- Discovery of 4-aminoquinolines as highly selective TGFβR1 inhibitors with an attenuated MAP4K4 profile for potential applications in immuno-oncology
-
The tumor microenvironment contains high concentrations of TGFβ, a crucial immunosuppressive cytokine. TGFβ stimulates immune escape by promoting peripheral immune tolerance to avoid tumoricidal attack. Small-molecule inhibitors of TGFβR1 are a prospective method for next-generation immunotherapies. In the present study, we identified selective 4-aminoquinoline-based inhibitors of TGFβR1 through structural and rational-based design strategies. This led to the identification of compound 4i, which was found to be selective for TGFβR1 with the exception of MAP4K4 in the kinase profiling assay. The compound was then further optimized to remove MAP4K4 activity, since MAP4K4 is vital for proper T-cell function and its inhibition could exacerbate tumor immunosuppression. Optimization efforts led to compound 4s that inhibited TGFβR1 at an IC50 of 0.79 ± 0.19 nM with 2000-fold selectivity against MAP4K4. Compound 4s represents a highly selective TGFβR1 inhibitor that has potential applications in immuno-oncology.
- Frett, Brendan,Kharbanda, Anupreet,Leung, Yuet-Kin,Li, Hong-yu,Tran, Phuc,Zhang, Lingtian
-
-
- N-pyridine-4-yl-benzamide Cdc37 inhibitor as well as derivative and application thereof
-
The invention discloses an N-pyridine-4-yl-benzamide Cdc37 inhibitor with a structure as shown in a general formula (I) as well as a derivative and application thereof. The compound disclosed by the invention can inhibit Cdc37 protein and downstream custo
- -
-
Paragraph 0117-0120
(2021/05/19)
-
- UREA DERIVATIVES AS CB1 ALLOSTERIC MODULATORS
-
Heteroaryl and aliphatic analogs of diarylurea-based cannabinoid 1 receptor (CB1 R) allosteric modulators of formula (I) are described. Exemplary analogs can provide improved potencies and pharmacokinetic properties. Methods of using the analogs to treat
- -
-
Page/Page column 61; 62
(2021/01/23)
-
- NEW BENZAMIDE DERIVATIVES AS PPAR-GAMMA MODULATORS
-
The present invention relates to novel benzamides derivatives of formula (I) as modulators of PPAR-gamma receptor, to processes for their preparation, to pharmaceutical compositions comprising said compounds and to said compound for use in the treatment of pathological conditions, disorders or diseases that can improve by modulation of PPAR-gamma receptor, such as cancer; metabolic diseases, inflammatory diseases, respiratory disorders, autoimmune diseases, neurodegenerative diseases, cardiovascular diseases and renal diseases.
- -
-
Paragraph 0097-0098
(2019/06/27)
-
- Synthesis and Pharmacological Evaluation of 1-Phenyl-3-Thiophenylurea Derivatives as Cannabinoid Type-1 Receptor Allosteric Modulators
-
We previously reported diarylurea derivatives as cannabinoid type-1 receptor (CB1) allosteric modulators, which were effective in attenuating cocaine-seeking behavior. Herein, we extended the structure-activity relationships of PSNCBAM-1 (2) at the central phenyl ring directly connected to the urea moiety. Replacement with a thiophene ring led to 11 with improved or comparable potencies in calcium mobilization, [35S]GTPγS binding, and cAMP assays, whereas substitution with nonaromatic rings led to significant attenuation of the modulatory activity. These compounds had no inverse agonism in [35S]GTPγS binding, a characteristic that is often thought to contribute to adverse psychiatric effects. While 11 had good metabolic stability in rat liver microsomes, it showed modest solubility and blood-brain barrier permeability. Compound 11 showed an insignificant attenuation of cocaine seeking behavior in rats, most likely due to its limited CNS penetration, suggesting that pharmacokinetics and distribution play a role in translating the in vitro efficacy to in vivo behavior.
