CN101501005A - Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, processes for preparing them, medicaments comprising these compounds, and their use - Google Patents
Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, processes for preparing them, medicaments comprising these compounds, and their use Download PDFInfo
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- CN101501005A CN101501005A CNA2007800294643A CN200780029464A CN101501005A CN 101501005 A CN101501005 A CN 101501005A CN A2007800294643 A CNA2007800294643 A CN A2007800294643A CN 200780029464 A CN200780029464 A CN 200780029464A CN 101501005 A CN101501005 A CN 101501005A
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Abstract
Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, processes for preparing them, medicaments comprising these compounds, and their use. The invention relates to compounds of the formula I in which the radicals R and R', A, D, E, G, L, p and R1 to R1O have the stated definitions, and also to their physiologically tolerated salts. The compounds are suitable, for example, as anti-obesity drugs and for treating cardiometabolic syndrome.
Description
The present invention relates to the imidazolidine-2,4-two ketones and the compatible salt of its physiology that are replaced by the arylamino arylalkyl.
To the tetrahydroglyoxaline-2 of similar, 4-two ketones are described (seeing US 5,411,981).
The purpose of this invention is to provide the compound that some show available therapeutic action.Purpose of the present invention particularly finds to be applicable to treatment metabolism syndrome, type ii diabetes and fat new compound.
Therefore, the compound that the present invention relates to formula I with and the compatible salt of physiology
Wherein
R, R ' are H, (C independently of one another
1-C
6)-alkyl, wherein (C
1-C
6)-alkyl can be by halogen, O-R14, S (O)
m-R12 or NR13R15 replace;
Perhaps R and R ' form the ring with 3 to 8 carbon atoms together, and one of them carbon atom can be by O, S (O)
m, NR13 or NR15 substitute;
M is 0,1,2;
N is 0,1,2,3,4;
P is 1,2,3,4,5;
Q is 1,2,3,4;
R is 2,3,4,5,6;
V is 0,1,2,3,4;
A, D, E, G, L are C or N independently of one another, wherein when it is defined as N, do not have corresponding R1, R2, R3, R4, R5 substituting group;
R1, R2, R3, R4, R5 are H, F, Cl, Br, I, CN, N independently of one another
3, NC, NO
2, CF
3, (C
1-C
8)-alkyl, (C
3-C
8)-cycloalkyl, (CH
2)
n-[(C
3-C
8)-cycloalkenyl group], (CH
2)
q-[(C
3-C
8)-cycloalkyl], (CH
2)
n-[(C
7-C
12)-bicyclic alkyl], (CH
2)
n-[(C
7-C
12)-bicycloenyl], (CH
2)
n-[(C
7-C
12)-tricyclic alkyl], diamantane-1-base, diamantane-2-base, (CH
2)
n-aryl, (CH
2)
n-heteroaryl, OCF
3, O-R11, NR13R15, NH-CN, S (O)
m-R12, SO
2-NH
2, SO
2-N=CH-N (CH
3)
2, SO
2-NH-CO-R12, SO
2-NH-CO-NHR12, SO
2-NH-CO-R16, SO
2-NH-[(C
1-C
8)-alkyl], SO
2-NH-[(C
3-C
8)-cycloalkyl], SO
2-NH-(CH
2)
r-OH, SO
2-NH-(CH
2)
n-aryl, SO
2-NH-(CH
2)
n-heteroaryl, SO
2-N[(C
1-C
8)-alkyl]
2, SO
2-R16, SF
5, CO-O[(C
1-C
8)-alkyl], CO-O[(C
3-C
8)-cycloalkyl], CO-O-(CH
2)
r-NH
2, CO-O-(CH
2)
n-aryl, CO-O-(CH
2)
n-heteroaryl, CO-NH
2, CO-NH-CN, CO-NH-[(C
1-C
8)-alkyl], CO-NH-(CH
2)
r-OH, CO-N[(C
1-C
8)-alkyl]
2, CO-NH-[(C
3-C
8)-cycloalkyl], CO-N[(C
3-C
8)-cycloalkyl]
2, C (=NH)-O-[(C
1-C
6-alkyl)], C (=NH)-NH
2, C (=NH)-NHOH, C (=NH)-[NHO-(C
1-C
6)-alkyl], C (=NH)-NR12R13, C (=NH)-R16, C (=NR13)-NR12R13, CO-NH-SO
2-R16, CO-NH-SO
2-NHR12, CO-R16, COOH, CO-(C
1-C
8)-alkyl, CO-(C
3-C
8)-cycloalkyl, CO-(CH
2)
n-[(C
7-C
12)-bicyclic alkyl], CO-(CH
2)
n-[(C
7-C
12)-tricyclic alkyl], CO-aryl, CO-heteroaryl, CH (OH)-aryl, CH (OH)-heteroaryl, CH[O-(C
1-C
6)-alkyl]-aryl, CH[O-(C
1-C
6)-alkyl]-heteroaryl, CHF-aryl, CHF-heteroaryl, CF
2-aryl, CF
2-heteroaryl, CHO, CH
2-OH, CH
2-CN, CH
2-O-R12, CH
2-O-(CH
2)
n-CO-O[(C
1-C
8)-alkyl], CH
2-O-(CH
2)
n-CO-NH
2, CH
2-O-(CH
2)
q-COOH, alkyl wherein, cycloalkyl, cycloalkenyl group, bicyclic alkyl, bicycloenyl and tricyclic alkyl can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C
1-C
6)-alkyl, (C
3-C
6)-cycloalkyl, O-(C
1-C
6)-alkyl, S (O)
m-(C
1-C
6)-alkyl, SO
2-NH
2, COOH, CONH
2, CO-O (C
1-C
6)-alkyl, CO-(C
1-C
6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
R6, R7, R8, R9, R10 are R11, NR17-bicyclic heterocycles, NR17-aryl, NR17-heteroaryl independently of one another, aryl wherein or heteroaryl can be carbocyclic fused with 5-or 6-person's aromatics or non-aromatics, one or more CH or CH in described aromatics or the non-aromatic carbocyclic
2Group can be substituted by Sauerstoffatom and wherein this 5-or 6-person's aromatics or non-aromatic carbocyclic can by F ,=O or-(C
1-C
6)-alkyl replaces, and wherein this bicyclic heterocycles can comprise 9 to 12 ring memberses and 5 CH or CH at the most
2Group can be independently of one another by N, NR20, O, S (O)
mOr C=O substitutes, and wherein this aryl or heteroaryl or bicyclic heterocycles can not be substituted or by following group list-or polysubstituted:
R11、F、Cl、Br、I、CN、N
3、NC、NO
2、CF
3、(CH
2)
n-O-R11、
(CH
2)
n-O-(CH
2)
r-OH、(CH
2)
n-O-CH(CH
2OH)
2、
(CH
2)
n-O-(CH
2)
n-CO-O-(CH
2)
r-NH
2、
(CH
2)
n-O-(CH
2)
n-CO-NH-(CH
2)
r-OH、(CH
2)
n-O-sugar, (CH2)
n-O-saccharic acid, (CH2)
n-O-glucoside, (CH2)
n-O-galactoside, (CH2)
n-O-glucuronide, O-R13, OCF3、(CH
2)
n-O-(CH
2)
r-NH
2、(CH
2)
n-NH-R11、
(CH
2)
n-N[(CH
2)
q-CO-O(C
1-C
6)-alkyl]2、(CH
2)
n-N[(CH
2)
q-COOH]
2、
(CH
2)
n-N[(CH
2)
q-CONH
2]
2、(CH
2)
n-NH-R13、(CH
2)
n-N(R13)
2、
(CH
2)
n-NH-CN、(CH
2)
n-NH-SO
2-R16、(CH
2)
n-NH-(CH
2)
n-SO
2-R12、
(CH
2)
n-NR12-CO-R16、(CH
2)
n-NR12-CO-NR12R13、
(CH
2)
n-NR12-CO-N(R12)
2、(CH
2)
n-NR12-CO-NHR11、
(CH
2)
n-NH-C(＝NH)-NH
2、(CH
2)
n-NH-C(＝NH)-R16、
(CH
2)
n-NH-C(＝NH)-NHR12、(CH
2)
n-NR12-C(＝NR13)-NHR12、
(CH
2)
n-NR12-C(＝NR12)-NR12R13、
(CH
2)
n-NH-(CH
2)
n-CO-O-(CH
2)
r-NH
2、
(CH
2)
n-NH-(CH
2)
n-CO-NH-[(C
1-C
8)-alkyl], (CH2)
n-NH-(CH
2)
n-CO-NH-(CH
2)
r-OH、
(CH
2)
n-NH-(CH
2)
n-CO-N[(C
1-C
8)-alkyl]2、
(CH
2)
n-NH-(CH
2)
n-CO-NH-[(C
3-C
8)-cycloalkyl], (CH2)
n-NH-(CH
2)
n-CO-N[(C
3-C
8)-cycloalkyl]2、
(CH
2)
n-NH-C(CH
3)
2-CO-O(C
1-C
8)-alkyl, (CH2)
n-NH-C(CH
3)
2-CO-O(C
3-C
8)-cycloalkyl, (CH2)
n-NH-C(CH
3)
2-CO-O-(CH
2)
r-NH
2、
(CH
2)
n-NH-C(CH
3)
2-Co-o-(CH
2)
n-aryl, (CH2)
n-NH-C(CH
3)
2-CO-O-(CH
2)
n-heteroaryl, (CH2)
n-NH-C(CH
3)
2-CO-NH
2、
(CH
2)
n-NH-C(CH
3)
2-Co-NH-[(C
1-C
8)-alkyl], (CH2)
n-NH-C(CH
3)
2-CO-NH-(CH
2)
r-OH、
(CH
2)
n-NH-C(CH
3)
2-CO-N[(C
1-C
8)-alkyl]2、
(CH
2)
n-NH-(CH
3)
2-CO-NH-[(C
3-C
8)-cycloalkyl], (CH2)
n-NH-C(CH
3)
2-CO-N[(C
3-C
8)-cycloalkyl]2、
(CH
2)
n-NH-C(CH
3)
2-COOH、S(O)
m-R12、SO
2-R16、
SO
2-N＝CH-N(CH
3)
2、
SO
2-NH-CO-R12、SO
2-NHR12、
SO
2-NH-(CH
2)
r-OH、SO
2-N[(C
1-C
8)-alkyl]2、SO
2-NH-(CH
2)
r-NH
2、
SF
5、COOH、CO-NH
2、(CH
2)
q-CN、(CH
2)
n-CO-NH-CN、
(CH
2)
n-CO-NH-piperidin-1-yl, (CH2)
n-CO-NH-SO
2-NHR12、
(CH
2)
n-CO-NH-SO
2-R18、(CH
2)
n-CHO、(CH
2)
n-C(＝NH)-NH
2、
(CH
2)
n-C(＝NH)-NHOH、(CH
2)
n-C(＝NH)-[NH-O-(C
1-C
6)-alkyl], (CH2)
n-C(＝NH)(R16)、(CH
2)
n-C(＝NR13)NHR12、
(CH
2)
n-C(＝NR12)NR12R13、(CH
2)
n-C(＝NH)O[(C
1-C
6)-alkyl], alkyl wherein and cycloalkyl can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C1-C
6)-alkyl, (C3-C
6)-cycloalkyl, O-(C1-C
6)-alkyl, S (O)m-(C
1-C
6)-alkyl, SO2-NH
2、COOH、CONH
2、CO-O(C
1-C
6)-alkyl, CO-(C1-C
6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
F、Cl、Br、I、CN、N
3、NC、NO
2、CF
3、(CH
2)
n-O-R11、(CH
2)
n-O-(CH
2)
r-OH、
(CH
2)
n-O-CH(CH
2OH)
2、(CH
2)
n-O-(CH
2)
n-CO-O-(CH
2)
r-NH
2、
(CH
2)
n-O-(CH
2)
n-CO-NH-(CH
2)
r-OH、(CH
2)
n-O-sugar, (CH2)
n-O-saccharic acid, (CH2)
n-O-glucoside, (CH2)
n-O-galactoside, (CH2)
n-O-glucuronide, O-R13, OCF3、(CH
2)
n-NH-R11、(CH
2)
n-NH-R13、(CH
2)
n-NH-CN、
(CH
2)
n-NH-SO
2-R16、(CH
2)
n-NH-(CH
2)
n-SO
2-R12、(CH
2)
n-NR12-CO-R16、
(CH
2)
n-NR12-CO-NR12R13、(CH
2)
n-NR12-CO-N(R12)
2、
(CH
2)
n-NR12-CO-NHR11、(CH
2)
n-NH-C(＝NH)-NH
2、
(CH
2)
n-NH-C(＝NH)-R16、(CH
2)
n-NH-C(＝NH)-NHR12、
(CH
2)
n-NR12-C(＝NR13)-NHR12、(CH
2)
n-NR12-C(＝NR12)-NR12R13、
(CH
2)
n-NH-(CH
2)
n-CO-O-(CH
2)
r-NH
2、
(CH
2)
n-NH-(CH
2)
n-CO-NH-[(C
1-C
8)-alkyl], (CH2)
n-NH-(CH
2)
n-CO-NH-(CH
2)
r-OH、(CH
2)
n-NH-(CH
2)
n-CO-N[(C
1-C
8)-alkyl]2、(CH
2)
n-NH-(CH
2)
n-CO-NH-[(C
3-C
8)-cycloalkyl], (CH2)
n-NH-(CH
2)
n-CO-N[(C
3-C
8)-cycloalkyl]2、
(CH
2)
n-NH-C(CH
3)
2-CO-O(C
1-C
8)-alkyl, (CH2)
n-NH-C(CH
3)
2-CO-O(C
3-C
8)-cycloalkyl, (CH2)
n-NH-C(CH
3)
2-CO-O-(CH
2)
r-NH
2、
(CH
2)
n-NH-C(CH
3)
2-CO-O-(CH
2)
n-aryl, (CH2)
n-NH-C(CH
3)
2-CO-O-(CH
2)
n-heteroaryl, (CH2)
n-NH-C(CH
3)
2-CO-NH
2、
(CH
2)
n-NH-C(CH
3)
2-CO-NH-[(C
1-C
8)-alkyl], (CH2)
n-NH-C(CH
3)
2-CO-NH-(CH
2)
r-OH、
(CH
2)
n-NH-C(CH
3)
2-CO-N[(C
1-C
8)-alkyl]2、
(CH
2)
n-NH-(CH
3)
2-CO-NH-[(C
3-C
8)-cycloalkyl], (CH2)
n-NH-C(CH
3)
2-CO-N[(C
3-C
8)-cycloalkyl]2、(CH
2)
n-NH-C(CH
3)
2-COOH、
S(O)
m-R12、SO
2-R16、SO
2-N＝CH-N(CH
3)
2、
SO
2-NH-CO-R12、
SO
2-NHR12、SO
2-NH-(CH
2)
r-OH、SO
2-N[(C
1-C
8)-alkyl]2、
SO
2-NH-(CH
2)
r-NH
2、SF
5、COOH、CONH
2、(CH
2)
q-CN、
(CH
2)
n-CO-NH-CN、(CH
2)
n-CO-NH-piperidin-1-yl, (CH2)
n-CO-NH-SO
2-NHR12、(CH
2)
n-CO-NH-SO
2-R18、(CH
2)
n-CHO、
(CH
2)
n-C(＝NH)NH
2、(CH
2)
n-C(＝NH)NHOH、(CH
2)
n-C(＝NH)(R16)、
(CH
2)
n-C(＝NR13)NHR12、(CH
2)
n-C(＝NR12)NR12R13、
(CH
2)
n-C(＝NH)O[(C
1-C
6)-alkyl], alkyl wherein and cycloalkyl can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C1-C
6)-alkyl, (C3-C
6)-cycloalkyl, O-(C1-C
6)-alkyl, S (O)m-(C
1-C
6)-alkyl, SO2-NH
2、COOH、CONH
2、
CO-[O(C
1-C
6)-alkyl], CO-(C1-C
6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
Wherein at least one among radicals R 6, R7, R8, R9 and the R10 always is defined as NR17-aryl or NR17-bicyclic heterocycles or NR17-heteroaryl;
Wherein four groups are to a pair of can the formation together in various situations-CH among R6 and R7 or R7 and R8 or R8 and R9 or R9 and the R10
2-CH
2-CH
2-or-CH
2-CH
2-CH
2-CH
2-group, wherein two-CH at the most
2-group can be substituted by-O-and wherein should-CH
2-CH
2-CH
2-or-CH
2-CH
2-CH
2-CH
2-group can be by F, (C
1-C
8)-alkyl or=O replaces;
R11 is H, (C1-C
8)-alkyl, (C2-C
10)-alkenyl, (C2-C
10)-alkynyl, (C3-C
8)-cycloalkyl, (CH2)
q-[(C
3-C
8)-cycloalkyl], (CH2)
n-[(C
7-C
12)-bicyclic alkyl], (CH2)
n-[(C
3-C
10)-cycloalkenyl group], (CH2)
n-[(C
3-C
10)-two cycloalkenyl group], (CH2)
n-[(C
7-C
12)-tricyclic alkyl], (CH2)
n-aryl, (CH2)
n-CO-[O-(C
1-C
8)-alkyl], (CH2)
n-CO-[O-(C
3-C
8)-cycloalkyl], (CH2)
n-CO-[(C
1-C
8)-alkyl], (CH2)
n-CO-[(C
3-C
8)-cycloalkyl], (CH2)
n-CO-aryl, (CH2)
n-CO-heteroaryl, (CH2)
n-CO-[O-(CH
2)
v-aryl], (CH2)
n-CO-[O-(CH
2)
v-heteroaryl], (CH2)
q-CO-NH
2、(CH
2)
q-COOH、(CH
2)
q-CO-NH-CN、
(CH
2)
n-P(O)(OH)[O-(C
1-C
6)-alkyl], (CH2)
n-P(O)[O-(C
1-C
6)-alkyl]2、
(CH
2)
n-P(O)(OH)(O-CH
2-aryl), (CH2)
n-P(O)(O-CH
2-aryl)2、
(CH
2)
n-P(O)(OH)
2、(CH
2)
n-SO
3H、(CH
2)
n-SO
2-NH
2、
(CH
2)
n-CO-NH-[(C
1-C
8)-alkyl], (CH2)
n-CO-N[(C
1-C
8)-alkyl]2、
(CH
2)
n-CO-NH-[(C
3-C
8)-cycloalkyl], (CH2)
n-CO-N[(C
3-C
8)-cycloalkyl]2、(C
2-C
10)-alkenyl-CO-O[(C1-C
6)-alkyl], (C2-C
10)-alkenyl-CONH2、(C
2-C
10)-alkenyl-COOH, (C2-C
10)-alkynyl-CO-O[(C1-C
6)-alkyl], (C2-C
10)-alkynyl-CONH2、
(C
2-C
10)-alkynyl-COOH, (CH2)
n-CR21[(CO-O(C
1-C
6)-alkyl)]2、
(CH
2)
n-CR21(CONH
2)
2、(CH
2)
n-CR21(COOH)
2、
(CH
2)
n-CR21R22CO-O[(C
1-C
6)-alkyl], (CH2)
n-CR21R22CONH
2、
(CH
2)
n-CR21R22COOH、(CH
2)
n-CO-R16、(CH
2)
n-C(CH
3)
2-CO-O[(C
1-C
8)-alkyl], (CH2)
n-C(CH
3)
2-CO-O[(C
3-C
8)-cycloalkyl], (CH2)
n-C(CH
3)
2-CO-O-(CH
2)
r-NH
2、(CH
2)
n-C(CH
3)
2-CO-O-(CH
2)
n-aryl, (CH2)
n-C(CH
3)
2-CO-O-(CH
2)
n-heteroaryl, (CH2)
n-C(CH
3)
2-CO-NH
2、
(CH
2)
n-C(CH
3)
2-CO-NH-[(C
1-C
8)-alkyl], (CH2)
n-C(CH
3)
2-CO-NH-(CH
2)
r-OH、(CH
2)
n-C(CH
3)
2-CO-N[(C
1-C
8)-alkyl]2、(CH
2)
n-C(CH
3)
2-CO-NH-[(C
3-C
8)-cycloalkyl], (CH2)
n-C(CH
3)
2-CO-N[(C
3-C
8)-cycloalkyl]2、(CH
2)
n-C(CH
3)
2-COOH、
(CH
2)
n-CO-NH-C(CH
3)
2-CO-O[(C
1-C
8)-alkyl], (CH2)
n-CO-NH-C(CH
3)
2-CONH
2、(CH
2)
n-CO-NH-C(CH
3)
2-COOH, alkyl wherein, alkenyl, alkynyl and cycloalkyl, bicyclic alkyl, cycloalkenyl group and two cycloalkenyl groups can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C1-C
6)-alkyl, (C3-C
6)-cycloalkyl, O-(C1-C
6)-alkyl, S (O)m-(C
1-C
6)-alkyl, SO2-NH
2、COOH、CONH
2、
CO-O(C
1-C
6)-alkyl, CO-(C1-C
6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
R12 is H, (C
1-C
8)-alkyl, (C
3-C
8)-cycloalkyl, (CH
2)
q-[(C
3-C
8)-cycloalkyl], (CH
2)
n-[(C
7-C
12)-bicyclic alkyl], (CH
2)
n-[(C
7-C
12)-tricyclic alkyl], (CH
2)
n-aryl, (CH
2)
n-heteroaryl, alkyl or cycloalkyl wherein can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C
1-C
6)-alkyl, O-(C
1-C
6)-alkyl, SO
2-NH
2, COOH, CONH
2, CO-O (C
1-C
6)-alkyl, CO-(C
1-C
6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
R13 is H, SO
2-[(C
1-C
8)-alkyl], SO
2-[(C
3-C
8)-cycloalkyl], SO
2-(CH
2)
n-aryl, SO
2-(CH
2)
n-heteroaryl, SO
2-(CH
2)
n-NH-R12, SO
2-(CH
2)
n-N (R12)
2, alkyl wherein and cycloalkyl can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, CF
3, (C
1-C
6)-alkyl, (C
3-C
6)-cycloalkyl, O-[(C
1-C
6)-alkyl], S (O)
m-[(C
1-C
6)-alkyl], SO
2-NH
2, COOH, CONH
2, CO-[O (C
1-C
6)-alkyl], CO-(C
1-C
6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
R14 is H, (C
1-C
8)-alkyl, (C
3-C
8)-cycloalkyl, (CH
2)
q-[(C
3-C
8)-cycloalkyl], (CH
2)
n-aryl, (CH
2)
n-heteroaryl, (CH
2)
n-CO-[O-(C
1-C
8)-alkyl], (CH
2)
n-CO-[O-(C
3-C
8)-cycloalkyl], (CH
2)
n-CO-[O-(CH
2)
n-aryl], (CH
2)
n-CO-[O-(CH
2)
n-heteroaryl], (CH
2)
n-CO-[(C
1-C
8)-alkyl], (CH
2)
n-CO-[(C
3-C
8)-cycloalkyl], (CH
2)
n-CO-aryl, (CH
2)
n-CO-heteroaryl, (CH
2)
q-CO-NH
2, (CH
2)
q-COOH, (CH
2)
n-SO
2-NH
2, (CH
2)
n-CO-NH-[(C
1-C
8)-alkyl], (CH
2)
n-CO-N[(C
1-C
8)-alkyl]
2, (CH
2)
n-CO-NH-[(C
3-C
8)-cycloalkyl], (CH
2)
n-CO-N[(C
3-C
8)-cycloalkyl]
2, (CH
2)
n-C (CH
3)
2-CO-O[(C
1-C
8)]-alkyl, (CH
2)
n-C (CH
3)
2-CO-O[(C
3-C
8)]-cycloalkyl, (CH
2)
n-C (CH
3)
2-CO-O-(CH
2)
r-NH
2, (CH
2)
n-C (CH
3)
2-CO-NH
2, (CH
2)
n-C (CH
3)
2-CO-NH-(CH
2)
r-OH, (CH
2)
n-C (CH
3)
2-COOH, alkyl wherein and cycloalkyl can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C
1-C
6)-alkyl, (C
3-C
6)-cycloalkyl, O-(C
1-C
6)-alkyl, S (O)
m-(C
1-C
6)-alkyl, SO
2-NH
2, COOH, CONH
2, CO-O (C
1-C
6)-alkyl, CO-(C
1-C
6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
R15 is H, (C
1-C
8)-alkyl, (C
3-C
8)-cycloalkyl, (CH
2)
n-aryl, (CH
2)
n-heteroaryl, (CH
2)
n-CO-[O-(C
1-C
8)-alkyl], (CH
2)
n-CO-[O-(C
3-C
8)-cycloalkyl], (CH
2)
n-CO-[O-(CH
2)
n-aryl], (CH
2)
n-CO-[O-(CH
2)
n-heteroaryl], CO-[(C
1-C
8)-alkyl], CO-[(C
3-C
8)-cycloalkyl], CO-aryl, CO-heteroaryl, (CH
2)
n-CO-NH
2, (CH
2)
q-COOH, (CH
2)
n-SO
2-NH
2, (CH
2)
n-CO-NH-[(C
1-C
8)-alkyl], (CH
2)
n-CO-N[(C
1-C
8)-alkyl]
2, (CH
2)
n-CO-NH-[(C
3-C
8)-cycloalkyl], (CH
2)
n-C (CH
3)
2-CO-NH
2, (CH
2)
n-C (CH
3)
2-COOH, alkyl wherein and cycloalkyl can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C
1-C
6)-alkyl, O-(C
1-C
6)-alkyl, SO
2-NH
2, COOH, CONH
2, CO-O (C
1-C
6)-alkyl, CO-(C
1-C
6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
R16 is ethylene imine-1-base, azetidine-1-base, 3-hydroxy azetidine-1-base, piperidines-1-base, 3-hydroxy piperidine-1-base, 4-hydroxy piperidine-1-base, 3-oxo-piperidine-1-base, 4-oxo-piperidine-1-base, tetramethyleneimine-1-base, 3-pyrrolidinol-1-base, 2-Cyanopyrolidine-1-base, morpholine-N-base, piperazine-1-base, 4-[(C
1-C
6)-alkyl] piperazine-1-base, piperazine-2-ketone-1-base, piperazine-2-ketone-4-base, piperazine-2,3-diketone-1-base, piperazine-2,6-diketone-1-base, piperazine-2,6-diketone-4-base, thiomorpholine-4-base, thiomorpholine-1,1-dioxide-4-base, NH-(CH
2)
r-OH, NH-CH (CH
2OH)
2, NH-C (CH
2OH)
3, N[(C
1-C
6)-alkyl-OH]
2, N[(C
1-C
6)-alkyl] [(C
1-C
6)-alkyl-OH], D-glucosamine-N-base, N-methyl D-glucosamine-N-base, NH-[(C
1-C
8)-alkyl]-CO-O (C
1-C
6)-alkyl, NH-[(C
1-C
8)-alkyl]-COOH, NH-[(C
1-C
8)-alkyl]-CONH
2, N[(C
1-C
6)-alkyl] [(C
1-C
8)-alkyl]-CO-O (C
1-C
6)-alkyl, N[(C
1-C
6)-alkyl] [(C
1-C
8)-alkyl]-COOH, N[(C
1-C
6)-alkyl] [(C
1-C
8)-alkyl]-CONH
2, NH-[C (H) (aryl)]-CO-O (C
1-C
6)-alkyl, NH-[C (H) (aryl)]-COOH, NH-[C (H) (aryl)]-CONH
2, N[(C
1-C
6)-alkyl] [C (H) (aryl)]-CO-O (C
1-C
6)-alkyl, N[(C
1-C
6)-alkyl] [C (H) (aryl)]-COOH, N[(C
1-C
6)-alkyl] [C (H) (aryl)]-CONH
2, NH-[C (H) (heteroaryl)]-CO-O (C
1-C
6)-alkyl, NH-[C (H) (heteroaryl)]-COOH, NH-[C (H) (heteroaryl)]-CONH
2, N[(C
1-C
6)-alkyl] [C (H) (heteroaryl)]-CO-O (C
1-C
6)-alkyl, N[(C
1-C
6)-alkyl] [C (H) (heteroaryl)]-COOH, N[(C
1-C
6)-alkyl] [C (H) (heteroaryl)]-CONH
2, N[(C
1-C
6)-alkyl] [(C
3-C
8)-cycloalkyl]-CO-O (C
1-C
6)-alkyl, N[(C
1-C
6)-alkyl] [(C
3-C
8)-cycloalkyl]-COOH, N[(C
1-C
6)-alkyl] [(C
3-C
8)-cycloalkyl]-CONH
2, NH-[(C
3-C
8)-cycloalkyl]-CO-O (C
1-C
6)-alkyl, NH-[(C
3-C
8)-cycloalkyl]-COOH, NH-[(C
3-C
8)-cycloalkyl]-CONH
2, NH-(CH
2)
r-SO
2-(C
1-C
6)-alkyl, NH-[(C
1-C
6)-alkyl]-SO
3H, NH-[(C
1-C
6)-alkyl]-SO
2-NH
2, N[(C
1-C
6)-alkyl] { [(C
1-C
6)-alkyl]-SO
3H}, alcohol wherein (OH) or ketone (C=O) functional group can be by F or CF
2Substitute;
R17 is R18, R13, (CH
2)
n-CO-[O-(C
1-C
8)-alkyl], (CH
2)
n-CO-[O-(C
3-C
8)-cycloalkyl], (CH
2)
n-CO-[(C
1-C
8)-alkyl], (CH
2)
n-CO-[(C
3-C
8)-cycloalkyl], (CH
2)
n-CO-aryl, (CH
2)
n-CO-heteroaryl, (CH
2)
n-CO-[O-(CH
2)
n-aryl], (CH
2)
n-CO-NH
2, (CH
2)
q-COOH, alkyl wherein and cycloalkyl can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C
1-C
6)-alkyl, (C
3-C
6)-cycloalkyl, O-(C
1-C
6)-alkyl, S (O)
m-(C
1-C
6)-alkyl, SO
2-NH
2, COOH, CONH
2, CO-[O (C
1-C
6)-alkyl], CO-(C
1-C
6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
R18 is (C
1-C
8)-alkyl, (C
3-C
8)-cycloalkyl, (CH
2)
q-[(C
3-C
8)-cycloalkyl], (CH
2)
n-aryl, (CH
2)
n-heteroaryl, alkyl wherein and cycloalkyl can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C
1-C
6)-alkyl, O-(C
1-C
6)-alkyl, SO
2-NH
2, COOH, CONH
2, CO-[O (C
1-C
6)-alkyl], CO-(C
1-C
6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
R20 is H, (C
1-C
6)-alkyl, (C
3-C
8)-cycloalkyl, aryl, [(C
1-C
6)-alkyl]-aryl;
R21 is H, F, CF
3, (C
1-C
6)-alkyl, (C
3-C
8)-cycloalkyl, OH, O-(C
1-C
6)-alkyl, O-(C
3-C
8)-cycloalkyl, O-(CH
2)
n-aryl, O-(CO)-(C
1-C
6)-alkyl, O-(CO)-(C
3-C
8)-cycloalkyl, O-(CO)-O-(C
1-C
6)-alkyl, O-(CO)-O-(C
3-C
8)-cycloalkyl, NH-[(C
1-C
6)-alkyl]-aryl, NH
2, NH-(C
1-C
6)-alkyl, NH-(CO)-(C
1-C
6)-alkyl;
R22 is H, CF
3, (C
1-C
6)-alkyl, aryl, [(C
1-C
6)-alkyl]-aryl.
The compound of the formula I that preferred wherein one or more groups are defined as follows separately with and the compatible salt of physiology:
Each (C naturally of R, R '
1-C
6)-alkyl, wherein (C
1-C
6)-alkyl can be replaced by halogen; Perhaps R and R ' form the ring with 3 to 8 carbon atoms together;
M is 0,1,2;
N is 0,1,2,3,4;
P is 1,2,3;
Q is 1,2,3;
R is 2,3,4;
V is 0,1,2,3;
A, D, E, G, L are C or N independently of one another, wherein when it is defined as N, do not have corresponding R1, R2, R3, R4, R5 substituting group;
R1, R2, R3, R4, R5 are H, F, Cl, Br, CN, NO independently of one another
2, CF
3, (C
1-C
8)-alkyl, (C
3-C
8)-cycloalkyl, (CH
2)
q-[(C
3-C
8)-cycloalkyl], (CH
2)
n-[(C
7-C
12)-bicyclic alkyl], (CH
2)
n-[(C
7-C
12)-tricyclic alkyl], diamantane-1-base, diamantane-2-base, (CH
2)
n-aryl, (CH
2)
n-heteroaryl, OCF
3, O-R11, NR13R15, S (O)
m-R12, SO
2-NH
2, SO
2-NH-[(C
1-C
8)-alkyl], SO
2-NH-[(C
3-C
8)-cycloalkyl], SO
2-NH-(CH
2)
n-aryl, SO
2-N[(C
1-C
8)-alkyl]
2, SO
2-R16, SF
5, CO-O[(C
1-C
8)-alkyl], CO-O-(CH
2)
r-NH
2, CO-NH
2, CO-NH-[(C
1-C
8)-alkyl], CO-N[(C
1-C
8)-alkyl]
2, C (=NH)-NH
2, C (=NH)-NHOH, C (=NH)-[NH-O-(C
1-C
6)-alkyl], C (=NH)-NR12R13, C (=NH)-R16, C (=NR13)-NR12R13, CO-NH-SO
2-R16, CO-NH-SO
2-NHR12, CO-R16, COOH, CO-(C
1-C
8)-alkyl, CO-(C
3-C
8)-cycloalkyl, CO-aryl, CO-heteroaryl, CH (OH)-aryl, CH (OH)-heteroaryl, CH[O-(C
1-C
6)-alkyl]-aryl, CH[O-(C
1-C
6)-alkyl]-heteroaryl, CHF-aryl, CHF-heteroaryl, CF
2-aryl, CH
2-O-R12, alkyl wherein, cycloalkyl, bicyclic alkyl and tricyclic alkyl can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C
1-C
6)-alkyl, (C
3-C
6)-cycloalkyl, O-(C
1-C
6)-alkyl, S (O)
m-(C
1-C
6)-alkyl, SO
2-NH
2, COOH, CONH
2, CO-O (C
1-C
6)-alkyl, CO-(C
1-C
6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
R6, R7, R8, R9, R10 are R11, NR17-bicyclic heterocycles, NR17-aryl, NR17-heteroaryl independently of one another, aryl wherein or heteroaryl can be carbocyclic fused with 5-or 6-person's aromatics or non-aromatics, one or more CH or CH in described aromatics or the non-aromatic carbocyclic
2Group can be substituted by Sauerstoffatom and wherein this 5-or 6-person's aromatics or non-aromatic carbocyclic can by F ,=O or-(C
1-C
6)-alkyl replaces, and bicyclic heterocycles wherein comprises 9 to 10 ring memberses and 5 CH or CH at the most
2Group can be independently of one another by N, NR20, O, S (O)
mOr C=O substitutes, and aryl wherein or heteroaryl or bicyclic heterocycles can not be substituted or by following group list-or polysubstituted:
R11、F、Cl、Br、CN、NO
2、CF
3、(CH
2)
n-O-R11、(CH
2)
n-O-(CH
2)
r-OH、
(CH
2)
n-O-CH(CH
2OH)
2、(CH
2)
n-O-(CH
2)
n-CO-O-(CH
2)
r-NH
2、
(CH
2)
n-O-sugar, (CH2)
n-O-saccharic acid, (CH2)
n-O-glucoside, (CH2)
n-O-galactoside, (CH2)
n-O-glucuronide, O-R13, OCF3、
(CH
2)
n-O-(CH
2)
r-NH
2、(CH
2)
n-NH-R11、
(CH
2)
n-N[(CH
2)
q-CO-O(C
1-C
6)-alkyl]2、(CH
2)
n-N[(CH
2)
q-COOH]
2、
(CH
2)
n-N[(CH
2)
q-CONH
2]
2、(CH
2)
n-NH-R13、(CH
2)
n-N(R13)
2、
(CH
2)
n-NH-CN、(CH
2)
n-NH-SO
2-R16、(CH
2)
n-NH-(CH
2)
n-SO
2-R12、
(CH
2)
n-NR12-CO-R16、(CH
2)
n-NR12-CO-NR12R13、
(CH
2)
n-NR12-CO-N(R12)
2、(CH
2)
n-NR12-CO-NHR11、
(CH
2)
n-NH-C(＝NH)-NH
2、(CH
2)
n-NH-C(＝NH)-R16、
(CH
2)
n-NH-C(＝NH)-NHR12、(CH
2)
n-NR12-C(＝NR13)-NHR12、
(CH
2)
n-NR12-C(＝NR12)-NR12R13、
(CH
2)
n-NH-(CH
2)
n-CO-O-(CH
2)
r-NH
2、
(CH
2)
n-NH-(CH
2)
n-CO-NH-[(C
1-C
8)-alkyl], (CH2)
n-NH-(CH
2)
n-CO-NH-(CH
2)
r-OH、
(CH
2)
n-NH-(CH
2)
n-CO-N[(C
1-C
8)-alkyl]2、
(CH
2)
n-NH-(CH
2)
n-CO-NH-[(C
3-C
8)-cycloalkyl], (CH2)
n-NH-C(CH
3)
2-CO-O(C
1-C
8)-alkyl, (CH2)
n-NH-C(CH
3)
2-CO-O-(CH
2)
r-NH
2、
(CH
2)
n-NH-C(CH
3)
2-CO-NH
2、
(CH
2)
n-NH-C(CH
3)
2-CO-NH-(CH
2)
r-OH、
(CH
2)
n-NH-C(CH
3)
2-COOH、S(O)
m-R12、SO
2-R16、
SO
2-N＝CH-N(CH
3)
2、SO
2-NH-CO-R12、SO
2-NHR12、
SO
2-NH-(CH
2)
r-OH、SO
2-N[(C
1-C
8)-alkyl]2、SO
2-NH-(CH
2)
r-NH
2、
SF
5、COOH、CO-NH
2、(CH
2)
q-CN、(CH
2)
n-CO-NH-piperidin-1-yl, (CH2)
n-CO-NH-SO
2-NHR12、(CH
2)
n-CO-NH-SO
2-R18、
(CH
2)
n-C(＝NH)NH
2、(CH
2)
n-C(＝NH)-NHOH、
C(＝NH)-[NH-O-(C
1-C
6)-alkyl], (CH2)
n-C(＝NH)(R16)、
(CH
2)
n-C(＝NR13)NHR12、(CH
2)
n-C(＝NR12)NR12R13、
(CH
2)
n-C(＝NH)O[(C
1-C
6)-alkyl], alkyl wherein and cycloalkyl can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C1-C
6)-alkyl, (C3-C
6)-cycloalkyl, O-(C1-C
6)-alkyl, S (O)m-(C
1-C
6)-alkyl, SO2-NH
2、
COOH、CONH
2、CO-O(C
1-C
6)-alkyl, CO-(C1-C
6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
F, Cl, Br, CN, CF
3, (CH
2)
n-O-R11, (CH
2)
n-O-(CH
2)
r-OH, (CH
2)
n-O-sugar, (CH
2)
n-O-saccharic acid, (CH
2)
n-O-glucoside, (CH
2)
n-O-galactoside, (CH
2)
n-O-glucuronide, O-R13, OCF3, (CH
2)
n-NH-R11, (CH
2)
n-NH-R13, (CH
2)
n-NH-CN, (CH
2)
n-NH-SO
2-R16, (CH
2)
n-NH-(CH
2)
n-SO
2-R12, (CH
2)
n-NR12-CO-NR12R13, (CH
2)
n-NR12-CO-N (R12)
2, (CH
2)
n-NR12-CO-NHR11, (CH
2)
n-NH-C (=NH)-NH
2, (CH
2)
n-NH-C (=NH)-R16, (CH
2)
n-NH-C (=NH)-NHR12, (CH
2)
n-NR12-C (=NR13)-NHR12, (CH
2)
n-NR12-C (=NR12)-NR12R13, (CH
2)
n-NH-(CH
2)
n-CO-NH-[(C
1-C
8)-alkyl], (CH
2)
n-NH-(CH
2)
n-CO-N[(C
1-C
8)-alkyl]
2, (CH
2)
n-NH-C (CH
3)
2-CO-O (C
1-C
8)-alkyl, (CH
2)
n-NH-C (CH
3)
2-CO-O (C
3-C
8)-cycloalkyl, (CH
2)
n-NH-C (CH
3)
2-CO-NH
2, (CH
2)
n-NH-C (CH
3)
2-CO-NH-(CH
2)
r-OH, (CH
2)
n-NH-C (CH
3)
2-CO-N[(C
1-C
8)-alkyl]
2, (CH
2)
n-NH-C (CH
3)
2-COOH, S (O)
m-R12, SO
2-R16, SO
2-NH-CO-R12, SO
2-NHR12, SO
2-NH-(CH
2)
r-OH, SO
2-N[(C
1-C
8)-alkyl]
2, SF
5, (CH
2)
n-COOH, (CH
2)
n-CONH
2, (CH
2)
q-CN, (CH
2)
n-CO-NH-CN, (CH
2)
n-CO-NH-SO
2-NHR12, (CH
2)
n-CO-NH-SO
2-R18, (CH
2)
n-C (=NH) NH
2, (CH
2)
n-C (=NH) NHOH, (CH
2)
n-C (=NH) (R16), (CH
2)
n-C (=NR13) NHR12, (CH
2)
n-C (=NR12) NR12R13, (CH
2)
n-C (=NH) O[(C
1-C
6)-alkyl], alkyl wherein and cycloalkyl can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C
1-C
6)-alkyl, (C
3-C
6)-cycloalkyl, O-(C
1-C
6)-alkyl, S (O)
m-(C
1-C
6)-alkyl, SO
2-NH
2, COOH, CONH
2, CO-[O (C
1-C
6)-alkyl] replace and alkyl wherein can be replaced by fluorine atom;
Wherein at least one among radicals R 6, R7, R8, R9 and the R10 always is defined as NR17-aryl or NR17-bicyclic heterocycles or NR17-heteroaryl;
Wherein four groups are to a pair of can the formation together in various situations-CH among R6 and R7 or R7 and R8 or R8 and R9 or R9 and the R10
2-CH
2-CH
2-or-CH
2-CH
2-CH
2-CH
2-group, wherein two-CH at the most
2-group can be substituted by-O-and wherein should-CH
2-CH
2-CH
2-or-CH
2-CH
2-CH
2-CH
2-group can by F, methyl or=O replaces;
R11 is H, (C1-C
6)-alkyl, (C2-C
6)-alkenyl, (C2-C
6)-alkynyl, (C3-C
7)-cycloalkyl, (CH2)
q-[(C
3-C
6)-cycloalkyl], (CH2)
n-[(C
7-C
10)-bicyclic alkyl], (CH2)
n-[(C
3-C
6)-cycloalkenyl group], (CH2)
n-[(C
7-C
10)-two cycloalkenyl group], (CH2)
n-[(C
7-C
12)-tricyclic alkyl], (CH2)
n-aryl, (CH2)
n-CO-[O-(C
1-C
6)-alkyl], (CH2)
n-CO-[O-(C
3-C
6)-cycloalkyl], (CH2)
n-CO-[(C
1-C
6)-alkyl], (CH2)
n-CO-[(C
3-C
6)-cycloalkyl], (CH2)
n-CO-aryl, (CH2)
n-CO-heteroaryl, (CH2)
n-CO-[O-(CH
2)
v-aryl], (CH2)
n-CO-[O-(CH
2)
v-heteroaryl], (CH2)
q-CO-NH
2、(CH
2)
q-COOH、(CH
2)
n-P(O)(OH)[O-(C
1-C
3)-alkyl], (CH2)
n-P(O)[O-(C
1-C
3)-alkyl]2、(CH
2)
n-P(O)(OH)(O-CH
2-aryl), (CH2)
n-P(O)(O-CH
2-aryl)2、(CH
2)
n-P(O)(OH)
2、(CH
2)
n-SO
3H、
(CH
2)
n-SO
2-NH
2、(CH
2)
n-CO-NH-[(C
1-C
6)-alkyl], (CH2)
n-CO-N[(C
1-C
6)-alkyl]2、(CH
2)
n-CO-NH-[(C
3-C
6)-cycloalkyl], (CH2)
n-CO-N[(C
3-C
6)-cycloalkyl]2、
(C
2-C
6)-alkenyl-CO-O[(C1-C
6)-alkyl], (C2-C
6)-alkenyl-CONH2、(C
2-C
6)-alkenyl-COOH, (C2-C
6)-alkynyl-CO-O[(C1-C
6)-alkyl], (C2-C
6)-alkynyl-CONH2、
(C
2-C
6)-alkynyl-COOH, (CH2)
n-CR21[(CO-O(C
1-C
4)-alkyl)]2、
(CH
2)
n-CR21(CONH
2)
2、(CH
2)
n-CR21(COOH)
2、
(CH
2)
n-CR21R22CO-O[(C
1-C
4)-alkyl], (CH2)
n-CR21R22CONH
2、
(CH
2)
n-CR21R22COOH、(CH
2)
n-CO-R16、(CH
2)
n-C(CH
3)
2-CO-O[(C
1-C
6)-alkyl], (CH2)
n-C(CH
3)
2-CO-O[(C
3-C
6)-cycloalkyl], (CH2)
n-C(CH
3)
2-CO-O-(CH
2)
n-aryl, (CH2)
n-C(CH
3)
2-CO-O-(CH
2)
n-heteroaryl, (CH2)
n-C(CH
3)
2-CO-NH
2、(CH
2)
n-C(CH
3)
2-CO-NH-[(C
1-C
6)-alkyl], (CH2)
n-C(CH
3)
2-CO-NH-(CH
2)
r-OH、(CH
2)
n-C(CH
3)
2-CO-N[(C
1-C
6)-alkyl]2、(CH
2)
n-C(CH
3)
2-CO-NH-[(C
3-C
6)-cycloalkyl], (CH2)
n-C(CH
3)
2-CO-N[(C
3-C
6)-cycloalkyl]2、(CH
2)
n-C(CH
3)
2-COOH、
(CH
2)
n-CO-NH-C(CH
3)
2-CO-O[(C
1-C
6)-alkyl], (CH2)
n-CO-NH-C(CH
3)
2-CONH
2、(CH
2)
n-CO-NH-C(CH
3)
2-COOH, alkyl wherein, alkenyl, alkynyl and cycloalkyl, bicyclic alkyl, tricyclic alkyl, cycloalkenyl group and two cycloalkenyl groups can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C1-C
6)-alkyl, (C3-C
6)-cycloalkyl, O-(C1-C
6)-alkyl, S (O)m-(C
1-C
6)-alkyl, SO2-NH
2、
COOH、CONH
2、CO-O(C
1-C
6)-alkyl, CO-(C1-C
6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
R12 is H, (C
1-C
6)-alkyl, (C
3-C
6)-cycloalkyl, (CH
2)
q-[(C
3-C
6)-cycloalkyl], (CH
2)
n-[(C
7-C
10)-bicyclic alkyl], (CH
2)
n-[(C
7-C
10)-tricyclic alkyl], (CH
2)
n-aryl, (CH
2)
n-heteroaryl, alkyl wherein, cycloalkyl, bicyclic alkyl or tricyclic alkyl can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C
1-C
3)-alkyl, O-(C
1-C
3)-alkyl, SO
2-NH
2, COOH, CONH
2, CO-O (C
1-C
3)-alkyl, CO-(C
1-C
3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
R13 is H, SO
2-[(C
1-C
6)-alkyl], SO
2-[(C
3-C
6)-cycloalkyl], SO
2-(CH
2)
n-aryl, SO
2-(CH
2)
n-heteroaryl, SO
2-(CH
2)
n-NH-R12, SO
2-(CH
2)
n-N (R12)
2, alkyl wherein and cycloalkyl can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C
1-C
3)-alkyl, (C
3-C
6)-cycloalkyl, O-[(C
1-C
3)-alkyl], S (O)
m-[(C
1-C
3)-alkyl], SO
2-NH
2, COOH, CONH
2, CO-[O (C
1-C
3)-alkyl], CO-(C
1-C
3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
R16 is ethylene imine-1-base, azetidine-1-base, piperidines-1-base, 3-hydroxy piperidine-1-base, 4-hydroxy piperidine-1-base, 3-oxo-piperidine-1-base, 4-oxo-piperidine-1-base, tetramethyleneimine-1-base, 3-pyrrolidinol-1-base, 2-Cyanopyrolidine-1-base, morpholine-N-base, piperazine-1-base, 4-[(C
1-C
3)-alkyl] piperazine-1-base, piperazine-2-ketone-1-base, piperazine-2-ketone-4-base, piperazine-2,6-diketone-1-base, piperazine-2,6-diketone-4-base, thiomorpholine-1,1-dioxide-4-base, NH-(CH
2)
r-OH, NH-CH (CH
2OH)
2, NH-C (CH
2OH)
3, N[(C
1-C
6)-alkyl-OH]
2, D-glucosamine-N-base, N-methyl D-glucosamine-N-base, NH-[(C
1-C
6)-alkyl]-CO-O (C
1-C
3)-alkyl, NH-[(C
1-C
3)-alkyl]-COOH, NH-[(C
1-C
3)-alkyl]-CONH
2, N[(C
1-C
3)-alkyl] [(C
1-C
3)-alkyl]-CO-O (C
1-C
3)-alkyl, N[(C
1-C
3)-alkyl] [(C
1-C
3)-alkyl]-COOH, N[(C
1-C
3)-alkyl] [(C
1-C
3)-alkyl]-CONH
2, NH-[C (H) (aryl)]-CO-O (C
1-C
3)-alkyl, NH-[C (H) (aryl)]-COOH, NH-[C (H) (aryl)]-CONH
2, N[(C
1-C
3)-alkyl] [C (H) (aryl)]-CO-O (C
1-C
3)-alkyl, N[(C
1-C
3)-alkyl] [C (H) (aryl)]-COOH, N[(C
1-C
3)-alkyl] [C (H) (aryl)]-CONH
2, NH-[C (H) (heteroaryl)]-CO-O (C
1-C
3)-alkyl, NH-[C (H) (heteroaryl)]-COOH, NH-[C (H) (heteroaryl)]-CONH
2, N[(C
1-C
3)-alkyl] [C (H) (heteroaryl)]-CO-O (C
1-C
3)-alkyl, N[(C
1-C
3)-alkyl] [C (H) (heteroaryl)]-COOH, N[(C
1-C
3)-alkyl] [C (H) (heteroaryl)]-CONH
2, N[(C
1-C
3)-alkyl] [(C
3-C
6)-cycloalkyl]-CO-O (C
1-C
3)-alkyl, N[(C
1-C
3)-alkyl] [(C
3-C
6)-cycloalkyl]-COOH, N[(C
1-C
3)-alkyl] [(C
3-C
6)-cycloalkyl]-CONH
2, NH-[(C
3-C
6)-cycloalkyl]-CO-O (C
1-C
3)-alkyl, NH-[(C
3-C
6)-cycloalkyl]-COOH, NH-[(C
3-C
6)-cycloalkyl]-CONH
2, NH-(CH
2)
r-SO
2-(C
1-C
3)-alkyl, NH-[(C
1-C
4)-alkyl]-SO
3H, NH-[(C
1-C
4)-alkyl]-SO
2-NH
2, N[(C
1-C
4)-alkyl] { [(C
1-C
4)-alkyl]-SO
3H}, alcohol wherein (OH) or ketone (C=O) functional group can be by F or CF
2Substitute;
R17 is R18, R13, (CH
2)
n-CO-[O-(C
1-C
3)-alkyl], (CH
2)
n-CO-[O-(C
3-C
6)-cycloalkyl], (CH
2)
n-CO-[(C
1-C
3)-alkyl], (CH
2)
n-CO-[(C
3-C
6)-cycloalkyl], (CH
2)
n-CO-aryl, (CH
2)
n-CO-heteroaryl, (CH
2)
n-CO-[O-(CH
2)
n-aryl], (CH
2)
n-CO-NH
2, (CH
2)
q-COOH, alkyl wherein and cycloalkyl can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C
1-C
3)-alkyl, (C
3-C
6)-cycloalkyl, O-(C
1-C
3)-alkyl, S (O)
m-(C
1-C
3)-alkyl, SO
2-NH
2, COOH, CONH
2, CO-[O (C
1-C
3)-alkyl], CO-(C
1-C
3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
R18 is (C
1-C
4)-alkyl, (C
3-C
6)-cycloalkyl, (CH
2)
q-[(C
3-C
6)-cycloalkyl], (CH
2)
n-aryl, (CH
2)
n-heteroaryl, alkyl wherein and cycloalkyl can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C
1-C
3)-alkyl, O-(C
1-C
3)-alkyl, SO
2-NH
2, COOH, CONH
2, CO-[O (C
1-C
3)-alkyl], CO-(C
1-C
6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
R20 is H, (C
1-C
3)-alkyl, (C
3-C
6)-cycloalkyl, aryl, [(C
1-C
6)-alkyl]-aryl;
R21 is H, F, CF
3, (C
1-C
3)-alkyl, (C
3-C
6)-cycloalkyl, OH, O-(C
1-C
3)-alkyl, O-(C
3-C
6)-cycloalkyl, O-(CH
2)
n-aryl, O-(CO)-(C
1-C
3)-alkyl, O-(CO)-(C
3-C
6)-cycloalkyl, O-(CO)-O-(C
1-C
3)-alkyl, O-(CO)-O-(C
3-C
6)-cycloalkyl, NH
2, NH-[(C
1-C
3)-alkyl]-aryl, NH-(C
1-C
3)-alkyl, NH-(CO)-(C
1-C
3)-alkyl;
R22 is H, CF
3, (C
1-C
3)-alkyl, aryl, [(C
1-C
6)-alkyl]-aryl.
