- 4-(7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)-3,6-DIHYDROPYRIDINE-1-(2H)-CARBOXAMIDE DERIVATIVES AS LIMK AND/OR ROCK KINASES INHIBITORS FOR USE IN THE TREATMENT OF CANCER
-
The present invention concerns a compound of formula (I), in particular as LIMK and/or ROCK kinases inhibitors. The present invention also concerns these new inhibitors for use for the treatment of a condition selected in the group consisting of: cancers, virion infections, ocular hypertension and glaucoma formation, Neurofibromatosis type 1 and 2, psoriatic lesions, inflammatory diseases and hyperalgesia, central sensitization and chronic pain, reproduction erectile dysfunction, and neuronal diseases. The present description discloses the syntheses and characterisation of exemplary compounds as well as pharmacological data thereof (e.g. pages 32 to 127; examples 1 to 96; families 1 to 8; compounds; biological studies; tables). An exemplary compound is e.g. 4-(5-m ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-phenyl-3,6-dihydropyridine-1-(2H)-carboxamide (example 1; compound 5).
- -
-
Paragraph 0129-0130
(2021/12/07)
-
- ARYL AND HETEROARYL COMPOUNDS, AND THERAPEUTIC USES THEREOF IN CONDITIONS ASSOCIATED WITH THE ALTERATION OF THE ACTIVITY OF GALACTOCEREBROSIDASE
-
The application is directed to compounds of formulae (IA) and (IB): (IA) and (IB), and their salts and solvates, wherein R1a, R2a, A1, A2, A3, A4, R1b, R2b, B1, B2, B3, and G are as set forth in the specification, as well as to methods for their preparation, pharmaceutical compositions comprising the same, and use thereof for the treatment and/or prevention of, e.g., lysosomal storage diseases, such as Krabbe's disease, and α-synucleinopathies, such as Parkinson's disease.
- -
-
Page/Page column 91
(2021/06/04)
-
- Fragment-Based Discovery of a Qualified Hit Targeting the Latency-Associated Nuclear Antigen of the Oncogenic Kaposi's Sarcoma-Associated Herpesvirus/Human Herpesvirus 8
-
The latency-associated nuclear antigen (LANA) is required for latent replication and persistence of Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8. It acts via replicating and tethering the virus episome to the host chromatin and exerts other functions. We conceived a new approach for the discovery of antiviral drugs to inhibit the interaction between LANA and the viral genome. We applied a biophysical screening cascade and identified the first LANA binders from small, structurally diverse compound libraries. Starting from a fragment-sized scaffold, we generated optimized hits via fragment growing using a dedicated fluorescence-polarization-based assay as the structure-activity-relationship driver. We improved compound potency to the double-digit micromolar range. Importantly, we qualified the resulting hit through orthogonal methods employing EMSA, STD-NMR, and MST methodologies. This optimized hit provides an ideal starting point for subsequent hit-to-lead campaigns providing evident target-binding, suitable ligand efficiencies, and favorable physicochemical properties.
- Kirsch, Philine,Jakob, Valentin,Oberhausen, Kevin,Stein, Saskia C.,Cucarro, Ivano,Schulz, Thomas F.,Empting, Martin
-
-
- Fragment-Based Discovery of a Qualified Hit Targeting the Latency-Associated Nuclear Antigen of the Oncogenic Kaposi's Sarcoma-Associated Herpesvirus/Human Herpesvirus 8
-
The latency-associated nuclear antigen (LANA) is required for latent replication and persistence of Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8. It acts via replicating and tethering the virus episome to the host chromatin and exerts other functions. We conceived a new approach for the discovery of antiviral drugs to inhibit the interaction between LANA and the viral genome. We applied a biophysical screening cascade and identified the first LANA binders from small, structurally diverse compound libraries. Starting from a fragment-sized scaffold, we generated optimized hits via fragment growing using a dedicated fluorescence-polarization-based assay as the structure-activity-relationship driver. We improved compound potency to the double-digit micromolar range. Importantly, we qualified the resulting hit through orthogonal methods employing EMSA, STD-NMR, and MST methodologies. This optimized hit provides an ideal starting point for subsequent hit-to-lead campaigns providing evident target-binding, suitable ligand efficiencies, and favorable physicochemical properties.
