- Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen
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WNT signaling is frequently deregulated in malignancy, particularly in colon cancer, and plays a key role in the generation and maintenance of cancer stem cells. We report the discovery and optimization of a 3,4,5-trisubstituted pyridine 9 using a high-throughput cell-based reporter assay of WNT pathway activity. We demonstrate a twisted conformation about the pyridine-piperidine bond of 9 by small-molecule X-ray crystallography. Medicinal chemistry optimization to maintain this twisted conformation, cognisant of physicochemical properties likely to maintain good cell permeability, led to 74 (CCT251545), a potent small-molecule inhibitor of WNT signaling with good oral pharmacokinetics. We demonstrate inhibition of WNT pathway activity in a solid human tumor xenograft model with evidence for tumor growth inhibition following oral dosing. This work provides a successful example of hypothesis-driven medicinal chemistry optimization from a singleton hit against a cell-based pathway assay without knowledge of the biochemical target.
- Adeniji-Popoola, Olajumoke,Aherne, Wynne,Blagg, Julian,Box, Gary,Clarke, Paul A.,Court, William,Crumpler, Simon,Dale, Trevor,De Haven Brandon, Alexis,Eccles, Suzanne A.,Esdar, Christina,Georgi, Katrin,Henley, Alan T.,Hobbs, Steve,Leuthner, Birgitta,Mallinger, Aurlie,Ortiz-Ruiz, Maria-Jesus,Pichowicz, Mark,Poeschke, Oliver,Raynaud, Florence,Rohdich, Felix,Schiemann, Kai,Smith, Elizabeth,Stieber, Frank,Stubbs, Mark,Tepoele, Robert,Thai, Ching,Valenti, Melanie,Waalboer, Dennis,Wienke, Dirk,Wood, Bozena,Workman, Paul
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Read Online
- Organocatalytic synthesis of (Het)biaryl scaffoldsviaphotoinduced intra/intermolecular C(sp2)-H arylation by 2-pyridone derivatives
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A uniqueN,O-bidentate ligand 6-oxo-1,6-dihydro-pyridone-2-carboxylic acid dimethylamide (L1) catalyzed direct C(sp2)-H (intra/intermolecular) arylation of unactivated arenes has been developed to expedite access to (Het)biaryl scaffolds under UV-irradiation at room temperature. The protocol tolerated diverse functional groups and substitution patterns, affording the target products in moderate to excellent yields. Mechanistic investigations were also carried out to better understand the reaction pathway. Furthermore, the synthetic applicability of this unified approach has been showcasedviathe construction of biologically relevant 4-quinolone, tricyclic lactam and sultam derivatives.
- Das, Tapas Kumar,Kundu, Mrinalkanti,Mondal, Biswajit,Ghosh, Prasanjit,Das, Sajal
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p. 208 - 218
(2021/12/29)
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- Five-membered heteroaromatic ring derivative as well as preparation method and application thereof
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The invention discloses a five-membered heteroaromatic ring derivative and a preparation method and application thereof, and the compound has obvious inhibition on DHODH. The blocking effect can be used as DHODH specific inhibitor, can be used for preparing medicines for treating diseases caused by fungal infection, can be used for preparing agricultural fungicides, and has wide application prospects.
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Paragraph 0144-0147
(2021/09/26)
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- Regioselective Synthesis of C3-Hydroxyarylated Pyrazoles
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Pyrazoles are ubiquitous structures in medicinal chemistry. We report the first regioselective route to C3-hydroxyarylated pyrazoles obtained through reaction of pyrazole N-oxides with arynes using mild conditions. Importantly, this method does not requir
- Brownsey, Duncan K.,Derksen, Darren J.,Gelfand, Benjamin S.,Gorobets, Evgueni,O'Sullivan, Leonie,Patel, Ketul V.,Rowley, Ben C.,Van Humbeck, Jeffrey F.
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supporting information
(2021/12/27)
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- Decarboxylative Suzuki-Miyaura coupling of (hetero)aromatic carboxylic acids using iodine as the terminal oxidant
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A novel methodology for the decarboxylative Suzuki-Miyaura-type coupling has been established. This process uses iodine or a bromine source as both the decarboxylation mediator and the terminal oxidant, thus avoiding the need for stoichiometric amounts of transition metal salts previously required. Our new protocol allows for the construction of valuable biaryl architectures through the coupling of (hetero)aromatic carboxylic acids with arylboronic acids. The scope of this decarboxylative Suzuki reaction has been greatly diversified, allowing for previously inaccessible non-ortho-substituted aromatic acids to undergo this transformation. The procedure also benefits from low catalyst loadings and the absence of stoichiometric transition metal additives.
