CN1195340A - Inhibitors of farnesyl-protein transferase - Google Patents

Inhibitors of farnesyl-protein transferase Download PDF

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CN1195340A
CN1195340A CN96194206A CN96194206A CN1195340A CN 1195340 A CN1195340 A CN 1195340A CN 96194206 A CN96194206 A CN 96194206A CN 96194206 A CN96194206 A CN 96194206A CN 1195340 A CN1195340 A CN 1195340A
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aryl
replace
alkyl
heterocycle
piperazine
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N·J·安东尼
T·M·奇卡罗内
R·P·戈麦斯
J·H·哈钦森
T·M·威廉斯
C·J·丁斯莫尔
G·E·斯托克
G·D·哈特曼
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Merck and Co Inc
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Priority claimed from US08/600,728 external-priority patent/US5856326A/en
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Abstract

The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.

Description

Farnesyl protein transferase inhibitor
Related application
Present patent application is the part continuation application of the unexamined application serial 08/470,690 of submission on June 6 nineteen ninety-five, and the latter is again the part continuation application of the unexamined application serial 08/412,829 of submission on March 29 nineteen ninety-five.
Background of invention
Ras albumen (Ha-Ras, Ki4a-Ras, Ki4b-Ras and N-Ras) is the integral part of the signal pipeline of contact cell surface growth factor receptors and the nuclear signal that starts cell proliferation.The biological study and the biochemical research of Ras effect show that the Ras role is regulated albumen as G.Under its inactivated state, Ras combines with GDP.When growth factor receptors activates, lure that Ras is exchanged into GTP with GDP into, and conformational change takes place.The GTP combining form of Ras can be propagated the growth-stimulating signal, stopped by the intrinsic GTP enzymic activity of Ras until this signal, the latter makes this albumen get back to the GDP combining form of its inactivation (D.R.Lowy and D.M, Willumsen, Ann.Rev.Biochem.62:851-891 (1993)).In a lot of human body cancers, comprise in colorectal carcinoma, exocrine pancreas cancer and the myeloid leukemia, all found the Ras gene (Ha-ras, Ki4a-ras, Ki4b-ras and N-ras) of sudden change.The protein product of these genes has lost its GTP enzymic activity, and propagates a kind of growth-stimulating signal in itself.
Ras must navigate to just has normal function and oncogenic function on the plasma membrane.Translate modification after Ras film location relates at least 3 kinds, and 3 kinds of modifications all occur in the C-terminal of Ras.This RasC end comprises a kind of precedence diagram, is referred to as " CAAX " or " Cys-Aaa 1-Aaa 2-Xaa " case (Cys is a halfcystine, and Aaa is a kind of aliphatic amino acid, and Xaa is any amino acid) (Willumsen et al., Nature 310:583-586 (1984)).Different because of concrete order, this figure can be used as the signal sequence of farnesyl-protein transferase or geranyl-enzymes such as geranyl protein transferase, the cysteine residues of these enzyme catalysiss CAAX figure respectively with C 15Or C 20Isoprenoid generation alkylation.(S.Clarke.，Ann.Rev.Biochem.61：355-386(1992)；W.R.Schafer?and?J.Rine，Ann.Rev.Genetics?30：209-237(1992))。Ras albumen is one of known some kinds of albumen that translation farnesylation in back can take place.Other farnesylation albumen comprises the gtp binding protein relevant with Ras, for example γ-the subunit of Rho, fungi conjugative element, stratum nucleare (nuclear lamins) and transducin (transducin).People such as James (J.Biol.Chem.269,14182 (1994)) have confirmed that a kind of Pxf of the peroxysome that associated also is a farnesylation.People such as James have also proposed, except that above listed those, also have the farnesylation albumen with unknown structure and function.
The inhibition of farnesylation protein transferase, demonstrated can block the Ras transformant in soft agar growth and change the others that it transforms phenotype.Also confirm, some inhibitor of farnesyl-protein transferase can optionally be blocked the interior processing of cell (N.E.Kohlet al., Science, the 260:1934-1937 (1993) and the G.L.James et al. of Ras oncoprotein, Science, 260:1937-1942 (1993)).Recently, show, a kind of inhibitor of farnesyl-protein transferase has been blocked ras dependent form growth of tumor (N.E.Kohl et al. in the nude mice, Proc.Natl.Acad.Sci U.S.A., 91:9141-9145 (1994)) and brought out (the N.E.Kohl et al. that disappears of mammary cancer and salivary-gland carcinoma in the ras sudden change mouse, Nature Medicine, 1:792-797 (1995)).
Lovastatin (Merck ﹠amp has been used in the indirect inhibition of farnesyl-protein transferase in the live body; Co., Rahway, NJ) and compactin (Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science 245:379 (1989)) confirmed.These medicines suppress the HMG-CoA reductase enzyme, comprise that promptly the cluster isoprene of farnesyl pyrophosphate produces the speed limit enzyme.Farnesyl-protein transferase utilizes farnesyl pyrophosphate to make the Cys sulfydryl of Ras CAAX case and farnesyl group that covalent modified (Reiss et al., Cell, 62:81-88 (1990) take place; Schaber et al., J.Biol.Chem., 265:14701-14704 (1990); Schafer et al., Science, 249:1133-1139 (1990); Manne et al., Proc.Natl.Acad, Sci USA, 87:7541-7545 (1990)).To the biosynthetic inhibition of farnesyl pyrophosphate, blocked the Ras film location in the culturing cell by suppressing the HMG-CoA reductase enzyme.Yet the direct inhibition of farnesyl-protein transferase can be more single-minded, and its side effect few side effects that can take place than the biosynthetic general inhibitor required dosage of isoprene.
The inhibitor of farnesyl-protein transferase (FPT enzyme) has been described to two big classes.The first kind is the analogue of farnesyl diphosphate (FPP), and the second class inhibitor is relevant with the protein Substrate (as Ras) of this enzyme.The peptide that existing people the describes inhibitor of deriving generally is to contain halfcystine, scheme relevant molecule with CAAX as protein prenyl signal.(Schaber?et?al.，ibid；Reiss?et.al.，ibid；Reiss?et?al.，PNAS，88：732-736(1991))。Such inhibitor can arrestin matter prenylization, serves as the substitution effect thing of farnesyl-protein transferase this kind of enzyme simultaneously, also can be that (U.S.Patent 5,141,851, University of Texas for the inhibitor of pure competition; N.E.Kohl et al., Science, 260:1934-1937 (1993); Graham, et al., J.Med.Chem., 37,725 (1994)).In general, the deletion of sulfydryl has been proved the inhibition drug effect that can reduce this compound significantly on the CAAX derivative.Yet sulfydryl has limited the treatment of FPT enzyme inhibitors potentially and has used, and this is relevant with pharmacokinetics, pharmacodynamics and toxicity.Therefore, the functional displacement of sulfydryl is desirable.
Recently existing people reports that farnesyl protein transferase inhibitor is the inhibitor of vascular smooth muscle cell proliferation, therefore, can be used for prevention and treatment arteriosclerosis and diabetic vascular disorder (JPH7-112930).
Recently existing people is open, and some randomly contains the inhibitor that the pulsating tricyclic compound of piperidines is the FPT enzyme (WO 95/10514, WO 95/10515 and WO 95/10516).What also existing people disclosed the farnesyl protein enzyme contains imidazoles inhibitor (WO 95/09001 and EP0 675 112A1).
Therefore, thus an object of the present invention is to develop the imitative peptide compounds that does not have the sulfydryl segment and can suppress the back translation farnesylation of farnesyl-protein transferase arrestin matter.A further purpose of the present invention is that exploitation contains the chemotherapy group compound of The compounds of this invention and the production method of The compounds of this invention.
Brief summary of the invention
The present invention comprises the imitative peptide that can suppress farnesyl-protein transferase and contains diethylenediamine compound.The compounds of this invention does not have the sulfydryl segment, thereby provide following unique advantage: improved pharmacokinetics behavior in animal body, prevent for example fast automatic oxidation of sulfydryl dependent form chemical reaction and generate disulphide and reduction general toxicity with interior living mercaptan.What further comprise among the present invention is chemotherapy group compound and the production method thereof that contains these farnesyl tranfering enzyme inhibitors.
Compound of the present invention can be that example illustrates with general formula A, B and C:
Figure A9619420600781
Detailed description of the invention
Compound of the present invention can be used for suppressing farnesyl-protein transferase and makes oncogene protein Ras farnesylation.In first specific embodiments of the present invention, the inhibitor of farnesyl-protein transferase can illustrate with following formula A or its pharmaceutically acceptable salt:
In the formula:
R 1aAnd R 1bBe independently selected from:
A) hydrogen,
B) aryl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2N-C (O)-, CN, NO 2, (R 10) 2N-C (NR 10)-, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-,
C) C that does not replace or replace 1-C 6Alkyl, wherein the C of replacement 1-C 6Substituting group on the alkyl is selected from aryl, heterocyclic radical, C unsubstituted or that replace 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2N-C (O)-, CN, (R 10) 2N-C (NR 10)-, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, and R 11OC (O) NR 10-;
R 2And R 3Be independently selected from: H, the C that does not replace or replace 1-C 8Alkyl, the C that does not replace or replace 2-C 8Alkenyl, the C that does not replace or replace 2-C 8Alkynyl, the aryl that does not replace or replace, the heterocycle that does not replace or replace, Or Wherein, substituting group is to be replaced by one or more groups in the following groups:
1) aryl or the heterocycle that does not replace or replaced by following groups:
A) C 1-C 4Alkyl,
b)(CH 2) pOR 6，
c)(CH 2) pNR 6R 7，
D) halogen,
e)CN，
2) C 3-C 6Cycloalkyl,
3)OR 6，
4)SR 6a，S(O)R 6a，SO 2R 6a，
5)-NR 6R 7
Figure A9619420600793
Figure A9619420600801
15) N 3, or
16) F; Or
R 2And R 3Be connected in and lump together formation-(CH on the same carbon atom 2) u-, one of them carbon atom is randomly by being selected from O, S (O) m,-NC (O)-and-N (COR 10)-group replace;
R 4And R 5Be independently selected from H and CH 3And R 2, R 3, R 4And R 5In any 2 randomly be connected on the same carbon atom;
R 6, R 7And R 7aBe independently selected from: H, C 1-C 4Alkyl, C 3-C 6Cycloalkyl, heterocycle, aryl, aroyl, 4-hetaroylpyrazol, arylsulfonyl, heteroaryl sulphonyl, these groups can be unsubstituted or be replaced by following groups:
A) C 1-C 4Alkoxyl group,
B) aryl or heterocycle,
C) halogen,
d)HO，
Figure A9619420600802
F)-SO 2R 11, or
G) N (R 10) 2Or
R 6And R 7Can be connected in the ring;
R 7And R 7aCan be connected in the ring;
R 6aBe selected from: C 1-C 4Alkyl, C 3-C 6Cycloalkyl, heterocycle, aryl, these groups can be unsubstituted or replace with following groups:
A) C 1-C 4Alkoxyl group,
B) aryl or heterocycle,
C) halogen,
d)HO，
F)-SO 2R 11, or
g)N(R 10) 2；
R 8Be independently selected from:
A) hydrogen,
B) aryl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, NO 2, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-and
C) C unsubstituted or that replaced by following groups 1-C 6Alkyl: aryl, cyano-phenyl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NH-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 10OC (O) NH-;
R 9Be selected from:
A) hydrogen,
B) C 2-C 6Alkenyl, C 2-C 6Alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, NO 2, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-and
C) C unsubstituted or that replaced by following groups 1-C 6Alkyl: perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-;
R 10Be independently selected from hydrogen, C 1-C 6Alkyl, benzyl and aryl;
R 11Be independently selected from C 1-C 6Alkyl and aryl;
A 1And A 2Be independently selected from: key ,-CH=CH-,-C ≡ C-,-C (O)-,-C (O) NR 10-,-NR 10C (O)-, O ,-N (R 10)-,-S (O) 2N (R 10)-,-N (R 10) S (O) 2-or S (O) m;
V is selected from:
A) hydrogen,
B) heterocycle,
C) aryl,
D) C 1-C 20Alkyl, wherein have 0-4 carbon atom be selected from O, S and N heteroatoms displacement and
E) C 2-C 20Alkenyl.
Its condition is: if A 1Be S (O) m, then V is not a hydrogen; If A 1Be a key, n is 0, and A 2Be S (O) m, then V is not a hydrogen;
W is a heterocycle;
X is-CH 2-,-C (=O)-or-S (=O) m-;
Y is an aryl unsubstituted or that replace, or heterocycle unsubstituted or that replace, and wherein the heterocycle of aryl of Qu Daiing or replacement is replaced by one or more following groups:
1) C unsubstituted or that replaced by following groups 1-C 4Alkyl:
A) C 1-C 4Alkoxyl group,
b)NR 6R 7，
C) C 3-C 6Cycloalkyl,
D) aryl or heterocycle,
e)HO，
F)-S (O) mR 6a, or
g)-C(O)NR 6R 7，
2) aryl or heterocycle,
3) halogen,
4)OR 6，
5)NR 6R 7
6)CN，
7)NO 2，
8)CF 3，
9)-S(O)mR 6a，
10)-C (O) NR 6R 7, or
11) C 3-C 6Cycloalkyl;
M is 0,1 or 2;
N is 0,1,2,3 or 4;
P is 0,1,2,3 or 4;
Q is 1 or 2;
R is 0-5, and its condition is that r is 0 when V is hydrogen;
S is 0 or 1;
T is 0 or 1; With
U is 4 or 5.
In second specific embodiments of the present invention, the inhibitor of farnesyl-protein transferase can illustrate with following formula B or its pharmaceutically acceptable salt:
In the formula:
R 1aAnd R 1bBe independently selected from:
A) hydrogen,
B) aryl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, CN (R 10) 2N-C (O)-, (R 10) 2N-C (NR 10)-, CN, NO 2, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-,
C) C that does not replace or replace 1-C 6Alkyl, wherein the C of replacement 1-C 6Substituting group on the alkyl is selected from aryl, heterocyclic radical, C unsubstituted or that replace 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2N-C (O)-, CN, (R 10) 2N-C (NR 10)-, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, and R 11OC (O) NR 10-;
R 2And R 3Be independently selected from: H, the C that does not replace or replace 1-C 8Alkyl, the C that does not replace or replace 2-C 8Alkenyl, the C that does not replace or replace 2-C 8Alkynyl, the aryl that does not replace or replace, the heterocycle that does not replace or replace, Or Wherein, substituting group is to be replaced by one or more groups in the following groups:
1) aryl or the heterocycle that does not replace or replaced by following groups:
A) C 1-C 4Alkyl,
b)(CH 2) pOR 6，
c)(CH 2) pNR 6R 7，
D) halogen,
e)CN，
2) C 3-C 6Cycloalkyl,
3)OR 6，
4)SR 6a，S(O)R 6a，SO 2R 6a，
5)-NR 6R 7，
Figure A9619420600843
Figure A9619420600851
15) N 3, or
16) F; Or
R 2And R 3Be connected in and lump together formation-(CH on the same carbon atom 2) u-, one of them carbon atom is randomly by being selected from O, S (O) m,-NC (O)-and-N (COR 10)-group replace;
R 4Be selected from H and CH 3And R 2, R 3And R 4In any 2 randomly be connected on the same carbon atom;
R 6, R 7And R 7aBe independently selected from: H, C 1-C 4Alkyl, C 3-C 6Cycloalkyl, heterocycle, aryl, aroyl, 4-hetaroylpyrazol, arylsulfonyl, heteroaryl sulphonyl, these groups can be unsubstituted or be replaced by following groups:
A) C 1-C 4Alkoxyl group,
B) aryl or heterocycle,
C) halogen,
d)HO，
Figure A9619420600852
F)-SO 2R 11, or
G) N (R 10) 2Or
R 6And R 7Can be connected in the ring;
R 7And R 7aCan be connected in the ring;
R 6aBe selected from: C 1-C 4Alkyl, C 3-C 6Cycloalkyl, heterocycle, aryl, these groups can be unsubstituted or replace with following groups:
A) C 1-C 4Alkoxyl group,
B) aryl or heterocycle,
C) halogen,
d)HO，
F)-SO 2R 11, or
g)N(R 10) 2；
R 8Be independently selected from:
A) hydrogen,
B) aryl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, NO 2, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-and
C) C unsubstituted or that replaced by following groups 1-C 6Alkyl: aryl, cyano-phenyl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NH-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 10OC (O) NH-;
R 9Be selected from:
A) hydrogen,
B) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, NO 2, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-and
C) C unsubstituted or that replaced by following groups 1-C 6Alkyl: perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-;
R 10Be independently selected from hydrogen, C 1-C 6Alkyl, benzyl and aryl;
R 11Be independently selected from C 1-C 6Alkyl and aryl;
A 1And A 2Be independently selected from: key ,-CH=CH-,-C ≡ C-,-C (O)-,-C (O) NR 10-,-NR 10C (O)-, O ,-N (R 10)-,-S (O) 2N (R 10)-,-N (R 10) S (O) 2-or S (O) m;
G is H 2Or O;
V is selected from:
A) hydrogen,
B) heterocycle,
C) aryl,
D) C 1-C 20Alkyl, wherein have 0-4 carbon atom be selected from O, S and N heteroatoms displacement and
E) C 2-C 20Alkenyl.
Its condition is: if A 1Be S (O) m, then V is not a hydrogen; If A 1Be a key, n is 0, and A 2Be S (O) m, then V is not a hydrogen;
W is a heterocycle;
X is-CH 2-,-C (=O)-or-S (=O) m-;
Z is an aryl unsubstituted or that replace, heteroaryl, arylmethyl, heteroaryl methyl, arylsulfonyl, heteroaryl sulphonyl, and wherein the group of Qu Daiing is replaced by one or more following groups:
1) C unsubstituted or that replaced by following groups 1-C 4Alkyl:
A) C 1-C 4Alkoxyl group,
b)NR 6R 7，
C) C 3-C 6Cycloalkyl,
D) aryl or heterocycle,
e)HO，
F)-S (O) mR 6a, or
g)-C(O)NR 6R 7，
2) aryl or heterocycle,
3) halogen,
4)OR 6，
5)NR 6R 7
6)CN，
7)NO 2，
8)CF 3，
9)-S(O)mR 6a，
10)-C (O) NR 6R 7, or
11) C 3-C 6Cycloalkyl;
M is 0,1 or 2;
N is 0,1,2,3 or 4;
P is 0,1,2,3 or 4;
Q is 1 or 2;
R is 0-5, and its condition is that r is 0 when V is hydrogen;
S is 0 or 1;
T is 0 or 1; With
U is 4 or 5.
In the 3rd specific embodiments of the present invention, the inhibitor of farnesyl-protein transferase can illustrate with following formula C or its pharmaceutically acceptable salt:
In the formula:
R 1aAnd R 1bBe independently selected from:
A) hydrogen,
B) aryl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2N-C (O)-, (R 10) 2N-C (NR 10)-, CN, NO 2, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-,
C) C that does not replace or replace 1-C 6Alkyl, wherein the C of replacement 1-C 6Substituting group on the alkyl is selected from aryl, heterocyclic radical, C unsubstituted or that replace 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2N-C (O)-, CN, (R 10) 2N-C (NR 10)-, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, and R 11OC (O) NR 10-;
R 2And R 3Be independently selected from: H, the C that does not replace or replace 1-C 8Alkyl, the C that does not replace or replace 2-C 8Alkenyl, the C that does not replace or replace 2-C 8Alkynyl, the aryl that does not replace or replace, the heterocycle that does not replace or replace, Or
Figure A9619420600892
Wherein, substituting group is to be replaced by one or more groups in the following groups:
1) aryl or the heterocycle that does not replace or replaced by following groups:
A) C 1-C 4Alkyl,
b)(CH 2) pOR 6，
c)(CH 2) pNR 6R 7，
D) halogen,
e)CN，
2) C 3-C 6Cycloalkyl,
3)OR 6，
4)SR 6a，S(O)R 6a，SO 2R 6a，
5)-NR 6R 7
Figure A9619420600893
Figure A9619420600901
15) N 3, or
16) F; Or
R 2And R 3Be connected in and lump together formation-(CH on the same carbon atom 2) u-, one of them carbon atom is randomly by being selected from O, S (O) m,-NC (O)-and-N (COR 10)-group replace;
R 4Be selected from H and CH 3And R 2, R 3And R 4In any 2 randomly be connected on the same carbon atom;
R 6, R 7And R 7aBe independently selected from: H, C 1-C 4Alkyl, C 3-C 6Cycloalkyl, heterocycle, aryl, aroyl, 4-hetaroylpyrazol, arylsulfonyl, heteroaryl sulphonyl, these groups can be unsubstituted or be replaced by following groups:
A) C 1-C 4Alkoxyl group,
B) aryl or heterocycle,
C) halogen,
d)HO，
Figure A9619420600902
F)-SO 2R 11, or
G) N (R 10) 2Or
R 6And R 7Can be connected in the ring;
R 7And R 7aCan be connected in the ring;
R 6aBe selected from: C 1-C 4Alkyl, C 3-C 6Cycloalkyl, heterocycle, aryl, these groups can be unsubstituted or replace with following groups:
A) C 1-C 4Alkoxyl group,
B) aryl or heterocycle,
C) halogen,
d)HO，
Figure A9619420600911
F)-SO 2R 11, or
g)N(R 10) 2；
R 8Be independently selected from:
A) hydrogen,
B) aryl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, NO 2, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-and
C) C unsubstituted or that replaced by following groups 1-C 6Alkyl: aryl, cyano-phenyl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NH-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 10OC (O) NH-;
R 9Be selected from:
A) hydrogen,
B) C 2-C 6Alkenyl, C 2-C 6Alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, NO 2, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-and
C) C unsubstituted or that replaced by following groups 1-C 6Alkyl: perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-;
R 10Be independently selected from hydrogen, C 1-C 6Alkyl, benzyl and aryl;
R 11Be independently selected from C 1-C 6Alkyl and aryl;
A 1And A 2Be independently selected from: key ,-CH=CH-,-C ≡ C-,-C (O)-,-C (O) NR 10-,-NR 10C (O)-, O ,-N (R 10)-,-S (O) 2N (R 10)-,-N (R 10) S (O) 2-or S (O) m;
G is O;
V is selected from:
A) hydrogen,
B) heterocycle,
C) aryl,
D) C 1-C 20Alkyl, wherein have 0-4 carbon atom be selected from O, S and N heteroatoms displacement and
E) C 2-C 20Alkenyl.
Its condition is: if A 1Be S (O) m, then V is not a hydrogen; If A 1Be a key, n is 0, and A 2Be S (O) m, then V is not a hydrogen;
W is a heterocycle;
X is-CH 2-,-C (=O)-or-S (=O) m-;
Z is an aryl unsubstituted or that replace, heteroaryl, arylmethyl, heteroaryl methyl, arylsulfonyl, heteroaryl sulphonyl, and wherein the group of Qu Daiing is replaced by one or more following groups:
1) C unsubstituted or that replaced by following groups 1-C 4Alkyl:
A) C 1-C 4Alkoxyl group,
b)NR 6R 7，
C) C 3-C 6Cycloalkyl,
D) aryl or heterocycle,
e)HO，
F)-S (O) mR 6a, or
g)-C(O)NR 6R 7，
2) aryl or heterocycle,
3) halogen,
4)OR 6，
5)NR 6R 7
6)CN，
7)NO 2，
8)CF 3，
9)-S(O)mR 6a，
10)-C (O) NR 6R 7, or
11) C 3-C 6Cycloalkyl;
M is 0,1 or 2;
N is 0,1,2,3 or 4;
P is 0,1,2,3 or 4;
Q is 1 or 2;
R is 0-5, and its condition is that r is 0 when V is hydrogen;
S is 1;
T is 0 or 1; With
U is 4 or 5.
A preferred version of The compounds of this invention can illustrate with following formula: compound or its pharmaceutically acceptable salt:
In the formula:
R 1aBe independently selected from: hydrogen or C 1-C 6Alkyl;
R 1bBe independently selected from:
A) hydrogen,
B) aryl, heterocycle, cycloalkyl, R 10O-,-N (R 10) 2Or C 2-C 6Alkenyl,
C) the unsubstituted or C that replaces 1-C 6Alkyl, wherein the C of replacement 1-C 6Substituting group on the alkyl is selected from aryl, heterocycle, cycloalkyl, alkenyl, R unsubstituted or that replace 10O-and-N (R 10) 2
R 3, R 4And R 5Be independently selected from H and CH 3
R 2Be H;
Figure A9619420600941
Or C 1-C 5Alkyl can be unbranched or side chain is arranged, and can be unsubstituted or replaced by following one or more groups:
1) aryl,
2) heterocycle,
3)OR 6，
4) SR 6a, SO 2R 6a, or
And R 2, R 3, R 4And R 5In any 2 can randomly be connected on the same carbon atom;
R 6, R 7And R 7aBe independently selected from: H; C 1-C 4Alkyl, C 3-C 6Cycloalkyl, aryl, heterocycle can be unsubstituted, or replaced by following groups:
A) C 1-C 4Alkoxyl group,
B) halogen, or
C) aryl or heterocycle;
R 6aBe selected from: C 1-C 4Alkyl or C 3-C 6Cycloalkyl, can be unsubstituted or replaced by following groups:
A) C 1-C 4Alkoxyl group,
B) halogen, or
C) aryl or heterocycle;
R 8Be independently selected from:
A) hydrogen,
B) C 1-C 6Alkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, C 1-C 6Perfluoroalkyl, F, Cl, R 10O-, R 10C (O) NR 10-, CN, NO 2, (R 10) 2N-C (NR 10)-, R 10C (O)-, R 10OC (O)-,-N (R 10) 2, or R 11OC (O) NR 10-and
C) by C 1-C 6Perfluoroalkyl, R 10O-, R 10C (O) NR 10-, (R 10) 2N-C (NR 10)-, R 10C (O)-, R 10OC (O)-,-N (R 10) 2, or R 11OC (O) NR 10The C of-replacement 1-C 6Alkyl;
R 9Be selected from:
A) hydrogen,
B) C 2-C 6Alkenyl, C 2-C 6Alkynyl, C 1-C 6Perfluoroalkyl, F, Cl, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, CN, NO 2, (R 10) 2N-C (NR 10)-, R 10C (O)-, R 10OC (O)-,-N (R 10) 2, or R 11OC (O) NR 10-and
C) unsubstituted or by C 1-C 6Perfluoroalkyl, F, Cl, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, CN, (R 10) 2N-C (NR 10)-, R 10C (O)-, R 10OC (O)-,-N (R 10) 2, or R 11OC (O) NR 10The C of-replacement 1-C 6Alkyl;
R 10Be independently selected from hydrogen, C 1-C 6Alkyl, benzyl or aryl;
R 11Be independently selected from C 1-C 6Alkyl and aryl;
A 1And A 2Be independently selected from: a key ,-CH=CH-,-C ≡ C-,-C (O)-,-C (O) NR 10-, O ,-N (R 10)-, or S (O) m;
V is selected from:
A) hydrogen,
B) be selected from following heterocyclic radical: pyrrolidyl, imidazolyl, pyridyl, thiazolyl, pyriconyl, 2-oxo pyridine base, indyl, quinolyl, isoquinolyl and thienyl,
C) aryl,
D) C 1-C 20Alkyl, wherein have 0-4 carbon atom be selected from O, S and N heteroatoms displacement and
E) C 2-C 20Alkenyl,
But its condition is if A 1Be S (O) m, then V is not a hydrogen, and if A 1Be a key, n is 0, A 2Be S (O) m, then V neither hydrogen;
W is selected from following heterocyclic radical: pyrrolidyl, imidazolyl, pyridyl, thiazolyl, pyriconyl, 2-oxo-piperidine base, indyl, quinolyl, or isoquinolyl;
X is-CH 2Or-C (=O)-;
Y is monocycle or bicyclic aryl, and perhaps monocycle or bicyclic heterocycle can be unsubstituted or replaced by following one or more groups:
A) C 1-C 4Alkyl,
B) C 1-C 4Alkoxyl group,
C) halogen, or
d)NR 6R 7；
M is 0,1 or 2;
N is 0,1,2,3 or 4;
P is 0,1,2,3 or 4;
R is 0-5, but r is 0 when V is hydrogen;
S is 0 or 1; And
T is 0 or 1.
In second preferred version of the present invention, the inhibitor of farnesyl-protein transferase can illustrate with following formula B compound or its pharmaceutically acceptable salt:
Figure A9619420600961
In the formula:
R 1aBe independently selected from: hydrogen or C 1-C 6Alkyl;
R 1bBe independently selected from:
A) hydrogen,
B) aryl, heterocycle, cycloalkyl, R 10O-,-N (R 10) 2Or C 2-C 6Alkenyl,
C) the unsubstituted or C that replaces 1-C 6Alkyl, wherein the C of replacement 1-C 6Substituting group on the alkyl is selected from aryl, heterocycle, cycloalkyl, alkenyl, R unsubstituted or that replace 10O-and-N (R 10) 2
R 3And R 4Be independently selected from H and CH 3
R 2Be H; Or C 1-C 5Alkyl can be unbranched or side chain is arranged, and can be unsubstituted or replaced by following one or more groups:
1) aryl,
2) heterocycle,
3)OR 6，
4) SR 6a, SO 2R 6a, or
Figure A9619420600963
And R 2, R 3, R 4And R 5In any 2 can randomly be connected on the same carbon atom;
R 6, R 7And R 7aBe independently selected from: H; C 1-C 4Alkyl, C 3-C 6Cycloalkyl, aryl, heterocycle can be unsubstituted, or replaced by following groups:
A) C 1-C 4Alkoxyl group,
B) halogen, or
C) aryl or heterocycle;
R 6aBe selected from: C 1-C 4Alkyl or C 3-C 6Cycloalkyl, can be unsubstituted or replaced by following groups:
A) C 1-C 4Alkoxyl group,
B) halogen, or
C) aryl or heterocycle;
R 8Be independently selected from:
A) hydrogen,
B) C 1-C 6Alkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, C 1-C 6Perfluoroalkyl, F, Cl, R 10O-, R 10C (O) NR 10-, CN, NO 2, (R 10) 2N-C (NR 10)-, R 10C (O)-, R 10OC (O)-,-N (R 10) 2, or R 11OC (O) NR 10-and
C) by C 1-C 6Perfluoroalkyl, R 10O-, R 10C (O) NR 10-, (R 10) 2N-C (NR 10)-, R 10C (O)-, R 10OC (O)-,-N (R 10) 2, or R 11OC (O) NR 10The C of-replacement 1-C 6Alkyl;
R 9Be selected from:
A) hydrogen,
B) C 2-C 6Alkenyl, C 2-C 6Alkynyl, C 1-C 6Perfluoroalkyl, F, Cl, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, CN, NO 2, (R 10) 2N-C (NR 10)-, R 10C (O)-, R 10OC (O)-,-N (R 10) 2, or R 11OC (O) NR 10-and
C) unsubstituted or by C 1-C 6Perfluoroalkyl, F, Cl, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, CN, (R 10) 2N-C (NR 10)-, R 10C (O)-, R 10OC (O)-,-N (R 10) 2, or R 11OC (O) NR 10The C of-replacement 1-C 6Alkyl;
R 10Be independently selected from hydrogen, C 1-C 6Alkyl, benzyl or aryl;
R 11Be independently selected from C 1-C 6Alkyl and aryl;
A 1And A 2Be independently selected from: a key ,-CH=CH-,-C ≡ C-,-C (O)-,-C (O) NR 10-, O ,-N (R 10)-, or S (O) m;
V is selected from:
A) hydrogen,
B) be selected from following heterocyclic radical: pyrrolidyl, imidazolyl, pyridyl, thiazolyl, pyriconyl, 2-oxo pyridine base, indyl, quinolyl, isoquinolyl and thienyl,
C) aryl,
D) C 1-C 20Alkyl, wherein have 0-4 carbon atom be selected from O, S and N heteroatoms displacement and
E) C 2-C 20Alkenyl,
But its condition is if A 1Be S (O) m, then V is not a hydrogen, and if A 1Be a key, n is 0, A 2Be S (O) m, then V neither hydrogen;
G is H 2Or O;
W is selected from following heterocyclic radical: pyrrolidyl, imidazolyl, pyridyl, thiazolyl, pyriconyl, 2-oxo-piperidine base, indyl, quinolyl, or isoquinolyl;
X is-CH 2Or-C (=O)-;
Z is monocycle or bicyclic aryl, monocycle or bicyclic heteroaryl, monocycle or bicyclic aryl methyl, monocycle or bicyclic heteroaryl methyl, monocycle or bicyclic aryl sulphonyl, monocycle or bicyclic heteroaryl sulphonyl can be unsubstituted or replaced by following one or more groups:
1) C unsubstituted or that replaced by following groups 1-C 4Alkyl:
A) C 1-C 4Alkoxyl group,
b)NR 6R 7，
C) C 3-C 6Cycloalkyl,
D) aryl or heterocycle,
e)HO，
F)-S (O) mR 6a, or
g)-C(O)NR 6R 7，
2) aryl or heterocycle,
3) halogen,
4)OR 6，
5)NR 6R 7
6)CN，
7)NO 2，
8)CF 3，
9)-S(O)mR 6a，
10)-C (O) NR 6R 7, or
11) C 3-C 6Cycloalkyl;
M is 0,1 or 2;
N is 0,1,2,3 or 4;
P is 0,1,2,3 or 4;
R is 0-5, and its condition is that r is 0 when V is hydrogen;
S is 0 or 1;
T is 0 or 1; With
U is 4 or 5,
But its condition be when G be H 2, and W is when being imidazolyl, substituting group (R 8) r-V-A 1(CR 1a 2) nA 2(CR 1a 2) n-is not H, and
Its condition be when X be-C (=O)-, or-S (=O) during m-, t is 1, and substituting group (R 8) r-V-A 1(CR 1a 2) nA 2(CR 1a 2) n-is not hydrogen.
Preferred compounds of the invention are following compound and pharmaceutically acceptable salt thereof:
2 (S)-butyl-1-(2,3-diamino third-1-yl)-4-(1-naphthoyl)-piperazine
1-(3-amino-2-(2-naphthyl methyl amino) third-1-yl)-2 (S)-butyl-4-(1-naphthoyl)-piperazine
2 (S)-butyl-1-{5-[1-(2-naphthyl methyl)]-4, the 5-glyoxalidine } methyl-4-(1-naphthoyl)-piperazine
1-[5-(1-benzyl imidazole) methyl]-2 (S)-butyl-4-(1-naphthoyl)-piperazine
1-{5-[1-(4-nitrobenzyl) imidazolyl] methyl }-2 (S)-butyl-4-(1-naphthoyl)-piperazine
1-(3-kharophen methylthio group-2 (R)-amino third-1-yl)-2 (S)-butyl-4-(1-naphthoyl)-piperazine
2 (S)-butyl-1-[2-(1-imidazolyl) ethyl] sulphonyl-4-(1-naphthoyl)-piperazine
2 (R)-butyl-1-imidazolyl-4-methyl-4-(1-naphthoyl)-piperazine
2 (S)-butyl-4-(1-naphthoyl)-1-(3-pyridylmethyl) piperazine
1-2 (S)-butyl-(2 (R)-(4-nitrobenzyl) amino-3-hydroxypropyl)-4-(1-naphthoyl)-piperazine
1-(2 (R)-amino-3-hydroxyl heptadecyl)-2 (S)-butyl-4-(1-naphthoyl)-piperazine
2 (S)-benzyl-1-imidazolyl-4-methyl-4-(1-naphthoyl)-piperazine
1-(2 (R)-amino-3-(3-benzylthio-) propyl group)-2 (S)-butyl-4-(1-naphthoyl)-piperazine
1-(2 (R)-amino-3-[3-(4-nitrobenzyl sulfenyl) propyl group]))-2 (S)-butyl-4-(1-naphthoyl)-piperazine
2 (S)-butyl-1-[(4-imidazolyl) ethyl]-4-(1-naphthoyl)-piperazine
2 (S)-butyl-1-[(4-imidazolyl) methyl]-4-(1-naphthoyl)-piperazine
2 (S) butyl-1-[(1-naphthalene-2-ylmethyl)-and 1H-imidazoles-5-yl) ethanoyl]-4-(1-naphthoyl)-piperazine
2 (S)-butyl-1-[(1-naphthalene-2-ylmethyl)-and 1H-imidazoles-5-yl) ethyl]-4-(1-naphthoyl)-piperazine
1-(2 (R)-amino-3-hydroxypropyl)-2 (S)-butyl-4-(1-naphthoyl)-piperazine
1-(2 (R)-amino-4-hydroxy butyl)-2 (S)-butyl-4-(1-naphthoyl)-piperazine
1-(2-amino-3-(2-benzyloxy phenyl) propyl group)-2 (S)-butyl-4-(1-naphthoyl)-piperazine
1-(2-amino-3-(2-hydroxy phenyl) propyl group)-2 (S)-butyl-4-(1-naphthoyl)-piperazine
1-[3-(4-imidazolyl) propyl group]-2 (S)-butyl-4-(1-naphthoyl)-piperazine
2 (S)-normal-butyl-4-(1-naphthoyl)-1-[1-(1-naphthyl methyl) imidazoles-5-ylmethyl]-piperazine
2 (S)-normal-butyl-4-(1-naphthoyl)-1-[1-(2-naphthyl methyl) imidazoles-5-ylmethyl]-piperazine
2 (S)-normal-butyl-1-[1-(4-cyano group benzyl) imidazoles-5-ylmethyl]-4-(1-naphthoyl)-piperazine
2 (S)-normal-butyl-1-[1-(4-methoxy-benzyl) imidazoles-5-ylmethyl]-4-(1-naphthoyl)-piperazine
2 (S)-normal-butyl-1-[1-(3-methyl-2-butene base) imidazoles-5-ylmethyl]-4-(1-naphthoyl)-piperazine
2 (S)-normal-butyl-1-[1-(4-luorobenzyl) imidazoles-5-ylmethyl]-4-(1-naphthoyl)-piperazine
2 (S)-normal-butyl-1-[1-(4-benzyl chloride base) imidazoles-5-ylmethyl]-4-(1-naphthoyl)-piperazine
1-[1-(4-bromobenzyl) imidazoles-5-ylmethyl]-2 (S)-normal-butyl-4-(1-naphthoyl)-piperazine
1-[1-(4-bromobenzyl) imidazoles-5-ylmethyl]-2 (S)-normal-butyl-4-(1-naphthoyl)-piperazine
2 (S)-normal-butyl-4-(1-naphthoyl)-1-[1-(4-trifluoromethyl benzyl) imidazoles-5-ylmethyl]-piperazine
2 (S)-normal-butyl-1-[1-(4-methyl-benzyl) imidazoles-5-ylmethyl]-4-(1-naphthoyl)-piperazine
2 (S)-normal-butyl-1-[1-(3-methyl-benzyl) imidazoles-5-ylmethyl]-4-(1-naphthoyl)-piperazine
1-[1-(4-phenylbenzyl) imidazoles-5-ylmethyl]-2 (S)-normal-butyl-4-(1-naphthoyl)-piperazine
2 (S)-normal-butyl-4-(1-naphthoyl)-1-[1-(2-phenylethyl) imidazoles-5-ylmethyl]-piperazine
2 (S)-normal-butyl-4-(1-naphthoyl)-1-[1-(4-trifluoromethoxy) imidazoles-5-ylmethyl]-piperazine
1-{[1-(4-cyano group benzyl)-1H-imidazoles-5-yl] ethanoyl }-2 (S)-normal-butyl-4-(1-naphthoyl)-piperazine
5 (S)-normal-butyl-1-(2, the 3-3,5-dimethylphenyl)-4-(4-imidazolyl methyl)-piperazine-2-ketone
5 (S)-normal-butyl-4-[1-(4-cyano group benzyl) imidazoles-5-ylmethyl]-1-(2, the 3-3,5-dimethylphenyl) piperazine-2-ketone
4-[1-(4-cyano group benzyl) imidazoles-5-ylmethyl]-1-(2,3-3,5-dimethylphenyl-5 (S)-(2-methoxy ethyl) piperazine-2-ketone
(S)-the 1-[3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-5-[2-(methylsulfonyl) ethyl]-2-piperazine ketone
(S)-the 1-[3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-5-[2-(ethylsulfonyl) ethyl]-2-piperazine ketone
(S)-1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-5-[2-(ethylsulfonyl) methyl]-2-piperazine ketone
(S)-1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-5-[N-ethyl-2-kharophen]-2-piperazine ketone
(±)-5-(2-butyne base)-1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-2-piperazine ketone
1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-2-piperazine ketone
5 (S)-butyl-4-[1-(4-cyano group benzyl-2-methyl)-5-imidazolyl methyl]-1-(2, the 3-3,5-dimethylphenyl)-piperazine-2-ketone
4-[1-(2-(4-cyano-phenyl)-2-propyl group)-5-imidazolyl methyl]-1-(3-chloro-phenyl-)-5 (S)-(2-methylsulfonyl ethyl) piperazine-2-ketone
5 (S)-normal-butyl-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-1-(2-aminomethyl phenyl) piperazine-2-ketone
4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-5 (S)-(2-fluoro ethyl)-1-(3-chloro-phenyl-) piperazine-2-ketone
4-[3-(4-cyano group benzyl) pyridin-4-yl]-1-(3-chloro-phenyl-)-5 (S)-(2-methylsulfonyl ethyl) piperazine-2-ketone
4-[5-(4-cyano group benzyl)-1-imidazolyl ethyl]-1-(3-chloro-phenyl-) piperazine-2-ketone.
