- COMPOUNDS AND METHODS FOR CD73 MODULATION AND INDICATIONS THEREFOR
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Disclosed are compounds of Formula I: or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer or a deuterated analog thereof, wherein R1, R2, R3, A, L, and G are as described in any of the embodiments described in this disclosure; compositions thereof; and uses thereof.
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Paragraph 0239
(2021/06/11)
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- COMPOUNDS AND METHODS FOR CD73 MODULATION AND INDICATIONS THEREFOR
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Disclosed are compounds of Formula (I): or a pharmaceutically acceptable salt, a solvate, a tautomer, a stereoisomer or a deuterated analog thereof, wherein R1, R2, R3, A, E, L, and G are as described in any of the embodiments described in this disclosure; compositions thereof; and uses thereof.
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Paragraph 0658; 0659
(2021/10/30)
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- Designing Functionally Selective Noncatechol Dopamine D1 Receptor Agonists with Potent in Vivo Antiparkinsonian Activity
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Dopamine receptors are important G protein-coupled receptors (GPCRs) with therapeutic opportunities for treating Parkinson's Disease (PD) motor and cognitive deficits. Biased D1 dopamine ligands that differentially activate G protein over β-arrestin recruitment pathways are valuable chemical tools for dissecting positive versus negative effects in drugs for PD. Here, we reveal an iterative approach toward modification of a D1-selective noncatechol scaffold critical for G protein-biased agonism. This approach provided enhanced understanding of the structural components critical for activity and signaling bias and led to the discovery of several novel compounds with useful pharmacological properties, including three highly GS-biased partial agonists. Administration of a potent, balanced, and brain-penetrant lead compound from this series results in robust antiparkinsonian effects in a rodent model of PD. This study suggests that the noncatechol ligands developed through this approach are valuable tools for probing D1 receptor signaling biology and biased agonism in models of neurologic disease.
- Martini, Michael L.,Ray, Caroline,Yu, Xufen,Liu, Jing,Pogorelov, Vladimir M.,Wetsel, William C.,Huang, Xi-Ping,McCorvy, John D.,Caron, Marc G.,Jin, Jian
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p. 4160 - 4182
(2019/09/12)
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- PYRIDAZINONES AND METHODS OF USE THEREOF
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Disclosed are compounds according to Formula (A), and related tautomers and pharmaceutical compositions. Also disclosed are therapeutic methods, e.g., of treating kidney diseases, using the compounds of Formula (A).
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Page/Page column 124
(2019/04/11)
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- One-Pot Highly Regioselective Synthesis of Indole-Fused Pyridazino[4,5- b ][1,4]benzoxazepin-4(3 H)-ones by a Smiles Rearrangement
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A simple and convenient synthesis of indole-fused pyridazino[4,5- b ][1,4]benzoxazepin-4(3 H)-ones is described. A range of 2-(1 H -indol-2-yl)phenols and 4,5-dichloropyridazin-3-ones are compatible with this reaction. A Smiles rearrangement is proposed as a key step in the highly regioselective construction of the products. The easy availability of the starting materials makes this an appealing method in organic synthesis.
- Jiang, Xiaolei,Hu, Fangdong
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supporting information
p. 1207 - 1210
(2018/03/23)
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- Melanin-Concentrating Hormone Receptor 1 Antagonists Lacking an Aliphatic Amine: Synthesis and Structure-Activity Relationships of Novel 1-(Imidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one Derivatives
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Aiming to discover melanin-concentrating hormone receptor 1 (MCHR1) antagonists with improved safety profiles, we hypothesized that the aliphatic amine employed in most antagonists reported to date could be removed if the bicyclic motif of the compound scaffold interacted with Asp123 and/or Tyr272 of MCHR1. We excluded aliphatic amines from our compound designs, with a cutoff value of pKa 8, and explored aliphatic amine-free MCHR1 antagonists in a CNS-oriented chemical space limited by four descriptors (TPSA, ClogP, MW, and HBD count). Screening of novel bicyclic motifs with high intrinsic binding affinity for MCHR1 identified the imidazo[1,2-a]pyridine ring (represented in compounds 6a and 6b), and subsequent cyclization of the central aliphatic amide linkage led to the discovery of a potent, orally bioavailable MCHR1 antagonist 4-[(4-chlorobenzyl)oxy]-1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one 10a. It exhibited low potential for hERG inhibition and phospholipidosis induction as well as sufficient brain concentration to exert antiobesity effects in diet-induced obese rats.
