cas 65766-32-7, 6-chloro-Nmethylpyrimidin-4-amine

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Discovery of 4,6-Disubstituted Pyrimidine Derivatives as Novel Dual VEGFR2/FGFR1 Inhibitors
Abnormalities in the FGFRs signaling pathway and VEGFR2 amplification often occur in a variety of tumors, and they synergistically promote tumor angiogenesis. Studies have shown that the up-regulation of FGF-2 is closely related to the resistance of VEGFR2 inhibitors. Activation of the FGFRs signal is a signal of compensatory angiogenesis after VEGFR2 resistance. Dual VEGFR2/FGFR1 inhibitors contribute to overcoming the resistance of VEGFR2 inhibitors and inhibit tumor growth significantly. Based on this, we designed and synthesized a series of 4,6-disubstituted pyrimidine derivatives as dual VEGFR2/FGFR1 inhibitors by the molecular hybridization strategy. 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-{6-[(4-methoxyphenyl)amino]pyrimidin-4-yl}-1-methylurea (8b) had the best inhibitory activities against VEGFR2 and FGFR1 at 10 μM (82.2 % and 101.0 %, respectively), it showed moderate antiproliferative activities against A549 and KG-1 cell lines as well. Besides, molecular docking was also carried out to study the binding mode of 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{6-[(4-methoxyphenyl)-amino]-pyrimidin-4-yl}-1-methylurea (8b) with VEGFR2 and FGFR1. These studies reveal that this series of compounds deserve further optimization.
Zhang, Jin-Yang,Xue, Wen-Jun,Wang, Min,Li, Wen,Dong, Ru,Li, Ming-Tao,Sun, Li-Ping
(2021/04/26)

A model used for fibroblast growth factor receptor inhibitors and use thereof (by machine translation)
The invention belongs to the field of medical technology, in particular of formula (I) indicated by the fibroblast growth factor receptor 4 (FGFR4) irreversible inhibitors, their pharmaceutically acceptable salt, compound solvent, polymorphs and tautomeri
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Paragraph 0110; 0113-0116

(2018/07/30)

Substituted p-chlorophenyl acetylpiperazine-containing compound as well as preparation method and application thereof
The application provides a substituted p-chlorophenyl acetylpiperazine-containing compound as well as a preparation method and application of the substituted p-chlorophenyl acetylpiperazine-containingcompound. The compound has the structure shown in the formula (I), and has better Akt1 inhibitory activity or growth inhibitory activity to MCL cell lines.
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Paragraph 0116; 0139; 0200-0203

(2019/01/06)

TAM KINASE INHIBITORS
Described herein are compounds, methods of making such compounds, compositions (e.g., pharmaceutical compositions/medicaments) that include such compounds, and methods of using such compounds to treat diseases, such as cancer.
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Paragraph 0173; 0174

(2018/11/10)

CHLOROBENZENE SUBSTITUTED AZAARYL COMPOUNDS
The invention provides a series of chlorobenzene substituted azaaryl compounds having activity in inhibiting cancer cell growth and low toxicity to normal cells. Particularly, the compounds of the invention have stronger inhibition effect on bladder cance
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Paragraph 0044; 0059

(2017/02/09)

PHENYL TETRAHYDROISOQUINOLINE COMPOUND SUBSTITUTED WITH HETEROARYL
The present invention provides a compound represented by the following formula [1] or a pharmaceutically acceptable salt thereof which has an excellent NHE3 inhibitory effect: ????????[Formula 15]?????A-Y [1] wherein A represents a structure represented b
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Paragraph 0320; 0321

(2017/06/29)

NEW TRPA1 ANTAGONISTS
The present invention relates to bicyclic heterocyclic derivatives of Forrmula (I), to the process for preparing such compounds and to their use in the treatment of a pathological condition or disease susceptible to amelioration by TRPA1 channel inhibition or antagonism.
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Page/Page column 40; 41

(2017/05/02)

NEW TRPA1 ANTAGONISTS
The present invention relates to compounds of Formula (I), to the process for preparing such compounds and to their use in the treatment of a pathological condition or disease susceptible to amelioration by TRPA1 channel inhibition or antagonism.
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Page/Page column 62; 63

