WO2020007234A1 - 用于抑制蛋白激酶活性的炔基(杂)芳环类化合物 - Google Patents
用于抑制蛋白激酶活性的炔基(杂)芳环类化合物 Download PDFInfo
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- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
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- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 description 1
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- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the present invention provides a novel alkynyl (hetero) aromatic ring compound, a composition containing the same and use thereof.
- the compound has a wide range of useful biological and pharmacological activities, especially for Abl kinase and its mutant type kinase. Very strong inhibitory activity.
- R 3 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
- R 4 is H and R 5 is selected from H or a 5- to 6-membered heteroaromatic ring containing one or more N, O or S heteroatoms, wherein the 5- to 6-membered heteroaromatic ring may be optionally Or more R 1d substitutions;
- the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient.
- a compound of the invention is provided in the pharmaceutical composition in an effective amount.
- a compound of the invention is provided in a therapeutically effective amount.
- a compound of the invention is provided in a prophylactically effective amount.
- Pharmaceutically acceptable salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
- Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like.
- other pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts and amine cations with counter ions such as halide, hydroxide, carboxylate, sulfate, phosphate, Nitrate, lower alkylsulfonate and arylsulfonate.
- Each R 1a is independently selected from H, halogen, oxo, -C 0-6 alkylene-OR a , -C 0-6 alkylene-NR b R c , -C 0-6 alkylene -C (O) R a , -C 0-6 alkylene-C (O) OR a , -C 0-6 alkylene-C (O) NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkylene-C 3-6 cycloalkyl, or -C 0-6 alkylene-3 to 7-membered heterocyclic group; or two or more R 1a Together with the atoms to which they are attached form a C 3-7 cycloalkyl or 3 to 7 membered heterocyclic group;
- Each R 1b is independently selected from H, -C 0-6 alkylene-OR a , -C 0-6 alkylene-NR b R c , -C 0-6 alkylene-C (O) R a , -C 0-6 alkylene-C (O) OR a , -C 0-6 alkylene-C (O) NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, -C 0-6 alkylene-C 3-6 cycloalkyl or -C 0-6 alkylene-3 to 7-membered heterocyclic group; or two or more R 1b and the atom to which they are attached Together form a C 3-7 cycloalkyl or a 3 to 7 membered heterocyclic group;
- Each R 1d is independently selected from H, halogen, -C 0-6 alkylene-CN, -C 0-6 alkylene-OR a , -C 0-6 alkylene-SR a , -C 0 -6 alkylene-NR b R c , -C 0-6 alkylene-C (O) R a , -C 0-6 alkylene-C (O) OR a , -C 0-6 alkylene -C (O) NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-6 alkylene-C 3 -6 cycloalkyl, -C 0-6 alkylene-3 to 7-membered heterocyclic group, -C 0-6 alkylene-C 6-10 aryl, or -C 0-6 alkylene-5 to 10-membered heteroaryl; or two or more
- ring A has ring A-1 of the following structure:
- X / Y / Z is independently CH; in another specific embodiment, X / Y / Z is independently N.
- R 5 when R 4 is H, R 5 is selected from H or a 5- to 6-membered heteroaromatic ring containing one or more N, O or S heteroatoms, wherein said The 5- to 6-membered heteroaromatic ring may be optionally substituted with one or more R 1d ; preferably, R 5 is selected from H or a 5- to 6-membered heteroaromatic ring containing one or more N heteroatoms, wherein said A 5- to 6-membered heteroaryl ring may be optionally substituted with one or more R 1d ; more preferably, R 5 is selected from H or a 5 heteroaromatic ring containing one or more N heteroatoms, wherein said 5 hetero
- the aromatic ring may be optionally substituted with one or more R 1d ; most preferably, R 5 is selected from H or imidazolyl, wherein said imidazolyl may be optionally substituted with one or more R 1d .
- the invention provides a compound of formula (III-b):
- the present invention also includes isotopically-labeled compounds, which are equivalent to those described in formula (I), but one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature.
- isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl.
- formulation examples illustrate representative pharmaceutical compositions that can be prepared according to the present invention.
- the present invention is not limited to the following pharmaceutical compositions.
- Exemplary formulation 7-tablet The compound of the present invention in dry powder form can be mixed with a dry gel binder in a weight ratio of about 1: 2. Add a smaller amount of magnesium stearate as a lubricant. This mixture is shaped in a tablet press into 450-900 mg tablets (each tablet contains 150-300 mg of active compound).
- a representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses.
- each dose provides about 0.01 to about 20 mg / kg of a compound of the invention, and preferred doses each provide about 0.1 to about 10 mg / kg, especially about 1 to about 5 mg / kg.
- an effective amount of a compound of the present invention is usually administered in a single or multiple doses at an average daily dose of 0.01 to 50 mg of the compound per kg of the patient's body weight, preferably 0.1 to 25 mg of the compound per kg of the patient's body weight.
- the compound of the present invention can be administered to the patient in need of such treatment at a daily dose range of about 1 mg to about 3500 mg per patient, preferably 10 mg to 1000 mg.
- the daily dose per patient may be 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 500, 600, 700, 800, 900 or 1000mg.
- Administration can be one or more times daily, weekly (or several days apart), or on an intermittent schedule.
- stop solution an acetonitrile solution containing 50ng / mL propranolol hydrochloride and 200ng / mL tolbutamide (internal standard). Take 25057.5 ⁇ L of phosphate buffer solution (pH7.4) into a 50 mL centrifuge tube, add 812.5 ⁇ L of human liver microsomes, and mix to obtain a liver microsome dilution with a protein concentration of 0.625 mg / mL.
- phosphate buffer solution pH7.4
- the reaction concentration of the corresponding compound was 1 ⁇ M, and the protein concentration was 0.5 mg / mL.
- 100 ⁇ L of each reaction solution was taken, added to the stop plate, and the reaction was stopped by vortexing for 3 minutes.
- the stop plate was centrifuged at 5000 ⁇ g for 10 min at 4 ° C. Take 100 ⁇ L of the supernatant into a 96-well plate pre-added with 100 ⁇ L of distilled water, mix well, and use LC-MS / MS for sample analysis.
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Abstract
提供一种对蛋白酪氨酸激酶具有抑制作用的炔基(杂)芳环类化合物,包含它们的药物组合物,以及它们的制备和用途。具体地,公开了式(I)所示的炔基(杂)芳环类化合物,其中环A、R 1、R 2、R 3、R 4、R 5、L和B如说明书中所定义,及其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、前药或同位素变体。该类化合物可用于治疗和/或预防蛋白酪氨酸激酶相关性疾病,例如抗肿瘤。
Description
本发明属于医药领域。具体地,本发明涉及对蛋白激酶活性具有抑制作用的炔基(杂)芳环类化合物,包含它们的药物组合物,以及它们的制备方法和用途。
蛋白酪氨酸激酶(PTKs)是一类能够催化ATP上γ-磷酸转移到蛋白酪氨酸残基上的激酶,通过催化多种蛋白酪氨酸残基上的酚羟基发生磷酸化,进而激活功能蛋白作用的蛋白质酶系。蛋白酪氨酸激酶在细胞内的信号传导通路中占据十分重要的地位,可调节细胞生长、分化、死亡等一系列生理生化过程。蛋白酪氨酸激酶的异常表达可以导致细胞增殖调节发生紊乱,进而导致肿瘤的发生。此外,蛋白酪氨酸激酶的异常表达还与肿瘤的侵袭和转移,肿瘤新生血管的生成,肿瘤的化疗抗药性密切相关。蛋白激酶已成为重要的疾病治疗靶标,非限制性的列出一部分的这类激酶,包括Ret(Reaaranged during transfection),ABL1(E255K)-phosphorylated,ABL1(F317I)-nonphosphorylated,ABL1(F317I)-phosphorylated,ABL1(F317L)-nonphosphorylated,ABL1(F317L)-phosphorylated,ABL1(H396P)-nonphosphorylated,ABL1(H396P)-phosphorylated,ABL1(M351T)-phosphorylated,ABL1(Q252H)-nonphosphorylated,ABL1(Q252H)-phosphorylated,ABL1(T315I)-nonphosphorylated,ABL1(T315I)-phosphorylated,ABL1(Y253F)-phosphorylated,ABL1-nonphosphorylated,ABL1-phosphorylated,ABL2,ALK(L1196M),AMPK-alpha1,AMPK-alpha2,ANKK1,AURKB,AURKC,AXL,BLK,BMX,BRAF,BRAF(V600E),BRK,BTK,CAMK1,CAMKK1,CAMKK2,CDC2L1,CDC2L2,CDC2L5,CDK11,CDK2,CDK5,CDK7,CDK8,CDKL1,CDKL2,CDKL3,CHEK2,CIT,CLK1,CLK4,CSF1R,CSK,CTK,DDR1,DDR2,DLK,EGFR,EGFR(E746-A750del),EGFR(G719C),EGFR(G719S),EGFR(L747-E749del,A750P),EGFR(L747-S752del,P753S),EGFR(L747-T751del,Sins),EGFR(L858R),EGFR(L858R,T790M),EGFR(L861Q),EGFR(S752-I759del),EGFR(T790M),EPHA1,EPHA2,EPHA3,EPHA4,EPHA5,EPHA6,EPHA7,EPHA8,EPHB1,EPHB2,EPHB4,EPHB6,ERBB2,ERBB4,ERK8,FAK,FER,FES,FGFR1,FGFR2,FGFR3,FGFR3(G697C),FGFR4,FGR,FLT1,FLT3,FLT3(D835H),FLT3(D835V),FLT3(D835Y),FLT3(ITD),FLT3(ITD,D835V),FLT3(ITD,F691L),FLT3(K663Q),FLT3(N841I),FLT3(R834Q),FLT4,FRK,FYN,GAK,GCN2(Kin.Dom.2,S808G),HCK,HIPK4,HPK1,IKK-alpha,IKK-beta,IRAK1,IRAK4,ITK,JAK1(JH1domain-catalytic),JAK2(JH1domain-catalytic),JAK3(JH1domain-catalytic),JNK1,JNK2,JNK3,KIT,KIT(A829P), KIT(D816H),KIT(D816V),KIT(L576P),KIT(V559D),KIT(V559D,T670I),KIT(V559D,V654A),LCK,LIMK1,LIMK2,LOK,LRRK2,LRRK2(G2019S),LTK,LYN,MAK,MAP3K2,MAP3K3,MAP4K2,MAP4K3,MAP4K4,MAP4K5,MEK5,MELK,MERTK,MET,MET(M1250T),MINK,MKNK2,MLK1,MLK2,MLK3,MST1,MST1R,MST2,MUSK,MYLK2,MYO3A,MYO3B,NDR2,NEK1,NEK11,NEK4,NEK5,NEK9,NLK,p38-alpha,p38-beta,p38-delta,p38-gamma,PCTK2,PDGFRA,PDGFRB,PFCDPK1(P.falciparum),PFTAIRE2,PFTK1,PKAC-alpha,PKAC-beta,PYK2,RAF1,RET,RET(M918T),RET(V804L),RET(V804M),RIPK1,RIPK2,RIPK4,ROCK2,RPS6KA4(Kin.Dom.1-N-terminal),RSK2(Kin.Dom.1-N-terminal),RSK3(Kin.DoN-terminal),S6K1,SIK,SLK,SRC,SRMS,SRPK1,STK33,STK35,STK36,SYK,TAK1,TAOK2,TAOK3,TEC,TESK1,TGFBR2,TIE1,TIE2,TNIK,TNK1,TNK2,TNNI3K,TRKA,TRKB,TRKC,TTK,TXK,TYK2(JH1domain-catalytic),TYRO3,ULK3,VEGFR2,YES,YSK4,ZAK,ZAP70或FGFR(Fibroblast growth factor receptor)。异常的蛋白激酶活性与多种疾病相关,这些疾病从无生命威胁的疾病如牛皮癣到极度严重的疾病例如癌。
