- Synthesis and anti-HBV activity of carbocyclic nucleoside hybrids with salient features of entecavir and aristeromycin
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Modified carbocyclic nucleosides (4a-g) constituting 7-deazapurine, 4′-methyl, exocyclic double bond and 2′,3′-hydroxy were synthesized. NOE and X-ray studies of4cconfirmed the α-configuration of 4′-methyl. The anti-HBV assay demonstrated4e(IC50/sub
- Baba, Masanori,Bal, Chandralata,Jha, Ashok Kumar,Neeladri, Seshubabu,Pallaka, Renuka Sivasankar,Samunuri, Ramakrishnamraju,Toyama, Masaaki
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Read Online
- Efficient and practical synthesis of 5′-deoxytubercidin and its analogues via Vorbrggen glycosylation
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An efficient and practical synthesis of naturally occurring marine nucleosides 5′-deoxytubercidins on a 10 gram scale in good overall yield is reported. The key step was the Vorbrggen glycosylation of pyrrolo[2,3-d]pyrimidines with 5-deoxy-1,2,3-tri-O-ace
- Song, Yang,Ding, Haixin,Dou, Yanhui,Yang, Ruchun,Sun, Qi,Xiao, Qiang,Ju, Yong
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Read Online
- Efficient halogenation synthesis method of aryl halide
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The invention discloses an efficient halogenation synthesis method of aryl halide. The method comprises the following step: in the presence of a catalyst (sulfoxide or oxynitride), a halogenation reagent and a solvent, carrying out a halogenation reaction on an aromatic ring compound to obtain the aryl halide. According to the present invention, in the presence of a catalyst (sulfoxide or nitrogenoxide), a halogenation reagent and a solvent, the aromatic ring is subjected to an efficient halogenation reaction, such that the very useful aryl halide can be obtained with high activity and high selectivity; and by adopting the method disclosed by the invention, aryl halides can be efficiently synthesized, and the method has a wide application prospect in actual production.
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Paragraph 0120-0123
(2021/03/31)
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- Scaffold-hopping identifies furano[2,3-d]pyrimidine amides as potent Notum inhibitors
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The carboxylesterase Notum is a key negative regulator of the Wnt signaling pathway by mediating the depalmitoleoylation of Wnt proteins. Our objective was to discover potent small molecule inhibitors of Notum suitable for exploring the regulation of Wnt signaling in the central nervous system. Scaffold-hopping from thienopyrimidine acids 1 and 2, supported by X-ray structure determination, identified 3-methylimidazolin-4-one amides 20–24 as potent inhibitors of Notum with activity across three orthogonal assay formats (biochemical, extra-cellular, occupancy). A preferred example 24 demonstrated good stability in mouse microsomes and plasma, and cell permeability in the MDCK-MDR1 assay albeit with modest P-gp mediated efflux. Pharmacokinetic studies with 24 were performed in vivo in mouse with single oral administration of 24 showing good plasma exposure and reasonable CNS penetration. We propose that 24 is a new chemical tool suitable for cellular studies to explore the fundamental biology of Notum.
