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16th December 2014 @ 22:51

Which molecules to make next in Open Source Malaria Series 4?

The full reasoning is below. The executive summary is that OSM needs these ten molecules:

OSM Christmas Top Ten

And if you'd like to synthesise them yourself (open source only please), or suggest better ones, you're free to do so. You can comment on this post below (easy login via Google), on Twitter, Github, G+ or email (opensourcemalaria at gmail).

 
1. Immediate Actions on the Frontrunners

Some good-looking compounds are known that possess chiral amine groups in the northwest, and some analogs are currently being synthesized in the lab: (note GHI=“Git Hub Issue”, e.g. GHI 242)

Benzylic Amines Series 4

Of interest here are:

  i) whether the compound activity arises from one of the enantiomers,

  ii) the metabolic profile of these compounds. Primary amines should be better than tertiary from the point of view of hERG and metabolic stability (the substitution of fluorophenyl for phenyl is for synthetic ease and won’t improve matters, but can be dealt with later), and

  iii) whether the mono-methyl substituent (in MMV670763) really does obliterate activity (a surprising result given the surrounding compounds)

Alice Williamson has said that the cyano substituent has caused solubility problems in the lab, so this will be changed to OCHF2, CF3 or Cl. Of these perhaps the most interesting compound will be the one containing the primary amine. So the immediate aim is to synthesize compounds A-C below racemic and enantiopure (using phenylglycine), to confirm activity and to check logD/clearance. The racemate could also be sent out to interested parties for a resolution. While the cLogP’s of these compounds are too high, the evaluation of these compounds has the other benefits of addressing the points above.

Priority Amines

Compounds D-F are of interest but secondary targets - these are available to synthesize by anyone, and would be tested as for A-C, and included in the first OSM Series 4 paper.

For the compounds with ethers/alcohols in the benzylic position, again there are compounds in development and there are relevant knowns:

Ethers Underway

The same comments apply about the cyano substituent generating solubility problems, so that will be changed in the compounds to be prioritized. The suitably altered alcohol (GHI235) and ether (GHI236) remain of interest, again with a view to separating enantiomers, most likely by HPLC using the services of a contributing lab. The exploration of alkyl substitution in the northwest is of interest, but the only known example of this substitution (MMV670762) was inactive. The compound with the dimethyl substitution will be prioritized, with the mono methyl as a backup. Hence these compounds can be added to the shortlist:

Priority Ethers

 

2. Parking the Amide Series For Now

The amide series possesses many active compounds, but recent data has suggested this series presents more of a hERG and Aldehyde Oxidase risk than the ether series, so will for the moment be parked. Relevant data:

Compounds sent for evaluation against the hERG ion channel at AstraZeneca

Results of Series 4 Aldehyde Oxidase Assay

The amides have also demonstrated extreme sensitivity to substitution in the northwest aromatic ring, without a significant increase in the potency:

Evaluation of Latest Series 4 Analogs in Ether and Amide Series

The amide series is therefore a lower priority than the ether series at present. The relevant synthetic chemistry that was being developed by Tom (carbonylation) will be written up as a community opportunity for someone interested in a methodology project.


3. Acting on the Aldehyde Oxidase Data

The data obtained from Pfizer:

Results of Series 4 Aldehyde Oxidase Assay

indicate that though AO activity is a risk for some members of the series, several potent compounds are not substrates. The inherited project data also show that simple blocking of the pyrazinyl ring reduce potency:

Aldehyde Oxidase Blocking

(note also that likely metabolites are inactive:)

Lactam AO products

Jamie Scott is making some analogs based on a triazolopyridine, (GHI 266 and 267) to see if the presence of the relevant ring nitrogen is important for potency, and this would allow testing in an AO assay:

Jamie Scott Targets

Given these findings, and Jamie's current efforts, there is low current need to modify the triazolopyrazine core further to try to reduce/investigate AO activity.



