The present invention provides kinase inhibitors, such as compounds of Formula (I) and Formula (II). The compounds may covalently or non-covalently bind a kinase (e.g., Janus kinase 3 (JAK3)). Also provided are pharmaceutical compositions, kits, methods, and uses that involve the compounds for reduc
The present invention provides kinase inhibitors, such as compounds of Formula (I) and Formula (II). The compounds may covalently or non-covalently bind a kinase (e.g., Janus kinase 3 (JAK3)). Also provided are pharmaceutical compositions, kits, methods, and uses that involve the compounds for reducing the activity of a kinase and/or treating and/or preventing a condition associated with aberrant activity of a kinase (e.g., a proliferative disease, inflammatory disorder, autoimmune disorder, painful condition, and/or viral infection). (I) (II)
대표청구항▼
1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof,wherein: W1 is N, W2 is N and W3 is CRX, or W1 is N, W2 is CH, and W3 is N;RY1 is a group of formula L3 is a bond or a linker selected from the group consisting of substituted and unsubstituted C1-6alkylene, substituted and
1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof,wherein: W1 is N, W2 is N and W3 is CRX, or W1 is N, W2 is CH, and W3 is N;RY1 is a group of formula L3 is a bond or a linker selected from the group consisting of substituted and unsubstituted C1-6alkylene, substituted and unsubstituted C2-6alkenylene, substituted and unsubstituted C2-6alkynylene, substituted and unsubstituted heteroC1-6alkylene, substituted and unsubstituted heteroC2-6alkenylene, and substituted and unsubstituted heteroC2-6alkynylene;G1 is NRG1a and G2 is N(RG2a)2, ORG2a, or C(RG2a)2; or G1 is CHRG1a and G2 is N(RG2a)2, ORG2a;each instance of RG1a and RG2a is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted hydroxyl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or RG1a and one instance of RG2a are joined to form the group —C(RB)2—C(RB)2—; represents a single or double bond;each instance of RD1, RD2, and RD3 is independently hydrogen or substituted or unsubstituted alkyl;RD4 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group;G5 is O, S, or NRE;each instance of RE and RG is independently hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group;each instance of RJ1 and RJ2 is independently hydrogen, halogen, or substituted or unsubstituted alkyl;each instance of RA and RC is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, —ORA1, —N(RA1)2, —SRA1, —CN, —SCN, —C(═NRA1)RA1, —C(═NRA1)ORA1, —C(═NRA1)N(RA1)2, —C(═O)RA1, —C(═O)ORA1, —C(═O)N(RA1)2, —NO2, —NRA1C(═O)RA1, —NRA1C(═O)ORA1, —NRA1C(═O)N(RA1)2, —OC(═O)RA1, —OC(═O)ORA1, or —OC(═O)N(RA1)2;each instance of RB is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, —ORA1, —N(RA1)2, —SRA1, —CN, —SCN, —C(═NRA1)RA1, —C(═NRA1)ORA1, —C(═NRA1)N(RA1)2, —C(═O)RA1, —C(═O)ORA1, —C(═O)N(RA1)2, —NO2, —NRA1C(═O)RA1, —NRA1C(═O)ORA1, —NRA1C(═O)N(RA1)2, —OC(═O)RA1, —OC(═O)ORA1, or —OC(═O)N(RA1)2; or two RB groups attached to the same carbon atom are joined to form a ═O group;each instance of RA1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted 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 RA1 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;a and k are each independently 0, 1, or 2, provided when k is 0, then RA is absent, and when a is 0, then RC is absent; andeach instance of RX and RZ is independently hydrogen, halogen, substituted or unsubstituted alkyl, cyclopropyl, —CN, —ORX1, or —NHRX1, wherein RX1 is hydrogen, substituted or unsubstituted alkyl, an oxygen protecting group when attached to an oxygen, or a nitrogen protecting group when attached to a nitrogen, or RX and RZ are joined to form a substituted or unsubstituted 5-membered heterocyclic ring, or a ring of formula: wherein RX2 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group; or RX and RE are joined to form a substituted or unsubstituted 5- to 6-membered heterocyclic ring, or a ring of formula: wherein RX is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group. 