- Atkinson, Benjamin N.,Bayle, Elliott D.,Bictash, Magda,Fish, Paul V.,Frew, Sarah,Jeganathan, Fiona,Jones, E. Yvonne,Mahy, William,Monaghan, Amy,Papageorgiou, George,Sipthorp, James,Steadman, David,Svensson, Fredrik,Zhao, Yuguang
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supporting information
(2020/01/03)
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- ASK1 INHIBITING PYRROLOPYRIMIDINE AND PYRROLOPYRIDINE DERIVATIVES
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The present invention relates to pyrrolopyrimidine compounds according to Formula (I) and their use in the prophylaxis and/or treatment of pain, inflammatory conditions, cardiovascular diseases, neurodegenerative diseases, neurological diseases, complications of type I diabetes, cancer and/or fibrotic diseases. In a particular aspect, the present compounds are ASK inhibitors, particularly ASK1 inhibitors. The present invention also provides methods for the production of a compound of the invention, pharmaceutical compositions comprising a compound of the invention, the use of the compounds in the prophylaxis and/or treatment of pain, inflammatory conditions, cardiovascular diseases, neurodegenerative diseases, neurological diseases, complications of type I diabetes, cancer and/or fibrotic diseases. (Formula (I))
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Paragraph 0165
(2019/02/02)
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- Piperidine-containing pyrrolopyrimidine compound and preparation method and application thereof
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The invention discloses a piperidine-containing pyrrolopyrimidine compound and a preparation method and application thereof. The piperidine-containing pyrrolopyrimidine compound adopts the structure shown in the general formula (I) or (II). The invention
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Paragraph 0101-0105
(2018/04/01)
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- Structural optimization elaborates novel potent Akt inhibitors with promising anticancer activity
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Targeting of Akt has been validated as a well rationalized approach to cancer treatment, and represents a promising therapeutic strategy for aggressive hematologic malignancies. We describe herein an exploration of novel Akt inhibitors for cancer therapy through structural optimization of previously described 4-(piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine derivatives. Our studies yielded a novel series of pyrrolopyrimidine based phenylpiperidine carboxamides capable of potent inhibition of Akt1. Notably, 10h exhibited robust antiproliferative effects in both mantle cell lymphoma cell lines and primary patient tumor cells. Low micromolar doses of 10h induced cell apoptosis and cell cycle arrest in G2/M phase, and significantly downregulated the phosphorylation of Akt downstream effectors GSK3β and S6 in Jeko-1 cells.
- Liu, Yang,Yin, Yanzhen,Zhang, Zhen,Li, Carrie J.,Zhang, Hui,Zhang, Daoguang,Jiang, Changying,Nomie, Krystle,Zhang, Liang,Wang, Michael L.,Zhao, Guisen
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p. 543 - 551
(2017/07/12)
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- Discovery of 4-(Piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine Derivatives as Akt Inhibitors
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A series of 4-(piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine derivatives was synthesized and evaluated as Akt inhibitors by optimization of a weak screening lead (1). Typically, compounds 5q and 5t significantly improved the Akt1 inhibitory potency with IC
- Liu, Yang,Yin, Yanzhen,Zhang, Jingya,Nomie, Krystle,Zhang, Liang,Yang, Dezhi,Wang, Michael L.,Zhao, Guisen
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p. 356 - 362
(2016/05/19)
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- 4'-SUBSTITUTED NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
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Provided is 4'-substituted nucleoside derivatives of Formula I and their use in the inhibition of HIV reverse transcriptase, the prophylaxis of infection by HIV, the treatment of infection by HIV, and the prophylaxis, treatment, and delay in the onset or progression of AIDS and/or ARC.
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Page/Page column 50; 51
(2015/12/08)
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- Discovery of a 4-aryloxy-1H-pyrrolo[3,2-c]pyridine and a 1-aryloxyisoquinoline series of TRPA1 antagonists
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A series of TRPA1 antagonists is described having a 4-aryloxy-1H-pyrrolo[3,2-c]pyridine or a 1-aryloxyisoquinoline scaffold. These compounds have high ligand efficiency and favorable physical properties and may thus serve as scaffolds for further optimization.
- Hu, Yun-Jin,St.-Onge, Miguel,Laliberté, Sébastien,Vallée, Frédéric,Jin, Shujuan,Bedard, Leanne,Labrecque, Jean,Albert, Jeffrey S.
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supporting information
p. 3199 - 3203
(2015/02/19)
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- Discovery and hit-to-lead optimization of pyrrolopyrimidines as potent, state-dependent Nav1.7 antagonists
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Herein we describe the discovery, optimization, and structure-activity relationships of novel potent pyrrolopyrimidine Nav1.7 antagonists. Hit-to-lead SAR studies of the pyrrolopyrimidine core, head, and tail groups of the molecule led to the identification of pyrrolopyrimidine 48 as exceptionally potent Nav1.7 blocker with good selectivity over hERG and improved microsomal stability relative to our hit molecule and pyrazolopyrimidine 8 as a promising starting point for future optimization efforts.