- Kirsch, Philine,Jakob, Valentin,Oberhausen, Kevin,Stein, Saskia C.,Cucarro, Ivano,Schulz, Thomas F.,Empting, Martin
-
p. 3924 - 3939
(2019/05/06)
-
- L -(-) -Quebrachitol as a Ligand for Selective Copper(0)-Catalyzed N-Arylation of Nitrogen-Containing Heterocycles
-
l-(-)-Quebrachitol (QCT) has been found as a ligand of copper powder for selective N-arylation of nitrogen-containing heterocycles with aryl halides. Furthermore, another potential catalytic system (copper powder/QCT/t-BuOK) was successfully adapted to unactivated aryl chlorides.
- Zhou, Qifan,Du, Fangyu,Chen, Yuanguang,Fu, Yang,Sun, Wenjiao,Wu, Ying,Chen, Guoliang
-
p. 8160 - 8167
(2019/06/28)
-
- Efficient use of a surfactant for copper-catalyzed coupling reaction of arylboronic acids with imidazoles in water
-
Copper-catalyzed oxidative coupling of arylboronic acids with imidazoles in water was realized by using an amphiphilic surfactant. By choosing an appropriate surfactant, reactions of a variety of arylboronic acids proceeded smoothly under mild and base-fr
- Inamoto, Kiyofumi,Nozawa, Kanako,Kadokawa, Jun,Kondo, Yoshinori
-
experimental part
p. 7794 - 7798
(2012/09/22)
-
- Theramutein modulators
-
This invention relates to agents that are inhibitors or activators of variant forms of endogenous proteins and novel methods of identifying such variants. Of particular interest are inhibitors and activators of endogenous protein variants, encoded by genes which have mutated, which variants often arise or are at least first identified as having arisen following exposure to a chemical agent which is known to be an inhibitor or activator of the corresponding unmutated endogenous protein.
- -
-
Page/Page column 188
(2010/02/17)
-
- Highly functional group tolerance in copper-catalyzed N-arylation of nitrogen-containing heterocycles under mild conditions
-
A copper-catalyzed process has been developed for the N-arylation reaction under very mild conditions in the absence of additional ligand. This protocol could not only tolerate an array of thermally sensitive functional groups, but also achieve high chemoselectivity.
- Zhu, Liangbo,Li, Gaocan,Luo, Liang,Guo, Peng,Lan, Jingbo,You, Jingsong
-
supporting information; experimental part
p. 2200 - 2202
(2009/07/01)
-
- Per-6-amino-β-cyclodextrin as an efficient supramolecular ligand and host for Cu(I)-catalyzed N-arylation of imidazole with aryl bromides
-
(Chemical Presented) Per-6-amino-β-cyclodextrin (per-6-ABCD), acting simultaneously as a supramolecular ligand for CuI and host for aryl bromides, catalyzes N-arylation of imidazole with aryl bromides under mild conditions. This simple method proceeds with excellent yield for the coupling of imidazole with various substituted aryl bromides demonstrating good tolerance of other functionalities.
- Suresh, Palaniswamy,Pitchumani, Kasi
-
experimental part
p. 9121 - 9124
(2009/04/11)
-
- THERAMUTEIN MODULATORS
-
This invention relates to agents that are inhibitors or activators of variant forms of endogenous proteins and novel methods of identifying such variants. Of particular interest are inhibitors and activators of endogenous protein variants, encoded by genes which have mutated, which variants often arise or are at least first identified as having arisen following exposure to a chemical agent which is known to be an inhibitor or activator of the corresponding unmutated endogenous protein.