- Quibell, Jacob M.,Duan, Guojian,Perry, Gregory J.P.,Larrosa, Igor
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supporting information
p. 6445 - 6448
(2019/06/07)
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- Visible-Light-Induced [4+2] Annulation of Thiophenes and Alkynes to Construct Benzene Rings
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The [4+2] annulation represents an elegant and versatile synthetic protocol for the construction of benzene rings. Herein, a strategy for visible-light induced [4+2] annulation of thiophenes and alkynes, to afford benzene rings, is presented. Under simple and mild reaction conditions, the ready availability and structural diversity of thiophenes and alkynes permit the facile synthesis of several substituted aromatic rings. Valuable drugs and amino acids are also well tolerated. Moreover, DFT calculations explain the high regioselectivity of the reaction.
- Song, Chunlan,Dong, Xin,Wang, Zhongjie,Liu, Kun,Chiang, Chien-Wei,Lei, Aiwen
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supporting information
p. 12206 - 12210
(2019/07/31)
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- Efficient synthesis of 4-substituted pyrazole via microwave-promoted Suzuki cross-coupling reaction
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Pyrazoles and their derivatives are important heterocycles found in nature and present in numerous bioactive compounds. In contrast to 3 or 5-aryl pyrazole, the preparation of 4-aryl pyrazole is fairly rare. Utilizing microwave irradiation, the synthesis of 4-substituted-arylpyrazole via Suzuki cross-coupling has been developed with a wide range of substrates. The remarkable advantages of this method are mild reaction conditions, simple operation, high yield, and short reaction time. Product structures were identified by MS, 1H NMR, 13C NMR, and elemental analysis.
- Cheng, Hua,Wu, Qiong-You,Han, Fan,Yang, Guang-Fu
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p. 705 - 709
(2014/06/09)
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- Enhanced heterogeneously catalyzed Suzuki-Miyaura reaction over SiliaCat Pd(0)
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The SiliaCat Pd(0) solid catalyst can be efficiently employed in the Suzuki-Miyaura cross-coupling of an ample variety of haloarenes, including economically viable chloroarenes. The catalyst can be extensively recycled without loss of activity and with low leaching of valued palladium, opening the route to widespread utilization of the method to afford high yields of biaryls devoid of contaminating by-products.
- Pandarus, Valerica,Desplantier-Giscard, Delphine,Gingras, Genevieve,Ciriminna, Rosaria,Demma Carà, Piera,Béland, Fran?ois,Pagliaro, Mario
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p. 4712 - 4716
(2013/08/23)
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- Selective methylation of NH-containing heterocycles and sulfonamides using n, N -dimethylformamide dimethylacetal based on calculated pKa Measurements
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The use of N,N-dimethylformamide dimethylacetal (DMF-DMA) as a suitable methylating agent for the methylation of NH-containing groups and heterocycles has been investigated. Use of ReactArray and calculated pKa measurements have allowed additional helpful information to be collated to determine optimum reaction conditions for a variety of substrates.
- Fairley, Gary,Hall, Catherine,Greenwood, Ryan
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p. 570 - 574
(2013/04/10)
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- A general method for Suzuki-Miyaura coupling reactions using lithium triisopropyl borates
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Conditions for the Suzuki-Miyaura coupling of lithium triisopropyl borates are reported, as well as a procedure for a one-pot lithiation, borylation, and subsequent Suzuki-Miyaura coupling of various heterocycles with aryl halides. These borate species are much more stable toward protodeboronation than the corresponding boronic acids and can conveniently be stored on benchtop at room temperature.
- Oberli, Matthias A.,Buchwald, Stephen L.
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supporting information
p. 4606 - 4609
(2012/10/30)
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- Pyrazole synthesis using a titanium-catalyzed multicomponent coupling reaction and synthesis of withasomnine
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The titanium-catalyzed 3-component coupling of an alkyne, isonitrile, and amine can be used to generate tautomers of 1,3-diimines. These diimines produced in situ undergo cyclization with hydrazine and hydrazine derivatives in a one-pot procedure to provi
- Majumder, Supriyo,Gipson, Kevin R.,Staples, Richard J.,Odom, Aaron L.
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experimental part
p. 2013 - 2023
(2011/02/28)
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- An improved synthesis of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester and its corresponding lithium hydroxy ate complex: application in Suzuki couplings
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An improved synthesis of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester via isolation of the corresponding lithium hydroxy ate complex is described. The hydroxy ate complex is available in one pot from 4-bromo-1-methyl-1H-pyrazole and triisopropyl borate, and is isolated by filtration in high yield. Furthermore, the resulting lithium hydroxy ate complex has long-term bench stability and can be employed directly in Suzuki couplings without the need for added base.