考虑到如此大量的蛋白激酶和众多与蛋白激酶相关的疾病,因此一直存在提供具有增加的选择性的新种类化合物的需求,这些化合物可以用作蛋白激酶抑制并由此用于治疗与蛋白酪氨酸激酶有关的疾病。
本发明涉及一族新的炔类杂芳基化合物及其在治疗癌症、骨病、代谢疾病和炎性疾病和其它疾病中的用途。
发明内容
本发明提供了一种新的炔基(杂)芳环类化合物及包含该化合物的组合物及其用途,其具有广泛有用的生物学和药理学活性,尤其对Abl激酶及其突变类型激酶具有很强的抑制活性。
对此,本发明采用的技术方案如下:
本发明的第一方面中,提供了一种式(I)所示的化合物,
其中,
环A选自以下结构的环A-1,A-2和A-3:
R
1选自H、C
1-6烷基、C
3-7环烷基、3至7元杂环基、C
6-10芳基或5至10元杂芳基;其中所述基团任选地被一个或多个R
1a取代;前提是当环A是A-1时,R
1不是H;
R
2选自H、CN、NO
2、OH、卤素、C
1-6烷基、C
1-6卤代烷基、C
1-6烷氧基或C
1-6卤代烷氧基;
L选自-C(O)N(R
1b)-、-N(R
1b)C(O)-或-N(R
1b)C(O)N(R
1b)-;
B选自CH或N;
R
3选自H、C
1-6烷基或C
1-6卤代烷基;
R
4和R
5选自:
1)R
5为H,R
4选自H、C
1-6烷基、-C
0-2亚烷基-C
3-7环烷基、-C
0-2亚烷基-3至7元杂环基或-C
0-2亚烷基-NR
1cR
2c,其中所述基团任选被一个或多个R
1d取代;或者
2)R
4为H,R
5选自H或含一个或多个N、O或S杂原子的5至6元杂芳环,其中所述5至6元杂芳环可任选地被一个或多个R
1d取代;
各个R
1a各自独立地选自H、卤素、氧代基、-C
0-6亚烷基-OR
a、-C
0-6亚烷基-NR
bR
c、-C
0-6亚烷基-C(O)R
a、-C
0-6亚烷基-C(O)OR
a、-C
0-6亚烷基-C(O)NR
bR
c、C
1-6烷基、C
1-6卤代烷基、-C
0-6亚烷基-C
3-6环烷基或-C
0-6亚烷基-3至7元杂环基;或者二个或二个以上的R
1a与它们所连接的原子一起形成C
3-7环烷基或3至7元杂环基;
各个R
1b各自独立地选自H、-C
0-6亚烷基-OR
a、-C
0-6亚烷基-NR
bR
c、-C
0-6亚烷基-C(O)R
a、-C
0-6亚烷基-C(O)OR
a、-C
0-6亚烷基-C(O)NR
bR
c、C
1-6烷基、C
1-6卤代烷基、-C
0-6亚烷基-C
3-6环烷基或-C
0-6亚烷基-3至7元杂环基;或者二个或二个以上的R
1b与它们所连接的原子一起形成C
3-7环烷基或3至7元杂环基;
R
1c和R
2c各自独立地选自H、卤素、-C
0-6亚烷基-CN、-C
0-6亚烷基-OR
a、-C
0-6亚烷基-SR
a、-C
0-6亚烷基-NR
bR
c、-C
0-6亚烷基-C(O)R
a、-C
0-6亚烷基-C(O)OR
a、-C
0-6亚烷基-C(O)NR
bR
c、C
1-6烷基、C
1-6卤代烷基、C
2-6烯基、C
2-6炔基、-C
0-6亚烷基-C
3-6环烷基、-C
0-6亚烷基-3至7元杂环基、-C
0-6亚烷基-C
6-10芳基或-C
0-6亚烷基-5至10元杂芳基;或者,R
1c、R
2c与它们所连接的氮原子一起形成C
3-7环烷基或3至7元杂环基;
各个R
1d各自独立地选自H、卤素、-C
0-6亚烷基-CN、-C
0-6亚烷基-OR
a、-C
0-6亚烷基-SR
a、-C
0-6亚烷基-NR
bR
c、-C
0-6亚烷基-C(O)R
a、-C
0-6亚烷基-C(O)OR
a、-C
0-6亚烷基-C(O)NR
bR
c、C
1-6烷基、C
1-6卤代烷基、C
2-6烯基、C
2-6炔基、-C
0-6亚烷基-C
3-6环烷基、-C
0-6亚烷基-3至7元杂环基、-C
0-6亚烷基-C
6-10芳基或-C
0-6亚烷基-5至10元杂芳基;或者二个或二个以上的R
1d与它们所连接的原子一起形成C
3-7环烷基或3至7元杂环基;
R
a、R
b和R
c独立地选自H、C
1-6烷基、C
1-6卤代烷基、C
3-7环烷基、3至7元杂环基、C
6-10芳基或5至10元杂芳基;
附加条件是,上述化合物不具有以下结构:
或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、前药或同位素变体。
在另一方面,本发明提供了含有本发明化合物和药学上可接受的赋形剂的药物组合物。在具体实施方案中,本发明化合物以有效量提供在所述药物组合物中。在具体实施方案中,本发明化合物以治疗有效量提供。在具体实施方案中,本发明化合物以预防有效量提供。
在另一方面,本发明提供了含有本发明化合物和药学上可接受的赋形剂的药物组合物,其还含有其它治疗剂。
在另一方面,本发明提供了包含本发明化合物、其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、前药或同位素变体,和其它治疗剂以及药学上可接受的载剂、佐剂或媒剂的试剂盒。
在另一个方面,本发明提供了一种在受试者中治疗与蛋白激酶相关的疾病的方法,所述方法包括向受试者给本发明化合物或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、前药或同位素变体,或者药物组合物。在具体实施方案中,所述蛋白激酶选自Ret(Reaaranged during transfection),ABL1(E255K)-phosphorylated,ABL1(F317I)-nonphosphorylated,ABL1(F317I)-phosphorylated,ABL1(F317L)-nonphosphorylated,ABL1(F317L)-phosphorylated,ABL1(H396P)-nonphosphorylated,ABL1(H396P)-phosphorylated,ABL1(M351T)-phosphorylated,ABL1(Q252H)-nonphosphorylated,ABL1(Q252H)-phosphorylated,ABL1(T315I)-nonphosphorylated,ABL1(T315I)-phosphorylated,ABL1(Y253F)-phosphorylated,ABL1-nonphosphorylated,ABL1-phosphorylated,ABL2,ALK(L1196M),AMPK-alpha1,AMPK-alpha2,ANKK1,AURKB,AURKC,AXL,BLK,BMX,BRAF,BRAF(V600E), BRK,BTK,CAMK1,CAMKK1,CAMKK2,CDC2L1,CDC2L2,CDC2L5,CDK11,CDK2,CDK5,CDK7,CDK8,CDKL1,CDKL2,CDKL3,CHEK2,CIT,CLK1,CLK4,CSF1R,CSK,CTK,DDR1,DDR2,DLK,EGFR,EGFR(E746-A750del),EGFR(G719C),EGFR(G719S),EGFR(L747-E749del,A750P),EGFR(L747-S752del,P753S),EGFR(L747-T751del,Sins),EGFR(L858R),EGFR(L858R,T790M),EGFR(L861Q),EGFR(S752-I759del),EGFR(T790M),EPHA1,EPHA2,EPHA3,EPHA4,EPHA5,EPHA6,EPHA7,EPHA8,EPHB1,EPHB2,EPHB4,EPHB6,ERBB2,ERBB4,ERK8,FAK,FER,FES,FGFR1,FGFR2,FGFR3,FGFR3(G697C),FGFR4,FGR,FLT1,FLT3,FLT3(D835H),FLT3(D835V),FLT3(D835Y),FLT3(ITD),FLT3(ITD,D835V),FLT3(ITD,F691L),FLT3(K663Q),FLT3(N841I),FLT3(R834Q),FLT4,FRK,FYN,GAK,GCN2(Kin.Dom.2,S808G),HCK,HIPK4,HPK1,IKK-alpha,IKK-beta,IRAK1,IRAK4,ITK,JAK1(JH1domain-catalytic),JAK2(JH1domain-catalytic),JAK3(JH1domain-catalytic),JNK1,JNK2,JNK3,KIT,KIT(A829P),KIT(D816H),KIT(D816V),KIT(L576P),KIT(V559D),KIT(V559D,T670I),KIT(V559D,V654A),LCK,LIMK1,LIMK2,LOK,LRRK2,LRRK2(G2019S),LTK,LYN,MAK,MAP3K2,MAP3K3,MAP4K2,MAP4K3,MAP4K4,MAP4K5,MEK5,MELK,MERTK,MET,MET(M1250T),MINK,MKNK2,MLK1,MLK2,MLK3,MST1,MST1R,MST2,MUSK,MYLK2,MYO3A,MYO3B,NDR2,NEK1,NEK11,NEK4,NEK5,NEK9,NLK,p38-alpha,p38-beta,p38-delta,p38-gamma,PCTK2,PDGFRA,PDGFRB,PFCDPK1(P.falciparum),PFTAIRE2,PFTK1,PKAC-alpha,PKAC-beta,PYK2,RAF1,RET,RET(M918T),RET(V804L),RET(V804M),RIPK1,RIPK2,RIPK4,ROCK2,RPS6KA4(Kin.Dom.1-N-terminal),RSK2(Kin.Dom.1-N-terminal),RSK3(Kin.DoN-terminal),S6K1,SIK,SLK,SRC,SRMS,SRPK1,STK33,STK35,STK36,SYK,TAK1,TAOK2,TAOK3,TEC,TESK1,TGFBR2,TIE1,TIE2,TNIK,TNK1,TNK2,TNNI3K,TRKA,TRKB,TRKC,TTK,TXK,TYK2(JH1domain-catalytic),TYRO3,ULK3,VEGFR2,YES,YSK4,ZAK,ZAP70或FGFR(Fibroblast growth factor receptor)。
在另一个方面,本发明提供了一种将本发明化合物用于制备抗肿瘤或其他疾病的药物的用途,在具体实施方案中,所述疾病是由Bcr-Abl导致的增殖性疾病。在具体实施方案中,所述疾病可选自:实体瘤、肉瘤、慢性髓性白血病、慢性粒细胞白血病、胃肠道间质瘤、急性粒细胞白血病、甲状腺癌、胃癌、直肠癌、多发性骨髓瘤、瘤形成以及其他增生性或增殖性疾病。在具体实施方案中,所述Bcr-Abl导致的病症是慢性粒细胞白血病、胃肠道间质瘤、急性粒细胞白血病、甲状腺癌或其组合。在具体实施方案中,口服、皮下、静脉内或肌肉内给药所述化合物。在具体实施方案中,长期给药所述化合物。
由随后的具体实施方式、实施例和权利要求,本发明的其它目的和优点将对于本领域技术人员显而易见。
定义
化学定义
下面更详细地描述具体官能团和化学术语的定义。
当列出数值范围时,既定包括每个值和在所述范围内的子范围。例如“C
1-6烷基”包括C
1、C
2、C
3、C
4、C
5、C
6、C
1-6、C
1-5、C
1-4、C
1-3、C
1-2、C
2-6、C
2-5、C
2-4、C
2-3、C
3-6、C
3-5、C
3-4、C
4-6、C
4-5和C
5-6烷基。
“C
1-6烷基”是指具有1至6个碳原子的直链或支链饱和烃基团,本文也称为“低级烷基”。在一些实施方案中,C
1-4烷基是特别优选的。所述烷基的实例包括但不限于:甲基(C
1)、乙基(C
2)、正丙基(C
3)、异丙基(C
3)、正丁基(C
4)、叔丁基(C
4)、仲丁基(C
4)、异丁基(C
4)、正戊基(C
5)、3-戊基(C
5)、戊基(C
5)、新戊基(C
5)、3-甲基-2-丁基(C
5)、叔戊基(C
5)和正己基(C
6)。不论烷基前是否修饰有“取代的”,烷基的每个独立地任选被取代,例如,1至5个取代基、1至3个取代基或1个取代基,适当的取代基如下定义。
“C
2-6烯基”是指具有2至6个碳原子和一个或多个碳-碳双键(例如,1、2或3个碳-碳双键)的直链或支链烃基团。一个或多个碳-碳双键可以在内部(例如,在2-丁烯基中)或端部(例如,在1-丁烯基中)。在一些实施方案中,C
2-4烯基是特别优选的。所述烯基的实例包括但不限于:乙烯基(C
2)、1-丙烯基(C
3)、2-丙烯基(C
3)、1-丁烯基(C
4)、2-丁烯基(C
4)、丁二烯基(C
4)、戊烯基(C
5)、戊二烯基(C
5)、己烯基(C
6),等等。不论烯基前是否修饰有“取代的”,烯基的每个独立地任选被取代,例如,1至5个取代基、1至3个取代基或1个取代基,适当的取代基如下定义。
“C
2-6炔基”是指具有2至6个碳原子、一个或多个碳-碳叁键(例如,1、2或3个碳-碳叁键)以及任选一个或多个碳-碳双键(例如,1、2或3个碳-碳双键)的直链或支链烃基团。在一些实施方案中,C
2-4炔基是特别优选的。在一些实施方案中,炔基不含有任何双键。一个或多个碳叁键可以在内部(例如,在2-丁炔基中)或端部(例如,在1-丁炔基中)。所述炔基的实例包括但不限于:乙炔基(C
2)、1-丙炔基(C
3)、2-丙炔基(C
3)、1-丁炔基(C
4)、2-丁炔基(C
4)、戊炔基(C
5)、己炔基(C
6),等等。不论炔基前是否修饰有“取代的”,炔基的每个独立地任选被取代,例如,1至5个取代基、1至3个取代基或1个取代基,适当的取代基如下定义。
“C
1-6亚烷基”是指除去C
1-6烷基的另一个氢而形成的二价基团,并且可以是取代或未取代的亚烷基。在一些实施方案中,C
1-4亚烷基是特别优选的。未取代的所述亚烷基包括但不限于:亚甲基(-CH
2-)、亚乙基(-CH
2CH
2-)、亚丙基(-CH
2CH
2CH
2-)、亚丁基(-CH
2CH
2CH
2CH
2-)、亚戊基(-CH
2CH
2CH
2CH
2CH
2-)、亚己基(-CH
2CH
2CH
2CH
2CH
2CH
2-),等等。示例性的取代的所述亚烷基,例如,被一个或多个烷基(甲基)取代的所述亚烷基,包括但不限于:取代的亚甲基(-CH(CH
3)-、-C(CH
3)
2-)、取代的亚乙基(-CH(CH
3)CH
2-、-CH
2CH(CH
3)-、-C(CH
3)
2CH
2-、-CH
2C(CH
3)
2-)、取代的亚丙基(-CH(CH
3)CH
2CH
2-、 -CH
2CH(CH
3)CH
2-、-CH
2CH
2CH(CH
3)-、-C(CH
3)
2CH
2CH
2-、-CH
2C(CH
3)
2CH
2-、-CH
2CH
2C(CH
3)
2-),等等。
“C
0-6亚烷基”包括化学键和如上定义的C
1-6亚烷基。
“C
1-6烷氧基”是指基团-OR,其中,R为取代或未取代的C
1-6烷基。在一些实施方案中,C
1-4烷氧基是特别优选的。具体的所述烷氧基包括但不限于:甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、仲丁氧基、正戊氧基、正己氧基和1,2-二甲基丁氧基。
“卤代”或“卤素”是指氟(F)、氯(Cl)、溴(Br)和碘(I)。在一些实施方案中,卤素基团是F、Cl或Br。在一些实施方案中,卤素基团是F或Cl。在一些实施方案中,卤素基团是F。
因此,“C
1-6卤代烷基”和“C
1-6卤代烷氧基”是指上述“C
1-6烷基”和“C
1-6烷氧基”,其被一个或多个卤素基团取代。在一些实施方案中,C
1-4卤代烷基是特别优选的,更优选C
1-2卤代烷基。在一些实施方案中,C
1-4卤代烷氧基是特别优选的,更优选C
1-2卤代烷氧基。示例性的所述卤代烷基包括但不限于:-CF
3、-CH
2F、-CHF
2、-CHFCH
2F、-CH
2CHF
2、-CF
2CF
3、-CCl
3、-CH
2Cl、-CHCl
2、2,2,2-三氟-1,1-二甲基-乙基,等等。示例性的所述卤代烷氧基包括但不限于:-OCH
2F、-OCHF
2、-OCF
3,等等。
“C
3-10环烷基”是指具有3至10个环碳原子和零个杂原子的非芳香环烃基团。在一些实施方案中,C
3-7环烷基是优选的,C
3-6环烷基是特别优选的,更优选C
5-6环烷基。环烷基还包括其中上述环烷基环与一个或多个芳基或杂芳基稠合的环体系,其中连接点在环烷基环上,且在这样的情况中,碳的数目继续表示环烷基体系中的碳的数目。示例性的所述环烷基包括但不限于:环丙基(C
3)、环丙烯基(C
3)、环丁基(C
4)、环丁烯基(C
4)、环戊基(C
5)、环戊烯基(C
5)、环己基(C
6)、环己烯基(C
6)、环已二烯基(C
6)、环庚基(C
7)、环庚烯基(C
7)、环庚二烯基(C
7)、环庚三烯基(C
7)、环辛基(C
8)、环辛烯基(C
8)、二环[2.2.1]庚基(C
7)、二环[2.2.2]辛基(C
8)、环壬基(C
9)、环壬烯基(C
9)、环癸基(C
10)、环癸烯基(C
10)、八氢-1H-茚基(C
9)、十氢萘基(C
10)、螺[4.5]癸基(C
10),等等。不论环烷基前是否修饰有“取代的”,环烷基的每个独立地任选被取代,例如,1至5个取代基、1至3个取代基或1个取代基,适当的取代基如下定义。
“3至10元杂环基”或是指具有环碳原子和1至4个环杂原子的3至10元非芳香环系的基团,其中,每个杂原子独立地选自氮、氧、硫、硼、磷和硅。在包含一个或多个氮原子的杂环基中,只要化合价允许,连接点可为碳或氮原子。在一些实施方案中,3至7元杂环基是优选的,其为具有环碳原子和1至3个环杂原子的3至7元非芳香环系;在一些实施方案中,3至6元杂环基是特别优选的,其为具有环碳原子和1至3个环杂原子的3至6元非芳香环系;更优选5至6元杂环基,其为具有环碳原子和1至3个环杂原子的5至6元非芳香环系。杂环基还包括其中上述杂环基环与一个或多个环烷基、芳基或杂芳基稠合的环体系,其中连接点在杂环基环上;且在这样的情况下,环成员的数目继续表示在杂环基环体系中环成员的数目。不论杂环基前是否修饰有“取代的”,杂环基的每个独立地任 选被取代,例如,1至5个取代基、1至3个取代基或1个取代基,适当的取代基如下定义。
示例性的包含一个杂原子的3元杂环基包括但不限于:氮杂环丙烷基、氧杂环丙烷基、硫杂环丙烷基(thiorenyl)。示例性的含有一个杂原子的4元杂环基包括但不限于:氮杂环丁烷基、氧杂环丁烷基和硫杂环丁烷基。示例性的含有一个杂原子的5元杂环基包括但不限于:四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、吡咯烷基、二氢吡咯基和吡咯基-2,5-二酮。示例性的包含两个杂原子的5元杂环基包括但不限于:二氧杂环戊烷基、氧硫杂环戊烷基(oxasulfuranyl)、二硫杂环戊烷基(disulfuranyl)和噁唑烷-2-酮。示例性的包含三个杂原子的5元杂环基包括但不限于:三唑啉基、噁二唑啉基和噻二唑啉基。示例性的包含一个杂原子的6元杂环基包括但不限于:哌啶基、四氢吡喃基、二氢吡啶基和硫杂环己烷基(thianyl)。示例性的包含两个杂原子的6元杂环基包括但不限于:哌嗪基、吗啉基、二硫杂环己烷基、二噁烷基。示例性的包含三个杂原子的6元杂环基包括但不限于:六氢三嗪基(triazinanyl)。示例性的含有一个杂原子的7元杂环基包括但不限于:氮杂环庚烷基、氧杂环庚烷基和硫杂环庚烷基。示例性的包含一个杂原子的8元杂环基包括但不限于:氮杂环辛烷基、氧杂环辛烷基和硫杂环辛烷基。示例性的与C
6芳基环稠合的5元杂环基(在本文中也称作5,6-双环杂环基)包括但不限于:二氢吲哚基、异二氢吲哚基、二氢苯并呋喃基、二氢苯并噻吩基、苯并噁唑啉酮基,等等。示例性的与C
6芳基环稠合的6元杂环基(本文还指的是6,6-双环杂环基)包括但不限于:四氢喹啉基、四氢异喹啉基,等等。
“C
6-14芳基”是指具有6-14个环碳原子和零个杂原子的单环或多环的(例如,双环或三环)4n+2芳族环体系(例如,具有以环状排列共享的6、10或14个π电子)的基团。在一些实施方案中,芳基具有六个环碳原子(“C
6芳基”;例如,苯基)。在一些实施方案中,芳基具有十个环碳原子(“C
10芳基”;例如,萘基,例如,1-萘基和2-萘基)。在一些实施方案中,芳基具有十四个环碳原子(“C
14芳基”;例如,蒽基)。在一些实施方案中,C
6-10芳基是特别优选的,更优选C
6芳基。芳基还包括其中上述芳基环与一个或多个环烷基或杂环基稠合的环系统,而且连接点在所述芳基环上,在这种情况下,碳原子的数目继续表示所述芳基环系统中的碳原子数目。不论芳基前是否修饰有“取代的”,芳基的每个独立地任选被取代,例如,1至5个取代基、1至3个取代基或1个取代基,适当的取代基如下定义。
“5至10元杂芳基”是指具有环碳原子和1-4个环杂原子的5-10元单环或双环的4n+2芳族环体系(例如,具有以环状排列共享的6或10个π电子)的基团,其中每个杂原子独立地选自氮、氧和硫。在含有一个或多个氮原子的杂芳基中,只要化合价允许,连接点可以是碳或氮原子。杂芳基双环系统在一个或两个环中可以包括一个或多个杂原子。杂芳基还包括其中上述杂芳基环与一个或多个环烷基或杂环基稠合的环系统,而且连接点在所述杂芳基环上,在这种情况下,碳原子的数目继续表示所述杂芳基环系统中的碳原子数目。在一些实施方案中,5至6元杂芳基是特别优选的,其为具有环碳原子和1-4个环杂原子的5-6元单环或双环的4n+2芳族环体系。不论杂芳基前是否修饰有“取代的”,杂芳 基的每个独立地任选被取代,例如,1至5个取代基、1至3个取代基或1个取代基,适当的取代基如下定义。
