- Efficient Manufacturing Process for the Selective Estrogen Receptor Degrader GDC-9545 (Giredestrant) via a Crystallization-Driven Diastereoselective Pictet-Spengler Condensation
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GDC-9545 is a selective estrogen receptor degrader that is being developed as a treatment for ER+/HER2- breast cancer. A robust, convergent manufacturing process for GDC-9545 was developed. The process features a Wenker aziridine synthesis to produce the key starting material tryptamine 11, a highly efficient C-N coupling between aminoazetidine 9 and 2,6-difluoro-4-bromobenzaldehyde diethyl acetal (33) to construct key intermediate 10, and a crystallization-driven diastereoselective Pictet-Spengler reaction to furnish the active pharmaceutical ingredient GDC-9545·tartrate.
- Angelaud, Rémy,Chung, Cheol K.,Clagg, Kyle,Dalziel, Michael E.,Fettes, Alec,Finet, Laure,Gosselin, Francis,Jenny, Christian,Kammerer, Michael,Lim, Ngiap-Kie,Mack, Kyle A.,McClory, Andrew,Wuitschik, Georg,Xu, Jie,Zhang, Haiming
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- HETEROCYCLIC COMPOUND INTERMEDIATE, PREPARATION METHOD THEREFOR AND APPLICATION THEREOF
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Disclosed by the invention is a heterocyclic compound, an intermediate, and a preparation method therefor and an application thereof. Provided by the invention are a heterocyclic compound as shown in formula I, and a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof. The heterocyclic compound hasa high P2X3 antagonistic activity, and has good selectivity, low toxicity, good metabolic stability and little taste influence.
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Paragraph 0416-0418
(2021/10/07)
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- First-Generation Asymmetric Synthesis of the Selective Estrogen Receptor Degrader GDC-9545 (Giredestrant) Featuring a Highly Efficient Pictet-Spengler Reaction and a C-N Coupling Reaction
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An asymmetric synthesis of the selective estrogen receptor degrader GDC-9545 (1) is described. The synthesis features a Friedel-Crafts indole functionalization and a strain-release aminoazetidine formation to construct the two key starting materials 2 and 4, respectively, a diastereoselective Pictet-Spengler reaction (98% yield, 95:5 dr) to assemble the tetrahydrocarboline core, and a highly efficient Pd-catalyzed C-N coupling (90% yield) using [t-BuBrettPhos Pd(allyl)]OTf as the catalyst and DBU as the base to furnish the final C-N bond. This expedient route produces GDC-9545·tartrate active pharmaceutical ingredient in a longest linear sequence of six steps in 37% overall yield with 99.0 area % HPLC purity without chromatographic purification.
- Chung, Cheol K.,Clagg, Kyle,Gosselin, Francis,Lim, Ngiap-Kie,Wuitschik, Georg,Xu, Jie,Zhang, Haiming
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- BRD9 BIFUNCTIONAL DEGRADERS AND THEIR METHODS OF USE
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The disclosure provides BRD9 bifunctional compounds of Formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, to their preparation, to pharmaceutical compositions comprising them, and to their use in the treatment of diseases and disorders mediated by a bromodomain-containing protein, such as bromodoma in-containing protein 9 (BRD9)
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Page/Page column 247; 248
(2021/04/01)
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- Inhibiting effect of trisubstituted pyrimidine derivative on protein kinase
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The invention discloses a trisubstituted pyrimidine derivative with a structure shown as general formula (I), and pharmaceutically acceptable salt, ester or solvent compound thereof. The derivative isa protein kinase inhibitor, can be used individually or in combination with other drugs for cancer treatment, and has tremendous clinical application value. General formula (I) is shown as the specification.
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Paragraph 0020-0023
(2019/09/14)
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- Discovery of 4-Aminoquinoline-3-carboxamide derivatives as potent reversible Bruton's tyrosine kinase inhibitors for the treatment of rheumatoid arthritis
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A structure-hopping strategy was applied to discover a series of novel 4-aminoquinoline-3-carboxamide derivatives as potent, reversible BTK inhibitors. Compared to the previously described cinnoline scaffold compounds, the 4-aminoquinoline analogues showed significantly improved drug-like properties, especially in their aqueous solubility. The most potent compound, 25, displayed a stronger inhibitory effect on both BTKWT (IC50 = 5.3 nM) and BTKC481S (IC50 = 39 nM). In a rodent collagen-induced arthritis model, compound 25 efficiently reduced paw swelling without a loss in body weight. On the basis of potency, drug-like properties, stability, and noncovalent mode of inhibition, our representative inhibitors could have a promising profile to be treatments for a wide range of autoimmune diseases.
