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Preparation and application of indolizine compound
The invention provides an indolizine compound for inhibiting a CBP/EP300Bromodomain receptor as well as a preparation method and application of the indolizine compound. The indolizine compound has a structure as shown in a formula I; the indolizine compound provided by the invention can be effectively combined with a CBP/EP300 bromodomain, and has good selectivity on other bromodomain family proteins; meanwhile, the indolizine compound provided by the invention is more stable in structure.
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Paragraph 0025; 0075-0078

(2021/08/14)

Discovery of selective fragment-sized immunoproteasome inhibitors
Proteasomes contribute to maintaining protein homeostasis and their inhibition is beneficial in certain types of cancer and in autoimmune diseases. However, the inhibition of the proteasomes in healthy cells leads to unwanted side-effects and significant effort has been made to identify inhibitors specific for the immunoproteasome, especially to treat diseases which manifest increased levels and activity of this proteasome isoform. Here, we report our efforts to discover fragment-sized inhibitors of the human immunoproteasome. The screening of an in-house library of structurally diverse fragments resulted in the identification of benzo[d]oxazole-2(3H)-thiones, benzo[d]thiazole-2(3H)-thiones, benzo[d]imidazole-2(3H)-thiones, and 1-methylbenzo[d]imidazole-2(3H)-thiones (with a general term benzoXazole-2(3H)-thiones) as inhibitors of the chymotrypsin-like (β5i) subunit of the immunoproteasome. A subsequent structure-activity relationship study provided us with an insight regarding growing vectors. Binding to the β5i subunit was shown and selectivity against the β5 subunit of the constitutive proteasome was determined. Thorough characterization of these compounds suggested that they inhibit the immunoproteasome by forming a disulfide bond with the Cys48 available specifically in the β5i active site. To obtain fragments with biologically more tractable covalent interactions, we performed a warhead scan, which yielded benzoXazole-2-carbonitriles as promising starting points for the development of selective immunoproteasome inhibitors with non-peptidic scaffolds.
Kollár, Levente,Gobec, Martina,Szilágyi, Bence,Proj, Matic,Knez, Damijan,ábrányi-Balogh, Péter,Petri, László,Imre, Tímea,Bajusz, Dávid,Ferenczy, Gy?rgy G.,Gobec, Stanislav,Keser?, Gy?rgy M.,Sosi?, Izidor
(2021/04/23)

Indolizine compound as well as preparation method and application thereof
The invention provides an indolizine compound as well as a preparation method and application thereof. The indolizine compound has a structure as shown in a formula I or a formula II, the indolizine compound can be effectively combined with a CBP/EP300 bromine structural domain, the inhibition rate can generally reach 90% or above, the indolizine compound has a good effect and has good selectivityon other bromine structural domain family proteins; moreover, the indolizine compound is stable in structure, and the synthesis method is simpler.
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Paragraph 0103; 0104; 0105

(2020/07/13)

TYK2 INHIBITORS AND USES THEREOF
The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of TYK2, and the treatment of TYK2-mediated disorders.
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Paragraph 00467

(2020/06/19)

Quinazoline compound and application thereof in medicine (by machine translation)
The invention relates to a quinazoline compound (shown in the formula I) and a medicinal salt thereof, which can be used for treating cancer. The invention also relates to a preparation method and a pharmaceutical composition containing the compounds. (by machine translation)
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Paragraph 0125-0128

(2020/08/22)

Small-compound enhancers for functional O-mannosylation of alpha-dystroglycan, and uses thereof
The present invention provides compounds that can enhance functional O-mannosylation of proteins including alpha-dystroglycan. Also provided are methods of preparation of the compounds defined by the formula I. Also provided are the methods of using the compounds or the pharmaceutical acceptable salts or prodrugs thereof in treating and preventing subjects suffering from the diseases including muscular dystrophies and cancers.
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Page/Page column 20; 21

(2019/03/14)

