Compounds, Compositions and Methods
AssigneeDenali Therapeutics Inc.
InventorsGiorgio Bonanomi, Anthony A. Estrada, Jianwen A. Feng, Brian Fox, Cinzia Maria Francini, Cheng Hu, Colin Philip Leslie, Maksim Osipov, Anantha Sudhakar, Zachary K. Sweeney, Javier De Vicente Fidalgo
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Abstract
The present disclosure relates generally to methods and compositions for preventing or arresting cell death and/or inflammation.
Claims23
A compound of Formula I:
- or a pharmaceutically acceptable salt, deuterated analog, stereoisomer, mixture of stereoisomers, tautomer, or prodrug thereof, wherein:
- X is N or CR4, wherein R4 is H or optionally substituted alkyl;
- Cy is optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
- Y1, Y2, and Y3 are independently CR5R6, S, SO, SO2, O, or NR7;
- R1 is cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, —SR8, —SOR8, —SO2R8, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
- or R1 and Y3 together form an optionally substituted heterocyclyl;
- R2 is cyano, hydrogen, halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
- or R1 and R2 together form an optionally substituted cycloalkyl or optionally substituted heterocyclyl;
- each R3 is independently halo, cyano, or optionally substituted alkyl;
- or two R3 together form an optionally substituted cycloalkyl or an optionally substituted heterocyclyl;
- R5 and R6 are independently cyano, halo, hydrogen, hydroxyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, —SH, —SR8, —SOR8, —SO2R8, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
- or R5 and R6 together with the carbon atom to which they are both attached form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, or oxo;
- or any two R5 groups attached to adjacent carbon atoms together form an optionally substituted cycloalkyl or optionally substituted heterocyclyl;
- R7 is hydrogen or optionally substituted alkyl;
- R8 is optionally substituted alkyl;
- and
- n is 0, 1, 2, 3, 4, or 5.
The compound of any of the preceding claims, wherein Cy is optionally substituted aryl or optionally substituted heteroaryl.
The compound of any of the preceding claims, wherein Cy is optionally substituted phenyl, optionally substituted pyridyl, or optionally substituted pyrazine.
The compound of any one of the preceding claims, wherein Cy is independently optionally substituted with one or more R10, wherein R10 is independently cyano, halo, nitro, oxo, —OR11, —SR11, —SF5, —NR11R12, —C(═O)R13, —C(═O)OR11, —OC(═O)OR11, —OC(═O)R13, —C(═O)NR11R12, —OC(═O)NR11R12, —NR11C(═O)NR11R12, —S(═O)1-2R13, —S(═O)1-2NR11R12, —NR11S(═O)1-2R13, —NR11S(═O)1-2NR11R12, —NR11C(═O)R13, —NR11C(═O)OR12, —C═NOR11, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl;
- wherein the C1-12 alkyl, C2-12 alkenyl and C2-12 alkynyl are optionally substituted with one or more halo;
- the C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl are independently optionally substituted with one or more cyano, halo, nitro, oxo, —OR14, —SR14, —SF5, —NR14R15, —S(═O)1-2R16, —S(═O)1-2NR14R15, —NR14S(═O)1-2R16, or R16;
- R11, R12, R14, and R15 are independently H or C1-12 alkyl optionally substituted with one or more halo, or two of R11 and R12 or two of R14 and R15 together with the atoms to which they are attached form a heterocyclyl optionally substituted with one or more halo or C1-12 alkyl optionally substituted with one or more halo;
- and
- R13 and R16 are independently C1-12 alkyl optionally substituted with one or more halo.
The compound of any of the preceding claims, wherein Cy is 5-cyano-pyrid-3-yl, 5-fluoro-pyrid-3-yl, 3-fluorophenyl, 3-cyanophenyl, 3-cyano-5-fluorophenyl, 5-methylpyrazin-2-yl, 3,4-difluorophenyl, or 3,5-difluorophenyl.
The compound of any of the preceding claims, wherein n is 0.
The compound of any of the preceding claims, wherein R1 and R2 are optionally substituted alkyl.