The specific examples of The compounds of this invention is following compound and pharmaceutically acceptable salt thereof:
1-{5-[1-(4-nitrobenzyl) imidazolyl] methyl }-2 (S)-butyl-4-(1-naphthoyl)-piperazine
1-[5-(1-benzyl imidazole) methyl]-2 (S)-butyl-4-(1-naphthoyl)-piperazine
1-(2 (R)-amino-3-(3-benzylthio-) propyl group)-2 (S)-butyl-4-(1-naphthoyl)-piperazine
Figure A9619420601033
1-(2 (R)-amino-3-[3-(4-nitrobenzyl sulfenyl) propyl group])-2 (S)-butyl-4-(1-naphthoyl)-piperazine
Figure A9619420601041
2 (S)-normal-butyl-1-[1-(4-cyano group benzyl) imidazoles-5-ylmethyl]-4-(1-naphthoyl)-piperazine
2 (S)-normal-butyl-1-[1-(4-cyano group benzyl) imidazoles-5-ylmethyl]-4-(2, the 3-3,5-dimethylphenyl) piperazine-5-ketone
Figure A9619420601043
2 (S)-normal-butyl-1-[1-(4-benzyl chloride base) imidazoles-5-ylmethyl]-4-(1-naphthoyl)-piperazine
1-{[1-(4-cyano group benzyl)-1H-imidazoles-5-yl] ethanoyl }-2 (S)-normal-butyl-4-(1-naphthoyl)-piperazine
Figure A9619420601052
1-[1-(4-cyano group benzyl) imidazoles-5-ylmethyl]-4-(2, the 3-3,5-dimethylphenyl)-2 (S)-(2-methoxy ethyl) piperazine-5-ketone
5 (S)-normal-butyl-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-1-(2-aminomethyl phenyl) piperazine-2-ketone
Figure A9619420601061
(S)-1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-5-[2-(methylsulfonyl) ethyl]-2-piperazine ketone
Figure A9619420601062
(S)-1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-5-[2-(ethylsulfonyl) ethyl]-2-piperazine ketone
Figure A9619420601063
(S)-1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-5-[2-(ethylsulfonyl) methyl]-2-piperazine ketone
Figure A9619420601071
1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-2-piperazine ketone
Figure A9619420601072
Compound of the present invention can have asymmetric center, thereby can exist with racemic modification, racemic mixture and various diastereomeric form, and therefore all possible isomer comprises that executing photoisomer all should comprise within the scope of the invention.As arbitrary variable (for example aryl, heterocycle, R 1, R 2Deng) when occurring (not comprising 1 time) more than 1 time in arbitrary constituent, being defined in each appearance of its each time appearance is independently.In addition, substituting group/or the combination of variable has only to be only permission when this bound energy produces stable compound.
" alkyl " used herein is meant the side chain that contains the defined amount carbon atom and the radical of saturated aliphatic alkyl of straight chain; " alkoxyl group " representative is by the alkyl that indicates carbonatoms that contains of an oxo bridge connection." halogen " used herein or " halogen " are meant fluorine, chlorine, bromine and iodine.
" aryl " used herein is meant in each ring and is at most 7 yuan any stable monocycle or bicyclic carbocyclic, and it is aromatic wherein having 1 ring at least.The example of this class aryl comprises phenyl, naphthyl, tetralyl, 2,3-indanyl, xenyl, phenanthryl, anthryl or acenaphthenyl.
5-7 unit's monocyclic heterocycles that term used herein " heterocycle " or " heterocyclic " representative are stable or stable 8-11 unit bicyclic heterocycle, can be saturated or unsaturated, and constitute by several carbon atoms and 1-4 heteroatoms that is selected from N, O and S, comprise any bicyclic radicals, wherein any one above-mentioned definition is heterocyclic fused to phenyl ring.This heterocyclic ring can be connected to any can causing and form on a kind of heteroatoms or carbon atom of rock steady structure.This comprises for the heterocyclic example, but be not limited to, azepines, benzimidazolyl-, the benzoisoxazole base, benzo furazan base, benzopyranyl, the benzo thiapyran base, benzofuryl, benzothiazolyl, benzothienyl benzoxazolyl, chromanyl, cinnolinyl, dihydro benzo furyl, the dihydrobenzo thienyl, the thiochroman base, thiochroman base sulfone, furyl, imidazolidyl, imidazolinyl, imidazolyl, indolinyl, indyl, the isochroman base, iso-dihydro-indole-group, isoquinolyl, the isothiazole alkyl, isothiazolyl, the isothiazole alkyl, morpholinyl, naphthyridine base oxadiazole base, 2-oxo azepines base oxazolyl, 2-oxo piperazinyl, 2-oxo-piperidine base, 2-oxo-pyrrolidine base, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidyl, pyrazolyl, pyridazinyl, pyrimidyl, pyrrolidyl, pyrryl, quinazolyl, quinolyl, quinoxalinyl, tetrahydrofuran base, tetrahydro isoquinolyl, tetrahydric quinoline group, thio-morpholinyl, the thio-morpholinyl sulfoxide, thiazolyl, thiazolinyl, the thienofuran base, the thienothiophene base, and thienyl.
" heteroaryl " used herein be meant in each ring and be at most 7 yuan any stable monocycle or bicyclic carbocyclic, wherein have at least 1 ring be aromatic series and, and wherein have 1-4 carbon atom to be selected from the heteroatoms replacement of N, O and S.The example of this class heterocyclic aryl comprises, but be not limited to benzimidazolyl-, the benzoisoxazole base, benzo furazan base, benzopyranyl, the benzo thiapyran base, benzofuryl, benzothiazolyl, benzothienyl benzoxazolyl, chromanyl, cinnolinyl, dihydro benzo furyl, the dihydrobenzo thienyl, the thiochroman base, thiochroman base sulfone, furyl, imidazolyl, indolinyl, indyl, the isochroman base, iso-dihydro-indole-group, isoquinolyl, isothiazolyl, naphthyridine base oxadiazole base, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidyl, pyrryl, quinazolyl, quinolyl, quinoxalinyl, tetrahydro isoquinolyl, tetrahydric quinoline group, thiazolyl, the thienofuran base, the thienothiophene base, and thienyl.
R in this article 2And R 3Definition in used term " group of replacement " be meant the C of replacement 1-8The C of alkyl, replacement 2-8The C of alkenyl, replacement 2-8The aryl of alkynyl, replacement or the heterocycle of replacement, substituent R 2And R 3Just be selected from these groups.
R in this article 6, R 7And R 7aDefinition in the C that replaces 1-8The C of alkyl, replacement 3-8The heteroaryl sulphonyl of the 4-hetaroylpyrazol of the aroyl of alkenyl, replacement, the aryl of replacement, replacement, the arylsulfonyl of replacement, replacement and the heterocycle of replacement comprise the link position that contains 1-3 substituent part and be connected to this compound rest part.
Term used herein " aryl of replacement " means and comprises 1 or 2 aryl that group replaces that are selected from following one group of group, and this group group includes, but are not limited to F, Cl, Br, CF 3, NH 2, N (C 1-C 6Alkyl) 2, NO 2, CN, (C 1-C 6Alkyl) O-,-OH, (C 1-C 6Alkyl) S (O) m-, (C 1-C 6Alkyl) C (O) NH-, H 2N-C (NH)-, (C 1-C 6Alkyl) C (O)-, (C 1-C 6Alkyl) OC (O)-, N 3, (C 1-C 6Alkyl) OC (O) NH-and C 1-C 20Alkyl.
Work as R 2And R 3Combining becomes-(CH 2) during u-, just form circular part.Such circular part includes, but are not limited to:
Figure A9619420601091
In addition, such circular part can randomly comprise 1 or several heteroatoms.Thisly contain heteroatomic circular part and example includes, but are not limited to:
From substituting group (for example from R 2, R 3, R 4Deng) the pointed key of line explanation signed on the ring system can be connected on any commutable ring carbon atom.
Be preferably R 1aAnd R 1bBe independently selected from: hydrogen ,-N (R 10) 2, R 10C (O) NR 10-, the perhaps unsubstituted or C that replaces 1-C 6Alkyl, wherein the C of replacement 1-C 6Substituting group on the alkyl is selected from unsubstituted or the phenyl that replaces ,-N (R 10) 2, R 10O-and R 10C (O) NR 10-.
Better be R 2Be selected from: H
Figure A9619420601093
With group unsubstituted or that replace, this group is selected from C 1-8Alkyl, C 2-8Alkenyl and C 2-8Alkynyl;
The group of wherein said replacement is replaced by following one or more groups: 1) aryl or heterocycle unsubstituted or that replaced by following groups;
A) C 1-C 4Alkyl,
b)(CH 2)pOR 6，
c)(CH 2)pNR 6R 7，
D) halogen, 2) C 3-C 6Cycloalkyl, 3) OR 64) SR 6a, S (O) R 6a, SO 2R 6a,
Figure A9619420601101
Figure A9619420601111
15) N 3, or
16)F，
Better be R 3Be selected from: hydrogen and C 1-C 6Alkyl.
Better be R 4And R 5Be hydrogen.
Better be R 6, R 7And R 7aBe selected from: hydrogen, the unsubstituted or C that replaces 1-C 6Alkyl, unsubstituted or the aryl and the cycloalkyl unsubstituted or that replace that replace.
Better be R 6aBe C unsubstituted or that replace 1-C 6Alkyl, unsubstituted or the aryl and the cycloalkyl unsubstituted or that replace that replace.
Better be R 9Be hydrogen or methyl.Best R 9Be hydrogen.
Better be R 10Be selected from H, C 1-C 6Alkyl and benzyl.
Better be A 1And A 2Be independently selected from: 1 key ,-C (O) NR 10-,-NR 10C (O)-, O ,-N (R 10)-,-S (O) 2N (R 10)-and-N (R 10) S (O) 2-.
Better be that V is selected from hydrogen, heterocycle and aryl.Best, V is a phenyl.
Better be that Y is selected from the unsubstituted or phenyl that replaces, the unsubstituted or naphthyl that replaces, the unsubstituted or pyridyl that replaces, unsubstituted or the furyl and the thienyl unsubstituted or that replace that replace.Best, Y is a phenyl unsubstituted or that replace.
Better be that Z is selected from the unsubstituted or phenyl that replaces, the unsubstituted or naphthyl that replaces, the unsubstituted or pyridyl that replaces, unsubstituted or the furyl and the thienyl unsubstituted or that replace that replace.Best, Z is a phenyl unsubstituted or that replace.
Better be that W is selected from imidazolinyl, imidazolyl, oxazolyl, pyrazolyl, pyrrolidyl, thiazolyl and pyridyl.Best, W is selected from imidazolyl and pyridyl.
Better be that n and r are 0,1 or 2 independently.
Better be that p is 1,2 or 3.
Better be that s is 0.
Better be that t is 1.
Better be, in the compound of formula B, when G is H2 and W when being imidazolyl, substituting group (R 8) r-V-A 1(CR 1a 2) nA 2(CR 1a 2) n-is not H.
Better be, in the compound of formula B, when X be-C (=O)-or-S (=O) during m-, t is 1, and substituting group (R 8) r-V-A 1(CR 1a 2) nA 2(CR 1a 2) n-is not H.
Intention is that any substituting group or variable are (as R on specific position of an intramolecularly 1a, R 9, n etc.) definition and it is irrelevant in other the locational definition of this intramolecularly.Therefore ,-N (R 10) 2Representative-NHH ,-NHCH 3,-NHC 2H 5Deng.Should be understood that, substituting group on the The compounds of this invention and replacement mode can be by the personnel selections with the general technical ability of this gate technique, to provide chemically stable and can be easily with technical known technology and the calm facile starting raw material synthetic compound of those methods proposed below.
The pharmaceutically acceptable salt of The compounds of this invention comprises the non-toxic salt commonly used of The compounds of this invention, can be from generating such as nontoxic mineral acid or organic acid.For example, such non-toxic salt commonly used comprises from mineral acid deutero-salt such as hydrochloric acid, Hydrogen bromide, sulfuric acid, thionamic acid, phosphoric acid, nitric acid; With salt from the preparation of organic acids such as acetate, propionic acid, succsinic acid, oxyacetic acid, stearyl, lactic acid, oxysuccinic acid, tartrate, citric acid, xitix, palmitinic acid, toxilic acid, hydroxymaleic acid, toluylic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, 2-acetoxy-benzoic acid, fumaric acid, toluenesulphonic acids, methylsulfonic acid, ethionic acid, oxalic acid, different ethionic acid, trifluoroacetic acid.
The pharmaceutically acceptable salt of The compounds of this invention can be synthetic from the The compounds of this invention that contains base with chemical process commonly used.In general, these salt or be to use ion exchange chromatography, or prepare by making this free alkali and stoichiometric quantity or reacting in a kind of suitable solvents or all kinds of SOLVENTS combination with excessive desired salify mineral acid or organic acid.
Be used for producing the reaction of The compounds of this invention, may be known on document or other standard operations such as the ester hydrolysis of experimental arrangement illustrated, blocking group fracture, can also adopt the reaction shown in the scheme 1～22 to prepare.Substituent R shown in these schemes, R aAnd R bRepresent substituent R 2, R 3, R 4And R 5Yet they are exemplary with the tie point of ring, and do not mean that and limit.
These reactions can be used to provide The compounds of this invention by linear precedence, also can be used for synthesizing some segments, are linked in sequence by means of the alkylated reaction described in these schemes then.
Scheme 1～22 general introduction
Needed intermediate, major part is commercial getting in some cases, also can prepare according to literature method.For example, in scheme 1, having summarized has the synthetic of piperazine that the 2-alkyl replaces, and this to be J.S.Kiely and S.R.Priebe basically exist Organic Preparations and Proceedings Int., 1990,22, the method described in the 761-768.Commercial get or can be according to the amino acid I preparation of the known method of the personnel that are familiar with this gate technique, that the Boc protection is arranged; can be in a kind of solvent such as methylene dichloride, chloroform, ethylene dichloride or dimethyl formamide; with various dewatering agents such as DCC (dicyclohexyl carbodiimide) or EDCHCl (1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride), be coupled on the N-benzylamino acid esters.Then, product II for example uses hydrogenchloride, or make it deprotection with trifluoroacetic acid in methylene dichloride with acid in chloroform or ethyl acetate, and cyclisation under weak basic condition, provides diketopiperazine III.III provides piperazine IV with lithium aluminum hydride reduction under ether refluxes, and the latter is protected and become Boc derivative V.This N-benzyl group can rupture under the standard processing conditions, for example carries the palladium hydrogenation 24～48 hours with the Pa Er device with 60psi hydrogen and 10% charcoal.Product VI can be handled with a kind of carboxylic acid with a kind of acyl chlorides or under the standard dehydration conditions, provides carboxylic acid amides VII; Final sour deprotection as described above provides intermediate VIII (scheme 2).Intermediate VIII can with various aldehyde for example IX carry out standard reductive alkylation.These aldehyde can be used such as O.P.Goel, U.Krolls, and M.Stier and S.Kesten exist Organic Syntheses, 1988.67, standard program such described in the 69-75 is from suitable amino acid preparation (scheme 3).This standard reductive alkylation can with various reductive agents such as triacetyl oxygen sodium borohydride or sodium cyanoborohydride, carry out at pH 5～7 in a kind of solvent such as ethylene dichloride, methyl alcohol or dimethyl formamide.Product X can use the trifluoroacetic acid deprotection and provide final compounds X I in methylene dichloride.Final compounds X I is isolating with salt form, for example, becomes a kind of trifluoroacetate, hydrochloride or acetate, and other salt.Further selective protection is to obtain XII for product diamines XI, and the latter can carry out standard reductive alkylation and obtain XIII subsequently with second kind of aldehyde.The removing and, can carry out of protecting group according to literature method to the conversion of cyclisation product such as glyoxalidine XV.
In addition, have protection piperazine intermediate VII can also with other aldehyde for example 1-trityl-4-imidazolyl formaldehyde or 1-trityl-4-imidazolyl acetaldehyde carry out standard reductive alkylation, provide such as the such product of XVI (scheme 4).Trityl-protecting group is removed to provide XVII from XVI, and perhaps substituting is, XVI can handle with a kind of alkylogen earlier, makes it deprotection subsequently again to provide alkylation imidazoles XVIII.Another kind of way is to make intermediate VIII alkylation or sulfonation with standard technique.Imidazoleacetic acid XIX can change into acetate XXI by standard step, and XXI can react with a kind of alkylogen earlier, handles with backflow methyl alcohol then, so that the alkylating imidazoleacetic acid ester of regiospecific XXII to be provided.Hydrolysis and condensation reagent for example 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (EDC) in the presence of with piperazine VIII reaction, cause for example XXIV of alkylating product.
If piperazine VIII be with a kind of aldehyde that a protected hydroxyl also arranged for example the XXV in the scheme 6 carry out standard reductive alkylation, these blocking groups are removed, thereby make this hydroxyl lose shielding (scheme 6,7).This alcohol can be oxidized to for example a kind of aldehyde under standard conditions, can make it then and for example Grignard reagent reaction of various organometallic reagents, to obtain secondary alcohol such as XXIX.In addition, the amino alcohol XXX of deprotection can (under the described in front condition) carry out standard reductive alkylation with various aldehyde fully, to obtain secondary amine such as XXXI (scheme 7) or tertiary amine.
The amino alcohol XXVII of Boc protection also can be used for for example XXXII (scheme 8) of Synthetic 2-aziridine methylpiperazine.A kind of solvent for example in the dimethyl formamide with 1,1 '-sulphonyl diimidazole and sodium hydride handle XXVII, cause generating aziridine XXXII.This aziridine a kind of nucleophilic reagent for example mercaptan in the presence of and in the presence of alkali, react, produce open-loop products XXXIII.
In addition, piperazine VIII can also with from amino acid derived aldehyde for example O-alkylation tyrosine react according to standard program, obtain such compound such as XXXIX.When R ' is an aryl, XXXIX can first hydrogenation so that phenol exposes true colours, make amino deprotection to produce XL with acid again.In addition, can also remove the amine protecting group among the XXXIX, produce such as the such O-alkylated phenol type amine of XLI.
Different because of the title of amino acid I, can be connected to various side chains on this piperazine.For example, when I is the aspartic acid β-benzyl ester of Boc protection, obtain the intermediate diketopiperazine XLII of n=1 and R=benzyl, as shown in scheme 10.Lithium aluminium hydride reduction subsequently makes this ester be reduced into pure XLIII, then can be in dimethyl formamide or tetrahydrofuran (THF) at alkaline condition for example under the sodium hydride, with for example alkyl iodide reaction of various alkylating agents.Then, can described in scheme 3～9, make resultant ether XLIV continue to be advanced to final product.
The N-aryl piperazines prepares can be described in scheme 11.A kind of arylamines XLV is reacted with two (chloroethyl) amine hydrochlorate (XLVI) in the backflow propyl carbinol, provide compounds X LVII.Then, can described in scheme 3～9, resulting piperazine XLVII be continued to be advanced to final product.
Piperazine-5-ketone can prepare as shown in the scheme 12.(preparing from I like that as previously described) has the reductive amination of the amino-aldehyde XLIX of Boc protection, produces compound L. and then, this compound reacts with bromoacetyl bromide under the Schotten-Baumann condition; In a kind of polar aprotic solvent such as dimethyl formamide, carry out closed loop, provide LI with a kind of alkali such as sodium hydride.This carboxylamine ester protecting group for example removes with hydrogen chloride gas with trifluoroacetic acid or in methyl alcohol or ethyl acetate in methylene dichloride under acidic conditions, can described in scheme 3～9 resulting piperazine be advanced to final product then.
Isomer piperazine-3-ketone prepares can be described in scheme 13.The imines that generates from the amino sweet ammonium aldehyde diethyl acetal of aryl carboxylic acid amides LII and 2-(LIII) can be included in the ethylene dichloride under various conditions with the sodium triacetoxy borohydride reduction, provides amine LIV.Amino acid I is coupled on the amine LIV, and resulting acid amides LV can be cyclized into undersaturated LVI when handling with aqueous acids in tetrahydrofuran (THF).Shortening provides needed intermediate LVII under standard conditions, and the latter is advanced to final product according to method described in the scheme 3～9.
Have described in the square case 14 of acquisition of the piperazine that alternate manner replaces.With after the trifluoroacetic acid deprotection, N-benzyl diethylenediamine V can be with a kind of aryl carboxylic acid acidylate.Resulting N-benzyl aryl carboxylic acid amides LIX can provide piperazine carboxylic acid amides LX at hydrogenation in the presence of a kind of catalyzer, can it be advanced to final product according to method described in the scheme 3～9 then.
Reaction scheme 15 provides an illustrative example, with the explanation substituent R 2With R 3Be combined to form-(CH 2) The compounds of this invention synthetic of u-.For example, 1-aminocyclohexane-1-carboxylic acid LXI can change into spiral shell piperazine LXVI according to the step described in scheme 1 and 2 basically.Piperazine intermediate LXIX is deprotection as before, and is advanced to final product according to the method described in the scheme 3～9.It being understood that to be used to provide the reagent that substituting group Y is 2-naphthyl and imidazolyl alkyl substituent, can easily be replaced with technical well-known and other reagent of being easy to obtain, on this piperazine so that other N-substituting group to be provided.
From the aldehyde XLIX of scheme 12, also can as shown in the scheme 16, carry out standard reductive alkylation with a kind of aniline.Product LXXI can change into a kind of piperazine ketone by carry out acidylate with chloroacetyl chloride, provides LXXII, carries out alkali subsequently and induces cyclisation and become LXXIII.Deprotection has the imidazole formaldehyde of protection to carry out standard reductive alkylation with a kind of subsequently, causes LXXV, and the latter can carry out alkylation with a kind of arylmethyl halides, to provide imidazole salts LXXVI.Carry out solvolysis with a kind of low-grade alkane alcohol such as methyl alcohol, or in the presence of trifluoroacetic acid, in methylene dichloride, handle and blocking group is finally removed, provide final product LXXVII with triethyl-silicane.
Scheme 17 explanation is a kind of also can to have the homoserine lactone LXXIX of replacement to be used for preparing the situation of a kind of piperazine ketone LXXXII of Boc protection.Intermediate LXXXII can carry out deprotection and standard reductive alkylation or acidylate as illustrated in the scheme in front.In addition, the hydroxylic moiety of intermediate LXXXII also can carry out methylsulfonylization and replace with a kind of nucleophilic reagent such as sulfur alcohol sodium salt, so that intermediate LXXXIII to be provided.Intermediate LXXXII also can oxidation, and to provide carboxylic acid on intermediate LXXXIV, the latter can be with the form utilization of ester or amide group.
That find, that a side chain is not arranged general formula LXXXVI amino acid in natural amino acid can be from the imines LXXXV of easy preparation, according to the prepared in reaction of explanation in the scheme 18.
The aldehyde that scheme 19～22 explanation can be used for The compounds of this invention synthetic that its variable W exists with the pyridyl form, have suitable replacement synthetic.Preparation is the similar synthetic strategy of the alkanol of variable W with other heterocyclic group, also is technical well-known. Scheme 1
Figure A9619420601171
Scheme 2
Figure A9619420601181
Scheme 3 Scheme 3 (continuing) Scheme 4
Figure A9619420601211
Scheme 5 Scheme 5 (continuing)
Figure A9619420601231
Scheme 6
Figure A9619420601241
Scheme 6 (continuing) Scheme 7
Figure A9619420601261
Scheme 8
Figure A9619420601271
Scheme 9
Figure A9619420601281
Scheme 9 (continuing)
Figure A9619420601291
Scheme 10 Scheme 11
Figure A9619420601311
Scheme 12 Scheme 12 (continuing)
Figure A9619420601331
Scheme 13
Figure A9619420601341
Scheme 14
Figure A9619420601351
Scheme 15
Figure A9619420601361
Scheme 15 (continuing)
Figure A9619420601371
Scheme 16 Scheme 16 (continuing) Scheme 17
Figure A9619420601401
Scheme 17 (continuing)
Figure A9619420601411
Scheme 18 Reaction scheme 19
Figure A9619420601431
Reaction scheme 20 Reaction scheme 21
Figure A9619420601451
Reaction scheme 22
Figure A9619420601461
The compounds of this invention can be used as medical agent and is used for Mammals, especially human.These compounds can be used for the treatment of cancer to patient's administration.Can include but not limited to colorectal carcinoma, exocrine pancreas cancer, myeloid leukemia and neurological tumour with the cancer types example of The compounds of this invention treatment.Such tumour can result from ras gene itself sudden change, can regulate the sudden change of the active protein of Ras (being nerve fiber protein (NF-1), neu, scr, abl, lck, fyn), or other mechanism.
The compounds of this invention can suppress the methodization of farnesyl-protein transferase and oncogenes albumen Ras.The compounds of this invention also can suppress tumor vessel to be taken place, thereby influences tumor growth (JRak et al.Cancer Research, 55:4575-4580 (1995)).More such angiogenesis inhibitor performances of The compounds of this invention also can be used for treating some blindness form relevant with retinal vesselization.
The compounds of this invention also can be used for suppressing other optimum and malignant proliferation disease, wherein Ras albumen owing to oncogenes results of mutation in other gene by the activation of distortion property (promptly, Ras gene itself does not activate into the oncogenes form because of sudden change), described inhibition is to realize by the The compounds of this invention to the administration significant quantity of this type of treatment of needs.For example, the NF-1 composition is a kind of optimum proliferative imbalance.
The compounds of this invention also may can be used for treating some viral infection, is particularly useful for treating hepatitis-δ and relevant virus (J.S.Glenn et al.Science, 256:1331-1333 (1992)).
The compounds of this invention also can be used for forming the restenosis (C.Indolfi et al.Nature medicine, 1:541-545 (1995)) that prevents behind the percutaneous puncture coronary angioplasty by suppressing neointima.
The compounds of this invention also can be used for the treatment of and prevent multicystic kidney disease (D.L.Schaffner etal.American Journal of Pathology, 142:1051-1060 (1993) and B.Cowley, Jr.et al.FASEB Journal, 2:A3160 (1988)).
The compounds of this invention also can be used for the treatment of fungi infestation.
The compounds of this invention can be learned practice or separately according to standard drug, perhaps better is combined into medical composition with pharmaceutically acceptable carrier or thinner and randomly known auxiliary agent such as alum, to Mammals, better human body administration.These compounds can per os ground or parenterally, comprises through intravenously, through intramuscular, through intraperitoneal, through subcutaneous, per rectum and local route of administration administration.
For the per os purposes according to chemotherapy compound of the present invention, the compound of selecting for use can be such as with tablet or Capsule form or with formulation administrations such as aqueous pharmaceutical or suspension liquors.Under the situation of the tablet of per os purposes, common carrier comprises lactose and W-Gum, and adds lubricant such as Magnesium Stearate usually.For the oral administration with capsule formulation, the available thinner comprises lactose and dried corn starch.When the per os purposes needs the aqueous suspension liquor, with effective constituent and emulsifying agent and suspension agent combination.If wish, can also add some sweetener and/or drug flavoring.For through intramuscular, through intraperitoneal, through subcutaneous and, prepare the sterile solution of effective constituent usually, and the pH of these solution should regulate suitably and cushion through intravenous purposes.For through intravenous purposes, the total concn of solute should be controlled, in the hope of giving said preparation with isotonicity.
Compound of the present invention also can with other well-known therapeutical agent administration in the lump, these therapeutical agents are to select according to its specific availability to the illness for the treatment of.For example, The compounds of this invention can be used for and known anticancer agents and cytotoxic agent combination.Similarly, The compounds of this invention can be used for and the medicament combination that can effectively treat and prevent following disease: NF-1, restenosis, multicystic kidney disease, hepatitis-δ and relevant virus infection, and fungi infestation.
If be mixed with fixed dosage, then such combination product adopts beneficial agents on interior The compounds of this invention of the following stated dosage range and the other medicines in the permissible dose scope thereof.When combination formula is inapplicable, compound of the present invention can also be in certain sequence on known drug acceptable medicament use.
A kind of medical composition is also contained in the present invention, and it can be used for cancer therapy, comprise the The compounds of this invention of a certain treatment significant quantity administration, have or do not have pharmaceutically acceptable carrier or thinner.Suitable compositions of the present invention comprises containing can accept carrier such as salt solution, pH level for such as 7.4 aqueous pharmaceutical on The compounds of this invention and the medicine.These solution can be introduced in patient's the blood flow with topica group injection (local bolus injection) method.
When according to compound of the present invention during to the human object administration, per daily dose will be determined by the prescription doctor usually, and this dosage is generally different because of the seriousness of age, body weight and the reaction of individual patients and patient's symptom.
In a kind of exemplary application, to the compound of a certain proper amt of Mammals administration of accepting cancer therapy.Dosage is about 0.1mg/kg body weight～about 60mg/kg body weight every day, is preferably about 0.5mg/kg body weight every day～about 40mg/kg body weight.
The compounds of this invention also can be used as a kind of composition, is used for determining rapidly the existence of a certain composition farnesyl-protein transferase (FPT enzyme) and the test of quantity.For example, composition to be tested can be divided into two parts, make these two parts to contact with the mixture of farnesyl pyrophosphate, and contain a kind of compound of the present invention in one of these mixtures with a kind of known action thing that contains the FPT enzyme (for example, the tetrapeptide of a halfcystine being arranged at its amine end).After this test, with one technical well-known enough period of each mixture incubation, make this FPT enzyme can allow this Substrate farnesylation, the chemical content of test mixture can be determined with well-known immunological technique, radiological chemistry technology or chromatographic technique.Because The compounds of this invention is the selective depressant of FPT enzyme, thereby for the existence of no change Substrate in the test that contains The compounds of this invention, not the existing or quantitatively reduce of Substrate quantity in the test mixture of no The compounds of this invention is exactly the indication of the existence of FPT enzyme in the composition to be tested.
It is evident that for the personnel that the general technical ability of this gate technique is arranged above-described a kind of like this test will can be used for differentiating the tissue sample that contains farnesyl-protein transferase and this enzyme is carried out quantitatively.Therefore, potent inhibitor compound of the present invention can be used for being intended to determine the reactive site burette test of the quantity of enzyme in the sample.The known action thing that contains the tissue extract of unknown quantity farnesyl-protein transferase, excessive FPT enzyme by some parts (for example, the tetrapeptide that a halfcystine is arranged at its amine end) and a series of samples of forming of farnesyl pyrophosphate, one section reasonable time of incubation in the presence of the The compounds of this invention of different concns.Make the enzymic activity of this sample suppress the concentration of 50% needed a kind of enough potent inhibitors (being the concentration much smaller inhibitor of its Ki), approximate half of concentration of this enzyme in this specific sample greatly than enzyme in test container.
Example
The example that is provided is intended to help further understand the present invention.The certain material, species and the condition that adopt, its intention is to further specify the present invention, and is not restrictive in its zone of reasonableness.It is with 40 * 100mm Waters PrepPa that the HPLC method is purified Anti-phase HPLC post (Delta-Pak TMC18 15 μ m, 100 ) finish.Gradient elution adopts 0.1% trifluoroacetic acid aqueous solution (solvent orange 2 A) and 0.1% trifluoroacetic acid acetonitrile solution (solvent B).The muriate salt is by means of making the trifluoroacetic acid salt brine solution by a Biorad AG 3 * 4 ion exchange resin columns (100～200 orders, Cl-type) obtain.Each example all utilizes the HPLC method to purify in the example of below mentioning 1～23,27,48 and 49.
Example 1
2 (S-)-butyl-1-(2,3-diamino third-1-yl)-4-(1-naphthoyl Base)-piperazine trihydrochloride salt
Steps A: 1-benzyl-3 (S)-normal-butyl piperazine-2,5-diketone
Title compound is to exist according to John S.Kiely and Stephen R.Priebe Organic Preparations and Procedures Int., 22 (6), the program preparation described in the 761-768 (1990).In view of the above, (9.33g, dichloromethane solution 45.2mmol) (0.5M) adds in the methylene dichloride (250ml) dicyclohexyl carbodiimide.This solution is cooled to 0 ℃ under nitrogen, and interpolation Boc-L-nor-leucine (10.5g, 45.2mmol).Resulting soup compound stirred 5 minutes, add then the N-n-benzylglycine ethyl ester (8.72g, 45.2mmol).This is reflected at 0 ℃ and stirred 2 hours, spends the night 20 ℃ of stirrings then.Throw out is removed by filter, allow hydrogen chloride gas pass through the dichloromethane solution bubbling 2～4 hours, show that until TLC this reaction finishes.Vacuum removal solvent, residue distribute between ethyl acetate (150ml) and saturated sodium bicarbonate solution (42ml).Dried over mgso, filtration and evaporation are washed, used to organic phase with saturated sodium-chloride.Thick diketopiperazine is developed with hexane, provides the white powder title compound. 1H?NMR(300MHz，CDCl 3)δ7.24-7.40(5H，m)，6.22(1H，brs)，4.07(1H，dt，J＝3，6Hz)，3.87(1H，d，J＝17Hz)，3.80(1H，d，J＝17?Hz)，1.88(2H，m)，1.35(4H，m)，0.91(3H，t，J＝7Hz).
Step B:4-benzyl-1-tertbutyloxycarbonyl-2 (S)-normal-butyl piperazine
The product of steps A (4.95g 0.019mol) is dissolved among the THF (200ml), is cooled to 0 ℃ on the following mechanical stirring of nitrogen limit.Slowly add lithium aluminum hydride (2.60g, 0.0685mol).This reaction refluxed 18 hours, was cooled to 0 ℃, and slowly added 5ml H successively 2O, 5ml 10% sodium hydroxide solution and 5ml H 2O stops reaction.Reactant stirred 30 minutes, filtered.The vacuum removal solvent, crude product is collected with methylene dichloride, uses dried over mgso.With the siccative filtering and removing, (4.35g 0.020mol) handles filtrate with di-t-butyl dicarbonate.At 20 ℃ after 2 hours, add saturated sodium bicarbonate.With two separate, organic phase is washed with saturated sodium-chloride water solution, uses dried over mgso then.Filter and evaporation, provide crude product, recycle silicon glue column chromatography is purified with 5% ethyl acetate-hexane solution wash-out.Obtain the spumescence title compound. 1HNMR(300MHz，DMSO-d 6)δ7.25(5H，m)，3.90(1H，br?s，)，3.73(1H，d，J＝13?Hz)，3.51(1H，d，J＝13Hz)，3.34(1H，d，J＝13Hz)，2.93(1H，m)，2.75(1H，d，J＝11Hz)，2.62(1H，d，J＝11Hz)，1.90(2H，m)，1.60(2H，m)，1.38(9H，s)，1.26(2H，m)，1.04(2H，m)，0.84?(3H，t，J＝7Hz).
Step C:1-tertbutyloxycarbonyl-2 (S)-normal-butyl piperazine
(3.75g 11.3mmol) is dissolved in the interior methyl alcohol (75ml) of Parr bottle this container argon purge to the product of step B.Carry palladium (0.80g) to wherein adding 10% charcoal, reactant hydrogenation 24 hours under the 60psi hydrogen pressure.(Celite) removes by filter catalyzer by diatomite, and filtrate vacuum-evaporation provides the oily title compound. 1H?NMR(300?MHz，CDCl 3)δ4.08(1H，br?s)，3.90(1H，d，J＝12Hz)，2.5-3.8(6H，m)，1.80(1H，m)，1.60(1H，m)，1.46(9H，s)，1.30(4H，m)，0.90(3H，t，J＝7Hz).
Step D:1-tertbutyloxycarbonyl-2 (S)-normal-butyl-4-(1-naphthoyl) -piperazine
In the dimethyl formamide (7ml) of drying, the degassing, add 1-tertbutyloxycarbonyl-2 (S)-normal-butyl piperazine (0.325g, 1.34mmol), I-hydroxybenzotriazole (HOBT) (0.203g, 1.34mmol) and 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDCHCl) (0.254g, 1.34mmol).The pH of reactant is adjusted to 7 with triethylamine, and reaction was stirred 2 hours.Decompression steams dimethyl formamide (DMF), and residue distributes between ethyl acetate and water.Organic phase is used dried over mgso with 2% aqueous potassium hydrogen sulfate, saturated sodium bicarbonate solution, saturated nacl aqueous solution washing.Obtain viscous crude shape title compound.
Step e: 2 (S)-normal-butyl-4-(1-naphthoyl)-piperazine hydrochloride
The product of step D is dissolved in the ethyl acetate, is cooled to-40 ℃ under nitrogen, and solution is saturated with HCl (g).Make solution in 30 minutes, go back up to 0 ℃, use nitrogen purging then.Decompression removes solvent.Product evaporates 3 times with ethyl acetate.Obtain the white solid title compound.
Step F: 2,3-two (t-butoxycarbonyl amino) propionic acid
(2.86g 0.0204mol) is suspended in and contains triethylamine (5.97ml is in 1: 1 water ,-dioxs (100ml) 0.0204mol) diaminopropionic acid one hydrochloride.(11.0g 0.0448mol), adds triethylamine so that pH regulator to 9.5 simultaneously in addition to add BOC-ON.Reactant spends the night in 20 ℃ of stirrings under nitrogen.Limpid solution with water dilution is with diethyl ether (5 * 100ml) extractions.The aqueous solution is adjusted to pH1 with 5% cold aqueous hydrochloric acid, uses ethyl acetate extraction.Dried over mgso is used in organic layer water, saturated nacl aqueous solution washing then.Resulting foams (5.46g) are used the ethyl acetate crystallization, provide the white solid title compound.
Step G:N-methoxyl group-N-methyl-2,3-two (t-butoxycarbonyl amino) third Acid amides
In the dimethyl formamide (25ml) 2,3-two (t-butoxycarbonyl amino) propionic acid (1.80g, 5.92mmol), with N-methoxyl group-N-methylamine hydrochloride (0.635g, 6.51mmol), EDCHCl (1.24g, 6.51mmol), N-hydroxybenzotriazole (0.80g, 5.92mmol) and triethylamine (0.825ml 5.92mmol) stirs together and spends the night.Decompression removes dimethyl formamide, and residue distributes between ethyl acetate and water.Organic phase is used dried over mgso with 10% hydrochloric acid, saturated sodium bicarbonate solution, saturated common salt water washing.Crude product is purified with 30% eluent ethyl acetate in the hexane with silica gel column chromatography.Obtain the spumescence title compound.
1HNMR(CDCl 3，300MHz)d?5.51(1H，br?d)，4.87(1H，brs)，4.72(1H，br?s)，3.77(3H，s)，3.50(1H，m)，3.40(1H，dt，J＝12，6Hz)，3.20(3H，s)，1.44(9H，s)，1.42(9H，s).
Step H:2,3-two (t-butoxycarbonyl amino) propionic aldehyde
(0.384g 10.14mmol) is suspended in the diethyl ether (20ml) lithium aluminum hydride, is cooled to-45 ℃ under nitrogen.So that temperature of reaction the speed below-35 ℃ of remaining on is added the N-methoxyl group-N-methyl-2 in 1: 1 ether-tetrahydrofuran (THF) (60ml), and 3-two (t-butoxycarbonyl amino) propionic acid amide (2.07g, 5.96mmol).Make reaction go back up to 5 ℃, be cooled to-45 ℃ then again, (3.08g, 22.6mmol) water (20ml) solution makes reaction terminating with sal enixum.Reactant stirred 1 hour at 20 ℃, passed through diatomite filtration then.Organic phase is used dried over mgso then with 10% citric acid and saturated common salt water washing.Obtain the spumescence title compound.NMR(CDCl 3，300Mhz)d9.61(1H，s)，5.60(1H，br?s)，4.88(1H，br?s)，4.24(1H，br?d，J＝6Hz)，3.68(1H，m)，3.50(1H，m)，1.40(9H，s)，1.39(9H，s).
Step I:1-[2.3-two (t-butoxycarbonyl amino) third-1-yl]-2 (S)- Butyl-4-(1-naphthoyl)-piperazine
(1.83g, 6.20mmol) (0.17ml, ethylene dichloride 2.9mmol) (20ml) solution is adjusted to pH 5.5 with triethylamine to 3 (S)-butyl-1-(1-naphthoyl) piperazine for (free alkali of the product of step e), acetate.(1.87g, 8.79mmol) with pulverizing molecular sieve (1g), this is reflected at and is cooled to 0 ℃ under the nitrogen to add sodium triacetoxy borohydride.Drip 2, (reactant spends the night 20 ℃ of stirrings 3-two (t-butoxycarbonyl amino) propionic aldehyde for 1.69g, ethylene dichloride 5.86mmol) (10ml) solution.Reactant is cooled to 0 ℃, makes reaction terminating with saturated sodium bicarbonate, stirs 1 hour.With 2 layers of separation, dried over mgso is used in organic layer saturated common salt water washing then.Crude product is purified with silica gel column chromatography, with 40～50% eluent ethyl acetates in the hexane, isolates spumescence title compound (Rf 0.30,50% ethyl acetate in the hexane).