- Yao, Xia,Sun, Xiuyun,Jin, Shuyu,Yang, Ling,Xu, Hongjiang,Rao, Yu
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p. 6561 - 6574
(2019/08/20)
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- Micromolecular reversible BTK inhibitor for treating rheumatoid arthritis
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The invention relates to a micromolecular reversible BTK inhibitor for treating rheumatoid arthritis, and specifically provides a compound. The compound is the compound as shown in a formula I, or a stereisomer, a geometrical isomer and a tautomer thereof, nitric oxide, aquo-complex, a solvate, a metabolite and pharmaceutically acceptable salts and prodrugs. The inventor finds that polysubstitutedquinolone compound or derivate thereof as shown in formula I can be used as the BTK inhibitor and is high in activity during treating rheumatoid arthritis.
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Paragraph 0157-0161
(2019/07/29)
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- Pd-Catalyzed, ortho C-H Methylation and Fluorination of Benzaldehydes Using Orthanilic Acids as Transient Directing Groups
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The direct, Pd-catalyzed ortho C-H methylation and fluorination of benzaldehydes have been accomplished using commercially available orthanilic acids as transient directing groups. In these reactions, the 1-fluoro-2,4,6-trimethylpyridinium salts can be either a bystanding F+ oxidant or an electrophilic fluorinating reagent. An X-ray crystal structure of a benzaldehyde ortho C-H palladation intermediate was obtained using triphenylphosphine as the stabilizing ligand.
- Chen, Xiao-Yang,Sorensen, Erik J.
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supporting information
p. 2789 - 2792
(2018/03/08)
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- IRAK4 INHIBITING AGENTS
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Provided are compounds of Formula I, or pharmaceutically acceptable salts thereof, and methods for their use and production. Formula (I) The compounds are IRAK-4 inhibitors useful for treating an inflammatory disease, an autoimmune disease, cancer, a cardiovascular disease, a disease of the central nervous system, a disease of the skin, an ophthalmic disease and condition, and a bone disease.
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Page/Page column 74
(2017/09/24)
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- Synthesis and Transformations of Functionalized Benzosiloxaboroles
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The synthesis and characterization of a series of fluorinated benzosiloxaboroles bearing synthetically useful formyl and cyano groups is reported. These compounds have been obtained by multistep syntheses starting with simple halogenated benzenes. The general synthetic protocol was based on the generation of ortho-boronated aryldimethylsilanes which undergo dehydrogenative cyclization upon hydrolytic workup due to activation of the Si–H bond by the adjacent boronic group. In some cases the synergy of adjacent boron- and silicon-based functionalities resulted in an unexpected hydrosilylation of the CHO group under mild aqueous conditions. The reduction of a benzosiloxaborole derivative bearing the formyl group at the ortho position with respect to the boron atom resulted in a structural transformation reflecting the higher stability of the carboxaborole heterocycle with respect to its silicon counterpart. Thus, a unique heterocyclic system featuring a central 10-membered ring comprising two borasiloxane linkages was isolated.
- Czub, Maja,Durka, Krzysztof,Luliński, Sergiusz,?osiewicz, Justyna,Serwatowski, Janusz,Urban, Mateusz,Wo?niak, Krzysztof
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p. 818 - 826
(2017/02/15)
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- IRAK4 INHIBITING AGENTS
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Provided are compounds of Formula (I), or pharmaceutically acceptable salts thereof, and methods for their use and production.
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Page/Page column 268; 269
(2016/03/13)
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- ALKENYL DIOXANE COMPOUND, LIQUID CRYSTAL COMPOSITION AND LIQUID CRYSTAL DISPLAY DEVICE
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A problem is to provide a liquid crystal compound satisfying at least one physical property such as high stability to heat and light, high clearing point, low minimum temperature of liquid crystal phase, small viscosity, suitable optical anisotropy, large dielectric anisotropy, suitable elastic constant and excellent compatibility with other liquid crystal compounds, a liquid crystal composition containing the compound, and a liquid crystal display device including the composition. The compound is represented by formula (1). In formula (1), for example, R1 is alkenyl; ring A1 and ring A2 are 1,4-cyclohexylene or 1,4-phenylene; Z1, Z2, Z3 are a single bond or —COO—; X1 is hydrogen or fluorine; L1, L2, L3 and L4 are hydrogen or fluorine; and a and b are each independently 0 or 1, a sum of a and b is 1, and when a is 1, at least one of ring A1 and ring A2 is 1,4-cyclohexylene.
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Paragraph 0147
(2016/10/17)
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- Compound
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PROBLEM TO BE SOLVED: To provide a difluorobenzyl halide derivative useful as a production intermediate for chemicals etc., such as pharmaceuticals, agrochemicals and liquid crystal materials, and a method for efficiently producing the difluorobenzyl halide derivative.SOLUTION: There is provided a compound expressed by general formula (I) (in the formula, Xand Xare each independently a chlorine atom, bromine atom or iodine atom; and Yand Yare each independently a hydrogen atom, fluorine atom or chlorine atom, provided that at least one of Yand Yis a fluorine atom).