示例性的含有一个杂原子的5元杂芳基包括但不限于:吡咯基、呋喃基和噻吩基。示例性的含有两个杂原子的5元杂芳基包括但不限于:咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基和异噻唑基。示例性的含有三个杂原子的5元杂芳基包括但不限于:三唑基、噁二唑基和噻二唑基。示例性的含有四个杂原子的5元杂芳基包括但不限于:四唑基。示例性的含有一个杂原子的6元杂芳基包括但不限于:吡啶基。示例性的含有两个杂原子的6元杂芳基包括但不限于:哒嗪基、嘧啶基和吡嗪基。示例性的含有三个或四个杂原子的6元杂芳基分别包括但不限于:三嗪基和四嗪基。示例性的含有一个杂原子的7元杂芳基包括但不限于:氮杂环庚三烯基、氧杂环庚三烯基和硫杂环庚三烯基。示例性的5,6-双环杂芳基包括但不限于:吲哚基、异吲哚基、吲唑基、苯并三唑基、苯并噻吩基、异苯并噻吩基、苯并呋喃基、苯并异呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噁二唑基、苯并噻唑基、苯并异噻唑基、苯并噻二唑基、茚嗪基和嘌呤基。示例性的6,6-双环杂芳基包括但不限于:萘啶基、喋啶基、喹啉基、异喹啉基、噌琳基、喹喔啉基、酞嗪基和喹唑啉基。
示例性的碳原子上的取代基包括但不局限于:卤素、-CN、-NO
2、-N
3、-SO
2H、-SO
3H、-OH、-OR
aa、-ON(R
bb)
2、-N(R
bb)
2、-N(R
bb)
3
+X
-、-N(OR
cc)R
bb、-SH、-SR
aa、-SSR
cc、-C(=O)R
aa、-CO
2H、-CHO、-C(OR
cc)
2、-CO
2R
aa、-OC(=O)R
aa、-OCO
2R
aa、-C(=O)N(R
bb)
2、-OC(=O)N(R
bb)
2、-NR
bbC(=O)R
aa、-NR
bbCO
2R
aa、-NR
bbC(=O)N(R
bb)
2、-C(=NR
bb)R
aa、-C(=NR
bb)OR
aa、-OC(=NR
bb)R
aa、-OC(=NR
bb)OR
aa、-C(=NR
bb)N(R
bb)
2、-OC(=NR
bb)N(R
bb)
2、-NR
bbC(=NR
bb)N(R
bb)
2、-C(=O)NR
bbSO
2R
aa、-NR
bbSO
2R
aa、-SO
2N(R
bb)
2、-SO
2R
aa、-SO
2OR
aa、-OSO
2R
aa、-S(=O)R
aa、-OS(=O)R
aa、-Si(R
aa)
3、-OSi(R
aa)
3、-C(=S)N(R
bb)
2、-C(=O)SR
aa、-C(=S)SR
aa、-SC(=S)SR
aa、-SC(=O)SR
aa、-OC(=O)SR
aa、-SC(=O)OR
aa、-SC(=O)R
aa、-P(=O)
2R
aa、-OP(=O)
2R
aa、-P(=O)(R
aa)
2、-OP(=O)(R
aa)
2、-OP(=O)(OR
cc)
2、-P(=O)
2N(R
bb)
2、-OP(=O)
2N(R
bb)
2、-P(=O)(NR
bb)
2、-OP(=O)(NR
bb)
2、-NR
bbP(=O)(OR
cc)
2、-NR
bbP(=O)(NR
bb)
2、-P(R
cc)
2、-P(R
cc)
3、-OP(R
cc)
2、-OP(R
cc)
3、-B(R
aa)
2、-B(OR
cc)
2、-BR
aa(OR
cc)、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基,其中,每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R
dd基团取代;
或者在碳原子上的两个偕氢被基团=O、=S、=NN(R
bb)
2、=NNR
bbC(=O)R
aa、=NNR
bbC(=O)OR
aa、=NNR
bbS(=O)
2R
aa、=NR
bb或=NOR
cc取代;
R
aa的每个独立地选自烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基,或者两个R
aa基团结合以形成杂环基或杂芳基环,其中,每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R
dd基团取代;
R
bb的每个独立地选自:氢、-OH、-OR
aa、-N(R
cc)
2、-CN、-C(=O)R
aa、-C(=O)N(R
cc)
2、-CO
2R
aa、 -SO
2R
aa、-C(=NR
cc)OR
aa、-C(=NR
cc)N(R
cc)
2、-SO
2N(R
cc)
2、-SO
2R
cc、-SO
2OR
cc、-SOR
aa、-C(=S)N(R
cc)
2、-C(=O)SR
cc、-C(=S)SR
cc、-P(=O)
2R
aa、-P(=O)(R
aa)
2、-P(=O)
2N(R
cc)
2、-P(=O)(NR
cc)
2、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基,或者两个R
bb基团结合以形成杂环基或杂芳基环,其中,每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R
dd基团取代;
R
cc的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基,或者两个R
cc基团结合以形成杂环基或杂芳基环,其中,每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R
dd基团取代;
R
dd的每个独立地选自:卤素、-CN、-NO
2、-N
3、-SO
2H、-SO
3H、-OH、-OR
ee、-ON(R
ff)
2、-N(R
ff)
2,、-N(R
ff)
3
+X
-、-N(OR
ee)R
ff、-SH、-SR
ee、-SSR
ee、-C(=O)R
ee、-CO
2H、-CO
2R
ee、-OC(=O)R
ee、-OCO
2R
ee、-C(=O)N(R
ff)
2、-OC(=O)N(R
ff)
2、-NR
ffC(=O)R
ee、-NR
ffCO
2R
ee、-NR
ffC(=O)N(R
ff)
2、-C(=NR
ff)OR
ee、-OC(=NR
ff)R
ee、-OC(=NR
ff)OR
ee、-C(=NR
ff)N(R
ff)
2、-OC(=NR
ff)N(R
ff)
2、-NR
ffC(=NR
ff)N(R
ff)
2、-NR
ffSO
2R
ee、-SO
2N(R
ff)
2、-SO
2R
ee、-SO
2OR
ee、-OSO
2R
ee、-S(=O)R
ee、-Si(R
ee)
3、-OSi(R
ee)
3、-C(=S)N(R
ff)
2、-C(=O)SR
ee、-C(=S)SR
ee、-SC(=S)SR
ee、-P(=O)
2R
ee、-P(=O)(R
ee)
2、-OP(=O)(R
ee)
2、-OP(=O)(OR
ee)
2、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基、杂芳基,其中,每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R
gg基团取代,或者两个偕R
dd取代基可结合以形成=O或=S;
R
ee的每个独立地选自烷基、卤代烷基、烯基、炔基、碳环基、芳基、杂环基和杂芳基,其中,每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R
gg基团取代;
R
ff的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基,或者两个R
ff基团结合形成杂环基或杂芳基环,其中,每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R
gg基团取代;
R
gg的每个独立地是:卤素、-CN、-NO
2、-N
3、-SO
2H、-SO
3H、-OH、-OC
1-6烷基、-ON(C
1-6烷基)
2、-N(C
1-6烷基)
2、-N(C
1-6烷基)
3
+X
-、-NH(C
1-6烷基)
2
+X
-、-NH
2(C
1-6烷基)
+X
-、-NH
3
+X
-、-N(OC
1-6烷基)(C
1-6烷基)、-N(OH)(C
1-6烷基)、-NH(OH)、-SH、-SC
1-6烷基、-SS(C
1-6烷基)、-C(=O)(C
1-6烷基)、-CO
2H、-CO
2(C
1-6烷基)、-OC(=O)(C
1-6烷基)、-OCO
2(C
1-6烷基)、-C(=O)NH
2、-C(=O)N(C
1-6烷基)
2、-OC(=O)NH(C
1-6烷基)、-NHC(=O)(C
1-6烷基)、-N(C
1-6烷基)C(=O)(C
1-6烷基)、-NHCO
2(C
1-6烷基)、-NHC(=O)N(C
1-6烷基)
2、-NHC(=O)NH(C
1-6烷基)、-NHC(=O)NH
2、-C(=NH)O(C
1-6烷基)、-OC(=NH)(C
1-6烷基)、-OC(=NH)OC
1-6烷基、-C(=NH)N(C
1-6烷基)
2、-C(=NH)NH(C
1-6烷基)、-C(=NH)NH
2、-OC(=NH)N(C
1-6烷基)
2、-OC(NH)NH(C
1-6烷基)、-OC(NH)NH
2、-NHC(NH)N(C
1-6烷基)
2、 -NHC(=NH)NH
2、-NHSO
2(C
1-6烷基)、-SO
2N(C
1-6烷基)
2、-SO
2NH(C
1-6烷基)、-SO
2NH
2、-SO
2C
1-6烷基、-SO
2OC
1-6烷基、-OSO
2C
1-6烷基、-SOC
1-6烷基、-Si(C
1-6烷基)
3、-OSi(C
1-6烷基)
3、-C(=S)N(C
1-6烷基)
2、C(=S)NH(C
1-6烷基)、C(=S)NH
2、-C(=O)S(C
1-6烷基)、-C(=S)SC
1-6烷基、-SC(=S)SC
1-6烷基、-P(=O)
2(C
1-6烷基)、-P(=O)(C
1-6烷基)
2、-OP(=O)(C
1-6烷基)
2、-OP(=O)(OC
1-6烷基)
2、C
1-6烷基、C
1-6卤代烷基、C
2-C
6烯基、C
2-C
6炔基、C
3-C
7碳环基、C
6-C
10芳基、C
3-C
7杂环基、C
5-C
10杂芳基;或者两个偕R
gg取代基可结合形成=O或=S;其中,X
-为反离子。
示例性的氮原子上取代基包括但不局限于:氢、-OH、-OR
aa、-N(R
cc)
2、-CN、-C(=O)R
aa、-C(=O)N(R
cc)
2、-CO
2R
aa、-SO
2R
aa、-C(=NR
bb)R
aa、-C(=NR
cc)OR
aa、-C(=NR
cc)N(R
cc)
2、-SO
2N(R
cc)
2、-SO
2R
cc、-SO
2OR
cc、-SOR
aa、-C(=S)N(R
cc)
2、-C(=O)SR
cc、-C(=S)SR
cc、-P(=O)
2R
aa、-P(=O)(R
aa)
2、-P(=O)
2N(R
cc)
2、-P(=O)(NR
cc)
2、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基,或者连接至氮原子的两个R
cc基团结合形成杂环基或杂芳基环,其中,每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R
dd基团取代,且其中R
aa、R
bb、R
cc和R
dd如上所述。
术语“药学上可接受的盐”是指,在可靠的医学判断范围内,适合与人和低等动物的组织接触而没有过度毒性、刺激性、变态反应等等,并且与合理的益处/危险比例相称的那些盐。药学上可接受的盐在本领域是众所周知的。例如,Berge等人在J.Pharmaceutical Sciences(1977)66:1-19中详细描述的药学上可接受的盐。本发明化合物的药学上可接受的盐包括衍生自合适的无机和有机酸和无机和有机碱的盐。药学上可接受的无毒的酸加成盐的实例是与无机酸形成的盐,例如盐酸、氢溴酸、磷酸、硫酸和高氯酸,或与有机酸形成的盐,例如乙酸、草酸、马来酸、酒石酸、枸橼酸、琥珀酸或丙二酸。也包括使用本领域常规方法形成的盐,例如,离子交换方法。其它药学上可接受的盐包括:已二酸盐、海藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡萄糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酯酸盐、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐、戊酸盐,等等。衍生自合适的碱的药学上可接受的盐包括碱金属、碱土金属、铵和N
+(C
1-4烷基)
4盐。代表性的碱金属或碱土金属盐包括钠、锂、钾、钙、镁盐,等等。如果合适的话,其它的药学上可接受的盐包括与反离子形成的无毒的铵盐、季铵盐和胺阳离子,反离子例如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根、低级烷基磺酸根和芳基磺酸根。
“活性代谢物“指式(I)化合物或其盐在体内代谢的药理学活性产物。化合物的前药和活性代谢物可使用业内已知或可获得的常规技术来测定。
给药的“受试者”包括但不限于:人(即,任何年龄组的男性或女性,例如,儿科受试者(例如,婴儿、儿童、青少年)或成人受试者(例如,年轻的成人、中年的成人或年长的成人))和/或非人的动物,例如,哺乳动物,例如,灵长类(例如,食蟹猴、恒河猴)、牛、猪、马、绵羊、山羊、啮齿动物、猫和/或狗。在一些实施方案中,受试者是人。在一些实施方案中,受试者是非人动物。本文可互换使用术语“人”、“患者”和“受试者”。
“疾病”、“障碍”和“病症”在本文中可互换地使用。
除非另作说明,否则,本文使用的术语“治疗”包括受试者患有具体疾病、障碍或病症时所发生的作用,它降低疾病、障碍或病症的严重程度,或延迟或减缓疾病、障碍或病症的发展(“治疗性治疗”),还包括受试者开始患有具体疾病、障碍或病症之前发生的作用(“预防性治疗”)。
“组合”以及相关术语是指同时或依次给药本发明的治疗剂。例如,本发明化合物可以与另一治疗剂以分开的单位剂型同时或依次给药,或与另一治疗剂一起呈单一单位剂型同时给药。
化合物
本文中,“本发明化合物”指的是以下的式(I)化合物-式(III)化合物(包括各式的子集,例如式(II-a)化合物),或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或活性代谢物。
在一个实施方案中,本发明涉及式(I)化合物:
其中,
环A选自以下结构的环A-1,A-2和A-3:
R
1选自H、C
1-6烷基、C
3-7环烷基、3至7元杂环基、C
6-10芳基或5至10元杂芳基;其中所述基团任选地被一个或多个R
1a取代;前提是当环A是A-1时,R
1不是H;
R
2选自H、CN、NO
2、OH、卤素、C
1-6烷基、C
1-6卤代烷基、C
1-6烷氧基或C
1-6卤代烷氧基;
L选自-C(O)N(R
1b)-、-N(R
1b)C(O)-或-N(R
1b)C(O)N(R
1b)-;
B选自CH或N;
R
3选自H、C
1-6烷基或C
1-6卤代烷基;
R
4和R
5选自:
1)R
5为H,R
4选自H、C
1-6烷基、-C
0-2亚烷基-C
3-7环烷基、-C
0-2亚烷基-3至7元杂环基或-C
0-2亚烷基-NR
1cR
2c,其中所述基团任选地被一个或多个R
1d取代;或者
2)R
4为H,R
5选自H或含一个或多个N、O或S杂原子的5至6元杂芳环,其中所述5至6元杂芳环可任选地被一个或多个R
1d取代;
各个R
1a各自独立地选自H、卤素、氧代基、-C
0-6亚烷基-OR
a、-C
0-6亚烷基-NR
bR
c、-C
0-6亚烷基-C(O)R
a、-C
0-6亚烷基-C(O)OR
a、-C
0-6亚烷基-C(O)NR
bR
c、C
1-6烷基、C
1-6卤代烷基、-C
0-6亚烷基-C
3-6环烷基或-C
0-6亚烷基-3至7元杂环基;或者二个或二个以上的R
1a与它们所连接的原子一起形成C
3-7环烷基或3至7元杂环基;
各个R
1b各自独立地选自H、-C
0-6亚烷基-OR
a、-C
0-6亚烷基-NR
bR
c、-C
0-6亚烷基-C(O)R
a、-C
0-6亚烷基-C(O)OR
a、-C
0-6亚烷基-C(O)NR
bR
c、C
1-6烷基、C
1-6卤代烷基、-C
0-6亚烷基-C
3-6环烷基或-C
0-6亚烷基-3至7元杂环基;或者二个或二个以上的R
1b与它们所连接的原子一起形成C
3-7环烷基或3至7元杂环基;
R
1c和R
2c各自独立地选自H、卤素、-C
0-6亚烷基-CN、-C
0-6亚烷基-OR
a、-C
0-6亚烷基-SR
a、-C
0-6亚烷基-NR
bR
c、-C
0-6亚烷基-C(O)R
a、-C
0-6亚烷基-C(O)OR
a、-C
0-6亚烷基-C(O)NR
bR
c、C
1-6烷基、C
1-6卤代烷基、C
2-6烯基、C
2-6炔基、-C
0-6亚烷基-C
3-6环烷基、-C
0-6亚烷基-3至7元杂环基、-C
0-6亚烷基-C
6-10芳基或-C
0-6亚烷基-5至10元杂芳基;或者,R
1c、R
2c与它们所连接的氮原子一起形成C
3-7环烷基或3至7元杂环基;
各个R
1d各自独立地选自H、卤素、-C
0-6亚烷基-CN、-C
0-6亚烷基-OR
a、-C
0-6亚烷基-SR
a、-C
0-6亚烷基-NR
bR
c、-C
0-6亚烷基-C(O)R
a、-C
0-6亚烷基-C(O)OR
a、-C
0-6亚烷基-C(O)NR
bR
c、C
1-6烷基、C
1-6卤代烷基、C
2-6烯基、C
2-6炔基、-C
0-6亚烷基-C
3-6环烷基、-C
0-6亚烷基-3至7元杂环基、-C
0-6亚烷基-C
6-10芳基或-C
0-6亚烷基-5至10元杂芳基;或者二个或二个以上的R
1d与它们所连接的原子一起形成 C
3-7环烷基或3至7元杂环基;
R
a、R
b和R
c独立地选自H、C
1-6烷基、C
1-6卤代烷基、C
3-7环烷基、3至7元杂环基、C
6-10芳基或5至10元杂芳基;
附加条件是,上述化合物不具有以下结构:
或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、前药或同位素变体。
在另一个实施方案中,本发明涉及式(I)化合物:
其中,
环A选自以下结构:
R
1选自C
1-6烷基、C
3-7环烷基、3至7元杂环基、C
6-10芳基或5至10元杂芳基,其中所述基团任选地被一个或多个R
1a取代;
R
2选自H、CN、NO
2、OH、卤素、C
1-6烷基、C
1-6卤代烷基、C
1-6烷氧基或C
1-6卤代烷氧基;
L选自-C(O)N(R
1b)-、-N(R
1b)C(O)-或-N(R
1b)C(O)N(R
1b)-;
B选自CH或N;
R
3选自C
1-6烷基或C
1-6卤代烷基;
R
4和R
5选自:
1)R
5为H,R
4选自H、C
1-6烷基、-C
0-2亚烷基-C
3-7环烷基、-C
0-2亚烷基-3至7元杂环基或-C
0-2 亚烷基-NR
1cR
2c,其中所述基团任选地被一个或多个R
1d取代;或者,
2)R
4为H,R
5选自H或含一个或多个N、O或S杂原子的5至6元杂芳环,其中所述5至6元杂芳环可任选地被一个或多个R
1d取代;
各个R
1a各自独立地选自H、卤素、氧代基、-C
0-6亚烷基-OR
a、-C
0-6亚烷基-NR
bR
c、-C
0-6亚烷基-C(O)R
a、-C
0-6亚烷基-C(O)OR
a、-C
0-6亚烷基-C(O)NR
bR
c、C
1-6烷基、C
1-6卤代烷基、-C
0-6亚烷基-C
3-6环烷基或-C
0-6亚烷基-3至7元杂环基;或者二个或二个以上的R
1a与它们所连接的原子一起形成C
3-7环烷基或3至7元杂环基;
各个R
1b各自独立地选自H、-C
0-6亚烷基-OR
a、-C
0-6亚烷基-NR
bR
c、-C
0-6亚烷基-C(O)R
a、-C
0-6亚烷基-C(O)OR
a、-C
0-6亚烷基-C(O)NR
bR
c、C
1-6烷基、C
1-6卤代烷基、-C
0-6亚烷基-C
3-6环烷基或-C
0-6亚烷基-3至7元杂环基;或者二个或二个以上的R
1b与它们所连接的原子一起形成C
3-7环烷基或3至7元杂环基;
R
1c和R
2c各自独立地选自H、卤素、-C
0-6亚烷基-CN、-C
0-6亚烷基-OR
a、-C
0-6亚烷基-SR
a、-C
0-6亚烷基-NR
bR
c、-C
0-6亚烷基-C(O)R
a、-C
0-6亚烷基-C(O)OR
a、-C
0-6亚烷基-C(O)NR
bR
c、C
1-6烷基、C
1-6卤代烷基、C
2-6烯基、C
2-6炔基、-C
0-6亚烷基-C
3-6环烷基、-C
0-6亚烷基-3至7元杂环基、-C
0-6亚烷基-C
6-10芳基或-C
0-6亚烷基-5至10元杂芳基;或者,R
1c、R
2c与它们所连接的氮原子一起形成C
3-7环烷基或3至7元杂环基;
各个R
1d各自独立地选自H、卤素、-C
0-6亚烷基-CN、-C
0-6亚烷基-OR
a、-C
0-6亚烷基-SR
a、-C
0-6亚烷基-NR
bR
c、-C
0-6亚烷基-C(O)R
a、-C
0-6亚烷基-C(O)OR
a、-C
0-6亚烷基-C(O)NR
bR
c、C
1-6烷基、C
1-6卤代烷基、C
2-6烯基、C
2-6炔基、-C
0-6亚烷基-C
3-6环烷基、-C
0-6亚烷基-3至7元杂环基、-C
0-6亚烷基-C
6-10芳基或-C
0-6亚烷基-5至10元杂芳基;或者二个或二个以上的R
1d与们所连接的原子一起形成C
3-7环烷基或3至7元杂环基;
R
a、R
b和R
c独立地选自H、C
1-6烷基、C
1-6卤代烷基、C
3-7环烷基、3至7元杂环基、C
6-10芳基或5至10元杂芳基;
附加条件是,上述化合物不具有以下结构:
