isomer). Analysis of the regioselectivity Rsel for the pyridine 2-position in the reaction of 2,6-dichloro-3-(methoxycarbonyl)pyridine with 1-methylpiperazine in 21 different solvents showed that Rsel could be predicted by the Kamlet-Taft equation: Rsel = 1.28990 + 0.03992α - 0.59417β - 0.46169π* (R2 = 0.95, p = 1.9 × 10-10). Rsel is thus mainly correlated with the ability of the solvent to function as a hydrogen-bond acceptor, as expressed by the solvatochromic β parameter. Thus, the 16:1 regioselectivity for the 2-isomer in DCM (β = 0.10) could be switched to a 2:1 selectivity for the 6-isomer in DMSO (β = 0.76). Copyright
- Bach, Peter,Marczynke, Michaela,Giordanetto, Fabrizio
-
p. 6940 - 6952
(2013/02/22)
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- NICOTINAMIDES AS JAK KINASE MODULATORS
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The present invention is directed to compounds of formula I and pharmaceutically acceptable salts, esters, and prodrugs thereof which are inhibitors of JAK kinase. The present invention is also directed to intermediates used in making such compounds, the preparation of such a compound, pharmaceutical compositions containing such a compound, methods of inhibition JAK kinase activity, methods of inhibition the platelet aggregation, and methods to prevent or treat a number of conditions mediated at least in part by JAK kinase activity, such as undesired thrombosis and Non Hodgkin's Lymphoma.
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Page/Page column 43
(2012/05/07)
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- BENZAMIDES AND NICOTINAMIDES AS SYK MODULATORS
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The present invention is directed to compounds of formula I and pharmaceutically acceptable salts, esters, and prodrugs thereof which are inhibitors of Syk kinase. The present invention is also directed to intermediates used in making such compounds, the preparation of such a compound, pharmaceutical compositions containing such a compound, methods of inhibition Syk kinase activity, methods of inhibition the platelet aggregation, and methods to prevent or treat a number of conditions mediated at least in part by Syk kinase activity, such as Non Hodgkin's Lymphoma.
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Page/Page column 142-143
(2012/05/20)
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- SUBSTITUTED PYRIDINE UREA COMPOUNDS
-
The present disclosure provides pyridine urea compounds useful in the treatment of p38 kinase mediated diseases, such as lymphoma and auto-inflammatory disease, having the structure of Formula (I): wherein R1, R2, R3, Rsu
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Page/Page column 26
(2012/06/16)
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- ANTI PARASITIC DIHYDROAZOLE COMPOUNDS AND COMPOSITIONS COMPRISING SAME
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The present invention relates to novel dihydroazole of formula (I) and salts thereof: Wherein R1, A1, A2, G, X and Y are as defined in the description, compositions thereof, processes for their preparation and their uses t
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- ANTIPARISITIC DIHYDROAZOLE COMPOUNDS AND COMPOSITIONS COMPRISING SAME
-
The present invention relates to novel dihydroazole of formula (I) and salts thereof: Wherein R1, A1, A2, G, X and Y are as defined in the description, compositions thereof, processes for their preparation and their uses t
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Page/Page column 37-38
(2011/07/06)
-
- Synthesis and cross coupling of a highly substituted 2-pyridylboronate: Application to the large scale synthesis of a mineralocorticoid antagonist
-
The large scale synthesis of functionalized 2-pyridylboronate 8 and optimization of its Suzuki-Miyaura coupling to chloropyrazoline (R)-7 to provide a scalable synthesis of mineralocorticoid antagonist (R)-1 is described.
- Boos, Charles,Bowles, Daniel M.,Cai, Cuiman,Casimiro-Garcia, Agustin,Chen, Xiangyang,Hulford, Catherine A.,Jennings, Sandra M.,Jason Kiser,Piotrowski, David W.,Sammons, Matthew,Wade, Robert A.
-
supporting information; experimental part
p. 7025 - 7029
(2012/01/05)
-
- 4, 5-DIHYDRO-LH-PYRAZOLE COMPOUNDS AND THEIR PHARMACEUTICAL USES
-
Mineralocorticoid receptor antagonists (MRa), pharmaceutical compositions containing such inhibitors and the use of such inhibitors to treat, for example, diabetic nephropathy and hypertension in mammals, including humans.
