IPC분류정보
국가/구분 |
United States(US) Patent
등록
|
국제특허분류(IPC7판) |
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출원번호 |
US-0436387
(2013-10-18)
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등록번호 |
US-10000483
(2018-06-19)
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국제출원번호 |
PCT/US2013/065689
(2013-10-18)
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국제공개번호 |
WO2014/063054
(2014-04-24)
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발명자
/ 주소 |
- Gray, Nathanael
- Balk, Steven
- Liu, Qingsong
- Chen, Sen
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출원인 / 주소 |
- Dana-Farber Cancer Institute, Inc.
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대리인 / 주소 |
Wolf, Greenfield & Sacks, P.C.
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인용정보 |
피인용 횟수 :
0 인용 특허 :
64 |
초록
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The present invention provides novel compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods and kits involving the compound
The present invention provides novel compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods and kits involving the compounds of Formula (I) or (II), or compositions thereof, for treating or preventing a wide range of diseases (e.g., proliferative diseases (e.g., cancers, benign neoplasms, angiogenesis, inflammatory diseases, autoimmune diseases) and metabolic diseases (e.g., diabetes (e.g., type 2 diabetes, gestational diabetes)) in a subject. Treatment of a subject with a disease using a compound of Formula (I) or (II), or compositions thereof, may downregulate the expression and/or inhibit the activity of a kinase (e.g., a tyrosine kinase, such as a Tec kinase, in particular, bone marrow on X chromosome kinase (BMX)), and therefore, suppress tyrosine kinase singling in the subject.
대표청구항
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1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof; wherein: is Ring A, wherein Ring A is a phenyl ring optionally substituted with k instances of RA; each instance of RA is independently hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alk
1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof; wherein: is Ring A, wherein Ring A is a phenyl ring optionally substituted with k instances of RA; each instance of RA is independently hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted, monocyclic, 5- or 6-membered heterocyclyl, —ORA1, —N(RA1)2, —SRA1, —CN, —C(═O)RA1, —C(═O)ORA1, —C(═O)N(RA1)2, —NO2, —N3, —NRA1C(═O)RA1, —NRA1C(═O)ORA1, —NRA1C(═O)N(RA1)2, —NRA1S(═O)2RA1, —NRA1S(═O)2ORA1, —NRA1S(═O)2N(RA1)2, —NRA1S(═O)RA1, —NRA1S(═O)ORA1, —NRA1S(═O)N(RA1)2, —OC(═O)RA1, —OC(═O)ORA1, —OC(═O)N(RA1)2, —OS(═O)RA1, —OS(═O)ORA1, —OS(═O)N(RA1)2, —OS(═O)2RA1, —OS(═O)2ORA1, —OS(═O)2N(RA1)2, —S(═O)RA1, —S(═O)ORA1, —S(═O)N(RA1)2, —S(═O)2RA1, —S(═O)2ORA1, or —S(═O)2N(RA1); wherein each occurrence of RA1 is independently hydrogen, optionally substituted acyl, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, 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;k is 0, 1, 2, or 3;M is a bond or an unsubstituted C1-3 hydrocarbon chain; is Ring C, wherein Ring C is a phenyl ring optionally fused with a monocyclic, 5- or 6-membered heterocyclic ring and is optionally substituted with n instances of RC;each instance of Rc is independently hydrogen, halogen, or optionally substituted methyl;n is 0, 1, or 2;L is a bond or an optionally substituted C1-3 hydrocarbon chain;RD is of the formula: wherein: RD1 is hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, —CN, —NO2, —ORD1a, —N(RD1a)2 ,—SRD1a, —CH2ORD1a, —CH2N(RD1a)2, —CH2SRD1a, —C(═O)RD1a, —C(═O)ORD1a, or —C(═O)N(RD1a)2, wherein each occurrence of RD1a is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl;RD2 is hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, —CN, —NO2, —ORD2a, —N(RD2a)2, —SRD2a,—CH2ORD2a, —CH2N(RD2a)2, —CH2SRD2a, —C(═O)RD2a, —C(═O)ORD2a, or —C(═O)N(RD2a)2, wherein each occurrence of RD2a is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl;RD3 is hydrogen, halogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, —CN, —NO2, —ORD3a, —N(RD3a)2, —SRD3a, —CH2ORD3a, —CH2N(RD3a)2, —CH2SRD3a, —C(═O)RD3a, —C(═O)ORD3a, or —C(═O)N(RD3a)2, wherein each occurrence of RD3a is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl;RD4 is a leaving group, wherein the leaving group is halogen, alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy, arylcarbonyloxy, aryloxy, alkoxy, N,O-dimethylhydroxylamino, pixyl, haloformate, phosphineoxide, epoxide, cyclic sulfate, or —OS(═O)rRz1, wherein: Rz1 is optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, or optionally substituted C2-6 alkynyl; andr is 1 or 2;RD5 is hydrogen, optionally substituted C1-6 alkyl, or a nitrogen protecting group;Y is O;a is 1 or 2; andz is 0, 1, 2, 3,4, 5, or 6;when an optionally substituted moiety referred to above is substituted with one or more substituents at a carbon atom, the one or more substituents at the carbon atom are independently halogen, —CN, —NO2, —N3, —SO2H, —SO3H, —OH, —ORaa, —ON(Rbb)2, —N(Rbb)2, —N(Rbb)3+X−, —N(ORcc)Rbb, —SH, —SRaa, —SSRcc, —C(═O)Raa, —CO2H, —CHO, —C(ORcc)2, —CO2Raa, —OC(═O)Raa, —OCO2Raa, —C(═O)N(Rbb)2, —OC(═O)N(Rbb)2, —NRbbC(═O)Raa, —NRbbCO2Raa, —NRbbC(═O)N(Rbb)2, —C(═NRbb)Raa, —C(═NRbb)ORaa, —OC(═NRbb)Raa, —OC(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —OC(═NRbb)N(Rbb)2, —NRbbC(═NRbb)N(Rbb)2, —C(═O)NRbbSO2Raa, —NRbbSO2Raa, —SO2N(Rbb)2, —SO2Raa, —SO2ORaa, —OSO2Raa, —S(═O)Raa, —OS(═O)Raa, —Si(Raa)3, —OSi(Raa)3—C(═S)N(Rbb)2, —C(═O)SRaa, —C(═S)SRaa, —SC(═S)SRaa, —SC(═O)SRaa, —OC(═O)SRaa, —SC(═O)ORaa, —SC(═O)Raa, —P(═O)(Raa)2, —OP(═O)(Raa)2, —OP(═O)(ORcc)2, —P(═O)(NRbb)2, —OP(═O)(NRbb)2, —NRbbP(═O)(ORcc)2, —NRbbP(═O)(NRbb)2, —P(Rcc)2, —OP(Rcc)2, —B(Raa)2, —B(ORcc)2, —BRaa(ORcc), C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, or C2-10 alkynyl, wherein each of the alkyl, alkenyl, and alkynyl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; or two geminal hydrogen atoms on the carbon atom are replaced with ═O, ═S, ═NN(Rbb)2, ═NNRbbC(═O)Raa, ═NNRbbC(═O)ORaa, ═NNRbbS(═O)2Raa, ═NRbb, or ═NORcc;when an optionally substituted moiety referred to above is substituted with one or more substituents at a nitrogen atom, the one or more substituents at the nitrogen atom are independently a nitrogen protecting group, —OH, —ORaa, —N(Rcc)2, —CN, —C(═O)Raa, —C(═O)N(Rcc)2, —CO2Raa, —SO2Raa, —C(═NRbb)Raa, —C(═NRcc)ORaa, —C(═NRcc)N(Rcc)2, —SO2N(Rcc)2, —SO2Rcc, —SO2ORcc, —SORaa, —C(═S)N(Rcc)2, —C(═O)SRcc, —C(═S)SRcc, —P(═O)(Raa)2, —P(═O)(NRcc)2, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, or C2-10 alkynyl, wherein each of the alkyl, alkenyl, and alkynyl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;wherein: each instance of Raa is, independently, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, or phenyl, wherein each of the alkyl, alkenyl, alkynyl, and phenyl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;each instance of Rbb is, independently, selected from hydrogen, —OH, —ORaa, —N(Rcc)2, —CN, —C(═O)Raa, —C(═O)N(Rcc)2, —CO2Raa, —SO2Raa, —C(═NRcc)ORaa, —C(═NRcc)N(Rcc)2, —SO2N(Rcc)2, —SO2Rcc, —SO2ORcc, —SORaa, —C(═S)N(Rcc)2, —C(═O)SRcc, —C(═S)SRcc, —P(═O)(Raa)2, —P(═O)(NRcc)2, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, and C2-10 alkynyl, wherein