4. Explore Changes in Northeast

The major synthetic focus is exploration of new substitution in the Northeast. What’s known about variation here is already on the wiki, but is repeated here, including some new more recent results. The para-substituent on the aromatic ring can be OCF3 or OCHF2 but seemingly not CH3:

 CH3 vs CF3 vs CHF2

Pyridyl has proven to be a poor choice, though there is a known potent compound with a substituted pyridine in this position, and clearly the pyridine helps lower logP:

Pyridine Substitution of Triazole

Aliphatic or other changes in the Northeast have to date proven to lower potency:

Aliphatic Triazole Substitution

Previous suggestions for analogs with variation in the Northeast include many suggestions from Alice in response to ESAC report

ESAC Report 2014

shown on GHI 261.

Suggestions for interesting compounds to make in the next round are these:

Northeast Shortlist

5. Summary of Metabolic Data vs. Solubility vs. cLogP

An important To Do items is to create a spreadsheet of all the available metabolic, solubility and predicted solubility data for Series 4 (shown as pictures on the wiki) to check:

i) impact of solubility on clearance
ii) accuracy of cLogP predictions vs. reality

This is an open To Do item that will be actioned and posted separately, though the results may alter compound design.

6. The Shortlist

Taking into account the above, and the need for a cLogP of less than 3, the 2014 Christmas Top 10 is as follows:

2014 Christmas Top Ten

If you'd like to contribute to OSM, you can

i) Make these compounds yourself, or others on this page. You need to work in the open.

ii) Suggest better compounds for the shortlist below (using a Google login) or on Twitter (@O_S_M), on Github or on Google+, or as a last resort (since it's not open) use email (opensourcemalaria at gmail)

iii) Do some predictive modeling of these compounds to suggest metabolic liabilities they may possess.

Happy holidays everyone!

 

(This post authored originally by Mat Todd. This content, as with all OSM content, is CC-BY)



Strings for molecules mentioned in this post

GHI242 CN(C)C(C1=CC=CC=C1)COC2=CN=CC3=NN=C(C4=CC=C(C#N)C=C4)N32 InChI=1S/C22H20N6O/c1-27(2)19(17-6-4-3-5-7-17)15-29-21-14-24-13-20-25-26-22(28(20)21)18-10-8-16(12-23)9-11-18/h3-11,13-14,19H,15H2,1-2H3 RQLWYQJRHWLJKI-UHFFFAOYSA-N

GHI241 CNC(C1=CC=CC=C1)COC2=CN=CC3=NN=C(C4=CC=C(C#N)C=C4)N32 InChI=1S/C21H18N6O/c1-23-18(16-5-3-2-4-6-16)14-28-20-13-24-12-19-25-26-21(27(19)20)17-9-7-15(11-22)8-10-17/h2-10,12-13,18,23H,14H2,1H3 FGPUCVLDQMTWKM-UHFFFAOYSA-N

GHI240 NC(C1=CC=CC=C1)COC2=CN=CC3=NN=C(C4=CC=C(C#N)C=C4)N32 InChI=1S/C20H16N6O/c21-10-14-6-8-16(9-7-14)20-25-24-18-11-23-12-19(26(18)20)27-13-17(22)15-4-2-1-3-5-15/h1-9,11-12,17H,13,22H2 RGOLJPNZJGCEBP-UHFFFAOYSA-N

MMV670437 FC(C=C1)=C(F)C=C1C(N(C)C)COC2=CN=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32 InChI=1S/C22H19F4N5O2/c1-30(2)18(14-5-8-16(23)17(24)9-14)12-32-20-11-27-10-19-28-29-21(31(19)20)13-3-6-15(7-4-13)33-22(25)26/h3-11,18,22H,12H2,1-2H3 PMIWBIXSAYKRGF-UHFFFAOYSA-N

