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11th November 2015 @ 12:05

Planning for the next round of synthesis is taking place over on GHI358.

This post only contains the strings for all the molecules mentioned there.


Nemesis 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

CRO 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

NW Aliphatic FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(C)(C)OC)N32 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

Sydney Grammar Pyridine OC(C1=CC=CC=C1)COC2=CN=CC3=NN=C(C4=CN=CC=C4)N32 InChI=1S/C18H15N5O2/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/h1-11,15,24H,12H2 GXHFRJHPAQDHIG-UHFFFAOYSA-N

Dimethyl Amine FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(C4=CC=CC=C4)N(C)C)N32 InChI=1S/C22H21F2N5O2/c1-28(2)18(15-6-4-3-5-7-15)14-30-20-13-25-12-19-26-27-21(29(19)20)16-8-10-17(11-9-16)31-22(23)24/h3-13,18,22H,14H2,1-2H3 WSXRPWJACRAQOI-UHFFFAOYSA-N

Homologous Alcohol FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(C4=CC=CC=C4)CO)N32 InChI=1S/C21H18F2N4O3/c22-21(23)30-17-8-6-15(7-9-17)20-26-25-18-10-24-11-19(27(18)20)29-13-16(12-28)14-4-2-1-3-5-14/h1-11,16,21,28H,12-13H2 MGANJQKOPZQELF-UHFFFAOYSA-N

Homologous Amine FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OCC(C4=CC=CC=C4)CN)N32 InChI=1S/C21H19F2N5O2/c22-21(23)30-17-8-6-15(7-9-17)20-27-26-18-11-25-12-19(28(18)20)29-13-16(10-24)14-4-2-1-3-5-14/h1-9,11-12,16,21H,10,13,24H2 ZAYFESUSYJEUPU-UHFFFAOYSA-N

Shackleford FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OC(C)C(C4=CC=CC=C4)O)N32 InChI=1S/C21H18F2N4O3/c1-13(19(28)14-5-3-2-4-6-14)29-18-12-24-11-17-25-26-20(27(17)18)15-7-9-16(10-8-15)30-21(22)23/h2-13,19,21,28H,1H3 XGFALCXCRQYLSD-UHFFFAOYSA-N

Swain FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OC(C)C4=CC=C(Cl)C(Cl)=C4)N32 InChI=1S/C20H14Cl2F2N4O2/c1-11(13-4-7-15(21)16(22)8-13)29-18-10-25-9-17-26-27-19(28(17)18)12-2-5-14(6-3-12)30-20(23)24/h2-11,20H,1H3 ILDZQTSEZGQWFR-UHFFFAOYSA-N

Reversed Amide FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(NC(C4=CC=NC(C(F)(F)F)=C4)=O)N32 InChI=1S/C19H11F5N6O2/c20-18(21)32-12-3-1-10(2-4-12)16-29-28-15-9-25-8-14(30(15)16)27-17(31)11-5-6-26-13(7-11)19(22,23)24/h1-9,18H,(H,27,31) NMZQYYGTOGZVCK-UHFFFAOYSA-N

MMV669848 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(CN4CC(C=CC=C5)=C5C4)N32 InChI=1S/C21H17F2N5O/c22-21(23)29-18-7-5-14(6-8-18)20-26-25-19-10-24-9-17(28(19)20)13-27-11-15-3-1-2-4-16(15)12-27/h1-10,21H,11-13H2

MMV668957 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(N4CCC(C5=CC=CC=C5)C4)N32 InChI=1S/C22H19F2N5O/c23-22(24)30-18-8-6-16(7-9-18)21-27-26-19-12-25-13-20(29(19)21)28-11-10-17(14-28)15-4-2-1-3-5-15/h1-9,12-13,17,22H,10-11,14H2

MMV669304 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(CCCC4=CC=CC=C4)N32 InChI=1S/C21H18F2N4O/c22-21(23)28-18-11-9-16(10-12-18)20-26-25-19-14-24-13-17(27(19)20)8-4-7-15-5-2-1-3-6-15/h1-3,5-6,9-14,21H,4,7-8H2