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Paragraph 0035; 0036
(2017/05/04)
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- NOVEL 3,5-DISUBSTITUTED-3H-IMIDAZO[4,5-B]PYRIDINE AND 3,5- DISUBSTITUTED -3H-[1,2,3]TRIAZOLO[4,5-B] PYRIDINE COMPOUNDS AS MODULATORS OF C-MET PROTEIN, ETC
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The present invention provides compounds useful as c-Met protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of c-Met kinase mediated disease or disorders with them.
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Paragraph 0569
(2015/03/04)
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- NOVEL 3,5-DISUBSTITUED-3H-IMIDAZO[4,5-B]PYRIDINE AND 3,5- DISUBSTITUED -3H-[1,2,3]TRIAZOLO[4,5-B] PYRIDINE COMPOUNDS AS MODULATORS OF C-MET PROTEIN KINASES
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The present invention provides compounds useful as C-met protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of C-met kinase mediated diseases or disorders with them.
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Paragraph 252
(2013/10/21)
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- 17α-HYDROXYLASE/C17,20-LYASE INHIBITORS
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The present invention provides compounds of Formula (I), or a pharmaceutically acceptable salt thereof, where R1, R2, R3, R4, R5 and R6 are as defined herein. The compounds of the present invention have been found to be useful as 17α-hydroxylase/C17,20-lyase inhibitors.
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Page/Page column 60-61
(2012/11/13)
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- The design and synthesis of indazole and pyrazolopyridine based glucokinase activators for the treatment of Type 2 diabetes mellitus
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Glucokinase activators represent a promising potential treatment for patients with Type 2 diabetes. Herein, we report the identification and optimization of a series of novel indazole and pyrazolopyridine based activators leading to the identification of 4-(6-(azetidine-1-carbonyl)-5-fluoropyridin-3- yloxy)-2-ethyl-N-(5-methylpyrazin-2-yl)-2H-indazole-6-carboxamide (42) as a potent activator with favorable preclinical pharmacokinetic properties and in vivo efficacy.
- Pfefferkorn, Jeffrey A.,Tu, Meihua,Filipski, Kevin J.,Guzman-Perez, Angel,Bian, Jianwei,Aspnes, Gary E.,Sammons, Matthew F.,Song, Wei,Li, Jian-Cheng,Jones, Christopher S.,Patel, Leena,Rasmusson, Tim,Zeng, Dongxiang,Karki, Kapil,Hamilton, Michael,Hank, Richard,Atkinson, Karen,Litchfield, John,Aiello, Robert,Baker, Levenia,Barucci, Nicole,Bourassa, Patricia,Bourbounais, Francis,D'Aquila, Theresa,Derksen, David R.,MacDougall, Margit,Robertson, Alan
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p. 7100 - 7105
(2013/01/15)
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- QUINAZOLINONE DERIVATIVES AS VIRAL POLYMERASE INHIBITORS
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Compounds of formula I: (I) wherein X, R2, R3, R5 and R6 are defined herein, are useful as inhibitors of the hepatitis C virus NS5B polymerase.
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Page/Page column 49
(2011/04/19)
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- NOVEL COMPOUNDS AS ANTAGONISTS OR INVERSE AGONISTS FOR OPIOID RECEPTORS
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This invention relates to novel compounds which are antagonists or inverse agonists at one or more of the opioid receptors, to pharmaceutical compositions containing them, to processes for their preparation, and to their use in therapy.
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Page/Page column 92; 93
(2010/09/07)
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- INHIBITORS OF JANUS KINASES
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The instant invention provides for compounds that inhibit the four known mammalian JAK kinases (JAK1, JAK2, JAK3 and TYK2). The invention also provides for compositions comprising such inhibitory compounds and methods of inhibiting the activity of JAK1, JAK2, JAK3 and TYK2 by administering the compound to a patient in need of treatment for myeloproliferative disorders or cancer
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Page/Page column 39
(2010/04/03)
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- INHIBITORS OF JANUS KINASES
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The instant invention provides for compounds that inhibit the four known mammalian JAK kinases (JAK1, JAK2, JAK3 and TYK2) and PDK1. The invention also provides for compositions comprising such inhibitory compounds and methods of inhibiting the activity of JAK1, JAK2, JAK3, TYK2 and PDK1 by administering the compound to a patient in need of treatment for myeloproliferative disorders or cancer.
