Tetracyclic anthraquinone derivatives
View Patent ↗Disclosed are a compound represented by formula (I) and a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , W, n are defined as in the present application. Also disclosed is a method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The compound and a salt thereof according to the present application possess good anticancer and/or antitumor activity, and good water solubility and stability, as well as good tolerance in animal bodies. Also disclosed is a process for preparing a compound represented by formula (I) of the present application, comprising reacting a compound represented by formula (II) with a compound represented by formula (III) in the presence of a condensation agent to obtain a compound represented by formula (I).
1. A compound represented by formula (I) and a pharmaceutically acceptable salt thereof,
wherein:
R 1 is selected from the group consisting of H, optionally substituted alkyl, and optionally substituted alkoxy;
R 2 is selected from the group consisting of H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (alkyleneoxy) m alkyl, optionally substituted heterocyclyl, optionally substituted alkyl, and optionally substituted —S(═O) 2 R;
R 3 is selected from the group consisting of H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (alkyleneoxy) m alkyl, optionally substituted heterocyclyl, optionally substituted alkyl, and optionally substituted —S(═O) 2 R;
or NR 2 R 3 represents optionally substituted heterocyclyl;
wherein R comprises optionally substituted alkyl, optionally substituted cyclohydrocarbyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
m is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11;
W is selected from the group consisting of O and NH;
R 4 is selected from the group consisting of H, F, and optionally substituted alkyl;
R 5 is selected from the group consisting of H, F, optionally substituted alkyl and OR 6 , wherein R 6 is selected from the group consisting of H and tetrahydropyran-2-yl; and
n is selected from the group consisting of 1, 2 and 3.
2. The compound of claim 1 , wherein R 1 is selected from the group consisting of H and OCH 3 .
3. The compound of claim 1 , wherein W is O.
4. The compound of claim 1 , wherein R 4 is CH 3 .
5. The compound of claim 1 , wherein R 5 is selected from the group consisting of OH and (tetrahydropyran-2-yl)oxy.
