- Potent MCH-1 receptor antagonists from cis-1,4-diaminocyclohexane-derived indane analogs
-
Benzimidazole and indane are the two key fragments in our potent and selective MCH-1 receptor (MCHR1) antagonists. To identify novel linkers connecting the two fragments, we investigated diamino-cycloalkane-derived analogs and discovered highly potent antagonists with cis-1,4-diaminocyclohexane as a unique spacer in this chemical class. Structural overlay suggested that cis-1-substituted-4-aminocyclohexane functions as a bioisostere of 4-substituted-piperidine and that the active conformation adopts a U-shaped orientation.
- Qian, Yimin,Conde-Knape, Karin,Erickson, Shawn D.,Falcioni, Fiorenza,Gillespie, Paul,Hakimi, Irina,Mennona, Francis,Ren, Yonglin,Salari, Hamid,So, Sung-Sau,Tilley, Jefferson W.
-
-
Read Online
- KRAS G12C Inhibitor compound and application thereof
-
The invention provides a KRAS G12C inhibitor compound and an application thereof, and particularly provides a compound as shown in a formula (I), and an optical isomer, a hydrate, a solvate or pharmaceutically acceptable salt thereof. The compound can be used as a KRAS G12C inhibitor and is used for treating diseases related to the activity or expression quantity of KRAS G12C.
- -
-
Paragraph 0141-0145
(2021/05/12)
-
- Method for preparing (1R, 3S)-3-aminocyclopentanol hydrochloride
-
The invention discloses a method for preparing (1R, 3S) 3-aminocyclopentanol hydrochloride, belongs to the field of organic chemical synthesis, and provides a process route to overcome the defects ofhigh price, difficulty in chiral control and the like in the prior art. The process route comprises the following steps: 1) oxidizing tert-butyl carbonate hydroxylamine into tert-butyl carbonate nitrosyl under the catalysis of copper chloride and 2-ethyl-2-oxazoline, then carrying out a hetero Diels-Alder reaction with cyclopentadiene in situ; 2) selectively reducing nitrogen-oxygen bonds in a zinc powder-acetic acid reaction system; 3) under the catalysis of lipase, reacting with vinyl acetate to optically and selectively realize chiral resolution; 4) reducing double bonds through palladium carbon hydrogenation; 5) under the alkaline condition of lithium hydroxide-methanol, performing deacetylation protection; and 6) removing tert-butyl carbonate protection in a hydrogen chloride isopropanol acid solution prepared from acetyl chloride and isopropanol in situ, and forming hydrochloride in situ to obtain a target product. The synthetic method has the beneficial effects that the synthetic method has the characteristics of novel and short route, high optical purity, low cost and the like.
- -
-
-
- Preparation method of (1R, 3S)-3-amino-1-cyclopentanol hydrochloride
-
The invention provides a preparation method of (1R, 3S)-3-amino-1-cyclopentanol hydrochloride. A target compound is synthesized through a chiral induction method, and specifically, cheap chiral hydroxy acid is used as a raw material and reacted with hydro
- -
-
-
- Intermediate for preparing bictegravir and preparation method thereof
-
The invention relates to the technical field of a drug, and concretely relates to an intermediate for preparing bictegravir and a preparation method thereof. The present invention provides two novel types of compounds and three routes for preparation of a compound (VI). Through substrate induction, chiral catalysis or synergistic effect of substrate induction and chiral catalysis, the stereoselectivity of a Diels-Alder reaction can be greatly improved, and a high chiral purity of a common intermediate (III) can be obtained; cut-out of N-O bond and reduction the double bond use catalytic hydrogenation, which can be environmentally friendly; the reaction conditions are mild, the yield is higher than the existing preparation method, the method is economic and effective, and is adapted to large-scale industrial production.
