CN1839128A - Mitotic kinesin inhibitors - Google Patents
Mitotic kinesin inhibitors Download PDFInfo
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- CN1839128A CN1839128A CN 200480023309 CN200480023309A CN1839128A CN 1839128 A CN1839128 A CN 1839128A CN 200480023309 CN200480023309 CN 200480023309 CN 200480023309 A CN200480023309 A CN 200480023309A CN 1839128 A CN1839128 A CN 1839128A
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Abstract
The present invention relates to dihydropyrrole compounds of the formula (I) that are useful for treating cellular proliferative diseases, for treating disorders associated with KSP kinesin activity, and for inhibiting KSP kinesin. The invention is also related to compositions which comprise these compounds, and methods of using them to treat cancer in mammals.
Description
Background of invention
The present invention relates to 2,2-two replaces 2, the 5-dihydro pyrrole derivates, and they are mitotic kinesins, the particularly inhibitor of mitotic kinesins KSP, and effectively treat cell proliferation disorders, cancer for example, hyperplasia, restenosis, cardiac hypertrophy, Immunological diseases and inflammation.
What be used for the treatment of cancer in therapeutical agent has taxanes and a vinca alkaloids.Taxan and vincaleucoblastine act on the microtubule that is present in the various kinds of cell structure.Microtubule is the important structure assembly of mitotic spindle.Mitotic spindle is responsible for genomic duplicate plate originally is distributed in each cell of two daughter cells that obtained by cell fission.Infer these medicines the destruction meeting of mitotic spindle is caused the cancer cells splitted is suppressed, and inducing cancer cell death.Yet microtubule also constitutes the cellularstructure of other types, comprises the passage that conducts in the cell in the nerve process.Because these medicines are not target with the mitotic spindle specifically, they have side effect, have limited their application thus.
People's improvement very interested is used for the treatment of the specificity of the medicine of cancer, because if the side effect relevant with the administration of these medicines can be reduced, its treatment benefit can be achieved.Traditionally, the remarkable improvement in the cancer therapy is with to identify the therapeutical agent with new role mechanism relevant.This example not only comprises bearing taxanes, and comprises the topoisomerase I inhibitor of having found camptothecin.From these two angles as seen, mitotic kinesins is the attractive target of new anti-cancer drug.
Mitotic kinesins is the necessary enzyme of mitotic spindle form, fit, and function, but is not the common segment of other micro-tubular structures.Mitotic kinesins played a significant role in mitotic all stages.These enzymes are " molecular moters ", and the Conversion of energy that they will discharge by the ATP hydrolysis is a mechanical force, and such mechanical force promotes the cell counter along the microtubule orientation movement.The catalyst structure domain of competent this task is about 340 amino acid whose dense structures.Mitotic division process, kinesin make the microtubule group constitute dipolar configuration, and this structure is exactly a mitotic spindle.Kinesin mediation karyomit(e) moves along spindle microtubule, and structural modification appears in the mitotic spindle relevant with mitotic specified phase.The experimental perturbation meeting of mitotic kinesins function causes the deformity or the dysfunction of mitotic spindle, causes the cell cycle to stop subsequently and death.
Certified in mitotic kinesins is KSP.KSP belongs to the evolution conservative kinesin matter subtribe of positive end direction microtubule engine, and it is assembled into the bipolar homotype tetramer of being made up of the antiparallel homodimer.The microtubule of KSP and mitotic spindle associates in the mitotic division process.Can prevent that the spindle pole in prometaphase from separating, and obtains monopolar spindle and cause that mitotic division stops and inducing apoptosis for the antibody of the anti-KSP of human body cell micro-injection.In other inhuman organisms, KSP makes the antiparallel microtubule be bundled into bundle with relevant kinesin and they is slided with respect to another person, forces two spindle poles separately thus.KSP also can mediate the gathering of microtubule on the elongation of later stage B spindle body and the spindle pole.
People KSP (being also referred to as HsEg5) open [Blangy etc., Cell, 83:1159-69 (1995); Whitehead etc., Arthritis Rheum., 39:1635-42 (1996); Galgio etc., J.Cell Biol., 135:339-414 (1996); Blangy etc., J Biol.Chem., 272:19418-24 (1997); Blangy, etc., Cell Motil Cytoskeleton, 40:174-82 (1998); Whitehead and R
aTtner, J.Cell Sci., 111:2551-61 (1998); Kaiser, etc., JBC274:18925-31 (1999); GenBank number of registration: X85137, NM004523 and U37426], and the fragment of KSP gene (TRIP5) be disclosed [Lee, etc., Mol Endocrinol., 9:243-54 (1995); GenBank number of registration L40372].Xenopus KSP homologue (Eg5) and Drosophila K-LP61F/KRP 130 have had report.
Quianzolinones has been considered to the inhibitor (PCT communique WO01/30768, May 3 calendar year 2001) of KSP at present.
Mitotic kinesins is to find and develop the attractive target of new mitotic division chemotherapeutics.So one object of the present invention is to be provided for suppressing compound, the method and composition of a kind of mitotic kinesins KSP.
Summary of the invention
The present invention relates to dihydro pyrrole derivates, they are used for the treatment of cell proliferation disorders, are used for the treatment of the obstacle relevant with KSP kinesin activity and are used to suppress the KSP kinesin.Compound of the present invention can be represented by the compound of formula I:
The accompanying drawing summary
The ORTE figure of Fig. 1 compound 2-5
The ORTEP figure of Fig. 2 compound 3-1.For the bonding diagram, most hydrogen atom is not represented.
Detailed Description Of The Invention
Compound establishment mitotic kinesins of the present invention and suc as formula shown in the compound of I:
Or its pharmaceutically acceptable salt or steric isomer, wherein:
A is 0 or 1;
B is D or 1;
M is 0,1 or 2;
N is 0,1,2 or 3;
R is 0 or 1;
S is 0 or 1;
T is 0,1 or 2;
U is 0 or 1;
R
1And R
2Be independently selected from: H, (C
1-C
6) alkyl, aryl, heterocyclic radical and (C
3-C
6) cycloalkyl, randomly be selected from R by 1,2 or 3
7Substituting group replace;
R
3Be selected from:
1) hydrogen;
2) C
1-C
10Alkyl;
3) C
1-C
10Alkyl-O-R
d,
4) C
2-C
10Alkenyl-O-R
d,
5) C
2-C
10Alkynyl group-O-R
d,
6) (C
1-C
6-alkylidene group)
nC
3-C
8Cycloalkyl-O-R
d,
7) C
1-C
10Alkyl-(C=O)
b-NR
cR
C ',
8) C
2-C
10Alkenyl-(C=O)
bNR
cR
C ',
9) C
2-C
10Alkynyl group-(C=O)
bNR
cR
C ',
10) (C
1-C
6-alkylidene group)
nC
3-C
8Cycloalkyl-(C=O)
bNR
cR
C ',
11) C
1-C
10Alkyl-S (O)
m-R
d,
12) C
2-C
10Alkenyl-S (O)
m-R
d,
13) C
2-C
10Alkynyl group-S (O)
m-R
d,
14) (C
1-C
6-alkylidene group)
nC
3-C
8Cycloalkyl-S (O)
m-R
d,
This alkyl, alkenyl, alkynyl group and cycloalkyl are randomly by one or more R that are selected from
6Substituting group replace;
R
4Be independently selected from:
1) (C=O)
aO
bC
1-C
10Alkyl,
2) (C=O)
aO
bAryl,
3)CO
2H，
4) halogen,
5)CN，
6)OH，
7) O
bC
1-C
6Perfluoroalkyl,
8)O
a(C＝O)
bNR
8R
9，
9)S(O)
mR
a，
10) S (O)
2NR
8R
9And
11)-OPO(OH)
2；
This alkyl, aryl, alkenyl, alkynyl group, heterocyclic radical and cycloalkyl randomly are selected from R by 1,2 and 3
7Substituting group replace;
R
5Be selected from:
1) hydrogen;
2) (C=O)
aO
bC
1-C
10Alkyl,
3) (C=O)
aO
bAryl,
4)CO
2H，
5) halogen,
6)CN，
7)OH，
8) O
bC
1-C
6Perfluoroalkyl,
9)O
a(C＝O)
bNR
8R
9，
10)S(O)
mR
a，
11) S (O)
2NR
8R
9And
12)-OPO(OH)
2；
This alkyl, aryl, alkenyl, alkynyl group, heterocyclic radical and cycloalkyl randomly are selected from R by 1,2 and 3
7Substituting group replace;
R
6Be independently selected from:
1) (C=O)
aO
bC
1-C
10Alkyl,
2) (C=O)
aO
bAryl,
3) C
2-C
10Alkenyl,
4) C
2-C
10Alkynyl group,
5) (C=O)
aO
bHeterocyclic radical,
6)CO
2H，
7) halogen,
8)CN，
9)OH，
10)
bC
1-C
6Perfluoroalkyl,
11)O
a(C＝O)
bNR
8R
9，
12)S(O)
mR
a，
13)S(O)
2NR
8R
9，
14) oxo,
15)CHO，
16)(N＝O)R
8R
9，
17) (C=O)
aO
bC
3-C
8Cycloalkyl and
18)-OPO(OH)
2；
This alkyl, aryl, alkenyl, alkynyl group, heterocyclic radical and cycloalkyl randomly are selected from R by 1,2 and 3
7Substituting group replace;
R
7Be selected from:
1) (C=O)
rO
s(C
1-C
10) alkyl,
2) O
r(C
1-C
3) perfluoroalkyl,
3) oxo,
4)OH，
5) halogen,
6)CN，
7) (C
2-C
10) alkenyl,
8) (C
2-C
10) alkynyl group,
9) (C=O)
rO
s(C
3-C
6) cycloalkyl,
10) (C=O)
rO
s(C
0-C
6) alkylidene group-aryl,
11) (C=O)
rO
s(C
0-C
6) the alkylidenyl-heterocyclic base,
12) (C=O)
rO
s(C
0-C
6) alkylidene group-N (R
b)
2,
13)C(O)R
a，
14) (C
0-C
6) alkylidene group-CO
2R
a,
15)C(O)H，
16) (C
0-C
6) alkylidene group-CO
2H and
17)(C＝O)
rN(R
b)
2，
18)S(O)
mR
a，
19) S (O)
2N (R
b)
2With
20)-OPO(OH)
2；
This alkyl, alkenyl, alkynyl group, cycloalkyl, aryl, alkylidene group and heterocyclic radical randomly by at the most 3 be selected from R
b, OH, (C
1-C
6) alkoxyl group, halogen, CO
2H, CN, O (C=O) C
1-C
6Alkyl, oxo, NO
2And N (R
b)
2Substituting group replace;
R
8And R
9Be independently selected from:
1)H，
2) (C=O) O
bC
1-C
10Alkyl,
3) (C=O) O
bC
3-C
8Cycloalkyl,
4) (C=O) O
bAryl,
5) (C=O) O
bHeterocyclic radical,
6) C
1-C
10Alkyl,
7) aryl,
8) C
2-C
10Alkenyl,
9) C
2-C
10Alkynyl group,
10) heterocyclic radical,
11) C
3-C
8Cycloalkyl,
12) SO
2R
aAnd
13)(C＝O)NR
b 2，
This alkyl, cycloalkyl, aryl, heterocyclic radical, alkenyl and alkynyl group randomly are selected from R by 1,2 and 3
7Substituting group replace, or
R
8And R
9Can constitute each ring of monocycle or bicyclic heterocycle while with the nitrogen that it connected and have 3-7 person and except that this nitrogen, randomly contain 1 or 2 additional heteroatoms that is selected from N, O or S, this monocycle or bicyclic heterocycle randomly are selected from R by 1,2 or 3
7Substituting group replace;
R
10And R
11Be independently selected from: F and-CH
2F;
R
12And R
13Be independently selected from: H and-CH
2F;
R
OxDo not exist or oxo;
R
aBe independently selected from: (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl, aryl or heterocyclic radical randomly are selected from R by 1,2 or 3
7Substituting group replace;
R
bBe independently selected from: H, (C
1-C
6) alkyl, aryl, heterocyclic radical, (C
3-C
6) cycloalkyl, (C=O) OC
1-C
6Alkyl, (C=O) C
1-C
6Alkyl, (C=O) aryl, (C=O) heterocyclic radical, (C=O) NR
eR
E 'Or S (O)
2R
a, randomly be selected from R by 1,2 or 3
7Substituting group replace;
R
cAnd R
C 'Be independently selected from: H, (C
1-C
6) alkyl, aryl, NH
2, OH, OR
a,-alkyl-OH ,-(C
1-C
6) alkyl-O-(C
1-C
6) alkyl, (C=O) OC
1-C
6Alkyl, (C=O) C
1-C
6Alkyl, (C=O) aryl, (C=O) heterocyclic radical, (C=O) NR
eR
E ', S (O)
2R
aWith-alkyl-N (R
b)
2, wherein this alkyl randomly is selected from R by 1,2 or 3
7Substituting group replace; Or
R
cAnd R
C 'Can constitute each ring of monocycle or bicyclic heterocycle while with the nitrogen that it connected and have 3-7 person and except that this nitrogen, randomly contain 1 or 2 additional heteroatoms that is selected from N, O or S, this monocycle or bicyclic heterocycle randomly are selected from R by 1,2 or 3
7Substituting group replace;
R
dBe selected from: H, (C
1-C
6) alkyl ,-(C
2-C
6) alkyl-OH ,-(C
1-C
6) alkyl-O-(C
1-C
6) alkyl and-(C
1-C
6) alkyl-N (R
b)
2, wherein this alkyl randomly is selected from R by 1,2 or 3
7Substituting group replace;
R
eAnd R
E 'Be independently selected from: H, (C
1-C
6) alkyl, aryl, heterocyclic radical and (C
3-C
6) cycloalkyl, randomly be selected from R by 1,2 or 3
7Substituting group replace; Or
R
eAnd R
E 'Can constitute each ring of monocycle or bicyclic heterocycle while with the nitrogen that it connected and have 3-7 person and except that this nitrogen, randomly contain 1 or 2 additional heteroatoms that is selected from N, O or S, this monocycle or bicyclic heterocycle randomly are selected from R by 1,2 and 3
7Substituting group replace.
Compound of the present invention effectively suppresses mitotic kinesins and suc as formula shown in the compound of II:
Or its pharmaceutically acceptable salt or steric isomer,
Wherein:
A is 0 or 1;
B is 0 or 1;
M is 0,1, or 2;
N is 0,1,2 or 3;
R is 0 or 1;
S is 0 or 1;
T is 0 or 1;
R
1And R
2Be independently selected from: H, (C
1-C
6) alkyl, aryl, heterocyclic radical and (C
3-C
6) cycloalkyl, randomly be selected from R by 1,2 or 3
7Substituting group replace;
R
3Be selected from:
1) hydrogen;
2) C
1-C
10Alkyl;
3) C
1-C
10Alkyl-O-R
d,
4) C
2-C
10Alkenyl-O-R
d,
5) C
2-C
10Alkynyl group-O-R
d,
6) (C
1-C
6-alkylidene group)
nC
3-C
8Cycloalkyl-O-R
d,
7) C
1-C
10Alkyl-(C=O)
b-NR
cR
C ',
8) C
2-C
10Alkenyl-(C=O)
bNRCR
C ',
9) C
2-C
10Alkynyl group-(C=O)
bNR
cR
C ',
10) (C
1-C
6-alkylidene group)
nC
3-C
8Cycloalkyl-(C=O)
bNR
cR
C ',
11) C
1-C
10Alkyl-S (O)
m-R
d,
12) C
2-C
10Alkenyl-S (O)
mR
d,
13) C
2-C
10Alkynyl group-S (O)
m-R
d,
14) (C
1-C
6-alkylidene group)
nC
3-C
8Cycloalkyl-S (O)
mR
d,
This alkyl, alkenyl, alkynyl group and cycloalkyl are randomly by one or more R that are selected from
6Substituting group replace;
R
4Be independently selected from:
1) (C=O)
aO
bC
1-C
10Alkyl,
2) (C=O)
aO
bAryl,
3)CO
2H，
4) halogen,
5)CN，
6)OH，
7) O
bC
1-C
6Perfluoroalkyl,
8)O
a(C＝O)
bNR
8R
9，
9)S(O)
mR
a，
10)S(O)
2NR
8R
9，
This alkyl, aryl, alkenyl, alkynyl group, heterocyclic radical and cycloalkyl randomly are selected from R by 1,2 and 3
7Substituting group replace;
R
5Be selected from:
1) hydrogen;
2) (C=O)
aO
bC
1-C
10Alkyl,
3) (C=O)
aO
bAryl,
4)CO
2H，
5) halogen,
6)CN，
7)OH，
O
bC
1-C
6Perfluoroalkyl,
9)O
a(C＝O)
bNR
8R
9，
10)S(O)
mR
a，
11) S (O)
2NR
8R
9And
12)-OPO(OH)
2；
This alkyl, aryl, alkenyl, alkynyl group, heterocyclic radical and cycloalkyl randomly are selected from R by 1,2 and 3
7Substituting group replace;
R
6Be independently selected from:
1) (C=O)
aO
bC
1-C
10Alkyl,
2) (C=O)
aO
bAryl,
3) C
2-C
10Alkenyl,
4) C
2-C
10Alkynyl group,
5) (C=O)
aO
bHeterocyclic radical,
6)CO
2H，
7) halogen,
8)CN，
9)OH，
10) O
bC
1-C
6Perfluoroalkyl,
11)O
a(C＝O)
bNR
8R
9，
12)S(O)
mR
a，
13)S(O)
2NR
8R
9，
14) oxo,
15)CHO，
16)(N＝O)R
8R
9，
17) (C=O)
aO
bC
3-C
8Cycloalkyl and
18)-OPO(OH)
2；
This alkyl, aryl, alkenyl, alkynyl group, heterocyclic radical and cycloalkyl randomly are selected from R by 1,2 or 3
7Substituting group replace;
R
7Be selected from:
1) (C=O)
rO
s(C
1-C
10) alkyl,
2) O
r(C
1-C
3) perfluoroalkyl,
3) oxo,
4)OH，
5) halogen,
6)CN，
7) (C
2-C
10) alkenyl,
8) (C
2-C
10) alkynyl group,
9) (C=O)
rO
s(C
3-C
6) cycloalkyl,
10) (C=O)
rO
s(C
0-C
6) alkylidene group-aryl,
11) (C=O)
rO
s(C
0-C
6) the alkylidenyl-heterocyclic base,
12) (C=O)
rO
s(C
0-C
6) alkylidene group-N (R
b)
2,
13)C(O)R
a，
14) (C
0-C
6) alkylidene group-CO
2R
a,
15)C(O)H，
16) (C
0-C
6) alkylidene group-CO
2H,
17)C(O)N(R
b)
2，
18)S(O)
mR
a，
19) S (O)
2N (R
b)
2With
20)-OPO(OH)
2；
This alkyl, alkenyl, alkynyl group, cycloalkyl, aryl, alkylidene group and heterocyclic radical randomly by at the most 3 be selected from R
b, OH, (C
1-C
6) alkoxyl group, halogen, CO
2H, CN, O (C=O) C
1-C
6Alkyl, oxo, NO
2And N (R
b)
2Substituting group replace;
R
8And R
9Be independently selected from:
1)H，
2) (C=O) O
bC
1-C
10Alkyl,
3) (C=O) O
bC
3-C
8Cycloalkyl,
4) (C=O) O
bAryl,
5) (C=O) O
bHeterocyclic radical,
6) C
1-C
10Alkyl,
7) aryl,
8) C
2-C
10Alkenyl,
9) C2-C10 alkynyl group,
10) heterocyclic radical,
11) C
3-C
8Cycloalkyl,
12) SO
2R
aAnd
13)(C＝O)NR
b2，
This alkyl, cycloalkyl, aryl, heterocyclic radical, alkenyl and alkynyl group randomly are selected from R by 1,2 or 3
7Substituting group replace, or
R
8And R
9Can constitute each ring of monocycle or bicyclic heterocycle while with the nitrogen that it connected and have 3-7 person and except that this nitrogen, randomly contain 1 or 2 additional heteroatoms that is selected from N, O or S, this monocycle or bicyclic heterocycle randomly are selected from R by 1,2 or 3
7Substituting group replace;
R
10Be selected from: F and-CH
2F;
R
13Be selected from: H and-CH
2F,
Condition is if t is 1, then R
13Be H;
R
OxDo not exist or oxo;
R
aBe independently selected from: (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl, aryl or heterocyclic radical randomly are selected from R by 1,2 or 3
7Substituting group replace;
R
bBe independently selected from: H, (C
1-C
6) alkyl, aryl, heterocyclic radical, (C
3-C
6) cycloalkyl, (C=O) OC
1-C
6Alkyl, (C=O) C
1-C
6Alkyl, (C=O) aryl, (C=O) heterocyclic radical, (C=O) NR
eR
E 'Or S (O)
2R
a, randomly be selected from R by 1,2 or 3
7Substituting group replace;
R
cAnd R
C 'Be independently selected from: H, (C
1-C
6) alkyl, aryl, NH
2, OH, OR
a.-(C
1-C
6) alkyl-OH ,-(C
1-C
6) alkyl-O-(C
1-C
6) alkyl, (C=O) OC
1-C
6Alkyl, (C=O) C
1-C
6Alkyl, (C=O) aryl, (C=O) heterocyclic radical, (C=O) NR
eR
E ', S (O)
2R
aWith-(C
1-C
6) alkyl-N (R
b)
2, wherein this alkyl randomly is selected from R by 1,2 or 3
7Substituting group replace; Or
R
cAnd R
C 'Can constitute monocycle or bicyclic heterocycle with the nitrogen that it connected and have 3-7 person and except that this nitrogen, randomly contain 1 or 2 additional heteroatoms that is selected from N, O or S in each ring simultaneously, this monocycle or bicyclic heterocycle randomly are selected from R by 1,2 and 3
7Substituting group replace;
R
dBe selected from: H, (C
1-C
6) alkyl ,-(C
2-C
6) alkyl-OH ,-(C
1-C
6) alkyl-O-(C
1-C
6) alkyl and-(C
1-C
6) alkyl-N (R
b)
2, wherein this alkyl randomly is selected from R by 1,2 or 3
7Substituting group replace;
R
eAnd R
E 'Be independently selected from: H, (C
1-C
6) alkyl, aryl, heterocyclic radical and (C
3-C
6) cycloalkyl, randomly be selected from R by 1,2 and 3
7Substituting group replace; Or
R
eAnd R
E 'Can constitute each ring of monocycle or bicyclic heterocycle while with the nitrogen that it connected and have 3-7 person and except that this nitrogen, randomly contain 1 or 2 additional heteroatoms that is selected from N, O or S, this monocycle or bicyclic heterocycle randomly are selected from R by 1,2 and 3
7Substituting group replace.
This compound is shown in the compound of formula III in embodiments of the present invention:
Or its pharmaceutically acceptable salt or steric isomer, wherein:
A is 0 or 1;
B is 0 or 1;
M is 0,1 or 2;
N is 0,1 or 2;
R is 0 or 1;
S is 0 or 1;
R
1And R
2Be independently selected from: H, (C
1-C
6) alkyl, aryl and (C
3-C
6) cycloalkyl, randomly be selected from R by 1,2 or 3
7Substituting group replace;
R
4Be independently selected from:
1) halogen,
2)OH，
3) O
bC
1-C
6Perfluoroalkyl,
R
5Be selected from:
1) hydrogen,
2) halogen,
3)OH，
4) O
bC
1-C
6Perfluoroalkyl,
R
7Be selected from:
1) (C=O)
rO
s(C
1-C
10) alkyl,
2) O
r(C
1-C
3) perfluoroalkyl,
3) oxo,
4)OH，
5) halogen,
6)CN，
7) (C
2-C
10) alkenyl,
8) (C
2-C
10) alkynyl group,
9) (C=O)
rO
s(C
3-C
6) cycloalkyl,
10) (C=O)
rO
s(C
0-C
6) alkylidene group-aryl,
11) (C=O)
rO
s(C
0-C
6) the alkylidenyl-heterocyclic base,
12) (C=O)
rO
s(C
0-C
6) alkylidene group-N (R
b)
2,
13)C(O)R
a，
14) (C
0-C
6) alkylidene group-CO
2R
a,
15)C(O)H，
16) (C
0-C
6) alkylidene group-CO
2H and
17)C(O)N(R
b)
2，
18) S (O)
mR
aAnd
19)S(O)
2N(R
b)
2；
This alkyl, alkenyl, alkynyl group, cycloalkyl, aryl, alkylidene group and heterocyclic radical randomly by at the most 3 be selected from R
b, OH, (C
1-C
6) alkoxyl group, halogen, CO
2H, CN, O (C=O) C
1-C
6Alkyl, oxo, NO
2And N (R
b)
2Substituting group replace;
R
8And R
9Be independently selected from:
1)H，
2) (C=O) O
bC
1-C
10Alkyl,
3) (C=O) O
bC
3-C
8Cycloalkyl,
4) (C=O) O
bAryl,
5) (C=O) O
bHeterocyclic radical,
6) C
1-C
10Alkyl,
7) aryl,
8) C
2-C
10Alkenyl,
9) C
2-C
10Alkynyl group,
10) heterocyclic radical,
11) C
3-C
8Cycloalkyl,
12) SO
2R
aAnd
13)(C＝O)NR
b2，
This alkyl, cycloalkyl, aryl, heterocyclic radical, alkenyl and alkynyl group randomly are selected from R by 1,2 and 3
7Substituting group replace, or
R
8And R
9Can constitute each ring of monocycle or bicyclic heterocycle while with the nitrogen that it connected and have 3-7 person and except that this nitrogen, randomly contain 1 or 2 additional heteroatoms that is selected from N, O or S, this monocycle or bicyclic heterocycle randomly are selected from R by 1,2 and 3
7Substituting group replace;
R
aBe independently selected from: (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl, aryl or heterocyclic radical randomly are selected from R by 1,2 or 3
7Substituting group replace;
R
bBe independently selected from: H, (C
1-C
6) alkyl, aryl, heterocyclic radical, (C
3-C
6) cycloalkyl, (C=O) OC
1-C
6Alkyl, (C=O) C
1-C
6Alkyl, (C=O) aryl, (C=O) heterocyclic radical, (C=O) NR
eR
E 'Or S (O)
2R
a, randomly be selected from R by 1,2 or 3
7Substituting group replace;
R
cAnd R
C 'Be independently selected from: H, (C
1-C
6) alkyl, aryl, NH
2, OH, OR
a,-alkyl-OH ,-(C
1-C
6) alkyl-O-(C
1-C
6) alkyl, (C=O) OC
1-C
6Alkyl, (C=O) C
1-C
6Alkyl, (C=O) aryl, (C=O) heterocyclic radical, (C=O) NR
eR
E ', S (O)
2R
aWith-(C
1-C
6) alkyl-N (R
b)
2, wherein this alkyl randomly is selected from R by 1,2 or 3
7Substituting group replace; Or
R
cAnd R
C 'Can constitute each ring of monocycle or bicyclic heterocycle while with the nitrogen that it connected and have 3-7 person and except that this nitrogen, randomly contain 1 or 2 additional heteroatoms that is selected from N, O or S, this monocycle or bicyclic heterocycle randomly are selected from R by 1,2 or 3
7Substituting group replace;
R
eAnd R
E 'Be independently selected from: H, (C
1-C
6) alkyl, aryl, heterocyclic radical and (C
3-C
6) cycloalkyl, randomly be selected from R by 1,2 or 3
7Substituting group replace; Or
R
eAnd R
E 'Can constitute each ring of monocycle or bicyclic heterocycle while with the nitrogen that it connected and have 3-7 person and except that this nitrogen, randomly contain 1 or 2 additional heteroatoms that is selected from N, O or S, this monocycle or bicyclic heterocycle randomly are selected from R by 1,2 and 3
7Substituting group replace.
Another embodiment of the present invention is suc as formula shown in the compound of IV:
Or its pharmaceutically acceptable salt or steric isomer, wherein:
A is 0 or 1;
B is 0 or 1;
M is 0,1 or 2;
R is 0 or 1;
S is 0 or 1;
R
1And R
2Be independently selected from: H and (C
1-C
6) alkyl, randomly be selected from R by 1,2 or 3
7Substituting group replace;
R
4Be independently selected from:
1) halogen,
2)OH，
3) O
bC
1-C
6Perfluoroalkyl,
R
7Be selected from:
1) (C=O)
rO
s(C
1-C
10) alkyl,
2) O
r(C
1-C
3) perfluoroalkyl,
3) oxo,
4)OH，
5) halogen,
6)CN，
7) (C
2-C
10) alkenyl,
8) (C
2-C
10) alkynyl group,
9) (C=O)
rO
s(C
3-C
6) cycloalkyl,
10) (C=O)
rO
s(C
0-C
6) alkylidene group-aryl,
11) (C=O)
rO
s(C
0-C
6) the alkylidenyl-heterocyclic base,
12) (C=O)
rO
s(C
0-C
6) alkylidene group-N (R
b)
2,
13)C(O)R
a，
14) (C
0-C
6) alkylidene group-CO
2R
a,
15)C(O)H，
16) (C
0-C
6) alkylidene group-CO
2H and
17)C(O)N(R
b)
2，
18) S (O)
mR
aAnd
19)S(O)
2N(R
b)
2；
This alkyl, alkenyl, alkynyl group, cycloalkyl, aryl, alkylidene group and heterocyclic radical randomly by at the most 3 be selected from R
b, OH, (C
1-C
6) alkoxyl group, halogen, CO
2H, CN, O (C=O) C
1-C
6Alkyl, oxo, NO
2And N (R
b)
2Substituting group replace;
R
8And R
9Be independently selected from:
1)H，
2) (C=O) O
bC
1-C
10Alkyl,
3) (C=O) O
bC
3-C
8Cycloalkyl,
4) (C=O) O
bAryl,
5) (C=O) O
bHeterocyclic radical,
6) C
1-C
10Alkyl,
7) aryl,
8) C
2-C
10Alkenyl,
9) C
2-C
10Alkynyl group,
10) heterocyclic radical,
11) C
3-C
8Cycloalkyl,
12) SO
2R
aAnd
13)(C＝O)NR
b 2，
This alkyl, cycloalkyl, aryl, heterocyclic radical, alkenyl and alkynyl group randomly are selected from R by 1,2 or 3
7Substituting group replace, or
R
8And R
9Can constitute each ring of monocycle or bicyclic heterocycle while with the nitrogen that it connected and have 3-7 person and except that this nitrogen, randomly contain 1 or 2 additional heteroatoms that is selected from N, O or S, this monocycle or bicyclic heterocycle randomly are selected from R by 1,2 and 3
7Substituting group replace;
R
aBe independently selected from: (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl, aryl or heterocyclic radical randomly are selected from R by 1,2 or 3
7Substituting group replace;
R
bBe independently selected from: H, (C
1-C
6) alkyl, aryl, heterocyclic radical, (C
3-C
6) cycloalkyl, (C=O) OC
1-C
6Alkyl, (C=O) C
1-C
6Alkyl, (C=O) aryl, (C=O) heterocyclic radical, (C=O) NR
eR
E 'Or S (O)
2R
a, randomly be selected from R by 1,2 or 3
7Substituting group replace;
R
cAnd R
C 'Be independently selected from: H, (C
1-C
6) alkyl, aryl, NH
2, OH, OR
a,-(C
1-C
6) alkyl-OH ,-(C
1-C
6) alkyl-O-(C
1-C
6) alkyl, (C=O) OC
1-C
6Alkyl, (C=O) C
1-C
6Alkyl, (C=O) aryl, (C=O) heterocyclic radical, (C=O) NR
eR
E ', S (O)
2R
aWith-(C
1-C
6) alkyl-N (R
b)
2, wherein this alkyl randomly is selected from R by 1,2 or 3
7Substituting group replace; Or
R
cAnd R
C 'Can constitute each ring of monocycle or bicyclic heterocycle while with the nitrogen that it connected and have 3-7 person and except that this nitrogen, randomly contain 1 or 2 additional heteroatoms that is selected from N, O or S, this monocycle or bicyclic heterocycle randomly are selected from R by 1,2 or 3
7Substituting group replace;
R
eAnd R
E 'Be independently selected from: H, (C
1-C
6) alkyl, aryl, heterocyclic radical and (C
3-C
6) cycloalkyl, randomly be selected from R by 1,2 or 3
7Substituting group replace; Or
R
eAnd R
E 'Can constitute each ring of monocycle or bicyclic heterocycle while with the nitrogen that it connected and have 3-7 person and except that this nitrogen, randomly contain 1 or 2 additional heteroatoms that is selected from N, O or S, this monocycle or bicyclic heterocycle randomly are selected from R by 1,2 and 3
7Substituting group replace.
Another embodiment of the present invention is suc as formula shown in the compound of V:
Or its pharmaceutically acceptable salt or steric isomer, wherein:
R
1And R
2Be independently selected from: H and (C
1-C
6) alkyl.
Another embodiment of the present invention is suc as formula shown in the compound of VI:
Or its pharmaceutically acceptable salt or steric isomer, wherein:
R
1And R
2Be independently selected from: H and (C
1-C
6) alkyl.
The specific examples of compound of the present invention comprises:
(2S)-4-(2, the 5-difluorophenyl)-N-[(3S, 4R)-3-fluoro-1-methyl piperidine-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
(2S)-4-(2, the 5-difluorophenyl)-N-[(3R, 4S)-3-fluoro-1-methyl piperidine-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
(2S)-4-(2, the 5-difluorophenyl)-N-[(3R, 4R)-3-fluoro-1-methyl piperidine-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
(2S)-4-(2, the 5-difluorophenyl)-N-[(3S, 4S)-3-fluoro-1-methyl piperidine-4-yl]-2-(hydroxymethyl)-N-methyl-2 phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
(2S)-4-(2, the 5-difluorophenyl)-N-[(3S, 4R)-3-fluoro-1-methyl piperidine-4-yl]-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
(2S)-4-(2, the 5-difluorophenyl)-N-[(3R, 4S)-3-fluoro-1-methyl piperidine-4-yl]-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
(2S)-4-(2, the 5-difluorophenyl)-N-[(3R, 4R)-3-fluoro-1-methyl piperidine-4-yl]-N-methyl-2-phenyl-2,5-dihydro-1H pyrroles-1-carboxylic acid amides
(2S)-4-(2, the 5-difluorophenyl)-N-[(2R, 4R)-2-(methyl fluoride)-1-methyl piperidine-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
(2-4-(2, the 5-difluorophenyl)-N-[(2S, 4S)-2-(methyl fluoride)-1-methyl piperidine-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides (2S)-4-(2, the 5-difluorophenyl)-N-[(3S, 4R)-3-fluoro-1-methyl isophthalic acid-bridging oxygen piperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
(2S)-4-(2, the 5-difluorophenyl)-N-[(3S, 4R)-3-fluorine piperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
(2S)-4-(2, the 5-difluorophenyl)-N-[(3S, 4R)-3-fluoro-1-sec.-propyl piperidines 4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-carboxylic acid amides
(2S)-4-(2, the 5-difluorophenyl)-N-[(3S, 4S)-3-fluorine piperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides or its pharmaceutically acceptable salt or steric isomer.