或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、前药或同位素变体。
在通式(I)的一个实施方案中,环A具有以下结构的环A-1:
当环A由结构A-1所表示时,其具体的实例包括以下结构:
在另一个实施方案中,环A具有以下结构的环A-2:
在一个具体实施方案中,X/Y/Z独立的为CH;在另一个具体实施方案中,X/Y/Z独立的为N。
当环A由结构A-2表示时,其具体实例包括以下结构:
在另一个实施方案中,环A具有以下结构的环A-3:
在一个具体实施方案中,X/Y/Z独立的为CH;在另一个具体实施方案中,X/Y/Z独立的为N。
当环A由结构A-3表示时,其具体实例包括以下结构:
在A的上述实施方案中,R
1选自H、C
1-6烷基、C
3-7环烷基、3至7元杂环基、C
6-10芳基或5至10元杂芳基,其中所述基团任选地被一个或多个R
1a取代;优选地,R
1选自C
1-4烷基、C
4-6环烷基或5至6元杂环基,其中所述基团任选地被一个或多个R
1a取代;优选地,R
1选自甲基、乙基、异丙基、环戊基、环己基、四氢呋喃基、哌啶基、哌嗪基或吗啉基,其中所述基团任选地被一个或多个R
1a取代;优选地,R
1选自甲基、乙基、异丙基、环戊基、环己基、四氢呋喃基、哌啶基、哌嗪基或吗啉基,其中所述基团任选地被一个或多个-OH取代;更优选地,R
1选自甲基、乙基、异丙基、环戊基或环己 基,其中所述基团任选地被一个或多个-OH取代。
在R
1的上述实施方案中,各个R
1a各自独立地选自H、卤素、氧代基、-C
0-6亚烷基-OR
a、-C
0-6亚烷基-NR
bR
c、-C
0-6亚烷基-C(O)R
a、-C
0-6亚烷基-C(O)OR
a、-C
0-6亚烷基-C(O)NR
bR
c、C
1-6烷基、C
1-6卤代烷基、-C
0-6亚烷基-C
3-6环烷基、-C
0-6亚烷基-3至7元杂环基,或者二个或二个以上的R
1a与它们所连接的原子一起形成C
3-7环烷基或3至7元杂环基,其中,所述的R
a、R
b和R
c各自独立地选自H、C
1-6烷基、C
1-6卤代烷基、C
3-7环烷基、3至7元杂环基、C
6-10芳基或5至10元杂芳基;优选地,各个R
1a各自独立地选自H、卤素、C
1-6烷基或-OH;更优选地,各个R
1a各自独立地选自H、C
1-6烷基或-OH。
在通式(I)的一个实施方案中,R
2选自H、CN、NO
2、OH、卤素、C
1-6烷基、C
1-6卤代烷基、C
1-6烷氧基或C
1-6卤代烷氧基;优选地,R
2选自H或C
1-4烷基;更优选地,R
2选自H、甲基、乙基或异丙基;最优选地,R
2选自H或甲基。
在通式(I)的一个实施方案中,L选自-C(O)N(R
1b)-、-N(R
1b)C(O)-或-N(R
1b)C(O)N(R
1b)-;优选地,L选自-C(O)N(R
1b)-或-N(R
1b)C(O)-。
在L的上述实施方案中,各个R
1b各自独立地选自H、-C
0-6亚烷基-OR
a、-C
0-6亚烷基-NR
bR
c、-C
0-6亚烷基-C(O)R
a、-C
0-6亚烷基-C(O)OR
a、-C
0-6亚烷基-C(O)NR
bR
c、C
1-6烷基、C
1-6卤代烷基、-C
0-6亚烷基-C
3-6环烷基或-C
0-6亚烷基-3至7元杂环基,或者二个或二个以上的R
1b与它们所连接的原子一起形成C
3-7环烷基或3至7元杂环基;优选地,各个R
1b各自独立地选自H、-C
0-6亚烷基-NR
bR
c、C
1-6烷基、C
1-6卤代烷基、-C
0-6亚烷基-C
3-6环烷基或-C
0-6亚烷基-3至7元杂环基;优选地,各个R
1b各自独立地选自H、C
1-4烷基、-C
0-6亚烷基-C
3-6环烷基或-C
0-6亚烷基-3至7元杂环基;优选地,各个R
1b各自独立地选自H或C
1-4烷基;更优选地,各个R
1b各自独立地选自H、甲基、乙基、异丙基、环丙基、环丁基、环戊基、环己基、四氢呋喃基、四氢吡咯、哌啶基、哌嗪基或吗啉基;最优选地,各个R
1b选自H;其中,所述的R
a、R
b和R
c独立地选自H、C
1-6烷基、C
1-6卤代烷基、C
3-7环烷基、3至7元杂环基、C
6-10芳基或5至10元杂芳基。
在通式(I)的一个实施方案中,B选自CH或N;优选地,B为CH。
在通式(I)的一个实施方案中,R
3选自H、C
1-6烷基或C
1-6卤代烷基;优选地,R
3选自C
1-6烷基或C
1-6卤代烷基;优选地,R
3选自C
1-4氟代烷基;更优选地,R
3选自-CF
2H、-CFH
2或-CF
3;最优选地,R
3选自-CF
3。
在通式(I)的一个实施方案中,当R
5为H时,R
4选自H、C
1-6烷基、-C
0-2亚烷基-C
3-7环烷基、-C
0-2亚烷基-3至7元杂环基或-C
0-2亚烷基-NR
1cR
2c,其中所述基团任选被一个或多个R
1d取代;优选地, R
4选自H、C
1-6烷基或-C
0-2亚烷基-NR
1cR
2c,其中所述基团任选被一个或多个R
1d取代;优选地,R
4选自H、-C
1-4烷基或-CH
2-NR
1cR
2c,其中所述基团任选被一个或多个R
1d取代;更优选地,R
4选自H、甲基、乙基、异丙基、叔丁基、
最优选地,R
4选自H、甲基、
在上述R
4和R
5的实施方案中,R
1c和R
2c各自独立地选自H、卤素、-C
0-6亚烷基-CN、-C
0-6亚烷基-OR
a、-C
0-6亚烷基-SR
a、-C
0-6亚烷基-NR
bR
c、-C
0-6亚烷基-C(O)R
a、-C
0-6亚烷基-C(O)OR
a、-C
0-6亚烷基-C(O)NR
bR
c、C
1-6烷基、C
1-6卤代烷基、C
2-6烯基、C
2-6炔基、-C
0-6亚烷基-C
3-6环烷基、-C
0-6亚烷基-3至7元杂环基、-C
0-6亚烷基-C
6-10芳基或-C
0-6亚烷基-5至10元杂芳基;或者,R
1c、R
2c与它们所连接的氮原子一起形成C
3-7环烷基或3至7元杂环基;其中,R
a、R
b和R
c独立地选自H、C
1-6烷基、C
1-6卤代烷基、C
3-7环烷基、3至7元杂环基、C
6-10芳基或5至10元杂芳基。
在通式(I)的一个实施方案中,当R
4为H时,R
5选自H或含一个或多个N、O或S杂原子的5至6元杂芳环,其中所述的5至6元杂芳环可任选地被一个或多个R
1d取代;优选地,R
5选自H或含一个或多个N杂原子的5至6元杂芳环,其中所述的5至6元杂芳环可任选地被一个或多个R
1d取代;更优选地,R
5选自H或含一个或多个N杂原子的5杂芳环,其中所述的5杂芳环可任选地被一个或多个R
1d取代;最优选地,R
5选自H或咪唑基,其中所述的咪唑基可任选地被一个或多个R
1d取代。
在上述R
4和R
5的实施方案中,各个R
1d各自独立地选自H、卤素、-C
0-6亚烷基-CN、-C
0-6亚烷基-OR
a、-C
0-6亚烷基-SR
a、-C
0-6亚烷基-NR
bR
c、-C
0-6亚烷基-C(O)R
a、-C
0-6亚烷基-C(O)OR
a、-C
0-6亚烷基-C(O)NR
bR
c、C
1-6烷基、C
1-6卤代烷基、C
2-6烯基、C
2-6炔基、-C
0-6亚烷基-C
3-6环烷基、-C
0-6亚烷基-3至7元杂环基、-C
0-6亚烷基-C
6-10芳基或-C
0-6亚烷基-5至10元杂芳基,或者二个或二个以上的R
1d与它们所连接的原子一起形成C
3-7环烷基或3至7元杂环基;其中,R
a、R
b和R
c独立地选自H、C
1-6烷基、C
1-6卤代烷基、C
3-7环烷基、3至7元杂环基、C
6-10芳基或5至10元杂芳基。
在另一个具体地实施方案中,本发明提供了式(II-a)和式(II-b)的化合物:
其中,
R
1选自C
1-4烷基、C
4-6环烷基或5至6元杂环基,其中所述基团任选地被一个或多个R
1a取代;
R
2选自H或C
1-4烷基;
L选自-C(O)NH-、-NHC(O)-或-NHC(O)NH-;
R
4和R
5选自:
1)R
5为氢,R
4选自H、C
1-4烷基或-CH
2-NR
1cR
2c;其中,R
1c和R
2c各自独立地选自C
1-6烷基、C
3-6环烷基或3至7元杂环基,或者,R
1c、R
2c和它们所连接的氮原子一起形成C
3-7环烷基或5至6元杂环基;
2)R
4为氢,R
5选自H或含一个或多个N杂原子的5至6元杂芳环,其中所述的5至6元杂芳环可任选地被一个或多个R
1d取代;
R
1a和R
1d如上文所定义。
在另一个具体实施方案中,本发明提供了式(II-a)和式(II-b)的化合物:
其中,
R
1选自甲基、乙基、异丙基、环戊基或环己基,其中所述基团任选地被一个或多个-OH取代;
R
2选自H或甲基;
L选自-C(O)NH-或-NHC(O);
R
4和R
5选自:
2)R
4为氢,R
5为H或咪唑基。
在另一个具体地实施方案中,本发明提供了式(III-a)化合物:
其中,
R
1选自C
1-4烷基或C
4-6环烷基,其中所述基团任选地被一个或多个-OH取代;
R
2选自H或C
1-4烷基;
R
4选自H或C
1-4烷基;
L选自-C(O)NH-或-NHC(O)-;
或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、前药或同位素变体。
在另一个具体实施方案中,本发明提供了式(III-b)化合物:
其中,
环A选自以下结构:
R
1选自C
1-4烷基或C
4-6环烷基,其中所述基团任选地被一个或多个-OH取代;
R
2选自H或C
1-4烷基;
L选自-C(O)NH-或-NHC(O)-;
或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、前药或同位素变体。
在另一个具体实施方案中,本发明提供了式(III-c)化合物:
其中,
R
1选自C
1-4烷基或C
4-6环烷基,其中所述基团任选被一个或多个-OH取代;
R
2选自H或C
1-4烷基;
L选自-C(O)NH-或-NHC(O)-;
或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、前药或同位素变体。
在另一个具体实施方案中,本发明涉及以下化合物:
本发明化合物可包括一个或多个不对称中心,且因此可以存在多种立体异构体形式,例如,对映异构体和/或非对映异构体形式。例如,本发明化合物可为单独的对映异构体、非对映异构体或几何异构体(例如顺式和反式异构体),或者可为立体异构体的混合物的形式,包括外消旋体混合物和富含一种或多种立体异构体的混合物。异构体可通过本领域技术人员已知的方法从混合物中分离,所述方法包括:手性高压液相色谱法(HPLC)以及手性盐的形成和结晶;或者优选的异构体可通过不对称合成来制备。
本领域技术人员将理解,有机化合物可以与溶剂形成复合物,其在该溶剂中发生反应或从该溶剂中沉淀或结晶出来。这些复合物称为“溶剂合物”。当溶剂是水时,复合物称为“水合物”。本发明涵盖了本发明化合物的所有溶剂合物。
术语“溶剂合物”是指通常由溶剂分解反应形成的与溶剂相结合的化合物或其盐的形式。这个物理缔合可包括氢键键合。常规溶剂包括包括水、甲醇、乙醇、乙酸、DMSO、THF、乙醚等。本文所述的化合物可制备成,例如,结晶形式,且可被溶剂化。合适的溶剂合物包括药学上可接受的溶剂合物且进一步包括化学计量的溶剂合物和非化学计量的溶剂合物。在一些情况下,所述溶剂合物将能够分离,例如,当一或多个溶剂分子掺入结晶固体的晶格中时。“溶剂合物”包括溶液状态的溶剂合物和可分离的溶剂合物。代表性的溶剂合物包括水合物、乙醇合物和甲醇合物。
术语“水合物”是指与水相结合的化合物。通常,包含在化合物的水合物中的水分子数与该水合物中该化合物分子数的比率确定。因此,化合物的水合物可用例如通式R·x H
2O代表,其中R是该化合物,和x是大于0的数。给定化合物可形成超过一种水合物类型,包括,例如,单水合物(x为1)、低级水合物(x是大于0且小于1的数,例如,半水合物(R·0.5 H
2O))和多水合物(x为大于1的数,例如,二水合物(R·2 H
2O)和六水合物(R·6 H
2O))。
本发明化合物可以是无定形或结晶形式(多晶型)。此外,本发明化合物可以以一种或多种结晶形式存在。因此,本发明在其范围内包括本发明化合物的所有无定形或结晶形式。术语“多晶型物”是指特定晶体堆积排列的化合物的结晶形式(或其盐、水合物或溶剂合物)。所有的多晶型物具有相同的元素组成。不同的结晶形式通常具有不同的X射线衍射图、红外光谱、熔点、密度、硬度、晶体形状、光电性质、稳定性和溶解度。重结晶溶剂、结晶速率、贮存温度和其他因素可导致一种结晶形式占优。化合物的各种多晶型物可在不同的条件下通过结晶制备。
本发明还包括同位素标记的化合物,它们等同于式(I)所述的那些,但一个或多个原子被原子质量或质量数不同于自然界常见的原子质量或质量数的原子所代替。可以引入本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素,分别例如
2H、
3H、
13C、
11C、
14C、
15N、
18O、
17O、
31P、
32P、
35S、
18F和
36Cl。含有上述同位素和/或其它原子的其它同位素的本发明化合物、其前 体药物和所述化合物或所述前体药物的药学上可接受的盐都属于本发明的范围。某些同位素标记的本发明化合物、例如引入放射性同位素(例如
3H和
14C)的那些可用于药物和/或底物组织分布测定。氚、即
3H和碳-14、即
14C同位素是特别优选的,因为它们容易制备和检测。进而,被更重的同位素取代,例如氘、即
2H,由于代谢稳定性更高可以提供治疗上的益处,例如延长体内半衰期或减少剂量需求,因而在有些情况下可能是优选的。同位素标记的本发明式(I)化合物及其前体药物一般可以这样制备,在进行下述流程和/或实施例与制备例所公开的工艺时,用容易得到的同位素标记的试剂代替非同位素标记的试剂。
此外,前药也包括在本发明的上下文内。本文所用的术语“前药”是指在体内通过例如在血液中水解转变成其具有医学效应的活性形式的化合物。药学上可接受的前药描述于T.Higuchi和V.Stella,Prodrugs as Novel Delivery Systems,A.C.S.Symposium Series的Vol.14,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,以及D.Fleisher、S.Ramon和H.Barbra“Improved oral drug delivery:solubility limitations overcome by the use of prodrugs”,Advanced Drug Delivery Reviews(1996)19(2)115-130,每篇引入本文作为参考。
前药为任何共价键合的本发明化合物,当将这种前药给予患者时,其在体内释放母体化合物。通常通过修饰官能团来制备前药,修饰是以使得该修饰可以通过常规操作或在体内裂解产生母体化合物的方式进行的。前药包括,例如,其中羟基、氨基或巯基与任意基团键合的本发明化合物,当将其给予患者时,可以裂解形成羟基、氨基或巯基。因此,前药的代表性实例包括(但不限于)式(I)化合物的羟基、巯基和氨基官能团的乙酸酯/酰胺、甲酸酯/酰胺和苯甲酸酯/酰胺衍生物。另外,在羧酸(-COOH)的情况下,可以使用酯,例如甲酯、乙酯等。酯本身可以是有活性的和/或可以在人体体内条件下水解。合适的药学上可接受的体内可水解的酯基包括容易在人体中分解而释放母体酸或其盐的那些基团。
药物组合物、制剂和试剂盒
在另一方面,本发明提供了药物组合物,其包含本发明化合物(还称为“活性组分”)和药学上可接受的赋形剂。在一些实施方案中,所述药物组合物包含有效量的活性组分。在一些实施方案中,所述药物组合物包含治疗有效量的活性组分。在一些实施方案中,所述药物组合物包含预防有效量的活性组分。
用于本发明的药学上可接受的赋形剂是指不会破坏一起调配的化合物的药理学活性的无毒载剂、佐剂或媒剂。可以用于本发明组合物中的药学上可接受的载剂、佐剂或媒剂包括(但不限于)离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人类血清白蛋白)、缓冲物质(如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白)、磷酸氢二 钠、磷酸氢钾、氯化钠、锌盐、硅胶、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇以及羊毛脂。
本发明还包括试剂盒(例如,药物包装)。所提供的试剂盒可以包括本发明化合物、其它治疗剂,以及含有本发明化合物、其它治疗剂的第一和第二容器(例如,小瓶、安瓿瓶、瓶、注射器和/或可分散包装或其它合适的容器)。在一些实施方案中,提供的试剂盒还可以任选包括第三容器,其含有用于稀释或悬浮本发明化合物和/或其它治疗剂的药用赋形剂。在一些实施方案中,提供在第一容器和第二容器中的本发明化合物和其它治疗剂组合形成一个单位剂型。
下列制剂实施例说明可根据本发明制备的代表性的药物组合物。然而,本发明不限于下列药物组合物。
示例性的制剂1-片剂:可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为0.3-30mg片剂(每个片剂含有0.1-10mg活性化合物)。
示例性的制剂2-片剂:可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为30-90mg片剂(每个片剂含有10-30mg活性化合物)。
示例性的制剂3-片剂:可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为90-150mg片剂(每个片剂含有30-50mg活性化合物)。
示例性的制剂4-片剂:可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为150-240mg片剂(每个片剂含有50-80mg活性化合物)。
示例性的制剂5-片剂:可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为240-270mg片剂(每个片剂含有80-90mg活性化合物)。
示例性的制剂6-片剂:可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为270-450mg片剂(每个片剂含有90-150mg活性化合物)。
示例性的制剂7-片剂:可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为450-900mg片剂(每个片剂含有150-300mg活性化合物)。
示例性的制剂8-胶囊剂:可以将干粉形式的本发明化合物与淀粉稀释剂以约1:1的重量比混合。 将该混合物填充到250mg胶囊中(每个胶囊含有125mg活性化合物)。
示例性的制剂9-液体:可以将本发明化合物(125mg)与蔗糖(1.75g)和黄原胶(4mg)混合,且可将得到的混合物共混,通过No.10筛目美国筛,然后与预先制备的微晶纤维素和羧甲基纤维素钠(11:89,50mg)的水溶液混合。将苯甲酸钠(10mg)、调味剂和着色剂用水稀释,并在搅拌下加入。然后,可以加入充足的水,得到5mL的总体积。
示例性的制剂10-注射剂:可以将本发明化合物溶解或悬浮在缓冲无菌盐水可注射的水性介质中,达到约5mg/mL的浓度。
给药
本发明提供的药物组合物可以通过许多途径给药,包括但不限于:口服给药、肠胃外给药、吸入给药、局部给药、直肠给药、鼻腔给药、口腔给药、阴道给药、通过植入剂给药或其它给药方式。例如,本文使用的肠胃外给药包括皮下给药、皮内给药、静脉内给药、肌肉内给药、关节内给药、动脉内给药、滑膜腔内给药、胸骨内给药、脑脊髓膜内给药、病灶内给药、和颅内的注射或输液技术。
通常,给予有效量的本文所提供的化合物。按照有关情况,包括所治疗的病症、选择的给药途径、实际给予的化合物、个体患者的年龄、体重和响应、患者症状的严重程度,等等,可以由医生确定实际上给予的化合物的量。
当用于预防本发明所述病症时,给予处于形成所述病症危险之中的受试者本文所提供的化合物,典型地基于医生的建议并在医生监督下给药,剂量水平如上所述。处于形成具体病症的危险之中的受试者,通常包括具有所述病症的家族史的受试者,或通过遗传试验或筛选确定尤其对形成所述病症敏感的那些受试者。
还可以长期给予本文所提供的药物组合物(“长期给药”)。长期给药是指在长时间内给予化合物或其药物组合物,例如,3个月、6个月、1年、2年、3年、5年等等,或者可无限期地持续给药,例如,受试者的余生。在一些实施方案中,长期给药意欲在长时间内在血液中提供所述化合物的恒定水平,例如,在治疗窗内。
可以使用各种给药方法,进一步递送本发明的药物组合物。例如,在一些实施方案中,可以推注给药药物组合物,例如,为了使化合物在血液中的浓度提高至有效水平。推注剂量取决于通过身体的活性组分的目标全身性水平,例如,肌内或皮下的推注剂量使活性组分缓慢释放,而直接递送至静脉的推注(例如,通过IV静脉滴注)能够更加快速地递送,使得活性组分在血液中的浓度快速升高至有效水平。在其它实施方案中,可以以持续输液形式给予药物组合物,例如,通过IV静脉滴注,从而在受试者身体中提供稳态浓度的活性组分。此外,在其它实施方案中,可以首先给予推注剂量的药物组合物,而后持续输液。
口服组合物可以采用散装液体溶液或混悬剂或散装粉剂形式。然而,更通常,为了便于精确地剂量给药,以单位剂量形式提供所述组合物。术语“单位剂型”是指适合作为人类患者及其它哺乳动物的单元剂量的物理离散单位,每个单位包含预定数量的、适于产生所需要的治疗效果的活性物质与合适药学赋形剂。典型的单位剂量形式包括液体组合物的预装填的、预先测量的安瓿或注射器,或者在固体组合物情况下的丸剂、片剂、胶囊剂等。在这种组合物中,所述化合物通常为较少的组分(约0.1至约50重量%,或优选约1至约40重量%),剩余部分为对于形成所需给药形式有用的各种载体或赋形剂以及加工助剂。