Preferred especially wherein one or more groups separately as following defined formula I compound with and the compatible salt of physiology:
R, R ' are (C independently of one another
1-C
3)-alkyl, wherein (C
1-C
3)-alkyl can be replaced by halogen or R and R ' form the ring with 3 to 6 carbon atoms together;
M is 0,1,2;
N is 0,1,2,3;
P is 1,2,3;
Q is 1,2;
R is 2,3,4;
V is 0,1,2;
A, D, E, G, L are C or N independently of one another, wherein when it is defined as N, do not have corresponding R1, R2, R3, R4, R5 substituting group;
R1, R2, R3, R4, R5 are H, F, Cl, Br, CN, CF independently of one another
3, (C
1-C
4)-alkyl, (C
3-C
6)-cycloalkyl, (CH
2)
q-[(C
3-C
6)-cycloalkyl], (CH
2)
n-[(C
7-C
10)-bicyclic alkyl], (CH
2)
n-[(C
7-C
10)-tricyclic alkyl], diamantane-1-base, diamantane-2-base, (CH
2)
n-aryl, (CH
2)
n-heteroaryl, OCF
3, O-(C
1-C
6)-alkyl, O-(C
3-C
7)-cycloalkyl, O-(CH
2)
n-aryl, O-(CH
2)
n-heteroaryl, NH-(C
1-C
4)-alkyl, N[(C
1-C
4)-alkyl]
2, NH-aryl, NH-heteroaryl, NH-SO
2-(C
1-C
4)-alkyl, NH-SO
2-aryl, S (O)
m-(C
1-C
4)-alkyl, S (O)
m-(C
3-C
6)-cycloalkyl, S (O)
m-aryl, SO
2-NH
2, SO
2-NH-[(C
1-C
4)-alkyl], SO
2-NH-[(C
3-C
6)-cycloalkyl], SO
2-NH-(CH
2)
n-aryl, SO
2-N[(C
1-C
4)-alkyl]
2, SF
5, CO-O[(C
1-C
4)-alkyl], CO-NH
2, CO-NH-[(C
1-C
4)-alkyl], CO-N[(C
1-C
4)-alkyl]
2, C (=NH)-NH
2, C (=N-OH) NH
2, COOH, CO-(C
1-C
6)-alkyl, CO-(C
3-C
6)-cycloalkyl, CO-aryl, CO-heteroaryl, CH (OH)-aryl, CH (OH)-heteroaryl, CH[O-(C
1-C
4)-alkyl]-aryl, CH[O-(C
1-C
4)-alkyl]-heteroaryl, CHF-aryl, CHF-heteroaryl, CF
2-aryl, alkyl wherein, cycloalkyl, bicyclic alkyl and tricyclic alkyl can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C
1-C
4)-alkyl, (C
3-C
6)-cycloalkyl, O-(C
1-C
4)-alkyl, S (O)
m-(C
1-C
3)-alkyl, SO
2-NH
2, COOH, CONH
2, CO-O (C
1-C
3)-alkyl, CO-(C
1-C
3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
R6, R7, R8, R9, R10 are NR17-bicyclic heterocycles, NR17-aryl, NR17-heteroaryl independently of one another, aryl wherein or heteroaryl can be carbocyclic fused with 5-or 6-person's aromatics or non-aromatics, one or more CH or CH in described aromatics or the non-aromatic carbocyclic
2Group can be substituted by Sauerstoffatom and wherein this 5-or 6-person's aromatics or non-aromatic carbocyclic can by F ,=O or-(C
1-C
6)-alkyl replaces, and wherein this bicyclic heterocycles comprises 9 to 10 ring memberses and 5 CH or CH at the most
2Group can be independently of one another by N, NR20, O, S (O)
mOr C=O substitutes, and wherein this aryl or heteroaryl or bicyclic heterocycles can not be substituted or by following group list-or polysubstituted:
R11、F、Cl、Br、CN、NO
2、CF
3、(CH
2)
n-O-R11、(CH
2)
n-O-(CH
2)
r-OH、
(CH
2)
n-O-CH(CH
2OH)
2、(CH
2)
n-O-(CH
2)
n-CO-O-(CH
2)
r-NH
2、
(CH
2)
n-O-saccharic acid, (CH2)
n-O-glucoside, (CH2)
n-O-galactoside, (CH2)
n-O-glucuronide, OCF3、O-R13、(CH
2)
n-O-(CH
2)
r-NH
2、
(CH
2)
n-NH-R11、(CH
2)
n-N[(CH
2)
q-CO-O(C
1-C
4)-alkyl]2、
(CH
2)
n-N[(CH
2)
q-COOH]
2、(CH
2)
n-N[(CH
2)
q-CONH
2]
2、
(CH
2)
n-NH-R13、(CH
2)
n-N(R13)
2、(CH
2)
n-NH-SO
2-R16、
(CH
2)
n-NH-(CH
2)
n-SO
2-R12、(CH
2)
n-NR12-CO-R16、
(CH
2)
n-NR12-CO-NR12R13、(CH
2)
n-NR12-CO-N(R12)
2、
(CH
2)
n-NR12-CO-NHR11、(CH
2)
n-NH-C(＝NH)-NH
2、
(CH
2)
n-NH-C(＝NH)-R16、(CH
2)
n-NH-C(＝NH)-NHR12、
(CH
2)
n-NR12-C(＝NR13)-NHR12、
(CH
2)
n-NR12-C(＝NR12)-NR12R13、
(CH
2)
n-NH-(CH
2)
n-CO-O-(CH
2)
r-NH2、
(CH
2)
n-NH-(CH
2)
n-CO-NH-[(C
1-C
8)-alkyl], (CH2)
n-NH-(CH
2)
n-CO-NH-(CH
2)
r-OH、
(CH
2)
n-NH-(CH
2)
n-CO-N[(C
1-C
8)-alkyl]2、
(CH
2)
n-NH-(CH
2)
n-CO-NH-[(C
3-C
8)-cycloalkyl], (CH2)
n-NH-C(CH
3)
2-CO-O(C
1-C
8)-alkyl, (CH2)
n-NH-C(CH
3)
2-CO-O-(CH
2)
r-NH
2、
(CH
2)
n-NH-C(CH
3)
2-CO-NH
2、
(CH
2)
n-NH-C(CH
3)
2-CO-NH-(CH
2)
r-OH、
(CH
2)
n-NH-C(CH
3)
2-COOH、S(O)
m-R12、SO
2-R16、
SO
2-N＝CH-N(CH
3)
2、SO
2-NH-CO-R12、SO
2-NHR12、
SO
2-NH-(CH
2)
r-OH、SO
2-N[(C
1-C
8)-alkyl]2、SO
2-NH-(CH
2)
r-NH
2、
SF
5、COOH、CO-NH
2、(CH
2)
q-CN、(CH
2)
n-CO-NH-piperidin-1-yl, (CH2)
n-CO-NH-SO
2-NHR12、(CH
2)
n-CO-NH-SO
2-R18、
(CH
2)
n-C(＝NH)NH
2、(CH
2)
n-C(＝NH)-NHOH、
C(＝NH)-[NH-O-(C
1-C
6)-alkyl], (CH2)
n-C(＝NH)(R16)、
(CH
2)
n-C(＝NR13)NHR12、(CH
2)
n-C(＝NR12)NR12R13、
(CH
2)
n-C(＝NH)O[(C
1-C
6)-alkyl], alkyl wherein and cycloalkyl can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C1-C
6)-alkyl, (C3-C
6)-cycloalkyl, O-(C1-C
6)-alkyl, S (O)m-(C
1-C
6)-alkyl, SO2-NH
2、
COOH、CONH
2、CO-O(C
1-C
6)-alkyl, CO-(C1-C
6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
H, F, Cl, Br, CN, CF
3, (C
1-C
6)-alkyl, (C
2-C
6)-alkenyl, (C
2-C
6)-alkynyl, (C
3-C
7)-cycloalkyl, (CH
2)
n-OH, (CH
2)
n-O-(C
1-C
4)-alkyl, (CH
2)
n-O-(C
3-C
6)-cycloalkyl, (CH
2)
n-O aryl, (CH
2)
n-O-glucoside, (CH
2)
n-O-glucuronide, OCF
3, O-R13, (CH
2)
n-NH-aryl, (CH
2)
n-NH-SO
2-(C
1-C
4)-alkyl, (CH
2)
n-NH-SO
2-aryl, (CH
2)
n-NH-CO-NH
2, (CH
2)
n-NH-CO-NH-(C
1-C
4)-alkyl, (CH
2)
n-NH-CO-NH-(C
3-C
6)-cycloalkyl, (CH
2)
n-NH-C (=NH)-NH
2, S (O)
m-(C
1-C
4)-alkyl, S (O)
m-aryl, SO
2-NH
2, SO
2-NH-(C
1-C
4)-alkyl, SO
2-N[(C
1-C
4)-alkyl]
2, SF
5, (CH
2)
n-CO-[O-(C
1-C
4)-alkyl], COOH, (CH
2)
q-COOH, CONH
2, (CH
2)
q-CONH
2, (CH
2)
n-C (=NH) NH
2, (CH
2)
n(=NH) NHOH, alkyl wherein and cycloalkyl can be replaced by fluorine atom-C, and aryl wherein or heteroaryl can be by halogen, CN, (C
1-C
3)-alkyl, (C
3-C
6)-cycloalkyl, O-(C
1-C
4)-alkyl, S (O)
m-(C
1-C
3)-alkyl, SO
2-NH
2, COOH, CONH
2, CO-[O (C
1-C
3)-alkyl] replace and alkyl wherein can be replaced by fluorine atom;
Wherein among radicals R 6, R7, R8, R9 and the R10 always is defined as NR17-aryl or NR17-bicyclic heterocycles or NR17-heteroaryl;
R11 is H, (C1-C
4)-alkyl, (C2-C
3)-alkenyl, (C2-C
4)-alkynyl, (C3-C
5)-cycloalkyl, (CH2)
q-[(C
3-C
4)-cycloalkyl], (CH2)
n-[(C
7-C
10)-bicyclic alkyl], (CH2)
n-[(C
3-C
6)-cycloalkenyl group], (CH2)
n-[(C
7-C
8)-two cycloalkenyl group], (CH2)
n-[(C
7-C
8)-tricyclic alkyl], (CH2)
n-aryl, (CH2)
n-CO-[O-(C
1-C
4)-alkyl], (CH2)
n-CO-[O-(C
3-C
5)-cycloalkyl], (CH2)
n-CO-[(C
1-C
3)-alkyl], (CH2)
n-CO-[(C
3-C
5)-cycloalkyl], (CH2)
n-CO-aryl, (CH2)
n-CO-heteroaryl, (CH2)
n-CO-[O-(CH
2)
v-aryl], (CH2)
n-CO-[O-(CH
2)
v-heteroaryl], (CH2)
q-CO-NH
2、(CH
2)
q-COOH、
(CH
2)
n-P(O)(OH)[O-(C
1-C
3)-alkyl], (CH2)
n-P(O)[O-(C
1-C
3)-alkyl]2、
(CH
2)
n-P(O)(OH)(O-CH
2-aryl), (CH2)
n-P(O)(O-CH
2-aryl)2、
(CH
2)
n-P(O)(OH)
2、(CH
2)
n-SO
3H、(CH
2)
n-SO
2-NH
2、
(CH
2)
n-CO-NH-[(C
1-C
6)-alkyl], (CH2)
n-CO-N[(C
1-C
4)-alkyl]2、
(CH
2)
n-CO-NH-[(C
3-C
5)-cycloalkyl], (CH2)
n-CO-N[(C
3-C
4)-cycloalkyl]2、(C
2-C
4)-alkenyl-CO-O[(C1-C
4)-alkyl], (C2-C
4)-alkenyl-CONH2、(C
2-C
4)-alkenyl-COOH, (C2-C
4)-alkynyl-CO-O[(C1-C
6)-alkyl], (C2-C
4)-alkynyl-CONH2、(C
2-C
4)-alkynyl-COOH, (CH2)
n-CR21[(CO-O(C
1-C
4)-alkyl)]2、
(CH
2)
n-CR21(CONH
2)
2、(CH
2)
n-CR21(COOH)
2、
(CH
2)
n-CR21R22CO-O[(C
1-C
4)-alkyl], (CH2)
n-CR21R22CONH
2、
(CH
2)
n-CR21R22COOH、(CH
2)
n-CO-R16、(CH
2)
n-C(CH
3)
2-CO-O[(C
1-C
3)-alkyl], (CH2)
n-C(CH
3)
2-CO-O[(C
3-C
5)-cycloalkyl], (CH2)
n-C(CH
3)
2-CO-NH
2、
(CH
2)
n-C(CH
3)
2-CO-NH-[(C
1-C
3)-alkyl], (CH2)
n-C(CH
3)
2-CO-NH-(CH
2)
r-OH、(CH
2)
n-C(CH
3)
2-CO-NH-[(C
3-C
5)-cycloalkyl], (CH2)
n-CO-NH-C(CH
3)
2-CO-O[(C
1-C
4)-alkyl], (CH2)
n-C(CH
3)
2-COOH、(CH
2)
n-CO-NH-C(CH
3)
2-CONH
2、
(CH
2)
n-CO-NH-C(CH
3)
2-COOH, alkyl wherein, alkenyl, alkynyl and cycloalkyl, bicyclic alkyl, cycloalkenyl group, two cycloalkenyl groups and tricyclic alkyl can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C1-C
4)-alkyl, (C3-C
6)-cycloalkyl, O-(C1-C
4)-alkyl, S (O)m-(C
1-C
4)-alkyl, SO2-NH
2、COOH、CONH
2、CO-O(C
1-C
4)-alkyl, CO-(C1-C
3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
R12 is H, (C
1-C
3)-alkyl, (C
3-C
5)-cycloalkyl, (CH
2)
q-[(C
3-C
5)-cycloalkyl], (CH
2)
n-[(C
7-C
8)-bicyclic alkyl], (CH
2)
n-[(C
7-C
8)-tricyclic alkyl], (CH
2)
n-aryl, (CH
2)
n-heteroaryl, alkyl wherein, cycloalkyl, bicyclic alkyl or tricyclic alkyl can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C
1-C
3)-alkyl, O-(C
1-C
3)-alkyl, SO
2-NH
2, COOH, CONH
2, CO-O (C
1-C
3)-alkyl, CO-(C
1-C
3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
R13 is H, SO
2-[(C
1-C
3)-alkyl], SO
2-[(C
3-C
5)-cycloalkyl], SO
2-(CH
2)
n-aryl, SO
2-(CH
2)
n-heteroaryl, SO
2-(CH
2)
n-NH-R12, SO
2-(CH
2)
n-N (R12)
2, alkyl wherein and cycloalkyl can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C
1-C
3)-alkyl, (C
3-C
6)-cycloalkyl, O-[(C
1-C
3)-alkyl], S (O)
m-[(C
1-C
3)-alkyl], SO
2-NH
2, COOH, CONH
2, CO-[O (C
1-C
3)-alkyl], CO-(C
1-C
3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
R16 is ethylene imine-1-base, azetidine-1-base, piperidines-1-base, 4-hydroxy piperidine-1-base, 3-oxo-piperidine-1-base, 4-oxo-piperidine-1-base, tetramethyleneimine-1-base, 3-pyrrolidinol-1-base, 2-Cyanopyrolidine-1-base, morpholine-N-base, piperazine-1-base, 4-[(C
1-C
3)-alkyl] piperazine-1-base, piperazine-2-ketone-1-base, piperazine-2-ketone-4-base, thiomorpholine-1,1-dioxide-4-base, NH-(CH
2)
r-OH, NH-CH (CH
2OH)
2, NH-C (CH
2OH)
3, N[(C
1-C
3)-alkyl-OH]
2, D-glucosamine-N-base, N-methyl D-glucosamine-N-base, NH-[(C
1-C
3)-alkyl]-CO-O (C
1-C
3)-alkyl, NH-[(C
1-C
3)-alkyl]-COOH, NH-[(C
1-C
3)-alkyl]-CONH
2, NH-[C (H) (aryl)]-CO-O (C
1-C
3)-alkyl, NH-[C (H) (aryl)]-COOH, NH-[C (H) (aryl)]-CONH
2, NH-[C (H) (heteroaryl)]-CO-O (C
1-C
3)-alkyl, NH-[C (H) (heteroaryl)]-COOH, NH-[C (H) (heteroaryl)]-CONH
2, NH-[(C
3-C
6)-cycloalkyl]-CO-O (C
1-C
3)-alkyl, NH-[(C
3-C
6)-cycloalkyl]-COOH, NH-[(C
3-C
6)-cycloalkyl]-CONH
2, NH-(CH
2)
r-SO
2-(C
1-C
3)-alkyl, NH-[(C
1-C
4)-alkyl]-SO
3H, NH-[(C
1-C
4)-alkyl]-SO
2-NH
2, N[(C
1-C
3)-alkyl] { [(C
1-C
4)-alkyl]-SO
3H}, alcohol wherein (OH) or ketone (C=O) functional group can be by F or CF
2Substitute;
R17 is R18, H, SO
2-CH
3, SO
2-aryl, (CH
2)
n-CO-[O-(C
1-C
3)-alkyl], (CH
2)
n-CO-[(C
1-C
3)-alkyl], (CH
2)
n-CO-aryl, (CH
2)
n-CO-NH
2, (CH
2)
q-COOH, alkyl wherein can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C
1-C
3)-alkyl, O-(C
1-C
3)-alkyl, S (O)
m-(C
1-C
3)-alkyl, SO
2-NH
2, COOH, CONH
2, CO-[O (C
1-C
3)-alkyl], CO-(C
1-C
3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
R18 is (C
1-C
4)-alkyl, (C
3-C
4)-cycloalkyl, (CH
2)
n-aryl, (CH
2)
n-heteroaryl, alkyl wherein and cycloalkyl can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C
1-C
3)-alkyl, O-(C
1-C
3)-alkyl, SO
2-NH
2, COOH, CONH
2, CO-[O (C
1-C
3)-alkyl], CO-(C
1-C
3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
R20 is H, (C
1-C
3)-alkyl, (C
3-C
6)-cycloalkyl, aryl, [(C
1-C
3)-alkyl]-aryl;
R21 is H, F, CF
3, (C
1-C
3)-alkyl, (C
3-C
4)-cycloalkyl, OH, O-(C
1-C
3)-alkyl, O-(C
3-C
4)-cycloalkyl, O-(CH
2)
n-aryl, O-(CO)-(C
1-C
3)-alkyl, O-(CO)-(C
3-C
4)-cycloalkyl, O-(CO)-O-(C
1-C
3)-alkyl, O-(CO)-O-(C
3-C
4)-cycloalkyl, NH
2, NH-[(C
1-C
2)-alkyl]-aryl, NH-(C
1-C
3)-alkyl, NH-(CO)-(C
1-C
3)-alkyl;
R22 is H, CF
3, (C
1-C
3)-alkyl, aryl, [(C
1-C
3)-alkyl]-aryl.
Preferred especially wherein one or more groups separately as following defined formula I compound with and the compatible salt of physiology:
R, R ' are (C independently of one another
1-C
3)-alkyl; Or R and R ' form the ring with 3 to 6 carbon atoms together;
M is 0,1,2;
N is 0,1,2;
P is 1,2;
Q is 1,2;
R is 2,3;
V is 0,1;
A, D, E, G, L are C or N independently of one another, wherein when it is defined as N, do not have corresponding R1, R2, R3, R4, R5 substituting group;
R1, R2, R3, R4, R5 are H, F, Cl, Br, CN, CF independently respectively-certainly
3, (C
1-C
4)-alkyl, (C
3-C
6)-cycloalkyl, (CH
2)
q-[(C
3-C
6)-cycloalkyl], diamantane-1-base, diamantane-2-base, (CH
2)
n-aryl, (CH
2)
n-heteroaryl, OCF
3, O-(C
1-C
4)-alkyl, O-(C
3-C
6)-cycloalkyl, O-(CH
2)
n-aryl, O-(CH
2)
n-heteroaryl, NH-(C
1-C
4)-alkyl, N[(C
1-C
4)-alkyl]
2, NH-aryl, NH-heteroaryl, NH-SO
2-(C
1-C
4)-alkyl, NH-SO
2-aryl, S (O)
m-(C
1-C
3)-alkyl, S (O)
m-(C
3-C
6)-cycloalkyl, S (O)
m-aryl, SO
2-NH
2, SO
2-NH-[(C
1-C
4)-alkyl], SO
2-NH-[(C
3-C
6)-cycloalkyl], SO
2-NH-(CH
2)
n-aryl, SO
2-N[(C
1-C
4)-alkyl]
2, SF
5, CO-O[(C
1-C
4)-alkyl], CO-NH
2, CO-NH-[(C
1-C
3)-alkyl], CO-N[(C
1-C
3)-alkyl]
2, COOH, CO-(C
1-C
3)-alkyl, CO-(C
3-C
6)-cycloalkyl, CO-aryl, CO-heteroaryl, CH (OH)-aryl, CH (OH)-heteroaryl, CH[O-(C
1-C
4)-alkyl]-aryl, CH[O-(C
1-C
4)-alkyl]-heteroaryl, CHF-aryl, CHF-heteroaryl, CF
2-aryl, alkyl or cycloalkyl wherein can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C
1-C
3)-alkyl, O-(C
1-C
4)-alkyl, S (O)
m-(C
1-C
3)-alkyl, SO
2-NH
2, COOH, CONH
2, CO-O (C
1-C
3)-alkyl, CO-(C
1-C
3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
R6, R7, R8, R9, R10 are NR17-bicyclic heterocycles, NR17-aryl, NR17-heteroaryl independently of one another, aryl wherein or heteroaryl can be carbocyclic fused with 5-or 6-person's aromatics or non-aromatics, one or more CH or CH in described aromatics or the non-aromatic carbocyclic
2Group can be substituted by Sauerstoffatom and wherein this 5-or 6-person's aromatics or non-aromatic carbocyclic can by F ,=O or-(C
1-C
3)-alkyl replaces, and wherein this bicyclic heterocycles comprises 9 to 10 ring memberses and 5 CH or CH at the most
2Group can be independently of one another by N, NR20, O, S (O)
mOr C=O substitutes, and wherein aryl or heteroaryl or bicyclic heterocycles can not be substituted or by following group list-or polysubstituted:
R11、F、Cl、Br、CN、NO
2、CF
3、(CH
2)
n-O-R11、(CH
2)
n-O-(CH
2)
r-OH、
(CH
2)
n-O-CH(CH
2OH)
2、(CH
2)
n-O-(CH
2)
n-CO-O-(CH
2)
r-NH
2、
(CH
2)
n-O-glucoside, (CH2)
n-O-galactoside, (CH2)
n-O-glucuronide, OCF3、O-R13、(CH
2)
n-O-(CH
2)
r-NH
2、(CH
2)
n-NH-R11、
(CH
2)
n-N[(CH
2)
q-CO-O(C
1-C
4)-alkyl]2、(CH
2)
n-N[(CH
2)
q-COOH]
2、
(CH
2)
n-N[(CH
2)
q-CONH
2]
2、(CH
2)
n-NH-R13、(CH
2)
n-N(R13)
2、
(CH
2)
n-NH-SO
2-R16、(CH
2)
n-NH-(CH
2)
n-SO
2-R12、
(CH
2)
n-NR12-CO-R16、(CH
2)
n-NR12-CO-NR12R13、
(CH
2)
n-NR12-CO-N(R12)
2、(CH
2)
n-NR12-CO-NHR11、
(CH
2)
n-NH-C(＝NH)-R16、(CH
2)
n-NR12-C(＝NR13)-NHR12、
(CH
2)
n-NR12-C(＝NR12)-NR12R13、
(CH
2)
n-NH-(CH
2)
n-CO-O-(CH
2)
r-NH
2、
(CH
2)
n-NH-(CH
2)
n-CO-NH-[(C
1-C
3)-alkyl], (CH2)
n-NH-(CH
2)
n-CO-NH-(CH
2)
r-OH、
(CH
2)
n-NH-(CH
2)
n-CO-N[(C
1-C
3)-alkyl]2、
(CH
2)
n-NH-(CH
2)
n-CO-NH-[(C
3-C
5)-cycloalkyl], (CH2)
n-NH-C(CH
3)
2-CO-O(C
1-C
4)-alkyl, (CH2)
n-NH-C(CH
3)
2-CO-O-(CH
2)
r-NH
2、
(CH
2)
n-NH-C(CH
3)
2-CO-NH
2、
(CH
2)
n-NH-C(CH
3)
2-CO-NH-(CH
2)
r-OH、
(CH
2)
n-NH-C(CH
3)
2-COOH、S(O)
m-R12、SO
2-R16、
SO
2-N＝CH-N(CH
3)
2、SO
2-NH-CO-R12、SO
2-NHR12、
SO
2-NH-(CH
2)
r-OH、SO
2-N[(C
1-C
3)-alkyl]2、SO
2-NH-(CH
2)
r-NH
2、
SF
5、COOH、CO-NH
2、(CH
2)
q-CN、(CH
2)
n-CO-NH-piperidin-1-yl, (CH2)
n-CO-NH-SO
2-NHR12、(CH
2)
n-CO-NH-SO
2-R18、
(CH
2)
n-C(＝NH)-NHOH、C(＝NH)-[NH-O-(C
1-C
3)-alkyl], (CH2)
n-C(＝NH)(R16)、(CH
2)
n-C(＝NR12)NR12R13、
(CH
2)
n-C(＝NH)O[(C
1-C
3)-alkyl], alkyl wherein and cycloalkyl can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C1-C
3)-alkyl, (C3-C
6)-cycloalkyl, O-(C1-C
3)-alkyl, S (O)m-(C
1-C
3)-alkyl, SO2-NH
2、
COOH、CONH
2、CO-O(C
1-C
3)-alkyl, CO-(C1-C
3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
H, F, Cl, Br, CN, CF
3, (C
1-C
6)-alkyl, (C
3-C
7)-cycloalkyl, (CH
2)
n-OH, (CH
2)
n-O-(C
1-C
4)-alkyl, (CH
2)
n-O-(C
3-C
6)-cycloalkyl, (CH
2)
n-O aryl, (CH
2)
n-O-glucoside, (CH
2)
n-O-glucuronide, OCF
3, O-R13, (CH
2)
n-NH-aryl, (CH
2)
n-NH-SO
2-(C
1-C
4)-alkyl, (CH
2)
n-NH-SO
2-aryl, (CH
2)
n-NH-CO-NH
2, (CH
2)
n-NH-CO-NH-(C
1-C
3)-alkyl, (CH
2)
n-NH-CO-NH-(C
3-C
6)-cycloalkyl, (CH
2)
n-NH-C (=NH)-NH
2, S (O)
m-(C
1-C
4)-alkyl, S (O)
m-aryl, SO
2-NH
2, SO
2-NH-(C
1-C
3)-alkyl, SO
2-N[(C
1-C
3)-alkyl]
2, SF
5, (CH
2)
n-CO-[O-(C
1-C
4)-alkyl], (CH
2)
n-COOH, (CH
2)
n-CONH
2, (CH
2)
n-C (=NH) NH
2, alkyl wherein and cycloalkyl can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C
1-C
3)-alkyl, (C
3-C
6)-cycloalkyl, O-(C
1-C
4)-alkyl, S (O)
m-(C
1-C
3)-alkyl, SO
2-NH
2, COOH, CONH
2, CO-[O (C
1-C
3)-alkyl] replace and alkyl wherein can be replaced by fluorine atom;
Wherein at least one among radicals R 6, R7, R8, R9 and the R10 always is defined as NR17-aryl or NR17-bicyclic heterocycles or NR17-heteroaryl;
R11 is H, (C1-C
4)-alkyl, (C3-C
5)-cycloalkyl, (CH2)
q-[(C
3-C
4)-cycloalkyl], (CH2)
n-[(C
7-C
8)-bicyclic alkyl], (CH2)
n-[(C
7-C
8)-tricyclic alkyl], (CH2)
n-aryl, (CH2)
n-CO-[O-(C
1-C
4)-alkyl], (CH2)
n-CO-[O-(C
3-C
5)-cycloalkyl], (CH2)
n-CO-[(C
1-C
3)-alkyl], (CH2)
n-CO-[(C
3-C
5)-cycloalkyl], (CH2)
n-CO-aryl, (CH2)
n-CO-heteroaryl, (CH2)
n-CO-[O-(CH
2)
v-aryl], (CH2)
n-CO-[O-(CH
2)
v-heteroaryl], (CH2)
q-CO-NH
2、(CH
2)
q-COOH、(CH
2)
n-P(O)(OH)[O-(C
1-C
3)-alkyl], (CH2)
n-P(O)[O-(C
1-C
3)-alkyl]2、(CH
2)
n-P(O)(OH)(O-CH
2-aryl), (CH2)
n-P(O)(O-CH
2-aryl)2、(CH
2)
n-P(O)(OH)
2、(CH
2)
n-SO
3H、
(CH
2)
n-SO
2-NH
2、(CH
2)
n-CO-NH-[(C
1-C
3)-alkyl], (CH2)
n-CO-N[(C
1-C
3)-alkyl]2、(CH
2)
n-CO-NH-[(C
3-C
5)-cycloalkyl], (C2-C
3)-alkenyl-CO-O[(C1-C
4)-alkyl], (C2-C
3)-alkenyl-CONH2、(C
2-C
3)-alkenyl-COOH, (C2-C
4)-alkynyl-CO-O[(C1-C
4)-alkyl], (C2-C
4)-alkynyl-CONH2、(C
2-C
4)-alkynyl-COOH, (CH2)
n-CR21[(CO-O(C
1-C
4)-alkyl)]2、(CH
2)
n-CR21(CONH
2)
2、
(CH
2)
n-CR21(COOH)
2、(CH
2)
n-CR21R22CO-O[(C
1-C
4)-alkyl], (CH2)
n-CR21R22CONH
2、(CH
2)
n-CR21R22COOH、(CH
2)
n-CO-R16、
(CH
2)
n-C(CH
3)
2-CO-O[(C
1-C
3)]-alkyl, (CH2)
n-C(CH
3)
2-CO-O[(C
3-C
5)]-cycloalkyl, (CH2)
n-C(CH
3)
2-CO-NH
2、(CH
2)
n-C(CH
3)
2-CO-NH-[(C
1-C
3)-alkyl], (CH2)
n-C(CH
3)
2-CO-NH-(CH
2)
r-OH、(CH
2)
n-C(CH
3)
2-CO-NH-[(C
3-C
5)-cycloalkyl], (CH2)
n-C(CH
3)
2-COOH、(CH
2)
n-CO-NH-C(CH
3)
2-CONH
2、
(CH
2)
n-CO-NH-C(CH
3)
2-CO-O[(C
1-C
4)-alkyl], (CH2)
n-CO-NH-C(CH
3)
2-COOH, alkyl wherein, cycloalkyl, bicyclic alkyl and tricyclic alkyl can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C1-C
4)-alkyl, (C3-C
6)-cycloalkyl, O-(C1-C
4)-alkyl, S (O)m-(C
1-C
4)-alkyl, SO2-NH
2、
COOH、CONH
2、CO-O(C
1-C
4)-alkyl, CO-(C1-C
3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
R12 is H, (C
1-C
3)-alkyl, (C
3-C
5)-cycloalkyl, (CH
2)
n-aryl, (CH
2)
n-heteroaryl, alkyl or cycloalkyl wherein can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C
1-C
3)-alkyl, O-(C
1-C
3)-alkyl, SO
2-NH
2, COOH, CONH
2, CO-O (C
1-C
3)-alkyl, CO-(C
1-C
3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
R13 is H, SO
2-[(C
1-C
3)-alkyl], SO
2-[(C
3-C
5)-cycloalkyl], SO
2-(CH
2)
n-aryl, SO
2-(CH
2)
n-heteroaryl, SO
2-(CH
2)
n-NH-R12, SO
2-(CH
2)
n-N (R12)
2, alkyl wherein and cycloalkyl can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C
1-C
3)-alkyl, (C
3-C
6)-cycloalkyl, O-[(C
1-C
3)-alkyl], S (O)
m-[(C
1-C
3)-alkyl], SO
2-NH
2, COOH, CONH
2, CO-[O (C
1-C
3)-alkyl], CO-(C
1-C
3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
R16 is ethylene imine-1-base, azetidine-1-base, piperidines-1-base, 4-hydroxy piperidine-1-base, 3-oxo-piperidine-1-base, 4-oxo-piperidine-1-base, tetramethyleneimine-1-base, 3-pyrrolidinol-1-base, 2-Cyanopyrolidine-1-base, morpholine-N-base, piperazine-1-base, 4-[(C
1-C
3)-alkyl] piperazine-1-base, piperazine-2-ketone-1-base, piperazine-2-ketone-4-base, thiomorpholine-1,1-dioxide-4-base, NH-(CH
2)
r-OH, NH-CH (CH
2OH)
2, NH-C (CH
2OH)
3, N[(C
1-C
3)-alkyl-OH]
2, D-glucosamine-N-base, N-methyl D-glucosamine-N-base, NH-[(C
1-C
3)-alkyl]-CO-O (C
1-C
3)-alkyl, NH-[(C
1-C
3)-alkyl]-COOH, NH-[(C
1-C
3)-alkyl]-CONH
2, NH-[C (H) (aryl)]-CO-O (C
1-C
3)-alkyl, NH-[C (H) (aryl)]-COOH, NH-[C (H) (aryl)]-CONH
2, NH-[C (H) (heteroaryl)]-CO-O (C
1-C
3)-alkyl, NH-[C (H) (heteroaryl)]-COOH, NH-[C (H) (heteroaryl)]-CONH
2, NH-[(C
3-C
6)-cycloalkyl]-CO-O (C
1-C
3)-alkyl, NH-[(C
3-C
6)-cycloalkyl]-COOH, NH-[(C
3-C
6)-cycloalkyl]-CONH
2, NH-(CH
2) r-SO
2-(C
1-C
3)-alkyl, NH-[(C
1-C
4)-alkyl]-SO
3H, NH-[(C
1-C
4)-alkyl]-SO
2-NH
2, N[(C
1-C
3)-alkyl] { [(C
1-C
4)-alkyl]-SO
3H}, alcohol wherein (OH) or ketone (C=O) functional group can be by F or CF
2Substitute;
R17 is H, R18, SO
2-CH
3, SO
2-aryl, (CH
2)
n-CO-[O-(C
1-C
3)-alkyl], (CH
2)
n-CO-[(C
1-C
3)-alkyl], (CH
2)
n-CO-aryl, (CH
2)
n-CO-NH
2, (CH
2)
q-COOH, alkyl wherein and cycloalkyl can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C
1-C
3)-alkyl, O-(C
1-C
3)-alkyl, S (O)
m-(C
1-C
3)-alkyl, SO
2-NH
2, COOH, CONH
2, CO-[O (C
1-C
3)-alkyl], CO-(C
1-C
3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
R18 is (C
1-C
4)-alkyl, (C
3-C
4)-cycloalkyl, (CH
2)
n-aryl, (CH
2)
n-heteroaryl, alkyl wherein and cycloalkyl can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C
1-C
3)-alkyl, O-(C
1-C
3)-alkyl, SO
2-NH
2, COOH, CONH
2, CO-[O (C
1-C
3)-alkyl], CO-(C
1-C
3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
R20 is H, (C
1-C
3)-alkyl, (C
3-C
5)-cycloalkyl, aryl, [(C
1-C
2)-alkyl]-aryl;
R21 is H, F, CF
3, (C
1-C
3)-alkyl, (C
3-C
4)-cycloalkyl, OH, O-(C
1-C
3)-alkyl, O-(C
3-C
4)-cycloalkyl, O-(CH
2)
n-aryl, O-(CO)-(C
1-C
3)-alkyl, O-(CO)-O-(C
1-C
3)-alkyl, NH
2, NH-[(C
1-C
2)-alkyl]-aryl, NH-(C
1-C
3)-alkyl, NH-(CO)-(C
1-C
3)-alkyl;
R22 is H, CF
3, (C
1-C
3)-alkyl, aryl, [(C
1-C
2)-alkyl]-aryl.
Further preferred especially wherein one or more groups separately as following defined formula I compound with and the compatible salt of physiology:
Each methyl naturally of R, R ';
Perhaps R and R ' form cyclohexyl ring together;
N is 0,1,2;
P is 1;
A, D, E, G, L are C or N independently of one another, wherein when it is defined as N, do not have corresponding R1, R2, R3, R4, R5 substituting group;
R1, R2, R5 are H, F, Cl, Br, I, CN, CF independently of one another
3, (C
1-C
4)-alkyl, O-(C
1-C
4)-alkyl, phenyl ,-O-phenyl, SF
5, alkyl wherein can be replaced by fluorine atom and phenyl wherein can be replaced by F, Cl, Br, I;
R3 is F, CN;
R4 is CF
3, (C
1-C
4)-alkyl, O-(C
1-C
4)-alkyl;
R6, R7, R8, R9, R10 are H, F, Cl, Br, I, (C independently of one another
1-C
4)-alkyl, O-(C
1-C
4)-alkyl, alkyl wherein can be replaced by fluorine atom, NR17-aryl, and aryl wherein can be by F, Cl, Br, I, (CH
2)
n-CO-NH
2, NH
2,-SO
2-NH
2, COOH, (CH
2)
n-P (O) is [O-(C (OH)
1-C
4)-alkyl], (CH
2)
n-P (O) (OH)
2Replace;
Wherein among radicals R 6, R7, R8, R9 and the R10 always is defined as the NR17-aryl;
R17 is H, (C
1-C
4)-alkyl.
Further especially preferably wherein R3 be that F or CN and R4 are CF
3The compound of formula I.
Further especially preferably wherein R3 be that CN and R4 are CF
3The compound of formula I.
Each compound of the formula I of C naturally of further preferred especially wherein A, D, E, G and L.
Further preferred especially wherein p is the compound of 1 formula I.
When group or substituting group (for example R12) occur in the compound of formula I when once above, it is independently of one another as described in the listed definition and can be identical or different.
The present invention further provides the stereoisomer mixture of formula I and the pure steric isomer of formula I, and the non-enantiomer mixture of formula I and pure diastereomer are provided.For example can separate these mixtures with the chromatogram approach.
The present invention relates to the compound of the formula I of tautomer, racemic modification, racemic mixture, stereoisomer mixture, pure steric isomer, non-enantiomer mixture, pure diastereomeric form.For example can separate these mixtures with the chromatogram approach.
Alkyl among substituent R 1 to R22 and R and the R ' can be a straight or branched.
Compare with initial compounds or basic compound, pharmaceutically useful salt is because its highly water-soluble is suitable for medical use especially.These salt must have pharmaceutically useful negatively charged ion or positively charged ion.The suitable pharmaceutically useful acid salt of The compounds of this invention is mineral acid example hydrochloric acid, Hydrogen bromide, phosphoric acid, metaphosphoric acid, nitric acid and vitriolic salt, and can be for example acetate, Phenylsulfonic acid, phenylformic acid, citric acid, ethyl sulfonic acid, fumaric acid, gluconic acid, hydroxyethanoic acid, hydroxyethylsulfonic acid, lactic acid, lactobionic acid, toxilic acid, oxysuccinic acid, methylsulfonic acid, succsinic acid, tosic acid and tartaric salt of organic acid.Suitable pharmaceutically useful basic salt is ammonium salt, an alkali metal salt (as sodium and sylvite), alkaline earth salt (as magnesium and calcium salt), tromethamine (2-amino-2-hydroxymethyl-1, ammediol), diethanolamine, Methionin or ethylenediamine salt.
Have can not medicinal anion salt for example trifluoroacetate also be included in the scope of the present invention, it can be used as and is used to prepare or the intermediate of the pharmaceutically useful salt of purifying and/or be used for non-treatment and use for example external application.
Compound of the present invention can also exist with different polymorphics, for example is amorphous and the crystallization polymorphic.The all polymorphics of The compounds of this invention all are included in the scope of the present invention and are another aspect of the present invention.
Hereinafter, the compound and its salt as herein described and the solvate that when relating to " compound of formula I ", all refer to above-mentioned formula I.
Alkyl is understood to mean the straight or branched hydrocarbon chain with 1 to 8 carbon, for example methyl, ethyl, sec.-propyl, tert-butyl, hexyl, heptyl, octyl group.Alkyl can be as mentioned above coverlet-or polysubstituted like that.
Cycloalkyl is understood to mean the ring system that comprises one or more rings, and it exists with saturated or the unsaturated form of part (having one or two pair key) and is only formed by carbon atom, for example cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl or adamantyl.
Cycloalkyl can be as mentioned above like that by suitable group list-or polysubstituted.
Aryl is understood to mean phenyl, naphthyl, xenyl, tetralyl, α-or beta-tetrahydro naphthalenone base, indanyl or dihydro 1-Indanone base.
Aryl can be as mentioned above like that by suitable group list-or polysubstituted.
Heteroaryl is understood to mean de-carbon and also comprises the heteroatoms for example aromatic ring and the ring system of nitrogen, oxygen or sulphur outward.This definition also comprises wherein this heteroaryl and phenyl ring condensed ring system.It comprises wherein one or more CH groups equally by C=O or C=S, preferred C=O alternate ring system.
Suitable heteroaryl has for example furyl, imidazolyl, benzimidazolyl-, indyl, indolinyl, pyrimidyl, pyridyl, pyrazinyl, pyrryl, thiazolyl, oxazolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazyl, isoxazolyl, pyridazinyl, 1,3,5-triazines base, 1,2, the 4-triazinyl; 2H-pyridazin-3-one, dihydrogen dazin-3,6-diketone, imidazolidin-2-one, 1,3-glyoxalidine-2-ketone, imidazolidine-2,5-diketone, quinoline, isoquinoline 99.9, quinoxaline, quinazoline system.
The key that connects this heteroaryl can be positioned on any possible atom; For example, pyridyl can be 2-, 3-or 4-pyridyl; Thienyl can be 2-or 3-thienyl; Furyl can be 2-or 3-furyl.
Also comprise these compound corresponding N-oxide compounds, that is, for example, 1-oxygen base-2-,-3-or-the 4-pyridyl.
This heteroaryl can be as mentioned above by suitable group list-or polysubstituted.
Bicyclic heterocycles is understood to mean aromatics and the non-aromatics second cycle line system with 9 to 12 ring memberses.Five CH at the most or CH in this two ring
2Group can be independently by N, NR20, O, S (O)
mOr C=O substitutes.
Suitable bicyclic heterocycles has for example benzoglyoxaline, benzotriazole, indazole, indoles, 2,3-indoline, 1,3-dihydrobenzo imidazoles-2-ketone, 3-indazolone, oxindole, isatin, indoline-3-ketone, 1-oxo-2-isoindoline, 2H-benzo [1,2,4] thiadiazine 1,1-dioxide, 1,3-dihydrobenzo [1,2,5] thiadiazoles 2,2-dioxide, benzo [1,3,2] dithiazole 1,1,3,3-tetroxide, asccharin, benzothiazole, benzoxazole.
The key that connects this bicyclic heterocycles can be positioned on any possible atom; For example, benzimidazolyl-can be 2-, 4-or 5-benzimidazolyl-; Indyl can be 2-or 3-, 4-, 5-, 6-or 7-indyl.
Also comprise these compound corresponding N-oxide compounds.
This bicyclic heterocycles can be as mentioned above by suitable group list-or polysubstituted.
Sugar is understood to mean polyol, for example D-aldose class: erythrose, threose (tetrose class); Ribose, pectinose, wood sugar, lyxose (pentasaccharides class); Allose, altrose, glucose, seminose, gulose, idose, semi-lactosi or talose (hexanal carbohydrate), it is α-or β-form in various situations, and in possible situation, is furanose or pyranose form; See Peter M.Collins, Robert J.Ferrier:Monosaccharides, John Wiley ﹠amp; Sons Ltd, Chichester, England; 1995, the 16-18 pages or leaves [ISBN 0 471 95,342 3].
Term sugar also is understood to include D-ketose class, for example erythrulose, ribulose, xylulose, psicose, fructose, sorbose or tagatose, and it is α-or β-form in various situations, and in possible situation, is furanose or pyranose form; See Peter M.Collins, Robert J.Ferrier:Monosaccharides, John Wiley ﹠amp; Sons Ltd, Chichester, England; 1995, the 19-21 pages or leaves [ISBN 0 471 95,342 3].
In addition, term sugar also is understood to include acyclic polyol, for example second-1,2-glycol, glycerine, 1,2,3,4-erythritol (for example threitol), 1,2,3,4,5-penta hydroxy group pentane (for example arabitol), 1,2,3,4,5,6-hexahydroxy-hexane (for example sorbyl alcohol) or D-glucosamine.