The particular instance of compound of the present invention is:
(2S)-4-(2, the 5-difluorophenyl)-N-[(3S, 4S)-3-fluoro-1-methyl piperidine-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
(2S)-4-(2, the 5-difluorophenyl)-N-[(3S, 4R)-3-fluoro-1-methyl piperidine-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
(2S)-4-(2, the 5-difluorophenyl)-N-[(3R, 4S)-3-fluoro-1-methyl piperidine-4-yl]-2-(hydroxymethyl)-N-methyl-2 phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
(2S)-4-(2, the 5-difluorophenyl)-N-[(2R, 4R)-2-(methyl fluoride)-1-methyl piperidine-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
(2S)-4-(2, the 5-difluorophenyl)-N-[(3R, 4S)-3-fluoro-1-methyl piperidine-4-yl]-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides or its pharmaceutically acceptable salt or steric isomer.
Compound of the present invention compound of the present invention can have asymmetric center, chiral axis and chirality plane (as E.L.Eliel and S.H.Wilen, Stereochemistry of CarbonCompounds, John Wiley ﹠amp; Sons, New York, 1994, the 1119-1190 page or leaf is described), and racemic modification, racemize miscellany and independent diastereomer appear, and all possible isomer and miscellany, comprising optical isomer, these steric isomers all belong to the present invention.In addition, compound disclosed herein can exist tautomer and two kinds of tautomers to belong in the scope of the present invention, even only show a kind of tautomeric structure.
As any variable part (R for example
4, R
7, R
10Deng) only occur once when above at any structure, its definition in various situations exists independently of one another.In addition, the combination of substituting group and variable part also allows, as long as such combination can access stable compound.From substituting group extend in the ring system lines representatives can with can replace the key that annular atoms links to each other arbitrarily.If this ring system is polynary ring, this key should only link to each other with any suitable carbon atom of adjacent loops.
Substituting group and the replacement mode that should understand on the The compounds of this invention can be selected by those of ordinary skills, thus provide chemically stable and can be easy to utilize technology known in the art and those methods hereinafter described, from the starting raw material synthetic compound of easy acquisition.If substituting group itself is replaced by more than one group, should understand so a plurality of groups and can be positioned on the same carbon or on different carbon, as long as obtain stable structure.Phrase " is randomly replaced by one or more substituting groups " should be equal to phrase " randomly by at least one substituting group replacement ", and preferred embodiment should be to have 0-3 substituting group in this type of situation.
" alkyl " comprises the side chain or the straight chain radical of saturated aliphatic alkyl of the carbon atom with given number as used herein.For example, C
1-C
10, as " C
1-C
10Alkyl " in be defined as comprise that straight or branched arranges have 1,2,3,4,5,6,7,8, the group of 9 or 10 carbon.For example, " C
1-C
10Alkyl " specifically comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group, hexyl, heptyl, octyl group, nonyl, decyl etc.Term " cycloalkyl " is meant the monocycle radical of saturated aliphatic alkyl of the carbon atom with given number.For example, " cycloalkyl " comprising: cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl etc.In embodiments of the present invention, term " cycloalkyl " comprises above-mentioned group and further comprises monocycle unsaturated aliphatic alkyl.For example, " cycloalkyl " is defined as comprising cyclopropyl in this embodiment, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, cyclopentenyl, cyclobutene base etc.
Term " alkylidene group " is meant hydrocarbon two bases of the carbon atom with given number.For example, " alkylidene group " comprises-CH
2-,-CH
2CH
2-etc.
When at phrase " C
1-C
6Aralkyl " and " C
1-C
6Heteroaralkyl " during middle the use, term " C
1-C
6" be meant the moieties of this group and do not comprise the aryl of this group and the atom number in the heteroaryl moieties.
" alkoxyl group " representative is through the ring-type or the non-annularity alkyl that specifies number carbon atom that have of oxo bridge connection.So " alkoxyl group " comprises the definition of abovementioned alkyl and cycloalkyl.
If do not stipulate the number of carbon atom, term " alkenyl " is meant the non-aromatic hydrocarbyl of straight chain, side chain or cyclic that contains 2-10 carbon atom and at least one carbon-to-carbon double bond.Carbon-to-carbon double bond of preferred existence, and can have four non-aromatics carbon-to-carbon double bonds at the most.So, " C
2-C
6Alkenyl " is meant the alkenyl with 2-6 carbon atom.Alkenyl comprises vinyl, propenyl, butenyl, 2-methyl butene base and cyclohexenyl.The straight chain of alkenyl, side chain or circular part can contain two keys, and if illustrate and be substituted alkenyl, it can be substituted.
Term " alkynyl group " is meant the non-aromatic hydrocarbyl of straight chain, side chain or cyclic that contains 2-10 carbon atom and at least one carbon-to-carbon three key.Can there be carbon-to-carbon three key at the most.So, " C
2-C
6Alkynyl group " is meant the alkynyl group with 2-6 carbon atom.Alkynyl group comprises ethynyl, proyl, butynyl, 3-methyl butynyl etc.The straight chain of alkynyl group, side chain or circular part can contain three key, and if mark and be substituted alkynyl group, it can be substituted.
In some cases, substituting group can define with the carbon atom of certain limit, and this scope comprises 0, for example (C
0-C
6) alkylidene group-aryl.If aryl is a phenyl, this definition should comprise phenyl itself and-CH
2Ph ,-CH
2CH
2Ph, CH (CH
3) CH
2CH (CH
3) Ph etc.
" aryl " is meant that any each ring contains the stable monocycle or the bicyclic carbocyclic of 7 atoms at the most as used herein, and wherein at least one ring is an aromatics.The example that this type of aryl is formed comprises phenyl, naphthyl, tetralyl, dihydro indenyl and biphenyl.Aryl substituent is that dicyclo and a ring are in the situation of non-aromatics therein, should understand connection and should pass through this aromatic ring.
The term heteroaryl represents that each ring contains the stable monocycle or the dicyclo ring of 7 atoms at the most as used herein, wherein at least one ring be aromatics and contain 1-4 heteroatoms that is selected from O, N and S.Heteroaryl in this range of definition includes but not limited to: acridyl, carbazyl, cinnolines base, quinoxalinyl, pyrazolyl, indyl, benzotriazole base, furyl, thienyl, benzothienyl, benzofuryl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, tetrahydroquinoline.As following heterocyclic definition, " heteroaryl " also is understood to include the N-oxide derivative of any nitrogenous heteroaryl.The heteroaryl substituting group is that dicyclo and ring are non-aromatics or when not containing heteroatoms therein, is interpreted as respectively to connect by aromatic ring or by containing heteroatomic ring.
Term " heterocycle " or " heterocyclic radical " are meant and contain 1-4 heteroatomic 5-to 10-member aromatics or non-aromatic heterocyclic that is selected from O, N and S as used herein, and comprise bicyclic radicals." heterocyclic radical " comprises the above-mentioned heteroaryl of mentioning, with and dihydro and tetrahydrochysene analogue.Other examples of " heterocyclic radical " include, but are not limited to following: benzimidazolyl-, benzofuryl, benzo furazan base; the benzopyrazoles base, benzotriazole base, benzothienyl, benzoxazolyl; carbazyl, carbolinyl, cinnolines base, furyl; imidazolyl, indoline base, indyl, indolizine base; indazolyl, isobenzofuran-base, pseudoindoyl, isoquinolyl; isothiazolyl, isoxazolyl, naphthopyridine base, oxadiazoles base; oxazolyl, oxazoline group, isoxazoline base, oxetanyl; pyranyl, pyrazinyl, pyrazolyl; pyridazinyl, pyridopyridine base, pyridazinyl; pyridyl, pyrimidyl, pyrryl; quinazolyl, quinolyl, quinoxalinyl; THP trtrahydropyranyl, tetrahydro thiapyran base, tetrahydro isoquinolyl; tetrazyl, tetrazolo pyridyl, thiadiazolyl group; thiazolyl, thienyl, triazolyl; azetidinyl, 1,4-dioxan base; six hydrogen azatropylidene bases, piperazinyl, piperidyl; the pyridin-2-ones base, pyrrolidyl, morpholinyl; thio-morpholinyl, dihydrobenzo imidazolyl, dihydro benzo furyl; the dihydrobenzo thienyl, dihydrobenzo oxazolyl, dihydrofuran base; the glyoxalidine base, indolinyl, dihydro-isoxazole base; the dihydro isothiazolyl, dihydro oxadiazoles base, dihydro-oxazole base; the dihydro pyrazinyl, pyrazoline base, dihydropyridine base; the dihydro-pyrimidin base, pyrrolin base, dihydroquinoline base; the dihydro tetrazyl, thiodiazoline base, dihydro-thiazolyl; the dihydro-thiophene base, dihydro triazolyl, dihydro azetidinyl; the methylenedioxyphenyl formyl radical, tetrahydrofuran base and tetrahydro-thienyl and its N-oxide compound.The substituent connection of heterocyclic radical can realize by carbon atom or heteroatoms.
Preferably, heterocycle is selected from 2-azatropylidene ketone, benzimidazolyl-, 2-diazepine ketone, imidazolyl, 2-imidazolidone, indyl, isoquinolyl, morpholinyl, piperidyl, piperazinyl, pyridyl, pyrrolidyl, 2-piperidone (piperidinone), 2-pyrimidone, 2-Pyrrolidone, quinolyl, tetrahydrofuran base, tetrahydro isoquinolyl and thienyl.
It will be understood by those skilled in the art that " halo " or " halogen " comprises chlorine as used herein, fluorine, bromine and iodine.
This alkyl, alkenyl, alkynyl group, cycloalkyl, aryl, heteroaryl and heterocyclic radical substituting group can be substituted or not replace, unless otherwise defined.For example, (C
1-C
6) alkyl can be selected from OH, oxo, halogen, alkoxyl group, dialkyl amido, or heterocyclic radical such as morpholinyl, replacements such as piperidyl by 1,2 or 3.In such a case, if substituting group is oxo and other substituting groups when being OH, then comprise following in the definition :-C=O) CH
2CH (OH) CH
3The OH of ,-(C=O) ,-CH
2(OH) CH
2CH (O) etc.
In some cases, R
8And R
9, R
cAnd R
C 'And R
fAnd R
F 'Be defined as they can constitute with the nitrogen that it connected monocycle or bicyclic heterocycle simultaneously each ring have 5-7 member, and except that this nitrogen, randomly contain 1 or 2 additional heteroatoms that is selected from N, O or S, this heterocycle is randomly by one or more R that are selected from
7Substituting group replace.The heterocyclic example that can form thus includes, but not limited to remember that this heterocycle randomly is selected from R by one or more (and in one embodiment, being 1,2 or 3)
7Substituting group replace:
In some cases, R
dAnd R
D 'Be defined as them and can constitute monocyclic heterocycles with the phosphorus that it connected and have 5-7 member in this ring simultaneously, and randomly contain 1 or 2 additional heteroatoms that is selected from N, O or S except that this nitrogen, this heterocycle is randomly by one or more R that are selected from
7Substituting group replace.The heterocyclic example that can form thus includes, but not limited to remember that this heterocycle randomly is selected from R by one or more (and in one embodiment, being 1,2 or 3)
7Substituting group replace:
In one embodiment, R
1Be selected from H and C
1-C
6Alkyl.
In one embodiment, R
2Be selected from H and C
1-C
6Alkyl.
In one embodiment, R
12Be H.
In one embodiment, R
3Be selected from-C
1-C
10Alkyl-O-Rg and-C
1-C
10Alkyl-NR
fR
F ', randomly be selected from R by 1-2
10Substituting group replace.
In one embodiment, R
4Be independently selected from halogen and OH.
In another embodiment, n is 2 and R
4Be independently selected from halogen.
In one embodiment, R
5Be independently selected from H, halogen and OH.
In one embodiment, u is 0.
In one embodiment, t is 1, R
10Be fluorine and R
13Be H.
In another embodiment, t is 0 and R
13It is methyl fluoride.
In one embodiment, R
OxDo not exist.
The present invention includes the compound of the formula I of free form, with and pharmaceutically acceptable salt and steric isomer.Some specific compounds that this paper exemplifies are the protonated salt of amine compound.Term " free form " is meant the aminated compounds of salt-independent shape.Described pharmaceutically acceptable salt not only comprises the salt that specific compound exemplifies, and comprises the typical pharmaceutically acceptable salt of the formula I compound of all free forms.The free form of specific salts compound can separate by means known in the art.For example, free form can be made by handling as NaOH, salt of wormwood, ammonia and the sodium bicarbonate aqueous solution of dilution with the alkali aqueous solution of suitably dilution.Free form on the solubleness in polar solvent, can be different from its salt form separately in some physical properties, but pharmaceutically is being equal to its free form separately based on this bronsted lowry acids and bases bronsted lowry salt of purpose of the present invention.
The pharmaceutically acceptable salt of The compounds of this invention can be from the The compounds of this invention that contains alkalescence or acidic moiety, synthetic by ordinary method.Usually, the salt of basic cpd or by ion-exchange chromatography preparation, perhaps by free alkali and stoichiometry or excessive required salify mineral acid or organic acid, in the various combination of appropriate solvent or solvent, react and make.Similarly, the salt of acidic cpd is made by reacting with suitable mineral alkali or organic bases.
So the pharmaceutically acceptable salt of The compounds of this invention comprises the conventional non-toxic salt by the The compounds of this invention of basic cpd of the present invention and mineral acid or organic acid reaction generation.For example, conventional non-toxic salt comprises derived from those of mineral acid, mineral acid is hydrochloric acid for example, Hydrogen bromide, sulfuric acid, thionamic acid, phosphoric acid, nitric acid etc., and from the salt of organic acid preparation, for example acetate, propionic acid, succsinic acid, oxyacetic acid, stearic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, xitix, pounce on acid, toxilic acid, hydroxymaleic acid, phenylacetic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, Sulphanilic Acid, 2-acetoxyl group-phenylformic acid, fumaric acid, toluenesulphonic acids, methylsulfonic acid, ethionic acid, oxalic acid, isethionic acid, trifluoroacetic acid etc.
When compound of the present invention was acidity, suitable " pharmaceutically acceptable salt " was meant the salt that can accept nontoxic alkali preparation from pharmacy, comprises mineral alkali and organic bases.Comprise aluminium, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese salt, inferior manganese, potassium, sodium and zinc etc. derived from the salt of mineral alkali.Preferred especially ammonium, calcium, lithium, magnesium, potassium and sodium salt.The salt that can accept organic nontoxic alkali preparation from pharmacy comprises the salt of one-level, secondary and tertiary amine, comprises the amine that derives from natural replacement, cyclammonium, and deacidite, arginine for example, trimethyl-glycine, caffeine, choline, N, N
1-dibenzyl ethylene diamine, diethylamine, 2-DEAE diethylaminoethanol, 2-dimethylaminoethanol, thanomin, quadrol, N-ethyl-morpholine, N-ethylpiperidine, glycosamine, glucosamine, Histidine, hydrabamine, Isopropylamine, dicyclohexylamine, Methionin, methylglucosamine, morpholine, piperazine, piperidines, versamid 900, PROCAINE HCL, PHARMA GRADE, purine class, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, Trometamol etc.When compound of the present invention was acidity, term " free form " was meant the compound of its salt-independent shape, and it is protonated that its acidic functionality still is.
The preparation of above-mentioned pharmaceutically acceptable salt and other typical pharmaceutically acceptable salts is disclosed in " Pharmaceutical Salts " J.Pham.Sci. of Berg etc. more all sidedly, among the 1977:66:1-19.
Also note, compound possibility inner salt of the present invention or zwitter-ion, because under physiological condition in the compound take off the proton acidic moiety for example carboxyl can be negatively charged ion, and this electric charge may by protonated or alkylating basic moiety for example the cationic charge of quaternary nitrogen atoms fall in internal balance.
| CDI | 1,1 '-carbonyl dimidazoles |
| CSPHPLC | The chiral solid phase high efficiency liquid chromatography |
| DAST | (diethylamino) sulfur trifluoride |
| DCE | 1, the 2-ethylene dichloride |
| DCM | Methylene dichloride |
| DMF | Dimethyl formamide |
| DMSO | Dimethyl sulfoxide (DMSO) |
| EtOAc | Ethyl acetate |
| IPAC | Isopropyl acetate |
| LAH | Lithium aluminium hydride |
| LiHMDS | Hexamethyl two silicon azide (disilazide) lithiums |
| MsCl | Methylsulfonyl chloride |
| NaHMDS | Hexamethyl two silicon sodiumazide |
| NOE | Nuclear Overhauser effect |
| PTC | Phase-transfer catalyst |
| TBSC1 | Tert-butyldimethylsilyl chloride |
| TEA | Triethylamine |
| TFA | Trifluoroacetic acid |
| THF | Tetrahydrofuran (THF) |
The standard treatment methods that exemplifies in the known or test method in document, compound of the present invention can utilize the prepared in reaction shown in the following route.Following example route is not limited to listed compound or any employed specified substituent of purpose for example.Substituting group shown in route numbering not necessarily with claims in used relevant, and usually be for clear, be expressed as a substituting group and link to each other, wherein a plurality of substituting groups of permission in the definition of following formula I with compound.
Route
Shown in route A, 2 of key, 2-two substituted-dihydro pyrroles intermediate A-8 can derive from the phenylglycocoll of the suitable replacement of easy acquisition.According to Van Betsbrugge etc. (Tetrahedron, 1997,53,9233-9240) described method prepares α-allyl group-α-phenylglycocoll A-3.The reduction of ester and obtain intermediate A-4 with the carbonyl dimidazoles cyclisation.The ruthenium oxidation of allylic alkene, the formation of ester subsequently and the alkylating of nitrogen obtain intermediate A-5.Cyclisation and decarboxylic reaction obtain intermediate A-6.Cyclocarbonyl can be used to mix the phenyl moiety of suitable replacement subsequently.Follow-up saponification and oxidation protection reaction obtain saturated intermediate A-8.The enantiomer of A-8 can often utilize the chiral chromatography technical point from.Ring nitrogen can activate carbonyl chloride A-9 with the phosgene reaction preparation subsequently.
Route B illustrates the preparation of ammonium fluoride phenylpiperidines B-5, from the saturated piperidone of N-.This cis and trans diastereomer be to can separating by silica gel chromatography usually, and this enantiomer often can utilize the chiral chromatography technical point from.
Shown in route C, this ammonium fluoride phenylpiperidines obtains The compounds of this invention C-1 with pyrrolin intermediate A-9 reaction subsequently.
Preparation and those groups that route D illustrates 2-methyl fluoride-4-amino piperidine compound are incorporated into compound of the present invention.Should be noted that the mixture displacement of the pendant hydroxyl group of intermediate D-3 usually obtains the intermediate D-4 and the ring homologous compound D-5 of two kinds of expections.These midbody compounds can separate by silica gel chromatography.
Route E illustrates the another kind of preparation method of 2-methyl fluoride-3-amino piperidine compound, does not wherein generate 7 Yuans ring steric isomers.
Shown in route F and G, the hydroxylic moiety of A-9 can carry out alkylation with plurality of reagents.
Shown in route H, the hydroxyl of Compound C-1 uses the replacement(metathesis)reaction of the amine that suitably replaces through corresponding aldehyde H-1, and reductive alkylation obtains The compounds of this invention H-2 subsequently.
Route I illustrates 2-one substituted-dihydro pyrroles synthetic of The compounds of this invention.The Methylimidazole part of intermediate compound I-7 obtains I-8 with the preparation and the displacement of amino piperidine.
The homologation that route J illustrates the 2-alkyl group side chain obtains The compounds of this invention J-3 and J-4.
Route K-M further illustrates the modification that begins from C-2 alkyl group side chain and intermediate aldehydes H-1.So in route K, aldehyde H-1 obtains oxy-compound K-1 with for example alkyl Grignard reagent processing of Grignard reagent.
Route L illustrates the homologization of C-2 side chain.Aldehyde H-1 reduces subsequently with processing of phosphino-acetic ester and coupling key and generates ester L-1.The oxidation of the reduction of follow-up ester and alcohol obtains aldehyde L-3, and it can generate The compounds of this invention L-4 by the suitable amine that replaces of reductive alkylation.The further alkylated reaction of L-4 also as shown in the figure.
Route M illustrate the conversion of C-2 side chain and hydroxylic moiety subsequently through replace with sodiumazide corresponding triflate be converted into amine and.
Route N illustrates difluoromethyl partly is incorporated into the C-2 side chain.
Route A
Route B
Route C
Route D
Route E
Route F
Route G
Route H
Route I
Route J
Route K
Route L
Route M
Route N
Practicality
Find that compound of the present invention can use in different application.Those skilled in the art should understand, can change mitotic division in many ways; That is to say, can influence mitotic division by the activity that improves or reduce component in the mitotic division approach.Rephrase the statement, by interference balancing, or by suppressing or activate some component to influence (for example interrupting) mitotic division.Similar approach can be used to change mitotic division.
In a preferred embodiment, compound of the present invention is used to regulate the formation of mitotic spindle, causes the long cell cycle to stop at mitotic division thus.So-called herein " adjusting " is meant the formation that changes mitotic spindle, comprises the formation that increases and reduce spindle body.So-called herein " mitotic spindle formation " is meant that by microtubule group structure under the mitotic kinesins effect be the group structureization of two electrode structures.So-called herein " mitotic spindle dysfunction " is meant that mitotic division stops and the formation of monopolar spindle.
The activity of effective combination of compound of the present invention and/or adjusting mitotic kinesins.In a preferred embodiment, this mitotic kinesins is a member (as U.S. Patent number 6,284,480, the 5 hurdles are described) of the mitotic kinesins of bimC subtribe.In another preferred embodiment, described mitotic kinesins is human body KSP, also can regulate by The compounds of this invention although derive from the activity of the mitotic kinesins of other biological., regulate being meant that increasing or reduce spindle pole separates herein, cause the sex change of mitotic division spindle pole, promptly launch, or cause the form disorder of mitotic spindle in addition.For such purpose, also comprise variant and/or the fragment of KSP in the definition of KSP.In addition, other mitotic kinesins can suppress with compound of the present invention.
Compound of the present invention can effectively be treated cell proliferation disorders.Can utilize the morbid state of method and composition treatment provided by the invention to include, but not limited to cancer (discussing hereinafter), autoimmune disorder, sacroiliitis, transplant rejection, inflammatory bowel, the hyperplasia that medical treatment caused after (comprising surgical operation, angioplasty etc.).Should be understood that in some cases cell may not be in excessively-or low-vegetative state (error state (ERST)), but still need treatment.For example, in wound healing process, cell may be bred in " normally ", but may wish that proliferation function strengthens.Similarly, as mentioned above, in agriculture field, cell may be in " normal " state, but can wish the proliferative adjusting, by directly improving the growth of farm crop, perhaps by suppressing that farm crop are existed the plant of disadvantageous effect or the output that biological growth increases crop.So, in one embodiment, the present invention includes the cell or the individuality that are applied to suffer from or be about to suffer from above-mentioned arbitrary disease or illness.
Compound provided herein, composition and method are particularly suitable for treating cancer, comprise solid tumor for example skin, mammary gland, brain, cervical cancer, carcinoma of testis etc.More specifically, can include, but are not limited to by the cancer of compound of the present invention, composition and method treatment:
Cardiovascular: sarcoma (angiosarcoma, fibrosarcoma, rhabdosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma;
Lung: bronchiogenic cancer (squamous cell does not break up minicell, does not break up maxicell, gland cancer), alveolar (bronchiole) cancer, segmental bronchus gonadoma, sarcoma, lymphoma, chondroma progonoma, mesothelioma; Gi tract: esophagus (squamous cell carcinoma, gland cancer, leiomyosarcoma, lymphoma), stomach (cancer, lymphoma, leiomyosarcoma), pancreas (duct adenocarcinoma, nesidioblastoma, glucagonoma, the stomach knurl, carcinoid tumor, vipoma), small intestine (gland cancer, lymphoma, carcinoid tumor, Ka Boqi sarcoma, leiomyoma, vascular tumor, lipoma, neurofibroma, fibroma), large intestine (gland cancer, tubular adenoma, villous adenoma, progonoma, leiomyoma); Urogenital tract: kidney (gland cancer, WilmShi knurl [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional-cell carinoma, gland cancer), prostate gland (gland cancer, sarcoma), testis (spermocytoma, teratoma, choriocarcinoma, sarcoma, mesenchymal cell cancer, fibroma, fibroadenoma, adenoma sample tumour, lipoma);
Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, adenoma, vascular tumor;
Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, pernicious giant cell tumor chordoma, osteochronfroma, osteoid osteoma and giant cell tumor;
Neural system: head (osteoma, vascular tumor, granuloma, vitiligoidea, osteitis deformans), meninges (meningioma, meninges sarcoma, neurospongioma), brain (astrocytoma, medulloblastoma, neurospongioma, ependymoma, the germinoma[pinealoma], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), the spinal nerves fibroma, meningioma, sarcoma);
Gynecology: uterus (carcinoma of endometrium), uterine cervix (uterine cervix heteroplasia before the cervical cancer, tumour), ovary (ovarian cancer [serocyst gland cancer, mucous bursa gland cancer, unfiled cancer], granulosa-theca cell tumor thecoma, gynandroblastoma, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, epithelial cancer, gland cancer, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), uterine tube (cancer);
Hematology: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphoblastic leukemia, the spinal cord proliferative disease, multiple myeloma, myelodysplastic syndrome), Hokdkin disease, non_hodgkin lymphoma [malignant lymphoma];
Skin: malignant melanoma, rodent cancer, squamous cell carcinoma, Ka Boqi sarcoma, moles dysplastic nevi, lipoma, vascular tumor, dermatofibroma, keloid, psoriasis; With
Suprarenal gland: neuroblastoma.So term " cancer cells " comprises the cell of suffering from above-mentioned arbitrary definite illness as used herein.
The activity that compound of the present invention can also pass through the fungi member of adjusting bimC kinesin subgroup is used as anti-tranquilizer, and as U.S. Patent number 6,284,480 is described.
Compound of the present invention can be separately or preferred and pharmaceutical acceptable carrier, vehicle or thinner combination, with pharmaceutical composition, is administered to Mammals according to the standard pharmaceutical practice, preferably human body.This compound can oral administration or parenterai administration, comprises intravenously, intramuscular, and intraperitoneal, subcutaneous, rectum and partial route of administration.
Term " composition " comprises the product of the specific components that contains specified quantitative as used herein, and any product that directly or indirectly obtains from the combination of the specific components of specified quantitative.
The pharmaceutical composition that contains activeconstituents can be the form that is fit to orally use, and for example, becomes tablet, rhombus lozenge, and water or oil suspension can disperse powder or granule, emulsion, hard or soft capsule, or syrup or elixir.The composition that is used to orally use can prepare according to making the currently known methods that pharmaceutical composition adopts, thereby and described composition can contain one or more reagent that are selected from sweeting agent, correctives, tinting material and sanitas pharmaceutically attractive in appearance and good to eat preparation is provided.Tablet contains the activeconstituents mixed mutually with the pharmaceutical acceptable excipient that is fit to the preparation tablet.These vehicle can be for example, inert diluent, lime carbonate for example, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent, for example, Microcrystalline Cellulose, croscarmellose sodium, W-Gum or alginic acid; Tackiness agent, starch for example, gelatin, polyvinylpyrrolidone or gum arabic, and lubricant, for example, Magnesium Stearate, stearic acid or talcum powder.Tablet is dressing not, perhaps they can be by known technology with its dressing with the unpleasant flavour of masking agents or postpone the disintegration in gi tract and absorb and obtain thus the slow releasing function of longer time.For example, can adopt water-soluble taste masking material for example hydroxypropyl-methylcellulose gum or hydroxypropyl-Mierocrystalline cellulose, for example ethyl cellulose of material of perhaps delaying time, cellulose acetate buryrate.
The preparation that orally uses also can be used as hard gelatin capsule and exists, wherein activeconstituents and inert solid diluent are mixed, this inert solid diluent is for example lime carbonate, calcium phosphate or kaolin, or as the soft gelatin capsule existence, wherein this activeconstituents and water or oil medium such as peanut oil, whiteruss or sweet oil are mixed.
Aqueous suspension contains the active substance that is mixed in the vehicle that is fit to the preparation aqueous suspension.This vehicle is a suspending agent, Xylo-Mucine for example, methylcellulose gum, hydroxypropylmethyl-Mierocrystalline cellulose, sodiun alginate, polyethylene-pyrrolidone, tragacanth and gum arabic; Dispersion or wetting agent can be natural phospholipids, Yelkin TTS for example, or the condensation product of alkylene oxide and lipid acid, polyoxyethylene stearic acid ester for example, or oxyethane and the long chain aliphatic alcohol condensation product of 17 carbon ethene-oxygen base hexadecanol for example, or oxyethane and derived from the condensation product of the partial ester of lipid acid and hexitol, polyoxyethylene sorbitol monooleate for example, or oxyethane and derived from the condensation product of the partial ester of lipid acid and hexitan, for example polyoxyethylene sorbitan monooleate.Aqueous suspension can also contain one or more sanitass, for example ethyl p-hydroxybenzoate or n-propyl, one or more tinting materials, one or more correctivess and one or more sweeting agents, for example sucrose, asccharin or aspartame.
Oil-based suspension can for example be prepared in the whiteruss by activeconstituents being suspended in vegetables oil such as peanut oil, sweet oil, sesame oil or Oleum Cocois or mineral oil.Oil-based suspension can contain thickening material, for example beeswax, paraffinum durum or hexadecanol.Can add sweeting agent for example above-mentioned those, and add correctives so that good to eat oral preparations to be provided.These compositions can for example butyl hydroxyanisole or alpha-tocopherol come anticorrosion by adding oxidation inhibitor.
Be fit to that but to make the dispersed powders agent and the granule of aqueous suspension be that activeconstituents and dispersion or wetting agent, suspensoid and one or more sanitass are mixed by adding entry.Suitable dispersion or wetting agent and suspending agent for example are above-mentioned those that mentioned.Other vehicle for example sweeting agent, correctives and tinting material also can exist.These compositions can for example xitix be next anticorrosion by adding oxidation inhibitor
Pharmaceutical composition of the present invention can also be the form of O/w emulsion.Oil phase can be a vegetables oil, for example sweet oil or peanut oil, or mineral oil, for example whiteruss and these miscellany.Suitable lubricant can be a natural gum, for example gum arabic or tragacanth, natural phospholipid, soybean lecithin for example, with ester or partial ester derived from lipid acid and hexitan, sorbitan monooleate for example, the condensation product of this partial ester and oxyethane, for example polyoxyethylene sorbitan monooleate.Emulsion can also contain sweeting agent, correctives, sanitas and oxidation inhibitor.
Syrup and elixir can be prepared with sweeting agent, for example glycerine, propylene glycol, Sorbitol Powder or sucrose.This type of preparation can also contain negative catalyst, sanitas, correctives and tinting material and oxidation inhibitor.
This pharmaceutical composition can be the form of sterilization injectable aqueous solutions.Operable in can accepting carrier and solvent is water, Ringer's solution and isotonic sodium chlorrde solution.
The sterilization injectable formulation can also be a kind of sterilization injectable oil-in-water microemulsion, and wherein this activeconstituents is dissolved in the oil phase.For example, activeconstituents at first can be dissolved in the miscellany of soybean oil and Yelkin TTS.This oil solution is added in water and the glycerine miscellany subsequently and handles and forms microemulsion.
Injectable solution or microemulsion can be introduced in patient's the blood by local bolus injection.Perhaps, can be preferably with solution or microemulsion to keep the mode administration of The compounds of this invention constant circulation concentration.In order to keep constant density, can adopt continuous intravenous administration device.The example of this device is Deltec CADD-PLUS
TM5400 type intravenously transferpumps.
This pharmaceutical composition can be to be used for the sterilization injectable water of intramuscular and subcutaneous administration or the form of oil-based suspension.This suspension can be according to known technique, utilize the suitable dispersion agent or the aqueous solution and suspending agent to prepare, as mentioned above.The sterilization injectable formulation can also be sterile solution or the suspension that is present in nontoxic non-enteron aisle acceptable diluent or the solvent, for example is present in the solution in the 1,3 butylene glycol.In addition, sterilization, nonvolatile oil are usually as solvent or suspending medium.For this purpose, can use the nonvolatile oil of any series, comprise synthetic glycerine one-or diester.In addition, lipid acid for example oleic acid can be used for the preparation of injectable agent.
The compound of formula I can also be used for the rectal administration of medicine with the form of suppository.These compositions can be by making medicine and suitable non-stimulated vehicle are mixed, and described non-stimulated vehicle be liquid under rectal temperature for solid at normal temperatures and melts the release medicine at internal rectum thus.This material comprises theobroma oil, glycerine gelatin, hydrogenated vegetable oil, the miscellany of the fatty acid ester of different molecular weight polyethylene glycol and polyoxyethylene glycol.
Use for the part, can adopt creme, ointment, gel, solution or the suspension etc. that contain formula I compound.(for purposes of this application, topical application should comprise mouthwass and gargle).
Compound of the present invention can carry out administration with form in the nose carrier and doser in suitable nose is used in the part, perhaps through the transdermal route administration, adopts the form administration of the transdermal patch that those of ordinary skills know.For the form administration with the transdermal administration system, obviously, using of dosage should be continuously rather than interruption in dosage regimen.Compound of the present invention can also adopt the miscellany administration of the fatty acid ester of matrix such as theobroma oil, glycerine gelatin, hydrogenated vegetable oil, different molecular weight polyethylene glycol and polyoxyethylene glycol as suppository.