each of the alkyl, alkenyl, and alkynyl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;each instance of Rcc is, independently, selected from hydrogen, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, and C2-10 alkynyl, wherein each of the alkyl, alkenyl, and alkynyl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;each instance of Rdd is, independently, selected from halogen, —CN, —NO2, —N3, —SO2H, —SO3H, —OH, —ORee, —ON(Rff)2, —N(Rff)2, —N(Rff)3+X−, —N(ORee)Rff, —SH, —SRee, —SSRee, —C(═O)Ree, —CO2H, —CO2Ree, —OC(═O)Ree, —OCO2Ree, —C(═O)N(Rff)2, —OC(═O)N(Rff)2, —NRffC(═O)Ree, —NRffCO2Ree, —NRffC(═O)N(Rff)2, —C(═NRff)ORee, —OC(═NRff)Ree, —OC(═NRff)ORee, —C(═NRff)N(Rff)2, —OC(═NRff)N(Rff)2, —NRffC(═NRff)N(Rff)2,—NRffSO2Ree, —SO2N(Rff)2 , —SO2Ree, —SO2ORee, —OSO2Ree, —S(═O)Ree, —Si(Ree)3, —OSi(Ree)3, —C(═S)N(Rff)2, —C(═O)SRee, —C(═S)SRee, —SC(═S)SRee, —P(═O)(Ree)2, —OP(═O)(Ree)2, —OP(═O)(ORee)2, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein each of the alkyl, alkenyl, and alkynyl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups, or two geminal Rdd substituents can be joined to form ═O or ═S;each instance of Ree is, independently, selected from C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein each of the alkyl, alkenyl, and alkynyl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups;each instance of Rff is, independently, selected from hydrogen, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein each of the alkyl, alkenyl, and alkynyl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups;each instance of Rgg is, independently, halogen, —CN, —NO2, —N3, —SO2H, —SO3H, —OH, —OC1-6 alkyl, —ON(C1-6 alkyl)2, —N(C1-6 alkyl)2, —N(C1-6 alkyl)3+X−, —NH(C1-6 alkyl)2+X−, —NH2(C1-6 alkyl)+X−, —NH3+X−, —N(OC1-6 alkyl)(C1-6 alkyl), —N(OH)(C1-6 alkyl), —NH(OH), —SH, —SC1-6 alkyl, —SS(C1-6 alkyl), —C(═O)(C1-6 alkyl), —CO2H, —CO2(C1-6 alkyl), —OC(═O)(C1-6 alkyl), —OCO2(C1-6 alkyl), —C(═O)NH2, —C(═O)N(C1-6 alkyl)2, —OC(═O)NH(C1-6 alkyl), —NHC(═O)(C1-6 alkyl), —N(C1-6 alkyl)C(═O)(C1-6 alkyl), —NHCO2(C1-6 alkyl), —NHC(═O)N(C1-6 alkyl)2, —NHC(═O)NH(C1-6 alkyl), —NHC(═O)NH2, —C(═NH)O(C1-6 alkyl), —OC(═NH)(C1-6 alkyl), —OC(═NH)OC1-6 alkyl, —C(═NH)N(C1-6 alkyl)2, —C(═NH)NH(C1-6 alkyl), —C(═NH)NH2, —OC(═NH)N(C1-6 alkyl)2, —OC(NH)NH(C1-6 alkyl), —OC(NH)NH2, —NHC(NH)N(C1-6 alkyl)2, —NHC(═NH)NH2, —NHSO2(C1-6 alkyl), —SO2N(C1-6 alkyl)2, —SO2NH(C1-6 alkyl), —SO2NH2, —SO2C1-6 alkyl, —SO2OC1-6 alkyl, —OSO2C1-6 alkyl, —SOC1-6 alkyl, —Si(C1-6 alkyl)3, —OSi(C1-6 alkyl)3, —C(═S)N(C1-6 alkyl)2, C(═S)NH(C1-6 alkyl), C(═S)NH2, —C(═O)S(C1-6 alkyl), —C(═S)SC1-6 alkyl, —SC(═S)SC1-6 alkyl, —P(═O)(C1-6 alkyl)2, —OP(═O)(C1-6 alkyl)2, —OP(═O)(OC1-6 alkyl)2, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, or C2-6 alkynyl; or two geminal Rgg substituents can be joined to form ═O or ═S; andX− is a counterion;when an optionally substituted moiety referred to above is substituted with a substituent at an oxygen atom, the substituent at the oxygen atom is an oxygen protecting group;when an optionally substituted moiety referred to above is substituted with a substituent at a sulfur atom, the substituent at the sulfur atom is an sulfur protecting group; andeach occurrence of the heterocyclyl or heterocyclic ring independently comprises 1 to 4 ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, as valency permits. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RD is of Formula (i-1): 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring C is a phenyl ring optionally substituted with n instances of Rc. 4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein L is a bond or —CH2—. 