- Mullens, Peter R.
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experimental part
p. 6783 - 6786
(2010/04/27)
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- AZABICYCLOHEPTYL COMPOUNDS SUITABLE FOR TREATING DISORDERS THAT RESPOND TO MODULATION OF THE DOPAMINE D3 RECEPTOR
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The present invention relates to a compound of the formula (I) wherein R1 is H, C1-C6-alkyl which may be substituted by C3-C6-cycloalkyl, fluorinated C1-C6-alkyl, C3-C6-cycloalkyl, fluorinated C3-C6-cycloalkyl, C3-C6-alkenyl, fluorinated C3-C6-alkenyl, formyl, acetyl or propionyl; A is phenylene, pyridylene, pyrimidylene, pyrazinylene, pyridazinylene or thiophenylene, which can be substituted by one ore more substituents selected from halogen, methyl, methoxy and CF3; E is NR5 or CH2, wherein R5 is H or C1-C3-alkyl; Ar is a cyclic radical selected from the group consisting of phenyl, a 5- or 6-membered heteroaromatic radical comprising as ring members 1, 2 or 3 heteroatoms selected from N, O and S and a phenyl ring fused to a saturated or unsaturated 5- or 6-membered carbocyclic or heterocyclic ring, where the heterocyclic ring comprises as ring members 1, 2 or 3 heteroatoms selected from N, O and S and/or 1, 2 or 3 heteroatom-containing groups each independently selected from NR8, where R8 is H, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkylcarbonyl or fluorinated C1-C4-alkylcarbonyl, and where the cyclic radical Ar may carry 1, 2 or 3 substituents Ra; wherein the variable Ra has the meanings given in the claims and in the description; and physiologically tolerated acid addition salts thereof. The invention also relates to the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for the treatment of a medical disorder susceptible to treatment with a dopamine D3 receptor ligand.
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Page/Page column 95
(2008/06/13)
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- 6-AMINO(AZA)INDANE COMPOUNDS SUITABLE FOR TREATING DISORDERS THAT RESPOND TO MODULATION OF THE DOPAMINE D3 RECPTOR
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The present invention relates to 6-amino(aza)indane compound of the formula (I) Wherein Ar is phenyl or an aromatic 5-or 6-membered C-bound heteroaromatic radical, wherein Ar may carry 1 radical Ra and wherein Ar may also carry I or 2 radicals Rb; X is N or CH; E is CR6R7 or NR 3; R1 is C 1-C4-alkyl, C3-C4-cycloalkyl, C3-C4-cycloalkylmethyl, C3-C4-alkenyl, fluorinated C1-C4-alkyl, fluorinated C3-C4-cycloalkyl, fluorinated C3-C4-cycloalkylmethyl, fluorinated C3-C4-alkenyl, formyl or C1-C3-alkylcarbonyl; R1a is H or R1a and R2 or R1a and R2a together are (CH2)n with n being 1, 2, 3 or 4; R2 and R2a each independently are H, CH3, CH2F, CHF2 or CF3; R3 is H or C,-C4-alkyl; and the physiologically tolerated acid addition salts of these compounds. The invention also relates to pharmaceutical compositions comprising at least one compound of the formula (I) or a pharmaceutically acceptable salt thereof and to a method for treating a medical disorder susceptible to treatment with a dopamine D3 receptor ligand, said method comprising administering an effective amount of at least one compound of the formula (I) or a pharmaceutically acceptable salt thereof.
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Page/Page column 91
(2008/06/13)
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- ARYLSULFONYLMETHYL OR ARYLSULFONAMIDE SUBSTITUTED AROMATIC COMPOUNDS SUITABLE FOR TREATING DISORDERS THAT RESPOND TO MADULATION OF THE DOPAMINE D3 RECEPTOR
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The present invention relates to aromatic compounds of the formula (I), wherein Ar is phenyl or an aromatic 5- or 6-membered C-bound heteroaromatic radical, wherein Ar may carry 1 radical Ra and wherein Ar may also carry 1 or 2 radicals Rb; X is N or CH; Y is O, S, -CH=N-, -CH=CH- or -N=CH-; A is CH2i O or S; E is CR6R7 or NR 3; R1 is C1-C4-alkyl, C3-C4-cycloalkyl, C3-C4-cycloalkylmethyl, C3-C4-alkenyl, fluorinated C1-C4--alkyl, fluorinated C3-C4-cycloalkyl, fluorinated C3-C4-cycloalkylmethyl, fluorinated C3-C4--alkenyl, formyl or C,-C3-alkylcarbonyl; R1a is H, C2-C4-alkyl, C3-C4-cycloalkyl, C3-C4-alkenyl, fluorinated C1-C4-alkyl, fluorinated C3-C4 -cycloalkyl, or R1a and R2 together are (CH2)n with n being 2 or 3, or R1a and R2a together are (CH2)n with n being 2 or 3; R2 and R2a are independently of each other H, CH3, CH2F, CHF2 or CF3; R3 is H or C1-C4-alkyl; R6, R7 independently of each other are selected from H, C1-C2-alkyl and fluorinated C1-C2-alkyl; and the physiologically tolerated acid addition salts thereof. The invention also relates to the use of a compound of the formula I or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for the treatment of a medical disorder susceptible to treatment with a dopamine D3 receptor ligand.