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Page/Page column 53
(2010/11/03)
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- FLUOROBORON COMPOUND HAVING AROMATIC RING OR SALT THEREOF, AND PROCESS FOR PRODUCTION OF COMPOUND HAVING CYCLIC ETHER-FUSED AROMATIC RING BY USING THE SAME
-
Provided is a fluoroboron compound which is highly safe and stable and is capable of forming a cyclic ether-fused ring by the intramolecular alkoxymethylation reaction, or a salt thereof. The compound can be synthesized by the intramolecular alkoxymethylation reaction of a fluoroboron compound represented by the formula (I) or a salt thereof in the presence of a metal catalyst. (wherein the moiety represented by the formula represents an aromatic ring; L represents a substituent such as a halogen atom; R represents a substituted or unsubstituted alkylene group having 1 or 2 carbon atoms; and M represents an alkali metal cation or the like, with the proviso that L and -R-OCH2BF3M are respectively located on contiguous carbon atoms on the aromatic ring, or in the case of a fused aromatic ring, on two carbon atoms adjacent to one carbon at the fused position).
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Page/Page column 2
(2009/06/27)
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- FUSED HETEROARYL MODULATORS OF GLUCOCORTICOID RECEPTOR, AP-1, AND/OR NF-KB ACTIVITY AND USE THEREOF
-
Novel non-steroidal compounds are provided which are useful in treating diseases or disorders associated with modulation of the glucocorticoid receptor, AP-1, and/or NF-κB activity, including metabolic and inflammatory and immune diseases or disorders, ha
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-
Page/Page column 87-88
(2009/10/09)
-
- CERTAIN CHEMICAL ENTITIES, COMPOSITIONS, AND METHODS
-
Chemical entities that modulate smooth muscle myosin and/or non-muscle myosin, and chemical entities, pharmaceutical compositions and methods of treatment of diseases and conditions associated with smooth muscle myosin and/or non-muscle myosin are described.
- -
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Page/Page column 233
(2008/06/13)
-
- NOVEL CRYSTALLINE SALT FORM OF AN ANTIDIABETIC COMPOUND
-
A novel crystalline anhydrous toluenesulfonic acid salt form of a selective PPAR gamma partial agonist which has a fused bicyclic aromatic group attached to an oxypropanoic acid moiety is stable and non-hygroscopic. The crystalline salt form is useful for
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Page/Page column 5-8
(2008/12/08)
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- ANTIDIABETIC OXAZOLIDINEDIONES AND THIAZOLIDINEDIONES
-
Pyridinyloxyphenyl and pyridinyloxybenzyl oxazolidine-2,4-diones and thiazolidine-2,4-diones are agonists or partial agonists of PPAR gamma and are useful in the treatment and control of hyperglycemia that is symptomatic of type II diabetes, as well as dy
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Page/Page column 24-25
(2008/06/13)
-
- Substituted heterocyclic compounds with CXCR3 antagonist activity
-
The present application discloses a compound, or enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrug of said compound, or pharmaceutically acceptable salts, solvates or esters of said compound, or of said prodrug, said compound having th
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Page/Page column 36
(2010/11/26)
-
- NOVEL CRYSTALLINE FORMS OF ANTIDIABETIC COMPOUNDS
-
A novel crystalline anhydrate of the free acid and a crystalline anhydrous besylate salt of a selective PPAR gamma partial agonist which has a fused bicyclic aromatic group attached to an oxypropanoic acid moiety are stable and non-hygroscopic. The compou
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Page/Page column 6-8
(2008/06/13)
-
- FUSED AROMATIC COMPOUNDS HAVING ANTI-DIABETIC ACTIVITY
-
Fused aromatic compounds of Formula (I) are PPAR gamma agonists or partial agonists and are useful in the treatment or control of type II diabetes, including hyperglycemia, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, and obes
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Page/Page column 51
(2010/11/23)
-
- NICOTINAMIDE DERIVATIVES AND THEIR USE AS THERAPEUTIC AGENTS
-
Methods of treating an SCD-mediated disease or condition in a mammal, preferably a human, are disclosed, wherein the methods comprise administering to a mammal in need thereof a compound of formula (I): where m, n, p, V, R1, R2, R3, R4, R5 and R6 are defi
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Page/Page column 47
(2010/10/19)
-
- PIPERAZINE-PIPERIDINES WITH CXCR3 ANTAGONIST ACTIVITY
-
The present application discloses a compound, or enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrug of said compound, or pharmaceutically acceptable salts, solvates or esters of said compound, or of said prodrug, said compound having th
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Page/Page column 78
(2008/06/13)
-
- AMINE-LINKED PYRIDYL AND PHENYL SUBSTITUTED PIPERAZINE-PIPERIDINES WITH CXCR3 ANTAGONIST ACTIVITY
-
The present application discloses a compound, or enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrug of said compound, or pharmaceutically acceptable salts, solvates or esters of said compound, or of said prodrug, said compound having th
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Page/Page column 133-134
(2008/06/13)
-
- AZAINDOLE DERIVATIVES AS INHIBITORS OF P38 KINASE
-
The invention is directed to methods to inhibit p38 kinase, preferably p38-α using compounds which are azaindoles wherein the azaindoles are coupled through an azacyclic linker to another cyclic moiety.