- Nguyen, Thuy,Gamage, Thomas F.,Decker, Ann M.,Barrus, Daniel,Langston, Tiffany L.,Li, Jun-Xu,Thomas, Brian F.,Zhang, Yanan
-
p. 9806 - 9823
(2019/11/11)
-
- C6-Selective Direct Arylation of 2-Phenylpyridine via an Activated N-methylpyridinium Salt: A Combined Experimental and Theoretical Study
-
An elegant pre-activation strategy, based on the formation of N-methylpyridinium iodide salts for C6-selective direct arylation of 2-phenylpyridines using Pd/Cu cooperative catalysis, has been developed. By this methodology, a wide range of unsymmetrical 2, 6-diarylpyridines were synthesized with high reactivity and regioselectivity as well as good functional group tolerance. In particular, challenging substrates bearing electron donating groups (EDGs), such as OMe, NMe2, were also successfully employed in this reaction. Deuterium incorporation studies revealed that the C?H bond acidity is improved significantly in N-methylpyridinium salts compared with their N-Oxide and N-iminopyridinium ylide counterparts, thus solving the long-standing problem associated with previous strategies for the synthesis of diaryl pyridines. Finally, the control experiments and DFT calculations supported a Pd-catalyzed and Cu-mediated mechanism in which a carbenoid copper species that is formed in-situ from N-methylpyridinium salts, participates in a Pd-catalyzed arylation followed by an iodide-promoted N-demethylation process. (Figure presented.).
- Yin, Changzhen,Zhong, Kangbao,Li, Wenjing,Yang, Xiao,Sun, Rui,Zhang, Chunchun,Zheng, Xueli,Yuan, Maolin,Li, Ruixiang,Lan, Yu,Fu, Haiyan,Chen, Hua
-
supporting information
p. 3990 - 3998
(2018/09/12)
-
- INHIBITORS OF BRUTON'S TYROSINE KINASE AND METHODS OF THEIR USE
-
The present disclosure is directed to compounds of Formula (I) and methods of their use and preparation, as well as compositions comprising compounds of Formula (I).
- -
-
Page/Page column 116
(2018/06/30)
-
- METHODS FOR EXTERNAL BASE-FREE SUZUKI COUPLINGS
-
The present disclosure describes a method of coupling a first aromatic compound to a second aromatic compound, the method comprising: (a) preparing a reaction mixture comprising the first aromatic compound, the second aromatic compound, a catalyst and water; the reaction mixture does not contain an external base, the reaction mixture having an initial pH of from 11 to 1; the catalyst having at least one group 10 atom; the first aromatic compound having a halogen, triflate or sulfonate substituent; the second aromatic compound having a boron-containing substituent; wherein, at least one of the first aromatic compound or the second aromatic compound includes one or more heteroatom; and (b) reacting the first aromatic compound and the second aromatic compound in the reaction mixture, the reaction mixture having a final pH following reaction of the first aromatic compound and the second aromatic compound.
- -
-
Paragraph 0042-0043
(2017/07/14)
-
- Design, synthesis and optimization of 7-substituted-pyrazolo[4,3-b]pyridine ALK5 (activin receptor-like kinase 5) inhibitors
-
A series of potent ALK5 inhibitors were designed using a SBDD approach and subsequently optimized to improve drug likeness. Starting with a 4-substituted quinoline screening hit, SAR was conducted using a ALK5 binding model to understand the binding site
- Sabat, Mark,Wang, Haixia,Scorah, Nick,Lawson, J. David,Atienza, Joy,Kamran, Ruhi,Hixon, Mark S.,Dougan, Douglas R.
-
p. 1955 - 1961
(2017/04/10)
-
- One-Pot Palladium-Catalyzed Cross-Coupling Treble of Borylation, the Suzuki Reaction and Amination
-
A methodology for a sequential palladium-catalyzed cross-coupling procedure consisting of borylation, the Suzuki reaction and amination has been developed for the assembly of molecules with multi-aryl backbones. The linchpin of this development is the meta-terarylphosphine ligand, Cy*Phine, which has been employed as an air- and moisture-stable precatalyst, Pd(Cy*Phine)2Cl2, to improve the efficiency of one-pot borylation–Suzuki reactions. Additionally, the reactivity of the Pd-Cy*Phine system could be tuned to furnish a one-pot, borylation–Suzuki reaction–amination (BSA) cross-coupling treble. The methodology successfully integrated complementary conditions for three distinctly different and modular reactions. Average yields of 74–94% could be achieved for each segment that cumulatively afforded 50–84% yield over the entire three-step sequence in a single pot. (Figure presented.).
- Jong, Howard,Eey, Stanley T.-C.,Lim, Yee Hwee,Pandey, Sangeeta,Iqbal, Nurul Azmah Bte,Yong, Fui Fong,Robins, Edward G.,Johannes, Charles W.
-
supporting information
p. 616 - 622
(2017/02/23)
-
- INHIBITORS OF BRUTON'S TYROSINE KINASE AND METHODS OF THEIR USE
-
The present disclosure is directed to compounds of formula I and methods of their use and preparation, as well as compositions comprising compounds of formula I.