- -
-
Paragraph 0102; 0103; 0104; 0105
(2019/01/08)
-
- Preparation method of (1R,3S)-3-amino cyclopentanol hydrochloride
-
The invention provides a preparation method of (1R,3S)-3-amino cyclopentanol hydrochloride. A urea peroxide-trifluoroacetic anhydride system is adopted as an oxidizing agent, and a compound I is subjected to oxidation reaction so as to generate a compound II and a compound II', so that the use of an oxidizing agent with high price and big risk is avoided. Hydrogen chloride obtained through esterification reaction of isopropanol and an acyl chloride compound is subjected to de-protection reaction with a compound III, so that the process stability is good compared with the way of directly feeding hydrogen chloride and carrying out de-protection reaction on the hydrogen chloride and the compound III, the condition that the (1R,3S)-3-amino cyclopentanol hydrochloride can be smoothly separatedout from a reaction solution is ensured, and the method is convenient to operate and friendly to the work environment. In addition, the preparation method provided by the invention is high in productyield and purity, low in production cost, high in safety, simple to operate, and suitable for large-scale production.
- -
-
Paragraph 0080-0082; 0085; 0087; 0089; 0091; 0093; 0095
(2018/12/02)
-
- Novel Imidazo[4,5-c]Quinoline And Imidazo[4,5-c][1,5]Naphthyridine Derivatives As LRRK2 Inhibitors
-
The present invention provides novel imidazo[4,5-c]quinoline and imidazo[4,5-c][1,5]naphthyridine derivatives of Formula (I), and the pharmaceutically acceptable salts thereof wherein R1, R1a, R1b, R2, R4, R5, R6, X and Z are as defined in the specification. The invention is also directed to pharmaceutical compositions comprising the compounds of Formula (I) and to use of the compounds in the treatment of diseases associated with LRRK2, such as neurodegenerative diseases including Parkinson's disease or Alzheimer's disease, cancer, Crohn's disease or leprosy.
- -
-
Paragraph 0176
(2017/04/04)
-
- An Efficient and Waste-Minimized One-Pot Procedure for the Preparation of N-Boc-γ-amino Alcohols Starting from α,β-Unsaturated Ketones in Flow
-
We report herein a clean multistep flow process that starting from α,β-unsaturated ketones 1 allows the preparation of N-Boc-γ-amino alcohols 3 in high yields. The final products have been isolated in pure form without any additional purification step. Th
- Ballerini, Eleonora,Maggi, Raimondo,Pizzo, Ferdinando,Piermatti, Oriana,Gelman, Dmitri,Vaccaro, Luigi
-
p. 474 - 479
(2016/03/04)
-
- Novel indazoles for the treatment and prophylaxis of respiratory syncytial virus infection
-
The invention provides novel compounds having the general formula: wherein R1, R2, R3, R4, R5, R7, A1, A2 and A3 are as described herein, compositions including the compounds and methods of using the compounds.
- -
-
Paragraph 0472-0473
(2016/08/17)
-
- POLYFLUORINATED COMPOUNDS ACTING AS BRUTON TYROSINE KINASE INHIBITORS
-
Described herein is a novel series of multi-fluoro-substituted pyrazolopyrimidine compounds or salts thereof. These compounds are Bruton's tyrosine kinase (BTK) inhibitors. These compounds may possess better BTK inhibition selectivity and pharmacokinetic properties. Disclosed herein are the synthesis methods of these compounds. Disclosed herein are novel synthesis methods of the multi-fluoro-substituted benzophenone and substituted phenoxy benzene. Also disclosed are pharmaceutical compositions comprising the BTK inhibitors described herein. The present invention also relates to pharmaceutical formulations comprising the compounds described herein as active ingredients. The present invention also includes the therapeutic methods by administering the BTK inhibitors and their formulations to treat and inhibit autoimmune disease, hypersensitivity disease, inflammatory diseases and cancer.
- -
-
Paragraph 0500; 0501
(2016/08/17)
-
- Novel indazoles for the treatment and prophylaxis of respiratory syncytial virus infection
-
The invention provides novel compounds having the general formula: wherein R1, R2, R3, R4, R5, R7, A1, A2 and A3 are as described herein, compositions including the compounds and methods of using the compounds.