MMV671652 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(N[C@H](C4=CC=C(F)C(F)=C4)CO)N32 InChI=1S/C20H15F4N5O2/c21-14-6-3-12(7-15(14)22)16(10-30)26-17-8-25-9-18-27-28-19(29(17)18)11-1-4-13(5-2-11)31-20(23)24/h1-9,16,20,26,30H,10H2/t16-/m0/s1

MMV669008 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(N4CC(OC5=CC(F)=C(F)C=C5)C4)N32 InChI=1S/C21H15F4N5O2/c22-16-6-5-14(7-17(16)23)31-15-10-29(11-15)19-9-26-8-18-27-28-20(30(18)19)12-1-3-13(4-2-12)32-21(24)25/h1-9,15,21H,10-11H2

MMV669353 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(N4CC(C5=CC=CC=C5)C4)N32 InChI=1S/C21H17F2N5O/c22-21(23)29-17-8-6-15(7-9-17)20-26-25-18-10-24-11-19(28(18)20)27-12-16(13-27)14-4-2-1-3-5-14/h1-11,16,21H,12-13H2

MMV671653 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(N4N=CC(C5=CC(F)=C(F)C=C5)=C4)N32 InChI=1S/C21H12F4N6O/c22-16-6-3-13(7-17(16)23)14-8-27-30(11-14)19-10-26-9-18-28-29-20(31(18)19)12-1-4-15(5-2-12)32-21(24)25/h1-11,21H

MMV671678 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(N4C=CN=C4CC5=CC(F)=C(F)C=C5)N32 InChI=1S/C22H14F4N6O/c23-16-6-1-13(9-17(16)24)10-18-28-7-8-31(18)20-12-27-11-19-29-30-21(32(19)20)14-2-4-15(5-3-14)33-22(25)26/h1-9,11-12,22H,10H2

MMV669360 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(COCC4=CC=C(F)C(F)=C4)N32 InChI=1S/C20H14F4N4O2/c21-16-6-1-12(7-17(16)22)10-29-11-14-8-25-9-18-26-27-19(28(14)18)13-2-4-15(5-3-13)30-20(23)24/h1-9,20H,10-11H2

MMV670243 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(CCCC4=CC(F)=C(F)C=C4)N32 InChI=1S/C21H16F4N4O/c22-17-9-4-13(10-18(17)23)2-1-3-15-11-26-12-19-27-28-20(29(15)19)14-5-7-16(8-6-14)30-21(24)25/h4-12,21H,1-3H2

The Crazy Hemiacetal FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OC(O)C(O)C4=CC=CC=C4)N32 InChI=1S/C20H16F2N4O4/c21-20(22)29-14-8-6-13(7-9-14)18-25-24-15-10-23-11-16(26(15)18)30-19(28)17(27)12-4-2-1-3-5-12/h1-11,17,19-20,27-28H LBNIPJYOUJPJNQ-UHFFFAOYSA-N

The Ketone FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(C(CC4=CC=NC(C(F)(F)F)=C4)=O)N32 InChI=1S/C20H12F5N5O2/c21-19(22)32-13-3-1-12(2-4-13)18-29-28-17-10-26-9-14(30(17)18)15(31)7-11-5-6-27-16(8-11)20(23,24)25/h1-6,8-10,19H,7H2 NRTCUOWGNGMJIN-UHFFFAOYSA-N

The Sulfoxide FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C([S+]([O-])CC4=CC=NC(C(F)(F)F)=C4)N32 InChI=1S/C19H12F5N5O2S/c20-18(21)31-13-3-1-12(2-4-13)17-28-27-15-8-25-9-16(29(15)17)32(30)10-11-5-6-26-14(7-11)19(22,23)24/h1-9,18H,10H2 JITAVHCKEWUUSI-UHFFFAOYSA-N

The Sulfone FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(S(CC4=CC=NC(C(F)(F)F)=C4)(=O)=O)N32 InChI=1S/C19H12F5N5O3S/c20-18(21)32-13-3-1-12(2-4-13)17-28-27-15-8-25-9-16(29(15)17)33(30,31)10-11-5-6-26-14(7-11)19(22,23)24/h1-9,18H,10H2 DHPQHOFGWSYVQF-UHFFFAOYSA-N