MMV670763 FC(C=C1)=C(F)C=C1C(N([H])C)COC2=CN=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32 InChI=1S/C21H17F4N5O2/c1-26-17(13-4-7-15(22)16(23)8-13)11-31-19-10-27-9-18-28-29-20(30(18)19)12-2-5-14(6-3-12)32-21(24)25/h2-10,17,21,26H,11H2,1H3 YFUIAROYVNJDHR-UHFFFAOYSA-N

MMV671651 FC(C=C1)=C(F)C=C1C(N([H])[H])COC2=CN=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32 InChI=1S/C20H15F4N5O2/c21-14-6-3-12(7-15(14)22)16(25)10-30-18-9-26-8-17-27-28-19(29(17)18)11-1-4-13(5-2-11)31-20(23)24/h1-9,16,20H,10,25H2 BIGCWGPLTSPPFJ-UHFFFAOYSA-N

Compound A: NC(C1=CC=CC=C1)COC2=CN=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32 InChI=1S/C20H17F2N5O2/c21-20(22)29-15-8-6-14(7-9-15)19-26-25-17-10-24-11-18(27(17)19)28-12-16(23)13-4-2-1-3-5-13/h1-11,16,20H,12,23H2 APNVCAYADQJJBZ-UHFFFAOYSA-N

Compound B: NC(C1=CC=CC=C1)COC2=CN=CC3=NN=C(C4=CC=C(OC(F)(F)F)C=C4)N32 InChI=1S/C20H16F3N5O2/c21-20(22,23)30-15-8-6-14(7-9-15)19-27-26-17-10-25-11-18(28(17)19)29-12-16(24)13-4-2-1-3-5-13/h1-11,16H,12,24H2 INWYDCAJFDBEMF-UHFFFAOYSA-N

Compound C: ClC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(N)C4=CC=CC=C4)N32 InChI=1S/C19H16ClN5O/c20-15-8-6-14(7-9-15)19-24-23-17-10-22-11-18(25(17)19)26-12-16(21)13-4-2-1-3-5-13/h1-11,16H,12,21H2 DNSLEDXZUCYMEH-UHFFFAOYSA-N

Compound D: CNC(C1=CC=CC=C1)COC2=CN=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32 InChI=1S/C21H19F2N5O2/c1-24-17(14-5-3-2-4-6-14)13-29-19-12-25-11-18-26-27-20(28(18)19)15-7-9-16(10-8-15)30-21(22)23/h2-12,17,21,24H,13H2,1H3 NXAYCBUWEUBZHA-UHFFFAOYSA-N

Compound E: CNC(C1=CC=CC=C1)COC2=CN=CC3=NN=C(C4=CC=C(OC(F)(F)F)C=C4)N32 InChI=1S/C21H18F3N5O2/c1-25-17(14-5-3-2-4-6-14)13-30-19-12-26-11-18-27-28-20(29(18)19)15-7-9-16(10-8-15)31-21(22,23)24/h2-12,17,25H,13H2,1H3 HGKAZGKLOVRNSC-UHFFFAOYSA-N

Compound F: ClC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(NC)C4=CC=CC=C4)N32 InChI=1S/C20H18ClN5O/c1-22-17(14-5-3-2-4-6-14)13-27-19-12-23-11-18-24-25-20(26(18)19)15-7-9-16(21)10-8-15/h2-12,17,22H,13H2,1H3 MEBGOUOIJWXZQK-UHFFFAOYSA-N

GHI235 OC(C1=CC=CC=C1)COC2=CN=CC3=NN=C(C4=CC=C(C#N)C=C4)N32 InChI=1S/C20H15N5O2/c21-10-14-6-8-16(9-7-14)20-24-23-18-11-22-12-19(25(18)20)27-13-17(26)15-4-2-1-3-5-15/h1-9,11-12,17,26H,13H2 DAFIYRWZRZBCCQ-UHFFFAOYSA-N