对于口服剂量,代表性的方案是,每天一个至五个口服剂量,尤其是两个至四个口服剂量,典型地是三个口服剂量。使用这些剂量给药模式,每个剂量提供大约0.01至大约20mg/kg的本发明化合物,优选的剂量各自提供大约0.1至大约10mg/kg,尤其是大约1至大约5mg/kg。
为了提供与使用注射剂量类似的血液水平,或比使用注射剂量更低的血液水平,通常选择透皮剂量,数量为大约0.01至大约20%重量,优选大约0.1至大约20%重量,优选大约0.1至大约10%重量,且更优选大约0.5至大约15%重量。
从大约1至大约120小时,尤其是24至96小时,注射剂量水平在大约0.1mg/kg/小时至至少10mg/kg/小时的范围。为了获得足够的稳定状态水平,还可以给予大约0.1mg/kg至大约10mg/kg或更多的预载推注。对于40至80kg的人类患者来说,最大总剂量不能超过大约2g/天。
适于口服给药的液体形式可包括合适的水性或非水载体以及缓冲剂、悬浮剂和分散剂、着色剂、调味剂,等等。固体形式可包括,例如,任何下列组份,或具有类似性质的化合物:粘合剂,例如,微晶纤维素、黄蓍胶或明胶;赋形剂,例如,淀粉或乳糖,崩解剂,例如,褐藻酸、Primogel或玉米淀粉;润滑剂,例如,硬脂酸镁;助流剂,例如,胶体二氧化硅;甜味剂,例如,蔗糖或糖精;或调味剂,例如,薄荷、水杨酸甲酯或橙味调味剂。
可注射的组合物典型地基于可注射用的无菌盐水或磷酸盐缓冲盐水,或本领域中已知的其它可注射的赋形剂。如前所述,在这种组合物中,活性化合物典型地为较少的组分,经常为约0.05至10%重量,剩余部分为可注射的赋形剂等。
典型地将透皮组合物配制为含有活性组分的局部软膏剂或乳膏剂。当配制为软膏剂时,活性组分典型地与石蜡或可与水混溶的软膏基质组合。或者,活性组分可与例如水包油型乳膏基质一起配制为乳膏剂。这种透皮制剂是本领域中公知的,且通常包括用于提升活性组分或制剂的稳定的皮肤渗透的其它组份。所有这种已知的透皮制剂和组份包括在本发明提供的范围内。
本发明化合物还可通过经皮装置给予。因此,经皮给药可使用贮存器(reservoir)或多孔膜类型、或者多种固体基质的贴剂实现。
用于口服给予、注射或局部给予的组合物的上述组份仅仅是代表性的。其它材料以及加工技术等 阐述于Remington's Pharmaceutical Sciences,17th edition,1985,Mack Publishing Company,Easton,Pennsylvania的第8部分中,本文以引用的方式引入该文献。
本发明化合物还可以以持续释放形式给予,或从持续释放给药系统中给予。代表性的持续释放材料的描述可在Remington's Pharmaceutical Sciences中找到。
本发明还涉及本发明化合物的药学上可接受的制剂。在一个实施方案中,所述制剂包含水。在另一个实施方案中,所述制剂包含环糊精衍生物。最常见的环糊精为分别由6、7和8个α-1,4-连接的葡萄糖单元组成的α-、β-和γ-环糊精,其在连接的糖部分上任选包括一个或多个取代基,其包括但不限于:甲基化的、羟基烷基化的、酰化的和磺烷基醚取代。在一些实施方案中,所述环糊精为磺烷基醚β-环糊精,例如,磺丁基醚β-环糊精,也称作Captisol。参见,例如,U.S.5,376,645。在一些实施方案中,所述制剂包括六丙基-β-环糊精(例如,在水中,10-50%)。
治疗
本发明提供了具有生物学性质的化合物,这些性质使这些化合物能够治疗或改善所关注的可能涉及激酶的疾病,这些疾病的症状,或由激酶介导的其它生理学事件的作用。例如,本发明化合物显示出抑制Ret(Reaaranged during transfection),ABL1(E255K)-phosphorylated,ABL1(F317I)-nonphosphorylated,ABL1(F317I)-phosphorylated,ABL1(F317L)-nonphosphorylated,ABL1(F317L)-phosphorylated,ABL1(H396P)-nonphosphorylated,ABL1(H396P)-phosphorylated,ABL1(M351T)-phosphorylated,ABL1(Q252H)-nonphosphorylated,ABL1(Q252H)-phosphorylated,ABL1(T315I)-nonphosphorylated,ABL1(T315I)-phosphorylated,ABL1(Y253F)-phosphorylated,ABL1-nonphosphorylated,ABL1-phosphorylated,ABL2,ALK(L1196M),AMPK-alpha1,AMPK-alpha2,ANKK1,AURKB,AURKC,AXL,BLK,BMX,BRAF,BRAF(V600E),BRK,BTK,CAMK1,CAMKK1,CAMKK2,CDC2L1,CDC2L2,CDC2L5,CDK11,CDK2,CDK5,CDK7,CDK8,CDKL1,CDKL2,CDKL3,CHEK2,CIT,CLK1,CLK4,CSF1R,CSK,CTK,DDR1,DDR2,DLK,EGFR,EGFR(E746-A750del),EGFR(G719C),EGFR(G719S),EGFR(L747-E749del,A750P),EGFR(L747-S752del,P753S),EGFR(L747-T751del,Sins),EGFR(L858R),EGFR(L858R,T790M),EGFR(L861Q),EGFR(S752-I759del),EGFR(T790M),EPHA1,EPHA2,EPHA3,EPHA4,EPHA5,EPHA6,EPHA7,EPHA8,EPHB1,EPHB2,EPHB4,EPHB6,ERBB2,ERBB4,ERK8,FAK,FER,FES,FGFR1,FGFR2,FGFR3,FGFR3(G697C),FGFR4,FGR,FLT1,FLT3,FLT3(D835H),FLT3(D835V),FLT3(D835Y),FLT3(ITD),FLT3(ITD,D835V),FLT3(ITD,F691L),FLT3(K663Q),FLT3(N841I),FLT3(R834Q),FLT4,FRK,FYN,GAK,GCN2(Kin.Dom.2,S808G),HCK,HIPK4,HPK1,IKK-alpha,IKK-beta,IRAK1,IRAK4,ITK,JAK1(JH1domain-catalytic),JAK2(JH1domain-catalytic), JAK3(JH1domain-catalytic),JNK1,JNK2,JNK3,KIT,KIT(A829P),KIT(D816H),KIT(D816V),KIT(L576P),KIT(V559D),KIT(V559D,T670I),KIT(V559D,V654A),LCK,LIMK1,LIMK2,LOK,LRRK2,LRRK2(G2019S),LTK,LYN,MAK,MAP3K2,MAP3K3,MAP4K2,MAP4K3,MAP4K4,MAP4K5,MEK5,MELK,MERTK,MET,MET(M1250T),MINK,MKNK2,MLK1,MLK2,MLK3,MST1,MST1R,MST2,MUSK,MYLK2,MYO3A,MYO3B,NDR2,NEK1,NEK11,NEK4,NEK5,NEK9,NLK,p38-alpha,p38-beta,p38-delta,p38-gamma,PCTK2,PDGFRA,PDGFRB,PFCDPK1(P.falciparum),PFTAIRE2,PFTK1,PKAC-alpha,PKAC-beta,PYK2,RAF1,RET,RET(M918T),RET(V804L),RET(V804M),RIPK1,RIPK2,RIPK4,ROCK2,RPS6KA4(Kin.Dom.1-N-terminal),RSK2(Kin.Dom.1-N-terminal),RSK3(Kin.DoN-terminal),S6K1,SIK,SLK,SRC,SRMS,SRPK1,STK33,STK35,STK36,SYK,TAK1,TAOK2,TAOK3,TEC,TESK1,TGFBR2,TIE1,TIE2,TNIK,TNK1,TNK2,TNNI3K,TRKA,TRKB,TRKC,TTK,TXK,TYK2(JH1domain-catalytic),TYRO3,ULK3,VEGFR2,YES,YSK4,ZAK,ZAP70或FGFR(Fibroblast growth factor receptor)的酪氨酸激酶活性,以及其它认为调节癌症的生长、发展和/或转移的酪氨酸激酶。
本发明的物质还用于治疗由Bcr-Abl激酶介导的下述疾病、障碍或病症:呼吸系统疾病、变态反应、类风湿性关节炎、骨关节炎、风湿性病症、银屑病、溃疡性结肠炎、局限性回肠炎、败血症性休克、增殖性病症、动脉粥样硬化、移植后的同种异体移植物排斥反应、糖尿病、中风、肥胖症或再狭窄、白血病、间质瘤、甲状腺癌、系统性肥大细胞病、嗜酸性粒细胞增多综合征、纤维变性、类风湿性关节炎、多关节炎、硬皮病、红斑狼疮、移植物抗宿主病、神经纤维瘤、肺高压、阿尔茨海默病、精原细胞瘤、无性细胞瘤、肥大细胞肿瘤、肺癌、支气管癌、无性细胞瘤、睾丸上皮内瘤形成、黑色素瘤、乳癌、神经母细胞瘤、乳头状/滤泡型甲状旁腺增生/腺瘤、结肠癌、结肠直肠腺瘤、卵巢癌、前列腺癌、成胶质细胞瘤、脑肿瘤、恶性神经胶质瘤、胰腺癌、恶性胸膜间皮瘤、成血管细胞瘤、血管瘤、肾癌、肝癌、肾上腺癌、膀胱癌、胃癌、直肠癌、阴道癌、宫颈癌、子宫内膜癌、多发性骨髓瘤、颈和头部肿瘤、瘤形成以及其他增生性或增殖性疾病、或其组合。
本发明因此提供了在治疗中、特别是在治疗由不适当的Bcr-Abl活性介导的疾病和病况中使用的(I)的化合物及其盐、溶剂合物、生理学上的功能性化合物。
在本文中提及的不适当的Bcr-Abl活性是在特定哺乳动物对象中偏离预期的正常Bcr-Abl活性的任何Bcr-Abl活性。不适当的Bcr-Abl活性可以呈例如以下形式:活性异常增加,或者Bcr-Abl活性的时机和或控制的畸变。这种不适当的活性则可以由例如导致不适当或失控的活化的蛋白激酶的过表达或突变所导致。
在另一个实施方案中,本发明涉及为了预防和/或治疗与失调的或不适当的Bcr-Abl活性有关的病症而调节、调控或抑制Bcr-Abl的方法。
在另一个实施方案中,所述由Bcr-Abl活性介导的病症是呼吸系统疾病。在另一个实施方案中,所述病症是增殖性病症。在又一个实施方案中,所述病症是癌症。在另一个实施方案中,所述病症是白血病。
另一个实施方案中,本发明提供了式(I)的化合物或其药学上可接受的盐或溶剂合物、或其生理学上的功能性衍生物在制备用于治疗由Bcr-Abl活性介导的病症的药物中的用途。
本发明的其他方面在于式(I)化合物或其药学上可接受的盐用于制备用于治疗Bcr-Abl介导的疾病或Bcr-Abl介导的病况的药物的用途。
在另一个实施方案中,本发明提供了一种治疗患有由Bcr-Abl活性介导的病症的哺乳动物的方法,所述方法包括:向所述哺乳动物给予有效量的式(I)的化合物或其药学上可接受的盐、溶剂合物或生理学上的功能性衍生物。
本发明化合物的有效量通常在平均日剂量为0.01mg至50mg化合物/千克患者体重,优选0.1mg至25mg化合物/千克患者体重,以单次或多次给药。通常,本发明化合物可向该有此治疗需要的患者以每位患者约1mg至约3500mg的日剂量范围给药,优选10mg至1000mg。例如,每位患者的日剂量可为10、20、30、40、50、60、70、80、90、100、150、200、250、300、350、400、500、600、700、800、900或1000mg。可每天、每周(或间隔数天)或以间歇时间表,给药一次或多次。例如,可在每周的基础上(例如每周一),每天给予所述化合物一次或多次,不定地或持续几周,例如4-10周。或者,可每天给药持续几天(例如2-10天),然后几天(例如1-30天)不给药所述化合物,不定地重复该循环或重复给定的次数,例如4-10个循环。例如,本发明化合物可每天给药持续5天,然后间断9天,然后再每天给药持续5天,然后间断9天,以此类推,不定地重复该循环或共重复4-10次。
组合治疗
本发明的化合物、其盐和溶剂合物和其生理学上的功能性衍生物可以单独使用或与用于治疗与多种蛋白激酶介导的疾病和病况的其他治疗剂组合使用。根据本发明的组合治疗因此包括给予至少一种式(I)化合物或其药学上可接受的盐或溶剂合物或其生理学上的功能性衍生物和使用至少一种其他的药学活性剂。一种或多种式(I)化合物和一种或多种其他药学活性剂可以一起给药或分开给药,当分开给药时,可以同时进行或以任何顺序相继进行。将选择一种或多种式(I)化合物和一种或多种其他药学活性剂的量和相对给药时机以实现期望的组合治疗效果。
对于癌症治疗,式(I)化合物可以与一种或多种抗癌剂组合。这样的药剂的实例可以在Cancer Principles and Practice of Oncology by V.T.Devita and S.Hellman(编),第6版(2001年2月15日),Lippincott Williams&Wilkins Publishers中找到。领域普通技术人员将能够识别哪种药剂组合可以基于药物和所涉及的癌症的特定特征而使用。这样的抗癌剂包括但不限于:(1)雌激素受体调节剂如 diethyltibestral,三苯氧胺,雷洛昔芬,艾多昔芬,LY353381,LY117081,托瑞米芬,氟甲睾酮,和SH646;(2)其他激素药剂包括芳香化酶抑制剂(例如氨鲁米特,四唑阿那曲唑,来曲唑和依西美坦),促黄体激素释放激素(LHRH)类似物,酮康唑,醋酸戈舍瑞林,亮丙瑞林,醋酸甲地孕酮和米非司酮;(3)雄激素受体调节素如非那雄胺和其他5α-还原酶抑制剂,尼鲁米特,氟他米特,比卡鲁胺,利阿唑,和乙酸阿比特龙;(4)类维生素A受体调节剂如贝沙罗汀,维甲酸,13-顺式-视黄酸,9-顺式-视黄酸,α-二氟甲基鸟氨酸,ILX23-7553,反式-N-(4’-羟基苯基)维甲酚酰胺,和N-4-羧基苯基维甲酚酰胺;(5)抗增殖剂如反义RNA和DNA寡核苷酸如G3139,ODN698,RVASKRAS,GEM231,和INX3001,和抗代谢物如依诺他滨,卡莫氟,喃氟啶,喷司他丁,去氧氟尿苷,三甲曲沙,氟达拉滨,卡培他滨,加洛他滨,阿糖胞苷烷磷酯,fosteabine钠水合物,雷替曲塞,paltitrexid,乙嘧替氟,噻唑羧胺核苷(tiazofurin),地西他滨,洛拉曲塞,培美曲塞,奈拉滨,2’-去氧-2’-甲叉基胞啶,2’-氟亚甲基-2’-去氧胞啶,N6-[4-去氧-4-[N2-[2(E),4(E)-十四碳二烯酰基]甘氨酰基氨基]-L-丙三氧基-B-L-甘露糖-吡喃庚糖基]腺嘌呤,aplidine,海鞘素,曲沙他滨,氨蝶呤,5-氟尿嘧啶,氟脲苷,甲氨蝶呤,亚叶酸,羟基脲,硫鸟嘌呤(6-TG),巯嘌呤(6-MP),阿糖胞苷,喷司他丁,磷酸氟达拉滨,克拉屈滨(2-CDA),天冬酰胺酶,吉西他滨,阿拉诺新,苦马豆素,洛美曲索,右丙亚胺,methioninase,和3-氨基吡啶-2-甲醛氨苯硫脲;(6)异戊二烯基-蛋白转移酶抑制剂包括法呢基-蛋白转移酶(FPTase),香叶酰香叶酰-蛋白转移酶I型(GGPTase-I),和香叶酰香叶酰-蛋白转移酶-II型(GGPTase-II,也称为Rab GGPTase);(7)HMG-CoA还原酶抑制剂如洛伐他汀,辛伐他汀,普伐他汀,阿托伐他汀,氟伐他汀和罗苏伐他汀;(8)血管生成抑制剂如酪氨酸激酶受体Flt-1(VEGFR1)和Flk-1/KDR(VEGFR2)抑制剂,表皮-衍生的、纤维原细胞-衍生的或血小板衍生的生长因子的抑制剂,MMP(基质金属蛋白酶)抑制剂,整合蛋白阻滞剂,干扰素-α,白介素-12,红细胞生成素(红细胞生成素-α),粒细胞-CSF(非尔司亭),粒细胞,巨噬细胞-CSF(沙格司亭),戊聚糖多硫酸酯,环氧酶抑制剂,甾族抗炎剂,羧基酰胺基三唑,康普立停A-4,角鲨胺,6-O-氯乙酰基-羰基)-烟霉醇,萨力多胺,血管抑素,肌钙蛋白-1,血管紧缩素II拮抗剂,肝素,羧肽酶U抑制剂,和对如下物质的抗体:VEGF,内皮抑素,ukrain,豹蛙酶,IM862,乙酰地那林(acetyldinanaline),5-氨基-1-[[3,5-二氯-4-(4-氯苯甲酰基)苯基]甲基]-1H-1,2,3-三唑-4-甲酰胺,CM101,角鲨胺,康普立停,RPI4610,NX31838,硫酸化磷酸甘露五糖,和3-[(2,4-二甲基吡咯-5-基)亚甲基]-2-吲哚啉酮(SU5416);(9)PPAR-γ激动剂,PPAR-δ激动剂,噻唑烷二酮(如DRF2725,CS-011,曲格列酮,罗格列酮,和吡格列酮),非诺贝特,二甲苯氧庚酸,安妥明,GW2570,SB219994,AR-H039242,JTT-501,MCC-555,GW2331,GW409544,NN2344,KRP297,NP0110,DRF4158,NN622,GI262570,PNU182716,DRF552926,2-[(5,7-二丙基-3-三氟甲基-1,2-苯并异噁唑-6-基)氧基]-2-甲基丙酸(在USSN 09/782,856中公开),和(2R)-7-(3-(2-氯-4-(4-氟苯氧基)苯氧基)丙氧基)-2-乙基色满-2-甲酸(在USSN60/235,708和60/244,697 中公开);(9)固有多药耐药抑制剂包括p-糖蛋白(P-gp)抑制剂,如LY335979,XR9576,OC144-093,R101922,VX853和PSC833(valspodar);(10)细胞增殖和存活信号传导抑制剂如EGFR抑制剂(例如吉非替尼、埃罗替尼、埃克替尼和奥西替尼(AZD9291)),ERB-2抑制剂(例如曲妥单抗),IGF1R抑制剂如MK-0646(dalotuzumab),CD20抑制剂(利妥昔单抗),细胞因子受体抑制剂,MET抑制剂,PI3K家族激酶抑制剂(例如LY294002),丝氨酸/苏氨酸激酶(包括但不限于Akt抑制剂如在(WO 03/086404,WO 03/086403,WO 03/086394,WO 03/086279,WO 02/083675,WO 02/083139,WO 02/083140和WO 02/083138)中描述,Raf激酶的抑制剂(例如BAY-43-9006),MEK抑制剂(例如CI-1040和PD-098059)和mTOR抑制剂(例如Wyeth CCI-779和Ariad AP23573);(11)双膦酸盐如依替膦酸盐,帕米膦酸盐,阿仑膦酸盐,利塞膦酸盐,唑来膦酸盐,伊班膦酸盐,因卡膦酸盐或英卡膦酸盐(cimadronate),氯膦酸盐,EB-1053,米诺膦酸盐,奈力膦酸盐,吡利膦酸盐(piridronate)和替鲁膦酸盐;(12)γ-分泌酶抑制剂,(13)干扰受体酪氨酸激酶(RTK)的药剂,包括c-Kit,Eph,PDGF,Flt3和c-Met的抑制剂;(14)干扰细胞周期检验点的药剂包括ATR,ATM,Chk1和Chk2激酶和CDK的抑制剂和CDC激酶抑制剂和尤其例如7-羟基星形孢菌素(7-hydroxystaurosporin),夫拉平度,CYC202(Cyclacel)和BMS-387032;(15)BCR-ABL抑制剂如PCI32765,AVL-292和AVL-101;(16)PARP抑制剂包括iniparib,奥拉帕尼,AGO14699,ABT888和MK4827;(16)ERK抑制剂;(17)mTOR抑制剂如雷帕霉素,42-(二甲基亚膦酰)雷帕霉素,替西罗莫司,依维莫司;(18)细胞毒性/细胞抑制剂。
“细胞毒性/细胞抑制剂”是指主要通过直接干扰细胞功能化导致细胞死亡或抑制细胞增殖或抑制或干扰细胞有丝分裂的化合物,包括烷基化剂,肿瘤坏死因子、嵌入剂、低氧可活化化合物、微管抑制剂/微管稳定化剂、有丝分裂驱动蛋白的抑制剂、组蛋白脱乙酰酶的抑制剂、参与有丝分裂进程的激酶的抑制剂、抗代谢物、生物反应调节剂、激素/抗激素治疗剂、造血生长因子、单克隆抗体靶向的治疗剂、拓扑异构酶抑制剂、蛋白酶体抑制剂。
细胞毒性剂的实例包括但不限于sertenef,恶病质素,瘤可宁,环磷酰胺,异环磷酰胺,氮芥,美法仑,尿嘧啶芥,噻替哌,白消安,卡莫司汀,环己亚硝脲,链脲菌素,他索纳明,氯尼达明,卡铂,六甲蜜胺,达卡巴嗪,甲基苄肼,泼尼氮芥,二溴卫矛醇,雷莫司汀,福莫司汀,奈达铂,奥沙利铂,替莫唑胺,庚铂(heptaplatin),雌氮芥,甲磺丙胺,曲洛磷胺,尼莫司汀,二溴螺氯胺,嘌嘧替派,洛铂,赛特铂,紫菜霉素,顺铂,伊洛福芬,右异环磷酰胺(dexifosfamide),顺式-胺二氯(2-甲基-吡啶)铂,苄基鸟嘌呤,葡磷酰胺,GPX100,(反式,反式,反式)-双-mu-(己烷-1,6-二胺)-mu-[二胺-铂(II)]双[二胺(氯)铂(II)]四氯化物,二吖丙啶基精胺(diarizidinylspermine),三氧化二砷,1-(11-十二烷基氨基-10-羟基十一烷基)-3,7-二甲基黄嘌呤,佐柔比星,阿霉素,道诺霉素,伊达比星,蒽醌,争光霉素,丝裂霉素C,更生霉素,plicatomycin,比生群,米托蒽醌,吡柔比星,吡萘菲特, 戊柔比星,氨柔比星,抗瘤酮,3’-去氨基-3’-吗啉代-13-去氧-10-羟基洋红霉素,卡那霉素,加柔比星(galarubicin),依利奈法德,MEN10755,和4-去甲氧基-3-去氨基-3-氮杂环丙烷基-4-甲基磺酰基-道诺霉素。
蛋白酶体抑制剂的实例包括但不限于乳胞素和硼替佐米。
微管抑制剂/微管稳定化剂的实例包括长春新碱、长春花碱、长春地辛、长春利定、长春瑞滨、硫酸长春地辛、3’,4’-二去氢-4’-去氧-8’-去甲长春碱二酒石酸盐,足叶草毒素(例如依托泊苷(VP-16)和替尼泊苷(VM-26)),紫杉醇,多西紫杉醇,根霉素,尾海兔素,mivobulin isethionate,auristatin,西马多丁,RPR109881,BMS184476,长春氟宁,cryptophycin,脱水长春碱,N,N-二甲基-L-缬氨酰-L-缬氨酰-N-甲基-L-缬氨酰-L-脯氨酰-L-脯氨酸-叔丁基酰胺,TDX258,埃博霉素(参见例如美国专利No.6,284,781和6,288,237)和BMS188797。
