| B-A is =C-N or N-C= |
This covers imidazole and pyrrazole |
Other heterocycles - triazoles, oxazole, constitutional isomers |
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saturated rings, ring expansion |
| R1 = five bicyclic heterocycles (6-5) |
Aza-indazole, indazole, N-bridged benzotriazines, benzamidizole |
5-6 connection, benzotriazole, saturated rings, ring expansion (6-6) |
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saturated rings include lactams |
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various additional nitrogen substitutions |
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oxazoles and thiazoles |
| R2 = alkyl, cycloalkyl, haloalkyl, O=, HO-, H2N-, alkyl-HN-, and (alkyl)2N- |
R2 = Me, R3 = iPr or Cypropyl in majority of examples |
Halides, Cyano |
| R3 = H, alky, cycloalkyl, alkenyl, heterocycloalkyl |
Ex. 92: R2=Me R3=CyPr-Me - 4.3 nM, 24 K, 2 uM |
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| alkyl can be substituted with F-, HO-, Me-, EtO-, NH2(O)C- |
Ex. 93: R2=R3=Et - 17.4 nM, 26 K, 2.4 uM |
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Ex. 95: R2=Me R3=1-Me-2-OH-ethyl - 11.4 nM, 24 K, 2.5 uM |
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These analogues lose 10-100-fold activity in WB assay compared to analogues with R2=Me R3=iPr/Cypr |
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Likely unable to change significantly and maintain activity |
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| R4= H, F, HO |
Limited claims may reflect lack of tolerability |
Cl, alkyl, OMe, CN, etc. |
| R4b=H, F, Cl, Br, NC, HO |
Limited claims may reflect lack of tolerability |
alkyl or carbonyl |
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Ex. 35: R4=F - 19 nM, 29 K, 130 nM |
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| R5= CH2-Q-R13 |
Q is a single atom linker - either a carbon or sulfur |
spirocycles, cyclic linkers |
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| R6= alkenyl |
Ex. 105: (benzamidazole) 78 nM, 24 K, 1.6 uM |
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| alkyl optionally substituted with 1-2 substituents including cycloalkyl, halogen, HO-, alkyl-O-, alkyl-HN-, (alkyl)2-N-, NC-, (alkyl)2(O)P-, (4-methoxyphenyl)methyl- |
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| or |
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| heterocycle: THP, dioxane, pyrrolidine, poperazine, morpholine, pyridine, pyrazole, tirazole, each can be substituted with 1-2 substituents including alkyl, halogen, or O= |
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| R10= alkyl and haloalkyl |
Ex. 76: 17 nM, 26 K, 520 nM |
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Ex. 86: 7 nM, 28 K, 690 nM |
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Ex. 94: 17 nM, 27 K, 2.4 uM |
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| Q= -C(R11)(R12)-,-SO-, or -SO2- |
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| R11= H, HO-, halogen, or R14-O-, R14-NH- |
No claim for R11 and R12 to come together to form a ring |
CN, disubstituted amines |
| R12= H or F |
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CN |
| R14= haloalkyl, alkyl optionally substituted with cycloalkyl, alkenyl, HO-, alkyl-O-, H2N-C(O)-, alkyl-HN-C(O)-, alkyl2-N-C(O)- |
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cycloalkyl or heterocyclylalkyl with no or short linear linker before |
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Shorter or longer linker |
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| R13= carbocyclyl, heterocyclyl, aryl, heteroaryl |
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| optionally substituted with 1-2 substituents of alkyl, haloalkyl, HO-, NC-, halogen, R15-(CH2)n-O-, R15(CH2)n-NH-, ((R15)(CH2))2-N-, R15-(CH2)n-S(O)-, R15-(CH2_n-S(O)2- |
Ex. 41: 4-O-(3-hydroxy-3-methyl-butyl)phenyl - 6.4 nM, 30 K, 140 nM |
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Ex. 44: 3,4-difluorophenyl - 16.9 nM, 26 K, 140 nM |
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Ex. 46: 4-Fluorophenyl - 15 nM, 27 K, 140 nM |
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Ex. 55: 4-hydroxy-phenyl - 3.7 nM, 29 K, 200 nM |
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Ex. 65: 4-O-(2-(dimethylamine)ethyl)phenyl - 17 nM, 26 K, 320 nM |
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Ex. 68: 4-O-(methylene4-pyran)phenyl - 18 nM, 28 K, 350 nM |
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Ex. 69: 4-O-oxetanephenyl - 8 nM, 29 K, 360 nM |
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Ex. 72: 4-Chlorophenyl - 18 nM, 30, 400 nM |
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Ex. 82: 4-(2-methyl)pyridyl - 3 nM, 27 K, 610 nM |
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Ex. 83: cyclohexyl - 24 nM, 24 K, 630 nM |
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Ex. 88: 4-Bromophenyl - 98 nM, 25 K, 930 nM |
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Ex. 90: 4-O-(cyanomethyl)phenyl - 20 nM, 19 K, 1.1 uM |
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Ex. 91: 4-N-methylpyrrazole - 8 nM, 29 K, 1.6 uM |
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Ex. 101: 4-O-(2-(dimethylamine)ethyl)phenyl - 11 nM, 30 K, 39 nM |
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| R15= alkyl, haloalkyl, NC-, alkyl-HN-, (alkyl)2-N-, (alkyl)2(HO)C-, aryl or heterocyclyl |
covers additional substituents extending from O, N, S(O), and S(O)2 substitutions from R13 |
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R13 and R15 are broadly covered |
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| R7=R8=R9= cycloalkyl optionally substituted with alkyl or 1-2 halogens |
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CN, aryl, heteroaryl, CF3 |
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Cyclopropyl substituted with O or N or S substituents |
| cyclopropylmethyl, haloalkyl, alkyl-O-, alkyl-HN-, (alkyl)2N-, alkyl-S- |
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| or |
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| alkyl straight or branched chain opitionally substituted with HO-, alkyl-O-, (alkyl)-HN-, (alkyl)2-N-, or morpholine |
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| or |
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| pyrrolidine, tetrahydrofuran, tetrahydropyran |
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| or |
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| haloalkyl-O- |
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