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Page/Page column 90
(2008/06/13)
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- AMINOETHYLAROMATIC COMPOUNDS SUITABLE FOR TREATING DISORDERS THAT RESPOND TO MODULATION OF THE DOPAMINE D3 RECEPTOR
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The present invention relates to aromatic compounds of the formula (I) wherein Ar is phenyl or an aromatic 5-or 6-membered C-bound heteroaromatic radical, wherein Ar may carry 1 radical Ra and wherein Ar may also carry 1 or 2 radicals Rb; X is N or CH; E is CR6R7 or NR3;R1 is C1-C4-alkyl, C3-C4-cycloalkyl, C3-C4-cycloalkylmethyl, C3-C4-alkenyl, fluorinated Cl-C4--alkyl, fluorinated C3-C4-cycloalkyl, fluorinated C3-C 4-cycloalkylmethyl, fluorinated C3-C4--alkenyl, formyl or C1-C3-alkylcarbonyl; R1a is H, C1-C4-alkyl, C3-C4-cycloalkyl, C3-C4-cycloalkylmethyl, C3-C4-alkenyl, fluorinated C1--C4-alkyl, fluorinated C3-C4-cycloalkyl, fluorinated C 3-C4-cycloalkylmethyl, fluorinated C3--C 4-alkenyl, or R1a and R2 together are (CH 2)n with n being 2, 3 or 4, or R1a and R 2a together are (CH2)n with n being 2, 3 or 4; R2 and R2a are independently of each other H, C1-C4-alkyl or fluorinated C1-C 4-alkyl or R2a and R2 together are (CH 2)m with m being 1, 2, 3, 4 or 5; R3 is H or C1-C4-alkyl; R6, R7 independently of each other are selected from H, fluorine, C1-C4-alkyl and fluorinated C1-C4-alkyl or together form a moiety (CH2)p with p being 2, 3, 4 or 5; and the physiologically tolerated acid addition salts thereof. The invention also relates to the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for the treatment of a medical disorder susceptible to treatment with a dopamine D3 receptor ligand.
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Page/Page column 107
(2010/11/08)
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- AMINOMETHYL SUBSTITUTED BICYCLIC AROMATIC COMPOUNDS SUITABLE FOR TREATING DISORDERS THAT RESPOND TO MODULATION OF THE DOPAMINE D3 RECEPTOR
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The present invention relates to an aminomethyl substituted bicyclic aromatic compound of the formula (I) wherein Ar is a cyclic radical selected from the group consisting of phenyl, a 5- or 6-membered C-bound heteroaromatic radical comprising as ring mem
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Page/Page column 97
(2010/11/08)
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- HETEROCYCLIC COMPOUNDS SUITABLE FOR TREATING DISORDERS THAT RESPOND TO MODULATION OF THE DOPAMINE D3 RECEPTOR
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The invention relates to compounds of the formula (I) wherein n is 0, 1 or 2; G is CH2 or CHR3; R1 is H, C,-C6-alkyl, C,-C6-alkyl substituted by C3-C6-cycloalkyl, Cl-C6-hydroxyalkyl, fluorinated C,-C6-alkyl, C3-C6-cycloalkyl, fluorinated C3-C6-cycloalkyl, C3-C6- alkenyl, fluorinated C3-C6-alkenyl, formyl, acetyl or propionyl; R2, R3 and R4 are, independently of each other, H, methyl, fluoromethyl, difluoromethyl, or trifluoromethyl; A is phenylene, pyridylene, pyrimidylene, pyrazinylene, pyridazinylene or thiophenylene, which can be substituted by one ore more substituents selected from halogen, methyl, methoxy and CF3; E is NR5 or CH2, wherein R5 is H or C1 -C3-alkyl; Ar is a cyclic radical selected from the group consisting of phenyl, a 5- or 6- -membered heteroaromatic radical comprising as ring members 1, 2 or 3 heteroatoms selected from N, O and S and a phenyl ring fused to a saturated or unsaturated 5- or 6-membered carbocyclic or heterocyclic ring, where the heterocyclic ring comprises as ring members 1, 2 or 3 heteroatoms selected from N, O and S and/or 1, 2 or 3 heteroatom-containing groups each independently selected from NR8, where R8 is H, C1-C4-alkyl, fluorinated C1-C4-alkyl, C1-C4-alkylcarbonyl or fluorinated C1-C4-alkylcarbonyl, and where the cyclic radical Ar may carry 1, 2 or 3 substituents Ra, wherein the variable Ra has the meanings given in the claims and in the description; and physiologically tolerated acid addition salts thereof. The invention also relates to the use of a compound of the formula I or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for the treatment of a medical disorder susceptible to treatment with a dopamine D3 receptor ligand.