- -
-
Page/Page column 221
(2008/12/07)
-
- A concept of supported amino acid ionic liquids and their application in metal scavenging and heterogeneous catalysis
-
Novel supported task-specific ionic liquids have been developed for the first time via the ionic-pair coupling of imidazolium cation of the modified polystyrene support with L-proline. The materials have shown an efficient metal scavenging ability (e.g., Cul, Pd(OAc)2, Pd0, and IrCl3) without the aid of a nonimmobilized ionic liquid, which relies on the highly synergistic effect of the coordination with the nitrogen atom and the COO- group of the L-proline moiety, electrostatic forces, and steric protection. The resulting metal-soaked supported ionic liquids can be used as efficient heterogeneous catalysts. These materials have been investigated in the Cul-catalyzed N-arylation of nitrogen-containing heterocycles and exhibit much higher catalytic activity and a more extensive structural range of aryl and heteroaryl halides than those exhibited by free L-proline in combination with Cul both in the ionic liquid ([BMIM][BF 4]) and in the corresponding homogeneous reaction conditions. The Cul-soaked catalyst 4a-2 can be recycled for nine runs at least without any considerable loss of activity. To the best of our knowledge, our catalytic process is among the most efficient approaches to the N-arylation of imidazoles with aryl halides so far reported. Furthermore, the Pd-soaked material 4a-2 also shows higher catalytic activity in the solvent-free hydrogenation of styrene to ethylbenzene. This new concept is generally applicable and may easily be extended to other supported task-specific ionic liquids.
- Chen, Wen,Zhang, Yuanyuan,Zhu, Liangbo,Lan, Jingbo,Xie, Rugang,You, Jingsong
-
p. 13879 - 13886
(2008/09/16)
-
- Copper-catalyzed N-arylation of imidazoles and benzimidazoles
-
(Chemical Equation Presented) 4,7-Dimethoxy-1,10-phenanthroline (L1c) was found to be an efficient ligand for the copper-catalyzed N-arylation of imidazoles and benzimidazoles with both aryl iodides and bromides under mild conditions. Further optimization of the system has revealed that the addition of poly(ethylene glycol) accelerates this reaction. A variety of hindered and functionalized imidazoles, benzimidazoles, and aryl halides were transformed in good to excellent yields. Heteroaryl halides were also coupled in moderate to good yields. We also present the results obtained from a series of coupling reactions, which directly compare the use of L1c with other recently reported ligands.
- Altman, Ryan A.,Koval, Erica D.,Buchwald, Stephen L.
-
p. 6190 - 6199
(2008/02/10)
-
- Highly efficient copper-catalyzed N-arylation of nitrogen-containing heterocycles with aryl and heteroaryl halides
-
(Chemical Equation Presented) New (S)-pyrrolidinylmethylimidazole ligands (4a-c) have been readily synthesized in a straightforward fashion from least expensive starting materials in short steps in high yields. Relatively mild and highly efficient Cul-catalyzed N-arylation procedures for imidazoles with aryl and heteroaryl bromides or chlorides have been developed in the presence of 4a and Cs2CO3. It is important to note that the protocol could tolerate functional groups such as ester, nitrile, nitro, ketone, free hydroxyl, and free primary amine on the aryl halide. The protocol could also be applicable to other π-electron-rich nitrogen heterocycles (pyrrole, pyrazole, indole, benzimidazole, and triazole), affording the N-arylazoles in good to excellent yields.
- Zhu, Liangbo,Cheng, Liang,Zhang, Yuxi,Xie, Rugang,You, Jingsong
-
p. 2737 - 2743
(2008/02/05)
-
- Simple copper salt-catalyzed N-arylation of nitrogen-containing heterocycles with aryl and heteroaryl halides
-
(Chemical Equation Presented) Relatively mild and highly efficient CuI-catalyzed N-arylation procedures for nitrogen-containing heterocycles (e.g., imidazoles, benzimidazoles, pyrroles, pyrazoles, indoles, triazoles, etc.) with aryl and heteroaryl halides have been developed. The protocols can be performed easily and tolerate a number of functional groups, such as ester, nitrile, nitro, ketone, free hydroxyl, and free primary amine on the aryl halide.
