- ISOINDOLINONE COMPOUNDS
-
Disclosed herein is a compound or pharmaceutically acceptable salts or stereoisomers thereof of of formula I wherein X1 is linear or branched C1-6 alkyl, C3-6 cycloalkyl, -C1-6 alkyl C3-6 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C1-6 alkyl C6-10 aryl, C1-6 alkyl 5-10 membered heteroaryl, wherein X1 is unsubstituted or substituted with one or more of halogen, linear or branched C1-6 alkyl, linear or branched C1-6 heteroalkyl, CF3, CHF2, -O-CHF2, -O-(CH2)2-OMe, OCF3, C1-6 alkylamino, -CN, -N(H)C(O)-C1- 6alkyl, -OC(O)-C1-6alkyl, -OC(O)-C1-4alkylamino, -C(O)O-C1-6alkyl, -COOH, - CHO, -C1-6alkylC(O)OH, -C1-6alkylC(O)O-C1-6alkyl, NH2, C1-6 alkoxy or C1-6 alkylhydroxy; X2 is hydrogen, C6-10 aryl, 5-10 membered heteroaryl, -O-(5-10 membered heteroaryl), 4-8 membered heterocycloalkyl, C1-4 alkyl 4-8 membered heterocycloalkyl, -O-(4-8 membered heterocycloalkyl), -O-C1-4 alkyl-(4-8 membered heterocycloalkyl), -OC(O)-C1-4alkyl-4-8 membered heterocycloalkyl or C6 aryloxy, wherein X2 is unsubstituted or substituted with one or more of linear or branched C1-6 alkyl, NH2, NMe2 or 5-6 membered heterocycloalkyl; n is 0, 1 or 2.
- -
-
Page/Page column 283-284
(2021/04/17)
-
- TRPML MODULATORS
-
The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.
- -
-
-
- SSAO INHIBITORS AND USE THEREOF
-
Provided are a compound of formula (I') or (I), a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which modulates the activity of SSAO, a pharmaceutical composition comprising a compound of formula (I') or (I), and a method of treating or preventing a disease in which SSAO plays a role.
- -
-
Paragraph 00672
(2021/05/07)
-
- Ligand Conformational Bias Drives Enantioselective Modification of a Surface-Exposed Lysine on Hsp90
-
Targeted covalent modification of surface-exposed lysines is challenging due to their low intrinsic reactivity and high prevalence throughout the proteome. Strategies for optimizing the rate of covalent bond formation by a reversibly bound inhibitor (kinact) typically involve increasing the reactivity of the electrophile, which increases the risk of off-target modification. Here, we employ an alternative approach for increasing kinact of a lysine-targeted covalent Hsp90 inhibitor, independent of the reversible binding affinity (Ki) or the intrinsic electrophilicity. Starting with a noncovalent ligand, we appended a chiral, conformationally constrained linker, which orients an arylsulfonyl fluoride to react rapidly and enantioselectively with Lys58 on the surface of Hsp90. Biochemical experiments and high-resolution crystal structures of covalent and noncovalent ligand/Hsp90 complexes provide mechanistic insights into the role of ligand conformation in the observed enantioselectivity. Finally, we demonstrate selective covalent targeting of cellular Hsp90, which results in a prolonged heat shock response despite concomitant degradation of the covalent ligand/Hsp90 complex. Our work highlights the potential of engineering ligand conformational constraints to dramatically accelerate covalent modification of a distal, poorly nucleophilic lysine on the surface of a protein target.
- Burlingame, Alma L.,Cuesta, Adolfo,Taunton, Jack,Wan, Xiaobo
-
supporting information
p. 3392 - 3400
(2020/03/06)
-
- 2-(BICYCLO-HETEROARYL)-ISONICOTINIC DERIVATIVES AS HISTONE DEMETHYLASE INHIBITORS
-
The invention relates to compounds of Formula (I) as described herein, useful as histone demethylase inhibitors. The invention also relates to pharmaceutical compositions comprising these compounds and to their use in therapy, including e.g., in the treatment of cancer.
- -
-
Paragraph 80
(2018/09/12)
-
- Saturated Heterocyclic Aminosulfonyl Fluorides: New Scaffolds for Protecting-Group-Free Synthesis of Sulfonamides
-
Cyclic saturated aminosulfonyl fluorides were synthesized as their HCl salts. The compounds were found to be stable upon storage and could be used for the protecting-group-free synthesis of sulfonamides. In the presence of the ?SO2F group, the nitrogen atom could be modified by means of acylation, arylation, or reductive amination to give products that have high potential for the synthesis of bioactive compounds.