6. The compound of claim 1 , wherein R 2 is selected from the group consisting of H, methyl, ethyl, (morpholinylmethyl)phenyl, 4-((morpholin-1-yl)methyl)phenyl, (dimethylaminomethyl)phenyl, 4-((dimethylamino)methyl)phenyl, 2-(2-(dimethylamino)ethoxy)ethyl, morpholin-1-yl, piperidin-1-yl, tetrahydropyrrol-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, (4-methylpiperazin)-1-yl, (4-ethylpiperazin)-1-yl, 2-(tetrahydropyrrol-1-yl)ethyl, 3-(tetrahydropyrrol-1-yl)propyl, (2-(morpholin-1-yl)pyridin)-4-yl, (2-(morpholin-1-yl)pyridin)-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, (pyridin-4-yl)methyl, (pyridin-3-yl)methyl, (pyridin-2-yl)methyl, 2-(pyridin-4-yl)ethyl, 2-(pyridin-3-yl)ethyl, 2-(pyridin-2-yl)ethyl, 2-(pyridin-4-yl)propyl, 2-(pyridin-3-yl)propyl, 2-(pyridin-2-yl)propyl, 2-((4-sulfamido)phenyl)ethyl, (3-(dimethylamino)propyl)piperazin-1-yl, 3-((4-sulfamido)phenyl)propyl, 3-((4-methyl)piperazin-1-yl)propyl, 3-((4-ethyl)piperazin-1-yl)propyl, 3-((4-propyl)piperazin-1-yl)propyl, 2-((4-methyl)piperazin-1-yl)ethyl, 2-((4-ethyl)piperazin-1-yl)ethyl, 2-((4-propyl)piperazin-1-yl)ethyl, 2-(dimethylamino)ethyl, 2-(diethylamino)ethyl, 2-(dipropylamino)ethyl, 2-(piperidin-1-yl)ethyl, 2-(morpholin-1-yl)ethyl, 2-(tetrahydropyrrol-1-yl)ethyl, 3-(dimethylamino)propyl, 3-(diethylamino)propyl, 3-(dipropylamino)propyl, 3-(piperidin-1-yl)propyl, 3-(morpholin-1-yl)propyl, 3-(tetrahydropyrrol-1-yl)propyl, 4-(dimethylamino)butyl, 4-(diethylamino)butyl, 4-(dipropylamino)butyl, 4-(piperidin-1-yl)butyl, 4-(morpholin-1-yl)butyl, 4-(tetrahydropyrrol-1-yl)butyl, 2-(2-(2-(2-(dimethylamino)ethoxy)ethoxy)ethoxy)ethyl, 2-(2-(2-(2-(diethylamino)ethoxy)ethoxy)ethoxy)ethyl, 2-(2-(2-(2-(dipropylamino)ethoxy)ethoxy)ethoxy)ethyl, 2-(2-(2-(2-(piperidin-1-yl)ethoxy)ethoxy)ethoxy)ethyl, 2-(2-(2-(2-(morpholin-1-yl)ethoxy)ethoxy)ethoxy)ethyl, 2-(2-(2-(2-(tetrahydropyrrol-1-yl)ethoxy)ethoxy)ethoxy)ethyl, 2-(2-(2-(dimethylamino)ethoxy)ethoxy)ethyl, 2-(2-(2-(diethylamino)ethoxy)ethoxy)ethyl, 2-(2-(2-(dipropylamino)ethoxy)ethoxy)ethyl, 2-(2-(2-(piperidin-1-yl)ethoxy)ethoxy)ethyl, 2-(2-(2-(morpholin-1-yl)ethoxy)ethoxy)ethyl, 2-(2-(2-(tetrahydropyrrol-1-yl)ethoxy)ethoxy)ethyl, 6-purinyl, mesyl, benzenesulfonyl, pyrazin-2-yl, pyrimidin-2-yl, 2-hydroxyethyl, 2-(2-hydroxyethoxy)ethyl, 2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethyl, 2-(2-(2-(2-(2-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethyl, 2-(2-(2-(2-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethyl, 2-(2-(2-(2-(2-(2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethyl, and 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl.
7. The compound of claim 1 , wherein R 3 is selected from the group consisting of H, methyl, ethyl, (morpholinylmethyl)phenyl, 4-((morpholin-1-yl)methyl)phenyl, (dimethylaminomethyl)phenyl, 4-((dimethylamino)methyl)phenyl, 2-(2-(dimethylamino)ethoxy)ethyl, morpholin-1-yl, piperidin-1-yl, tetrahydropyrrol-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, (4-methylpiperazin)-1-yl, (4-ethylpiperazin)-1-yl, 2-(tetrahydropyrrol-1-yl)ethyl, 3-(tetrahydropyrrol-1-yl)propyl, (2-(morpholin-1-yl)pyridin)-4-yl, (2-(morpholin-1-yl)pyridin)-5-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, (pyridin-4-yl)methyl, (pyridin-3-yl)methyl, (pyridin-2-yl)methyl, 