When compound administration of the present invention was in human object, per daily dose generally can be determined by the doctor in charge, and this dosage generally decides according to age, body weight and the reaction of individual patients and the seriousness of patient's symptom.
In one is used for example, an amount of compound administration is given the Mammals of standing cancer therapy.The amount of administration in the scope of about 0.1mg/kg body weight-Yue 60mg/kg body weight/day, preferred 0.5mg/kg body weight-Yue 40mg/kg body weight/day.
Compound of the present invention can also be united use with known therapeutical agent and anticarcinogen.For example, compound of the present invention and known anticarcinogen are united use.The combination medicine form of compound disclosed herein and other anticarcinogens or chemotherapeutics belongs in the scope of the present invention.The example of this type of medicine can be referring to V.T.Devita and S.Hellman (editor) Cancer Principles and Practiceof Oncology, the 6th edition (February 15 calendar year 2001), Lippincott Williams; WilkinsPublishers.Those of ordinary skills should be able to understand medicine cooperative programs should based on the concrete property of medicine and at cancer use.This kind anti-cancer drugs comprises, but be not limited to, following medicine: estrogenic agents, androgen receptor modulator, vitamin A acid (retinoid) receptor modulators, cytotoxicity/cytostatics, antiproliferative agents, isopentene group protein transferase inhibitor, HMG-CoA reductase inhibitor and other angiogenesis inhibitors, inhibitor, cell death inducer and the cell cycle chechpoint agent interfering of cell proliferation and survival signal.When with radiotherapy when co-administered, compound of the present invention is effective especially.
In one embodiment, compound of the present invention is also united with known anticarcinogen effectively, comprises following medicine: estrogenic agents, androgen receptor modifier, the retinoic acid receptor (RAR) conditioning agent, cytotoxic agent, antiproliferative agents, isopentene group protein transferase inhibitor, the HMG-CoA reductase inhibitor, hiv protease inhibitor, reverse transcriptase inhibitors and other angiogenesis inhibitors.
No matter " estrogen receptor modulator " be meant its mechanism compound that can disturb or suppress oestrogenic hormon and receptors bind how.The example of estrogen receptor modulator includes, but not limited to tamoxifen (tamoxifen), raloxifene (raloxifene), idoxifene, LY353381, LY117081, toremifene, fulvestrant, 4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(piperidino) oxyethyl group] phenyl]-2H-1-chromene-3-yl]-phenyl-2,2-dimethyl propylene acid esters, 4,4 '-dihydroxy benzophenone-2,4-dinitrophenyl-hydrazone and SH646.
No matter " androgen receptor modulator " be meant its mechanism compound that can disturb or suppress the male sex hormone bind receptor how.The example of androgen receptor modulator comprises finasteride and other 5 inhibitor, Nilutamide, and flutamide, than Ka Mite, liarozole and abiraterone acetate.
No matter " retinoic acid receptor (RAR) modulator " be meant its mechanism compound that can disturb or suppress the vitamin A acid bind receptor how.The example of retinoic acid receptor (RAR) modulator comprises retinoic acid, 13-cis (cis)-vitamin A acid, 9-cis-vitamin A acid, alpha-difluoromethyl ornithine, ILX23-7553, trans-N-(4 '-hydroxy phenyl) thunder for Mi Te (retinamide) and N-4-carboxyl phenyl thunder for Mi Te.
" cytotoxicity/cytostatics " is meant mainly by direct interference cell activity or inhibition or interference cell reduction division and causes necrocytosis or suppress the compound of cell proliferation, comprise alkylating agent, tumour necrosis factor, intercalator, but the hypoxemia activated compounds, Antitubulin/microtubule stabilizer, the inhibitor of mitotic kinesins, participate in the kinase whose inhibitor of mitotic division process, antimetabolite; The biological respinse improving agent; Hormone/hormone antagonist therapeutical agent, hemopoieticgrowth factor, monoclonal antibody target therapeutic agent, topoisomerase enzyme inhibitor, proteoplast inhibitor and ubiquitin ligase inhibitor.
The example of cytotoxic agent includes, but not limited to sertenef; tumour necrosis factor, ifosfamide, tasonermin; lonidamine, carboplatin, altretamine; prednimustine, mitolactol, MCNU; the safe mustargen of good fortune, S 254, oxaliplatin; Temozoromide, heptaplatin, estramustine; Bis amine, Z-4828, nimustine; Spirobromine, fast rice tongue pool, happy platinum; satraplatin, profiromycin, cis-platinum; irofulven; dexifosfamide, cis-amine dichloro (2-methyl-pyridine) platinum, benzyl guanine; glufosfamide; GPX100, (trans, trans; trans)-two-mu-(hexane-1; the 6-diamines)-and mu-[diamines-platinum (II)] two [diamines (chlorine) platinum (n)] tetrachloride, diazetidine base spermine, ARSENIC TRI OXIDE 98; 1-(11-dodecyl amino-10-hydroxyl 11 amino)-3; the 7-dimethyl xanthine, zorubicin, idarubicin; daunorubicin; than mulberry that, mitoxantrone, Perarubicin; pinafide; valrubicin, amrubicin, anti-ketone knurl; 3 '-deaminizating-3 '-morpholino-13-deoxidation-10-hydroxyl carminomycin; the At mycin, galarubicin, elinafide; MEN10755 and 4-demethoxylation-3-deaminizating-3-ethylenimine base-4-methyl sulphonyl-daunorubicin (referring to WO00/50032).
But an example of hypoxemia activated compounds is a Win-59075.
The example of proteoplast inhibitor includes but not limited to lactacystin and MLN-341 (Velcade).
The example of microtubule inhibitor/microtubule stabilizer comprises taxol, vindesine sulfate, 3 '; 4 '-dihydro-4 '-deoxidation-8 '-remove first vinblastine, how western Japanese yew, rhizomycin; dolastatin, mivobulin isethionate, auristatin; cemadotin, RPR109881, BMS184476; vinflunine; cryptophycin, 2,3; 4; 5,6-five fluoro-N-(3-fluoro-4-p-methoxy-phenyl) benzsulfamide, F 81097; N; N-dimethyl-L-is valyl-and L-is valyl-and N-methyl-L-is valyl-L-prolyl-L-proline(Pro)-t-butyl amide, TDX258, epoxythio ketone (epothilones) is (referring to for example United States Patent (USP) 6; 284; 781 and 6,288,237) and BMS188797.
Some examples of topoisomerase enzyme inhibitor are topotecan; hycaptamine; irinotecan; rubitecan; 6-ethoxy-c acyl group-3 '; 4 '-O-external form-benzylidene-chartreusin; 9-methoxyl group-N; N-dimethyl-5-nitropyrazole also [3; 4; 5-kl] acridine-2-(6H) propylamine; 1-amino-9-ethyl-5-fluoro-2; 3-dihydro-9-hydroxy-4-methyl-1H; 12H-benzo [de] pyrans also [3 ', 4 ': b, 7] indolizine also [1; 2b] quinoline-10; 13 (9H, 15H) diketone, lurtotecan; 7-[2-(N-sec.-propyl amino) ethyl]-(20S) camptothecine; BNP1350, BNPI1100, BN80915; BN80942; the phosphoric acid etoposide, Vumon, sobuzoxane; 2 '-dimethylamino-2 '-deoxidation-etoposide; GL331, N-[2-(dimethylamino) ethyl]-9-hydroxyl-5,6-dimethyl-6H-pyrido [4; 3-b] carbazole-1-carboxylic acid amides; asulacrine, (5a, 5aB; 8aa; 9b)-9-[2-[N-[2-(dimethylamino) ethyl]-the N-methylamino] ethyl]-5-[4-hydroxyl-3, the 5-Dimethoxyphenyl]-5,5a; 6; 8,8a, 9-six hydrogen furans (3 '; 4 ': 6; 7) naphtho-(2,3-d)-1,3-dioxole-6-ketone; 2; 3-(methylene radical dioxy base)-5-methyl-7-hydroxyl-8-methoxyl group benzo [c]-phenanthridines, 6,9-two [(2-amino-ethyl) amino] benzo [g] isoquinoline 99.9-5; the 10-diketone; 5-(3-amino propyl amino)-7,10-dihydroxyl-2-(2-hydroxyethyl amino methyl)-6H-pyrazolo [4,5; 1-de] acridine-6-ketone; N-[1-[2 (diethylamino) ethylamino]-7-methoxyl group-9-oxo-9H-thioxanthene-4-ylmethyl] methane amide, N-(2-(dimethylamino) ethyl) acridine-4-carboxylic acid amides, 6-[[2-(dimethylamino) ethyl] amino]-3-hydroxyl-7H-indenes [2; 1-c] quinoline-7-ketone, and dimesna.
Mitotic kinesins, and particularly the example of the inhibitor of people's mitotic kinesins KSP is disclosed in PCT communique WO 01/30768 and WO 01/98278, WO03/050,064 (June 19,2003), WO 03/050,122 (June 19,2003), WO03/049,527 (June 19,2003), WO 03/049,679 (June 19,2003), WO03/049,678 (June 19,2003) and WO 03/39460 (May 15,2003) and PCT co-pending application US 03/06403 (submission on May 4th, 2003), US 03/15861 (submission on May 19th, 2003), US 03/15810 (submission on May 19th, 2003), USO3/18482 (submission on June 12nd, 2003) and US 03/18694 (submission on June 12nd, 2003).In one embodiment, the inhibitor of mitotic kinesins comprises, but is not limited to inhibitor, the inhibitor of MKLP1, the inhibitor of CENP-E, the inhibitor of MCAK, the inhibitor of Kifl4, the inhibitor of Mphosphl and the inhibitor of Rab6-KIFL of KSP.
" participate in the kinase whose inhibitor of mitotic division process " and include, but not limited to the kinase whose inhibitor of aurora type (aurora), the inhibitor of Polo sample kinases (PLK) (the particularly inhibitor of PLK-1), the inhibitor of bub-1 and bub-R
1Inhibitor.
" antiproliferative agents " comprises sense-rna and DNA oligonucleotide, G3139 for example, ODN698; RVASKRAS, GEM231 and INX3001, and antimetabolite; enocitabine for example, carmofur, Tegafur; spray Tuo Tading, the pyridine of how western fluorine urine, trimetrexate; NSC-118218, capecitabine, galocitabine; Cytarbine Ocfostate, fosteabine sodium hydrate, raltitrexed; paltitrexid, emitefur, tiazofurine; decitabing; nolatrexed, pemetrexed, nelzarabine; 2 '-deoxidation-2 '-the methylene radical cytidine; 2 '-fluorine methylene radical-2 '-Deoxyribose cytidine, N-[5-(2,3-dihydro-benzofuryl) alkylsulfonyl]-N '-(3; the 4-dichlorophenyl) urea, N6-[4-deoxidation-4-[N
2-[2 (E), smooth two enoyl-s in 4 (E)-14] glycyl amino]-L-glycerine-B-L-sweet dew-pyrans heptose base] VITAMIN B4, aplidine; ecteinascidin; troxacitabine, the amino 4-oxo-4,6 of 4-[2-; 7; 8-tetrahydrochysene-3H-Mi Dingbing [5,4-b] [1,4] thiazine-6-base-(S)-ethyl]-2; 5-thienyl-L-L-glutamic acid; aminopterin, 5-flurouracil, alanosin; 11-ethanoyl-8-(carbamoyloxy methyl) 4-formyl radical-6-methoxyl group-14-oxa--1; 11-diaza Fourth Ring third (7.4.1.0.0)-14 carbon-2,4,6-triolefin-9-yl acetate; swainsonine; lometrexol, dexrazoxane, methioninase; 2 '-cyano group-2 '-'-deoxy-n 4-palmitoyl-1-B-D-arabinofuranosyl cytosine(Cyt) and 3-aminopyridine-2-carboxylic aldehyde thiosemicarbazone.
The example of the therapeutical agent of monoclonal antibody target comprises that those contain cytotoxic agent or the radioisotopic therapeutical agent that links to each other with cancer cells specificity or targeted cells monoclonal antibody specific.Example comprises Bexxar.
" HMG-CoA reductase inhibitor " is meant the inhibitor of 3-hydroxy-3-methyl glutaraldehyde-CoA reductase enzyme.The HMG-CoA reductase enzyme is had the active compound of inhibition can be identified by analytical procedure well known in the art at an easy rate.For example, referring to United States Patent (USP) 4,231, described in 938 the 6th hurdles and the WO 84/02131 30-33 page or leaf or the analytical test of quoting.Term " HMG-CoA reductase inhibitor " and " inhibitor of HMG-CoA reductase enzyme " have identical meanings when this paper uses.
The example of operable HMG-CoA reductase inhibitor includes but not limited to: lovastatin (lovastatin) (MEVACOR
_, referring to United States Patent (USP) 4,231,938,4,294,926 and 4,319,039); Simvastatin (Simvastatin) (ZOCORO
_, referring to United States Patent (USP) 4,444,784,4,820,850 and 4,916,239); Pravastatin (pravastatin) (PRAVACHOLO
_, referring to United States Patent (USP) 4,346,227,4,537,859,4,410,629,5,030,447 and 5,180,589); Fluvastatin (LESCOLO
_, referring to United States Patent (USP) 5,354,772,4,911,165,4,929,437,5,189,164,5,118,853,5,290,946 and 5,356,896) and Zarator (LIPITOR
_), referring to United States Patent (USP) 5,273,995,4,681,893,5,489,691 and 5,342,952).The structural formula of operable these and other HMG-CoA reductase inhibitors is disclosed in M.Yalpani in the inventive method, " Cholesterol Lowering Drugs ", Chemistry ﹠amp; Among the Industry, the 97th page of pp.85-89 (52 months 1996) and United States Patent (USP) 4,782,084 and 4,885,314.Term HMG-CoA reductase inhibitor used herein comprises that all pharmacy with HMG-CoA reductase active of described compound can accept lactone and open loop acid form (promptly, wherein lactonic ring is opened and is formed free acid) and salt and ester, and the application of these salt, ester, open loop acid and lactone form belongs in the scope of the present invention.The example of lactone part and corresponding open loop acid form thereof is shown in structure I and II.
In the HMG-CoA reductase inhibitor that the acid of open loop therein form may exist, can preferentially generate salt and ester-formin from open loop acid, and all forms belong in the implication of term used herein " HMG-CoA reductase inhibitor ".Preferably, this HMG-CoA reductase inhibitor is selected from lovastatin and Simvastatin, and Simvastatin most preferably.In the literary composition, the term of relevant HMG-CoA reductase inhibitor " pharmaceutically acceptable salt " should be meant the non-toxic salt of compound used therefor of the present invention, they generally prepare by free acid and suitable organic or inorganic alkali reaction, particularly those form cationic salt, sodium for example, potassium, aluminium, calcium, lithium, magnesium, zinc and tetramethyl-ammonium, and those salt that forms from amine, for example ammonia, quadrol, the N-methylglucosamine, Methionin, arginine, ornithine, choline, N, N '-dibenzyl quadrol, chloroprocaine, diethanolamine, PROCAINE HCL, PHARMA GRADE, N-benzyl styroyl amine, 1-p-benzyl chloride base-2-tetramethyleneimine-1 '-Ji-tolimidazole, diethylamine, piperazine and three (hydroxymethyl) aminomethane.Other examples of the salt form of HMG-CoA reductase inhibitor can include, but not limited to acetate; benzene sulfonate, benzoate, supercarbonate; hydrosulfate, bitartrate, borate; bromide, ethylenediamine tetraacetic acid(EDTA) calcium, camsylate; carbonate, muriate, clavulanate; Citrate trianion, dihydrochloride, editate; edisylate, estolate, esylate; fumarate, gluceptate, gluconate; glutaminate, glycoloyl is to propylhomoserin phenyl-arsonate, Sucrets; hydrabamine, hydrobromide, hydrochloride; Hydroxynaphthoate, iodide, isothionate; lactic acid salt, Lactobionate, lauroleate; malate, maleate, mandelate; mesylate, Methylsulfate, mucate; napsylate, nitrate, oleate; oxalate, pamoate, palmitate; panthothenate, phosphate/phosphor acid hydrogen salt, Polygalacturonate; salicylate, stearate, subacetate; succinate, tannate, tartrate; teoclate, tosylate, triethiodide and valerate.
The ester derivative of described HMG-CoA reductase inhibiter compounds can be used as prodrug, when they are absorbed in the blood of warm-blooded animal, can cracking discharge medicament forms and allow medicine to produce improved therapeutic efficiency.
" isopentene group protein transferase inhibitor " is meant the compound of a kind of or arbitrary combination that suppresses the isopentene group protein transferase, comprise farnesyl-protein transferase (FPTase), geranyl geranyl-protein transferase I type (GGPTase-I) and geranyl geranyl-protein transferase II type (GPTase-II is also referred to as RabGGPTase).Isopentene group-protein transferase suppresses examples for compounds and comprises: (±)-6-[amino (4-chloro-phenyl-) (1-methyl isophthalic acid H-imidazoles-5-yl) methyl]-4-(3-chloro-phenyl-)-1-methyl-2 (1H)-quinolinone; (-)-6-[amino (4-chloro-phenyl-) (1-methyl isophthalic acid H-imidazoles-5-yl) methyl]-4-(3-chloro-phenyl-)-1-methyl-2 (1H)-quinolinone; (+)-6-[amino (4-chloro-phenyl-) (1-methyl isophthalic acid H-imidazoles-5-yl) methyl]-4-(3-chloro-phenyl-)-1-methyl-2 (1H)-quinolinone; 5 (S)-normal-butyls-(2; the 3-3,5-dimethylphenyl)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-2-piperazine ketone; (S)-1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-5-[2-(ethylsulfonyl) methyl]-2-piperazine ketone; 5 (S)-normal-butyls-(2-aminomethyl phenyl)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-2-piperazine ketone; 1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-2-methyl-5-imidazolyl methyl]-2-piperazine ketone; 1-(2; 2-xenyl ethyl)-and 3-[N-(1-(4-cyano group benzyl)-1H-imidazoles-5-base ethyl) formamyl] piperidines; 4-{5-[4-methylol-4-(4-chloropyridine-2-ylmethyl)-piperidines-1-ylmethyl]-glyoxal ethyline-1-ylmethyl } cyanobenzene; 4-{5-[4-methylol-4-(3-benzyl chloride base)-piperidines-1-ylmethyl]-glyoxal ethyline-1-ylmethyl } cyanobenzene; 4-{3-[4-(2-oxo-2H-pyridine-1-yl) benzyl]-3H-imidazol-4 yl methyl } cyanobenzene; 4-{3-[4-(5-chloro-2-oxo-2H-[1; 2 '] dipyridyl-5 '-yl)-3H-imidazol-4 yl methyl } cyanobenzene; 4-{3-[4-2-oxo-2H-[1; 2 '] dipyridyl-5 '-yl)-3H-imidazol-4 yl methyl } cyanobenzene; 4-[3-(2-oxo-1-dihydropyridine-4-ylmethyl)-3H-imidazol-4 yl methyl] cyanobenzene; 18; 19-dihydro-19-oxo-5H; 17H-6; 10; 12; 16-diformazan androstene (dimetheno)-1H-imidazoles [4; 3-c] [1; 11; 4] two oxa-s nitrogen heterocyclic-nonadecine-9-formonitrile HCN; (±)-19; 20-dihydro-19-oxo-5H-18; 21-ethane is (ethano)-12 also; 14-ethene is (etheno)-6 also; 10-methylene-22H-benzo [d] imidazo [4; 3-k] [1; 6; 9; 12] oxa-three azepines-ring octadecine-9-formonitrile HCN; 19; 20-dihydro-19-oxo-5H; 17H-18; 21-ethane is (ethano)-6 also; 10:12; 16-two methylenes-22H-imidazo [3; 4-h] [1; 8; 11; 14] oxa-three azepines-ring eicosine-9-formonitrile HCN; (±)-19; 20-dihydro-3-methyl isophthalic acid 9-oxo-5H-18; 21-ethane is (ethano)-12 also; 14-ethene is (etheno)-6 also; 10-methylene-22H-benzo [d] imidazo [4; 3-k] [1; 6; 9,12] oxa--three nitrogen heterocyclic octadecine-9-formonitrile HCN.
Other examples of isopentene group protein transferase inhibitor can be referring to following document and patent: WO 96/30343, and WO 97/18813, and WO 97/21701, WO 97/23478, WO97/38665, and WO 98/28980, WO 98/29119, and WO 95/32987, U.S. Patent number 5,420,245, U.S. Patent number 5,523,430, U.S. Patent number 5,532,359, U.S. Patent number 5,510,510, U.S. Patent number 5,589,485, U.S. Patent number 5,602,098, European patent communique 0 618 221, European patent communique 0 675 112, European patent communique 0 604181, European patent communique 0696593, WO 94/19357, WO 95/08542, and WO 95/11917, WO95/12612; WO95/12572, WO 95/10514, U.S. Patent number 5,661,152, WO95/10515, WO 95/10516, and WO 95/24612, WO 95/34535, WO95/25086, and WO96/05529, WO 96/06138, WO 96/06193, and WO 96/16443, and WO 96/21701, WO96/21456, WO 96/22278, and WO 96/24611, and WO 96/24612, WO96/05168, WO 96/05169, and WO 96/00736, U.S. Patent number 5,571,792, WO 96/17861, WO96/33159, WO96/34850, WO 96/34851, and WO 96/30017, and WO 96/30018, and WO 96/30362, WO96/30363, WO 96/31111, and WO 96/31477, WO96/31478, WO 96/31501, and WO 97/00252, and WO 97/03047, WO 97/03050, WO97/04785, and WO 97/02920, WO 97/17070, and WO 97/23478, and WO 97/26246, WO 97/30053, and WO 97/44350, and WO 98/02436, with U.S. Patent number 5,532,359.The example that isopentene group protein transferase inhibitor vasoactive generates is referring to European J.ofCancer, Vol.35, No.9, pp.1394-1401 (1999).
No matter " angiogenesis inhibitor " be meant the mechanism compound that can suppress neovascularization how.The compound of angiogenesis inhibitor includes, but not limited to tyrosine kinase inhibitor, for example tyrosine kinase receptor Flt-1 (VEGFR
1) and Flk-1/KDR (VEGFR
20) inhibitor, the inhibitor of the somatomedin of the epidermis derivation, the inoblast derivation or thrombocyte derivation, MMP (matrix metalloproteinase) inhibitor, integrin blocker, interferon-' alpha ', il-1 2, xylan polysulfate, cyclooxygenase inhibitors comprises that non-steroidal antiinflammatory drugs (NSAIDs) is as acetylsalicylic acid and Ibuprofen BP/EP and selective cyclooxygenase-2 inhibitor such as celecoxib and Luo Fen former times cloth (PNAS, Vol.89, p.7384 (1992); JNCI, Vol.69, p.475 (1982); Arch.Opthalmol., Vol.108, p.573 (1990); Anat.Rec., Vol.238, p.68 (1994); FEBS Letters, Vol.372, p.83 (1995); Clin, Orthop.Vol.313, p.76 (1995); J.Mol.Endocrinol., Vol.16, p.107 (1996); Jpn.J.Pharmacol., Vol.75, p.105 (1997); Cancer Res., Vol.57, p.1625 (1997); Cell, Vol.93, p.705 (1998); Intl.J.Mol.Med., Vol.2, p.715 (1998); J.Biol.Chem., Vol.274, p.9116 (1999)), steroid antiphlogiston (reflunomide for example, mineralocorticoid, dexamethasone, prednisone, Ultracortene-H, prednisolone, Betamethasone Valerate), the carboxamido triazole, combretastatin A-4, squalamine, 6-O-chloracetyl-carbonyl)-aspergillus fumigatus cedrol, Thalidomide, angiostatin, troponin-1, the Angiotensin II antagonist is (referring to Fernandez etc., J.Lab.Clin.Med.105:141-145 (1985)) and the antibody of VEGF (referring to, Nature Biotechnology, Vol.17, pp.963-968 (October 1999); Kim etc., Nature, 362,841-844 (1993); WO 00/44777; With WO 00/61186).
Other adjustings or suppress vasculogenesis and also can comprise the medicine (referring to the summary of Clin.Chem.La.Med.38:679-692 (2000)) of regulating or suppressing aggegation and fibrinolytic system with the therapeutical agent of compound associating of the present invention.The example of the medicine of this type of adjusting or inhibition aggegation and fibrinolysis approach comprises, but be not limited to, heparin (referring to Thromb.Haemost.80:10-23 (1998)), low molecular weight heparin and carboxypeptidase U the inhibitor inhibitor of active enzyme thrombin activated fiber protein dissolution [TAFIa] inhibitor (but be also referred to as) (referring to Thrombosis Res.101:329-354 (2001)).The TAFIa inhibitor has been disclosed in PCT communique WO 03/013,526 and the United States Patent (USP) series number 60/349,925 (submission on February 18th, 2002).
" medicine at the interference cell cycle outpost of the tax office " is meant that the protein kinase that suppresses transducer cell cycle pass card signal causes the compound of cancer cells to DNA disrupting agent sensitivity.This type of medicine comprises the inhibitor of ATR, ATM, Chk1 and Chk2 kinases and cdk and the kinase whose inhibitor of cdc and especially for example make 7-hydroxyl staurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.
" inhibitor of cell proliferation and survival signal pathway " is meant the medicine in the signal transduction cascade downstream that suppresses cell surface receptor and those surface receptors.Medicine comprises the inhibitor (for example gefitinib and erlotinib) of the inhibitor of EGFR in addition, the inhibitor of ERB-2 (for example Si Tuman cloth), the inhibitor of IGFR, the inhibitor of cytokine receptor, the inhibitor of MET, the inhibitor of PI3K (for example LY294002), serine/threonine kinase (includes but not limited to the inhibitor of Akt, for example WO 02/083064, WO 02/083139, described in WO 02/083140 and the WO02/083138), the kinase whose inhibitor of Raf (for example BAY-43-9006), the inhibitor (for example Wyeth CCI-779) of the inhibitor of MEK (for example CI-1040 and PD-098059) and mTOR.This type of medicine comprises micromolecular inhibitor compound and antibody antagonist.
" cell death inducer " comprises the TNF receptor family member activator of (comprising the TRAIL acceptor).
Relate to the application of the NSAID that becomes effective cox 2 inhibitor with the combination of NSAID class.For the purpose of this paper, if a kind of NSAID suppresses the IC of COX-2 in cell or microsome test
50When being less than or equal to 1 μ M, it is effective that this NSAID is considered to.
The present invention also comprises and is the combination of the NSAID of selective COX-2-2 inhibitor.Purpose for this specification sheets, be defined as having restraining effect to COX-2 as the NSAID of the selective depressant of COX-2 and be higher than specific compounds at least 100 times of COX-1, this is the IC to COX-2 that is assessed in cell by hereinafter described or the microsome test
50With IC to COX-2
50Ratio measure.This compounds includes, but are not limited to following those disclosed: United States Patent (USP) 5,474,995 is issued to December 12 nineteen ninety-five; United States Patent (USP) 5,861,419 is issued on January 19th, 1999; United States Patent (USP) 6,001,843 is issued on December 14th, 1999; United States Patent (USP) 6,020,343 is issued on February 1st, 2000; United States Patent (USP) 5,409,944 is issued to April 25 nineteen ninety-five; United States Patent (USP) 5,436,265 is issued to July 25 nineteen ninety-five; United States Patent (USP) 5,536,752 is issued to July 16 in 1996; United States Patent (USP) 5,550,142 is issued on August 27th, 1996; United States Patent (USP) 5,604,260 is issued on February 18th, 1997; United States Patent (USP) 5,698,584 is issued on December 16th, 1997; United States Patent (USP) 5,710,140 is issued on January 20th, 1998; WO94/15932 is disclosed in July 21 in 1994; United States Patent (USP) 5,344,991 is issued on June 6th, 1994; United States Patent (USP) 5,134,142 is issued on June 28th, 1992; United States Patent (USP) 5,380,738 is issued to January 10 nineteen ninety-five; United States Patent (USP) 5,393,790 is issued to February 20 nineteen ninety-five; United States Patent (USP) 5,466,823 is issued to November 14 nineteen ninety-five; United States Patent (USP) 5,633,272 is issued on May 27th, 1997 and United States Patent (USP) 5,932,598, is issued on August 3rd, 1999, and above-mentioned document all is hereby incorporated by.
The inhibitor that is specially adapted to the COX-2 in the methods of treatment of the present invention is:
3-phenyl-4-(4-(methyl sulphonyl) phenyl)-2-(5H)-furanone; With
5-chloro-3-(4-methyl sulphonyl) phenyl-2-(2-methyl-5-pyridyl) pyridine;
Or its pharmaceutically acceptable salt.
General and the concrete synthetic method for preparing above-mentioned cox 2 inhibitor compound is referring to United States Patent (USP) 5,474,995 (being issued to December 12 nineteen ninety-five), United States Patent (USP) 5,861,419 (being issued on January 19th, 1999) and United States Patent (USP)s 6,001,843 (being issued on December 14th, 1999), above-mentioned document all is incorporated herein by reference.
Be considered to the specific inhibitor of COX-2 and therefore be applicable to that compound of the present invention includes, but not limited to following:
Or its pharmaceutically acceptable salt.
Be considered to the specific inhibitor of COX-2 and therefore be applicable to compound of the present invention, and synthetic method, can be referring in following patent, application co-pending and the document, it is hereby incorporated by: WO 94/15932, is disclosed on June 21st, 1994; United States Patent (USP) 5,344,991 is issued on July 6th, 1994; United States Patent (USP) 5,134,142 is issued on June 28th, 1992; United States Patent (USP) 5,380,738 is issued to January 10 nineteen ninety-five; United States Patent (USP) 5,393,790 is issued to February 20 nineteen ninety-five; United States Patent (USP) 5,466,823 is issued to November 14 nineteen ninety-five; United States Patent (USP) 5,633,272 is issued on May 27th, 1997; With United States Patent (USP) 5,932,598, be issued on August 3rd, 1999.
Be considered to the specific inhibitor of COX-2 and therefore be applicable to compound of the present invention, and synthetic method, can be referring in following patent, application co-pending and the document, it is hereby incorporated by: United States Patent (USP) 5,474,995, be issued to December 12 nineteen ninety-five; United States Patent (USP) 5,861,419 is issued on January 19th, 1999; United States Patent (USP) 6,001,843 is issued on December 14th, 1999; United States Patent (USP) 6,020,343 is issued on February 1st, 2000; United States Patent (USP) 5,409,944 is issued to April 25 nineteen ninety-five; United States Patent (USP) 5,436,265 is issued to June 25 nineteen ninety-five; United States Patent (USP) 5,536,752 is issued on June 16th, 1996; United States Patent (USP) 5,550,142 is issued on August 27th, 1996; United States Patent (USP) 5,604,260 is issued on February 18th, 1997; United States Patent (USP) 5,698,584 is issued on December 16th, 1997; With United States Patent (USP) 5,710,140, be issued on January 20th, 1998.
Other examples of angiogenesis inhibitor include, but not limited to endostation; ukrain, ranpirnase, IM862; 5-methoxyl group-4-[2-methyl-3-(3-methyl-2-butene base) Oxyranyle]-1-oxaspiro [2; 5] suffering-6-base (chloracetyl) carbamate, ethanoyl dinanaline, 5-amino-1-[[3; 5-two chloro-4-(4-chlorobenzene formacyl) phenyl] methyl]-1H-1; 2,3-triazole-4-methane amide, CM101; squalamine; combretastatin, RPI4610, NX31838; sulfation sweet dew pentose phosphate; 7,7-(carbonyl-two [imino--N-methyl-4,2-pyrrolo-carbonyl-imino-[N-methyl-4; 2-pyrroles]-the carbonyl imino-]-two-(1; the 3-napadisilate), and 3-[(2,4-dimethyl pyrrole-5-yl) methylene radical]-2-dihydroindolone (SU5416).
As mentioned above, " integrin blocker " is meant selectivity antagonism, inhibition or hinders physiology part and α
vβ
3Integrin bonded compound is meant selectivity antagonism, inhibition or hinders physiology part and α
vβ
5Integrin bonded compound is meant selectivity antagonism, inhibition or hinders physiology part and α
vβ
3Integrin and α
vβ
5Both bonded compounds of integrin, and be meant that antagonism, inhibition or obstruction are expressed in the active compound of the specific integrin on the capillary endothelial cells.This term also is meant α
vβ
6, α
vβ
8, α
1β
1, α
2β
1, α
5β
1, α
6β
1And α
6β
4Integrin.Term also is meant α
vβ
3, α
vβ
5, α
vβ
6, α
vβ
8, α
1β
1, α
2β
1, α
5β
1, α
6β
1And α
6β
4The arbitrary combination of integrin.
Some specific exampless of tyrosine kinase inhibitor comprise N-(trifluoromethyl)-5-methyl isoxzzole-4-methane amide, 3-[(2,4-dimethyl pyrrole-5-agent) indole-2-ketone methylene radical), 17-(allyl amino)-17-demethoxylation geldanamycin, 4-(3-chloro-4-fluorophenyl amino)-7-methoxyl group-6-[3-(4-morpholinyl) propoxy-] quinazoline, N-(3-ethynyl phenyl)-6,7-two (2-methoxy ethoxy)-4-quinazoline amine, BIBX1382,2,3,9,10,11,12-six hydrogen-10-(hydroxymethyl)-10-hydroxyl-9-methyl-9,12-epoxy-1H-two indoles also [1,2,3-fg:3 ', 2 ', 1 '-kl] pyrrolo-[3,4-i] tetraene-1-ketone between [1,6] benzodiazepine heterocycle suffering, SH
268, genistein, STI571, CEP2563,4-(3-chloro-phenyl-amino)-5,6-dimethyl-7H-pyrrolo-[2,3-d] the pyrimidine methanesulfonates, 4-(3-bromo-4-hydroxy phenyl) amino-6,7-dimethoxyquinazoline e, 4-(4 '-hydroxy phenyl) amino-6, the 7-dimethoxyquinazoline, SU6668, STI571A, N-4-chloro-phenyl--4-(4-pyridylmethyl)-1-phthalazines amine, and EMD121974.