- -
-
Page/Page column 567; 568
(2017/09/02)
-
- Pd-Catalyzed Suzuki coupling reactions of aryl halides containing basic nitrogen centers with arylboronic acids in water in the absence of added base
-
The Pd-catalyzed Suzuki coupling reactions of a series of aryl chlorides and aryl bromides containing basic nitrogen centers with arylboronic acids in water in the absence of added base are reported. The reactions proceed either partially or entirely under acidic conditions. After surveying twenty-two phosphorus ligands, high yields of products were obtained with aryl chlorides only when a bulky ligand, 2-(di-tert-butyl-phosphino)-1-phenyl-1H-pyrrole (cataCXiumPtB) was used. In contrast, aryl bromides produced high yields of products in the absence of both added base and added ligand. In order to explore the Suzuki coupling process entirely under acidic conditions, a series of reactions were conducted in buffered acidic media using several model substrates. 4-Chlorobenzylamine, in the presence of cataCXiumPtB, produced high yields of product at buffered pH 6.0; the yields dropped off precipitously at buffered pH 5.0 and lower. The fall-off in yield was attributed to the decomposition of the Pd-ligand complex due to the protonation of the ligand in the more acidic aqueous media. In contrast, in the absence of an added ligand, 4-amino-2-chloropyridine produced quantitative yields at buffered pH 3.5 and 4.5 while 4-amino-2-bromopyridine produced quantitative yields in a series of buffered media ranging from pH 4.5 to 1.5. These substrates are only partially protonated in acidic media and can behave as active Pd ligands in the Suzuki catalytic cycle.
- Li, Zhao,Gelbaum, Carol,Campbell, Zachary S.,Gould, Paul C.,Fisk, Jason S.,Holden, Bruce,Jaganathan, Arvind,Whiteker, Gregory T.,Pollet, Pamela,Liotta, Charles L.
-
supporting information
p. 15420 - 15432
(2017/12/15)
-
- POLYCYCLIC COMPOUNDS AS INHIBITORS OF BRUTON'S TYROSINE KINASE
-
The present disclosure is directed to compounds of Formula (I) as Bruton's kinase inhibitors and their preparation, as well as compositions comprising compounds of Formula (I).
- -
-
Page/Page column 103; 117
(2017/07/06)
-
- Palladium-Catalyzed Suzuki Reactions in Water with No Added Ligand: Effects of Reaction Scale, Temperature, pH of Aqueous Phase, and Substrate Structure
-
The heterogeneous palladium-catalyzed Suzuki reactions between model aryl bromides (4-bromoanisole, 4-bromoaniline, 4-amino-2-bromopyridine, and 2-bromopyridine) and phenylboronic acid have been successfully conducted in water with no added ligand at the 100 mL scale using 20-40 mmol of aryl bromide. The product yields associated with these substrates were optimized, and key reaction parameters affecting the yields were identified. The results clearly indicate that the reaction parameters necessary to achieve high yields are substrate-dependent. In addition, it is demonstrated that aqueous Suzuki reactions of substrates containing basic nitrogen centers can produce quantitative yields of desired products in the absence of added ligand.
- Li, Zhao,Gelbaum, Carol,Heaner, William L.,Fisk, Jason,Jaganathan, Arvind,Holden, Bruce,Pollet, Pamela,Liotta, Charles L.
-
supporting information
p. 1489 - 1499
(2016/08/30)
-
- Aqueous Suzuki Coupling Reactions of Basic Nitrogen-Containing Substrates in the Absence of Added Base and Ligand: Observation of High Yields under Acidic Conditions
-
A series of aqueous heterogeneous Suzuki coupling reactions of substrates containing basic nitrogen centers with phenylboronic acid in the absence of added base and ligand is presented. High yields of products were obtained by employing aryl bromides containing aliphatic 1°, 2°, and 3° amine substituents, and good to high yields were obtained by employing a variety of substituted bromopyridines. In the former series, the pH of the aqueous phase changed from basic to acidic during the course of the reaction, while in the latter series the aqueous phase was on the acidic side of the pH scale throughout the entire course of reaction. A mechanistic interpretation for these observations, which generally preserves the oxo palladium catalytic cycle widely accepted in the literature, is presented.
- Li, Zhao,Gelbaum, Carol,Fisk, Jason S.,Holden, Bruce,Jaganathan, Arvind,Whiteker, Gregory T.,Pollet, Pamela,Liotta, Charles L.
