Ring expanded analogues of the indole hit

[MFernflower]

While analogues of indole hit are currently under investigation they have all currently been either monocyclic or an indole-shaped ring system (indazole for example) - there have been no 6+6 bicyclic systems tested (quinoxaline etc) as of the time of writing this. Some digging into commercial libraries have found precursors that can be funneled into the chloramine-T one-pot protocol currently being worked on by @maratsydney after one or two synthetic steps (methyl esterifcation of the raw acids and DIBAL-H reduction of the methyl esters of each precursor)

http://www.matrixscientific.com/006735.html Methyl 2-naphthoate - 13 USD a gram - might be already in lab stock? http://www.matrixscientific.com/010038.html Quinoline-6-carboxylic acid - 20 USD per two grams - might be already in lab stock? https://www.sigmaaldrich.com/catalog/product/aldrich/703818?lang=en&region=AU - 61 AUD for a single gram from sigma - Methyl 6-quinoxalinecarboxylate https://www.sigmaaldrich.com/catalog/product/aldrich/635995?lang=en&region=AU - Benzodioxane ring system - 6-boronic acid is less than 80 AUD per gram

Unfortunately, the closest 6+6 analogue of indole is 1,2,3,4‐tetrahydroquinoline but finding the needed boronic acid is difficult as commercial coverage of 6 subbed 1,2,3,4‐tetrahydroquinoline cores is spotty and expensive

Update 6/25/2018 - The Tetrahydroquinoline 6-COOH is purchasable from ENAMINE - https://www.enaminestore.com/catalog/EN300-37427

LogP will take huge hit but I feel these compounds are a logical follow on from the indole hit

[david1597]

Some thoughts (inc. comments from a quick discussion with @mattodd and @edwintse).

• In terms of synthetic feasibility: should be relatively straightforward and simple to do.

• In terms of desirability: maybe. It’d be good to have defined reasons eg improved “insert some ADME/DMPK property” for further compounds we make. @mcoster made a succinct post about this recently:

There seem to be a number of recent structural changes that benefit potency... However, we also need to keep in mind what these changes do to the ADME/DMPK properties... to prioritise future directions, it would be really helpful to chart out the key structures, with not only the potency, but also cLogP and other key indicators....

• That said, there is an argument to look at them anyway, as even if clogP or another parameter isn't ideal, as we could subsequently combine with a LHS that is good in that respect.

• @edwintse pointed out that the naphthyl has already been made (with phenylethanol on the LHS) [OSM-S-297] which had a potency of 415 nM. cLogP is indeed a bit high at 4.2.

• @mattodd summed up the initial observation that it "seems like we need something in para position and then potentially H-bond donor in meta. Tetrahydroquinoline would be obvious, or 3,4-dihydroquinoline. Those would be structurally in between naphthyl and indole."

• I think we wait until we get the next set of results from Dundee and then make some decisions, (Dundee received our June shipment last week) although no problem with starting that discussion now! Good one for starting this as a separate issue @MFernflower - some of our recent issues have become quite lengthy with lots of separate ideas in them.

[MFernflower]

54

So just as a point of reference these are the three compounds that will most likely be telling of some SAR aspect? @david1597 @mattodd

http://www.matrixscientific.com/010038.html https://www.sigmaaldrich.com/catalog/product/aldrich/635995?lang=en&region=AU

UPDATE JULY 7TH: going off the latest batch of potency results it seems the quinolinyl and tetrahydroquinolinyl compounds would be the most telling and are the two that should actually be synthesized

I still cannot find a commercial source for the tetrahydroquinoline-6-subbed precursor (either BOC protected aldehyde or unprotected boronic acid) - might need to make it?

[mattodd]

Looks good, and let's leave this here for a bit (it really needs to go onto the DKNYS page on the wiki), but we do at the moment have several sub-100 nM compounds where we can imagine adding a benzylic hydroxyl (as per Pfizer compounds) that would likely increase potency and solubility more, so I'd say those specific compounds are currently of a higher priority. We need, in the coming week or so, to bring up to date the current target hitlist for chemistry.

[MFernflower]

A chemistry update would be fantastic so I can get back into the rhythm of things @Mattodd @edwintse @maratsydney