CONJUGATES OF CEREBLON BINDING COMPOUNDS AND G12C MUTANT KRAS, HRAS OR NRAS PROTEIN MODULATING COMPOUNDS AND METHODS OF USE THEREOF
Conjugates of a cereblon-binding compound and compounds having modulatory activity against G12C mutant KRAS, HRAS or NRAS G12C proteins are provided. Methods associated with preparation and use of such conjugates, pharmaceutical compositions comprising such conjugates and methods to modulate the activity of G12C mutant KRAS, HRAS or NRAS G12C proteins for treatment of disorders, such as cancer, are also provided.
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Paragraph 0318

(2018/02/15)

SUBSTITUTED QUINAZOLINE COMPOUNDS AND THEIR USE AS INHIBITORS OF G12C MUTANT KRAS, HRAS AND/OR NRAS PROTEINS
Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I) or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein R, R1, R2a, R2b, R2c, A, B, L1 and E are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.
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Page/Page column 93-94

(2017/02/09)

2-SUBSTITUTED QUINAZOLINE COMPOUNDS COMPRISING A SUBSTITUTED HETEROCYCLIC GROUP AND METHODS OF USE THEREOF
Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I): (I) or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein R1, R2a, R2b, R2c, R3a, R3b, R4a, R4b, R5a, R5b, R6, A, G1, G2, L1, L2, m1, m2, n, X and E are as defined herein, and wherein at least one of R3a, R3b, R4a or R4b is not H. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.
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Page/Page column 180; 181

(2017/06/12)

INHIBITORS OF KRAS G12C MUTANT PROTEINS
Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I): or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein A, B R1, R2a, R2b, R3a, R3b, R4a, R4b, G1, G2, m1, m2, L1, L2 and E are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.
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Page/Page column 102

(2017/07/29)

NOVEL COMPOUND WITH ANTIBACTERIAL ACTIVITY
A compound represented by the general formula (I) or a salt thereof having a potent antibacterial activity against bacteria that have acquired resistance to quinolones, and a medicament for prophylactic and/or therapeutic treatment of an infectious disease containing the compound or a salt thereof as an active ingredient, as well as a medicament for prophylactic and/or therapeutic treatment of an infectious disease containing a combination of the compound or a salt thereof, and a quinolone.
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Paragraph 0194

(2016/04/26)

METHODS AND COMPOSITIONS FOR INHIBITION OF RAS
Inhibitors of Ras protein, methods to modulate the activity of Ras protein, and methods of treatment of disorders mediated by Ras protein are provided. A method for regulating activity of a K-Ras, H-Ras or N-Ras mutant protein with a compound is described. Disorders that can be treated include cancer, such as hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer, or lung cancer.
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Page/Page column 0260-0261

(2016/04/20)

SUBSTITUTED QUINAZOLINE COMPOUNDS AND METHODS OF USE THEREOF
Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have one of the following structures (I), (II) or (III): or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein R1, R2a, R2b, R2c, R3a, R3b, R4a, R4b, R5a, R5b, R6, A, B, G1, G2, L1, L2, m1, m2, n, x, y, X and E are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.
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Page/Page column 231

(2016/10/31)

Small molecules enhance functional O-mannosylation of Alpha-dystroglycan
Alpha-dystroglycan (α-DG), a highly glycosylated receptor for extracellular matrix proteins, plays a critical role in many biological processes. Hypoglycosylation of α-DG results in various types of muscular dystrophies and is also highly associated with progression of majority of cancers. Currently, there are no effective treatments for those devastating diseases. Enhancing functional O-mannosyl glycans (FOG) of α-DG on the cell surfaces is a potential approach to address this unmet challenge. Based on the hypothesis that the cells can up-regulate FOG of α-DG in response to certain chemical stimuli, we developed a cell-based high-throughput screening (HTS) platform for searching chemical enhancers of FOG of α-DG from a large chemical library with 364,168 compounds. Sequential validation of the hits from a primary screening campaign and chemical works led to identification of a cluster of compounds that positively modulate FOG of α-DG on various cell surfaces including patient-derived myoblasts. These compounds enhance FOG of α-DG by almost ten folds, which provide us powerful tools for O-mannosylation studies and potential starting points for the development of drug to treat dystroglycanopathy.
Lv, Fengping,Li, Zhi-Fang,Hu, Wenhao,Wu, Xiaohua
supporting information
p. 7661 - 7670
(2015/12/18)