- -
-
Paragraph 0471; 0472
(2015/06/17)
-
- SUBSTITUTED BENZAMIDES AND THEIR USES
-
Provided herein are Substituted Benzamides, compositions, and method of their manufacture and use.
- -
-
Paragraph 0646
(2015/12/01)
-
- TETRACYCLIC HETEROCYCLE COMPOUNDS USEFUL AS HIV INTEGRASE INHIBITORS
-
The present invention relates to Tetracyclic Heterocycle Compounds of Formula (I) and pharmaceutically acceptable salts or prodrug thereof, wherein n, X, Y, Z, R1, R2, and R3 are as defined herein. The present invention also relates to compositions comprising at least one Tetracyclic Heterocycle Compound, and methods of using the Tetracyclic Heterocycle Compounds for treating or preventing HIV infection in a subject.
- -
-
Page/Page column 26-28
(2015/04/15)
-
- HETEROARYL SUBSTITUTED PYRIDYL COMPOUNDS USEFUL AS KINASE MODULATORS
-
Compounds having the following formula (I) or a stereoisomer or a pharmaceutically-acceptable salt thereof, wherein R2 is a monocyclic heteroaryl group, and R1, R3, R4, R5 and R6 are as defined herein, are useful as kinase modulators, including IRAK-4 inhibition.
- -
-
Paragraph 00281
(2019/03/15)
-
- NOVEL INDAZOLES FOR THE TREATMENT AND PROPHYLAXIS OF RESPIRATORY SYNCYTIAL VIRUS INFECTION
-
The invention provides novel compounds having the general formula: formula (I) wherein R1, R2, R3, R4, R5, R7, A1, A2 and A3 are as described herein, compositions including the compounds and methods of using the compounds.
- -
-
Page/Page column 95; 96
(2014/02/15)
-
- PYRROLOPYRAZINE KINASE INHIBITORS
-
The present invention relates to the use of novel pyrrolopyrazine derivatives of Formula I, wherein the variables are defined as described herein, which inhibit JAK and SYK and are useful for the treatment of auto-immune and inflammatory diseases.
- -
-
Page/Page column 138; 139
(2013/03/28)
-
- SUBSTITUTED BENZAMIDES AND THEIR USES
-
Provided herein are Substituted Benzamides, compositions, and method of their manufacture and use.
- -
-
Page/Page column 144
(2013/11/05)
-
- Identification of imidazo-pyrrolopyridines as novel and potent JAK1 inhibitors
-
A therapeutic rationale is proposed for the treatment of inflammatory diseases, such as rheumatoid arthritis (RA), by specific targeting of the JAK1 pathway. Examination of the preferred binding conformation of clinically effective, pan-JAK inhibitor 1 led to identification of a novel, tricyclic hinge binding scaffold 3. Exploration of SAR through a series of cycloamino and cycloalkylamino analogues demonstrated this template to be highly tolerant of substitution, with a predisposition to moderate selectivity for the JAK1 isoform over JAK2. This study culminated in the identification of subnanomolar JAK1 inhibitors such as 22 and 49, having excellent cell potency, good rat pharmacokinetic characteristics, and excellent kinase selectivity. Determination of the binding modes of the series in JAK1 and JAK2 by X-ray crystallography supported the design of analogues to enhance affinity and selectivity.