(CH
2)
nThe name of-O-sugar is meant and can forms ether on any hydroxy functional group that saccharide residue exists; When the end group hydroxy functional group by sugar connects, form glycosidic link.
(CH
2)
nThe name of-O-glucoside is meant that the end group hydroxyl by glucose connects.
(CH
2)
nThe name of-O-galactoside is meant that the end group hydroxyl by semi-lactosi connects.
Saccharic acid is meant glyconic acid; A representative instance is a maltonic acid; These acid can exist with the closed loop of free form or formation lactone (sees Peter M.Collins, Robert J.Ferrier:Monosaccharides, John Wiley ﹠amp; Sons Ltd, Chichester, England; 1995, the 126-129 pages or leaves [ISBN 0 471 95,342 3]).
Term " saccharic acid " also refers to derive from the poly-hydroxy dicarboxylic acid of sugar; In some cases, these acid also can exist with the closed loop as lactone.The example of these aldaric acids has D-glucaric acid, tetrahydroxyadipic acid (glactaric acid) or tartrate (to see Peter M.Collins, Robert J.Ferrier:Monosaccharides, John Wiley ﹠amp; Sons Ltd, Chichester, England; 1995, the 138-139 pages or leaves [ISBN 0 471 95,342 3]).
Term " saccharic acid " comprises that also those ends at poly-hydroxy replacement chain comprise the monosaccharide derivatives (alditol acids) of aldehyde functional group and carboxylic acid functional.Representative instance comprises D-glucuronic acid, D-galacturonic acid and D-mannuronic acid.These uronic acids also can exist with open loop or closed loop (lactone form) (sees Peter M.Collins, Robert J.Ferrier:Monosaccharides, John Wiley ﹠amp; Sons Ltd, Chichester, England; 1995, the 313-314 pages or leaves [ISBN 0 471 95,342 3]).
Term " saccharic acid " also comprises L-xitix (vitamins C).
(CH
2)
nThe name of-O-saccharic acid is meant with the ether form and is connected in saccharic acid by hydroxyl, perhaps is connected in saccharic acid with the form of glucosides by the end group hydroxy functional group or with the form of the ester hydroxy functional group by this carboxylic acid.
(CH
2)
nThe name of-O-glucuronide is meant with the form of the glucosides end group hydroxy functional group by the D-glucuronic acid and is connected in the D-glucuronic acid.
(CH
2)
nThe name of-O-saccharic acid also is understood to mean those and wraps double bond containing pyran derivate.It is for example hydroxylated 5 that these derivatives comprise, 6-dihydro-4H-pyrans-2-formic acid or its ester.An example is 4,5,6-trihydroxy--5,6-dihydro-4H-pyrans-2-methyl-formiate.
The hydroxy functional group of described sugar and saccharic acid can exist, exist with benzylization, acidylate (particularly benzoylation or acetylize) or alkylation (particularly methylating) form with free form independently of one another; Thereby two hydroxyls also can form acetonide with the acetone reaction.
The present invention also comprises the solvate or the hydrate of formula I compound.
Therefore the compound of formula I is cannaboid 1 acceptor (CB1R) conditioning agent and is applicable to that humans and animals treats or prevent disease based on the destruction of Endocannabinoids system.
Without limitation for example, the compound of formula I can be used as psychotropic, in particular for the treatment psychosis, comprise anxiety, depressive state, psychological disorders, insomnia, delirium, obsessive compulsive neurosis, general psychosis, schizophrenia, the children's of hypoerkinesia attention-deficit hyperactivity disease (ADHD), also can be used for treating the illness relevant with using nervine material, especially have in the dependent situation in substance abuse and/or to this material, comprise alcohol dependence and nicotine dependence, also comprise Cocaine, metamfetamine and heroine dependency (are seen, for example, BehaviouralPharmacology 2005,16:275-296).At for example Ken Mackie:Annu.Rev.Pharmacol.Toxicol.46,101-122 (2006), S.C.Black:Curr.Opin.Investig.Drugs 5, people such as 389-394 (2004), V.Di Marzio: Nat.Rev.Drug Discov.3, people: J.Pharmacol.Exp.Ther.312 such as 771-784 (2004), B.Le Foll, people: Br.J.Pharmacol.141 such as 875-883 (2005) or L.Walter can find the summary to the treatment interference method of CBR1-mediation among the 775-785 (2004).
The compound of formula I of the present invention can be used as be used for the treatment of migraine, stress, illness, panic attack, epilepsy, the motion in psychosoma source be impaired, especially ataxia or Parkinson's disease, tremble and dystonic medicine.
The compound of formula I of the present invention also can be used as and is used for the treatment of dysmnesia, amentia, in particular for treating dementia, the alzheimer's disease relevant with the age and being used for the treatment of alertness or the medicine of awakening reduction.
In addition, can also treat local asphyxia, head injury and treatment neurodegenerative disease as neuroprotective, comprise tarantism, Huntington chorea, tourette's syndrome with the compound of formula I.
The compound of formula I of the present invention also can be used as the medicine for the treatment of pain; Described pain comprises the chronic pain in neuropathic pain, acute periphery pain, inflammation source.
The compound of formula I of the present invention also can be used as and is used for the treatment of eating disorder (for example disease of eating too much at one meal, apositia and exessive appetite), is used for the treatment of the drugs of addiction to sweet food, carbohydrate, medicine, alcohol or other addicted substance.
The compound of formula I of the present invention is specially adapted to treat obesity or exessive appetite and is used for the treatment of type ii diabetes and can be used for treating dyslipidemia and metabolism syndrome.Therefore, the compound of formula I of the present invention can be used for treating obesity and the risk relevant with obesity, especially cardiovascular risk.
In addition, compound of the present invention also can be used as the medicine for the treatment of following illness: disorder of gastrointestinal tract, diarrhoea, stomach and intestinal ulcer, vomiting, bladder disorders and dysuria, the illness in internal secretion source, cardiovascular disorder, ypotension, hemorrhagic shock, septic shock, chronic liver cirrhosis, fatty degeneration of liver, nonalcoholic fatty liver disease, asthma, Raynaud's syndrome, glaucoma, growing barrier, termination of pregnancy, premature labor, inflammatory syndromes, immune illness, especially autoimmunity and neural inflammatory conditions rheumatic arthritis for example, reactive arthritis, the illness that causes demyelinization, multiple sclerosis, infectious diseases and virus disease be encephalitis for example, Ischemic Stroke, and can be used as and be used for cancer chemotherapy, be used for the treatment of lucky crust syndrome and be used for the treatment of osteoporotic medicine.
Find that also the compound of formula I of the present invention can be used as the medicine of treatment polycystic ovarian syndrome (PCOS).
According to the present invention, the compound of formula I particularly can be used for treating psychotic symptoms, especially the children's of schizophrenia, alertness reduction and hypoerkinesia attention-deficit hyperactivity disease (ADHD), eating disorder and obesity, type ii diabetes, memory defective and cognitive defect, alcohol addiction, nicotine addiction promptly are used for alcohol and tobacco withdrawal.
The compound of formula I of the present invention is particularly useful for treatment and prevention eating disorder, limited appetite, metabolic disturbance, disorder of gastrointestinal tract, inflammatory syndromes, immune illness, mental illness, alcohol addiction and nicotine addiction.
According to an one aspect, the present invention relates to compound, its pharmaceutically useful salt and its solvate of formula I or the purposes that hydrate is used for the treatment of above-mentioned obstacle and disease.
The compound of formula I also can with other activeconstituents Combined Preparation.
The amount that obtains the required formula I compound of required biological action depends on many factors, for example selected particular compound, required purposes, administering mode and patient's clinical setting.Per daily dose is generally per kilogram of body weight 0.3mg to 100mg every day (being generally 3mg to 50mg), for example 3-10mg/kg/ days.Intravenous dosages can and can be aptly be carried out administration with the form of the input of per minute per kilogram 10ng to 100ng for for example 0.3mg to 1.0mg/kg.The suitable transfusion that is used for these purposes for example every milliliter can comprise 0.1ng to 10mg, 1ng to 10mg usually.Single dose can comprise for example 1mg to 10g activeconstituents.Therefore, the ampulla that is used to inject can comprise for example 1mg to 100mg activeconstituents, can for example tablet or capsule for example can comprise 1.0 to 1000mg, common 10 to 600mg activeconstituentss by the single-dose preparations of oral administration.Have the pharmaceutical compositions that can accept carrier though the compound of formula I is preferably, it can be used for the treatment of above-mentioned situation with the form of compound itself.Can and can not damage the angle of patient's health with other component compatibility of said composition from it, described carrier should be acceptable.This carrier can be a solid or/and liquid and preferably be configured to single dose with described compound, tablet for example, and it can comprise the activeconstituents of 0.05 to 95% weight.Can there be other pharmaceutically active substances equally, comprises the compound of another kind of formula I.Pharmaceutical composition of the present invention can be prepared with one of known method of pharmacy, these methods comprise substantially with component with pharmacology acceptable carrier and/or mixed with excipients to.
Pharmaceutical composition of the present invention is those compositions that are suitable for oral, rectum, part, per os (for example hypogloeeis) and parenteral (for example subcutaneous, intramuscular, intracutaneous or intravenously) administration, though optimum administering mode in each individual situation, depend on the type of used formula I compound in sanatory character and severity and each situation.The sustained release preparation of coated preparation and dressing also is included in the scope of the present invention.The preparation of preferred acidproof and resistant to gastric juice.The suitable dressing of resistant to gastric juice comprises the anionic polymer of cellulose acetate phthalate, polyvinyl acetate phthalate, Hydroxypropyl Methylcellulose Phathalate and methacrylic acid and methyl methacrylate.
The suitable formulations that is used for oral administration can be the form of individual, for example capsule of each self-contained a certain amount of formula I compound, cachet, lozenge or tablet; Powder or particle; Be arranged in the solution or the suspensoid of moisture or non-aqueous liquid; Or oil-in-water or water-in-oil emulsion.As already mentioned, these compositions can wherein make any suitable method of pharmacy of the step that activeconstituents contacts with carrier (it can be made up of one or more other components) be prepared with comprising.Generally speaking, these compositions are by activeconstituents and liquid vehicle and/or the finely divided all even homogeneous phase of solid carrier ground being mixed, if necessary this formed product being prepared thereafter.For example, therefore, tablet can be by randomly preparing described compound with the powder of one or more other compositions or particle compression or moulding.Compressed tablet can be by will randomly being mixed with tackiness agent, lubricant, inert diluent and/or the free-flowing form of a kind of (or multiple) surfactant/dispersant such as the compound compressing tablet of powder or particle form is prepared in suitable machine.Matrix band can be by being prepared with the wetting powder compound moulding of inert liquid diluent in suitable machine.
The pharmaceutical composition that is suitable for per os (hypogloeeis) administration comprises lozenge (it comprises compound and correctives (being generally sucrose) and gum arabic or the tragakanta of formula I) and pastille (it is compound as described in inert base comprises in as gelatin and glycerine or sucrose and gum arabic).
The suitable drugs composition that is used for parenteral admin preferably includes the aseptic aqueous compositions of formula I compound, and said preparation preferably oozes with expection recipient's blood etc.These preparations are preferably by intravenous administration, though also can be subcutaneous with the form of injection, intramuscular or intradermal administration.These preparations can be preferably by described compound and water is admixed together and make the solution of acquisition aseptic and ooze with blood etc. and to be prepared.The injectable composition of the present invention comprises the active compound of 0.1 to 5% weight usually.
The suitable drugs composition that is used for rectal administration is preferably the form of single dose suppository.These compositions can be by for example cocoa butter is admixed together and the mixture forming of gained is prepared with the compound of formula I and one or more conventional solid carriers.
The suitable drugs composition that is used to be applied topically to skin is preferably the form of ointment, creme, lotion, paste, sprays, aerosol or finish.The available carrier comprises the combination of Vaseline, lanolin, polyethylene glycols, alcohols and two or more these materials.Usually to account for said composition 0.1 to 15% weight, the concentration of preferred 0.5 to 2% weight exists activeconstituents.
Also can carry out transdermal administration.Being used for suitable drugs composition that transdermal uses can be for being suitable for the single plaster form with patient's epidermis long-term close contact.Such plaster is included in the aqueous solution that randomly has been cushioned aptly, dissolve and/or be scattered in goo or be scattered in activeconstituents in the polymkeric substance.Suitable activity component concentration is about 1% to 35%, is preferably about 3% to 15%.For example as Pharmaceutical Research, 2 (6): described in 318 (1986), can come with the ad hoc fashion release of active ingredients by electrotransport or iontophoresis.
Other the suitable activeconstituents that is used for described combined prod has:
All antidiabetic drugs of in Rota Liste 2005, the 12 chapters, mentioning; At Rota Liste2005, all diet pill/appetite-inhibiting agents of mentioning in the 1st chapter; All lipid lowering agents of in Rota Liste 2005, the 58 chapters, mentioning.Can be with the compound associating of these medicines and formula I of the present invention, in particular for the collaborative improvement of effect.The combination of this activeconstituents can be carried out administration by giving the described activeconstituents of patient's individual application, perhaps can carry out administration with the form that many activeconstituentss wherein are present in the combined preparation in a kind of pharmaceutical preparation.Most of activeconstituentss of mentioning below all at USPDictionary of USAN and International Drug Names, US Pharmacopeia, are disclosed among the Rockville2001.
Antidiabetic drug comprises Regular Insulin and insulin derivates, for example
(seeing www.lantus.com) or HMR 1964 or
(insulin detemir) or those materials of describing in WO2005005477 (Novo Nordisk), the Regular Insulin of quick acting (seeing US6,221,633) for example can suck Regular Insulin
, or oral insulin for example IN-105 (grace through multiple) or Oral-lyn
TM(Generex Biotechnology), GLP-1 derivative and GLP-1 agonist, for example Exenatide, profit draw glycopeptide or Novo Nordisk Co.,Ltd in WO 98/08871, WO2005027978, WO2006037811, WO2006037810, Zealand in WO01/04156 or Beaufour-Ipsen in WO 00/34331 those disclosed compound, pramlintide acetate (
Amylin Pharmaceuticals), BIM-51077, PC-DAC:Exendin-4 (a kind of with the covalently bound Exendin-4 analogue of recombinant human albumin), for example as people such as D.Chen, agonist described in the Proc.Natl.Acad.Sci.USA 104 (2007) 943, at those compounds described in the WO 2006124529, and orally active blood sugar reducing component.
Antidiabetic drug also comprises the agonist of sugared dependency insulin-releasing polypeptide (GIP) acceptor, for example at the agonist described in the WO 2006121860.
Orally active blood sugar reducing component preferably includes sulfonylurea,
Biguanides,
Meglitinides,
Oxadiazole alkane two ketones,
Thiazolidinediones,
Glucosidase inhibitor,
The inhibitor of glycogen phosphorylase,
Glucagon antagonist,
Glucokinase activators,
The inhibitor of fructose-1,
The conditioning agent of glucose transporter 4 (GLUT4),
Glutamine: the inhibitor of fructose-6-phosphate esteramides transferring enzyme (GFAT),
The GLP-1 agonist,
Potassium channel openers, for example than that ground that, cromakalim, diazoxide or as people such as R.D.Carr, Diabetes 52,2003,2513.2518, people such as J.B.Hansen, Current MedicinalChemistry 11,2004, people such as 1595-1615, T.M.Tagmose, J.Med.Chem.47,2004, people such as 3202-3211 or M.J.Coghlan, J.Med.Chem.44,2001, those materials described in the 1627-1653, or Novo Nordisk Co.,Ltd is at those materials described in WO 97/26265 and the WO 99/03861
The inhibitor of dipeptidyl peptidase-IV (DPP-IV),
Insulin sensitizer,
Participate in stimulating the inhibitor of glyconeogenesis and/or glycogenolytic liver enzyme,
The heavy uptake modulator of glucose uptake modulator, glucose transport conditioning agent and glucose,
The inhibitor of 11 β-HSD1,
The inhibitor of albumen-tyrosine phosphatase 1B (PTP1B),
The conditioning agent of sodium dependent glucose translocator 1 or 2 (SGLT1, SGLT2),
Change the compound of lipid metabolism, as effective lipidemia composition and effective component for reducing blood fat,
Reduce the compound of nutrition picked-up,
Increase the compound of heat production,
PPAR and RXR conditioning agent and
Act on the activeconstituents of the ATP-dependency potassium channel of β cell.
In one embodiment of the invention, with the compound of formula I with HMG-CoA reductase inhibitor such as Simvastatin, fluvastatin, Pravastatin, lovastatin, atorvastatin, Cerivastatin, superstatin, L-659699 Combined Preparation.
In one embodiment of the invention, with compound and the cholesterol absorption inhibitor of formula I, for example Yi Zemaibu, tiqueside, Pamaqueside, FM-VP4 (sitostanol/campesterol Ascorbic acid 2-phosphate; Forbes Medi-Tech, WO2005042692, WO2005005453), MD-0727 (Microbia Inc., WO2005021497, WO2005021495) or as WO2002066464, WO2005000353 (Kotobuki Pharmaceutical Co.Ltd.) or WO2005044256 or WO2005062824 (Merck ﹠amp; Co.) or the compound described in WO2005061451 and WO2005061452 (AstraZeneca AB) and WO2006017257 (Phenomix) or the WO2005033100 (Lipideon Biotechnology AG) or as WO2004097655, WO2004000805, WO2004000804, WO2004000803, WO2002050068, WO2002050060, WO2005047248, WO2006086562, WO2006102674, WO2006116499, WO2006121861, WO2006122186, WO2006122216, WO2006127893, WO2006137794, WO2006137796, WO2006137782, WO2006137793, WO2006137797, WO2006137795, WO2006137792, compound described in the WO2006138163 is Combined Preparation together.
In one embodiment of the invention, with compound and the Vytorin of formula I
TM(a kind of Yi Zemaibu is with the fixed combination of Simvastatin) Combined Preparation.
In one embodiment of the invention, with the compound of formula I fixed combination Combined Preparation with Yi Zemaibu and atorvastatin.
In one embodiment of the invention, with the compound of formula I fixed combination Combined Preparation with Yi Zemaibu and fenofibrate.
In another embodiment of the invention, with the compound of formula I fixed combination Combined Preparation with fenofibrate and superstatin.
In another embodiment of the invention, with the compound of formula I with Synordia (R) (fixed combination of a kind of fenofibrate and metformin) Combined Preparation.
In one embodiment of the invention, with the compound of formula I with ISIS-301012 (a kind of antisense oligonucleotide that can regulate the apolipoprotein B gene) Combined Preparation.
In one embodiment of the invention, with compound and the PPAR delta agonists of formula I, rosiglitazone, pioglitazone, JTT-501, GI262570, R-483, CS-011 (Li Gelie ketone) Combined Preparation together for example.
In one embodiment of the invention, with compound and the Competact of formula I
TM(a kind of U-72107A is with the fixed combination of hydrochloric acid metformin) Combined Preparation.
In one embodiment of the invention, with compound and the Tandemact of formula I
TM(a kind of pioglitazone is with the fixed combination of glimepiride) Combined Preparation.
In another embodiment of the invention, with the compound of formula I with U-72107A and the Angiotensin II agonist fixed combination Combined Preparation of TAK-536 for example.
In one embodiment of the invention, with the compound of formula I with PPAR alfa agonists for example GW9578, GW-590735, K-111, LY-674, KRP-101, DRF-10945, LY-518674 or as at those compound Combined Preparation described in WO2001040207, WO2002096894, the WO2005097076.
In one embodiment of the invention, with the compound of formula I with mix PPAR α/gamma agonist for example Na Geliezha, LY-510929, ONO-5129, E-3030, AVE 8042, AVE 8134, AVE 0847, CKD-501 (sulfuric acid Lip river NN-2344 (lobeglitazone sulfate)) or as people such as PCT/US 00/11833, PCT/US 00/11490, DE10142734.4 or J.P.Berger, TRENDS in Pharmacological Sciences 28 (5), 244-251, those compounds described in 2005 are Combined Preparation together.
In one embodiment of the invention, with the compound of formula I with PPAR delta agonists GW-501516 or for example as at those compound Combined Preparation described in WO2006059744, WO2006084176, WO2006029699, the WO2007039172-WO2007039178.
In one embodiment, with the compound of formula I with Mei Tageliesen or with MBX-2044 or other parts PPAR gamma agonist/antagonist Combined Preparation.
In one embodiment of the invention, with the compound of formula I and the special class of shellfish, fenofibrate, chlorine Bei Te, bezafibrate Combined Preparation together for example.
In one embodiment of the invention, with compound and the MTP inhibitor of formula I, for example implitapide, BMS-201038, R-103757, AS-1552133 or as at those compounds described in WO2005085226, WO2005121091, WO2006010423 Combined Preparation together.
In one embodiment of the invention, the compound of formula I is for example held in the palm a match cloth or JTT-705 with the CETP inhibitor or as at those compound Combined Preparation described in WO2006002342, WO2006010422, WO2006012093, WO2006073973, WO2006072362, WO2006097169, the WO2007041494.
In one embodiment of the invention, compound and the bile acide absorption inhibitor of formula I (are seen, for example, US 6,245,744, US 6,221,897 or WO00/61568), for example HMR 1741 or as at those compounds described in DE 10 2,005 033099.1 and DE 10 2,005 033100.9, WO2007009655-56 Combined Preparation together.
In one embodiment of the invention, with compound and the polymer-type bile acid adsorbent of formula I, QUESTRAN, colesevelam Combined Preparation together for example.
In one embodiment of the invention, with compound and the ldl receptor inductor (seeing US 6,342,512) of formula I, for example HMR1171, HMR1586 or as at those compounds described in WO2005097738 Combined Preparation together.
In one embodiment of the invention, with compound and the ABCA1 expression facilitator of formula I, for example, those compounds described in WO2006072393 are Combined Preparation together.
In another embodiment of the invention, with the compound of formula I RNAi therapeutical agent Combined Preparation with target PCSK9 (preceding convertase subtilisin/kexin 9).
In one embodiment, with the compound of formula I with
(omega-fatty acid; The ethyl ester of high density timnodonic acid and docosahexenoic acid) Combined Preparation together.
In one embodiment of the invention, with compound and the ACAT inhibitor of formula I, avasimibe or SMP-797 Combined Preparation together for example.
In one embodiment of the invention, with compound and the oxidation inhibitor of formula I, OPC-14117, probucol, tocopherol, xitix, β-Hu Luobusu or selenium Combined Preparation together for example.
In one embodiment of the invention, with compound and the VITAMIN of formula I, vitamin B6 or vitamin B12 Combined Preparation together for example.
In one embodiment of the invention, with compound and the lipoprotein lipase conditioning agent of formula I, the bromine that for example ends sharp flat (NO-1886) is Combined Preparation together.
In one embodiment of the invention, with compound and the ATP-citrate lyase inhibitor of formula I, SB-204990 Combined Preparation together for example.
In one embodiment of the invention, with compound and the inhibitor for squalene synthetic enzyme of formula I, BMS-188494, TAK-475 or the compound described in WO2005077907, JP2007022943 Combined Preparation together for example.
In one embodiment of the invention, with compound and lipoprotein (a) antagonist of formula I, Ji Kabin (CI-1027) Combined Preparation together for example.
In one embodiment of the invention, with the compound of formula I and the agonist of GPR109A (HM74A receptor stimulant); NAR agonist (nicotinic acid receptor agonists), for example nicotinic acid or with MK-0524A bonded " nicotinic acid of slowly-releasing ", or as at those compounds described in WO2006045565, WO2006045564, WO2006069242, WO2006124490, WO2006113150, WO2007017261, WO2007017262, WO2007017265, WO2007015744, WO2007027532 Combined Preparation together.
In another embodiment of the invention, with the compound of formula I and the agonist of GPR116, for example at those compounds described in WO2006067531, WO2006067532 Combined Preparation together.
In one embodiment of the invention, with compound and the lipase inhibitor of formula I, for example orlistat or west are for his (ATL-962) Combined Preparation together of department.
In one embodiment of the invention, with the compound of formula I with the Regular Insulin Combined Preparation.
In one embodiment, with compound and the sulfonylurea of formula I, tolbutamide, Glyburide, Glipizide, gliclazide or glimepiride Combined Preparation together for example.
In one embodiment, with the compound of formula I with the material that strengthens insulin secretion KCP-265 (WO2003097064) or for example as at those compound Combined Preparation described in the WO2007026761.
In one embodiment, the compound of formula I and glucose-dependency Regular Insulin are discharged the agonist of acceptor (GDIR), for example APD-668 Combined Preparation together.
In one embodiment, with compound and the biguanides of formula I, metformin Combined Preparation together for example.
In another embodiment, with compound and the meglitinides of formula I, repaglinide, nateglinide or mitiglinide Combined Preparation together for example.
In another embodiment, with compound and mitiglinide and the glitazone of formula I, for example U-72107A combines Combined Preparation.
In another embodiment, with the Combined Preparation that combines of the compound of formula I and mitiglinide and alpha-glucosidase inhibitor.
In one embodiment, compound and thiazolidinedione with formula I, for example troglitazone, ciglitazone, pioglitazone, rosiglitazone or as in WO 97/41097 (Dr.Reddy ' s ResearchFoundation) disclosed those compounds, especially 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolyl methoxyl group] phenyl] methyl]-2, the 4-thiazolidinedione is Combined Preparation together.
In one embodiment, with compound and the alpha-glucosidase inhibitor of formula I, miglitol or acarbose Combined Preparation together for example.
In one embodiment, with the compound of formula I and the activeconstituents that acts on the ATP dependency potassium channel of β cell, tolbutamide, Glyburide, Glipizide, glimepiride or repaglinide Combined Preparation together for example.
In one embodiment, with the compound of formula I with more than one above-claimed cpd Combined Preparation, for example with Combined Preparation such as sulfonylurea and metformin, sulfonylurea and acarbose, repaglinide and metformin, Regular Insulin and sulfonylurea, Regular Insulin and metformin, Regular Insulin and troglitazone, Regular Insulin and lovastatins.
In one embodiment, with the compound of formula I and the inhibitor of glycogen phosphorylase, for example PSN-357 or FR-258900 or as at those compounds described in WO2003084922, WO2004007455, WO2005073229-31, WO2005067932 Combined Preparation together.
In one embodiment, with compound and the glucagon receptor antagonist of formula I, for example A-770077 or NNC-25-2504 or as at the compound described in WO2004100875, WO2005065680 Combined Preparation together.
In one embodiment, with compound and the glucokinase activators of formula I, LY-2121260 (WO2004063179) for example, PSN-105, PSN-110, GKA-50, or for example at WO2004072031, WO2004072066, WO2005080360, WO2005044801, WO2006016194, WO2006058923, WO2006112549, WO2006125972, WO2007017549, WO2007017649, WO2007007910, WO2007007040-42, WO2007006760-61, WO2007006814, WO2007007886, WO2007028135, WO2007031739, WO2007041365, WO2007041366, WO2007037534, WO2007043638, WO2007053345, WO2007051846, WO2007051845, WO2007053765, those compounds described in the WO2007051847 are Combined Preparation together.
In one embodiment, with compound and the glyconeogenesis inhibitor of formula I, FR-225654 Combined Preparation together for example.
In one embodiment, compound and fructose-1 with formula I, 6-diphosphatase (FBPase) inhibitor, for example CS-917 (MB-06322) or MB-07803 or as at those compounds described in WO2006023515, WO2006104030, WO2007014619 Combined Preparation together.
In one embodiment, the compound of formula I and glucose transporter 4 (GLUT4) conditioning agent, for example KST-48 (people: Arzneim.-Forsch.Drug Res.54 (12) such as D.-O.Lee, 835 (2004)) Combined Preparation together.
In one embodiment, with compound and the glutamine of formula I: fructose-6-phosphate esteramides transferring enzyme (GFAT) inhibitor, for example at the compound described in WO2004101528 Combined Preparation together.
In one embodiment, compound and dipeptidyl peptidase-IV (DPP-IV) inhibitor, for example Vildagliptin (LAF-237) with formula I, Xi Gelieting (MK-0431), phosphoric acid Xi Gelieting, Sha Gelieting (BMS-477118), GSK-823093, PSN-9301, SYR-322, SYR-619, TA-6666, TS-021, GRC-8200, GW-825964X, KRP-104, DP-893, ABT-341, ABT-279, or its another kind of salt, or as at WO2003074500, WO2003106456, WO2004037169, WO200450658, WO2005058901, WO2005012312, WO2005/012308, WO2006039325, WO2006058064, PCT/EP2005/007821, PCT/EP2005/008005, PCT/EP2005/008002, PCT/EP2005/008004, PCT/EP2005/008283, DE 10 2,005 012874.2, DE 10 2,005 012873.4, JP2006160733, WO2006071752, WO2006065826, WO2006078676, WO2006073167, WO2006068163, WO2006090915, WO2006104356, WO2006127530, WO2006111261, WO2007015767, WO2007024993, those compounds described in the WO2007029086 are Combined Preparation together.
In one embodiment, with compound and the Janumet of formula I
TM(a kind of phosphoric acid Xi Gelieting is with the fixed combination of hydrochloric acid metformin) Combined Preparation.
In one embodiment, with the compound of formula I and 11-beta-hydroxysteroid dehydrogenase 1 (11 β-HSD1) inhibitor, for example BVT-2733, JNJ-25918646, INCB-13739, or for example at WO200190090-94, WO200343999, WO2004112782, WO200344000, WO200344009, WO2004112779, WO2004113310, WO2004103980, WO2004112784, WO2003065983, WO2003104207, WO2003104208, WO2004106294, WO2004011410, WO2004033427, WO2004041264, WO2004037251, WO2004056744, WO2004058730, WO2004065351, WO2004089367, WO2004089380, WO2004089470-71, WO2004089896, WO2005016877, WO2005097759, WO2006010546, WO2006012227, WO2006012173, WO2006017542, WO2006034804, WO2006040329, WO2006051662, WO2006048750, WO2006049952, WO2006048331, WO2006050908, WO2006024627, WO2006040329, WO2006066109, WO2006074244, WO2006078006, WO2006106423, WO2006132436, WO2006134481, WO2006134467, WO2006135795, WO2006136502, WO2006138695, WO2006133926, WO2007003521, WO2007007688, US2007066584, WO2007047625, WO2007051811, those compounds described in the WO2007051810 are Combined Preparation together.
In one embodiment, compound and albumen-tyrosine phosphatase 1B (PTP1B) inhibitor with formula I, for example, at the compound described in WO200119830-31, WO200117516, WO2004506446, WO2005012295, WO2005116003, PCT/EP2005/005311, PCT/EP2005/005321, PCT/EP2005/007151, DE 10 2,004 060542.4, WO2007009911, WO2007028145 Combined Preparation together.
In one embodiment, compound and sodium dependent glucose translocator 1 or 2 (SGLT1 with formula I, SGLT2) conditioning agent, KGA-2727 for example, T-1095, SGL-0010, AVE2268, SAR7226 and She Gelie clean (sergliflozin), or for example at WO2004007517, WO200452903, WO200452902, PCT/EP2005/005959, WO2005085237, JP2004359630, WO2005121161, WO2006018150, WO2006035796, WO2006062224, WO2006058597, WO2006073197, WO2006080577, WO2006087997, WO2006108842, WO2007000445, among the WO2007014895 or A.L.Handlon at Expert Opin.Ther.Patents (2005) 15 (11), the compound described in the 1531-1540 is Combined Preparation together.
In one embodiment, with compound and the GPR40 conditioning agent of formula I, for example at the compound described in WO2007013689, WO2007033002 Combined Preparation together.
In one embodiment, with compound and the GPR119b conditioning agent of formula I, for example at the compound described in WO2004041274 Combined Preparation together.
In one embodiment, with compound and the GPR119 conditioning agent of formula I, for example at the compound described in WO2005061489 (PSN-632408), WO2004065380, WO2007003960-62 and WO2007003964 Combined Preparation together.
In another embodiment, with the compound of formula I with GPR120 conditioning agent Combined Preparation.
In one embodiment, compound and hormone-sensitive lipase (HSL) and/or inhibitor of phospholipase enzymes with formula I, for example, at the compound described in WO2005073199, WO2006074957, WO2006087309, WO2006111321, WO2007042178 Combined Preparation together.
In one embodiment, with compound and acetyl CoA carboxylase (ACC) inhibitor of formula I, disclosed those compounds Combined Preparation together in WO199946262, WO200372197, WO2003072197, WO2005044814, WO2005108370, JP2006131559, WO2007011809, WO2007011811, WO2007013691 for example.
In another embodiment, with the compound of formula I with xanthine oxidoreductase enzyme (XOR) conditioning agent Combined Preparation.
In one embodiment, with compound and phosphoenolpyruvate carboxykinase (PEPCK) inhibitor of formula I, the Combined Preparation together of those compounds described in WO2004074288 for example.
In one embodiment, compound and glycogen synthase kinase-3 β (GSK-3 β) inhibitor with formula I, for example, the Combined Preparation together of the compound described in US2005222220, WO2005085230, PCT/EP2005/005346, WO2003078403, WO2004022544, WO2003106410, WO2005058908, US2005038023, WO2005009997, US2005026984, WO2005000836, WO2004106343, EP1460075, WO2004014910, WO2003076442, WO2005087727, WO2004046117.
In one embodiment, compound and the serum/glucocorticosteroid of formula I are regulated kinases (SGK) inhibitor, for example, at the compound described in WO2006072354 Combined Preparation together.
In one embodiment, with compound and the RUP3 receptor stimulant of formula I, for example, at the compound described in WO2007035355 Combined Preparation together.
In one embodiment, with compound and protein kinase C β (PKC β) inhibitor of formula I, the appropriate woods of Lu Bo Combined Preparation together for example.
In another embodiment, with the compound of formula I activator with the gene of coding ataxia telangiectasis sudden change (ATM) protein kinase, chloroquine Combined Preparation together for example.
In one embodiment, with compound and the endothelin A receptor antagonist of formula I, A Fushengtan (SPP-301) Combined Preparation together for example.
In one embodiment, with compound and " I-KB kinases " inhibitor (IKK inhibitor) of formula I, for example, at the compound described in WO2001000610, WO2001030774, WO2004022553, WO2005097129 Combined Preparation together.
In one embodiment, with compound and glucocorticoid receptor (GR) conditioning agent of formula I, for example at the compound described in WO2005090336, WO2006071609, WO2006135826 Combined Preparation together.
In another embodiment, with the compound of formula I and following compound coupling:
The CART conditioning agent (see " Cocaine-and amphetamine-regulated influence of transcribing " to mouse energy metabolism, anxiety and stomach emptying, Asakawa, people such as A.: Hormone and MetabolicResearch (2001), 33 (9), 554-558);
The NPY antagonist, for example hydrochloric acid N-{4-[(4-amido quinazoline-2-base is amino) methyl] cyclohexyl methyl } naphthalene-1-sulphonamide (CGP71683A);
NPY-5 receptor antagonist such as L-152804 or for example at the compound described in the WO2006001318;
NPY-4 receptor antagonist, for example compound described in WO2007038942;
NPY-2 receptor antagonist, for example compound described in WO2007038943;
Peptide YY3-36 (PYY3-36) or similar compound, for example CJC-1682 (PYY3-36 that closes by Cys34 and human serum albumin yoke) or CJC-1643 (derivative of PYY3-36, it closes with the serum albumin yoke in vivo) or at those compounds described in WO2005080424, the WO2006095166;
Derivative as the fat statin of the described peptide of WO2006096847;
CB1R (Cannabined receptor 1) antagonist (Rimonabant for example, SR147778, SLV-319, AVE-1625, MK-0364 or its salt, or as for example EP0656354, WO 00/15609, WO2001/64632, WO2001/64633, WO2001/64634, WO 02/076949, WO2005080345, WO2005080328, WO2005080343, WO2005075450, WO2005080357, WO200170700, WO2003026647-48, WO200302776, WO2003040107, WO2003007887, WO2003027069, US6,509,367, WO200132663, WO2003086288, WO2003087037, WO2004048317, WO2004058145, WO2003084930, WO2003084943, WO2004058744, WO2004013120, WO2004029204, WO2004035566, WO2004058249, WO2004058255, WO2004058727, WO2004069838, US20040214837, US20040214855, US20040214856, WO2004096209, WO2004096763, WO2004096794, WO2005000809, WO2004099157, US20040266845, WO2004110453, WO2004108728, WO2004000817, WO2005000820, US20050009870, WO200500974, WO2004111033-34, WO200411038-39, WO2005016286, WO2005007111, WO2005007628, US20050054679, WO2005027837, WO2005028456, WO2005063761-62, WO2005061509, WO2005077897, WO2006047516, WO2006060461, WO2006067428, WO2006067443, WO2006087480, WO2006087476, WO2006100208, WO2006106054, WO2006111849, WO2006113704, WO2007009705, WO2007017124, WO2007017126, WO2007018459, WO2007016460, WO2007020502, WO2007026215, WO2007028849, WO2007031720, WO2007031721, WO2007036945, WO2007038045, WO2007039740, US20070015810, WO2007046548, those compounds described in the WO2007047737);
Regulate the compound of Cannabined receptor 1/ Cannabined receptor 2 (CB1/CB2), the compound described in for example WO2007001939, WO2007044215, WO2007047737;
MC4 agonist (N-[2-(3a-benzyl-2-methyl-3-oxo-2 for example, 3,3a, 4,6,7-six hydrogen pyrazolos [4,3-e] pyridine-5-yl)-1-(4-chloro-phenyl-)-2-oxoethyl]-1-amino-1,2,3,4-naphthane-2-methane amide (WO01/91752)) or LB53280, LB53279, LB53278 or THIQ, MB243, RY764, CHIR-785, PT-141 or as WO2005060985, WO2005009950, WO2004087159, WO2004078717, WO2004078716, WO2004024720, US20050124652, WO2005051391, WO2004112793, WOUS20050222014, US20050176728, US20050164914, US20050124636, US20050130988, US20040167201, WO2004005324, WO2004037797, WO2005042516, WO2005040109, WO2005030797, US20040224901, WO200501921, WO200509184, WO2005000339, EP1460069, WO2005047253, WO2005047251, WO2005118573, EP1538159, WO2004072076, WO2004072077, WO2006021655-57, WO2007009894, WO2007015162, WO2007041061, those compounds described in the WO2007041052;
Orexin receptor antagonists (hydrochloric acid 1-(2-Jia base benzoxazole-6-yl)-3-[1 for example, 5] naphthyridines-4-base urea (SB-334867-A) or as for example WO200196302, WO200185693, WO2004085403, WO2005075458, WO2006067224 described in those compounds);
(for example 3-cyclohexyl-1-(4 for the histamine H 3 receptor agonist, 4-dimethyl-1,4,6,7-tetrahydrochysene-imidazo [4,5-c] pyridine-5-yl) third-1-ketone oxalate (WO 00/63208) or those compounds described in WO200064884, WO2005082893, WO2006107661, WO2007003804, WO2007016496, WO2007020213);
Histamine H 1/ histamine H 3 conditioning agents, for example betahistine or its dihydrochloride;
CRF antagonist (for example [2-methyl-9-(2,4, the 6-trimethylphenyl)-9H-1,3,9-three azepines fluorenes-4-yl]-dipropylamine (WO 00/66585));
CRF BP antagonist (for example Urocortin (urocortin));
The Urocortin agonist;
β-3 adrenoceptor agonists, hydrochloric acid 1-(4-chloro-3-methylsulfonyl aminomethyl phenyl)-2-[2-(2,3-dimethyl-1H-indoles-6-base oxygen base) ethylamino for example] ethanol (WO 01/83451) or Suo Labeilong (GW-427353) or N-5984 (KRP-204) or those compounds described in JP2006111553, WO2002038543, WO2007048840-843;
MSH (melanotropin) agonist;
MCH (melanin-concentrating hormone) receptor antagonist (NBI-845 for example, A-761, A-665798, A-798, ATC-0175, T-226296, T-71, GW-803430 or as WO2005085200, WO2005019240, WO2004011438, WO2004012648, WO2003015769, WO2004072025, WO2005070898, WO2005070925, WO2004039780, WO2004092181, WO2003033476, WO2002006245, WO2002089729, WO2002002744, WO2003004027, FR2868780, WO2006010446, WO2006038680, WO2006044293, WO2006044174, JP2006176443, WO2006018280, WO2006018279, WO2006118320, WO2006130075, WO2007018248, WO2007012661, WO2007029847, WO2007024004, WO2007039462, WO2007042660, WO2007042668, WO2007042669, US2007093508, US2007093509, WO2007048802, those compounds described in the JP2007091649);
CCK-A agonist ({ 2-[4-(4-chloro-2 for example, the 5-Dimethoxyphenyl)-and 5-(2-cyclohexyl ethyl) thiazol-2-yl formamyl]-5,7-dimethyl indole-1-yl } acetate trifluoroacetate (WO99/15525) or SR-146131 (WO 0244150) or SSR-125180) or at those compounds described in the WO2005116034;
Serotonin reuptake inhibitors (for example dexfenfluramine);
The fixed combination of pooled serum element/dopamine reuptake inhibitor (for example Bupropion) or Bupropion and TREXUPONT;
Plain energy of pooled serum and norepinephrine energy compound (for example WO 00/71549);
5-HT receptor stimulant, for example 1-(3-ethyl benzofuran-7-yl) piperazine oxalate (WO01/09111);
Mix Dopamine HCL/norepinephrine/vagusstoff reuptake inhibitor (for example for Suo Fenxin);
5-HT2C receptor stimulant (for example hydrochloric acid Rocca look woods (APD-356) or BVT-933 or at those compounds described in WO200077010, WO200077001-02, WO2005019180, WO2003064423, WO200242304, WO2005035533, WO2005082859, WO2006077025, the WO2006103511);
5-HT6 receptor modulators, for example E-6837 or BVT-74316 or those compounds described in for example WO2005058858, WO2007054257;
Bombesin receptor agonist (BRS-3 agonist);
The galanin receptors antagonist;
Tethelin (for example human growth hormone or AOD-9604);
Growth hormone releasing compounds (6-benzyloxy-1-(2-diisopropylaminoethyl ethylamino formyl radical)-3,4-dihydro-1H-isoquinoline 99.9-2-formic acid uncle-butyl ester (WO 01/85695));
Secretagogue receptor antagonist (braingut petide antagonist), for example A-778193 or those compounds described in WO2005030734;
TRH agonist (seeing that for example EP 0 462 884);
Uncoupling protein 2-or 3-conditioning agent;
The Leptin agonist (see, for example, Lee, Daniel W.; Leinung, Matthew C.; Rozhavskaya-Arena, Marina; What Grasso, Patricia. may can be used as the fat method of treatment comes the Leptin agonist.Drugs of the Future(2001)，26(9)，873-881)；
DA agonist (bromocriptine, Doprexin);
Lipase/amylase inhibitor (for example WO 00/40569);
Diacylglycerol O-acyltransferase (DGATs) inhibitor, for example BAY-74-4113 or the compound described in for example US2004/0224997, WO2004094618, WO200058491, WO2005044250, WO2005072740, JP2005206492, WO2005013907, WO2006004200, WO2006019020, WO2006064189, WO2006082952, WO2006120125, WO2006113919, WO2006134317, WO2007016538;
Fatty acid synthetase (FAS) inhibitor, for example C75 or at those compounds described in the WO2004005277;
Stearoyl-coa δ 9 desaturases (SCD1) inhibitor, for example, at the compound described in WO2007009236, WO2007044085, WO2007046867, WO2007046868, the WO20070501124;
Oxyntomodulin;
Oleoyl-oestrone;
Or the agonist of Thyroid Hormone Receptors or partial agonist (thyroid hormone receptor agonists), for example: KB-2115 or those compounds described in WO20058279, WO200172692, WO200194293, WO2003084915, WO2004018421, WO2005092316, WO2007003419, WO2007009913, WO2007039125.
In one embodiment, this other composition is that tartrate cuts down Ni Kelan (a kind of partial agonists of α 4-β 2 nAChRs).
In one embodiment, this other activeconstituents is curvature Kui Ming.
In one embodiment, this other activeconstituents conditioning agent that is enzyme SIRT1.
In one embodiment of the invention, this other activeconstituents is a Leptin; See, for example, " prospect is used in the Leptin treatment ", Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2 (10), 1615-1622.
In one embodiment, this other activeconstituents is Dextrofenfluramine or amphetamine.
In one embodiment, this other activeconstituents is Phenfluoramine or dexfenfluramine.
In another embodiment, this other activeconstituents is a sibutramine.
In one embodiment, this other activeconstituents is Mazindol or branch Temin.
In one embodiment, this other activeconstituents is a Diphenylazetidinone derivates, for example, as US 6,992,067 or US 7,205, described in 290.
In one embodiment, with compound and the food fibre of formula I, preferred insoluble dietary fibre (see, for example,
(people such as Zunft H J is used for the treatment of the angle beans pulp preparation of hypercholesterolemia, ADVANCES IN THERAPY (September calendar year 2001-October), 18 (5), 230-6.) Caromax is a kind of product that comprises the angle beans, derives from Nutrinova, NutritionSpecialties ﹠amp; Food Ingredients GmbH, Industriepark
, 65926Frankfurt/Main) Combined Preparation together.Should with
Combination can in a kind of preparation, realize, compound that perhaps can be by individual application formula I and
Realize.Can also with
Form with food is used, and for example uses with the form of bakery product or grain strip.
Be understood that and think that any suitable combination of The compounds of this invention and one or more above-claimed cpds and optional one or more other pharmacological active substances all drops in protection scope of the present invention.
Li Gelie ketone
Oleoyl-oestrone
DP-893 tartrate cuts down Ni Kelan
Curvature Kui Ming
Suo Labeilong hydrochloric acid Rocca look woods
E-6837 is for Suo Fenxin
CKD-501 (sulfuric acid Lip river NN-2344)
Other suitable activeconstituentss that are used for combined preparation have:
At all antiepileptic drugs described in the Rote Liste 2006, the 15 chapters;
At all antihypertensive drugs described in the Rote Liste 2006, the 17 chapters;
At all the low penetration enhancers (hypotonies) described in the Rote Liste 2006, the 19 chapters;
At all antithrombotics described in the Rote Liste 2006, the 20 chapters;
At the sclerosis of all arteries described in the Rote Liste 2006, the 25 chapters medicine;
Inhibitor at all beta receptors, calcium channel blocker and the renin-angiotensin system described in the Rote Liste 2006, the 27 chapters;
Specified all diuretic(s) and the dabbling medicine of promotion in the Rote Liste 2006, the 36 and 37 chapters;
In the Rote Liste 2006, the 39 chapters specified all give up medicine/the be used for the treatment of medicine of habituation illness;
Specified all coronary heart disease medicines and gi tract medicine in the Rote Liste 2006, the 55 and 60;
Specified all migraine agents, neuropathy preparation and Parkinson's disease medicine in the Rote Liste 2006, the 61,66 and 70 chapters.
The present invention further provides the method for preparing compound of Formula I, the compound of its Chinese style I obtains by handling similarly with following reacting flow chart:
Method " A ":
Method " A "
In first method " A ", this operation is the isocyanic ester that the suitable aniline that replaces of quilt of formula A that radicals R 1 to R5 is wherein existed with protected form if necessary transforms accepted way of doing sth B.This conversion for example can be carried out in toluene or can carry out with trichloromethylchloroformate or triphosgene with phosgene.Subsequently, under the situation that adds alkali (for example triethylamine), make this isocyanic ester B and wherein R and R ' separately suc as formula I in the reactant salt of ester of the methyl esters of defined amino acid J or other ester (for example tert-butyl ester) or amino acid J, thereby obtain the urea of formula K.This urea ring-closure reaction be can be carried out at (preferably under acidic conditions) under alkalescence or the acidic conditions, thereby the imidazolidine-2 of formula L, 4-diketone obtained.For example, can be halogen atom, preferred bromine atoms or by being one or more with Z wherein as defined substituting group and Y among the top formula I by the amido functional group of suitable protection (isoindole-1 for example, 3-diketone-2-base or N=CH-N (CH
3)
2) and V be halogen atom, preferred chlorine or bromine atom or O-SO for example
2-C
6H
4-4-CH
3Group or O-SO
2-CH
3Group or O-SO
2-CF
3Thereby the compound of the suitable compound Q alkylation formula L that replaces of the quilt of group obtains the compound of formula M to be come further to transform to the compound of formula H, and this compound is the particular case that formula I compound ortho position replaces.Can be under the Buchwald-Hartwig condition (for example: people such as S.L.Buchwald: Acc.Chem.Res.1998,31,805; People such as J.F.Hartwig: J.Org.Chem.1999,64,5575-5580; People such as J.P.Wolfe: J.Org.Chem.2000,65,144-1157; People such as M.D.Charles: Org.Lett.2005,7,3965-68) M is further transformed the compound of accepted way of doing sth H.In M, the W in reactant O is defined as NH respectively
2During with Br, Y ' is defined as Br and NH respectively
2
Perhaps can be by itself and the definition of V are wherein further changed into compound H with the L alkylation with compound L as the compound reaction that Y2 as described in just now and wherein can be defined as the formula N of NH or N-protected group.Can by will be wherein V can such as top definition and wherein Y1 be bromine or NH
2P with may substituted R19-W (compound O) reaction under Buchwald-Hartwig condition for example obtain compound N.In this case, when Y1 was defined as Br, W was defined as NH
2, be defined as NH and work as Y1
2The time W be defined as Br.R19 is defined as being substituted or unsubstituted aryl, heteroaryl or bicyclic heteroaryl.
