Hydrophobically tagged janus kinase inhibitors and uses thereof
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07D-239/48
C07D-401/14
C07D-403/12
C07D-487/04
출원번호
US-0305845
(2015-04-23)
등록번호
US-9862688
(2018-01-09)
국제출원번호
PCT/US2015/027294
(2015-04-23)
국제공개번호
WO2015/164604
(2015-10-29)
발명자
/ 주소
Gray, Nathanael S.
Tan, Li
출원인 / 주소
Dana-Farber Cancer Institute, Inc.
대리인 / 주소
Wolf, Greenfield & Sacks, P.C.
인용정보
피인용 횟수 :
3인용 특허 :
60
초록▼
The present invention provides Janus kinase inhibitors, such as compounds of Formula (I) and Formula (II) wherein RY1 and RY2 comprise a tagged hydrophobic moiety RH. The compounds may covalently or non-covalently bind a kinase (e.g., Janus kinase 3 (JAK3)). The hydrophobic moiety RH may signal to t
The present invention provides Janus kinase inhibitors, such as compounds of Formula (I) and Formula (II) wherein RY1 and RY2 comprise a tagged hydrophobic moiety RH. The compounds may covalently or non-covalently bind a kinase (e.g., Janus kinase 3 (JAK3)). The hydrophobic moiety RH may signal to the intracellular protein homeostasis machinery to induce degradation of the targeted kinase. 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).
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 or L1-RH; L3 is a bond or a linker selected from the group consisting of substituted and unsubstituted C1-6alkylene, sub
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 or L1-RH; 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)-L1-RH, O-L1-RH, or C(RG2a)-L1-RH; or G1 is CHRG1a and G2 is N(RG2a)-L1-RH or O-L1-RH;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—;L1 is a linker selected from the group consisting of substituted and unsubstituted alkylene, substituted and unsubstituted alkenylene, substituted and unsubstituted alkynylene, substituted and unsubstituted heteroalkylene, substituted and unsubstituted heteroalkenylene, substituted and unsubstituted heteroalkynylene, substituted and unsubstituted heterocyclylene, substituted and unsubstituted carbocyclylene, substituted and unsubstituted arylene, substituted and unsubstituted heteroarylene, and combinations thereof;RH is a hydrophobic group selected from the group consisting of substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroarylalkyl, substituted and unsubstituted carbocycylalkyl, and substituted and unsubstituted heterocyclylalkyl; 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 RX2 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group when attached to a nitrogen atom. 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 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)-L1-RH, O-L1-RH, or C(RG2a)-L1-RH; or G1 is CHRG1a and G2 is N(RG2a)-L1-RH or O-L1-RH;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—;L1 is a linker selected from the group consisting of substituted and unsubstituted alkylene, substituted and unsubstituted alkenylene, substituted and unsubstituted alkynylene, substituted and unsubstituted heteroalkylene, substituted and unsubstituted heteroalkenylene, substituted and unsubstituted heteroalkynylene, substituted and unsubstituted heterocyclylene, substituted and unsubstituted carbocyclylene, substituted and unsubstituted arylene, substituted and unsubstituted heteroarylene, and combinations thereof;RH is a hydrophobic group selected from the group consisting of substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heteroarylalkyl, substituted and unsubstituted carbocycylalkyl, and substituted and unsubstituted heterocyclylalkyl; 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)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 RX2 is hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group when attached to a nitrogen atom. 3. The compound of claim 1, wherein both RJ1 and RJ2 are hydrogen. 4. The compound of claim 1, wherein a is 1 or 2 and at least one instance of RC is halogen. 5. The compound of claim 1, wherein each of RD1, RD2, and RD3 is hydrogen. 6. The compound of claim 1, wherein the group is attached meta to the point of attachment 7. The compound of claim 1, wherein the group is attached para to the point of attachment 8. The compound of claim 1, wherein L1 is and each instance of n is independently 1, 2, 3, or 4. 9. The compound of claim 1, wherein -L1-RH represents a group of the formula: 10. The compound of claim 1, wherein RH is: wherein: each occurrence of RH1 is independently halogen, —CN, substituted or unsubstituted C1-6 alkyl, —ORH1a, or —N(RH1a)2, wherein each instance of RH1a is independently substituted or unsubstituted C1-6 alkyl; andq is 0, 1, 2, or 3. 11. The compound of claim 1, wherein the ring system: is of the formula: 12. The compound of claim 1 of the formula: or a pharmaceutically acceptable salt thereof. 13. The compound of claim 1 selected from the group consisting of: and pharmaceutically acceptable salts thereof. 14. The compound of claim 2 of the formula: or a pharmaceutically acceptable salt thereof. 15. The compound of claim 2 selected from the group consisting of: and pharmaceutically acceptable salts 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 reducing the activity of a Janus kinase (JAK) or a receptor tyrosine kinase (RTK) 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) or the receptor tyrosine kinase (RTK). 18. A method of treating a condition associated with aberrant activity of a Janus kinase (JAK) or a receptor tyrosine kinase (RTK) 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. 19. A kit comprising: a compound of claim 1, or a pharmaceutically acceptable salt thereof; andinstructions for using the kit. 20. The compound of claim 1, wherein G1 is NRG1a. 21. The compound of claim 1, wherein G1 is CHRG1a. 22. The compound of claim 1, wherein G2 is N(RG2a)-L1-RH. 23. The compound of claim 1, wherein G2 is O-L1-RH. 24. The compound of claim 1, wherein RG1a and one instance of RG2a are joined to form the group —C(RB)2—C(RB)2—. 25. The compound of claim 1, wherein represents a single bond or double bond. 26. The compound of claim 1, wherein RG2a is hydrogen or substituted or unsubstituted C1-6 alkyl. 27. The compound of claim 1, wherein L3 is a bond or unsubstituted C1-3alkylene. 28. The compound of claim 1, wherein at least one instance of RA is substituted or unsubstituted C1-6 alkyl. 29. The compound of claim 1, wherein RG is hydrogen or —CH3. 30. The compound of claim 1, wherein RX is hydrogen, —F, —Br, —Cl, —CN, or —ORX1. 31. The compound of claim 1, wherein G5 is NRE; and RE is hydrogen or —CH3. 32. The compound of claim 1, wherein a is 0, 1, or 2. 33. The compound of claim 1, wherein RD3 is —CH2N(RD1a)2 or —CH2ORD1a. 34. The compound of claim 1, wherein RD4 is hydrogen. 35. The compound of claim 10, wherein q is 0. 36. The method of claim 17, wherein the Janus kinase is JAK3. 37. The method of claim 18, wherein the Janus kinase is JAK3. 38. The method of claim 17, wherein the receptor tyrosine kinase is an epidermal growth factor receptor (EGFR) tyrosine kinase. 39. The method of claim 18, wherein the receptor tyrosine kinase is an epidermal growth factor receptor (EGFR) tyrosine kinase. 40. The method of claim 18, wherein the hematological malignancy is leukemia or lymphoma.
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