- Chakka, Nagasree,Bregman, Howie,Du, Bingfan,Nguyen, Hanh Nho,Buchanan, John L.,Feric, Elma,Ligutti, Joseph,Liu, Dong,McDermott, Jeff S.,Zou, Anruo,McDonough, Stefan I.,Dimauro, Erin F.
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scheme or table
p. 2052 - 2062
(2012/04/17)
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- ASK1 INHIBITING PYRROLOPYRIMIDINE DERIVATIVES
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This invention relates to pyrrolopyrimidine derivatives of formula (I): where R1, X, p, R4, R2and R3are as defined herein, and their use as pharmaceuticals.
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Page/Page column 11; 43
(2012/06/30)
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- KINASE INHIBITORS, COMPOSITIONS COMPRISING THEM, AND METHODS OF THEIR USE
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Inhibitors of LIM kinase 2 are disclosed, along with pharmaceutical compositions comprising them and methods of their use
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Page/Page column 13
(2009/03/07)
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- LIMK2 INHIBITORS, COMPOSITIONS COMPRISING THEM, AND METHODS OF THEIR USE
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Inhibitors of LIM kinase 2 are disclosed, along with pharmaceutical compositions comprising them and methods of their use. Particular compounds are of the formula:
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Page/Page column 7
(2009/10/30)
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- Novel class of LIM-kinase 2 inhibitors for the treatment of ocular hypertension and associated glaucoma
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The discovery of a pyrrolopyrimidine class of LIM-kinase 2 (LIMK2) inhibitors is reported. These LIMK2 inhibitors show good potency in enzymatic and cellular assays and good selectivity against ROCK. After topical dosing to the eye in a steroid induced mouse model of ocular hypertension, the compounds reduce intraocular pressure to baseline levels. The compounds also increase outflow facility in a pig eye perfusion assay. These results suggest LIMK2 may be an effective target for treating ocular hypertension and associated glaucoma.
- Harrison, Bryce A.,Whitlock, N. Andrew,Voronkov, Michael V.,Almstead, Zheng Y.,Gu, Kun-Jian,Mabon, Ross,Gardyan, Michael,Hamman, Brian D.,Allen, Jason,Gopinathan, Suma,McKnight, Beth,Crist, Mike,Zhang, Yulian,Liu, Ying,Courtney, Lawrence F.,Key, Billie,Zhou, Julia,Patel, Nita,Yates, Phil W.,Liu, Qingyun,Wilson, Alan G. E.,Kimball, S. David,Crosson, Craig E.,Rice, Dennis S.,Rawlins, David B.
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supporting information; experimental part
p. 6515 - 6518
(2010/03/31)
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- SUBSTITUTED PIPERIDINES HAVING PROTEIN KINASE INHIBITING ACTIVITY
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The invention provides PKA and PKB kinase-inhibiting compounds of the formula (I); or salts, solvates, tautomers or N-oxides thereof, wherein E is a five membered heteroaryl ring containing 1, 2, 3 or 4 heteroatoms selected from O, N and S provided that no more than 1 heteroatom may be other than N; q and r are each is 0 or 1; provided that q+r is 1 or 2; T is N or a group CR5; J1-J2 is N=C(R6), (R7)C=N, (R8)N- C(O), (R8)2C-C(O), N=N or (R7)C=C(R6); Q3 is a bond or a saturated C1-3 hydrocarbon linker group optionally substituted by fluorine and hydroxy; G is NR2R3, CN or OH; m and n are each 0 or 1, provided that m+n is 1 or 2, and provided also that m or n are each 0 when the adjacent ring member of ring E is S or O; R1a and R1b are the same or different and each is hydrogen or a substituent R10; or R1a and R1b together with the carbon atoms or heteroatoms to which they are attached form a 5 or 6-membered aryl or heteroaryl ring, wherein the aryl or heteroaryl rings are optionally substituted by one or more substituents R10; and R2, R3, R4, R5, R7, R6, R8, and R10 are as defined in the claims.