拓扑异构酶抑制剂的一些实例为拓扑替康,hycaptamine,伊立替康,鲁比替康,6-乙氧基丙酰基-3’,4’-O-外-苄叉基-教酒菌素,勒托替康,7-[2-(N-异丙基氨基)乙基]-(20S)喜树碱,BNP1350,BNPI1100,BN80915,BN80942,磷酸依托泊苷,替尼泊苷,索布佐生,2’-二甲基氨基-2’-去氧-依托泊苷,GL331,N-[2-(二甲基氨基)乙基]-9-羟基-5,6-二甲基-6H-吡啶并[4,3-b]咔唑-1-甲酰胺,asulacrine,2,3-(亚甲基二氧基)-5-甲基-7-羟基-8-甲氧基苯并[c]-菲啶鎓,5-(3-氨基丙基氨基)-7,10-二羟基-2-(2-羟基乙基氨基甲基)-6H-吡唑并[4,5,1-de]吖啶-6-酮,N-[1-[2-(二乙基氨基)乙基氨基]-7-甲氧基-9-氧代-9H-硫代黄嘌呤-4-基甲基]甲酰胺,N-(2-(二甲基氨基)乙基)吖啶-4-甲酰胺,6-[[2-(二甲基氨基)乙基]氨基]-3-羟基-7H-茚并[2,1-c]喹啉-7-酮,和地美司钠。
组蛋白脱乙酰酶抑制剂”的实例包括但不限于伏立诺他,曲古抑菌素A,oxamflatin,PXD101,MG98,丙戊酸和scriptaid。
“参与有丝分裂进程的激酶的抑制剂”包括但不限于极光激酶抑制剂、Polo样激酶抑制剂(PLK;特别是PLK-1的抑制剂),bub-1抑制剂和bub-R1抑制剂。“极光激酶抑制剂”的实例为VX-680。
“抗增殖剂包括反义RNA和DNA寡核苷酸如G3139,ODN698,RVASKRAS,GEM231和INX3001,和抗代谢物如依诺他滨,卡莫氟,喃氟啶,喷司他丁,去氧氟尿苷,三甲曲沙,氟达拉滨,卡培他滨,加洛他滨,阿糖胞苷烷磷酯,fosteabine钠水合物,雷替曲塞,paltitrexid,乙嘧替氟,噻唑羧胺核苷,地西他宾,洛拉曲塞,培美曲塞,奈拉滨,2’-去氧-2’-甲叉基胞啶,2’-氟亚甲基-2’-去氧胞啶,N6-[4-去氧-4-[N2-[2,4-十四碳二烯酰基]甘氨酰基氨基]-L-丙三氧基-B-L-甘露糖-吡喃庚糖基]腺嘌呤,aplidine,海鞘素,曲沙他滨,氨蝶呤,5-氟尿嘧啶,氟脲苷,甲氨蝶呤,亚叶酸,羟基脲,硫鸟嘌呤(6-TG),巯嘌呤(6-MP),阿糖胞苷,喷司他丁,磷酸氟达拉滨,克拉屈滨(2-CDA),天冬酰胺酶,吉西他滨,阿拉诺新,苦马豆素,洛美曲索,右丙亚胺,methioninase,和3-氨基吡啶-2-甲醛氨苯硫脲。
在癌症治疗中使用的与式(I)化合物组合的合适的药剂的非限定性实例包括但不限于:阿巴瑞克;阿地白介素;阿仑单抗;阿利维A酸;别嘌呤醇;六甲蜜胺;氨磷汀;阿那曲唑;三氧化二砷;天冬酰胺酶;阿扎胞苷;苯达莫司汀;贝伐单抗;贝沙罗汀;争光霉素;硼替佐米;白消安;卡普睾酮;卡培他滨;卡铂;卡莫司汀;西妥昔单抗;瘤可宁;顺铂;克拉屈滨;氯法拉滨;环磷酰胺;阿糖腺苷;达卡巴嗪;更生霉素,放线菌素D;达肝素钠;促红细胞生成素;达沙替尼;道诺霉素;地加瑞克;地尼白介素;右丙亚胺;多西他赛;阿霉素;曲他雄酮丙酸酯;依库丽单抗;Elliott's B溶液;伊曲泼帕;表柔比星;重组人促红细胞生成素;埃罗替尼;雌氮芥;磷酸依托泊苷;依托泊苷;依维莫司;依西美坦;菲格司亭;氟脲苷;氟达拉滨;氟尿嘧啶;氟维司群;易瑞沙;特罗凯;奥西罗;吉西他滨;吉妥单抗;醋酸戈舍瑞林;醋酸组胺瑞林;羟基脲;替依莫单抗;伊达比星;异环磷酰胺;甲磺酸伊马替尼;干扰素α-2a;干扰素α-2b;伊立替康;伊莎匹隆;拉帕替尼;雷利度胺;来曲唑;亚叶酸;醋酸亮丙瑞林;左旋咪唑;洛莫司汀;meclorethamine,氮芥;醋酸甲地孕酮;美法仑,L-PAM;巯嘌呤;美司钠;甲氨蝶呤;甲氧沙林;丝裂霉素C;米托坦;米托蒽醌;苯丙酸诺龙;奈拉滨;尼罗替尼;诺莫单抗(Nofetumomab);奥法木单抗(ofatumumab);奥普瑞白介素;奥沙利铂;紫杉醇;帕利夫明;帕米膦酸二钠;帕尼单抗(panitumumab);帕唑帕尼;培加酶;培门冬酶;培非格司亭Pegfilgrastim);培美曲塞二钠;喷司他丁;哌泊溴烷;普乐沙福;普卡霉素,光神霉素);卟菲尔钠;普拉曲沙;甲基苄肼;奎纳克林;拉布立酶;盐酸雷洛昔芬;利妥昔单抗;罗咪酯肽;罗米司亭;沙格司亭;沙格司亭;赛特铂;索拉非尼;链脲菌素;马来酸舒尼替尼;三苯氧胺;替莫唑胺;替西罗莫司;替尼泊苷;睾内酯;硫鸟嘌呤;噻替哌;拓扑替康;托瑞米芬;托西莫单抗;曲妥珠单抗;维甲酸;尿嘧啶芥;戊柔比星;长春花碱;长春新碱;长春瑞滨;伏立诺他;和唑来膦酸。
对于本领域技术人员清楚的是,在适当时,所述其他一种或多种治疗成分可以以盐,例如碱金属盐或胺盐或酸加成、或前药、或酯例如低级烷基酯、或溶剂合物例如水合物的形式使用,以优化治疗成分的活性和/或稳定性和/或物理特性如溶解性。还清楚的是,在适当时,所述治疗成分可以以光学纯形式使用。
上述组合可以合宜地以药物组合物形式使用,因此包含上述组合以及药学上可接受的稀释剂或载体的药物组合物代表本发明的另一方面。这些组合特别可用于呼吸系统疾病,并合宜地适用于吸入或鼻内递送。
这种组合的各化合物可以以分开的或者组合的药物组合物的形式相继或同时给药。优选地,各化合物以组合的药物组合物的形式同时给药。本领域技术人员容易了解已知治疗剂的合适剂量。
实施例
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制 本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则份数和百分比为重量份和重量百分比。
通常,在制备流程中,各反应在惰性溶剂中,在室温至回流温度(如0℃~100℃,优选0℃~80℃)下进行。反应时间通常为0.1-60小时,优选地为0.5-24小时。
本文所用的缩写具有以下含义:
APCI | 大气压力化学游离法 |
HAC | 冰乙酸 |
POCl 3 | 三氯氧磷 |
Raney-Ni | 雷尼镍 |
TEA | 三乙胺 |
DCM | 二氯甲烷 |
NBS | N-溴代琥珀酰亚胺 |
DMF | N,N-二甲基甲酰胺 |
ACN | 乙腈 |
DIEA | N,N-二异丙基乙胺 |
THF | 四氢呋喃 |
NIS | N-碘代琥珀酰亚胺 |
实施例1 3-((8-氨基-3-乙基咪唑并[1,5-a]吡嗪-1-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲
基)-3-(三氟甲基)苯基)苯甲酰胺(化合物I-1)的制备。
采用以下路线进行合成:
步骤1化合物(3-氯吡嗪-2-基)甲胺的合成
氮气保护下将2-氰基-3-氯吡嗪(1.5g,10.8mmol)和Raney-Ni(50%slurry in water,0.5g)加入到15mL冰乙酸中,氢气置换三次,在3个大气压的氢气氛下于50℃搅拌过夜。反应完全后过滤,滤液浓缩,残留物溶于乙酸乙酯,用饱和碳酸氢钠溶液洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色油状物0.82g,收率53%。LC-MS(APCI):m/z=144(M+1)
+。
步骤2化合物N-((3-氯吡嗪-2-基)甲基)丙酰胺的合成
将(3-氯吡嗪-2-基)甲胺(0.82g,5.7mmol)和三乙胺(0.86g,8.5mmol)溶于10mL二氯甲烷,冰浴下缓慢滴加丙酰氯(0.63g,6.8mmol),滴加完毕撤去冰浴,室温搅拌过夜,TLC检测反应完全,反应液分别用1N盐酸,5%NaHCO
3溶液和饱和食盐水洗涤。有机相用无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色油状物0.7g,收率62%。LC-MS(APCI):m/z=200(M+1)
+。
步骤3化合物8-氯-3-乙基咪唑并[1,5-a]吡嗪的合成
将N-((3-氯吡嗪-2-基)甲基)丙酰胺(0.7g,3.5mmol)溶于15mL无水乙腈,加入三氯氧磷(2.1g,14mmol),升温至60℃反应过夜。反应完全后蒸除溶剂,残留物缓慢加入冰水中,用乙酸乙酯(10mL*3)萃取,有机相分别用饱和碳酸氢钠溶液和饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体0.51g,收率80%。LC-MS(APCI):m/z=182(M+1)
+。
步骤4化合物1-溴-8-氯-3-乙基咪唑并[1,5-a]吡嗪的合成
将8-氯-3-乙基咪唑并[1,5-a]吡嗪(0.51g,2.8mmol)溶于10mL DMF中,冰浴下分批加入NBS(0.55g,3.1mmol),自然升至室温反应过夜。反应完全后,向反应液中加入20mL水,用乙酸乙酯(10mL*3)萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体0.51g,收率70%。LC-MS(APCI):m/z=260(M+1)
+。
步骤5化合物1-溴-3-乙基咪唑并[1,5-a]吡嗪-8-胺的合成
向50mL封管中加入1-溴-8-氯-3-乙基咪唑并[1,5-a]吡嗪(0.51g,2.0mmol)和10mL浓氨水,油浴升温至120℃反应过夜。反应完全后冷却至室温,旋蒸蒸除溶剂,得白色粉末状固体0.4g,收 率84%。LC-MS(APCI):m/z=241(M+1)
+。
步骤6化合物3-乙基-1-((三甲基硅基)乙炔基)咪唑并[1,5-a]吡嗪-8-胺的合成
将1-溴-3-乙基咪唑并[1,5-a]吡嗪-8-胺(170mg,0.71mmol),三甲基硅基乙炔(90mg,0.92mmol),Pd(PPh
3)
4(23mg,0.02mmol),CuI(8mg,0.04mmol)和0.24mL N,N-二异丙基乙胺加入到5mL DMF中,氮气置换三次,升温到90℃,反应3小时。反应完全后冷却至室温,加入15mL水,用乙酸乙酯(15mL*3)萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体120mg,收率66%。LC-MS(APCI):m/z=259(M+1)
+。
步骤7化合物3-乙基-1-乙炔基咪唑并[1,5-a]吡嗪-8-胺的合成
将3-乙基-1-((三甲基硅基)乙炔基)咪唑并[1,5-a]吡嗪-8-胺(120mg,0.47mmol)溶于5mL四氢呋喃,加入四丁基氟化铵(0.25g,0.94mmol),于室温下搅拌1小时。旋蒸蒸除溶剂,加入10mL水,用乙酸乙酯(10mL*3)萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体75mg,收率88%。LC-MS(APCI):m/z=187(M+1)
+。
步骤8化合物3-((8-氨基-3-乙基咪唑并[1,5-a]吡嗪-1-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺的合成
将3-碘-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(160mg,0.31mmol),3-乙基-1-乙炔基咪唑并[1,5-a]吡嗪-8-胺(75mg,0.4mmol),Pd(PPh
3)
4(11mg,0.01mmol),CuI(4mg,0.02mmol)和0.12mL N,N-二异丙基乙胺加入到3mL DMF中,氮气置换三次,升温到90℃,反应3小时。反应完全后冷却至室温,加入10mL水,用乙酸乙酯(10mL*3)萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体110mg,收率62%。LC-MS(APCI):m/z=576(M+1)
+。
1H NMR(400MHz,DMSO-d
6)δ10.57(s,1H),8.23(d,J=2.1Hz,2H),8.11–8.05(m,1H),7.92(dd,J=8.0,2.0Hz,1H),7.71(d,J=8.5Hz,1H),7.60(d,J=4.9Hz,1H),7.52(d,J=8.1Hz,1H),7.11(d,J=4.9Hz,1H),6.77–6.62(m,2H),3.59(s,2H),2.93(q,J=7.5Hz,2H),2.55(s,3H),2.49-2.40(m,8H),2.33(s,3H),1.30(t,J=7.5Hz,3H).
实施例2 3-((8-氨基-3-乙基咪唑并[1,5-a]吡嗪-1-基)乙炔基)-4-甲基-N-(3-(三氟甲基)苯基)苯甲酰胺
(化合物I-2)的制备。
根据实施例1中所述的合成方法,用化合物3-碘-4-甲基-N-(3-(三氟甲基)苯基)苯甲酰胺替代步骤 8中的3-碘-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺来进行制备,得到标题化合物I-2。LC-MS(APCI):m/z=464(M+1)
+。
1H NMR(400MHz,DMSO-d
6)δ10.60(s,1H),8.29–8.21(m,2H),8.08(d,J=7.9Hz,1H),7.92(dd,J=8.0,2.0Hz,1H),7.65–7.57(m,2H),7.53(d,J=8.1Hz,1H),7.47(d,J=7.5Hz,1H),7.11(d,J=5.0Hz,1H),6.71(s,2H),2.93(q,J=7.5Hz,2H),2.55(s,3H),1.31(t,J=7.5Hz,3H).
实施例3 3-((8-氨基-3-甲基咪唑并[1,5-a]吡嗪-1-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲
基)-3-(三氟甲基)苯基)苯甲酰胺(化合物I-3)的制备。
根据实施例1中所述的合成方法,用化合物乙酰氯替代步骤2中化合物丙酰氯来进行制备,得到标题化合物I-3。LC-MS(APCI):m/z=562(M+1)
+。
1H NMR(400MHz,DMSO-d
6)δ10.57(s,1H),8.22(dd,J=6.4,2.0Hz,2H),8.08(dd,J=8.6,2.1Hz,1H),7.92(dd,J=7.9,1.9Hz,1H),7.71(d,J=8.6Hz,1H),7.54(dd,J=15.7,6.3Hz,2H),7.16(d,J=26.6Hz,1H),6.69(s,2H),3.60(s,2H),2.55(d,J=3.5Hz,6H),2.50-2.42(m,8H),2.38(s,3H).
实施例4 3-((8-氨基-3-异丙基咪唑并[1,5-a]吡嗪-1-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲
基)-3-(三氟甲基)苯基)苯甲酰胺(化合物I-4)的制备。
根据实施例1中所述的合成方法,用化合物异丁基酰氯替代步骤2中化合物丙酰氯来进行制备,得到标题化合物I-4。LC-MS(APCI):m/z=590(M+1)
+。
1H NMR(400MHz,DMSO-d
6)δ10.56(s,1H),8.23(dd,J=5.6,2.0Hz,2H),8.08(dd,J=8.5,2.2Hz,1H),7.92(dd,J=8.0,2.0Hz,1H),7.71(d,J=8.6Hz,1H),7.66(d,J=5.0Hz,1H),7.52(d,J=8.1Hz,1H),7.10(d,J=5.0Hz,1H),6.70(s,2H),3.60(s,2H), 3.47-3.41(m,1H),2.55(s,3H),2.50-2.41(m,8H),2.37(d,J=5.0Hz,3H),1.31(d,J=6.8Hz,6H).
实施例5 3-((4-氨基-7-乙基-7H-吡咯并[2,3-d]嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)
甲基)-3-(三氟甲基)苯基)苯甲酰胺(化合物I-5)的制备。
采用以下路线进行合成:
步骤1化合物5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺的合成
将7H-吡咯并[2,3-d]嘧啶-4-胺(0.4g,3.0mmol)溶于10mL DMF中,冰浴下分批加入NIS(0.74g,3.3mmol),加料完毕撤去冰浴,于室温下反应3小时,TLC检测反应至完全。向反应液中加入20mL水,用乙酸乙酯(30mL*3)萃取,有机相用20mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体0.56g,收率73%。LC-MS(APCI):m/z=261(M+1)
+。
步骤2化合物7-乙基-5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺的合成
将5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺(0.56g,2.2mmol)和碳酸钾(0.61g,4.4mmol)溶于10mL DMF中,冰浴下缓慢滴加碘乙烷(0.37g,2.4mmol),滴加完毕后继续搅拌30分钟,撤去冰浴,室温下反应2小时。TLC检测反应完全,向反应液中加入20mL水,用乙酸乙酯(30mL*3)萃取,有机相用20mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体0.5g,收率80%。LC-MS(APCI):m/z=289(M+1)
+。
步骤3化合物7-乙基-5-((三甲基硅基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-4-胺的合成
将7-乙基-5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺(190mg,0.66mmol),三甲基硅基乙炔(84mg,0.86mmol),Pd(PPh
3)
4(23mg,0.02mmol),CuI(8mg,0.04mmol)和0.24mL N,N-二异丙基乙胺加入到5mL DMF中,氮气置换三次,升温到90℃,反应3小时。反应完全后冷却至室温,加入15mL水,用乙酸乙酯(15mL*3)萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体120mg,收率70%。LC-MS(APCI):m/z=259(M+1)
+。
步骤4化合物7-乙基-5-乙炔基-7H-吡咯并[2,3-d]嘧啶-4-胺的合成
将7-乙基-5-((三甲基硅基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-4-胺(120mg,0.47mmol)溶于5mL四氢呋喃,加入四丁基氟化铵(0.25g,0.94mmol),于室温下搅拌1小时。旋蒸蒸除溶剂,加入10mL水,用乙酸乙酯(10mL*3)萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体75mg,收率88%。LC-MS(APCI):m/z=187(M+1)
+。
步骤5化合物3-((4-氨基-7-乙基-7H吡咯并[2,3-d]嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺的合成
将3-碘-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(160mg,0.31mmol)和7-乙基-5-乙炔基-7H-吡咯并[2,3-d]嘧啶-4-胺(75mg,0.4mmol),Pd(PPh
3)
4(11mg,0.01mmol),CuI(4mg,0.02mmol)和0.12mL N,N-二异丙基乙胺加入到3mL DMF中,氮气置换三次,升温到90℃,反应3小时。反应完全后冷却至室温,加入10mL水,用乙酸乙酯(10mL*3)萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体115mg,收率66%。LC-MS(APCI):m/z=576(M+1)
+。
1H NMR(400MHz,DMSO-d
6)δ10.55(s,1H),8.22(d,J=2.2Hz,1H),8.17(d,J=1.8Hz,2H),8.07(d,J=8.6Hz,1H),7.88(dd,J=7.9,1.9Hz,1H),7.79(s,1H),7.71(d,J=8.6Hz,1H),7.50(d,J=8.0Hz,1H),6.67(s,2H),4.19(q,J=7.3Hz,2H),3.58(s,2H),2.54(s,3H),2.49-2.36(m,8H),2.27(s,3H),1.37(t,J=7.2Hz,3H).
实施例6 3-((4-氨基-7-乙基-7H-吡咯并[2,3-d]嘧啶-5-基)乙炔基)-4-甲基-N-(3-(三氟甲基)苯基)苯
甲酰胺(化合物I-6)的制备。
根据实施例5中所述的合成方法,用化合物3-碘-4-甲基-N-(3-(三氟甲基)苯基)苯甲酰胺替代步骤 5中的3-碘-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺来进行制备,得到标题化合物I-6。LC-MS(APCI):m/z=464(M+1)
+。
1H NMR(400MHz,DMSO-d
6)δ10.58(s,1H),8.26(s,1H),8.20–8.14(m,2H),8.08(d,J=8.0Hz,1H),7.89(dd,J=8.0,2.0Hz,1H),7.79(s,1H),7.61(t,J=8.0Hz,1H),7.48(dd,J=16.7,7.9Hz,2H),6.68(s,2H),4.19(q,J=7.3Hz,2H),2.54(s,3H),1.37(t,J=7.2Hz,3H).
