摘要:
The invention provides a compound for use as a protein kinase B inhibitor, the compound being a compound of the formula (I) or salts, solvates, tautomers or N-oxides thereof, wherein T is N or CR5; J1-J2 is N═C(R6), (R7)C═N, (R8)N—C(O), (R8)2C—C(O), N═N or (R7)C═C(R6); E is a monocyclic carbocyclic or heterocyclic group of 5 or 6 ring members, the heterocyclic group containing up to 3 heteroatoms selected from O, N and S; Q1 is a bond or a saturated C1-3 hydrocarbon linker group, one of the carbon atoms in the linker group being optionally be replaced by an oxygen or nitrogen atom, or an adjacent pair of carbon atoms may be replaced by CONRq or NRqCO where Rq is hydrogen or methyl, or Rq is a C1-4 alkylene chain linked to R1 or a carbon atom of Q1 to form a cyclic moiety; and wherein the carbon atoms of the linker group Q1 may optionally bear one or more substituents selected from fluorine and hydroxy; Q2 is a bond or a saturated hydrocarbon linker group containing from 1 to 3 carbon atoms, wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group may optionally bear one or more substituents selected from fluorine and hydroxy, provided that the hydroxy group when present is not located at a carbon atom a with respect to the G group; and provided that when E is aryl or heteroaryl, then Q2 is other than a bond; G is hydrogen, NR2R, OH or SH provided that when E is aryl or heteroaryl and Q2 is a bond, then G is hydrogen; R1 is hydrogen or an aryl or heteroaryl group, with the proviso that when R1 is hydrogen and G is NR2R3, then Q2 is a bond; and R2, R3, R4, R6 and R8 are as defined in the claims.
摘要:
The invention provides a compound for use as a protein kinase B inhibitor, the compound being a compound of the formula (Ic) or salts, tautomers or N-oxides thereof.
摘要:
The invention provides a compound for use in the prophylaxis or treatment of a disease state or condition mediated by protein kinase B, the compound having the formula (I): or salts, solvates, tautomers or N-oxides thereof, wherein T is N or CR5; J1-J2 is N═C(R6), (R7)C═N, (R8)N—C(O), (R8)2C—C(O), N═N or (R7)C═C(R6); A is an optionally substituted saturated C1-7 hydrocarbon linker group having a maximum chain length of 5 atoms extending between R1 and NR2R3 and a maximum chain length of 4 atoms extending between E and NR2R3, one of the carbon atoms in the linker group being optionally replaced by oxygen or nitrogen; E is a monocyclic or bicyclic carbocyclic or heterocyclic group or an acyclic group X-G wherein X is CH2, O, S or NH and G is a C1-4 alkylene chain wherein one of the carbon atoms is optionally replaced by O, S or NH; R1 is hydrogen or an aryl or heteroaryl group; R2 and R3 are each hydrogen, optionally substituted C1-4 hydrocarbyl or optionally substituted C1-4 acyl; or NR2R3 forms an imidazole group or a saturated monocyclic heterocyclic group having 4-7 ring members; or NR2R3 and A together form a saturated monocyclic heterocyclic group having 4-7 ring members which is optionally substituted by C1-4alkyl; or NR2R3 and the adjacent carbon atom of linker group A together form a cyano group; or R1, A and NR2R3 together form a cyano group; and R4, R5, R6, R7 and R8 are each independently selected from hydrogen and various substituents as defined in the claims.