(2017/08/01)

AMINE-SUBSTITUTED ARYL OR HETEROARYL COMPOUNDS AS EHMT1 AND EHMT2 INHIBITORS
The present disclosure relates to amine-substituted aryl or heteroaryl compounds. The present disclosure also relates to pharmaceutical compositions containing these compounds and methods of treating a disorder (e.g., sickle cell anemia) via inhibition of a methyltransferase enzyme selected from EHMT1 and EHMT2, by administering an amine-substituted aryl or heteroaryl compound disclosed herein or a pharmaceutical composition thereof to subjects in need thereof. The present disclosure also relates to the use of such compounds for research or other non-therapeutic purposes.
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Paragraph 0950-0953

(2017/11/10)

USES OF SALT-INDUCIBLE KINASE (SIK) INHIBITORS
The present disclosure provides methods of treating and/or preventing inflammatory bowel disease (IBD) and graft-versus-host disease (GVHD) using salt-inducible kinase (SIK) inhibitors, such as macrocyclic SIK inhibitors of Formula (I), imidazolyl SIK inh
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Paragraph 00403-00404

(2016/04/20)

FGFR4 INHIBITORS
We provide FGFR inhibitors, their salts, methods of manufacture, and methods of use.
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Page/Page column 34

(2016/10/31)

Substituted pyrimidine derivatives with Akt inhibiting activity, and preparation method and application thereof
The invention relates to novel substituted pyrimidine derivatives with Akt inhibiting activity and a preparation method thereof, a pharmaceutical composition comprising the substituted pyrimidine derivatives and salts thereof, and application of the substituted pyrimidine derivatives and salts thereof in preparing drugs for preventing and/or treating tumors. The structural formula of the compounds is disclosed as Formula (I) or Formula (II). The compounds have the advantages of novel structure, outstanding Akt inhibiting activity, high safety and low preparation cost, and have favorable application prospects in preparing antineoplastic drugs.
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Paragraph 0093; 0094; 0095; 0096

(2016/12/16)

PYRIMIDINE FGFR4 INHIBITORS
Provided herein are compounds of Formula I useful as FGFR4 inhibitors, as well as methods of use of the same.
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Page/Page column 36

(2015/05/05)

Integrating docking scores, interaction profiles and molecular descriptors to improve the accuracy of molecular docking: Toward the discovery of novel Akt1 inhibitors
A set of forty-seven Akt1 inhibitors was used for the development of molecular docking based QSAR model by using nonlinear regression. The integration of docking scores, key interaction profiles and molecular descriptors remarkably improved the accuracy of the QSAR models, providing reasonable statistical parameters (Rtrain2 = 0.948, R test2 = 0.907 and Qcv2 = 0.794). The established MD-SVR model based structural modification of new 4-amino-pyrimidine derivatives was further performed, and six compounds 56a,b and 60a-d with good prediction activities were synthesized and biologically evaluated. All of these compounds exhibited promising Akt1 inhibitory and antiproliferative activities, suggesting the reliability and good application value of the established MD-SVR model in the development of Akt1 inhibitors.
Zhan, Wenhu,Li, Daqiang,Che, Jinxin,Zhang, Liangren,Yang, Bo,Hu, Yongzhou,Liu, Tao,Dong, Xiaowu
p. 11 - 20
(2014/03/21)

Microwave-assisted synthesis of substituted pyrrolo[2,3-d]pyrimidines
A new synthetic route to triaryl pyrrolo[2,3-d]pyrimidines from common 4,6-dichloropyrimidine has been developed. The triarylated compounds are synthesized by three cross-coupling reactions using three different catalysts. The introduction of a C-6 aryl group was achieved in a two-step process under Sonogashira conditions [Pd(dba)2/CuI] followed by intramolecular cyclization, and application of Suzuki-Miyaura conditions [Pd(PPh 3)4; PdCl2(PPh3)2] led to C-4 and C-5 diarylation. This sequence allows a flexible synthetic approach to highly arylated pyrrolopyrimidines containing different aryl groups. A new synthetic route to triaryl pyrrolo[2,3-d]pyrimidines from common 4,6-dichloropyrimidine has been developed. The triarylated compounds are synthesized by three cross-coupling reactions using three different catalysts. Copyright
Prieur, Vanessa,Rubio-Martinez, Jaime,Font-Bardia, Merce,Guillaumet, Gerald,Pujol, M. Dolors
p. 1514 - 1524
(2014/03/21)

