National Institute of Biological Sciences, Beijing
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초록▼
The invention provides compounds that inhibit human MLKL, and pharmaceutically acceptable salts, hydrates and stereoisomers thereof. The compounds are employed in pharmaceutical compositions, and methods of making and use, including treating a person in need thereof with an effective amount of the c
The invention provides compounds that inhibit human MLKL, and pharmaceutically acceptable salts, hydrates and stereoisomers thereof. The compounds are employed in pharmaceutical compositions, and methods of making and use, including treating a person in need thereof with an effective amount of the compound or composition.
대표청구항▼
1. A method of treating an MLKL-mediated disorder selected from ischemia-reperfusion damage, neurodegeneration, and inflammation, comprising treating a person in need thereof with an MLKL-inhibitor compound of formula I: wherein: each of R1-R4 is independently H, or optionally substituted, optional
1. A method of treating an MLKL-mediated disorder selected from ischemia-reperfusion damage, neurodegeneration, and inflammation, comprising treating a person in need thereof with an MLKL-inhibitor compound of formula I: wherein: each of R1-R4 is independently H, or optionally substituted, optionally hetero-, optionally cyclic C1-C18 hydrocarbyl, or optionally substituted heteroatom, and R1 and R2 are optionally joined to form a ring;n is 0, 1 or 2; and or a pharmaceutically acceptable salt, hydrate or stereoisomer the compound. 2. The method of claim 1 wherein: (a) one of R1-R4 is alkylcarbocylic. 3. The method of claim 1 wherein: (b) one of R1-R4 is fluoroalkyl. 4. The method of claim 1 wherein: (c) R4 is alkylcyano or alkylCR, wherein R is H, or optionally substituted, optionally hetero-, optionally cyclic C1-C18 hydrocarbyl. 5. The method of claim 1 wherein: (d) R1 and R2 are joined to form a ring. 6. The method of claim 1 wherein: two or three of R1-R4 is Me. 7. The method of claim 2 wherein: two or three of R1-R4 is Me. 8. The method of claim 3 wherein: two or three of R1-R4 is Me. 9. The method of claim 4 wherein: two or three of R1-R4 is Me. 10. The method of claim 5 wherein: two or three of R1-R4 is Me. 11. The method of claim 1 wherein: n is 2. 12. The method of claim 2 wherein: n is 2. 13. The method of claim 3 wherein: n is 2. 14. The method of claim 4 wherein: n is 2. 15. The method of claim 5 wherein: n is 2. 16. The method of claim 6 wherein: n is 2. 17. The method of claim 1 wherein: the optionally substituted, optionally hetero-, optionally cyclic C1-C18 hydrocarbyl is optionally-substituted, optionally hetero-, optionally cyclic alkyl, alkenyl or alkynyl, or optionally-substituted, optionally hetero-aryl; andthe optionally substituted heteroatom is halogen, optionally substituted hydroxyl (alkoxy), optionally substituted acyl (formyl, alkanoyl, carbamoyl, carboxyl, amido), optionally substituted amino (amino, alkylamino, dialkylamino, amido, sulfamidyl), optionally substituted thiol, (mercapto, alkylthiol, aryl thiol), optionally substituted sulfinyl or sulfonyl (alkylsulfinyl, arylsulfinyl, alkyl sulfonyl, arylsulfonyl), nitro, or cyano. 18. The method of claim 1, wherein the compound comprises a formula of a novel compound of Table 1 or 2. 19. The method of claim 1 further comprising the subsequent step of detecting a resultant amelioration of the disorder. 20. The method of claim 16 wherein the disorder is ischemia-reperfusion damage. 21. The method of claim 16 wherein the disorder is neurodegeneration. 22. The method of claim 16 wherein the disorder is inflammation. 23. An MLKL-inhibitor compound of formula I: wherein: each of R1-R4 is independently H, or optionally substituted, optionally hetero-, optionally cyclic C1-C18 hydrocarbyl, or optionally substituted heteroatom, and R1 and R2 are optionally joined to form a ring; andn is 0, 1 or 2; and(a) one of R1-R4 is alkylcarbocylic;(b) one of R1-R4 is fluoroalkyl;(c) R4 is alkylcyano or alkylCR, wherein R is H, or optionally substituted, optionally hetero-, optionally cyclic C1-C18 hydrocarbyl; or(d) R1 and R2 are joined to form a ring; or a pharmaceutically acceptable salt, hydrate or stereoisomer the compound.
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