The present invention provides novel compounds according to Formula (I): where Ring A, Ring B, X, L1, L2, RA, RC, RD, RE, m, n, and p are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of human diseases associated with kin
The present invention provides novel compounds according to Formula (I): where Ring A, Ring B, X, L1, L2, RA, RC, RD, RE, m, n, and p are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of human diseases associated with kinase activity, for example, proliferative diseases, neurodegenerative diseases, metabolic disorders, inflammatory diseases, and cardiovascular diseases.
대표청구항▼
1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof; wherein: Ring A is a carbocyclic, heterocyclic, heteroaryl, or aryl ring;each instance of RA is independently selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alk
1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof; wherein: Ring A is a carbocyclic, heterocyclic, heteroaryl, or aryl ring;each instance of RA is independently selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —ORA1, —N(RA1)2, and —SRA1, wherein each occurrence of RA1 is independently hydrogen, acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or two RA1 groups are joined to form an optionally substituted heterocyclic ring;m is 0, 1, 2, 3, or 4;Ring B is a group of the formula: RB1 is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —ORB1a, —N(RB1a)2, and —SRB1a, wherein each occurrence of RB1a is independently hydrogen, acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RB1a groups are joined to form an optionally substituted heterocyclic ring;WB is N or CRB2, wherein RB2 is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —ORB2a, —N(RB2a)2, and —SRB2a, wherein each occurrence of RB2a is independently hydrogen, acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two RB2a groups are joined to form an optionally substituted heterocyclic ring;or RB1 and RB2 are joined to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted aryl ring;L1 is ═C(RL1a)—, —O—, —S—, —NRL1bC(═O)—, —C(═O)NRL1b—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NRL1bC(═S)—, —C(═S)NRL1b—, trans-CH═CH—, cis-CH═CH—, —S(═O)2O—, —OS(═O)2—, —S(═O)2NRL1b—, —NRL1bS(═O)2—, or an optionally substituted C2-4 hydrocarbon chain, optionally wherein on methylene unit of the hydrocarbon chain is replaced with ═C(RL1a)—, —O—, —S—, —NRL1b—, —NRL1bC(═O)—, —C(═O)NRL1b—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NRL1bC(═S)—, —C(═S)NRL1b—, trans-CH═CH—, cis-CH═CH—, —S(═O)2O—, —OS(═O)2—, —S(═O)2NRL1b—, or —NRL1bS(═O)2—, wherein RL1a is hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, or —NO2, and RL1b is hydrogen, C1-6 alkyl, or a nitrogen protecting group; represents a single or double bond;X is an optionally substituted C1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain is replaced with —O—, —S—, or —NRX—, wherein RX is hydrogen, C1-6 alkyl, or a nitrogen protecting group;L2 is a bond, —O—, —S—, —NRL2a—, —NRL2aC(═O)—, —C(═O)NRL2a—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NRL2aC(═S)—, —C(═S)NRL2a—, trans-CRL2b═CRL2b—, cis-CRL2b═CRL2b—, —C≡C—, —OC(RL2b)2—, —C(RL2b)2O—, —NRL2aC(RL2b)2—, —C(RL2b)2NRL2a—, —SC(RL2b)2—, —C(RL2b)2S—, —S(═O)2O—, —OS(═O)2—, —S(═O)2NRL2a—, —NRL2aS(═O)2—, or an optionally substituted C1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain is replaced with —O—, —S—, —NRL2aNRL2aC(═O)—, —C(═O)NRL2a—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NRL2aC(═S)—, —C(═S)NRL2a—, trans-CRL2b═CRL2b—, cis-CRL2b═CRL2b—, —C≡C—, —S(═O)2O—, —OS(═O)2—, —S(═O)2NRL2a—, or —NRL2aS(═O)2—, wherein RL2a is hydrogen, C1-6 alkyl, or a nitrogen protecting group, and wherein each occurrence of RL2b is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two RL2b groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;each instance of RC is independently selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —ORC1, —N(RC1)2, and —SRC1, wherein each occurrence of RC1 is independently hydrogen, acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or two RC1 groups are joined to form an optionally substituted heterocyclic ring;n is 0, 1, 2, 3, or 4;each instance of RD is independently selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —ORD1, —N(RD1)2, and —SRD1, wherein each occurrence of RD1 is independently hydrogen, acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or two RD1 groups are joined to form an optionally substituted heterocyclic ring;p is 0, 1, 2, 3, or 4;RE is a group of the formula: wherein: L3 is a bond, —O—, —S—, —NRL3a—, —NRL3aC(═O)—, —C(═O)NRL3a—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NRL3aC(═S)—, —C(═S)NRL3a—, trans-CRL3b═CRL3b—, cis-CRL3b═CRL3b—, —C≡C—, —OC(RL3b)2—, —C(RL3b)2O—, —NRL3aC(RL3b)2—, —C(RL3b)2NRL3a—, —SC(RL3b)2—, —S(═O)2O—, —OS(═O)2—, —S(═O)2NRL3a—, —NRL3aS(═O)2—, or an optionally substituted C1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain is replaced with —O—, —S—, —NRL3a—, —NRL3aC(═O)—, —C(═O)NRL3a—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NRL3aC(═S)—, —C(═S)NRL3a—, trans-CRL3b═CRL3b—, cis-CRL3b═CRL3b—, —C≡C—, —S(═O)2O—, —OS(═O)2—, —S(═O)2NRL3a—, or —NRL3aS(═O)2—, wherein RL3a is hydrogen, C1-6 alkyl, or a nitrogen protecting group, and wherein each occurrence of RL3b is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two RL3b groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;L4 is a bond or an optionally substituted C1-4 hydrocarbon chain;RE1 