GHI235 (Fluoro Analog) OC(C1=CC(F)=C(F)C=C1)COC2=CN=CC3=NN=C(C4=CC=C(C#N)C=C4)N32 InChI=1S/C20H13F2N5O2/c21-15-6-5-14(7-16(15)22)17(28)11-29-19-10-24-9-18-25-26-20(27(18)19)13-3-1-12(8-23)2-4-13/h1-7,9-10,17,28H,11H2 HHHWRCNBDNZMPN-UHFFFAOYSA-N

GHI236 COC(C1=CC=CC=C1)COC2=CN=CC3=NN=C(C4=CC=C(C#N)C=C4)N32 InChI=1S/C21H17N5O2/c1-27-18(16-5-3-2-4-6-16)14-28-20-13-23-12-19-24-25-21(26(19)20)17-9-7-15(11-22)8-10-17/h2-10,12-13,18H,14H2,1H3 QAGSTSUWCMAMBB-UHFFFAOYSA-N

GHI239 CC(OC)COC1=CN=CC2=NN=C(C3=CC=C(C#N)C=C3)N21 InChI=1S/C16H15N5O2/c1-11(22-2)10-23-15-9-18-8-14-19-20-16(21(14)15)13-5-3-12(7-17)4-6-13/h3-6,8-9,11H,10H2,1-2H3 PDPLSDFAIQBTIZ-UHFFFAOYSA-N

GHI238 COC(C)(C)COC1=CN=CC2=NN=C(C3=CC=C(C#N)C=C3)N21 InChI=1S/C17H17N5O2/c1-17(2,23-3)11-24-15-10-19-9-14-20-21-16(22(14)15)13-6-4-12(8-18)5-7-13/h4-7,9-10H,11H2,1-3H3 QCZSLJNWYVZRRV-UHFFFAOYSA-N

MMV672723 FC(C=C1)=C(F)C=C1C(O)(C)COC2=CN=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32 InChI=1S/C21H16F4N4O3/c1-21(30,13-4-7-15(22)16(23)8-13)11-31-18-10-26-9-17-27-28-19(29(17)18)12-2-5-14(6-3-12)32-20(24)25/h2-10,20,30H,11H2,1H3 NBSLUXDUMZFLCA-UHFFFAOYSA-N

MMV672687 FC(C=C1)=C(F)C=C1C(O)COC2=CN=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32 InChI=1S/C20H14F4N4O3/c21-14-6-3-12(7-15(14)22)16(29)10-30-18-9-25-8-17-26-27-19(28(17)18)11-1-4-13(5-2-11)31-20(23)24/h1-9,16,20,29H,10H2 BXEWPSCIVPVASC-UHFFFAOYSA-N

MMV670762 FC(OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(F)(F)F)N32)F InChI=1S/C14H9F5N4O2/c15-13(16)25-9-3-1-8(2-4-9)12-22-21-10-5-20-6-11(23(10)12)24-7-14(17,18)19/h1-6,13H,7H2 VZIMTSNALAAOKI-UHFFFAOYSA-N

Compound G: OC(C1=CC=CC=C1)COC2=CN=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32 InChI=1S/C20H16F2N4O3/c21-20(22)29-15-8-6-14(7-9-15)19-25-24-17-10-23-11-18(26(17)19)28-12-16(27)13-4-2-1-3-5-13/h1-11,16,20,27H,12H2 GEHCMLKWLSBHDX-UHFFFAOYSA-N

Compound H: OC(C1=CC=CC=C1)COC2=CN=CC3=NN=C(C4=CC=C(OC(F)(F)F)C=C4)N32 InChI=1S/C20H15F3N4O3/c21-20(22,23)30-15-8-6-14(7-9-15)19-26-25-17-10-24-11-18(27(17)19)29-12-16(28)13-4-2-1-3-5-13/h1-11,16,28H,12H2 ZBQZXWIEUVKEGD-UHFFFAOYSA-N