Step J:1-(2,3-diamino third-1-yl)-2 (S)-butyl-4-(1 -naphthoyl)-piperazine hydrochloride
To 1-[2,3-two (t-butoxycarbonyl amino) third-1-yl] (2.13g adds trifluoroacetic acid (25ml) in methylene dichloride 3.75mmol) (75ml) solution to-2 (S)-butyl-4-(1-naphthoyl)-piperazine.At 20 ℃ after 25 minutes, solvent is steamed, residue distributes between chloroform and 20% aqueous sodium hydroxide solution.Dried over mgso is used in organic layer saturated common salt water washing.Obtain the free alkali of title compound, be yellow gluey (1.72g).A this material (52mg) is by using a 100mm Waters PrepPak Anti-phase post (DeltaPak TMC-18,50mM, 100 ) preparation HPLC purify, pure products separates with the gradient elution method, use be the 100%[0.1% trifluoroacetic acid aqueous solution] (solvent orange 2 A) to 50% solvent orange 2 A and 50%[0.1% trifluoroacetic acid-acetonitrile solution] (solvent B).Merge pure fraction and steam solvent, crude product is dissolved in the water, by a radical ion exchange column (Biorad AG 3 * 4 ion exchange resin, chloride type).After the lyophilize, obtain the white solid title compound.Analytical calculation value C 22H 32N 404.45HCl:
C，49.78；H，6.92；N，10.56。Measured value: C, 49.75; H, 6.72; N, 10.36.
Example 2
1-(3-amino-2-(2-naphthyl methyl amino) third-1-yl)-2 (S) -butyl-4-(1-naphthoyl)-piperazine trihydrochloride salt
Steps A: 1-[2-amino-3-(t-butoxycarbonyl amino) third-1-yl]- 2 (S)-butyl-4-(1-naphthoyl)-piperazine
To 4-(2,3-diamino third-1-yl)-2 (S)-butyl-1-(1-naphthoyl) piperazine (0.476g, add in methylene dichloride 1.29mmol) (10ml) solution tert-Butyl dicarbonate (0.282g, 1.29mmol).Reactant stirred 2 hours altogether at 20 ℃, termination reaction then, water extraction.Dried over mgso is used in organic phase saturated common salt water washing.Crude product is purified with silica gel column chromatography, earlier with 5% methyl alcohol chloroformic solution, use 5% (9: 1 methanol-hydrogen ammonium oxide) chloroformic solution wash-out then, isolates title compound as staple crop FAB ms (m+1) 469.
Step B:1-[3-t-butoxycarbonyl amino-2-(2-naphthyl methyl amino) third -1-yl]-2 (S)-butyl-4-(1-naphthoyl)-piperazine
Title compound prepares according to program described in the example 1 step D; different is to use the amino third-1-yl of 1-[2-amino-3-(tertbutyloxycarbonyl)]-2 (S)-butyl-4-(1-naphthoyl)-piperazine (0.287g; 0.613mmol), naphthalene-2-formaldehyde (0.95g; 0.613mmol), sodium triacetoxy borohydride (0.194g; 0.919mmol), in methylene dichloride (15ml), carry out at pH6.Crude product is purified with silica gel column chromatography, with 5% methyl alcohol chloroformic solution (Rf 0.30) wash-out, isolates the foam title compound.FAB?ms(m+1)609。
Step C:1-(3-amino-2-(2-naphthyl methyl amino) third-1-yl) -2 (S)-butyl-4-(1-naphthoyl)-piperazine trihydrochloride salt
1-[3-t-butoxycarbonyl amino-2-(2-naphthyl methyl amino) third-1-yl]-2 (S)-butyl-4-(1-naphthoyl)-piperazine (0.313g; 0.514mmol) methylene dichloride (10ml) solution with trifluoroacetic acid (5ml) deprotection, and change into free alkali (255mg) according to the program described in example 1 step e.40mg is by the purification of preparation HPLC, adopts with solvent orange 2 A and B (from example 1; 95% → 5% solvent orange 2 A) gradient elution of carrying out.Ion-exchange as previously discussed and lyophilize provide the white solid title compound.FAB?ms(m+1)509。Analyze: calculated value C 33H 40N 4O0.05H 2O4.45HCl:
C，59.00；H，6.68；N，8.34。Measured value: C, 59.00; H, 6.51; N, 8.44.
Example 3
2 (S)-butyl-1-{5-[1-(2-naphthyl methyl)]-4, the 5-glyoxalidine } first Base-4-(1-naphthoyl)-piperazine two (trifluoroacetic acid) salt
1-(3-amino-2-(2-naphthyl methyl amino) third-1-yl)-2 (S)-butyl-4-(1-naphthoyl)-piperazine (0.105g; 0.207mmol), tertiary butyl isocyanic ester (1.5ml) and silver cyanide (0.023g, 0.207mmol) under nitrogen in tube sealing 90 ℃ of heated overnight.Decompression removes volatile matter, and residue is purified with silica gel column chromatography, with 5-10% methyl alcohol chloroformic solution wash-out, provides free alkali (73mg).This free alkali is purified with the preparation HPLC described in the example 1, uses solvent orange 2 A and B (from example 1; 95% → 5% solvent orange 2 A) carries out gradient elution.Lyophilize provides the white solid title compound.FAB?ms(m+1)519。Analyze: calculated value C 34H 38N 4O0.85H 2O3.75TFA:
C，51.84；H，4.55；N，5.83。Measured value: C, 51.83; H, 4.56; N, 6.32.
Example 4
1-[5-(1-benzyl imidazole) methyl]-2 (S)-butyl-4-(1-naphthoyl Base)-piperazine dihydrochloride
Under nitrogen in 20 ℃, to 2 (S)-butyl-1-[5-(3-trityl imidazole)] methyl-4-(1-naphthoyl)-piperazine (and 63mg, add in acetonitrile 0.103mmol) (0.5ml) solution bromotoluene (0.012ml, 0.103mmol).Reactant stirs and spends the night, and vacuum concentration is collected with the methylene dichloride (2ml) that contains triethyl-silicane (0.100ml).Add trifluoroacetic acid, reactant stirred 1 hour at 20 ℃.Steam solvent, residue is purified with HPLC (95% → 5% solvent orange 2 A).Pure fraction merges, and changes into HCl salt described in example 1 step e.Behind the cooling drying, isolate the white solid title compound.FAB?ms(m+1)467。Analyze: calculated value C 30H 34N 4O0.05H 2O3.70HCl:
C，59.81；H，6.32；N，9.30。Measured value: C, 59.78; H, 6.33; N, 9.30.
Example 5
1-{5-[1-(4-nitrobenzyl)] imidazolyl methyl }-2 (S)-butyl-4- (1-naphthoyl)-piperazine two (trifluoroacetic acid) salt
Title compound is to prepare according to the program described in the example 4; different is to use nitrobenzyl bromine (0.043g; 0.199mmol) and 2 (S)-butyl-1-[5-(3-trityl imidazole)] methyl-4-(1-naphthoyl)-piperazine (123mg, acetonitrile 0.199mmol) (2ml) solution.Crude product in ethylene dichloride (4ml) with triethyl-silicane (0 127ml, 0.80mmol) and trifluoroacetic acid (2ml) processing.Preparation HPLC (95～5% solvent orange 2 A) provides the white solid title compound.FAB?ms(m+1)512。Analyze: calculated value C 30H 33N 5O 32CF 2CO 2H0.03H 2O:
C，41.42；H，3.98；N，10.18。Measured value: C, 41.43; H, 3.96; N, 10.51.
Example 6
1-(3-kharophen methylthio group-2 (R)-amino third-1-yl)-2 (S)-Ding Base-4-(1-naphthoyl)-piperazine two (trifluoroacetic acid) salt
1-(3-kharophen methylthio group-2 (R)-amino third-1-yl)-2 (S)-butyl-4-(1-naphthoyl)-piperazine dihydrochloride and N-hydroxymethyl acetamide (0.010g; 0.105mmol) (press M Bodansky; A.Bodansky; " The Practice ofPeptide Synthesis "; Sprmger-Verlag; 1984, p.82 described in method preparation) dissolving 0.5 hour in trifluoroacetic acid.The vacuum removal solvent, residue is purified with preparation HPLC (85～60% solvent orange 2 A).After the lyophilize, isolate the solid state title compound.FAB?ms(m+1)457。Analyze: calculated value C 25H 36N 4O 2S2CF 2CO 2H1.9H 2O:
C，44.38；H，5.12；N，6.64。Measured value: C, 44.35; H, 5.11; N, 6.97.
Example 7
2 (S)-butyl-1-[2-(1-imidazolyl) ethyl] alkylsulfonyl-4-(1-naphthalene Formyl radical)-piperazine two (trifluoroacetic acid) salt
Steps A: 2 (S)-butyl-4-(1-naphthoyl)-1-vinylsulfonyl Piperazine
To 3 (S)-butyl-1-(1-naphthoyl) piperazine (0.095g, 0.285mmol) and diisopropylethylamine (0.119ml, add in methylene dichloride 0.685mmol) (3ml) solution chloroethyl SULPHURYL CHLORIDE (0.038ml, 0.314mmol).Reactant stirs under nitrogen and spends the night, and uses the saturated sodium bicarbonate termination reaction, uses ethyl acetate extraction.After dried over mgso, isolate title compound.
Step B:2 (S)-butyl-1-[2-(1-imidazolyl) ethyl] alkylsulfonyl-4- (1-naphthoyl)-piperazine two (trifluoroacetic acid) salt
Sodium hydride in being suspended in dimethyl formamide (2ml) (60% oil based dispersions, 0.024g, 0.598mmol) add imidazoles (0.043g, 0.627mmol).Under nitrogen, reactant is cooled to 0 ℃, adds 2 (S)-butyl-4-(1-naphthoyl)-1-vinylsulfonyl piperazine (0.011g, dimethyl formamide 0.29mmol) (5ml) solution.Reactant spends the night 20 ℃ of stirrings.The vacuum removal dimethyl formamide, residue is dissolved in the ethyl acetate.This solution is used dried over mgso with saturated sodium bicarbonate solution, saturated aqueous common salt extraction.Crude product earlier with silica gel column chromatography with 8% methyl alcohol chloroformic solution wash-out, use preparation HPLC (80～40% solvent orange 2 A) purification then.Trifluoroacetate is dissolved in the water, and between saturated sodium bicarbonate and ethyl acetate, distributes.Organic phase with the saturated common salt water washing, use dried over mgso.Obtain the spumescence title compound.FAB?ms(m+1)455。Analyze: calculated value C 25H 36N 4O 2S0.8H 2O:
C，61.46；H，6.79；N，11.95。Measured value: C, 61.44; H, 6.97; N, 10.72.
Example 8
2 (R)-butyl-1-imidazolyl-4-methyl-4-(1-naphthoyl)-piperazine Piperazine
Steps A: 2 (R)-butyl-4-(1-naphthoyl)-(1-three for 1-[4- The phenmethyl imidazolyl) methyl] piperazine
In the presence of the pulverizing molecular sieve; in ethylene dichloride (7ml); make 3 (R)-butyl-1-(1-naphthoyl) piperazine (0.202g; 0.607mmol) (according in the example 1 the described method of (S) enantiomorph being prepared) and 1-trityl imidazole-4-formaldehyde (0.226g; 0.667mmol), sodium triacetoxy borohydride (0.321g, 1.52mmol) reaction.PH is adjusted to 5～6 with triethylamine/acetate.Reactant stirs and spends the night, and uses the saturated sodium bicarbonate termination reaction then.Organic layer with the saturated common salt water washing, use dried over mgso.Crude product is purified with silica gel column chromatography, earlier with 30% acetate hexane solution, use 5% methyl alcohol chloroform wash-out then, obtains title compound.
Step B:2 (R)-butyl-1-imidazolyl-4-methyl-4-(1-naphthoyl Base)-piperazine two (trifluoroacetic acid) salt
To 2 (R)-butyl-4-(1-naphthoyl)-1-[4-(1-trityl imidazole base) methyl] (0.381g, (1.0ml 11.80mmol), adds trifluoroacetic acid (8ml) to piperazine subsequently to add triethyl-silicane in dichloromethane solution 0.616mmol).After 1 hour, with solvent evaporation, residue distributes between water and hexane.Water is injected directly into (100～40% solvent orange 2 A) on the preparation HPLC post, isolates title compound after the lyophilize.FAB?ms(m+1)377。Analyze: calculated value C 25H 36N 4O 22.35CF 3CO 2H0.32H 2O:
C，48.93；H，4.52；N，7.98。Measured value: C, 48.93; H, 4.55; N, 8.26.
Example 9
2 (S)-butyl-4-(1-naphthoyl)-1-(3-pyridylmethyl) piperazine two Hydrochloride
Described in example 8 steps A; in the presence of the pulverizing molecular sieve; in ethylene dichloride (7ml) in pH5～6; make 3 (S)-butyl-1-(1-naphthoyl) piperazine hydrochloride (0.200g; 0.601mmol) and pyridine-3-formaldehyde (0.062ml; 0.661mmol), sodium triacetoxy borohydride (0.321g, 1.52mmol) reaction.Crude product is purified with silica gel column chromatography, with 30% acetone hexane solution wash-out, uses preparation HPLC (80～75% solvent orange 2 A) to purify subsequently.After ion-exchange, isolate title compound.FAB?ms(m+1)388。Analyze: calculated value C 25H 29N 3O2.3HCl0.95H 2O:
C，61.49；H，6.85；N，8.60。Measured value: C, 61.49; H, 7.01; N, 8.76.
Example 10
1-2 (S)-butyl-(2 (R)-(4-nitrobenzyl) amino-3-hydroxypropyl) -4-(1-naphthoyl)-piperazine dihydrochloride
According to program described in example 8 steps A; 4-nitrobenzaldehyde (0.493g is arranged; 0.327mmol), sodium triacetoxy borohydride (0.173g; 0.817mmol); in ethylene dichloride; (120mg 0.326mmol) changes into title compound to make 1-(2 (R)-amino-3-hydroxypropyl)-2 (S)-butyl-4-(1-naphthoyl) piperazine.Crude product is purified with preparation HPLC (100～75% solvent orange 2 A), after ion-exchange becomes HCl salt and lyophilize, obtains title compound.FAB?ms(m+1)505。Analyze: calculated value C 25H 29N 3O3.6HCl0.10H 2O:
C，54.69；H，6.30；N，8.80。Measured value: C, 54.66; H, 5.85; N, 8.31.
Example 11
1-(2 (R)-amino-3-hydroxyl heptadecyl)-2 (S)-butyl-4-(1 -naphthoyl)-piperazine two (trifluoroacetic acid) salt
Steps A: 1-(2 (R)-t-butoxycarbonyl amino-2-formyl ethyl)-2 (S)- Butyl-4-(1-naphthoyl)-piperazine
Oxalyl chloride (1.36ml, methylene dichloride 14.9mmol) (35ml) solution is cooled to-65 ℃ under nitrogen, and (reactant stirred 2 minutes for 2.30ml, methylene dichloride 32.4mol) (7ml) solution to add dimethyl sulfoxide (DMSO).Add 1-(2 (R)-amino-3-hydroxypropyl)-2 (S)-butyl-4-(1-naphthoyl)-piperazine (3.19g6.79mmol) solution at-10 ℃ in this solution, reactant stirred 15 minutes in this temperature.Reactant is cooled to-55 ℃, and the interpolation triethylamine (4.76ml, 34mmol).Reactant stirred 5 minutes, went back up to room temperature then.Add extra methylene dichloride, the extraction of reactant water.Organic phase is with 2% sal enixum, water, dilute sodium bicarbonate solution, saturated common salt water washing.After dried over mgso, obtain title compound.
Step B:1-(2 (R)-amino-3-hydroxyl heptadecyl)-2 (S)-butyl- 4-(1-naphthoyl)-piperazine two (trifluoroacetic acid) salt
In a flame-dried three-necked flask, under nitrogen, (0.25g, anhydrous tetrahydro furan 0.53mmol) (5ml) solution is cooled to 0 ℃ to make 1-(2 (R)-t-butoxycarbonyl amino-2-formyl ethyl)-2 (S)-butyl-4-(1-naphthoyl)-piperazine.(1.01ml 1M diethyl ether solution 1.01mmol), allows reactant go back up to room temperature to add chlorination heptadecyl magnesium solution with syringe.Reactant saturated sodium bicarbonate solution termination reaction, ethyl acetate extraction then.After dried over mgso, crude product is purified with silica gel column chromatography, with 25% ethyl acetate isohexane solution, use 5% methyl alcohol chloroformic solution wash-out then.Product behind the purifying is dissolved in the methylene dichloride (7ml), handles with trifluoroacetic acid (3.5ml).After 45 minutes, the vacuum removal solvent, residue is purified with preparation HPLC (95～40% solvent orange 2 A).Separate two kinds of isomer.After the lyophilize, isolate title compound diastereomer A (retention time 8.405 minutes, the gradient in 15 minutes is 100～50% solvent orange 2 As), FAB ms (m+1) 566 analyzes: calculated value C 36H 59N 3O 22.35CF 3CO 2H0.35H 2O.C，58.19；H，7.44；N，5.00。Measured value: C, 58.21; H, 7.46; N, 5.36.After the lyophilize, also isolate title compound diastereomer B (retention time 9.269 minutes, the gradient in 15 minutes is 100～50% solvent orange 2 As), FABms (m+1) 566 analyzes: calculated value C 36H 59N 3O 22.35CF 3CO 2H0.05H 2O.C，58.56；H，7.42；N，5.03。Measured value: C, 58.53; H, 7.41; N, 5.17.
Example 12
2 (S)-benzyl-1-imidazolyl-4-methyl-4-(1-naphthoyl)-piperazine
Steps A: 1,3 (S)-dibenzyl piperazine-2,5-diketone
Title compound prepares according to program described in example 1 steps A, different is to use Boc-L-phenylalanine (12.8g, 48.2mmol), N-n-benzylglycine ethyl ester (9.32g, 48.2mmol) and dicyclohexyl carbodiimide (96.5ml 0.5M dichloromethane solution, 48.2mmol).Thick diketopiperazine is developed with hexane, provides the white powder title compound. 1HNMR(300?MHz，CD 3OD)δ7.0-7.4(10H，m)，4.61(1H，d，J＝16Hz)，4.37(1H，t，J＝5Hz)，4.24(1H，d，J＝16Hz)，3.42(1H，d，J＝18Hz)，3.28(1H，dd，J＝4，16Hz)，2.96(1H，dd，J＝6，16Hz)，2.55(1H，d，J＝18Hz).
Step B:1-tertbutyloxycarbonyl-2 (S), 4 (S)-dibenzyl piperazines
This title compound is according to the preparation of program described in the example 1 step B, and different is to use 1,3 (S)-dibenzyl piperazine-2, the 5-diketone (5.01g, 17.1mmol) and lithium aluminum hydride (2.33g, 61.4mmol), add subsequently di-t-butyl dicarbonate (4.02g, 18.4mmol).Crude product is purified with silica gel column chromatography, with 7.5% ethyl acetate-hexane solution wash-out.Obtain the white solid title compound. 1H?NMR(300MHz，CD 3OD)δ7.2-7.4(5H，m)，7.0-7.2(5H，m)，4.15(1H，m)，3.90(1H，d，J＝15Hz)，3.60(1H，d，J＝15Hz)，3.15(1H，m)，2.95(3H，m)，2.7(1H，d，J＝13Hz)，2.02(1H，dt，J＝6，13Hz)，1.95(1H，br?d)，1.35(9H，s).
Step C:2 (S)-benzyl-1-tert-butoxycarbonyl-piperazine
This title compound is according to the preparation of program described in the example 1 step C, and different is to use 1-tertbutyloxycarbonyl-2 (S), and (4.78g 11.3mmol) carries palladium (1.04g) with 10% charcoal to 4-dibenzyl piperazine.Obtain the oily title compound.
1H?NMR(300MHz，CD 3OD)δ7.25(5H，m)，4.35(1H，m)，4.00(1H，d，J＝12?Hz)，2.7-3.3(7H，m)，1.25(9H，s).
Step D:2 (S)-benzyl-1-tertbutyloxycarbonyl-4-(1-naphthoyl)- Piperazine
This title compound is according to the described program preparation of example 1 steps A, different is to use 2 (S)-benzyl-1-tert-butoxycarbonyl-piperazine (0.292g, 1.06mmol), 2,3-mesitylenic acid (0.159g, 1.06mmol), HOBT (0.157g, 1.02mmol), EDCHCl (0.213g, 1.11mmol) and pH can be transferred to 7 triethylamine.Obtain viscous crude shape title compound. 1HNMR(DMSO-d 6，300MHz)δ7.15(2H，m)，6.06(1H，m)，4.42(1H，m)，3.6-4.2(2H，m)，2.7-3.24(4H，m)，2.24(3H，s)，2.03-2.20(3H，4s)，1.10-1.6(15H，m)，0.72-1.00(3H，m)。
Step e: 2 (S)-benzyl-4-(1-naphthoyl)-1-[4-(1-triphen Methylimidazolyl) methyl] piperazine
Described in example 8 steps A; in the presence of the pulverizing molecular sieve; in ethylene dichloride (7ml); make 3 (S)-benzyl-1-(1-naphthoyl) piperazine (0.173g; 0.472mmol) and 1-trityl imidazole-4-formaldehyde (0.160g; 0.472mmol), sodium triacetoxy borohydride (0.300g, 1.42mmol) reaction.Obtain the oily title compound.
Step F: 2 (S)-benzyl-1-imidazolyl-4-methyl-4-(1-naphthoyl Base)-piperazine two (trifluoroacetic acid) salt
With triethyl-silicane (0.300ml; 1.89mmo) add 2 (S)-benzyl-4-(1-naphthoyl)-1-[4-(1-trityl imidazole base) methyl to] piperazine (0.310g; 0.472mmol) methylene dichloride (5ml) solution in, add trifluoroacetic acid (5ml) subsequently.After 1 hour solvent is steamed, residue distributes between water and hexane.Water is injected directly into (85～45% solvent orange 2 A) on the preparation HPLC post, isolates title compound after the lyophilize.FAB?ms?(m+1)411。Analyze: calculated value C 26H 26N 4O 22.75CF 3CO 2H0.05H 2O:
C，52.11；H，4.14；N，7.72。Measured value: C, 52.10; H, 4.03; N, 8.16.
Example 13
1-(2 (R)-amino-3-(3-benzylthio-) propyl group)-2 (S)-butyl-4 -(1-naphthoyl)-piperazine two (trifluoroacetic acid) salt
Steps A: the methyl 1-[(1-aziridinyl)]-2 (S)-butyl-4-(1- Naphthoyl)-piperazine
(1.67g, dimethyl formamide 3.56mmol) (DMF) (10ml) is cooled to 0 ℃ in nitrogen with 1-(2 (R)-butoxy carbonyl amino-3-hydroxypropyl)-2 (S)-butyl-4-(1-naphthoyl)-piperazine.Add sodium hydride (0.427g, 10.6mmol, 60% oily dispersion liquid), then add 1,1 again '-the sulphonyl diimidazole (0.704g, 3.56mol).Reactant is warmed to 20 ℃, kept 1 hour, be cooled to 0 ℃ again, then the water termination reaction.Vacuum distillation DMF, residue distributes between ethyl acetate and water.Organic phase is used dried over mgso after washing with saturated brine.Crude product carries out silica gel column chromatography purifies, and uses the hexane mixed solution of 70% ethyl acetate and the chloroform mixed solution wash-out of 5% methyl alcohol successively.Obtain the principal product title compound, FAB ms (m+1) 352.Also isolate more a spot of 1-[(1-butoxy carbonyl aziridinyl) methyl]-2 (S)-butyl-4-(1-naphthoyl)-piperazine.
Step B:1-(2 (R)-amino-3-(3-benzylthio-) propyl group)-2 (S)- Butyl-4-(1-naphthoyl)-piperazine two (trifluoroacetic acid) salt
The 1-[(1-aziridinyl) methyl] (0.05g, 0.142mmol) (0.100ml's-2 (S)-butyl-4-(1-naphthoyl)-piperazine 0.852mmol) and in methyl alcohol (4ml) solution of triethylamine (0.200ml) refluxed 18 hours at benzyl sulfhydrate.Crude product uses the silica gel column chromatography of the chloroform mixed solution wash-out of 3% methyl alcohol to purify earlier, purifies with preparation HPLC (85%-10% solvent orange 2 A) then.After lyophilize, obtain title compound.FAB?ms(m+1)476。Analyze: calculated value: C 29H 37N 3OS2.6CF 3CO 2H0.3H 2O:
C, 52.83; H, 521; N, 5.40 measured values: C, 52.78; H, 5.17; N, 5.66.
Example 14
1-(2 (R)-amino-3-[3-(4-nitrobenzyl sulfenyl) propyl group]))-2 (S)- Butyl-4-(1-naphthoyl)-piperazine two (trifluoroacetic acid) salt
1-[(1-butoxy carbonyl aziridinyl) methyl]-2 (S)-butyl-4-(1-naphthoyl)-piperazine (0.050g; 0.111mmol) methyl alcohol (4ml) solution (0.070g refluxed 2 hours 0.333mmol) and in the mixture of triethylamine (0.200ml) to the nitrobenzyl thioesters at acetate.Crude product carries out silica gel column chromatography purifies, with the chloroformic solution wash-out of 3% methyl alcohol.Product behind the purifying was handled 20 minutes with the dichloromethane solution of 33% trifluoroacetic acid.Product after the solvent evaporation is refining with preparation HPLC (85%-10% solvent orange 2 A).After lyophilize, obtain title compound.FAB?ms(m+1)529。Analyze: calculated value: C 29H 36N 4O 32CF 3CO 2H0.08H 2O:
C，51.94；H，5.23；N，7.34。Measured value: C, 51.87; H, 5.06; N, 7.47.
Example 15
2 (S)-butyl-1-[(4-imidazolyl) ethyl]-4-(1-naphthoyl)-piperazine The piperazine dihydrochloride
Steps A: N-methyl-N-methoxyl group-2-(1-trityl-1H-miaow Azoles-4-yl) ethanamide
(1.04g, (2.48g, (4.46ml 32mmol), at room temperature stirs this suspension 18 hours trityl bromide 6.40mmol) to add triethylamine in DMF 7.68mmol) (40ml) solution toward 4-imidazoleacetic acid.After this, this mixture 3-hydroxyl-1,2,3-phentriazine-4 (3H)-ketone (HOOBT) (1.31g, 8mmol), N, the O-dimethyl hydroxylamine hydrochloride (1.56g, 16mmol) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) (1.53g, 8mmol) handle, at room temperature stirred 24 hours.Add saturated aqueous solution of sodium bicarbonate (50ml) and water (50ml) then, gained mixture ethyl acetate extraction (2 * 100ml).The extract that merges is used saturated NaHCO successively 3The aqueous solution (100ml) and salt solution (50ml) washing, solvent vacuum-evaporation.Residue is suspended in the ether (20ml), and white solid obtains the white solid title compound after filtering. 1NMR (CD 3OD, 300MHz) δ 7.37 (10H, m), 7.16 (6H, m), 6.84 (1H, s), 3.73 (2H, s), 3.68 (3H, s) and 3.18 (3H, s) ppm. Step B:2-(1-trityl-1H-imidazol-4 yl) acetaldehyde
Toward the product of steps A (300mg, 0.73mmol) in new distillatory is cooled to solution among-40 ℃ the THF (15ml) with dry ice/acetone, add lithium aluminum hydride (33.2mg, 0.874mmol).Allow formed suspension be warmed to+5 ℃, kept 30 minutes at 0 ℃ then.After this, reaction mixture is cooled to-40 ℃ again, successively water (33 μ l), 1.0NNaOH (33 μ l) and water (100 μ l) termination reaction.With gained suspension stirring 30 minutes, filtration, vacuum removal solvent.Residue is dissolved in the methylene dichloride (5ml), uses the washing of 10% aqueous citric acid solution (5ml) and water (5ml) successively.With organic layer drying (MgSO 4), solvent obtains title compound after vacuum-evaporation. 1HNMR (CDCl 3, 300 MHz) δ 9.79 (1H, t, J=3Hz), 7.44 (1H, s), 7.4-7.1 (15H, m), 6.76 (1H, s) and 3.63 (2H, d, J=3Hz) ppm. Step C:2 (S)-butyl-1-[(4-imidazolyl) ethyl]-4-(1-naphthoyl Base)-piperazine two (trifluoroacetic acid) salt
Product (89mg toward step B; 0.263mmol) and 3 (S)-butyl-1-benzoyl-piperazine hydrochloride (62.6mg; 0.188mmol) 1, add in 2-ethylene dichloride (4ml) solution 3A molecular sieve (400mg) and sodium triacetoxy borohydride (200mg, 0.94mmol).This mixture at room temperature stirred 4 days.Then this mixture is filtered by sintered glass.Filtrate is diluted with methylene dichloride (50ml), water (25ml) washing.Solvent vacuum-evaporation, residue is purified by dodging chromatogram, with 2-5% ethanol/methylene wash-out, obtains the oily title compound of trityl as protecting group.This oil is dissolved in methylene dichloride (2ml) and the trifluoroacetic acid (1ml), uses triethyl silicane (2) to handle then, obtain a kind of colourless solution.This solution at room temperature stirred 3 hours, then vacuum evaporating solvent.In the residue water-soluble (20ml) that generates, with hexane (20ml) washing.Water layer obtains this title compound after lyophilize. 1HNMR (CD 3OD, 300 MHz) δ 8.83 (1H, s), 8.08-7.75 (3H.m), 7.67-7.49 (4H, m), 7.45 (1H, s), 4.5-3.8 (2H, m), 3.65-2.95 (9H, m), 2.0-1.3 (4H, m) and 2.2-0.2 (5H, m) ppm. analyzes: calculated value C 24H 30N 4O 3.45TFA 0.75H 2O
C，46.54；H，4.42；N，7.03。Measured value: C, 46.54; H, 4.41; N, 7.35.FAB HRMS accurate mass calculated value: C 23H 31N 4O 391.249787 (MH +), measured value 391.249028.
Example 16
2 (S)-butyl-1-[(4-imidazolyl) methyl]-4-(1-naphthoyl)- Piperazine two (trifluoroacetic acid) salt
Product (102mg toward step C; 0.30mmol) and 3 (S)-butyl-1-naphthoyl piperazine hydrochloride (62.6mg; 0.188mmol) 1; add sodium triacetoxy borohydride (200mg in 2-ethylene dichloride (5ml) solution; 0.94mmol) and triethylamine to pH=5.5, at room temperature stirred then 18 hours.After this, mixture is filtered.Filtrate is dissolved in behind vacuum concentration in the ethyl acetate (25ml), uses saturated NaHCO successively 3The aqueous solution (10ml) and salt solution (10ml) washing.Solvent vacuum-evaporation, residue is purified by dodging chromatogram, with 3-8% ethanol/methylene wash-out, obtains the title compound of trityl as protecting group.This oil is dissolved in methylene dichloride (4ml) and the trifluoroacetic acid (2ml), handles till disappearing with triethyl silicane then, obtain a kind of colourless solution.At room temperature continue to stir 10 minutes, solvent is fallen in vacuum-evaporation.The white solid that generates is partially soluble in water (7ml), filtration, filtrate prepare HPLC device and Waters PrepPak chromatographic column (47 * 300mm with Nova Prep 5000 types, C18,15 μ m, 100 dusts) being prepared HPLC purifies, with the speed wash-out (chromatography A) of 5-95% acetonitrile/water (0.1%TFA), obtain title compound after the freeze-drying with 100ml/ minute. 1HNMR (DMSO-d 6, 400 MHz, 150 ℃) and δ 8.53 (1H, s), 7.94 (2H, m), 7.79 (1H, m), 7.53 (3H, m), 7.41 (1H, m), 7.40 (1H, s), 4.12 (1H, d, J=4.8Hz), 3.95 (1H, d, J=4.8Hz), 3.70 (1H, s), 3.63 (1H, s), 3.48 (1H, s), 3.40 (1H, s), 3.01 (1H, s), 2.82 (1H, s), 2.74 (1H, s), 1.70 (1H, m), 1.49 (1H, m) .1.18 (2H, s), 1.08 (2H, s) (J=5.5Hz) ppm. analyzes and 0.77: calculated value C for 3H, t 23H 29N 4O 22TFA 0.70H 2O
C，52.55；H，5.13；N，9.08。Measured value: C, 52.54; H, 5.11; N, 9.35.FAB MS Mass Calculation value C 23H 30N 4O 377 (MH +), measured value 377.
Example 17
2 (S)-butyl-1-[(1-naphthalene-2-ylmethyl)-1H-imidazoles-5-yl) Ethanoyl]-4-(1-naphthoyl)-piperazine dihydrochloride
Steps A: the preparation of 1H-imidazoles-4-methyl acetate hydrochloride
(4.00g blasts hydrogen chloride gas till saturated in methyl alcohol 24.6mmol) (100ml) solution toward 1H-imidazoles-4-acetic acid hydrochloride.Allow this solution at room temperature leave standstill 18 hours, obtain the solid title compound that is white in color behind the vacuum evaporating solvent. 1H NMR (CDCl 3, 400MHz) δ 8.85 (1H, s), 7.45 (1H, s), 3.89 (2H, s) and 3.75 (3H, s) ppm.
The preparation of step B:1-trityl-1H-imidazol-4 yl methyl acetate
Toward the product of steps A (7.48g, add in methylene dichloride 42.4mmol) (200ml) suspension triethylamine (17.7ml, 127mmol) and trityl bromide (16.4g 50.8mmol), stirred 72 hours then.After this, reaction mixture is used saturated NaHCO successively 3The aqueous solution (100ml) and water (100ml) washing.With organic layer vacuum-evaporation, residue obtains the white solid title compound with dodging chromatographic purification (the hexane solution gradient elution of 30-100% ethyl acetate). 1H NMR (CDCl 3, 400MHz) δ 7.35 (1H, s), 7.31 (9H, m), 7.22 (6H, m), 6.76 (1H, s), 3.68 (3H, s) and 3.60 (2H, s) ppm.
Step C:2-[1-(naphthalene-2-ylmethyl)-1H-imidazoles-5-acetate first The preparation of ester
(4.36g adds 2-brooethyl naphthalene to the product of past step B in acetonitrile 11.4mmol) (70ml) solution, be heated to 55 ℃ and kept 4 hours.After this, reaction mixture is cooled to room temperature, filters and collect the white precipitate that is generated.Filtrate is concentrated into 30ml, is heated to 55 ℃, keeps 18 hours.After this, reaction mixture is cooled to room temperature.Filter and collect the white precipitate that is generated.Filtrate is concentrated into the 10ml volume, is heated to 55 ℃, keeps 1 hour.After this, again reaction mixture is cooled to room temperature, with ethyl acetate (25ml) dilution.Filter and collect the throw out that generates, be incorporated in the methyl alcohol (100ml) reflux 30 minutes with preceding 2 times throw out.After this, remove solvent under vacuum, the gained residue distributes between methylene dichloride (200ml) and sodium bicarbonate (100ml).The organic layer vaporising under vacuum is to doing, and residue is purified (0-6% ethanol/methylene gradient) with dodging chromatogram, obtains the pale solid title compound. 1HNMR (CDCl 3, 400MHz) δ 7.82 (2H, m), 7.75 (1H, m), 7.70 (1H, s), 7.49 (3H, m), 7.20 (1H, d, J=8.4Hz), 7.06 (1H, s), 5.32 (2H, s), 3.57 (3H, s) and 3.49 (2H, s) ppm.
Step D:2-[1-(naphthalene-2-ylmethyl)-1H-imidazoles-5-yl] acetate The preparation of hydrochloride
2-[1-(naphthalene-2-ylmethyl)-1H-imidazoles-5-methyl acetate is dissolved in the 2.5N hydrochloric acid (50ml), is heated to 55 ℃, keeps 3 hours.After this, solution is concentrated into dried under vacuum, obtains the white solid title compound. 1H NMR (CD 3OD, 400 MHz) δ 8.92 (1H, s), 7.94 (1H, d, J=8.6Hz), 7.88 (2H, m), 7.83 (1H, s), 7.54 (3H, m), 7.43 (1H, d, J=14Hz), 5.60 (2H, s) and 3.82 (2H, s) ppm.
Step e: 2 (S)-butyl-1-[(1-naphthalene-2-ylmethyl)-the 1H-imidazoles -5-yl) ethanoyl]-preparation of 4-(1-naphthoyl)-piperazine dihydrochloride
Product (100mg toward step D; 0.330mmol), 3 (S)-butyl-1-naphthoyl piperazine hydrochloride (100mg; 0.300mmol) and 3-hydroxyl-1; 2; 3-phentriazine-4 (3H)-ketone (HOOBT) (54mg, add in DMF 0.33mmol) (2ml) solution 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) (63mg, 0.33mmol) and triethylamine (161 μ l; 1.1mmol), formed suspension was stirred 18 hours.After this, add saturated NaHCO 3The aqueous solution (7ml) filters the precipitation that is generated.Solids is dissolved in the methylene dichloride again water (25ml) and salt solution (20ml) washing.Vacuum-evaporation removes solvent, and residue is purified with preparation HPLC (chromatography A), obtains title compound after lyophilize. 1HNMR (CDCl 3, 400MHz) (1H, m), (15H, m), (2H, m), (2H, m), (7H, m), (9H, m) ppm. analyzes 1.8-0.2 4.15-2.50 4.79-4.34 5.69-5.50 8.03-7.27 δ 8.98: calculated value C 35H 35N 4O2HCl0.65H 2O:
C，67.30，H，6.16；N，8.97。Measured value: C, 67.25, H, 6.16; N, 9.15.FAB HRMS accurate mass calculated value: C 35H 36N 4O 2545.291652 (MH +), measured value: 545.292050.
Example 18
2 (S)-butyl-1-[(1-naphthalene-2-ylmethyl)-1H-imidazoles-5-yl) Ethyl]-4-(1-naphthoyl)-piperazine two (trifluoroacetic acid) salt
Steps A: N-methyl-N-methoxyl group-2-[1-(naphthalene-2-ylmethyl)- 1H-imidazoles-5-yl)] preparation of ethanamide
Toward 2-[1-(naphthalene-2-ylmethyl)-1H-imidazoles-5-yl] acetic acid hydrochloride (0.819mg, 2.70mmol) DMF (15ml) solution in add N successively, O-dimethyl hydroxyl ammonia hydrochloric acid salt (293mg, 3.0mmol), 3-hydroxyl-1,2, and 3-phentriazine-4 (3H)-ketone (HOOBT) (489mg, 3.0mmol), 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) (575mg, 3.0mmol) and triethylamine (1.67ml, 12.0mmol).This mixture at room temperature stirred 18 hours.Add saturated NaHCO then 3The aqueous solution (30ml) and water (30ml), mixture dichloromethane extraction (2 * 50ml).The organic extract that merges washs with salt solution (50ml), and vacuum-evaporation removes solvent.Residue is purified by dodging chromatogram, with 2-4% ethanol/methylene gradient elution, obtains the oily title compound. 1HNMR (CDCl 3, 400 MHz) δ 7.80 (2H, m), 7.74 (1H, m), 7.56 (1H, s), 7.47 (3H, m), 7.22 (1H, d, J=8.6Hz), 6.97 (1H, s), 5.37 (2H, s), 3.58 (2H, s), 3.51 (3H, s) and 3.12 (3H, s) ppm.
Step B:2-[1-(naphthalene-2-ylmethyl) (1H-imidazoles-5-yl)] second The preparation of aldehyde
By the past lithium aluminum hydride (40.8mg of sleeve pipe, 1.07mmol) add the product (243mg of steps A in the suspension in be cooled to-45 ℃ tetrahydrofuran (THF) (5ml) with dry ice/acetone batch, 0 895mmol) tetrahydrofuran (THF) (5ml) solution, its adding speed should be able to holding temperature＜-35 ℃.Add finish after, allow this solution be warmed to+5 ℃, be cooled to-35 ℃ then again.Water (1ml) solution that adds sal enixum (272mg) in this solution.Mixture at room temperature stirred 30 minutes, passed through diatomite filtration then.The diatomite layer pad washs with ethyl acetate (25ml).The filtrate that merges is used saturated sodium bicarbonate solution (10ml) and water (10ml) washing successively.Organic layer is infused the buttery title compound clearly after with dried over mgso, filtration and evaporation. 1HNMR (CDCl 3, 400MHz) δ 9.50 (1H, t, 2Hz), 7.85-7.70 (3H, m), 7.64 (1H, s), 7.53-7.40 (3H, m), 7.16 (1H, d, J=12Hz), 7.06 (1H, s), 5.20 (2H, s) and 3.53 (2H, m) ppm.