- Zhersh, Sergey A.,Blahun, Oleksandr P.,Sadkova, Iryna V.,Tolmachev, Andrey A.,Moroz, Yurii S.,Mykhailiuk, Pavel K.
-
supporting information
p. 8343 - 8349
(2018/06/04)
-
- A structure-guided optimization of pyrido[2,3-d]pyrimidin-7-ones as selective inhibitors of EGFRL858R/T790Mmutant with improved pharmacokinetic properties
-
Structural optimization of pyrido[2,3-d]pyrimidin-7-ones was conducted to yield a series of new selective EGFRT790Minhibitors with improved pharmacokinetic properties. One of the most promising compound 9s potently suppressed EGFRL858R/T790Mkinase and inhibited the proliferation of H1975?cells with IC50values of 2.0?nM and 40?nM, respectively. The compound dose-dependently induced reduction of the phosphorylation of EGFR and downstream activation of ERK in NCI[sbnd]H1975?cells. It also exhibited moderate plasma exposure after oral administration and an oral bioavailability value of 16%. Compound 9s may serve as a promising lead compound for further drug discovery overcoming the acquired resistance of non-small cell lung cancer (NSCLC) patients.
- Yu, Lei,Huang, Minhao,Xu, Tianfeng,Tong, Linjiang,Yan, Xiao-e,Zhang, Zhang,Xu, Yong,Yun, Caihong,Xie, Hua,Ding, Ke,Lu, Xiaoyun
-
p. 1107 - 1117
(2016/12/30)
-
- 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.
- -
-
-
- HETEROCYCLIC COMPOUNDS AS NAV CHANNEL INHIBITORS AND USES THEREOF
-
The present invention relates to heterocyclic compounds of formula (I) wherein: Z1 is C(R)(R), C(O), C(S), or C(NR); 2 Z is C(R)(R), 0, S, SO, S02, or NR; X is -O-, -S-, -S02-, -SO-, -C(O)-, -C02-, -C(O)N(R)-, -NRC(O)-, -NRC(O) N(R)-, -NRSO2-, or -N(R)-; or X is absent; A is an optionally substituted C1_6 aliphatic, C5-10 aryl, 3-8 membered saturated or partially unsaturated carbocyclic ring, 3-7 membered heterocylic ring, or a 5-6 membered heteroaryl ring; Y is -CH2-, -O-, -S-, -S02-, -SO-, -C(O)-, -C02-, -C(O)N(R)-, -NRC(O)-, - NRC(O)N(R)-, -NRS02-, or -N(R)-; B is an optionally substituted C5-10 aryl or 5-6 membered heteroaryl ring; m is 0, 1, 2, or 3; n is 0, 1, 2, or 3; q is 0, 1, 2, or 3; and r is 1 or 2; and pharmaceutically acceptable compositions thereof, useful as Navl.6 inhibitors.
- -
-
-
- NOVEL INDOLE DERIVATIVE COMPOUND AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME
-
The present invention provides a novel indole derivative compound, an isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. The compound according to the present invention can selectively inhibit histone deacetylase (HDAC), and thus can be used to effectively treat a disease associated with histone deacetylase (HDAC) activity.
- -
-
Paragraph 1038-1040
(2015/07/16)
-
- Discovery of 5-chloro-4-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)oxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1 H)-one (BMS-903452), an antidiabetic clinical candidate targeting GPR119
-
G-protein-coupled receptor 119 (GPR119) is expressed predominantly in pancreatic β-cells and in enteroendocrine cells in the gastrointestinal tract. GPR119 agonists have been shown to stimulate glucose-dependent insulin release by direct action in the pancreas and to promote secretion of the incretin GLP-1 by action in the gastrointestinal tract. This dual mechanism of action has generated significant interest in the discovery of small molecule GPR119 agonists as a potential new treatment for type 2 diabetes. Herein, we describe the discovery and optimization of a new class of pyridone containing GPR119 agonists. The potent and selective BMS-903452 (42) was efficacious in both acute and chronic in vivo rodent models of diabetes. Dosing of 42 in a single ascending dose study in normal healthy humans showed a dose dependent increase in exposure and a trend toward increased total GLP-1 plasma levels.
- Wacker, Dean A.,Wang, Ying,Broekema, Matthias,Rossi, Karen,Oconnor, Steven,Hong, Zhenqiu,Wu, Ginger,Malmstrom, Sarah E.,Hung, Chen-Pin,Lamarre, Linda,Chimalakonda, Anjaneya,Zhang, Lisa,Xin, Li,Cai, Hong,Chu, Cuixia,Boehm, Stephanie,Zalaznick, Jacob,Ponticiello, Randolph,Sereda, Larisa,Han, Song-Ping,Zebo, Rachel,Zinker, Bradley,Luk, Chiuwa Emily,Wong, Richard,Everlof, Gerry,Li, Yi-Xin,Wu, Chunyu K.,Lee, Michelle,Griffen, Steven,Miller, Keith J.,Krupinski, John,Robl, Jeffrey A.
