304-54-1

Upstream product

• 64252-02-4 3-(β-nitro-β-methylvinyl)indole 
• 4771-72-6 α-methyl-β-(3-indolyl)-1-nitroethane 
• 299-26-3 1-(1H-indol-3-yl)propan-2-amine 
• 371-27-7 2,2,2-trifluoroethylbutyrate 
• 108-20-3 di-isopropyl ether 
• 61535-48-6 C₂₆H₂₆N₂O₅S 
• 1039646-91-7 2,3-bis(4-methylbenzoic acid)succinic acid 
• 1100753-75-0 N-octanoylglycine 2,2,2-trifluoroethyl ester 
• 61587-85-7 (S)-2-(((benzyloxy)carbonyl)amino)-3-(1H-indol-3-yl)propyl 4-methylbenzenesulfonate 
• 1201-26-9 3-(1H-indolyl)acetone 
• 113997-58-3 (R)-1-(1H-indol-3-yl)-N-((R)-1-phenylethyl)propan-2-amine 
• 113997-59-4 (S,S)-N-α-phenetyl-1-indol-3-yl-2-aminopropane 
• 113997-60-7 (S)-1-(1H-indol-3-yl)-N-((R)-1-phenylethyl)propan-2-amine 
• 120-72-9 indole 

Downstream Products

• 1292798-84-5 (R)-N-[1-(1H-indol-3-yl)propan-2-yl]-2-methoxyacetamide 
• 7795-51-9 (+)-alpha-Methyltryptamine 
• 7795-52-0 (-)-alpha-Methyltryptamine 
• 1193314-21-4 (1R,3S)-5'-chloro-3-methyl-2,3,4,9-tetrahydrospiro[β-carboline-1,3'-indol]-2'(1'H)-one 

Relevant academic research and scientific papers

Stereoselective Cascade to C3-Methylated Strictosidine Derivatives Employing Transaminases and Strictosidine Synthases

(S)-Strictosidine represents the first key intermediate in the biosynthesis of several pharmaceutically relevant monoterpenoid indole alkaloids. Optically pure C3-methyl-substituted strictosidine derivatives were prepared by setting up the two stereogenic centers at the β-carboline core via two enzymatic steps catalyzed by the enzymes transaminase and strictosidine synthase in a one-pot cascade fashion. The two enzymatic steps were performed simultaneously as well as in a stepwise fashion. The amination of the prochiral ketones led to optically pure amines with up to >98% enantiomeric excess. Depending on the enzyme used, the (S)- and (R)-enantiomers were prepared in most cases. Selected amines were then condensed with secologanin in a Pictet-Spengler reaction catalyzed by strictosidine synthase leading to diastereomerically pure products (>98% diastereomeric excess).

PROCESSES FOR MAKING SERD TRICYCLIC COMPOUNDS HAVING A SUBSTITUTED PHENYL OR PYRIDINYL MOIETY

Provided herein are processes for the preparation of compounds useful in the treatment of cancer.

Guanidine-containing compound as well as preparation method and application thereof

The invention discloses a cyanoguanidine-containing compound as well as a preparation method and application thereof. The invention also discloses a composition containing the cyanoguanidine-structured compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The invention also discloses application thereof in preparation of analgesic drugs. The compounds of the invention are useful in the treatment of various pain.

REGIMENS OF ESTROGEN RECEPTOR ANTAGONISTS

Provided herein are methods of administering estrogen receptor antagonists for use in treatment of cancer. The antagonists (such as a hexahydro pyrido[3,4-b]indole, AZD9496, RAD-1901, ARN-810, endoxifen, or fulvestrant) may be an inhibitor of both activating function 1 and activating function 2 of the estrogen receptor. Also provided are combinations of above inhibitors with a secondary agent, which is a CDK 4/6 inhibitor (such as, palbocociclib, ribociclib, abemaciclib, lerociclib, and trilaciclib).