Step C:2 (S)-butyl-1-[(1-naphthalene-2-ylmethyl)-the 1H-imidazoles -5-yl) ethyl]-system of 4-(1-naphthoyl)-piperazine two (trifluoroacetic acid) salt Be equipped with
Product (58.4mg toward step B; 0.232mmol) and 3 (S)-butyl-1-naphthoyl piperazine hydrochloride (96.5mg; 0.279mmol) 1; adding 3 molecular sieves (250mg) and sodium triacetoxy borohydride in the solution among 2-ethylene dichloride (10ml) and the DMF (5ml) (236.5mg, 1.12mmol).This mixture at room temperature stirred 18 hours, filtered then.Filtrate is with methylene dichloride (100ml) dilution, with saturated sodium bicarbonate (50ml) washing.With organic layer drying (MgSO 4), filtration and vacuum-evaporation.With dodge chromatography (2-5% ethanol/methylene wash-out), with preparation HPLC (chromatography A) purify, obtain title compound earlier by the back for residue. 1H NMR (CD 3OD, 400 MHz) δ 9.04 (1H, s), 8.17-7.30 (15H, m), 5.65 (2H, s), 4.6-2.2 (11H, m) and 1.6-0.2 (9H, m) ppm.FAB HRMS accurate mass calculated value: C 35H 39N 4O531.312387 (MH +), measured value 531.313011.
Embodiment 19
1-(2 (R)-amino-3-hydroxypropyl)-2 (S)-butyl-4-(1-naphthalene first Acyl group)-piperazine two (trifluoroacetic acid) salt
Steps A: N-Boc-O-benzyl Serine-(N '-methoxyl group) methane amide
Under argon shield with N-Boc-O-benzyl Serine (Bachem company; 5.0g, 16.9mmol) and HOBT (2.29g 16.9mmol) is dissolved in the dry DMF (100ml).In this solution, add N, and O-dimethyl hydroxyl amine hydrochlorate (1.98g, 20.3mmol), then at 0 ℃, adding EDC hydrochloride (3.56g, 18.6mmol).Add the 4-methylmorpholine and make pH, this mixture was at room temperature stirred 3 hours to～7 (4.5ml).This solution dilutes with EtOAc, is poured into then among the 0.5N HCl.After EtOAc extraction (2 times), organic layer water and salt water washing successively, drying (MgSO 4) and vacuum-evaporation, obtain light yellow oil.Through column chromatography (silica gel; Hexane/EtOAc 2: 1) purification obtains title compound oil, Rf (silica gel; Hexane/EtOAc 1: 1)=0.45 oil.
Step B:N-Boc-O-benzyl Serine aldehyde
(5.7g, anhydrous diethyl ether 16.9mmol) (20ml) drips of solution is added to LAH, and (0.705g is 18.5mmol) in-50 ℃ of suspension in ether (80ml) with acid amides that steps A obtains.After dropwising, this solution stirred 45 minutes at 0 ℃, and cooling is got back to-50 ℃ then, slowly adds KHSO again 4Solution (4g is in 11ml water).At room temperature this mixture was stirred 1 hour then,, use 10% citric acid solution, saturated NaHCO successively by diatomite filtration 3Solution and salt water washing, dry (MgSO 4) and evaporation, obtain a kind of oil, can be used in Rf (silica gel in the next step same as before; Hexane/EtOAc 2: 1)=0.58.
Step C:1-(2 (R)-N-Boc-amino-3-benzyloxy propyl group)-2 (S) -butyl-4-(1-naphthoyl)-piperazine
Use Et 3N will derive from piperazine hydrochloride (1.7g, CH 574mmol) of example 1 step e 2Cl 2(25ml) pH regulator to 6 of solution, add successively then new grind and activatory 4 molecular sieves and sodium triacetoxy borohydride (4.85g, 22.9mmol).Be dissolved in 20ml CH 0 ℃ of time dropping with 20 minutes 2Cl 2In the aldehyde that derives from step B (2.08g 747mmol), at room temperature stirs this mixture 16 hours then.After this, this mixture is by diatomite filtration, with EtOAc dilution, use H successively 2O, KHSO 4Solution, NaHCO 3Solution and salt water washing.Dry (MgSO 4) after solution after vacuum-evaporation, obtain a kind of light yellow oil, pass through column chromatography (silica gel again; Hexane/EtOAc 1: 1) purification obtains spumescence title compound, Rf (silica gel; Hexane/EtOAc 2: 1)=0.15.
Step D:1-(2 (R)-N-Boc-amino-3-hydroxypropyl)-2 (S) -butyl-4-(1-naphthoyl)-piperazine
(700mg 1.25mmol) is dissolved among the MeOH that 20ml contains 150 μ l acetate, adds 20% Pd (OH) then with the benzylic ether of step C 2/ charcoal (500mg) is with this mixture hydrogenation 16 hours under 50psi (pound/square inch) pressure.Behind diatomite filtration, remove solvent, residue is purified (EtOAc/ hexane 1: 1,5% MeOH/EtOAc then) by silica gel column chromatography, obtains the oily title compound.
Step e: 1-(2 (R)-amino-3-hydroxypropyl)-2 (S)-butyl-4 -(1-naphthoyl)-piperazine two (trifluoroacetic acid) salt
EtOAc (10ml) solution of the N-Boc amine (140mg) of step D is handled until saturated with HCl (gas).After 5 minutes, clean this solution, obtain a kind of solid after removing solvent with argon gas, with it further with preparation HPLC (the C-18 post of purifying; H 2O/CH 3CN contains 0.1% TGA; Gradient).Should be water-soluble freezing, obtain the Powdered title compound of a kind of water-absorbent after the freeze-drying.FAB mass spectrum m/z=370 (M+1).Analytical calculation value C 22H 32N 3O 22.35TFA:
C, 50.31; H, 5.27; N, 6.59 measured values: C, 50.28; H, 549; N, 6.70
Example 20
1-(2 (R)-amino-4-hydroxy butyl)-2 (S)-butyl-4-(1-naphthoyl)-piperazine dihydrochloride
According to the program of example 19 steps A-E, but with N-Boc-O-benzyl homoserine (Bachem) as starting raw material, obtain the title compound of dihydrochloride form.FAB mass spectrum m/z=384 (M+1).Analyze: calculated value C 23H 33N 3O 21.5HCl:
C, 54.04; H, 7.20; N, 8.22 measured values: C, 53.95; H, 7.23; N, 8.50.
Example 21
1-(2-amino-3-(2-benzyl chloro phenyl) propyl group)-2 (S)-butyl-4 -(1-naphthoyl)-piperazine two (trifluoroacetic acid) salt
Steps A: D, L-N-Boc-is former-L-Tyrosine methyl ester
With 2 steps ((Boc) 2O/K 2CO 3THF/H 2O solution is used the EtOAc solution of diazomethane then) from D, the former tyrosine of L-(Sigma company) makes the crystalline solid title compound.
Step B:3-(2-hydroxy phenyl)-2-(N-Boc-amino) propyl alcohol
Toward the ester of steps A (1.34g, 4.54mmol) add in the solution in 0 ℃ THF (20ml) in batches LAH (400mg, 10.5mmol).At room temperature after 4 hours, dropwise add 0.4ml H successively 2O, 0.4ml 1N NaOH and 1.2ml H 2O.This soup compound was stirred 1 hour,, use THF drip washing by diatomite filtration, remove solvent after residue through chromatogram purification (silica gel; Hexane/EtOAc 1: 1), obtain the title compound of solid form.Rf (silica gel; Hexane/EtOAc 1: 1)=0.45.
Step C:3-(2-benzyl hydrogen base phenyl)-2-(N-Boc-amino) propyl alcohol
With the alcohol of step B (280mg, 1.05mmol), bromotoluene (150 μ l, 1.26mmol) and Cs 2CO 3(513mg, 1.57mmol) mixture in DMF (10ml) at room temperature reaches under the argon shield and stirred 16 hours.Then this mixture is poured in the water, with EtOAc extraction 2 times, first water is used the salt water washing then, drying (MgSO 4) and the evaporation after obtain a kind of oil.This oil is through chromatogram purification (silica gel; Hexane/EtOAc 2: 1) obtains the oily title compound after.Rf (silica gel; Hexane/EtOAc 2: 1)=0.36.
Step D:3-(2-benzyloxy phenyl)-2-(N-Boc-amino) propyl alcohol
(280mg is 0.78mmol) at 3mlDMSO, 3ml CH for the alcohol of past step C under room temperature and argon shield 2Cl 2With 0.55ml Et 3Add pyridine SO in the solution among the N 3(500mg 3.14mmol), stirs this mixture 1 hour title complex then.This solution is poured into saturated NaHCO 3In the solution, with EtOAc extraction 2 times, water and salt water washing successively, dry (MgSO 4), under vacuum, concentrate then.The oily title compound that obtains thus can be used for next step same as before.Rf (silica gel; Hexane/EtOAc 4: 1)=0.41.
Step e: 1-(2-N-Boc-amino-3-(2-benzyloxy phenyl) third Base 2 (S)-butyl-4-(1-naphthoyl)-piperazine
Adopt the described method of example 19 step C to make the aldehyde of step D and piperazine hydrochloride coupling of example 1 step e by standard reductive alkylation.Through chromatogram purification (silica gel; Hexane/EtOAc 3: 2) obtain title compound, its form is 1: 1 a non-enantiomer mixture.Rf (silica gel; Hexane/EtOAc=0.51 and 0.45.
Step F: 1-(2-amino-3-(2-benzyloxy phenyl) propyl group)-2 (S) -butyl-4-(1-naphthoyl)-piperazine two (trifluoroacetic acid) salt
EtOAc (15ml) solution of the N-Boc amine (70mg) of step e is handled until saturated with HCl (gas).After 15 minutes, clean this solution, remove solvent then and obtain a kind of solid with argon gas.With preparation HPLC purification (C-18 post, H 2O/CH 3CN contains 0.1% TFA; Gradient elution), after lyophilize, obtain Powdered title compound.The FAB mass spectrum, m/z=536 (M+1).Analytical calculation value C 35H 41N 3O 22.2TFA0.35H 2O:
C, 59.68; H, 5.58; N, 5.30 measured values: C, 59.70; H, 5.60; N, 5.56.
Example 22
1-(2-amino-3-(2-hydroxy phenyl) propyl group)-2 (S)-butyl-4 -(1-naphthoyl)-piperazine two (trifluoroacetic acid) salt, diastereomer A
Steps A: 1-(2-N-Boc-amino-3-(2-hydroxy phenyl) propyl group) -2 (S)-butyl-4-(1-naphthoyl)-piperazine
1-(2-N-Boc-amino-3-(2-benzyloxy phenyl) propyl group)-2 (S)-butyl-4-(1-naphthoyl)-piperazine (derives from example 19, step e; 290mg, 0.5mmol), acetate (60 μ l, 1.0mmol) and 20% Pd (OH) 2The mixture of/charcoal (100mg) in MeOH (20ml) hydrogenation 5 hours under 67psi pressure.Solution is by diatomite filtration, obtains a kind of oil after removing solvent, and this oil demonstrates 2 spot that obviously separate on silica gel thin-layer chromatography.Column chromatography (silica gel; Hexane: EtOAc 1: 1) provide:
A) the diastereomer A of title compound, Rf (silica gel; Hexane/EtOAc 1: 1)=0.49.
B) the diastereomer B of title compound, Rf (silica gel; Hexane/EtOAc 1: 1)=0.35.
Step B:1-(2-amino-3-(2-hydroxy phenyl) propyl group)-2 (S)- Butyl-4-(1-naphthoyl)-piperazine two (trifluoroacetic acid) salt, diastereomer A
Derive from the N-Boc amine of steps A, promptly diastereomer A uses HCl (gas) deprotection in EtOAc.Be prepared HPLC (C-18 post after removing solvent; H 2O/CH 3CN contains 0.1% TFA; Gradient) purifies, obtain (after the freeze-drying) Powdered title compound.The FAB mass spectrum, m/z=446 (M+1) analytical calculation value C 28H 35N 3O 22TFA:
C, 57.05; H, 5.54; N, 6.24 measured values: C, 57.08; H, 5.64; N, 6.32.
Example 23
1-[3-(4-imidazolyl) propyl group]-2 (S)-butyl-4-(1-naphthoyl) -piperazine two (trifluoroacetic acid) salt
Steps A: 3-(4-imidazolyl) ethyl propionate
Adopt standard chemical process, make this title compound from urinating sharp acid (Aldrich company) with 2 steps (, in ethanol, carrying out hydrogenation with 10%Pd-C then) with HCl esterification in ethanol. 1H?NMR(CDCl 3)：δ1.23(3H，t)，2.65(2H，t)，2.94(2H，t)，4.15(2H，q)，6.81(1H，S)，7.56(1H，s).
Step B:3-(4-imidazolyl) propyl alcohol
In 30 minutes toward derive from steps A ester (120g, 71.4mmol) add in the solution in 0 ℃ anhydrous THF (230ml) in batches LAH (2.99g, 78.6mmol).Mixture at room temperature stirs 2h, and cooling is got back to 0 ℃ then, and it is (careful dropwise to add entry (4.2ml)! ).Then drip 10.6ml 1N NaOH, the gained soup compound at room temperature stirred 1 hour.By behind the diatomite filtration with EtOAc washing, infused oily title compound (8.16g) clearly after removing solvent.
1H?NMR(CD 3OD)：δ1.84(2H，pentet)，2.68(2H，t)，3.58(2H，t)，6.88(1H，s)，7.80(1H，s).
Step C:3-(4-N-Boc-imidazolyl) propyl alcohol
Derive from step B imidazoles (166mg, 1.32mmol), (Boc) 2O (302mg, 1.38mmol) and K 2CO 3(190mg 1.38mmol) stirred 2 hours in THF (10ml).Filter final vacuum and remove solvent, obtain desired oily compound.Rf (silica gel; 5% MeOH/CHCl 3)=0.17.This oil can be used for next step same as before.
Step D:1-[3-(4-imidazolyl) propyl group]-2 (S)-butyl-4-(1- Naphthoyl)-piperazine two (trifluoroacetic acid) salt
With derive from step C alcohol (～1.32mmol) be dissolved in 4ml DMSO, 4ml CH 2Cl 2With 0.92ml Et 3Among the N, add pyridine SO then in batches 3Title complex (600mg, 5.28mmol).After 3 hours, mixture is poured among the EtOAc, uses saturated NaHCO successively 3Solution and salt solution extraction obtain corresponding aldehyde after the drying evaporation, and need not further purifies just can use.
According to the described program of example 19 step C, make this aldehyde and the piperazine coupling that derives from example 1 step e by standard reductive alkylation, again through column chromatography purification (silica gel; 5% Me0H/CHCl 3) obtain product, this product is dissolved in 10ml uses among the saturated EtOAc of HCl (gas).Remove solvent, residue is with preparing HPLC (C-18; H 2O/CH 3CN contains 0.1% TFA; Gradient) purifies.The freezing aqueous solution provides a kind of hygroscopic powder shape title compound after lyophilize.The FAB mass spectrum, m/z=405 (M+1) analyzes: calculated value C 25H 32N 4O2.35TFA 0.4H 2O:
C, 52.48; H, 5.21; N, 8.24 measured values: C, 52.45; H, 5.22; N, 8.27.
Example 24
2 (S)-normal-butyl-4-(1-naphthoyl)-1-[1-(1-naphthyl methyl) Imidazoles-5-ylmethyl]-piperazine two (trifluoroacetic acid) salt
According to example 4 described programs, from 2 (S)-normal-butyl-1-[5-(3-trityl imidazole base) methyl]-(0.124g, 0.200mmol) (0.046g 0.21mmol) has made title compound to 4-(1-naphthoyl)-piperazine with 1-brooethyl naphthalene.Preparing HPLC through anti-phase purifies (with 30%-75% acetonitrile/0.1% TFA; The 0.1%TFA aqueous solution of 70%-25% carried out gradient elution 50 minutes) and lyophilize after obtain title compound.FAB?ms(m+1)517。Analyze: calculated value C 34H 36N 4O0.05H 2O2.0TFA:
C，60.55；H，5.22；N，7.43。Measured value: C, 60.48; H, 5.12; N, 7.42.
Example 25
2 (S)-normal-butyl-4-(1-naphthoyl)-1-[1-(2-naphthyl methyl) Imidazoles-5-ylmethyl]-piperazine two (trifluoroacetic acid) salt
According to example 4 described programs, from 2 (S)-normal-butyl-1-[5-(3-trityl imidazole base) methyl]-(0.124g, 0.200mmol) (0.046g 0.21mmol) has made title compound to 4-(1-naphthoyl)-piperazine with 2-brooethyl naphthalene.Preparing HPLC through anti-phase purifies (with 30%-75% acetonitrile/0.1% TFA; The 0.1% TFA aqueous solution of 70%-25% carried out gradient elution 50 minutes) and lyophilize after obtain title compound.FAB?ms(m+1)517。Analyze: calculated value C 34H 36N 4O1.7H 2O2.0TFA:
C, 58.87; H, 5.38; N, 7.23 measured values: C, 58.90; H, 4.93; N, 7.13.
Example 26
2 (S)-normal-butyl-1-[1-(4-cyano group benzyl) imidazoles-5-ylmethyl]-4 -(1-naphthoyl)-piperazine two (trifluoroacetic acid) salt
According to example 4 described programs, from 2 (S)-normal-butyl-1-[5-(3-trityl imidazole base) methyl]-(0.124g, 0.200mmol) (0.041g 0.21mmol) has made title compound to 4-(1-naphthoyl)-piperazine with the 4-cyano-benzyl bromide.Preparing HPLC through anti-phase purifies (with 25%-65% acetonitrile/0.1% TFA; The 0.1%TFA aqueous solution of 75%-35% carried out gradient elution 50 minutes) and lyophilize after obtain title compound.FAB?ms(m+1)492。Analyze: calculated value C 31H 33N 5O0.35H 2O2.0TFA:
C, 57.91; H, 4.96; N, 9.65 measured values: C, 57.93; H, 4.91; N, 9.55.
Example 27
2 (S)-normal-butyl-1-[1-(4-methoxy-benzyl) imidazoles-5-ylmethyl]-4 -(1-naphthoyl)-piperazine two (trifluoroacetic acid) salt
According to example 4 described programs; from 2 (S)-normal-butyl-1-[5-(3-trityl imidazole base) methyl]-4-(1-naphthoyl)-piperazine (0.124g; 0.200mmol) and 4-methoxy-benzyl chlorine (0.041ml; 0.21mmol); and in reaction mixture, add potassiumiodide (100mg), made title compound.Preparing HPLC through anti-phase purifies (with 25%-65% acetonitrile/0.1%TFA; The 0.1% TFA aqueous solution of 75%-35% carried out gradient elution 50 minutes) and lyophilize after obtain title compound.FAB?ms(m+1)497。Analyze: calculated value C 31H 36N 4O 21.7H 2O2.0TFA:
C, 53.40; H, 5.30; N, 7.12 measured values: C, 53.37; H, 4.78; N, 7.00.
Example 28
2 (S)-normal-butyl-1-[1-(3-methyl-2-butene base) imidazoles-5-Ji Jia Base]-4-(1-naphthoyl)-piperazine two (trifluoroacetic acid) salt
According to example 4 described programs, from 2 (S)-normal-butyl-1-[5-(3-trityl imidazole base) methyl]-(0.124g, 0.200mmol) (0.024ml 0.21mmol) has made title compound to 4-(1-naphthoyl)-piperazine with 4-bromo-2-methyl-2-butene.Preparing HPLC through anti-phase purifies (with 5%-95% acetonitrile/0.1% TFA; The 0.1% TFA aqueous solution of 95%-5% carried out gradient elution 50 minutes) and lyophilize after obtain title compound.FAB?ms(m+1)445。Analyze: calculated value C 28H 36N 4O1.8H 2O2.0 TFA:
C, 54.51; H, 5.95; N, 7.95 measured values: C, 54.54; H, 5.39; N, 7.73.
Example 29
2 (S)-normal-butyl-1-[1-(4-luorobenzyl) imidazoles-5-ylmethyl]-4- (1-naphthoyl)-piperazine two (trifluoroacetic acid) salt
According to example 4 described programs, from 2 (S)-normal-butyl-1-[5-(3-trityl imidazole base) methyl]-(0.124g, 0.200mmol) (0.026ml 0.21mmol) has made title compound to 4-(1-naphthoyl)-piperazine with the 4-fluoro benzyl bromide.Preparing HPLC through anti-phase purifies (with 25%-65% acetonitrile/0.1% TFA; The 0.1%TFA aqueous solution of 75%-35% carried out gradient elution 50 minutes) and lyophilize after obtain title compound.FAB?ms(m+1)485。Analyze: calculated value C 30H 33FN 4O3.0H 2O2.0TFA:
C, 53.26; H, 5.39; N, 7.31 measured values: C, 53.21; H, 4.56; N, 7.08.
Example 30
2 (S)-normal-butyl-1-[1-(4-benzyl chloride base) imidazoles-5-ylmethyl]-4- (1-naphthoyl)-piperazine two (trifluoroacetic acid) salt
According to example 4 described programs; from 2 (S)-normal-butyl-1-[5-(3-trityl imidazole base) methyl]-4-(1-naphthoyl)-piperazine (0.124g; 0.200mmol) and the 4-chlorobenzyl chloride (0.034mg 0.21ml), and adds sodium iodide (100mg) in reaction mixture.Made title compound.Preparing HPLC through anti-phase purifies (with 25%-65% acetonitrile/0.1% TFA; The 0.1% TFA aqueous solution of 75%-35% carried out gradient elution 50 minutes) and lyophilize after obtain title compound.FAB?ms(m+1)501。Analyze: calculated value C 30H 33ClN 4O4.8H 2O2.0TFA:
C, 50.07; H, 5.51; N, 6.87 measured values: C, 50.10; H, 4.25, N, 6.48.
Example 31
1-[1-(4-bromobenzyl) imidazoles-5-ylmethyl]-2 (S)-normal-butyl-4- (1-naphthoyl)-piperazine two (trifluoroacetic acid) salt
According to example 4 described programs; from 2 (S)-normal-butyl-1-[5-(3-trityl imidazole base) methyl]-4-(1-naphthoyl)-piperazine (0.124g; 0.200mmol) and the 4-bromo benzyl bromo (0.053mg 0.21ml), and adds sodium iodide (100mg) in reaction mixture.Made title compound.Preparing HPLC through anti-phase purifies (with 30%-65% acetonitrile/0.1% TFA; The 0.1% TFA aqueous solution of 70%-35% carried out gradient elution 50 minutes) and lyophilize after obtain title compound.FAB?ms(m+1)545。Analyze: calculated value C 30H 33BrN 4O1.7H 2O2.0TFA:
C, 50.78; H, 4.81; N, 6.97 measured values: C, 50.81; H, 4.39; N, 6.88.
Example 32
2 (S)-normal-butyl-4-(1-naphthoyl)-1-[1-(4-trifluoromethyl benzyl Base) imidazoles-5-ylmethyl]-piperazine two (trifluoroacetic acid) salt
According to example 4 described programs, from 2 (S)-normal-butyl-1-[5-(3-trityl imidazole base) methyl]-(0.124g, 0.200mmol) (0.053mg 0.21mmol) has made title compound to 4-(1-naphthoyl)-piperazine with 4-trifluoromethyl benzyl bromine.Preparing HPLC through anti-phase purifies (with 30%-65% acetonitrile/0.1% TFA; The 0.1% TFA aqueous solution of 70%-35% carried out gradient elution 50 minutes) and lyophilize after obtain title compound.FAB?ms(m+1)535。Analyze: calculated value C 30H 33BrN 4O2.0TFA:
C, 55.12, H, 4.63; N, 7.35 measured values: C, 57.46; H, 4.98; N, 7.84.
Example 33
2 (S)-normal-butyl-1-[1-(4-methyl-benzyl) imidazoles-5-ylmethyl]-4 -(1-naphthoyl)-piperazine two (trifluoroacetic acid) salt
According to example 4 described programs; from 2 (S)-normal-butyl-1-[5-(3-trityl imidazole base) methyl]-4-(1-naphthoyl)-piperazine (0.124g; 0.200mmol) and 4-methyl-benzyl bromine (0.029ml; 0.21mmol); but in reaction mixture, add sodium iodide (100mg), made title compound.Preparing HPLC through anti-phase purifies (with 30%-65% acetonitrile/0.1% TFA; The 0.1% TFA aqueous solution of 70%-35% carried out gradient elution 50 minutes) and lyophilize after obtain title compound.FAB?ms(m+1)481。Analyze: calculated value C 31H 36N 4O2.6H 2O2.0TFA:
C, 55.64; H, 5.76; N, 7.42 measured values: C, 55.61; H, 5.09; N, 7.43.
Example 34
2 (S)-normal-butyl-1-[1-(3-methyl-benzyl) imidazoles-5-ylmethyl]-4-(1-naphthoyl)-piperazine two (trifluoroacetic acid) salt
According to example 4 described programs, from 2 (S)-normal-butyl-1-[5-(3-trityl imidazole base) methyl]-(0.124g, 0.200mmol) (0.029mg 0.21mmol) has made title compound to 4-(1-naphthoyl)-piperazine with 3-methyl-benzyl bromine.Preparing HPLC through anti-phase purifies (with 25%-65% acetonitrile/0.1% TFA; The 0.1%TFA aqueous solution of 75%-35% carried out gradient elution 50 minutes) and lyophilize after obtain title compound.FAB?ms(m+1)481。Analyze: calculated value C 31H 36N 4O2.0TFA:
C, 67.26; H, 6.92; N, 10.12 measured values: C, 69.60; H, 6.98; N, 10.51.
Example 35
1-[1-(4-phenylbenzyl) imidazoles-5-ylmethyl]-2 (S)-normal-butyls-4 -(1-naphthoyl)-piperazine two (trifluoroacetic acid) salt
According to example 4 described programs, from 2 (S)-normal-butyl-1-[5-(3-trityl imidazole base) methyl]-(0.124g, 0.200mmol) (0.029mg 0.21mmol) has made title compound to 4-(1-naphthoyl)-piperazine with 4-phenylbenzyl bromine.Preparing HPLC through anti-phase purifies (with 30%-65% acetonitrile/0.1% TFA; The 0.1%TFA aqueous solution of 70%-35% carried out gradient elution 50 minutes) and lyophilize after obtain title compound.FAB ms(m+1)543。Analyze: calculated value C 36H 38N 4O4.95H 2O2.0TFA:
C，55.87；H，5.85；N，6.52。Measured value: C, 55.55; H, 4.58; N, 6.23.
Example 36
2 (S)-normal-butyl-4-(1-naphthoyl)-1-[1-(2-phenylethyl) Imidazoles-5-ylmethyl]-piperazine two (trifluoroacetic acid) salt
According to example 4 described programs; from 2 (S)-normal-butyl-1-[5-(3-trityl imidazole base) methyl]-4-(1-naphthoyl)-piperazine (0.124g; 0.200mmol) and 2-phenylethyl bromine (0.029ml; 0.21mmol); but add sodium iodide (120mg); and refluxed 12 hours, made title compound.Preparing HPLC through anti-phase purifies (with 30%-65% acetonitrile/0.1% TFA; The 0.1% TFA aqueous solution of 70%-35% carried out gradient elution 50 minutes) and lyophilize after obtain title compound.FAB?ms(m+1)481。Analyze: calculated value C 36H 38N 4O4.20H 2O2.0TFA:
C, 53.60; H, 5.96; N, 7.14. measured value: C, 53.54; H, 4.86; N, 6.86.
Example 37
2 (S)-normal-butyl-4-(1-naphthoyl)-1-[1-(4-trifluoromethoxy) Imidazoles-5-ylmethyl]-piperazine two (trifluoroacetic acid) salt
According to example 4 described programs; from 2 (S)-normal-butyl-1-[5-(3-trityl imidazole base) methyl]-4-(1-naphthoyl)-piperazine (0.124g; 0.200mmol) and 4-trifluoromethoxy bromine (0.032ml; 0.21mmol); but add sodium iodide (120mg); and refluxed 12 hours, made title compound.Preparing HPLC through anti-phase purifies (with 35%-70% acetonitrile/0.1% TFA; The 0.1% TFA aqueous solution of 65%-30% carried out gradient elution 50 minutes) and lyophilize after obtain title compound.FAB?ms(m+1)551。Analyze: calculated value C 31H 33F 3N 4O 24.00H 2O2.0TFA:
C, 49.42; H, 5.09; N, 6.59. measured value: C, 48.95; H, 4.06; N, 6.26.
Example 38
1-{[1-(4-cyano group benzyl)-1H-imidazoles-5-yl] ethanoyl }-2 (S) The preparation of-normal-butyl-4-(1-naphthoyl)-piperazine trifluoroacetate
Steps A: the preparation of 1H-imidazoles-4-methyl acetate hydrochloride
(4.00g, methyl alcohol 24.6mmol) (100ml) solution is saturated with hydrogen chloride gas for 1H-imidazoles-4-acetic acid hydrochloride.Formed solution at room temperature left standstill 18 hours.Solvent obtains the title compound of white solid after vacuum-evaporation. 1H NMR (CDCl 3, 400 MHz) δ 8.85 (1H, s), 7.45 (1H, s), 3.89 (2H, s) and 3.75 (3H, s) ppm.
The preparation of step B:1-(trityl)-1H-imidazol-4 yl methyl acetate
Toward the product that derives from steps A (24.85g, add in DMF 0.141mmol) (115ml) solution triethylamine (57.2ml, 0.412mmol) and trityl bromide (55.3g, 0.171mol), with gained suspension stirring 24 hours.Use ethyl acetate (EtOAc) (1 liter) and water (350ml) that reaction mixture is diluted then.The saturated NaHCO of organic phase 3The aqueous solution (350ml) washing, dry (Na 2SO 4), and carry out vacuum-evaporation.Residue is with dodging chromatogram purification (SiO 2, the 0-100% ethyl acetate/hexane; Gradient elution), obtain the title compound of white solid. 1H NMR (CDCl 3, 400 MHz) δ 7.35 (1H, s), 7.31 (9H, m), 7.22 (6H, m), 6.76 (1H, s), 3.68 (3H, s) and 3.60 (2H, s) ppm.
Step C:[1-(4-cyano group benzyl)-1H-imidazoles-5-yl] methyl acetate Preparation
(8.00g, (4.10g 20.92mmol), heated 3 hours at 55 ℃ then to add the bromine p-tolunitrile in acetonitrile 20.9mmol) (70ml) solution toward the product that derives from step B.Make the reaction mixture cool to room temperature then, filter and collect the imidazole salts (white precipitate) that is generated.Filtrate was 55 ℃ of heating 18 hours.The reaction mixture cool to room temperature, and carry out vacuum-evaporation.In residue, add EtOAc (70ml), filter and collect formed white depositions.The imidazole salts that is precipitated out is merged, be suspended in the methyl alcohol (100ml) reflux 30 minutes.Then, under vacuum, remove solvent.The gained residue is suspended among the EtOAc (75ml), filters to isolate solids, and washs (EtOAc).The saturated NaHCO of this solids 3The aqueous solution (300ml) and CH 2Cl 2(300ml) handle, at room temperature stirred 2 hours.Tell organic layer, drying (MgSO 4), vacuum-evaporation, obtain the white solid title compound. 1HNMR (CDCl 3, 400 MHz) δ 7.65 (1H, d, J=8Hz), 7.53 (1H, s), 7.15 (1H, d, J=8Hz), 7.04 (1H, s), 5.24 (2H, s), 3.62 (3H, s) and 3.45 (2H, s) ppm.
Step D:[1-(4-cyano group benzyl)-1H-imidazoles-5-yl] preparation of acetate
(4.44g, (17.4ml 17.4mmol) at room temperature stirs 18 hours to [1-(4-cyano group benzyl)-1H-imidazoles-5-yl] methyl acetate for (100ml) solution of THF 17.4mmol) and 1M lithium hydroxide.Add 1M HCl (17.4ml), vacuum-evaporation removes THF.This aqueous solution freeze-drying is obtained containing the white solid title compound of lithium chloride. 1H NMR (CD 3OD, 400 MHz) δ 8.22 (1H, s), 7.74 (1H, d, J=8.4Hz), 7.36 (1H, d, J=8.4Hz), 7.15 (1H, s), 5.43 (2H, s) and 3.49 (2H, s) ppm.
Step e: 1-{[1-(4-cyano group benzyl)-1H-imidazoles-5-yl] ethanoyl } The preparation of-2 (S)-normal-butyl-4-(1-naphthoyl)-piperazine trifluoroacetate
Toward the acid (100mg that derives from step D, 0.35mmol), example _ step _ amine hydrochloride (117mg, 0.35mmol), HOOBT (58mg, triethylamine (0.123ml 0.35mmol), 0.88mmol) DMF (2ml) solution in add EDC (75mg, 0.38mmol).Under agitation at room temperature reacted 16 hours, with the EtOAc dilution, organic layer is used saturated NaHCO successively 3The aqueous solution and salt water washing, dry (Na 2SO 4), and carry out vacuum-evaporation.Residue is with preparing HPLC purification (C-18; 95: 5-5: water/CH of 95 3CN contains 0.1% trifluoroacetic acid; Gradient elution).Obtain the white solid title compound after the level lease making lyophilize of collecting. 1H NMR (CD 3OD, 400 MHz) δ 9.00-8.90 (1H, m), 8.05-7.94 (2H, m), 7.94-7.40 (10H, m), 5.60-5.40 (2H, m), 5.00-2.80 (9H, m), 1.90-1.15 (4H, m) and 1.05-0.40 (5H, m) ppm. analyzes: calculated value: C 32H 33N 5O 21.40TFA; 0.55 H 2O:
C, 60.65; H, 5.19; N, 10.16. measured value: C, 60.66; H, 5.17; N, 10.06.
Example 39
5 (S)-normal-butyl-1-(2, the 3-3,5-dimethylphenyl)-4-(4-imidazolyl methyl) Piperazine-2-ketone two (trifluoroacetic acid) salt
Steps A: N-methoxyl group-N-methyl-2 (S)-(t-butoxycarbonyl amino)-oneself Acid amides
With 2 (S)-(t-butoxycarbonyl amino) caproic acid (24.6g; 0.106mol), N; O-dimethyl hydroxyl amine hydrochlorate (15.5g; 0.15mol), EDC hydrochloride (22.3g; 0.117mol) and HOBT (14.3g, 0.106mol) anhydrous, the degassing DMF (300ml) in stir under nitrogen protection at 20 ℃.Add N-methylmorpholine and make pH=7.Under agitation react a night, steam DMF under high vacuum, residue distributes between ethyl acetate and 2% sal enixum.Organic phase is used saturated sodium bicarbonate, water and salt water washing successively, uses dried over mgso then.Obtain title compound after under vacuum, removing solvent.
Step B:2 (S)-(t-butoxycarbonyl amino) hexanal
(5.00g, ether 0.131mol) (250ml) suspension is cooled to-45 ℃ to the lithium aluminum hydride of under nitrogen protection mechanical stirring.(holding temperature is lower than-35 ℃ simultaneously for 28.3g, ether 0.103mol) (125ml) solution to add the product that derives from steps A.After interpolation finishes, will react (mixture) and be warmed to 5 ℃, and then be cooled to-45 ℃.(holding temperature is lower than-5 ℃ for 27.3g, the 0.200mol) aqueous solution, and after the termination, reaction (mixture) was at room temperature stirred 1 hour slowly to add sal enixum.By diatomite filtration, with the ether evaporation, resistates distributes between ethyl acetate and 2% sal enixum with mixture.Through with the saturated brine washing,, obtain title compound with dried over mgso and after removing solvent.
Step C:N-(2, the 3-3,5-dimethylphenyl)-2 (S)-(t-butoxycarbonyl amino) -hexylamine
Under nitrogen protection, (8.32ml 68.3mmol) is dissolved in the ethylene dichloride with 23 dimethyl aniline.Add acetate and make pH=5, (17.2g is 80.8mmol) with the molecular sieve of pulverizing (4g) to add sodium triacetoxy borohydride.At 20 ℃, dropwise slowly add product (13.3g, ethylene dichloride 62.1mmol) (80ml) solution that derives from step B.Reaction (mixture) is stirred and is spent the night, and uses the saturated sodium bicarbonate solution stopped reaction then.Remove water layer, organic layer washs with saturated brine, uses dried over mgso.With obtaining title compound after the hexane crystallization.
Step D:4-tertbutyloxycarbonyl-5 (S)-normal-butyl-1-(2, the 3-dimethyl benzene Base) piperazine-2-ketone
Derive from step C product (8.50g, ethyl acetate 26.5mmol) (250ml) solution with saturated sodium bicarbonate (150ml) 0 ℃ of fierce stirring.(2.33ml, 29.1mmol), reaction (mixture) was stirred 1 hour at 0 ℃ to add chloroacetyl chloride.Be separated two, ethyl acetate is used dried over mgso with the saturated brine washing.Crude product is dissolved among the DMF (300ml) under nitrogen protection, and it is cooled to 0 ℃.Add sodium hydride (1.79g, 60% oily dispersion liquid 44.9mmol) are emitted speed to keep moderate hydrogen in batches.After 30 minutes, add extra sodium hydride (0.8g) again.To react (mixture) restir 30 minutes, use the saturated ammonium chloride termination reaction then.Vacuum steams DMF, and residue distributes between ethyl acetate and water.Organic phase is water and saturated brine washing successively, uses dried over mgso.Crude product is purified in the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column, with 20-30% ethyl acetate/hexane wash-out, obtains title compound.
Step e: 5 (S)-normal-butyl-1-(2, the 3-3,5-dimethylphenyl)-4-[4-(1 -trityl imidazole base) methyl] piperazine-2-ketone
(0.570g, ethyl acetate 1.58mmol) (50ml) solution is cooled to-15 ℃ under nitrogen protection to derive from the product of step D.Bubbling fed HCl gas 15 minutes, and this reaction soln is warmed to 0 ℃, kept 2 hours.Under vacuum, remove solvent, the gained solids is dissolved in the ethylene dichloride (20ml).Add sodium triacetoxy borohydride (0.502g, 2.37mmol) and 1-trityl-4-imidazolyl formaldehyde (0.534g, 1.58mmol).Reaction (mixture) is spent the night 20 ℃ of stirrings, is poured in the saturated sodium bicarbonate solution then.Organic phase is used dried over mgso after washing with saturated brine.Carry out silica gel column chromatography with 4% ethanol/methylene as elutriant and purify, obtain title compound.
Step F: 5 (S)-normal-butyl-1-(2, the 3-3,5-dimethylphenyl)-4-(4- Imidazolyl methyl) piperazine-2-ketone two (trifluoroacetic acid) salt
(0.233g adds the trifluoroacetic acid (2ml) of triethyl silicane (0.254ml) in methylene dichloride 0.40mmol) (6ml) solution, reaction (mixture) was stirred 2 hours at 20 ℃ toward the product that derives from step e.Under vacuum, remove volatile matter, allow residue between hexane and water-methanol two-phase, distribute.Water is injected preparation HPLC post, with 15%-60% acetonitrile/0.1%TFA; The 0.1% TFA aqueous solution mixing gradient elution of 85%-40% 50 minutes, thus obtain purifying.After lyophilize, isolate title compound.FAB?ms(m+1)341。Analyze: calculated value C 20H 28N 4O2.0TFA:
C, 50.80; H, 5.15; N, 9.87. measured value: C, 51.31; H, 5.41; N, 10.11.
Example 40
5 (S)-normal-butyl-4-[1-(4-cyano group benzyl) imidazoles-5-ylmethyl]-1 -(2, the 3-3,5-dimethylphenyl) piperazine-2-ketone two (trifluoroacetic acid) salt
At 20 ℃ with 4-cyano-benzyl bromide (0.043g, 0.22mmol) join 5 (S)-normal-butyl-1-(2 that derive from example 39 step e, the 3-3,5-dimethylphenyl)-and 4-[4-(1-trityl imidazole base) methyl] (0.120g is in acetonitrile 0.21mmol) (10ml) solution for piperazine-2-ketone.After 48 hours, vacuum removal solvent, crude product are dissolved in the methylene dichloride (6ml).Add triethyl silicane (0.13ml) and trifluoroacetic acid (2ml), reaction (mixture) was stirred 2 hours at 20 ℃.The vacuum removal volatile matter, residue distributes between hexane and water-methanol two-phase.Water is injected into anti-phase and prepares in the HPLC post, with 30%-60% acetonitrile/0.1%TFA; The 0.1% TFA aqueous solution mixing gradient elution of 70%-40% 50 minutes, thus obtain purifying.After lyophilize, from water-acetonitrile solution, isolate title compound.FAB?ms(m+1)456。Analyze: calculated value C 28H 33N 5O0.7H 2O2.0TFA:
C, 55.28; H, 5.13; N, 10.07. measured value: C, 55.27; H, 5.20; N, 10.41.
Example 41
4-[1-(4-cyano group benzyl) imidazoles-5-ylmethyl]-1-(2, the 3-diformazan The base phenyl)-5 (S)-(2-methoxy ethyl) piperazine-2-ketone two (trifluoroacetic acid) salt
Steps A: N-methoxyl group-N-methyl-4-benzyloxy-2 (S)-(tertiary butyloxycarbonyl Base is amino) butyramide
According to example 39, the described program of steps A, use EDCHCl (0.680g, 3.55mmol), HOBT (0.436g, 3.23mmol) and N, (0.473g, 4.85mmol) (1.00g 3.23mmol) changes into title compound to the O-dimethyl hydroxylamine hydrochloride under pH 7 conditions in DMF (50ml) with 4-benzyloxy-2 (S)-(t-butoxycarbonyl amino) butyric acid.Through obtaining being the title compound of transparent adhesive tape form after the aftertreatment.