Can when finishing, remove any blocking group that exists in the compound H, and if necessary, can be with the standard reaction of the NH of NR17 or N-protected group to group Y " further transform.
The formula H has here constituted a kind of particular case of formula I, the group Y among its Chinese style I "-R19 is positioned on the ortho position; Do necessary modifications in detail, between this group also may reside in the position or contraposition on.
A kind of modification of method " A " is method " A ' ":
Method " A ' "
In method " A ' ",, thereby form compound K with the isocyanic ester J ' reaction of amine A and amino acid ester.Can as method " A ", carry out other step.
In another kind of method " B "
Method " B "
Under the situation that adds alkali (for example triethylamine), with isocyanic ester B and wherein specific substituting group randomly protected (wherein being a limiting examples of ester) in the methyl ester shown in this schema and wherein Y be bromine or protected amido functional group (N-CO-CH for example
3Or N=CH-N (CH
3)
2) the suitable amino acid ester derivative C reaction that replaces of quilt, thereby obtain the urea of formula F.This amino acid ester derivative C can by Z wherein can be one or more described in top formula I substituting group and wherein Y be that bromine or protected amido functional group and X are (CH
2)
p(wherein U is defined as Cl, Br, I, O-SO to-U group
2-C
6H
4-4-CH
3, O-SO
2-CH
3Or O-SO
2-CF
3) Compound D and R wherein and R ' react under alkylation conditions suc as formula the amino acid ester of defined formula E among the I separately and be prepared.Perhaps, the compound of formula C can be by (Z and Y are as mentioned above and X=(CH with aldehyde D with amino acid derivative E
2)
p-CHO) reduction amination obtains.Can under alkalescence or acidic conditions (preferred acidic condition), make urea F closed loop, thereby obtain the imidazolidine-2 of formula G, 4-diketone.According to the Y in the formula G compound is bromine or NH
2, be NH with W wherein with it
2Or the compound of the formula O of bromine reacts under the Buchwald-Hartwig condition, makes the compound of formula H.
Can remove any blocking group that exists in the compound H when finishing, and if necessary, the standard reaction of NH that can be by NR17 makes Y " further reaction.
Formula H shown in this article has constituted the group Y among its Chinese style I "-R19 is positioned at a kind of Special Circumstances of the formula I on the ortho position; Do necessary modifications on the details, between this group also may reside in the position or contraposition on.
In another kind of method (method " C ")
Method " C "
With isocyanic acid right-methoxy-benzyl ester B ' and R wherein and R ' separately suc as formula defined amino acid ester among the I for example E under alkaline condition, react, thereby obtain urea K '.Under acid or alkalescence (preferred acidic) condition, make urea K ' closed loop, thereby obtain the imidazolidine-2 of formula L ', 4-diketone.Compound M ' is by with compound L ' react under alkylation conditions with compound Q and obtain.Each defines Z in the compound Q, V and Y in the method " A " freely.Right-methoxy-benzyl oxidation among the compound M ' can be eliminated, thereby obtain compound T.According to people: SYNLETT 2004 such as for example J.-B.Lan, people such as 1095-1097 or D.M.T.Chan: Tetrahedron Lett.1998,39, the described method of 2933-2936, with the imide nitrogen atom N-arylation in the formula T compound, obtain the compound of formula G ' with the aryl boric acid of formula S.According to the Y ' in the formula G ' compound is bromine or NH
2, be NH with W wherein with it
2Or the compound of the formula O of bromine reacts the compound that can make formula H under the Hartwig-Buchwald condition.
Can when finishing, remove any blocking group in the compound H, and if necessary, can make group Y with the standard reaction of the NH of NR17 " further react.
Formula H shown in this article has constituted the group Y among its Chinese style I "-R19 is positioned at a kind of particular case of adjacent formula I; Do necessary modifications in detail, between this group also can be positioned at the position or contraposition on.
Find another kind of method " D " be particularly useful for synthesis of alkyl-, cycloalkyl-, cycloalkenyl group, aryl alkylene-, the heteroaryl alkylidene group-, aryloxy-, heteroaryloxy, alkoxyl group-, alkylthio-, cycloalkylthio-, arylthio-, heteroarylthio-, alkyl-carbonyl-, naphthene base carbonyl-, aryl carbonyl-, the heteroaryl carbonyl-, aryl-and the N3-aryl of heteroaryl-replacement-or the imidazolidine-2 of N3-heteroaryl-replacement, 4-two ketones.
Method " D "
In order to prepare wherein for example compound of R2=alkyl, cycloalkyl, cycloalkenyl group, aryl or heteroaryl or another kind of above-mentioned group, can be with wherein randomly protected radical protection of amido functional group and R2 the compound of formula A ' of halogen, preferred bromine or chlorine and alkyl-, cycloalkyl-, cycloalkenyl group-, aryl-or heteroaryl boric acid or its ester derivative or R2 trifluoro boric acid ester at for example J.Zhou and G.C.Fu, J.Am.Chem.Soc.126 (2004) 1340-1341; F.Gonz á les-Bobes and G.C.Fu, J.Am.Chem.Soc.128 (2006) 5360-5361; D.J.Wallace and C.-Y.Chen, Tetrahedron Letters 43 (2002) 6987-6990; People such as T.E.Barder, J.Am.Chem.Soc.127 (2005) 4685-4696; People such as D.W.Old, J.Am.Chem.Soc.120 (1998) 9722; T.E.Barder and St.L.Buchwald react under the described condition of Org.Lett.6 (2004) 2649-2652.Can as described in method " A " and " B ", the compd A that is replaced by R2 thus further be reacted.
In method " D ", also can be the compd A of halogen, preferred chlorine or bromine with R2 wherein ' under palladium catalysis with two boron compounds, for example two valeryl two boron reactions, thus obtain wherein that R2 is-B (O-C (CH
3)
2-C (CH
3)
2-O) formula A " the boric acid aryl ester.In another step, can be with this compound and organohalogen compound R2-Hal reaction, be the compound of the formula A of cycloalkyl or aryl for example thereby obtain R2 wherein.Next, can obtain the reaction of formula H compound subsequently according to method " A " or " B ".
Wherein R2 be-the O/S-alkyl ,-the O/S-cycloalkyl ,-O/S-CH
2-aryl ,-O/S-CH
2-heteroaryl ,-the O/S-aryl ,-compound of the formula A of O/S-heteroaryl can be the compound of the formula A ' of halogen, preferred bromine or chlorine by R2 wherein, by with corresponding alcohols or phenols or thio-alcohol or sulfydryl aryl and-heteroaryl class material and cesium carbonate react under palladium or copper catalysis that make (also can be referring to R.Frlan and D.Kikelj; Synthesis 14 (2006) 2271-2285; People such as A.V.Vorogushin, J.Am.Chem.Soc.127 (2005) 8146-8149; F.Y.Kwong and St.L.Buchwald, Org.Lett.4 (2002) 3517-3520).
Wherein R2 is-CH
2-aryl or-CH
2The compound of the formula A of-heteroaryl for example can be by formula A " compound by with halogen wherein preferably the halogenated methyl aryl of bromine or chlorine or halogenated methyl heteroaryl under alkaline condition and palladium catalysis, react and obtain (also can be referring to S.M.Nobre and A.L.Monteiro, Tetrahedron Letters 45 (2004) 8225-8228; People such as S.Langle, Tetrahedron Letters 44 (2003) 9255-9258).
Also can in another kind of method " E ", acquisition can pass through the compound that method " D " obtains:
Method " E "
In order to prepare wherein for example compound of R2=alkyl, cycloalkyl, cycloalkenyl group, aryl or heteroaryl or another kind of above-mentioned group, can with the compound of formula K1 or L1 (its for example can as described in the method " A ", obtain and wherein R2 be halogen, preferred bromine or chlorine) with alkyl-, cycloalkyl-, cycloalkenyl group-, aryl-or heteroaryl boric acid or its ester derivative or R2 trifluoro-acetate at for example J.Zhou and G.C.Fu, J.Am.Chem.Soc.126 (2004) 1340-1341; F.Gonz á les-Bobes and G.C.Fu, J.Am.Chem.Soc.128 (2006) 5360-5361; D.J.Wallace and C.-Y.Chcn, Tetrahedron Letters 43 (2002) 6987-6990; People such as T.E.Barder, J.Am.Chem.Soc.127 (2005) 4685-4696; People such as D.W.Old, J.Am.Chem.Soc.120 (1998) 9722; T.E.Barder and St.L.Buchwald react under the described condition of Org.Lett.6 (2004) 2649-2652.Can as described in method " A " and " B ", further transform compound K 1 ' and the L1 ' that is replaced by R2 thus.
Described in method " D ", the operation in the method " E " also can be for compound K 1 or L1 and two boron compounds, for example two valeryl two boron reactions, and R2 is thereby obtain wherein
Formula K1 " or L1 " the boric acid aryl ester.In another step, these compounds and organohalogen compound R2-Hal can be reacted, be for example cycloalkyl or the formula K1 ' of aryl or the compound of L1 ' thereby obtain wherein R2.The reaction that is used to obtain The compounds of this invention subsequently can be carried out as described in top method " A " or " B ".
Can also can be prepared by the K1 or the conversion in L1 stage with the compound of other definition with R2 of method " D " preparation with method " E ".
Come with the following examples that further the present invention will be described, but the present invention is not limited to product described in the embodiment and embodiment.
General experimental technique:
1H NMR：
1H NMR spectrum is upward measured at 300K at 500MHz instrument (Bruker DRX 500) in deuterated dimethyl sulfoxide.Data: δ is unit with ppm, and multiplicity (s, unimodal; D, doublet; The t triplet; Q, quartet; M, multiplet), x H (number of hydrogen atoms)
HPLC/MS：
The mensuration of HPLC-MS is carried out on Waters LCT instrument.
Post: YMC Jsphere 33 x 24 μ m; Gradient [A]: (acetonitrile+0.05% trifluoroacetic acid): (water+0.05% trifluoroacetic acid) 5:95 (0 minute) is to 95:5 (3 minutes); Gradient [B]: (acetonitrile+0.05% trifluoroacetic acid): (water+0.05% trifluoroacetic acid) 5:95 (0 minute) to 95:5 (2.5 minutes) to 95:5 (3.0 minutes); Gradient [C]: (acetonitrile+0.05% trifluoroacetic acid): (water+0.05% trifluoroacetic acid) 5:95 (0 minute) to 95:5 (3.4 minutes) to 95:5 (4.4 minutes); Gradient [D]: (acetonitrile+0.05% trifluoroacetic acid): (water+0.05% trifluoroacetic acid) 2:98 (1 minute) to 95:5 (5 minutes) to 95:5 (6.25 minutes); Gradient [E]: (acetonitrile+0.05% trifluoroacetic acid): (water+0.05% trifluoroacetic acid) 5:95 (0 minute) to 5:95 (0.5 minute) to 95:5 (3.5 minutes) to 95:5 (4.0 minutes); Gradient [F]: post: YMC Jsphere ODS H8020 x 2mm, 4 μ m; (water+0.05% trifluoroacetic acid): (acetonitrile+0.05% trifluoroacetic acid) 96:4 (0 minute) to 5:95 (2 minutes) to 96:4 (2.4 minutes); Detector: Tecan-LCT.
The chromatogram purification method:
[RP1]: flow velocity: 30ml/min; Gradient: acetonitrile/water+0.1% trifluoroacetic acid; 30 minutes.Post: XTerra C18 5 μ m 30 x 100mm; Detect: MS (ESI), UV (DAD).
[RP2]: flow velocity: 150ml/min; Gradient: acetonitrile/water+0.1% trifluoroacetic acid; 20 minutes.Post: XTerra C18 10 μ m 50 x 250mm; Detect: MS (ESI), UV (DAD).
Embodiment 1:4-[4,4-dimethyl-2,5-dioxo-3-(2-phenyl amino benzyl) imidazolidine-1-yl]-2-trifluoromethyl benzonitrile
1) preparation of 4-(4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl)-2-trifluoromethyl benzonitrile (1.1):
Compound 1.1 can be prepared with method " A ".For this reason, 14.74g (79.21mmol) 4-amino-2-trifluoromethyl benzonitrile is dissolved in the 200ml anhydrous acetonitrile.This solution under agitation is added drop-wise in the toluene solution of 20% phosgene that is heated to 70 ℃, then it was stirred 1 hour.With chilled reaction soln concentrating under reduced pressure, with resistates with toluene dissolving and with its concentrating under reduced pressure once more.At last, resistates is dissolved in the 150ml anhydrous acetonitrile and this solution and 15.5g (79.21mmol) hydrochloric acid 2-amino-2-methyl propionic acid uncle-butyl ester are mixed.In this reaction mixture, slowly drip 12.02g (118.8mmol) triethylamine, then it was at room temperature stirred 45 minutes.Modestly this mixture with 50ml concentrated hydrochloric acid mixed and it was stirred 1 hour down at 70 ℃ thereafter.Should chilled reaction mixture concentrating under reduced pressure and resistates and ethyl acetate and water is admixed together.Take out organic phase,, wash with water then, use dried over sodium sulfate, filtration and its concentrating under reduced pressure with the saturated sodium carbonate solution washing.Resistates is carried out purifying with silica gel chromatography, carry out wash-out with 2:1 heptane/ethyl acetate.Obtain 21.2g (yield is 90%) 4-(4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl)-2-trifluoromethyl benzonitrile 1.1, its fusing point is 208-211 ℃.
2) 4-[3-(2-bromobenzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-preparation of 2-trifluoromethyl benzonitrile (1.2):
Compound 1.2 can be prepared with method " A "., 21.2g (71.32mmol) compound 1.1 and 17.83g (71.32mmol) 2-bromobenzyl bromide are dissolved in the 200ml anhydrous acetonitrile for this reason, admixed together and it was at room temperature stirred 5 hours with 12.32g salt of wormwood.For aftertreatment, this reaction mixture and water is admixed together, by coming this mixture is extracted,, filter and its concentrating under reduced pressure with the organic phase dried over sodium sulfate with the ethyl acetate jolting.Resistates is carried out purifying with silica gel chromatography, carry out wash-out with 3:1 heptane/ethyl acetate.Obtain the 4-[3-(2-bromobenzyl)-4 of 28.5g (yield is 86%), 4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-2-trifluoromethyl benzonitrile (1.2), its fusing point is 56-58 ℃.
3) 4-[4,4-dimethyl-2,5-dioxo-3-(2-phenyl amino benzyl) imidazolidine-1-yl]-preparation of 2-trifluoromethyl benzonitrile (1):
In order to prepare the compound of embodiment 1, can operate according to method " A ".For this reason, under argon gas atmosphere, with 49.98mg (0.107mmol) compound 1.2,14.98mg (0.161mmol) aniline, 104.8mg cesium carbonate, 2.4mg palladium (II) and 12.4mg 9,9-dimethyl-4,5-two (diphenylphosphino) xanthene join successively in the no Shui diox of 20ml and with this mixture and stirred 8 hours down at 80 ℃.Should chilled reaction mixture and water and ethyl acetate admixed together, take out organic phase, with dried over sodium sulfate and with its concentrating under reduced pressure.Resistates is carried out purifying (method [RP1]) with chromatography.Obtain the compound of 45mg (yield is 88%) embodiment 1, its molecular weight is 478.16 (C
26H
21F
3N
4O
2); Retention time R
t=2.33 minutes [B]; MS (ESI): 479.43 (MH
+).
The compound of embodiment 2,4-{3-[2-(4-fluorophenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 496.15 (C to 2-trifluoromethyl benzonitrile
26H
20F
4N
4O
2); Retention time R
t=2.25 minutes [B]; MS (ESI): 497.28 (MH
+)),
With the compound of embodiment 3,4-{3-[2-(4-cyano group-3-trifluoromethyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 571.14 (C to 2-trifluoromethyl benzonitrile
28H
19F
6N
5O
2); Retention time R
t=2.17 minutes [B]; MS (ESI): 572.38 (MH
+)),
The compound of embodiment 4,4-{3-[2-(4-chloro-phenyl-amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 512.12 (C to 2-trifluoromethyl benzonitrile
26H
20ClF
3N
4O
2); Retention time R
t=2.35 minutes [B]; MS (ESI): 513.01 (MH
+)),
The compound of embodiment 5,4-{3-[2-(4-trifluoromethyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 546.14 (C to 2-trifluoromethyl benzonitrile
27H
20F
6N
4O
2); Retention time R
t=2.34 minutes [B]; MS (ESI): 547.09 (MH
+)),
The compound of embodiment 11,4-{3-[2-(2,4 difluorobenzene base amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 514.14 (C to 2-trifluoromethyl benzonitrile
26H
19F
5N
4O
2); Retention time R
t=2.32 minutes [B]; MS (ESI): 515.17 (MH
+)),
The compound of embodiment 12,4-{3-[2-(4-trifluoromethoxy-phenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 562.14 (C to 2-trifluoromethyl benzonitrile
27H
20F
6N
4O
3); Retention time R
t=2.46 minutes [B]; MS (ESI): 563.15 (MH
+)),
The compound of embodiment 13,4-{3-[2-(2,4 dichloro benzene base amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 546.08 (C to 2-trifluoromethyl benzonitrile
26H
19Cl
2F
3N
4O
2); Retention time R
t=2.52 minutes [B]; MS (ESI): 547.14 (MH
+)),
The compound of embodiment 14,4-{3-[2-(2-chloro-4-methyl sulphonyl phenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 590.10 (C to 2-trifluoromethyl benzonitrile
27H
22ClF
3N
4O
4S); Retention time R
t=2.01 minutes [B]; MS (ESI): 591.17 (MH
+)),
The compound of embodiment 20,4-{3-[2-(3,4-dichlorophenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 546.08 (C to 2-trifluoromethyl benzonitrile
26H
19Cl
2F
3N
4O
2); Retention time R
t=2.50 minutes [B]; MS (ESI): 547.11 (MH
+)),
The compound of embodiment 21,4-{3-[2-(2-chloro-phenyl-amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 512.12 (C to 2-trifluoromethyl benzonitrile
26H
20ClF
3N
4O
2); Retention time R
t=2.37 minutes [B]; MS (ESI): 513.11 (MH
+)),
The compound of embodiment 22,4-{3-[2-(3-chloro-phenyl-amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 512.12 (C to 2-trifluoromethyl benzonitrile
26H
20ClF
3N
4O
2); Retention time R
t=2.39 minutes [B]; MS (ESI): 513.13 (MH
+)),
The compound of embodiment 26,4-{3-[2-(4-Pentafluorosulfanyl phenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 604.11 (C to 2-trifluoromethyl benzonitrile
26H
20F
8N
4O
2S); Retention time R
t=2.42 minutes [B]; MS (ESI): 605.21 (MH
+)),
The compound of embodiment 27,4-{3-[2-(4-methyl sulphonyl phenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 556.13 (C to 2-trifluoromethyl benzonitrile
27H
23F
3N
4O
4S); Retention time R
t=1.92 minutes [B]; MS (ESI): 557.23 (MH
+)),
The compound of embodiment 31,4-{3-[2-(2,2-difluoro benzo [1,3] dioxole-4-base is amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 558.13 (C to 2-trifluoromethyl benzonitrile
27H
19F
5N
4O
4); Retention time R
t=2.38 minutes [B]; MS (ESI): 559.22 (MH
+)),
The compound of embodiment 32,4-{3-[2-(2,2-difluoro benzo [1,3] dioxole-5-base is amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 558.13 (C to 2-trifluoromethyl benzonitrile
27H
19F
5N
4O
4); Retention time R
t=2.42 minutes [B]; MS (ESI): 559.20 (MH
+)),
The compound of embodiment 33,4-{3-[2-(4-cyano-phenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 503.15 (C to 2-trifluoromethyl benzonitrile
27H
20F
3N
5O
2); Retention time R
t=2.09 minutes [B]; MS (ESI): 545.28 (MH
++ CH
3CN)),
The compound of embodiment 34,4-{3-[2-(3-trifluoromethyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 546.14 (C to 2-trifluoromethyl benzonitrile
27H
20F
6N
4O
2); Retention time R
t=2.39 minutes [B]; MS (ESI): 547.18 (MH
+)),
The compound of embodiment 44,4-{3-[2-(2-fluorophenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 496.15 (C to 2-trifluoromethyl benzonitrile
26H
20F
4N
4O
2); Retention time R
t=2.28 minutes [B]; MS (ESI): 497.18 (MH
+)),
The compound of embodiment 45,4-(4,4-dimethyl-2,5-dioxo-3-{2-[4-(piperidines-1-alkylsulfonyl) phenyl amino] benzyl }-imidazolidine-1-yl)-(molecular weight is 625.19 (C to 2-trifluoromethyl benzonitrile
31H
30F
3N
5O
4S); Retention time R
t=2.23 minutes [B]; MS (ESI): 626.25 (MH
+)),
The compound of embodiment 46,4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-N, (molecular weight is 585.16 (C to the N-dimethyl benzene sulfonamide
28H
26F
3N
5O
4S); Retention time R
t=2.05 minutes [B]; MS (ESI): 586.19 (MH
+)),
The compound of embodiment 47,4-(4,4-dimethyl-3-{2-[4-(morpholine-4-alkylsulfonyl) phenyl amino] benzyl }-2,5-dioxo alkyl imidazole-1-yl)-(molecular weight is 627.17 (C to 2-trifluoromethyl benzonitrile
30H
28F
3N
5O
5S); Retention time R
t=2.02 minutes [B]; MS (ESI): 628.23 (MH
+)),
The compound of embodiment 53,4-{3-[2-(2-cyano group-4-fluorophenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 521.14 (C to 2-trifluoromethyl benzonitrile
27H
19F
4N
5O
2); Retention time R
t=2.18 minutes [B]; MS (ESI): 522.19 (MH
+)),
The compound of embodiment 60,4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } (molecular weight is 536.16 (C to methyl benzoate
28H
23F
3N
4O
4); Retention time R
t=2.16 minutes [B]; MS (ESI): 537.14 (MH
+)),
The compound of embodiment 67,4-{3-[2-(4-p-methoxy-phenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 508.17 (C to 2-trifluoromethyl benzonitrile
27H
23F
3N
4O
3); Retention time R
t=2.29 minutes [B]; MS (ESI): 509.22 (MH
+)),
The compound of embodiment 72,4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-(molecular weight is 554.15 (C to the 3-fluorophenyl carbamate
28H
22F
4N
4O
4); Retention time R
t=2.20 minutes [B]; MS (ESI): 555.12 (MH
+)),
The compound of embodiment 73,4-{3-[2-(2-fluoro-4-cyano-phenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 521.14 (C to 2-trifluoromethyl benzonitrile
27H
19F
4N
5O
2); Retention time R
t=2.11 minutes [B]; MS (ESI): 522.13 (MH
+)),
The compound of embodiment 74,4-{3-[2-(2-fluoro-4-p-methoxy-phenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 526.16 (C to 2-trifluoromethyl benzonitrile
27H
22F
4N
4O
3); Retention time R
t=2.28 minutes [B]; MS (ESI): 527.10 (MH
+)),
The compound of embodiment 75,4-{3-[2-(3,4-Dimethoxyphenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 538.18 (C to 2-trifluoromethyl benzonitrile
28H
25F
3N
4O
4); Retention time R
t=2.12 minutes [B]; MS (ESI): 539.10 (MH
+)),
The compound of embodiment 76,4-{3-[2-(4-benzyloxy-2-fluorophenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 602.19 (C to 2-trifluoromethyl benzonitrile
33H
26F
4N
4O
3); Retention time R
t=2.52 minutes [B]; MS (ESI): 603.14 (MH
+)),
The compound of embodiment 77,4-{3-[2-(4-benzyloxy phenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 584.20 (C to 2-trifluoromethyl benzonitrile
33H
27F
3N
4O
3); Retention time R
t=2.50 minutes [B]; MS (ESI): 585.14 (MH
+)),
The compound of embodiment 78,4-{3-[2-(4-cyano methyl phenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 517.17 (C to 2-trifluoromethyl benzonitrile
28H
22F
3N
5O
2); Retention time R
t=2.10 minutes [B]; MS (ESI): 518.15 (MH
+)),
The compound of embodiment 79, (4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenyl) (molecular weight is 614.19 (C to diethyl phosphonate
30H
30F
3N
4O
5P); Retention time R
t=2.00 minutes [B]; MS (ESI): 615.10 (MH
+)),
The compound of embodiment 82, (4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenyl) (molecular weight is 550.18 (C to methyl acetate
29H
25F
3N
4O
4); Retention time R
t=2.18 minutes [B]; MS (ESI): 551.14 (MH
+)),
The compound of embodiment 120,4-{3-[2-(4-formyl radical phenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 506.49 (C to 2-trifluoromethyl benzonitrile
27H
21F
3N
4O
3); Retention time R
t=2.02 minutes [B]; MS (ESI): 507.11 (MH
+)),
The compound of embodiment 127,4-{3-[2-(4-isopropyl phenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 536.20 (C to 2-trifluoromethyl benzonitrile
29H
27F
3N
4O
3); Retention time R
t=2.36 minutes [B]; MS (ESI): 537.16 (MH
+)),
The compound of embodiment 145, (4R, 5S, 6S)-and 6-(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenoxy group)-4,5-dihydroxyl-5,6-dihydro-4H-pyrans-2-methyl-formiate (
1H NMR:8.34, d, 1H; 8.25, s, 1H; 8.09, d, 1H; 7.42, m, 2H; 7.2, m, 1H; 7.12, m, 1H; 7.02, d, 2H; 6.92, m, 3H; 5.98, s, 1H; 5.65, s, 1H; 5.47, d, 1H; 4.6, s, 2H; 4.12, m, 1H; 3.71, s, 3H; 3.69, m, 1H; 1.4, s, 6H; Molecular weight is 566.19 (C
33H
29F
3N
4O
8); MS (ESI): 667.21 (MH
+),
The compound of embodiment 197, (4R, 5S, 6S)-4,5-diacetoxy-6-(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenoxy group)-5,6-dihydro-4H-pyrans-2-methyl-formiate (
1H NMR:8.34, d, 1H; 8.23, s, 1H; 8.07, d, 1H; 7.49, s, 1H; 7.45, d, 1H; 7.21, t, 1H; 7.14, d, 1H; 6.99, d, 2H; 6.96, t, 1H; 6.91, d, 2H; 6.14, d, 1H; 5.91, d, 1H; 5.34, t, 1H; 5.21, t, 1H; 4.58, s, 2H; 3.74, s, 3H; 2.1, s, 6H; 1.38, s, 6H),
Be to be prepared like the compounds with embodiment 1, difference is at the synthetic three phases, substitutes aniline with following compound:
4-fluoroaniline (for 2),
4-cyano group-3-5-trifluoromethylaniline (for 3),
4-chloroaniline (for 4),
4-5-trifluoromethylaniline (for 5),
2,4 difluorobenzene amine (for 11),
4-trifluoro-methoxyaniline (for 12),
2,4 dichloro aniline (for 13),
2-chloro-4-methyl sulphonyl aniline (for 14),
3,4-dichlorphenamide bulk powder (for 20),
2-chloroaniline (for 21),
3-chloroaniline (for 22),
4-Pentafluorosulfanyl aniline is (for 26; This compound by 4-nitro Pentafluorosulfanyl benzene (CAS#2613-27-6) by catalytic reduction in ethanol makes with hydrogen and palladium on carbon (10%); Similar with the preparation of isometry compound 51.3),
4-methyl sulphonyl aniline (for 27),
2,2-difluoro benzo [1,3] dioxole-4-base amine (for 31),
2,2-difluoro benzo [1,3] dioxole-5-base amine (for 32),
4-cyano-aniline (for 33),
3-5-trifluoromethylaniline (for 34),
2-fluoroaniline (for 44),
4-(piperidines-1-alkylsulfonyl) phenyl amine (for 45),
4-amino-N, N-dimethyl benzene sulfonamide (for 46),
4-(morpholine-4-alkylsulfonyl) phenyl amine (for 47),
2-cyano group-4-fluoroaniline (for 53),
4-Methyl anthranilate (for 60),
4-anisidine (for 67),
3-fluoro-4-Methyl anthranilate (for 72),
4-cyano group-2-fluoroaniline (for 73),
2-fluoro-4-anisidine (for 74),
3,4-dimethoxyaniline (for 75),
2-fluoro-4-benzyloxy-aniline (for 76),
The 4-benzyloxy-aniline (for (for 77),
(4-aminophenyl) acetonitrile (for 78),
(4-aminophenyl) diethyl phosphonate (for 79),
(4-aminophenyl) methyl acetate (for 82),
4-aminobenzaldehyde (for 120),
4-isopropoxy aniline (for 127),
(2R, 3R, 4R, 5S, 6R)-3,4,5-triacetyl oxygen base-6-(4-amino-benzene oxygen) tetrahydropyrans-2-methyl-formiate (for 145 and 197).
Embodiment 6:4-[3-(5-methoxyl group-2-phenyl amino benzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-2-trifluoromethyl benzonitrile
1) 4-[3-(2-bromo-5-methoxy-benzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-preparation of 2-trifluoromethyl benzonitrile 6.2:
1.5g (5.05mmol) compound 1.1 and 1.695g (6.06mmol) 2-bromo-5-methoxy-benzyl bromine and 2.06g cesium carbonate are reacted in the 10ml acetonitrile, and describedly like that it is carried out aftertreatment as 1, the 2 stage of embodiment.Obtain 2.45g (yield is 98%) 4-[3-(2-bromo-5-methoxy-benzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-2-trifluoromethyl benzonitrile (6.2).
1H NMR：8.35，d，1H；8.25，s，1H；8.1，d，1H；7.55，d，1H；7.1，s，1H；6.88，d，1H；4.6，s，2H；3.76，s，3H；1.42，s，6H。
2) 4-[3-(5-methoxyl group-2-phenyl amino benzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-preparation of 2-trifluoromethyl benzonitrile 6:
As 1, the 3 stage of embodiment described like that further with aniline reaction, thereby obtain the compound of embodiment 6.Obtain 4-[3-(5-methoxyl group-2-phenyl amino benzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-(molecular weight is 508.17 (C to 2-trifluoromethyl benzonitrile 6
27H
23F
3N
4O
3); Retention time R
t=2.19 minutes [B]; MS (ESI): 509.14 (MH
+)).
The compound of embodiment 7,4-{3-[2-(4-fluorophenyl amino)-5-methoxy-benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 526.16 (C to 2-trifluoromethyl benzonitrile
27H
22F
4N
4O
3); Retention time R
t=2.19 minutes [B]; MS (ESI): 527.13 (MH
+)),
With the compound of embodiment 8,4-{3-[5-methoxyl group-2-(4-trifluoromethyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 576.15 (C to 2-trifluoromethyl benzonitrile
28H
22F
6N
4O
3); Retention time R
t=2.30 minutes [B]; MS (ESI): 577.15 (MH
+)),
The compound of embodiment 9,4-{3-[2-(4-chloro-phenyl-amino)-5-methoxy-benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 542.13 (C to 2-trifluoromethyl benzonitrile
27H
22ClF
3N
4O
3); Retention time R
t=2.29 minutes [B]; MS (ESI): 543.12 (MH
+)),
The compound of embodiment 10,4-{3-[2-(4-cyano group-3-trifluoromethyl amino)-5-methoxy-benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 601.15 (C to 2-trifluoromethyl benzonitrile
29H
21F
6N
5O
3); Retention time R
t=2.12 minutes [B]; MS (ESI): 602.19 (MH
+))
Be to be prepared as the compound of embodiment 6, difference is, in its synthetic subordinate phase, substitutes aniline with following compound:
4-fluoroaniline (for 7),
4-5-trifluoromethylaniline (for 8),
4-chloroaniline (for 9),
4-cyano group-3-5-trifluoromethylaniline (for 10).
Embodiment 15:4-{3-[5-fluoro-2-(4-fluorophenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-2-trifluoromethyl benzonitrile
1) 4-[3-(2-bromo-5-luorobenzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-preparation of 2-trifluoromethyl benzonitrile 15.2:
Compound 15.2 makes by compound 1.1 is reacted with 2-bromo-5-fluoro benzyl bromide as described in the embodiment 6.2.Yield with 95% obtains 4-[3-(2-bromo-5-luorobenzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-(molecular weight is 483.02 (C to 2-trifluoromethyl benzonitrile
20H
14BrF
4N
3O
2); Retention time R
t=2.10 minutes [B]; MS (ESI): 484.26 (MH
+))
2) 4-{3-[5-fluoro-2-(4-fluorophenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-preparation of 2-trifluoromethyl benzonitrile 15:
As 1, the 3 stage of embodiment described like that further with 4-fluoroaniline reaction, thereby obtain the compound of embodiment 15.Obtain 4-{3-[5-fluoro-2-(4-fluorophenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 514.14 (C to 2-trifluoromethyl benzonitrile 15
26H
19F
5N
4O
2); Retention time R
t=2.28 minutes [B]; MS (ESI): 515.21 (MH
+).)
The compound of embodiment 16,4-{3-[2-(4-chloro-phenyl-amino)-5-luorobenzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 530.11 (C to 2-trifluoromethyl benzonitrile
26H
19ClF
4N
4O
2); Retention time R
t=2.38 minutes [B]; MS (ESI): 531.21 (MH
+)),
The compound of embodiment 18,4-[3-(5-fluoro-2-phenyl amino benzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-(molecular weight is 496.15 (C to 2-trifluoromethyl benzonitrile
26H
20F
4N
4O
2); Retention time R
t=2.28 minutes [B]; MS (ESI): 497.20 (MH
+))
Be to be prepared as the compound of embodiment 15, difference is, in its synthetic subordinate phase, substitutes the 4-fluoroaniline with following compound:
4-chloroaniline (for 16),
Aniline (for 18).
Embodiment 17:4-{3-[2-(4-fluorophenyl amino)-5-trifluoromethyl benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-2-trifluoromethyl benzonitrile
1) 4-[3-(2-bromo-5-trifluoromethyl benzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-preparation of 2-trifluoromethyl benzonitrile 17.2:
Compound 17.2 is as described in the embodiment 6.2, by what compound 1.1 and 2-bromo-5-trifluoromethyl benzyl bromine reaction were made.Yield with 96% obtains 4-[3-(2-bromo-5-trifluoromethyl benzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-2-trifluoromethyl benzonitrile.(molecular weight is 533.01 (C
21H
14BrF
6N
3O
2); Retention time R
t=2.21 minutes [B]; MS (ESI): 534.14 (MH
+))
2) 4-{3-[2-(4-fluorophenyl amino)-5-trifluoromethyl benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-preparation of 2-trifluoromethyl benzonitrile 17:
As 1, the 3 stage of embodiment described like that further with 4-fluoroaniline reaction, thereby obtain the compound of embodiment 17.Obtain 4-{3-[2-(4-fluorophenyl amino)-5-trifluoromethyl benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-2-trifluoromethyl benzonitrile 17.(molecular weight is 564.13 (C
27H
19F
7N
4O
2); Retention time R
t=3.13 minutes [C]; MS (ESI): 565.17 (MH
+).)
The compound of embodiment 19,4-{3-[2-(4-chloro-phenyl-amino)-5-trifluoromethyl benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 580.11 (C to 2-trifluoromethyl benzonitrile
27H
19ClF
6N
4O
2); Retention time R
t=3.21 minutes [C]; MS (ESI): 581.18 (MH
+))
Be to be prepared as the compound of embodiment 17, difference is, in its synthetic subordinate phase, substitutes the 4-fluoroaniline with 4-chloroaniline (for 19).
Embodiment 109:4-{5-chloro-2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } methyl benzoate
1) 4-[3-(2-bromo-4-benzyl chloride base)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-preparation of 2-trifluoromethyl benzonitrile 109.2:
Compound 109.2 is as described in the embodiment 1.2, by (being made by N-bromine succinimide bromination by 2-bromo-4-chloro-1-methylbenzene with the 2-bromo-1-brooethyl-4-chlorobenzene of compound 1.1 with alternative 2-bromobenzyl bromide;
1H NMR:7.82, d, 1H; 7.65, s, 1H; 7.5, d, 1H; 4.72 s 2H) reacts and is prepared.Obtain 4-[3-(2-bromo-4-benzyl chloride base)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-2-trifluoromethyl benzonitrile.(molecular weight is 498.99 (C
20H
14BrClF
3N
3O
2); Retention time R
t=2.30 minutes [B]; MS (ESI): 541.04 (MH
++ CH
3CN).)
2) 4-{5-chloro-2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } methyl benzoate 109:
As 1, the 3 stage of embodiment described like that further with 4-Methyl anthranilate reaction, thereby obtain the compound of embodiment 109.Obtain 4-{5-chloro-2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } methyl benzoate 109.(molecular weight is 570.12 (C
28H
22ClF
3N
4O
4); Retention time R
t=2.30 minutes [B]; MS (ESI): 571.21 (MH
+).)
The compound of embodiment 123,4-{5-chloro-2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } [molecular weight is 612.17 (C to phenylformic acid uncle-butyl ester
31H
28ClF
3N
4O
4);
1H NMR:8.38, s, 1H; 8.35, d, 1H; 8.2, s, 1H; 8.07, d, 1H; 7.8, d, 2H; 7.57, d, 1H; 7.3, s, 1H; 7.18, d, 1H; 6.9, d, 2H; 4.56, s, 2H; 1.52, s, 9H; 1.39, s, 6H] and be as the compound of embodiment 109, to be prepared, difference is, in its synthetic subordinate phase, substitutes the 4-Methyl anthranilate with 4-benzaminic acid uncle-butyl ester.
Embodiment 110:4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-p-methoxy-phenyl amino } methyl benzoate
1) 4-[3-(2-bromo-4-methoxy-benzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-preparation of 2-trifluoromethyl benzonitrile 110.2:
Compound 110.2 is as described in the embodiment 1.2, by (being made by N-bromine succinimide bromination by 2-bromo-4-methoxyl group-1-methylbenzene with the 2-bromo-1-brooethyl-4-anisole of compound 1.1 with alternative 2-bromobenzyl bromide;
1H NMR:7.56, d, 1H; 7.23, s, 1H; 7.0, d, 1H; 4.74, s, 2H; 3.8 s 3H) reacts and is prepared.Obtain 4-[3-(2-bromo-4-methoxy-benzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-2-trifluoromethyl benzonitrile.(molecular weight is 495.04 (C
21H
17BrF
3N
3O
3);
1H NMR:8.38, d, 1H; 8.25, s, 1H; 8.1, d, 1H; 7.5, d, 1H; 7.22, s, 1H; 6.95, d, 1H; 4.6, s, 2H; 3.79, s, 3H; 1.4, s, 6H.)
2) 4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-p-methoxy-phenyl amino } methyl benzoate 110:
As 1, the 3 stage of embodiment described like that further with 4-Methyl anthranilate reaction, thereby obtain the compound of embodiment 110.Obtain 4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-p-methoxy-phenyl amino } methyl benzoate 110.(molecular weight is 566.17 (C
29H
25F
3N
4O
5); Retention time R
t=2.17 minutes [B]; MS (ESI): 567.22 (MH
+).
The compound of embodiment 124,4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-p-methoxy-phenyl amino } [molecular weight is 608.22 (C to phenylformic acid uncle-butyl ester
32H
31F
3N
4O
5); Retention time R
t=2.37 minutes [B]; MS (ESI): 553.14 (MH
+-C
4H
6)] be as the compound of embodiment 110, to be prepared, difference is, in its synthetic subordinate phase, substitutes the 4-Methyl anthranilate with 4-benzaminic acid tert-butyl ester.
Embodiment 111:4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } methyl benzoate
1) 4-[3-(2-bromo-4-luorobenzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-preparation of 2-trifluoromethyl benzonitrile 111.2:
Compound 111.2 is as described in the embodiment 1.2, by (the free radical bromination makes by carrying out in tetrachloromethane with N-bromine succinimide by 2-bromo-4-fluoro-1-methylbenzene with the 2-bromo-1-brooethyl-4-chlorobenzene of compound 1.1 and alternative 2-bromobenzyl bromide;
1H NMR:7.7, m, 1H; 7.65, d, 1H; 7.3, m, 1H; 4.75, s, 2H).(molecular weight is 483.02 (C
20H
14BrF
4N
3O
3);
1HNMR:8.37, d, 1H; 8.25, s, 1H; 8.1, d, 1H; 7.65, m, 2H; 7.27, m, 1H; 4.62, s, 2H; 1.41, s, 6H).
2) 4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } methyl benzoate 111:
Described like that as 1, the 3 stage of embodiment, further with the reaction of 4-Methyl anthranilate, thereby obtain the compound of embodiment 111.Obtain 4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } methyl benzoate 111.(molecular weight is 554.15 (C
28H
22F
4N
4O
4); Retention time R
t=2.21 minutes [B]; MS (ESI): 555.22 (MH
+)).
The compound of embodiment 125,4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } [molecular weight is 596.20 (C to phenylformic acid uncle-butyl ester
31H
28F
4N
4O
4); Retention time R
t=2.42 minutes [B]; MS (ESI): 541.14 (MH
+-C
4H
6)] as embodiment 111, be prepared, difference is, in its synthetic subordinate phase, substitutes the 4-Methyl anthranilate with 4-benzaminic acid uncle-butyl ester.
In a similar fashion, by reacting the compound (6-{2-[3-(4-cyano group-3-trifluoromethyl)-5 that obtains embodiment 265 with 6-amino-nicotinic acid methyl esters with 111.2,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } nicotinic acid methyl ester (form of trifluoroacetate)).
Embodiment 126:4-{5-cyano group-2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenylformic acid uncle-butyl ester
1) 4-[3-(2-bromo-4-cyano group benzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-preparation of 2-trifluoromethyl benzonitrile 126.2:
Compound 126.2 is as described in the embodiment 1.2, by (being made by N-bromine succinimide bromination by 3-bromo-4-benzonitrile with the 2-bromo-1-brooethyl-4-cyano group benzene of compound 1.1 with alternative 2-bromobenzyl bromide;
1H NMR:8.25, s, 1H; 7.9, d, 1H; 7.81, d, 1H; 4.78 s 3H) reacts and is prepared.(molecular weight is 490.02 (C
21H
14BrF
3N
4O
2);
1H NMR:8.35, d, 1H; 8.25, m, 2H; 8.1, d, 1H; 7.88, d, 1H; 7.78, d, 1H; 4.68, s, 2H; 1.49, s, 6H.)
2) 4-{5-cyano group-2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenylformic acid uncle-butyl ester 126:
Described like that as 1, the 3 stage of embodiment, further with 4-benzaminic acid uncle-butyl ester reaction, thereby obtain the compound of embodiment 126.Obtain 4-{5-cyano group-2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenylformic acid uncle-butyl ester 126.(molecular weight is 603.20 (C
32H
28F
3N
5O
4); Retention time R
t=2.28 minutes [B]; MS (ESI): 548.16 (MH
+-C
4H
8)).
Embodiment 146:4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-dimethylamino alkylsulfonyl phenyl amino } phenylformic acid uncle-butyl ester
1) 3-bromo-4-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-N, the preparation of N-dimethyl benzene sulfonamide 146.2:
Compound 146.2 is as described in the embodiment 1.2, by 3-bromo-4-brooethyl-N with compound 1.1 and alternative 2-bromobenzyl bromide, N-dimethyl benzene sulfonamide (146.3, by with 3-bromo-4, N, N-trimethylbenzene sulfonamide and N-bromine succinimide and N, N '-azo-group two (2-methyl propionitrile) react in tetrachloromethane and to make) react and be prepared.Obtain 3-bromo-4-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-N, the N-dimethyl benzene sulfonamide.(molecular weight is 572.03 (C
22H
20BrF
3N
4O
4S); Retention time R
t=2.38 minutes [B]; MS (ESI): 573.25 (MH
+).)
2) 4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-dimethylamino alkylsulfonyl phenyl amino } phenylformic acid uncle-butyl ester 146:
With embodiment described mode of 1, the 3 stage similarly, further with 4-benzaminic acid uncle-butyl ester reaction, thereby obtain the compound of embodiment 146.Obtain 4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-dimethylamino alkylsulfonyl phenyl amino } phenylformic acid uncle-butyl ester 146.(molecular weight is 685.21 (C
33H
34F
3N
5O
6S); Retention time R
t=2.85 minutes [C]; MS (ESI): 630.18 (MH
+-C
4H
8)).
Embodiment 23:3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-1-(2-phenyl amino benzyl) imidazolidine-2,4-diketone
1) 3-(4-fluoro-3-trifluoromethyl)-5,5-methylimidazole alkane-2, the preparation of 4-diketone (23.1):
Compound 23.1 can be prepared with method " A ".For this reason, 1.5g (9.76mmol) hydrochloric acid 2-amino-2-methyl methyl propionate is suspended in the 20ml anhydrous tetrahydro furan and acyl group-the 2-trifluoromethylbenzene is admixed together with itself and 1.38ml (9.76mmol) triethylamine and 2g (9.76mmol) 1-fluoro-4-isocyanide.This mixture was stirred 1 hour down at 70 ℃, it is cooled off a little, add the 10ml concentrated hydrochloric acid and also this mixture was stirred 2 hours down at 70 ℃.Should chilled reaction mixture and ethyl acetate and water admixed together; Take out organic phase, use dried over sodium sulfate, filtration and its concentrating under reduced pressure.Resistates is carried out purifying (method [RP2]) with chromatography and it is dissolved in the ethyl acetate again, with this solution drying, concentrating under reduced pressure is dissolved in it in methylene dichloride again, with just-heptane makes its crystallization.Obtain 2.8g 3-(4-fluoro-3-trifluoromethyl)-5,5-methylimidazole alkane-2,4-diketone (23.1), its fusing point are 111-114 ℃.
Molecular weight is 290.06 (C
12H
10F
4N
2O
2); Retention time R
t=1.55 minutes [B]; MS (ESI): 291.27 (MH
+).
2) 1-(2-bromobenzyl)-3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-imidazolidine-2, the preparation of 4-diketone (23.2):
Compound 23.2 can be prepared with method " A ".For this reason, with preparation 1.2 described methods compound 23.1 and 2-bromobenzyl bromide are reacted.Yield with 93% obtains 1-(2-bromobenzyl)-3-(4-fluoro-3-trifluoromethyl)-5,5-methylimidazole alkane-2,4-diketone.Molecular weight is 458.02 (C
19H
15BrF
4N
2O
2); Retention time R
t=2.80 minutes [C]; MS (ESI): 459.04 (MH
+).
3) 3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-1-(2-phenyl amino benzyl) imidazolidine-2, the preparation of 4-diketone 23:
In order to prepare the compound of embodiment 23, can operate according to method " A ".Make compound 23.2 and aniline reaction similarly with the method in 1, the 3 stage of embodiment.Yield with 81% obtains compound 23.Molecular weight is 471.14 (C
25H
21F
4N
3O
2); Retention time R
t=2.34 minutes [B]; MS (ESI): 472.11 (MH
+).
The compound of embodiment 24,1-[2-(4-fluorophenyl amino) benzyl]-3-(4-fluoro-3-trifluoromethyl)-5,5-methylimidazole alkane-2, the 4-diketone, (molecular weight is 489.14 (C
25H
20F
5N
3O
2); Retention time R
t=2.34 minutes [B]; MS (ESI): 490.11 (MH
+);
With the compound of embodiment 25,1-[2-(4-chloro-phenyl-amino) benzyl]-3-(4-fluoro-3-trifluoromethyl)-5,5-methylimidazole alkane-2, (molecular weight is 505.11 (C to the 4-diketone
25H
20ClF
4N
3O
2); Retention time R
t=2.45 minutes [B]; MS (ESI): 506.11 (MH
+);
The compound of embodiment 52,1-[2-(2,4 difluorobenzene base amino) benzyl]-3-(4-fluoro-3-trifluoromethyl)-5,5-methylimidazole alkane-2, the 4-diketone, (molecular weight is 507.13 (C
25H
19F
6N
3O
2); Retention time R
t=2.34 minutes [B]; MS (ESI): 507.98 (MH
+),
The compound of embodiment 134,4-{2-[3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } benzonitrile, (molecular weight is 496.15 (C
26H
20F
4N
4O
2); Retention time R
t=2.14 minutes [B]; MS (ESI): 497.18 (MH
+)
Be to be prepared as the compound of embodiment 23, difference is, in this synthetic phase III, substitutes aniline with following compound:
4-fluoroaniline (for 24),
4-chloroaniline (for 25),
2,4 difluorobenzene amine (for 52),
4-aminobenzonitrile (for 134).
