- The synthesis and SAR of 2-amino-pyrrolo[2,3-d]pyrimidines: A new class of Aurora-A kinase inhibitors
-
A new class of Aurora-A inhibitors have been identified based on the 2-amino-pyrrolo[2,3-d]pyrimidine scaffold. Here, we describe the synthesis and SAR of this novel series. We report compounds which exhibit nanomolar activity in the Aurora-A biochemical
- Moriarty, Kevin J.,Koblish, Holly K.,Garrabrant, Thomas,Maisuria, Jahanvi,Khalil, Ehab,Ali, Farah,Petrounia, Ioanna P.,Crysler, Carl S.,Maroney, Anna C.,Johnson, Dana L.,Galemmo Jr., Robert A.
-
-
Read Online
- Development of the First Covalent Monopolar Spindle Kinase 1 (MPS1/TTK) Inhibitor
-
Monopolar spindle kinase 1 (MPS1/TTK) is a key element of the mitotic checkpoint and clinically evaluated as a target in the treatment of aggressive tumors such as triple-negative breast cancer. While long drug-target residence times have been suggested to be beneficial in the context of therapeutic MPS1 inhibition, no irreversible inhibitors have been reported. Here we present the design and characterization of the first irreversible covalent MPS1 inhibitor, RMS-07, targeting a poorly conserved cysteine in the kinase's hinge region. RMS-07 shows potent MPS1 inhibitory activity and selectivity against all protein kinases with an equivalent cysteine but also in a broader kinase panel. We demonstrate potent cellular target engagement and pronounced activity against various cancer cell lines. The covalent binding mode was validated by mass spectrometry and an X-ray crystal structure. This proof of MPS1 covalent ligandability may open new avenues for the design of MPS1-specific chemical probes or drugs.
- Chaikuad, Apirat,Cou?ago, Rafael M.,Da Silva Santiago, André,Dos Reis, Caio V.,Gehringer, Matthias,Gerstenecker, Stefan,Hu, Zexi,Knapp, Stefan,Kudolo, Mark,Laufer, Stefan,Massirer, Katlin B.,Mezzomo, Priscila,Schwalm, Martin P.,Serafim, Ricardo A. M.,Takarada, Jessica E.,Zender, Lars
-
supporting information
p. 3173 - 3192
(2022/02/25)
-
- Preparation method of palbociclib parent nucleus structure compound
-
The invention provides a preparation method of a palbociclib mother nucleus structure compound. The preparation method comprises the following step: preparing the palbociclib parent nucleus structurecompound as shown in a formula (I) which is described in the specification by taking cytosine or an intermediate 1 or an intermediate 2 as a starting raw material, wherein the intermediate 1 and the intermediate 2 are as described in the specification, and X is selected from halogen. The method is wide in the source of the starting material, simple in operation process, less in side reaction and high in purity, and accords with the concept of modern green industrial production.
- -
-
Paragraph 0063-0065
(2020/07/15)
-
- Preparation method for 5-bromo-2-chloro-N-cyclopentylpyrimidine-4-amine
-
The invention relates to the field of pharmaceutical synthesis, and discloses a preparation method for 5-bromo-2-chloro-N-cyclopentylpyrimidine-4-amine. The method is capable of firstly using 5-bromo-2,4-dichloropyrimidine as a raw material, and preparing the 5-bromo-2-chloro-N-cyclopentylpyrimidine-4-amine through two steps of ammonification and alkylation. The side reactions are less, the yieldand the purity are high, and the quality is stable. Cyclopentylamine is not used, so a defect that difficultly separated by-products are easily generated while the cyclopentylamine is used as an amination reagent is overcome.