Microwave-Assisted Synthesis of Substituted Pyrrolo[2,3-d]pyrimidines
A new synthetic route to triaryl pyrrolo[2,3-d]pyrimidines from common 4,6-dichloropyrimidine has been developed. The triarylated compounds are synthesized by three cross-coupling reactions using three different catalysts. The introduction of a C-6 aryl group was achieved in a two-step process under Sonogashira conditions [Pd(dba)2/CuI] followed by intramolecular cyclization, and application of Suzuki-Miyaura conditions [Pd(PPh3)4; PdCl2(PPh3)2] led to C-4 and C-5 diarylation. This sequence allows a flexible synthetic approach to highly arylated pyrrolopyrimidines containing different aryl groups.
Prieur, Vanessa,Rubio-Martínez, Jaime,Font-Bardia, Mercè,Guillaumet, Gérald,Pujol, M. Dolors
p. 1514 - 1524
(2015/10/05)

The first example of the Fischer-Hepp type rearrangement in pyrimidines
A N-nitroso moiety can be used for the activation of chloropyrimidines toward a nucleophilic substitution reaction with amines. The subsequent treatment of the obtained products with aq H2SO4 can lead to either N-denitrosation to obtain 4,6-pyrimidinediamines or to a Fischer-Hepp type rearrangement to obtain 5-nitroso-4,6-pyrimidinediamines. It was found that the outcome of the reaction strongly depends on the structure of the pyrimidines. Activation of the pyrimidine ring by three groups with a positive mesomeric effect is crucial for the intramolecular nitroso group migration.
Cikotiene, Inga,Jonusis, Mantas,Jakubkiene, Virginija
p. 1819 - 1825
(2013/10/22)

Potent and selective aminopyrimidine-based B-Raf inhibitors with favorable physicochemical and pharmacokinetic properties
Recent clinical data provided proof-of-concept for selective B-Raf inhibitors in treatment of B-RafV600E mutant melanoma. Pyrazolopyridine-type B-Raf inhibitors previously described by the authors are potent and selective but exhibit low solubility requiring the use of amorphous dispersion-based formulation for achieving efficacious drug exposures. Through structure-based design, we discovered a new class of highly potent aminopyrimidine-based B-Raf inhibitors with improved solubility and pharmacokinetic profiles. The hinge binding moiety possesses a basic center imparting high solubility at gastric pH, addressing the dissolution limitation observed with our previous series. In our search for an optimal linker-hinge binding moiety system, amide-linked thieno[3,2-d]pyrimidine analogues 32 and 35 (G945), molecules with desirable physicochemical properties, emerged as lead compounds with strong efficacy in a B-RafV600E mutant mouse xenograft model. Synthesis, SAR, lead selection, and evaluation of key compounds in animal studies will be described.
Mathieu, Simon,Gradl, Stefan N.,Ren, Li,Wen, Zhaoyang,Aliagas, Ignacio,Gunzner-Toste, Janet,Lee, Wendy,Pulk, Rebecca,Zhao, Guiling,Alicke, Bruno,Boggs, Jason W.,Buckmelter, Alex J.,Choo, Edna F.,Dinkel, Victoria,Gloor, Susan L.,Gould, Stephen E.,Hansen, Joshua D.,Hastings, Gregg,Hatzivassiliou, Georgia,Laird, Ellen R.,Moreno, David,Ran, Yingqing,Voegtli, Walter C.,Wenglowsky, Steve,Grina, Jonas,Rudolph, Joachim
experimental part
p. 2869 - 2881
(2012/06/01)