- Zhu, Liangbo,Guo, Peng,Li, Gaocan,Lan, Jingbo,Xie, Rugang,You, Jingsong
-
p. 8535 - 8538
(2008/03/11)
-
- 4,7-Dimethoxy-1,10-phenanthroline: An excellent ligand for the Cu-catalyzed N-arylation of imidazoles
-
4,7-Dimethoxy-1,10-phenanthroline (L) was found to be an efficient ligand for the copper-catalyzed N-arylation of imidazole with aryl iodides and bromides under mild conditions. A variety of hindered and functionalized imidazoles and aryl halides were transformed in good to excellent yields.
- Altman, Ryan A.,Buchwald, Stephen L.
-
p. 2779 - 2782
(2007/10/03)
-
- 1, 3, 4-BENZOTRIAZEPIN-2-ONE SALTS AND THEIR USE AS CCK RECEPTOR LIGANDS
-
This invention relates to pharmaceutically acceptable salts of compounds of formula (I) wherein: W is N or N+-O-; R2 is an optionally substituted C1 to C18 hydrocarbyl group wherein up to three C atoms may optionally be replaced by N, O and/or S atoms. R3 is -(CR11R12)m-X-(CR13R14)p-R9; m is 0, 1, 2, 3 or 4; p is 0, 1 or 2; X is a bond, -CR15=CR16-, -C≡C-, C(O)NH, NHC(O), C(O)NMe, NMeC(O), C(O)O, NHC(O)NH, NHC(O)O, OC(O)NH, NH, O, CO, SO2, SO2NH, C(O)NHNH, R9 is H ; C1 to C6 alkyl ; or phenyl, naphthyl, pyridyl, benzimidazolyl, indazolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolinyl, isoindolinyl, indolyl, isoindolyl or 2-pyridonyl substituted with -L-Q. R4 is an optionally substituted C1 to C18 hydrocarbyl group wherein up to three C atoms may optionally be replaced by N, O and/or S atoms ; and Such salts are useful, for example, for the treatment of gastrin related disorders.
- -
-
-
- IMIDAZO-PYRIDINE DERIVATIVES AS LIGANDS FOR GABA RECEPTORS
-
The present invention is directed to 3-phenylimidazol[4,5-b]pyridine derivatives, that are selective ligands for GABAA receptors. These compounds are useful in the treatment and prevention of disorders of the central nervous system, including anxiety and convulsions.
- -
-
Page/Page column 14
(2008/06/13)
-
- EFFICIENT LIGAND-MEDIATED ULLMANN COUPLING OF ANILINES AND AZOLES
-
The present invention provides of method of preparing phenyl-substituted azoles. This method uses an efficient ligand-accelerated Ullmann coupling reaction of anilines with azoles. The coupling products are useful for preparing factor Xa inhibitors.
- -
-
-
- Efficient ligand-mediated ullmann coupling of anilnies and azoles
-
The present invention provides of method of preparing phenyl-substituted azoles. This method uses an efficient ligand-accelerated Ullmann coupling reaction of anilines with azoles. The coupling products are useful for preparing factor Xa inhibitors.
- -
-
-
- Preparation of Substituted N-Phenyl-4-aryl-2-pyrimidinamines as Mediator Release Inhibitors
-
The role of immunologically released mediators, such as histamine, leukotrienes, and platelet-activating factor, is well-established for asthma and other allergic disorders.Developing therapeutic agents which would block mediator release from mast cells and other relevant cell types would provide a rational approach to asthma therapy.Using human basophil as a screen, a series of 4-aryl-2-(phenylamino)pyrimidines was found which inhibited mediator release.These compounds were prepared by condensing acetyl heterocycles with dimethylformamide dimethyl acetal to form enaminones which are cyclized with aryl guanidines to give pyrimidines.After examining a large number of analogs, N--4-(2-pyridinyl)-2-pyrimidinamine (1-27) was chosen for toxicological evaluation.
- Paul, Rolf,Hallett, William A.,Hanifin, John W.,Reich, Marvin F.,Johnson, Bernard D.,et al.
-
p. 2716 - 2725
(2007/10/02)
-
- 4,5,6-substituted-N-(substituted-phenyl)-2-pyrimidinamines
-
This disclosure describes novel 4,5,6-substituted-N-(substituted-phenyl)-2-pyrimidinamines having anti-asthmatic activity.
- -
-
-