Step B:4-(1-benzyloxy ethyl)-2 (S)-(t-butoxycarbonyl amino) fourth Aldehyde
According to example 39, the described program of step B with the reduction of steps A product, just makes this title compound with lithium aluminum hydride.
Step C:N-(2, the 3-3,5-dimethylphenyl)-4-(2-benzyloxy ethyl)- 2-(S)-(t-butoxycarbonyl amino) butylamine
According to example 39, the described program of step B, with 2,3-xylidine (0.505ml, 4.14mmol), sodium triacetoxy borohydride (1.20g, the molecular sieve of pulverizing 5.65mmol) (1g) in ethylene dichloride (20ml) under the condition of pH 5 product from step C prepared this title compound.This title product is to purify through silica gel column chromatography, with what obtain behind the 15% ethyl acetate/hexane wash-out.
Step D:5 (S)-(2-benzyloxy ethyl)-4-tertbutyloxycarbonyl-1-(2,3 -3,5-dimethylphenyl) piperazine-2-ketone
This title compound is according to example 39, the described program of step D, with chloroacetyl chloride (0.21ml, 2.57mmol) from the preparation of the product of step C in ethyl acetate/saturated sodium bicarbonate of 1: 1 of 60ml, then allow crude product and sodium hydride (0.373g, 60% oily dispersion liquid 9.32mmol) reacts in DMF (30ml).Through after the aftertreatment, crude product carries out silica gel column chromatography purifies, and with 30% ethyl acetate/hexane wash-out, obtains title compound.
Step e: 4-tertbutyloxycarbonyl-1-(2, the 3-3,5-dimethylphenyl)-5 (S)-(2 -hydroxyethyl) piperazine-2-ketone
The product of step D is dissolved in the methyl alcohol (40ml), adds 10% Pd/C (0.160g).Under the hydrogen pressure of 60 psi and under shaking, react a night.Remove by filter catalyzer, obtain title compound after the solvent evaporation.
Step F: 4-tertbutyloxycarbonyl-1-(2, the 3-3,5-dimethylphenyl)-5 (S)-(2 -methoxy ethyl) piperazine-2-ketone
(0.241g 0.688mmol) is dissolved in and contains methyl-iodide (0.21ml among DMF 3.44mmol) (10ml), with this solution stirring, makes it be cooled to 0 ℃ under nitrogen protection with the product of step e.(0.070g, 60% oily dispersion liquid 1.72mmol), under agitation reacted 1 hour to add sodium hydride.The water termination reaction, vacuum removal DMF.Residue distributes between ethyl acetate and water, and organic phase is washed with saturated brine, uses dried over mgso.Crude product is purified with silica gel column chromatography, with 40% ethyl acetate/hexane wash-out, obtains title compound.
Step G:1-(2, the 3-3,5-dimethylphenyl)-5 (S)-(2-methoxy ethyl) -4-[4-(1-trityl imidazole base) methyl] piperazine-2-ketone
According to example 39, the described program of step e changes into title compound with the product of step F, and different is to use 30% trifluoroacetic acid to begin deprotection 1 hour in methylene dichloride (10ml).The vacuum removal volatile matter, residue is dissolved in the ethylene dichloride.Add triethylamine, make pH=5.Add the triacetyl sodium borohydride (0.100g, 0.468mmol) and 1-trityl-4-imidazolyl formaldehyde (0.1164g, 0.343mmol).Reaction (mixture) is spent the night 20 ℃ of stirrings, is poured in the saturated sodium bicarbonate solution then.Dried over mgso is used in organic phase salt water washing.Carry out column chromatography with 5% methyl alcohol/chloroform give elutriant and purify, obtain title compound.
Step H:4-[1-(4-cyano group benzyl) imidazoles-5-ylmethyl]-1-(2, The 3-3,5-dimethylphenyl)-5 (S)-(2-methoxy ethyl) piperazine-2-ketone two (trifluoro second Acid) salt
According to example 40 described programs, with 4-cyano-benzyl bromide (0.061g, 0.312mmol) in acetonitrile (10ml), make the product (0.182g of step G, 0.312mmol) change into title compound, then allow this thick imidazole salts and triethyl silicane (0.13ml) and trifluoroacetic acid (2ml) in methylene dichloride (6ml), react.Prepare HpLC with anti-phase and purify, with 0%-70% acetonitrile/0.1% TFA; The 0.1% TFA aqueous solution of 100%-30% carries out mixing in 60 minutes gradient elution.After lyophilize, from water, isolate title compound.FAB ms(m+1)458。Analyze: calculated value C 27H 31N 5O 20.35H 2O2.0TFA:
C, 53.81; H, 4.91; N, 10.21. measured value: C, 53.83; H, 4.95; N, 10.29.
Example 42
(S)-1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-5- Imidazolyl methyl]-5-[2-(methylsulfonyl) ethyl]-system of 2-piperazine ketone dihydrochloride Be equipped with
Steps A: the preparation of 1-trityl-4-(methylol)-imidazoles
At room temperature toward 4-(methylol) imidazole hydrochloride (35.0g, add in dry DMF 260mmol) (250ml) solution triethylamine (90.6ml, 650mmol).From this solution, be settled out a kind of white solid.Dropwise add chlorine tritane (76.1g, DMF 273mmol) (500ml) solution.Reaction mixture was stirred 20 hours, be poured on then on ice, filter, wash with frozen water.Formed product filters with Leng diox furnishing soup compound, and vacuum-drying obtains the title compound of white solid form, and its purity is enough to and can uses in next step.
The preparation of step B:1-trityl-4-(acetoxy-methyl)-imidazoles
The alcohol of steps A (260mmol prepares above) is suspended in the 500ml pyridine.(74ml 780mmol), under agitation reacted 48 hours, and material becomes even in this process dropwise to add diacetyl oxide.This solution is poured among 2 liters of EtOAc, water (3 * 1 liters), the 5% HCl aqueous solution (2 * 1 liters), saturated sodium bicarbonate aqueous solution and salt water washing successively, dry then (Na 2SO 4), filter and carry out vacuum concentration, obtain crude product.Isolate the acetate of white powder form, its purity is enough to and can uses in next step reaction.
Step C:1-(4-cyano group benzyl)-5-(acetoxy-methyl)-imidazoles hydrogen The preparation of bromate
The product of step B (85.8g, 225mmol) and α-bromo-paratolunitrile (50.1g, 232mmol) solution in 500ml EtOAc stirred 20 hours at 60 ℃, formed a kind of light-yellow precipitate in this process.To react (mixture) cool to room temperature, obtain bromination imidazole salts solid after the filtration.Filtrate is concentrated into the 200ml volume under vacuum, 60 ℃ of heating 2 hours, be cooled to room temperature again, and filter once more.Filtrate is concentrated into the 100ml volume under vacuum, again 60 ℃ of heating 2 hours, be cooled to room temperature again, concentrates under vacuum, obtains a kind of light yellow solid.All these solid matters are merged, be dissolved in the 500ml methyl alcohol, be warmed to 60 ℃ then.After 2 hours, solution concentrates under vacuum again, obtains a kind of white solid, with the hexane development, removes soluble substance.Under vacuum, remove residual solvent, obtain the title product hydrobromate of white solid form, need not further purification and just can be used in the next step.
The preparation of step D:1-(4-cyano group benzyl)-5-(methylol)-imidazoles
0 ℃ toward the acetic ester of step C (50.4g, 150mmol) add in the solution in 1.5 liters of 3: 1 THF/ water lithium hydroxide monohydrate (18.9g, 450mmol).After 1 hour, reaction mixture is concentrated under vacuum, with EtOAc (3 liters) dilution, water, saturated NaHCO successively 3The aqueous solution and salt water washing.Solution drying (Na 2SO 4), obtain a kind of crude product of light yellow bulk solids form behind filtration and the vacuum concentration, its purity is enough to be used in the next step, therefore need not further purification.
The preparation of step e: 1-(4-cyano group benzyl)-5-imidazole formaldehyde
At room temperature (21.5g, (56ml 402mmol), adds SO to the alcohol of past step D then to add triethylamine in DMSO 101mmol) (500ml) solution earlier 3-pyridine complex (40.5g, 254mmol).After 45 minutes, reaction mixture is poured among 2.5 liters of EtOAc water (4 * 1 liters) and salt water washing, drying (Na 2SO 4), the aldehyde of the powder type that obtains behind filtration and the vacuum concentration being white in color, its purity is enough to be used in subsequently the step (step L), therefore need not further purification.
Step F: (S)-2-(t-butoxycarbonyl amino)-N-methoxyl group-N-first The preparation of-4-(methylthio group) butyramide
Under nitrogen protection at 20 ℃ with L-N-Boc-methionine(Met) (30.0g; 0.120mol), N, the O-dimethyl hydroxylamine hydrochloride (14.1g, 0.144mol), DEC hydrochloride (27.7g; 0.144mol) and HOBT (19.5g, 0.144mol) stirring together in dry DMF (300ml).Add N again, (2.3g, 23mmol), make pH is 7-8 to the O-dimethyl hydroxylamine hydrochloride.Reaction is under agitation spent the night, and DMF is distilled to half of original volume under high vacuum, and residue is at ethyl acetate and saturated NaHCO 3Distribute between the solution.Organic phase is used saturated sodium bicarbonate, water, 10% citric acid and salt water washing successively, uses dried over sodium sulfate then.Obtain title compound behind the vacuum removal solvent.
Step G:(S)-2-(t-butoxycarbonyl amino)-4-(methylthio group) butyraldehyde Preparation
At room temperature (5.02g, ether 0.132mol) (500ml) suspension stirred 1 hour with lithium aluminum hydride.Under nitrogen protection, this solution is cooled to-50 ℃, add ether (200ml) solution of step F product (39.8g, about 0.120mol) with 30 fens clock times, and holding temperature is lower than-40 ℃.After adding, will react (mixture) and be warmed to 5 ℃, and then be cooled to-45 ℃.Thin-layer chromatographic analysis discloses reaction not exclusively.Again solution is warmed to 5 ℃, stirred 30 minutes, be cooled to-50 ℃ then.Slowly add sal enixum (72g, water 0.529mol) (200ml) solution, and holding temperature is lower than-20 ℃.With mixture be warmed to 5 ℃, by obtaining the aldehyde of title behind diatomite filtration and the vacuum concentration.
Step H:(S)-2-(t-butoxycarbonyl amino)-N-(3-chloro-phenyl-) The preparation of-4-(methylthio group) butylamine
Under nitrogen protection; toward the 3-chloroaniline (10.3ml, 97.4mmol), the product of step G (23.9g, 97.4mmol) and acetate (27.8ml; 487mmol) add in the solution in ethylene dichloride (250ml) sodium triacetoxy borohydride (41.3g, 195mmol).Reaction is under agitation spent the night, and uses the saturated sodium bicarbonate solution termination reaction then.Solution CHCl 3Dilution, organic phase is water, 10% citric acid and salt water washing successively.The solution dried over sodium sulfate obtains crude product behind vacuum concentration, it is carried out silica gel column chromatography purify, and with 20% ethyl acetate/hexane wash-out, obtains title compound.
Step I:(S)-4-(uncle Ding Qing carbonyl)-1-(3-chloro-phenyl-)-5 The preparation of-[2-(methylthio group) ethyl] piperazine-2-ketone
With the product of step H (22.0g, ethyl acetate 63.8mmol) (150ml) solution with saturated sodium bicarbonate (150ml) 0 ℃ of fierce stirring.(5.6ml, 70.2mmol), reaction mixture stirred 2 hours at 0 ℃ dropwise to add chloroacetyl chloride.Be separated two, ethyl acetate is mutually with using dried over sodium sulfate after 10% citric acid and the saturated brine washing.Gained crude product (27.6g) is dissolved among the DMF (300ml) behind vacuum concentration, is cooled to 0 ℃ then under argon shield.(63.9g 196mmol), under agitation reacted 2 days, allowed it be warmed to room temperature to add cesium carbonate.(10g 30mmol), under agitation reacted 16 hours to add another part cesium carbonate.Vacuum distilling goes out DMF, and residue distributes between ethyl acetate and water.Organic phase is used dried over sodium sulfate after washing with saturated brine.Crude product carries out silica gel column chromatography purifies, and with 20-25% ethyl acetate/hexane wash-out, obtains title compound.
Step J:(S)-4-(tertbutyloxycarbonyl)-1-(3-chloro-phenyl-)-5 The preparation of-[2-(methylsulfonyl) ethyl] piperazine-2-ketone
(14.2g, methyl alcohol 37mmol) (300ml) solution is cooled to 0 ℃, adds Magnesium monoperoxyphthalate (54.9g, methyl alcohol 111mmol) (210ml) solution with 20 fens clock times with the product of step I.Remove ice bath, allow solution be warming up to room temperature.After 45 minutes,, add 2N Na then with reaction mixture vacuum concentration half to original volume 2S 2O 3Solution makes reaction terminating.Solution is poured into EtOAc and saturated NaHCO 3In the solution, organic phase salt water washing, drying (Na 2SO 4), obtain the crude product sulfone behind filtration and the vacuum concentration.It is carried out silica gel column chromatography purify,, obtain title compound with 60-100% ethyl acetate/hexane wash-out.
Step K: (S)-1-(3-chloro-phenyl-)-5-[2-(methylsulfonyl) second Base] preparation of piperazine-2-ketone
0 ℃ with anhydrous HCl gas bubbling feed the Boc-protection of step J piperazine ketone (1.39g, 3, in EtOAc 33mmol) (30ml) solution.The gained saturated solution was stirred 35 minutes, behind vacuum concentration, obtain the hydrochloride of white powder.This material is suspended among the EtOAc, uses rare NaHCO 3Solution-treated.Water extracts with EtOAc, and drying (Na is carried out in the salt water washing of the organic mixture of merging then 2SO 4), filtration and vacuum concentration.Resulting amine concentrates from toluene again, obtains being applicable to the title substance of next step.
Step L:(S)-1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl) -5-imidazolyl methyl]-5-[2-(methylsulfonyl) ethyl]-2-piperazine ketone dihydrochloride Preparation
Toward the amine of step K (898mg, 2.83mmol) and the imidazole formaldehyde of step e (897mg, 4.25mmol) at 15ml 1, add in the solution in the 2-ethylene dichloride sodium triacetoxy borohydride (1.21g, 57.mmol).Under agitation reacted 23 hours, and used saturated NaHCO at 0 ℃ then 3The solution termination reaction.Solution is poured into CHCl 3In, water layer CHCl 3Strip.The organism that the merges dry (Na of the laggard row of salt water washing 2SO 4), filtration and vacuum concentration.Products therefrom is used silica gel column chromatography (95: 5: 0.5-90: 10: 0 EtOAc: MeOH: NH 4Cl) purify, the product that obtains is called in the EtOAc/ methyl alcohol, handles with 2.1 equivalent 1M HCl/ diethyl ether solutions then.Behind vacuum concentration, isolate the product dihydrochloride of white powder.
Example 43
(S)-1-(3-chloro-phenyl--4-[1-(4-cyano group benzyl)-5-miaow The azoles ylmethyl]-5-[2-(ethylsulfonyl) ethyl]-preparation of 2-piperazine ketone dihydrochloride
Steps A: (S)-preparation of N-(tertbutyloxycarbonyl) homoserine lactone
Toward (S)-homoserine lactone hydrochloride (11.0g, 79.9mmol) and Di-tert butyl pyrocarbonate (19.2g, 88.0mmol) in the solution in the methylene dichloride of 0 ℃ of 160ml with time of 3 minutes adding diisopropyl ethyl amine (13.9ml, 79.9mmol).Allow this solution be warmed to temperature.After 3 hours, add another part Di-tert butyl pyrocarbonate (1.75g, 8.0mmol) and diisopropyl ethyl amine (0.70ml, 4.0mmol), mixture restir 2.5 hours.Solution is used 10% citric acid, saturated NaHCO successively 3With the salt water washing, carry out drying (Na then 2SO 4), filtration and vacuum concentration.The gained material is purified with silica gel column chromatography (50% EtOAc/ hexane), obtains pure title compound.
Step B:(S)-preparation of N-(tertbutyloxycarbonyl) homoserine lactonaphthol
(7.0g, (72.0ml, 1M in THF 72mmol), keep temperature of reaction and are lower than-72 ℃ the lactone of past steps A simultaneously 35mmol) dropwise to add diisobutylaluminium hydride in the solution in 175ml-78 ℃ THF.After 3 hours, add another part diisobutylaluminium hydride (10.0ml, 10mmol), add again after 1 hour another part (20.0ml, 20mmol).Through after 1 hour,,, be warming up to room temperature then more then with saturated sodium tartrate potassium solution termination reaction with-78 ℃ EtOAc.Solution is poured among the EtOAc, with the dry (Na of the laggard row of salt water washing 2SO 4), filtration and vacuum concentration.The gained material obtains the title lactonaphthol with silica gel column chromatography (50% EtOAc/ hexane).
Step C:(S)-3-(tertbutyloxycarbonyl)-N-(3-chloro-phenyl-)-4 The preparation of-hydroxyl-1-butylamine
Toward the lactonaphthol of step B (4.49g, 22.2mmol) and the 3-chloroaniline (2.58ml, 24.4mmol) add in the solution in the methylene dichloride under the 50ml room temperature acetate (1.27ml, 22.2mmol).After 10 minutes, add sodium triacetoxy borohydride (6.59g, 31.1mmol), with this solution stirring 1.5 hours.Use saturated NaHCO 3Aqueous solution termination reaction is used CH 2Cl 2Two-phase is isolated in dilution.Organism drying (Na 2SO 4), obtain a kind of solid behind filtration and the vacuum concentration, obtain the described amine of title after with silica gel column chromatography (EtOAc/ hexane) it being purified.
Step D:(S)-and N-[2-(t-butoxycarbonyl amino)-4-hydroxyl butyl]-2 The preparation of-chloro-N-(3-chloro-phenyl-) ethanamide
(5.29g 16.9mmol) is dissolved in the saturated NaHCO of 60ml EtOAc and 60ml to the anils of step C 3In the solution, be cooled to 0 ℃ then.Under fierce the stirring, and the dropping chloroacetyl chloride (1.48ml, 18.5mmol).After 2 hours, water and EtOAc diluted reaction mixture, organic layer salt water washing, drying (Na 2SO 4), obtain the chlor(o)acetamide of title behind filtration and the vacuum concentration, need not further purifies just can use.
Step e: (S)-4-(tertbutyloxycarbonyl)-1-(3-chloro-phenyl-)-5 The preparation of-(2-hydroxyethyl) piperazine-2-ketone
Toward the chlor(o)acetamide of step D (6.32g, 16.1mmol) add in the DMF solution of 0 ℃ of 80ml cesium carbonate (15.8g, 48.3mmol).This solution stirring is shown that until thin-layer chromatographic analysis starting material is exhausted till (about 5 hours).Solution is poured among the EtOAc water and salt water washing, drying (Na 2SO 4), obtain crude product behind filtration and the vacuum concentration, with silica gel column chromatography (90: 1: 0-95: 5: 0.15 CHCl 3: MeOH: NH 4OH) purification obtains containing the product of a small amount of DMF impurity.
Step F: (S)-4-(tertbutyloxycarbonyl)-1-(3-chloro-phenyl-)-5 The preparation of-[2-(mesyloxy) ethyl] piperazine-2-ketone
Toward the alcohol of step e (3.58g, add in 0 ℃ of dichloromethane solution of 50ml 10.1mmol) diisopropyl ethyl amine (3.5ml, 20.2mmol), then add methylsulfonyl chloride (0.936ml, 12.1mmol).With this solution stirring 45 minutes, use 10% citric acid termination reaction then.With the salt water washing of this solution, drying (Na 2SO 4), obtain crude product behind filtration and the vacuum concentration, need not further purification and just can be used in the next step.
Step G:(S)-4-(tertbutyloxycarbonyl)-1-(3-chloro-phenyl-)-5 The preparation of-[2-(ethylmercapto group) ethyl] piperazine-2-ketone
The methylsulfonyl thing of past step F (3.6g, and adding sulfur alcohol sodium in the DMF solution that 100ml 8.3mmol) is 0 ℃ (1.4g, 16.6mmol).After 2 hours, reaction mixture is poured among the EtOAc, uses saturated NaHCO 3With the salt water washing, drying (Na 2SO 4), obtain crude product behind filtration and the vacuum concentration, need not further purification and just can be used in the next step.
Step H:(S)-4-(tertbutyloxycarbonyl)-1-(3-chloro-phenyl-)-5 The preparation of-[2-(ethylsulfonyl) ethyl] piperazine-2-ketone
(3.12g adds Magnesium monoperoxyphthalate (11.6g, 23.5mmol) solution in the methyl alcohol under the 50ml room temperature to the product of past step G in methyl alcohol 7.82mmol) (50ml) solution.After 45 minutes, add 2N Na 2S 2O 3Solution makes reaction terminating.Reaction mixture is poured into EtOAc and saturated NaHCO 3In the solution, organic layer salt water washing, drying (Na 2SO 4), obtain the crude product sulfone behind filtration and the vacuum concentration.It is carried out silica gel column chromatography purify,, obtain title compound with 2% methyl alcohol/chloroform wash-out.
Step I:(S)-1-(3-chloro-phenyl-)-5-[2-(ethylsulfonyl) second Base] preparation of piperazine-2-ketone
(1.75g is in 0 ℃ of EtOAc solution of 20ml 4.06mmol) anhydrous HCl gas bubbling to be fed the piperazine ketone of Boc protection of step H.Formed saturated solution was stirred 30 minutes, behind vacuum concentration, obtain the title compound hydrochloride of white powder.This material is suspended among the EtOAc, uses rare NaHCO then 3The aqueous solution is handled.Water extracts with EtOAc, the organic mixture of the merging dry (Na of the laggard row of salt water washing 2SO 4), filtration and vacuum concentration.The described amine of resulting title concentrates from toluene again.Obtain being applicable to the title compound of next step.
Step J:(S)-1-(3-chloro-phenyl--4-[1-(4-cyano group benzyl) -5-imidazolyl methyl]-5-[2-(ethylsulfonyl) ethyl]-2-piperazine ketone dihydrochloride Preparation
Toward the amine of step I (480mg, 1.45mmol), the imidazole formaldehyde of example 42 step e (460mg, 2.2mmol) and acetate (0.415ml, 10ml 1 7.25mmol), add in the 2-dichloroethane solution sodium triacetoxy borohydride (615mg, 2.9mmol).Under agitation reacted 18 hours, and used saturated NaHCO at 0 ℃ then 3The solution termination reaction.Solution is poured into CH 2Cl 2In, the organic phase dry (Na of the laggard row of salt water washing 2SO 4), filtration and vacuum concentration.Products therefrom silica gel column chromatography (2-5% MeOH:CHCl 3) purify, obtain expecting product and less polarity boron complexes.A kind of compound dissolution in back in methylene dichloride (1ml) and benzene (5ml), was handled 18 hours with Tri N-Propyl Amine (1ml), under vacuum, concentrated then.Residue silica gel column chromatography (2-5% MeOH:CHCl 3) purify, merge with preceding a collection of product, it is dissolved in the EtOAc/ methyl alcohol, handle with 2.1 equivalent 1M HCl/ diethyl ether solutions.Behind vacuum concentration, isolate the product hydrochloride of white powder.
Example 44
(S)-1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-5- Imidazolyl methyl]-5-[2-(ethylsulfonyl) methyl]-system of 2-piperazine ketone dihydrochloride Be equipped with
Steps A: (S)-2-(t-butoxycarbonyl amino)-N-(3-chloro-phenyl-) -3-[(trityl) sulfo-]-preparation of 1-propylamine
(0.709ml adds the 4 molecular sieves that 1.2g pulverizes in the dichloromethane solution under 30ml room temperature 6.70mmol) toward the 3-chloroaniline.(3.35g 16.7mmol), then drips N-methylmorpholine, makes pH reach 6.5 to add sodium triacetoxy borohydride.(3.15g, 7.04mmol) (according to people such as S.L.Graham: pharmaceutical chemistry magazine (1994) the 37th volume, the preparation of method described in the 725-732 page or leaf) was with this solution stirring 48 hours to add L-S-trityl-N-Boc-half Guang ammonium aldehyde.Use saturated NaHCO 3Aqueous solution termination reaction with the EtOAc dilution, is separated 2.Organism salt water washing, drying (Na 2SO 4), obtain a kind of oil behind filtration and the vacuum concentration, recycle silicon glue column chromatography (15% EtOAc/ hexane) is purified it, obtains the amine of title.
Step B:(S)-N-[2-(t-butoxycarbonyl amino)-3-((trityl) Sulfo-) propyl group]-preparation of 2-chloro-N-(3-chloro-phenyl-) ethanamide
(2.77g 4.95mmol) is dissolved in the saturated NaHCO of 73ml EtOAc and 73ml with the anils of steps A 3In the solution, be cooled to 0 ℃ then.Under fierce the stirring, drip chloroacetyl chloride (0.533ml, 6.69mmol).After 3 hours, water and EtOAc dilute reaction mixture, organic layer salt water washing, drying (Na 2SO 4), obtain crude product behind filtration and the vacuum concentration, the chlor(o)acetamide of title, need not further purifies just can use.
Step C:(S)-4-(tertbutyloxycarbonyl)-1-(3-chloro-phenyl-)-5 The preparation of-[S-(trityl) thiomethyl] piperazine-2-ketone
Add in the 53ml0 ℃ of DMF solution of the chlor(o)acetamide (3.29g crude product, 4.95mmol in theory) of step B cesium carbonate (4.84g, 14.85mmol).With this solution stirring 48 hours, allow it be warmed to room temperature.Solution is poured among the EtOAc water and salt water washing, drying (Na 2SO 4), obtain the oily crude product behind filtration and the vacuum concentration.With its purification, obtain white solid product with silica gel column chromatography (20% EtOAc/ hexane).
Step D:(S)-4-(tertbutyloxycarbonyl)-1-(3-chloro-phenyl-)-5 The preparation of-(thiomethyl) piperazine-2-ketone
(625mg 1.04mmol) is warmed to 30 ℃ at the EtOAc (38ml) of the degassing and the solution in the ethanol (12ml) with the piperazine ketone of step C.Add AgNO 3(177mg, 1.04mmol) and pyridine (0.084ml, 8ml ethanolic soln 1.04mmol) is heated to backflow then.After 45 minutes, reaction mixture is concentrated under vacuum, be dissolved in again then among the 26ml degassing EtOAc.With H 2S gas bubbling fed this solution 2.5 minutes, added gac after 4 minutes.This material by diatomite filtration, is used the EtOAc drip washing of the degassing, vacuum concentration, and then CH from outgasing 2Cl 2In concentrate, the crude product that obtains need not further to purify just can use.
Step e: (S)-4-(tertbutyloxycarbonyl)-1-(3-chloro-phenyl-)-5 The preparation of-[(ethylmercapto group) methyl] piperazine-2-ketone
The 3ml THF solution of the mercaptan (about 1.04mmol) of step D is joined NaH through sleeve pipe, and (51.4mg, 60% suspension in mineral oil is in 0 ℃ of THF suspension of 2ml 1.28mmol).After 10 minutes, add methyl iodide (0.079ml, 0.988mmol), with this solution stirring 1.5 hours.Reaction mixture is poured among the EtOAc, uses saturated NaHCO 3With the salt water washing, drying (Na 2SO 4), obtain crude product behind filtration and the vacuum concentration.With silica gel column chromatography (1% MeOH/CH 2Cl 2) purify, obtain title product.
Step F: (S)-4-(tertbutyloxycarbonyl)-1-(3-chloro-phenyl-)-5 The preparation of-[(ethylsulfonyl) methyl] piperazine-2-ketone
(217mg adds Magnesium monoperoxyphthalate (835mg, 2ml MeOH solution 1.69mmol) to the thioether of past step e in 0 ℃ of MeOH solution of 3ml 0.563mmol).Reaction is under agitation spent the night, and allows it be warmed to room temperature.Solution is cooled to 0 ℃, adds 4ml 2NNa 2S 2O 3Solution makes reaction terminating, concentrates under vacuum then.Residue is at EtOAc and saturated NaHCO 3Distribute organic phase salt water washing, drying (Na between the solution 2SO 4), obtain white waxy solid crude product sulfone behind filtration and the vacuum concentration.
Step G:(S)-1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl) -5-imidazolyl methyl]-5-[2-(ethylsulfonyl) methyl]-2-piperazine ketone two hydrochloric acid The preparation of salt
(224mg adds 2.5ml trifluoroacetic acid (TFA) to the piperazine ketone of the Boc-protection of past step F in ℃ dichloromethane solution of 5ml0 0.538mmol).After 45 minutes, reaction mixture is concentrated under vacuum, carry out component distillation to remove excessive TFA with benzene then.Residue is dissolved in 4ml 1, in the 2-ethylene dichloride, is cooled to 0 ℃ then.Add the Powdered molecular sieves of 4 (340mg) in this solution, (285mg 1.34mmol) with several triethylamines, makes pH=6 then to add sodium triacetoxy borohydride.Adding derives from example 42, and (125mg 0.592mmol), under agitation reacts at 0 ℃ the imidazole formaldehyde of step e.After 2 days, reaction mixture is poured among the EtOAc, uses rare NaHCO 3Drying (Na is carried out in the aqueous solution and salt water washing then 2SO 4), filtration and vacuum concentration.Crude product is dissolved in the methyl alcohol, is injected in the preparation HPLC post, with 15%-50% acetonitrile/0.1 TFA; The 0.1% TFA aqueous solution of 85%-50% carries out 60 minutes mixing gradient elution, thereby with its purification.Behind vacuum concentration, products therefrom is at methylene dichloride and NaHCO 3Distribute water CH between the aqueous solution 2Cl 2Extraction.Organic solution salt water washing, drying (Na 2SO 4), filter, be concentrated into and obtain the product free alkali after doing, it is dissolved in CH 2Cl 2In, handle with 2.1 equivalent 1M HCl/ diethyl ether solutions.Behind vacuum concentration, isolate the product dihydrochloride of white powder.
Example 45
(S)-1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-5-imidazoles Ylmethyl]-5-[N-ethyl-2-kharophen]-preparation of 2-piperazine ketone dihydrochloride
Steps A: (S)-4-(tertbutyloxycarbonyl)-1-(3-chloro-phenyl-)-5 The preparation of-[2-(oxo) ethyl] piperazine-2-ketone
Past oxalyl chloride (0.608ml, and usefulness adding in 2-3 minute DMSO in-78 ℃ of dichloromethane solutions 6.97mmol) (0.990ml, 13.9mmol).Under agitation reacted 10 minutes, and added alcohol (2.06g, 10ml dichloromethane solution 5.81mmol), and keep temperature of reaction to be lower than-70 ℃ of example 43 step e then with 5 fens clock times.Reaction mixture was stirred 10 minutes, add triethylamine (2.43ml) then, reaction mixture stirred 5 minutes at-78 ℃, allowed it be warmed to room temperature then.After 45 minutes, solution is poured in the methylene dichloride, uses saturated NH successively 4Cl solution, 10% citric acid solution, water and salt water washing, this solution drying (Na 2SO 4), obtain the aldehyde of title behind filtration and the vacuum concentration.
Step B:(S)-4-(tertbutyloxycarbonyl)-5-(carboxymethyl)-1-(3 -chloro-phenyl-) preparation of piperazine-2-ketone
Aldehyde (1.52g toward steps A, 4.31mmol) add Textone (585mg in the solution at room temperature in 2-methyl-2-propyl alcohol (50ml) and 2-methyl-2-butene (10ml), 5.17mmol) and SODIUM PHOSPHATE, MONOBASIC (595mg, 4.31mmol) solution in 10ml water.The reaction mixture yellowing slowly faded in 45 minutes then, became the pale pink look.Solution is poured among the EtOAc, with saturated sodium sulfite solution washing, water layer 2.75M KHSO 4Solution is acidified to pH3, extracts several times with EtOAc.Organic extract drying (the Na that merges 2SO 4), obtain the carboxylic acid of title behind filtration and the vacuum concentration.
Step C:(S)-4-(tertbutyloxycarbonyl)-5-[N-ethyl-2-acetyl Amino]-preparation of 1-(3-chloro-phenyl-) piperazine-2-ketone
The product of step B (200mg, 0.56mmol), ethylamine hydrochloride (114mg, 1.4mmol), the EDC hydrochloride (140mg, 0.73mmol) and the HOBT hydrate (113mg 0.84mmol) stirs in 0 ℃ dry DMF (3ml) under nitrogen protection together.After 1 hour, solution is warmed to room temperature, and stirring is spent the night.Vacuum removal DMF, residue distributes between ethyl acetate and water.Organic phase is used 10% citric acid, saturated sodium bicarbonate, water and salt water washing successively, uses dried over sodium sulfate.Obtain title compound behind the vacuum removal solvent.
Step D:(S)-1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)- The 5-imidazolyl methyl]-5-[N-ethyl-2-kharophen]-2-piperazine ketone dihydrochloride Preparation
With being similar to example 42, the method described in step K and the L, (184mg 0.47mmol) has made title product from the product of step C.This product comes out with the white solid isolated in form.
Example 46
(±)-5-(2-butyne base)-1-(3-chloro-phenyl-)-4-[1-(4 -cyano group benzyl)-the 5-imidazolyl methyl]-preparation of 2-piperazine ketone dihydrochloride
The preparation of steps A: 1-(methylsulfonyl)-2-butyne
Toward 2-butyne alcohol (10.0ml, add in 0 ℃ of dichloromethane solution of 200ml 134mmol) methylsulfonyl chloride (23.4g, 134mmol), then drip diisopropyl ethyl amine (30ml, 174mmol).1.5 after hour, this solution is poured into 0.5N KHSO 4In the solution, organic layer salt water washing.Solution drying (Na 2SO 4), obtain title product behind filtration and the vacuum concentration.
Step B:(±)-the 2-[(phenmethyl) imino-]-preparation of 4-hexynoic acid ethyl ester
Toward glycine ethyl ester hydrochloride (10.11g, add in 200ml dichloromethane solution 72.4mmol) phenyl aldehyde (7.36ml, 72.4mmol), triethylamine (20.0ml, 143mmol) and sal epsom (6g).This solution was at room temperature stirred 16 hours, filter, under vacuum, concentrate then by frit.Residue distributes between ether and water, organic layer salt water washing.Solution drying (Na 2SO 4), obtain a kind of light yellow oil behind filtration and the vacuum concentration.(9.90g 51.8mmol) is dissolved among the 200ml THF, is cooled to-78 ℃ under nitrogen atmosphere to get the part of this oil.(51.8ml, 1M 51.8mmol), obtain a kind of shiny red solution dropwise to add the THF solution of potassium tert.-butoxide.After 20 minutes, (8.05g, 20ml THF solution 54.4mmol) allows this solution be warmed to room temperature to splash into the methylsulfonyl thing that derives from steps A by sleeve pipe.After 2 hours, reaction mixture is poured among the EtOAc, used saturated NaHCO successively 3Solution and salt water washing drying (Na 2SO 4), obtain title product behind filtration and the vacuum concentration.
Step C:(±)-the 2-[(tertbutyloxycarbonyl) amino]-system of 4-hexynoic acid ethyl ester Be equipped with
The solution of step B product (about 51.8mmol) at room temperature stirs in the 5%HCl aqueous solution (100ml).After 12 hours, under vacuum, this solution concentration provided a kind of orange oil.This product is dissolved among the 50ml THF, at room temperature adds saturated NaHCO then 3Solution (50ml), then add Di-tert butyl pyrocarbonate (11.3g, 51.8mmol).After 6 hours, reaction mixture is poured among the EtOAc, used saturated NaHCO 3Solution and salt water washing, drying (Na 2SO 4), obtain title compound behind filtration and the vacuum concentration.
Step D:(±)-the 2-[(tertbutyloxycarbonyl) amino]-preparation of 4-hexynoic acid
0 ℃ add in the solution of step C product (about 51.8mmol) in THF (100ml) and water (20ml) lithium hydroxide monohydrate (6.5g, 155mmol).This solution was stirred 1 hour at 0 ℃, be warmed to room temperature then.After 48 hours, this solution is concentrated under vacuum.Aqueous mixture extracts with EtOAc, 0 ℃ with 10% HCl acidified aqueous solution, use 3 parts of dichloromethane extractions then.Dichloromethane extract drying (the Na that merges 2SO 4), obtain a kind of orange oily title product behind filtration and the vacuum concentration.
Step e: (±)-2-(t-butoxycarbonyl amino)-N-methoxyl group-N-first The preparation of base-4-hexin acid amides
Product (the 10.58g of step D; 46.6mmol), N, the O-dimethyl hydroxylamine hydrochloride (9.09g, 93.2mmol), HOBT hydrate (9.44g; 69.9mmol) and triethylamine (13.0ml, 93.2mmol) stirring together in 0 ℃ dry DMF (150ml) under nitrogen protection.(11.5g 60.0mmol), under agitation reacted 3 hours to add the EDC hydrochloride.Solution distributes between 2: 1 ethyl acetate/hexane and water, successively water, the 10% HCl aqueous solution, saturated NaHCO 3Dried over sodium sulfate is used in solution and salt water washing then.Obtain orange oily title compound behind the vacuum removal solvent.
The preparation of step F: (±)-2-(t-butoxycarbonyl amino)-4-hexin aldehyde
(1.56g, ether 41.1mmol) (150ml) suspension at room temperature stirred 30 minutes lithium aluminum hydride.Under nitrogen atmosphere, this solution is cooled to-55 ℃, adds step e product (11.10g, ether 41.1mmol) (150ml) solution, and holding temperature is lower than-50 ℃ with 15 fens clock times.After adding, reaction mixture is warmed to 5 ℃, is cooled to-40 ℃ then.The 25ml aqueous solution that slowly adds sal enixum (21.8g) keeps temperature to be lower than-35 ℃.Mixture is warmed to room temperature, stirs 1 hour by obtaining the aldehyde of title behind diatomite filtration and the vacuum concentration.
Step G:(±)-2-(t-butoxycarbonyl amino)-N-(3-chloro-phenyl-) -4-butine amine
Toward 3 chloroaniline (4.33ml under nitrogen atmosphere, 40.9mmol), add in the product (about 41mmol) of step F and 0 ℃ of solution of 4 molecular sieves (10g) in ethylene dichloride (100ml) pulverized sodium triacetoxy borohydride (12.9g, 61.5mmol).Under agitation reacted 1 hour, and be warmed to room temperature then.After 3 hours solution is poured among the EtOAc, successively water, saturated NaHCO 3Solution and salt water washing.This solution obtains crude product behind dried over sodium sulfate and vacuum concentration.
Step H:(±)-N-[2-(t-butoxycarbonyl amino)-4-hexin base]-2 The preparation of-chloro-N-(3-chloro-phenyl-) ethanamide
Step G product (1.68g, 5.22mmol) and triethylamine (1.2ml, 15ml CH 8.61mmol) 2Cl 2Solution is cooled to 0 ℃.(0.457ml 5.74mmol), under agitation reacts at 0 ℃ to splash into chloroacetyl chloride.After 30 minutes, splash into another part chloroacetyl chloride (0.20ml) and triethylamine (0.5ml).After 30 minutes, reaction mixture is poured among the EtOAc, with the 10% HCl aqueous solution, saturated NaHCO 3The aqueous solution and salt water washing.Solution drying (Na 2SO 4), obtain a kind of brown oil behind filtration and the vacuum concentration.Obtain title product after with silica gel column chromatography (20-35% EtOAc/ hexane) it being purified.
Step I:(±)-4-(tertbutyloxycarbonyl)-5-(2-butyne base)-1- The preparation of (3-chloro-phenyl-)-2-piperazine ketone
(1.68g adds Cs in 0 ℃ of anhydrous DMF solution of 15ml 4.23mmol) to the product of past step H 2CO 3(3.08g, 9.48mmol).With this solution stirring 30 minutes, allow it be warmed to room temperature then.After 14 hours, reaction mixture is poured in the 50% EtOAc/ hexane water and salt water washing, drying (Na 2SO 4), obtain crude product behind filtration and the vacuum concentration.Obtain title product after with silica gel column chromatography (20-40%EtOAc/ hexane) it being purified.
Step J:(±)-5-(2-butyne base)-1-(3-chloro-phenyl-)-4- The preparation of [1-(4-cyano group benzyl)-5-imidazolyl methyl]-2-piperazine ketone dihydrochloride
Piperazine ketone (1.03g, adding 4ml trifluoroacetic acid (TFA) in ℃ dichloromethane solution of 7ml0 2.85mmol) toward the Boc protection that derives from step I.After 4 hours, reaction mixture is warmed to room temperature, and restir 6 hours.Solution is carried out vacuum concentration, carries out component distillation to remove excessive TFA with benzene.A part of residue is dissolved in 6ml 1, in the 2-ethylene dichloride, and is cooled to 0 ℃.Add the molecular sieve (600mg) that 4 pulverize in this solution, then add sodium triacetoxy borohydride (214mg, 1.02mmol).(186mg 0.881mmol), under agitation reacts at 0 ℃, after 24 hours, reaction mixture is poured among the EtOAc, uses rare NaHCO to add the imidazole formaldehyde that derives from example 42 step e 3Dry (the Na of the laggard row of the aqueous solution and salt water washing 2SO 4), filtration and vacuum concentration.With silica gel column chromatography (2-5%MeOH: CH 2Cl 2) obtain a kind of white foam body after the purification, with its molten CH 2Cl 2In, handle with 2.1 equivalent 1M HCl/ diethyl ether solutions.Behind vacuum concentration, isolate the product dihydrochloride of white powder.