Also belong in the method for the present invention with the combination medicine form of compound except that anticancer compound.For example, the combination of compound of the present invention and PPAR-γ (being PPAR-gamma) agonist and PPAR-δ (being PPAR-delta) agonist is applicable to some malignant disease of treatment.PPAR-γ and PPAR-δ are nuclear peroxisome proliferator (proliferator) activated receptor γ and δ.PPAR-γ has reported in literature (referring to J.Cardiovasc.Phannacol.1998 in expression on the endotheliocyte and the participation effect in vasculogenesis thereof; 31:909-913; J.Biol.Chem.1999; 274:9116-9121; Invest.Ophthalnzol Vis.Sci.2000; 41:2309-2317).Recently, the PPAR-gamma agonist has been proved in the vasculogenesis reaction of vitro inhibition to VEGF; Troglitazone (rosiglitazone) and rosiglitazone (rosiglitazone) maleate suppress the deterioration (Arch.Ophthamol.2001 of retinene neovascularization in the mouse; 119:709-717).The example of PPAR-gamma agonist and PPAR-γ/alfa agonists includes, but not limited to thiazolidinediones (DRF for example
2725, CS-011, troglitazone, rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, chlorine Bei Te, GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926,2-[(5,7-dipropyl-3-Trifluoromethyl-1,2-benzisoxa oxazole-6-yl) the oxygen base]-2 Methylpropionic acid (being disclosed in USSN09/782,856), with 2 (R)-7-(3-(2-chloro-4-(4-good fortune phenoxy group) phenoxy group) propoxy-)-2-ethyl chroman-2-carboxylic acid (being disclosed in USSN 60/235,708 and 60/244,697).
Another embodiment of the present invention is that compound disclosed herein and gene therapy are united the application in the treatment cancer.The summary of the gene strategy of relevant treatment cancer is referring to Hall etc. (Am JHum Genet 61:785-789,1997) and Kufe etc. (pp876-889, BC Decker, Hamilton 2000 for Cancer Medicine, 5th Ed).Gene therapy can be used to apply any tumor suppressor gene.The example of this genoid comprises, but be not limited to, p53, it can be carried (referring to for example U.S. Patent number 6 through the gene transmission of recombinant virus mediation, 069,134), uPA/uPAR antagonist (" Adenovirus-Mediated Delivery of a uPA/uPAR AntagonistSuppresses Angiogenesis-Dependent Tumor Growth and Dissemination inMice; " Gene Therapy, August 1998; 5 (8): 1105-13), and interferon-gamma (J Immunol2000; 164:217-222).
Compound of the present invention can also with intrinsic multidrug resistance (MDR), the inhibitor of particularly relevant with the high level expression of translocator NOR is united use.This type of MDR inhibitor comprises p-glycoprotein (P-gp), LY335979 for example, XR9576, OC144-093, R
101922, VX853 and PSC833 (valspodar).
Compound of the present invention can be united to make and is used for treating n or V with antiemetic, comprise acute, delaying type, late period and early onset vomiting, these vomitings may be by the The compounds of this invention list with or with radiotherapy share cause.In order to prevent or treat vomiting, compound of the present invention can share in other antiemetic, antagonists of neurokinine-1 receptor especially, 5HT3 receptor antagonist, ondansetron for example, granisetron, Novaban, and zatisetron, the GABAB receptor stimulant, baclofen for example, reflunomide is dexamethasone (dexamethasone) for example, Triamcinolone Acetonide, Triamcinolone Acetonide, flunisolide, budesonide, Benecorten or other drug for example are disclosed in U.S. Patent number 2,789,118,2,990,401,3,048,581,3,126,375,3,929,768,3,996,359,3,928,326 and 3,749, in 712, dopamine antagonist medicine, for example phenothiazines (prochlorperazine for example, fluphenazine, thioridazine and mesoridazine), metoclopramide or dronabinol.In order to treat or prevent to use the vomiting that The compounds of this invention may cause, the preferred employing and the conjoint therapy that is selected from the antiemetic of antagonists of neurokinine-1 receptor, 5HT3 receptor antagonist and reflunomide.
The antagonists of neurokinine-1 receptor co-administered with The compounds of this invention is disclosed in comprehensively, and for example U.S. Patent number 5,162, and 339,5,232,929,5,242,930,5,373,003,5,387,595,5,459,270,5,494,926,5,496,833,5,637,699,5,719,147; European patent communique EP 0 360 390,0 394 989,0,428 434,0 429 366,0 430 771,0 436 334,0 443 132,0 482 539,0 498 069,0 499 313,0 512 901,0 512 902,0 514273,0 514 274,0 514 275,0 514 276,0 515 681,0 517 589,0 520 555,0 522 808,0 528 495,0 532 456,0 533 280,0 536 817,0 545 478,0 558156,0 577 394,0 585 913,0 590 152,0 599 538,0 610 793,0 634 402,0 686 629,0 693 489,0 694 535,0 699 655,0 699 674,0 707 006,0 708101,0 709 375,0 709 376,0 714891,0 723 959,0 733 632 and 0 776 893; Pct international patent communique WO 90/05525,90/05729,91/09844,91/18899,92/01688,92/06079,92/12151,92/15585,92/17449,92/20661,92/20676,92/21677,92/22569,93/00330,93/00331,93/01159,93/01165,93/01169,93/01170,93/06099,93/09116,93/10073,93/14084,93/14113,93/18023,93/19064,93/21155,93/21181,93/23380,93/24465,94/00440,94/01402,94/02461,94/02595,94/03429,94/03445,94/04494,94/04496,94/05625,94/07843,94/08997,94/10165,94/10167,94/10168,94/10170,94/11368,94/13639,94/13663,94/14767,94/15903,94/19320,94/19323,94/20500,94/26735,94/26740,94/29309,95/02595,95/04040,95/04042,95/06645,95/07886,95/07908,95/08549,95/11880,95/14017,95/15311,95/16679,95/17382,95/18124,95/18129,95/19344,95/20575,95/21819,95/22525,95/23798,95/26338,95/28418,95/30674,95/30687,95/33744,96/05181,96/05193,96/05203,96/06094,96/07649,96/10562,96/16939,96/18643,96/20197,96/21661,96/29304,96/29317,96/29326,96/29328,96/31214,96/32385,96/37489,97/01553,97/01554,97/03066,97/08144,97/14671,97/17362,97/18206,97/19084,97/19942 and 97/21702; British patent gazette numbers 2266529,2268931,2269170,2269590,2271774,2292144,2293168,2293169 and 2302689.The preparation of these compounds is disclosed in above-mentioned patent and the bulletin comprehensively, and its content is hereby incorporated by.
In one embodiment, the antagonists of neurokinine-1 receptor of uniting use with The compounds of this invention is selected from: 2-(R)-(1-(R)-(3,5-two (trifluoromethyl) phenyl) oxyethyl group)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H, 4H-1,2, the 4-triazolo) methyl) morpholine, or its pharmaceutically acceptable salt, it is disclosed in U.S. Patent number 5,719, in 147.
Compound of the present invention can also with the treatment anaemia medication combined administration.This type of treatment for anemia medicine for example is continuous eythropoiesis receptor activators (for example erythropoietin α).
Compound of the present invention can also reduce the medication combined administration of disease with the treatment neutrophilic granulocyte.This type of neutrophilic granulocyte therapeutical agent for example is generation and the hemopoieticgrowth factor of function, for example Filgrastim (G-CSF) who regulates neutrophilic granulocyte.The example of G-CSF comprises filgrastim.
Compound of the present invention can also with immunostimulant Combined Preparation, for example LEVAMISOLE HCL, isoprinosine and Zadaxin.
So, comprise compound of the present invention and the combined utilization that is selected from the second following compound in the scope of the present invention: 1) estrogenic agents, 2) androgen receptor modifier, 3) retinoic acid receptor (RAR) conditioning agent, 4) cytotoxicity/cytostatics, 5) antiproliferative, 6) the isopentene group protein transferase inhibitor, 7) HMG-CoA reductase inhibitor, 8) hiv protease inhibitor, 9) reverse transcriptase inhibitors, 10) angiogenesis inhibitor, 11) PPAR-gamma agonist, 12) PPAR-delta agonists, the 13) inhibitor of intrinsic multidrug resistance, 14) antiemetic, 15) treatment for anemia agent, 16) neutrophilic granulocyte reduces Remedies, 17) immunostimulant, the 18) inhibitor of cell proliferation and survival signal, 19) cell death inducer cell cycle chechpoint agent interfering and 20).
Be meant that at the middle term of quoting of The compounds of this invention " administration " and its version (for example " using " compound) prodrug with described compound or this compound is incorporated in the animal system that needs treatment.When compound of the present invention or its prodrug and one or more other promoting agents (for example, cytotoxic agent etc.) are united when providing, " administration " and version thereof are interpreted as separately and comprise described compound or its prodrug and other drug is parallel and order is introduced.
Term " composition " comprises the product of the specific components that contains specified quantitative as used herein, and any product that is directly or indirectly obtained by the combination of the specific components of specified quantitative.
Term " treatment significant quantity " is meant the active compound that searched out by researchist, animal doctor, clinician and other clinical positions person or medicament produce biology or medical response in tissue, system, animal or human's body amount as used herein.
Term " treatment cancer " or " treatment for cancer " are to point to suffer from the Mammals administration of carcinous illness and alleviate carcinous illness by kill cancer cell, and produce the result who suppresses growth of cancers and/or migration.
In one embodiment; angiogenesis inhibitor as second compound is selected from: tyrosine kinase inhibitor; the inhibitor of epidermis derivative growth factor, the inhibitor of inoblast derivative growth factor, the inhibitor of thrombocyte salt solution somatomedin; MMP (matrix metalloproteinase) inhibitor; the integrin blocker, interferon-' alpha ', il-1 2; xylan polysulfate; cyclooxygenase inhibitors, carboxamide groups triazole, combretastatin A-4; squalamine; 6-O-chloracetyl-carbonyl)-and aspergillus fumigatus cedrol, Thalidomide, angiostatin; troponin-1, or the antibody of VEGF.In one embodiment, this estrogen receptor modulator is tamoxifen or raloxifene.
Also comprise a kind of treatment method for cancer in the scope of claims, this method comprises with the compound of formula I of treatment significant quantity and radiotherapy and/or with to be selected from following compound co-administered: 1) estrogenic agents, 2) androgen receptor modifier, 3) retinoic acid receptor (RAR) conditioning agent, 4) cytotoxicity/cytostatics, 5) antiproliferative, 6) isopentene group protein transferase inhibitor, 7) HMG-CoA reductase inhibitor, 8) hiv protease inhibitor, 9) reverse transcriptase inhibitors, 10) angiogenesis inhibitor, 11) the PPAR-gamma agonist, 12) PPAR-delta agonists, 13) inhibitor of intrinsic multidrug resistance, 14) antiemetic, 15) the treatment for anemia agent, 16) neutrophilic granulocyte reduces Remedies, 17) immunostimulant, the 18) inhibitor of cell proliferation and survival signal, 19) cell cycle chechpoint agent interfering and 20) cell death inducer.
Another embodiment of the present invention relates to a kind of treatment method for cancer, and this method comprises compound and taxol or the Si Tuman cloth Combined Preparation with the formula I of treatment significant quantity.
The present invention further comprises the method for a kind of treatment or preventing cancer, and this method comprises compound and the cox 2 inhibitor Combined Preparation with the formula I of treatment significant quantity.
The present invention also comprises a kind of being used for the treatment of or the pharmaceutical composition of preventing cancer, wherein contain the compound of the formula I that treats significant quantity and be selected from following compound: 1) estrogenic agents, 2) androgen receptor modifier, 3) retinoic acid receptor (RAR) conditioning agent, 4) cytotoxicity/cytostatics, 5) antiproliferative, 6) isopentene group protein transferase inhibitor, 7) HMG-CoA reductase inhibitor, 8) HTV proteinase inhibitor, 9) reverse transcriptase inhibitors, 10) angiogenesis inhibitor, 11) PPAR-gamma agonist, 12) the PPAR-delta agonists; 13) inhibitor of cell proliferation and survival signal, 14) cell cycle chechpoint agent interfering and 15) cell death inducer.
The invention further relates to compound of the present invention and screening other in conjunction with the application in the method for the compound of KSP.For compound of the present invention being used for screening method, make KSP be connected, and add in test compound of the present invention (it is a mitotic division reagent) with support in conjunction with the compound of KSP kinesin.Perhaps, compound of the present invention is connected and adds KSP with support.Can comprise specific antibody from wherein searching out the type of compounds that becomes new wedding agent, the non-natural wedding agent of in chemical library screening, identifying, peptide analogs etc.Interested especially is to be used to screen the shaker test that human body cell is had hypotoxic candidate agent.Multiple test can be used for this purpose, comprises the interior protein-protein binding analysis of body of mark, electrophoretic mobility shift assay, protein bound immunoassay, functional analysis (phosphorylation test etc.) etc.
Mensuration to the keying action of mitogenic agent and KSP can be taked multiple mode.In a preferred embodiment, with mitogenic agent (compound of the present invention) mark, for example, also directly measure keying action with fluorescein or radioactivity group.For example, this can be by linking to each other all or part of KSP with solid support, mitogenic agent (the compound for example of the present invention that adds mark, wherein at least one atom is by detectable isotopic), excessive reagent is removed in washing, thus and the amount realization of the marker that exists on the mensuration solid support.As known in the art, knownly can adopt different blockading and washing step.
So-called " mark " is meant that compound directly or indirectly is labeled substance markers, produces detectable signal thus, for example, radio isotope, fluorescein-labelled, enzyme, antibody, particulate is magnetic particle for example, chemiluminescent labeling or specific combination molecule etc.The specific combination molecule is right, biological example element and streptavidin, digoxin and anti-digoxin etc.With regard to specific binding members, the complement member is general with the molecule that can be supplied to detect, according to the currently known methods mark, and is as listed above.Marker can directly or indirectly produce detectable signal.
In some embodiments, a kind of component of a mark.For example, can use at the locational kinesin of tyrosine
125I or use the fluorophore mark.In addition, can be with more than one component of different marker marks; For example, use
125The I labelled protein, and with fluorophore mark mitogenic agent.
Compound of the present invention can also be as the competitor of screening other drug material standed for." candidate bioactive agent " or " drug candidates " or be equal to literal and be meant any determined bioactive molecule, protein for example, oligopeptide, organic molecule, polysaccharide, polynucleotide etc.They may directly or indirectly change the expression of cell proliferation phenotype or cell proliferation sequence, comprise nucleotide sequence and protein sequence.In other cases, screening cellular proliferation protein keying action and/or active variation.This type of screening can be carried out in the microtubule existence or not.In screening combination of proteins effect or active situation, preferred embodiment do not comprise known molecular, for example paradigmatic structure such as microtubule and the energy such as ATP in conjunction with specified protein.The preferred implementation of this paper analysis comprise its endogenous native state not with cellular proliferation protein bonded candidate agent, be called " exogenous " reagent herein.In another preferred embodiment, exogenous agents does not comprise the antibody of KSP yet.
Although they are organic molecules usually, candidate agent can comprise the number of chemical type, preferably has greater than 100 and less than the little organic compound of about 2,500 Dalton molecular weights.Candidate agent contain with protein structurally interact, particularly hydrogen bond and lipotropy combine necessary functional group, generally include at least one amine, carbonyl, hydroxyl, ether or carboxyl, preferably contain two chemical functional groups at least.Candidate agent often contains ring carbon or heterocycle structure and/or aromatics or the poly-aromatic structure that is replaced by one or more above-mentioned functional groups.Candidate agent can find in biomolecules that also this biomolecules comprises peptide, carbohydrate, lipid acid, steroide, purine, pyrimidine, their derivative, analog or its combination.Peptide especially preferably.
Candidate agent derives from multiple source, comprises the library of synthetic or natural compounds.For example, many modes can be used at random and directly synthetic multiple different organic compound and biomolecules, comprise the expression of oligonucleotide at random.In addition, the library of the natural compounds of bacterium, fungi, plant and substrate extract form can obtain or be easy to produce.In addition, the library of natural or synthetic generation and compound are easy to chemistry, physics and the modification of biological activity method by routine.Known pharmacological agents can be directly or is carried out chemical modification at random, acidylate for example, alkylation, esterification, amidation generating structure analogue.
Competitive screening is analyzed and can be finished by the drug candidates in the KSP and first sample is mixed.Second sample contains mitogenic agent, KSP and drug candidates.Can under microtubule existence or non-existent condition, carry out.Measure the keying action of the drug candidates of above-mentioned two kinds of samples, the variation of keying action or difference mean that existence can and may regulate its active reagent in conjunction with KSP between two kinds of samples.That is to say that if the keying action of the drug candidates in second sample is different from first sample, then this drug candidates can be in conjunction with KSP.
In a preferred embodiment, the keying action of candidate agent is measured by competitive binding analysis.In this embodiment, competitor is known KSP bound fraction, antibody for example, peptide, binding partners, part etc.In some cases, may have competitive keying action between this candidate agent and this bound fraction, and this bound fraction is replaced this candidate agent.
In one embodiment, this candidate agent of mark.With candidate agent or competitor, or the two at first joins and reaches the time that is enough to allow association reaction among the KSP, if there are the bonded words.Can under any temperature, cultivate, thereby impel active the best, be generally about 4 ℃-Yue 40 ℃.
Select culture cycle to reach optimum activity, promote high flux screening fast but also can optimize to reach.Common 0.1-1 hour should be enough.Excessive reagent generally is removed or washes off.Adding second component subsequently, is to exist or non-existent marker components subsequently, to confirm keying action.
In a preferred embodiment, at first add competitor, add candidate agent subsequently.Emulative replacement reaction shows that this candidate agent combines with KSP, and thus can be in conjunction with the activity that also may regulate KSP.In this embodiment, can be with two kinds of component marks.For example, if the mark competitor, the existence of marker in washing soln signifying that reaction has taken place to replace reagent.In addition, if the mark candidate agent, the existence of marker on support signifying to have taken place to replace reaction.
In another embodiment, at first add candidate agent, and cultivate and washing, add competitor subsequently.Not the existing of competitor keying action can represent this candidate agent with higher avidity in conjunction with KSP.Thus, if the mark candidate agent, the existence of marker on support simultaneously not existing of competitor keying action, can signify that this candidate agent can be in conjunction with KSP.
The binding site of identifying KSP may have value.This can carry out in many ways.In one embodiment, in case identify that KSP can be in conjunction with mitogenic agent, then with this KSP fragmentation or modification, and revision test is to identify in conjunction with necessary composition.
Can regulate the active candidate agent of KSP by screening and can test out regulating effect, comprise candidate agent and KSP are mixed, as mentioned above, and the bioactive variation of mensuration KSP.Thus, in this embodiment, candidate agent should also change as defined herein biology or chemical-biological activities in conjunction with KSP (though this may be unnecessary).This method comprises to the cell that changes cell cycle distribution, cell survival or to screening method in the in-vitro screening method of existence, form, activity, distribution or the content of mitotic spindle and the body, and is generally as mentioned below.
In addition, different sieve method can be used to identify in conjunction with natural KSP can debond Modified K SP drug candidates.
Can adopt positive control and negative control in the analysis.Preferred all contrasts and test sample carry out in triplicate to obtain the result of statistical significance.The cultivation of all samples reaches the time that is enough to protein bound.After the cultivation, wash the material that all samples are removed non-specific combination, and measure bonded, the amount of the reagent that is mark generally.For example, when adopting radio-labeling, sample can be counted the amount of the compound that combines with mensuration in scintillometer.
Screening can be adopted multiple other reagent in analyzing.Comprising for example salt, neutral protein (for example albumin), washing composition etc., they can be used for promoting best protein-protein keying action and/or reduce non-special or background interaction.Can use other reagent that can improve test efficiency, proteinase inhibitor for example, ribozyme inhibitor, biocide etc.Can be with any miscellany that the order adding component of necessary keying action can be provided.
These and other aspects of the present invention will be clearer from the instruction of this paper.
Analyze
The The compounds of this invention of describing among the embodiment has kinesin by following experimental test and discovery and suppresses active.Other tests are known from document and are easily those skilled in the art and implement.
1. kinesin ATPase in vitro tests
The clone and the expression in the KSP motion structure territory of people's polyhistidine tag (KSP (367H))
Expressing the plasmid of human body KSP motion structure domain construction clones as template with pBluescript total length people's KSP structure (Blangy etc., Cell, vol.83, ppl 159-1169,1995) by PCR.With the terminal primer 5 of N-'-GCAACGATTAATATGGCGTCGCAGCCAAATTCGTCTGCGAAG (SEQ.ID.NO.:1) and C-end primer 5 '-GCAACGCTCGAGTCAGTGAT
GATGGTGGTGATGCTGATTCACTTCAGGCTTATTCAATAT (SEQ.ID.NO.:2) increase this motion structure territory and neck joining region.The PCR product is with AseI and XhoI digestion, is connected to the NdeI/XhoI digestion product of pRSETa (Invitrogen) and is transformed among the E.coli BL21 (DE3).
Cell grows to OD under 37 ℃
600Be 0.5.After culture was cooled to room temperature, the expression of KSP was induced with 100 μ M IPTG and is continued overnight incubation.Cell washs 1 time by centrifugation and with ice-cold PBS.To precipitate quick-frozen and be stored in-80 ℃.
Protein purification
Fused cell precipitation group ice is suspended in molten born of the same parents' damping fluid (50mM K-HEPES, pH8.0,250mM KCl once more on ice, 0.1% tween, 10mM imidazoles, 0.5mM Mg-ATP, 1mM PMSF, 2mM benzimidine, 1x adequate proteins enzyme inhibitors cocktail (Roche)) in.Cell suspension and 1mg/ml N,O-Diacetylmuramidase and 5mM mercaptoethanol were cultivated on ice 10 minutes, ultrasonic subsequently (3 * 30 seconds).All subsequent disposal are carried out under 4 ℃.Lysate is 40, under the 000xg centrifugal 40 minutes.Dilution supernatant liquor and be carried in buffer A (50mMK-HEPES, pH6.8,1mM MgCl on the SP agarose column (Pharmacia, 5ml cartridge case)
2, 1mM EGTA, 10 μ M Mg-ATP, 1mM DTT) in and with the 0-750mM KCl gradient elution in the buffer A.Merging contains the cut of KSP and is incubated 1 hour with Ni-NTA resin (Qiagen).Resin is cultivated subsequently 15 minutes 3 times and is washed with buffer B with buffer B (molten born of the same parents' damping fluid reduces PMSF and proteinase inhibitor cocktail) washing 3 times.At last, this is known cultivate and wash 15 minutes totally 3 times also in the impouring post with damping fluid C (except that pH6.0 with the buffer B wash-out).KSP is with elution buffer (identical with buffer B except that 150mM KCl and 250mM imidazoles) wash-out.Merge the cut contain KSP, in sucrose, reach 10% and be stored in-80 ℃.
Prepare microtubule from the isolating tubulin of oily ox brain.The purifying tubulin of 1mg/ml (＞97% no MAP) under 37 ℃ in the presence of 10 μ M taxols, 1mM DTT, 1mM GTP in BRB80 damping fluid (80mM K-PIPES, 1mM EGTA, 1mMMgCl
2, pH6.8) middle polymerization.The gained microtubule is separated with unpolymerized tubulin and remove supernatant liquor by ultracentrifugation.The precipitation that will contain microtubule is rolled into a ball resuspending gently and is contained in 10 μ M taxols among the BRB80, and 1mM DTT is in 50g/ml Ampicillin Trihydrate and the 5ug/ml paraxin ester.
With this kinesin motion structure territory and microtubule, 1mM ATP (1: 1 MgCl
2: Na-ATP) and compound under 23 ℃ in containing 80mM K-HEPES (pH7.0), 1mM EGTA, 1mMDTT, 1mM MgCl
2With cultivate in the damping fluid of 50mM KCl.Final buffer compositions dilution 2-10 with 80mM HEPES and 50mM EDTA doubly stops this reaction (perhaps, the liquor capacity that increases at 1: 1 to stop buffer (1.8M KCl and 50mM EDTA)).Utilize quinaldine red/ammonium molybdate test, measure the free phosphorus hydrochlorate (for example, the miscellany of 40 μ l reaction volumes+40 μ l stop buffers adds 120 μ l quencher C) that the ATP hydrolysis reaction obtains by the quencher C that adds 1.5 times of volumes.Quencher A contains 0.1mg/ml quinaldine red and 0.14% polyvinyl alcohol; Quencher B contains 12.3mM ammonium molybdate tetrahydrate in 1.15M sulfuric acid.Quencher C is the quencher A of 2: 1 ratios: quencher B.This is reflected at 23 ℃ and is incubated 5-10 minute down, measures the absorbancy of phosphorus-molybdate mixture under 540nm.
Compound 3-1 among the embodiment, 4-2,5-3,5-4,7-1,7-2,7-3,8-6a/8-6b, 9-1,10-2,11-1,12-1,12-2 and 12-3 are in above-mentioned test determination and find IC
50≤ 50 μ M.
II. cell proliferation test
The cell bed board in 96 hole tissue culture wares, is made its density be logarithmic growth and allow to spend the night during 24,48 and 72 hours and adheres to.Next day, compound joins in all flat boards with the half log titre of 10 points.Each titration series is according to carrying out in triplicate, and keeps 0.1% constant DMSO concentration in entire test.Also comprise the contrast of the single usefulness of 0.1%DMSO.Each diluted chemical compound series is to carry out in serum free medium.In the test in the substratum of 200 μ l volumes the final concentration of serum be 5%.Add the blue staining agent of Alamar of 20 microlitres in each sample in the time of 24,48 and 72 hours on the titration flat board and the control wells, add medicine subsequently also once more 37 ℃ of cultivations.On the CytoFluorII plate reader with the 530-560 nano wave length excite, 590 nanometers are transmitted in 6-12 hour post analysis Alamar blue-fluorescence degree.
The average percent inhibition of cell growth obtains cytotoxicity EC during by the compound concentration on the drafting X axis and each the titration point on the Y-axis
50Be defined as separately 100% growth rate of this test, contrast and will be worth with the growth of the cell of compound treatment and this with the growth of the cell in the control wells of vehicle treated.Adopt inner proprietary software to calculate the percentage cytotoxicity values and with logic 4 parametric line The Fitting Calculation flex points.Cytotoxic percentage is defined as:
% cytotoxicity rate: (fluorescence
Contrast)-(fluorescence
Sample) * 100 * (fluorescence
Contrast)
-1
Flex point is reported as cytotoxicity EC
50
The mitotic division of III.FACS stops and apoptotic assessment
Facs analysis is assessed a kind of compound by the dna content of measuring processed cell mass and is suppressed cell mitogen and cause apoptotic performance.With cell with 1.4 * 106 cell/6cm
2The density inoculation of tissue culture ware also makes its adhesion spend the night.Cell was with compound treatment 8-16 hour of carrier (0.1%DMSO) or titration series subsequently.After the processing, by at the appointed time interior effect of trypsinase and centrifugation harvested cell.The rinsing and being fixed in 70% ethanol in PBS of cell precipitation group is stored in and spends the night under 4 ℃ or the longer time.
For facs analysis, precipitate at least 500,000 fixed cell and remove 70% ethanol by suction.Subsequently this cell 4 ℃ down with RNase A (50Kunitz unit/ml) and iodate third ingot (50pg/ml) cultivation 30 minutes, and analyze with Becton Dickinson FACSCaliber.With Modfit cell cycle analysis prototype software (Verity Inc.) analytical data (deriving from 10,000 cells).
The cell percentage (by mensuration iodate third ingot fluorescence) of G2/M in mutually that is the cell cycle by drawing each the titration point on compound concentration and the Y-axis on the X-axis obtains the EC that mitotic division stops
50Utilize SigmaPlot programanalysis data, with logic 4 parametric line The Fitting Calculation flex points.Flex point is reported as the EC that mitotic division stops
50Adopt similar approach to measure the apoptotic EC of compound
50So the percentage of each titration point place apoptotic cell (by the iodate third ingot fluorometric assay) is plotted on the Y-axis, and similarly analyzes according to the method described above.
IV. detect the IFM method of monopolar spindle
The method of immunofluorescence dyeing that is used for DNA, tubulin and other center protein (pericentrin) is described as (2000) J.Cell Biol.150:975-988 such as Kapoor basically.For the research of cell cultures, with the cell bed board on the glass compartment slide that tissue culture is handled and make its adhesion spend the night.Cell was cultivated 4-16 hour with compound of interest subsequently.After cultivation finishes, aspirate substratum and medicine and remove compartment and packing ring from slide.Make Premeabilisation of cells according to reference scheme subsequently, fixing, wash and blockade and be used for the non-specific antibody combination.The tumor biopsy dewaxing of paraffin being inlayed with dimethylbenzene and before blockading with ethanol series liquid in aquation.(mouse monoclonal resists-alpha-tubulin antibody slide, derives from the clone DM1A of the dilution in 1: 500 of Sigma at primary antibody; Derive from the anti-pericentrin antibody of rabbit polyclonal of Covance, 1: 2000 the dilution) in 4 ℃ of following overnight incubation.After the washing, this slide coupling secondary antibody (anti-mouse IgG of FITC coupling monkey of tubulin that is diluted to 15 μ g/ml under the room temperature; The anti-rabbit igg of the red coupling monkey of Texas that is used for pericentrin) cultivated 1 hour.With the after scouring slide and with Hoechst 33342 counterstaining to show DNA.The immunostaining sample carries out imaging with Metamorph decurl and imaging software with 100x oil immersion object lens on the Nikon epifluorescence microscope.
Embodiment
The embodiment that provides helps further to understand the present invention.Initial principle, kind and the condition of using only is to illustrate the present invention and do not limit its reasonable range.
Route 1
Step 1:4-allyl group-4-phenyl-1,3-oxazoles alkane-2-ketone (1-4)
In the suspension of 15.8g (416mmol) LAH powder in the 600mL ether, add 18.3g (90mmol) be present in α-allyl group-α-phenylglycine ethyl ester in the 75mL ether (
1- 3) (according to Van Betsbrugge etc., Tetrahedron, 1997,53,9233-9240) and make and add speed and maintain slight backflow.Stir under the room temperature spend the night after, the quencher of 27mL water is used in this reaction carefully, adds the 15%NaOH of 27mL subsequently and adds the water of 82mL at last.Add a certain amount of NaSO
4, this mixture was stirred 1 hour.Filter out solid and concentrate this solution.Resistates is dissolved in the CH of 300mL
2Cl
2, use Na
2SO
4Dry also concentrating obtains amino alcohol, and it is a water white oil.(4.5g 25mmol) is dissolved in 50mLCH with this amino alcohol
2Cl
2And be cooled to 0 ℃.Add 5.4mL (53mmol) triethylamine and 4.5g (28mmol) 1,1 '-carbonyl dimidazoles subsequently, this miscellany is heated to room temperature and stirred 4 hours.This reaction joins separating funnel subsequently, with 1M HCl, water washing 2 times, uses Na
2SO
4Dry and the concentrated oxazolidone that obtains
1-4, it is a water white oil.
1-4Data:
1H NMR (500MHz, CDCl
3) δ 7.4-7.2 (m, 5H), 6.6 (s, 1H), 5.6-5.5 (m, 1H), 5.2 (m, 2H), 4.5 (d, 1H), 4.35 (d, 1H), 2.8 (m, 1H), 2.6 (m, 1H) ppm.
Step 2: diester (1-5)
With 68g's (334.6mmol)
1-4At 500mL CH
2Cl
2In solution be cooled to-78 ℃ and ozone is blown into this solution until keeping light blue.Subsequently with O
2In this solution, be blown into 15 minutes, after this feed 30 minutes N
2At this moment, add 491mL (6.7moles) dimethyl sulphur, this solution stirring is spent the night slowly rises to room temperature simultaneously.Volatile matter is removed by rotary evaporation and is obtained brown oil.This material is suspended among the 1L tBuOH, and adds the 2-methyl-2-butene of 200mL (1.9moles).Drip 160g (1.33moles) NaH to this solution subsequently
2PO
4And 70g (774mmol) NaClO
2At 800mL H
2In the miscellany among the O.Behind reinforced the finishing, this miscellany continues to stir 4 hours.After separating each layer, concentrate organism, resistates is dissolved in EtOAc and places separating funnel by rotary evaporation, and from this Reaction Separation water.After the separation, water extracts with 3xEtOAc, uses Na
2SO
4The yellow natural gum of drying and concentrated obtaining～90g.This resistates is suspended in 500mL MeOH, and will be blown into this solution until approaching backflow with HCl gas.Add a cover and allow stirring to spend the night in this flask, be cooled to room temperature simultaneously.Remove volatile matter by rotary evaporation, this resistates is carried in CH on the silicagel column
2Cl
2In and obtain this methyl esters with EtOAc/ hexane wash-out, it is a light orange natural gum.This resistates is dissolved in the THF of 500mL, is cooled to 0 ℃, add the bromo-acetic acid tert-butyl of 32.6mL (220.5mmol), add the NaH (60% suspension of 264.6mmol) of 10.6g subsequently.Make this miscellany rise to room temperature and stirring is spent the night, use saturated NH
4The quencher of Cl solution, and with EtOAc extraction 2 times.The organic layer that merges is used the salt water washing subsequently, uses Na
2SO
4Drying concentrates and resistates obtains with EtOAc/ hexane purifying by silica gel chromatography
1-5, it is thick light yellow natural gum.
1-5Data:
1H NMR (500MHz, CDCl
3) δ 7.4-7.3 (m, 5H), 4.65 (d, 1H), 4.55 (d, 1H), 3.9 (d, 1H), 3.65 (s, 3H), 3.5 (d, 1H), 3.35 (d, 1H), 3.2 (d, 1H), 1.4 (s, 9H) ppm.HRMS (ES) C
18H
23NO
6M+Na: calculated value 372.1423. measured value: 372.1412.
Step 3:7a-phenyl dihydro-1H-pyrrolo-[1,2-c] [1,3] oxazole-3,6 (5H)-diketone (1-6)
To 18.6g (53mmol)
1-5In the solution in 150mL THF in the 1M THF solution of the LiHMDS of-78 ℃ of following Dropwise 5 8.6mL (58.6mmol).Stir under this temperature after 1 hour, remove cooling bath and order reaction and rise to room temperature and stir and spend the night.The saturated NH of this miscellany
4The quencher of Cl solution with EtOAc extraction 2 times, with salt water washing 2 times, is used Na
2SO
4Dry and concentrated.Resistates is dissolved in 60mL formic acid and descends heating 24 hours at 100 ℃.Remove volatile matter and resistates CH under the vacuum
2Cl
2/ hexane/Et
2The O development obtains
1-6, it is a beige solid.