Compound I: ClC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(O)C4=CC=CC=C4)N32 InChI=1S/C19H15ClN4O2/c20-15-8-6-14(7-9-15)19-23-22-17-10-21-11-18(24(17)19)26-12-16(25)13-4-2-1-3-5-13/h1-11,16,25H,12H2 KDXBMCNZHBPMID-UHFFFAOYSA-N

Compound J: COC(C1=CC=CC=C1)COC2=CN=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32 InChI=1S/C21H18F2N4O3/c1-28-17(14-5-3-2-4-6-14)13-29-19-12-24-11-18-25-26-20(27(18)19)15-7-9-16(10-8-15)30-21(22)23/h2-12,17,21H,13H2,1H3 YDHUWNKEIONDLX-UHFFFAOYSA-N

Compound K: COC(C1=CC=CC=C1)COC2=CN=CC3=NN=C(C4=CC=C(OC(F)(F)F)C=C4)N32 InChI=1S/C21H17F3N4O3/c1-29-17(14-5-3-2-4-6-14)13-30-19-12-25-11-18-26-27-20(28(18)19)15-7-9-16(10-8-15)31-21(22,23)24/h2-12,17H,13H2,1H3 XZNMMEOLACDFOM-UHFFFAOYSA-N

Compound L: ClC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(OC)C4=CC=CC=C4)N32 InChI=1S/C20H17ClN4O2/c1-26-17(14-5-3-2-4-6-14)13-27-19-12-22-11-18-23-24-20(25(18)19)15-7-9-16(21)10-8-15/h2-12,17H,13H2,1H3 FJXGOWUTCAFUKB-UHFFFAOYSA-N

Compound M: COC(C)(C)COC1=CN=CC2=NN=C(C3=CC=C(OC(F)F)C=C3)N21 InChI=1S/C17H18F2N4O3/c1-17(2,24-3)10-25-14-9-20-8-13-21-22-15(23(13)14)11-4-6-12(7-5-11)26-16(18)19/h4-9,16H,10H2,1-3H3 QPGDQEMNKJULOO-UHFFFAOYSA-N

Compound N: COC(C)(C)COC1=CN=CC2=NN=C(C3=CC=C(OC(F)(F)F)C=C3)N21 InChI=1S/C17H17F3N4O3/c1-16(2,25-3)10-26-14-9-21-8-13-22-23-15(24(13)14)11-4-6-12(7-5-11)27-17(18,19)20/h4-9H,10H2,1-3H3 JLRZYQRSTMYUNL-UHFFFAOYSA-N

Compound O: ClC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(C)(C)OC)N32 InChI=1S/C16H17ClN4O2/c1-16(2,22-3)10-23-14-9-18-8-13-19-20-15(21(13)14)11-4-6-12(17)7-5-11/h4-9H,10H2,1-3H3 CSHXFYLIRDWKAB-UHFFFAOYSA-N

Compound P: COC(C)COC1=CN=CC2=NN=C(C3=CC=C(OC(F)F)C=C3)N21 InChI=1S/C16H16F2N4O3/c1-10(23-2)9-24-14-8-19-7-13-20-21-15(22(13)14)11-3-5-12(6-4-11)25-16(17)18/h3-8,10,16H,9H2,1-2H3 JOIANTFQDWQBSI-UHFFFAOYSA-N

Compound Q: COC(C)COC1=CN=CC2=NN=C(C3=CC=C(OC(F)(F)F)C=C3)N21 InChI=1S/C16H15F3N4O3/c1-10(24-2)9-25-14-8-20-7-13-21-22-15(23(13)14)11-3-5-12(6-4-11)26-16(17,18)19/h3-8,10H,9H2,1-2H3 KMHXMKGJDPCJNH-UHFFFAOYSA-N

Compound R: ClC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(C)OC)N32 InChI=1S/C15H15ClN4O2/c1-10(21-2)9-22-14-8-17-7-13-18-19-15(20(13)14)11-3-5-12(16)6-4-11/h3-8,10H,9H2,1-2H3 PCMAXZRFAMSVAN-UHFFFAOYSA-N