- Igawa, Hideyuki,Takahashi, Masashi,Kakegawa, Keiko,Kina, Asato,Ikoma, Minoru,Aida, Jumpei,Yasuma, Tsuneo,Kawata, Yayoi,Ashina, Shuntaro,Yamamoto, Syunsuke,Kundu, Mrinalkanti,Khamrai, Uttam,Hirabayashi, Hideki,Nakayama, Masaharu,Nagisa, Yasutaka,Kasai, Shizuo,Maekawa, Tsuyoshi
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supporting information
p. 1116 - 1139
(2016/02/23)
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- HETEROAROMATIC COMPOUNDS AND THEIR USE AS DOPAMINE D1 LIGANDS
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The present invention provides, in part, compounds of Formula (I): and pharmaceutically acceptable salts thereof; processes for the preparation of; intermediates used in the preparation of; and compositions containing such compounds or salts, and their uses for treating D1-mediated (or D1 -associated) disorders including, e.g., schizophrenia (e.g., its cognitive and negative symptoms), schizotypal personality disorder, cognitive impairment (e.g., cognitive impairment associated with schizophrenia, AD, PD, or pharmacotherapy therapy), ADHD, Parkinson's disease, anxiety, and depression.
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Page/Page column 110; 111
(2015/11/24)
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- HETEROAROMATIC COMPOUNDS AND THEIR USE AS DOPAMINE D1 LIGANDS
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The present invention provides, in part, compounds of Formula (I) and pharmaceutically acceptable salts thereof; processes for the preparation of; intermediates used in the preparation of; and compositions containing such compounds or salts, and their uses for treating D1-mediated (or D1 -associated) disorders including, e.g., schizophrenia (e.g., its cognitive and negative symptoms), schizotypal personality disorder, cognitive impairment (e.g., cognitive impairment associated with schizophrenia, AD, PD, or pharmacotherapy therapy), ADHD, Parkinson's disease, anxiety, and depression.
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Page/Page column 128
(2015/11/10)
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- HETEROAROMATIC COMPOUNDS AND THEIR USE AS DOPAMINE D1 LIGANDS
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The present invention provides, in part, compounds of Formula I: and pharmaceutically acceptable salts thereof; processes for the preparation of; intermediates used in the preparation of; and compositions containing such compounds or salts, and their uses for treating D1-mediated (or D1 -associated) disorders including, e.g., schizophrenia (e.g., its cognitive and negative symptoms), schizotypal personality disorder, cognitive impairment (e.g., cognitive impairment associated with schizophrenia, AD, PD, or pharmacotherapy therapy), ADHD, Parkinson's disease, anxiety, and depression.
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Page/Page column 133
(2015/11/16)
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- HETEROAROMATIC COMPOUNDS AND THEIR USE AS DOPAMINE D1 LIGANDS
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The present invention provides, in part, compounds of Formula I: and pharmaceutically acceptable salts thereof and N-oxides of the foregoing; processes for the preparation of; intermediates used in the preparation of; and compositions containing such compounds, salts or N-oxides, and their uses for treating D1-mediated (or D1-associated) disorders including, e.g., schizophrenia (e.g., its cognitive and negative symptoms), cognitive impairment (e.g., cognitive impairment associated with schizophrenia, AD, PD, or pharmacotherapy therapy), ADHD, impulsivity, compulsive gambling, overeating, autism spectrum disorder, MCI, age-related cognitive decline, dementia, RLS, Parkinson's disease, Huntington's chorea, anxiety, depression, MDD, TRD, and bipolar disorder.
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Paragraph 0384; 0385
(2014/05/20)
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- HETEROAROMATIC COMPOUNDS AND THEIR USE AS DOPAMINE D1 LIGANDS
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The present invention provides, in part, compounds of Formula I: and pharmaceutically acceptable salts thereof and N-oxides thereof; processes and intermediates for preparation of; and compositions and uses thereof. The present invention further provides D1 agonists with reduced D1R desensitization, D1 agonists with a reduced β- arrestin recruitment activity relative to Dopamine, D1 agonists interacting significantly with the Ser188 but not significantly with the Ser202 of a D1R when binding to the D1R, D1 agonists interacting less strongly with the Asp103 and interacting less strongly with the Ser198 of a D1R when binding to the D1R, and their uses.
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Page/Page column 85; 86
(2014/05/24)
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- PYRIDAZINONE GLUCOKINASE ACTIVATORS
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Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of metabolic diseases and disorders such as, for example, type II diabetes mellitus.