The Urea FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(N([H])C(N([H])C4=CC(C(F)(F)F)=NC=C4)=O)N32 InChI=1S/C19H12F5N7O2/c20-17(21)33-12-3-1-10(2-4-12)16-30-29-15-9-25-8-14(31(15)16)28-18(32)27-11-5-6-26-13(7-11)19(22,23)24/h1-9,17H,(H2,26,27,28,32) MXAOEFDAAVOYKX-UHFFFAOYSA-N

The Triazole FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(C4=CN(C5=CC(C(F)(F)F)=NC=C5)[N][N]4)N32 InChI=1S/C20H11F5N8O/c21-19(22)34-13-3-1-11(2-4-13)18-30-29-17-9-26-8-15(33(17)18)14-10-32(31-28-14)12-5-6-27-16(7-12)20(23,24)25/h1-10,19H XXNFDIRYVMBYOF-UHFFFAOYSA-N

The Burns FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(C(C(F)(F)F)N([H])C4=CC=NC(C(F)(F)F)=C4)N32 InChI=1S/C20H12F8N6O/c21-18(22)35-12-3-1-10(2-4-12)17-33-32-15-9-29-8-13(34(15)17)16(20(26,27)28)31-11-5-6-30-14(7-11)19(23,24)25/h1-9,16,18H,(H,30,31) ORWCWEGIHLHCSF-UHFFFAOYSA-N

The Tianyi OC(C1=CC=CC=C1)COC2=CN=CC3=NC(C)=C(C4=CC=C(OC(F)F)C=C4)N32 InChI=1S/C22H19F2N3O3/c1-14-21(16-7-9-17(10-8-16)30-22(23)24)27-19(26-14)11-25-12-20(27)29-13-18(28)15-5-3-2-4-6-15/h2-12,18,22,28H,13H2,1H3 VGNPLLBRBOUQAA-UHFFFAOYSA-N

Chase Hop1 FC(C=C1)=C(F)C=C1CCOC2=CN=CC(N3N=NN=C3C4=CC=C(Cl)C=C4)=N2 InChI=1S/C19H13ClF2N6O/c20-14-4-2-13(3-5-14)19-25-26-27-28(19)17-10-23-11-18(24-17)29-8-7-12-1-6-15(21)16(22)9-12/h1-6,9-11H,7-8H2 HHZUPBCYYAXEQO-UHFFFAOYSA-N

Chase Hop2 FC(C=C1)=C(F)C=C1CCOC2=NC=NC(NC3=NN=C(C4=CC=C(Cl)C=C4)S3)=N2 InChI=1S/C19H13ClF2N6OS/c20-13-4-2-12(3-5-13)16-27-28-19(30-16)26-17-23-10-24-18(25-17)29-8-7-11-1-6-14(21)15(22)9-11/h1-6,9-10H,7-8H2,(H,23,24,25,26,28) BDGBDNWYLOQTMB-UHFFFAOYSA-N

MMV639565 OSM-S-272 FC1=C(F)C=CC(CCOC2=CN=CC3=NN=C(C4=CC=C(Cl)C=C4)N32)=C1 InChI=1S/C19H13ClF2N4O/c20-14-4-2-13(3-5-14)19-25-24-17-10-23-11-18(26(17)19)27-8-7-12-1-6-15(21)16(22)9-12/h1-6,9-11H,7-8H2 PMHUSEXABGDNGS-UHFFFAOYSA-N

MMV669846 OSM-S-273 FC1=C(F)C=CC(CCOC2=CN=CC3=NC=C(C4=CC=C(Cl)C=C4)N32)=C1 InChI=1S/C20H14ClF2N3O/c21-15-4-2-14(3-5-15)18-10-25-19-11-24-12-20(26(18)19)27-8-7-13-1-6-16(22)17(23)9-13/h1-6,9-12H,7-8H2 MQHQNFQVEXYAMO-UHFFFAOYSA-N

MMV670250 OSM-S-274 FC1=C(F)C=CC(CCOC2=CN=CC3=CN=C(C4=CC=C(Cl)C=C4)N32)=C1 InChI=1S/C20H14ClF2N3O/c21-15-4-2-14(3-5-15)20-25-11-16-10-24-12-19(26(16)20)27-8-7-13-1-6-17(22)18(23)9-13/h1-6,9-12H,7-8H2 JHORUMGXLQTHAD-UHFFFAOYSA-N

 

This post authored by Mat Todd.