Example 47
1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl) imidazolyl methyl]-2 -piperazine ketone dihydrochloride
The preparation of steps A: N-(3-chloro-phenyl-) ethylenediamine-hydrochloride
(30.0ml dropwise adds 4N HCl 1 in 0 ℃ of dichloromethane solution of 500ml 284mmol), the solution in the 4-diox (80ml, 320mmol HCl) toward the 3-chloroaniline.This solution is warmed to room temperature, under vacuum, is concentrated into the dried white powder that obtains then.With this powder and 2-oxazolidone (24.6g, 282mmol) together under nitrogen atmosphere 160 ℃ of heating 10 hours, solids fusing in this process, and observed gas and emitted.After the reaction mixture cooling, form light brown solid crude product diamine hydrochloride.
The preparation of step B:N-(tertbutyloxycarbonyl)-N '-(3-chloro-phenyl-) quadrol
The amine hydrochlorate (about 282mmol, the coarse raw materials for preparing above) of steps A is dissolved in 500mlTHT and the saturated NaHCO of 500ml 3In the aqueous solution, be cooled to 0 ℃, add then Di-tert butyl pyrocarbonate (61.6g, 282mmol).After 30 hours, reaction mixture is poured among the EtOAc water and salt water washing, drying (Na 2SO 4), obtain brown oily title carbamate behind filtration and the vacuum concentration, need not further purification and just can be used in the next step.
Step C:N-[2-(uncle Ding Qing formamyl) ethyl]-N-(3-chlorobenzene Base)-preparation of 2-chlor(o)acetamide
Step B product (77g, about 282mmol) and triethylamine (67ml, 500ml CH 480mmol) 2Cl 2Solution is cooled to 0 ℃.(25.5ml 320mmol), keeps 0 ℃, under agitation reacts to splash into chloroacetyl chloride.After 3 hours, splash into another part chloroacetyl chloride (3.0ml).After 30 minutes, reaction mixture is poured among the EtOAc (2 liters), successively water, saturated NH 4The Cl aqueous solution, saturated NaHCO 3The salt water washing of the aqueous solution.Solution drying (Na 2SO 4), obtain brown buttery title chlor(o)acetamide behind filtration and the vacuum concentration, need not further purification and just can be used in the next step.
Step D:4-(tertbutyloxycarbonyl)-1-(3-chloro-phenyl-)-2-piperazine ketone Preparation
In the 700ml anhydrous DMF solution of the chlor(o)acetamide that derives from step C (about 282mmol), add K 2CO 3(88g 0.64mmol), places 70-75 ℃ oil bath to heat 20 hours this solution, and cool to room temperature concentrates under vacuum then, removes about 500ml DMF.In the remaining material impouring 33% EtOAc/ hexane, water and salt water washing, drying (Na 2SO 4), obtain brown oily product behind filtration and the vacuum concentration.With its purification, obtain pure products with silica gel column chromatography (25-50%EtOAc/ hexane), and the product sample (HPLC purity assay about 65%) that contains small amount of polar impurity.
The preparation of step e: 1-(3-chloro-phenyl-)-2-piperazine ketone
(17.19g, 55.4mmol) in the solution in-78 ℃ 500ml EtOAc, formed saturated solution is warmed to 0 ℃ to the piperazine ketone that the Boc that anhydrous HCl gas bubbling feeding is derived from step D protects, and stirs 12 hours.Bubbling feeds nitrogen to drive away excessive HCl in the reaction mixture, then this mixture is warmed to room temperature.Solution obtains the hydrochloride of white powder behind vacuum concentration.It is dissolved in 300ml CH 2Cl 2In, and handle with the rare o aqueous solution.Water CH 2Cl 2(8 * 300ml) extractions are till thin-layer chromatographic analysis shows extraction fully.Organic mixture drying (the Na that merges 2SO 4), obtain the unhindered amina of the light brown oily of title behind filtration and the vacuum concentration.
Step F: 1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-5- Imidazolyl methyl]-preparation of 2-piperazine ketone dihydrochloride
Toward 0 ℃ 1 of the 200ml of the amine (55.4mmol prepares above) of step e, the 2-dichloroethane solution adds 4 mealy molecular sieves (10g), then add sodium triacetoxy borohydride (17.7g, 83.3mmol).Adding derives from example 42, and (11.9g 56.4mmol) under agitation reacts at 0 ℃ the imidazole formaldehyde of step e.After 26 hours, in reaction mixture impouring EtOAc, use rare NaHCO 3Solution washing, water layer is stripped with EtOAc.The organism that the merges dry (Na of the laggard row of salt water washing 2SO 4), filtration and vacuum concentration.Products therefrom is dissolved in benzene/CH of 5: 1 of 500ml 2Cl 2In, add propylamine (20ml) then.Mixture was stirred 12 hours, behind vacuum concentration, obtain a kind of light yellow foam.With silica gel column chromatography (2-7% MeOH/CH 2Cl 2) with its purification, resulting white foam is dissolved in CH 2Cl 2In, handle with 2.1 equivalent 1M HCl/ diethyl ether solutions.Behind vacuum concentration, isolate the product dihydrochloride of white powder.
Example 48
5 (S)-butyl-4-[1-(4-cyano group benzyl)-2-methyl-5-imidazolyl first Base]-1-(2, the 3-3,5-dimethylphenyl)-piperazine-2-ketone dihydrochloride
Steps A: 4-bromo-glyoxal ethyline-5-formaldehyde
According to S.P.Watson: synthesising communication, 22, method described in the 2971-2977 (1992) prepares 4-bromo-5-methylol-glyoxal ethyline.(4.18g, solution 21.9mmol) refluxed 16 hours in 1: 1 methylene dichloride/diox (200ml) with Manganse Dioxide (16.1g) 4-bromo-5-methylol-glyoxal ethyline.Cooled reaction mixture obtains the light yellow solid title compound by diatomite filtration after concentrating.
1H?NMR(CDCl 3，300MHz)δ9.57(1H，s)，2.52(3H，s)。
Step B:4-bromo-1-(4-cyano group benzyl)-glyoxal ethyline-5-first Aldehyde
(1.05g, (1.02g is in N,N-DIMETHYLACETAMIDE 5.39mmol) in (15ml) solution 5.39mmol) to join 4-bromo-glyoxal ethyline-5-formaldehyde with the 4-cyano-benzyl bromide.This solution is cooled to-10 ℃, and the adding powdered potassium carbonate (0.745g, 5.39mmol).Under agitation-10 ℃ of reactions 2 hours, again 20 ℃ of reactions 4 hours.The reaction mixture dilute with water is used ethyl acetate extraction.Organic phase is water and saturated brine washing successively, uses dried over mgso.After solvent evaporation, obtain a kind of white solid.
1H?NMR(CDCl 3，400MHz)δ9.68(1H，s)，7.64(2H，d，J＝7Hz)，7.15(2H，d，J＝7Hz)，5.59(2H，s)，2.40(3H，s)。
Step C:1-(4-cyano group benzyl)-glyoxal ethyline-5-formaldehyde
4-bromo-1-(4-cyano group benzyl)-glyoxal ethyline-5-formaldehyde (1.33g, 4.37mmol) and imidazoles (0.600g, 8.74mmol) solution in 1: 1 ethyl acetate/ethanol (150ml) stirs with 10% palladium/charcoal (0.020g) catalyzer under 1 atm hydrogen pressure.After 2 hours, reaction mixture obtains the white solid title compound by diatomite filtration after concentrating.
1H?NMR(DMSO-d 6?400MHz)δ9.62(1H，s)，7.90(1H，s)，7.81(2H，d，J＝8Hz)，7.20(2H，d，J＝8Hz)，5.64(2H，s)，2.33(3H，s)。
Step D:5 (S)-butyl-4-[1-(4-cyano group benzyl)-2-methyl-5 -imidazolyl methyl]-1-(2, the 3-3,5-dimethylphenyl)-piperazine-2-ketone dihydrochloride
With sodium triacetoxy borohydride (0.265g, 1.25mmol) join 1-(4-cyano group benzyl)-2-imidazoles-5-formaldehyde (0.190g, 0.843mmol), 5 (S)-butyl-1-sodium triacetoxy borohydride piperazine-2-keto hydrochloride (0.250g, 0.843mmol), N-methylmorpholine (0.093mml, 0.843mmol) in the solution in ethylene dichloride (10ml), according to example 39, the described method of step e is carried out.Title compound is purified with preparation HPLC, carries out gradient elution with the 70-45% solvent orange 2 A.Isolate free alkali, and convert it into dihydrochloride.Obtain the title compound of white solid form.FAB?ms：470(m+1)。Analyze: calculated value C 29H 35N 5O2HCl1.45H 2O:
C, 61.25; H, 7.07; N, 12.32 measured values: C, 61.56; H, 6.99; N, 11.32.
Example 49
4-[1-(2-(4-cyano-phenyl)-2-propyl group)-5-imidazoles methyl]-1 -(3-chloro-phenyl-)-5 (S)-(2-methylsulfonyl ethyl) piperazine-2-ketone two hydrochloric acid Salt
Steps A: 4-(t-butyldimethylsilyloxy ylmethyl)-1-trityl miaow Azoles
(2.83g, (5.80g, 17.05mmol) (3.48g is in the suspension among DMF 51.1mmol) (200ml) containing imidazoles 18.76mmol) to join 4-methylol-1-trityl imidazole with tert-butyldimethylsilyl chloride.After 15 minutes, obtain colourless transparent solution, it is at room temperature stirred.After reacting completely, remove DMF under vacuum, residue distributes between ethyl acetate and water.With organic phase water successively and saturated brine washing, use dried over mgso.Obtain transparent gelationus title compound.
Step B:5-t-butyldimethylsilyloxy ylmethyl-1-(4-cyano group benzyl) Imidazoles
(4.66g, 10.26mmol) (2.01g, acetonitrile 10.26mmol) (50ml) solution refluxed 4 hours with 1-brooethyl-4-cyano group benzene with 4-(t-butyldimethylsilyloxy ylmethyl)-1-trityl imidazole.With the reaction mixture cooling, under vacuum, remove acetonitrile, residue is dissolved in the methyl alcohol (30ml), this solution was refluxed 2 hours, cooling evaporates methyl alcohol then.Residue distributes between ethyl acetate and saturated sodium bicarbonate.Crude product carries out silica gel column chromatography purifies, with 3% methyl alcohol/chloroform wash-out.Obtain the title compound of white solid form.
Step C:5-t-butyldimethylsilyloxy ylmethyl-1-[2-(4-cyano group Phenyl)-and the 2-propyl group] imidazoles
(1.005g, THF 3.07mmol) (25ml) solution is cooled to-78 ℃ under nitrogen atmosphere with 5-t-butyldimethylsilyloxy ylmethyl-1-(4-cyano group benzyl) imidazoles.Add hexamethyl two silicon Lithium Azides (4.61ml, 1M THF solution), under agitation, in 30 minutes, be warmed to-60 ℃ then-78 ℃ of reactions 1 hour.Reaction mixture is cooled to-78 ℃.(0.287ml 4.61mmol), continues to stir 2 hours at-78 ℃ again, is warmed to 0 ℃ then in 2 hours to add methyl-iodide.After 30 minutes, reaction mixture is cooled to-78 ℃, adds hexamethyl two silicon Lithium Azides (4.61ml, 1M THF solution).After 1 hour, (0.287ml 4.61mmol), allows reaction mixture be warmed to ambient temperature overnight to add methyl-iodide.The water termination reaction is used ethyl acetate extraction, and organic phase is washed with saturated brine.Crude product carries out silica gel column chromatography purified, with 6: 4 ethyl acetate/dichloromethane wash-out.Obtain golden oily title compound.
1H?NMR(CDCl 3，400MHz)δ7.78(1H，s)，7.61(2H，d，J＝8Hz)，7.15(2H，d，J＝8Hz)，7.02(1H，s)，4.00(2H，s)，1.99(6H，s)，0.79(9H，s)，-0.74(6H，s)。
Step D:1-[2-(4-cyano-phenyl)-2-propyl group)]-5-methylol miaow Azoles
To fluoridize four-N-fourth ammonium (2.99ml, 1M THF solution) and join uncle's 5-fourth oxygen dimethylsilane oxygen ylmethyl-1-[2-(4-cyano-phenyl)-2-propyl group] (0.750g is in THF 2.72mmol) (10ml) solution for imidazoles.At room temperature, in reaction mixture impouring ethyl acetate, extract with saturated sodium bicarbonate solution through after 2 hours.Organic phase extracts with saturated brine, uses dried over mgso.Crude product carries out silica gel column chromatography purifies, and with 3% methanol/ethyl acetate wash-out, obtains the title compound of semi-solid.
1H?NMR(CDCl 3，400MHz)δ7.77(1H，s)，7.62(2H，d，J＝8Hz)，7.19(2H，d，J＝8Hz)，7.02(1H，s)，4.01(2H，s)，2.57(1H，br?s)，2.01(6H，s)。
Step e: 1-[2-(4-cyano-phenyl)-2-propyl group] imidazoles-5-formaldehyde
With 1-[2-(4-cyano-phenyl)-2-propyl group)]-(0.450g, 1.87mmol) (1.62g's 5-hydroxy methylimidazole together 18.7mmol) refluxed 5 hours for De diox (20ml) solution and Manganse Dioxide.With the reaction mixture cooling, by diatomite filtration, also concentrated.Crude product is purified with silica gel column chromatography, isolates the title compound of semi-solid.
1H?NMR(CDCl 3，400MHz)δ9.37(1H，s)，8.11(1H，s)，7.92(1H，s)，7.58(2H，d，J＝8Hz)，7.15(2H，d，J＝8Hz)，2.01(6H，s)。
Step F: 4-[1-(2-(4-cyano-phenyl)-2-propyl group)-5-miaow The azoles methyl]-1-(3-chloro-phenyl-)-5 (S)-(2-methylsulfonyl ethyl) piperazine-2 -ketone dihydrochloride
This title compound is according to example 39; the described program preparation of step e; different has been to use 1-(3-chloro-phenyl-)-5 (S)-(2-methylsulfonyl ethyl) piperazine-2-keto hydrochloride (0.297g; 0.84mmol), 1-[2-(4-cyano-phenyl)-2-propyl group] imidazoles-5-formaldehyde (0.200g; 0.84mmol), N-methylmorpholine (0.092ml; 0.84mmol) and sodium triacetoxy borohydride (0.267g, 1.26mmol).Crude product is purified with preparation HPLC, with 80-58% solvent orange 2 A gradient elution.Pure fraction is merged, and change into hydrochloride, obtain title compound.FAB?ms：540(M+1)。Analyze: calculated value C 27H 30ClN 5O 3S2HCl3H 2O:
C, 48.62; H, 5.74; N, 10.50 measured values: C, 48.62; H, 5.73; N, 9.89.
Example 50
5 (S)-normal-butyl-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-1 -(2-aminomethyl phenyl) piperazine-2-ketone dihydrochloride
Steps A: N-(2-aminomethyl phenyl)-2 (S)-(t-butoxycarbonyl amino)-oneself Amine
This title compound is according to example 39, the described program preparation of step C, different has been to use Ortho Toluidine (0.32ml, 3.00mmol), 2 (S)-(t-butoxycarbonyl amino) hexanal (0.538,2.50mmol), sodium triacetoxy borohydride (0.795g, 3.75mmol), (10ml) carries out at ethylene dichloride.Thick product is purified with column chromatography, obtains title compound.
Step B:4-tertbutyloxycarbonyl-5 (S)-normal-butyl-1-(2-aminomethyl phenyl) Piperazine-2-ketone
This title compound is basically according to example 39, the described program preparation of step D, different has been to use N-(2-aminomethyl phenyl)-2 (S)-(t-butoxycarbonyl amino) hexylamine (0.506g, 1.65mmol), chloroacetyl chloride (0.158ml, 1.98mmol), in ethyl acetate-saturated sodium bicarbonate of 0 ℃, carry out.The crude product that obtains thus is dissolved among the DMF (15ml), is cooled to 0 ℃ under nitrogen atmosphere, (1.61g 4.95mmol) handles with cesium carbonate.Under agitation, at room temperature reacted then 2 hours 0 ℃ of reaction 2 hours.Use the saturated ammonium chloride termination reaction, use ethyl acetate extraction.Obtain title compound after the evaporation of extract drying.
Step C:5 (S)-normal-butyl-4-[1-(4-cyano group benzyl)-5-imidazolyl Methyl]-1-(2-aminomethyl phenyl) piperazine-2-ketone dihydrochloride
(0.534g is 1.50mmol) with trifluoroacetic acid (4ml) deprotection in methylene dichloride (10ml) for the product of step B.This title compound is according to example 39, the described program preparation of step e, different has been to use 5 (S)-normal-butyl-1-(2-aminomethyl phenyl) piperazine-2-ketone two (trifluoroacetic acid) salt, 1-(4-cyano group benzyl imidazole)-5-formaldehyde (0.317g, 1.50mmol) and sodium triacetoxy borohydride (0.477g, 2.25mmol), in ethylene dichloride (15ml), carry out.Crude product is injected preparation HPLC post, purify with acetonitrile/0.1%TFA and 0.1% TFA aqueous solution mixing gradient elution.Each pure fraction is merged, change into hydrochloride, obtain the title compound of white solid form.FAB?ms：(m+1)442。Analyze: calculated value C 27H 31N 5O2.5HCl2.05H 2O:
C, 56.95; H, 6.66; N, 12.30 measured values: C, 56.93; H, 5.75; N, 11.55.
Example 51
4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-5 (S)-(2-fluorine second Base)-1-(3-chloro-phenyl-) piperazine-2-ketone dihydrochloride
Steps A: 4-tertbutyloxycarbonyl-1-(3-chloro-phenyl-)-5 (S)-(2-fluorine Ethyl)-piperazine-2-ketone
4-tertbutyloxycarbonyl-1-(3-chloro-phenyl-)-5 (S)-(2-mesyloxy ethyl)-piperazine-2-ketone (0.433g, 1.00mmol) and fluoridize uncle's fourth ammonium (3.0ml, 1MTHF solution) at room temperature in acetonitrile (5ml) the stirring 72 hours.Use the saturated sodium bicarbonate termination reaction, use ethyl acetate extraction.With organic extract drying, concentrated, and,, obtain a kind of viscous crude shape title compound with 20% ethyl acetate/hexane wash-out with the column chromatography purification.
Step B:4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-5 (S)-(2 -fluoro ethyl)-1-(3-chloro-phenyl-) piperazine-2-ketone dihydrochloride
(0.191g is 0.54mmol) with trifluoroacetic acid (4ml) deprotection in methylene dichloride (10ml) for 4-tertbutyloxycarbonyl-1-(3-chloro-phenyl-)-5 (S)-(2-fluoro ethyl)-piperazine-2-ketone.This title compound is pressed example 39, the described program preparation of step e, different is to use 1-(3-chloro-phenyl-)-5 (S)-(2-fluoro ethyl) piperazine-2-ketone two (trifluoroacetic acid) salt, 1-(4-cyano group benzyl imidazole)-5-formaldehyde (0.114g, 0.54mmol) and sodium triacetoxy borohydride (0.172g, 2.25mmol), in ethylene dichloride (5ml), carry out.Crude product is injected preparation HPLC post, purify with acetonitrile/0.1% TFA and 0.1% TFA aqueous solution mixing gradient elution.Each pure fraction is merged, change into hydrochloride, obtain the title compound of white solid form.FAB?ms：(m+1)452。Analyze: calculated value C 24H 23ClFN 5O2HCl1.7H 2O:
C, 51.90; H, 5.15; N, 12.61 measured values: C, 52.22; H, 5.10; N, 12.22.
Example 52
4-[3-(4-cyano group benzyl) pyridin-4-yl]-1-(3-chloro-phenyl-)- 5 (S)-(2-methylsulfonyl ethyl)-piperazine-2-ketone
Steps A: 3-(4-cyano group benzyl) pyridine-4-carboxylate methyl ester
With about 3 minutes time with the 4-cyano-benzyl bromide (625mg, anhydrous THF (4ml) solution 3.27mmol) joins 0 ℃ the active Zn (dust under argon atmospher at leisure; In THF 250mg) (2ml) suspension.
Remove ice bath, at room temperature with soup compound restir 30 minutes.(540mg 2.5mmol), then adds dichloro two (triphenyl phosphine) nickel (II) (50mg) to add 3-bromopyridine-4-carboxylate methyl ester then.The reddish-brown mixture that is generated stirred 3 hours at about 40-45 ℃.With the mixture cooling, be allowed to condition between EtOAc (100ml) and 5% aqueous citric acid solution (50ml) and distribute.Organic layer H 2(Na is used in 2 * 50ml) washings to O 2SO 4Dry.Residue is purified with silica gel column chromatography after the solvent evaporation, with 35% EtOAc/ hexane wash-out, provides the transparent jelly of 420mg.FAB?ms(M+1)253。
Step B:3-(4-cyano group benzyl)-4-(methylol) pyridine
This title compound is that the ester (415mg) by steps A at room temperature makes with sodium borohydride (300mg) reduction in methyl alcohol (5ml).Stir after 4 hours, with solution evaporation, product is purified with silica gel column chromatography, with 2% methyl alcohol/chloroform wash-out, provides title compound.FAB?ms(M+1)225。
Step C:3-(4-cyano group benzyl)-4-pyridine aldehydes
This title compound is that (240mg 1.07mmol) makes with activated manganese dioxide (1.0g) oxidation in backflow De diox by the alcohol of step B.Obtain title compound, fusing point 80-83 ℃ after filtration and the solvent evaporation.
Step D:4-[3-(4-cyano group benzyl) pyridin-4-yl]-1-(3-chlorine Phenyl)-5 (S)-(2-methylsulfonyl ethyl)-piperazine-2-ketone
This compound is gone up substantially according to example 39; the described same method preparation of step e; different is; step C product (referring to above) with equivalent replaces imidazole formaldehyde; 1-(3-chloro-phenyl-)-5 (S)-(2-methylsulfonyl ethyl)-piperazine-2-ketone with equivalent replaces piperazine ketone, makes title compound thus.FAB?ms?523。Analyze: calculated value C 27H 27ClN 4O 3S0.15CHCl 3:
C, 60.28; H, 5.06; N, 10.36 measured values: C, 60.37; H, 5.03; N, 10.64.
Example 53
4-[5-(4-cyano group benzyl) 1-imidazolyl methyl]-1-(3-chloro-phenyl-) Piperazine-2-ketone
Steps A: 1-trityl-4-(4-cyano group benzyl)-imidazoles
(3.57g, (0.315ml 3.60mmol), under agitation reacts at 20 ℃ in argon atmospher to add ethylene dibromide in THF 54.98mmol) (50ml) suspension toward active zinc powder.This suspension is cooled to 0 ℃, dropwise adds α-bromo-p-methylphenyl nitrile (9.33g, THF 47.6mmol) (100ml) solution with 10 fens clock times.Then under agitation 20 ℃ the reaction 6 hours, disposable adding chlorination two (triphenyl phosphine) nickel (II) (2.4g, 3.64mmol) and 5-iodine trityl imidazole (15.95g, 36.6mmol).The gained mixture stirred 16 hours at 20 ℃, added saturated NH then 4Cl solution (100ml) makes reaction terminating, and mixture was stirred 2 hours.Add saturated NaHCO 3Solution makes pH=8, gained solution with EtOAc extraction (2 * 250ml), use MgSO 4Drying, vacuum evaporating solvent.Residue carries out chromatogram purification (SiO 2, 0-20% EtOAc/CH 2Cl 2) obtain the title compound of white solid form. 1H NMR δ CDCl 3(7.54 (2H, d, J=7.9Hz), 7.38 (1H, s), 7.36-7.29 (11H, m), 7.15-7.09 (6H, m), 6.58 (1H, s) and 3.93 (2H, s) ppm.
Step B:1-methyl acetyl-5-(4-cyano group benzyl)-imidazoles
Toward 1-trityl-4-(4-cyano group benzyl)-imidazoles (3.01g, 6.91mmol) and add methyl bromoacetate in acetonitrile (50ml) solution (0.687ml, 7.26mmol), mixture heated 16 hours at 55 ℃, then vacuum evaporating solvent.Solids is developed with EtOAc, filters and collects, and is dissolved in the methyl alcohol (60ml).This suspension heated 20 minutes under refluxing, and cooled off, is evaporated to dried then.Residue is developed with EtOAc, filters the title compound that obtains the white solid form. 1H NMR δ CDCl 3(7.61 (2H, d, J=7.9Hz), 7.53 (1H, s), 7.27 (2H, d, J=7.9Hz), 6.89 (1H, s), 4.47 (2H, s), 3.98 (2H, s) and 3.66 (3H, s) ppm.
Step C:1-hydroxyethyl-5-(4-cyano group benzyl)-imidazoles
(80.7mg 2.1mmol) handles 1-methyl acetyl-5-(4-cyano group benzyl)-imidazoles (0.113g, 0 ℃ of methyl alcohol (2ml) solution 0.472mmol) with sodium borohydride.After 1 hour, add saturated NH 4Cl solution (2ml) makes reaction terminating.Add saturated NaHCO 3, (MgSO is used in 3 * 25ml) extractions to mixture with ethyl acetate 4Drying and vacuum-evaporation.With chromatography (SiO 2, 10% MeOH/CH 2Cl 2) isolate the title compound of white solid form.
1H NMR δ CDCl 3(7.61 (2H, d, J=7.9Hz), 7.55 (1H, s), 7.27 (2H, d, J=7.9Hz), 6.83 (1H, s), 4.05 (2H.s), 3.87 (2H, t, J=5.1Hz) and 3.74 (2H, t, J=5.1Hz) ppm.
Step D:2-(5-(4-cyano group benzyl)-imidazolyl) ethyl methane sulfonate ester
With Hunigs alkali (0.489ml, 2.81mmol) and methylsulfonyl chloride (0.219ml 2.81mmol) handles 1-hydroxyethyl-5-(4-cyano group benzyl)-imidazoles (0.532g, 0 ℃ of methylene dichloride (70ml) solution 2.34mmol).After 2 hours, add saturated NaHCO 3Solution (50ml) makes reaction terminating, and mixture is used MgSO with methylene dichloride (50ml) extraction 4Drying, vacuum evaporating solvent.The title compound that obtains need not further to purify just can use.
1H NMR δ CDCl 3(7.62 (2H, d, J=7.9Hz), 7.54 (1H, s), 7.29 (2H, d, J=7.9Hz), 6.87 (1H, s), 4.25 (2H, t), 4.10-4.00 (4H, m), 3.74 (2H, t, J=5.1Hz) and 2.90 (3H, s) ppm.
Step e: 4-[5-(4-cyano group benzyl)-1-imidazolyl methyl]-1-(3 -chloro-phenyl-) piperazine-2-ketone
With 2-(5-(4-cyano group benzyl)-imidazolyl) ethyl methane sulfonate ester (24mg, 0.079mmol) DMF (0.2ml) solution join 3-(chloro-phenyl-) piperazine-2-ketone (17.7mg, 0.084mmol), sodium iodide (50mg, 0.336mmol) and Hunigs alkali (0.0146ml, 0.084mmol) in.Mixture stirred 12 hours at 55 ℃, and solvent is fallen in vacuum-evaporation then.Residue is purified with the preparation thin-layer chromatography, with 10% saturated ammonia/acetonitrile wash-out, obtains title compound. 1H NMR δ CDCl 3(7.61 (2H, d, J=8.4Hz), 7.56 (1H, s), 7.35-7.20 (7H, m), 7.16 (1H, d, J=8Hz), 6.85 (1H, s), 4.03 (2H, s), 3.83 (2H, t, J=6.5Hz), 3.61 (2H, t, J=5.4Hz), 3.27 (2H, s), 2.68 (2H, t is J=5.4Hz) with 2.57 (2H, t, J=6.5Hz) ppm.
Example 54
The vitro inhibition of ras farnesyl tranfering enzyme
The farnesyl-protein transferase test.Partially purified ox FPT enzyme and Ras peptide (Ras-CVLS, Ras-CVIM and Ras-CAIL) are respectively according to (Schaber Et Al., J. Biol. Chem.265:14701-14704 (1990), Pompliano, Et Al., Biochemistry31:3800 (1992) and Gibbs Et Al., PNASU.S.A.86:6630-6634 (1989)) described method prepares.Ox FPT enzyme test 60 minutes in 31 ℃ of 100 μ l volumes that containing following ingredients: 100mM N-(2-hydroxyethyl) piperazine-N-(2 ethane sulfonic aicd) (HEPES), pH 7.4,5mM MgCl 2, 5mM dithiothreitol (DTT) (DTT), 100mM [ 3H]-farnesyl diphosphate ([ 3H]-FPP; 740 CBq/mmol, NEN), 650 nM Ras-CVLS and 10 μ g/ml FPT enzymes.Reaction causes with the FPT enzyme, stops with 1ml 1.0M HCl ethanolic soln.Utilize a Tom Tec Mach II cell harvestor that throw out is collected on the filter leaching material, use 100% washing with alcohol, drying is with a LKB β-plate count device counting.Test is linear for two kinds of Substrates, FPT enzyme and time; Utilized between the reaction period less than 10% [ 3H]-FPP.The compound dissolution of purifying and dilutes 20 times and tests in 100% dimethyl sulfoxide (DMSO) (DMSO).The amount of incorporating under the radioactivity amount of incorporating under test compound exists or not with test compound relatively is used for weighing percent inhibition.
Human body FPT enzyme is according to people such as Omer, the described method preparation of Biochemistry 32:5167-5176 (1993).The test of human body FPT enzymic activity is with the above, and different is to add 0.1% (weight/volume) polyoxyethylene glycol, 20,000,10 μ MZnCl in reaction mixture 2With 100nM Ras-CVIM.Reaction was carried out 30 minutes, stopped with 100 μ l 30% (volume/volume) trichoroacetic acid(TCA) (TCA) ethanolic solns, and handled like that the ox enzyme is described by above.
More than listed The compounds of this invention described in each example and in following each table, all test and test its inhibition activity, and find its IC human body FPT enzyme with the above 50Be≤50 μ M.
Example 55
Ras farnesylation test in the live body
The clone of using in this test is Rat1 or the cell-derived a kind of v-ras clone of NIH3T3 from having expressed viral Ha-ras p21.Test is basically according to DeClue, and people such as J.E. carry out in method described in the Cancer Research 51:712-717 (1991).The cell that reaches 50～75% symphysis rates on the 10cm culture dish is handled (ultimate density of solvent methanol or dimethyl sulfoxide (DMSO) is 0.1%) with test compound.At 37 ℃ after 4 hours, adding 10% conventional DMEM, 2% foetal calf serum and 400mCi[ 35S] 3ml of methionine(Met) (1000Ci/mmol) do not have among the methionine(Met) DMEM these cells carried out mark.After spending 20 hours again, cytolysis at the molten born of the same parents' buffer reagent of 1ml (1% NP40/20mM HEPES, pH 7.5/5mMMgCl 2/ 1mM DTT/10mg/ml aprolinen/2mg/ml leupeptin (leupeptin)/2mg/ml antipain/0.5mM PMSF) in, molten cytosol is with 100, and 000xg made it clarification in centrifugal 45 minutes.The some parts of molten cytosols that contain the precipitable counting of equivalent acid are transferred to 1ml with IP buffer reagent (molten born of the same parents' buffer reagent of no DTT), carry out immunoprecipitation (Furth, people such as M.E., J.Virol.43:294-304 (1982)) with ras obligate monoclonal antibody Y13-259.After 2 hours antibody of 4 ℃ are cultivated, add 25% suspension that 200ml scribbles the albumin A-agarose of exempting from the mouse IgG of the Chinese People's Anti-Japanese Military and Political College, kept 45 minutes.Immunoprecipitate IP buffer reagent (20nM HEPES, pH 7.5/1mM EDTA/1% Triton X-100 0.5% deoxycholate salt/0.1%/SDS/0.1MNaCl) wash 4 times, in SDS-PAGE sample buffer reagent, boil, be added on 13% acrylamide gel.When the dyestuff forward position reaches the bottom, make this gel sets, thermal treatment under light, drying and autoradiograph.Relatively the intensity of the corresponding band of the ras albumen of farnesylation and non-farnesylation determines that farnesyl shifts proteic inhibition percentage.
Example 56
Growth inhibition test in the live body
For the biology consequence of determining that the FPT enzyme suppresses, tested the influence of The compounds of this invention to the no anchorage dependent form growth of the Rat1 cell that changes with v-ras, v-raf or v-mos oncogene.In this analyzes, also can comprise the cell that changes by v-Raf and v-Mos, Ras be brought out the specificity that cell changes with the assessment The compounds of this invention.
The Rat1 cell that changes with v-ras, v-raf or v-mos is with every plate (diameter 35mm) 1 * 10 4The density of cell is inoculated in 0.3% top agarose of the above culture medium A of bottom-layer agar sugar (0.6%) (having added the Dulbecco modification Eagle's medium of 10% foetal calf serum).The two-layer The compounds of this invention (1000 times with used ultimate density in the test are dissolved in the methyl alcohol) that all contains 0.1% methyl alcohol or proper concn.These cells are fed twice with the 0.5ml culture medium A of the The compounds of this invention that contains 0.1% methyl alcohol or this concentration weekly.Culture is inoculated back 16 days and is taken Photomicrograph, compares.
Example 57
Table 1～18 show, of the present invention other compound preparation according to program described in the example 1～53.These compounds are intended to become illustrative, and are not intended to become restrictive.In table 2, the stereochemistry that contains amino carbon atom is (R or S) as noted, perhaps if do not know, just these two kinds of isolating steric isomers is appointed as " A " or " B ".
Table 1
Chemical formula R FAB ms (m+1)
Analyze (calculated value, measured value)
Figure A9619420602102
Table 2
The upright structure X Y (M+1) of FAB amine mass spectrum analyzes (calculated value, measured value) A n-Bu 2-O (CH 2) 13CH 3642.5 C 42H 63N 3O 22.55HCl
C，68.46；H，8.97；N，5.70.
C，68.40；H，8.70；N，5.61.B n-Bu 2-O(CH 2) 13CH 3 642.6 C 42H 63N 3O 2·2.65HCl
C，68.63；H，8.99；N，5.72.
C，68.66；H，8.90；N，5.70.A n-Bu 2-O(CH 2) 11CH 3 614.4 C 40H 59N 3O 2·2.8HCl
C，67.09；H，8.70；N，5.87.
C，67.03；H，8.66；N，5.76.B n-Bu 2-O(CH 2) 11CH 3 614.4 C 40H 59N 3O 2·2.85HCl·0.05H 2O
C，66.84；H，8.69；N，5.85.
C，67.20；H，8.70；N，5.45.
The upright structure X Y (M+1) of FAB amine mass spectrum analyzes (calculated value, measured value) A n-Bu 2-O (CH 2) 9CH 3586.5 C 38H 55N 3O 23HCl0.25hexane
C，66.18；H，8.65；N，5.86.
C，66.14；H，8.44；N，5.50.B n-Bu 2-O(CH 2) 9CH 3?586.5 C 38H 55N 3O 2·3HCl·0.15hexane
C，65.97；H，8.55；N，5.93.
C，66.04；H，8.41；N，5.57.A n-Bu 2-O(CH 2) 7CH 3?558 C 36H 51N 3O 2·2.15HCl·0.65H 2
C，66.73；H，8.47；N，6.49.
C，66.74；H，8.46；N，6.52.B n-Bu 2-O(CH 2) 7CH 3?558 C 36H 51N 3O 2·2.15HCl·0.65H 2O
C，66.82；H，8.42；N，6.49.
C，66.85；H，8.43；N，6.52.A n-Bu 2-O(CH 2) 3Ph 564 C 37H 45N 3O 2·2HCl·1.05H 2O
C，67.78；H，7.55；N，6.41.
C，67.78；H，7.52；N，6.26.B n-Bu 2-O(CH 2) 3Ph 564 C 37H 45N 3O 2·2HC·1.05H 2O
C，67.78；H，7.55；N，6.41.
C，67.78；H，7.44；N，6.33.A n-Bu 3-OCH 2Ph 536 C 35H 41N 3O 2·3.55HCl
C，63.19；H，6.75；N，6.32.
C，63.12；H，6.61；N，6.47.B n-Bu 3-OCH 2Ph 536 C 35H 41N 3O 2·3.55HCl·0.4H 2O
C，62.52；H，6.80；N，6.25.
C，62.14；H，6.69；N，6.65.
The upright structure X Y (M+1) of FAB amine mass spectrum analyzes (calculated value, measured value) A n-Bu 3-O (CH 2) 13CH 3642 C 42H 63N 3O 22.4HCl
C，69.15；H，9.04；N，5.76.
C，69.08；H，9.08；N，5.73.B n-Bu 3-O(CH 2) 13CH 3?642.5 C 42H 63N 3O 2·2.35HCl·0.25H 2O
C，69.15；H，9.04；N，5.76.
C，69.08；H，9.08；N，5.73.R n-Bu 4-O(CH 2) 13CH 3?642 C 42H 63N 3O 2·2.2HCl·1H 2O
C，68.14；H，9.15；N，5.68.
C，68.13；H，9.03；N，5.68.S n-Bu 4-O(CH 2) 13CH 3?642 C 42H 63N 3O 2·2.8HCl
C，67.79；H，8.91；N，5.65.
C，67.77；H，9.80；N，5.64.S n-Bu 4-OCH 2Ph 536 C 35H 41N 3O 2·2.15HCl·1H 2O
C，66.49；H，7.20；N，6.65.
C，66.48；H，7.15；N，6.62.R/S H 2-O(CH 2) 13CH 3?586 C 38H 55N 3O 2·1.5HCl·0.3H 2O
C，66.88；H，8.58；N，6.16.
C，66.82；H，8.64；N，6.15.
Table 3
FAB
Mass spectrum Y (M+1) analyzes (calculated value, measured value) 3-SO 2Me 506 C 27H 31N 5O 3S3.0HCl0.10H 2O
C，52.61；H，5.59；N，11.36.
C，52.63；H，5.41；N，10.72.3-OCF 3 512.23 C 27H 28N 5O 2F 3·2.30HCl·0.50H 2O
C，53.66；H，5.22；N，11.59.
C，53.73；H，5.23；N，10.86.
Table 4
Figure A9619420602151
FAB
Mass spectrum X Y (M+1) analyzes (calculated value, measured value) CH 2OCH 2Ph CF 3574 C 32H 30N 5O 2F 31.40HCl0.30H 2O
C，61.02；H，5.12；N，11.12.
C，61.01；H，5.10；N，10.78.CH 2SO 2Et CF 3 560 C 27H 28N 5O 3F 3S
·3.20HCl·0.10H 2O
C，47.86；H，4.67；N，10.34.
C，47.89；H，4.49；N，9.92.CH 2SO 2Ph CF 3 608 C 31H 28N 5O 3F 3S·2.10HCl
C，54.42；H，4.43；N，10.24.
C，54.43；H，4.42；N，9.98.CH 2SO 2Me Cl 512 C 25H 26N 5O 3ClS
·2.0HCl·0.25CHCl 3·0.25H 2O
C，48.97；H，4.68；N，11.31.
C，48.95；H，4.64；N，11.51.
Table 4 (continuing)
FAB
Mass spectrum X Y (M+1) analyzes (calculated value, measured value) CH 2SO 2Et Cl 526 C 26H 28N 5O 3C1S2HCl0.25CHCl 3
C，5O.14；H，4.85；N，11.14.
C，50.20；H，4.91；N，10.93.CONHMe CF 3 511 C 26H 25N 6O 2F 3·1.90HCl·1.70H 2O
C，51.20；H，5.01；N，13.78.
C，51.17；H，4.99；N，13.36.CONHEt CF 3 525 C 27H 27N 6O 2F 3·1.60HCl·0.10H 2O
C，55.54；H，4.97；N，14.39.
C，55.57；H，4.87；N，15.28.CH 2SO 2Ph Cl 574 C 30H 28N 5O 3ClS·2HCl·0.30H 2O
C，55.23；H，4.73；N，10.73.
C，55.25；H，4.57；N，10.61.
Table 4 (continuing)
FAB
Mass spectrum X Y (M+1) analyzes (calculated value, measured value) CONHMe Cl 477 C 25H 25N 6O 2Cl2HCl
·0.105CHCl 3·0.85H 2O
C，52.24；H，5.03；N，14.56.
C，52.21；H，5.07；N，14.98.CONHEt Cl 491 C 26H 27N 6O 2Cl·2HCl·0.25CHCl 3
C，53.10；H，4.97；N，14.15
C，53.32；H，5.21；N，13.77.CONHc-Pr Cl 503 C 27H 27N 6O 2Cl·2HCl·0.40CHCl 3
C，52.77；H，4.75；N，13.47.
C，53.01；H，4.99；N，13.32.CONHc-Pr CF 3 537 C 28H 27N 6O 2F 3
·2.45HCl·0.55dioxane
C，53.81；H，5.06；N，12.47.
C，53.76；H，5.09；N，12.44.