-
p. 8520 - 8529
(2016/09/28)
-
- The effects of CO2pressure and pH on the Suzuki coupling of basic nitrogen containing substrates
-
The Suzuki coupling reaction of basic nitrogen containing substrates (2-bromo- and 2-chloro-4-aminopyridine, and 2-bromo and 2-chloropyridine) with phenylboronic acid using Pd(TPP)2Cl2/K3PO4in acetonitrile-water
- Senter,Rumple,Medina-Ramos,Houle,Cheng,Gelbaum,Fisk,Holden,Pollet,Eckert,Liotta, Charles L.
-
supporting information
p. 7598 - 7602
(2015/02/18)
-
- Ortho-(Dimesitylboryl)phenylphosphines: Positive boryl effect in the palladium-catalyzed suzuki-miyaura coupling of 2-chloropyridines
-
Catalytic systems combining ortho-(dimesitylboryl) phenylphosphines and palladium precursors have been evaluated in the Suzuki-Miyaura couplings of chloro-N-heterocycles, in particular 2-chloro pyridines, with arylboronic acids. The Lewis basic character of the substrates does not interfere with the Lewis acidic site of the ligands, even for a substrate featuring free NH2 groups. The influence of several reaction parameters has been studied and the ortho-dimesitylboryl moiety was actually found to substantially enhance the catalytic performance. The role of this group has been examined using preformed phosphine-borane/Pd complexes and the formation of an original phosphine/h4-boratabutadiene complex has been identified as a possible deactivation pathway. Regioselective coupling of 2,6-dichloro-3-nitropyridine with phosphine-borane/Pd catalysts has also been explored, and sequential double cross-couplings were found to give a direct and efficient access to unsymmetrical 2,6-diarylpyridines.
- Malacea, Raluca,Chahdoura, Faouzi,Devillard, Marc,Saffon, Nathalie,Gomez, Montserrat,Bourissou, Didier
-
p. 2274 - 2284
(2013/10/01)
-
- Expanded heterogeneous Suzuki-Miyaura coupling reactions of aryl and heteroaryl chlorides under mild conditions
-
A mesoporous LTA zeolite (MP-LTA)-supported palladium catalyst was developed for the highly efficient Suzuki-Miyaura reaction of aryl and heteroaryl chlorides. The couplings of various aryl chlorides with arylboronic acids in aqueous ethanol were efficiently achieved in the presence of 1.0 mol% of the catalyst. Furthermore, the scope of this catalyst was extended to the coupling of heteroaryl chlorides. Regardless of the substituents, all of the coupling reactions were very clean and highly efficient under mild heating. It shows that our catalyst is one of the most powerful heterogeneous catalysts for the coupling of a wide range of aryl and heteroaryl chlorides. The catalyst could be repetitively used at least 10 times without a significant loss of its catalytic activity. Compared to mesoporous SBA-15 and MCM-41 materials, the MP-LTA support proved to be very stable and robust to prevent degradation upon reuse.
- Lee, Dong-Hwan,Choi, Minkee,Yu, Byung-Woo,Ryoo, Ryong,Taher, Abu,Hossain, Shahin,Jin, Myung-Jong
-
supporting information; experimental part
p. 2912 - 2920
(2010/04/01)
-
- A highly active catalyst for Suzuki-Miyaura cross-coupling reactions of heteroaryl compounds
-
(Chemical Equation Presented) Unprecedented activity: Catalysts derived from Pd and bulky dialkylphosphinobiaryl ligands are shown to be highly stable and active in Suzuki-Miyaura reactions of heteroaryl halides and heteroaryl boronic acids/esters (e.g., 3-or 4-pyridine, indole, and N-protected pyrrole derivatives). Furthermore, this catalyst system is not inhibited by the presence of highly basic aminopyridines or aminopyrimidines.
- Billingsley, Kelvin L.,Anderson, Kevin W.,Buchwald, Stephen L.
-
p. 3484 - 3488
(2007/10/03)
-
- Thiazolopyridine
-
The present invention relates to compounds of formula I wherein R1 and R2 are described hereinbelow. These compounds have high affinity to A2A receptors and good selectivity to A1 and A3 receptors. These compounds are useful, inter alia, in the treatment of Alzheimer's disease, depression, Parkinson's disease and ADHD.
- -
-
Page/Page column 8; 19
(2010/02/11)
-
- Direct synthesis of hetero-biaryl compounds containing an unprotected NH2 group via Suzuki-Miyaura reaction
-
Hetero-biaryl compounds were prepared via the Suzuki-Miyaura coupling reaction of hetero-aryl moieties containing an unprotected NH2 group and arylboronic acids. D-t-BPF was found to be an efficient ligand for the cross-coupling of NH2/su
- Itoh, Takahiro,Mase, Toshiaki
-
p. 3573 - 3577
(2007/10/03)
-