METHODS OF TREATING ESTROGEN RECEPTOR-ASSOCIATED DISEASES

The present disclosure provides methods of treating estrogen receptor-associated diseases, disorders, and conditions.

Efficient Manufacturing Process for the Selective Estrogen Receptor Degrader GDC-9545 (Giredestrant) via a Crystallization-Driven Diastereoselective Pictet-Spengler Condensation

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.

Preparation method of chiral alpha-methyl arylethylamine

The invention provides a preparation method of chiral alpha-methyl arylethylamine, and relates to the technical field of organic synthesis medicines. Boc-amino acid methyl ester is used as an initial raw material, Boc-amino alcohol is obtained through reduction, Boc-amino alcohol reacts with thionyl chloride and is oxidized through sodium periodate to obtain a sulfonamide compound, and then the sulfonamide compound is reduced through sodium borohydride promoted by lewis acid and a protecting group is removed under the acidic condition to obtain a target compound. According to the method, raw materials are cheap and easy to obtain, a single optical isomer product is obtained by using chiral raw materials, the problem of column chromatography resolution is solved, generation of a large amount of solid wastes and isomers is avoided, atom economy is improved, the product purity is high, the yield is high, and the production cost is effectively reduced. In addition, the mild reduction system is used for replacing the original high-pressure hydrogenation reaction, the process operation is relatively simple, and the method is more suitable for large-scale industrial production.

The base-free van Leusen reaction of cyclic imines on water: Synthesis of N-fused imidazo 6,11-dihydro β-carboline derivatives

Construction of imidazoles has been demonstrated on water under base-free conditions. The reaction of dihydro β-carboline imines and p-toluenesulfonylmethyl isocyanides furnished the corresponding substituted N-fused imidazo 6,11-dihydro β-carboline derivatives in very good yields under ambient conditions. The use of deuterium oxide (D2O) as a solvent enabled the incorporation of deuterium isotopes in the imidazole ring.

Virtual screening-driven discovery of dual 5-HT6/5-HT2A receptor ligands with pro-cognitive properties

A virtual screening campaign aimed at finding structurally new compounds active at 5-HT6R provided a set of candidates. Among those, one structure, 4-(5-{[(2-{5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)amino]methyl}furan-2-yl)phenol (1, 5-HT6R Ki = 91 nM), was selected as a hit for further optimization. As expected, the chemical scaffold of selected compound was significantly different from all the serotonin receptor ligands published to date. Synthetic efforts, supported by molecular modelling, provided 43 compounds representing different substitution patterns. The derivative 42, 4-(5-{[(2-{5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)amino]methyl}furan-2-yl)phenol (5-HT6R Ki = 25, 5-HT2AR Ki = 32 nM), was selected as a lead and showed a good brain/plasma concentration profile, and it reversed phencyclidine-induced memory impairment. Considering the unique activity profile, the obtained series might be a good starting point for the development of a novel antipsychotic or antidepressant with pro-cognitive properties.

SOLID FORMS OF 3-((1R,3R)-1-(2,6-DIFLUORO-4-((1-(3-FLUOROPROPYL)AZETIDIN-3-YL)AMINO)PHENYL)-3-METHYL-1,3,4,9-TETRAHYDRO-2H-PYRIDO[3,4-B]INDOL-2-YL)-2,2-DIFLUOROPROPAN-1-OL AND PROCESSES FOR PREPARING FUSED TRICYCLIC COMPOUNDS COMPRISING A SUBSTITUTED PHENYL OR PYRIDINYL MOIETY, INCLUDING METHODS OF THEIR USE

Provided herein are solid forms, salts such as compound B, and formulations of 3-((lR,3R)-l-(2,6-difluoro-4-((l-(3-fluoropropyl) azetidin-3-yl)amino)phenyl)-3-methyl-l,3,4,9-tetrahydro-2H- pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-l-ol, processes and synthesis thereof, and methods of their use in the treatment of cancer.