摘要翻译:本发明提供了一种用于预防或治疗由蛋白激酶B介导的疾病状态或病症的化合物,其具有式(I):或其盐,溶剂合物,互变异构体或N-氧化物,其中T为N或 CR5; J1-J2是N-C(R6),(R7)C-N,(R8)N-C(O),(R8)2C-C(O),N-N或(R7)C-C(R6) A是在R 1和NR 2 R 3之间延伸的最大链长度为5个原子并且在E和NR 2 R 3之间延伸的4个原子的最大链长度的任选取代的饱和C 1-7烃连接基团,连接基团中的一个碳原子是任选的 用氧或氮代替; E是单环或双环碳环或杂环基或非环基X-G,其中X是CH 2,O,S或NH,G是C 1-4亚烷基链,其中一个碳原子任选被O,S或NH取代; R1是氢或芳基或杂芳基; R2和R3各自为氢,任选取代的C 1-4烃基或任选取代的C 1-4酰基; 或NR 2 R 3形成具有4-7个环成员的咪唑基或饱和单环杂环基; 或NR2R3和A一起形成具有4-7个环成员的饱和单环杂环基,其任选被C 1-4烷基取代; 或NR2R3和连接基团A的相邻碳原子一起形成氰基; 或R 1,A和NR 2 R 3一起形成氰基; 且R 4,R 5,R 6,R 7和R 8各自独立地选自氢和权利要求中所定义的各种取代基。
摘要:
The invention provides a compound of the formula (I) or a salt, solvate, tautomer or N-oxide thereof for use in the treatment or prophylaxis of a disease state or condition mediated by protein kinase A and/or protein kinase B; wherein the ring Q is a benzene ring; J2-J1 is N═CR7 or R1aN—CO; G is OH or NR5R6; E is CONR7, NR7CO, C(R8)═C(R8) or (X)m(CR8R8a)n where X is O, S or NR7; provided that when J2-J1 is R1aN—CO, E is other than NR7CO; m and n are each 0 or 1, where m+n=1 or 2; A is a bond and R4 and R4a are absent or A is a saturated optionally substituted C1-7 hydrocarbon linker group having a maximum chain length of 5 atoms extending between E and G, one carbon atom in the linker group A being optionally replaced by O or N; R1, R1a, R2, and R3 are each H; halogen; C1-6 hydrocarbyl optionally substituted by halogen, OH or C1-2 alkoxy; CN; CONHR8; NH2; NHCOR10 or NHCONHR10; R4 is H or C1-4 alkyl; R4a is H, C1-4 alkyl or a group R9; R5 and R6 are each selected from H, R9 and C1-4 hydrocarbyl optionally substituted by halogen, C1-2 alkoxy or R9; or NR5R6 forms a saturated 4-7 membered monocyclic heterocyclic group; R7 is H or C1-4 alkyl; R8 and R8a each H or saturated C1-4 hydrocarbyl optionally substituted by fluorine; R9 is a monocyclic or bicyclic carbocyclic or heterocyclic group containing up to 3 ring heteroatoms selected from N, O and S; or R4, R4a and A together form a saturated monocyclic 4-7 membered heterocycle; or NR5R6, R4 and A form a saturated 4-7 membered monocyclic heterocycle; or R4, together with R7 or R8 and A and E form a 4-7 membered saturated monocyclic heterocycle; or NR5R6 and R7 or R8 together with A and E form a 4-7 membered saturated monocyclic heterocycle; and R10 is optionally substituted phenyl or benzyl.
摘要:
The invention provides PKA and PKB kinase-inhibiting compounds of the formula (I): or salts, solvates, tautomers or N-oxides thereof, wherein E is a five membered heteroaryl ring containing 1, 2, 3 or 4 heteroatoms selected from O, N and S provided that no more than 1 heteroatom may be other than N; q and r are each is 0 or 1; provided that q+r is 1 or 2; T is N or a group CR5; J1-J2 is N═C(R6), (R7)C═N, (R8)N—C(O), (R8)2C—C(O), N═N or (R7)C═C(R6); Q3 is a bond or a saturated C1-3 hydrocarbon linker group optionally substituted by fluorine and hydroxy; G is NR2R3, CN or OH; m and n are each 0 or 1, provided that m+n is 1 or 2, and provided also that m or n are each 0 when the adjacent ring member of ring E is S or O; R1a and R1b are the same or different and each is hydrogen or a substituent R10; or R1a and R1b together with the carbon atoms or heteroatoms to which they are attached form a 5 or 6-membered aryl or heteroaryl ring, wherein the aryl or heteroaryl rings are optionally substituted by one or more substituents R10; and R2, R3, R4, R5, R7, R6, R8, and R10 are as defined in the claims.