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Page/Page column 56
(2010/04/03)
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- INHIBITORS OF JANUS KINASES
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The instant invention provides for compounds that inhibit the four known mammalian JAK kinases (JAK1, JAK2, JAK3 and TYK2) and PDK1. The invention also provides for compositions comprising such inhibitory compounds and methods of inhibiting the activity of JAK1, JAK2, JAK3, TYK2 and PDK1 by administering the compound to a patient in need of treatment for myeloproliferative disorders or cancer.
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Page/Page column 47
(2010/01/12)
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- DIARYL, DIPYRIDINYL AND ARYL-PYRIDINYL DERIVATIVES AND USES THEREOF
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Compounds of Formula (I) that act as antagonists at the mu, kappa and/or delta opioid receptors and therefore useful in the treatment of diseases, conditions and/or disorders that benefit from such antagonism in animals are described herein. Formula (I) where R, R1, R2a, R2b, R3, R4, V, R6, R7, R8, R9, W and X are described herein.
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Page/Page column 23
(2008/12/05)
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- INHIBITORS OF JANUS KINASES
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The instant invention provides for compounds that inhibit the four known mammalian JAK kinases (JAK1, JAK2, JAK3 and TYK2) and PDK1. The invention also provides for compositions comprising such inhibitory compounds and methods of inhibiting the activity of JAK1, JAK2, JAK3 TYK2 and PDK1 by administering the compound to a patient in need of treatment for myeloproliferative disorders or cancer.
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Page/Page column 82
(2009/01/23)
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- OXAZOLE TYROSINE KINASE INHIBITORS
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The invention provides a compound which is an amide of the formula (1), or a salt, solvate, N-oxide or tautomer thereof; wherein: a is 0 or 1; b is 0 or 1 : provided that the sum of a and b is 0 or 1; T is O or NH Ar1 is a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S, and being optionally substituted by one or more substituents R1; Ar2 Js a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R2; and R1 and R2are as defined in the claims. The compounds are inhibitors of kinases and in particular FLT3, FLT4 and Aurora kinases.
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Page/Page column 82-83
(2009/01/20)
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- HISTAMINE-3 RECEPTOR ANTAGONISTS
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This invention is directed to a compound of formula Ias defined herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical composition containing a compound of formula I, a process of preparation of a compound of formula I, a method of treatment of a disorder or condition that may be treated by antagonizing histamine H3 receptors, the method comprising administering to a mammal in need of such treatment a compound of formula I as described above, and a method of treatment of a disorder or condition selected from the group consisting of depression, mood disorders, schizophrenia, anxiety disorders, Alzheimer's disease, attention-deficit hyperactivity disorder (ADHD), psychotic disorders, cognitive disorders, sleep disorders, obesity, dizziness, epilepsy, motion sickness, respiratory diseases, allergy, allergy- induced airway responses, allergic rhinitis, nasal congestion, allergic congestion, congestion, hypotension, cardiovascular disease, diseases of the GI tract, hyper and hypo motility and acidic secretion of the gastro- intestinal tract, the method comprising administering to a mammal in need of such treatment a compound of formula I as described above.
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Page/Page column 69-70
(2010/11/27)
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- COMPOUNDS HAVING THROMBOPOIETIN RECEPTOR AGONISM
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A compound represented by the general formula (I): wherein R1 is a hydrogen atom, a halogen atom, or the like; R2, R3, and R4 are each independently a hydrogen atom, a halogen atom, C1-C15 alkyl optionally substituted with one or more C1-C12 alkyloxy or the like, or the like; R5 is a hydrogen atom or the like; R6 and R7 are a hydrogen atom or the like; R8 is C1-C3 alkyl or the like; R9 is a hydrogen atom or the like), a prodrug, a pharmaceutically acceptable salt, or solvate thereof.
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Page/Page column 14
(2010/11/08)
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- NOVEL BIAROMATIC COMPOUNDS THAT ACTIVATE PPAR TYPE RECEPTORS, AND USE THEREOF IN COSMETIC OR PHARMACEUTICAL COMPOSITIONS
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The invention relates to novel biaromatic compounds that correspond to the general formula (I) and also to the method for preparing them, and to their use in pharmaceutical compositions for use in human or veterinary medicine (in dermatology, and also in the field of cardiovascular diseases, immune diseases and/or lipid metabolism-related diseases), or alternatively in cosmetic compositions.
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Page/Page column 58
(2010/10/20)
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- Process for the preparation of ring compounds
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In a process for the preparation of ring compounds via a combinatorial synthesis, the reaction procedure is based on a Suzuki coupling, subsequent halo-demetallation and finally a further Suzuki coupling. The Suzuki couplings are each carried out with a boronic acid or a boronic acid ester. The reaction procedure uses provides novel ring compounds and uses novel synthesis units used for this purpose. The novel ring compounds are suitable for use as constituents in liquid-crystalline mixtures.
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