-
supporting information
p. 7499 - 7508
(2014/12/11)
-
- FUSED BICYCLIC COMPOUNDS AS INHIBITORS FOR PI3 KINASE
-
The invention relates to compounds of formula (I) for the regulation of phosphoinositides 3-kinases activity and related diseases.
- -
-
Page/Page column 145
(2010/09/18)
-
- BENZIMIDAZOLE AND AZA-BENZIMIDAZOLE CARBOXAMIDES
-
This invention provides compounds of Formula I which are PAFR antagonists: I and the pharmaceutically acceptable salts thereof. The compounds are useful for treating PAF-mediated disorders, and can be used in methods for treating atherosclerosis and preve
- -
-
Page/Page column 47
(2010/05/14)
-
- BIARYL CARBOXAMIDES
-
This invention provides compounds of Formula (I) which are PAFR antagonists: Formula (I) and the pharmaceutically acceptable salts thereof. The compounds are useful for treating PAF-mediated disorders, and can be used in methods for treating atherosclerosis and preventing or reducing risk for atherosclerotic disease events. The compounds are also useful for treating or ameliorating pain, e.g. inflammatory pain and/or nociceptive pain, and for treating or ameliorating autoimmune and/or inflammatory diseases, among other conditions.
- -
-
Page/Page column 45
(2010/08/04)
-
- CHEMICAL COMPOUNDS
-
Quinazoline derivatives of formula (I); for use in the treatment of proliferative diseases such as cancer and in the preparation of medicaments for use in the treatment of proliferative diseases, and to processes for their preparation, as well as pharmaceutical compositions containing them as active ingredient.
- -
-
-
- Cathepsin cysteine protease inhibitors
-
This invention relates to a novel class of compounds which are cysteine protease inhibitors, including but not limited to, inhibitors of Cathepsins K and L. These compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis.
- -
-
-
- Novel, nonpeptidic cyanamides as potent and reversible inhibitors of human cathepsins K and L
-
Compounds containing a 1-cyanopyrrolidinyl ring were identified as potent and reversible inhibitors of cathepsins K and L. The original lead compound 1 inhibits cathepsins K and L with IC50 values of 0.37 and 0.45 μM, respectively. Modification of compound 1 by replacement of the quinoline moiety led to the synthesis of N-(1-cyano-3-pyrrolidinyl)benzenesulfonamide (2). Compound 2 was found to be a potent inhibitor of cathepsins K and L with a Ki value of 50 nM for cathepsin K. Replacement of the 1-cyanopyrrolidine of compound 2 by a 1-cyanoazetidine increased the potency of the inhibitor by 10-fold. This increase in potency is probably due to an enhanced chemical reactivity of the compound toward the thiolate of the active site of the enzyme. This is demonstrated when the assay is performed in the presence of glutathione at pH 7.0 which favors the formation of a GSH thiolate anion. Under these assay conditions, there is a loss of potency in the 1-cyanoazetidine series due to the formation of an inactive complex between the GSH thiolate and the 1-cyanoazetidine inhibitors. 1-Cyanopyrrolidinyl inhibitors exhibited time-dependent inhibition which allowed us to determine the association and dissociation rate constants with human cathepsin K. The kinetic data obtained showed that the increase of potency observed between different 1-cyanopyrrolidinyl inhibitors is due to an increase of kon values and that the association of the compound with the enzyme fits an apparent one-step mechanism. 13C NMR experiments performed with the enzyme papain showed that compound 2 forms a covalent isothiourea ester adduct with the enzyme. As predicted by the kinetic analysis, the addition of the irreversible inhibitor E64 to the enzyme-cyanopyrrolidinyl complex totally abolished the signal of the isothiourea bond as observed by 13C NMR, thereby demonstrating that the formation of the covalent bond with the active site cysteine residue is reversible. Finally, compound 2 inhibits bone resorption in an in vitro assay involving rabbit osteoclasts and bovine bone with an IC50 value of 0.7 μM. 1-Cyanopyrrolidine represents a new class of nonpeptidic compounds that inhibit cathepsin K and L activity and proteolysis of bone collagen.
- Falgueyret,Oballa,Okamoto,Wesolowski,Aubin,Rydzewski,Prasit,Riendeau,Rodan,Percival
-
-