摘要:
The invention provides compounds of the formula (I) having PKA and PKB kinase inhibiting compounds of the formula (I): GP 1 J T 2 J N 4 R N H (I) or salts, solvates, tautomers or N-oxides thereof, wherein (1) GP is a group GP1: HET 2a a Q G (HNCO)f 7 (R)x N * (GP1) (2) GP is a group GP2: 10 (R)r O 2a a QG (CH2)w N V H N * (GP2) wherein HET is a monocyclic or bicyclic heterocyclic group containing up to 4 heteroatom ring members; the ring V is a monocyclic or bicyclic heteroaryl group of 5 to 10 ring members; and J1, J2, R4, R7, R10, Q2a, Ga, x, w and f are as defined in the claims
摘要翻译:本发明提供具有式(I)的PKA和PKB激酶抑制化合物的式(I)化合物:GP 1 JT 2 JN 4 RNH(I)或其盐,溶剂合物,互变异构体或N-氧化物,其中(1) GP是组GP1:HET 2a a QG(HNCO)f 7(R)x N *(GP1)(2)GP是组GP2:10(R)r O 2a a QG(CH 2)w NVHN * )其中HET是含有至多4个杂原子环成员的单环或双环杂环基; 环V是5至10个环成员的单环或双环杂芳基; 并且J1,J2,R4,R7,R10,Q2a,Ga,x,w和f如权利要求中所定义
摘要:
The invention provides compounds of the formula (I): or salts, solvates, tautomers or N-oxides thereof, wherein J1-J2 is CH═CH, N═CH, CH═N, HN—C(O) or CH2CO; T is N or CH and GP is as defined in the claims. The compounds have activity as inhibitors of PKA and PKB kinases and are useful in the treatment of cancers.
摘要:
Compounds of the formula (I), and salts, solvates, tautomers and N-oxide thereof, wherein TG is selected from groups (1) and (2): wherein the asterisk (*) represents the point of attachment of the group E to the group X; R1a is an optionally substituted aryl or heteroaryl group; R1b is hydrogen or a group R1a; X is an optionally substituted bicyclic heterocyclic group having 8 to 12 ring members of which up to 5 are heteroatoms selected from O, N and S; and A, E, R2, R3, R4, Q1 and Q2 are as defined in the claims; provided that when E is aryl or heteroaryl, then Q2 is other than a bond; and further provided that the moiety (a) is other than a group (BG1) or (BG2); wherein (BG1) and (BG2) are each optionally substituted; T is N or CRZ; J1-J2 is selected from N═C(RZ), (RZ)C═N, (RZ)N—C(O), (RZ)2C—C(O), N═N and (RZ)C═C(R6); J4-J3 is a group N═C(RZ) or a group (RZ)N—CO; and RZ is hydrogen or a substituent. The compounds of the formula (I) have PKA and PKB kinase inhibiting activity and are useful in the treatment of cancers.
摘要:
The present invention provides methods, devices, and systems for in vivo treatment of cell proliferative disorders. The invention can be used to treat solid tumors, such as brain tumors. The methods rely on non-thermal irreversible electroporation (IRE) or supra-poration to cause cell death in treated tumors. In embodiments, the methods comprise the integration of ultra-short electric pulses, both temporally and spatially, to achieve the desired modality of cell death.
摘要:
Disclosed are compounds of the formula I or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein W is a bond, —C(═S)—, —S(O)—, —S(O)2—, —C(═O)—, —O—, —C(R6)(R7)—, —N(R5)— or —C(═N(R5))—; X is —O—, —N(R5)— or —C(R6)(R7)—; provided that when X is —O—, U is not —O—, —S(O)—, —S(O)2—, —C(═O)— or —C(═NR5)—; U is a bond, —S(O)—, —S(O)2—, —C(O)—, —O—, —P(O)(OR15)—, —C(═NR5)—, —(C(R6)(R7))b— or —N(R5)—; wherein b is 1 or 2; provided that when W is —S(O)—, —S(O)2—, —O—, or —N(R5)—, U is not —S(O)—, —S(O)2—, —O—, or —N(R5)—; provided that when X is —N(R5)— and W is —S(O)—, —S(O)2—, —O—, or —N(R5)—, then U is not a bond; and R1, R2, R3, R4, R5, R6, and R7 are as defined in the specification; and pharmaceutical compositions comprising the compounds of formula I. Also disclosed is the method of inhibiting aspartyl protease, and in particular, the methods of treating cardiovascular diseases, cognitive and neurodegenerative diseases, and the methods of inhibiting of Human Immunodeficiency Virus, plasmepins, cathepsin D and protozoal enzymes.Also disclosed are methods of treating cognitive or neurodegenerative diseases using the compounds of formula I in combination with a cholinesterase inhibitor or a muscarinic antagonist.