The compound of any of the preceding claims, wherein R1 and R2 together form a cyclopropyl ring.
The compound of any of the preceding claims, wherein R1 is difluoromethyl, cyanomethyl, methyl, or ethyl.
The compound of any of the preceding claims, wherein R2 is methyl.
A compound of or a pharmaceutically acceptable salt, deuterated analog, stereoisomer, mixture of stereoisomers, tautomer, or prodrug thereof, that is:
- 3-(5-fluoro-3-pyridyl)-6,6-dimethyl-1,2,3,7,8,9-hexahydropyrazolo[1,2-a]diazepin-5-one;
- 4-ethyl-7-(3-fluorophenyl)-4-methyl-1,3,7,8,9,9a-hexahydropyrrolo[2,1-c][1,4]oxazepin-5-one;
- 4-(6,6-dimethyl-5-oxo-1,2,3,7,8,9-hexahydropyrazolo[1,2-a]diazepin-3-yl)benzonitrile;
- 3-(3-fluorophenyl)-6,6-dimethyl-1,2,3,7,8,9-hexahydropyrazolo[1,2-a]diazepin-5-one;
- 3-(6,6-dimethyl-5-oxo-1,2,3,7,8,9-hexahydropyrazolo[1,2-a]diazepin-3-yl)-5-fluoro-benzonitrile;
- 6,6-dimethyl-3-(5-methylpyrazin-2-yl)-1,2,3,7,8,9-hexahydropyrazolo[1,2-a]diazepin-5-one;
- 3-(3,4-difluorophenyl)-6,6-dimethyl-1,2,3,7,8,9-hexahydropyrazolo[1,2-a]diazepin-5-one;
- 3-(3,5-difluorophenyl)-6,6-dimethyl-1,2,3,7,8,9-hexahydropyrazolo[1,2-a]diazepin-5-one;
- 5-(6,6-dimethyl-5-oxo-1,2,3,7,8,9-hexahydropyrazolo[1,2-a]diazepin-3-yl)pyridine-3-carbonitrile;
- 6-(difluoromethyl)-6-methyl-3-(5-methylpyrazin-2-yl)-1,2,3,7,8,9-hexahydropyrazolo[1,2-a]diazepin-5-one;
- 3-(5-fluoro-3-pyridyl)spiro[1,2,3,7,8,9-hexahydropyrazolo[1,2-a]diazepine-6,1′-cyclopropane]-5-one;
- 7-(5-fluoro-3-pyridyl)-4,4-dimethyl-2,7,8,9-tetrahydro-1H-pyrazolo[1,2-d][1,4,5]oxadiazepin-5-one;
- 6-(difluoromethyl)-3-(5-fluoro-3-pyridyl)-6-methyl-1,2,3,7,8,9-hexahydropyrazolo[1,2-a]diazepin-5-one;
- 2-[6-methyl-3-(5-methylpyrazin-2-yl)-5-oxo-1,2,3,7,8,9-hexahydropyrazolo[1,2-a]diazepin-6-yl]acetonitrile;
- 2-[3-(5-fluoro-3-pyridyl)-6-methyl-5-oxo-1,2,3,7,8,9-hexahydropyrazolo[1,2-a]diazepin-6-yl]acetonitrile;
- 5-[6-(difluoromethyl)-6-methyl-5-oxo-1,2,3,7,8,9-hexahydropyrazolo[1,2-a]diazepin-3-yl]pyridine-3-carbonitrile;
- 7,7-difluoro-3-(5-fluoro-3-pyridyl)-6,6-dimethyl-2,3,8,9-tetrahydro-1H-pyrazolo[1,2-a]diazepin-5-one;
- 5-[6-(difluoromethyl)-6-methyl-5-oxo-2,3,7,8,9,9a-hexahydro-1H-pyrrolo[1,2-a]azepin-3-yl]pyridine-3-carbonitrile;
- or
- 6-(difluoromethyl)-6-ethyl-3-(5-methylpyrazin-2-yl)-1,2,3,7,8,9-hexahydropyrazolo[1,2-a]diazepin-5-one.
Dependencies are inferred from the claim text.