16th June 2015 @ 01:21

OSM recently received data from Syngene on the latest set of Series 4 compounds screened against the malaria parasite. While no 'killer' compounds were discovered, the data has provided some interesting SAR data. 

This post aims to stimulate discussion about the 10-30 compounds that we should aim to synthesise next. Comments below, on GitHub or via Twitter are very welcome - email should be avoided but you are also always welcome to contact us at opensourcemalaria@gmail.com. Over the next week or so, this list will be refined following input from the community, here are some suggestions based on the data.

I'm going to use letters to label each compound to prevent any mix-up with the previous target molecules.

Triazolopyrazine Core

1. Remaining 'Top Ten' Compounds

A few compounds from the previous wish list remain unsynthesised.

The latest data showed compounds featuring an aliphatic group at Y to be inactive. Two remaining compounds featuring a heterocyclic aliphatic substituent (A and B) should be synthesised to further investigate substitution at this position. Additionally, the proposed compound (C) featuring an aliphatic replacement at X should also be synthesised.

 

2. Exploration of substituted pyridines at X and or Y

Different unsubstituted pyridine isomers at Y were found to be inactive, whereas the 2-CF3 substituted compound OSM-S-278 showed promising activity in the initial screen. This result suggests that tempering the electronics of the pyridine ring could provide some promising results. A range of 2-, 3- and 4-substituted pyridine aldehydes are commercially available and so compounds of type D could be synthetically accessible.

Question Is 2-substitution typically preferred?

 

Compound E is a composite of MMV688895 and MMV67093 andis proposed a compound with lower CLogP and potentially greater activity.

3. Polar Benzylic Groups

The latest screen confirmed the activity of compounds containing a polar benzylic group. However, mono methylated amine OSM-S- 281 showed no activity. Despite potential metabolic flags, compound could be synthesised to evaluate the activity of a disubstituted amine and confirm the pattern of results shown for MMV671651 MMV670763 and MMV670437 with regard to amine substitution. Compounds G-J would probe the effect of extending the polar side chain. MMV670947, the 3,4-difluorophenyl analogue of G displayed potency of 25 nM a promising starting point for optimisation. 

 


4. Additional substitution on side chain X

 Further substitition on side chain could also be explored.

5. Modification to the core

The initial CRO/Pfizer data set revealed a potent compound MMV669846 containing an imidazopyrazine core. This has been under explored so far. The presence of one less nitrogen serves to increase the CLogP and so further analogues could be designed to include substituted pyridines to decrease the lipophilicity (O and P).

Jamie Scott at The University of Edinburgh synthesised some ether triazolopyridine analogues, which although active were found to be less potent than their corresponding triazolopyrazine. One interesting result can be found in comparison of potency data for JS16-1 and MMV670994. This data would suggest that in the case of amides, changing core from triazolopyrazine to triazolopyridine destroys activity.


6. Suggestions from Dr Mrinalkanti Kundu, Associate Director TCG Lifesciences, India.

Mrinal Suggested several compounds following the last OSM synthesis consultation. These thoughtful suggestions will be considered for the next round of synthesis.

Post originally authored by Alice Williamson


Strings

OSM-S-275  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

OSM-S-276  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

A  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

B  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

C  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

OSM-S-258  InChI=1S/C18H14ClN5O/c19-15-4-2-1-3-13(15)7-10-25-17-12-21-11-16-22-23-18(24(16)17)14-5-8-20-9-6-14/h1-6,8-9,11-12H,7,10H2

OSM-S-278 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

D

MMV670936  InChI=1S/C19H12F5N5O/c20-13-3-1-11(7-14(13)21)5-6-30-17-10-25-9-16-27-28-18(29(16)17)12-2-4-15(26-8-12)19(22,23)24/h1-4,7-10H,5-6H2

E  InChI=1S/C19H12F5N5O2/c20-12-3-1-10(5-13(12)21)14(30)9-31-17-8-25-7-16-27-28-18(29(16)17)11-2-4-15(26-6-11)19(22,23)24/h1-8,14,30H,9H2