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Page/Page column 115
(2008/12/06)
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- SUBSTITUTED PIPERIDINES CONTAINING A HETEROARYLAMIDE OR HETEROARYLPHENYL MOIETY
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The invention provides compounds of the formula (I) having PKA and PKB kinase inhibiting compounds of the formula (I): GP 1 J T 2 J N 4 R N H (I) or salts, solvates, tautomers or N-oxides thereof, wherein (1) GP is a group GP1: HET 2a a Q G (HNCO)f 7 (R )x N * (GP1) (2) GP is a group GP2: 10 (R )r O 2a a QG (CH2)w N V H N * (GP2) wherein HET is a monocyclic or bicyclic heterocyclic group containing up to 4 heteroatom ring members; the ring V is a monocyclic or bicyclic heteroaryl group of 5 to 10 ring members; and J1, J2, R4, R7, R10, Q2a, Ga, x, w and f are as defined in the claims
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Page/Page column 107
(2008/12/06)
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- AXL KINASE INHIBITORS
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Axl kinase inhibitory compounds are disclosed, as well as compositions and methods of using the same in the treatment of cancer and other conditions mediated by and/or associated with Axl kinase.
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Page/Page column 36
(2008/12/08)
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- 4-Piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine compounds
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Substituted 4-piperidin-1-yl-7H-pyrrolo[2,3-D]pyrimidine compounds are disclosed, as well as compositions comprising them and methods of their use for the treatment, prevention and management of various diseases and disorders.
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Page/Page column 10
(2008/06/13)
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- Monocyclic-7H-pyrrolo[2,3-d]pyrimidine compounds, compositions, and methods of use
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Novel pyrrolo[2,3-d]pyrimidine compounds useful as inhibitors of the enzyme protein tyrosine kinases such as Janus Kinase 3 as well as immunosuppressive agents for organ transplants, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, Leukemia and other autoimmune diseases are described.
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Page/Page column 25
(2008/06/13)
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- Pyrrolo[2,3-d]pyrimidine compounds
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A compound of the formula wherein R1, R2 and R3 are as defined above, which are inhibitors of the enzyme protein tyrosine kinases such as Janus Kinase 3 and as such are useful therapy as immunosuppressive agents for organ transplants, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, Leukemia and other autoimmune diseases.
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- Synthesis of certain 5-substituted 2'-deoxytubercidin derivatives
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The synthesis of the 7-deaza-2'-deoxy-adenine derivatives 7b-d with chloro, bromo, or methyl substituents at C(5) is described. Glycosylation of the 5-substituted 4-chloropyrrolo[2,3-d]pyrimidines 4b-d with 2-deoxy-3,5-di-O-(4-toluoyl)-α-D-erythro-pentofuranosyl chloride (3) gave the β-D-nucleosides 5b-d, exclusively. They were deblocked (→ 6b-d) and converted into the tubercidin derivatives 7b-d.
- Seela,Thomas
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p. 897 - 903
(2007/10/02)
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- Synthesis and Antiviral Activity of Certain 4- and 4,5-Disubstituted 7-pyrrolopyrimidines
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In vitro evaluation of a series of previously prepared tubercidin analogues revealed that certain 5-halogen-substituted analogues were active against human cytomegalovirus (HCMV) at concentrations lower than those that produced comparable cytotoxicity in
- Pudlo, Jeffrey S.,Saxena, Naveen K.,Nassiri, M. Reza,Turk, Steven R.,Drach, John C.,Townsend, Leroy B.
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p. 2086 - 2092
(2007/10/02)
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