MMV668823 FC1=C(F)C=CC(CCOC2=CN=C(Cl)C3=NN=C(C4=CC=C(OC(F)F)C=C4)N32)=C1 InChI=1S/C20H13ClF4N4O2/c21-17-19-28-27-18(12-2-4-13(5-3-12)31-20(24)25)29(19)16(10-26-17)30-8-7-11-1-6-14(22)15(23)9-11/h1-6,9-10,20H,7-8H2 FOQQXRIKYKUBGB-UHFFFAOYSA-N

MMV669102 FC1=C(F)C=CC(CCOC2=CN=C(N(CC)CC)C3=NN=C(C4=CC=C(OC(F)F)C=C4)N32)=C1 InChI=1S/C24H23F4N5O2/c1-3-32(4-2)22-23-31-30-21(16-6-8-17(9-7-16)35-24(27)28)33(23)20(14-29-22)34-12-11-15-5-10-18(25)19(26)13-15/h5-10,13-14,24H,3-4,11-12H2,1-2H3 XEJMUSAAKCRDEX-UHFFFAOYSA-N

MMV669541 FC1=C(F)C=CC(CCOC2=CN=C(C)C3=NN=C(C4=CC=C(OC(F)F)C=C4)N32)=C1 InChI=1S/C21H16F4N4O2/c1-12-19-27-28-20(14-3-5-15(6-4-14)31-21(24)25)29(19)18(11-26-12)30-9-8-13-2-7-16(22)17(23)10-13/h2-7,10-11,21H,8-9H2,1H3 ZOSZOZWECBRIDQ-UHFFFAOYSA-N

MMV669311 FC1=C(F)C=CC(CCOC2=CN=C(N)C3=NN=C(C4=CC=C(OC(F)F)C=C4)N32)=C1 InChI=1S/C20H15F4N5O2/c21-14-6-1-11(9-15(14)22)7-8-30-16-10-26-17(25)19-28-27-18(29(16)19)12-2-4-13(5-3-12)31-20(23)24/h1-6,9-10,20H,7-8H2,(H2,25,26) XAQYLJFKZCILRM-UHFFFAOYSA-N

MMV675960 FC1=C(F)C=CC(CCOC2=CN=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32)=C1 InChI=1S/C20H14F4N4O2/c21-15-6-1-12(9-16(15)22)7-8-29-18-11-25-10-17-26-27-19(28(17)18)13-2-4-14(5-3-13)30-20(23)24/h1-6,9-11,20H,7-8H2 DEEWBVYNQGALDU-UHFFFAOYSA-N

MMV669025 FC1=C(F)C=CC(CCOC2=CNC(C3=NN=C(C4=CC=C(OC(F)F)C=C4)N32)=O)=C1 InChI=1S/C20H14F4N4O3/c21-14-6-1-11(9-15(14)22)7-8-30-16-10-25-19(29)18-27-26-17(28(16)18)12-2-4-13(5-3-12)31-20(23)24/h1-6,9-10,20H,7-8H2,(H,25,29) ZXMYJCVYBZFJIJ-UHFFFAOYSA-N

MMV668822 FC1=C(F)C=CC(CCOC2=C[N+]([O-])=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32)=C1 InChI=1S/C20H14F4N4O3/c21-15-6-1-12(9-16(15)22)7-8-30-18-11-27(29)10-17-25-26-19(28(17)18)13-2-4-14(5-3-13)31-20(23)24/h1-6,9-11,20H,7-8H2 CUNPWKYJVCNHNZ-UHFFFAOYSA-N

Jamie1: ClC1=CC=CC=C1CCOC2=CC=CC3=NN=C(C4=CC=C(C#N)C=C4)N32 InChI=1S/C21H15ClN4O/c22-18-5-2-1-4-16(18)12-13-27-20-7-3-6-19-24-25-21(26(19)20)17-10-8-15(14-23)9-11-17/h1-11H,12-13H2 APTFJFHOJWNXBX-UHFFFAOYSA-N