OSM-S-279  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

OSM-S-283  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

OSM-S-281  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

F  InChI=1S/C22H21F2N5O2/c1-28(2)18(15-6-4-3-5-7-15)14-30-20-13-25-12-19-26-27-21(29(19)20)16-8-10-17(11-9-16)31-22(23)24/h3-13,18,22H,14H2,1-2H3

MMV670947  InChI=1S/C21H16F4N4O3/c22-16-6-3-13(7-17(16)23)14(10-30)11-31-19-9-26-8-18-27-28-20(29(18)19)12-1-4-15(5-2-12)32-21(24)25/h1-9,14,21,30H,10-11H2

G  InChI=1S/C21H18F2N4O3/c22-21(23)30-17-8-6-15(7-9-17)20-26-25-18-10-24-11-19(27(18)20)29-13-16(12-28)14-4-2-1-3-5-14/h1-11,16,21,28H,12-13H2

H InChI=1S/C21H19F2N5O2/c22-21(23)30-17-8-6-15(7-9-17)20-27-26-18-11-25-12-19(28(18)20)29-13-16(10-24)14-4-2-1-3-5-14/h1-9,11-12,16,21H,10,13,24H2

I  InChI=1S/C21H19F2N5O3/c22-21(23)31-16-8-6-15(7-9-16)20-27-26-18-10-25-11-19(28(18)20)29-12-17(30-13-24)14-4-2-1-3-5-14/h1-11,17,21H,12-13,24H2

J  InChI=1S/C21H18F2N4O4/c22-21(23)31-16-8-6-15(7-9-16)20-26-25-18-10-24-11-19(27(18)20)29-12-17(30-13-28)14-4-2-1-3-5-14/h1-11,17,21,28H,12-13H2

K  InChI=1S/C22H20F2N4O3/c1-14(18(13-29)15-5-3-2-4-6-15)30-20-12-25-11-19-26-27-21(28(19)20)16-7-9-17(10-8-16)31-22(23)24/h2-12,14,18,22,29H,13H2,1H3

L  InChI=1S/C20H16F2N4O4/c21-20(22)29-14-8-6-13(7-9-14)18-25-24-15-10-23-11-16(26(15)18)30-19(28)17(27)12-4-2-1-3-5-12/h1-11,17,19-20,27-28H

M  InChI=1S/C20H16F2N4O3/c21-20(22)28-15-8-6-14(7-9-15)19-25-24-16-11-23-12-17(26(16)19)29-18(27)10-13-4-2-1-3-5-13/h1-9,11-12,18,20,27H,10H2

N  InChI=1S/C20H17F2N5O2/c21-20(22)28-15-8-6-14(7-9-15)19-26-25-17-11-24-12-18(27(17)19)29-16(23)10-13-4-2-1-3-5-13/h1-9,11-12,16,20H,10,23H2

MMV669846  InChI=1S/C20H14ClF2N3O/c21-15-4-2-14(3-5-15)18-10-25-19-11-24-12-20(26(18)19)27-8-7-13-1-6-16(22)17(23)9-13/h1-6,9-12H,7-8H2  

O  InChI=1S/C20H15F3N4O2/c21-20(22,23)17-7-6-14(8-25-17)15-9-26-18-10-24-11-19(27(15)18)29-12-16(28)13-4-2-1-3-5-13/h1-11,16,28H,12H2

P  InChI=1S/C19H15F4N5O2/c1-29-15(13-3-5-17(20)27-8-13)10-30-18(6-24)28-11-25-9-14(28)12-2-4-16(26-7-12)19(21,22)23/h2-9,11,15H,10H2,1H3/b18-6+

JS 16-1  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)

MMV670944  InChI=1S/C18H11F3N6O2/c19-14-7-11(5-6-23-14)24-17(28)13-8-22-9-15-25-26-16(27(13)15)10-1-3-12(4-2-10)29-18(20)21/h1-9,18H,(H,23,24,28)

MK-001: 1/C20H14F2N6O2/c1-29-17(12-3-5-15(21)16(22)6-12)11-30-19-10-24-9-18-26-27-20(28(18)19)13-2-4-14(7-23)25-8-13/h2-6,8-10,17H,11H2,1H3/t17-/m0/s1