Embodiment 28:4-[2,4-dioxo-1-(2-phenyl amino benzyl)-1,3-diaza spiro [4.5] last of the ten Heavenly stems-3-yl]-2-trifluoromethyl benzonitrile
1) preparation of 4-(2,4-dioxo-1,3-diazaspiracyclic [4.5] last of the ten Heavenly stems-3-yl)-2-trifluoromethyl benzonitrile (28.1):
Compound 28.1 can be prepared with method " A ".For this reason, at first under argon gas atmosphere, add 5.3ml phosgene solution (20% toluene solution).Under 75 ℃, slowly to wherein dripping the 4-cyano group-solution of 3-5-trifluoromethylaniline in the 15ml anhydrous acetonitrile.After adding, with this mixture 75 ℃ of following restir 90 minutes.With this mixture concentrating under reduced pressure.Then, with resistates with the toluene redissolve and with its concentrating under reduced pressure once more.At last, resistates is dissolved in the 15ml anhydrous tetrahydro furan, admixed together with 0.72g 1-amino-1-naphthenic acid, drip the 1.05ml triethylamine and also this mixture was at room temperature stirred 2 hours.After it is at room temperature left standstill a night, with this reaction mixture and the 5ml concentrated hydrochloric acid is admixed together and it was stirred 2 hours under refluxing.Should chilled reaction mixture and saturated sodium bicarbonate solution is admixed together and with ethyl acetate it is extracted.With the organic phase dried over mgso, filter and its concentrating under reduced pressure.Obtain 0.62g 4-(2,4-dioxo-1,3-diaza spiro [4.5] last of the ten Heavenly stems-3-yl)-2-trifluoromethyl benzonitrile (28.1).
1H NMR：9.21，s，1H；8.30，d，1H；8.19，s，1H；8.02，d，1H；1.8-1.5，m，9H；1.4-1.25，m，1H。
2) 4-[1-(2-bromobenzyl)-2,4-dioxo-1,3-diaza spiro [4.5] last of the ten Heavenly stems-3-yl]-preparation of 2-trifluoromethyl benzonitrile (28.2):
Compound 28.2 can be prepared with method " A ".For this reason, as described in the embodiment 1.2, make compound 28.1 and 2-benzyl bromide bromine reaction.Yield with 98% obtains compound 28.2.
1H NMR：8.45，d，1H；8.26，s，1H；8.10，d，1H；7.7-7.25，m，4H；4.6，s，2H；2.1-1.55，m，9H；1.2，m，1H。
3) 4-[2,4-dioxo-1-(2-phenyl amino benzyl)-1,3-diaza spiro [4.5] last of the ten Heavenly stems-3-yl]-preparation of 2-trifluoromethyl benzonitrile (28):
In order to prepare the compound of embodiment 28, can operate according to method " A ".Make 28.2 and aniline reaction similarly with embodiment 1.2 described methods.28: molecular weight is 518.19 (C
29H
25F
3N
4O
2); Retention time R
t=3.19 minutes [C]; MS (ESI): 519.24 (MH
+).
Embodiment 29:4-[4,4-dimethyl-2,5-dioxo-3-(3-phenyl amino benzyl) imidazolidine-1-yl]-2-trifluoromethyl benzonitrile
The compound of embodiment 29 is like the class of operation with the compound of embodiment 1, react by 3-bromo benzyl bromo to obtain with compound 1.1 and alternative 2-bromobenzyl bromide, thereby obtain compound 29.2 (
1H NMR:8.35, d, 1H; 8.25, s, 1H; 8.10, d, 1H; 7.7, s, 1H; 7.5, m, 2H; 7.3, t, 1H; 4.6, s, 2H; 1.4, s, 6H).Describedly in another step, make 29.2 and aniline reaction as 1, the 3 stage of embodiment, thus the compound of embodiment 29.Molecular weight is 478.16 (C
26H
21F
3N
4O
2); Retention time R
t=2.53 minutes [B]; MS (ESI): 479.48 (MH
+).
Embodiment 30:4-[4,4-dimethyl-2,5-dioxo-3-(4-phenyl amino benzyl) imidazolidine-1-yl]-2-trifluoromethyl benzonitrile
The compound of embodiment 30 is like the class of operation with the compound of embodiment 1, by the 4-benzyl bromide bromine reaction with compound 1.1 and alternative 2-bromobenzyl bromide obtain compound 30.2 (
1H NMR:8.35, d, 1H; 8.25, s, 1H; 8.10, d, 1H; 7.55, d, 2H; 7.4, d, 2H; 4.6, s, 2H; 1.4 s 6H) obtains.Describedly in another step, make 30.2 and aniline reaction as 1, the 3 stage of embodiment, thereby obtain the compound of embodiment 30.Molecular weight is 478.16 (C
26H
21F
3N
4O
2); Retention time R
t=2.54 minutes [B]; MS (ESI): 479.41 (MH
+).
Embodiment 35:4-{3-[2,4-two chloro-6-(4-fluorophenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-2-trifluoromethyl benzonitrile
2-bromo-4, the preparation of 6-dichloro benzyl bromine 35.3:
A) the 2-bromo-4,6-dichlorobenzoic acid 35.5:
4.85ml nitrous acid uncle-butyl ester is added drop-wise under 0 ℃ in the suspension of 6.5g cupric bromide (II) in the 100ml anhydrous acetonitrile.In 5 minutes, in this bottle-green solution, add 5g2-amino-4,6-dichlorobenzoic acid in batches.This mixture was stirred 2 hours down at 0 ℃, it is heated stir a night to room temperature and with it.This mixture is evaporated to only about half of volume; The hydrochloric acid that adds 70ml1N also extracts this mixture with the 60ml Di Iso Propyl Ether.Organic phase and 70ml2N sodium hydroxide solution is admixed together.Take out water and it is transferred to pH2 with hydrochloric acid.By coming water is extracted,, filter and its concentrating under reduced pressure with the organic phase dried over mgso with the Di Iso Propyl Ether jolting.Obtain 2-bromo-4,6-dichlorobenzoic acid 35.5.
1H NMR：14.2，s，1H；7.9，d，1H；7.8，d，1H。
B) (2-bromo-4,6-dichlorophenyl) methyl alcohol 35.4:
Be dissolved in 2.5g acid 35.5 in the 25ml anhydrous tetrahydro furan and under 0 ℃ under agitation to the tetrahydrofuran solution that wherein drips 9.26ml 1M lithium aluminum hydride.This reaction mixture was also at room temperature stirred 2 hours at 0 ℃ of following restir in 30 minutes.For aftertreatment, under the refrigerative situation, this mixture is transferred to pH2 and itself and ethyl acetate and water is admixed together with 2.5N sulfuric acid.Take out organic phase, with dried over mgso and with its concentrating under reduced pressure.Obtain (2-bromo-4,6-dichlorophenyl) methyl alcohol 35.4 and it is not used for next step with being further purified.
C) the 2-bromo-4,6-dichloro benzyl bromine 35.3:
3.1g benzylalcohol 35.4 is dissolved in the 40ml anhydrous methylene chloride and under 5 ℃ to wherein dripping the solution of 0.455ml phosphorus tribromide in the 10ml methylene dichloride.This reaction mixture is stirred night and it being neutralized with the 5ml saturated aqueous sodium carbonate.Take out organic phase, use dried over mgso, filtration and its concentrating under reduced pressure.Resistates is carried out purifying with silica gel column chromatography, with just-heptane is as eluent.Obtain 2-bromo-4,6-dichloro benzyl bromine 35.3.
1H NMR：7.9，s，1H；7.8，s，1H；4.75，s，2H。
1) 4-[3-(2-bromo-4,6-dichloro benzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-preparation of 2-trifluoromethyl benzonitrile 35.2:
Compound 35.2 is as embodiment 6.2 is described, and by with compound 1.1 and 2-bromo-4,6-dichloro benzyl bromine 35.3 reacts and is prepared.Yield with 83% obtains 4-[3-(2-bromo-4,6-dichloro benzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-2-trifluoromethyl benzonitrile.
1H NMR：8.35，d，1H；8.2，s，1H；8.05，d，1H；7.9，s，1H；7.8，s，1H；4.9，s，2H；1.35，s，6H。
2) 4-{3-[2,4-two chloro-6-(4-fluorophenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-preparation of 2-trifluoromethyl benzonitrile 35:
As 1, the 3 stage of embodiment described like that further with 4-fluoroaniline reaction, thereby obtain the compound of embodiment 35.Obtain 4-{3-[2,4-two chloro-6-(4-fluorophenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-2-trifluoromethyl benzonitrile 35.(molecular weight is 564.07 (C
26H
18Cl
2F
4N
4O
2); Retention time R
t=2.98 minutes [B]; MS (ESI): 606.23 (MH
++ CH
3CN).)
The compound of embodiment 36,4-{3-[2,4-two chloro-6-(2,4 difluorobenzene base amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 582.06 (C to 2-trifluoromethyl benzonitrile
26H
17Cl
2F
5N
4O
2); Retention time R
t=2.98 minutes [B]; MS (ESI): 583.32 (MH
+),
With the compound of embodiment 37,4-{3-[2,4-two chloro-6-(4-chloro-phenyl-amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 580.04 (C to 2-trifluoromethyl benzonitrile
26H
18C1
3F
3N
4O
2); Retention time R
t=3.09 minutes [B]; MS (ESI): 581.32 (MH
+),
With the compound of embodiment 104,4-{3,5-two chloro-2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } (molecular weight is 604.08 (C to methyl benzoate
28H
21Cl
2F
3N
4O
4); Retention time R
t=2.52 minutes [B]; MS (ESI): 605.17 (MH
+),
Be prepared as embodiment 35, difference is, in its synthetic subordinate phase, substitutes the 4-fluoroaniline with following compound:
2,4 difluorobenzene amine (for 36),
4-chloroaniline (for 37),
4-Methyl anthranilate (for 104).
Embodiment 38:4-{3-[3,5-two chloro-2-(4-fluorophenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-2-trifluoromethyl benzonitrile
2-bromo-3, the preparation of 5-dichloro benzyl bromine 38.3:
2-bromo-3,5-dichloro benzyl bromine 38.3 are to use and 2-bromo-4, the mode that 6-dichloro benzyl bromine 35.3 is identical, but by 3,5-two chloro-o-amino benzoic acids begin via 2-bromo-3, and 5-dichlorobenzoic acid 38.5 and (2-bromo-3,5-dichlorophenyl) methyl alcohol 38.4 prepare.2-bromo-3,5-dichloro benzyl bromine 38.3:
1H NMR:7.8, s, 1H; 7.55, s, 1H; 4.75, s, 2H.
1) 4-[3-(2-bromo-3,5-dichloro benzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-preparation of 2-trifluoromethyl benzonitrile 38.2:
Compound 38.2 is as embodiment 6.2 is described, and by with compound 1.1 and 2-bromo-3,5-dichloro benzyl bromine reacts and is prepared.Yield with 55% obtains 4-[3-(2-bromo-3,5-dichloro benzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-2-trifluoromethyl benzonitrile.
1H NMR：8.35，d，1H；8.25，s，1H；8.1，d，1H；7.7，s，1H；7.65，s，1H；4.65，s，2H；1.45，s，6H。
2) 4-{3-[3,5-two chloro-2-(4-fluorophenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-preparation of 2-trifluoromethyl benzonitrile 38:
As 1, the 3 stage of embodiment described like that further with 4-fluoroaniline reaction, thereby obtain the compound of embodiment 38.Obtain 4-{3-[3,5-two chloro-2-(4-fluorophenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-2-trifluoromethyl benzonitrile 38.(molecular weight is 564.07 (C
26H
18Cl
2F
4N
4O
2); Retention time R
t=2.37 minutes [B]; MS (ESI): 565.17 (MH
+)).
The compound of embodiment 39,4-{3-[3,5-two chloro-6-(2,4 difluorobenzene base amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 582.06 (C to 2-trifluoromethyl benzonitrile
26H
17Cl
2F
5N
4O
2); Retention time R
t=2.42 minutes [B]; MS (ESI): 583.16 (MH
+)),
With the compound of embodiment 40,4-{3-[3,5-two chloro-6-(4-chloro-phenyl-amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 580.04 (C to 2-trifluoromethyl benzonitrile
26H
18Cl
3F
3N
4O
2); Retention time R
t=2.47 minutes [B]; MS (ESI): 581.14 (MH
+)),
Be to be prepared as the compound of embodiment 38, difference is, in its synthetic subordinate phase, substitutes the 4-fluoroaniline with following compound:
2,4 difluorobenzene amine (for 39),
4-chloroaniline (for 40).
Embodiment 41:4-{3-[5-chloro-2-(4-fluorophenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-2-trifluoromethyl benzonitrile
1) 4-[3-(2-bromo-5-benzyl chloride base)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-preparation of 2-trifluoromethyl benzonitrile 41.2:
Compound 41.2 is as embodiment 6.2 is described, is prepared by compound 1.1 and 2-bromo-5-chlorine bromotoluene (being made by reacting with the lithium aluminum hydride reaction and with thus obtained benzylalcohol and phosphorus tribromide by 2-bromo-5-chloro-benzoic acid) reacted.Yield with 64% obtains 4-[3-(2-bromo-5-benzyl chloride base)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-2-trifluoromethyl benzonitrile.
1H NMR：8.35，d，1H；8.25，s，1H；8.1，d，1H；7.65，m，2H；7.33，d，1H；4.6，s，2H；1.45，s，6H。
2) 4-{3-[5-chloro-2-(4-fluorophenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-preparation of 2-trifluoromethyl benzonitrile 41:
As 1, the 3 stage of embodiment described like that further with 4-fluoroaniline reaction, thereby obtain the compound of embodiment 41.Obtain 4-{3-[5-chloro-2-(4-fluorophenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-2-trifluoromethyl benzonitrile 41.(molecular weight is 530.11 (C
26H
19ClF
4N
4O
2); Retention time R
t=2.37 minutes [B]; MS (ESI): 531.17 (MH
+)).
The compound of embodiment 42,4-{3-[5-chloro-6-(2,4 difluorobenzene base amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 548.10 (C to 2-trifluoromethyl benzonitrile
26H
18ClF
5N
4O
2); Retention time R
t=2.38 minutes [B]; MS (ESI): 549.17 (MH
+)),
With the compound of embodiment 43,4-{3-[5-chloro-6-(4-chloro-phenyl-amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 546.08 (C to 2-trifluoromethyl benzonitrile
26H
19Cl
2F
3N
4O
2); Retention time R
t=2.48 minutes [B]; MS (ESI): 547.15 (MH
+)),
Be to be prepared as the compound of embodiment 41, difference is, in its synthetic subordinate phase, substitutes the 4-fluoroaniline with following compound:
2,4 difluorobenzene amine (for 42),
4-chloroaniline (for 43).
Embodiment 48:4-{3-[2,5-two (4-chloro-phenyl-amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-2-trifluoromethyl benzonitrile
In the preparation (yield is 40%) of embodiment 43 compounds, the yield with 23% has obtained the compound as the embodiment 48 of other product.Molecular weight is 637.12 (C
32H
24Cl
2F
3N
5O
2); Retention time R
t=2.58 minutes [B]; MS (ESI): 638.20 (MH
+).
Embodiment 49:1-[2-(2,4 difluorobenzene base amino) benzyl]-5,5-dimethyl-3-(4-Phenoxyphenyl) imidazolidine-2,4-diketone
1) 5,5-dimethyl-3-(4-Phenoxyphenyl) imidazolidine-2, the preparation of 4-diketone (49.1):
Compound 49.1 can be prepared with method " A "., 7.8g hydrochloric acid 2-amino-2-methyl propionic acid uncle-butyl ester at room temperature is suspended in the 100ml anhydrous tetrahydro furan, with itself and 8.9g isocyanic acid 4-phenoxy group phenyl ester with the 8.4ml triethylamine is admixed together and this mixture was at room temperature stirred 2 hours for this reason.Add 20ml concentrated hydrochloric acid and with this mixture under refluxing restir 2 hour thereafter.Should chilled reaction mixture and water and ethyl acetate admixed together; With the organic phase saturated sodium bicarbonate solution, with concentrated sodium chloride solution washing, use dried over mgso then, filtration and with its concentrating under reduced pressure.Resistates is stirred with Di Iso Propyl Ether, it is leached, with some Di Iso Propyl Ethers it is washed again through suction filtration, dry then.Yield with 97% obtains 49.1, and its fusing point is 165 ℃.Molecular weight is 296.11 (C
17H
16N
2O
3); Retention time R
t=1.95 minutes; MS (ESI): 297.42 (MH
+).
2) 1-(2-bromobenzyl)-5,5-dimethyl-3-(4-Phenoxyphenyl) imidazolidine-2, the preparation of 4-diketone (49.2):
Compound 49.2 can be prepared with method " A ".For this reason, as described in the embodiment 1.2, make compound 49.1 and 2-benzyl bromide bromine reaction.Yield with 98% obtains compound 49.2.Molecular weight is 464.07 (C
24H
21BrN
2O
3); Retention time R
t=2.58 minutes [B]; MS (ESI): 465.33 (MH
+).
3) 1-[2-(2,4 difluorobenzene base amino) benzyl]-5,5-dimethyl-3-(4-Phenoxyphenyl) imidazolidine-2, the preparation of 4-diketone (49):
In order to prepare the compound of embodiment 49, can operate according to method " A ".Make 49.2 and 2,4 difluorobenzene amine reaction similarly with embodiment 1.2 described methods.49: molecular weight is 513.18 (C
30H
25F
2N
3O
3); Retention time R
t=2.41 minutes [B]; MS (ESI): 514.23 (MH
+).
Embodiment 50:3-[4-(4-chlorophenoxy)-3-trifluoromethyl]-1-[2-(2,4 difluorobenzene base amino) benzyl]-5,5-methylimidazole alkane-2,4-diketone
1) 3-[4-(4-chlorophenoxy)-3-trifluoromethyl]-5,5-methylimidazole alkane-2, the preparation of 4-diketone (50.1):
Compound 50.1 can be prepared with method " A ".For this reason, at first at room temperature 0.51g carbonic acid two (N-succinimido) ester is joined in the 15ml anhydrous acetonitrile and with its lentamente (1 hour) admixed together with 0.29g 4-(4-the chlorophenoxy)-solution of 3-trifluoromethyl amine in the 10ml anhydrous acetonitrile.This reaction mixture is at room temperature stirred a night.With this reaction mixture concentrating under reduced pressure; Resistates is stirred with ethyl acetate and it is cooled off on ice bath, and precipitation is leached.With filtrate with 1N hydrochloric acid then with the saturated sodium bicarbonate solution washing, use dried over mgso, filtration and with its concentrating under reduced pressure.For further processing, with this crude product ([4-(4-chlorophenoxy)-3-trifluoromethyl] carboxylamine 2,5-dioxo tetramethyleneimine-1-base ester) at room temperature be dissolved in the 10ml anhydrous acetonitrile and in succession that it is admixed together with 0.15g hydrochloric acid 2-amino-2-methyl methyl propionate and 0.14ml triethylamine, with its stirring 2 hours under refluxing.Slowly to wherein drip 2ml concentrated hydrochloric acid, subsequently this reaction mixture under refluxing stirred 2 hour thereafter.Carefully under agitation should chilled reaction mixture admixed together and by coming it is extracted with the ethyl acetate jolting with saturated sodium bicarbonate solution, with the organic phase dried over mgso, filter and its concentrating under reduced pressure.Resistates is carried out purifying (silica gel with chromatography; 98/2 methylene chloride), thereby obtain 3-[4-(4-chlorophenoxy)-3-trifluoromethyl with 53% yield]-5,5-methylimidazole alkane-2,4-diketone.
1H NMR：8.62，s，1H；7.9，d，1H；7.7，dd，1H；7.5，m，2H；7.15，m，3H；1.4，s，6H。
2) 1-(2-bromobenzyl)-3-[4-(4-chlorophenoxy)-3-trifluoromethyl]-5,5-methylimidazole alkane-2, the preparation of 4-diketone (50.2):
Compound 50.2 can be prepared with method " A ".For this reason, as described in the embodiment 1.2, make compound 50.1 and 2-benzyl bromide bromine reaction.Yield with 97% obtains compound 50.2.
Molecular weight is 566.02 (C
25H
19BrClF
3N
2O
3); Retention time R
t=2.86 minutes [B]; MS (ESI): 608.16 (MH
++ CH
3CN).
3) 3-[4-(4-chlorophenoxy)-3-trifluoromethyl]-1-[2-(2,4 difluorobenzene base amino) benzyl]-5,5-methylimidazole alkane-2, the preparation of 4-diketone (50):
In order to prepare the compound of embodiment 50, can operate according to method " A ".Make 50.2 and 2,4 difluorobenzene amine reaction similarly with embodiment 1.2 described methods.50: molecular weight is 615.13 (C
31H
23ClF
5N
3O
3); Retention time R
t=2.99 minutes [B]; MS (ESI): 616.26 (MH
+).
Embodiment 51:4-{3-[2-(2,4 difluorobenzene base amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-2-Pentafluorosulfanyl benzonitrile
A) preparation of 4-amino-2-Pentafluorosulfanyl benzonitrile 51.9:
1) 3-Pentafluorosulfanyl phenyl amine 51.3
2g (8mmol) 3-nitro Pentafluorosulfanyl benzene (CAS # 2613-26-5) is dissolved in the 20ml ethanol, admixed together and it is hydrogenated to and stops to absorb hydrogen under 5.5 crust with 0.1g palladium on carbon (10%).Subsequently, with this reaction mixture filtration and with its concentrating under reduced pressure.Molecular weight is 219.01 (C
6H
6F
5NS); Retention time R
t=1.74 minutes [C]; MS (ESI): 261.07 (MH
++ CH
3CN).
2) 2-(3-Pentafluorosulfanyl phenyl) isoindole-1,3-diketone 51.4
Be suspended in 4ml acetate with 1.01g (6.84mmol) Tetra hydro Phthalic anhydride 1.5g (6.84mmol) 3-Pentafluorosulfanyl phenyl amine 51.3 and make its boiling 2 hours under refluxing.Should chilled reaction mixture and 40ml water admixed together, in ultra sonic bath, handled 30 minutes, filter then.With the resistates water, then with the small amount of ethanol washing, then with its drying under reduced pressure.Obtain 2-(3-Pentafluorosulfanyl phenyl) isoindole-1,3-diketone 51.4, its fusing point are 188-190 ℃.
3) 2-(4-nitro-3-Pentafluorosulfanyl phenyl) isoindole-1,3-diketone 51.5
And 2-(2-nitro-5-Pentafluorosulfanyl phenyl) isoindole-1,3-diketone 51.6
With 1g (2.863mmol) 2-(3-Pentafluorosulfanyl phenyl) isoindole-1,3-diketone 51.4 is dissolved under 0 ℃ in the 3.29ml concentrated nitric acid and with this mixture and stirred 2 hours down at 0 ℃.Make this mixture at room temperature leave standstill a night thereafter.This reaction soln is joined in the 50g frozen water also with this mixture stirring 1 hour; , will precipitate and leach, wash with water through suction filtration thereafter, dry and it is carried out purifying with silica gel chromatography, with toluene as eluent.Ratio with 1:2 obtains 2-(4-nitro-3-Pentafluorosulfanyl phenyl) isoindole-1,3-diketone 51.5 (its fusing point is 200-203 ℃) and 2-(2-nitro-5-Pentafluorosulfanyl phenyl) isoindole-1,3-diketone 51.6 (its fusing point is 175-177 ℃).
4) 2-(4-amino-3-Pentafluorosulfanyl phenyl) isoindole-1,3-diketone 51.7
With 1.94g (4.92mmol) 2-(4-nitro-3-Pentafluorosulfanyl phenyl) isoindole-1,3-diketone 51.5 is dissolved in the 20ml methyl alcohol, with 53mg 10% palladium carbon admixed together and with its at room temperature 5 the crust hydrogen-pressure under hydrogenation.After this reaction finishes, this mixture is removed by filter catalyzer and filtrate is concentrated.With resistates at methylene dichloride and just-stir in the mixture of heptane, through filtered off with suction and with its drying under reduced pressure.Obtain 2-(4-amino-3-Pentafluorosulfanyl phenyl) isoindole-1,3-diketone 51.7, its fusing point are 176-178 ℃.
5) 4-(1,3-dioxo-1,3-xylylenimine-2-yl)-2-Pentafluorosulfanyl benzonitrile 51.8
0.46ml (8.24mmol) half vitriol oil slowly is added drop-wise to 1g (2.74mmol) 2-(4-amino-3-Pentafluorosulfanyl phenyl) isoindole-1 under 0 ℃, in the solution of 3-diketone 51.7 in acetate.This mixture was stirred 10 minutes down at 0 ℃; Thereafter, under condition of stirring slowly to wherein drip the 189.4mg Sodium Nitrite in 2ml water solution and the solution of gained stirred 30 minutes down at 0 ℃.At last, this drips of solution is added in 246mg (2.74mmol) cuprous cyanide (I) and the solution of 536mg (8.23mmol) potassium cyanide in 5ml water that is cooled to 0 ℃.This reaction mixture was stirred 30 minutes down at 0 ℃, then with its restir 3 hours at room temperature.After this reaction finishes, this mixture is added to the water and with water with twice of ethyl acetate oscillation extraction.With the organic phase dried over mgso, filter, filtrate is concentrated and resistates is carried out purifying with silica gel chromatography, at first carry out wash-out with 20/1 toluene/ethyl acetate then with toluene.Obtain 4-(1,3-dioxo-1,3-xylylenimine-2-yl)-2-Pentafluorosulfanyl benzonitrile 51.8.
1H NMR：8.4，m，2H；8.1-7.95，m，5H。
6) 4-amino-2-Pentafluorosulfanyl benzonitrile 51.9
And N-(4-cyano group-3-Pentafluorosulfanyl phenyl) phthalic diamide ethyl ester 51.10
610mg (1.63mmol) 4-(1,3-dioxo-1,3-xylylenimine-2-yl)-2-Pentafluorosulfanyl benzonitrile 51.8 is dissolved in the 30ml ethanol and itself and 100mg (1.956mmol) hydrazine hydrate (100%) is admixed together.This mixture is at room temperature stirred a night.With this mixture concentrating under reduced pressure and with resistates with chromatography carry out purifying (preparation HPLC thereafter; Purospher STARRP-18e (10 μ m); Eluent: acetonitrile/water (0.5% trifluoroacetic acid) 5/95 → 95/5[45 minute]).Obtain 4-amino-2-Pentafluorosulfanyl benzonitrile 51.9 (
1H NMR:7.65, s, 1H; 7.2, s, 1H; 6.8, m, 3H) and N-(4-cyano group-3-Pentafluorosulfanyl phenyl) phthalic diamide ethyl ester 51.10 (
1H NMR:11.3, s, 1H; 8.6, s, 1H; 8.2, d, 1H; 8.1, d, 1H; 7.95, d, 1H; 7.75, m, 1H; 7.7, m, 2H; 4.2, q, 2H; 1.15, t, 3H).
B) 4-{3-[2-(2,4 difluorobenzene base amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-preparation of 2-Pentafluorosulfanyl benzonitrile 51:
1) 4-(4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl)-2-Pentafluorosulfanyl benzonitrile 51.1:
In order to prepare compound 51.1, can operate according to method " A ".505mg amine 51.9 and 227.1mg triphosgene are dissolved in the 15ml anhydrous tetrahydro furan.Under 0 ℃, in 30 minutes, to wherein dripping the 2.5ml tetrahydrofuran (THF) contain the 0.864ml triethylamine, then with this mixture 5 ℃ of following restir 10 minutes.To the hydrochloride that wherein adds 404.7mg 2-amino-2-methyl propionic acid uncle-butyl ester, this mixture is heated to room temperature and with its restir 2 hours at room temperature.With this reaction mixture and the 2.5ml concentrated hydrochloric acid is admixed together and with its restir 2 hours at room temperature.For aftertreatment, this mixture and water and ethyl acetate is admixed together, take out organic phase, with the saturated nacl aqueous solution washing, use dried over mgso, filtration and with its concentrating under reduced pressure.[RP1] carries out chromatogram purification according to method.The fraction concentrating under reduced pressure that will comprise product, by repeat with methylene dichloride the vibration resistates is extracted, with organic phase with dried over mgso and with its concentrating under reduced pressure.Yield with 41% obtains 51.1.
1H NMR：8.85，s，1H；8.4，s，1H；8.3，d，1H；8.02，d，1H；1.4，s，6H。
2) 4-[3-(2-bromobenzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-preparation of 2-Pentafluorosulfanyl benzonitrile 51.2:
Compound 51.2 is as embodiment 6.2 is described, by what compound 51.1 and 2-benzyl bromide bromine reaction were prepared.Yield with 71% obtains 4-[3-(2-bromobenzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-2-Pentafluorosulfanyl benzonitrile.
1H NMR：8.45，s，1H；8.35，d，1H；8.1，d，1H；7.65，d，1H；7.58，d，1H；7.4，t，1H；7.25，t，1H；4.65，s，2H；1.45，s，6H。
3) 4-{3-[2-(2,4 difluorobenzene base amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-preparation of 2-Pentafluorosulfanyl benzonitrile 51:
Described like that as 1, the 3 stage of embodiment, further with the reaction of 2,4 difluorobenzene amine, thereby obtain the compound of embodiment 51.Obtain 4-{3-[2-(2,4 difluorobenzene base amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-2-Pentafluorosulfanyl benzonitrile 51.Molecular weight is 572.11 (C
25H
19F
7N
4O
2S); Retention time R
t=2.36 minutes [B]; MS (ESI): 573.13 (MH
+);
1H NMR:8.42, s, 1H; 8.35, d, 1H; 8.08, d, 1H; 7.45, d, 1H; 7.41, s, 1H; 7.26, t, 1H; 7.2, t, 1H; 6.9, m, 3H; 4.6, s, 2H; 1.4, s, 6H.
Embodiment 55:4-{3-[2-(4-fluorophenyl amino)-4-trifluoromethyl benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-2-trifluoromethyl benzonitrile
1) 4-[3-(2-bromo-4-trifluoromethyl benzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-preparation of 2-trifluoromethyl benzonitrile 55.2:
Compound 55.2 is as embodiment 6.2 is described, by what compound 1.1 and 2-bromo-4-trifluoromethyl benzyl bromine reaction were prepared.Yield with 78% obtains 4-[3-(2-bromo-4-trifluoromethyl benzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-2-trifluoromethyl benzonitrile.
1H NMR：8.36，d，1H；8.25，s，1H；8.1，d，1H；8.05，s，1H；7.85，d，1H；7.73，d，1H；4.7，s，2H；1.48，s，6H。
2) 4-{3-[2-(4-fluorophenyl amino)-4-trifluoromethyl benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-preparation of 2-trifluoromethyl benzonitrile 55:
Described like that as 1, the 3 stage of embodiment, further with the reaction of 4-fluoroaniline, thereby obtain the compound of embodiment 55.Obtain 4-{3-[2-(4-fluorophenyl amino)-4-trifluoromethyl benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-2-trifluoromethyl benzonitrile 55.Molecular weight is 564.13 (C
27H
19F
7N
4O
2); Retention time R
t=2.40 minutes [B]; MS (ESI): 565.09 (MH
+).
The compound of embodiment 56,4-{3-[2-(2,4 difluorobenzene base amino)-4-trifluoromethyl benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 582.13 (C to 2-trifluoromethyl benzonitrile
27H
18F
8N
4O
2); Retention time R
t=2.40 minutes [B]; MS (ESI): 583.07 (MH
+)),
The compound of embodiment 57,4-{3-[2-(4-chloro-phenyl-amino)-4-trifluoromethyl benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 580.11 (C to 2-trifluoromethyl benzonitrile
27H
19ClF
6N
4O
2); Retention time R
t=2.51 minutes [B]; MS (ESI): 581.06 (MH
+)),
The compound of embodiment 106,4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-trifluoromethyl amino } (molecular weight is 604.15 (C to methyl benzoate
29H
22F
6N
4O
4); Retention time R
t=2.31 minutes [B]; MS (ESI): 605.21 (MH
+)),
The compound of embodiment 122,4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-two-methyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-trifluoromethyl amino } (molecular weight is 646.20 (C to phenylformic acid uncle-butyl ester
32H
28F
6N
4O
4); Retention time R
t=2.50 minutes [B]; MS (ESI): 591.14 (MH
+-C
4H
8)),
With the compound of embodiment 165,4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-trifluoromethyl amino } (molecular weight is 618.17 (C to ethyl benzoate
30H
24F
6N
4O
4); Retention time R
t=2.38 minutes [B]; MS (ESI): 619.15 (MH
+))
Be to be prepared as the compound of embodiment 55, difference is, in its synthetic subordinate phase, substitutes the 4-fluoroaniline with following compound:
2,4 difluorobenzene amine (for 56),
4-chloroaniline (for 57),
4-Methyl anthranilate (for 106),
4-benzaminic acid uncle-butyl ester (for 122),
4-subcutin (for 165).
Embodiment 58:2-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-the 5-fluorobenzamide
With the compound dissolution of 150mg (0.288mmol) embodiment 53 in the 1.5ml methylene dichloride.Under 5 ℃, to wherein adding 19.5mg hydrogen sulfate tetrabutylammonium, containing the 0.133ml water and the 0.148ml hydrogen peroxide (30%) of 180mg sodium hydroxide.This mixture is heated to be stirred 2 hours to room temperature and with it.Thereafter, again to wherein adding 148 μ l hydrogen peroxide and with this mixture restir 2 hours.Thereafter, again to wherein adding 148 μ l hydrogen peroxide and with this mixture restir 2 hours.For aftertreatment, in this reaction mixture, add less water and methylene dichloride, take out organic phase and it is carried out purifying (method [RP1]) with chromatography.Yield with 52% obtains 2-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-5-fluorobenzamide 58.Molecular weight is 539.15 (C
27H
21F
4N
5O
3); Retention time R
t=2.04 minutes [B]; MS (ESI): 540.06 (MH
+).
The compound 4-{3-[2-of embodiment 54 (4-cyano-phenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-the 2-trifluoromethyl benzamide makes with compound 33 similarly.Molecular weight is 521.16 (C
27H
22F
3N
5O
3); Retention time R
t=1.72 minutes [B]; MS (ESI): 522.10 (MH
+).
Embodiment 59:4-{4,4-dimethyl-3-[2-(aminomethyl phenyl amino) benzyl]-2,5-dioxo alkyl imidazole-1-yl }-2-trifluoromethyl benzonitrile
With the compound dissolution of 53mg embodiment 1 in the 1.1ml acetonitrile.In this solution, add the 10.4mg sodium cyanoborohydride.Subsequently, to formalin solution that wherein drips 0.18ml 37% and 0.05ml glacial acetic acid.This mixture was at room temperature stirred 2 hours; Thereafter, again through after 2 hours, again to sodium cyanoborohydride that wherein drips equal amts and formalin solution.For aftertreatment, this mixture is filtered with silica gel short column, filtrate decompression is concentrated and it is carried out purifying (method [RP1]) with chromatography.Yield with 60% obtains 4-{4,4-dimethyl-3-[2-(aminomethyl phenyl amino) benzyl]-2,5-dioxo alkyl imidazole-1-yl }-2-trifluoromethyl benzonitrile 59.Molecular weight is 492.17 (C
27H
23F
3N
4O
2); Retention time R
t=2.33 minutes [B]; MS (ESI): 493.05 (MH
+).
Embodiment 61:4-{4,4-dimethyl-2,5-dioxo-3-[2-(pyridin-4-yl amino) benzyl] imidazolidine-1-yl }-2-trifluoromethyl benzonitrile; Trifluoroacetate
1) 4-[3-(2-aminobenzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-preparation of 2-trifluoromethyl benzonitrile 61.2:
The compound of embodiment 61.2 can be prepared with method " A ".The compound of 370mg (0.794mmol) embodiment 1.2 is contained 216mg benzophenone imine, 776mg cesium carbonate, 9mg palladium (II) and 46mg9 with 2.8ml under argon gas atmosphere, 9-dimethyl-4, no Shui diox of 5-two (diphenylphosphino) xanthene is admixed together.This mixture was stirred 6 hours down at 95 ℃; In chilled reaction mixture, add 7.5ml 1N hydrochloric acid.This mixture was at room temperature stirred 10 minutes and it is neutralized with aqueous sodium hydroxide solution.For aftertreatment, by this reaction mixture being extracted with methylene dichloride jolting 3 times, with the organic phase dried over mgso, filtration and with its concentrating under reduced pressure.Resistates is carried out purifying (method [RP2]) with chromatography.Yield with 78% obtains 4-[3-(2-aminobenzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-2-trifluoromethyl benzonitrile 61.2.Molecular weight is 402.13 (C
20H
17F
3N
4O
2); Retention time R
t=1.61 minutes [B]; MS (ESI): 403.06 (MH
+).
2) 4-{4,4-dimethyl-2,5-dioxo-3-[2-(pyridin-4-yl amino) benzyl] imidazolidine-1-yl }-2-trifluoromethyl benzonitrile; The preparation of trifluoroacetate 61:
The compound of embodiment 61 can be prepared with method " A ".With the compound of 50mg (0.124mmol) embodiment 61.2 under argon gas atmosphere with contain 30mg 4-bromopyridine, uncle 30mg-sodium butylate, 5.7mg three (dibenzalacetone) two palladiums (0) and 7.7mg (R)-(+)-2,2 '-two (diphenylphosphino)-1, the 1ml dry toluene of 1 '-dinaphthalene is admixed together.This mixture was stirred 8 hours down at 90 ℃.For aftertreatment, this reaction mixture is filtered with the silica gel short column and filtrate decompression is concentrated.Resistates is carried out purifying (method [RP1]) with chromatography.Obtain 4-{4,4-dimethyl-2,5-dioxo-3-[2-(pyridin-4-yl amino) benzyl] imidazolidine-1-yl }-trifluoroacetate of 2-trifluoromethyl benzonitrile 61.Molecular weight is 479.15 (free alkali) (C
25H
20F
3N
5O
2); Retention time R
t=1.41 minutes [B]; MS (ESI): 480.13 (MH
+).
The compound of embodiment 83,4-{3-[2-(6-methoxypyridine-3-base is amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 509.16 (C to 2-trifluoromethyl benzonitrile
26H
22F
3N
5O
3); Retention time R
t=1.97 minutes [B]; MS (ESI): 510.08 (MH
+)),
The compound of embodiment 84,4-(4,4-dimethyl-3-{2-[4-(morpholine-4-alkylsulfonyl)-3-trifluoromethyl amino] benzyl }-2,5-dioxo alkyl imidazole-1-yl)-(molecular weight is 695.16 (C to 2-trifluoromethyl benzonitrile
31H
27F
6N
5O
5S); Retention time R
t=2.51 minutes [B]; MS (ESI): 696.15 (MH
+)),
The compound of embodiment 85,4-{3-[2-(2-fluoro-4-Trifluoromethoxyphen-l amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 580.13 (C to 2-trifluoromethyl benzonitrile
27H
19F
7N
4O
3); Retention time R
t=2.45 minutes [B]; MS (ESI): 581.07 (MH
+)),
The compound of embodiment 86,4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-(molecular weight is 601.16 (C to N-(2-hydroxyethyl) benzsulfamide
28H
26F
3N
5O
5S); Retention time R
t=2.17 minutes [C]; MS (ESI): 602.24 (MH
+)),
The compound of embodiment 87,2-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } (molecular weight is 536.16 (C to methyl benzoate
28H
23F
3N
4O
4); Retention time R
t=2.44 minutes [B]; MS (ESI): 527.10 (MH
+)),
The compound of embodiment 88,3-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } (molecular weight is 536.16 (C to methyl benzoate
28H
23F
3N
4O
4); Retention time R
t=2.25 minutes [B]; MS (ESI): 537.11 (MH
+)),
The compound of embodiment 89,4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } (molecular weight is 594.17 (C to dimethyl isophthalate
30H
25F
3N
4O
6); Retention time R
t=2.33 minutes [B]; MS (ESI): 595.13 (MH
+)),
The compound of embodiment 90,5-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } (molecular weight is 537.16 (C to pyridine-2-methyl-formiate
27H
22F
3N
5O
4); Retention time R
t=1.76 minutes [B]; MS (ESI): 538.08 (MH
+)),
The compound of embodiment 91,4-{4,4-dimethyl-2,5-dioxo-3-[2-(6-5-flumethiazine-3-base is amino) benzyl] imidazolidine-1-yl }-(molecular weight is 547.14 (free alkali) (C to 2-trifluoromethyl benzonitrile trifluoroacetate
26H
19F
6N
5O
2); Retention time R
t=2.18 minutes [B]; MS (ESI): 548.06 (MH
+),
The compound of embodiment 96,2-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-(molecular weight is 554.15 (C to the 5-fluorophenyl carbamate
28H
22F
4N
4O
4); Retention time R
t=2.42 minutes [B]; MS (ESI): 555.22 (MH
+),
The compound of embodiment 112,4-{4,4-dimethyl-3-[2-(4-nitrophenyl amino) benzyl]-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 523.14 (C to 2-trifluoromethyl benzonitrile
26H
20F
3N
5O
4); Retention time R
t=2.66 minutes [C]; MS (ESI): 524.33 (MH
+),
Behind the acidic hydrolysis that carries out Schiff alkali, the compound of embodiment 113,4-{3-[2-(4-aminophenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 493.17 (C to 2-trifluoromethyl benzonitrile
26H
22F
3N
5O
2); Retention time R
t=1.48 minutes [B]; MS (ESI): 494.14 (MH
+),
The compound of embodiment 128,4-{4,4-dimethyl-2,5-dioxo-3-[2-(4-Phenoxyphenyl amino) benzyl] imidazolidine-1-yl }-(molecular weight is 570.18 (C to 2-trifluoromethyl benzonitrile
32H
25F
3N
4O
3); Retention time R
t=2.44 minutes [B]; MS (ESI): 571.17 (MH
+),
The compound of embodiment 129,5-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-(molecular weight is 566.17 (C to the O-Anisic Acid methyl esters
29H
25F
3N
4O
5); Retention time R
t=2.08 minutes [B]; MS (ESI): 567.17 (MH
+),
The compound of embodiment 138, (4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenoxy group) (molecular weight is 580.19 (C to ethyl acetate
30H
27F
3N
4O
5); Retention time R
t=2.19 minutes [B]; MS (ESI): 581.14 (MH
+),
The compound of embodiment 140,4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-(molecular weight is 566.17 (C to the O-Anisic Acid methyl esters
29H
25F
3N
4O
5); Retention time R
t=2.03 minutes [B]; MS (ESI): 567.15 (MH
+),
The compound of embodiment 141,
(molecular weight is 730.22 (C
38H
33F
3N
4O
8); Retention time R
t=2.19 minutes [B]; MS (ESI): 731.19 (MH
+),
The compound of embodiment 142,4-{4,4-dimethyl-3-[2-(2-methyl-4-oxo-4H-1,3-benzo dioxine-6-base is amino) benzyl]-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 564.16 (C to 2-trifluoromethyl benzonitrile
29H
23F
3N
4O
5); Retention time R
t=2.15 minutes [B]; MS (ESI): 565.15 (MH
+),
The compound of embodiment 150,2-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-methyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } (molecular weight is 594.17 (C to dimethyl terephthalate (DMT)
30H
25F
3N
4O
6); Retention time R
t=2.29min.[B]; MS (ESI): 595.23 (MH
+),
The compound of embodiment 151,4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-(molecular weight is 585.16 (C to N-ethylbenzene sulphonamide
28H
26F
3N
5O
4S); Retention time R
t=2.03min.[B]; MS (ESI): 586.25 (MH
+),
The compound of embodiment 152,3-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-N-[1-dimethylamino methylene] (molecular weight is 612.17 (C to benzsulfamide
29H
27F
3N
6O
4S); Retention time R
t=1.97 minutes [B]; MS (ESI): 613.27 (MH
+),
The compound of embodiment 179,4-{3-[2-(6-methoxyl group pyridazine-3-base amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(free alkali: molecular weight is 510.16 (C for the trifluoroacetate of 2-trifluoromethyl benzonitrile
25H
21F
3N
6O
3); Retention time R
t=1.45 minutes [B]; MS (ESI): 511.30 (MH
+)),
The compound of embodiment 180,4-{3-[2-(2-methoxy pyrimidine-5-base amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(free alkali: molecular weight is 510.16 (C for the trifluoroacetate of 2-trifluoromethyl benzonitrile
25H
21F
3N
6O
3); Retention time R
t=1.94 minutes [B]; MS (ESI): 511.31 (MH
+)),
The compound of embodiment 181,4-{4,4-dimethyl-3-[2-(3-picoline-4-base amino) benzyl]-2,5-dioxo alkyl imidazole-1-yl }-(free alkali: molecular weight is 493.17 (C for the trifluoroacetate of 2-trifluoromethyl benzonitrile
26H
22F
3N
6O
2); Retention time R
t=1.44 minutes [B]; MS (ESI): 494.31 (MH
+)),
The compound of embodiment 199,4-{3-[2-(2,2-dimethyl-4-oxo-4H-benzo [1,3] dioxine-7-base is amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 578.17 (C to 2-trifluoromethyl benzonitrile
30H
25F
3N
4O
5); Retention time R
t=2.11 minutes [B]; MS (ESI): 579.19 (MH
+)),
The compound of embodiment 200,4-{4,4-dimethyl-2,5-dioxo-3-[2-(3-oxo-1,3-dihydroisobenzofuran-5-base is amino) benzyl] imidazolidine-1-yl }-(molecular weight is 534.15 (C to 2-trifluoromethyl benzonitrile
28H
21F
3N
4O
4); Retention time R
t=2.47 minutes [C]; MS (ESI): 535.26 (MH
+)),
The compound of embodiment 201,4-{4,4-dimethyl-2,5-dioxo-3-[2-(1-oxo-1,3-dihydroisobenzofuran-5-base is amino) benzyl] imidazolidine-1-yl }-(molecular weight is 534.15 (C to 2-trifluoromethyl benzonitrile
28H
21F
3N
4O
4); Retention time R
t=2.33 minutes [B]; MS (ESI): 535.19 (MH
+)),
The compound of embodiment 202,6-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } (molecular weight is 628.22 (C to naphthalene-2-formic acid uncle-butyl ester
35H
31F
3N
4O
4); Retention time R
t=3.27 minutes [C]; MS (ESI): 629.50 (MH
+)),
The compound of embodiment 208,4-{3-[2-(2,4-two tert.-butoxies pyrimidine-5-base is amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-(molecular weight is 624.26 (C to 2-trifluoromethyl benzonitrile
32H
35F
3N
6O
4); Retention time R
t=1.92 minutes [B]; MS (ESI): 625.39 (MH
+)),
The compound of embodiment 211,5-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-(molecular weight is 608.22 (C to O-Anisic Acid uncle-butyl ester
32H
31F
3N
4O
5); Retention time R
t=2.37 minutes [B]; MS (ESI): 553.22 (MH
+-C
4H
8))
Be as the compound of embodiment 61 by compound 61.2 and following compound reaction are obtained:
5-bromo-2-methoxypyridine (for 83),
4-(4-bromo-2-trifluoromethyl benzenesulfonyl) morpholine (for 84, by what reaction at room temperature made in acetonitrile with 4-bromo-2-trifluoromethyl benzene sulfonyl chloride and morpholine and salt of wormwood:
1H NMR:8.22, s, 1H; 8.15, d, 1H; 8.0, d, 1H; 3.65, m, 4H; 3.15, m, 4H),
1-bromo-2-fluoro-4-(trifluoromethoxy) benzene (for 85),
4-bromo-N-(2-hydroxyethyl) benzsulfamide (for 86),
2-methyl-bromobenzoate (for 87),
3-methyl-bromobenzoate (for 88),
4-bromine dimethyl isophthalate (for 89),
5-bromopyridine-2-methyl-formiate (for 90),
5-bromo-2-5-flumethiazine (for 91),
2-bromo-5-fluorophenyl carbamate is (for 96; This methyl esters obtains by 2-bromo-5-fluorobenzoic acid and methyl alcohol are reacted under sulfuric acid catalysis:
1H NMR:7.8, m, 1H; 7.65, m, 1H; 7.4, m, 1H; 3.85, s, 3H),
1-bromo-4-oil of mirbane (for 112),
(4-bromophenyl) [1-phenylmethylene] amine is (for 113; This Schiff alkali is by obtaining 4-bromophenyl amine and phenyl aldehyde reaction:
1H NMR:8.65, s, 1H; 7.95, d, 2H; 7.61-7.5, m, 5H; 7.25, d, 2H),
1-bromo-4-phenoxy group benzene (for 128),
5-bromo-O-Anisic Acid methyl esters (for 129),
(4-bromine phenoxy group) ethyl acetate (for 138),
4-bromo-O-Anisic Acid methyl esters (for 140 and 141),
6-bromo-2-methyl benzo [1,3] dioxine-4-ketone (for 142),
2-bromo terephthalic acid dimethyl ester (for 150),
4-bromo-N-ethylbenzene sulphonamide (for 151),
3-bromo-N-[1-dimethylamino methylene] benzsulfamide (prepares with dimethylformamide dimethyl acetal by 3-bromobenzene sulphonamide similarly with following 4-bromine isomer 68.3 described methods that (molecular weight is 289.97 (C
9H
11BrN
2O
2S); Retention time R
t=1.64min.[B]; MS (ESI): 291.03/293.05 (MH
+))), for 152),
3-chloro-6-methoxyl group pyridazine (for 179),
5-bromo-2-methoxy pyrimidine (for 180),
4-bromo-3-picoline (for 181),
7-bromo-2,2-dimethylbiphenyl [1,3] dioxine-4-ketone (for 199),
6-bromo-3H-isobenzofuran-1-ketone (for 200),
5-bromo-3H-isobenzofuran-1-ketone (for 201),
6-bromonaphthalene-2-formic acid uncle-butyl ester (making by lithium salts reaction) (for 202) with thionyl chloride and uncle-butanols by corresponding carboxylic acid,
5-bromo-2,4-two tert.-butoxy pyrimidines (for 208),
5-bromo-O-Anisic Acid uncle-butyl ester is (for 211; Make by lithium salts reaction by 5-bromo-O-Anisic Acid) thionyl chloride and uncle-butanols.