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Page/Page column 58
(2010/11/24)
-
- Nicotinamide derivatives and their use as therapeutic agents
-
Methods of treating an SCD-mediated disease or condition in a mammal, preferably a human, are disclosed, wherein the methods comprise administering to a mammal in need thereof a compound of formula (I): where m, n, p, V, R1, R2, R3, R4, R5 and R6 are defi
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-
Page/Page column 20; 22
(2008/06/13)
-
- An efficient synthesis of 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxylic acid
-
An efficient synthesis of 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxylic acid (1), a carboxylic acid moiety of a potent dopamine D2 and D3 and serotonin-3 (5-HT3) receptors antagonist, (R)-5-bromo-N-(1-ethyl-4-methyl
- Hirokawa,Horikawa,Kato
-
p. 1847 - 1853
(2007/10/03)
-
- SELECTIVITY OF NUCLEOPHILIC SUBSTITUTION ON 3-SUBSTITUTED 2,6-DICHLOROPYRIDINES WITH ALKOXIDE. PYRIDINOPHANE PREPARATION
-
Electron withdrawing groups at the 3-position of 2,6-dichloropyridines were found to assist nucleophilc displacement of 2-chloro group with alkoxide.Pyridinophanes were prepared via stepwise substitution.
- Kawato, Toshio,Newkome, George R.
-
p. 1097 - 1104
(2007/10/02)
-
- Substituted pyridinesulfonamide compounds, herbicidal composition containing them, and method of preparing these compounds
-
A substituted pyridinesulfonamide compound and a salt thereof represented by the following general formula I: group, each of R1 and R2 independently represents a hydrogen atom, an alkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, an alkoxyalkyl group, a haloalkoxyalkyl group, a cycloalkyl group, a halocycloalkyl group, an alkoxycarbonyl group, a haloalkoxycarbonyl group, a phenyl group or a halophenyl group, provided that when one of R1 and R2 represents a hydrogen atom, the other represents one of the groups excluding the hydrogen atom; R1 and R2 together with an adjacent nitrogen atom may constitute a heterocycle; Y represents, a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkylthio group, a haloalkylthio group, an alkoxyalkyl group, a haloalkoxyalkyl group, or an group (wherein each of R3 and R4 represents a hydrogen atom or an alkyl group); nrepresents 0 or an integer of l or 2; and each of X1 and X2 independently represents a methyl group, a methoxy group or an ethoxy group. The compounds of formula I are effective as herbicides for corn fields.
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-
-
- Antiemetic, psychosomatic and antipsychotic heterocyclic pyridine carboxamides
-
The present invention provides new basically substituted pyridinecarboxamides having the formula I STR1 wherein R1 represents lower alkyl and --OR1 is in the adjacent position to the carboxamide group, R2 represents lower alkyl or an ethylene radical which is attached to one of the trivalent radicals designated as A and the nitrogen atom located between it to form a 6-membered ring, A represents a divalent saturated hydrocarbon radical which encompasses at most a single ring with 5 or 6 ring members and contains not more than 7 carbon atoms and whose two linkage positions are separated by (3-m) to 4 carbon atoms, or, if R2 is an ethylene radical, represents the 1-propanyl-3-ylidene radical, if m s 1, or the 1,2,4-butane-triyl radical, if m is 0, And one of the factors m and n is 0 and the other is 1, and, if desired, the ring B is further substituted, and the acid addition salts of the compounds of the formula I. These new substances possess useful pharmacological properties, in particular antiemetic, psychosomatic and antipsychotic activity and can be used for the treatment of thought disturbances and of states of psychomotor excitation. Specific embodiments are N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2,6-dimethoxynicotinamide and the pharmaceutically acceptable acid addition salts thereof.
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