2-(pyridin-4-yl)ethyl, 2-(pyridin-3-yl)ethyl, 2-(pyridin-2-yl)ethyl, 2-(pyridin-4-yl)propyl, 2-(pyridin-3-yl)propyl, 2-(pyridin-2-yl)propyl, 2-((4-sulfamido)phenyl)ethyl, (3-(dimethylamino)propyl)piperazin-1-yl, 3-((4-sulfamido)phenyl)propyl, 3-((4-methyl)piperazin-1-yl)propyl, 3-((4-ethyl)piperazin-1-yl)propyl, 3-((4-propyl)piperazin-1-yl)propyl, 2-((4-methyl)piperazin-1-yl)ethyl, 2-((4-ethyl)piperazin-1-yl)ethyl, 2-((4-propyl)piperazin-1-yl)ethyl, 2-(dimethylamino)ethyl, 2-(diethylamino)ethyl, 2-(dipropylamino)ethyl, 2-(piperidin-1-yl)ethyl, 2-(morpholin-1-yl)ethyl, 2-(tetrahydropyrrol-1-yl)ethyl, 3-(dimethylamino)propyl, 3-(diethylamino)propyl, 3-(dipropylamino)propyl, 3-(piperidin-1-yl)propyl, 3-(morpholin-1-yl)propyl, 3-(tetrahydropyrrol-1-yl)propyl, 4-(dimethylamino)butyl, 4-(diethylamino)butyl, 4-(dipropylamino)butyl, 4-(piperidin-1-yl)butyl, 4-(morpholin-1-yl)butyl, 4-(tetrahydropyrrol-1-yl)butyl, 2-(2-(2-(2-(dimethylamino)ethoxy)ethoxy)ethoxy)ethyl, 2-(2-(2-(2-(diethylamino)ethoxy)ethoxy)ethoxy)ethyl, 2-(2-(2-(2-(dipropylamino)ethoxy)ethoxy)ethoxy)ethyl, 2-(2-(2-(2-(piperidin-1-yl)ethoxy)ethoxy)ethoxy)ethyl, 2-(2-(2-(2-(morpholin-1-yl)ethoxy)ethoxy)ethoxy)ethyl, 2-(2-(2-(2-(tetrahydropyrrol-1-yl)ethoxy)ethoxy)ethoxy)ethyl, 2-(2-(2-(dimethylamino)ethoxy)ethoxy)ethyl, 2-(2-(2-(diethylamino)ethoxy)ethoxy)ethyl, 2-(2-(2-(dipropylamino)ethoxy)ethoxy)ethyl, 2-(2-(2-(piperidin-1-yl)ethoxy)ethoxy)ethyl, 2-(2-(2-(morpholin-1-yl)ethoxy)ethoxy)ethyl, 2-(2-(2-(tetrahydropyrrol-1-yl)ethoxy)ethoxy)ethyl, 6-purinyl, mesyl, benzenesulfonyl, pyrazin-2-yl, pyrimidin-2-yl, 2-hydroxyethyl, 2-(2-hydroxyethoxy)ethyl, 2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethyl, 2-(2-(2-(2-(2-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethyl, 2-(2-(2-(2-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethyl, 2-(2-(2-(2-(2-(2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethyl, and 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl.
8. The compound of claim 1 , wherein NR 2 R 3 is selected from the group consisting of piperidin-1-yl, morpholin-1-yl, tetrahydropyrrol-1-yl, (4-(2-hydroxyethyl))piperazin-1-yl, (4-methyl)piperazin-1-yl, (4-ethyl)piperazin-1-yl, (4-propyl)piperazin-1-yl, 4-(3-hydroxypropyl)piperazin-1-yl, 3-(morpholin-1-yl)propyl, adenin-1-yl, (4-(3-(dimethylamino)propyl)piperazin)-1-yl, (4-(2-(dimethylamino)ethyl)piperazin)-1-yl, (4-(3-(diethylamino)propyl)piperazin)-1-yl, (4-(2-(diethylamino)ethyl)piperazin)-1-yl, (4-(2-(piperidin-1-yl)ethyl)piperazin)-1-yl, (4-(3-(piperidin-1-yl)propyl)piperazin)-1-yl, (4-(2-(morpholin-1-yl)ethyl)piperazin)-1-yl, (4-(3-(morpholin-1-yl)propyl)piperazin)-1-yl, (4-(2-(tetrahydropyrrol-1-yl)ethyl)piperazin)-1-yl, and (4-(3-(tetrahydropyrrol-1-yl)propyl)piperazin)-1-yl.