实施例7 3-((4-氨基-7-乙基-7H-吡咯并[2,3-d]嘧啶-5-基)乙炔基)-4-甲基-N-(3-(三氟甲基)吡啶-2-
基)苯甲酰胺(化合物I-7)的制备。
根据实施例5中所述的合成方法,用化合物3-碘-4-甲基-N-(3-(三氟甲基)吡啶-2-基)苯甲酰胺替代步骤5中的3-碘-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺来进行制备,得到标题化合物I-7。LC-MS(APCI):m/z=465(M+1)
+。
1H NMR(400MHz,DMSO-d
6)δ11.24(s,1H),8.46(d,J=8.5Hz,1H),8.26(d,J=1.9Hz,1H),8.19–8.10(m,2H),7.94(dd,J=8.0,1.9Hz,1H),7.79(s,1H),7.66(d,J=7.5Hz,1H),7.46(d,J=8.1Hz,1H),6.67(s,2H),4.19(q,J=7.3Hz,2H),2.53(s,3H),1.37(t,J=7.2Hz,3H).
实施例8 3-((4-氨基-7-乙基-7H-吡咯并[2,3-d]嘧啶-5-基)乙炔基)-N-(3-(三氟甲基)苯基)苯甲酰胺
(化合物I-8)的制备。
根据实施例5中所述的合成方法,用化合物3-碘-N-(3-(三氟甲基)苯基)苯甲酰胺替代步骤5中的3-碘-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺来进行制备,得到标题化合物I-8。LC-MS(APCI):m/z=450(M+1)
+。
1H NMR(400MHz,DMSO-d
6)δ10.55(s,1H),8.25(s,1H),8.21– 8.16(m,2H),8.10(d,J=8.0Hz,1H),7.86(dd,J=8.0,2.0Hz,1H),7.77(s,1H),7.61(d,J=8.0Hz,2H),7.46(dd,J=16.7,7.9Hz,2H),6.66(s,2H),4.21(q,J=7.3Hz,2H),1.35(t,J=7.2Hz,3H).
实施例9 3-((4-氨基-7-乙基-7H-吡咯并[2,3-d]嘧啶-5-基)乙炔基)-N-(4-((二甲基氨基)甲基)-3-(三氟
甲基)苯基)-4-甲基苯甲酰胺(化合物I-9)的制备。
根据实施例5中所述的合成方法,用化合物N-(4-((二甲基氨基)甲基)-3-(三氟甲基)苯基)-3-碘-4-甲基苯甲酰胺替代步骤5中的3-碘-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺来进行制备,得到标题化合物I-9。LC-MS(APCI):m/z=521(M+1)
+。
1H NMR(400MHz,DMSO-d
6)δ10.54(s,1H),8.24–8.14(m,3H),8.08(d,J=8.5Hz,1H),7.88(d,J=8.0Hz,1H),7.79(s,1H),7.71(d,J=8.7Hz,1H),7.50(d,J=8.1Hz,1H),6.67(s,2H),4.19(q,J=7.5Hz,2H),3.51(s,2H),2.54(s,3H),2.19(s,6H),1.37(t,J=7.2Hz,3H).
实施例10 3-((4-氨基-7-乙基-7H-吡咯并[2,3-d]嘧啶-5-基)乙炔基)-4-甲基-N-(3-(4-甲基-1H-咪唑
-1-基)-5-(三氟甲基)苯基)苯甲酰胺(化合物I-10)的制备。
根据实施例5中所述的合成方法,用化合物3-碘-4-甲基-N-(3-(4-甲基-1H-咪唑-1-基)-5-(三氟甲基)苯基)苯甲酰胺替代步骤5中的3-碘-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺来进行制备,得到标题化合物I-10。LC-MS(APCI):m/z=544(M+1)
+。
1H NMR(400MHz,DMSO-d
6)δ10.72(s,1H),8.30(s,1H),8.25(d,J=1.9Hz,1H),8.20–8.15(m,3H),7.90(dd,J=7.9,1.9Hz,1H),7.79(s,1H),7.74(s,1H),7.53(d,J=8.1Hz,2H),6.66(s,2H),4.19(q,J=7.2Hz,2H),2.55(s,3H),2.18(s,3H), 1.37(t,J=7.2Hz,3H).
实施例11 3-((4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)乙炔基)-4-甲基-N-(3-(4-甲基-1H-咪唑-1-
基)-5-(三氟甲基)苯基)苯甲酰胺(化合物I-11)的制备。
根据实施例5中所述的合成方法,用化合物碘甲烷替代步骤2中的碘乙烷,用化合物3-碘-4-甲基-N-(3-(4-甲基-1H-咪唑-1-基)-5-(三氟甲基)苯基)苯甲酰胺替代步骤5中的3-碘-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺来进行制备,得到标题化合物I-11。LC-MS(APCI):m/z=530(M+1)
+。
1H NMR(400MHz,DMSO-d
6)δ10.72(s,1H),8.31(s,1H),8.25–8.19(m,2H),8.17(d,J=2.7Hz,2H),7.91(dd,J=8.0,2.0Hz,1H),7.79(s,1H),7.74(s,1H),7.53(d,J=8.2Hz,2H),6.69(s,2H),3.74(s,3H),2.55(s,3H),2.19(s,3H).
实施例12 3-((4-氨基-7-异丙基-7H-吡咯并[2,3-d]嘧啶-5-基)乙炔基)-4-甲基-N-(3-(4-甲基-1H-咪唑
-1-基)-5-(三氟甲基)苯基)苯甲酰胺(化合物I-12)的制备。
根据实施例5中所述的合成方法,用化合物2-碘丙烷替代步骤2中的碘乙烷,用化合物3-碘-4-甲基-N-(3-(4-甲基-1H-咪唑-1-基)-5-(三氟甲基)苯基)苯甲酰胺替代步骤5中的3-碘-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺来进行制备,得到标题化合物I-12。LC-MS(APCI):m/z=558(M+1)
+。
1H NMR(400MHz,DMSO-d
6)δ10.73(s,1H),8.31(d,J=2.3Hz,1H),8.22(d,J=1.4Hz,1H),8.19(d,J=1.9Hz,1H),8.17(d,J=3.6Hz,2H),7.91(dd,J=8.1,2.0Hz,1H),7.88(s,1H),7.74(s,1H),7.53(d,J=8.1Hz,1H),7.51–7.48(m,1H),6.65(s,2H),4.93(p,J=6.9Hz, 1H),2.56(s,3H),2.19(s,3H),1.47(d,J=6.7Hz,6H).
实施例13 3-((4-氨基-7-异丙基-7H-吡咯并[2,3-d]嘧啶-5-基)乙炔基)-4-甲基-N-(3-(三氟甲基)苯基)
苯甲酰胺(化合物I-13)的制备。
根据实施例5中所述的合成方法,用化合物2-碘丙烷替代步骤2中的碘乙烷,用化合物3-碘-4-甲基-N-(3-(三氟甲基)苯基)苯甲酰胺替代步骤5中的3-碘-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺来进行制备,得到标题化合物I-13。LC-MS(APCI):m/z=478(M+1)
+。
1H NMR(400MHz,DMSO-d
6)δ10.58(s,1H),8.26(s,1H),8.20–8.13(m,2H),8.08(d,J=8.2Hz,1H),7.89(d,J=8.8Hz,2H),7.61(t,J=8.0Hz,1H),7.48(dd,J=17.4,7.9Hz,2H),6.65(s,2H),4.93(p,J=6.8Hz,1H),2.55(s,3H),1.46(d,J=6.8Hz,6H).
实施例14 3-((4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)乙炔基)-4-甲基-N-(3-(三氟甲基)苯基)苯
甲酰胺(化合物I-14)的制备。
根据实施例5中所述的合成方法,用化合物碘甲烷替代步骤2中的碘乙烷,用化合物3-碘-4-甲基-N-(3-(三氟甲基)苯基)苯甲酰胺替代步骤5中的3-碘-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺来进行制备,得到标题化合物I-14。LC-MS(APCI):m/z=450(M+1)
+。
1H NMR(400MHz,DMSO-d
6)δ10.58(s,1H),8.26(t,J=1.9Hz,1H),8.18(d,J=1.9Hz,1H),8.10–8.06(m,1H),7.89(dd,J=8.0,2.0Hz,1H),7.71(s,1H),7.61(t,J=8.0Hz,1H),7.52–7.44(m,2H),6.67(s,2H),3.73(s,3H),2.54(s,3H).
实施例15 3-((4-氨基-7-异丙基-7H-吡咯并[2,3-d]嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-
基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(化合物I-15)的制备。
根据实施例5中所述的合成方法,用化合物2-碘丙烷替代步骤2中的碘乙烷来进行制备,得到标题化合物I-15。LC-MS(APCI):m/z=590(M+1)
+。
1H NMR(400MHz,CDCl
3)δ8.32(s,1H),8.02–7.95(m,2H),7.89(d,J=9.0Hz,1H),7.86(s,1H),7.80–7.72(m,2H),7.38(d,J=8.1Hz,2H),6.65(s,2H),5.06(s,1H),3.65(s,2H),2.57(d,J=12.9Hz,11H),2.34(s,3H),1.53(d,J=6.8Hz,6H).
实施例16 3-((4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)
甲基)-3-(三氟甲基)苯基)苯甲酰胺(化合物I-16)的制备。
根据实施例5中所述的合成方法,用化合物碘甲烷替代步骤2中的碘乙烷来进行制备,得到标题化合物I-16。LC-MS(APCI):m/z=562(M+1)
+。
1H NMR(400MHz,DMSO-d
6)δ10.54(s,1H),8.22(d,J=2.1Hz,1H),8.17(d,J=2.0Hz,2H),8.07(dd,J=8.6,2.1Hz,1H),7.88(dd,J=7.9,1.9Hz,1H),7.73–7.68(m,2H),7.50(d,J=8.1Hz,1H),6.66(s,2H),3.74(s,3H),3.57(s,2H),2.54(s,3H),2.41(s,8H),2.21(s,3H).
实施例17 N-(3-((4-氨基-7-乙基-7H-吡咯并[2,3-d]嘧啶-5-基)乙炔基)-4-甲基苯基)-3-(三氟甲基)苯
甲酰胺(化合物I-17)的制备。
根据实施例5中所述的合成方法,用化合物N-(3-碘-4-甲基苯基)-3-(三氟甲基)苯甲酰胺替代步骤5中3-碘-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺来进行制备,得到标题化合物I-17。LC-MS(APCI):m/z=464(M+1)
+。
1H NMR(400MHz,DMSO-d
6)δ10.50(s,1H),8.31(s,1H),8.27(d,J=7.8Hz,1H),8.16(s,1H),8.00–7.95(m,2H),7.81(d,J=7.8Hz,1H),7.79–7.77(m,1H),7.68(dd,J=8.4,2.2Hz,1H),7.32(d,J=8.3Hz,1H),6.66(s,2H),4.18(q,J=7.2Hz,2H),2.44(s,3H),1.40–1.35(t,J=7.2Hz,3H).
实施例18 N-(3-((4-氨基-7-乙基-7H-吡咯并[2,3-d]嘧啶-5-基)乙炔基)-4-甲基苯基)-4-((4-甲基哌嗪
-1-基)甲基)-3-(三氟甲基)苯甲酰胺(化合物I-18)的制备。
根据实施例5中所述的合成方法,用化合物N-(3-碘-4-甲基苯基)-4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯甲酰胺替代步骤5中3-碘-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺来进行制备,得到标题化合物I-18。LC-MS(APCI):m/z=576(M+1)
+。
1H NMR(400MHz,DMSO-d
6)δ10.47(s,1H),8.26(d,J=1.7Hz,1H),8.24(dd,J=8.1,1.8Hz,1H),8.16(s,1H),7.96(d,J=2.3Hz,1H),7.93(d,J=8.1Hz,1H),7.78(s,1H),7.67(dd,J=8.3,2.3Hz,1H),7.31(d,J=8.5Hz,1H),6.65(s,2H),4.18(q,J=7.2Hz,2H),3.69(s,2H),2.44(s,11H),2.20(s,3H),1.37(t,J=7.2Hz,3H).
实施例19 N-(3-((4-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)乙炔基)-4-甲基苯基)-4-((4-甲基哌嗪
-1-基)甲基)-3-(三氟甲基)苯甲酰胺(化合物I-19)的制备。
根据实施例5中所述的合成方法,用化合物碘甲烷替代步骤2中碘乙烷,用化合物N-(3-碘-4-甲基苯基)-4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯甲酰胺替代步骤5中3-碘-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺来进行制备,得到标题化合物I-19。LC-MS(APCI):m/z=562(M+1)
+。
1H NMR(400MHz,DMSO-d
6)δ10.46(s,1H),8.30–8.21(m,2H),8.17(s,1H),7.99–7.88(m,2H),7.68(d,J=9.4Hz,2H),7.31(d,J=8.4Hz,1H),6.64(s,2H),3.71(d,J=10.1Hz,5H),2.44(s,3H),2.50–2.45(m,8H),2.28(s,3H).
实施例20 N-(3-((4-氨基-7-环戊基-7H-吡咯并[2,3-d]嘧啶-5-基)乙炔基)-4-甲基苯基)-4-甲基-3-(三
氟甲基)苯甲酰胺(化合物I-20)的制备。
根据实施例5中所述的合成方法,用化合物碘环戊烷替代步骤2中碘乙烷,用化合物N-(3-碘-4-甲基苯基)-4-甲基-3-(三氟甲基)苯甲酰胺替代步骤5中3-碘-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺来进行制备,得到标题化合物I-20。LC-MS(APCI):m/z=518(M+1)
+。
1H NMR(400MHz,DMSO-d
6)δ10.43(s,1H),8.26(s,1H),8.16(s,2H),7.98(d,J=2.2Hz,1H),7.83(s,1H),7.68–7.60(m,2H),7.31(d,J=8.4Hz,1H),6.66(s,2H),5.03(p,J=7.5Hz,1H),2.53(s,3H),2.44(s,3H),2.10(d,J=7.7Hz,2H),1.88(p,J=9.1,8.6Hz,4H),1.68(s,2H).
实施例21 N-(3-((4-氨基-7-乙基-7H-吡咯并[2,3-d]嘧啶-5-基)乙炔基)-4-甲基苯基)-3-(4-甲基-1H-咪
唑-1-基)-5-(三氟甲基)苯甲酰胺(化合物I-21)的制备。
根据实施例5中所述的合成方法,用化合物N-(3-碘-4-甲基苯基)-3-(4-甲基-1H-咪唑-1-基)-5-(三氟甲基)苯甲酰胺替代步骤5中3-碘-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺来进行制备,得到标题化合物I-21。LC-MS(APCI):m/z=544(M+1)
+。
1H NMR(400MHz,DMSO-d
6)δ10.73(s,1H),8.29(s,1H),8.24(d,J=1.9Hz,1H),8.20–8.15(m,3H),7.92(dd,J=7.9,1.9Hz,1H),7.78(s,1H),7.73(s,1H),7.51(d,J=8.1Hz,2H),6.67(s,2H),4.18(q,J=7.2Hz,2H),2.54(s,3H),2.18(s,3H),1.36(t,J=7.2Hz,3H).
实施例22 3-((4-氨基-7-((1r,4r)-4-羟基环己基)-7H-吡咯并[2,3-d]嘧啶-5-基)乙炔基)-4-甲基
-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(化合物I-22)的制备。
采用以下路线合成:
步骤1化合物4-(4-氨基-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)环己烷-1-酮的合成
将5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺(1.34g,5.15mmol),4-羟基环己酮乙二醇缩醛(1.22g,7.7mmol)和三苯基膦(4.05g,15.45mmol)加入到30mL无水四氢呋喃中,氮气保护,冰浴下缓慢滴加偶氮二甲酸二异丙酯(2.1g,10.3mmol),滴加完毕自然升至室温反应过夜。TLC检测反应完全,旋蒸蒸除溶剂,加入20mL乙酸乙酯,室温搅拌0.5小时,过滤,滤饼用5mL乙酸乙酯淋洗,干燥得到1.5g白色固体,加入20mL丙酮溶解,冰浴下缓慢滴加6M盐酸至PH=3,反应液于室温下反应3小时。旋蒸蒸除溶剂,加乙酸乙酯溶解,饱和碳酸氢钠溶液洗涤,干燥,浓缩得白色固体1.1g,收率60%。LC-MS(APCI):m/z=357(M+1)
+。
步骤2化合物4-(4-氨基-5-((三甲基硅基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-7-基)环己烷-1-酮的合成
将4-(4-氨基-5-碘-7H-吡咯并[2,3-d]嘧啶-7-基)环己烷-1-酮(0.55g,1.54mmol),三甲基硅基乙炔(0.2g,2.0mmol),Pd(PPh
3)
4(58mg,0.05mmol),CuI(19mg,0.1mmol)和0.4mL N,N-二异丙基乙胺加入到10mL DMF中,氮气置换三次,升温到90℃,反应3小时。反应完全后冷却至室温,加入20mL水,用乙酸乙酯(20mL*3)萃取,有机相用15mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体0.33g,收率66%。LC-MS(APCI):m/z=327(M+1)
+。
步骤3化合物4-(4-氨基-5-乙炔基-7H-吡咯并[2,3-d]嘧啶-7-基)环己烷-1-酮的合成
将4-(4-氨基-5-((三甲基硅基)乙炔基)-7H-吡咯并[2,3-d]嘧啶-7-基)环己烷-1-酮(0.33g,1.0mmol)溶于5mL四氢呋喃,加入四丁基氟化铵(0.52g,2.0mmol),室温下搅拌1小时。旋蒸蒸除溶剂,加入10mL水,用乙酸乙酯(10mL*3)萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体224mg,收率88%。LC-MS(APCI):m/z=255(M+1)
+。
步骤4化合物3-((4-氨基-7-(4-氧代环己基)-7H-吡咯并[2,3-d]嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺的合成
将3-碘-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-(3-(三氟甲基)苯基)苯甲酰胺(224mg,0.43mmol)和4-(4-氨基-5-乙炔基-7H-吡咯并[2,3-d]嘧啶-7-基)环己烷-1-酮(142mg,0.56mmol),Pd(PPh
3)
4(16mg,0.01mmol),CuI(5mg,0.02mmol)和0.12mL N,N-二异丙基乙胺加入到5mL DMF中,氮气置换三次,升温到90℃,反应3小时。反应完全后冷却至室温,加入15mL水,用乙酸乙酯(15mL*3)萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体184mg,收率66%。LC-MS(APCI):m/z=644(M+1)
+。
步骤5化合物3-((4-氨基-7-((1r,4r)-4-羟基环己基)-7H-吡咯并[2,3-d]嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺的合成
将3-((4-氨基-7-(4-氧代环己基)-7H-吡咯并[2,3-d]嘧啶-5-基)乙炔基)-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯甲酰胺(184mg,0.28mmol)溶于10mL甲醇,冰浴下缓慢加入硼氢化钠(32mg,0.84mmol),自然升至室温反应1小时。TLC检测反应完全,加入10mL水,用乙酸乙酯(10mL*3)萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体120mg,收率65%。LC-MS(APCI):m/z=646(M+1)
+。
1H NMR(400MHz,DMSO-d
6)δ10.59(s,1H),8.23(s,1H),8.16(d,J=6.6Hz,2H),8.09(d,J=8.7Hz,1H),7.90(d,J=8.1Hz,1H),7.84(s,1H),7.71(d,J=8.6Hz,1H),7.49(d,J=8.1Hz,1H),6.65(s,2H),4.70(d,J=4.2Hz,1H),4.52(s,1H),3.61(s,2H),3.54(s,1H),2.54(s,3H),2.50–2.44(s,8H),2.39(s,3H),2.00–1.86(m,6H),1.39(s,2H).