- -
-
Paragraph 0133-0138; 0144-0147; 0151-0154; 0158-0161
(2020/02/08)
-
- Compound and organic electroluminescent device
-
The invention provides a compound, which is shown as a following general formula (I) or (II) in the specification, wherein, X is selected from CR 4 or N; R 1 to R 4 are respectively and independentlyselected from hydrogen, C1-C10 alkyl groups, substituted or unsubstituted C5 -C60 aryl or heteroaryl groups, the substituent of aryl or heteroaryl groups is selected from deuterium, fluorine, methyl group, methoxy group, cyano group, phenyl group, biphenyl group, naphthyl group, phenanthryl group, and substituted or unsubstituted anthracyl group, the substituent of the anthracyl group is selectedfrom the group consisting of phenyl, biphenyl, terphenyl, naphthyl, and phenanthryl; and a dotted line and Cy in the general formula (II) represent a five- or six-membered aromatic or heteroaromatic ring fused to a pyrimidine ring. The compound can be used in an organic electroluminescent device. The invention also provides an organic electroluminescent device comprising the above compound.
- -
-
Paragraph 0165; 0166; 0167; 0168
(2019/01/08)
-
- PROGNOSTIC BIOMARKERS FOR TTK INHIBITOR CHEMOTHERAPY
-
The present invention provides a method for identifying a tumor - in a human individual or in an animal - that is susceptible to treatment with a TTK inhibitor, said method comprising: a] providing a sample of a tumor; b] determining the presence of a mutated CTNNB1 gene in said tumor sample, wherein said mutation is located in exon 3 of CTNNB1 and whereby the presence of a mutated CTNNB1 gene indicates that the tumor is susceptible to treatment with a TTK inhibitor. In an alternative aspect, step b] of the above defined method is replaced by the step of determining the presence of a mutated CTNNB1 protein in said tumor sample, wherein said mutation is located in exon 3 of CTNNB1 and whereby the presence of a mutated CTNNB1 protein indicates that the tumor is susceptible to treatment with a TTK inhibitor. In a further alternative, step b] comprises determining an altered expression of a CTNNB1 regulated gene, whereby an altered expression of a CTNNB1 regulated gene indicates that the tumor is susceptible to treatment with a TTK inhibitor.
- -
-
Page/Page column 29
(2016/10/31)
-
- (5,6-DIHYDRO)PYRIMIDO[4,5-E]INDOLIZINES
-
The invention relates to a compound of Formula (I) wherein, R1 and R2 independently are selected from the group consisting of optionally substituted (6-10C)aryl and (1-5C)heteroaryl groups. The compounds can be used in pharmaceutical compositions, in particular in the treatment of cancer.
- -
-
Page/Page column 24
(2015/11/17)
-
- COMPOUNDS FOR REGULATING FAK AND/OR SRC PATHWAYS
-
The present application provides novel optionally substituted fused pyridine and pyrimidine bicyclic compounds and pharmaceutically acceptable salts thereof. Also provided are methods for preparing these compounds. These compounds are useful in co-regulating FAK and/or Src activity by administering a therapeutically effective amount of one or more of the compounds to a subject. By doing so, these compounds are effective in treating conditions associated with the dysregulation of the FAK and/or Src pathway. Advantageously, these compounds perform as dual FAK and/or Src inhibitors. A variety of conditions can be treated using these compounds and include diseases which are characterized by inflammation or abnormal cellular proliferation. In one embodiment, the disease is cancer.
- -
-
Page/Page column 170
(2015/03/28)
-
- Novel Mps1 kinase inhibitors: From purine to pyrrolopyrimidine and quinazoline leads
-
Mps1, also known as TTK, is a mitotic checkpoint protein kinase that has become a promising new target of cancer research. In an effort to improve the lead-likeness of our recent Mps1 purine lead compounds, a scaffold hopping exercise has been undertaken.
- Bursavich, Matthew G.,Dastrup, David,Shenderovich, Mark,Yager, Kraig M.,Cimbora, Daniel M.,Williams, Brandi,Kumar, D. Vijay
-
p. 6829 - 6833
(2014/01/06)
-
- HETEROCYCLIC INHIBITORS OF HISTAMINE RECEPTORS FOR THE TREATMENT OF DISEASE
-
The present invention relates to compounds and methods which may be useful as inhibitors of H4R for the treatment or prevention of inflammatory, autoimmune, allergic, and ocular diseases.