1-6Data:
1HNMR (500MHz, CDCl) δ 7.5-7.3 (m, 5H), 4.7 (d, 1H), 4.3 (d, 1H), 4.2 (d, 1H), 3.5 (d, 1H), 3.1 (d, 1H), 2.95 (d, 1H), 2.9 (d, 1H) ppm.
Step 4:6-(2, the 5-difluorophenyl)-7a-phenyl-5,7a-dihydro-1H-pyrrolo-[1,2-c] [1,3] oxazole-3-ketone (1-7)
To 2.2g (10mmol)
1-7Drip the 1M solution of 12.2mL (12.2mmol) NaHMDS in THF down in-78 ℃ in the suspension in 150mL THF.Stir after 30 minutes, this solution is warming up to 0 ℃ and kept 1 hour.This solution is cooled to-78 ℃ and add 4.35g (12.2mmol) N-phenyl two (fluoroform sulphonamide) at 10mL THF solution extremely subsequently.Remove cooling bath and make this miscellany rise to room temperature and stir and spend the night.The saturated NH of this miscellany
4The quencher of Cl solution with EtOAc extraction 2 times, with salt water washing 2 times, is used Na
2SO
4Dry and concentrated.Resistates is dissolved in the water of the DME of 75mL and 18mL.Add 1.29g (30mmol) LiCl, 3.2g (30mmol) Na to this compound
2CO
3, and 4.8g (30mmol) 2,5-difluorophenyl boric acid.This solution N
2Outgased 1 minute, subsequently with the tetrakis triphenylphosphine palladium (0) of lover 630mg (0.5mmol).This is reflected at 90 ℃ heated 3 hours down, be cooled to room temperature, use saturated NaHCO
3Dilution and with EtOAc extraction 2 times.Na is used in the organic layer salt water washing that merges
2SO
4Drying, concentrate and resistates by silica gel chromatography CH
2Cl
2/ hexane purifying obtains
1-7, it is a white solid.
1-7Data:
1H NMR (500MHz, CDCl
3) δ 7.5-7.3 (m, 5H), 7.1-6.9 (m, 3H), 6.8 (s, 1H), 4.9 (d, 1H), 4.75 (d, 1H), 4.5 (d, 1H), 4.25 (d, 1H) ppm.HRMS (ES) C
18H
13F
2NO
2M+H: calculated value 314.0987. measured value: 314.0993.
Step 5:2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-4-(2, the 5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrroles (1-8)
With 1.75g (5.6mmol)
1-7Suspension in 15mL EtOH and 10mL 3MnaOH heated 3 hours at 60 ℃, was cooled to room temperature and transfers to contain EtOAc and brinish separating funnel.Separate each layer, water extracts 2 times with EtOAc, and the organic phase of merging is used Na with salt water washing 2 times
2SO
4Dry and the concentrated white solid that obtains.In flask, add 30mL CH
2Cl
2, 1.5g (22.3mmol) imidazoles and 1.76g (11.7mmol) TBSC1, and the gained suspension stirred spend the night.This reaction CH
2Cl
2Dilution washes with water 2 times, uses Na
2SO
4Drying concentrates and resistates obtains with EtOAc/ hexane purifying by silica gel chromatography
1-8, it is a white solid.
1-8Data:
1H NMR (500MHz, CDCl
3) δ 7.6-7.3 (m, 5H), 7.1-6.9 (m, 3H), 6.75 (s, 1H), 4.25 (d, 1H), 4.1 (d, 1H), 3.95 (d, 1H), 3.75 (d, 1H), 0.9 (s, 9H), 0.1 (s, 3H), 0.05 (s, 3H) ppm.
Step 6: the enantiomer of intermediate 1-8 splits
The fractionation of enantiomer splits with 150mL/min with ChiralpakADO 10 * 50cm post and the hexane (containing 0.1% diethylamine) that contains 1% Virahol on chromatogram.Eluent on 4 * 250mmChiralpakAD5 post with the hexane (containing 0.1% diethylamine) that contains 1% Virahol with 1mL/ minute analysis HPLC test confirm first wash-out, active enantiomer has R
t=5.5 minutes and second enantiomer have R
t=6.9 minutes.
Step 7 (2S)-2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-4-(2, the 5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrroles-1-carbonyl chlorine 1-9
The first wash-out enantiomer of 1.31g (3.3mmol) will be added under 0 ℃ in the solution of 1.95g (6.6mmol) triphosgene in 25mL THF
1-8In the solution of 915 μ L (6.6mmol) triethylamines in 10mL THF.Remove ice bath and make this reaction rise to room temperature and stirred 3 hours.This is reflected between water and the EtOAc and distributes, organic solution Na
2SO
4Dry and concentrated obtaining
1-9, it is a brown oil.
1-9Data: the C of HRMS (ES) M+H
24H
2SClF
2NO
2Si: calculated value 464.1619. measured value: 464.1625.
Route 1A
Another of diester 1-5 is synthetic
To 14.8g (73mmol) 1-4 and 110mL CH
2Cl
2, 110mL CH
3Ruthenium chloride (III) hydrate that adds about 200mg in the two-phase miscellany of CN and 320mL water.Gradation adds sodium periodate (85.6g, 400mmol) while vigorous stirring in 1 hour subsequently.After feeding in raw material fully, should react under the room temperature and stir 4 hours.This miscellany dilutes with 500mL water and 1.5L EtOAc, and this solid by filtration is removed.Filtrate is placed separating funnel, separate phase, water extracts 2 times with EtOAc, and the organic phase of merging is with salt water washing 2 times and use Na
2SO
4Dry.After concentrating, the Vandyke brown solid is dissolved in the MeOH of 250mL and slowly the temperature that HCl (g) is blown into this solution and the speed that is blown into can not make this solution is higher than 35 ℃.After 5 minutes, this reaction is added a cover and at room temperature stir and spend the night.Remove volatile matter on rotatory evaporator, resistates obtains the methyl esters of 13.6g (58mmol) by silica gel chromatography with EtOAc/ hexane purifying, and it is a viscous oil.This resistates is dissolved in 200mL THE subsequently, is cooled to 0 ℃ and add the bromo-acetic acid tert-butyl of 10.3mL (70mmol), adds 2.8g NaH (60% suspension of 70mmol) subsequently.The room temperature that rises to this miscellany is used saturated NH after also stirring and spending the night
4Cl solution quencher and with EtOAc extraction 2 times.Na is used in the organic layer salt water washing that merges
2SO
4Drying concentrates and resistates obtains 1-5 by silica gel chromatography with EtOAc/ hexane purifying, and it is a water white oil.
Route 1B
Step 1:4-methylene radical-2-phenyl proline methyl ester (1B-2)
The aqueous solution (300mL) of phenyl glycine methyl ester-HCl (100g) is neutralized to pH8 with 10N NaOH.(3 * 200mL) extract the aqueous solution with EtOAc.The organic extract liquid MgSO that merges
4Drying is filtered and is concentrated.(56.7g, also (34.9mL, 36.4g 344mmol) handle resistates with phenyl aldehyde 344mmol) to be dissolved in trimethyl orthoformate (100mL).Stir after 2 hours this reaction Et
2(3 * 50mL) washings of O (200mL) dilution and water.This organic solution MgSO
4Drying is filtered and is concentrated.(26.8g 100mmol) is dissolved in methylene dichloride (240mL) and with 10N NaOH, methacrylic dichloro (50.0g, 400mmol and the Bu of 160mL with the imines resistates of a part
4NHSO
4(3.59g) handle.Stir under the room temperature after 10 hours, this reaction is with the methylene dichloride dilution and separate this organic solution, uses MgSO
4Drying is filtered and is concentrated.This resistates is dissolved in Et again
2O/1N HCl (200mL/200mL) also stirred 2 hours.Water phase separated and with 10NNaOH neutralization (to pH8).(3 * 200mL) extract this water mixture with EtOAc.The organic solution MgSO that merges
4Drying is filtered and is concentrated.Water-soluble and the neutralization (to pH8) with resistates.This mixture is used MgSO subsequently with EtOAc (X3) extraction
4Drying is filtered and concentrated obtaining slightly
1B-2This resistates is by purification by flash chromatography (SiO
2The 30%EtOAc/ hexane) obtain pure
1B- 2
1B-2Data:
1H NMR (500MHz, CDCl
3) δ 7.51 (m, 2H), 7.42 (m, 3H), 5.03 (s, 1H), 4.95 (s, 1H), 3.71 (m, 5H), 3.41 (m, 1H), 2.80 (m, 1H) ppm.
Step 2:7a-phenyl dihydro-1H-pyrrolo-[1,2-c] [1.3] oxazoles-3,6 (5H)-diketone (1-6)
With LiAlH
4(7.14g, 188mmol) suspension in THF (500mL) is cooled to 0 ℃ and use ester
1B-2(10.2g, 47mmol) solution-treated in THF (50mL) is about 20 minutes.0 ℃ is stirred after 30 minutes down, and this reaction is carefully by adding entry (7.1mL), the 15%NaOH aqueous solution (7.1mL) and H
2O (21.3mL) quencher.Add solid Na
2SO
4And this miscellany was stirred 40 minutes.Filter this miscellany and concentrated.With this resistates (8.2g, 43.3mmol) be dissolved in methylene dichloride (300mL) and with triethylamine (9.0mL, 6.5g, 65.0mmol) and carbonyl dimidazoles (9.14g, 56.4mmol) processing.Stir to stir under the room temperature after 48 hours, this reaction is with the methylene dichloride dilution and with 1N HCl and salt water washing.This organic solution is concentrated and need not to be further purified.With resistates
1B-3(9.2g, 42.8mmol) solution in methylene dichloride (200mL) is cooled to-78 ℃ and ozone fed this solution till keeping blueness.This solution of purifying also uses dimethyl sulphide (35mL) to handle.After rising to ambient temperature overnight gradually, this solution concentration is a yellow solid.This solid Et
2The O development obtains pure
1-6 1-6Data:
1H NMR (500MHz, CDCl
3) δ 7.5-7.3 (m, 5H), 4.7 (d, 1H), 4.3 (d, 1H), 4.2 (d, 1H), 3.5 (d, 1H), 3.1 (d, 1H), 2.95 (d, 1H), 2.9 (d, 1H) ppm.
Route 1C
Step 1:(2R)-[(ethoxy carbonyl) amino] (phenyl) acetate (1C-2)
1 hour introversion (R)-(-)-2-phenylglycocoll (
1C-1, 4kg) add in 0 ℃ of mixture in THF and 5NNaOH (10.6L) Vinyl chloroformate and keep in temperature be lower than 10 ℃.Behind reinforced the finishing, 0-10 ℃ was descended this reaction aging 15 minutes and analyzed to reach complete.This reaction with 37%HCl quencher (to pH=1, temperature 2.3L) and in keeping＜25 ℃.Add toluene (20L) and after stirring/placement, separate water layer.Analyze the yield of organic layer and solvent is changed to toluene, separate water layer.Analyze the yield of organic layer and solvent is changed to toluene.
1C-2Slurries be directly used in next step reaction.(2R)-[(ethoxy carbonyl) amino]-(phenyl) acetate: mp154-156 ℃;
1HNMR (CDCl
3, 400MHz) show rotational isomer～1.1: 1 mixtures: δ=12.12 (bs, 2H), 7.99 (d, J=5.3Hz, 1H), and 7.45-7.32 (m, 10H), 5.78 (d, J=6.2Hz, 1H), 5.41 (d, J=7.1Hz, 1H), 5.25 (d, J=5.7Hz, 1H), 4.12 (m, 2H), 4.05 (m, 2H), 1.24 (t, J=6.9Hz, 3H), 1.06 (t, J=7.0Hz, 3H);
13C NMR (CDCl
3, 100MHz): δ=175.1,173.6,157.3,155.8,137.4,136.1,129.0,128.7,128.6,128.2,127.2,127.1,62.1,61.5,58.3,57.7,14.4,14.1; MS m/z 224 ([M+H]
+, C
11H
14NO
4, calculated value 224.09).
Step 2:(2S, 4R)-5-oxo-24-phenylbenzene-13-oxazolidine-3-carboxylic acid, ethyl ester (1C-3)
In 1-2 hour, add the solution of phenyl aldehyde dimethylacetal (3L) in toluene (5mL/g) down in decompression (350torr) in 85 ℃ of solution in toluene to 1C-2 and PhSO3H (42.7gm).Toluene/MeOH is removed in distillation in the reaction process.After reacting completely, this solution be cooled to room temperature and with THF (36L) dilution till evenly.This organic solution is used saturated NaHCO subsequently with 10%NaHSO3 (7.5L) washing
3(9L) washing.Finish the back solvent be changed to toluene and with dilution with toluene to the 7.5mL/g cumulative volume (with respect to the test yield).These slurries are heated to 75 ℃ and ageing to evenly.After slowly cooling off,
1C-3Crystallization.But when these slurries reach 40 ℃, add heptane (2.5mL/g).These slurries are cooled to room temperature and solid collected by filtration.This solid is with the washing of 1: 1 toluene/heptane (5mL/g) and be dried to constant weight under nitrogen.(2S, 4R)-5-oxo-2,4-phenylbenzene-1,3-oxazoles alkane-3-carboxylic acid, ethyl ester: mp197-199 ℃;
1H NMR (CDCl
3, 400Hz): δ=7.46-7.37 (m, 10H), 6.77 (bs, 1H), 5.45 (bs, 1H), 3.96 (m, 2H), 3.86 (m, 2H), 0.84 (t, J=7.1Hz, 3H);
13C NMR (CDCl
3, 100MHz): δ=130.2,129.1,129.0,218.8,126.7,90.3,61.9,60.3,13.8; MS m/z 312 ([M+H]
+, C
18H
18NO
4, calculated value 312.12).
Step 3:(2S, 4S)-4-allyl group-5-oxo-2,4-phenylbenzene-1,3-oxazoles alkane-3-carboxylic acid, ethyl ester (1C-4)
Add the solution of two (trimethyl silyl) ammonification sodium in THF (7L) in 1 hour in-10 ℃ of solution in THF (40L) to 1C-3 and allyl group-Br (1.67L), and holding temperature＜5 ℃.After 5 minutes, analyze this reaction and reach complete.This reaction is diluted with 1N HCl (22.5L) quencher and with heptane (20L).Separating water layer and organic layer washs with saturated brine (12L).Solvent is changed to MeOH and azeotropic vaporization and removes and anhydrate until reaching KF＜900ppm.
1C-4Solution be directly used in next reaction.(2S, 4S)-4-allyl group-5-oxo-2,4-phenylbenzene-1,3-oxazoles alkane-3-carboxylic acid, ethyl ester:
1H NMR (CDCl
3, 400Hz): δ=7.60-7.52 (m, 2H), 7.39-7.33 (m, 8H), 6.55 (m, 1H), 5.84 (m, 1H), 5.38 (m, 2H), 4.16 (m, 2H), 3.72-3.12 (m, 2H), 1.17 (t, J=7.0Hz, 3H);
13C NMR (CDCl
3, 100MHz): δ=172.5,164.0,137.5,131.0,130.5,129.7,128.3,128.1,127.4,126.2,122.0,89.5,62.0,42.2,40.4,14.2; MSm/z 352 ([M+H]
+, C
21H
22NO
4, calculated value 352.15).
Step 4:(2S)-and the 2-[(ethoxy carbonyl) amino 1-2-phenyl penta-obtusilic acid methyl esters (1C-5)
0.25 hour introversion
1C-4Add the 30%NaOMe be contained among the MeOH (535mL) in 23 ℃ of solution in MeOH (20L), and holding temperature＜30 ℃.After 4 hours, analyze this reaction and reach complete.This reaction is diluted with 5%NaHSO3 (40L) quencher and with IPAc (20L).Separate water layer and organic layer 10%KH
2PO
4(12L). washing.Solvent is changed to MeCN and is directly used in following reaction.(2S)-and the 2-[(ethoxy carbonyl) amino]-2-phenyl penta-obtusilic acid methyl esters:
1H NMR (CDCl, 400Hz): δ=7.46-7.43 (m, 2H), 7.39-7.27 (m, 3H), 6.23 (bs, 1H), 5.76-5.66 (m, 1H), and 5.20-5.14 (m, 2H), 4.10-4.00 (m, 2H), 3.68 (s, 3H), 3.53 (bs, 1H), 3.20 (dd, J=13.7,7.6Hz, 1H) 1.27-1.15 (m, 3H);
13C NMR (CDCl
3, 100MHz): δ=172.6,154.3,139.8,132.3,128.4,127.8,125.9,119.4,65.0,60.6,53.1,37.8,14.4; MS m/z300 ([M+Na]
+, C
15H
19NNaO
4, calculated value 300.12).
Step 5:4-[(ethoxy carbonyl) phenyl-D-proline methyl ester (1C-6)
To
1C-5Add entry (12L) in 23 ℃ of solution in MeCN (42L), add I subsequently
2(8kg).After 6 hours, analyze this reaction and reach complete.This reaction 10%Na
2SO3 (35L) quencher extracts with 50wt%NaOH (4L) alkalization and with IPAc (35L).Separate water layer and reject, organic layer extracts with 6N HCl (35L).Separate organic layer.Water layer is cooled to-10 ℃, adds IPAc (35L), and slowly use the 10N NaOH neutralization of 22L.Separate water layer and reject and storage
1C-6Solution.The 4-[(ethoxy carbonyl) oxygen base]-2-phenyl-D-proline methyl ester:
1HNMR (CDCl
3, 400Hz) show, and 2: 1 mixtures of diastereomer: δ=7.55-7.47 (m, 5H), 7.34-7.22 (m, 5H), and 5.18-5.11 (m, 2H), 4.22-4.11 (m, 4H), 3.68 (s, 6H), 3.33-3.24 (m, 4H), 3.10 (d, J=14.1Hz, 2H), 3.05 (b, 2H), 2.34 (dd J=14.3,5.5Hz, 1H), 2.22 (dd J=14.3,4.1Hz, 1H), and 1.31-1.23 (m, 6H);
13CNMR (CDCl
3, 100MHz): δ=175.2,175.1,154.7,154.4,142.0,141.5,128.3,128.2,127.5,127.4,126.0,125.7,78.5,77.6,71.7,71.0,63.8,52.9,52.8,52.7,52.0,51.8,43.2,42.9,14.1,14.0; MS m/z 294 ([M+H]
+, C
15H
20NO
5, calculated value 294.13).
Step 6:(5S)-5-(hydroxymethyl)-5-Phenylpyrrolidine-3-alcohol (1C-7)
Under-50 ℃ to carbonate
1C-6(5.0g 17.0mmol) adds R in the solution in THF (50mL)
eThe 3.5M toluene solution of d-Al (17.0mL, 59.7mmol, 3.5mole.).This reaction mixture rose to room temperature and ageing 2 hours.0 ℃ down this reaction (45mL is equal to the R of about 1.5mole with the quencher of 2.0M Rochelle salts solution
eD-Al) fully ageing under the room temperature and in 5 hours.After the water phase separated, make blended organic solution be changed to n-BuOAc by the component distillation that reduces pressure down (about 20torr, 60 ℃).After adding the n-BuOAc of 200mL, detect among the GC THF, toluene and methyl cellosolve be less than 0.1% and KF be 0.11%.MS m/z 194 ([M+H]
+, C
11H
15NO
2, calculated value 193.11).
Step 7:(7aS)-6-hydroxyl-7a-phenyl tetrahydrochysene-H-pyrrolo-[1,2-c] [1,3] oxazole-3-ketone (1C-8)
(ageing is 1 hour 1.25moleq.) and under the room temperature for 3.46g, 21.3mmol to drip CDI in the described n-BuOAc solution of step 6.Join the 2N HCl solution of 30mL in this reaction mixture and ageing 1 hour.Water phase separated and with 30mL n-BuOAc extraction adds the NaCl of 6.0g afterwards.Gac (Darco KB) to the organic layer adding 150mg that merges spends the night this miscellany ageing.Filter out charcoal through the Solka-Floc pad.Data:
1H NMR (400MHz, CDCl
3): δ 7.47-7.28 (m, 7H), 4.65 (d, J=8.3Hz, 1H), 4.64-4.59 (m, 0.4H), 4.57-4.51 (m, 1H), 4.51 (d, J=8.8Hz, 0.4H), 4.33 (d, J=8.3Hz, 1H), 4.28 (dd, J=13.1,6.7Hz, 0.4H), 4.15 (d, J=8.8Hz, 0.4H), 3.92 (d, J=12.7Hz, 1H), 3.28 (dd, J=12.7,3.9Hz, 1H), 3.18 (dd, J=13.1,2.7Hz, 0.4H), 2.63 (d, J=13.6Hz, 0.4H), 2.50 (dd, J=13.7,5.1Hz, 1H), 2.40 (brd, J=13.7Hz, 1H), 2.25 (dd, J=13.6,6.8Hz, 0.4H).
Step 8:(7aS)-7a-phenyl dihydro-1H-pyrrolo-[1,2-c] [1,3] oxazole-3,6 (5H)-diketone (1C-9)
To be contained among the n-BuOAc
IC-8(thick, a part of above-mentioned solution 1.40g analyzes, and 6.38mmol) decompression concentrates down and adding 14mL MeCN in coarse crystallization.Solvent ratio is n-BuOAc: MeCN=8 among the GC: 92.To this solution drip AcOH (1.10mL, 19.2mmol, 3.0mole.), in 30 minutes, drip under the room temperature TPAP (33.6mg, 0.095mmol, 1.5mol%) and NaOCl (9.SmL, 19.2mmol, 2.0M solution 3.0mole.) (can in HPLC, find about 5% chlorizate).After 30 minutes, this reaction mixture dilutes and water phase separated with the AcOEt of 12mL.The saturated Na of organic phase
2The S2O3 aqueous solution and salt water washing.Organic solvent is changed to MTBE and filters out precipitation, washs with MTBE.The ketone that obtains
1C-978% (1.08g, 4.97mmol, 99.4% area, 97.0w/w%, 0.5% chlorizate area).
Route 1D
(2S)-and 2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-4-(2, the 5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrroles-1-carbonyl chlorine 1-9
In the flask that has overhead, thermopair and nitrogen/vacuum inlet, add S-TBS pyrroline solid
1-8(180gms) and add IPAC (1.26L).This solution of continuously stirring extremely became evenly in about 30 minutes.
In another has the flask of overhead, thermopair and nitrogen/vacuum inlet, add IPAC (1.26L) and this solution is cooled to-5 ℃.Add triphosgene (67gms) and slowly add lutidine (173ml) subsequently.The solution of S-TBS pyrroline is slowly joined in this solution subsequently.This reaction then is regarded as reacting completely by analyzing when amine is converted into the transformation efficiency of product＞99A% by HPLC under HPLC monitoring and the 200nm.This reaction is by adding the 10wt% aqueous citric acid solution quencher of 1.8L in the phase reaction mixture.Separate each layer and organic layer water (240mL) washing 2 times.Organic layer is concentrated into 900ml (water-content is 105ug/ml) subsequently and is directly used in linked reaction.HPLC analyzes and confirms that 99.96% is converted into urea chloride.
Route 1E
2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-4-(2, the 5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrroles (1-8)
Step 1:6-(2, the 5-difluorophenyl)-7a-phenyl-57a-dihydro-1H-pyrrolo-[1,2-c] [1,3] oxazole-3-ketone (1-7)
In the 20L chuck with 231g (1.06moles)
1-6Solution top vigorous stirring in 11L THF 1 hour is cooled to-70 ℃ subsequently.Drip the solution of NaHMDS in THF of 1.28L (1.28moles) to this suspension.Stir after 3 hours, add 478.9g (1.28moles) solid N-phenyl two (fluoroform sulphonamide), continue subsequently to stir 1.5 hours, afterwards by adding the saturated NH of 2L
4The quencher of the Cl aqueous solution.After this solution reaches room temperature, add the water of 2L and the EtOAc of 2L, separate the EtOAc extraction of each layer and water layer with 2L.Na is used in the organic layer salt water washing that merges
2SO
4Dry and concentrated by rotary evaporation.Have DME and the 1.2L water that in the jacketed reactor that stirs at the top resistates is dissolved in 6L, this solution N at 20L
2The blast air degassing 1 hour.In this reactor, add 201.6g (1.28moles)
2, 5-difluorophenyl boric acid, 134g (3.19moles) LiCl, 338g (3.19moles) Na
2CO
3And 24.6g (21mmol) tetrakis triphenylphosphine palladium (0), and this is reflected at 90 ℃ of following heating 2 hours.After this stage, the DME of about 4.5L is removed in distillation, and residual solution is cooled to room temperature and joins 6L water and 8L CH
2Cl
2In.Separate each layer, the water layer CH of 2L
2Cl
2Extraction merges organic layer, uses the 4L water washing, uses Na
2SO
4Dry and concentrate by rotary evaporation and to obtain dark red solid and determine.This resistates CHCl of 500mL
3Handle, and filtration obtains brown solid.Concentrated filtrate is to～300mL and collect second batch of solid.Merge with first, and the EtOAc of material that merges and 500mL processing is spent the night.Filter this suspension and obtain beige solid, filtrate is concentrated into～250mL and collect second crowd, merge with first, the material of merging (～205g) the EtOAc recrystallization from 1.6L obtains
1-7, it is a white solid.
1-7Data:
1H NMR (500MHz, CDCl) δ 7.5-7.3 (m, 5H), 7.1-6.9 (m, 3H), 6.8 (s, 1H), 4.9 (d, 1H), 4.75 (d, 1H), 4.5 (d, 1H), 4.25 (d, 1H) ppm.HRMS (ES) C
18H
13F
2NO
2M+H: calculated value 314.0987.
Measured value: 314.0993.
Step 2:2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl)-4-(2, the 5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrroles (1-8)
In the 10L round-bottomed flask with 109.4g (349mmol)
1-7Suspension in 2.2L EtOH and 105mL (1.05moles) 10M NaOH is in 60 ℃ of down heating 4 hours, is cooled to room temperature and ageing is spent the night.In this mixture, add the dense HCl of 90.2mL (1.08moles) and remove and desolvate by rotary evaporation.Resistates is suspended in the 2L acetonitrile and passes through the rotary evaporation drying once more.With the CH of this solid suspension at 3.8L
2Cl
2In 200mL DMF, add 118.7g (1.75moles) imidazoles, add 110.5 (733mmol) TBSCI subsequently.At N
2Light gas stream stir after 15 hours down, this reaction joins water and the 2LCH of 4L
2Cl
2In, separate each layer, and the water layer CH of 2L
2Cl
2Extraction.The organic extract liquid that merges is used the water washing of 4 * 4L subsequently, uses Na
2SO
4Dry and concentrated by rotary evaporation.Resistates is dissolved in the MeOH of 500mL and the 2M MeNH of 500mL
2MeOH solution, stirred 4 hours, concentrate by rotary evaporation subsequently.This resistates places under the high vacuum and reaches constant until weight, and material is crushed and stampped with mortar to be obtained
1-8, it is a beige solid.
1-8Data:
1H NMR (500MHz, CDCl
3) δ 7.6-7.3 (m, 5H), 7.1-6.9 (m, 3H), 6.75 (s, 1H), 4.25 (d, 1H), 4.1 (d, 1H), 3.95 (d, 1H), 3.75 (d, 1H), 0.9 (s, 9H), 0.1 (s, 3H), 0.05 (s, 3H) ppm.
Route 2
Step 1:3-fluoro-4-oxo-piperidine-1-benzyl carboxylate (2-2)
In 10.0g (43mmol) 4-oxo-solution of 1-piperidine carboxylic acid benzyl ester in 25mL DMF, add the triethylamine of 14.3mL (103mmol) and add 6.53mL (52mmol) TMSCl subsequently.This is reflected at 80 ℃ of following heated overnight, is cooled to room temperature and joins subsequently in the separating funnel that contains hexane.This miscellany is at saturated NaHCO
3Distribute in the aqueous solution, separate, use the salt water washing, use MgSO
4Dry and concentrated by rotary evaporation.Resistates is dissolved in the CH of 500mL
3CN and handle with 16.7g (47mmol) Selectfluor.After 90 minutes, this reaction is concentrated into about half original volume, between EtOAc and salt solution, distributes, separate, use MgSO
4Drying is filtered and is concentrated by rotary evaporation.This resistates is carried on the silicagel column and obtains with EtOAc/ hexane wash-out
2-2, it is a water white oil.
Step 2:3-fluoro-4-(methylamino) piperidines-1-benzyl carboxylate (2-2a)
To 9.4g (37.5mmol)
2-2 at 150mL 1, adds solution and 11.9g (56.2mmol) Na (OAc) 3BH of 37.5mL (74.9mmol) methylamine in THF in the solution in the 2-ethylene dichloride.Stir after 2 hours the saturated K2CO of this reaction
3Aqueous solution quencher distributes with EtOAc, separates water extraction 3x EtOAc.MgSO is used in the organic extract liquid salt water washing that merges
4Drying is filtered and is concentrated by rotary evaporation.Resistates is carried on the silicagel column and with 80: 10: 10CHCl
3/ EtOAc/MeOH wash-out obtains
2-2aCis and two kinds of isomer of trans, it is a water white oil.
2-2aThe data of trans isomer, at first come out (confirming) by the NOE analytical method by wash-out:
1H NMR (600MHz, CD
2Cl
2) δ 7.4-7.3 (m, 5H), 5.1 (m, 2H), 4.4-4.1 (m, 2H), 3.9 (m, 1H), 3.15-3.05 (m, 2H), 2.75 (m, 1H), 2.4 (s, 3H), 2.0 (m, 1H), 1.25 (m, 1H) ppm.
2-2aThe data of cis isomer, second come out by wash-out (confirming) by the NOE analytical method:
1H NMR (600MHz, CD
2Cl
2) δ 7.4-7.2 (m, 5H), 5.1 (m, 2H), 4.9-4.7 (m 1H), 4.4 (m, 1H), 4.15 (m, 1H), 3.1-2.9 (m, 2H), 2.6 (m, 1H), 2.4 (s, 3H), 1.8 (m, 1H), 1.6 (m, 1H) ppm.HRMS (ES) C
14H
19F
1N
2O
2M+H: calculated value 267.1504. measured value: 267.1500.
Step 3:(3R, 45)-the 4-[(tert-butoxycarbonyl) (methyl) amino]-3-fluorine piperidines-1-benzyl carboxylate (2-3)
To 7.67g (28.8mmol) cis-2-2a at 150mL CH
2Cl
2In solution in add 12.1mL (86.5mmol) triethylamine and 9.44g (43.3mmol) tert-Butyl dicarbonate.Stir after 1 hour, this is reflected at CH
2Cl
2And H
2Distribute between the O, MgSO is used in organic phase salt water washing
4Drying is filtered and is concentrated by rotary evaporation.Resistates is carried on the silicagel column and with EtOAc/ hexane wash-out obtains racemize cis-
2-3, it is a white solid.The fractionation of this enantiomer is carried out under 150mL/min with ChiralpakAd 10 * 50cm post and the hexane (containing 0.1% diethylamine) that contains 20% Virahol by chromatography.Elutriant uses the analysis mode HPLC analytical test of hexane (containing 0.1% diethylamine) under 1mL/min that contains 20% Virahol to show on 4 * 250mm Chiralpak ADo post, the enantiomer of first wash-out (
2-3Enantiomer) have Rt=5.90 minute, and second enantiomer (
2-3) had Rt=6.74 minute.
2-3Data: HRMS (ES) C
19H
27F
1N
2O
4M+Na: calculated value 389.1847. measured value: 389.1852.
Step 4:(3R, 4S)-3-fluoro-1-methyl piperidine-4-ylmethyl t-butyl carbamate (2-4)
To 4.6g (12.6mmol) the second wash-out enantiomer
2-3Add the 1 of 29.7mL (314mmol) and 10% carbon of catalytic amount in the solution in 150mL EtOH and carry Pd.After stirring was spent the night, this reaction concentrated through diatomite filtration with by rotary evaporation.Resistates is dissolved in the MeOH of 75mL, adds the AcOH of 2mL and 37% formalin of 3.1mL (38mmol), this miscellany was stirred 1 hour.At this moment, add 1.58g (25.1mmol) and be present in the NaCNBH3 among the 10mLMeOH and make this reaction aging 2 hours, join saturated NaHCO afterwards
3The aqueous solution.Extraction 3 * CH
2Cl
2After, organic phase washes with water, uses MgSO
4Drying is filtered and is concentrated by rotary evaporation and obtains
2-4, it is a water white oil.The data of 2-4: HRMS (ES) C
12H
23FN
2O
2M+H: calculated value 247.1817. measured value: 247.1810.
Step 5:(3R, 4S)-3-fluoro-N, 1-lupetidine-4-amine (2-5)
To 3.0g (12.2mmol)
2-4Being blown into HCl gas in the solution in 100mL EtOAc rises to tangible until this solution.Subsequently this flask was added a cover and stirred 4 hours.Remove volatile matter by rotary evaporation, resistates Et
2O develops and places under the high vacuum and obtains white solid.15%Na with this material and 25mL
2CO
3Aqueous solution is also with 5 * 50mL 2: 1CHCl
3/ EtOH extraction.Organism concentrates by rotary evaporation and heating as mild as a dove, resistates is dissolved in the CHCl of 200mL
3, use Na
2SO
4Drying, concentrated obtaining
2-5, it is a water white oil.
2-5Data:
1HNMR (500MHz, CDCl
3) δ 4.8 (m, 1H), 3.15 (m, 1H), 2.85 (m, 1H), 2.5 (s, 3H), 2.45 (m, 1H), 2.3 (s, 3H), 2.2-2.0 (m, 2H), 1.9-1.7 (m, 2H) ppm.HRMS (ES) C
7H
15FN
2M+H: calculated value 147.1292. measured value: 147.1300.
Route 2A
Step 1:3-fluoro-4-oxo-piperidine-1-benzyl carboxylate (2-2)
In the 22-L round-bottomed flask that has mechanical stirrer, add Cbz-ketone
2-1(2.5kg, 10.7mol), the N,N-DIMETHYLACETAMIDE of 5.0L, triethylamine (3.0L, 21.5mol).The adding trimethylsilyl chloride (2.0L, 15.7mol).This miscellany was heated to 60 ℃ and ageing 4 hours.After being cooled to 10 ℃, this miscellany 5% sodium bicarbonate of 10L and 10L just-heptane in quencher and keep in temperature be lower than 20 ℃.Organic layer washs with 2.5% sodium bicarbonate aqueous solution of 10L.Final organic layer dried over sodium sulfate is filtered and decompression concentrates down, and solvent is changed to 10L MeCN.