实施例23 3-((4-氨基-7-((1r,4r)-4-羟基环己基)-7H-吡咯并[2,3-d]嘧啶-5-基)乙炔基)-4-甲基
-N-(3-(三氟甲基)苯基)苯甲酰胺(化合物I-23)的制备。
根据实施例22中所述的合成方法,用化合物3-碘-4-甲基-N-(3-(三氟甲基)苯基)苯甲酰胺替代步骤4中3-碘-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-(3-(三氟甲基)苯基)苯甲酰胺来进行制备,得到标题化合物I-23。LC-MS(APCI):m/z=534(M+1)
+。
1H NMR(400MHz,DMSO-d
6)δ10.40(s,1H),8.22(s,1H),8.16(d,J=7.9Hz,2H),7.93(d,J=2.3Hz,1H),7.82(s,1H),7.66–7.60(m,2H),7.55(s,1H),7.33(s, 1H),6.65(s,2H),4.70(d,J=4.4Hz,1H),4.53(dd,J=10.8,5.9Hz,1H),3.54(d,J=4.4Hz,1H),2.53(s,3H),1.97–1.86(m,6H),1.38(s,2H).
实施例24 3-((4-氨基-7-((1r,4r)-4-羟基环己基)-7H-吡咯并[2,3-d]嘧啶-5-基)乙炔基)-4-甲基-N-(4-
甲基-3-(三氟甲基)苯基)苯甲酰胺(化合物I-24)的制备。
根据实施例22中所述的合成方法,用化合物3-碘-4-甲基-N-(4-甲基-3-(三氟甲基)苯基)苯甲酰胺替代步骤4中3-碘-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-(3-(三氟甲基)苯基)苯甲酰胺来进行制备,得到标题化合物I-24。LC-MS(APCI):m/z=548(M+1)
+。
1H NMR(400MHz,DMSO-d
6)δ10.42(s,1H),8.26(s,1H),8.16(d,J=7.9Hz,2H),7.96(d,J=2.3Hz,1H),7.83(s,1H),7.68–7.61(m,2H),7.31(d,J=8.4Hz,1H),6.66(s,2H),4.68(d,J=4.4Hz,1H),4.51(dd,J=10.8,5.9Hz,1H),3.53(d,J=4.4Hz,1H),2.53(s,3H),2.44(s,3H),1.99–1.86(m,6H),1.39(s,2H).
实施例25 N-(3-((4-氨基-7-((1r,4r)-4-羟基环己基)-7H-吡咯并[2,3-d]嘧啶-5-基)乙炔基)-4-甲基苯
基)-4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯甲酰胺(化合物I-25)的制备。
根据实施例22中所述的合成方法,用化合物N-(3-碘-4-甲基苯基)-4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯甲酰胺替代步骤4中3-碘-4-甲基-N-(4-((4-甲基哌嗪-1-基)甲基)-(3-(三氟甲基)苯基)苯甲酰胺来进行制备,得到标题化合物I-25。LC-MS(APCI):m/z=646(M+1)
+。
1H NMR(400MHz,DMSO-d
6)δ10.32(s,1H),8.22(s,1H),8.18(d,J=6.6Hz,2H),8.12(d,J=8.7Hz,1H),7.93(d,J=8.1Hz,1H),7.82(s, 1H),7.70(d,J=8.6Hz,1H),7.44(d,J=8.1Hz,1H),6.66(s,2H),4.73(d,J=4.2Hz,1H),4.53(s,1H),3.64(s,2H),3.54(s,1H),2.53(s,3H),2.49–2.43(s,8H),2.38(s,3H),1.97–1.85(m,6H),1.38(s,2H).
生物活性测试。
生物实施例1:生物化学激酶分析
试剂和耗材:ABL(ThermoFisher,Cat.No PV3585),ABL
T315I(Thermo Fisher,Cat.No.PR7429B),ATP(Sigma,Cat.No.A7699-1G),DMSO(Sigma,Cat.No.D2650),96孔板(Corning,Cat.No.3365),384孔板(Greiner,Cat.No.784076),缓冲液(Thermo Fisher,Cat.No.PR4876B)。
具体实验方法:
化合物配制:将受试化合物溶于DMSO配成20mM母液。使用前将化合物在DMSO中稀释成0.1mM,并做3倍梯度稀释11个浓度。加药时再用缓冲液稀释成4倍终浓度的稀释液。
激酶检测方法:配制缓冲液后,将酶与预先稀释配制的不同浓度化合物混合,室温放置30分钟,每个浓度双复孔。加入对应底物及ATP,室温反应60分钟(其中设置阴阳性对照)。反应完毕加入抗体检测,室温孵育60分钟后Evnvision检测,采集数据。根据XLfit5软件进行数据分析及拟图,其中A表示IC
50≤5nM,B表示IC
50为5-50nM,C表示IC
50为50-100nM,D表示IC
50>100nM。
在上述激酶抑制实验中测试了本发明化合物,发现本发明化合物对ABL和ABL
T315I具有强效的活性。代表性实施例化合物的结果归纳于如下表1中。
表1:
实施例编号 | ABL IC 50(nM) | ABL T315I IC 50(nM) |
实施例1 | A | A |
实施例2 | B | C |
实施例3 | A | A |
实施例4 | A | A |
实施例5 | A | A |
实施例6 | A | A |
实施例7 | A | B |
实施例8 | A | A |
实施例9 | A | A |
实施例10 | B | B |
实施例11 | A | B |
实施例12 | B | B |
实施例13 | B | B |
实施例14 | A | A |
实施例15 | A | A |
实施例16 | A | A |
实施例17 | A | A |
实施例18 | A | A |
实施例19 | A | A |
实施例20 | B | C |
实施例21 | A | B |
实施例22 | A | A |
实施例23 | A | B |
实施例24 | A | B |
实施例25 | A | A |
生物实施例2:细胞增殖分析
检测实施例化合物对Ba/F3,Ba/F3 Bcr-Abl
T315I细胞活性的抑制效应。
耗材及试剂:RPMI-1640培养基(GIBCO,目录号A10491-01)、胎牛血清(GIBCO,目录号10099141)、抗生素(Penicillin-Streptomycin),IL-3(PeproTech),嘌呤霉素;细胞系:Ba/F3,Ba/F3 Bcr-Abl T315I(购自美国标准生物品收藏中心,ATCC),活细胞检测试剂盒CellTiter-Glo4(Promega,目录号G7572),96孔黑壁透明平底细胞培养板(Corning,目录号3340)。
实验方法:1.制备细胞板将Ba/F3,Ba/F3 Bcr-Abl T315I细胞分别种于96孔板中,并在Ba/F3细胞中加入8ng/ml IL-3,细胞板置于二氧化碳培养箱中过夜培养。2.用DMSO溶解被测化合物并进行3.16倍梯度稀释,9个化合物浓度,设置三复孔实验。3.化合物处理细胞将化合物转移到细胞板中,化合物起始浓度为10μM。细胞板置于二氧化碳培养箱中培养3天。4.检测向细胞板中加入CellTiter-Glo试剂,室温孵育30分钟使发光信号稳定。采用PerkinElmer Envision多标记分析仪读数,其中A表示IC
50≤10nM,B表示IC
50为10-20nM,C表示IC
50为20-50nM,D表示IC
50为50-1000nM,E表示IC
50>1000nM。
在上述细胞增殖抑制实验中测试了本发明化合物,发现本发明化合物对癌细胞Ba/F3 Bcr-Abl
T315I具有强效的活性以及优于癌细胞Ba/F3 parental的优异选择性。代表性实施例对癌细胞的体外增殖的抑制作用的结果归纳于下表2中。
表2
生物实施例3:代谢稳定性评价分析
微粒体实验:人肝微粒体:0.5mg/mL,Xenotech;辅酶(NADPH/NADH):1mM,Sigma Life Science;氯化镁:5mM,100mM磷酸盐缓冲剂(pH为7.4)。
储备液的配制:精密称取一定量的实施例化合物和对照品化合物的粉末,并用DMSO分别溶解至5mM。
磷酸盐缓冲液(100mM,pH7.4)的配制:取预先配好的150mL的0.5M磷酸二氢钾和700mL的0.5M磷酸氢二钾溶液混合,再用0.5M磷酸氢二钾溶液调节混合液pH值至7.4,使用前用超纯水稀释5倍,加入氯化镁,得到磷酸盐缓冲液(100mM),其中含100mM磷酸钾,3.3mM氯化镁,pH为7.4。
配制NADPH再生系统溶液(含有6.5mM NADP,16.5mM G-6-P,3U/mL G-6-P D,3.3mM氯化镁),使用前置于湿冰上。
配制终止液:含有50ng/mL盐酸普萘洛尔和200ng/mL甲苯磺丁脲(内标)的乙腈溶液。取25057.5 μL磷酸盐缓冲液(pH7.4)至50mL离心管中,分别加入812.5μL人肝微粒体,混匀,得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。
样品的孵育:用含70%乙腈的水溶液将相应化合物的储备液分别稀释至0.25mM,作为工作液,备用。分别取398μL的人肝微粒体稀释液加入96孔孵育板中(N=2),分别加入2μL 0.25mM的的工作液中,混匀。
代谢稳定性的测定:在96孔深孔板的每孔中加入300μL预冷的终止液,并置于冰上,作为终止板。将96孔孵育板和NADPH再生系统置于37℃水浴箱中,100转/分钟震荡,预孵5min。从孵育板每孔取出80μL孵育液加入终止板,混匀,补充20μL NADPH再生系统溶液,作为0min样品。再向孵育板每孔加入80μL的NADPH再生系统溶液,启动反应,开始计时。相应化合物的反应浓度为1μM,蛋白浓度为0.5mg/mL。分别于反应10、30、90min时,各取100μL反应液,加入终止板中,涡旋3min终止反应。将终止板于5000×g,4℃条件下离心10min。取100μL上清液至预先加入100μL蒸馏水的96孔板中,混匀,采用LC-MS/MS进行样品分析。
数据分析:通过LC-MS/MS系统检测相应化合物及内标的峰面积,计算化合物与内标峰面积比值。通过化合物剩余量的百分率的自然对数与时间作图测得斜率,并根据以下公式计算t
1/2和CL
int,其中V/M即等于1/蛋白浓度。
在上述人肝微粒体实验中测试了本发明化合物,发现本发明化合物具有优异的代谢稳定性。代表性实施例化合物的结果归纳于下表3中。
表3:
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明,不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干简单推演或替换,都应当视为属于本发明的保护范围。
Claims (19)
- 式(I)化合物或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、前药或同位素变体:其中,环A选自以下结构:R 1选自C 1-6烷基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基,其中所述基团任选地被一个或多个R 1a取代;R 2选自H、CN、NO 2、OH、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基或C 1-6卤代烷氧基;L选自-C(O)N(R 1b)-、-N(R 1b)C(O)-或-N(R 1b)C(O)N(R 1b)-;B选自CH或N;R 3选自C 1-6烷基或C 1-6卤代烷基;R 4和R 5选自:1)R 5为H,R 4选自H、C 1-6烷基、-C 0-2亚烷基-C 3-7环烷基、-C 0-2亚烷基-3至7元杂环基或-C 0-2亚烷基-NR 1cR 2c,其中所述基团任选地被一个或多个R 1d取代;或者,2)R 4为H,R 5选自H或含一个或多个N、O或S杂原子的5至6元杂芳环,其中所述5至6元杂芳环可任选地被一个或多个R 1d取代;各个R 1a各自独立地选自H、卤素、氧代基、-C 0-6亚烷基-OR a、-C 0-6亚烷基-NR bR c、-C 0-6亚烷基-C(O)R a、-C 0-6亚烷基-C(O)OR a、-C 0-6亚烷基-C(O)NR bR c、C 1-6烷基、C 1-6卤代烷基、-C 0-6亚烷基-C 3-6环烷基或-C 0-6亚烷基-3至7元杂环基;或者二个或二个以上的R 1a与它们所连接的原子一起形成C 3-7环烷基或3至7元杂环基;各个R 1b各自独立地选自H、-C 0-6亚烷基-OR a、-C 0-6亚烷基-NR bR c、-C 0-6亚烷基-C(O)R a、-C 0-6亚烷基-C(O)OR a、-C 0-6亚烷基-C(O)NR bR c、C 1-6烷基、C 1-6卤代烷基、-C 0-6亚烷基-C 3-6环烷基或-C 0-6 亚烷基-3至7元杂环基;或者二个或二个以上的R 1b与它们所连接的原子一起形成C 3-7环烷基或3至7元杂环基;R 1c和R 2c各自独立地选自H、卤素、-C 0-6亚烷基-CN、-C 0-6亚烷基-OR a、-C 0-6亚烷基-SR a、-C 0-6亚烷基-NR bR c、-C 0-6亚烷基-C(O)R a、-C 0-6亚烷基-C(O)OR a、-C 0-6亚烷基-C(O)NR bR c、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C 0-6亚烷基-C 3-6环烷基、-C 0-6亚烷基-3至7元杂环基、-C 0-6亚烷基-C 6-10芳基或-C 0-6亚烷基-5至10元杂芳基;或者,R 1c、R 2c与它们所连接的氮原子一起形成C 3-7环烷基或3至7元杂环基;各个R 1d各自独立地选自H、卤素、-C 0-6亚烷基-CN、-C 0-6亚烷基-OR a、-C 0-6亚烷基-SR a、-C 0-6亚烷基-NR bR c、-C 0-6亚烷基-C(O)R a、-C 0-6亚烷基-C(O)OR a、-C 0-6亚烷基-C(O)NR bR c、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-C 0-6亚烷基-C 3-6环烷基、-C 0-6亚烷基-3至7元杂环基、-C 0-6亚烷基-C 6-10芳基或-C 0-6亚烷基-5至10元杂芳基;或者二个或二个以上的R 1d与它们所连接的原子一起形成C 3-7环烷基或3至7元杂环基;R a、R b和R c独立地选自H、C 1-6烷基、C 1-6卤代烷基、C 3-7环烷基、3至7元杂环基、C 6-10芳基或5至10元杂芳基;附加条件是,上述化合物不具有以下结构:
- 权利要求1-3中任一项的化合物,其中,R 1选自C 1-4烷基、C 4-6环烷基或5至6元杂环基,其中所述基团任选地被一个或多个R 1a取代;优选地,R 1选自甲基、乙基、异丙基、环戊基、环己基、四氢呋喃基、哌啶基、哌嗪基或吗啉基,其中所述基团任选地被一个或多个-OH取代。
- 权利要求1-4中任一项的化合物,其中,R 2选自H或C 1-4烷基,R 3选自C 1-4氟代烷基,L选自-C(O)N(R 1b)-、-N(R 1b)C(O)-或-N(R 1b)C(O)N(R 1b)-,B选自CH或N,其中R 1b选自H或C 1-4烷基;优选地,R 2选自H或甲基,R 3选自三氟甲基,L选自-C(O)NH-、-NHC(O)-或-NHC(O)NH-,B选自CH。
- 权利要求1-5中任一项的化合物,其中,R 5为H,R 4选自H、C 1-6烷基或-C 0-2亚烷基-NR 1cR 2c;其中所述基团任选地被一个或多个R 1d取代。
- 权利要求6的化合物,其中,R 4选自H。
- 权利要求6的化合物,其中,R 4选自-C 1-4烷基;优选地,R 4选自甲基、乙基、异丙基或叔丁基。
- 权利要求1-5中任一项的化合物,其中,R 4为H,R 5选自H或含一个或多个N杂原子的5至6元杂芳环;其中所述5至6元杂芳环可任选地被一个或多个R 1d取代。
- 权利要求10的化合物,其中,R 5选自含一个或多个N杂原子的5杂芳环,其中所述5元杂芳环可任选地被一个或多个R 1d取代;优选地,R 5选自咪唑基,其可任选地被一个或多个R 1d取代。
- 药物组合物,其含有权利要求1-15中任一项的化合物或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、前药或同位素变体,和药学上可接受的赋形剂;优选地,其还含有其它治疗剂。
- 权利要求1-15中任一项的化合物或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、前药或同位素变体在制备用于治疗与蛋白激酶相关的疾病的药物的用途。
- 一种在受试者中治疗与蛋白激酶相关的疾病的方法,所述方法包括向受试者给药权利要求1-15任一项的化合物或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、前药或同位素变体,或者权利要求16的药物组合物。
- 权利要求17的用途或权利要求18的方法,其中所述的所述蛋白激酶选自:Ret(Reaaranged during transfection),ABL1(E255K)-phosphorylated,ABL1(F317I)-nonphosphorylated,ABL1(F317I)-phosphorylated,ABL1(F317L)-nonphosphorylated,ABL1(F317L)-phosphorylated,ABL1(H396P)-nonphosphorylated,ABL1(H396P)-phosphorylated,ABL1(M351T)-phosphorylated,ABL1(Q252H)-nonphosphorylated,ABL1(Q252H)-phosphorylated,ABL1(T315I)-nonphosphorylated,ABL1(T315I)-phosphorylated,ABL1(Y253F)-phosphorylated,ABL1-nonphosphorylated, ABL1-phosphorylated,ABL2,ALK(L1196M),AMPK-alpha1,AMPK-alpha2,ANKK1,AURKB,AURKC,AXL,BLK,BMX,BRAF,BRAF(V600E),BRK,BTK,CAMK1,CAMKK1,CAMKK2,CDC2L1,CDC2L2,CDC2L5,CDK11,CDK2,CDK5,CDK7,CDK8,CDKL1,CDKL2,CDKL3,CHEK2,CIT,CLK1,CLK4,CSF1R,CSK,CTK,DDR1,DDR2,DLK,EGFR,EGFR(E746-A750del),EGFR(G719C),EGFR(G719S),EGFR(L747-E749del,A750P),EGFR(L747-S752del,P753S),EGFR(L747-T751del,Sins),EGFR(L858R),EGFR(L858R,T790M),EGFR(L861Q),EGFR(S752-I759del),EGFR(T790M),EPHA1,EPHA2,EPHA3,EPHA4,EPHA5,EPHA6,EPHA7,EPHA8,EPHB1,EPHB2,EPHB4,EPHB6,ERBB2,ERBB4,ERK8,FAK,FER,FES,FGFR1,FGFR2,FGFR3,FGFR3(G697C),FGFR4,FGR,FLT1,FLT3,FLT3(D835H),FLT3(D835V),FLT3(D835Y),FLT3(ITD),FLT3(ITD,D835V),FLT3(ITD,F691L),FLT3(K663Q),FLT3(N841I),FLT3(R834Q),FLT4,FRK,FYN,GAK,GCN2(Kin.Dom.2,S808G),HCK,HIPK4,HPK1,IKK-alpha,IKK-beta,IRAK1,IRAK4,ITK,JAK1(JH1domain-catalytic),JAK2(JH1domain-catalytic),JAK3(JH1domain-catalytic),JNK1,JNK2,JNK3,KIT,KIT(A829P),KIT(D816H),KIT(D816V),KIT(L576P),KIT(V559D),KIT(V559D,T670I),KIT(V559D,V654A),LCK,LIMK1,LIMK2,LOK,LRRK2,LRRK2(G2019S),LTK,LYN,MAK,MAP3K2,MAP3K3,MAP4K2,MAP4K3,MAP4K4,MAP4K5,MEK5,MELK,MERTK,MET,MET(M1250T),MINK,MKNK2,MLK1,MLK2,MLK3,MST1,MST1R,MST2,MUSK,MYLK2,MYO3A,MYO3B,NDR2,NEK1,NEK11,NEK4,NEK5,NEK9,NLK,p38-alpha,p38-beta,p38-delta,p38-gamma,PCTK2,PDGFRA,PDGFRB,PFCDPK1(P.falciparum),PFTAIRE2,PFTK1,PKAC-alpha,PKAC-beta,PYK2,RAF1,RET,RET(M918T),RET(V804L),RET(V804M),RIPK1,RIPK2,RIPK4,ROCK2,RPS6KA4(Kin.Dom.1-N-terminal),RSK2(Kin.Dom.1-N-terminal),RSK3(Kin.DoN-terminal),S6K1,SIK,SLK,SRC,SRMS,SRPK1,STK33,STK35,STK36,SYK,TAK1,TAOK2,TAOK3,TEC,TESK1,TGFBR2,TIE1,TIE2,TNIK,TNK1,TNK2,TNNI3K,TRKA,TRKB,TRKC,TTK,TXK,TYK2(JH1domain-catalytic),TYRO3,ULK3,VEGFR2,YES,YSK4,ZAK,ZAP70或FGFR(Fibroblast growth factor receptor)。
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JP7162372B2 (ja) | 2022-10-28 |
JP2021530467A (ja) | 2021-11-11 |
US11840535B2 (en) | 2023-12-12 |
EP3795571B1 (en) | 2024-05-08 |
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CN110194772A (zh) | 2019-09-03 |
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