Table 4 (continuing)
FAB
Mass spectrum X Y (M+1) analyzes (calculated value, measured value) NHCOMe Cl 477 C 25H 25N 6O 2Cl
·2HCl·0.60CHCl 3·2.0H 2O
C，46.76；H，4.84；N，12.78.
C，46.79；H，4.46；N，12.37.CONMe 2 CF 3 525 C 27H 27N 6O 2F 3·2.0HCl·0.10H 2O
C，54.12；H，4.91；N，14.02.
C，54.10；H，4.96；N，13.79.SO 2Et Cl 512 C 25H 26N 5O 3ClS·2.0HCl·0.10H 2O
C，51.18；H，4.84；N，11.94.
C，51.24；H，5.19；N，11.10.CH 2SMe Cl 480 C 25H 26N 5OClS
·0.15CHCl 3·0.05H 2O
C，52.83；H，4.98；N，12.25.
C，52.82；H，5.36；N，11.85.
Table 4 (continuing)
Figure A9619420602191
FAB
Mass spectrum X Y (M+1) analyzes (calculated value, measured value) (±) C ≡ CMe Cl 458 C 26H 24N 5OCl2.0HCl1.00H 2O
C，56.89；H，5.14；N，12.76.
C，56.99；H，5.20；N，12.42.
Table 5
Figure A9619420602201
FAB
Mass spectrum X Y (M+1) analyzes (calculated value, measured value) CH 2CH 2H 386 C 23H 23N 5O1.40HCl0.40H 2O
C，62.29；H，5.73；N，15.79.
C，26.26；H，5.71；N，15.43.CH 2CO H 400 C 23H 21N 5O 2·2.6HCl·1.70H 2O
C，52.71；H，5.19；N，13.36.
C，52.82；H，5.21；N，13.04.CH 2 H 372 C 22H 21N 5O·2.0HCl·2.60H 2O
C，53.80；H，5.79；N，14.26.
C，52.86；H，5.98；N，13.92CH 2 3-Cl 406 C 22H 20N 5OCl·2.50HCl·0.90H 2O
C，51.48；H，4.77；N，13.65.
C，51.55；H，4.75；N，13.34
Table 5 (continuing)
Figure A9619420602211
FAB
Mass spectrum X Y (M+1) analyzes (calculated value, measured value) NHSO 2H C 21H 20N 6O 3S1.0HCl2.60H 2O
C，48.53；H，5.08；N，16.17
C，48.60；H，5.19；N，15.80.CH 2CH 2CO 3-Cl 448 C 24H 22N 5O 2Cl·1.0HCl·1.10H 2O
C，57.17；H，5.04；N，13.89.
C，57.22；H，4.94；N，13.47.CH 2 2，3-Cl 2 440 C 22H 19N 5OCl 2·2.0HCl·0.60H 2O
C，50.42；H，4.27；N，13.36.
C，50.51；H，4.56；N，12.18.CH 2 2-Br 450 C 22H 20N 5OBr·2.0HCl·0.30H 2O
C，49.98；H，4.31；N，13.25.
C，49.94；H，4.47；N，12.53.
Table 5 (continuing)
Figure A9619420602221
FAB
Mass spectrum X Y (M+1) analyzes (calculated value, measured value) CH 23-CF 3440 C 23H 20N 5OF 31.70HCl0.40H 2O
C，54.40；H，4.47；N，13.79.
C，54.45；H，4.49；N，13.82.CH 2 4-Cl C 22H 20N 5OCl·1.50HCl·0.80H 2O
C，55.71；H，4.91；N，14.77.
C，55.81；H，4.94；N，14.11.CH 2CO 3-Cl C 23H 20N 5O 2Cl·1.40HCl·1.10H 2O
C，54.73；H，4.71；N，13.87.
C，54.80；H，4.73；N，13.46.CH 2 3-F C 22H 20N 5OF·2HCl
·0.35CHCl 3·0.95H 2O
C，51.50；H，4.69；N，13.44.
C，51.56；H，4.73；N，13.30.
Table 5 (continuing)
Figure A9619420602231
FAB
Mass spectrum X Y (M+1) analyzes (calculated value, measured value) CH 23-Br C 22H 20N 5OBr1.40HCl1.30H 2O
C，50.35；H，4.61；N，13.34.
C，50.36；H，4.63；N，12.84.
Table 6
FAB
Mass spectrum X Y Z (M+1) analyzes (calculated value, measured value) 4-CN CH 25-CH 2CH 2CO 554 C 27H 28N 5O 4ClS1.30HCl1.20H 2O
C，52.05；H，5.13；N，11.24.
C，52.09；H，5.15；N，10.95.3-CN CH 2 5-CH 2 512 C 25H 26N 5O 3ClS·
2.0HCl·0.10CHCl 3·0.6OH 2O
C，49.61；H，4.86；N，11.52.
C，49.63；H，5.01；N，11.14.2-CN CH 2 5-CH 2 512 C 25H 26N 5O 3ClS·2HCl·0.35H 2O
C，50.79；H，4.89；N.11.84.
C，50.82；H，5.29；N，11.90.4-CN CH 2 4-CH 2CH 2CO?554 C 27H 28N 5O 4ClS
·2.0HCl·0.50CHCl 3·0.60H 2O
C，47.36；H，4.58；N，10.04.
C，47.35；H，4.60；N，9.66.
Table 6 (continuing)
FAB
Mass spectrum X Y Z (M+1) analyzes (calculated value, measured value) 4-CN (CH 2) 24-CH 2CH 2CO C 28H 30N 5O 4ClS
·1.0HCl·0.40CHCl 3·0.95H 2O
C，50.96；H，5.01；N，10.46.
C，50.91；H，5.02；N，10.13.
Table 7
Figure A9619420602261
FAB
Mass spectrum X Y (M+1) analyzes (calculated value, measured value) 4-Me CH 2CH 2SO 2Me 526 C 26H 28N 5O 3ClS
·2HCl·0.35CHCl 3·0.85H 2O
C，48.24；H，4.92；N，10.67.
C，48.25；H，4.93；N，10.36.4-Me H 420 C 23H 22N 5OCl·2.0HCl·0.90H 2O
C，54.27；H，5.11；N，13.76.
C，54.21；H，5.37；N，12.97.2-Me H 420 C 23H 22N 5OCl·3.20HCl·0.10H 2O
C，51.31；H，4.76；N，13.01.
C，51.30；H，4.74；N，12.87.
Table 8
Figure A9619420602271
Chemical formula Y FAB ms analytical calculation value
(m+1) measured value 3-CF 3496 C 27H 28F 3N 5O2HCl1.55H 2C
C，54.36；H，5.59；N，11.74
C，54.40；H，5.29；N，11.263-CH 3 442 C 27H 31N 5O·2HCl
C，63.01；H，6.47；N，13.61
C，63.45；H，6.71；N，13.532，3-(CH 2) 4 482 C 30H 35N 5O·5.2HCl·0.1H 2C
C，53.66；H，6.06；N，10.43
C，53.62；H，5.30；N，9.353-OCH 3 458 C 27H 31N 5O 2·2HCl
C，61.13；H，6.27；N，13.20
C，62.43；H，6.53；N，13.24
Table 8 (continuing)
Figure A9619420602281
Chemical formula Y FAB ms analytical calculation value
(m+1) measured value 3-Cl 463 C 26H 28ClN 5O2HCl0.75H 2C
C，56.94；H，5.79；N，12.77
C，56.92；H，5.59；N，12.302-CH 3，3-Cl 477 C 27H 30ClN 5O 2·2HCl·3.1H 2O
C，53.62；H，6.37；N，11.58
C，53.44；H，5.37；N，10.76H 428 C 26H 29N 5O·3.9HCl·2H 2O
C，51.63；H，6.51；N，11.58
C，51.59；H，5.10；N，10.35
Table 8 (continuing)
Figure A9619420602291
Chemical formula Y FAB ms analytical calculation value
(m+1) measured value 3-F 446 C 26H 28FN 5O2HCl2.55H 2C
C，55.87；H，6.22；N，12.53
C，55.83；H，5.84；N，11.71
Table 9
Chemical formula
FAB msR (m+1) calculated value
Analyze
Measured value CH 2CH 2OCH 2CF 3566 C 27H 25F 6N 5O 22HCl0.67H 2O
C，49.85；H，4.39；N，10.77
C，49.86；H，4.26；N，10.33
Figure A9619420602302
?524 C 28H 28F 3N 5O 2·2HCl
C，56.38；H，5.07；N，11.74
C，56.21；H，5.27；N，11.46CH 2CH 2N 3 509 C 25H 23F 3N 8O 2·2HCl·2.35H 2O
C，48.14；H，4.80；N，17.96
C，48.79；H，4.38；N，16.99CH 2CH 2NHCOCH 3 525 C 27H 27F 3N 6O 2·2HCl·0.7H 2O
C，53.16；H，5.02；N，13.78
C，53.30；H，5.07；N，13.39CH 2CH 2NHCOC 2H 5 539 C 28H 29F 3N 6O 2·2HCl·3.66H 2O
C，52.43；H，5.39；N，13.10
C，52.44；H，5.20；N，12.48
Table 9 (continuing)
Chemical formula R FAB ms
The analytical calculation value
(m+1)
Measured value CH 2CH 2SO 2CH (CH 3) 2574 C 28H 30F 3N 5O 3S2HCl1.35H 2O
C，50.13；H，5.21；N，10.44
C，50.10；H，4.88；N，10.08CH 2CH 2SCH(CH 3) 2 542 C 28H 30F 3N 5OS·2HCl·0.75H 2O
C，53.55；H，5.38；N，11.51
C，53.57；H，5.33；N，11.04CH 2CH 2S(O)CH(CH 3) 2 558 C 28H 30F 3N 5O 2S·2HCl·0.7H 2O
C，52.29；H，5.23；N，10.89
C，52.27；H，5.08；N，10.35
Table 10
Figure A9619420602321
Chemical formula R FAB ms
Analyze measured value
(m+1) calculated value
Figure A9619420602322
462 C 26H 31N 5O 32CF 2CO 2H2.8H 2C
C，48.69；H，5.26；N，9.46
C，48.70；H，4.42；N，9.12 470 C 29H 35N 5O·2HCl·0.3CH 2Cl 2
0.6C 6H 14
C，63.76；H，7.48；N，11.30
C，64.77；H，7.07；N，11.26
Figure A9619420602324
431 C 27H 34N 4O·2HCl
Figure A9619420602325
C，64.41；H，7.21；N，11.13
C，66.35；H，7.28；N，11.25
445 C 28H 36N 4O·2HCl·1.3H 2O
C，62.17；H，7.56；N，10.36
C，62.15；H，7.09；N，9.83
Figure A9619420602326
470 C 29H 35N 5O·2HCl·3.05H 2O
C，58.30；H，7.27；N，11.72
C，58.30；H，6.28；N，10.90 548，550 C 29H 34BrN 5O·2HCl·0.1H 2O
C，55.89；H，5.85；N，11.24
C，55.91；H，5.96；N，10.73
Table 11
Figure A9619420602331
Chemical formula
FAB?ms
The analytical calculation value
R Y (m+1) measured value
Figure A9619420602332
Cl 511 C 26H 27ClN 4O 3S
·2HCl·2.85H 2O
C，49.16；H，5.51；N，8.82
C，49.17；H，4.74；N，8.87
Figure A9619420602333
F 496 C 25H 26FN 5O 3S
·2HCl·1.65H 2O
C，50.20；H，5.27；N，11.71
C，50.19；H，4.90；N，11.44 Cl 527 C 26H 28ClN 5O 3S
·2HCl·0.55H 2O
C，51.29；H，5.15；N，11.50
C，51.32；H，5.39；N，11.31
Figure A9619420602335
Cl 530 C 26H 32ClN 5O 3S
·3HCl·0.6HCl
C，48.02；H，5.61；N，10.77
C，48.30；H，5.91；N，9.78
Table 12
Figure A9619420602341
Chemical formula
FAB ms calculated value
R (m+1) analyzes measured value 545 C 26H 30ClN 5O 4S
·2HCl·0.75H 2O
C，49.53；H，5.36；N，11.11
C，49.56；H，5.58；N，10.65
Figure A9619420602343
552 C 28H 29ClN 5O 3S
·2HCl
C，53.90；H，5.01；N，11.22
C，54.06；H，5.78；N，10.67
Figure A9619420602344
396 C 17H 20ClN 4O 3S
·2HCl·0.7H 2O
C，42.41；H，4.90；N，11.64
C，42.98；H，5.49；N，11.06 544 C 26H 30ClN 5O 4S
·2HCl·0.75H 2O
C，49.51；H，5.36；N，11.11
C，49.74；H，5.66；N，10.11
Table 12 (continuing)
Figure A9619420602351
FABms
The analytical calculation value
R (m+1) measured value
Figure A9619420602352
524 C 27H 27ClN 4O 3S0.55CHCl 3
C，58.67；H，4.92；N，10.03
C，58.71；H，4.94；N，9.95 523 C 28H 28ClN 3O 3S·0.1CHCl
·0.2CH 3OH
C，62.89；H，5.39；N，7.78
C，62.87；H，5.37；N，7.84
Table 13
Chemical formula
R FAB?ms
The analytical calculation value
(m+1) measured value
563 C 30H 31ClN 4O 3S
·2HCl·1.8H 2O
C，53.90；H，5.52；N，8.38
C，53.90；H，5.38；N，7.82
Figure A9619420602363
540 C 27H 30ClN 5O 3S
·2HCl·1.35H 2O
C，50.88；H，5.49；N，10.99
C，51.37；H，5.51；N，10.20
Figure A9619420602364
512 C 25H 26ClN 5O 3S·
2HCl·0.3H 2O
C，50.86；H，4.88；N，11.86
C，51.06；H，5.33；N，10.87 415 C 28H 27ClN 4O 3S
·3HCl·4H 2O
C，36.25；H，6.42；N，9.39
C，38.12；H，5.91；N，7.41
Figure A9619420602366
580 C 25H 30ClN 5O 5S 2
·2HCl·0.85H 2O
C，44.93；H，5.08；N，10.48
C，44.96；H，5.08；N，9.96
Table 14
Chemical formula
FAB ms calculated value R 1R 2(m+1) analyze
Measured value
Figure A9619420602372
H 355 C 19H 19ClN 4O
·2HCl·0.5H 2O
C，52.25；H，5.08；N，12.83
C，52.31；H，5.14；N，12.23 CH 2CH 2F 452 C 24H 23ClFN 5O
·2HCl·1.70H 2O
C，51.90；H，5.15；N，12.61
C，52.22；H，5.10；N，12.22
Figure A9619420602374
C 24H 22ClN 5O 2·1HCl
H 448 ·0.30CHCl 3·0.85H 2O
C，54.50；H，4.71；N，13.08
C，54.51；H，4.69；N，12.87
Table 15
Figure A9619420602381
Chemical formula R Y FABms analytical calculation value
(m+1) measured value
Figure A9619420602382
2,3-(CH 2) 4426 C 26H 27N 5O
·2HCl·0.15H 2O
C，62.31；H，5.89；N，13.97
C，62.38；H，6.18；N，13.27
Figure A9619420602383
2-CH 3，3-Cl 420 C 23H 22ClN 5O
·2HCl·1.0H 2O
C，54.08；H，5.13；N，13.71
C，54.57；H，5.77；N，12.92 3-Cl 420 C 22H 18ClN 5O 2
·2HCl·0.5H 2O
C，56.78；H，4.33；N，15.05
C，56.79；H，4.69；N，13.47
Table 16
Figure A9619420602391
Chemical formula
FAB ms R (m+1) analytical calculation value
Measured value 506 C 32H 35N 5O3.2CF 3CO 2H
·2.65H 2O
C，54.14；H，5.75；N，9.15
C，54.15；H，5.74；N，9.18
Figure A9619420602393
484 C 29H 33N 5O 2·4HCl·3H 2O
C，51.03；H，6.35；N，10.26
C，51.02；H，5.66；N，9.67 506 C 32H 35N 5O·2HCl·1.7H 2C
C，63.09；H，6.68；N，10.26
C，51.02；H，5.66；N，9.67
Table 17
Figure A9619420602401
Chemical formula
FAB?msR
(m+1) analytical calculation value
Measured value
Figure A9619420602402
347 C 21H 22N 4O0.2CHCl 3
·0.4CH 3OH
C，67.71；H，6.26；N，14.62
C，67.71；H，6.26；N，14.53 358 C 23H 23N 3O·0.55CHCl 3
C，66.85；H，5.61；N，9.93
C，66.87；H，5.70；N，10.03
Table 18
FAB?mass
Mass spectrum
(M+1) Analyze (calculated value, measured value)
Figure A9619420602411
C 29H 33N 5O 21.0HCl
0.25CHCl 3·0.70H 2O
C，62.45；H，6.39；N，12.45.
C，62.45；H，6.46；N，12.37. 406 C 22H 20N 5OCl·2.60HCl
C，53.97；H，4.78；N，14.30
C，53.97；H，5.21；N，13.10.
Figure A9619420602413
526 C 26H 28N 5O 3ClS·2.0HCl·1.20H 2O
C，50.32；H，5.26；N，11.28
C，50.31；H，5.31；N，10.72.
Table 18 (continuing)The FAB mass spectrum (M+1) Analyze (calculated value, measured value)
Figure A9619420602421
420 C 23H 22N 5OCl2.0HCl2.10H 2O
C，52.06；H，5.36；N，13.20
C，51.99；H，5.36；N，12.57.

Claims (42)

1. formula A compound or its optically active isomer or its pharmaceutically acceptable salt that can suppress farnesyl-protein transferase:
Figure A9619420600021
In the formula:
R 1aAnd R 1bBe independently selected from:
A) hydrogen,
B) aryl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2N-C (O)-, CN, NO 2, (R 10) 2N-C (NR 10)-, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-,
C) C that does not replace or replace 1-C 6Alkyl, wherein the C of replacement 1-C 6Substituting group on the alkyl is selected from aryl, heterocyclic radical, C unsubstituted or that replace 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2N-C (O)-, CN, (R 10) 2N-C (NR 10)-, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, and R 11OC (O) NR 10-;
R 2And R 3Be independently selected from: H, the C that does not replace or replace 1-C 8Alkyl, the C that does not replace or replace 2-C 8Alkenyl, the C that does not replace or replace 2-C 8Alkynyl, the aryl that does not replace or replace, the heterocycle that does not replace or replace
Figure A9619420600022
Or
Figure A9619420600023
Wherein, substituting group is to be replaced by one or more groups in the following groups:
1) aryl or the heterocycle that does not replace or replaced by following groups:
A) C 1-C 4Alkyl,
b)(CH 2) pOR 6，
c)(CH 2) pNR 6R 7，
D) halogen,
e)CN，
2) C 3-C 6Cycloalkyl,
3)OR 6，
4)SR 6a，S(O)R 6a，SO 2R 6a，
Figure A9619420600031
15) N 3, or
16) F; Or
R 2And R 3Be connected in and lump together formation-(CH on the same carbon atom 2) u-, one of them carbon atom randomly by be selected from O, S (O) m ,-NC (O)-and-N (COR 10)-group replace;
R 4And R 5Be independently selected from H and CH 3And R 2, R 3, R 4And R 5In any 2 randomly be connected on the same carbon atom;
R 6, R 7And R 7aBe independently selected from: H, C 1-C 4Alkyl, C 3-C 6Cycloalkyl, heterocycle, aryl, aroyl, 4-hetaroylpyrazol, arylsulfonyl, heteroaryl sulphonyl, these groups can be unsubstituted or be replaced by following groups:
A) C 1-C 4Alkoxyl group,
B) aryl or heterocycle,
C) halogen,
d)HO，
Figure A9619420600041
F)-SO 2R 11, or
G) N (R 10) 2Or
R 6And R 7Can be connected in the ring;
R 7And R 7aCan be connected in the ring;
R 6aBe selected from: C 1-C 4Alkyl, C 3-C 6Cycloalkyl, heterocycle, aryl, these groups can be unsubstituted or replace with following groups:
A) C 1-C 4Alkoxyl group,
B) aryl or heterocycle,
C) halogen,
d)HO，
Figure A9619420600042
F)-SO 2R 11, or
g)N(R 10) 2；
R 8Be independently selected from:
A) hydrogen,
B) aryl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, NO 2, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-and
C) C unsubstituted or that replaced by following groups 1-C 6Alkyl: aryl, cyano-phenyl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NH-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 10OC (O) NH-;
R 9Be selected from:
A) hydrogen,
B) C 2-C 6Alkenyl, C 2-C 6Alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, NO 2, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-and
C) C unsubstituted or that replaced by following groups 1-C 6Alkyl: perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-;
R 10Be independently selected from hydrogen, C 1-C 6Alkyl, benzyl and aryl;
R 11Be independently selected from C 1-C 6Alkyl and aryl;
A 1And A 2Be independently selected from: key ,-CH=CH-,-C ≡ C-,-C (O)-,-C (O) NR 10-,-NR 10C (O)-, O ,-N (R 10)-,-S (O) 2N (R 10)-,-N (R 10) S (O) 2-or S (O) m;
V is selected from:
A) hydrogen,
B) heterocycle,
C) aryl,
D) C 1-C 20Alkyl, wherein have 0-4 carbon atom be selected from O, S and N heteroatoms displacement and
E) C 2-C 20Alkenyl.
Its condition is: if A 1Be S (O) m, then V is not a hydrogen; If A 1Be a key, n is 0, and A 2Be S (O) m, then V is not a hydrogen;
W is a heterocycle;
X is-CH 2-,-C (=O)-or-S (=O) m-;
Y is an aryl unsubstituted or that replace, or heterocycle unsubstituted or that replace, and wherein the heterocycle of aryl of Qu Daiing or replacement is replaced by one or more following groups:
1) C unsubstituted or that replaced by following groups 1-C 4Alkyl:
A) C 1-C 4Alkoxyl group,
b)NR 6R 7、
C) C 3-C 6Cycloalkyl,
D) aryl or heterocycle,
e)HO，
F)-S (O) mR 6a, or
g)-C(O)NR 6R 7，
2) aryl or heterocycle,
3) halogen,
4)OR 6，
5)NR 6R 7
6)CN，
7)NO 2，
8)CF 3，
9)-S(O)mR 6a，
10)-C (O) NR 6R 7, or
11) C 3-C 6Cycloalkyl;
M is 0,1 or 2;
N is 0,1,2,3 or 4;
P is 0,1,2,3 or 4;
Q is 1 or 2;
R is 0-5, and its condition is that r is 0 when V is hydrogen;
S is 0 or 1;
T is 0 or 1; With
U is 4 or 5.
2. formula B compound or its optically active isomer or its pharmaceutically acceptable salt that can suppress farnesyl-protein transferase:
Figure A9619420600071
In the formula:
R 1aAnd R 1bBe independently selected from:
A) hydrogen,
B) aryl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, CN (R 10) 2N-C (O)-, (R 10) 2N-C (NR 10)-, CN, NO 2, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-,
C) C that does not replace or replace 1-C 6Alkyl, wherein the C of replacement 1-C 6Substituting group on the alkyl is selected from aryl, heterocyclic radical, C unsubstituted or that replace 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2N-C (O)-, CN, (R 10) 2N-C (NR 10)-, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, and R 11OC (O) NR 10-;
R 2And R 3Be independently selected from: H, the C that does not replace or replace 1-C 8Alkyl, the C that does not replace or replace 2-C 8Alkenyl, the C that does not replace or replace 2-C 8Alkynyl, the aryl that does not replace or replace, the heterocycle that does not replace or replace, Or Wherein, substituting group is to be replaced by one or more groups in the following groups:
1) aryl or the heterocycle that does not replace or replaced by following groups:
A) C 1-C 4Alkyl,
b)(CH 2) pOR 6，
c)(CH 2) pNR 6R 7，
D) halogen,
e)CN，
2) C 3-C 6Cycloalkyl,
3)OR 6，
4)SR 6a，S(O)R 6a，SO 2R 6a，
15) N 3, or
16) F; Or
R 2And R 3Be connected in and lump together formation-(CH on the same carbon atom 2) u-, one of them carbon atom is randomly by being selected from O, S (O) m,-NC (O)-and-N (COR 10)-group replace;
R 4Be selected from H and CH 3And R 2, R 3And R 4In any 2 randomly be connected on the same carbon atom;
R 6, R 7And R 7aBe independently selected from: H, C 1-C 4Alkyl, C 3-C 6Cycloalkyl, heterocycle, aryl, aroyl, 4-hetaroylpyrazol, arylsulfonyl, heteroaryl sulphonyl, these groups can be unsubstituted or be replaced by following groups:
A) C 1-C 4Alkoxyl group,
B) aryl or heterocycle,
C) halogen,
d)HO，
F)-SO 2R 11, or
G) N (R 10) 2Or
R 6And R 7Can be connected in the ring;
R 7And R 7aCan be connected in the ring;
R 6aBe selected from: C 1-C 4Alkyl, C 3-C 6Cycloalkyl, heterocycle, aryl, these groups can be unsubstituted or replace with following groups:
A) C 1-C 4Alkoxyl group,
B) aryl or heterocycle,
C) halogen,
d)HO，
Figure A9619420600092
F)-SO 2R 11, or
g)N(R 10) 2；
R 8Be independently selected from:
A) hydrogen,
B) aryl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, NO 2, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-and
C) C unsubstituted or that replaced by following groups 1-C 6Alkyl: aryl, cyano-phenyl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NH-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 10OC (O) NH-;
R 9Be selected from:
A) hydrogen,
B) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, NO 2, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-and
C) C unsubstituted or that replaced by following groups 1-C 6Alkyl: perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-;
R 10Be independently selected from hydrogen, C 1-C 6Alkyl, benzyl and aryl;
R 11Be independently selected from C 1-C 6Alkyl and aryl;
A 1And A 2Be independently selected from: key ,-CH=CH-,-C ≡ C-,-C (O)-,-C (O) NR 10,-NR 10C (O)-, O ,-N (R 10)-,-S (O) 2N (R 10)-,-N (R 10) S (O) 2-or S (O) m;
G is H 2Or O;
V is selected from:
A) hydrogen,
B) heterocycle,
C) aryl,
D) C 1-C 20Alkyl, wherein have 0-4 carbon atom be selected from O, S and N heteroatoms displacement and
E) C 2-C 20Alkenyl.
Its condition is: if A 1Be S (O) m, then V is not a hydrogen; If A 1Be a key, n is 0, and A 2Be S (O) m, then V is not a hydrogen;
W is a heterocycle;
X is-CH 2-,-C (=O)-or-S (=O) m-;
Z is an aryl unsubstituted or that replace, heteroaryl, arylmethyl, heteroaryl methyl, arylsulfonyl, heteroaryl sulphonyl, and wherein the group of Qu Daiing is replaced by one or more following groups:
1) C unsubstituted or that replaced by following groups 1-C 4Alkyl:
A) C 1-C 4Alkoxyl group,
b)NR 6R 7，
C) C 3-C 6Cycloalkyl,
D) aryl or heterocycle,
e)HO，
F)-S (O) mR 6a, or
g)-C(O)NR 6R 7，
2) aryl or heterocycle,
3) halogen,
4)OR 6，
5)NR 6R 7
6)CN、
7)NO 2，
8)CF 3，
9)-S(O)mR 6a，
10)-C (O) NR 6R 7, or
11) C 3-C 6Cycloalkyl;
M is 0,1 or 2;
N is 0,1,2,3 or 4;
P is 0,1,2,3 or 4;
Q is 1 or 2;
R is 0-5, and its condition is that r is 0 when V is hydrogen;
S is 0 or 1;
T is 0 or 1; With
U is 4 or 5,
But its condition be when G be H 2, and W is when being imidazolyl, substituting group (R 8) r-V-A 1(CR 1a 2) nA 2(CR 1a 2) n-is not H, and
Its condition be when X be-C (=O)-, or-S (=O) during m-, t is 1, and substituting group (R 8) r-V-A 1(CR 1a 2) nA 2(CR 1a 2) n-is not hydrogen.
3. formula C compound or its optically active isomer or its pharmaceutically acceptable salt that can suppress farnesyl-protein transferase:
Figure A9619420600121
In the formula:
R 1aAnd R 1bBe independently selected from:
A) hydrogen,
B) aryl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, R 10O-, R 11S (O) m-, R 10C (O) NR 10, (R 10) 2N-C (O)-, (R 10) 2N-C (NR 10)-, CN, NO 2, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-,
C) C that does not replace or replace 1-C 6Alkyl, wherein the C of replacement 1-C 6Substituting group on the alkyl is selected from aryl, heterocyclic radical, C unsubstituted or that replace 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2N-C (O)-, CN, (R 10) 2N-C (NR 10)-, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, and R 11OC (O) NR 10-;
R 2And R 3Be independently selected from: H, the C that does not replace or replace 1-C 8Alkyl, the C that does not replace or replace 2-C 8Alkenyl, the C that does not replace or replace 2-C 8Alkynyl, the aryl that does not replace or replace, the heterocycle that does not replace or replace,
Figure A9619420600122
Or Wherein, substituting group is to be replaced by one or more groups in the following groups:
1) aryl or the heterocycle that does not replace or replaced by following groups:
A) C 1-C 4Alkyl,
b)(CH 2) pOR 6，
c)(CH 2) pNR 6R 7，
D) halogen,
e)CN，
2) C 3-C 6Cycloalkyl,
3)OR 6，
4)SR 6a，S(O)R 6a，SO 2R 6a，
Figure A9619420600131
15) N 3, or
16) F; Or
R 2And R 3Be connected in and lump together formation-(CH on the same carbon atom 2) u-, one of them carbon atom is randomly by being selected from O, S (O) m,-NC (O)-and-N (COR 10)-group replace;
R 4Be selected from H and CH 3And R 2, R 3And R 4In any 2 randomly be connected on the same carbon atom;
R 6, R 7And R 7aBe independently selected from: H, C 1-C 4Alkyl, C 3-C 6Cycloalkyl, heterocycle, aryl, aroyl, 4-hetaroylpyrazol, arylsulfonyl, heteroaryl sulphonyl, these groups can be unsubstituted or be replaced by following groups:
A) C 1-C 4Alkoxyl group,
B) aryl or heterocycle,
C) halogen,
d)HO，
F)-SO 2R 11, or
G) N (R 10) 2Or
R 6And R 7Can be connected in the ring;
R 7And R 7aCan be connected in the ring;
R 6aBe selected from: C 1-C 4Alkyl, C 3-C 6Cycloalkyl, heterocycle, aryl, these groups can be unsubstituted or replace with following groups:
A) C 1-C 4Alkoxyl group,
B) aryl or heterocycle,
C) halogen,
d)HO，
F)-SO 2R 11, or
g)N(R 10) 2；
R 8Be independently selected from:
A) hydrogen,
B) aryl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, NO 2, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-and
C) C unsubstituted or that replaced by following groups 1-C 6Alkyl: aryl, cyano-phenyl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NH-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 10OC (O) NH-;
R 9Be selected from:
A) hydrogen,
B) C 2-C 6Alkenyl, C 2-C 6Alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, NO 2, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-and
C) C unsubstituted or that replaced by following groups 1-C 6Alkyl: perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-;
R 10Be independently selected from hydrogen, C 1-C 6Alkyl, benzyl and aryl;
R 11Be independently selected from C 1-C 6Alkyl and aryl;
A 1And A 2Be independently selected from: key ,-CH=CH-,-C ≡ C-,-C (O)-,-C (O) NR 10-,-NR 10C (O)-, O ,-N (R 10)-,-S (O) 2N (R 10)-,-N (R 10) S (O) 2-or S (O) m;
G is O;
V is selected from:
A) hydrogen,
B) heterocycle,
C) aryl,
D) C 1-C 20Alkyl, wherein have 0-4 carbon atom be selected from O, S and N heteroatoms displacement and
E) C 2-C 20Alkenyl.
Its condition is: if A 1Be S (O) m, then V is not a hydrogen; If A 1Be a key, n is 0, and A 2Be S (O) m, then V is not a hydrogen;
W is a heterocycle;
X is-CH 2-,-C (=O)-or-S (=O) m-;
Z is an aryl unsubstituted or that replace, heteroaryl, arylmethyl, heteroaryl methyl, arylsulfonyl, heteroaryl sulphonyl, and wherein the group of Qu Daiing is replaced by one or more following groups:
1) C unsubstituted or that replaced by following groups 1-C 4Alkyl:
A) C 1-C 4Alkoxyl group,
b)NR 6R 7，
C) C 3-C 6Cycloalkyl,
D) aryl or heterocycle,
e)HO，
F)-S (O) mR 6a, or
g)-C(O)NR 6R 7，
2) aryl or heterocycle,
3) halogen,
4)OR 6，
5)NR 6R 7
6)CN，
7)NO 2，
8)CF 3，
9)-S(O)mR 6a，
10)-C (O) NR 6R 7, or
11) C 3-C 6Cycloalkyl;
M is 0,1 or 2;
N is 0,1,2,3 or 4;
P is 0,1,2,3 or 4;
Q is 1 or 2;
R is 0-5, and its condition is that r is 0 when V is hydrogen;
S is 1;
T is 0 or 1; With
U is 4 or 5.
4. according to formula A compound or its optically active isomer or its pharmaceutically acceptable salt of claim 1:
In the formula:
R 1aBe independently selected from: hydrogen or C 1-C 6Alkyl;
R 1bBe independently selected from:
A) hydrogen,
B) aryl, heterocycle, cycloalkyl, R 10O-,-N (R 10) 2Or C 2-C 6Alkenyl,
C) the unsubstituted or C that replaces 1-C 6Alkyl, wherein the C of replacement 1-C 6Substituting group on the alkyl is selected from aryl, heterocycle, cycloalkyl, alkenyl, R unsubstituted or that replace 10O-and-N (R 10) 2
R 3, R 4And R 5Be independently selected from H and CH 3
R 2Be H; Or C 1-C 5Alkyl can be unbranched or side chain is arranged, and can be unsubstituted or replaced by following one or more groups:
1) aryl,
2) heterocycle,
3)OR 6，
4) SR 6a, SO 2R 6a, or
Figure A9619420600173
And R 2, R 3, R 4And R 5In any 2 can randomly be connected on the same carbon atom;
R 6, R 7And R 7aBe independently selected from: H; C 1-C 4Alkyl, C 3-C 6Cycloalkyl, aryl, heterocycle can be unsubstituted, or replaced by following groups:
A) C 1-C 4Alkoxyl group,
B) halogen, or
C) aryl or heterocycle;
R 6aBe selected from: C 1-C 4Alkyl or C 3-C 6Cycloalkyl, can be unsubstituted or replaced by following groups:
A) C 1-C 4Alkoxyl group,
B) halogen, or
C) aryl or heterocycle;
R 8Be independently selected from:
A) hydrogen,
B) C 1-C 6Alkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, C 1-C 6Perfluoroalkyl, F, Cl, R 10O-, R 10C (O) NR 10-, CN, NO 2, (R 10) 2N-C (NR 10)-, R 10C (O)-, R 10OC (O)-,-N (R 10) 2, or R 11OC (O) NR 10-and
C) by C 1-C 6Perfluoroalkyl, R 10O-, R 10C (O) NR 10-, (R 10) 2N-C (NR 10)-, R 10C (O)-, R 10OC (O)-,-N (R 10) 2, or R 11OC (O) NR 10The C of-replacement 1-C 6Alkyl;
R 9Be selected from:
A) hydrogen,
B) C 2-C 6Alkenyl, C 2-C 6Alkynyl, C 1-C 6Perfluoroalkyl, F, Cl, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, CN, NO 2, (R 10) 2N-C (NR 10)-, R 10C (O)-, R 10OC (O)-,-N (R 10) 2, or R 11OC (O) NR 10-and
C) unsubstituted or by C 1-C 6Perfluoroalkyl, F, Cl, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, CN, (R 10) 2N-C (NR 10)-, R 10C (O)-, R 10OC (O)-,-N (R 10) 2, or R 11OC (O) NR 10The C of-replacement 1-C 6Alkyl;
R 10Be independently selected from hydrogen, C 1-C 6Alkyl, benzyl or aryl;
R 11Be independently selected from C 1-C 6Alkyl and aryl;
A 1And A 2Be independently selected from: a key ,-CH=CH-,-C ≡ C-,-C (O)-,-C (O) NR 10-, O ,-N (R 10)-, or S (O) m;
V is selected from:
A) hydrogen,
B) be selected from following heterocyclic radical: pyrrolidyl, imidazolyl, pyridyl, thiazolyl, pyriconyl, 2-oxo pyridine base, indyl, quinolyl, isoquinolyl and thienyl,
C) aryl,
D) C 1-C 20Alkyl, wherein have 0-4 carbon atom be selected from O, S and N heteroatoms displacement and
E) C 2-C 20Alkenyl,
But its condition is if A 1Be S (O) m, then V is not a hydrogen, and if A 1Be a key, n is 0, A 2Be S (O) m, then V neither hydrogen;
W is selected from following heterocyclic radical: pyrrolidyl, imidazolyl, pyridyl, thiazolyl, pyriconyl, 2-oxo-piperidine base, indyl, quinolyl, or isoquinolyl;
X is-CH 2Or-C (=O)-;
Y is monocycle or bicyclic aryl, and perhaps monocycle or bicyclic heterocycle can be unsubstituted or replaced by following one or more groups:
A) C 1-C 4Alkyl,
B) C 1-C 4Alkoxyl group,
C) halogen, or
d)NR 6R 7；
M is 0,1 or 2;
N is 0,1,2,3 or 4;
P is 0,1,2,3 or 4;
R is 0-5, but r is 0 when V is hydrogen;
S is 0 or 1; And
T is 0 or 1.
5. according to formula B compound or its pharmaceutically acceptable salt of claim 2: In the formula:
R 1aBe independently selected from: hydrogen or C 1-C 6Alkyl;
R 1bBe independently selected from:
A) hydrogen,
B) aryl, heterocycle, cycloalkyl, R 10O-,-N (R 10) 2Or C 2-C 6Alkenyl,
C) the unsubstituted or C that replaces 1-C 6Alkyl, wherein the C of replacement 1-C 6Substituting group on the alkyl is selected from aryl, heterocycle, cycloalkyl, alkenyl, R unsubstituted or that replace 10O-and-N (R 10) 2
R 3And R 4Be independently selected from H and CH 3R 2Be H; Or C 1-C 5Alkyl can be unbranched or side chain is arranged, and can be unsubstituted or replaced by following one or more groups:
1) aryl,
2) heterocycle,
3)OR 6，
4) SR 6a, SO 2R 6a, or
Figure A9619420600202
And R 2, R 3, R 4And R 5In any 2 can randomly be connected on the same carbon atom;
R 6, R 7And R 7aBe independently selected from: H; C 1-C 4Alkyl, C 3-C 6Cycloalkyl, aryl, heterocycle can be unsubstituted, or replaced by following groups:
A) C 1-C 4Alkoxyl group,
B) halogen, or
C) aryl or heterocycle;
R 6aBe selected from: C 1-C 4Alkyl or C 3-C 6Cycloalkyl, can be unsubstituted or replaced by following groups:
A) C 1-C 4Alkoxyl group,
B) halogen, or
C) aryl or heterocycle;
R 8Be independently selected from:
A) hydrogen,
B) C 1-C 6Alkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, C 1-C 6Perfluoroalkyl, F, Cl, R 10O-, R 10C (O) NR 10-, CN, NO 2, (R 10) 2N-C (NR 10)-, R 10C (O)-, R 10OC (O)-,-N (R 10) 2, or R 11OC (O) NR 10-and
C) by C 1-C 6Perfluoroalkyl, R 10O-, R 10C (O) NR 10-, (R 10) 2N-C (NR 10)-, R 10C (O)-, R 10OC (O)-,-N (R 10) 2, or R 11OC (O) NR 10The C of-replacement 1-C 6Alkyl;
R 9Be selected from:
A) hydrogen,
B) C 2-C 6Alkenyl, C 2-C 6Alkynyl, C 1-C 6Perfluoroalkyl, F, Cl, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, CN, NO 2, (R 10) 2N-C (NR 10)-, R 10C (O)-, R 10OC (O)-,-N (R 10) 2, or R 11OC (O) NR 10-and
C) unsubstituted or by C 1-C 6Perfluoroalkyl, F, Cl, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, CN, (R 10) 2N-C (NR 10)-, R 10C (O)-, R 10OC (O)-,-N (R 10) 2, or R 11OC (O) NR 10The C of-replacement 1-C 6Alkyl;
R 10Be independently selected from hydrogen, C 1-C 6Alkyl, benzyl or aryl;
R 11Be independently selected from C 1-C 6Alkyl and aryl;
A 1And A 2Be independently selected from: a key ,-CH=CH-,-C ≡ C-,-C (O)-,-C (O) NR 10-, O ,-N (R 10)-, or S (O) m;
V is selected from:
A) hydrogen,
B) be selected from following heterocyclic radical: pyrrolidyl, imidazolyl, pyridyl, thiazolyl, pyriconyl, 2-oxo pyridine base, indyl, quinolyl, isoquinolyl and thienyl,
C) aryl,
D) C 1-C 20Alkyl, wherein have 0-4 carbon atom be selected from O, S and N heteroatoms displacement and
E) C 2-C 20Alkenyl,
But its condition is if A 1Be S (O) m, then V is not a hydrogen, and if A 1Be a key, n is 0, A 2Be S (O) m, then V neither hydrogen;
G is H 2Or O;
W is selected from following heterocyclic radical: pyrrolidyl, imidazolyl, pyridyl, thiazolyl, pyriconyl, 2-oxo-piperidine base, indyl, quinolyl, or isoquinolyl;
X is-CH 2Or-C (=O)-;
Z is monocycle or bicyclic aryl, monocycle or bicyclic heteroaryl, monocycle or bicyclic aryl methyl, monocycle or bicyclic heteroaryl methyl, monocycle or bicyclic aryl sulphonyl, monocycle or bicyclic heteroaryl sulphonyl can be unsubstituted or replaced by following one or more groups:
1) C unsubstituted or that replaced by following groups 1-C 4Alkyl:
A) C 1-C 4Alkoxyl group,
b)NR 6R 7，
C) C 3-C 6Cycloalkyl,
D) aryl or heterocycle,
e)HO，
F)-S (O) mR 6a, or
g)-C(O)NR 6R 7，
2) aryl or heterocycle,
3) halogen,
4)OR 6，
5)NR 6R 7
6)CN，
7)NO 2，
8)CF 3，
9)-S(O)mR 6a，
10)-C (O) NR 6R 7, or
11) C 3-C 6Cycloalkyl;
M is 0,1 or 2;
N is 0,1,2,3 or 4;
P is 0,1,2,3 or 4;
R is 0-5, and its condition is that r is 0 when V is hydrogen;
S is 0 or 1;
T is 0 or 1; With
U is 4 or 5,
But its condition be when G be H 2, and W is when being imidazolyl, substituting group (R 8) r-V-A 1(CR 1a 2) nA 2(CR 1a 2) n-is not H, and
Its condition be when X be-C (=O)-, or-S (=O) during m-, t is 1, and substituting group (R 8) r-V-A 1(CR 1a 2) nA 2(CR 1a 2) n-is not hydrogen.