Jamie 2: O=C(NC1=CC(Cl)=CC=C1)C2=CC=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32 InChI=1S/C20H13ClF2N4O2/c21-13-3-1-4-14(11-13)24-19(28)16-5-2-6-17-25-26-18(27(16)17)12-7-9-15(10-8-12)29-20(22)23/h1-11,20H,(H,24,28) NVCZJGCEAVJDRA-UHFFFAOYSA-N

Jamie 3: O=C(NC1=CC(C(F)(F)F)=NC=C1)C2=CC=CC3=NN=C(C4=CC=C(C#N)C=C4)N32 InChI=1S/C20H11F3N6O/c21-20(22,23)16-10-14(8-9-25-16)26-19(30)15-2-1-3-17-27-28-18(29(15)17)13-6-4-12(11-24)5-7-13/h1-10H,(H,25,26,30) PGPJMFWOQCDCCV-UHFFFAOYSA-N

MMV675947 OSM-S-254 O=C(NC1=CC(Cl)=CC=C1C)C2=CN=CC(N23)=NN=C3C4=CC=C(OC(F)F)C=C4 InChI=1S/C20H14ClF2N5O2/c1-11-2-5-13(21)8-15(11)25-19(29)16-9-24-10-17-26-27-18(28(16)17)12-3-6-14(7-4-12)30-20(22)23/h2-10,20H,1H3,(H,25,29) QKXZFYOMVFGRGS-UHFFFAOYSA-N

MMV675952 OSM-S-257 O=C(NC1=CC(Cl)=CC=C1C)C2=CN=CC(N23)=NN=C3C4=CC=C(OC)C=C4 InChI=1S/C20H16ClN5O2/c1-12-3-6-14(21)9-16(12)23-20(27)17-10-22-11-18-24-25-19(26(17)18)13-4-7-15(28-2)8-5-13/h3-11H,1-2H3,(H,23,27) NFXWTMUWMZSIFL-UHFFFAOYSA-N

MMV675946 OSM-S-204 O=C(NC1=C(F)C(Cl)=CC=C1)C2=CN=CC(N23)=NN=C3C4=CC=C(OC(F)F)C=C4 InChI=1S/C19H11ClF3N5O2/c20-12-2-1-3-13(16(12)21)25-18(29)14-8-24-9-15-26-27-17(28(14)15)10-4-6-11(7-5-10)30-19(22)23/h1-9,19H,(H,25,29) WBRLFZGDBUVKSB-UHFFFAOYSA-N

MMV675951 OSM-S-256 O=C(NC1=C(F)C(Cl)=CC=C1)C2=CN=CC(N23)=NN=C3C4=CC=C(OC)C=C4 InChI=1S/C19H13ClFN5O2/c1-28-12-7-5-11(6-8-12)18-25-24-16-10-22-9-15(26(16)18)19(27)23-14-4-2-3-13(20)17(14)21/h2-10H,1H3,(H,23,27) FWGBPGUTIFKBOZ-UHFFFAOYSA-N

MMV675963 OSM-S-271 O=C(NC1=CC(Cl)=CC=C1)C2=CN=CC(N23)=NN=C3C4=CC=C(OC(F)(F)F)C=C4 InChI=1S/C19H11ClF3N5O2/c20-12-2-1-3-13(8-12)25-18(29)15-9-24-10-16-26-27-17(28(15)16)11-4-6-14(7-5-11)30-19(21,22)23/h1-10H,(H,25,29) KPPYAXXEDYTONY-UHFFFAOYSA-N

MMV669542 OSM-S-202 O=C(NC1=CC(Cl)=CC=C1)C2=CN=CC(N23)=NN=C3C4=CC=C(OC(F)F)C=C4 InChI=1S/C19H12ClF2N5O2/c20-12-2-1-3-13(8-12)24-18(28)15-9-23-10-16-25-26-17(27(15)16)11-4-6-14(7-5-11)29-19(21)22/h1-10,19H,(H,24,28) AJGOFYWOTIIYLR-UHFFFAOYSA-N