The MeCN of adding 7.5L and Selectfluor in the 50-L jacketed vessel (4.1kg, 11.5mol).These slurries be cooled to 10 ℃ and add salt of wormwood (0.37kg, 2.68mol).Temperature is 10-15 in the gradation solution of transfer silicomethane ether in MeCN and the maintenance.Make final slurries 10-15 ℃ of following ageing 2 hours.This is reflected at quencher in the 100L extractor of ethyl acetate of 2N hydrochloric acid with 20L and 30L.Organic layer is with the 2N hydrochloric acid of 20L, the 20wt% sodium-chlor washing of 10L, with dried over sodium sulfate and filtration.Filtrate concentrates and under reduced pressure washs with dry EtOAc and reaches KF=16000gg/mL, and solvent under reduced pressure is changed to～10L THF subsequently.
Step 2:3-fluoro-4-(methylamino) piperidines-1-benzyl carboxylate (2-2a)
In round-bottomed flask, Cbz fluorine ketone (10.3mol) is dissolved in the tetrahydrofuran (THF) (30L).Add 2M solution (2.00 equivalents of methylamine in tetrahydrofuran (THF); 20.6moles; 10.3L) in, will stir 30 minutes under this miscellany room temperature.This miscellany is cooled to 0 ℃, adds acetate (20.6moles; 1.17L; 1.236kg), continue down to stir 30 minutes at 0 ℃ subsequently.With sodium triacetoxy borohydride (12.36moles; 2.62kg) in 15 minutes gradation join this solution, this reaction mixture 0 ℃ of following ageing until reacting completely by the HPLC analysis and judgement.This reaction mixture is slowly transferred in the cylindrical extractor of 100L, this extractor contain 12M aqueous hydrochloric acid (30.9moles, 2.575L), water (30L) and toluene (140mol, 15L).After the vigorous stirring 15 minutes, separate the further water of each layer and toluene layer (10L) washing.The water layer that merges shifts back extractor.(82.4mole, 8.24L), and this miscellany extracts 1 time with IPAC (30L) aqueous sodium hydroxide solution of adding 10M.
Organic layer is dry and concentrated with sodium sulfate (3kg).Resistates is dissolved in 8: 2, and (vol: vol) ethanol: water (23kg ethanol and 7.2kg water), (9.83mol, 952g 667mL) join this solution and adding crystal seed with 85% phosphoric acid.Stirring this miscellany under the room temperature spends the night.Precipitated crystal solid and by filter collecting.This solid was with 8: 2 ethanol: water washing and vacuum chamber inner drying obtain the 2.1kg solid.
With this solid suspension in 36L EtOH and 4L water miscellany and this miscellany be heated to 70 ℃-80 ℃ and dissolve until all solids.Remove thermal source and clear soln cis isomer miscellany
2-2aInoculation.Stir under the room temperature spend the night after, precipitated crystal solid and collect by filtering.This solid product obtains white solid at the vacuum chamber inner drying.
Step 3:(3R, 4S)-the 4-[(tert-butoxycarbonyl) (methyl) amino]-3-fluorine piperidines-1-benzyl carboxylate 2-3
In the extractor of 50L, add 20L water and 1.06kgNa
2CO
3, stir miscellany and dissolve until all solids.Adding IPAC (20L) and CBZ amine carboxylate salt (1.85kg, 5.3mol).Each layer separated in mixed back.Water layer extracts with other 5L IPAC.The organic layer dried over sodium sulfate that merges.After filtering out siccative, should batch join in the 72L round-bottomed flask, and add Boc
2O solution (1.0M, 4.8L).The HPLC test confirms that transformation efficiency is 98% after 45 minutes.Add additional Boc
2O solution (50mL).After this batch ageing 15 hours, the concentrated minimum volume that reaches under the vacuum is with MeOH (10L-15L) purifying.It is about 14.3kg that this batch is diluted to gross weight with methyl alcohol.The HPLC test confirms the required product of about 1.9kg.
(Diacel ChemicalIndustries, Ltd.) (30ID * 25cm) goes up and splits the chiral solid phase post fluorine piperidines at 20 microns Chiralpak AD by chromatographic separation.The racemic modification methanol-eluted fractions of per injection 54g amount.Collect required (3R, 4S) enantiomer, 98%ee that minimum retention time enantiomer obtains 45g (85% rate of recovery).Repeat this separation method and will be not the required cut of homogeneous injection merge and concentrate.
Step 4:[(3R, 4S)-3-fluoro-1-methyl piperidine-4-ylmethyl t-butyl carbamate (2-4)
The concentrated solution (4L) that obtains from the chiral separation step is proved the Cbz-Boc-diamines that contains 489.5g (1.3mol)
2-3In this solution, add formaldehyde (37% in water, 430mL, 5.3mol) and this miscellany following 4 hours of hydrogen-pressure and 5%Pd/C (183g).Filtering this reaction mixture removes catalyzer and distributes between the 0.5M sodium bicarbonate of the EtOAc of 8L and 8L.Organic layer washs with the 0.5M sodium bicarbonate of 8L.The water layer that merges extracts with 8L EtOAc.The organic layer that merges dried over sodium sulfate and filtration.Filtrate is directly used in following step.
Step 6:(3R, 4S)-3-fluoro-N, 1-lupetidine-4-amine (2-5)
The diamines that will contain the Boc protection
2-4The ethyl acetate solution of (327g is by the HPLC Analysis and Identification) joins in the 12L flask and at 28 ℃ and concentrates down.When this batch had the cumulative volume of 1.5L, this batch was changed to solvent the ethanol that adds 8L subsequently, constant volume distillation down simultaneously.
In another 12L round-bottomed flask, add 1.5L ethanol (200 checks, refining).Subsequently the 436mL Acetyl Chloride 98Min. is joined in the ethanol and by means of the water-bath holding temperature and be lower than 35 ℃.With this solution stirring 1 hour.Contain 302g Boc protection diamines
2-4Ethanolic soln slowly join HCl subsequently, holding temperature＜30 ℃.When reinforced finishing, solid begins to come out from this solution crystallization.This reaction is stirred by the GC monitoring and with these slurries and is spent the night.This solid by filtration is separated and filter cake washs with 85% ethanol, 15% ethyl acetate of 2L.Filter cake is used N with under the final vacuum
2Air stream drying spend the night and obtain the required product of 243g
2-5, it is a dihydrochloride.It is 99.3%ee that GC analyzes this batch of surface.
In bottle, add about 200mg 2-5 (fluorine piperidines 2HCl) and be suspended in the methyl alcohol (＜500 μ L).With heating gun this sample is heated to dissolving.After 2 hours, find to occur big three-dimensional crystals.By removing the residual solvent fractional crystallization.Select single crystallization to carry out unidirectional crystallization x-ray.Data gathering is in Bruker Smart Apex system.This crystallization is the size of no color chips and 0.24mm * 0.22mm * 0.14mm.Unit cell is defined as oblique system in scan rate collection in 5 seconds and automatic index with structure cell.
With 5 seconds scan rates this structure elucidation after the quadrant data gathering is oblique crystal P21 spacer.Be used for the information of the final explanation of relevant analytic structure is made form referring to table 1-5.The computer graphics of the structure of 2-5 as shown in Figure 1.
Crystal data and the structure refinement of table 1.2-5
Empirical formula C
8H
21Cl
2FN
2O
Formula weighs 251.17
Temperature 298 (2) K
Wavelength 0.71073_
Crystallographic system, spacer oblique crystal, P2 (1)
Unit cell size: a=7.286 (2) _ α=90 °.
b＝7.637(2)_ β＝105.295(5)°
c＝12.378(4)_ γ＝90°
Volume 664.3 (4)
O3
Z, the density 2 of calculating, 1.256Mg/m
3
Uptake factor 0.477mm
-1
F(000) 268
Crystallite size 0.24 * 0.22 * 0.14mm
1.71-26.35 ° of the θ scope of data gathering
Critical exponent (Limiting indices)-9＜=h＜=9 ,-9＜=k＜=9 ,-15＜=1＜=15
The reflection 5309/2674[R (int)=0.0227 of set/uniqueness]
θ spends fully=and 26.35 99.7%
Absorption correction does not have
The refine method is in F
2Last complete matrix (Full-matrix) Shaozheng is square
Data/restriction/parameter 2674/1/135
F
2On the goodness of fit 1.055
Final R index [I＞2sigma (I)] R
1=0.0383, wR
2=0.0939
R index (all data) R1=0.0409, wR2=0.0959
Absolute structure parameter 0.02 (6)
Maximum difference peak and paddy 0.310 and-0.135e_-3
Table 2.
2-5Atomic coordinate (* 10
4) and equivalent isotropy displacement parameter (_
2* 10
3).U (eq) is defined as the 3rd vestige of quadrature Uij tensor.
| x | y | z | U(eq) | |
| C(1) C(2) C(3) C(4) C(5) C(6) C(7) C(11) Cl(1) Cl(2) F(1) N(1) N(2) O(11) | 10896(3) 10015(3) 7954(3) 7708(3) 8554(3) 11521(4) 5074(3) 6300(5) 2362(1) 8214(1) 10991(2) 10618(3) 7187(3) 5695(3) | 4999(4) 6778(3) 6708(3) 5658(3) 3861(3) 2227(3) 8626(4) 5224(6) 4966(1) 1057(1) 7785(2) 3989(2) 8513(2) 4422(3) | 3165(2) 2967(2) 2311(2) 1234(2) 1506(2) 2315(2) 1808(3) 4909(3) 194(1) 4028(1) 2346(1) 2104(2) 2056(2) 3856(2) | 45(1) 40(1) 36(1) 43(1) 44(1) 53(1) 62(1) 85(1) 53(1) 55(1) 55(1) 39(1) 39(1) 68(1) |
Table 3.
2-5Bond distance [_] and bond angle [°].
| C(1)-N(1) C(1)-C(2) C(1)-H(1A) C(1)-H(1B) C(2)-F(1) C(2)-C(3) C(2)-H(2) C(3)-N(2) C(3)-C(4) C(3)-H(3) C(4)-C(5) C(4)-H(4A) C(4)-H(4B) C(5)-N(1) C(5)-H(5A) C(5)-H(5B) C(6)-N(1) C(6)-H(6A) C(6)-H(6B) C(6)-H(6C) C(7)-N(2) C(7)-H(7A) C(7)-H(7B) C(7)-H(7C) C(11)-O(11) C(11)-H(11A) C(11)-H(11B) C(11)-H(11C) N(1)-H(1) N(2)-H(2A) N(2)-H(2B) O(11)-H(11) N(1)-C(1)-C(2) N(1)-C(1)-H(1A) | 1.491(3) 1.495(3) 0.9700 0.9700 1.406(3) 1.508(3) 0.9800 1.489(3) 1.525(3) 0.9800 1.505(3) 0.9700 0.9700 1.494(3) 0.9700 0.9700 1.490(3) 0.9600 0.9600 0.9600 1.491(3) 0.9600 0.9600 0.9600 1.402(4) 0.9600 0.9600 0.9600 0.77(2) 0.9000 0.9000 0.8200 111.88(18) 109.2 | C(2)-C(1)-H(1A) N(1)-C(1)-H(1B) C(2)-C(1)-H(1B) H(1A)-C(1)-H(1B) F(1)-C(2)-C(1) F(1)-C(2)-C(3) C(1)-C(2)-C(3) F(1)-C(2)-H(2) C(1)-C(2)-H(2) C(3)-C(2)-H(2) N(2)-C(3)-C(2) N(2)-C(3)-C(4) C(2)-C(3)-C(4) N(2)-C(3)-H(3) C(2)-C(3)-H(3) C(4)-C(3)-H(3) C(5)-C(4)-C(3) C(5)-C(4)-H(4A) C(3)-C(4)-H(4A) C(5)-C(4)-H(4B) C(3)-C(4)-H(4B) H(4A)-C(4)-H(4B) N(1)-C(5)-C(4) N(1)-C(5)-H(5A) C(4)-C(5)-H(5A) N(1)-C(5)-H(5B) C(4)-C(5)-H(5B) H(5A)-C(5)-H(5B) N(1)-C(6)-H(6A) N(1)-C(6)-H(6B) H(6A)-C(6)-H(6B) N(1)-C(6)-H(6C) H(6A)-C(6)-H(6C) H(6B)-C(6)-H(6C) | 109.2 109.2 109.2 107.9 109.28(19) 107.49(17) 112.33(18) 109.2 109.2 109.2 110.26(17) 110.51(17) 111.07(18) 108.3 108.3 108.3 109.71(19) 109.7 109.7 109.7 109.7 108.2 110.49(18) 109.6 109.6 109.6 109.6 108.1 109.5 109.5 109.5 109.5 109.5 109.5 |
| N(2)-C(7)-H(7A) N(2)-C(7)-H(7B) H(7A)-C(7)-H(7B) N(2)-C(7)-H(7C) H(7A)-C(7)-H(7C) H(7B)-C(7)-H(7C) O(11)-C(11)-H(11A) O(11)-C(11)-H(11B) H(11A)-C(11)-H(11B) O(11)-C(11)-H(11C) H(11A)-C(11)-H(11C) H(11B)-C(11)-H(11C) C(1)-N(1)-C(6) | 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 111.2(2) | C(1)-N(1)-C(5) C(6)-N(1)-C(5) C(1)-N(1)-H(1) C(6)-N(1)-H(1) C(5)-N(1)-H(1) C(3)-N(2)-C(7) C(3)-N(2)-H(2A) C(7)-N(2)-H(2A) C(3)-N(2)-H(2B) C(7)-N(2)-H(2B) H(2A)-N(2)-H(2B) C(11)-O(11)-H(11) | 110.83(17) 111.57(19) 107.9(17) 110.0(17) 105.1(18) 113.99(19) 108.8 108.8 108.8 108.8 107.6 109.5 |
Table 4.
2-5Each diversity displacement parameter (_
2* 10
3)
Anisotropy shift factor index is :-2pi
2[h
2A*
2U11+...+2h ka*b*U12]
| U11 | U22 | U33 | U23 | U13 | U12 | |
| C(1) C(2) C(3) C(4) C(5) C(6) C(7) C(11) Cl(1) Cl(2) F(1) N(1) N(2) O(11) | 45(1) 41(1) 38(1) 43(1) 44(1) 59(2) 37(1) 69(2) 70(1) 68(1) 41(1) 47(1) 37(1) 59(1) | 49(1) 41(1) 39(1) 43(1) 39(1) 40(1) 68(2) 112(3) 52(1) 58(1) 49(1) 36(1) 43(1) 80(2) | 38(1) 37(1) 35(1) 40(1) 46(1) 62(2) 78(2) 77(2) 43(1) 43(1) 75(1) 40(1) 39(1) 63(1) | 0(1) -6(1) -1(1) -9(1) -9(1) 7(1) -12(2) -25(2) -3(1) -10(1) 2(1) 4(1) -6(1) 0(1) | 6(1) 8(1) 13(1) 4(1) 8(1) 21(1) 12(1) 21(2) 25(1) 21(1) 18(1) 18(1) 15(1) 14(1) | 3(1) -5(1) -3(1) 0(1) -5(1) 12(1) 8(1) 7(2) -10(1) -3(1) -9(1) 2(1) 0(1) 5(1) |
The hydrogen coordination (* 10 of table 5.2-5
4) and isotropy displacement parameter (2 * 10
3).
| x | y | z | U(eq) | |
| H(1A) H(1B) H(2) H(3) H(4A) H(4B) H(5A) H(5B) H(6A) H(6B) H(6C) H(7A) H(7B) H(7C) H(11A) H(11B) H(11C) H(2A) H(2B) H(11) H(1) | 12248 10335 10113 7231 6367 8336 7885 8403 12857 11341 10945 4507 4671 4683 7656 5699 5960 7550 7704 6251 11060(30) | 5118 4358 7348 6126 5558 6256 3246 3198 2358 1615 1575 7821 9795 8333 5114 4665 6441 8924 9209 3486 4510(30) | 3517 3675 3689 2773 853 740 1973 820 2661 1617 2802 1218 1577 2468 5184 5421 4843 1463 2644 3866 1710(20) | 54 54 48 44 52 52 52 52 79 79 79 92 92 92 128 128 128 46 46 102 29(6) |
Route 3
(2S)-4-(2, the 5-difluorophenyl)-N-[(3R, 4S)-3-fluoro-1-methyl piperidine-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides (3-1)
To 1.6g (3.45mmol) urea chloride
1-9That adds the amine of 630mg (4.31mmol) solution in 25mL THF
2-5, the DMAP of 1.44mL (10.3mmol) triethylamine and catalytic amount.Stir after 24 hours under the room temperature, this is reflected at EtOAc and saturated NaHCO
3Distribute between the aqueous solution, organism is taken drugs with salt solution, uses Na
2SO
4Drying and concentrated by rotary evaporation.Resistates obtains-the light yellow gluey thing of 1.7g with EtOAc/ hexane purifying by silica gel chromatography.It is dissolved in the CH of 75mL
3CN adds the 3mL triethylamine trihydrofluoride, will stir 24 hours under this miscellany room temperature.Add 3mL triethylamine trihydrofluoride and this once more and be reflected at 37 ℃ of heating 24 hours down.This reflection joins saturated NaHCO subsequently
3The aqueous solution with 3x EtOAc extraction, is used the salt water washing, uses Na
2SO
4Dry and concentrated by rotary evaporation.This resistates is by silica gel chromatography EtOAc-20: 1: 1EtOH/NH
4OH/H
2The O purifying obtains 3-1, and it is a white solid.
3-1Data:
1H NMR (500MHz, CDCl
3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.3 (s, 1H), 5.25 (m, 1H), 4.9 (d, 1H), 4.8 (d, 1H), 4.6 (d, 1H), 4.45 (m, 1H), 4.1-4.0 (m, 2H), 3.2-3.1 (m, 1H), 3.1 (s, 3H), 3.0 (m, 1H), 2.4-2.3 (m, 1H), 2.3 (s, 3H), and 2.3-2.2 (m, 2H), 1.7 (m, 1H) ppm.HRMS (ES) C25H
2The M+H:460.2207. measured value of F3N3O2: 460.2213.
Route 3A
(2S)-4-(2, the 5-difluorophenyl)-N-[(3R, 4S)-3-fluoro-1-methyl piperidine-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides (3-1)
In the flask that has overhead, thermopair and nitrogen/vacuum inlet, in IPAC (0.9L), add urea chloride
1-9Add 0.9L DMF, 111gms fluorine diamines to this solution
2-5With 540ml di-isopropyl ethyl.This solution is at 60 ℃ of product yields that heated 15 hours and analyzed urea chloride down.When the product yield of urea chloride by HPLC under 200nm＞this reflection is regarded as fully 98% the time.Make this reaction be cooled to 5 ℃ and adding 450ml6N HCl.Make this ageing of solution reach fully (＞99A% is under 200nm), about 2 hours until the holder silylation reactive.
Acetate isopropyl esters (3L) and subsequently 8wt% sodium bicarbonate aqueous solution (2L) being joined in this reaction mixture is warming up to 15-20 ℃ with it.Separate each layer and pasture and water usefulness 3L IPAC extraction subsequently 1 time.The organic layer that merges 1L water washing 2 times.The organic solution of washing is concentrated into 5 liters, and is transferring in another flask through 1 μ m polypropylene filter membrane under 35-40 ℃.Continue distillation until the volume that reaches 1L, this is reflected at 2 hours internal cooling to room temperature subsequently.In 2 hours, slowly add heptane (1L).The slurries of gained be filtered on the sintered glass funnel and crystallized product with 2: 1 heptane of 500ml: isopropyl acetate washing 3 times, washing as an alternative.This solid
3-1Use the nitrogen gas stream dried overnight.This solid
1H NMR and HRMS data are equivalent to the data of the product of route 3.
The single crystal of selecting a kind of above-mentioned preparation method to obtain carries out the data gathering of monocrystalline X ray in Bruker Smart Apex system.Crystal is that colourless polyhedron and size are 0.14mm * 0.13mm * 0.13mm.This unit cell draws this structure cell with scan rate collection in 30 seconds and automatic index and is defined as iris.Resolving this structure at quadrant data gathering larynx with 30 seconds scan rates is iris P2
12
12
1Spacer.
Be used for the information of the final explanation of relevant analytic structure is made form referring to table 6-10.The computer graphics of the structure of 3-1 as shown in Figure 2.
Crystal data and the structure refinement of table 6.3-1
Empirical formula C
25H
28F
3N
3O
2
Formula weighs 459.50
Temperature 298 (2) K
Wavelength 0.71073_
Crystallographic system, the spacer oblique crystal, P2 (1) 2 (1) 2 (1)
Unit cell size: a=11.3916 (14) _ α=90 °.
b＝11.4808(14)_ β＝90°
c＝17.718(2)_ γ＝90°
Volume 2317.3 (5)
O3
Z, the density 4 of calculating, 1.317Mg/m
3
Uptake factor 0.101mm
-1
F(000) 968
Crystallite size 0.14 * 0.13 * 0.13mm
The θ scope 2.11-26435O of data gathering
Critical exponent (Limiting indices)-14＜=h＜=14 ,-14＜=k＜=14 ,-22＜=l＜=22
The reflection 22539/2698[R (int)=0.0405 of set/uniqueness]
θ spends fully=and 26.35 99.8%
Absorption correction does not have
The refine method is in F
2Last complete matrix (Full-matrix) Shaozheng is square
Data/restriction/parameter 2698/0/301
F
2On the goodness of fit 1.157
Final R index [I＞2sigma (I)] R1=0.0429, wR2=0.0993
R index (all data) R1=0.0550, wR2=0.1047
Absolute structure parameter 0 (10)
Maximum difference peak and paddy 0.165 and-0.120e_
-3
Table 7. compound
3-1Atomic coordinate (* 10
4) and equivalent isotropy displacement parameter (_
2* 10
3)
U (eq) is defined as the 3rd vestige of quadrature Uij tensor
| x | y | z | U(eq) | |
| C(5) C(25) O(2) F(3) F(1) O(1) C(18) C(1) N(1) C(12) C(20) N(2) F(2) C(4) C(17) C(2) C(11) C(24) C(3) N(3) C(19) C(15) C(21) C(16) C(6) C(13) C(14) C(7) C(10) C(9) C(22) C(8) C(23) | -2267(3) 5273(3) 24(2) 4039(2) -3491(2) -2142(2) 313(2) -1779(2) -501(2) -1597(2) 2315(2) 1463(2) 177(2) -303(2) -680(3) -2267(2) -3201(3) 2651(3) -1487(2) 4491(2) 1830(3) -1705(4) 3404(2) -754(3) -2088(2) -2555(3) -2613(4) -1323(3) -3518(3) -2748(3) 4183(3) -1644(3) 3449(3) | 6218(3) 3363(4) 5125(1) 6650(2) 9889(2) 5028(2) 6092(2) 6659(2) 6935(2) 9968(2) 5486(2) 6357(2) 12521(2) 8186(2) 10679(2) 7865(2) 5372(2) 4586(2) 8695(2) 4230(2) 7139(3) 12401(3) 6016(2) 11868(3) 5851(2) 10532(3) 11716(3) 5615(3) 4678(3) 4452(3) 5085(3) 4917(3) 3691(2) | 2092(2) 2054(3) 1748(1) 1452(1) 691(1) 2243(1) 1508(1) 1327(2) 1354(1) 1225(1) 1637(1) 1377(1) 1590(1) 1463(2) 1453(2) 1205(1) 626(2) 1056(2) 1296(1) 1726(2) 769(2) 1043(2) 1983(2) 1362(2) 671(1) 918(2) 818(2) 89(2) 26(2) -544(2) 2291(2) -508(2) 1414(2) | 53(1) 93(1) 50(1) 74(1) 73(1) 63(1) 39(1) 41(1) 41(1) 44(1) 40(1) 42(1) 105(1) 50(1) 53(1) 44(1) 53(1) 52(1) 42(1) 60(1) 58(1) 78(1) 52(1) 68(1) 40(1) 55(1) 71(1) 57(1) 64(1) 70(1) 64(1) 73(1) 63(1) |
Table 8.
3-1Bond distance [_] and bond angle [°].
| C(5)-O(1) C(5)-C(1) C(5)-H(5A) C(5)-H(5B) C(25)-N(3) C(25)-H(25A) C(25)-H(25B) C(25)-H(25C) O(2)-C(18) F(3)-C(21) F(1)-C(13) O(1)-H(1) C(18)-N(1) C(18)-N(2) C(1)-N(1) C(1)-C(2) C(1)-C(6) N(1)-C(4) C(12)-C(13) C(12)-C(17) C(12)-C(3) C(20)-N(2) C(20)-C(24) C(20)-C(21) C(20)-H(20) | 1.399(3) 1.550(4) 0.9700 0.9700 1.457(4) 0.9600 0.9600 0.9600 1.233(3) 1.393(3) 1.358(4) 0.8200 1.368(3) 1.364(3) 1.490(3) 1.508(3) 1.528(4) 1.466(3) 1.381(4) 1.386(4) 1.473(3) 1.468(3) 1.508(4) 1.512(4) 0.9800 | N(2)-C(19) F(2)-C(16) C(4)-C(3) C(4)-H(4A) C(4)-H(4B) C(17)-C(16) C(17)-H(17) C(2)-C(3) C(2)-H(2) C(11)-C(10) C(11)-C(6) C(11)-H(11) C(24)-C(23) C(24)-H(24A) C(24)-H(24B) N(3)-C(22) N(3)-C(23) C(19)-H(19A) C(19)-H(19B) C(19)-H(19C) C(15)-C(14) C(15)-C(16) C(15)-H(15) C(21)-C(22) C(21)-H(21) | 1.464(3) 1.360(4) 1.500(3) 0.9700 0.9700 1.376(4) 0.9300 1.313(4) 0.9300 1.376(4) 1.385(4) 0.9300 1.511(4) 0.9700 0.9700 1.446(4) 1.448(4) 0.9600 0.9600 0.9600 1.360(5) 1.367(5) 0.9300 1.492(4) 0.9800 |
| C(6)-C(7) C(13)-C(14) C(14)-H(14) C(7)-C(8) C(7)-H(7) C(10)-C(9) C(10)-H(10) C(9)-C(8) C(9)-H(9) C(22)-H(22A) C(22)-H(22B) C(8)-H(8) C(23)-H(23A) C(23)-H(23B) O(1)-C(5)-C(1) O(1)-C(5)-H(5A) C(1)-C(5)-H(5A) O(1)-C(5)-H(5B) C(1)-C(5)-H(5B) H(5A)-C(5)-H(5B) N(3)-C(25)-H(25A) N(3)-C(25)-H(25B) H(25A)-C(25)-H(25B) N(3)-C(25)-H(25C) H(25A)-C(25)-H(25C) H(25B)-C(25)-H(25C) C(5)-O(1)-H(1) O(2)-C(18)-N(1) O(2)-C(18)-N(2) N(1)-C(18)-N(2) N(1)-C(1)-C(2) N(1)-C(1)-C(6) C(2)-C(1)-C(6) N(1)-C(1)-C(5) C(2)-C(1)-C(5) C(6)-C(1)-C(5) | 1.377(4) 1.372(4) 0.9300 1.377(4) 0.9300 1.362(4) 0.9300 1.368(5) 0.9300 0.9700 0.9700 0.9300 0.9700 0.9700 116.7(2) 108.1 108.1 108.1 108.1 107.3 109.5 109.5 109.5 109.5 109.5 109.5 109.5 121.6(2) 121.0(2) 117.3(2) 99.73(19) 112.2(2) 111.3(2) 113.1(2) 107.1(2) 112.6(2) | C(18)-N(1)-C(4) C(18)-N(1)-C(1) C(4)-N(1)-C(1) C(13)-C(12)-C(17) C(13)-C(12)-C(3) C(17)-C(12)-C(3) N(2)-C(20)-C(24) N(2)-C(20)-C(21) C(24)-C(20)-C(21) N(2)-C(20)-H(20) C(24)-C(20)-H(20) C(21)-C(20)-H(20) C(18)-N(2)-C(19) C(18)-N(2)-C(20) C(19)-N(2)-C(20) N(1)-C(4)-C(3) N(1)-C(4)-H(4A) C(3)-C(4)-H(4A) N(1)-C(4)-H(4B) C(3)-C(4)-H(4B) H(4A)-C(4)-H(4B) C(16)-C(17)-C(12) C(16)-C(17)-H(17) C(12)-C(17)-H(17) C(3)-C(2)-C(1) C(3)-C(2)-H(2) C(1)-C(2)-H(2) C(10)-C(11)-C(6) C(10)-C(11)-H(11) C(6)-C(11)-H(11) C(20)-C(24)-C(23) C(20)-C(24)-H(24A) C(23)-C(24)-H(24A) C(20)-C(24)-H(24B) C(23)-C(24)-H(24B) H(24A)-C(24)-H(24B) | 124.2(2) 121.18(19) 111.32(19) 115.7(2) 124.5(3) 119.7(2) 114.8(2) 113.3(2) 110.1(2) 105.9 105.9 105.9 122.5(2) 115.44(19) 117.40(19) 102.5(2) 111.3 111.3 111.3 111.3 109.2 120.3(3) 119.9 119.9 113.6(2) 123.2 123.2 121.0(3) 119.5 119.5 109.4(2) 109.8 109.8 109.8 109.8 108.2 |
| C(2)-C(3)-C(12) C(2)-C(3)-C(4) C(12)-C(3)-C(4) C(22)-N(3)-C(23) C(22)-N(3)-C(25) C(23)-N(3)-C(25) N(2)-C(19)-H(19A) N(2)-C(19)-H(19B) H(19A)-C(19)-H(19B) N(2)-C(19)-H(19C) H(19A)-C(19)-H(19C) H(19B)-C(19)-H(19C) C(14)-C(15)-C(16) C(14)-C(15)-H(15) C(16)-C(15)-H(15) F(3)-C(21)-C(22) F(3)-C(21)-C(20) C(22)-C(21)-C(20) F(3)-C(21)-H(21) C(22)-C(21)-H(21) C(20)-C(21)-H(21) F(2)-C(16)-C(15) F(2)-C(16)-C(17) C(15)-C(16)-C(17) C(7)-C(6)-C(11) C(7)-C(6)-C(1) C(11)-C(6)-C(1) F(1)-C(13)-C(14) F(1)-C(13)-C(12) C(14)-C(13)-C(12) C(15)-C(14)-C(13) C(15)-C(14)-H(14) C(13)-C(14)-H(14) C(6)-C(7)-C(8) C(6)-C(7)-H(7) C(8)-C(7)-H(7) | 130.7(2) 110.5(2) 118.7(2) 110.8(2) 109.7(3) 111.2(3) 109.5 109.5 109.5 109.5 109.5 109.5 117.7(3) 121.1 121.1 108.3(2) 111.3(2) 110.4(2) 109.0 109.0 109.0 119.6(3) 117.7(3) 122.8(3) 117.3(3) 122.9(2) 119.7(2) 117.6(3) 118.8(3) 123.6(3) 119.9(3) 120.0 120.0 121.5(3) 119.3 119.3 | C(9)-C(10)-C(11) C(9)-C(10)-H(10) C(11)-C(10)-H(10) C(10)-C(9)-C(8) C(10)-C(9)-H(9) C(8)-C(9)-H(9) N(3)-C(22)-C(21) N(3)-C(22)-H(22A) C(21)-C(22)-H(22A) N(3)-C(22)-H(22B) C(21)-C(22)-H(22B) H(22A)-C(22)-H(22B) C(9)-C(8)-C(7) C(9)-C(8)-H(8) C(7)-C(8)-H(8) N(3)-C(23)-C(24) N(3)-C(23)-H(23A) C(24)-C(23)-H(23A) N(3)-C(23)-H(23B) C(24)-C(23)-H(23B) H(23A)-C(23)-H(23B) | 120.9(3) 119.5 119.5 118.9(3) 120.5 120.5 112.1(2) 109.2 109.2 109.2 109.2 107.9 120.4(3) 119.8 119.8 111.3(2) 109.4 109.4 109.4 109.4 108.0 |
Table 9.
3-1Each diversity displacement parameter (_
2* 10
3)
Anisotropy shift factor index is :-2pi
2[h
2A*
2U11+...+2h ka*b*U12]
| C(5) C(25) O(2) F(3) F(1) O(1) C(18) C(1) N(1) C(12) C(20) N(2) F(2) C(4) C(17) C(2) C(11) C(24) C(3) N(3) C(19) C(15) C(21) C(16) C(6) C(13) | 52(2) 53(2) 43(1) 58(1) 65(1) 63(1) 42(1) 35(1) 39(1) 60(2) 41(1) 41(1) 144(2) 45(1) 69(2) 41(1) 49(2) 55(2) 49(1) 40(1) 53(2) 127(3) 46(1) 105(3) 40(1) 67(2) | 57(2) 89(3) 33(1) 57(1) 68(1) 58(1) 32(1) 38(1) 28(1) 35(1) 36(1) 35(1) 40(1) 30(1) 37(1) 41(1) 51(2) 44(1) 39(1) 58(1) 49(2) 38(2) 51(2) 35(1) 33(1) 53(2) | 50(2) 136(3) 75(1) 109(1) 86(1) 69(1) 42(1) 50(1) 55(1) 36(1) 43(1) 50(1) 131(2) 74(2) 53(2) 50(1) 58(2) 58(2) 38(1) 82(2) 73(2) 68(2) 58(2) 65(2) 48(1) 47(2) | 2(1) 38(3) 13(1) 18(1) 5(1) 21(1) 1(1) 4(1) 4(1) 2(1) 8(1) 9(1) -4(1) 6(1) 2(1) -2(1) 5(1) -3(1) 2(1) 20(1) 24(1) 1(2) -6(1) -2(1) 7(1) 0(1) | 4(1) 3(2) -4(1) -2(1) -14(1) 9(1) -2(1) 2(1) -2(1) 6(1) 2(1) 4(1) -27(2) -6(1) 3(2) -1(1) -6(1) -2(1) 5(1) 9(1) 10(2) -3(2) -1(1) -5(2) -2(1) 4(1) | -5(1) 21(2) 0(1) -15(1) 19(1) -6(1) 2(1) 1(1) 3(1) 12(1) 4(1) 4(1) -12(1) 3(1) 9(1) 9(1) 0(1) 5(1) 9(1) 13(1) 7(1) 25(2) -1(1) 3(2) 6(1) 19(2) |
| C(14) C(7) C(10) C(9) C(22) C(8) C(23) | 99(3) 51(2) 61(2) 82(2) 43(2) 75(2) 65(2) | 53(2) 66(2) 55(2) 61(2) 81(2) 83(2) 42(1) | 62(2) 56(2) 75(2) 67(2) 67(2) 63(2) 83(2) | 4(2) -8(2) 0(2) -18(2) 12(2) -19(2) 3(2) | -6(2) 1(1) -21(2) -23(2) -6(1) 0(2) 8(2) | 35(2) 5(2) -6(2) 14(2) -3(2) 21(2) 12(2) |
Table 10.