9. A compound selected from the group consisting of:
wherein W is O, R 1 is OCH 3 , R 4 is CH 3 , R 5 is OH,
n and NR 2 R 3 are shown in the following table:
No.
n
NR 2 R 3
1
3
2
2
3
3
4
2
5
3
6
2
7
3
8
2
9
3
10
2
11
3
12
2
13
3
14
2
15
3
16
2
17
3
18
2
19
3
20
2
21
3
22
2
23
3
24
2
25
3
26
2
27
3
28
2
29
3
30
2
31
3
32
2
33
3
34
2
35
3
36
2
37
3
38
2
39
3
40
2
41
3
42
2
43
3
44
2
45
3
46
2
47
3
48
2
49
3
50
2
51
3
52
2
53
3
54
2
55
3
56
2
57
3
58
2
59
3
60
2
61
3
62
2
63
3
64
2
65
3
66
2
NH 2
67
3
NH 2
68
2
NHCH 3
69
3
NHCH 3
70
2
N(CH 3 ) 2
71
3
N(CH 3 ) 2
72
2
73
3
74
2
75
2
88
2
90
2
91
2
92
2
93
2
94
2
95
2
77) 10-((3′-(pyrrol-1-yl)-2′,3′,6′-trideoxy-alphal-L-lyxo-hexylpyranyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-13-oxo-14-(4-((4-(2-hydroxy)ethyl)piperazin-1-yl)-4-oxo-butyrato)-1-methoxy-5,12-naphthalenedione acetate;
78) 10-((3′-(pyrrol-1-yl)-2′,3′,6′-trideoxy-alphal-L-lyxo-hexylpyranyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-13-oxo-14-(4-((3-(morpholin-1-yl)propyl)amino)-4-oxo-butyrato)-1-methoxy-5,12-naphthalenedione acetate;
79) 10-((3′-(pyrrol-1-yl)-2′,3′,6′-trideoxy-alphal-L-lyxo-hexylpyranyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-13-oxo-14-(4-((4-methyl)piperazin-1-yl)amino)-4-oxo-butyrato)-1-methoxy-5,12-naphthalenedione acetate;
80) 10-((3′-(pyrrol-1-yl)-2′,3′,6′-trideoxy-alphal-L-lyxo-hexylpyranyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-13-oxo-14-(4-(4-ethylpiperazin-1-yl)-4-oxo-butyrato)-1-methoxy-5,12-naphthalenedione acetate;
81) 10-((3′-(pyrrol-1-yl)-2′,3′,6′-trideoxy-alphal-L-lyxo-hexylpyranyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-13-oxo-14-(4-((3-(4-methylpiperazin-1-yl)propyl)amino)-4-oxo-butyrato)-1-methoxy-5,12-naphthalenedione acetate;
82) 10-((3′-(pyrrol-1-yl)-2′,3′,6′-trideoxy-alphal-L-lyxo-hexylpyranyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-13-oxo-14-(4-((pyridin-4-yl)methyl)amino)-4-oxo-butyrato)-1-methoxy-5,12-naphthalenedione acetate;
83) 10-((3′-(pyrrol-1-yl)-2′,3′,6′-trideoxy-alphal-L-lyxo-hexylpyranyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-13-oxo-14-(4-((pyridin-3-yl)methyl)amino)-4-oxo-butyrato)-1-methoxy-5,12-naphthalenedione acetate;
84) 10-((3′-(pyrrol-1-yl)-2′,3′,6′-trideoxy-alphal-L-lyxo-hexylpyranyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-13-oxo-14-(4-(2-(pyridin-2-yl)ethyl)amino)-4-oxo-butyrato)-1-methoxy-5,12-naphthalenedione acetate;
85) 10-((3′-(pyrrol-1-yl)-2′,3′,6′-trideoxy-alphal-L-lyxo-hexylpyranyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-13-oxo-14-(4-(2-(pyridin-3-yl)ethyl)amino)-4-oxo-butyrato)-1-methoxy-5,12-naphthalenedione acetate;
86) 10-((3′-(pyrrol-1-yl)-2′,3′,6′-trideoxy-alphal-L-lyxo-hexylpyranyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-13-oxo-14-(4-(2-(pyridin-4-yl)ethyl)amino)-4-oxo-butyrato)-1-methoxy-5,12-naphthalenedione acetate;
87) 10-((3′-(pyrrol-1-yl)-2′,3′,6′-trideoxy-alphal-L-lyxo-hexylpyranyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-13-oxo-14-(4-(4-(3-(dimethylamino)propyl)piperazin-1-yl)-4-oxo-butyrato)-1-methoxy-5,12-naphthalenedione acetate;
89) 10-((3′-(pyrrol-1-yl)-2′,3′,6′-trideoxy-alphal-L-lyxo-hexylpyranyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-13-oxo-14-(4-((2-(morpholin-1-yl)ethyl)amino)-4-oxo-butyrato)-1-methoxy-5,12-naphthalenedione acetate;
96) 10-((3′-(pyrrol-1-yl)-2′,3′,6′-trideoxy-alphal-L-lyxo-hexylpyranyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-13-oxo-14-(4-((2-(morpholin-1-yl)ethyl)amino)-4-oxo-butyrato)-1-methoxy-5,12-naphthalenedione phosphate; and
99) 10-((3′-(pyrrol-1-yl)-2′,3′,6′-trideoxy-alphal-L-lyxo-hexylpyranyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-13-oxo-14-(4-((2-(morpholin-1-yl)ethyl)amino)-4-oxo-butyrato)-1-methoxy-5,12-naphthalenedione hydrochloride.