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Page/Page column 29; 48
(2009/10/30)
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- A thienopyridazinone-based melanin-concentrating hormone receptor 1 antagonist with potent in vivo anorectic properties
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Melanin-concentrating hormone receptor antagonists containing thieno- and a benzopyridazinone cores were designed and tested as potential anorectic agents. These ligands showed high affinity for the receptor, potent functional activity in vitro, and good oral bioavailability in rats. The thiophene analogue exhibited low iv clearance, long half-life, and high brain penetration. In obese rats, the thienopyridazinone demonstrated a dose-dependent reduction in feeding and body weight with doses between 1 and 10 mg kg-1.
- Dyck, Brian,Markison, Stacy,Zhao, Liren,Tamiya, Junko,Grey, Jonathan,Rowbottom, Martin W.,Zhang, Mingzhu,Vickers, Troy,Sorensen, Katie,Norton, Christi,Wen, Jenny,Heise, Christopher E.,Saunders, John,Conlon, Paul,Madan, Ajay,Schwarz, David,Goodfellow, Val S.
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p. 3753 - 3756
(2007/10/03)
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- Novel formation of 1,3-oxazepine heterocycles via palladium-catalyzed intramolecular coupling reaction
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The oxazepine ring systems containing pyridazinone moiety were constructed via palladium-catalyzed intramolecular coupling reaction. The best conditions for this reaction were Pd(OAc)2 as a palladium source, 1,1′-bis(diphenylphosphino)-ferrocene (DPPF) as the ligand, and K2CO3 as base at 80 °C in toluene. The products have potential applications as biological and medicinal relevant compounds.
- Ma, Chen,Liu, Shao-Jie,Xin, Liang,Falck,Shin, Dong-Soo
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p. 9002 - 9009
(2007/10/03)
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- 2- (3-AMINOPYRROLIDIN-1-YL) PYRIDINES AS MELANIN-CONCENTRATING HORMONE RECEPTOR AN TAGONISTS
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Melanin-concentrating hormone (MCH) receptor antagonists are disclosed having utility for the treatment of MCH receptor-based disorders such as obesity. The compounds of this invention have the following structure: including stereoisomers, prodrugs, and pharmaceutically acceptable salts thereof, wherein R1, R2, R5, Het, X and Cyc are as defined herein. Also disclosed are compositions containing a compound of this invention, as well as methods relating to the use thereof.
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Page/Page column 36
(2010/02/14)
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- Synthetic studies on isoquinoline derivatives with multidrug resistance (MDR) modulating activity
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Tetrahydropyridazino-1,4-oxazinoisoquinoline derivatives with multidrug Resist. (MDR) modulating activity were designed and synthesized. A key step for cyclization of 1,4-oxazine ring was developed using K2CO3 and CH3CN in one-pot. Among prepared compounds, 2-(4-fluorobenzyl)-9,10-dimethoxy-12-methyl-6,7,11b,12-tetrahydropyridazino[4', 5',5,6] [1,4]oxazine-[3,4,-a]isoquinolin-1(2H)-one (1f) exhibited significant MDR reversing activity and low toxicity, which might be as potential MDR agent.
- Ma, Chen,Cho, Su-Dong,Falck,Shin, Dong-Soo
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- Hydrazinecarboxylic acids
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Disclosed are certain 3-phenylpyridazines, compositions thereof which are herbicidal and methods of using such compositions for controlling undesired plants. Intermediates useful in preparing the 3-phenylpyridazines are disclosed.
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- 3-pyrazolyloxypyridazines, herbicidal compositions and uses thereof
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Disclosed are certain 3-pyrazolyloxypyridazines, compositions thereof which are herbicidal and methods of using such composition for controlling undesired plants. Also disclosed are mixtures of such pyridazines and acetanilide herbicides, to which mixture a safener may be added, if desired. Intermediate compounds useful in preparing the pyrazolyloxypyridazines are also disclosed.
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- 3-phenoxypyridazines, herbicidal compositions and uses thereof
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Disclosed are certain 3-phenoxypyridazines, compositions thereof which are herbicidal and methods of using such compositions for controlling undesired plants. Intermediate compounds useful in preparing the phenoxypyridazines are also disclosed.
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- A large scale synthesis of 3-chloro-5-methoxypyridazine
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A large scale synthesis of 3-chloro-5-methoxypyridazine was developed (18 moles) that relies on the protection of the pyridazinone nitrogen of 4,5-dichloro-3(2H)-pyridazinone as the tetrahydropyranyl derivative 2. The 5-chloro position of the protected pyridazinone was selectively displaced with methoxide to give 3 followed by catalytic hydrogenation of the 4-chloro group to give 4. Removal of the protecting group with acid followed by phosphorous oxychloride treatment gave the target compound 6 in good yield. This route is superior to the previously described synthesis of this compound.
- Bryant,Kunng,South
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p. 1473 - 1476
(2007/10/03)
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