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CH2ORE1a, —CH2N(RE1a)2, —CH2SRE1a, —ORE1a, —N(RE1a)2, and —SRE1a, wherein each occurrence of RE1a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two RE1a groups are joined to form an optionally substituted heterocyclic ring;RE2 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CH2ORE2a, —CH2N(RE2a)2, —CH2SRE2a, —ORE2a, —N(RE2a)2, and —SRE2a, wherein each occurrence of RE2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl or two RE2a groups are joined to form an optionally substituted heterocyclic ring;RE3 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CH2ORE3a, —CH2N(RE3a)2, —CH2SRE3a, —ORE3a, —N(RE3a)2, and —SRE3a, wherein each occurrence of RE3a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two RE3a groups are joined to form an optionally substituted heterocyclic ring;or RE1 and RE3 or RE2 and RE3 or RE1 and RE2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;RE4 is a leaving group;Y is O, S, or NRE5, wherein RE5 is hydrogen, C1-6 alkyl, or a nitrogen protecting group;a is 1 or 2; andz is 0, 1, 2, 3, 4, 5, or 6. 2. The compound of claim 1, wherein L1 is the group ═C(RL1a)— attached to Ring A by the double bond, and attached to Ring B by the single bond. 3. The compound of claim 1, wherein is of the formula: 4. The compound of claim 1, wherein is of the formula: 5. The compound of claim 1, wherein is of the formula: 6. The compound of claim 1, wherein is of the formula: 7. The compound of claim 1, wherein WB is CRB2; and Ring B is a group of formula: 8. The compound of claim 1, wherein X is —NRX—. 9. The compound of claim 1, wherein L2 is —NRL2aC(═O) —. 10. The compound of claim 1, wherein RE is a group of formula: 11. The compound of claim 10, wherein Y is O; L3 is —NRL3a—; RE1 is hydrogen; RE2 is hydrogen; and RE3 is —CH2N(RE3a)2. 12. The compound of claim 1, wherein the compound is of formula: or a pharmaceutically acceptable salt thereof. 13. The compound of claim 1, wherein the compound is of formula: or a pharmaceutically acceptable salt thereof. 14. The compound of claim 1, wherein the compound is of formula: or a pharmaceutically acceptable salt thereof. 15. The compound of claim 1, wherein the compound is of formula: or a pharmaceutically acceptable salt thereof. 16. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 17. A method of treating a proliferative disease, neurodegenerative disease, stroke, inflammatory disease, or metabolic disorder comprising administering to a subject in need thereof an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof. 18. A method of screening a library of compounds of claim 1 to identify one or more compounds that are useful in the treatment of a proliferative disease in a subject, the method comprising: providing at least two different compounds of claim 1, or pharmaceutically acceptable salts thereof; andperforming at least one assay using the different compounds, or pharmaceutically acceptable salts thereof, to detect one or more characteristics associated with the proliferative disease. 19. A kit comprising: a container comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof; andinstructions for administering to a subject the compound, or the pharmaceutically acceptable salt thereof. 20. The compound of claim 1, wherein Ring A is a monocyclic or bicyclic, heteroaryl ring. 21. The compound of claim 1, wherein is of the formula: 22. The compound of claim 1, wherein each instance of RA is independently hydrogen, halogen, or optionally substituted alkyl. 23. The compound of claim 7, wherein RB1 is hydrogen, halogen, or optionally substituted alkyl; and RB2 is hydrogen, halogen, or optionally substituted alkyl. 24. The compound of claim 1, wherein L2 is —C(=O)NRL2a—. 25. The compound of claim 1, wherein each instance of RC is independently hydrogen, halogen, or optionally substituted alkyl. 26. The compound of claim 1, wherein each instance of RD is independently hydrogen, halogen, or optionally substituted alkyl. 27. The compound of claim 10, wherein Y is O; L3 is —NRL3a—; and each of RE1, RE2, and RE3 is hydrogen. 28. The compound of claim 1, wherein the compound is of formula: or a pharmaceutically acceptable salt thereof. 29. The compound of claim 1, wherein the compound is of formula: or a pharmaceutically acceptable salt thereof. 30. The compound of claim 1, wherein Ring A is a monocyclic or bicyclic, heterocyclic ring. 31. The compound of claim 2, wherein Ring A is a monocyclic or bicyclic, heteroaryl ring. 32. The compound of claim 2, wherein Ring A is a monocyclic or bicyclic, heterocyclic ring. 33. The method of claim 17, wherein the method is a method of treating a proliferative disease. 34. The method of claim 33, wherein the proliferative disease is cancer. 35. The method of claim 33, wherein the proliferative disease is melanoma, lung cancer, cervical cancer, or kidney cancer. 36. The method of claim 17, wherein the method is a method of treating a neurodegenerative disease, wherein the neurodegenerative disease is Parkinson's disease or Alzheimer's disease. 37. The method of claim 17, wherein the method is a method of treating an inflammatory disease, wherein the inflammatory disease is rheumatoid arthritis. 38. The method of claim 17, wherein the method is a method of treating a metabolic disorder, wherein the metabolic disorder is diabetes. 39. The method of claim 17, wherein the compound is of formula: or a pharmaceutically acceptable salt thereof.
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