In a similar fashion, the compound of embodiment 260 (4-{3-[4-fluoro-2-(6-methoxypyridine-3-base is amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-2-trifluoromethyl benzonitrile; Molecular weight is 527.15 (C
26H
21F
4N
5O
3); Retention time R
t=2.80 minutes [D]; MS (ESI): 528.21 (MH
+)),
The compound of embodiment 261 (4-{3-[4-fluoro-2-(2-methoxy pyrimidine-5-base is amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-2-trifluoromethyl benzonitrile; Molecular weight is 528.15 (C
25H
20F
4N
6O
3); Retention time R
t=2.66 minutes [D]; MS (ESI): 529.23 (MH
+)),
The compound of embodiment 263 (4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } benzsulfamide, molecular weight is 575.12 (C
26H
21F
4N
5O
4S); Retention time R
t=2.54 minutes [D]; MS (ESI): 576.20 (MH
+), by acid hydrolysis 4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino }-N-[1-dimethylamino methylene] benzsulfamide (262) prepares,
The compound of embodiment 271 (4-{3-[2-(1H-benzoglyoxaline-5-base is amino)-4-luorobenzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-2-trifluoromethyl benzonitrile (
1H NMR:14.2, s (broad peak), 1H; 9.22, s, 1H; 8.35, d, 1H; 8.21, s, 1H; 8.13, s, 1H; 8.07, d, 1H; 7.71, d, 1H; 7.58, t, 1H; 7.23, m, 2H; 7.05, d, 1H; 6.85, t, 1H; 4.6, s, 2H; 1.4, s, 6H),
Be by compound 4-[3-(2-amino-4-luorobenzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-2-trifluoromethyl benzonitrile (260.1; Its preparation sees below) by obtaining with following compound reaction:
5-bromo-2-methoxypyridine (for 260),
5-bromo-2-methoxy pyrimidine (for 261),
4-bromo-N-[1-dimethylamino methylene] benzsulfamide 68.3 (for 262 and 263),
5/6-bromobenzene and imidazoles-1-formic acid uncle-butyl ester is (for 271; 5/6-bromobenzene and imidazoles-1-formic acid uncle-butyl ester (271.1) is to make by 4-dimethylaminopyridine-catalytic 5-bromo-1H-benzoglyoxaline and the reaction of two carbonic acid, two-tert-butyl ester in acetonitrile, and molecular weight is 296.01 (C
12H
13BrN
2O
2); Retention time R
t=2.65 minutes [E]; MS (ESI): 297.08 (MH
+)).
Embodiment 62:4-{4,4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenylformic acid
The compound dissolution of 64mg embodiment 60 in 0.32ml diox (warm), is mixed it and it was stirred 1 hour down at 75 ℃ with the 0.36ml concentrated hydrochloric acid.For aftertreatment, this reaction mixture is mixed with minor amounts of acetonitrile and it is carried out purifying (method [RP1]) with chromatography.After lyophilize, obtain 4-{4,4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenylformic acid 62.Molecular weight is 522.15 (C
27H
21F
3N
4O
4); Retention time R
t=1.88 minutes [B]; MS (ESI): 523.16 (MH
+).
In an identical manner, obtain compound 80,92,118,119,130,131,132,133,156,159,166,168,169,227,228,209,210,212 by its ester 72,82,115,117,124,123,126,125,192,194,195,193,196,225,226,202,203,211:
80:4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-the 3-fluorobenzoic acid;
1H NMR:12.6, s, 1H; 8.32, d, 1H; 8.2, s (broad peak), 2H; 8.03, d, 1H; 7.6, m, 3H; 7.35, t, 1H; 7.25, m, 2H; 6.7, t, 1H; 4.58, s, 2H; 1.35, s, 6H.
92:(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenyl) acetate; Molecular weight is 536.16 (C
28H
23F
3N
4O
4); Retention time R
t=1.95 minutes [B]; MS (ESI): 537.26 (MH
+).
118:4-{2-[5,5-dimethyl-3-(4-methylthio group-3-trifluoromethyl)-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenylformic acid; Molecular weight is 543.14 (C
27H
24F
3N
3O
4S); Retention time R
t=2.38 minutes [C]; MS (ESI): 544,30 (MH
+).
119:4-{2-[3-(4-methylsulfonyl-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenylformic acid; Molecular weight is 575.13 (C
27H
24F
3N
3O
6S); Retention time R
t=2.17 minutes [C]; MS (ESI): 576.13 (MH
+).
130:4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-p-methoxy-phenyl amino } phenylformic acid; Molecular weight is 552.16 (C
28H
23F
3N
4O
5); Retention time R
t=1.91 minutes [B]; MS (ESI): 553.15 (MH
+).
131:4-{5-chloro-2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenylformic acid; Molecular weight is 556.11 (C
27H
20ClF
3N
4O
4); Retention time R
t=2.00 minutes [B]; MS (ESI): 556.11 (MH
+).
132:4-{5-cyano group-2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenylformic acid; Molecular weight is 547.14 (C
28H
20F
3N
5O
4); Retention time R
t=1.86 minutes [B]; MS (ESI): 548.14 (MH
+).
133:4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } phenylformic acid; Molecular weight is 540.14 (C
27H
20F
4N
4O
4); Retention time R
t=1.96 minutes [B]; MS (ESI): 541.14 (MH
+).
156:4-{5-fluoro-2-[3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenylformic acid; Molecular weight is 533.13 (C
26H
20F
5N
3O
4); Retention time R
t=2.00 minutes [B]; MS (ESI): 534.25 (MH
+).
159:4-{2-[3-(4-cyano group-3-cyclopropyl phenyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } phenylformic acid; Molecular weight is 512.18 (C
29H
25FN
4O
4); Retention time R
t=1.94 minutes [B]; MS (ESI): 513.24 (MH
+).
166:4-{2-[3-(4-cyano group-3-aminomethyl phenyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } phenylformic acid; Molecular weight is 486.17 (C
27H
23FN
4O
4); Retention time R
t=1.85 minutes [B]; MS (ESI): 487.31 (MH
+).
168:4-{2-[3-(2-tert-butyl pyridin-4-yl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } phenylformic acid x HCI; Molecular weight (free acid) 504.21 (C
28H
29FN
4O
4); Retention time R
t=1.50 minutes [B]; MS (ESI): 505.18 (MH
+).
169:4-{2-[3-(3-tert-butyl-4-cyano-phenyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } phenylformic acid; Molecular weight is 528.21 (C
30H
29FN
4O
4); Retention time R
t=2.06 minutes [B]; MS (ESI): 529.16 (MH
+).
227:4-{2-[3-(6-cyanobiphenyl-3-yl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } phenylformic acid; Molecular weight is 548.18 (C
32H
25FN
4O
4); Retention time R
t=1.96 minutes [B]; MS (ESI): 549.23 (MH
+).
228:4-{2-[3-(4 '-chloro-6-cyanobiphenyl-3-yl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } phenylformic acid; Molecular weight is 582.14 (C
32H
24ClFN
4O
4); Retention time R
t=2.06 minutes [B]; MS (ESI): 583.19 (MH
+).
209:6-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } naphthalene-2-formic acid; Molecular weight is 572.16 (C
31H
23F
3N
4O
4); Retention time R
t=2.54 minutes [C]; MS (ESI): 573.41 (MH
+).
210:4 '-and 2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } biphenyl-4-formic acid; Molecular weight is 598.18 (C
33H
25F
3N
4O
4); Retention time R
t=2.52 minutes [B]; MS (ES
-): 597.10 (M-H
+).
212:5-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-O-Anisic Acid; Molecular weight is 552.16 (C
28H
23F
3N
4O
5); Retention time R
t=1.94 minutes [B]; MS (ESI): 553.23 (MH
+).
In an identical manner, only be to use the Hydrogen bromide in glacial acetic acid, obtain compound 99,100,101,108 by its ester 87,88,89,96:
99:2-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenylformic acid; Molecular weight is 522.15 (C
27H
21F
3N
4O
4); Retention time R
t=2.12 minutes [B]; MS (ESI): 523.11 (MH
+).
100:3-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenylformic acid; Molecular weight is 522.15 (C
27H
21F
3N
4O
4); Retention time R
t=1.94 minutes [B]; MS (ESI): 523.11 (MH
+).
101:4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } m-phthalic acid; Molecular weight is 566.14 (C
28H
21F
3N
4O
6); Retention time R
t=1.79 minutes [B]; MS (ESI): 567.12 (MH
+).
108:2-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-the 5-fluorobenzoic acid; Molecular weight is 540.14 (C
27H
20F
3N
4O
4); Retention time R
t=2.12 minutes [B]; MS (ESI): 541.22 (MH
+).
In an identical manner, also obtained compound 102 and 103, and obtained compound 105 and 107 by ester 104 and 106 by ester 90:
102:5-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } pyridine-2-formic acid; Molecular weight is 523.14 (C
26H
20F
3N
5O
4); Retention time R
t=1.52 minutes [B]; MS (ESI): 524.09 (MH
+).
103:5-{4-bromo-2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } pyridine-2-formic acid; Molecular weight is 601.05 (C
26H
19BrF
3N
5O
4); Retention time R
t=1.68 minutes [B]; MS (ESI): 602.01 (MH
+).
105:4-{3,5-two chloro-2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenylformic acid; Molecular weight is 590.07 (C
27H
19Cl
2F
3N
4O
4); Retention time R
t=2.18 minutes [B]; MS (ESI): 591.12 (MH
+).
107:4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-trifluoromethyl amino } phenylformic acid; Molecular weight is 590.13 (C
28H
20F
6N
4O
4); Retention time R
t=2.00 minutes [B]; MS (ESI): 591.20 (MH
+).
Embodiment 63:2-tert-butyl-4-[4,4-dimethyl-2,5-dioxo-3-(2-phenyl amino benzyl) imidazolidine-1-yl] benzonitrile
1) 2-tert-butyl-4-nitrobenzonitrile 63.3:
1.1g 2-tert-butyl-4-nitrophenyl amine solvent is admixed together with the sulfuric acid of itself and 2ml 30% in the 5ml glacial acetic acid and under ice-cooled situation.In 30 minutes, 0 ℃ slowly to wherein adding the 460mg Sodium Nitrite, then this mixture was stirred 5 hours down at 0 ℃.This solution is filtered and it is added drop-wise under 75 ℃ in 1.9g potassium cyanide and the solution of 1.3g cupric cyanide in 20ml water.With this mixture 75 ℃ of following restir 1 hour.Should chilled reaction mixture leach and water washs it through suction filtration.Resistates is stirred in methyl alcohol, filter, filtrate decompression is concentrated.Resistates is carried out purifying with silica gel chromatography, with 80/20 just-heptane/ethyl acetate carries out wash-out.Yield with 61% obtains 63.3.
1H NMR：8.25-8.15，m，3H；1.51，s，9H。
2) preparation of 4-amino-2-tert-butyl benzonitrile 63.4:
The compound of 0.6g embodiment 63.3 at room temperature is suspended in the 19.4ml hydroiodic acid HI (57%) and with it to descend to stir 4 hours at 80 ℃.Should be dissolved in the ethyl acetate by chilled reaction mixture, with saturated sodium thiosulfate solution, saturated sodium bicarbonate solution and saturated nacl aqueous solution it is washed carefully in succession subsequently, use dried over mgso, filter and its concentrating under reduced pressure.Resistates is carried out purifying with silica gel chromatography, with 70/30 just-heptane/ethyl acetate carries out wash-out.Yield with 88% obtains 63.4.Molecular weight is 174.11 (C
11H
14N
2); Retention time R
t=1.89 minutes [B]; MS (ESI): 175.22 (MH
+).
3) preparation of 2-tert-butyl-4-(4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl) benzonitrile 63.1:
In order to prepare compound 63.1, can operate according to method " A ".For this reason, the toluene solution that at first under argon gas atmosphere, in flask, adds 2.5ml 20% phosgene.Slowly in this solution, drip the compound that 0.45g is dissolved in the embodiment 63.4 in the 10ml acetonitrile, then this mixture was stirred 90 minutes down at 75 ℃.Should chilled reaction mixture concentrating under reduced pressure, admixed together and it is concentrated once more with toluene.Be dissolved in the 10ml anhydrous tetrahydro furan resistates also that this solution and 0.36g hydrochloric acid 2-amino-2-methyl methyl propionate is admixed together.Slowly in this mixture, add the 0.5ml triethylamine, then it was at room temperature stirred 2 hours.After adding the 2.4ml concentrated hydrochloric acid, this mixture was stirred 2 hours under refluxing.For aftertreatment, should chilled reaction mixture admixed together and extract with saturated sodium bicarbonate solution carefully with ethyl acetate.With this organic extract dried over mgso, filter and its concentrating under reduced pressure.Resistates is carried out purifying with silica gel chromatography, with 70/30 just-heptane/ethyl acetate carries out wash-out.Yield with 76% obtains compound 63.1.Molecular weight is 285.14 (C
16H
19N
3O
2); Retention time R
t=1.88 minutes [B]; MS (ES-): 284.50 ((M-H)
+
4) 4-[3-(2-bromobenzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-preparation of 2-tert-butyl benzonitrile 63.2:
Compound 63.2 is as embodiment 6.2 is described, by what compound 63.1 and 2-benzyl bromide bromine reaction were prepared.Yield with 98% obtains 4-[3-(2-bromobenzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-2-tert-butyl benzonitrile.Molecular weight is 453.10 (C
23H
24Br
3N
3O
2); Retention time R
t=2.65 minutes [B]; MS (ESI): 454.38 (MH
+).
5) 2-tert-butyl-4-[4,4-dimethyl-2,5-dioxo-3-(2-phenyl amino benzyl) imidazolidine-1-yl] preparation of benzonitrile 63:
As 1, the 3 stage of embodiment described like that further with aniline reaction, thereby obtain the compound of embodiment 63.Obtain 2-tert-butyl-4-[4,4-dimethyl-2,5-dioxo-3-(2-phenyl amino benzyl) imidazolidine-1-yl] benzonitrile 63.Molecular weight is 466.23 (C
29H
30N
4O
2); Retention time R
t=3.09 minutes [C]; MS (ESI): 467.29 (MH
+).
With like the compounds of embodiment 63 by making compound 63.2 and 2, the 4-difluoroaniline reacts and the compound of acquisition embodiment 64,2-tert-butyl-4-{3-[2-(2,4-difluorophenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl } (molecular weight is 502.21 (C to benzonitrile
29H
28F
2N
4O
2); Retention time R
t=2.81 minutes [B]; MS (ESI): 503.45 (MH
+)).
The compound of embodiment 157,4-{2-[3-(3-tert-butyl-4-cyano-phenyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } methyl benzoate obtains in a similar manner.For this reason, make 63.1 with the reaction of 2-bromo-1-brooethyl-4-fluorobenzene, thereby obtain 4-[3-(2-bromo-4-luorobenzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-2-tert-butyl benzonitrile (157.2; Molecular weight is 471.09 (C
23H
23BrFN
3O
2); Retention time R
t=2.31 minutes [B]; MS (ESI): 472.24 (MH
+)).4-Methyl anthranilate and 157.2 is reacted under these conditions, thereby obtain the compound of embodiment 157; Molecular weight is 542.23 (C
31H
31FN
4O
4); Retention time R
t=2.31 minutes [B]; MS (ESI): 543.31 (MH
+).
In a similar fashion, make 157.2 with 4-benzaminic acid uncle-butyl ester reaction, obtain compound 196 (4-{2-[3-(3-tert-butyl-4-cyano-phenyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino phenylformic acid uncle-butyl ester; Molecular weight is 584.27 (C
34H
37FN
4O
4); Retention time R
t=2.60 minutes [B]; MS (ESI): 529.18 (MH
+-C
4H
8)).
In a similar fashion, make 157.2 with 2,4 difluorobenzene amine reaction, obtain compound 221 (2-tert-butyl-4-{3-[2-(2,4 difluorobenzene base amino)-4-luorobenzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl } benzonitrile; Molecular weight is 520.20 (C
29H
27F
3N
4O
2); Retention time R
t=2.80 minutes [B]; MS (ESI): 521.23 (MH
+)).
Embodiment 65:5,5-dimethyl-1-(2-phenyl amino benzyl)-3-(2-5-flumethiazine-4-yl) imidazolidine-2,4-diketone
1) 2-(trifluoromethyl) pyridine N-oxides 65.3:
5.1g (35mmol) 5-flumethiazine at room temperature is dissolved in the 100ml anhydrous methylene chloride, and between 17.3g-the chlorine peroxybenzoic acid is admixed together and it was at room temperature stirred 72 hours.Thereafter, with this mixture and the 1N sodium hydroxide solution is admixed together and with it with dichloromethane extraction four times; With the organic phase that is merged dried over mgso, filter and its concentrating under reduced pressure.Crude product is soluble in water, stir, filter, filtrate decompression is concentrated.Yield with 47% obtains 65.3.
1H NMR：8.46，d，1H；7.96，d，1H；7.7，m，1H；7.5，m，1H。
2) 4-nitro-2-5-flumethiazine N-oxide compound 65.4:
At first under 0 ℃, 65.3 compounds of 2.66g embodiment are joined in the 8.5ml vitriol oil; Subsequently, under 0 ℃, slowly to wherein dripping nitrating acid (the 13.3ml nitrosonitric acid and the 8.5ml vitriol oil).Subsequently, this reaction mixture was stirred 4 hours down at 120 ℃.Be poured on the frozen water with this reaction mixture cooling and with it, with salt of wormwood it neutralized carefully.With this mixture dichloromethane extraction, use dried over mgso, filter and with its concentrating under reduced pressure.Resistates is carried out purifying with silica gel chromatography, with 70/30 just-heptane/ethyl acetate carries out wash-out.Yield with 26% obtains compound 65.4.
1H NMR：8.69，d，1H；8.59，d，1H；8.5，m，1H。
3) 2-5-flumethiazine-4-base amine 65.5:
The compound of 0.86g embodiment 65.4 at room temperature is dissolved in the 50ml dehydrated alcohol, with its under the argon gas with 88mg palladium/carbon (10%) catalyst mix to and with its hydrogenation 3 hours under room temperature and 5 crust.Use degree of depth filter membrane through filtered off with suction this reaction mixture, it is washed and filtrate decompression is concentrated with ethanol.Resistates is carried out purifying with silica gel chromatography, carry out wash-out with 95/5 methylene chloride.Yield with 88% obtains compound 65.5.
1H NMR：8.10，d，1H；6.9，s，1H；6.65，d，1H；6.52，s，2H。
4) 2-methyl-2-[3-(2-5-flumethiazine-4-yl) urea groups] methyl propionate 65.6:
At first under argon gas atmosphere, add the solution (20%) of 3.8ml phosgene in toluene.Under 75 ℃, be dissolved in compound 65.5 in the 20ml anhydrous acetonitrile to wherein slowly dripping 0.58g; Then this mixture was stirred 4 hours down at 80 ℃.This mixture is repeated concentrating under reduced pressure with toluene.Resistates is dissolved in the 20ml anhydrous tetrahydro furan and itself and 0.55g aminoguanidine hydrochloride methyl isobutyrate is admixed together.In this mixture, slowly drip the 0.76ml triethylamine, then it was at room temperature stirred 4 hours, make it leave standstill a night then.This reaction mixture and water is admixed together and use ethyl acetate extraction.With the organic phase dried over mgso, filter and its concentrating under reduced pressure.Resistates is carried out purifying with silica gel chromatography, carry out wash-out with 95/5 methylene chloride.Yield with 59% obtains urea 65.6.Molecular weight is 305.09 (C
12H
14F
3N
3O
3); Retention time R
t=1.66 minutes [B]; MS (ESI): 306.44 (MH
+).
5) 5,5-dimethyl-3-(2-5-flumethiazine-4-yl) imidazolidine-2,4-diketone 65.1:
0.52g compound 65.6 at room temperature is dissolved in the 15ml anhydrous tetrahydro furan, mixes with the 1.7ml concentrated hydrochloric acid and it was stirred 4 hours down at 80 ℃.With the cooling of this mixture, be dissolved in ethyl acetate and, use dried over mgso, filtration and its concentrating under reduced pressure with the saturated sodium bicarbonate solution washing.Resistates is carried out purifying with silica gel chromatography, carry out wash-out with 95/5 methylene chloride.Obtain compound 65.1 with quantitative yield.Molecular weight is 273.07 (C
11H
10F
3N
3O
2); Retention time R
t=1.62 minutes [B]; MS (ESI): 274.33 (MH
+).
6) 1-(2-bromobenzyl)-5,5-dimethyl-3-(2-5-flumethiazine-4-yl) imidazolidine-2,4-diketone 65.2:
0.18g compound 65.1 at room temperature is dissolved in the 10ml anhydrous acetonitrile, mixes with 0.18g2-bromobenzyl bromide and 0.24g cesium carbonate and it was at room temperature stirred 4 hours, make it leave standstill a night then.With this reaction mixture concentrating under reduced pressure, that resistates is soluble in water and with methylene dichloride it is extracted.With the organic phase dried over mgso, filter and its concentrating under reduced pressure.Yield with 89% obtains 65.2.Molecular weight is 441.03 (C
18H
15BrF
3N
3O
2); Retention time R
t=2.45 minutes [B]; MS (ESI): 442.29 (MH
+).
7) 5,5-dimethyl-1-(2-phenyl amino benzyl)-3-(2-5-flumethiazine-4-yl)-imidazolidine-2,4-diketone 65:
As 1, the 3 stage of embodiment described like that further with aniline reaction, thereby obtain the compound of embodiment 65.Obtain 5,5-dimethyl-1-(2-phenyl amino benzyl)-3-(2-5-flumethiazine-4-yl) imidazolidine-2,4-diketone 65.Molecular weight is 454.16 (C
24H
21F
3N
4O
2); Retention time R
t=2.25 minutes [B]; MS (ESI): 455.19 (MH
+).
The compound of embodiment 66,1-[2-(2,4 difluorobenzene base amino) benzyl]-5,5-dimethyl-3-(2-5-flumethiazine-4-yl) imidazolidine-2, (molecular weight is 490.14 (C to the 4-diketone
24H
19F
5N
4O
2); Retention time R
t=2.27 minutes [B]; MS (ESI): 491.16 (MH
+)), be to obtain by compound 65.2 and 2,4 difluorobenzene amine are reacted like the compounds with embodiment 65.
Embodiment 68:5,5-4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } benzsulfamide
1) 4-[3-(2-aminobenzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-another kind of 2-trifluoromethyl benzonitrile 61.2 is synthetic:
Compound embodiment 61.2 also can be prepared with the another kind of approach of method " A ": a) (2-2-bromomethylphenyl) carboxylamine uncle-butyl ester 68.1:
1.3g (2-hydroxymethyl phenyl) carboxylamine uncle-butyl ester is dissolved in the 20ml methylene dichloride; Then, under 5 ℃, to wherein dripping the solution of 630mg phosphorus tribromide in 5ml DCM.Subsequently, this reaction mixture was stirred 2 hours down at 5 ℃.For aftertreatment, this mixture is admixed together with solid sodium bicarbonate and 1ml water carefully, stirred 30 minutes down at 5 ℃, with the short column filtration and with its concentrating under reduced pressure.Yield with 67% obtains (2-2-bromomethylphenyl) carboxylamine uncle-butyl ester.
1H NMR：8.71，s，1H；7.45，d，1H；7.42，d，1H；7.3，t，1H；7.1，t，1H；4.78，2，2H；1.45，s，9H。
B) 2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] and phenyl } carboxylamine uncle-butyl ester 68.2:
1.1g 4-(4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl)-2-trifluoromethyl benzonitrile 1.1 and 1.1g compound 68.1 are dissolved in the 11ml anhydrous acetonitrile, admixed together and it was at room temperature stirred 5 hours with the 1.5g cesium carbonate.For aftertreatment, that this reaction mixture is admixed together and by coming it is extracted with the ethyl acetate jolting with water.With the organic phase dried over sodium sulfate, filter and its concentrating under reduced pressure.Resistates is carried out purifying (method [RP2]) with chromatography.From the fraction that comprises required product, remove acetonitrile by distillation; Aqueous residue is neutralized with saturated sodium bicarbonate solution,, use dried over sodium sulfate, filter and its concentrating under reduced pressure by coming it is extracted with the methylene dichloride jolting.Obtain 2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl carboxylamine uncle-butyl ester 68.2.
1H NMR：8.81，s，1H；8.25，d，1H；8.23，s，1H；8.08，d，1H；7.41，d，1H；7.3，d，1H；7.22，t，1H；7.12，t，1H；4.55，s，2H；1.45，s，9H；1.35，s，6H。
C) 4-[3-(2-aminobenzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-2-trifluoromethyl benzonitrile hydrochloride (61.2 salt):
0.369g compound 68.2 is dissolved in the 3.7ml ethyl acetate and the diethyl ether solution of itself and 1.47ml2MHCl is admixed together, it was at room temperature stirred 24 hours.The diethyl ether solution that adds twice HCl again, each 4 equivalents also all make this solution left standstill 24 hours at every turn.For aftertreatment,, resistates is dissolved in acetonitrile/water and with its lyophilize with this reaction mixture concentrating under reduced pressure.Obtain 4-[3-(2-aminobenzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl with quantitative yield]-2-trifluoromethyl benzonitrile hydrochloride.Molecular weight (free alkali) is 402.13 (C
20H
17F
3N
4O
2); Retention time R
t=1.59 minutes [B]; MS (ESI): 403.14 (MH
+).
2) 4-bromo-N-[1-dimethylamino methylene] preparation of benzsulfamide 68.3:
0.325g 4-bromobenzene sulphonamide and 0.82g dimethylformamide dimethyl acetal be mixed together in the 1.6ml anhydrous dimethyl formamide and with it at room temperature stirred 90 minutes.For aftertreatment, this reaction mixture and 10ml water is admixed together, will precipitate and leach through suction filtration, filter and with its drying under reduced pressure.Yield with 85% obtains 4-bromo-N-[1-dimethylamino methylene] benzsulfamide.Molecular weight is 289.97 (C
9H
11BrN
2O
2S); Retention time R
t=1.3 minutes [B]; MS (ESI): 290.96 (MH
+).
3) 4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-N-[1-dimethylamino methylene] preparation of benzsulfamide 68.4:
With like embodiment 61 described class of operation, feasible free alkali and compound 68.3 reactions from 68.1.c.Yield with 94% obtains 4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-N-[1-dimethylamino methylene] benzsulfamide.Molecular weight is 612.17 (C
29H
27F
3N
6O
4S); Retention time R
t=2.37 minutes [C]; MS (ESI): 613.24 (MH
+).
4) 5,5-4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } benzsulfamide 68:
0.143g compound 68.4 is dissolved in the 2.3ml ethanol, mixes with the 1.15ml concentrated hydrochloric acid and it was stirred 2 hours under refluxing.Should chilled reaction mixture carefully with the solid sodium bicarbonate neutralization and with its concentrating under reduced pressure.Resistates mixed with water and by coming its extraction three times with the ethyl acetate jolting, with the organic phase dried over mgso, filtration and with its concentrating under reduced pressure.Resistates is carried out purifying (method [RP1]) with chromatography.Yield with 64% obtains 5,5-4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } benzsulfamide.Molecular weight is 557.13 (C
26H
22F
3N
5O
4S); Retention time R
t=1.85 minutes [B]; MS (ESI): 558.28 (MH
+).
Compound 81 (4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-(molecular weight is 575.12 (C to 3-fluorobenzene sulphonamide
26H
21F
4N
5O
4S); Retention time R
t=1.87 minutes [B]; MS (ESI): 576.11 (MH
+)) be by 4-{2-[3-(4-cyano group-3-trifluoromethyl)-5 with described method just, 5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-N-[1-dimethylamino methylene]-(molecular weight is 630.16 (C to 3-fluorobenzene sulphonamide 81.1
29H
26F
4N
6O
4S); Retention time R
t=1.92 minutes [B]; MS (ESI): 631.11 (MH
+), it is by 4-bromo-N-[1-dimethylamino methylene]-3-fluorobenzene sulphonamide 81.2 and the free alkali acquisition that derives from 68.1.c) obtain.
Compound 98 4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-2, (molecular weight is 593.11 (C to 5-difluoro benzsulfamide
26H
20F
5N
5O
4S); Retention time R
t=1.88 minutes [B]; MS (ESI): 594.18 (MH
+)) be by 4-{2-[3-(4-cyano group-3-trifluoromethyl)-5 with described method just, 5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-N-[1-dimethylamino methylene]-2, (molecular weight is 648.15 (C to 5-difluoro benzsulfamide 98.1
29H
25F
5N
6O
4S); Retention time R
t=1.95 minutes [B]; MS (ESI): 649.08 (MH
+), it is by 4-bromo-N-[1-dimethylamino methylene]-2,5-difluoro benzsulfamide 98.2 and the free alkali that derives from 68.1.c) obtain.
Embodiment 69:5,5-4-{5-[4,4-dimethyl-2,5-dioxo-3-(2-phenyl amino benzyl) imidazolidine-1-yl] pyridine-2-formonitrile HCN
1) 2-[3-(6-cyanopyridine-3-yl) urea groups]-preparation of 2 Methylpropionic acid methyl esters 69.3:
At first under argon gas, add the solution (20%) of 3.8ml phosgene in toluene; Under 75 ℃,, then this mixture was stirred 4 hours down at 80 ℃ slowly to wherein dripping the 5-amino-2-cyanopyridine of 0.43g in the 20ml anhydrous acetonitrile.With chilled this mixture concentrating under reduced pressure, admixed together and with its concentrating under reduced pressure once more with toluene.Resistates is dissolved in the 20ml anhydrous tetrahydro furan and itself and 0.55g hydrochloric acid 2-amino-2-methyl methyl propionate is admixed together; Under agitation, slowly, then this mixture was at room temperature stirred 8 hours to wherein dripping the 0.76ml triethylamine.For aftertreatment, this mixture and water is admixed together, with ethyl acetate it is extracted then.With the organic phase dried over mgso, filter and its concentrating under reduced pressure.Obtain 2-[3-(6-cyanopyridine-3-yl) urea groups with quantitative yield]-the 2 Methylpropionic acid methyl esters.Molecular weight is 262.10 (C
12H
14N
4O
3); Retention time R
t=1.6 minutes [B]; MS (ESI): 263.49 (MH
+).
2) preparation of 5-(4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl) pyridine-2-formonitrile HCN 69.1:
0.94g urea 69.3 at room temperature is dissolved in the 20ml anhydrous tetrahydro furan, admixed together and it was stirred 3 hours down at 80 ℃ with the 3.6ml concentrated hydrochloric acid.Should be dissolved in the ethyl acetate by chilled reaction mixture,, use dried over mgso, filtration and its concentrating under reduced pressure with saturated sodium bicarbonate solution washing.Crude product is stirred with methyl-tert-butyl ether, it is leached through suction filtration, washing, dry then.Yield with 52% obtains 5-(4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl) pyridine-2-formonitrile HCN.Molecular weight is 230.08 (C
11H
10N
4O
2); Retention time R
t=1.31 minutes [B]; MS (ESI): 231.24 (MH
+),
3) 5-[3-(2-bromobenzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl] preparation of pyridine-2-formonitrile HCN 69.2:
Compound 69.2 is described like that by making 69.1 to react with 1-bromo-2-brooethyl benzene and to obtain as 1, the 2 stage of embodiment.Molecular weight is 398.03 (C
18H
15BrN
4O
2); Retention time R
t=2.24 minutes [B]; MS (ESI): 399.32 (MH
+).
4) 5,5-4-{5-[4,4-dimethyl-2,5-dioxo-3-(2-phenyl amino benzyl) imidazolidine-1-yl] pyridine-2-formonitrile HCN 69:
The compound of embodiment 69, molecular weight are 411.16 (C
24H
21N
5O
2); Retention time R
t=2.04 minutes [B]; MS (ESI): 412.37 (MH
+) be with like the embodiment compounds in 1, the 3 stage by obtaining with aniline reaction.
The compound of embodiment 70,5-{3-[2-(2,4 difluorobenzene base amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl } (molecular weight is 447.37 (C to pyridine-2-formonitrile HCN
24H
19F
2N
5O
2); Retention time R
t=2.07 minutes [B]; MS (ESI): 448,40 (MH
+)) obtain by compound 69.2 and 2,4 difluorobenzene amine are reacted similarly with compound 69.
Embodiment 71:5,5-1-[2-(2,4 dichloro benzene base amino) benzyl]-3-(2-ethoxy pyridine-4-yl)-5,5-methylimidazole alkane-2,4-diketone
1) 2-[3-(2-ethoxy pyridine-4-yl) urea groups]-preparation of 2 Methylpropionic acid uncle-butyl ester 71.3:
As described in 69.3 the preparation, substitute 5-amino-2-cyanopyridine and, obtained 2-[3-(2-ethoxy pyridine-4-yl) urea groups with 2-oxyethyl group-4-aminopyridine with alternative its methyl esters of the tert-butyl ester of 2-amino-2-methyl propionic acid]-2 Methylpropionic acid uncle-butyl ester.Molecular weight is 323.18 (C
16H
25N
3O
4); Retention time R
t=1.28 minutes [B]; MS (ESI): 324.16 (MH
+).
2) 3-(2-ethoxy pyridine-4-yl)-5,5-methylimidazole alkane-2, the preparation of 4-diketone 71.1:
Under as preparation 69.1 described conditions, also obtained compound 71.1.Molecular weight is 249.11 (C
12H
15N
3O
3); Retention time R
t=1.06 minutes [B]; MS (ESI): 250.08 (MH
+).
3) 1-(2-bromobenzyl)-3-(2-ethoxy pyridine-4-yl)-5,5-methylimidazole alkane-2, the preparation of 4-diketone 71.2:
As embodiment described sample of 1, the 2 stage by making 71.1 to obtain compound 71.2 with 1-bromo-2-brooethyl benzene reaction.Molecular weight is 417.06 (C
19H
20BrN
3O
3); Retention time R
t=21.97 minutes [B]; MS (ESI): 418.10 (MH
+).
4) 5,5-1-[2-(2,4 dichloro benzene base amino) benzyl]-3-(2-ethoxy pyridine-4-yl)-5,5-methylimidazole alkane-2,4-diketone 71:
With like the embodiment compounds in 1, the 3 stage by obtaining the compound of embodiment 71 with 2,4 dichloro aniline reaction, its molecular weight is 498.12 (C
25H
24Cl
2N
4O
3); Retention time R
t=2.84 minutes [B]; MS (ESI): 499.40 (MH
+).
Embodiment 93 and 94:
(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenyl) phosphonic acids mono ethyl ester 93
With
(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenyl) phosphonic acids 94
The compound of 0.17g embodiment 79 at room temperature is dissolved in the no Shui diox of 3ml, mixes with the 0.23ml concentrated hydrochloric acid and it was stirred 4 hours down at 80 ℃.Thereafter, again to wherein add the 0.43ml concentrated hydrochloric acid and with this mixture 80 ℃ of following restir 8 hours.Should chilled reaction mixture concentrating under reduced pressure and resistates carried out purifying (method [RP1]) with chromatography.Obtain monoesters 93 and phosphonic acids 94.
93: molecular weight is 586.15 (C
28H
26F
3N
4O
5P); Retention time R
t=1.75 minutes [B]; MS (ESI): 587.10 (MH
+).
94: molecular weight is 558.12 (C
26H
22F
3N
4O
5P); Retention time R
t=1.92 minutes [C]; MS (ESI): 559.26 (MH
+).
Embodiment 95:4-{3-[2-(4-amino-3-fluorophenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-2-trifluoromethyl benzonitrile
1) N '-(2-fluoro-4-nitrophenyl)-N, the preparation of N-dimethyl carbonamidine 95.1:
5g 2-fluoro-4-N-methyl-p-nitroaniline is dissolved in the 35ml anhydrous dimethyl formamide, at room temperature admixed together and it was stirred 90 minutes with the 19.90g dimethylformamide dimethyl acetal.For aftertreatment, in this reaction mixture, add 250ml water, will precipitate and leach through suction filtration, wash with water, then drying.Yield with 85% obtains N '-(2-fluoro-4-nitrophenyl)-N, N-dimethyl carbonamidine.Molecular weight is 211.07 (C
9H
10FN
3O
2); Retention time R
t=0.49 minute [B]; MS (ESI): 212.03 (MH
+).
2) N '-(4-amino-2-fluorophenyl)-N, the preparation of N-dimethyl carbonamidine 95.2:
5.37g compound 95.1 is dissolved in the 110ml methyl alcohol.Add the 747mg Raney nickel, this mixture is hydrogenated under 5 crust stops to absorb hydrogen then.For aftertreatment, catalyzer leached and filtrate decompression concentrated and remove most of solvent.Make the product precipitation by adding entry, filter and it is washed with less water.Filtrate is repeated to extract with methylene dichloride and the isopropanol mixture of 4:1.With the extract concentrating under reduced pressure, dry then.Yield with 83% obtains N '-(4-amino-2-fluorophenyl)-N, N-dimethyl carbonamidine.Molecular weight is 181.10 (C
9H
12FN
3); Retention time R
t=0.15 minute [B]; MS (ESI): 182.10 (MH
+).
3) N '-(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-the 2-fluorophenyl)-N, the preparation of N-dimethyl carbonamidine 95.3:
Describedly like that further make compound 95.2 and compound 1.2 reactions as 1, the 3 stage of embodiment, thereby obtain the compound of embodiment 95.3.Acquisition N '-(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-the 2-fluorophenyl)-N, N-dimethyl carbonamidine.Molecular weight is 566.20 (C
29H
26F
4N
6O
2); Retention time R
t=1.55 minutes [B]; MS (ESI): 567.10 (MH
+).
4) 4-{3-[2-(4-amino-3-fluorophenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-2-trifluoromethyl benzonitrile 95:
520mg compound 95.3 is dissolved in the mixed solution of uncle-butanol/water (10ml), mix with the 30mg palladium hydroxide and with its 60 ℃ and 6 the crust under carry out hydrogenation.Obtain 4-{3-[2-(4-amino-3-fluorophenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-2-trifluoromethyl benzonitrile.
Molecular weight is 511.16 (C
26H
21F
4N
5O
2); Retention time R
t=1.58 minutes [B]; MS (ESI): 512.26 (MH
+).
Embodiment 97:2-(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenyl) ethanamide:
265mg compound 78 is dissolved in the 0.56ml glacial acetic acid and itself and 0.44ml Hydrogen bromide (33% acetic acid solution) is admixed together.This mixture was stirred 2 hours down at 75 ℃, second day with it 100 ℃ of following restir 8 hours.Chilled this solution and water is admixed together, and concentrating under reduced pressure also carries out purifying (method [RP1]) with chromatography to it.Yield with 42% obtains 97.Molecular weight is 535.18 (C
28H
24F
3N
5O
3); Retention time R
t=2.18 minutes [C]; MS (ESI): 536.21 (MH
+).
Embodiment 113:4-{3-[2-(4-aminophenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-2-trifluoromethyl benzonitrile
This compound not only can obtain by the hydrolysis (as mentioned above) of corresponding benzal compound, and can be by also original acquisition the in the mixture of methyl alcohol and methylene dichloride with nitro-compound 112 usefulness Raney nickels and hydrogen.
1H NMR：8.35，d，1H；8.24，s，1H；8.07，d，1H；7.33，d，1H；7.08，t，1H；6.96，s，1H；6.83，s，1H；6.79，d，2H；6.72，t，1H；6.57，d，2H；4.8，s，2H；4.59，s，2H；1.41，s，6H。
Embodiment 114:1-[2-(2,4 difluorobenzene base amino) benzyl]-3-(4-methanesulfinyl-3-trifluoromethyl)-5,5-methylimidazole alkane-2,4-diketone
1) 5,5-dimethyl-3-(4-methylthio group-3-trifluoromethyl) imidazolidine-2, the preparation of 4-diketone (114.1):
Compound 114.1 can be prepared with method " A ".For this reason, with 1.04g4-methylthio group-3-trifluoromethyl amine solvent in the 25ml anhydrous acetonitrile.This solution under agitation is added drop-wise in the toluene solution of 20% phosgene that is heated to 70 ℃, then it was stirred 2 hours down at 80 ℃.With chilled this reaction soln concentrating under reduced pressure, with resistates with toluene dissolving and with its concentrating under reduced pressure once more.At last, resistates is dissolved in the 25ml anhydrous tetrahydro furan and this solution is under agitation admixed together with 0.88g hydrochloric acid 2-amino-2-methyl propionic acid uncle-butyl ester.Slowly in this reaction mixture, drip the 1.05ml triethylamine, then it was at room temperature stirred 4 hours.With this reaction mixture and water is admixed together and with ethyl acetate it is extracted.With the organic phase dried over mgso, filter and it is concentrated.Obtaining 2-methyl-2-[3-(4-methylthio group-3-trifluoromethyl) urea groups] (molecular weight is 392.13 (C to propionic acid uncle-butyl ester
17H
23F
3N
2O
3S); Retention time R
t=2.40 minutes [B]; MS (ESI): 337.26 (MH
+-C
4H
8)).This urea is dissolved in the 20ml tetrahydrofuran (THF), admixed together and it was stirred 2 hours down at 80 ℃ with the 4.9ml concentrated hydrochloric acid.Should chilled reaction mixture concentrating under reduced pressure and resistates and ethyl acetate and water is admixed together.Take out organic phase, wash with water then, use dried over sodium sulfate, filtration and its concentrating under reduced pressure with saturated sodium bicarbonate solution.Resistates is carried out purifying with silica gel chromatography, and the methylene chloride with 96/4 is carried out wash-out.Obtain 21.2g (yield is 90%) 5,5-dimethyl-3-(4-methylthio group-3-trifluoromethyl) imidazolidine-2,4-diketone 114.1.Molecular weight is 318.06 (C
13H
13F
3N
2O
2S); Retention time R
t=1.93 minutes [B]; MS (ES
-): 317.07 (M-H
+).
2) 3-(4-methanesulfinyl-3-trifluoromethyl)-5,5-methylimidazole alkane-2, the preparation of 4-ketone (114.1a):
The 470mg sodium periodate is dissolved in the 5ml water and under with the ice bath cooling with its slowly and 640mg be dissolved in 114.1 admixed together in the 10ml tetrahydrofuran (THF).This mixture is at room temperature stirred a night.Add the 210mg sodium periodate again and with this mixture restir 8 hours.This reaction mixture with water mixed and extract with ethyl acetate thereafter.With the organic phase dried over mgso, filter and its concentrating under reduced pressure.It is carried out chromatogram purification (silica gel; 96/4 methylene chloride), obtain 3-(4-methanesulfinyl-3-trifluoromethyl)-5,5-methylimidazole alkane-2,4-diketone (114.1a).Molecular weight is 334.05 (C
13H
13F
3N
2O
3S); Retention time R
t=1.69 minutes [B]; MS (ES
-): 335.19 (M-H
+).
3) 1-(2-bromobenzyl)-3-(4-methanesulfinyl-3-trifluoromethyl)-5,5-methylimidazole alkane-2, the preparation of 4-diketone (114.2):
Compound 114.2 usefulness such as compound 1.2 described methods are prepared.For this reason, 114.1a and 2-bromobenzyl bromide are reacted in containing the acetonitrile of salt of wormwood.Obtain 1-(2-bromobenzyl)-3-(4-methanesulfinyl-3-trifluoromethyl)-5,5-methylimidazole alkane-2,4-diketone, its molecular weight are 502.01 (C
20H
18BrF
3N
2O
3S); Retention time R
t=2.24 minutes [B]; MS (ESI): 503.21 (MH
+).
4) 1-[2-(2,4 difluorobenzene base amino) benzyl]-3-(4-methylene alkylsulfonyl-3-trifluoromethyl)-5,5-methylimidazole alkane-2, the preparation of 4-diketone (114):
Make 114.2 under preparation compound 1 described condition, to react, obtain 114 with 2,4 difluorobenzene amine.Molecular weight is 551.13 (C
26H
22F
5N
3O
3S); Retention time R
t=2.06 minutes [B]; MS (ESI): 552.17 (MH
+).
Embodiment 115:4-{2-[5,5-dimethyl-3-(4-methylthio group-3-trifluoromethyl)-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } methyl benzoate
Make 114.1 with 2-benzyl bromide bromine reaction, obtain 1-(2-bromobenzyl)-5,5-dimethyl-3-(4-methylthio group-3-trifluoromethyl) imidazolidine-2,4-diketone (115.2).It is further reacted under as preparation compound 1 described condition with the 4-Methyl anthranilate, obtains 4-{2-[5,5-dimethyl-3-(4-methylthio group-3-trifluoromethyl)-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } methyl benzoate; Molecular weight is 557.15 (C
28H
26F
3N
3O
4S); Retention time R
t=2.22 minutes [B]; MS (ESI): 558.21 (MH
+).
In a similar fashion, by 114.2 usefulness 4-Methyl anthranilates obtain 116 (4-{2-[3-(4-methanesulfinyl-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino methyl benzoate; Molecular weight is 573.15 (C
28H
26F
3N
3O
5S); Retention time R
t=1.91 minutes [B]; MS (ESI): 574.19 (MH
+).
The compound of embodiment 117,4-{2-[3-(4-methylsulfonyl-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } (molecular weight is 589.14 (C to methyl benzoate
28H
26F
3N
3O
6S); Retention time R
t=2.47 minutes [C]; MS (ESI): 590.06 (MH
+)) be by with 4-Methyl anthranilate and 1-(2-bromobenzyl)-3-(4-methylsulfonyl-3-trifluoromethyl)-5,5-methylimidazole alkane-2,4-diketone (117.2) reaction obtains.117.2 can pass through 2-bromobenzyl bromide and 3-(4-methylsulfonyl-3-trifluoromethyl)-5,5-methylimidazole alkane-2,4-diketone (117.1) reaction obtains.
117.1 (
1H NMR:8.8, s, 1H; 8.37, d, 1H; 8.2, s, 1H; 5.1, d, 1H; 3.32, s, 3H; 1.42, s, 6H) by 114.1 by between usefulness-oxidation of chlorine peroxybenzoic acid obtains.
Embodiment 121:4-{3-[2-(4-aminophenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-2-trifluoromethyl benzonitrile trifluoroacetic acid:
This trifluoroacetate 121 obtains by unhindered amina 113 and trifluoroacetic acid are reacted in acetonitrile.
1H NMR:9.3, s (broad peak), 2H; 8.35, d, 1H; 8.21, s, 1H; 8.05, d, 1H; 7.8, s, 1H; 7.5, d, 1H; 7.28, t, 1H; 7.2, d, 1H; 7.12, d, 2H; 7.08, t, 1H; 6.9, d, 2H; 4.56, s, 2H; 1.35, s, 6H.
Embodiment 135:4-{3-[2-(4-hydroxy phenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-2-trifluoromethyl benzonitrile:
Be dissolved in 110mg compound 127 in the 3.3ml anhydrous methylene chloride and under-10 ℃, under agitation sneak into 1.025ml boron trichloride solution (xylene solution of 1M) to wherein dripping.This mixture was stirred 2 hours down at-10 ℃, then it is heated to 0 ℃ and with it 0 ℃ of following restir 1 hour.Stirred 1 hour down at 0 ℃ to Dropwise 5 equivalent boron trichloride solution wherein and with this mixture again.At last, again Dropwise 5 equivalent boron trifluoride and with this mixture 0 ℃ of following restir 1 hour.This reaction mixture is arrived with the 1.1ml methanol mixed, stirred 30 minutes, then it is under reduced pressure concentrated three times with methyl alcohol.Resistates is carried out purifying (method [RP1]) with chromatography, obtains 4-{3-[2-(4-hydroxy phenyl amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-2-trifluoromethyl benzonitrile.Molecular weight is 494.15 (C
26H
21F
3N
4O
3); Retention time R
t=2.50 minutes [C]; MS (ESI): 495.33 (MH
+).
Embodiment 136:4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } benzamide:
1) 4-(3-{2-[4-(benzotriazole-1-carbonyl) phenyl amino] benzyl-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl)-preparation of 2-trifluoromethyl benzonitrile 136.1:
With 550.2mg acid 62,207.7mg 1-methylsulfonyl-1H-benzotriazole (people: J.Org.Chem.2005 such as A.R.Katritzky; 70,9191-9197) and the 0.205ml triethylamine be dissolved in the 5.5ml anhydrous tetrahydro furan and and under reflux temperature, stirred 6 hours it.Adding 1 equivalent benzotriazole derivatives and triethylamine more also stirs this mixture one night under reflux temperature.Second day, should chilled reaction mixture concentrating under reduced pressure, be dissolved in the 10ml methylene dichloride and by with the water jolting with its extracting twice, take out organic phase, use dried over mgso, filtration and with its concentrating under reduced pressure.Resistates is carried out purifying (silica gel with chromatography; 1/9 to 1/2 just-heptane/ethyl acetate).Obtain 4-(3-{2-[4-(benzotriazole-1-carbonyl) phenyl amino] benzyl-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl)-2-trifluoromethyl benzonitrile.Molecular weight is 623.18 (C
33H
24F
3N
7O
3); Retention time R
t=2.75 minutes [B]; MS (ES
-): 622.14 (M-H
+).