MK-002: 1/C20H12F4N6O2/c21-14-4-2-11(5-15(14)22)16(32-20(23)24)10-31-18-9-26-8-17-28-29-19(30(17)18)12-1-3-13(6-25)27-7-12/h1-5,7-9,16,20H,10H2/t16-/m0/s1

MK-003: 1/C20H15ClF2N4O2/c1-28-17(13-4-7-15(22)16(23)8-13)11-29-19-10-24-9-18-25-26-20(27(18)19)12-2-5-14(21)6-3-12/h2-10,17H,11H2,1H3/t17-/m0/s1

MK-004: 1/C21H16ClN5O2/c1-28-18(16-4-2-3-5-17(16)22)13-29-20-12-24-11-19-25-26-21(27(19)20)15-8-6-14(10-23)7-9-15/h2-9,11-12,18H,13H2,1H3/t18-/m0/s1

MK-005: 1/C21H15F2N5O2/c1-29-18(15-6-16(22)8-17(23)7-15)12-30-20-11-25-10-19-26-27-21(28(19)20)14-4-2-13(9-24)3-5-14/h2-8,10-11,18H,12H2,1H3/t18-/m0/s1

MK-006: 1/C20H15ClF3N5O2/c1-30-15(13-6-7-26-16(8-13)20(22,23)24)11-31-18-10-25-9-17-27-28-19(29(17)18)12-2-4-14(21)5-3-12/h2-10,15H,11H2,1H3/t15-/m0/s1

MK-007: 1/C19H13ClF3N5O/c20-14-3-1-13(2-4-14)18-27-26-16-10-24-11-17(28(16)18)29-8-6-12-5-7-25-15(9-12)19(21,22)23/h1-5,7,9-11H,6,8H2

MK-008: 1/C21H16F5N5O3/c1-32-15(13-6-7-28-16(8-13)21(24,25)26)11-33-18-10-27-9-17-29-30-19(31(17)18)12-2-4-14(5-3-12)34-20(22)23/h2-10,15,20H,11H2,1H3/t15-/m0/s1

MK-009: 1/C20H14F5N5O2/c21-19(22)32-14-3-1-13(2-4-14)18-29-28-16-10-26-11-17(30(16)18)31-8-6-12-5-7-27-15(9-12)20(23,24)25/h1-5,7,9-11,19H,6,8H2

MK-010: 1/C21H15F3N6O2/c1-31-16(15-6-7-27-17(8-15)21(22,23)24)12-32-19-11-26-10-18-28-29-20(30(18)19)14-4-2-13(9-25)3-5-14/h2-8,10-11,16H,12H2,1H3/t16-/m0/s1

MK-011: 1/C21H13F5N6O2/c22-20(23)34-15(14-5-6-29-16(7-14)21(24,25)26)11-33-18-10-28-9-17-30-31-19(32(17)18)13-3-1-12(8-27)2-4-13/h1-7,9-10,15,20H,11H2/t15-/m0/s1

MK-012: 1/C20H13F3N6O/c21-20(22,23)16-9-13(5-7-26-16)6-8-30-18-12-25-11-17-27-28-19(29(17)18)15-3-1-14(10-24)2-4-15/h1-5,7,9,11-12H,6,8H2