Effect of substituent structure on pyrimidine electrophilic substitution: A rebuttal
The report about a series of unexpected and obscure effects influencing the electrophilic nitrosation of activated pyrimidines (Tetrahedron 2007, 63, 5394) was shown to be erroneous. Instead of electrophilic substitution at position 5 of the pyrimidine ring, N-nitrosation of the secondary amino group in the 4-position of the pyrimidine ring took place. Moreover it was shown that the synthetic sequence for the preparation of purines is also incorrect.
Jakubkiene, Virginija,?ikotiene, Inga
scheme or table
p. 2294 - 2298
(2012/04/10)

Discovery of 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl- piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), A potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase
A novel series of N-aryl-N′-pyrimidin-4-yl ureas has been optimized to afford potent and selective inhibitors of the fibroblast growth factor receptor tyrosine kinases 1, 2, and 3 by rationally designing the substitution pattern of the aryl ring. On the b
Guagnano, Vito,Furet, Pascal,Spanka, Carsten,Bordas, Vincent,Le Douget, Micka?l,Stamm, Christelle,Brueggen, Josef,Jensen, Michael R.,Schnell, Christian,Schmid, Herbert,Wartmann, Markus,Berghausen, Joerg,Drueckes, Peter,Zimmerlin, Alfred,Bussiere, Dirksen,Murray, Jeremy,Graus Porta, Diana
experimental part
p. 7066 - 7083
(2011/12/04)

RAF INHIBITOR COMPOUNDS AND METHODS OF USE THEREOF
Compounds of Formula I are useful for inhibition of Raf kinases. Methods of using compounds of Formula I and stereoisomers, tautomers, prodrugs and pharmaceutically acceptable salts thereof, for in vitro, in situ, and in vivo diagnosis, prevention or trea
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Page/Page column 43-44

(2011/04/14)

COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS
The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of the Abl, ARG, BCR-Abl, BRK, EphB, Fms, Fyn, KDR, c-Kit, LCK, PDGF-R, b-Raf, c-Raf, SAPK2, Src, Tie2 and TrkB kinases.
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Page/Page column 78

(2008/06/13)

Bis-aryl urea compounds and methods of use
The present invention relates to compounds of Formulas I and II, wherein A1, A2, B1, B2, Q, X1, X2, Y and R3 are defined herein, synthetic intermediates, and pharmaceutical compositions, comprising such compounds. The compounds and compositions are capable of modulating various protein kinase receptors such as Tie-2 and, therefore, influencing kinase related disease states and conditions. The compounds, for example, are capable of treating cancer caused by unregulated angiogenesis, and inflammation as well as other proliferative disorders.
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Page/Page column 39

(2010/11/26)

Effect of substituent structure on pyrimidine electrophilic substitution
In an investigation into the electrophilic nitrosation reactions of a series of 4,6-disubstituted pyrimidine derivatives, a subtle interplay between the electronic nature of the C-4 and C-6 substituents and reactivity was found where these were chloro-, mono- or disubstituted amino groups. Effects such as the presence of an aryl group or two alkyl groups on the amino moiety impede the progress of the reaction despite the presence of a second activating group.
van der Westhuyzen, Christiaan W.,Rousseau, Amanda L.,Parkinson, Christopher J.
p. 5394 - 5405
(2008/01/07)

PYRIMIDINE UREA DERIVATIVES AS KINASE INHIBITORS
The invention relates to compounds of formula (I) wherein the substituents X1, R1, R2, R3 and R4 have the meaning as set forth and explained in the description of the invention, to processes for the preparation of these compounds, pharmaceutical compositions containing same, the use thereof optionally in combination with one or more other pharmaceutically active compounds for the therapy of a disease which responds to an inhibition of protein kinase activity, and a method for the treatment of such a disease.
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Page/Page column 161; 229-230

(2008/06/13)

Composition and antiviral activity of substituted azaindoleoxoacetic piperazine derivatives
This invention provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with azaindoleoxoacetyl piperazine derivatives. These compounds possess unique antiviral activity, whether used alone or in combination with other antivirals, antiinfectives, immunomodulators or HIV entry inhibitors. More particularly, the present invention relates to the treatment of HIV and AIDS.
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Page 121

(2008/06/13)