2. A compound of Formula (II): or a pharmaceutically acceptable salt thereof,wherein: W1 is N, W2 is N and W3 is CRX, or W1 is N, W2 is CH, and W3 is N; is selected from the group consisting of: wherein t is 2, 3, 4, 5, or 6; RY2 is hydrogen, substituted or unsubstituted alkyl, —C(═O)RA2, a nitrogen protecting group if attached to a nitrogen atom, or a group of formula RA2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;L3 is a bond or a linker selected from the group consisting of substituted and unsubstituted C1-6alkylene, substituted and unsubstituted C2-6alkenylene, substituted and unsubstituted C2-6alkynylene, substituted and unsubstituted heteroC1-6alkylene, substituted and unsubstituted heteroC2-6alkenylene, and substituted and unsubstituted heteroC2-6alkynylene;G1 is NRG1a and G2 is N(RG2a)2, ORG2a, or C(RG2a)2; or G1 is CHRG1a and G2 is N(RG2a)2, ORG2a;each instance of RG1a and RG2a is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted hydroxyl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or RG1a and one instance of RG2a are joined to form the group —C(RB)2—C(RB)2—; represents a single or double bond;each instance of RD1, RD2, and RD3 is independently hydrogen or substituted or unsubstituted alkyl;RD4 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group;G5 is O, S, or NRE;each instance of RE and RG is independently hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group;each instance of RJ1 and RJ2 is independently hydrogen, halogen, or substituted or unsubstituted alkyl;each instance of RA and RC is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, —ORA1, —N(RA1)2, —SRA1, —CN, —SCN, —C(═NRA1)RA1, —C(═NRA1)ORA1, —C(═NRA1)N(RA1)2, —C(═O)RA1, —C(═O)ORA1, —C(═O)N(RA1)2, —NO2, —NRA1C(═O)RA1, —NRA1C(═O)ORA1, —NRA1C(═O)N(RA1)2, —OC(═O)RA1, —OC(═O)ORA1, or —OC(═O)N(RA1)2;each instance of RB is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, —ORA1, —N(RA1)2, —SRA1, —CN, —SCN, —C(═NRA1)RA1, —C(═NRA1)ORA1, —C(═NRA1)N(RA1)2, —C(═O)RA1, —C(═O)ORA1C(═O)N(RA1)2, —NO2, —NRA1C(═O)RA1, —NRA1C(═O)ORA1, —NRA1C(═O)N(RA1)2, —OC(═O)RA1, —OC(═O)ORA1, or —OC(═O)N(RA1)2; or two RB groups attached to the same carbon atom are joined to form a ═O group;each instance of RA1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted 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 RA1 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;a and k are each independently 0, 1, or 2, provided when k is 0, then RA is absent, and when a is 0, then RC is absent; andeach instance of RX and RZ is independently hydrogen, halogen, substituted or unsubstituted alkyl, cyclopropyl, —CN, —ORX1, or —NHRX1, wherein RX1 is hydrogen, substituted or unsubstituted alkyl, an oxygen protecting group when attached to an oxygen, or a nitrogen protecting group when attached to a nitrogen, or RX and RZ are joined to form a substituted or unsubstituted 5-membered heterocyclic ring, or a ring of formula: wherein RX2 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group;or RX and RE are joined to form a substituted or unsubstituted 5- to 6-membered heterocyclic ring, or a ring of formula: wherein RX2 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group. 3. The compound of claim 1, wherein the group is attached meta to the point of attachment 4. The compound of claim 1, wherein the group is attached para to the point of attachment 5. The compound of claim 1, wherein the ring system: is a bicyclic ring system of formula: wherein RX2 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group. 6. The compound of claim 1, wherein the ring system: is of the formula: 7. The compound of claim 1, wherein the ring system: is of the formula: 8. The compound of claim 1 of the Formula: or a pharmaceutically acceptable salt thereof. 9. The compound of claim 1 of the Formula: or a pharmaceutically acceptable salt thereof. 10. The compound of claim 1 selected from the group consisting of: and pharmaceutically acceptable salts thereof. 11. The compound of claim 2 of the Formula: or a pharmaceutically acceptable salt thereof. 12. The compound of claim 2 of the Formula: wherein: each instance of RY4 is independently hydrogen, halogen, —ORY3, —N(RY3)2, —C(═O)ORY3, —C(═O)N(RY3)2, provided at least one RY4 group is not hydrogen; andRY3 is independently hydrogen, substituted or unsubstituted alkyl, or two RY3 groups attached to a N atom are joined to form a substituted or unsubstituted 5- to 6-membered heterocyclic ring, wherein: each instance of RY4 is independently hydrogen, halogen, —ORY3, —N(RY3)2, —C(═O)ORY3, —C(═O)N(RY3)2, provided at least one RY4 group is not hydrogen;RY3 is independently hydrogen, substituted or unsubstituted alkyl, or two RY3 groups attached to a N atom are joined to form a substituted or unsubstituted 5- to 6-membered heterocyclic ring. In certain embodiments, one RY4 is halogen, —ORY3, —N(RY3)2, —C(═O)ORY3, —C(═O)N(RY3)2, and the other two RY4 groups are hydrogen; andeach instance of RY5 is independently hydrogen or —CH3, or a pharmaceutically acceptable salt thereof. 13. The compound of claim 2 selected from the group consisting of: and pharmaceutically acceptable salts thereof. 14. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 15. A method of reducing the activity of a Janus kinase (JAK) in a subject in need thereof, the method comprising administering to the subject a compound of claim 1, or a pharmaceutically acceptable salt thereof, in an amount sufficient to reduce the activity of the Janus kinase (JAK). 16. A method of treating a condition associated with aberrant activity of a Janus kinase in a subject in need thereof, the method comprising administering to the subject a compound of claim 1, or a pharmaceutically acceptable salt thereof, in an amount sufficient to treat the condition, wherein the condition is a hematological malignancy. 17. A kit comprising: a compound of claim 1, or a pharmaceutically acceptable salt thereof; andinstructions for using the kit. 18. A labeled compound of Formula (I) or (II): or a pharmaceutically acceptable salt thereof;wherein: Group is selected from the group consisting of: wherein t is 2, 3, 4, 5, or 6; L1 is a linking group selected from the group consisting of substituted or unsubstituted alkylene; substituted or unsubstituted alkenylene; substituted or unsubstituted alkynylene; substituted or unsubstituted heteroalkylene; substituted or unsubstituted heteroalkenylene; substituted or unsubstituted heteroalkynylene; substituted or unsubstituted heterocyclylene; substituted or unsubstituted carbocyclylene; substituted or unsubstituted arylene; substituted or unsubstituted heteroarylene; and combinations thereof;B is a label;W1 is N, W2 is N and W3 is CRX, or W1 is N, W2 is CH, and W3 is N; represents a single or double bond;each instance of RD1, RD2, and RD3 is independently hydrogen or substituted or unsubstituted alkyl;RD4 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group;G5 is O, S, or NRE;each instance of RE and RG is independently hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group;each instance of RJ1 and RJ2 is independently hydrogen, halogen, or substituted or unsubstituted alkyl;each instance of RA and RC is independently halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, —ORA1, —N(RA1)2, —SRA1, —CN, —SCN, —C(═NRA1)RA1, —C(═NRA1)ORA1, —C(═NRA1)N(RA1)2, —C(═O)RA1, —C(═O)ORA1, —C(═O)N(RA1)2, —NO2, —NRA1C(═O)RA1, —NRA1C(═O)ORA1, —NRA1C(═O)N(RA1)2, —OC(═O)RA1, —OC(═O)ORA1, or —OC(═O)N(RA1)2;each instance of RA1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted 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 RA1 groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;a and k are each independently 0, 1, or 2, provided when k is 0 then RA is absent, and when a is 0 then RC is absent; andeach instance of RX and RZ is independently hydrogen, halogen, substituted or unsubstituted alkyl, cyclopropyl, —CN, —ORX1, or —NHRX1, wherein RX1 is hydrogen, substituted or unsubstituted alkyl, an oxygen protecting group when attached to an oxygen, or a nitrogen protecting group when attached to a nitrogen, or RX and RZ are joined to form a substituted or unsubstituted 5-membered heterocyclic ring, or a ring of formula: wherein RX2 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group;or RX and RE are joined to form a substituted or unsubstituted 5- to 6-membered heterocyclic ring, or a ring of formula: wherein RX2 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group. 19. The labeled compound of claim 18: 20. A pharmaceutical composition comprising a compound of claim 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 21. A kit comprising: a compound of claim 2, or a pharmaceutically acceptable salt thereof; andinstructions for using the kit. 22. A method of reducing the activity of a Janus kinase (JAK) in a subject in need thereof, the method comprising administering to the subject a compound of claim 2, or a pharmaceutically acceptable salt thereof, in an amount sufficient to reduce the activity of the Janus kinase (JAK). 23. A method of treating a condition associated with aberrant activity of a Janus kinase in a subject in need thereof, the method comprising administering to the subject a compound of claim 2, or a pharmaceutically acceptable salt thereof, in an amount sufficient to treat the condition, wherein the condition is a hematological malignancy. 24. The method of claim 16, wherein the hematological malignancy is leukemia or lymphoma. 25. The method of claim 16, wherein the Janus kinase is Janus kinase 3 (JAK3). 26. The method of claim 23, wherein the hematological malignancy is leukemia or lymphoma. 27. The method of claim 23, wherein the Janus kinase is Janus kinase 3 (JAK3).
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