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Page/Page column 105-106
(2010/11/08)
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- Photochemistry of Phenyl-Substituted 1-Methylpyrazoles
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Direct irradiation of 1-methyl-4-phenylpyrazole (2) in methanol results in regiospecific phototransposition to 1-methyl-4-phenylimidazole (4) and in photocleavage to (E)/(Z)-3-(N-methylamino)-2-phenylpropenenitrile (5) and (E)/(Z)-2-(N-methylaimno)-1-phenylethenyl isocyanide (6). Deuterium labeling confirms that the phototransposition occurs via the P4 permutation pathway. Separate experiments show that 5 and 6 undergo (Z) → (E) isomerization and photocyclization to imidazole 4. Quantum yields for these reactions show that the sequence 2 → 6 → 4 is a major pathway for the P4 phototransposition of 2 → 4. Isocyanides were also detected as intermediates in the P4 phototransposition of a variety of other pyrazoles confirming the generality of this pathway in pyrazole photochemistry. Direct irradiation of 1-methyl-5-phenylpyrazole (3) resulted in the formation of 1-methyl-5-phenylimidazole (7), 1-methyl-2-phenylimidazole (8), and 1-methyl-4-phenylimidazole (4). Deuterium labeling revealed that these products were formed by P4, P6, and P7 permutation pathways, respectively. (E)/(Z)-3-(N-methylamino)-3-phenylpropenenitrile (9) and (E)/(Z)-2-(N-methylamino)-2-phenylethenyl isocyanide (10) photocleavage products were also formed in this reaction. Irradiation of 3 in furan solvent did not result in phototransposition but led to the formation of endo and exo adducts formed by Diels-Alder reaction of furan with 4-phenyl-5-methyl-1,5-diazabicyclo[2.1.0]pent-2-ene. This constitutes the first direct evidence for the formation of a 1,5-diazabicyclo[2.1.0]hex-2-ene from photolysis of a pyrazole and is consistent with the electrocyclic ring closure - heteroatom migration mechanism suggested for the P6 and P7 phototranspositions.
- Pavlik, James W.,Kebede, Naod
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p. 8325 - 8334
(2007/10/03)
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- Process for the synthesis of 1,4-disubstituted pyrazoles
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The present invention relates to a process for the synthesis of 1,4-disubstituted pyrazoles. A monosubstituted hydrazine is reacted with the product of reaction of an acetal with an N-substituted halomethyliminium salt, preferably N,N-dimethylchloromethyl
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- FORMATION OF PYRAZOLES AND OF IMIDAZOLES FROM PHENACYL KETAL HYDRAZONES OF ALDEHYDES
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The cyclization of phenacyl ethylene ketal (pek) hydrazones of glyoxals, benzaldehyde and acetaldehyde to pyrazoles is described; in the case of the hydrazones of benzaldehyde and acetaldehyde, the corresponding imidazoles are also formed.A mechanism is suggested for the formation of the imidazoles.
- Scarpetti, David,Kano, Kunio,Anselme, Jean-Pierre
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p. 1073 - 1082
(2007/10/02)
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- AN UNEXPECTED CYCLIZATION PATH TO SOME PYRAZOLES
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The treatment of ketal hydrazones of arylglyoxals (2) with 75percent sulfuric acid leads to 3-aroyl-4-phenyl-1-methylpyrazoles (6) as well as 4-phenyl-1-methylpyrazole (7) and the corresponding benzoic acids.Possible mechanisms are discussed.
- Kano, Kunio,Scarpetti, David,Anselme, Jean-Pierre
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p. 6151 - 6154
(2007/10/02)
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