3-1Hydrogen atom coordination (* 10
4) and the isotropy displacement parameter (_
2* 10
3)
| x | y | z | U(eq) | |
| H(5A) H(5B) H(25A) H(25B) H(25C) H(1) H(20) H(4A) H(4B) H(17) H(2) H(11) H(24A) H(24B) H(19A) H(19B) H(19C) H(15) | -1881 -3096 4878 5963 5495 -1483 1926 287 -61 -13 -3046 -3743 3051 1951 1181 2463 2087 -1730 | 6648 6408 2968 3742 2810 4815 5057 8479 8355 10353 8007 5520 4959 4208 7275 6789 7865 13206 | 2493 2114 2458 2246 1674 2120 2045 1116 1977 1669 1077 1006 637 863 435 492 980 983 | 64 64 139 139 139 95 48 60 60 64 53 63 62 62 88 88 88 93 |
| H(21) H(14) H(7) H(10) H(9) H(22A) H(22B) H(8) H(23A) H(23B) | 3171 -3273 -572 -4268 -2970 4894 3787 -1106 3028 3677 | 6536 12049 5933 4360 3989 5438 4700 4760 3288 3120 | 2395 597 100 9 -950 2487 2707 -890 1812 1038 | 62 85 69 76 84 77 77 88 76 76 |
Route 4
(2S)-4-(2, the 5-difluorophenyl)-N-[(3S, 4R)-3-fluoro-1-methyl piperidine-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides (4-2)
This compound to be preparing with the identical mode of preparation 3-1, but except from chiral column according to described the mixing of route 2 steps 3
2-3The first wash-out enantiomer outside.
4-2Data:
1HNMR (500MHz, CDCl
3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.3 (s, 1H), 5.4 (bs, 1H), 5.2 (d, 1H), 4.9 (m, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 4.0 (m, 1H), 3.8 (m, 1H), 3.2 (s, 3H), 3.0 (m, 1H), 2.5-2.2 (m, 3H), 2.4 (s, 3H), 1.8-1.6 (m, 2H) ppm.HRMS (ES) C
25H
28F
3N
3O
2M+H: calculated value 460.2207. measured value: 460.2229.
Route 5
Route 5 (continuously)
(2S)-4-(2, the 5-difluorophenyl)-N-[(3R, 4R)-3-fluoro-1-methyl piperidine-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides (5-3)
This compound will but handle to make with the identical mode of preparation 3-1
2-2aThe trans isomer mix synthetic in outside.The fractionation of the enantiomer of " trans-2-3 " is carried out under 150mL/min with Chiralpak AD_10 * 50cm post and the hexane (containing 0.1% diethylamine) that contains 15%EtOH by chromatography.Analysis HPLC test under 1mL/min shows that the first wash-out enantiomer had Rt=7.30 minute and second enantiomer had Rt=11.59 minute to elutriant with the hexane (containing 0.1% diethylamine) that contains 15%EtOH at 4 * 250mm Chiralpak AD_ post.The further processing of the first wash-out enantiomer (having unknown absolute stereo chemistry) obtained trans amine
5-1, with its be increased to according to route 2 described same routes in 5-3 synthetic.
5-3Synthetic:
1H NMR (500MHz, CDCl
3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.3 (s, 1H), 5.0-4.7 (m, 4H), 4.5 (m, 1H), 4.0 (m, 1H), 3.8 (m, 1H), 3.3 (m, 1H), 2.9 (s, 3H), 2.85 (m, 1H), 2.35 (s, 3H), 2.2-1.9 (m, 3H), 1.7 (m, 1H) ppm.HRMS (ES) C
25H
28F
3N
3O
2M+H: calculated value 460.2207.Measured value: 460.2231.The absolute stereo chemistry of the piperidines of compound 5-3 and 5-4 also for measure and shown in stereochemistry show that obtaining test determines.
(2S)-4-(2, the 5-difluorophenyl)-N-[(3S, 4S)-3-fluoro-1-methyl piperidine-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides (5-4)
This compound is made in the mode identical with 5-3, increases by the second wash-out isomer that separates trans-2-3 from chiral column but handle.
5-4Data:
1H NMR (500MHz, CDCl
3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.3 (s, 1H), 5.4 (m, 1H), 4.9-4.6 (m, 3H), 4.4 (m, 1H), 4.0 (m, 1H), 3.85 (m, 1H), 3.25 (m, 1H), 3.0 (s, 3H), 2.85 (m, 1H), 2.35 (s, 3H), 2.2-1.9 (m, 4H) ppm.HRMS (ES) C25H
2The M+H:460.2207. measured value of 8F3N3O2: 460.2229.
Route 6
Step 1:(2S, 4S)-4-hydroxyl-2-Phenylpyrrolidine-1-carboxylic acid tert-butyl ester (6-2)
In the flame-dried flask that has stirring rod, add (2S, 4S)-and the 4-{[tertiary butyl (dimethyl) silyl] the oxygen base }-2-Phenylpyrrolidine-1-carboxylic acid tert-butyl ester (6-1, from (S)-(-)-4-chloro-3-hydroxybutyronitrile by Synlett such as Maeda 2001, the method preparation of 1808-1810,7.8g, 20.7mmol) and anhydrous acetonitrile (20.0mL).(10.1mL 62.0mmol) handles and at N gained solution with triethylamine trihydrofluoride
2The following stirring.This is reflected at 40 ℃ and stirred 12 hours down.EtOAc (100mL) dilution and impouring 5%NaHCO are used in this reaction subsequently
3The aqueous solution.After stopping to emit gas, organic layer is used 5%NaHCO again
3Solution washing 3 times.The organic layer dried over mgso is filtered and the concentrated crude product that obtains.Obtain from EtOAc/ hexane recrystallization that (2S, 4S)-4-hydroxyl-2-Phenylpyrrolidine-1-carboxylic acid tert-butyl ester (6-2), it is the white crystal solid.
1H NMR (300MHz, CDCl
3) rotational isomer δ 7.38-7.18 (m, 5H), 4.90 (m, 1H), 4.42 (m, 1H), 3.88 (m, 1H), 3.56 (dd, J=11.5,4.0Hz, 1H), 2.60 (m, 1H), 2.03 (m, 1H), 1.50 and 1.20 (br s, 9H); MS measured value 208.0, theoretical value 208.1 (M-C (CH
3)
3).
Step 2:(2S)-4-oxo-2-Phenylpyrrolidine-1-carboxylic acid tert-butyl ester (6-3)
In the flame-dried flask that has stirring rod, add the 150mL anhydrous methylene chloride, it is cooled to-78 ℃.Add successively oxalyl chloride (3.8mL, 44mmol) and DMSO (4.8mL, 61mmol).And should react and stir 10 minutes.Dropping be present in the 10mL anhydrous methylene chloride (2S, 4S)-(6-2,2.28g 8.73mmol) and at-78 ℃ stirred 1 hour down 4-hydroxyl-2-Phenylpyrrolidine-1-carboxylic acid tert-butyl ester.Add triethylamine (12mL, 87mmol) and this was reflected in 1 hour rise to room temperature.After finishing, this reaction 5%NaHCO
3, salt water washing and use MgSO
4Dry.Organic layer concentrates and obtains thick (2S)-4-oxo-2-Phenylpyrrolidine-1-carboxylic acid tert-butyl ester (6-3).With EtOAc/ hexane recrystallization.
1H NMR (300MHz, CDCl
3) δ 7.35 (m, 3H), 7.17 (m, 2H), 5.38 (m, 1H), 4.08 (d, J=19.5Hz, 1H), 3.90 (d, J=19.3Hz, 1H), 3.13 (dd, J=18.8,9.8Hz, 1H), 2.58 (dd, J=18.6,2.4Hz, 1H), 1.40 (br s, 9H); MS measured value 206.0, theoretical value 206.1 (M-C (CH
3) 3).
Step 3:(2S)-and 2-phenyl-4-{[(trifluoromethyl) alkylsulfonyl] the oxygen base }-2,5-dihydro-1H-pyrroles-1-carboxylic acid tert-butyl ester (6-4)
(6-3,0.16g is 0.62mmol) with anhydrous THF (2mL) to add ketone (2S)-4-oxo-2-Phenylpyrrolidine-1-carboxylic acid tert-butyl ester in the flame-dried flask that has stirring rod.Gained solution be cooled to-78 ℃ and with the hexamethyl dimethyl silanyl lithamide that drips (LHMDS, 0.68mL, 1M 0.68mmoL) handle in THF.This is reflected at-78 ℃ of following stirrings 1 hour and adds N-(5-chloropyridine-2-yl)-1,1 successively, 1-three fluoro-N-[(trifluoromethyls) alkylsulfonyl] Toluidrin (0.27g, 068mmol).This reaction is warming up to 0 ℃ and stirred altogether 4 hours.This reaction is with Et2O (10mL) dilution and use H continuously
2O (IOmL) and salt solution (10mL) washing.Organic layer MgSO
4Drying is filtered and is concentrated.Thick resistates obtains (2S)-2-phenyl-4-{[(trifluoromethyl by flash column chromatography purifying (0-20%EtOAc/ hexane gradient, 15 minutes)) alkylsulfonyl] the oxygen base }-2,5-dihydro-1H-pyrroles-1-carboxylic acid tert-butyl ester (6-4).
1H NMR (300MHz, CDCl
3) main rotational isomer: δ 7.30 (m, 5H), 5.72 (m, 1H), 5.48 (m, 1H), 4.42 (m, 2H), 1.18 (s, 9H); MS measured value 379.0 theoretical values 379.1 (M-CH
3).
Step 4:(2S)-and 4-(2, the 5-difluorophenyl)-2-phenyl-N, N-dimethyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides (6-5)
In the flame-dried flask that has stirring rod, add (2S)-2-phenyl-4-{[(trifluoromethyl) alkylsulfonyl] the oxygen base }-2,5-dihydro-1H-pyrroles-1-carboxylic acid tert-butyl ester (6-4,0.250g; 0.636mmoD, 2,5-difluorophenyl boric acid (0.251g; 1.59mmol), Na
2CO
3(0.202g, 1.91mmol) and LiCl (0.081g, 1.91mmol).This solid is dissolved in 20mL 4: 1DME/H
2O and outgas with nitrogen.Add Pd (PPh3) 4 (0.037g, 0.032mmol) and be sealed in this reaction under the nitrogen and be heated to 90 ℃ 2 hours.After finishing, this is reflected at 5%NaHCO
3The aqueous solution and EtOAc (distribute between 3 * 50mL), and the organic layer MgSO that merges
4Dry.After the filtration, organic layer concentrates and nitrile flash column chromatography purifying (SiO
2, the 0-20%EtOAc/ hexane gradient) and obtain (2S)-4-(2, the 5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid tert-butyl ester (6-5).
Step 5:1-{[(2S)-and 4-(2, the 5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrroles-1-yl] carbonyl }-3-methyl isophthalic acid H-imidazoles-3-(6-6)
In the flame-dried flask that has stirring rod, under nitrogen, add
6-5(0.63g is 1.75mmol) with anhydrous CH
2Cl
2(10mL).Gained solution is handled with trifluoroacetic acid (5mL) and was stirred 1.5 hours down at 25 ℃.After finishing, this reaction concentrates, and is dissolved in CH
2Cl
2(50mL) and use 5%NaHCO
3(50mL) washing.Dry organic layer (MgSO
4), filtration and decompression concentrate down.The gained unhindered amina is dissolved in anhydrous THF (10mL) and (0.31g 1.93mmol) handles with carbonyl dimidazoles.Gained solution refluxes hour until finishing.Concentrate this reaction, be dissolved in EtOAc (50mL) and use H
2O and salt water washing.Dry organic layer (the MgSO that merges
4) and concentrate.Thick acylimidazole is dissolved in anhydrous CH
3CN and with MeI (2.2mL 36mmol) handles.Gained solution stirs down at 25 ℃ and spends the night.After finishing, this reaction concentrates and obtains
6-6, it is orange solids: LRMSm/z (M+H) measured value 365.9, theoretical value 366.1.
Route 7
(2S)-4-(2, the 5-difluorophenyl)-N[(3R, 4S)-3-fluoro-1-methyl piperidine-4-yl]-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides (7-1)
To 75mg (0.15mmol)
6-6Add 40mg (0.18mmol) amine in the solution in 1mL THF
2-5Two-HCl salt and 106L (0.76mmol) triethylamine.Stirred 72 hours under the room temperature, this is reflected at CH
2Cl
2With saturated NaHCO
3Distribute between the aqueous solution, MgSO is used in organism salt water washing
4Dry and concentrated by rotary evaporation.Resistates by silica gel chromatography with 80: 10: 10CHCl
3/ EtOAc/MeOH purifying obtains
7-1, it is a white solid.
7-1Data: HRMS (ES) C
24H
26F
3N
3The M+H of O: calculated value 430.2101. measured value: 430.2116.
(2S)-4-(2, the 5-difluorophenyl)-N-[(3S, 4R)-3-fluoro-1-methyl piperidine-4-yl]-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides (7-2)
This compound is according to being similar to
7-1Mode prepare, use
4-1Substitute as starting raw material.
7-2Data: HRMS (ES) C
24H
26F
3N
3The M+H of O: calculated value 430.2101. measured value: 430.2119.
(2S)-4-(2, the 5-difluorophenyl)-N-[(3R, 4R)-3-fluoro-1-methyl piperidine-4-yl]-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides (7-3)
This compound is according to being similar to
7-1Mode prepare, use
5-1Substitute as starting raw material.
7-3Data RMS (ES) C
24H
26F
3N
3The M+H of O: calculated value 2101. measured values: 430.2115.Compound
7-3The absolute stereo chemistry of piperidines go back undetermined but shown in stereochemistry be determined by experiment that.
The simple modifications of the method shown in following compounds pass course 1-7 and the route G-N prepares, but replaces employed those times of above-mentioned route with the reagent that suitably replaces.
| R 1 | R 2 | R 3 | R 4 | R 5 |
| Me | CH 2OH | Me | Cl | H |
| Me | CH 2OH | Me | Br | H |
| Me | CH 2OH | Me | CN | H |
| Me | CH 2OH | Me | Me | H |
| Me | CH 2OH | Me | CF 3 | H |
| Me | CH 2OH | Me | NO 2 | H |
| Me | CH 2OH | Me | F | OH |
| Me | CH 2OH | Me | F | NH 2 |
| Me | CH 2OH | Me | F | F |
| Me | CH 2OH | Me | F | SH |
Route 8
The 4-[(tert-butoxycarbonyl) (methyl) amino 1-2-(hydroxymethyl) piperidines-1-benzyl carboxylate (8-2)
To 2.0g (6.8mmol)
8-1(be reported in: S.J.Hayes, T.C.Malone, G.Johnson J.Org.Chem.1991,56,4084-4086) at 100mL CH
2Cl
2In solution in add 3.33mL (23.9mmol) triethylamine, drip 2.44g (15.4mmol) the SO3-pyridine that is present among the 50mL DMSO subsequently.Stir after 5 hours under the room temperature, this miscellany is at CH
2Cl
2And H
2Distribute between the O, separate each phase, with 2 * 1M HCl, saturated NaHCO
3MgSO is used in the aqueous solution, salt water washing
4Dry and the concentrated ketone that obtains.The MeNH that in 2.1g (7.2mmol) is dissolved in this ketone among the 35mLMeOH, adds 1mL AcOH and 14.4mL (28.9mmol)
22M solution in MeOH.Stir after 1 hour, add the NaCNBH3 among 910mg (14.4mmol) the 5mL MeOH and should react stirring and spend the night.The saturated NH of this reaction
4CH is used in the quencher of the C1 aqueous solution
2Cl
2NaHCO is used in extraction
3, H
2MgSO is used in O, salt water washing
4Dry and concentrated 2.0g (7.2mmol) amine that obtains.This material is dissolved in 25mL CH
2Cl
2, tert-Butyl dicarbonate and 1.8mL (12.9mmol) triethylamine of adding 1.78g (8.2mmol), and with gained miscellany stirring 72 hours.This reaction is subsequently at CH
2Cl
2With saturated NaHCO
3The aqueous solution distributes, and separates, and uses H
2The O washing, salt solution is used MgSO
4Dry and concentrated.Resistates obtains the miscellany of 1.85g (4.6mmol) diastereomer with EtOAc/ hexane purifying by silica gel chromatography.It is dissolved in 20mL THF and 1mL of MeOH, is cooled to 0 ℃ and adding 496mg (22.8mmol) LiBH
4Rise to room temperature and stir spend the night after, the saturated NH of this reaction
4The quencher of the C1 aqueous solution with the EtOAc extraction, is used H
2MgSO is used in O, salt water washing
4Dry and concentrated obtaining
8-2, it is no coloring agent.
8-2Data: LRMS (ES) C
20H
30N
2O
5M+H: calculated value 379. measured values: 379.
[2-(methylol)-1-methyl piperidine-4-yl] methyl carbamic acid tert-butyl ester (8-3)
Be present among the 30mL EtOH to 1.08g (2.9mmol)
8-2Add 1 of 7mL (74mmol), 10% carbon that 4-changes hexadiene and catalytic amount carries Pd.After stirring was spent the night, this reacted through diatomite filtration, concentrated by rotary evaporation, and was dissolved in 25mL MeOH.To wherein adding 2mLAcOH and 700 μ L (8.6mmol), 37% formalin.After stirring is spent the night, add 540mg (8.6mmol) and be present in the NaCNBH3 among the 5mL MeOH and should react stirring 1 hour.Except that desolvating, resistates is at EtOAc and NaHCO by rotary evaporation
3Distribute between the aqueous solution, Na is used in organic phase salt water washing
2SO
4Dry and concentrated.Resistates is dissolved in CH
2Cl
2, filter and concentrated obtaining
8-3, it is a water white oil.
8-3Data: LRMS (ES) C
13H
26N
2O
3M+H: calculated value 259. measured values: 259.
[2-(methyl fluoride)-1-methyl piperidine-4-yl] the methyl carbamic acid tert-butyl ester (8-4) and (6-fluoro-1-methyl nitrogen heterocyclic heptyl amice-4-yl) methyl carbamic acid tert-butyl ester (8-5)
To 350 μ L (2.6mmol) (diethylamino) sulfur trifluorides (DAST) at 15mL CH
2Cl
2In solution in add down at-78 ℃ and to be present in 5mL CH
2Cl
2In 520mg (2.0mmol).Make this sluggish rise to that room temperature and stirring are spent the night and use the frozen water quencher subsequently.This miscellany is at additional C H
2Cl
2And distribute between a small amount of 3M KOH, organic phase washes with water, uses Na
2SO
4Dry and concentrated.Be carried in resistates on the silicagel column and use EtOAc-20: 1: 1EtOH/NH
4OH/H
2O.First product of wash-out is the ring expansion product
8-5, it is a water white oil, and second product of wash-out is
8-4, it is a water white oil.
8-5With
8-4Both are separated into the enantiomer miscellany of trans diastereomer.This structure is determined by a large amount of 1D and 2D NMR spectrum.
8-5Data:
1H NMR (600MHz, CD2Cl2) δ 4.75 (m, 1H), 4.1-3.9 (m, 1H), 2.9-2.7 (m, 3H), 2.75 (s, 3H), 2.4 (s, 3H), 2.35 (m, 1H), 2.1-1.7 (m, 4H), 1.4 (s, 9H) ppm.
8-4Data:
1H NMR (500MHz, CD2Cl2) δ 4.8-4.5 (m, 2H), 4.1-4.0 (m, 1H), 3.2 (m, 1H), 2.75 (m, 2H), 2.7 (s, 3H), 2.45 (s, 3H), 1.9-1.5 (m, 4H), 1.45 (s, 9H) ppm.
(25)-4-(2, the 5-difluorophenyl)-N-[(2R, 4R)-2-(methyl fluoride)-1-methyl piperidine-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides (8-6a) and (2S)-4-(2, the 5-difluorophenyl)-N-[(2S, 4S)-2-(methyl fluoride)-1-methyl piperidine-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides (8-6b)
With 80mg (0.31mmol)
8-4Solution in 30mL EtOAc is with the HCl gas shield and at room temperature stirred 1 hour.This reaction concentrates by rotary evaporation subsequently and the gained white solid is suspended among the 1mL THF.To the 1-9 that wherein adds 156mg (0.34mmol), the DMAP of 268L (1.54mmol) diisopropyl ethyl amine and catalytic amount.After 50 ℃ of following heated overnight, add 500 μ L trifluoroacetic acids and at room temperature continue and stir, use saturated NaHCO afterwards
3Aqueous solution quencher.This miscellany is at CH
2Cl
2Between distribute, MgSO is used in organic phase salt water washing
4Drying, and concentrate.Be carried in resistates on the silicagel column and use CHCl
3-80: 10: 10CHCl
3/ EtOAc/MeOH wash-out obtains
8-6aWith
8-6b, it is inseparable miscellany-no coloring agent.The M+H of the data of 8-6a/8-6b: HRMS (ES) C26H30F3N3O2: calculated value 474.2363. measured value: 474.2374.
The simple modifications of the method shown in following compounds pass course 1-8 and the route G-N prepares, but replaces employed those reagent of this route with the reagent that suitably replaces.
| R 1 | R 2 | R 3 | R 4 | R 5 |
| Me | CH 2OH | Me | Cl | H |
| Me | CH 2OH | Me | Br | H |
| Me | CH 2OH | Me | CN | H |
| Me | CH 2OH | Me | Me | H |
| Me | CH 2OH | Me | CF 3 | H |
| Me | CH 2OH | Me | NO 2 | H |
| Me | CH 2OH | Me | F | OH |
| Me | CH 2OH | Me | F | NH 2 |
| Me | CH 2OH | Me | F | F |
| Me | CH 2OH | Me | F | SH |
Route 9
(2S)-4-(2, the 5-difluorophenyl)-N-[(3R, 4S)-3-fluoro-1-methyl isophthalic acid-oxo bridge piperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides (9-1)
To 20mg (0.044mmol)
3-1At 1mL CH
2Cl
2In solution in add down 11mg (～0.048mmol) mCPBA in 0 ℃.Remove ice bath and should react stirring 30 minutes.This miscellany is at EtOAc and saturated NaHCO
3Distribute between the aqueous solution, separate, use H
2Na is used in O, salt water washing
2SO
4Dry and concentrated by rotary evaporation.Be carried in resistates on the silicagel column and use EtOAc-20: 1: 1 EtOH/NH
4OH/H
2The O wash-out obtains 9-1, and it is a white foam.
9-1Data:
1H NMR (500MHz, CDCl
3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.25 (s, 1H), 5.0-4.9 (m, 2H), 4.7 (m, 1H), 4.5 (m, 1H), 4.3-4.2 (m, 1H), 4.0 (m, 2H), 3.7 (m, 1H), 3.4-3.3 (m, 2H), 3.3 (s, 3H), 3.2 (s, 3H), 2.5-1.9 (bs, 2H), 1.8 (m, 1H) ppm.HRMS (ES) C
25H
28F
3N
3O
3M+H: calculated value 476.2156; Measured value 476.2165.
Route 10
Step 1:(3R, 4S)-4-[{[(2S)-4-(2, the 5-difluorophenyl)-2-(methylol)-2-phenyl-2,5-dihydro-1H-pyrroles-1-yl] carbonyl } (methyl) amino]-3-fluorine piperidines-1-benzyl carboxylate (10-1):
In the solution of 885mg (2.4mmol) 2-3 (from first isomer of chromatography eluant) among 12mLEtOAc, add the 4M solution of 12mL (48mmol) HCl in dioxan down in 0 ℃.Remove ice bath, continue to stir 2 hours, and remove volatile matter by rotary evaporation subsequently.Resistates is at EtOAc and the saturated NaHCO that contains 5mL 1M NaOH
3Distribute between the aqueous solution, separate and water 2x EtOAc extraction.The organic extract liquid that merges is used NaHCO once more
3, brine treatment, use Na
2SO
4Drying and the concentrated amine that obtains 590mg (2.2mmol).In being present in this material among the 5mL THF, 215mg (0.81mmol) adds 340mg (0.73mmol)
1-9, the DMAP of 306 μ L (2.2mmol) triethylamines and catalytic amount.After stirring is spent the night, this reaction judge by LC/MS finish～40%, add the DMAP of another part.This reaction is subsequently at EtOAc and saturated NaHCO
3Between distribute organic phase NaHCO
3, H
2Na is used in O, salt water washing
2SO
4Dry and concentrated.Resistates obtains with EtOAc/ hexane purifying by silica gel chromatography
10- 1, it is a water white oil.
10-1Data: LRMS (ES) C
38H
46F
3N
3O
4The M+H of Si: calculated value 694.4. measured value: 694.3.
Step 2:(2S)-4-(2, the 5-difluorophenyl)-N-[(3R, 4S)-3-fluorine piperidin-4-yl]-the 2-methylol)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides (10-2):
To 405mg (0.58mmol)
10-1Add 1.38mL (14.6mmol) 1 in the solution in 4mL EtOH, 100mg 10% carbon carries palladium, and stir subsequently and spend the night.This reaction is through diatomite filtration, concentrates and resistates is dissolved in 3mL CH
2Cl
2To wherein adding the 3mL trifluoroacetic acid, continue to stir 1 hour, and subsequently this miscellany at EtOAc and saturated NaHCO
3The 5%Na of+25mL
2CO
3Distribute between the aqueous solution.Organic phase NaHCO
3H is used in washing again
2Na is used in O, salt water washing
2SO
4Dry and concentrated by rotary evaporation.Resistates is carried on the silicagel column and uses EtOAc-20: 1: 1EtOH/NH
4OH/H
2The O wash-out obtains
10-2, it is a white solid.-5% impurity subsequently by reverse-phase chromatography with 95: 5-5: 95H
2O/CH
3CN (both contain 0.1%TFA) removes.Cut NaHCO
3Alkalization obtains pure B-2, and it is a white solid.The data of 10-2:
1H NMR (500MHz, CDCl
3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.3 (s, 1H), 5.2 (bs, 1H), 4.9 (m, 1H), 4.8-4.6 (m, 2H), 4.45 (m, 1H), 4.2-4.1 (m, 1H), 4.0 (m, 1H), 3.3-3.2 (m, 2H), 3.1 (s, 3H), 2.85-2.7 (m, 2H), 2.1 (m, 1H), 1.7 (m, 2H) ppm.HRMS (ES) C
24H
26F
3N
3O
2M+H: calculated value 446.2050. measured value: 446.2059.
Route 11
(2S)-4-(2, the 5-difluorophenyl)-N-[(3R, 4S)-3-fluoro-1-sec.-propyl piperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2.5-dihydro-1H-pyrroles-1-carboxylic acid amides (11-1)
To 38mg (0.085mmol)
10-2At 1mL 1, add acetate, 25L (0.34mmol) acetone and 27mg (0.13mmol) Na (OAc) of 20ml (0.34mmol) in the solution in the 2-ethylene dichloride
3BH.After stirring was spent the night, this was reflected at EtOAc and saturated NaHCO
3Distribute between the aqueous solution, organic phase is used NaHCO once more
3, H
2Na is used in O, salt water washing
2SO
4Dry and concentrated by rotary evaporation.Resistates by reverse-phase chromatography with 95: 5-5: 95H
2O/CH
3CN (both contain 0.1%TFA) purifying.Cut NaHCO
3Alkalization obtains
11-1, it is colourless.
11-1Data:
1H NMR (500MHz, CDCl
3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.3 (s, 1H), 5.3 (m, 1H), 4.95-4.8 (m, 2H), 4.6 (m, 1H), 4.45 (m, 1H), 4.1-4.0 (m, 2H), 3.2 (m, 1H), 3.15 (s, 3H), 3.0 (m, 1H), 2.8 (m, 1H), 2.45-2.25 (m, 3H), 1.75 (m, 1H), 1.1-1.0 (m, 6H) ppm.HRMS (ES) C
27H
32F
3N
3O
2The M+H:488.2519. measured value: 488.2517.
Route 12
(2S)-4-(2, the 5-difluorophenyl)-N-[(3S, 4R)-3-fluorine piperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides (12-1)
This compound with
10-2Identical mode prepares, but except increasing
2-3Enantiomer outside.
12-1Data: HRMS (ES) C
24H
26F
3N
3O
2M+H: calculated value 446.2050. measured value: 446.2069.
(2S)-4-(2, the 5-difluorophenyl)-N-[(3R, 4R)-3-fluorine piperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides (12-2)
This compound with
10-2Identical mode prepares, but increases except in synthetic
2-2aThe trans isomer outside." trans-
2-3" the enantiomer hexane (containing 0.1% diethylamine) that utilizes Chiralpak AD_10 * 50cm post and contain 15%EtOH by chromatogram split with 150mL/min.Elutriant is used confirmation at 4 * 250mm Chiralpak AD_ post and the hexane (containing 0.1% diethylamine) that contains 15%EtOH with the analysis HPLC of 1mL/min, and the enantiomer of first wash-out had Rt=7.30 minute and second enantiomer had Rt=11.59 minute.The enantiomer of this first wash-out (having unknown absolute stereo chemistry) further obtains trans amine through handling, and it is increased to
12-2Synthetic in according to the same routes shown in the route 10.
12-2Data: HRMS (ES) C24H
2The M+H of 6F3N3O2: calculated value 446.2050. measured value: 446.2069.
The absolute stereo chemistry of the piperidines of compound 12-2 and 12-3 not after measured but shown in stereochemistry definite by using.
(2S)-4-(2, the 5-difluorophenyl)-N-[(3S, 4S)-3-fluorine piperidines 4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides (12-3)
This compound with
10-2Identical mode is made, and except increasing by the second wash-out isomer that separates " trans-2-3 " from chiral column.
12-3Data: HRMS (ES) C
24H
26F
3N
3O
2M+H: calculated value 446.2050. measured value: 446.2068.
Sequence table
<110>Merck&Co.，Inc.
Coleman，Paul J.
Cox，Christopher D.
Garbaccio，Robert M.
Hartman，George D.