2) 4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } preparation of benzamide 136:
430.3mg compound 136.1 is dissolved in the 2.5ml anhydrous tetrahydro furan and itself and the solution of 0.2ml ammonia in tetrahydrofuran (THF) (methanol solution of 7N) is admixed together.This solution was at room temperature left standstill 3 days, carry out purifying (method [RP1]) with its concentrating under reduced pressure and with chromatography then.Obtain 4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } benzamide 136.Molecular weight is 521.16 (C
27H
22F
3N
5O
3); Retention time R
t=1.75 minutes [B]; MS (ESI): 522.19 (MH
+).
The compound of embodiment 137,4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-(molecular weight is 595.20 (C to benzamide to N-(2-hydroxyl-1-hydroxymethyl ethyl)
30H
28F
3N
5O
5); Retention time R
t=1.64 minutes [B]; MS (ESI): 596.22 (MH
+)),
The compound of embodiment 149,4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-(molecular weight is 565.19 (C to N-(2-hydroxyethyl) benzamide
29H
26F
3N
5O
4); Retention time R
t=1.74 minutes [B]; MS (ESI): 566.27 (MH
+)),
The compound of embodiment 161, N-carbamyl ylmethyl-4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } (molecular weight is 578.18 (C to benzamide
29H
25F
3N
6O
4); Retention time R
t=1.69 minutes [B]; MS (ESI): 579.16 (MH
+)),
The compound of embodiment 162,2-(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } benzoyl-amido)-(molecular weight is 663.26 (C to 2 Methylpropionic acid uncle-butyl ester
35H
36F
3N
5O
5); Retention time R
t=2.26 minutes [B]; MS (ESI): 664.39 (MH
+)),
The compound of embodiment 163,4-(4,4-dimethyl-2,5-dioxo-3-{2-[4-(piperidines-1-carbonyl) phenyl amino] benzyl } imidazolidine-1-yl)-(molecular weight is 589.62 (C to 2-trifluoromethyl benzonitrile
32H
30F
3N
5O
3); Retention time R
t=2.14 minutes [B]; MS (ESI): 590.18 (MH
+)),
Be as described in 136 by 136.1 by obtaining with the reaction of following compound:
2-amino the third-1,3-glycol (for 137),
2-monoethanolamine (for 149),
2-amino acetamide (for 161),
2-amino-2-methyl propionic acid uncle-butyl ester (for 162),
Piperidines (for 163)
And diisopropyl ethyl amine.
Embodiment 143: hydrochloric acid 4-{2-[3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-N-hydroxyl benzamidine:
With the compound dissolution of 250mg embodiment 134 in 2.5ml ethanol and it is admixed together with 70mg oxammonium hydrochloride and 102mg triethylamine in succession.This mixture was stirred 2 hours down at 65 ℃.For aftertreatment, with this reaction mixture and water is admixed together and with twice of ethyl acetate shaking out.Organic phase is carried out purifying (method [RP1]) with dried over mgso and with chromatography.To comprise the fraction lyophilize of product, and be dissolved in the amount of ethyl acetate and also it is carried out acidifying with the hydrochloric acid of 2N in ether.With this reaction mixture concentrating under reduced pressure, resistates is dissolved in the mixed solution of water and acetonitrile and once more with its lyophilize.Obtain 4-{2-[3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-hydrochloride of N-hydroxyl benzamidine, molecular weight is 529.17 (C
26H
23F
4N
5O
3); Retention time R
t=1.51 minutes [B]; MS (ESI): 530.13 (MH
+).
Embodiment 144: hydrochloric acid 4-{2-[3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } benzamidine:
The compound of embodiment 144 is changing into imido-ester and is also obtaining subsequently with behind the hydrochloric acid reaction with ammonia react by 134.Free alkali: molecular weight is 513.17 (C
26H
23F
4N
5O
2); Retention time R
t=1.52 minutes [B]; MS (ESI): 514.24 (MH
+).
Perhaps, compound 144 can be by obtaining 143 pressure hydrations (5 crust, 10% drapes over one's shoulders the Pd gac, methyl alcohol, 20 hours).
Embodiment 148:N-(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenyl) ethanamide:
The compound of embodiment 148 is by reacting acquisition with 113 with Acetyl Chloride 98Min. and sodium bicarbonate in acetonitrile.Molecular weight is 535.18 (C
28H
24F
3N
5O
3); Retention time R
t=1.92 minutes [B]; MS (ESI): 536.27 (MH
+).
Embodiment 153:3-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } benzsulfamide:
The compound of embodiment 153 is prepared by eliminate its dimethylamino methylene blocking group with hydrochloric acid as embodiment 68 is described.Obtained 3-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } (molecular weight is 557.13 (C to benzsulfamide
26H
22F
3N
5O
4S); Retention time R
t=1.91 minutes [B]; MS (ESI): 558.26 (MH
+)).
Embodiment 154:4-{5-fluoro-2-[3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } methyl benzoate:
1) 1-(2-bromo-4-luorobenzyl)-3-(4-fluoro-3-trifluoromethyl)-5,5-methylimidazole alkane-2, the preparation of 4-diketone 154.2:
Title compound is prepared by reacting under 1.2 described conditions as mentioned with 2-bromo-1-brooethyl-4-fluorobenzene 23.1.
1H NMR：7.98，m，1H；7.9，m，1H；7.7-7.6，m，3H；7.26，m，1H；4.6，s，2H；1.4，s，6H。
2) 4-{5-fluoro-2-[3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } preparation of methyl benzoate 154:
Make 154.2 with the 4-Methyl anthranilate as above further reaction under the preparation embodiment described condition of 1, the 3 stage.Obtaining molecular weight is 547.15 (C
27H
22F
5N
3O
4) 154; Retention time R
t=2.27 minutes [B]; MS (ESI): 548.26 (MH
+).
The compound of embodiment 192,4-{5-fluoro-2-[3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenylformic acid uncle-butyl ester is to obtain with 4-benzaminic acid uncle-butyl ester in a similar fashion.Molecular weight is 589.20 (C
30H
28F
5N
3O
4); Retention time R
t=2.56 minutes [B]; MS (ESI): 534.23 (MH
+-C4H8).
The compound of embodiment 247,5-{5-fluoro-2-[3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-the O-Anisic Acid methyl esters is to obtain with 5-bromo-O-Anisic Acid methyl esters in a similar fashion.Molecular weight is 577.16 (C
28H
24F
5N
3O
5); Retention time R
t=2.21 minutes [B]; MS (ESI): 578.17 (MH
+).
Embodiment 155:2-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } terephthalic acid 1-methyl ester:
0.2g compound 150 at room temperature is dissolved in the no Shui diox of 5ml, admixed together and it was stirred 30 hours down at 80 ℃ with 0.25ml Hydrogen bromide (62%).Should chilled reaction mixture concentrating under reduced pressure and it is carried out purifying (method [RP1]) with chromatography.Obtain mono-methyl 2-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } terephthalic acid 1-methyl ester.
1H NMR：13.15，s，1H；9.2，s，1H；8.25，d，1H；8.17，s，1H；8.05，d，1H；7.97，d，1H；7.62，d，1H；7.4，m，3H；7.28，m，2H，4.6，s，2H；3.8，s，3H；1.35，s，6H。
Embodiment 158:4-{2-[3-(4-cyano group-3-cyclopropyl phenyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } methyl benzoate:
1) preparation of 4-amino-2-cyclopropyl benzonitrile (158.3):
Under argon gas atmosphere, the 269mg palladium is joined in 916mg 2-chloro-4-aminobenzonitrile, 773mg cyclopropylboronic acid, 5.094g potassiumphosphate and the suspension of 673mg tricyclohexyl phosphine in the mixed solution of 10.5ml toluene and 1.74ml water.This mixture is stirred a night down at 80 ℃.Should chilled reaction mixture and water and ethyl acetate admixed together, filter and filtrate extracted three times with the mixed solution of ethyl acetate with toluene.With the organic phase dried over mgso, filter and its concentrating under reduced pressure.Resistates is carried out purifying (method [PR1]) with chromatography, obtain 4-amino-2-cyclopropyl benzonitrile.
1H NMR:7.3, d, 1H; 6.4, d, 1H; 6.1, d, 1H; 4.0, s (broad peak), 2H; 2.0, m, 1H; 1.0, m, 2H; 0.65, m, 2H.
2) preparation of 2-cyclopropyl-4-(4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl) benzonitrile (158.1):
Compound 158.1 be with as 1.1 described methods, be prepared with hydrochloric acid 2-amino-2-methyl propionic acid uncle-butyl ester photoreactive gas (toluene solution) reaction by making 158.3.Molecular weight is 269.11 (C
15H
15N
3O
2); Retention time R
t=1.43 minutes [B]; MS (ESI): 270.18 (MH
+).
3) 4-[3-(2-bromo-4-luorobenzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-preparation of 2-cyclopropyl benzonitrile (158.2):
Under as preparation 1.2 described conditions, make compound 158.1 and 2-bromo-1-brooethyl-4-fluorobenzene reaction, obtain 158.2.Molecular weight is 455.06 (C
22H
19BrFN
3O
2); Retention time R
t=2.15 minutes [B]; MS (ESI): 456.02 (MH
+).
4) 4-{2-[3-(4-cyano group-3-cyclopropyl phenyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } preparation of methyl benzoate (158):
As above under the described condition of preparation in 1, the 3 stage of embodiment, make 158.2 further to react with the 4-Methyl anthranilate.Obtain molecular weight and be 526.20 158 (C
30H
27F
4N
4O
4); Retention time R
t=2.19 minutes [B]; MS (ESI): 527.28 (MH
+).
The compound of embodiment 194 (4-{2-[3-(4-cyano group-3-cyclopropyl phenyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } phenylformic acid uncle-butyl ester) be in a similar fashion, react with 4-benzaminic acid uncle-butyl ester and to obtain by making 158.2.Molecular weight is 568.24 (C
33H
33FN
4O
4); Retention time R
t=2.49 minutes [B]; MS (ESI): 513.26 (MH
+-C
4H
8).
Embodiment 160:4-{2-[3-(4-cyano group-3-aminomethyl phenyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } methyl benzoate:
In the compound of embodiment 160 synthetic, as the preparation of the compound of embodiment 158, operate: 2-methyl-4-nitrobenzonitrile (with like the class of operation of synthetic compound 63.4) is reduced into 4-amino-2-methyl benzonitrile (160.3 with hydroiodic acid HI;
1H NMR:7.3, d, 1H; 6.48, s, 1H; 6.42, d, 1H; 6.02, s, 2H; 227, s, 3H).Use standard method, aniline 160.3 is changed into compound 160.1 (4-(4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl)-2-methyl benzonitrile with hydrochloric acid 2-amino-2-methyl propionic acid uncle-butyl ester photoreactive gas (toluene solution);
1H NMR:8.7, s, 1H; 7.88, d, 1H; 7.55, s, 1H; 7.44, d, 1H; 1.4 s 3H), next makes itself and 2-bromo-1-brooethyl-4-fluorobenzene reaction, thereby obtain 160.2 (4-[3-(2-bromo-4-luorobenzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-2-methyl benzonitrile; Molecular weight is 429.04 (C
20H
17BrFN
3O
2); Retention time R
t=2.08 minutes [B]; MS (ESI): 430.05 (MH
+)).Make 160.2 with 4-Methyl anthranilate reaction, obtain title compound 160.Molecular weight is 500.18 (C
28H
25FN
4O
4); Retention time R
t=2.14 minutes [B]; MS (ESI): 501.23 (MH
+).
The compound of embodiment 195 (4-{2-[3-(4-cyano group-3-aminomethyl phenyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } phenylformic acid uncle-butyl ester) be in a similar fashion, react with 4-benzaminic acid uncle-butyl ester and to obtain by making 160.2.Molecular weight is 542.23 (C
31H
31FN
4O
4); Retention time R
t=2.40 minutes [B]; MS (ESI): 487.21 (MH
+-C
4H
8).
Embodiment 167:4-{2-[3-(2-tert-butyl pyridin-4-yl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } methyl benzoate HCI trifluoroacetic acid:
The compound of embodiment 167 is by 2-tert-butyl pyridin-4-yl amine → 3-(2-tert-butyl pyridin-4-yl)-5,5-methylimidazole alkane-2, and (molecular weight is 261.14 (C to 4-diketone 167.1
14H
19N
3O
2); Retention time R
t=0.91 minute [B]; MS (ESI): 262.19 (MH
+)) → 1-(2-bromo-4-luorobenzyl)-3-(2-tert-butyl pyridin-4-yl)-5,5-methylimidazole alkane-2, (molecular weight is 447.09 (C to 4-diketone 167.2
21H
23BrFN
3O
2); Retention time R
t=1.59 minutes [B]; MS (ESI): 448.07 (MH
+)) → 4-{2-[3-(2-tert-butyl pyridin-4-yl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } (free alkali: molecular weight is 518.23 (C to methyl benzoate HCl trifluoroacetic acid 167
29H
31FN
4O
4); Retention time R
t=1.68 minutes [B]; MS (ESI): 519.18 (MH
+)) order obtain.
The compound of embodiment 193 (compound 167 corresponding tert-butyl esters) is prepared with 4-benzaminic acid uncle-butyl ester in a similar fashion.Molecular weight is 560.27 (C
32H
37FN
4O
4); Retention time R
t=1.94 minutes [B]; MS (ESI): 561.35 (MH
+).
Embodiment 170:4-{5-fluoro-2-[3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-N-((2S, 3R, 4R, 5R)-2,3,4,5, and 6-penta hydroxy group hexyl) benzamide:
The compound of embodiment 170 is by making 156 to react in dimethyl formamide with hydrochloric acid N-(3-dimethylaminopropyl)-N '-ethyl carbodiimide, I-hydroxybenzotriazole, ethyl diisopropyl amine and D-glucosamine and to be prepared.Obtain 4-{5-fluoro-2-[3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-N-((2S, 3R, 4R, 5R)-2,3,4,5, and 6-penta hydroxy group hexyl) benzamide; Molecular weight is 696.22 (C
32H
33F
5N
4O
8); Retention time R
t=1.86 minutes [C]; MS (ESI): 697.33 (MH
+).
Embodiment 164:2-(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } benzoyl-amido) ethyl sulfonic acid:
In a similar fashion; only be to use compound and the taurine of embodiment 62; obtain the compound of embodiment 164; 2-(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5; 5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } benzoyl-amido) (molecular weight is 629.15 (C to ethyl sulfonic acid
29H
26F
3N
5O
6S); Retention time R
t=1.63 minutes [B]; MS (ESI): 630.25 (MH
+)).
Embodiment 171:1-{4-fluoro-2-[4-(4-hydroxy piperidine-1-carbonyl) phenyl amino] benzyl }-3-(4-fluoro-3-trifluoromethyl)-5,5-methylimidazole alkane-2, the 4-diketone:
In a similar fashion and use compound and the piperidines-4-alcohol of embodiment 156, obtain the compound of embodiment 171,1-{4-fluoro-2-[4-(4-hydroxy piperidine-1-carbonyl) phenyl amino] benzyl }-3-(4-fluoro-3-trifluoromethyl)-5,5-methylimidazole alkane-2, (molecular weight is 616.21 (C to the 4-diketone
31H
29F
5N
4O
4); Retention time R
t=2.18 minutes [C]; MS (ESI): 617.24 (MH
+)).
Embodiment 172:1-{4-fluoro-2-[4-(piperazine-1-carbonyl) phenyl amino] benzyl }-3-(4-fluoro-3-trifluoromethyl)-5,5-methylimidazole alkane-2, the 4-dione hydrochloride:
The compound of embodiment 172 is prepared as described in 170, and difference is that the amine component of used alternative D-glucosamine is a piperazine, and subsequently with in the hydrochloric acid Zai diox this acid amides being changed into hydrochloride.Molecular weight (free alkali) is 601.21 (C
30H
28F
5N
5O
3); Retention time R
t=1.71 minutes [C]; MS (ESI): 602.25 (MH
+).
Embodiment 173:4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-N-(3-methylsulfonyl propyl group) benzamide:
In a similar fashion and use compound and the 3-methylsulfonyl propyl group amine of embodiment 62; make the compound of embodiment 173; 4-{2-[3-(4-cyano group-3-trifluoromethyl)-5; 5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-(molecular weight is 641.19 (C to N-(3-methylsulfonyl propyl group) benzamide
31H
30F
3N
5O
5S); Retention time R
t=1.79 minutes [B]; MS (ESI): 642.18 (MH
+)).
Embodiment 174:4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-N-piperidines-1-yl-benzamide:
With the compound dissolution of 100mg embodiment 62 in the 2.5ml dimethyl formamide and successively with itself and 45.9mg hydrochloric acid N-(3-dimethylaminopropyl)-N '-ethyl carbodiimide, 36.6mg I-hydroxybenzotriazole with the 30.9mg ethyl diisopropyl amine is admixed together and it was at room temperature stirred 30 minutes.Add 0.031ml N-amino piperidine and with this mixture restir 6 hour thereafter.For aftertreatment, it is carried out purifying (method [RP1]) with this reaction mixture concentrating under reduced pressure and with chromatography.Obtain 4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-N-piperidines-1-yl-benzamide; Molecular weight is 604.24 (C
32H
31F
3N
6O
3); Retention time R
t=1.60 minutes [B]; MS (ESI): 605.24 (MH
+).
Embodiment 237:(R)-1-(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } benzoyl) tetramethyleneimine-2-formonitrile HCN:
In a similar fashion; only be to use the compound of embodiment 133 and (R)-tetramethyleneimine-2-formonitrile HCN; make the compound of embodiment 237; (R)-1-(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5; 5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } benzoyl) (molecular weight is 618.20 (C to tetramethyleneimine-2-formonitrile HCN
32H
26F
4N
6O
3); Retention time R
t=2.01 minutes [B]; MS (ESI): 619.22 (MH
+)).
Embodiment 175:N-(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenyl) Toluidrin:
The compound of embodiment 175 is by making 113 to react in acetonitrile with methylsulfonyl chloride and sodium bicarbonate and to obtain.Molecular weight is 571.15 (C
27H
24F
3N
5O
4S); Retention time R
t=1.95 minutes [B]; MS (ESI): 572.24 (MH
+).
As another kind of reaction product, obtain the compound of embodiment 176,
Molecular weight is 649.12 (C
28H
26F
3N
5O
6S
2); Retention time R
t=2.06 minutes [B]; MS (ESI): 650.26 (MH
+).
Embodiment 177:(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenyl amino) methyl acetate:
The compound of embodiment 177 is by making 113 to react in acetonitrile with monobromo-acetic acid methyl esters and sodium bicarbonate and to obtain.Molecular weight is 565.19 (C
29H
26F
3N
5O
4); Retention time R
t=1.96 minutes [B]; MS (ESI): 566.29 (MH
+).
As another kind of reaction product, obtain the compound of embodiment 178, [(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenyl) the methoxycarbonyl methylamino] methyl acetate
Molecular weight is 637.21 (C
32H
30F
3N
5O
6); Retention time R
t=2.14 minutes [B]; MS (ESI): 638.31 (MH
+).
Embodiment 182:(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenoxy group) acetate:
The compound of embodiment 182 by make 191 with 4N hydrochloric acid Zai diox in react and obtain.Molecular weight is 552.16 (C
28H
23F
3N
4O
5); Retention time R
t=1.93 minutes [B]; MS (ESI): 553.17 (MH
+).
Embodiment 183:3-(4-carboxyl phenyl amino)-4-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenylformic acid:
1) preparation of 3-bromo-4-tolyl acid uncle-butyl ester (183.1):
2g 3-bromo-4-tolyl acid is suspended in the 9.4g thionyl chloride and with it to descend to stir 2 hours at 60 ℃.Should chilled reaction mixture concentrating under reduced pressure, it is dissolved in the 20ml acetonitrile, admixed together and it was at room temperature stirred 20 hours with uncle 887mg-butanols lithium.For aftertreatment, that this reaction mixture and ethyl acetate and water is admixed together.Take out organic phase, use dried over mgso, filtration and its concentrating under reduced pressure.Resistates is carried out purifying (silica gel with chromatography; Just-and heptane), obtain 3-bromo-4-tolyl acid uncle-butyl ester.
1H NMR：8.0，s，1H；7.8，d，1H；7.5，d，1H；2.4，s，3H；1.55，s，9H。
2) preparation of 3-bromo-4-bromo methyl acid uncle-butyl ester (183.2):
In chlorobenzene, under 120 ℃, compound 183.1 is carried out the free radical bromination with N-bromine succinimide and dibenzoyl peroxide, obtain 183.2,3-bromo-4-bromo methyl acid uncle-butyl ester.
1H NMR：8.06，s，1H；7.9，d，1H；7.75，d，1H；4.78，s，2H；1.55，s，9H。
3) 3-bromo-4-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] preparation of phenylformic acid uncle-butyl ester (183.3):
As above under the described condition of compound of preparation embodiment 6.2, compound 1.1 is reacted with 183.2, thereby obtains 183.3.
1H NMR：8.35，d，1H；8.25，s，1H；8.1，d，1H；8.09，s，1H；7.88，d，1H；7.7，d，2H；4.69，s，2H；1.55，s，9H；1.43，s，6H。4) 3-(uncle 4--butoxy carbonyl phenyl amino)-4-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] preparation of phenylformic acid uncle-butyl ester (214):
As above under the preparation compound 126 described conditions, obtain 214 by making 183.3 with 4-benzaminic acid uncle-butyl ester reaction.Molecular weight is 678.26 (C
36H
37F
3N
4O
6); Retention time R
t=2.62 minutes [B]; MS (ESI): 623.20 (MH
+-C
4H
8).
5) 3-(4-carboxyl phenyl amino)-4-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenylformic acid 183:
Embodiment 62 is described as mentioned carries out the ester cracking with 214 like that, thereby forms 183.183: molecular weight is 566.14 (C
28H
21F
3N
4O
6); Retention time R
t=1.69 minutes [B]; MS (ESI): 567.17 (MH
+).
Embodiment 185,220,187,188 and 189 compound get with similar sequential system:
185:4-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-(molecular weight is 590.13 (C to 3-(4-trifluoromethyl amino) phenylformic acid
28H
20F
6N
4O
4); Retention time R
t=2.04 minutes [B]; MS (ESI): 591.15 (MH
+)), by 183.3 → 4-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-(215, molecular weight is 646.20 (C to 3-(4-trifluoromethyl amino) phenylformic acid uncle-butyl ester
32H
28F
6N
4O
4); Retention time R
t=2.55 minutes [B]; MS (ESI): 647.23 (MH
+)) → 185 sequential system gets;
220:4-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-(molecular weight is 540.14 (C to 3-(4-fluorophenyl amino) phenylformic acid
27H
20F
4N
4O
4); Retention time R
t=1.95 minutes [B]; MS (ESI): 541.15 (MH
+)), by 183.3 → 4-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-(216, molecular weight is 596.20 (C to 3-(4-fluorophenyl amino) phenylformic acid uncle-butyl ester
31H
28F
4N
4O
4); Retention time R
t=2.46 minutes [B]; MS (ESI): 597.19 (MH
+)) → 220 sequential system gets;
187:4-(4-carboxyl phenyl amino)-3-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] (molecular weight is 566.14 (C to phenylformic acid
28H
21F
3N
4O
6); Retention time R
t=1.68 minutes [B]; MS (ESI): 567.17 (MH
+)), by 187.1 (4-bromo-3-tolyl acid uncle-butyl ester,
1H NMR:7.85, s, 1H; 7.72, d, 1H; 7.62, d, 1H; 2.4, s, 3H; 1.53, s, 9H) → 187.2 (4-bromo-3-bromo methyl acid uncle-butyl ester,
1H NMR:8.12, s, 1H; 7.8, d, 1H; 7.75, d, 1H; 4.8, s, 2H; 1.56, s, and 9H) → 187.3 (4-bromo-3-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenylformic acid uncle-butyl ester, molecular weight is 565.08 (C
25H
23BrF
3N
3O
4); Retention time R
t=3.03 minutes [C]; MS (ESI): 566.14 (MH
+)) → 217 (4-(uncle 4--butoxy carbonyl phenyl amino)-3-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenylformic acid uncle-butyl ester; Molecular weight is 678.26 (C
36H
37F
3N
4O
6); Retention time R
t=2.67 minutes [B]; MS (ESI): 623.23 (MH
+-C
4H
8)) → 187 (compound 187.1,187.2,187.3 and 217 be compound 183.1,183.2,183.3 and 214 isomer and with the there described method make) sequential system get;
188:3-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-(molecular weight is 590.13 (C to 4-(4-trifluoromethyl amino) phenylformic acid
28H
20F
6N
4O
4); Retention time R
t=2.09 minutes [B]; MS (ESI): 591.17 (MH
+), by 187.3 → 3-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-(218, molecular weight is 646.20 (C to 4-(4-trifluoromethyl amino) phenylformic acid uncle-butyl ester
32H
28F
6N
4O
4); Retention time R
t=2.59 minutes [B]; MS (ESI): 591.16 (MH
+-C
4H
8)) → 188 sequential system gets;
189:3-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-(molecular weight is 540.14 (C to 4-(4-fluorophenyl amino) phenylformic acid
27H
20F
4N
4O
4); Retention time R
t=1.98 minutes [B]; MS (ESI): 541.16 (MH
+), by 187.3 → 3-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-(219, molecular weight is 596.20 (C to 4-(4-fluorophenyl amino) phenylformic acid uncle-butyl ester
31H
28F
4N
4O
4); Retention time R
t=2.49 minutes [B]; MS (ESI): 541.16 (MH
+-C
4H
8)) → 189 sequential system gets.
Embodiment 184:4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-trifluoromethyl amino } the phenylformic acid sodium salt
The sodium salt of acid 107 is at room temperature to stir by adding solid sodium bicarbonate in the solution of this acid in the mixed solution of water and acetonitrile and with this mixture to obtain in 30 minutes.By adding
IPR-64 H
+Type (weak acid) is removed excessive sodium bicarbonate.After with filtration of syringe-type strainer and lyophilize, obtain 184;
1H NMR:8.35, d, 1H; 8.24, s, 1H; 8.1, d, 2H; 8.0, s, 1H; 7.79, d, 2H; 7.7, d, 1H; 7.44, s, 1H; 7.26,1H; 6.9, d, 2H; 4.62, s, 2H; 1.42, s, 6H.
Embodiment 190:4-{2-[3-(4-cyano group-3-aminomethyl phenyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } benzamide:
The compound of embodiment 190 is prepared as described in 170, and difference is that used acid constituents is that compound 166 and used amine component are ammonia (the dense aqueous solution).Molecular weight is 485.18 (C
27H
24FN
5O
3); Retention time R
t=1.68 minutes [B]; MS (ESI): 486.22 (MH
+).
Embodiment 191:(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenoxy group) acetate uncle-butyl ester:
The compound of embodiment 191 is by making 135 to react in acetonitrile with monobromo-acetic acid uncle-butyl ester and cesium carbonate and to obtain.Molecular weight is 608.22 (C
32H
31F
3N
4O
5); Retention time R
t=3.04 minutes [C]; MS (ESI): 609.25 (MH
+).
Embodiment 198:4-{3-[2-(6-hydroxyl pyridazine-3-base is amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-2-trifluoromethyl benzonitrile trifluoroacetic acid:
The compound dissolution of 275mg embodiment 179 is in the 10ml anhydrous acetonitrile, admixed together and be heated to 85 ℃ and reach 4 hours with 219mg potassiumiodide and 169 μ l trimethylsilyl chloride.Should chilled reaction mixture concentrating under reduced pressure and resistates and ethyl acetate and water is admixed together.Organic phase is carried out purifying (method [RP1]) with chromatography, obtains 4-{3-[2-(6-hydroxyl pyridazine-3-base the is amino) benzyl of trifluoroacetic acid salt form]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-2-trifluoromethyl benzonitrile.Molecular weight is 496.14 (C
24H
19F
3N
6O
3); Retention time R
t=1.63 minutes [C]; MS (ESI): 497.16 (MH
+).
Embodiment 204:1-[4-fluoro-2-(8-oxo-5,6,7,8-naphthane-2-base is amino) benzyl]-3-(4-fluoro-3-trifluoromethyl)-5,5-methylimidazole alkane-2, the 4-diketone:
1) 1-(2-amino-4-luorobenzyl)-3-(4-fluoro-3-trifluoromethyl)-5,5-methylimidazole alkane-2, the preparation of 4-diketone (204.2):
204.2 be and preparation compound 61.2 described methods similarly, react with benzophenone imine and to obtain by making 154.2.Molecular weight is 413.11 (C
19H
16F
5N
3O
2); Retention time R
t=2.45 minutes [C]; MS (ESI): 414.23 (MH
+).
2) 1-[4-fluoro-2-(8-oxo-5,6,7,8-naphthane-2-base is amino)-benzyl]-3-(4-fluoro-3-trifluoromethyl)-5,5-methylimidazole alkane-2, the preparation of 4-diketone (204):
Make 204.2 with 7-bromo-3,4-dihydro-2H-naphthalene-1-ketone reacts under the described condition of compound as preparation embodiment 61, obtain 1-[4-fluoro-2-(8-oxo-5,6,7,8-naphthane-2-base is amino) benzyl]-3-(4-fluoro-3-trifluoromethyl)-5,5-methylimidazole alkane-2,4-diketone (204).Molecular weight is 557.17 (C
29H
24F
5N
3O
2); Retention time R
t=2.33 minutes [B]; MS (ESI): 558.25 (MH
+).
The compound of embodiment 205,1-[4-fluoro-2-(3-oxo indane-5-base is amino) benzyl]-3-(4-fluoro-3-trifluoromethyl)-5,5-methylimidazole alkane-2, (molecular weight is 543.15 (C to the 4-diketone
28H
22F
5N
3O
3); Retention time R
t=2.09 minutes [B]; MS (ESI): 544.24 (MH
+)),
The compound of embodiment 206,1-[4-fluoro-2-(1-oxo indane-5-base is amino) benzyl]-3-(4-fluoro-3-trifluoromethyl)-5,5-methylimidazole alkane-2, (molecular weight is 543.15 (C to the 4-diketone
28H
22F
5N
3O
3); Retention time R
t=2.07 minutes [B]; MS (ESI): 544.23 (MH
+)),
The compound of embodiment 207,1-[2-(2,2-dimethyl-4-oxo chroman-6-base is amino)-4-luorobenzyl]-3-(4-fluoro-3-trifluoromethyl)-5,5-methylimidazole alkane-2, (molecular weight is 587.18 (C to the 4-diketone
30H
26F
5N
3O
4); Retention time R
t=2.38 minutes [B]; MS (ESI): 588.25 (MH
+)),
The compound of embodiment 213,1-[4-fluoro-2-(4-methylsulfonyl phenyl amino) benzyl]-3-(4-fluoro-3-trifluoromethyl)-5,5-methylimidazole alkane-2, (molecular weight is 567.12 (C to the 4-diketone
26H
22F
5N
3O
4S); Retention time R
t=2.00 minutes [B]; MS (ESI): 568.10 (MH
+)),
The compound of embodiment 222,3-{5-fluoro-2-[3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } benzsulfamide HCl salt, molecular weight (free alkali) is 568.12 (C
25H
21F
5N
4O
4S); Retention time R
t=2.39 minutes [C]; MS (ESI): 569.41 (MH
+), by using hydrochloric acid hydrolysis N-[1-dimethylamino methylene]-3-{5-fluoro-2-[3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } (222.1, molecular weight is 623.16 (C to benzsulfamide
28H
26F
5N
5O
4S); Retention time R
t=2.48 minutes [C]; MS (ESI): 624.33 (MH
+)) make,
The compound of embodiment 230,4-{5-fluoro-2-[3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } benzsulfamide, molecular weight is 568.12 (C
25H
21F
5N
4O
4S); Retention time R
t=1.88 minutes [B]; MS (ESI): 569.31 (MH
+), by hydrochloric acid hydrolysis N-[1-dimethylamino methylene]-4-{5-fluoro-2-[3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-(230.1, molecular weight is 623.16 (C to benzsulfamide
28H
26F
5N
5O
4S); Retention time R
t=1.95 minutes [B]; MS (ESI): 624.05 (MH
+)) make,
The compound of embodiment 239,1-[4-fluoro-2-(4-oxo chroman-6-base is amino) benzyl]-3-(4-fluoro-3-trifluoromethyl)-5,5-methylimidazole alkane-2,4-diketone, molecular weight are 559.15 (C
28H
22F
5N
3O
4); Retention time R
t=2.19 minutes [B]; MS (ESI): 560.22 (MH
+)
Be as the described condition of compound of preparation embodiment 204 under by make compound 204.2 with below compound react and obtain:
6-bromine indan-1-one (for 205),
5-bromine indan-1-one (for 206),
6-bromo-2,2-dimethylchroman-4-ketone (for 207),
1-bromo-4-methylsulfonyl benzene (for 213),
3-bromo-N-[1-dimethylamino methylene] benzsulfamide (making by making the reaction of 3-bromobenzene sulphonamide and dimethylformamide dimethyl acetal, for 222.1 and 222),
4-bromo-N-[1-dimethylamino methylene] benzsulfamide (making by making the reaction of 4-bromobenzene sulphonamide and dimethylformamide dimethyl acetal, for 230.1 and 230),
6-bromine chroman-4-on-(for 239, also using cesium carbonate as alkali as catalyzer) with dichloride [1,3-two (2, the 6-diisopropyl phenyl)-imidazoles-2-subunit] (3-chloropyridine base) palladium (II).
Embodiment 210:4 '-and 2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } biphenyl-4-formic acid:
1) 4 '-preparation of bromo biphenyl-4-formic acid uncle-butyl ester (210.1):
Compound 210.1 is to be made by 4 '-bromo biphenyl-4-formic acid, thionyl chloride and uncle-butanols lithium as 183.1 preparation is described.
1H NMR：7.99，d，2H；7.8，d，2H；7.7，s，4H；1.57，s，9H。
2) 4 '-preparation of { 2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } biphenyl-4-formic acid uncle-butyl ester (203):
Under the described condition of compound, make compound 61.2 and 210.1 reactions, thereby obtain 203 as preparation embodiment 61.Molecular weight is 654.24 (C
37H
33F
3N
4O
4); Retention time R
t=3.43 minutes [C]; MS (ESI): 655.51 (MH
+).
3) 4 '-preparation of { 2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } biphenyl-4-formic acid (210):
Compound 210 is to obtain by the acidic hydrolysis of ester 203 (similar with 62 preparation method).Molecular weight is 598.18 (C
33H
25F
3N
4O
4); Retention time R
t=2.52 minutes [B]; MS (ES-): 597.10 (M-H
+).
Embodiment 223:(4-{2-[4-{2-[3-(6-cyanobiphenyl-3-yl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } methyl benzoate:
1) preparation of 5-phenylaniline-2-formonitrile HCN (223.3):
With 534mg phenyl-boron dihydroxide, 79mg palladium (II), 287mg2-dicyclohexyl phosphino--2 ', 6 '-dimethoxy-biphenyl, 1.486g potassiumphosphate (K
3PO
4) and 305mg 2-chloro-4-aminobenzonitrile is suspended in the 7ml toluene and it was being stirred 12 hours under argon gas atmosphere under 80 ℃.Should chilled reaction mixture and water and ethyl acetate is admixed together and it is filtered.The mixed solution of filtrate with ethyl acetate and toluene extracted three times.Take out organic phase, use dried over mgso, filtration and its concentrating under reduced pressure.
1H NMR:7.52-7.42, m, 6H; 6.63, m, 2H; 6.25, s (broad peak), 2H.
2) preparation of 5-(4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl) biphenyl-2-formonitrile HCN (223.1):
Compound 223.1 be with as 1.1 described methods, be prepared with hydrochloric acid 2-amino-2-methyl propionic acid uncle-butyl ester photoreactive gas (toluene solution) reaction by making 223.3.
1H NMR：8.73，s，1H；8.09，d，1H；7.75，s，1H；7.69，d，1H；7.62-7.5，m，5H；1.42，s，6H。
3) 5-[3-(2-bromo-4-luorobenzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl] preparation of biphenyl-2-formonitrile HCN (223.2):
Under as preparation 1.2 described conditions, make compound 223.1 and 2-bromo-1-brooethyl-4-fluorobenzene reaction, obtain 223.2.Molecular weight is 491.06 (C
25H
19BrFN
3O
2); Retention time R
t=2.68 minutes [B]; MS (ESI): 492.31 (MH
+).
4) (4-{2-[4-{2-[3-(6-cyanobiphenyl-3-yl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } preparation of methyl benzoate (223):
Make 223.2 further to react like that as the preparation in top 1, the 3 stage of embodiment is described with the 4-Methyl anthranilate.Obtaining molecular weight is 562.20 (C
33H
27FN
4O
4) 223; Retention time R
t=2.87 minutes [C]; MS (ESI): 563.29 (MH
+).
The compound of embodiment 225 (4-{2-[3-(6-cyanobiphenyl-3-yl)-5,5--methyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } phenylformic acid uncle-butyl ester, molecular weight is 604.24 (C
36H
33FN
4O
4); Retention time R
t=3.22 minutes [C]; MS (ESI): 605.36 (MH
+)) be to obtain by 223.2 usefulness 4-benzaminic acid uncles-butyl ester in a similar fashion.
The compound of embodiment 224 (4-{2-[3-(4 '-chloro-6-cyanobiphenyl-3-yl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } methyl benzoate, molecular weight is 596.16 (C
33H
26ClFN
4O
4); Retention time R
t=3.03 minutes [C]; MS (ESI): 597.16 (MH
+)) be in a similar fashion, by 5-amino-4 '-chlordiphenyl-2-formonitrile HCN (224.3,
1H NMR:7.59-7.49, m, 5H; 6.63, m, 2H; 6.3, s (broad peak), 2H) → 4 '-chloro-5-(4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl) biphenyl-2-formonitrile HCN (224.1,
1H NMR:8.75, s, 1H; 8.09, d, 1H; 7.76, s, 1H; 7.7, d, 1H; 7.62, m, 4H; 1.42, s, 6H) → 5-[3-(2-bromo-4-luorobenzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-4 '-chlordiphenyl-2-formonitrile HCN (224.2,
1H NMR:8.12, d, 1H; 7.82, s, 1H; 7.78, d, 1H; 7.69-7.6, m, 6H; 7.28, t, 1H; 4.61, s, 2H; 1.4, s, order 6H) → 224 obtains.
The compound of embodiment 226 (4-{2-[3-(4 '-chloro-6-cyanobiphenyl-3-yl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } phenylformic acid uncle-butyl ester,
1H NMR:8.39, s, 1H; 8.1, d, 1H; 7.8-7.52, m, 9H; 7.1, d, 1H; 6.94, m, 3H; 4.55, s, 2H; 1.51, s, 9H; 1.35 s is to be obtained by 224.2 usefulness 4-benzaminic acid uncles-butyl ester in a similar fashion 6H).
Embodiment 229:2-(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenyl) dimethyl malonate:
1) 2-(4-nitrophenyl) dimethyl malonate (229.1):
With 2.0g dimethyl malonate, 3.36g 1-bromo-4-oil of mirbane, 9.64g potassiumphosphate, 85mg palladium (II) and 394mg 9,9-dimethyl-4,5-two (diphenylphosphino) xanthene are dissolved under argon gas atmosphere in the no Shui diox of 25ml and with it and stirred 8 hours down at 90 ℃.For aftertreatment, this reaction mixture is filtered with short column and filtrate decompression is concentrated.Resistates is carried out purifying (silica gel with chromatography; Just-heptane/15-35% ethyl acetate).Obtain 2-(4-nitrophenyl) dimethyl malonate (229.1).Molecular weight is 253.05 (C
11H
11NO
6); Retention time R
t=1.88 minutes [B]; MS (ESI): 254.03 (MH
+).
2) preparation of hydrochloric acid 2-(4-aminophenyl) dimethyl malonate (229.2):
Under the situation that adds palladium on carbon (10%), 349mg compound 229.1 is hydrogenated in methyl alcohol and stops to absorb hydrogen.The crude product that leaches is carried out purifying (method [RP1]) with chromatography.To comprise the fraction concentrating under reduced pressure of product, resistates will be dissolved in the ethyl acetate, with mixed in hydrochloric acid and with its concentrating under reduced pressure.Thus obtained resistates is dissolved in the mixed solution of acetonitrile and water and this solution lyophilize.Obtain hydrochloric acid 2-(4-aminophenyl) dimethyl malonate 229.2.Molecular weight is 223.08 (C
11H
13NO
4); Retention time R
t=0.52 minute [B]; MS (ESI): 224.17 (MH
+).
3) 2-(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1--ylmethyl] phenyl amino } phenyl) dimethyl malonate (229):
The 229th, obtaining as preparing to react under the compound 1 described condition by making compound 229.2 and compound 1.2.Molecular weight is 608.18 (C
31H
27F
3N
4O
6); Retention time R
t=2.14 minutes [B]; MS (ESI): 609.13 (MH
+).
Corresponding two-tert-butyl ester 235 is by similarly from 235.1 (2-(4-nitrophenyl) propanedioic acid di-t-butyl esters;
1H NMR:8.24, d, 2H; 7.68, d, 2H; 4.97, s, 1H; 1.41, s, 18H) → 235.2 (hydrochloric acid 2-(4-aminophenyl) propanedioic acid di-t-butyl ester; Molecular weight (free alkali) is 307.17 (C
17H
25NO
4); Retention time R
t=1.53 minutes [C]; MS (ESI): 252.24 (MH
+-C
4H
8)) → 235 (2-(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenyl) propanedioic acid di-t-butyl ester; Molecular weight is 692.28 (C
37H
39F
3N
4O
6); Retention time R
t=2.59 minutes [B]; MS (ESI): 637.22 (MH
+-C
4H
8)) order obtain.
Embodiment 231:2-(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenyl)-2-Methylpropanedioic acid dimethyl ester:
1) preparation of 2-methyl-2-(4-nitrophenyl) dimethyl malonate (231.1):
640mg compound 229.1 is dissolved in the 12ml anhydrous tetrahydro furan and with it mixes with 138mg sodium hydride (60% dispersion liquid in mineral oil).This mixture was at room temperature stirred 1 hour, then to wherein drip 393 μ l methyl iodide in the 5ml anhydrous tetrahydro furan solution and the mixture of gained at room temperature stirred a night.For aftertreatment, carefully that this reaction mixture and water and ethyl acetate is admixed together.Take out organic phase, use dried over mgso, filtration and its concentrating under reduced pressure.Resistates is carried out purifying (silica gel with chromatography; Just-heptane/0-10% ethyl acetate).Obtain 2-methyl-2-(4-nitrophenyl) dimethyl malonate (231.1);
1H NMR:8.22, d, 2H; 7.61, d, 2H; 3.71, s, 6H; 1.82, s, 3H.
2) preparation of hydrochloric acid 2-(4-aminophenyl)-2-Methylpropanedioic acid dimethyl ester (231.2):
231.2 be as described in top 229.1 the preparation, to obtain.Molecular weight is 237.10 (C
12H
15NO
4); Retention time R
t=0.80 minute [C]; MS (ESI): 238.21 (MH
+).
3) preparation of 2-(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenyl)-2-Methylpropanedioic acid dimethyl ester (231):
The 231st, obtaining as preparing to react under the compound 1 described condition by making compound 231.2 and compound 1.2.Molecular weight is 622.20 (C
32H
29F
3N
4O
6); Retention time R
t=2.20 minutes [B]; MS (ESI): 623.29 (MH
+).
Corresponding di-t-butyl ester 236 is by similarly from 236.1 (2-methyl-2-(4-nitrophenyl) propanedioic acid two-tert-butyl esters;
1H NMR:8.22, d, 2H; 7.64, d, 2H; 1.71, s, 3H; 1.41, s, 18H) → 236.2 (hydrochloric acid 2-(4-aminophenyl)-2-Methylpropanedioic acid di-t-butyl ester; Molecular weight (free alkali) is 321.19 (C
18H
27NO
4); Retention time R
t=1.61 minutes [C]; MS (ESI): 322.21 (MH
+)) → 236 (2-(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenyl)-2-Methylpropanedioic acid di-t-butyl ester; Molecular weight is 706.29 (C
38H
41F
3N
4O
6); Retention time R
t=2.66 minutes [B]; MS (ESI): 707.38 (MH
+)) order obtain.
Embodiment 232:2-(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } benzyl) dimethyl malonate:
1) preparation of 2-methyl-2-(4-nitrophenyl) dimethyl malonate (232.1):
Under as preparation compound 231.1 described conditions, use 4-nitrobenzyl bromine, obtain 2-methyl-2-(4-nitrophenyl) dimethyl malonate the dimethyl malonate alkylation.Molecular weight is 267.07 (C
12H
13NO
6); Retention time R
t=1.97 minutes [B]; MS (ESI): 268.05 (MH
+).
2) preparation of hydrochloric acid 2-(4-aminobenzyl) dimethyl malonate (232.2):
232.2 as top preparation 229.1 is described, obtain.Molecular weight is 237.10 (C
12H
15NO
4); Retention time R
t=0.70 minute [C]; MS (ESI): 238.22 (MH
+).
3) preparation of 2-(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } benzyl) dimethyl malonate (232):
The 232nd, be prepared as preparing to react under the compound 1 described condition by making compound 232.2 and compound 1.2.Molecular weight is 622.20 (C
32H
29F
3N
4O
6); Retention time R
t=2.21 minutes [B]; MS (ESI): 623.21 (MH
+).
Embodiment 233:2-(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenyl)-the 2-Methylpropanedioic acid:
As when preparing the compound of embodiment 62 described, mix in ester 236 and the hydrochloric acid Zai diox, obtain acid 233.Molecular weight is 594.17 (C
30H
25F
3N
4O
6); Retention time R
t=1.83 minutes [B]; MS (ESI): 595.33 (MH
+).
The compound of embodiment 234 (2-(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } benzyl) propanedioic acid) be to obtain by compound 232 in a similar fashion.
1H NMR :～12.85, s (very wide), 2H; 8.32, d, 1H; 8.22, s, 1H; 8.06, d, 1H; 7.55, s, 1H; 7.45, d, 1H; 7.21, m, 2H; 7.08, d, 2H; 6.98, m, 1H; 6.81, d, 2H; 4.59, s, 2H; 3.55-3.3, wide water fignal center, 2.92, s (broad peak), 2H; 1.38, s, 6H.
The compound of embodiment 238 (2-(4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenyl) propanedioic acid) be to obtain by compound 235 in a similar fashion.Molecular weight is 580.15 (C
29H
23F
3N
4O
6); Retention time R
t=1.78 minutes [B]; MS (ESI): 581.17 (MH
+).As another kind of product, also obtained phenyl acetic acid derivatives 92 ((4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenyl) acetate).
Embodiment 240:N-(4-{5-fluoro-2-[3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenyl) Toluidrin:
1) 1-[2-(4-aminophenyl amino)-4-luorobenzyl]-3-(4-fluoro-3-trifluoromethyl)-5,5-methylimidazole alkane-2, the preparation of 4-diketone (240.1):
The preparation of compound 240.1 is similar to compound 113, and still, difference is, does not use aniline 61.2, but makes aniline 204.2 and the reaction of Schiff alkali (4-bromophenyl) [1-phenylmethylene] amine.Carry out hydrogenolysis subsequently, obtain 1-[2-(4-aminophenyl amino)-4-luorobenzyl]-3-(4-fluoro-3-trifluoromethyl)-5,5-methylimidazole alkane-2,4-diketone.Molecular weight is 504.15 (C
25H
21F5N
4O
2); Retention time R
t=1.81 minutes [C]; MS (ESI): 505.15 (MH
+).
2) preparation of N-(4-{5-fluoro-2-[3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenyl) Toluidrin (240):
150mg compound 240.1 is dissolved in the 5ml acetonitrile and itself and 145mg cesium carbonate and 41mg methylsulfonyl chloride is admixed together.Subsequently, this mixture was stirred 6 hours down at 60 ℃; Second day, add 1.2 equivalent methylsulfonyl chlorides again and with this mixture 60 ℃ of following restir 8 hours.For aftertreatment, this reaction mixture is filtered, filtrate decompression is concentrated and resistates is carried out purifying (method [RP1]) with chromatography.Obtain N-(4-{5-fluoro-2-[3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenyl) Toluidrin.Molecular weight is 582.13 (C
26H
23F
5N
4O
4S); Retention time R
t=3.88 minutes [C]; MS (ESI): 583.14 (MH
+).
As another kind of product, also obtained
(241).Molecular weight is 660.11 (C
27H
25F
5N
4O
6S
2); Retention time R
t=2.49 minutes [B]; MS (ES
-): 659.03 (M-H
+).