- Kulagowski, Janusz J.,Blair, Wade,Bull, Richard J.,Chang, Christine,Deshmukh, Gauri,Dyke, Hazel J.,Eigenbrot, Charles,Ghilardi, Nico,Gibbons, Paul,Harrison, Trevor K.,Hewitt, Peter R.,Liimatta, Marya,Hurley, Christopher A.,Johnson, Adam,Johnson, Tony,Kenny, Jane R.,Bir Kohli, Pawan,Maxey, Robert J.,Mendonca, Rohan,Mortara, Kyle,Murray, Jeremy,Narukulla, Raman,Shia, Steven,Steffek, Micah,Ubhayakar, Savita,Ultsch, Mark,Van Abbema, Anne,Ward, Stuart I.,Waszkowycz, Bohdan,Zak, Mark
-
experimental part
p. 5901 - 5921
(2012/08/27)
-
- COMPOUNDS USEFUL AS PROTEIN KINASES INHIBITORS
-
The present invention relates to compounds useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, co
- -
-
Page/Page column 42
(2009/04/25)
-
- DIAMINOCYCLOHEXANE AND DIAMINOCYCLOPENTANE DERIVATIVES
-
Provided herein are compounds of the formula (I) as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of obesity, hyperphagia, anxiety, depression and related disorders and diseases.
- -
-
Page/Page column 19-20
(2008/12/06)
-
- 4-CYCLOALKYLAMINOPYRAZOLO PYRIMIDINE NMDA/NR2B ANTAGONISTS
-
Compounds represented by Formula (I): or pharmaceutically acceptable salts thereof, are effective as NMDA/NR2B antagonists useful for treating neurological conditions such as, for example, pain, Parkinson's disease, Alzheimer's disease, epilepsy, depression, anxiety, ischemic brain injury including stroke, and other conditions.
- -
-
-
- Pyrimidine derivatives as IL-8 receptor antagonists
-
Compounds containing the pyrimidine nucleus and their use to treat diseases and conditions related to inappropriate Interleukin-8 receptor activity are disclosed. The compounds are of the formula I In these compounds, Q is preferably unsubstituted and substituted heterocyclyl; U is usually hydrogen or fluorine; and V is preferably hydrogen, halogen, alkyl, —O—alkyl or —S-alkyl. A representative example is:
- -
-
-
- Preparation and evaluation of 1,3-diaminocyclopentane-linked dihydropyrimidinone derivatives as selective α(1a)-receptor
-
Several 1,3-diaminocyclopentane linked α(1a)-receptor antagonists were prepared using a divergent chemical strategy that allows for rapid analysis of all stereochemical permutations for their effect on α1-receptor binding. (C) 2000 Published by Elsevier Science Ltd.
- Barrow, James C.,Glass, Kristen L.,Selnick, Harold G.,Freidinger, Roger M.,Chang, Raymond S.L.,O'Malley, Stacey S.,Woyden, Carla
-
p. 1917 - 1920
(2007/10/03)
-
- On the possibility of carbamate-directed hydroboration. An approach to the asymmetric synthesis of 1-aminocyclopentane-1,3-dicarboxylic acid
-
Hydroboration (using BH3) of 1-substituted 3-cyclopentenes 3, 9 and 17 and an enantioselective synthesis of the excitatory amino acid 1- aminocyclopentane-1,3-dicarboxylic acid via asymmetric hydroboration [90% de, 45% ee using (+)-IpcBH2] of cyclopentene 17 are described.
- Hodgson, David M.,Thompson, Alison J.,Wadman, Sjoerd,Keats, Clare J.
-
p. 10815 - 10834
(2007/10/03)
-
- 2-6-diaminopurine precursors
-
The present invention relates to compounds of formula (IV): STR1 wherein Ra and Rb each represent a hydrogen atom or together form an alkylidene group.
- -
-
-
- Carbamate-directed hydroboration: Enantioselective synthesis of the excitatory amino acid 1-aminocyclopentane-1,3-dicarboxylic acid
-
Carbamate-directed hydroboration (using BH3) of 1-substituted 3- cyclopentenes 2, 6 and 9 and an enantioselective synthesis of the excitatory amine acid 1-aminocyclopentane-1,3-dicarboxylic acid via carbamate-directed asymmetric hydroboration [90% de, 45% ee using (+)-IpcBH2] of cyclopentene 2 are described.
- Hodgson, David M.,Thompson, Alison J.,Wadman, Sjoerd
-
p. 3357 - 3358
(2007/10/03)
-