10. A process for preparing a compound represented by formula (I) of claim 1 , comprising
reacting a compound represented by formula (II) with a compound represented by formula (III) in the presence of a condensation agent to obtain a compound represented by formula (I),
wherein:
R 1 is selected from the group consisting of H, optionally substituted alkyl, and optionally substituted alkoxy;
W is selected from the group consisting of O and NH;
R 4 is selected from the group consisting of H, F, and optionally substituted alkyl;
R 5 is selected from the group consisting of H, F, optionally substituted alkyl and OR 6 , wherein R 6 is selected from the group consisting of H and tetrahydropyran-2-yl;
n is selected from the group consisting of 1, 2 and 3;
R 7 and R 8 are independently selected from the group consisting of H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (alkyleneoxy) m alkyl, optionally substituted heterocyclyl, optionally substituted alkyl, and optionally substituted —S(═O) 2 R, provided that groups represented by R 7 and R 8 do not comprise NH or NH 2 ; or NR 7 R 8 represents optionally substituted heterocyclyl;
wherein R comprises optionally substituted alkyl, optionally substituted cyclohydrocarbyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and
m is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11; and
optionally, contacting the compound represented by formula (III) having an amino-protecting group at N-terminus with a deprotection reactant to conduct a deprotection reaction to obtain the compound represented by formula (I), where the group represented by R 7 or R 8 comprises NH or NH 2 .
11. The process of claim 10 , further comprising adding a catalyst.
12. The process of claim 11 , wherein the catalyst is selected from 4-dimethylaminopyridine, 4-pyrrolidinylpyridine and a mixture thereof.
13. The process of claim 10 , wherein the amino-protection group is selected from the group consisting of Fmoc (fluorenylmethoxycarbony), Boc (t-butyloxycarboryl), CBZ (carbobenzoxy), Tr (trityl), Alloc (allyloxycarbonyl), Teoc (trimethylsilylethoxycarbonyl), methoxycarbonyl, ethoxycarbonyl, Pht (phthaloyl), Tos (tosyl), Ns (o/p-nitrobenzenesulfonyl), Tfa (trifluoroacetyl), pivaloyl, benzoyl, Dmb (2,4-dimethoxybenzyl), PMB (p-methoxybenzyl), and Bn (benzyl).
14. The process of claim 10 , wherein the condensation agent is selected from the group consisting of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), benzotriazol-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU), 6-chlorobenzotriazol-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), O-(7-azabenzotriazol-1-yl)-di(tetrahydropyrrolyl)carbenium hexafluophosphate (HAPyU), O-(benzotriazol-1-yl)-di(tetrahydropyrrolyl)carbenium hexafluophosphate (HBPyU), O-benzotriazol-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), 2-succinimido-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU), 2-(5-norbornen-2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborate quaternary ammonium salt (TNTU), benzotriazol-1-yloxytri(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol-1-yl-oxytripyrrolidino-phosphonium hexafluorophosphate (PyBOP), (3H-1,2,3-triazolo[4,5-b]pyridin-3-oxy)tri-1-pyrrolidinylphosphonium hexafluorophosphate (PyAOP), diphenylphosphinyl chloride (DPP-Cl), diphenyl phosphoryl azide (DPPA), cyanodiethylphosphate (DECP), bis(2-oxo-3-oxazolidinyl)phosphinyl chloride (BOP-Cl) and mixtures thereof.