6. can suppress compound or its pharmaceutically acceptable salt of farnesyl-protein transferase, these compounds are:
2 (S)-butyl-1-(2,3-diamino third-1-yl)-4-(1-naphthoyl)-piperazine
1-(3-amino-2-(2-naphthyl methyl amino) third-1-yl)-2 (S)-butyl-4-(1-naphthoyl)-piperazine
2 (S)-butyl-1-{5-[1-(2-naphthyl methyl)]-4, the 5-glyoxalidine } methyl-4-(1-naphthoyl)-piperazine
1-[5-(1-benzyl imidazole) methyl]-2 (S)-butyl-4-(1-naphthoyl)-piperazine
1-{5-[1-(4-nitrobenzyl) imidazolyl] methyl }-2 (S)-butyl-4-(1-naphthoyl)-piperazine
1-(3-kharophen methylthio group-2 (R)-amino third-1-yl)-2 (S)-butyl-4-(1-naphthoyl)-piperazine
2 (S)-butyl-1-[2-(1-imidazolyl) ethyl] sulphonyl-4-(1-naphthoyl)-piperazine
2 (R)-butyl-1-imidazolyl-4-methyl-4-(1-naphthoyl)-piperazine
2 (S)-butyl-4-(1-naphthoyl)-1-(3-pyridylmethyl) piperazine
1-2 (S)-butyl-(2 (R)-(4-nitrobenzyl) amino-3-hydroxypropyl)-4-(1-naphthoyl)-piperazine
1-(2 (R)-amino-3-hydroxyl heptadecyl)-2 (S)-butyl-4-(1-naphthoyl)-piperazine
2 (S)-benzyl-1-imidazolyl-4-methyl-4-(1-naphthoyl)-piperazine
1-(2 (R)-amino-3-(3-benzylthio-) propyl group)-2 (S)-butyl-4-(1-naphthoyl)-piperazine
1-(2 (R)-amino-3-[3-(4-nitrobenzyl sulfenyl) propyl group]))-2 (S)-butyl-4-(1-naphthoyl)-piperazine
2 (S)-butyl-1-[(4-imidazolyl) ethyl]-4-(1-naphthoyl)-piperazine
2 (S)-butyl-1-[(4-imidazolyl) methyl]-4-(1-naphthoyl)-piperazine
2 (S)-butyl-1-[(1-naphthalene-2-ylmethyl)-and 1H-imidazoles-5-yl) ethanoyl]-4-(1-naphthoyl)-piperazine
2 (S)-butyl-1-[(1-naphthalene-2-ylmethyl)-and 1H-imidazoles-5-yl) ethyl]-4-(1-naphthoyl)-piperazine
1-(2 (R)-amino-3-hydroxypropyl)-2 (S)-butyl-4-(1-naphthoyl)-piperazine
1-(2 (R)-amino-4-hydroxy butyl)-2 (S)-butyl-4-(1-naphthoyl)-piperazine
1-(2-amino-3-(2-benzyloxy phenyl) propyl group)-2 (S)-butyl-4-(1-naphthoyl)-piperazine
1-(2-amino-3-(2-hydroxy phenyl) propyl group)-2 (S)-butyl-4-(1-naphthoyl)-piperazine
1-[3-(4-imidazolyl) propyl group]-2 (S)-butyl-4-(1-naphthoyl)-piperazine
2 (S)-normal-butyl-4-(1-naphthoyl)-1-[1-(1-naphthyl methyl) imidazoles-5-ylmethyl]-piperazine
2 (S)-normal-butyl-4-(1-naphthoyl)-1-[1-(2-naphthyl methyl) imidazoles-5-ylmethyl]-piperazine
2 (S)-normal-butyl-1-[1-(4-cyano group benzyl) imidazoles-5-ylmethyl]-4-(1-naphthoyl)-piperazine
2 (S)-normal-butyl-1-[1-(4-methoxy-benzyl) imidazoles-5-ylmethyl]-4-(1-naphthoyl)-piperazine
2 (S)-normal-butyl-1-[1-(3-methyl-2-butene base) imidazoles-5-ylmethyl]-4-(1-naphthoyl)-piperazine
2 (S)-normal-butyl-1-[1-(4-luorobenzyl) imidazoles-5-ylmethyl]-4-(1-naphthoyl)-piperazine
2 (S)-normal-butyl-1-[1-(4-benzyl chloride base) imidazoles-5-ylmethyl]-4-(1-naphthoyl)-piperazine
1-[1-(4-bromobenzyl) imidazoles-5-ylmethyl]-2 (S)-normal-butyl-4-(1-naphthoyl)-piperazine
1-[1-(4-bromobenzyl) imidazoles-5-ylmethyl]-2 (S)-normal-butyl-4-(1-naphthoyl)-piperazine
2 (S)-normal-butyl-4-(1-naphthoyl)-1-[1-(4-trifluoromethyl benzyl) imidazoles-5-ylmethyl]-piperazine
2 (S)-normal-butyl-1-[1-(4-methyl-benzyl) imidazoles-5-ylmethyl]-4-(1-naphthoyl)-piperazine
2 (S)-normal-butyl-1-[1-(3-methyl-benzyl) imidazoles-5-ylmethyl]-4-(1-naphthoyl)-piperazine
1-[1-(4-phenylbenzyl) imidazoles-5-ylmethyl]-2 (S)-normal-butyl-4-(1-naphthoyl)-piperazine
2 (S)-normal-butyl-4-(1-naphthoyl)-1-[1-(2-phenylethyl) imidazoles-5-ylmethyl]-piperazine
2 (S)-normal-butyl-4-(1-naphthoyl)-1-[1-(4-trifluoromethoxy) imidazoles-5-ylmethyl]-piperazine
1-{[1-(4-cyano group benzyl)-1H-imidazoles-5-yl] ethanoyl }-2 (S)-normal-butyl-4-(1-naphthoyl)-piperazine
5 (S)-normal-butyl-1-(2, the 3-3,5-dimethylphenyl)-4-(4-imidazolyl methyl)-piperazine-2-ketone
5 (S)-normal-butyl-4-[1-(4-cyano group benzyl) imidazoles-5-ylmethyl]-1-(2, the 3-3,5-dimethylphenyl) piperazine-2-ketone
4-[1-(4-cyano group benzyl) imidazoles-5-ylmethyl]-1-(2,3-3,5-dimethylphenyl-5 (S)-(2-methoxy ethyl) piperazine-2-ketone
(S)-the 1-[3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-5-[2-(methylsulfonyl) ethyl]-2-piperazine ketone
(S)-the 1-[3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-5-[2-(ethylsulfonyl) ethyl]-2-piperazine ketone
(S)-1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-5-[2-(ethylsulfonyl) methyl]-2-piperazine ketone
(S)-1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-5-[N-ethyl-2-kharophen]-2-piperazine ketone
(±)-5-(2-butyne base)-1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-2-piperazine ketone
1-(3-chloro-phenyl-)-4--[1-(4-cyano group benzyl)-5-imidazolyl methyl]-2-piperazine ketone
5 (S)-butyl-4-[1-(4-cyano group benzyl-2-methyl)-5-imidazolyl methyl]-1-(2, the 3-3,5-dimethylphenyl)-piperazine-2-ketone
4-[1-(2-(4-cyano-phenyl)-2-propyl group)-5-imidazolyl methyl]-1-(3-chloro-phenyl-)-5 (S)-(2-methylsulfonyl ethyl) piperazine-2-ketone
5 (S)-normal-butyl-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-1-(2-aminomethyl phenyl) piperazine-2-ketone
4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-5 (S)-(2-fluoro ethyl)-1-(3-chloro-phenyl-) piperazine-2-ketone
4-[3-(4-cyano group benzyl) pyridin-4-yl]-1-(3-chloro-phenyl-)-5 (S)-(2-methylsulfonyl ethyl) piperazine-2-ketone
4-[5-(4-cyano group benzyl)-1-imidazolyl ethyl]-1-(3-chloro-phenyl-) piperazine-2-ketone.
7. can suppress compound or its pharmaceutically acceptable salt or its optically active isomer of farnesyl-protein transferase, these compounds are: table 1 Table 2 Upright structure X YR n-Bu 2-O (CH 2) 13CH 3S n-Bu 2-O (CH 2) 13CH 3R n-Bu 2-O (CH 2) 11CH 3S n-Bu 2-O (CH 2) 11CH 3R n-Bu 2-O (CH 2) 9CH 3S n-Bu 2-O (CH 2) 9CH 3R n-Bu 2-O (CH 2) 7CH 3S n-Bu 2-O (CH 2) 7CH 3R n-Bu 2-O (CH 2) 3PhS n-Bu 2-O (CH 2) 3PhR n-Bu 3-OCH 2Ph Table 2 (continuing) Upright structure X YS n-Bu 3-OCH 2PhR n-Bu 3-O (CH 2) 13CH 3S n-Bu 3-O (CH 2) 13CH 3R n-Bu 4-O (CH 2) 13CH 3S n-Bu 4-O (CH 2) 13CH 3S n-Bu 4-OCH 2PhR/S H 2-O (CH 2) 13CH 3 Table 3
Figure A9619420600301
Y3-SO 2Me3-OCF 3 Table 4 X YCH 2OCH 2Ph CF 3CH 2SO 2Et CF 3CH 2SO 2Ph CF 3CH 2SO 2Me ClCH 2SO 2Et ClCONHMe CF 3CONHEt CF 3CH 2SO 2Ph ClCONHMe ClCONHEt ClCONHc-Pr ClCONHc-Pr CF 3 Table 4 (continuing)
Figure A9619420600321
X YNHCOMe ClCONMe 2CF 3SO 2Et ClCH 2SMe Cl (±) C ≡ CMe Cl Table 5 X YCH 2CH 2HCh 2CO HCH 2HCH 23-ClNHSO 2HCH 2CH 2CO 3-ClCH 22,3-Cl 2CH 22-BrCH 23-CF 3CH 24-ClCH 2CO 3-ClCH 23-FCH 23-Br Table 6 X Y Z4-CN CH 25-CH 2CH 2CO3-CN CH 25-CH 22-CN CH 25-CH 24-CN CH 24-CH 2CH 2CO4-CN (CH 2) 24-CH 2CH 2CO Table 7
Figure A9619420600351
X Y4-Me CH 2CH 2SO 2Me4-Me H2-Me H Table 8
Figure A9619420600361
Y
3-CF 3
3-CH 3
2，3-(CH 2) 4
3-OCH 3
3-Cl
2-CH 3.3-Cl
H
3-F Table 9
Figure A9619420600371
RCH 2CH 2OCH 2CF 3 CH 2CH 2N 3CH 2CH 2NHCOCH 3CH 2CH 2NHCOC 2H 5CH 2CH 2SO 2CH (CH 3) 2CH 2CH 2SCH (CH 3) 2CH 2CH 2S (O) CH (CH 3) 2 Table 10
Figure A9619420600381
Figure A9619420600382
Table 11
Figure A9619420600391
R Y
Figure A9619420600392
Table 12 Table 12 (continuing)
Figure A9619420600411
Table 13 Table 14
Figure A9619420600431
R 1 R 2
Figure A9619420600432
Table 15
Figure A9619420600441
R Y
Figure A9619420600442
Table 16
Figure A9619420600451
R
Figure A9619420600452
Table 17
Figure A9619420600461
R Table 18
Figure A9619420600471
8. according to compound or its pharmaceutically acceptable salt of claim 6, this compound is:
1-{5-[1-(4-nitrobenzyl)] imidazolyl methyl }-2 (S)-butyl-4-(1-naphthoyl)-piperazine
9. according to compound or its pharmaceutically acceptable salt of claim 6, or its optically active isomer, this compound is:
1-[5-(1-benzyl imidazole) methyl]-2 (S)-butyl-4-(1-naphthoyl)-piperazine
10. according to compound or its pharmaceutically acceptable salt of claim 6, or its optically active isomer, this compound is:
1-(2 (R)-amino-3-(3-benzylthio-) propyl group)-2 (S)-butyl-4-(1-naphthoyl)-piperazine
Figure A9619420600491
11. according to compound or its pharmaceutically acceptable salt of claim 6, or its optically active isomer, this compound is:
1-(2 (R)-amino-3-(4-nitrobenzyl sulfenyl) propyl group)-2 (S)-butyl-4-(1-naphthoyl)-piperazine
Figure A9619420600492
12. according to compound or its pharmaceutically acceptable salt of claim 6, or its optically active isomer, this compound is:
2 (S)-normal-butyl-1-[1-(4-cyano group benzyl) imidazoles-5-ylmethyl]-4-(1-naphthoyl)-piperazine
13. according to compound or its pharmaceutically acceptable salt of claim 6, or its optically active isomer, this compound is:
2 (S)-normal-butyl-1-[1-(4-cyano group benzyl) imidazoles-5-ylmethyl]-4-(2, the 3-3,5-dimethylphenyl) piperazine-5-ketone
Figure A9619420600502
14. according to compound or its pharmaceutically acceptable salt of claim 6, or its optically active isomer, this compound is:
2 (S)-normal-butyl-1-[1-(4-benzyl chloride base) imidazoles-5-ylmethyl]-4-(1-naphthoyl)-piperazine
15. according to compound or its pharmaceutically acceptable salt of claim 6, or its optically active isomer, this compound is:
1-{[1-(4-cyano group benzyl)-1H-imidazoles-5-yl] ethanoyl }-2 (S)-normal-butyl-4-(1-naphthoyl)-piperazine
16. according to compound or its pharmaceutically acceptable salt of claim 6, or its optically active isomer, this compound is:
1-[1-(4-cyano group benzyl) imidazoles-5-ylmethyl]-4-(2, the 3-3,5-dimethylphenyl)-2 (S)-(2-methoxymethoxy ethyl) piperazine-5-ketone
Figure A9619420600512
17. according to compound or its pharmaceutically acceptable salt of claim 6, or its optically active isomer, this compound is:
5 (S)-normal-butyl-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-1-(2-aminomethyl phenyl) piperazine-2-ketone
18. according to compound or its pharmaceutically acceptable salt of claim 6, or its optically active isomer, this compound is:
(S)-1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-the 5-[(2-methylsulfonyl) ethyl]-2-piperazine ketone
Figure A9619420600522
19. according to compound or its pharmaceutically acceptable salt of claim 6, or its optically active isomer, this compound is:
(S)-1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-the 5-[(2-ethylsulfonyl) ethyl]-2-piperazine ketone
20. according to compound or its pharmaceutically acceptable salt of claim 6, or its optically active isomer, this compound is:
(S)-1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-the 5-[(2-ethylsulfonyl) methyl]-2-piperazine ketone
Figure A9619420600531
21. according to compound or its pharmaceutically acceptable salt of claim 6, or its optically active isomer, this compound is:
1-(3-chloro-phenyl-)-4-[1-(4-cyano group benzyl)-5-imidazolyl methyl]-2-piperazine ketone
Figure A9619420600532
22. contain the pharmaceutical composition of the pharmaceutical carrier and the compound of the claim 1 that is dispersed in treatment significant quantity wherein.
23. contain the pharmaceutical composition of the pharmaceutical carrier and the compound of the claim 2 that is dispersed in treatment significant quantity wherein.
24. contain the pharmaceutical composition of the pharmaceutical carrier and the compound of the claim 3 that is dispersed in treatment significant quantity wherein.
25. contain the pharmaceutical composition of the pharmaceutical carrier and the compound of the claim 6 that is dispersed in treatment significant quantity wherein.
26. a method that suppresses farnesyl-protein transferase, this method comprise the composition to the claim 22 of the administration treatment significant quantity of this treatment of needs.
27. a method that suppresses farnesyl-protein transferase, this method comprise the composition to the claim 23 of the administration treatment significant quantity of this treatment of needs.
28. a method that suppresses farnesyl-protein transferase, this method comprise the composition to the claim 24 of the administration treatment significant quantity of this treatment of needs.
29. a method that suppresses farnesyl-protein transferase, this method comprise the composition to the claim 25 of the administration treatment significant quantity of this treatment of needs.
30. a method that suppresses farnesyl-protein transferase, this method comprise containing pharmaceutical carrier and being dispersed in the formula B compound of treatment significant quantity wherein or the pharmaceutical composition of its pharmaceutically acceptable salt the administration treatment significant quantity of this treatment of needs:
Figure A9619420600541
In the formula:
R 1aAnd R 1bBe independently selected from:
A) hydrogen,
B) aryl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, CN (R 10) 2N-C (O)-, (R 10) 2N-C (NR 10)-, CN, NO 2, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-,
C) C that does not replace or replace 1-C 6Alkyl, wherein the C of replacement 1-C 6Substituting group on the alkyl is selected from aryl, heterocyclic radical, C unsubstituted or that replace 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2N-C (O)-, CN, (R 10) 2N-C (NR 10)-, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, and R 11OC (O) NR 10-;
R 2And R 3Be independently selected from: H, the C that does not replace or replace 1-C 8Alkyl, the C that does not replace or replace 2-C 8Alkenyl, the C that does not replace or replace 2-C 8Alkynyl, the aryl that does not replace or replace, the heterocycle that does not replace or replace,
Figure A9619420600542
Or
Figure A9619420600543
Wherein, substituting group is to be replaced by one or more groups in the following groups:
1) aryl or the heterocycle that does not replace or replaced by following groups:
A) C 1-C 4Alkyl,
b)(CH 2) pOR 6，
c)(CH 2) pNR 6R 7，
D) halogen,
e)CN，
2) C 3-C 6Cycloalkyl,
3)OR 6，
4)SR 6a，S(O)R 6a，SO 2R 6a，
Figure A9619420600551
15) N 3, or
16) F; Or
R 2And R 3Be connected in and lump together formation-(CH on the same carbon atom 2) u-, one of them carbon atom is randomly by being selected from O, S (O) m,-NC (O)-and-N (COR 10)-group replace;
R 4Be selected from H and CH 3And R 2, R 3And R 4In any 2 randomly be connected on the same carbon atom;
R 6, R 7And R 7aBe independently selected from: H, C 1-C 4Alkyl, C 3-C 6Cycloalkyl, heterocycle, aryl, aroyl, 4-hetaroylpyrazol, arylsulfonyl, heteroaryl sulphonyl, these groups can be unsubstituted or be replaced by following groups:
A) C 1-C 4Alkoxyl group,
B) aryl or heterocycle,
C) halogen,
d)HO，
Figure A9619420600562
F)-SO 2R 11, or
G) N (R 10) 2Or
R 6And R 7Can be connected in the ring;
R 7And R 7aCan be connected in the ring;
R 6aBe selected from: C 1-C 4Alkyl, C 3-C 6Cycloalkyl, heterocycle, aryl, these groups can be unsubstituted or replace with following groups:
A) C 1-C 4Alkoxyl group,
B) aryl or heterocycle,
C) halogen,
d)HO，
F)-SO 2R 11, or
g)N(R 10) 2；
R 8Be independently selected from:
A) hydrogen,
B) aryl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, NO 2, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-and
C) C unsubstituted or that replaced by following groups 1-C 6Alkyl: aryl, cyano-phenyl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NH-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 10OC (O) NH-;
R 9Be selected from:
A) hydrogen,
B) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, NO 2, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-and
C) C unsubstituted or that replaced by following groups 1-C 6Alkyl: perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-;
R 10Be independently selected from hydrogen, C 1-C 6Alkyl, benzyl and aryl;
R 11Be independently selected from C 1-C 6Alkyl and aryl;
A 1And A 2Be independently selected from: key ,-CH=CH-,-C ≡ C-,-C (O)-,-C (O) NR 10-,-NR 10C (O)-, O ,-N (R 10)-,-S (O) 2N (R 10)-,-N (R 10) S (O) 2-or S (O) m;
G is H 2
V is selected from:
A) hydrogen,
B) heterocycle,
C) aryl,
D) C 1-C 20Alkyl, wherein have 0-4 carbon atom be selected from O, S and N heteroatoms displacement and
E) C 2-C 20Alkenyl.
Its condition is: if A 1Be S (O) m, then V is not a hydrogen; If A 1Be a key, n is 0, and A 2Be S (O) m, then V is not a hydrogen;
W is an imidazolyl;
X is-CH 2-,-C (=O)-or-S (=O) m-;
Z is an aryl unsubstituted or that replace, heteroaryl, arylmethyl, heteroaryl methyl, arylsulfonyl, heteroaryl sulphonyl, and wherein the group of Qu Daiing is replaced by one or more following groups:
1) C unsubstituted or that replaced by following groups 1-C 4Alkyl:
A) C 1-C 4Alkoxyl group,
b)NR 6R 7，
C) C 3-C 6Cycloalkyl,
D) aryl or heterocycle,
e)HO，
F)-S (O) mR 6a, or
g)-C(O)NR 6R 7，
2) aryl or heterocycle,
3) halogen,
4)OR 6，
5)NR 6R 7
6)CN，
7)NO 2，
8)CF 3，
9)-S(O)mR 6a，
10)-C (O) NR 6R 7, or
11) C 3-C 6Cycloalkyl;
M is 0,1 or 2;
N is 0,1,2,3 or 4;
P is 0,1,2,3 or 4;
Q is 1 or 2;
R is 0-5, and its condition is that r is 0 when V is hydrogen;
S is 0 or 1;
T is 1; With
U is 4 or 5;
Its condition is substituting group (R 8) r-V-A 1(CR 1a 2) nA 2(CR 1a 2) n-is H.
31. a method that suppresses farnesyl-protein transferase, this method comprise containing pharmaceutical carrier and being dispersed in the formula B compound of treatment significant quantity wherein or the pharmaceutical composition of its pharmaceutically acceptable salt the administration treatment significant quantity of this treatment of needs:
In the formula:
R 1aAnd R 1bBe independently selected from:
A) hydrogen,
B) aryl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, CN (R 10) 2N-C (O)-, (R 10) 2N-C (NR 10)-, CN, NO 2, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-,
C) C that does not replace or replace 1-C 6Alkyl, wherein the C of replacement 1-C 6Substituting group on the alkyl is selected from aryl, heterocyclic radical, C unsubstituted or that replace 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2N-C (O)-, CN, (R 10) 2N-C (NR 10)-, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, and R 11OC (O) NR 10-;
R 2And R 3Be independently selected from: H, the C that does not replace or replace 1-C 8Alkyl, the C that does not replace or replace 2-C 8Alkenyl, the C that does not replace or replace 2-C 8Alkynyl, the aryl that does not replace or replace, the heterocycle that does not replace or replace,
Figure A9619420600592
Or
Figure A9619420600593
Wherein, substituting group is to be replaced by one or more groups in the following groups:
1) aryl or the heterocycle that does not replace or replaced by following groups:
A) C 1-C 4Alkyl,
b)(CH 2) pOR 6，
c)(CH 2) pNR 6R 7，
D) halogen,
e)CN，
2) C 3-C 6Cycloalkyl,
3)OR 6，
4)SR 6a，S(O)R 6a，SO 2R 6a，
5)-NR 6R 7
Figure A9619420600601
Figure A9619420600611
15) N 3, or
16) F; Or
R 2And R 3Be connected in and lump together formation-(CH on the same carbon atom 2) u-, one of them carbon atom randomly by be selected from O, S (O) m ,-NC (O)-and-N (COR 10)-group replace;
R 4Be selected from H and CH 3And R 2, R 3And R 4In any 2 randomly be connected on the same carbon atom;
R 6, R 7And R 7aBe independently selected from: H, C 1-C 4Alkyl, C 3-C 6Cycloalkyl, heterocycle, aryl, aroyl, 4-hetaroylpyrazol, arylsulfonyl, heteroaryl sulphonyl, these groups can be unsubstituted or be replaced by following groups:
A) C 1-C 4Alkoxyl group,
B) aryl or heterocycle,
C) halogen,
d)HO、
Figure A9619420600612
F)-SO 2R 11, or
G) N (R 10) 2Or
R 6And R 7Can be connected in the ring;
R 7And R 7aCan be connected in the ring;
R 6aBe selected from: C 1-C 4Alkyl, C 3-C 6Cycloalkyl, heterocycle, aryl, these groups can be unsubstituted or replace with following groups:
A) C 1-C 4Alkoxyl group,
B) aryl or heterocycle,
C) halogen,
d)HO，
F)-SO 2R 11, or
g)N(R 10) 2；
R 8Be independently selected from:
A) hydrogen,
B) aryl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) HR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, NO 2, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-and
C) C unsubstituted or that replaced by following groups 1-C 6Alkyl: aryl, cyano-phenyl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NH-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 10OC (O) NH-;
R 9Be selected from:
A) hydrogen,
B) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, NO 2, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-and
C) C unsubstituted or that replaced by following groups 1-C 6Alkyl: perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-;
R 10Be independently selected from hydrogen, C 1-C 6Alkyl, benzyl and aryl;
R 11Be independently selected from C 1-C 6Alkyl and aryl;
A 1And A 2Be independently selected from: key ,-CH=CH-,-C ≡ C-,-C (O)-,-C (O) NR 10-,-NR 10C (O)-, O ,-N (R 10)-,-S (O) 2N (R 10)-,-N (R 10) S (O) 2-or S (O) m;
G is H 2Or O;
V is selected from:
A) hydrogen,
B) heterocycle,
C) aryl,
D) C 1-C 20Alkyl, wherein have 0-4 carbon atom be selected from O, S and N heteroatoms displacement and
E) C 2-C 20Alkenyl.
Its condition is: if A 1Be S (O) m, then V is not a hydrogen; If A 1Be a key, n is 0, and A 2Be S (O) m, then V is not a hydrogen;
W is a heterocycle;
X is-C (=O)-or-S (=O) m-;
Z is an aryl unsubstituted or that replace, heteroaryl, arylmethyl, heteroaryl methyl, arylsulfonyl, heteroaryl sulphonyl, and wherein the group of Qu Daiing is replaced by one or more following groups:
1) C unsubstituted or that replaced by following groups 1-C 4Alkyl:
A) C 1-C 4Alkoxyl group,
b)NR 6R 7，
C) C 3-C 6Cycloalkyl,
D) aryl or heterocycle,
e)HO，
F)-S (O) mR 6a, or
g)-C(O)NR 6R 7，
2) aryl or heterocycle,
3) halogen,
4)OR 6，
5)NR 6R 7
6)CN，
7)NO 2，
8)CF 3，
9)-S(O)mR 6a，
10)-C (O) NR 6R 7, or
11) C 3-C 6Cycloalkyl;
M is 0,1 or 2;
N is 0,1,2,3 or 4;
P is 0,1,2,3 or 4;
Q is 1 or 2;
R is 0-5, and its condition is that r is 0 when V is hydrogen;
S is 0 or 1;
T is 0 or 1; With
U is 4 or 5;
Its condition is if t is 1, then substituting group (R 8) r-V-A 1(CR 1a 2) nA 2(CR 1a 2) n-is H.
32. a treatment method for cancer, this method comprise the composition to the claim 22 of the administration treatment significant quantity of this treatment of needs.
33. a treatment method for cancer, this method comprise the composition to the claim 23 of the administration treatment significant quantity of this treatment of needs.
34. a treatment method for cancer, this method comprise the composition to the claim 24 of the administration treatment significant quantity of this treatment of needs.
35. a treatment method for cancer, this method comprise the composition to the claim 25 of the administration treatment significant quantity of this treatment of needs.
36. a method for the treatment of the optimum proliferative imbalance of nerve fiber protein, this method comprise the composition to the claim 23 of the administration treatment significant quantity of this treatment of needs.
37. the method for the blindness that a treatment is relevant with retinal vesselization, this method comprise the composition to the claim 23 of the administration treatment significant quantity of this treatment of needs.
38. a method for the treatment of hepatitis-δ and relevant virus infection, this method comprise the composition to the claim 23 of the administration treatment significant quantity of this treatment of needs.
39. a method for the treatment of prevention of restenosis, this method comprise the composition to the claim 23 of the administration treatment significant quantity of this treatment of needs.
40. a method for the treatment of polycystic disease, this method comprise the composition to the claim 23 of the administration treatment significant quantity of this treatment of needs.
41. treatment or prevention are selected from the method for the optimum proliferative imbalance of cancer, nerve fiber protein, some blindness, hepatitis-δ and relevant virus infection, restenosis and the polycystic disease relevant with retinal vesselization, this method comprises containing pharmaceutical carrier and being dispersed in the formula B compound of treatment significant quantity wherein or the pharmaceutical composition of its pharmaceutically acceptable salt the administration treatment significant quantity of this treatment of needs and prevention:
In the formula:
R 1aAnd R 1bBe independently selected from:
A) hydrogen,
B) aryl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, CN (R 10) 2N-C (O)-, (R 10) 2N-C (NR 10)-, CN, NO 2, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-,
C) C that does not replace or replace 1-C 6Alkyl, wherein the C of replacement 1-C 6Substituting group on the alkyl is selected from aryl, heterocyclic radical, C unsubstituted or that replace 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2N-C (O)-, CN, (R 10) 2N-C (NR 10)-, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, and R 11OC (O) NR 10-;
R 2And R 3Be independently selected from: H, the C that does not replace or replace 1-C 8Alkyl, the C that does not replace or replace 2-C 8Alkenyl, the C that does not replace or replace 2-C 8Alkynyl, the aryl that does not replace or replace, the heterocycle that does not replace or replace,
Figure A9619420600652
Or
Figure A9619420600653
Wherein, substituting group is to be replaced by one or more groups in the following groups:
1) aryl or the heterocycle that does not replace or replaced by following groups:
A) C 1-C 4Alkyl,
b)(CH 2) pOR 6，
c)(CH 2) pNR 6R 7，
D) halogen,
e)CN，
2) C 3-C 6Cycloalkyl,
3)OR 6，
4)SR 6a，S(O)R 6a，SO 2R 6a，
5)-NR 6R 7
15) N 3, or
16) F; Or
R 2And R 3Be connected in and lump together formation-(CH on the same carbon atom 2) u-, one of them carbon atom is randomly by being selected from O, S (O) m,-NC (O)-and-N (COR 10)-group replace;
R 4Be selected from H and CH 3And R 2, R 3And R 4In any 2 randomly be connected on the same carbon atom;
R 6, R 7And R 7aBe independently selected from: H, C 1-C 4Alkyl, C 3-C 6Cycloalkyl, heterocycle, aryl, aroyl, 4-hetaroylpyrazol, arylsulfonyl, heteroaryl sulphonyl, these groups can be unsubstituted or be replaced by following groups:
A) C 1-C 4Alkoxyl group,
B) aryl or heterocycle,
C) halogen,
d)HO，
F)-SO 2R 11, or
G) N (R 10) 2Or
R 6And R 7Can be connected in the ring;
R 7And R 7aCan be connected in the ring;
R 6aBe selected from: C 1-C 4Alkyl, C 3-C 6Cycloalkyl, heterocycle, aryl, these groups can be unsubstituted or replace with following groups:
A) C 1-C 4Alkoxyl group,
B) aryl or heterocycle,
C) halogen,
d)HO，
Figure A9619420600672
F)-SO 2R 11, or
g)N(R 10) 2；
R 8Be independently selected from:
A) hydrogen,
B) aryl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, NO 2, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-and
C) C unsubstituted or that replaced by following groups 1-C 6Alkyl: aryl, cyano-phenyl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NH-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 10OC (O) NH-;
R 9Be selected from:
A) hydrogen,
B) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, NO 2, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-and
C) C unsubstituted or that replaced by following groups 1-C 6Alkyl: perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-;
R 10Be independently selected from hydrogen, C 1-C 6Alkyl, benzyl and aryl;
R 11Be independently selected from C 1-C 6Alkyl and aryl;
A 1And A 2Be independently selected from: key ,-CH=CH-,-C ≡ C-,-C (O)-,-C (O) NR 10-,-NR 10C (O)-, O ,-N (R 10)-,-S (O) 2N (R 10)-,-N (R 10) S (O) 2-or S (O) m;
G is H 2
V is selected from:
A) hydrogen,
B) heterocycle,
C) aryl,
D) C 1-C 20Alkyl, wherein have 0-4 carbon atom be selected from O, S and N heteroatoms displacement and
E) C 2-C 20Alkenyl.
Its condition is: if A 1Be S (O) m, then V is not a hydrogen; If A 1Be a key, n is 0, and A 2Be S (O) m, then V is not a hydrogen;
W is an imidazolyl;
X is-CH 2-,-C (=O)-or-S (=O) m-;
Z is an aryl unsubstituted or that replace, heteroaryl, arylmethyl, heteroaryl methyl, arylsulfonyl, heteroaryl sulphonyl, and wherein the group of Qu Daiing is replaced by one or more following groups:
1) C unsubstituted or that replaced by following groups 1-C 4Alkyl:
A) C 1-C 4Alkoxyl group,
b)NR 6R 7，
C) C 3-C 6Cycloalkyl,
D) aryl or heterocycle,
e)HO，
F)-S (O) mR 6a, or
g)-C(O)NR 6R 7，
2) aryl or heterocycle,
3) halogen,
4)OR 6，
5)NR 6R 7
6)CN，
7)NO 2，
8)CF 3，
9)-S(O)mR 6a，
10)-C (O) NR 6R 7, or
11) C 3-C 6Cycloalkyl;
M is 0,1 or 2;
N is 0,1,2,3 or 4;
P is 0,1,2,3 or 4;
Q is 1 or 2;
R is 0-5, and its condition is that r is 0 when V is hydrogen;
S is 0 or 1;
T is 1; With
U is 4 or 5;
Its condition is substituting group (R 8) r-V-A 1(CR 1a 2) nA 2(CR 1a 2) n-is H.
42. treatment or prevention are selected from the method for the optimum proliferative imbalance of cancer, nerve fiber protein, some blindness, hepatitis-δ and relevant virus infection, restenosis and the polycystic disease relevant with retinal vesselization, this method comprises containing pharmaceutical carrier and being dispersed in the formula B compound of treatment significant quantity wherein or the pharmaceutical composition of its pharmaceutically acceptable salt the administration treatment significant quantity of this treatment of needs and prevention:
In the formula:
R 1aAnd R 1bBe independently selected from:
A) hydrogen,
B) aryl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, CN (R 10) 2N-C (O)-, (R 10) 2N-C (NR 10)-, CN, NO 2, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-,
C) C that does not replace or replace 1-C 6Alkyl, wherein the C of replacement 1-C 6Substituting group on the alkyl is selected from aryl, heterocyclic radical, C unsubstituted or that replace 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2N-C (O)-, CN, (R 10) 2N-C (NR 10)-, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, and R 11OC (O) NR 10-;
R 2And R 3Be independently selected from: H, the C that does not replace or replace 1-C 8Alkyl, the C that does not replace or replace 2-C 8Alkenyl, the C that does not replace or replace 2-C 8Alkynyl, the aryl that does not replace or replace, the heterocycle that does not replace or replace,
Figure A9619420600702
Or
Figure A9619420600703
Wherein, substituting group is to be replaced by one or more groups in the following groups:
1) aryl or the heterocycle that does not replace or replaced by following groups:
A) C 1-C 4Alkyl,
b)(CH 2) pOR b，
c)(CH 2) pNR 6R 7，
D) halogen,
e)CN，
2) C 3-C 6Cycloalkyl, 3) OR 6, 4) and SR 6a, S (O) R 6a, SO 2R 6a,
Figure A9619420600711
15) N 3, or 16) F; Or
R 2And R 3Be connected in and lump together formation-(CH on the same carbon atom 2) u-, one of them carbon atom is randomly by being selected from O, S (O) m,-NC (O)-and-N (COR 10)-group replace;
R 4Be selected from H and CH 3And R 2, R 3And R 4In any 2 randomly be connected on the same carbon atom;
R 6, R 7And R 7aBe independently selected from: H, C 1-C 4Alkyl, C 3-C 6Cycloalkyl, heterocycle, aryl, aroyl, 4-hetaroylpyrazol, arylsulfonyl, heteroaryl sulphonyl, these groups can be unsubstituted or be replaced by following groups:
A) C 1-C 4Alkoxyl group,
B) aryl or heterocycle,
C) halogen,
d)HO，
Figure A9619420600721
F)-SO 2R 11, or
G) N (R 10) 2Or
R 6And R 7Can be connected in the ring;
R 7And R 7aCan be connected in the ring;
R 6aBe selected from: C 1-C 4Alkyl, C 3-C 6Cycloalkyl, heterocycle, aryl, these groups can be unsubstituted or replace with following groups:
A) C 1-C 4Alkoxyl group,
B) aryl or heterocycle,
C) halogen,
d)HO，
Figure A9619420600722
F)-SO 2R 11, or
g)N(R 10) 2；
R 8Be independently selected from:
A) hydrogen,
B) aryl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, NO 2, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-and
C) C unsubstituted or that replaced by following groups 1-C 6Alkyl: aryl, cyano-phenyl, heterocycle, C 3-C 10Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NH-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 10OC (O) NH-;
R 9Be selected from:
A) hydrogen,
B) alkenyl, alkynyl, perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, NO 2, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-and
C) C unsubstituted or that replaced by following groups 1-C 6Alkyl: perfluoroalkyl, F, Cl, Br, R 10O-, R 11S (O) m-, R 10C (O) NR 10-, (R 10) 2NC (O)-, R 10 2N-C (NR 10)-, CN, R 10C (O)-, R 10OC (O)-, N 3,-N (R 10) 2, or R 11OC (O) NR 10-;
R 10Be independently selected from hydrogen, C 1-C 6Alkyl, benzyl and aryl;
R 11Be independently selected from C 1-C 6Alkyl and aryl;
A 1And A 2Be independently selected from: key ,-CH=CH-,-C ≡ C-,-C (O)-,-C (O) NR 10-,-NR 10C (O)-, O ,-N (R 10)-,-S (O) 2N (R 10)-,-N (R 10) S (O) 2-or S (O) m;
G is H 2Or O;
V is selected from:
A) hydrogen,
B) heterocycle,
C) aryl,
D) C 1-C 20Alkyl, wherein have 0-4 carbon atom be selected from O, S and N heteroatoms displacement and
E) C 2-C 20Alkenyl.
Its condition is: if A 1Be S (O) m, then V is not a hydrogen; If A 1Be a key, n is 0, and A 2Be S (O) m, then V is not a hydrogen;
W is a heterocycle;
X is-C (=O)-or-S (=O) m-;
Z is an aryl unsubstituted or that replace, heteroaryl, arylmethyl, heteroaryl methyl, arylsulfonyl, heteroaryl sulphonyl, and wherein the group of Qu Daiing is replaced by one or more following groups:
1) C unsubstituted or that replaced by following groups 1-C 4Alkyl:
A) C 1-C 4Alkoxyl group,
b)NR 6R 7，
C) C 3-C 6Cycloalkyl,
D) aryl or heterocycle,
e)HO，
F)-S (O) mR 6a, or
g)-C(O)NR 6R 7，
2) aryl or heterocycle,
3) halogen,
4)OR 6，
5)NR 6R 7
6)CN，
7)NO 2，
8)CF 3，
9)-S(O)mR 6a，
10)-C (O) NR 6R 7, or
11) C 3-C 6Cycloalkyl;
M is 0,1 or 2;
N is 0,1,2,3 or 4;
P is 0,1,2,3 or 4;
Q is 1 or 2;
R is 0-5, and its condition is that r is 0 when V is hydrogen;
S is 0 or 1;
T is 0 or 1; With
U is 4 or 5;
Its condition is if t is 1, then substituting group (R 8) r-V-A 1(CR 1a 2) nA 2(CR 1a 2) n-is H.
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