MK-001: N1=CC2=NN=C(N2C(=C1)OC[C@H](c1cc(c(cc1)F)F)OC)c1cnc(cc1)C#N
MK-002: N1=CC2=NN=C(N2C(=C1)OC[C@H](c1cc(c(cc1)F)F)OC(F)F)c1cnc(cc1)C#N
MK-003: N1=CC2=NN=C(N2C(=C1)OC[C@H](c1cc(c(cc1)F)F)OC)c1ccc(cc1)Cl
MK-004: N1=CC2=NN=C(N2C(=C1)OC[C@H](c1ccccc1Cl)OC)c1ccc(cc1)C#N
MK-005: N1=CC2=NN=C(N2C(=C1)OC[C@H](c1cc(cc(c1)F)F)OC)c1ccc(cc1)C#N
MK-006: N1=CC2=NN=C(N2C(=C1)OC[C@H](c1cc(ncc1)C(F)(F)F)OC)c1ccc(cc1)Cl
MK-007: N1=CC2=NN=C(N2C(=C1)OCCc1cc(ncc1)C(F)(F)F)c1ccc(cc1)Cl
MK-008: O(c1ccc(cc1)C1=NN=C2N1C(=CN=C2)OC[C@H](c1cc(ncc1)C(F)(F)F)OC)C(F)F
MK-009: O(c1ccc(cc1)C1=NN=C2N1C(=CN=C2)OCCc1cc(ncc1)C(F)(F)F)C(F)F
MK-010: O([C@H](c1cc(ncc1)C(F)(F)F)COC1=CN=CC2=NN=C(N12)c1ccc(cc1)C#N)C
MK-011: O([C@H](c1cc(ncc1)C(F)(F)F)COC1=CN=CC2=NN=C(N12)c1ccc(cc1)C#N)C(F)F
MK-012: N1=CC2=NN=C(N2C(=C1)OCCc1cc(ncc1)C(F)(F)F)c1ccc(cc1)C#N

Attached Files
27th April 2015 @ 12:47

Dr Mrinalkanti Kundu, Associate Director TCG Lifesciences, India, wrote to the OSM email address with some new suggestions on which molecules to make next. These suggestions have been adapted from the Christmas Top 10 list as well as all the SAR data on the wiki.

Series 4 Suggestions from Mrinal

Thank you Mrinal! The structures are in the attached PDF and image file. Discussion can happen below (just sign in via Google) or on the G+ community or by starting an Issue on Github. Any comments/suggestions, please go ahead - Mrinal is also monitoring these channels. Ought these to be included in the next round of synthesis, or should they perhaps replace any of the compounds listed in the Christmas Top 10?

 

(This post authored by Mat)

Strings:

MK-001: N1=CC2=NN=C(N2C(=C1)OC[C@H](c1cc(c(cc1)F)F)OC)c1cnc(cc1)C#N
MK-002: N1=CC2=NN=C(N2C(=C1)OC[C@H](c1cc(c(cc1)F)F)OC(F)F)c1cnc(cc1)C#N
MK-003: N1=CC2=NN=C(N2C(=C1)OC[C@H](c1cc(c(cc1)F)F)OC)c1ccc(cc1)Cl
MK-004: N1=CC2=NN=C(N2C(=C1)OC[C@H](c1ccccc1Cl)OC)c1ccc(cc1)C#N
MK-005: N1=CC2=NN=C(N2C(=C1)OC[C@H](c1cc(cc(c1)F)F)OC)c1ccc(cc1)C#N
MK-006: N1=CC2=NN=C(N2C(=C1)OC[C@H](c1cc(ncc1)C(F)(F)F)OC)c1ccc(cc1)Cl
MK-007: N1=CC2=NN=C(N2C(=C1)OCCc1cc(ncc1)C(F)(F)F)c1ccc(cc1)Cl
MK-008: O(c1ccc(cc1)C1=NN=C2N1C(=CN=C2)OC[C@H](c1cc(ncc1)C(F)(F)F)OC)C(F)F
MK-009: O(c1ccc(cc1)C1=NN=C2N1C(=CN=C2)OCCc1cc(ncc1)C(F)(F)F)C(F)F
MK-010: O([C@H](c1cc(ncc1)C(F)(F)F)COC1=CN=CC2=NN=C(N12)c1ccc(cc1)C#N)C
MK-011: O([C@H](c1cc(ncc1)C(F)(F)F)COC1=CN=CC2=NN=C(N12)c1ccc(cc1)C#N)C(F)F
MK-012: N1=CC2=NN=C(N2C(=C1)OCCc1cc(ncc1)C(F)(F)F)c1ccc(cc1)C#N

MK-001: 1/C20H14F2N6O2/c1-29-17(12-3-5-15(21)16(22)6-12)11-30-19-10-24-9-18-26-27-20(28(18)19)13-2-4-14(7-23)25-8-13/h2-6,8-10,17H,11H2,1H3/t17-/m0/s1