- -
-
Page/Page column 125; 126
(2011/10/05)
-
- New substituted spiro[cycloalkyl-1,3'-indo]-2'(1'H)-one derivatives and their use as p38 mitogen-activated kinase inhibitors
-
This invention is directed to new inhibitors of the p38 mitogen-activated protein kinase having the general formula (I) to processes for their preparation; to pharmaceutical compositions comprising them; and to their use in therapy.
- -
-
Page/Page column 50
(2009/10/21)
-
- HETEROCYCLIC COMPOUNDS
-
The invention relates to compounds of formula I and salts thereof wherein the substituents are as defined in the specification, processes for the preparation thereof; to pharmaceuticals containing such compounds, in particular for the use in one or more Protein tyrosine kinase mediated diseases.
- -
-
Page/Page column 30; 31
(2009/08/18)
-
- Design and synthesis of 7H-pyrrolo[2,3-d]pyrimidines as focal adhesion kinase inhibitors. Part 1
-
A series of 2-amino-9-aryl-7H-pyrrolo[2,3-d]pyrimidines were designed and synthesized to target focal adhesion kinase (FAK). A number of these pyrrolopyrimides exhibited low micromolar inhibitory activities against focal adhesion kinase, and their prelimi
- Choi, Ha-Soon,Wang, Zhicheng,Richmond, Wendy,He, Xiaohui,Yang, Kunyong,Jiang, Tao,Sim, Taebo,Karanewsky, Donald,Gu, Xiang-Ju,Zhou, Vicki,Liu, Yi,Ohmori, Osamu,Caldwell, Jeremy,Gray, Nathanael,He, Yun
-
p. 2173 - 2176
(2007/10/03)
-
- 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 di
- -
-
Page/Page column 19-20
(2008/06/13)
-
- COMPOUNDS AND COMPOSITIONS AS INDUCERS OF KERATINOCYTE DIFFERENTIATION
-
The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to induce undifferentiated keratinocytes to differentiate into terminally differentiated keratinocytes. The invention further provi
- -
-
Page/Page column 16-17
(2008/06/13)
-
- 2-CYANOPYRROLOPYRIMIDINES AND PHARMACEUTICAL USES THEREOF
-
The invention relates to pyrrolo pyrimidines of formula (I), wherein Y represents -(CH2)t-O- or -(CH2)r-S-, p is 1 or 2, r is 1, 2 or 3, t is 1, 2 or 3, or Y is -(CH2)j- or -CH=CH-, j is 1 or 2; p is 1 or 2, or Y is -(CH2)f-, f is 1 or 2, p is 1, and the further radicals and symbols have the meaning as defined herein; their preparation, their use as pharmaceuticals, pharmaceutical compositions containing them, the use of such a compound for the manufacture of a pharmaceutical preparation for the treatment of neuropathic pain and to a method for the treatment of such a disease in animals, especially in humans.
- -
-
Page/Page column 35
(2010/02/08)
-
- Synthesis of 2-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
-
1,3-Dihydro-2H-indol-2-ones (oxindoles) and 1,3-dihydro-2H-pyrrolopyridin-2-ones (azaoxindoles) are useful scaffolds that have been explored for various pharmaceutical uses. Herein we report the synthesis of 2-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin
- Cheung, Mui,Harris, Philip A.,Lackey, Karen E
-
p. 999 - 1001
(2007/10/03)
-
- Studies on the synthesis of the derivatives of 5-(dihydroxyboryl)-cytosines and -isocytosines
-
Boron derivatives of isocytosine, containing a dihydroxyboryl group in the 5-position, have been prepared for the first time. Reaction of appropriate pyrimidines with n-butyllithium and subsequent boronation at -100°C with triethylborate, followed by catalytic hydrogenation, gave hydrolytically stable N,N-dimethyl-5-(dihydroxyboryl)isocytosine 8a and N-methyl-5-(dihydroxyboryl)isocytosine 8b. Theoretical calculations suggest that the corresponding boron derivatives of cytosine cannot be obtained as thermodynamically stable compounds.
- Wojtowicz-Rajchel, Hanna,Suchowiak, Marek,Fiedorow, Piotr,Golankiewicz, Krzysztof
-
p. 841 - 845
(2007/10/03)
-