15. The process of claim 10 , wherein the deprotection reactant is selected from the group consisting of hydrogen gas, NH 3 , aminoethanol, dimethylamine, diethylamine, piperidine, piperazine, 1,8-diazacyclo[5,4,0]hendecene-7 (DBU), hydrochloric acid, phosphoric acid, acetic acid, formic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and mixtures thereof.
16. The process of claim 10 , wherein the compound represented by formula (III) is obtained by a reaction of a compound represented by formula (IV) with HNR 7 R 8 ,
wherein:
n is selected from the group consisting of 1, 2 and 3;
R 7 and R 8 are independently selected from the group consisting of H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (alkyleneoxy) m alkyl, optionally substituted heterocyclyl, optionally substituted alkyl, and optionally substituted —S(═O) 2 R;
or NR 7 R 8 represents optionally substituted heterocyclyl;
wherein R comprises optionally substituted alkyl, optionally substituted cyclohydrocarbyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and
m is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11.
17. The process of claim 16 , further comprising adding an alkaline compound.
18. The process of claim 17 , wherein the alkaline compound is selected from the group consisting of triethylamine, pyridine, diisopropylethylamine, trimethylamine, N-methylpyrrolidine, N-methylpiperidine, N-methylmorpholine, N-ethylpyrrolidine, N-ethylpiperidine, N-ethylmorpholine and mixtures thereof.
19. The process of claim 10 , further comprising adding an activator.
20. The process of claim 19 , wherein the activator is selected from the group consisting of N-hydroxysuccinimide (HOSu), 1-hydroxy-7-azobenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), N-hydroxyphthalimide (NHPI), N-hydroxy-1,8-naphthalimide (NHNI), pentafluorophenol (PFPOH), 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU), 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), O-(7-azabenzotriazole-1-yl)-di(tetrahydropyrrolyl)carbenium hexafluophosphate (HAPyU), O-(benzotriazole-1-yl)-di(tetrahydropyrrolyl)carbenium hexafluophosphate (HBPyU), O-benzotriazole-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), 2-succinimido-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU), 2-(5-norbornen-2,3-dicarboximido)-1,1,3,3-tetramethyluronium tetrafluoroborate quaternary ammonium salt (TNTU), benzotriazole-1-yloxytri(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol-1-yl-oxytripyrrolidino-phosphonium hexafluorophosphate (PyBOP), (3H-1,2,3-triazolo[4,5-b]pyridin-3-oxy)tri-1-pyrrolidinylphosphonium hexafluorophosphate (PyAOP), diphenylphosphinyl chloride (DPP-Cl), diphenyl phosphoryl azide (DPPA), cyanodiethylphosphate (DECP), bis(2-oxo-3-oxazolidinyl)phosphinyl chloride (BOP-Cl) and mixtures thereof.
21. A formulation, comprising a compound represented by formula (I) of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
22. The formulation of claim 21 , which is a formulation for injection.
23. The process of claim 22 , wherein the formulation for injection is a conventional powder injection, a freeze-dried powder injection, a hydro-injection, an emulsion, a solution or a suspension.
24. A method for treating tumor and/or cancer, comprising administering to a subject in need thereof a therapeutically effective amount of the compound represented by formula (I) of claim 1 or a pharmaceutically acceptable salt thereof;
wherein the tumor and/or cancer is selected from the group consisting of liver cancer, breast cancer, small cell lung cancer, large cell lung cancer, ovarian cancer, pancreatic cancer, kidney clear cell adenocarcinoma, epidermal carcinoma, melanoma, and prostatic cancer.