INHIBITORS OF KRAS G12C
Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I): or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein R1, R2a, R3a, R3b, R4a, R4b, G1, G2, L1, L2, m1, m2, A, B, W, X, Y, Z and E are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.
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Page/Page column 253

(2015/04/28)

QUINAZOLINES AND AZAQUINAZOLINES AS DUAL INHIBITORS OF RAS/RAF/MEK/ERK AND PI3K/AKT/PTEN/MTOR PATHWAYS
The present application provides novel quinazolines and azaquinazolines and pharmaceutically acceptable salts thereof. Also provided are methods for preparing these compounds. These compounds are useful in for co-regulating RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR pathways by administering a therapeutically effective amount of one or more of the compounds of formula (I), wherein X, Y, T and R4, and R6 to R8' are defined herein, to a patient. By doing so, these compounds are effective in treating conditions associated with the dysregulation of the RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/mTOR pathways. A variety of conditions can be treated using these compounds and include diseases which are characterized by abnormal cellular proliferation. In one embodiment/ the disease is cancer.
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Page/Page column 48; 49

(2014/10/29)

CHEMICAL COMPOUNDS
The invention is directed to substituted quinoline derivatives. Specifically, the invention is directed to compounds according to Formula (I): wherein R1, R2, R3; R4; and R5 are defined herein. The compounds of the invention are inhibitors of lactate dehydrogenase A and can be useful in the treatment of cancer and diseases associated with tumor cell metabolism, such as cancer, and more specifically cancers of the breast, colon, prostate and lung. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting lactate dehydrogenase A activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
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Page/Page column 128

(2013/07/05)

RAF KINASE INHIBITORS
Described herein are compounds, pharmaceutical compositions and methods for the inhibition of RAF kinae mediated signaling. Said compounds, pharmaceutical compositions and methods have utility in the treatment of human disease and disorders.
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Page/Page column 129

(2012/10/07)

OXO-HETEROCYCLIC SUBSTITUTED CARBOXYLIC ACID DERIVATIVES AND THE USE THEREOF
The present application relates to novel carboxylic acid derivatives having an oxo-substituted azaheterocyclic partial structure, processes for their preparation, their use for the treatment and/or prophylaxis of diseases, and their use for producing medicaments for the treatment and/or prophylaxis of diseases, especially for the treatment and/or prevention of cardiovascular disorders.
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Page/Page column 95

(2011/02/26)

SUBSTITUTED 3-PHENYLPROPIONIC ACIDS AND THE USE THEREOF
The present application relates to novel 3-phenylpropionic acid derivatives, to processes for their preparation, to their use for the treatment and/or prevention of diseases and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of cardiovascular disorders.
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Page/Page column 24

(2011/06/23)

Compounds and Compositions as Protein Kinase Inhibitors
The present invention provides compounds of Formula I or II: wherein R1, R1b, R2, R3, R4, R5, R6 and R7 are defined herein. The compounds of Formula (I) or (II) and pharmaceutical compositions thereof are useful for the treatment of B-Raf-associated diseases.
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(2011/04/14)

CHLOROTHIOPHENE-AMIDES AS INHIBITORS OF COAGULATION FACTORS XA AND THROMBIN
The present invention relates to compounds of the formula I wherein R1; R2; R3; R4; R5, R13, R16, X and M have the meanings indicated in the claims. The compounds of formula I are valuable pharmacologically active compounds. They exhibit a strong anti-thrombotic effect and are suitable, for example, for the therapy and prophylaxis of cardio-vascular disorders like thromboembolic diseases or restenoses. They are reversible inhibitors of the blood clotting enzymes factor Xa (FXa) and thrombin and can in general be applied in conditions in which an undesired activity of factor Xa and/or thrombin are present or for the cure or prevention of which an inhibition of factor Xa and thrombin are intended. The invention furthermore relates to processes for the preparation of compounds of the formula I, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.
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Page/Page column 87

(2009/10/18)

4 AND 5-Halo substituted 2-indanamine compounds
2-Indanamine compounds having 4 and 5-halo substituents are inhibitors of phenylethanolamine N-methyltransferase.
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(2008/06/13)