OSM-S-201 O=C(NC1=C(C)C(Cl)=CC=C1)C2=CN=CC(N23)=NN=C3C4=CC=C(OC(F)F)C=C4 InChI=1S/C20H14ClF2N5O2/c1-11-14(21)3-2-4-15(11)25-19(29)16-9-24-10-17-26-27-18(28(16)17)12-5-7-13(8-6-12)30-20(22)23/h2-10,20H,1H3,(H,25,29) IVENWLQUYSRINV-UHFFFAOYSA-N

MMV675950 OSM-S-255 O=C(NC1=C(C)C(Cl)=CC=C1)C2=CN=CC(N23)=NN=C3C4=CC=C(OC)C=C4 InChI=1S/C20H16ClN5O2/c1-12-15(21)4-3-5-16(12)23-20(27)17-10-22-11-18-24-25-19(26(17)18)13-6-8-14(28-2)9-7-13/h3-11H,1-2H3,(H,23,27) LIAWHOKMZQICES-UHFFFAOYSA-N

Compound S: OC(C1=CC=CC=C1)COC2=CN=CC3=NN=C(C4CCCCC4)N32 InChI=1S/C19H22N4O2/c24-16(14-7-3-1-4-8-14)13-25-18-12-20-11-17-21-22-19(23(17)18)15-9-5-2-6-10-15/h1,3-4,7-8,11-12,15-16,24H,2,5-6,9-10,13H2 LWDWZIVAQMSZHL-UHFFFAOYSA-N

Compound T: OC(C1=CC=CC=C1)COC2=CN=CC3=NN=C(C4=CC=CC=C4)N32 InChI=1S/C19H16N4O2/c24-16(14-7-3-1-4-8-14)13-25-18-12-20-11-17-21-22-19(23(17)18)15-9-5-2-6-10-15/h1-12,16,24H,13H2 HQWUAOFYEUBLBZ-UHFFFAOYSA-N

Compound U: OC(C1=CC=CC=C1)COC2=CN=CC3=NN=C(C4COC4)N32 InChI=1S/C16H16N4O3/c21-13(11-4-2-1-3-5-11)10-23-15-7-17-6-14-18-19-16(20(14)15)12-8-22-9-12/h1-7,12-13,21H,8-10H2 ZLHKTQHFEDMDIZ-UHFFFAOYSA-N

Compound V: OC(C1=CC=CC=C1)COC2=CN=CC3=NN=C(C4=CN=C(C(F)(F)F)C=C4)N32 InChI=1S/C19H14F3N5O2/c20-19(21,22)15-7-6-13(8-24-15)18-26-25-16-9-23-10-17(27(16)18)29-11-14(28)12-4-2-1-3-5-12/h1-10,14,28H,11H2 YUTTVQUFLHMVCQ-UHFFFAOYSA-N

Compound W: OC(C1=CC=CC=C1)COC2=CN=CC3=NN=C(C4CNCCC4)N32 InChI=1S/C18H21N5O2/c24-15(13-5-2-1-3-6-13)12-25-17-11-20-10-16-21-22-18(23(16)17)14-7-4-8-19-9-14/h1-3,5-6,10-11,14-15,19,24H,4,7-9,12H2 SNDLBGDEOQPBOQ-UHFFFAOYSA-N

Compound X: OC(C1=CC=CC=C1)COC2=CN=CC3=NN=C(CC)N32 InChI=1S/C15H16N4O2/c1-2-13-17-18-14-8-16-9-15(19(13)14)21-10-12(20)11-6-4-3-5-7-11/h3-9,12,20H,2,10H2,1H3 ZMELTVBBQIUHNR-UHFFFAOYSA-N

 

 

 

Attached Files