＜120〉mitotic kinesins inhibitor
<130>21481Y
<150>60/495,637
<151>2003-08-15
<150>60/563,580
<151>2004-04-19
<160>2
＜170〉the FastSEQ form is the 4.0th edition
<210>1
<211>42
<212>DNA
＜213〉artificial sequence
<220>
＜223〉complete synthesis nucleotide sequence
<400>1
gcaacgatta atatggcgtc gcagccaaat tcgtctgcga ag 42
<210>2
<211>60
<212>DNA
＜213〉artificial sequence
<220>
＜223〉complete synthesis nucleotide sequence
<400>2
gcaacgctcg agtcagtgat gatggtggtg atgctgattc acttcaggct tattcaatat 60
Claims (40)
1. the compound of formula I:
Or its pharmaceutically acceptable salt or steric isomer, wherein:
A is 0 or 1;
B is 0 or 1;
M is 0,1 or 2;
N is 0,1,2 or 3;
R is 0 or 1;
S is 0 or 1;
T is 0,1 or 2;
U is 0 or 1;
R
1And R
2Be independently selected from: H, (C
1-C
6) alkyl, aryl, heterocyclic radical and (C
3-C
6) cycloalkyl, randomly be selected from R by 1,2 or 3
7Substituting group replace;
R
3Be selected from:
1) hydrogen;
2) C
1-C
10Alkyl;
3) C
1-C
10Alkyl-O-R
d,
4) C
2-C
10Alkenyl-O-R
d,
5) C
2-C
10Alkynyl group-O-R
d,
6) (C
1-C
6-alkylidene group)
nC
3-C
8Cycloalkyl-O-R
d,
7) C
1-C
10Alkyl-(C=O)
b-NR
cR
C ',
8) C
2-C
10Alkenyl-(C=O)
bNR
cR
C ',
9) C
2-C
10Alkynyl group-(C=O)
bNR
cR
C ',
10) (C
1-C
6-alkylidene group)
nC
3-C
8Cycloalkyl-(C=O)
bNR
cR
C ',
11) C
1-C
10Alkyl-S (O)
m-R
d,
12) C
2-C
10Alkenyl-S (O)
m-R
d,
13) C
2-C
10Alkynyl group-S (O)
m-R
d,
14) (C
1-C
6-alkylidene group)
nC
3-C
8Cycloalkyl-S (O)
m-R
d,
This alkyl, alkenyl, alkynyl group and cycloalkyl are randomly by one or more R that are selected from
6Substituting group replace;
R
4Be independently selected from:
1) (C=O)
aO
bC
1-C
10Alkyl,
2) (C=O)
aO
bAryl,
3)CO
2H，
4) halogen,
5)CN，
6)OH，
7) O
bC
1-C
6Perfluoroalkyl,
8)O
a(C＝O)
bNR
8R
9，
9)S(O)
mR
a，
10) S (O)
2NR
8R
9And
11)-OPO(OH)
2；
This alkyl, aryl, alkenyl, alkynyl group, heterocyclic radical and cycloalkyl randomly are selected from R by 1,2 and 3
7Substituting group replace;
R
5Be selected from:
1) hydrogen;
2) (C=O)
aO
bC
1-C
10Alkyl,
3) (C=O)
aO
bAryl,
4)CO
2H，
5) halogen,
6)CN，
7)OH，
8) O
bC
1-C
6Perfluoroalkyl,
9)O
a(C＝O)
bNR
8R
9，
10)S(O)
mR
a，
11) S (O)
2NR
8R
9And
12)-OPO(OH)
2；
This alkyl, aryl, alkenyl, alkynyl group, heterocyclic radical and cycloalkyl randomly are selected from R by 1,2 and 3
7Substituting group replace;
R
6Be independently selected from:
1) (C=O)
aO
bC
1-C
10Alkyl,
2) (C=O)
aO
bAryl,
3) C
2-C
10Alkenyl,
4) C
2-C
10Alkynyl group,
5) (C=O)
aO
bHeterocyclic radical,
6)CO
2H，
7) halogen,
8)CN，
9)OH，
10)
bC
1-C
6Perfluoroalkyl,
11)O
a(C＝O)
bNR
8R
9，
12)S(O)
mR
a，
13)S(O)
2NR
8R
9，
14) oxo,
15)CHO，
16)(N＝O)R
8R
9，
17) (C=O)
aO
bC
3-C
8Cycloalkyl and
18)-OPO(OH)
2；
This alkyl, aryl, alkenyl, alkynyl group, heterocyclic radical and cycloalkyl randomly are selected from R by 1,2 and 3
7Substituting group replace;
R
7Be selected from:
1) (C=O)
rO
s(C
1-C
10) alkyl,
2) O
r(C
1-C
3) perfluoroalkyl,
3) oxo,
4)OH，
5) halogen,
6)CN，
7) (C
2-C
10) alkenyl,
8) (C
2-C
10) alkynyl group,
9) (C=O)
rO
s(C
3-C
6) cycloalkyl,
10) (C=O)
rO
s(C
0-C
6) alkylidene group-aryl,
11) (C=O)
rO
s(C
0-C
6) the alkylidenyl-heterocyclic base,
12) (C=O)
rO
s(C
0-C
6) alkylidene group-N (R
b)
2,
13)C(O)R
a，
14) (C
0-C
6) alkylidene group-CO
2R
a,
15)C(O)H，
16) (C
0-C
6) alkylidene group-CO
2H and
17)(C＝O)
rN(R
b)
2，
18)S(O)
mR
a，
19) S (O)
2N (R
b)
2With
20)-OPO(OH)
2；
This alkyl, alkenyl, alkynyl group, cycloalkyl, aryl, alkylidene group and heterocyclic radical randomly by at the most 3 be selected from R
b, OH, (C
1-C
6) alkoxyl group, halogen, CO
2H, CN, O (C=O) C
1-C
6Alkyl, oxo, NO
2And N (R
b)
2Substituting group replace;
R
8And R
9Be independently selected from:
1)H，
2) (C=O) O
bC
1-C
10Alkyl,
3) (C=O) O
bC
3-C
8Cycloalkyl,
4) (C=O) O
bAryl,
5) (C=O) O
bHeterocyclic radical,
6) C
1-C
10Alkyl,
7) aryl,
8) C
2-C
10Alkenyl,
9) C
2-C
10Alkynyl group,
10) heterocyclic radical,
11) C
3-C
8Cycloalkyl,
12) SO
2R
aAnd
13)(C＝O)NR
b 2，
This alkyl, cycloalkyl, aryl, heterocyclic radical, alkenyl and alkynyl group randomly are selected from R by 1,2 and 3
7Substituting group replace, or
R
8And R
9Can constitute each ring of monocycle or bicyclic heterocycle while with the nitrogen that it connected and have 3-7 person and except that this nitrogen, randomly contain 1 or 2 additional heteroatoms that is selected from N, O or S, this monocycle or bicyclic heterocycle randomly are selected from R by 1,2 or 3
7Substituting group replace;
R
10And R
11Be independently selected from: F and-CH
2F;
R
12And R
13Be independently selected from: H and-CH
2F;
R
OxDo not exist or oxo;
R
aBe independently selected from: (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl, aryl or heterocyclic radical randomly are selected from R by 1,2 or 3
7Substituting group replace;
R
bBe independently selected from: H, (C
1-C
6) alkyl, aryl, heterocyclic radical, (C
3-C
6) cycloalkyl, (C=O) OC
1-C
6Alkyl, (C=O) C
1-C
6Alkyl, (C=O) aryl, (C=O) heterocyclic radical, (C=O) NR
eR
E 'Or S (O)
2R
a, randomly be selected from R by 1,2 or 3
7Substituting group replace;
R
cAnd R
C 'Be independently selected from: H, (C
1-C
6) alkyl, aryl, NH
2, OH, OR
a,-alkyl-OH ,-(C
1-C
6) alkyl-O-(C
1-C
6) alkyl, (C=O) OC
1-C
6Alkyl, (C=O) C
1-C
6Alkyl, (C=O) aryl, (C=O) heterocyclic radical, (C=O) NR
eR
E ', S (O)
2R
aWith-alkyl-N (R
b)
2, wherein this alkyl randomly is selected from R by 1,2 or 3
7Substituting group replace; Or
R
cAnd R
C 'Can constitute each ring of monocycle or bicyclic heterocycle while with the nitrogen that it connected and have 3-7 person and except that this nitrogen, randomly contain 1 or 2 additional heteroatoms that is selected from N, O or S, this monocycle or bicyclic heterocycle randomly are selected from R by 1,2 or 3
7Substituting group replace;
R
dBe selected from: H, (C
1-C
6) alkyl ,-(C
2-C
6) alkyl-OH ,-(C
1-C
6) alkyl-O-(C
1-C
6) alkyl and-(C
1-C
6) alkyl-N (R
b)
2, wherein this alkyl randomly is selected from R by 1,2 or 3
7Substituting group replace;
R
eAnd R
E 'Be independently selected from: H, (C
1-C
6) alkyl, aryl, heterocyclic radical and (C
3-C
6) cycloalkyl, randomly be selected from R by 1,2 or 3
7Substituting group replace; Or
R
eAnd R
E 'Can constitute each ring of monocycle or bicyclic heterocycle while with the nitrogen that it connected and have 3-7 person and except that this nitrogen, randomly contain 1 or 2 additional heteroatoms that is selected from N, O or S, this monocycle or bicyclic heterocycle randomly are selected from R by 1,2 and 3
7Substituting group replace.
2. the compound of the formula II of claim 1:
Or its pharmaceutically acceptable salt or steric isomer,
Wherein:
A is 0 or 1;
B is 0 or 1;
M is 0,1, or 2;
N is 0,1,2 or 3;
R is 0 or 1;
S is 0 or 1;
T is 0 or 1;
R
1And R
2Be independently selected from: H, (C
1-C
6) alkyl, aryl, heterocyclic radical and (C
3-C
6) cycloalkyl, randomly be selected from R by 1,2 or 3
7Substituting group replace;
R
3Be selected from:
1) hydrogen;
2) C
1-C
10Alkyl;
3) C
1-C
10Alkyl-O-R
d,
4) C
2-C
10Alkenyl-O-R
d,
5) C
2-C
10Alkynyl group-O-R
d,
6) (C
1-C
6-alkylidene group)
nC
3-C
8Cycloalkyl-O-R
d,
7) C
1-C
10Alkyl-(C=O)
b-NR
cR
C ',
8) C
2-C
10Alkenyl-(C=O)
bNRCR
C ',
9) C
2-C
10Alkynyl group-(C=O)
bNR
cR
C ',
10) (C
1-C
6-alkylidene group)
nC
3-C
8Cycloalkyl-(C=O)
bNR
cR
C ',
11) C
1-C
10Alkyl-S (O)
m-R
d,
12) C
2-C
10Alkenyl-S (O)
mR
d,
13) C
2-C
10Alkynyl group-S (O)
m-R
d,
14) (C
1-C
6-alkylidene group)
nC
3-C
8Cycloalkyl-S (O)
mR
d,
This alkyl, alkenyl, alkynyl group and cycloalkyl are randomly by one or more R that are selected from
6Substituting group replace;
R
4Be independently selected from:
1) (C=O)
aO
bC
1-C
10Alkyl,
2) (C=O)
aO
bAryl,
3)CO
2H，
4) halogen,
5)CN，
6)OH，
7) O
bC
1-C
6Perfluoroalkyl,
8)O
a(C＝O)
bNR
8R
9，
9)S(O)
mR
a，
10)S(O)
2NR
8R
9，
This alkyl, aryl, alkenyl, alkynyl group, heterocyclic radical and cycloalkyl randomly are selected from R by 1,2 and 3
7Substituting group replace;
R
5Be selected from:
1) hydrogen;
2) (C=O)
aO
bC
1-C
10Alkyl,
3) (C=O)
aO
bAryl,
4)CO
2H，
5) halogen,
6)CN，
7)OH，
O
bC
1-C
6Perfluoroalkyl,
9)O
a(C＝O)
bNR
8R
9，
10)S(O)
mR
a，
11) S (O)
2NR
8R
9And
12)-OPO(OH)
2；
This alkyl, aryl, alkenyl, alkynyl group, heterocyclic radical and cycloalkyl randomly are selected from R by 1,2 and 3
7Substituting group replace;
R
6Be independently selected from:
1) (C=O)
aO
bC
1-C
10Alkyl,
2) (C=O)
aO
bAryl,
3) C
2-C
10Alkenyl,
4) C
2-C
10Alkynyl group,
5) (C=O)
aO
bHeterocyclic radical,
6)CO
2H，
7) halogen,
8)CN，
9)OH，
10) O
bC
1-C
6Perfluoroalkyl,
11)O
a(C＝O)
bNR
8R
9，
12)S(O)
mR
a，
13)S(O)
2NR
8R
9，
14) oxo,
15)CHO，
16)(N＝O)R
8R
9，
17) (C=O)
aO
bC
3-C
8Cycloalkyl and
18)-OPO(OH)
2；
This alkyl, aryl, alkenyl, alkynyl group, heterocyclic radical and cycloalkyl randomly are selected from R by 1,2 or 3
7Substituting group replace;
R
7Be selected from:
1) (C=O)
rO
s(C
1-C
10) alkyl,
2) O
r(C
1-C
3) perfluoroalkyl,
3) oxo,
4)OH，
5) halogen,
6)CN，
7) (C
2-C
10) alkenyl,
8) (C
2-C
10) alkynyl group,
9) (C=O)
rO
s(C
3-C
6) cycloalkyl,
10) (C=O)
rO
s(C
0-C
6) alkylidene group-aryl,
11) (C=O)
rO
s(C
0-C
6) the alkylidenyl-heterocyclic base,
12) (C=O)
rO
s(C
0-C
6) alkylidene group-N (R
b)
2,
13)C(O)R
a，
14) (C
0-C
6) alkylidene group-CO
2R
a,
15)C(O)H，
16) (C
0-C
6) alkylidene group-CO
2H,
17)C(O)N(R
b)
2，
18)S(O)
mR
a，
19) S (O)
2N (R
b)
2With
20)-OPO(OH)
2；
This alkyl, alkenyl, alkynyl group, cycloalkyl, aryl, alkylidene group and heterocyclic radical randomly by at the most 3 be selected from R
b, OH, (C
1-C
6) alkoxyl group, halogen, CO
2H, CN, O (C=O) C
1-C
6Alkyl, oxo, NO
2And N (R
b)
2Substituting group replace;
R
8And R
9Be independently selected from:
1)H，
2) (C=O) O
bC
1-C
10Alkyl,
3) (C=O) O
bC
3-C
8Cycloalkyl,
4) (C=O) O
bAryl,
5) (C=O) O
bHeterocyclic radical,
6) C
1-C
10Alkyl,
7) aryl,
8) C
2-C
10Alkenyl,
9) C2-C10 alkynyl group,
10) heterocyclic radical,
11) C
3-C
8Cycloalkyl,
12) SO
2R
aAnd
13)(C＝O)NR
b2，
This alkyl, cycloalkyl, aryl, heterocyclic radical, alkenyl and alkynyl group randomly are selected from R by 1,2 or 3
7Substituting group replace, or
R
8And R
9Can constitute each ring of monocycle or bicyclic heterocycle while with the nitrogen that it connected and have 3-7 person and except that this nitrogen, randomly contain 1 or 2 additional heteroatoms that is selected from N, O or S, this monocycle or bicyclic heterocycle randomly are selected from R by 1,2 or 3
7Substituting group replace;
R
10Be selected from: F and-CH
2F;
R
13Be selected from: H and-CH
2F,
Condition is if t is 1, then R
13Be H;
R
OxDo not exist or oxo;
R
aBe independently selected from: (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl, aryl or heterocyclic radical randomly are selected from R by 1,2 or 3
7Substituting group replace;
R
bBe independently selected from: H, (C
1-C
6) alkyl, aryl, heterocyclic radical, (C
3-C
6) cycloalkyl, (C=O) OC
1-C
6Alkyl, (C=O) C
1-C
6Alkyl, (C=O) aryl, (C=O) heterocyclic radical, (C=O) NR
eR
E 'Or S (O)
2R
a, randomly be selected from R by 1,2 or 3
7Substituting group replace;
R
cAnd R
C 'Be independently selected from: H, (C
1-C
6) alkyl, aryl, NH
2, OH, OR
a.-(C
1-C
6) alkyl-OH ,-(C
1-C
6) alkyl-O-(C
1-C
6) alkyl, (C=O) OC
1-C
6Alkyl, (C=O) C
1-C
6Alkyl, (C=O) aryl, (C=O) heterocyclic radical, (C=O) NR
eR
E ', S (O)
2R
aWith-(C
1-C
6) alkyl-N (R
b)
2, wherein this alkyl randomly is selected from R by 1,2 or 3
7Substituting group replace; Or
R
cAnd R
C 'Can constitute monocycle or bicyclic heterocycle with the nitrogen that it connected and have 3-7 person and except that this nitrogen, randomly contain 1 or 2 additional heteroatoms that is selected from N, O or S in each ring simultaneously, this monocycle or bicyclic heterocycle randomly are selected from R by 1,2 and 3
7Substituting group replace;
R
dBe selected from: H, (C
1-C
6) alkyl ,-(C
2-C
6) alkyl-OH ,-(C
1-C
6) alkyl-O-(C
1-C
6) alkyl and-(C
1-C
6) alkyl-N (R
b)
2, wherein this alkyl randomly is selected from R by 1,2 or 3
7Substituting group replace;
R
eAnd R
E 'Be independently selected from: H, (C
1-C
6) alkyl, aryl, heterocyclic radical and (C
3-C
6) cycloalkyl, randomly be selected from R by 1,2 and 3
7Substituting group replace; Or
R
eAnd R
E 'Can constitute each ring of monocycle or bicyclic heterocycle while with the nitrogen that it connected and have 3-7 person and except that this nitrogen, randomly contain 1 or 2 additional heteroatoms that is selected from N, O or S, this monocycle or bicyclic heterocycle randomly are selected from R by 1,2 and 3
7Substituting group replace.
3. the compound of the formula III of claim 2:
Or its pharmaceutically acceptable salt or steric isomer, wherein:
A is 0 or 1;
B is 0 or 1;
M is 0,1 or 2;
N is 0,1 or 2;
R is 0 or 1;
S is 0 or 1;
R
1And R
2Be independently selected from: H, (C
1-C
6) alkyl, aryl and (C
3-C
6) cycloalkyl, randomly be selected from R by 1,2 or 3
7Substituting group replace;
R
4Be independently selected from:
1) halogen,
2)OH，
3) O
bC
1-C
6Perfluoroalkyl,
R
5Be selected from:
1) hydrogen,
2) halogen,
3)OH，
4) O
bC
1-C
6Perfluoroalkyl,
R
7Be selected from:
1) (C=O)
rO
s(C
1-C
10) alkyl,
2) O
r(C
1-C
3) perfluoroalkyl,
3) oxo,
4)OH，
5) halogen,
6)CN，
7) (C
2-C
10) alkenyl,
8) (C
2-C
10) alkynyl group,
9) (C=O)
rO
s(C
3-C
6) cycloalkyl,
10) (C=O)
rO
s(C
0-C
6) alkylidene group-aryl,
11) (C=O)
rO
s(C
0-C
6) the alkylidenyl-heterocyclic base,
12) (C=O)
rO
s(C
0-C
6) alkylidene group-N (R
b)
2,
13)C(O)R
a，
14) (C
0-C
6) alkylidene group-CO
2R
a,
15)C(O)H，
16) (C
0-C
6) alkylidene group-CO
2H and
17)C(O)N(R
b)
2，
18) S (O)
mR
aAnd
19)S(O)
2N(R
b)
2；
This alkyl, alkenyl, alkynyl group, cycloalkyl, aryl, alkylidene group and heterocyclic radical randomly by at the most 3 be selected from R
b, OH, (C
1-C
6) alkoxyl group, halogen, CO
2H, CN, O (C=O) C
1-C
6Alkyl, oxo, NO
2And N (R
b)
2Substituting group replace;
R
8And R
9Be independently selected from:
1)H，
2) (C=O) O
bC
1-C
10Alkyl,
3) (C=O) O
bC
3-C
8Cycloalkyl,
4) (C=O) O
bAryl,
5) (C=O) O
bHeterocyclic radical,
6) C
1-C
10Alkyl,
7) aryl,
8) C
2-C
10Alkenyl,
9) C
2-C
10Alkynyl group,
10) heterocyclic radical,
11) C
3-C
8Cycloalkyl,
12) SO
2R
aAnd
13)(C＝O)NR
b2，
This alkyl, cycloalkyl, aryl, heterocyclic radical, alkenyl and alkynyl group randomly are selected from R by 1,2 and 3
7Substituting group replace, or
R
8And R
9Can constitute each ring of monocycle or bicyclic heterocycle while with the nitrogen that it connected and have 3-7 person and except that this nitrogen, randomly contain 1 or 2 additional heteroatoms that is selected from N, O or S, this monocycle or bicyclic heterocycle randomly are selected from R by 1,2 and 3
7Substituting group replace;
R
aBe independently selected from: (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl, aryl or heterocyclic radical randomly are selected from R by 1,2 or 3
7Substituting group replace;
R
bBe independently selected from: H, (C
1-C
6) alkyl, aryl, heterocyclic radical, (C
3-C
6) cycloalkyl, (C=O) OC
1-C
6Alkyl, (C=O) C
1-C
6Alkyl, (C=O) aryl, (C=O) heterocyclic radical, (C=O) NR
eR
E 'Or S (O)
2R
a, randomly be selected from R by 1,2 or 3
7Substituting group replace;
R
cAnd R
C 'Be independently selected from: H, (C
1-C
6) alkyl, aryl, NH
2, OH, OR
a,-alkyl-OH ,-(C
1-C
6) alkyl-O-(C
1-C
6) alkyl, (C=O) OC
1-C
6Alkyl, (C=O) C
1-C
6Alkyl, (C=O) aryl, (C=O) heterocyclic radical, (C=O) NR
eR
E ', S (O)
2R
aWith-(C
1-C
6) alkyl-N (R
b)
2, wherein this alkyl randomly is selected from R by 1,2 or 3
7Substituting group replace; Or
R
cAnd R
C 'Can constitute each ring of monocycle or bicyclic heterocycle while with the nitrogen that it connected and have 3-7 person and except that this nitrogen, randomly contain 1 or 2 additional heteroatoms that is selected from N, O or S, this monocycle or bicyclic heterocycle randomly are selected from R by 1,2 or 3
7Substituting group replace;
R
eAnd R
E 'Be independently selected from: H, (C
1-C
6) alkyl, aryl, heterocyclic radical and (C
3-C
6) cycloalkyl, randomly be selected from R by 1,2 or 3
7Substituting group replace; Or
R
eAnd R
E 'Can constitute each ring of monocycle or bicyclic heterocycle while with the nitrogen that it connected and have 3-7 person and except that this nitrogen, randomly contain 1 or 2 additional heteroatoms that is selected from N, O or S, this monocycle or bicyclic heterocycle randomly are selected from R by 1,2 and 3
7Substituting group replace.
4. the compound of the formula IV of claim 3:
Or its pharmaceutically acceptable salt or steric isomer, wherein:
A is 0 or 1;
B is 0 or 1;
M is 0,1 or 2;
R is 0 or 1;
S is 0 or 1;
R
1And R
2Be independently selected from: H and (C
1-C
6) alkyl, randomly be selected from R by 1,2 or 3
7Substituting group replace;
R
4Be independently selected from:
1) halogen,
2)OH，
3) O
bC
1-C
6Perfluoroalkyl,
R
7Be selected from:
1) (C=O)
rO
s(C
1-C
10) alkyl,
2) O
r(C
1-C
3) perfluoroalkyl,
3) oxo,
4)OH，
5) halogen,
6)CN，
7) (C
2-C
10) alkenyl,
8) (C
2-C
10) alkynyl group,
9) (C=O)
rO
s(C
3-C
6) cycloalkyl,
10) (C=O)
rO
s(C
0-C
6) alkylidene group-aryl,
11) (C=O)
rO
s(C
0-C
6) the alkylidenyl-heterocyclic base,
12) (C=O)
rO
s(C
0-C
6) alkylidene group-N (R
b)
2,
13)C(O)R
a，
14) (C
0-C
6) alkylidene group-CO
2R
a,
15)C(O)H，
16) (C
0-C
6) alkylidene group-CO
2H and
17)C(O)N(R
b)
2，
18) S (O)
mR
aAnd
19)S(O)
2N(R
b)
2；
This alkyl, alkenyl, alkynyl group, cycloalkyl, aryl, alkylidene group and heterocyclic radical randomly by at the most 3 be selected from R
b, OH, (C
1-C
6) alkoxyl group, halogen, CO
2H, CN, O (C=O) C
1-C
6Alkyl, oxo, NO
2And N (R
b)
2Substituting group replace;
R
8And R
9Be independently selected from:
1)H，
2) (C=O) O
bC
1-C
10Alkyl,
3) (C=O) O
bC
3-C
8Cycloalkyl,
4) (C=O) O
bAryl,
5) (C=O) O
bHeterocyclic radical,
6) C
1-C
10Alkyl,
7) aryl,
8) C
2-C
10Alkenyl,
9) C
2-C
10Alkynyl group,
10) heterocyclic radical,
11) C
3-C
8Cycloalkyl,
12) SO
2R
aAnd
13)(C＝O)NR
b2，
This alkyl, cycloalkyl, aryl, heterocyclic radical, alkenyl and alkynyl group randomly are selected from R by 1,2 or 3
7Substituting group replace, or
R
8And R
9Can constitute each ring of monocycle or bicyclic heterocycle while with the nitrogen that it connected and have 3-7 person and except that this nitrogen, randomly contain 1 or 2 additional heteroatoms that is selected from N, O or S, this monocycle or bicyclic heterocycle randomly are selected from R by 1,2 and 3
7Substituting group replace;
R
aBe independently selected from: (C
1-C
6) alkyl, (C
3-C
6) cycloalkyl, aryl or heterocyclic radical randomly are selected from R by 1,2 or 3
7Substituting group replace;
R
bBe independently selected from: H, (C
1-C
6) alkyl, aryl, heterocyclic radical, (C
3-C
6) cycloalkyl, (C=O) OC
1-C
6Alkyl, (C=O) C
1-C
6Alkyl, (C=O) aryl, (C=O) heterocyclic radical, (C=O) NR
eR
E 'Or S (O)
2R
a, randomly be selected from R by 1,2 or 3
7Substituting group replace;
R
cAnd R
C 'Be independently selected from: H, (C
1-C
6) alkyl, aryl, NH
2, OH, OR
a,-(C
1-C
6) alkyl-OH ,-(C
1-C
6) alkyl-O-(C
1-C
6) alkyl, (C=O) OC
1-C
6Alkyl, (C=O) C
1-C
6Alkyl, (C=O) aryl, (C=O) heterocyclic radical, (C=O) NR
eR
E ', S (O)
2R
aWith-(C
1-C
6) alkyl-N (R
b)
2, wherein this alkyl randomly is selected from R by 1,2 or 3
7Substituting group replace; Or
R
cAnd R
C 'Can constitute each ring of monocycle or bicyclic heterocycle while with the nitrogen that it connected and have 3-7 person and except that this nitrogen, randomly contain 1 or 2 additional heteroatoms that is selected from N, O or S, this monocycle or bicyclic heterocycle randomly are selected from R by 1,2 or 3
7Substituting group replace;
R
eAnd R
E 'Be independently selected from: H, (C
1-C
6) alkyl, aryl, heterocyclic radical and (C
3-C
6) cycloalkyl, randomly be selected from R by 1,2 or 3
7Substituting group replace; Or
R
eAnd R
E 'Can constitute each ring of monocycle or bicyclic heterocycle while with the nitrogen that it connected and have 3-7 person and except that this nitrogen, randomly contain 1 or 2 additional heteroatoms that is selected from N, O or S, this monocycle or bicyclic heterocycle randomly are selected from R by 1,2 and 3
7Substituting group replace.
5. the compound of the formula V of claim 4:
Or its pharmaceutically acceptable salt or steric isomer,
Wherein:
R
1And R
2Be independently selected from: H and (C
1-C
6) alkyl.
6. the compound of the formula VI of claim 2:
Or its pharmaceutically acceptable salt or steric isomer,
Wherein:
R
1And R
2Be independently selected from: H and (C
1-C
6) alkyl.
7. compound:
(2S)-4-(2, the 5-difluorophenyl)-N-[(3S, 4R)-3-fluoro-1-methyl piperidine-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
(2S)-4-(2, the 5-difluorophenyl)-N-[(3R, 4S)-3-fluoro-1-methyl piperidine-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
(2S)-4-(2, the 5-difluorophenyl)-N-[(3R, 4R)-3-fluoro-1-methyl piperidine-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
(2S)-4-(2, the 5-difluorophenyl)-N-[(3S, 4S)-3-fluoro-1-methyl piperidine-4-yl]-2-(hydroxymethyl)-N-methyl-2 phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
(2S)-4-(2, the 5-difluorophenyl)-N-[(3S, 4R)-3-fluoro-1-methyl piperidine-4-yl]-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
(2S)-4-(2, the 5-difluorophenyl)-N-[(3R, 4S)-3-fluoro-1-methyl piperidine-4-yl]-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
(2S)-4-(2, the 5-difluorophenyl)-N-[(3R, 4R)-3-fluoro-1-methyl piperidine-4-yl]-N-methyl-2-phenyl-2,5 dihydros-1H-pyrroles-1-carboxylic acid amides
(2S)-4-(2, the 5-difluorophenyl)-N-[(2R, 4R)-2-(methyl fluoride)-1-methyl piperidine-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
(2S)-4-(2, the 5-difluorophenyl)-N-[(2S, 4S)-2-(methyl fluoride)-1-methyl piperidine-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
(2S)-4-(2, the 5-difluorophenyl)-N-[(3S, 4R)-3-fluoro-1-methyl isophthalic acid-oxo bridge piperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
(2S)-4-(2, the 5-difluorophenyl)-N-[(3S, 4R)-3-fluorine piperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
(2S)-4-(2, the 5-difluorophenyl)-N-[(3S, 4R)-3-fluoro-1-sec.-propyl piperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
(2S)-4-(2, the 5-difluorophenyl)-N-[(3S, 4S)-3-fluorine piperidin-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
Or its pharmaceutically acceptable salt.
8. compound, it is:
(2S)-4-(2, the 5-difluorophenyl)-N-[(3S, 4S)-3-fluoro-1-methyl piperidine-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
Or its pharmaceutically acceptable salt.
9. compound, it is:
(2S)-4-(2, the 5-difluorophenyl)-N-[(3S, 4R)-3-fluoro-1-methyl piperidine-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
Or its pharmaceutically acceptable salt.
10. compound, it is:
(2S)-4-(2, the 5-difluorophenyl)-N-[(3R, 4S)-3-fluoro-1-methyl piperidine-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
Or its pharmaceutically acceptable salt.
11. a compound, it is:
(2S)-4-(2, the 5-difluorophenyl)-N-[(2R, 4R)-2-(methyl fluoride)-1-methyl piperidine-4-yl]-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
Or its pharmaceutically acceptable salt.
12. a compound, it is:
(2S)-4-(2, the 5-difluorophenyl)-N-[(3R, 4S)-3-fluoro-1-methyl piperidine-4-yl]-N-methyl-2-phenyl-2,5-dihydro-1H-pyrroles-1-carboxylic acid amides
Or its pharmaceutically acceptable salt.
13. the compound of claim 1 is selected from:
Or its pharmaceutically acceptable salt or steric isomer.
14. a pharmaceutical composition, it contains the compound and the pharmaceutical acceptable carrier of claim 1.
15. the treatment or the method for preventing cancer in the Mammals of this treatment of needs, this method comprise the compound to the claim 1 of this administration treatment significant quantity.
A kind of method for the treatment of cancer or preventing cancer of 16 claims 15, wherein this cancer is selected from brain, genitourinary tract, lymphsystem, stomach, larynx and lung.
17. a kind of treatment of claim 15 or the method for preventing cancer, wherein this cancer is selected from histocytic lymphoma, adenocarcinoma of lung, small cell lung cancer, gioblastomas and mammary cancer.
18. method for preparing the pharmaceutical composition of the compound that contains claim 1 and pharmaceutical acceptable carrier.
19. further containing, the composition of claim 14 is selected from the second following compound:
1) estrogenic agents,
2) androgen receptor modifier,
3) retinoic acid receptor (RAR) conditioning agent,
4) cytotoxicity/cell suppresses base,
5) antiproliferative,
6) isopentene group protein transferase inhibitor,
7) HMG-CoA reductase inhibitor,
8) hiv protease inhibitor,
9) reverse transcriptase inhibitors,
10) angiogenesis inhibitor and
11) PPAR-gamma agonist,
12) PPAR-delta agonists;
13) inhibitor of cell proliferation and survival signal,
14) the cell cycle chechpoint agent interfering and
15) cell death inducer.
20. the composition of claim 20; wherein this second compound is that angiogenesis inhibitor is selected from: tyrosine kinase inhibitor; the inhibitor of epidermis derivative growth factor; the inhibitor of inoblast derivative growth factor, the inhibitor of thrombocyte salt solution somatomedin, MMP inhibitor; the integrin blocker; interferon-' alpha ', il-1 2, xylan polysulfate; cyclooxygenase inhibitors; the carboxamide groups triazole, combretastatin A-4, squalamine; 6-O-chloracetyl-carbonyl)-aspergillus fumigatus cedrol (fumagillol); Thalidomide, angiostatin, the antibody of troponin-1 or VEGF.
21. the composition of claim 14 further contains the proteoplast inhibitor.
22. the further aurora type kinase of the composition of claim 14 inhibitor.
23. the composition of claim 14 further contains R
aThe f kinase inhibitor.
24. the composition of claim 14 further contains the serine/threonine kinase inhibitor.
25. the composition of claim 14 further contains the inhibitor of the another kind of mitotic kinesins that is not KSP.
26. the composition of claim 20, wherein this second compound is the estrogenic agents that is selected from tamoxifen and raloxifene.
27. a treatment method for cancer, this method comprises the compound and the radiotherapy of the claim 1 of co-administered treatment significant quantity.
28. the treatment or the method for preventing cancer, this method comprise co-administered treatment significant quantity claim 1 compound and be selected from following compound:
1) estrogenic agents,
2) androgen receptor modifier,
3) retinoic acid receptor (RAR) conditioning agent,
4) cytotoxicity/cytostatics,
5) antiproliferative,
6) isopentene group protein transferase inhibitor,
7) HMG-CoA reductase inhibitor,
8) HTV proteinase inhibitor,
9) reverse transcriptase inhibitors,
10) angiogenesis inhibitor,
11) PPAR-gamma agonist,
12) PPAR-delta agonists,
13) inhibitor of intrinsic multidrug resistance,
14) antiemetic,
15) treatment for anemia agent,
16) neutrophilic granulocyte reduces Remedies,
17) immunostimulant,
18) inhibitor of cell proliferation and survival signal,
19) the cell cycle chechpoint agent interfering and
20) cell death inducer.
29. a treatment method for cancer, this method comprises the compound and the radiotherapy of the claim 1 for the treatment of significant quantity and is selected from following compound co-administered:
1) estrogenic agents,
2) androgen receptor modifier,
3) retinoic acid receptor (RAR) conditioning agent,
4) cytotoxicity/cytostatics,
5) antiproliferative,
6) isopentene group protein transferase inhibitor,
7) HMG-CoA reductase inhibitor,
8) hiv protease inhibitor,
9) reverse transcriptase inhibitors,
10) angiogenesis inhibitor,
11) PPAR-gamma agonist,
12) PPAR-delta agonists,
13) inhibitor of intrinsic multidrug resistance,
14) antiemetic,
15) treatment for anemia agent,
16) neutrophilic granulocyte reduces Remedies,
17) immunostimulant,
18) inhibitor of cell proliferation and survival signal,
19) the cell cycle chechpoint agent interfering and
20) cell death inducer.
30. the treatment or the method for preventing cancer, this method comprises compound and the taxol or the Si Tumanbu of the claim 1 of administering therapeutic significant quantity.
31. the treatment or the method for preventing cancer, this method comprises the compound and the GPIIb/IIIa antagonist of the claim 1 of administering therapeutic significant quantity.
32. the method for claim 31, wherein this GPIIb/IIIa antagonist is a Tirofiban.
33. the treatment or the method for preventing cancer, this method comprises the compound and the cox 2 inhibitor of the claim 1 of co-administered treatment significant quantity.
34. the treatment or the method for preventing cancer, this method comprises the compound and the proteoplast inhibitor of the claim 1 of co-administered treatment significant quantity.
35. the treatment or the method for preventing cancer, this method comprises the compound and the inhibition of aurora type kinase of the claim 1 of co-administered treatment significant quantity.
36. the treatment or the method for preventing cancer, this method comprises the compound and the R of the claim 1 of co-administered treatment significant quantity
aThe f kinase inhibitor.
37. the treatment or the method for preventing cancer, this method comprises the compound and the serine/threonine kinase inhibitor of the claim 1 of co-administered treatment significant quantity.
38. the treatment or the method for preventing cancer, this method comprise the inhibitor of the mitotic kinesins of the compound of claim 1 of co-administered treatment significant quantity and non-KSP.
39. regulate the method that mitotic spindle forms for one kind, this method comprises the compound of the claim 1 of administering therapeutic significant quantity.
40. a method that suppresses mitotic kinesins KSP, this method comprises the compound of the claim 1 of administering therapeutic significant quantity.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US49563703P | 2003-08-15 | 2003-08-15 | |
| US60/495,637 | 2003-08-15 | ||
| US60/563,580 | 2004-04-19 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1839128A true CN1839128A (en) | 2006-09-27 |
| CN100549006C CN100549006C (en) | 2009-10-14 |
Family
ID=37016149
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004800233097A Expired - Fee Related CN100549006C (en) | 2003-08-15 | 2004-08-11 | The mitotic kinesins inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100549006C (en) |
-
2004
- 2004-08-11 CN CNB2004800233097A patent/CN100549006C/en not_active Expired - Fee Related
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| Publication number | Publication date |
|---|---|
| CN100549006C (en) | 2009-10-14 |
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