5. The compound of claim 1, wherein the compound is of Formula (I-1): or a pharmaceutically acceptable salt thereof. 6. The compound of claim 1, wherein the compound is of Formula (I-2): or a pharmaceutically acceptable salt thereof. 7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein M is a bond. 8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein M is trans-CH═CH—. 9. The compound of claim 1, wherein the compound is of Formula (I-3): or a pharmaceutically acceptable salt thereof. 10. The compound of claim 1, wherein the compound is of Formula (I-4): or a pharmaceutically acceptable salt thereof. 11. The compound of claim 1, wherein the compound is of Formula (I-5): or a pharmaceutically acceptable salt thereof. 12. The compound of claim 1, wherein the compound is of Formula (I-6): or a pharmaceutically acceptable salt thereof. 13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: Rc is optionally substituted methyl; andn is 1. 14. The compound of claim 1, wherein the compound is of the formula: or a pharmaceutically acceptable salt thereof. 15. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. 16. A method for treating a disease characterized by overexpression of bone marrow kinase on X chromosome (BMX) or associated with aberrant activity of BMX, the method comprising: administering to a subject in need thereof a compound of claim 1, or a pharmaceutically acceptable salt thereof, in an amount effective to treat the disease, wherein the disease is prostate cancer or lymphoma. 17. A method of suppressing kinase signaling in a biological sample or subject, the method comprising: administering to the biological sample or subject a compound of claim 1, or a pharmaceutically acceptable salt thereof, in an amount effective to suppress the kinase signaling. 18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein M is an unsubstituted C2 hydrocarbon chain. 19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0. 20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RD is of the formula: 21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein RD is of the formula: 22. The compound of claim 1, wherein the compound is of the formula: or a pharmaceutically acceptable salt thereof. 23. The compound of claim 1, wherein the compound is of the formula: or a pharmaceutically acceptable salt thereof. 24. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring C is a phenyl ring fused with a monocyclic, 5- or 6-membered heterocyclic ring and is optionally substituted with n instances of Rc. 25. The compound of claim 1, wherein the compound is of the formula: or a pharmaceutically acceptable salt thereof. 26. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein at least one instance of RA is —NRA1S(═O)2RA1. 27. The compound of claim 1, wherein the compound is of the formula: or a pharmaceutically acceptable salt thereof. 28. The pharmaceutical composition of claim 15, wherein the compound is of the formula: 29. The method of claim 16, wherein the compound is of the formula: 30. The method of claim 17, wherein the compound is of the formula: 31. The method of claim 16, wherein the disease is prostate cancer. 32. The method of claim 16, wherein the disease is lymphoma. 33. The method of claim 32, wherein the lymphoma is Waldenström's macroglobulinemia. 34. The method of claim 32, wherein the lymphoma is Hodgkin's lymphoma. 35. The method of claim 32, wherein the lymphoma is non-Hodgkin's lymphoma. 36. The method of claim 32, wherein the lymphoma is B-cell lymphoma. 37. The method of claim 32, wherein the lymphoma is T-cell lymphoma.
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