MK-002: 1/C20H12F4N6O2/c21-14-4-2-11(5-15(14)22)16(32-20(23)24)10-31-18-9-26-8-17-28-29-19(30(17)18)12-1-3-13(6-25)27-7-12/h1-5,7-9,16,20H,10H2/t16-/m0/s1

MK-003: 1/C20H15ClF2N4O2/c1-28-17(13-4-7-15(22)16(23)8-13)11-29-19-10-24-9-18-25-26-20(27(18)19)12-2-5-14(21)6-3-12/h2-10,17H,11H2,1H3/t17-/m0/s1

MK-004: 1/C21H16ClN5O2/c1-28-18(16-4-2-3-5-17(16)22)13-29-20-12-24-11-19-25-26-21(27(19)20)15-8-6-14(10-23)7-9-15/h2-9,11-12,18H,13H2,1H3/t18-/m0/s1

MK-005: 1/C21H15F2N5O2/c1-29-18(15-6-16(22)8-17(23)7-15)12-30-20-11-25-10-19-26-27-21(28(19)20)14-4-2-13(9-24)3-5-14/h2-8,10-11,18H,12H2,1H3/t18-/m0/s1

MK-006: 1/C20H15ClF3N5O2/c1-30-15(13-6-7-26-16(8-13)20(22,23)24)11-31-18-10-25-9-17-27-28-19(29(17)18)12-2-4-14(21)5-3-12/h2-10,15H,11H2,1H3/t15-/m0/s1

MK-007: 1/C19H13ClF3N5O/c20-14-3-1-13(2-4-14)18-27-26-16-10-24-11-17(28(16)18)29-8-6-12-5-7-25-15(9-12)19(21,22)23/h1-5,7,9-11H,6,8H2

MK-008: 1/C21H16F5N5O3/c1-32-15(13-6-7-28-16(8-13)21(24,25)26)11-33-18-10-27-9-17-29-30-19(31(17)18)12-2-4-14(5-3-12)34-20(22)23/h2-10,15,20H,11H2,1H3/t15-/m0/s1

MK-009: 1/C20H14F5N5O2/c21-19(22)32-14-3-1-13(2-4-14)18-29-28-16-10-26-11-17(30(16)18)31-8-6-12-5-7-27-15(9-12)20(23,24)25/h1-5,7,9-11,19H,6,8H2

MK-010: 1/C21H15F3N6O2/c1-31-16(15-6-7-27-17(8-15)21(22,23)24)12-32-19-11-26-10-18-28-29-20(30(18)19)14-4-2-13(9-25)3-5-14/h2-8,10-11,16H,12H2,1H3/t16-/m0/s1

MK-011: 1/C21H13F5N6O2/c22-20(23)34-15(14-5-6-29-16(7-14)21(24,25)26)11-33-18-10-28-9-17-30-31-19(32(17)18)13-3-1-12(8-27)2-4-13/h1-7,9-10,15,20H,11H2/t15-/m0/s1

MK-012: 1/C20H13F3N6O/c21-20(22,23)16-9-13(5-7-26-16)6-8-30-18-12-25-11-17-27-28-19(29(17)18)15-3-1-14(10-24)2-4-15/h1-5,7,9,11-12H,6,8H2

Attached Files
22nd March 2015 @ 21:18

The 'top ten' Series Four compounds have been defined as:

 

I (Alice) will firstly take care of compounds 14 at Sydney University meaning that we'd like to open up compounds 510 for synthesis by the community.

Two proposed synthetic routes for  5 - 10 could be accessed are:

1 Condensation of corresponding aldehyde

This route has been well established in the project and works well. Its limitation is that late stage of the right hand aryl/aromatic group is not possible.

 

2 Synthesis of triazalopyrazine core, functionalisation and cross coupling

Synthesis of chlorotriazolopyrazine, bromination and subsequent dervitisation. Tom MacDonald worked on this route as part of his honours proect and showed that the first two steps work. Development of this route would enable more expedent access of the desired compounds.

 

If you have time to synthesise some of these molecules in your laboratory or if you have access to any related compounds or building blocks then please get in touch, either below, on GitHub, Twitter or email (opensourcemalaria@gmail.com). Thanks on behalf of the @O_S_M Consortium.

 

(Originally Authored by Alice)

Attached Files
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