Embodiment 243:4-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-2 hydroxybenzoic acid:
The compound dissolution of 115mg embodiment 199 in the 1.5ml diox, is mixed with 0.5ml4N hydrochloric acid De dioxane solution and it was at room temperature left standstill 4 days.For aftertreatment, with this reaction mixture concentrating under reduced pressure, with resistates acetonitrile and water dissolution, then with its lyophilize.Obtaining molecular weight is 538.14 (C
27H
21F
3N
4O
5) 243; Retention time R
t=1.96 minutes [B]; MS (ESI): 539.12 (MH
+).
Embodiment 244:1-[2-(2,2-dimethyl-4-oxo-4H-benzo [1,3] dioxine-6-base is amino)-4-luorobenzyl]-3-(4-fluoro-3-trifluoromethyl)-5,5-methylimidazole alkane-2, the 4-diketone:
1) the 6-bromo-2, the preparation of 2-dimethylbiphenyl [1,3] dioxine-4-ketone (244.1):
The 5g5-bromo ortho-oxybenzoic acid was heated in the mixture of 5ml trifluoroacetic anhydride 5 hours at the 25ml trifluoroacetic acid with 6.7g acetone under refluxing.For aftertreatment, with this reaction mixture concentrating under reduced pressure.Resistates is extracted it with the sodium hydrogen carbonate solution neutralization multiplexing ether of laying equal stress on.With the organic phase dried over mgso, filter and its concentrating under reduced pressure.Resistates is carried out purifying (silica gel with chromatography; 9/1 just-heptane/ethyl acetate).Obtain 244.1.
1H NMR：7.98，s，1H；7.88，d，1H；7.13，d，1H；1.7，s，6H。
2) 1-[2-(2,2-dimethyl-4-oxo-4H-benzo [1,3] dioxine-6-base is amino)-4-fluoro-benzyl]-3-(4-fluoro-3-trifluoromethyl)-5,5-methylimidazole alkane-2, the preparation of 4-diketone (244):
Make 204.2 with 6-bromo-2,2-dimethylbiphenyl [1,3] dioxine-4-ketone (244.1) reacts under the described condition of compound as preparation embodiment 61, obtain 1-[2-(2,2-dimethyl-4-oxo-4H-benzo [1,3] dioxine-6-base is amino)-the 4-luorobenzyl]-3-(4-fluoro-3-trifluoromethyl)-5,5-methylimidazole alkane-2,4-diketone (244).Molecular weight is 589.16 (C
29H
24F
5N
3O
5); Retention time R
t=2.32 minutes [B]; MS (ESI): 590.17 (MH
+).
Embodiment 245:5-{5-fluoro-2-[3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-2 hydroxybenzoic acid:
As above compound 244 is hydrolyzed into compound 245 by 199 preparations under the 243 described conditions.Obtain 5-{5-fluoro-2-[3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-2 hydroxybenzoic acid (245).Molecular weight is 549.13 (C
26H
20F
5N
3O
5); Retention time R
t=2.06 minutes [B]; MS (ESI): 550.13 (MH
+).
Embodiment 246:4-{3-[2-(2,4-dihydroxy-pyrimidine-5-base is amino) benzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-2-trifluoromethyl benzonitrile:
Make compound 208 carry out acidic hydrolysis (4N hydrochloric acid De dioxane solution), obtain compound 246.Molecular weight is 512.14 (C
24H
19F
3N
6O
4); Retention time R
t=1.62 minutes [B]; MS (ESI): 513.11 (MH
+).
Embodiment 248:5-{5-fluoro-2-[3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-O-Anisic Acid:
140mg ester 247 is dissolved in the 4ml anhydrous tetrahydro furan, mixes, then it was at room temperature stirred 22 hours with the 311mg potassium silanolate.For aftertreatment, with this reaction mixture concentrating under reduced pressure; With resistates 10ml water dissolution: use the 1N hcl acidifying, come for twice water is extracted by methylene dichloride/Virahol jolting with 3/1.With the organic phase dried over mgso, filter and its concentrating under reduced pressure.Resistates and acetonitrile and water is admixed together, then with its lyophilize.Obtain 5-{5-fluoro-2-[3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-O-Anisic Acid (248).Molecular weight is 563.14 (C
27H
22F
5N
3O
5); Retention time R
t=2.01 minutes [B]; MS (ESI): 564.15 (MH
+).
Embodiment 249:4-{5-fluoro-2-[3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-the O-Anisic Acid methyl esters:
Make 204.2 with 4-bromo-O-Anisic Acid methyl esters as the preparation embodiment 61 the described condition of compound under react, obtain 4-{5-fluoro-2-[3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-O-Anisic Acid methyl esters (249).Molecular weight is 577.16 (C
28H
24F
5N
3O
5); Retention time R
t=4.06 minutes [D]; MS (ESI): 578.25 (MH
+).
As another kind of reaction product, also obtained compound
Embodiment 252:4-{5-fluoro-2-[3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino }-O-Anisic Acid:
As prepare 248 described, ester 249 and potassium silanolate are reacted in tetrahydrofuran (THF), obtain carboxylic acid 252.Molecular weight is 563.14 (C
27H
22F
5N
3O
5); Retention time R
t=1.95 minutes [B]; MS (ESI): 564.15 (MH
+).
In a similar fashion, obtained 251 by 250
Molecular weight is 714.19 (C
35H
28F
5N
3O
8); Retention time R
t=1.88 minutes [B]; MS (ESI): 714.19 (MH
+).
Embodiment 253:5-{3-[2-(2,4 difluorobenzene base amino)-4-luorobenzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-4 '-fluorine biphenyl-2-formonitrile HCN:
The compound of embodiment 253 (5-{3-[2-(2,4 difluorobenzene base amino)-4-luorobenzyl]-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl }-4 '-fluorine biphenyl-2-formonitrile HCN, molecular weight is 558.16 (C
31H
22F
4N
4O
2); Retention time R
t=2.38 minutes [B]; MS (ESI): 559.15 (MH
+)) be with the preparation embodiment 223 the described mode of compound similarly, by 4-amino-2-benzyl chloride nitrile → 5-amino-4 '-fluorine biphenyl-2-formonitrile HCN (253.3,
1H NMR:7.54-7.49, m, 3H; 7.31, t, 2H, 6.61, m, 2H; 6.25, s, 2H) → 5-(4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl)-4 '-fluorine biphenyl-2-formonitrile HCN (253.1,
1H NMR:8.73, s, 1H; 8.09, d, 1H; 7.74, s, 1H; 7.65, m, 3H; 7.41, m, 2H; 1.42, s, 6H) → 5-[3-(2-bromo-4-luorobenzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-4 '-fluorine biphenyl-2-formonitrile HCN (253.2,
1H NMR:8.1, d, 1H; 7.8, s, 1H; 7.75, d, 1H; 7.69-7.59, m, 4H; 7.41, t, 1H; 4.61, s, 2H; 1.4, s, 6H) → 253 the order that (makes by reacting with 2,4 difluorobenzene base amine by 253.2) obtains.
The compound of embodiment 256 (4-{2-[3-(6-cyano group-4 '-fluorine biphenyl-3-yl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } phenylformic acid uncle-butyl ester, molecular weight is 622.23 (C
36H
32F
2N
4O
4); Retention time R
t=2.56 minutes [B]; MS (ESI): 623.23 (MH
+)) be to obtain with 4-benzaminic acid uncle-butyl ester by 253.2 in a similar fashion.
Embodiment 254:1-[4-fluoro-2-(6-fluorine pyridin-3-yl amino) benzyl]-3-(4-fluoro-3-trifluoromethyl)-5,5-methylimidazole alkane-2, the 4-diketone:
Make 204.2 with 5-bromo-2-fluorine pyridine as the preparation embodiment 61 the described condition of compound under react, obtain 1-[4-fluoro-2-(6-fluoro-pyridin-3-yl amino) benzyl]-3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-imidazolidine-2,4-diketone (254).Molecular weight is 508.13 (C
24H
18F
6N
4O
2); Retention time R
t=2.95 minutes [E]; MS (ESI): 509.12 (MH
+).
Embodiment 255:5-{5-fluoro-2-[3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } pyridine-2-methyl-formiate:
Make 204.2 with 5-bromopyridine-2-methyl-formiate as the preparation embodiment 61 the described condition of compound under react, obtain 5-{5-fluoro-2-[3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } pyridine-2-methyl-formiate (255).Molecular weight is 548.14 (C
26H
21F
5N
4O
4); Retention time R
t=2.64 minutes [C]; MS (ESI): 549.11 (MH
+).
Embodiment 257:5-{5-fluoro-2-[3-(4-fluoro-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } pyridine-2-formic acid:
As prepare 248 described, ester 255 and potassium silanolate are reacted in tetrahydrofuran (THF), obtain carboxylic acid 257.Molecular weight is 534.13 (C
25H
19F
5N
4O
4); Retention time R
t=2.32 minutes [D]; MS (ESI): 535.16 (MH
+).
Embodiment 258:4-{2-[3-(6-cyano group-4 '-fluorine biphenyl-3-yl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } phenylformic acid:
The compound dissolution of 160mg embodiment 256 in the 3.2ml diox, is mixed with 1.6ml4N hydrochloric acid De dioxane solution and it was at room temperature stirred 8 hours.For aftertreatment, with this reaction mixture concentrating under reduced pressure, with resistates acetonitrile and water dissolution, then with its lyophilize.Obtaining molecular weight is 566.17 (C
32H
24F
2N
4O
4) 258; Retention time R
t=2.77 minutes [C]; MS (ESI): 567.13 (MH
+).
Embodiment 259:2-(4-{2-[3-(6-cyano group-4 '-fluorine biphenyl-3-yl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } phenyl)-the 2-Methylpropanedioic acid:
The compound of embodiment 259 is as the preparation of embodiment 233 is described, obtains by corresponding tert-butyl ester.Di-t-butyl ester 259.3 is by 236.1 (2-methyl-2-(4-nitrophenyl)-propanedioic acid di-t-butyl ester;
1H NMR:8.22, d, 2H; 7.64, d, 2H; 1.71, s, 3H; 1.41, s, 18H) → 236.2 (hydrochloric acid 2-(4-aminophenyl)-2-Methylpropanedioic acid di-t-butyl ester; Molecular weight (free alkali) is 321.19 (C
18H
27NO
4); Retention time R
t=1.61 minutes [C]; MS (ESI): 322.21 (MH
+)) → 259.3 (2-(4-{2-[3-(6-cyano group-4 '-fluorine biphenyl-3-yl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino phenyl)-2-Methylpropanedioic acid di-t-butyl ester (by with 253.3 reactions)) order obtain.Make the reaction of this crude product and 4N hydrochloric acid De dioxane solution, obtain compound 259; Molecular weight is 638.19 (C
35H
28F
2N
4O
6); Retention time R
t=2.59 minutes [D]; MS (ESI): 639.30 (MH
+).
260.1 preparation: 4-[3-(2-amino-4-luorobenzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-2-trifluoromethyl benzonitrile:
With preparation 61.2 described methods similarly, make 111.2 with benzophenone imine reaction, thereby obtain 260.1.Molecular weight is 420.12 (C
20H
16F
4N
4O
2); Retention time R
t=2.71 minutes [E]; MS (ESI): 421.08 (MH
+).
Embodiment 264:4-{2-[3-(6-cyano group-4 '-fluorine biphenyl-3-yl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } benzsulfamide:
1) 5-[3-(2-amino-4-luorobenzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-4 '-preparation of fluorine biphenyl-2-formonitrile HCN (264.1):
As 61.2 preparation is described, make compound 253.2 (5-[3-(2-bromo-4-luorobenzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-4 '-fluorine biphenyl-2-formonitrile HCN) with benzophenone imine reaction, thereby obtain 264.1.Molecular weight is 446.15 (C
25H
20F
2N
4O
2); Retention time R
t=2.78 minutes [E]; MS (ESI): 447.12 (MH
+).
2) 4-{2-[3-(6-cyano group-4 '-fluorine biphenyl-3-yl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino }-N-[1-dimethylamino-methylene radical] preparation of benzsulfamide (264.2):
Compound 264.2 is described methods of preparation of using as 68.4, obtains by making 264.1 and 68.3 reactions.Molecular weight is 656.20 (C
34H
30F
2N
6O
4S); Retention time R
t=1.73 minutes [F]; MS (ESI): 657.15 (MH
+).
3) 4-{2-[3-(6-cyano group-4 '-fluorine biphenyl-3-yl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } preparation of benzsulfamide (264):
Compound 264 is to obtain by handling (80 ℃) with concentrated hydrochloric acid in the Zai diox with 264.2.Molecular weight is 601.15 (C
31H
25F
2N
5O
4S); Retention time R
t=2.60 minutes [E]; MS (ESI): 602.24 (MH
+).
Embodiment 266:6-{2-[3-(4-cyano group-3-trifluoromethyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl]-5-fluorophenyl amino } nicotinic acid:
Ester 256 and potassium silanolate are reacted in tetrahydrofuran (THF), obtain carboxylic acid 266.Molecular weight is 541.13 (C
26H
19F
4N
5O
4); Retention time R
t=2.42 minutes [E]; MS (ESI): 542.13 (MH
+).
Embodiment 267:4-{5-fluoro-2-[3-(4-fluoro-3-thiophene-2-base phenyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } the methyl benzoate trifluoroacetate:
1) preparation of 4-fluoro-3-thiophene-2-base phenyl amine (267.4):
With 768mg thiophene-2-boric acid, 90mg palladium (II), 328mg2-dicyclohexyl phosphino--2 ', 6 '-dimethoxy-1,1 '-biphenyl, 1.7g potassiumphosphate and 562mg3-chloro-4-fluoroaniline join in the 8ml dry toluene.This mixture is being stirred a night under argon gas atmosphere under 80 ℃.Should chilled reaction mixture and water and ethyl acetate admixed together, filter, come filtrate is extracted for three times by mixture jolting with ethyl acetate and toluene.With the organic phase that is merged dried over mgso, filter, filtrate decompression is concentrated.[RP1] carries out chromatogram purification to resistates with method.Obtain 4-fluoro-3-thiophene-2-base-phenyl amine (267.4).Molecular weight is 193.03 (C
10H
8FNS); Retention time R
t=1.18 minutes [B]; MS (ESI): 235.08 (MH
++ CH
3CN).
2) 2-[3-(4-fluoro-3-thiophene-2-base phenyl) urea groups]-preparation of 2-methyl-methyl propionate (267.3):
According to method " A ' "; the trifluoroacetate of 0.12g compound 267.4 at room temperature is dissolved in the 5ml anhydrous tetrahydro furan; mix with the 0.17ml triethylamine, drip then and sneak into the solution of 0.10g isocyanide acyl group methylpropanoic acid methyl esters in the 2ml anhydrous tetrahydro furan.This mixture was at room temperature stirred 2 hours.For aftertreatment, with this mixture concentrating under reduced pressure, resistates is stirred with water, filter, wash with water, dry then.Obtain 2-[3-(4-fluoro-3-thiophene-2-base phenyl) urea groups]-2-methyl-methyl propionate (267.3).Molecular weight is 336.39 (C
16H
17FN
2O
3S); Retention time R
t=1.46 minutes [F]; MS (ESI): 337.05 (MH
+).
3) 3-(4-fluoro-3-thiophene-2-base phenyl)-5,5-methylimidazole alkane-2, the preparation of 4-diketone (267.2):
0.62g compound 267.3 at room temperature is dissolved in the 5ml anhydrous tetrahydro furan, mixes with the 0.62ml concentrated hydrochloric acid and it was stirred 2 hours down at 80 ℃.Should chilled reaction mixture be dissolved in the ethyl acetate and with the saturated sodium bicarbonate solution washing, with the organic phase dried over mgso, filtration and with its concentrating under reduced pressure.Resistates is stirred with Di Iso Propyl Ether, filter, dry then.Obtain 3-(4-fluoro-3-thiophene-2-base-phenyl)-5,5-methylimidazole alkane-2,4-diketone (267.2).Molecular weight is 304.06 (C
15H
13FN
2O
2S); Retention time R
t=2.25 minutes [E]; MS (ESI): 346.09 (MH
++ CH
3CN).
4) 1-(2-bromo-4-luorobenzyl)-3-(4-fluoro-3-thiophene-2-base phenyl)-5,5-methylimidazole alkane-2, the preparation of 4-diketone (267.1):
Under as preparation 1.2 described conditions, make compound 267.2 and 2-bromo-1-brooethyl-4-fluorobenzene reaction, obtain 267.1.Molecular weight is 490.01 (C
22H
17BrF
2N
2O
2S); Retention time R
t=3.05 minutes [E]; MS (ESI): 493.08 (MH
+).
5) 4-{5-fluoro-2-[3-(4-fluoro-3-thiophene-2-base phenyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } preparation of methyl benzoate trifluoroacetate (267):
Make 267.1 further to react with the 4-Methyl anthranilate like that as the preparation in top 1, the 3 stage of embodiment is described.Obtaining molecular weight is 561.15 (C
30H
25F
2N
3O
4S) 267; Retention time R
t=3.08 minutes [E]; MS (ESI): 562.28 (MH
+).
Embodiment 268:4-(2-{3-[3-(5-acetyl thiophene-2-yl)-4-fluorophenyl]-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl }-5-fluorophenyl amino) methyl benzoate:
The compound of embodiment 268, (
1H NMR:8.49, s, 1H; 8.01, d, 1H; 7.98, d, 1H; 7.82, d, 2H; 7.69, d, 1H; 7.6-7.47, m, 3H; 7.13, d, 1H; 6.98-6.2, m, 3H; 4.56, s, 2H; 3.8, s, 3H; 2.6, s, 3H; 1.38, s, 6H) be with to the similar mode of preparation of the compound of embodiment 267, by 3-chloro-4-fluoroaniline → 1-[5-(5-amino-2-fluorophenyl) thiophene-2-yl] (268.4, molecular weight is 235.04 (C to ethyl ketone
12H
10FNOS); Retention time R
t=1.54 minutes [B]; MS (ESI): 236.17 (MH
+)) → 2-{3-[3-(5-acetyl thiophene-2-yl)-4-fluorophenyl] urea groups }-(268.3, molecular weight is 378.43 (C to the 2 Methylpropionic acid methyl esters
18H
19FN
2O
4S); Retention time R
t=1.36 minutes [F]; MS (ESI): 379.05 (MH
+)) → 3-[3-(5-acetyl thiophene-2-yl)-4-fluorophenyl]-5,5-methylimidazole alkane-2, (268.2, molecular weight is 346.07 (C to the 4-diketone
17H
15FN
2O
3S); Retention time R
t=2.08 minutes [E]; MS (ESI): 347.18 (MH
+)) → 3-[3-(5-acetyl thiophene-2-yl)-4-fluorophenyl]-1-(2-bromo-4-luorobenzyl)-5,5-methylimidazole alkane-2, (268.1, molecular weight is 532.02 (C to the 4-diketone
24H
19BrF
2N
2O
3S); Retention time R
t=2.87 minutes [E]; MS (ESI): 533.05/535.03 (MH
+)) → 4-(2-{3-[3-(5-acetyl thiophene-2-yl)-4-fluorophenyl]-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl }-5-fluorophenyl amino) order of methyl benzoate (268) obtains.
Embodiment 269:4-(2-{3-[3-(5-cyano thiophene-2-yl)-4-fluorophenyl]-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl }-5-fluorophenyl amino) methyl benzoate:
(molecular weight is 586.14 (C to the compound of embodiment 269
31H
24F
2N
4O
4S); Retention time R
t=3.02 minutes [E]; MS (ESI): 587.17 (MH
+)) be with to the similar mode of preparation of the compound of embodiment 267, (269.4, molecular weight is 218.03 (C by 3-chloro-4-fluoroaniline → 5-(5-amino-2-fluorophenyl) thiophene-2-formonitrile HCN
11H
7FN
2S); Retention time R
t=1.74 minutes [B]; MS (ESI): 260.19 (MH
++ CH
3CN)) → and 2-{3-[3-(5-cyano thiophene-2-yl)-4-fluorophenyl] urea groups }-(269.3, molecular weight is 361.40 (C to the 2 Methylpropionic acid methyl esters
17H
16FN
3O
3S); Retention time R
t=1.38 minutes [F]; MS (ESI): 362.05 (MH
+)) → 5-[5-(4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl)-2-fluorophenyl] (269.2, molecular weight is 329.06 (C to thiophene-2-formonitrile HCN
16H
12FN
3O
2S); Retention time R
t=2.17 minutes [E]; MS (ESI): 659.31 (2M+H
+)) → 5-{5-[3-(2-bromo-4-luorobenzyl)-4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl]-the 2-fluorophenyl } thiophene-2-formonitrile HCN (269.1,
1H NMR:8.1-8.01, m, 2H; 7.77, d, 1H; 7.66-758, m, 4H; 7.29, m, 1H; 4.61, s, 2H; 1.41, s, 6H) → 4-(2-{3-[3-(5-cyano thiophene-2-yl)-4-fluorophenyl]-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl }-5-fluorophenyl amino) order of methyl benzoate (269) obtains.
Embodiment 270:4-{5-fluoro-2-[3-(4-fluoro-3-thiophene-2-base phenyl)-5,5-dimethyl-2,4-dioxo alkyl imidazole-1-ylmethyl] phenyl amino } phenylformic acid:
As 248 preparation is described, ester 267 and potassium silanolate are reacted in tetrahydrofuran (THF), obtain carboxylic acid 270.Molecular weight is 547.13 (C
29H
23F
2N
3O
4S); Retention time R
t=2.69 minutes [E]; MS (ESI): 548.22 (MH
+).
Pharmacology test:
In vitro tests:
Use the external function test of reconstitution cell:
The function test test is to carry out with FLIPR technology (" fluorescence imaging is read the plate instrument ", Molecular DevicesCorp.).
For this reason, measure the interior Ca of part inductive cell in the reorganization HEK293 cell (this cell had both been expressed Cannabined receptor (CB1 or CB2), expressed G-Protein G α 16 again)
2+Change in concentration.For these researchs, seed cells in the 96 hole microtiter plates (60 000 cells/well) and it is grown a night.Remove substratum and cell is cultivated in the buffer reagent that comprises fluorescence dye Fluo-4.After with this dye load, pair cell washs, and adds the substances that is dissolved in the buffer reagent, this mixture was cultivated 20 minutes, add a kind of known cannabinoid receptor agonists in damping fluid as reference agonist, last, in FLIPR equipment, measure Ca in the cell
2+The variation of concentration.
With the result be expressed as with respect to contrast (0%: no substances and do not have the similar experiment of reference agonist, promptly only use buffer reagent; 100%: no substances, but the similar experiment with excessive reference agonist) per-cent changes and calculates dosage/effect curves with it, and measures IC
50Value.The result:
Can from following table 1, obtain to compare the value of the function test of (comprising and the selectivity shown in cannaboid 2 acceptors are compared) with cannaboid 1 acceptor.
Table 1:
| Embodiment number | hCB1R：FLIPR；IC 50[nM] | hCB2R：FLIPR；IC 50[nM] |
| 1 | 10 | >10000 |
| 2 | 11 | >10000 |
| 3 | 22 | |
| 4 | 4 | |
| 5 | 44 | >10000 |
| 11 | 0.7 | >10000 |
| 14 | 108 | |
| 20 | 21 | |
| 21 | 10 | |
| 22 | 46 |
| 30 | 208 | >10000 |
| 33 | 4 | |
| 35 | 15 | |
| 36 | 11 | >10000 |
| 37 | 21 | |
| 38 | 70 | |
| 39 | 69 | |
| 40 | 30 | |
| 41 | 28 | |
| 42 | 12 | >10000 |
| 43 | 77 | |
| 44 | 7 | |
| 55 | 10 | |
| 56 | 8 | >10000 |
| 57 | 36 | >10000 |
| 60 | 2 | >10000 |
| 64 | 16 | >10000 |
| 65 | 145 | |
| 66 | 25 | >10000 |
| 67 | 1 | >10000 |
| 68 | 44 | |
| 72 | 24 | |
| 73 | 7 | >10000 |
| 74 | 4 | >10000 |
| 75 | 49 | >10000 |
| 78 | 4 | >10000 |
| 80 | 33 |
| 81 | 144 | >10000 |
| 82 | 52 | >10000 |
| 83 | 9 | >10000 |
| 85 | 7 | >10000 |
| 90 | 39 | >10000 |
| 91 | 30 | >10000 |
| 92 | 137 | >10000 |
| 95 | 31 | |
| 97 | 7 | >10000 |
| 104 | 15 | |
| 105 | 49 | |
| 106 | 12 | |
| 107 | 112 | |
| 113 | 4 | |
| 125 | 110 | |
| 127 | 7 | |
| 130 | 32 | |
| 131 | 15 | |
| 133 | 10 | |
| 135 | 1 | |
| 136 | 5 | >10000 |
| 137 | >10000 | |
| 138 | 4 | >10000 |
| 140 | >10000 | |
| 142 | >10000 | |
| 143 | 13 | >10000 |
| 144 | >10000 |
| 145 | 14 | |
| 148 | 11 | |
| 154 | 8 | |
| 156 | 10 | |
| 158 | 9 | |
| 159 | 2 | |
| 164 | 137 | |
| 166 | 76 | |
| 169 | 9 | |
| 175 | 9 | |
| 177 | 1 | |
| 178 | 4 | |
| 180 | 1 | |
| 181 | 8 | |
| 190 | 76 | |
| 197 | 19 | |
| 198 | 23 | |
| 200 | 8 | |
| 201 | 5 | |
| 204 | 46 | |
| 205 | 17 | |
| 206 | 24 | |
| 208 | 13 | |
| 209 | 62 | |
| 213 | 117 | |
| 221 | 10 | |
| 227 | 16 |
| 228 | 61 | |
| 232 | 112 | |
| 233 | 22 | |
| 238 | 10 | |
| 239 | 103 | |
| 240 | 11 | |
| 243 | 99 | |
| 246 | 7 | |
| 253 | 29 | |
| 254 | 2 | |
| 255 | 28 | |
| 258 | 31 |
With combining of CB1 acceptor:
Test compound: will be diluted with 27 μ l, 100% DMSO (methyl-sulphoxide) by the compound (3 μ l, 10mM, 100% DMSO) that suction moves on in the 96 hole PP microtiter plates.This solution is handled, by in various situations, 10 these solution of μ l being transferred in the new PP microtiter plate and add 20 μ l, 100% DMSO again to come again it to be carried out 3-and doubly dilute.In various situations, 6 these solution of μ l are transferred in the new 96-hole PP microtiter plate and tested damping fluid with 144 μ l it is prepared.Its final concentration scope is 10 μ M to 0.005 μ M.
Negative control: will be dissolved in AM 251 in the test damping fluid that contains 1% DMSO join be arranged in microtiter plate dilution series in contrast.Its final concentration is 1 μ M.
Blank: the test damping fluid that will contain 1% DMSO joins in the dilution series of microtiter plate as blank.
The test parameter general introduction:
Data analysis:
High contrast: do not add under the compound situation
3The H combination
Low contrast: exist under 1 μ M AM, 251 situations
3The H combination
This value is to calculate with the raw data of having proofreaied and correct.
The value of being reported is to obtain with the average form of twice mensuration.IC
50Value is by using program Xlfit, and the calculating that formula 205 carries out obtains.The Ki value is by IC with the Cheng-Prusoff equation
50Obtain with the Kd value:
Document: Cheng, Y.-C. and Prusoff, W.H. (1973) Biochem.Pharmacol 22,3099-3108
Result: the K of embodiment compound
iValue; Table 2:
| Embodiment number | HCB1R; In conjunction with K i[nM] |
| 1 | 13 |
| 5 | 7 |
| 6 | 21 |
| 7 | 15 |
| 8 | 15 |
| 9 | 13 |
| 10 | 24 |
| 11 | 1 |
| 12 | 0.9 |
| 13 | 0.9 |
| 15 | 2 |
| 16 | 2 |
| 17 | 3 |
| 18 | 5 |
| 19 | 5 |
| 23 | 10 |
| 24 | 11 |
| 25 | 6 |
| 26 | 39 |
| 27 | 17 |
| 28 | 87 |
| 29 | 107 |
| 32 | 3 |
| 34 | 14 |
| 42 | 1 |
| 50 | 11 |
| 51 | 2 |
| 52 | 3 |
| 53 | 2 |
| 55 | 8 |
| 56 | 3 |
| 60 | 1 |
| 61 | 19 |
| 62 | 16 |
| 63 | 9 |
| 64 | 5 |
| 66 | 7 |
| 67 | 1 |
| 68 | 16 |
| 69 | 113 |
| 70 | 27 |
| 110 | 5 |
| 111 | 1 |
| 112 | 1 |
| 120 | 5 |
| 126 | 23 |
| 128 | 2 |
| 129 | 10 |
| 132 | 6 |
| 134 | 4 |
| 137 | 51 |
| 140 | 26 |
| 142 | 3 |
| 144 | 19 |
| 149 | 6 |
| 151 | 155 |
| 153 | 20 |
| 157 | 5 |
| 160 | 3 |
| 161 | 8 |
| 165 | 16 |
| 167 | 7 |
| 170 | 113 |
| 171 | 120 |
| 172 | 8 |
| 173 | 34 |
| 174 | 144 |
| 176 | 130 |
| 179 | 16 |
| 223 | 4 |
| 224 | 6 |
| 227 | 36 |
By these testing datas as can be seen, the compound of formula I of the present invention works with CB1R antagonist form, therefore is very suitable for treating metabolism syndrome, type ii diabetes and obesity.
In vivo test:
" the breast consumption of mouse "
Come the appetite effect that subtracts of substances is studied with this test.Use the female NMRI mouse of body weight 25-35g.Make mouse custom raising at least one week of condition and adapted to the condensed milk supplied with 2 days.
Give mouse fasting 24 hours, but it is freely intake.Testing the same day, animal independently is put in each cage; Cage covers can install the suction pipe that is filled with milk.Substances is by oral, intraperitoneal or subcutaneous administration.After administration, be put back into mouse in its cage and make it after 30 minutes, can obtain this milk.In 7 hours, read newborn consumption situation every 30 minutes; Simultaneously, note the considerable change of animal behavior.
" to the hypothermic antagonistic action of CB1-mediation "
Measure the effectiveness of cannabinoid CB 1 receptor (CB1) antagonist with this test.The CB1 antagonist prevention that measured is is tested or the hypothermic degree of antagonism CB1 agonist induction.
Use the female NMRI mouse of body weight 25-35g.Make mouse custom raising at least one week of condition.
In the time of 0 minute, the CB1 antagonist of testing by using gives that animal is oral, intravenously or intraperitoneal administration come animal is handled.After 30 minutes, with the dosage of 1.25mg/kg mouse is carried out the intraperitoneal administration with CB1 agonist CP55.940.This administration makes the body temperature of animal in 30 minutes decline 5-6 ℃.Before giving substances initial 30 minutes and give substances after every 30 minutes (just facing if appropriate give substances before) per rectum take temperature, test constantly 4 hours.
The effectiveness of substances is that the form with the reduction per-cent of area under the temperature-time curve provides, and described curve is by at first using average basal body temperature, secondly with only forming with the temperature-time curve of the animal of CB1 antagonist processing.
" intestinal motility of mouse "
Come the influence of research trial material itself at first in this way to small bowel motility, secondly with its study to what extent can prevent or antagonism to the specificity inducing action of small bowel motility, for example cannabinoid CB 1 agonist CP55.940 is to delay current in the intestines.
Use the female NMRI mouse of body weight 25-35g.Make mouse custom raising at least one week of condition.
Give mouse fasting 24 hours, but it is freely intake.Substances can be by oral, intravenously, subcutaneous administration, but can not be by the intraperitoneal administration.If the antagonism specific effect, then before the specific effector thing, gave substances in 30-120 minute.After administration 30 minutes, with gavage really the weighting agent of the quantitative empty calory that is colored import in the stomach of animal.After 30 minutes (at this moment, this weighting agent that is colored fills small intestine about 80%), dissect with sacrifice of animal and to small intestine.Intestinal motility is that the per-cent form with the current total length than small intestine of this weighting agent that is colored provides.Therapeutic action is to provide with the form of per-cent equally with this current difference with the solvent contrast.
Claims (20)
- The compound of formula I with and the compatible salt of physiologyWhereinR, R ' are H, (C independently of one another 1-C 6)-alkyl, wherein (C 1-C 6)-alkyl can be by halogen, O-R14, S (O) m-R12 or NR13R15 replace;Perhaps R and R ' form the ring with 3 to 8 carbon atoms together, and one of them carbon atom can be by O, S (O) m, NR13 or NR15 substitute;M is 0,1,2;N is 0,1,2,3,4;P is 1,2,3,4,5;Q is 1,2,3,4;R is 2,3,4,5,6;V is 0,1,2,3,4;A, D, E, G, L are C or N independently of one another, wherein when it is defined as N, do not have corresponding R1, R2, R3, R4, R5 substituting group;R1, R2, R3, R4, R5 are H, F, Cl, Br, I, CN, N independently of one another 3, NC, NO 2, CF 3, (C 1-C 8)-alkyl, (C 3-C 8)-cycloalkyl, (CH 2) n-[(C 3-C 8)-cycloalkenyl group], (CH 2) q-[(C 3-C 8)-cycloalkyl], (CH 2) n-[(C 7-C 12)-bicyclic alkyl], (CH 2) n-[(C 7-C 12)-bicycloenyl], (CH 2) n-[(C 7-C 12)-tricyclic alkyl], diamantane-1-base, diamantane-2-base, (CH 2) n-aryl, (CH 2) n-heteroaryl, OCF 3, O-R11, NR13R15, NH-CN, S (O) m-R12, SO 2-NH 2, SO 2-N=CH-N (CH 3) 2, SO 2-NH-CO-R12, SO 2-NH-CO-NHR12, SO 2-NH-CO-R16, SO 2-NH-[(C 1-C 8)-alkyl], SO 2-NH-[(C 3-C 8)-cycloalkyl], SO 2-NH-(CH 2) r-OH, SO 2-NH-(CH 2) n-aryl, SO 2-NH-(CH 2) n-heteroaryl, SO 2-N[(C 1-C 8)-alkyl] 2, SO 2-R16, SF 5, CO-O[(C 1-C 8)-alkyl], CO-O[(C 3-C 8)-cycloalkyl], CO-O-(CH 2) r-NH 2, CO-O-(CH 2) n-aryl, CO-O-(CH 2) n-heteroaryl, CO-NH 2, CO-NH-CN, CO-NH-[(C 1-C 8)-alkyl], CO-NH-(CH 2) r-OH, CO-N[(C 1-C 8)-alkyl] 2, CO-NH-[(C 3-C 8)-cycloalkyl], CO-N[(C 3-C 8)-cycloalkyl] 2, C (=NH)-O-[(C 1-C 6-alkyl)], C (=NH)-NH 2, C (=NH)-NHOH, C (=NH)-[NHO-(C 1-C 6)-alkyl], C (=NH)-NR12R13, C (=NH)-R16, C (=NR13)-NR12R13, CO-NH-SO 2-R16, CO-NH-SO 2-NHR12, CO-R16, COOH, CO-(C 1-C 8)-alkyl, CO-(C 3-C 8)-cycloalkyl, CO-(CH 2) n-[(C 7-C 12)-bicyclic alkyl], CO-(CH 2) n-[(C 7-C 12)-tricyclic alkyl], CO-aryl, CO-heteroaryl, CH (OH)-aryl, CH (OH)-heteroaryl, CH[O-(C 1-C 6)-alkyl]-aryl, CH[O-(C 1-C 6)-alkyl]-heteroaryl, CHF-aryl, CHF-heteroaryl, CF 2-aryl, CF 2-heteroaryl, CHO, CH 2-OH, CH 2-CN, CH 2-O-R12, CH 2-O-(CH 2) n-CO-O[(C 1-C 8)-alkyl], CH 2-O-(CH 2) n-CO-NH 2, CH 2-O-(CH 2) q-COOH, wherein said alkyl, cycloalkyl, cycloalkenyl group, bicyclic alkyl, bicycloenyl and tricyclic alkyl can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C 1-C 6)-alkyl, (C 3-C 6)-cycloalkyl, O-(C 1-C 6)-alkyl, S (O) m-(C 1-C 6)-alkyl, SO 2-NH 2, COOH, CONH 2, CO-O (C 1-C 6)-alkyl, CO-(C 1-C 6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;R6, R7, R8, R9, R10 are R11, NR17-bicyclic heterocycles, NR17-aryl, NR17-heteroaryl independently of one another, aryl wherein or heteroaryl can be carbocyclic fused with 5-or 6-person's aromatics or non-aromatics, one or more CH or CH in described aromatics or the non-aromatic carbocyclic 2Group can be substituted by Sauerstoffatom and wherein this 5-or 6-person's aromatics or non-aromatic carbocyclic can by F ,=O or-(C 1-C 6)-alkyl replaces, and described bicyclic heterocycles can comprise 9 to 12 ring memberses and 5 CH or CH at the most 2Group can be independently of one another by N, NR20, O, S (O) mOr C=O substitutes, and aryl wherein or heteroaryl or bicyclic heterocycles can not be substituted or by following group list-or polysubstituted:R11、F、Cl、Br、I、CN、N 3、NC、NO 2、CF 3、(CH 2) n-O-R11、 (CH 2) n-O-(CH 2) r-OH、(CH 2) n-O-CH(CH 2OH) 2、 (CH 2) n-O-(CH 2) n-CO-O-(CH 2) r-NH 2、 (CH 2) n-O-(CH 2) n-CO-NH-(CH 2) r-OH、(CH 2) n-O-sugar, (CH2) n-O-saccharic acid, (CH2) n-O-glucoside, (CH2) n-O-galactoside, (CH2) n-O-glucuronide, O-R13, OCF3、(CH 2) n-O-(CH 2) r-NH 2、(CH 2) n-NH-R11、 (CH 2) n-N[(CH 2) q-CO-O(C 1-C 6)-alkyl]2、(CH 2) n-N[(CH 2) q-COOH] 2、 (CH 2) n-N[(CH 2) q-CONH 2] 2、(CH 2) n-NH-R13、(CH 2) n-N(R13) 2、 (CH 2) n-NH-CN、(CH 2) n-NH-SO 2-R16、(CH 2) n-NH-(CH 2)n-SO 2-R12、 (CH 2) n-NR12-CO-R16、(CH 2) n-NR12-CO-NR12R13、 (CH 2) n-NR12-CO-N(R12) 2、(CH 2) n-NR12-CO-NHR11、 (CH 2) n-NH-C(＝NH)-NH 2、(CH 2) n-NH-C(＝NH)-R16、 (CH 2) n-NH-C(＝NH)-NHR12、(CH 2) n-NR12-C(＝NR13)-NHR12、 (CH 2) n-NR12-C(＝NR12)-NR12R13、 (CH 2) n-NH-(CH 2) n-CO-O-(CH 2) r-NH 2、 (CH 2) n-NH-(CH 2) n-CO-NH-[(C 1-C 8)-alkyl], (CH2) n-NH-(CH 2) n-CO-NH-(CH 2) r-OH、 (CH 2) n-NH-(CH 2) n-CO-N[(C 1-C 8)-alkyl]2、 (CH 2) n-NH-(CH 2) n-CO-NH-[(C 3-C 8)-cycloalkyl], (CH2) n-NH-(CH 2) n-CO-N[(C 3-C 8)-cycloalkyl]2、 (CH 2) n-NH-C(CH 3) 2-CO-O(C 1-C 8)-alkyl, (CH2) n-NH-C(CH 3) 2-CO-O(C 3-C 8)-cycloalkyl, (CH2) n-NH-C(CH 3) 2-CO-O-(CH 2)r-NH 2、 (CH 2) n-NH-C(CH 3) 2-CO-O-(CH 2) n-aryl, (CH2) n-NH-C(CH 3) 2-CO-O-(CH 2) n-heteroaryl, (CH2) n-NH-C(CH 3) 2-CO-NH 2、 (CH 2) n-NH-C(CH 3) 2-CO-NH-[(C 1-C 8)-alkyl], (CH2) n-NH-C(CH 3) 2-CO-NH-(CH 2) r-OH、 (CH 2) n-NH-C(CH 3) 2-CO-N[(C 1-C 8)-alkyl]2、 (CH 2) n-NH-(CH 3) 2-Co-NH-[(C 3-C 8)-cycloalkyl], (CH2) n-NH-C(CH 3) 2-CO-N[(C 3-C 8)-cycloalkyl]2、 (CH 2) n-NH-C(CH 3) 2-COOH、S(O) m-R12、SO 2-R16、 SO 2-N＝CH-N(CH 3) 2、SO 2-NH-CO-R12、SO 2-NHR12、 SO 2-NH-(CH 2) r-OH、SO 2-N[(C 1-C 8)-alkyl]2、SO 2-NH-(CH 2) r-NH 2、 SF 5、COOH、CO-NH 2、(CH 2) q-CN、(CH 2) n-CO-NH-CN、 (CH 2) n-CO-NH-piperidin-1-yl, (CH2) n-CO-NH-SO 2-NHR12、 (CH 2) n-CO-NH-SO 2-R18、(CH 2) n-CHO、(CH 2) n-C(＝NH)-NH 2、 (CH 2) n-C(＝NH)-NHOH、(CH 2) n-C(＝NH)-[NH-O-(C 1-C 6)-alkyl], (CH2) n-C(＝NH)(R16)、(CH 2) n-C(＝NR13)NHR12、 (CH 2) n-C(＝NR12)NR12R13、(CH 2) n-C(＝NH)O[(C 1-C 6)-alkyl], alkyl wherein and cycloalkyl can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C1-C 6)-alkyl, (C3-C 6)-cycloalkyl, O-(C1-C 6)-alkyl, S (O)m-(C 1-C 6)-alkyl, SO2-NH 2、COOH、CONH 2、CO-O(C 1-C 6)-alkyl, CO-(C1-C 6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
F、Cl、Br、I、CN、N 3、NC、NO 2、CF 3、(CH 2) n-O-R11、(CH 2) n-O-(CH 2) r-OH、 (CH 2) n-O-CH(CH 2OH) 2、(CH 2) n-O-(CH 2) n-CO-O-(CH 2) r-NH 2、 (CH 2) n-O-(CH 2) n-CO-NH-(CH 2) r-OH、(CH 2) n-O-sugar, (CH2) n-O-saccharic acid, (CH2) n-O-glucoside, (CH2) n-O-galactoside, (CH2) n-O-glucuronide, O-R13, OCF3、(CH 2) n-NH-R11、(CH 2) n-NH-R13、(CH 2) n-NH-CN、 (CH 2) n-NH-SO 2-R16、(CH 2) n-NH-(CH 2) n-SO 2-R12、(CH 2) n-NR12-CO-R16、 (CH 2) n-NR12-CO-NR12R13、(CH 2) n-NR12-CO-N(R12) 2、 (CH 2)n-NR12-CO-NHR11、(CH 2) n-NH-C(＝NH)-NH 2、 (CH 2) n-NH-C(＝NH)-R16、(CH 2) n-NH-C(＝NH)-NHR12、 (CH 2) n-NR12-C(＝NR13)-NHR12、(CH 2) n-NR12-C(＝NR12)-NR12R13、 (CH 2) n-NH-(CH 2) n-CO-O-(CH 2) r-NH 2、 (CH 2) n-NH-(CH 2) n-CO-NH-[(C 1-C 8)-alkyl], (CH2) n-NH-(CH 2) n-CO-NH-(CH 2) r-OH、(CH 2) n-NH-(CH 2) n-CO-N[(C 1-C 8)-alkyl]2、(CH 2) n-NH-(CH 2) n-CO-NH-[(C 3-C 8)-cycloalkyl], (CH2) n-NH-(CH 2) n-CO-N[(C 3-C 8)-cycloalkyl]2、 (CH 2) n-NH-C(CH 3) 2-CO-O(C 1-C 8)-alkyl, (CH2) n-NH-C(CH 3) 2-CO-O(C 3-C 8)-cycloalkyl, (CH2) n-NH-C(CH 3) 2-CO-O-(CH 2) r-NH 2、 (CH 2) n-NH-C(CH 3) 2-CO-O-(CH 2) n-aryl, (CH2) n-NH-C(CH 3) 2-CO-O-(CH 2) n-heteroaryl, (CH2) n-NH-C(CH 3) 2-CO-NH 2、 (CH 2) n-NH-C(CH 3) 2-CO-NH-[(C 1-C 8)-alkyl], (CH2) n-NH-C(CH 3) 2-CO-NH-(CH 2) r-OH、 (CH 2) n-NH-C(CH 3) 2-CO-N[(C 1-C 8)-alkyl]2、 (CH 2) n-NH-(CH 3) 2-CO-NH-[(C 3-C 8)-cycloalkyl], (CH2) n-NH-C(CH 3) 2-CO-N[(C 3-C 8)-cycloalkyl]2、(CH 2) n-NH-C(CH 3) 2-COOH、 S(O) m-R12、SO 2-R16、SO 2-N＝CH-N(CH 3) 2、SO 2-NH-CO-R12、 SO 2-NHR12、SO 2-NH-(CH 2) r-OH、SO 2-N[(C 1-C 8)-alkyl]2、 SO 2-NH-(CH 2) r-NH 2、SF 5、COOH、CONH 2、(CH 2) q-CN、 (CH 2) n-CO-NH-CN、(CH 2) n-CO-NH-piperidin-1-yl, (CH2) n-CO-NH-SO 2-NHR12、(CH 2) n-CO-NH-SO 2-R18、(CH 2) n-CHO、 (CH 2) n-C(＝NH)NH 2、(CH 2) n-C(＝NH)NHOH、(CH 2) n-C(＝NH)(R16)、 (CH 2) n-C(＝NR13)NHR12、(CH 2) n-C(＝NR12)NR12R13、 (CH 2) n-C(＝NH)O[(C 1-C 6)-alkyl], alkyl wherein and cycloalkyl can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C1-C 6)-alkyl, (C3-C 6)-cycloalkyl, O-(C1-C 6)-alkyl, S (O)m-(C 1-C6)-alkyl, SO2-NH 2、COOH、CONH 2、 CO-[O(C 1-C 6)-alkyl], CO-(C1-C 6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;
Wherein at least one among radicals R 6, R7, R8, R9 and the R10 always is defined as NR17-aryl or NR17-bicyclic heterocycles or NR17-heteroaryl;Wherein four groups are to a pair of can the formation together in various situations-CH among R6 and R7 or R7 and R8 or R8 and R9 or R9 and the R10 2-CH 2-CH 2-or-CH 2-CH 2-CH 2-CH 2-group, wherein two-CH at the most 2-group can be substituted by-O-and wherein-CH 2-CH 2-CH 2-or-CH 2-CH 2-CH 2-CH 2-group can be by F, (C 1-C 8)-alkyl or=O replaces;R11 is H, (C1-C 8)-alkyl, (C2-C 10)-alkenyl, (C2-C 10)-alkynyl, (C3-C 8)-cycloalkyl, (CH2) q-[(C 3-C 8)-cycloalkyl], (CH2) n-[(C 7-C 12)-bicyclic alkyl], (CH2) n-[(C 3-C 10)-cycloalkenyl group], (CH2) n-[(C 3-C 10)-two cycloalkenyl group], (CH2) n-[(C 7-C 12)-tricyclic alkyl], (CH2) n-aryl, (CH2) n-CO-[O-(C 1-C 8)-alkyl], (CH2) n-CO-[O-(C 3-C 8)-cycloalkyl], (CH2) n-CO-[(C 1-C 8)-alkyl], (CH2) n-CO-[(C 3-C 8)-cycloalkyl], (CH2) n-CO-aryl, (CH2) n-CO-heteroaryl, (CH2) n-CO-[O-(CH 2) v-aryl], (CH2) n-CO-[O-(CH 2) v-heteroaryl], (CH2) q-CO-NH 2、(CH 2) q-COOH、(CH 2) q-CO-NH-CN、 (CH 2) n-P(O)(OH)[O-(C 1-C 6)-alkyl], (CH2) n-P(O)[O-(C 1-C 6)-alkyl]2、 (CH 2) n-P(O)(OH)(O-CH 2-aryl), (CH2) n-P(O)(O-CH 2-aryl)2、 (CH 2) n-P(O)(OH) 2、(CH 2) n-SO 3H、(CH 2) n-SO 2-NH 2、 (CH 2) n-CO-NH-[(C 1-C 8)-alkyl], (CH2) n-CO-N[(C 1-C 8)-alkyl]2、 (CH 2) n-CO-NH-[(C 3-C 8)-cycloalkyl], (CH2) n-CO-N[(C 3-C 8)-cycloalkyl]2、(C 2-C 10)-alkenyl-CO-O[(C1-C 6)-alkyl], (C2-C 10)-alkenyl-CONH2、(C 2-C 10)-alkenyl-COOH, (C2-C 10)-alkynyl-CO-O[(C1-C 6)-alkyl], (C2-C 10)-alkynyl-CONH2、 (C 2-C 10)-alkynyl-COOH, (CH2) n-CR21[(CO-O(C 1-C 6)-alkyl)]2、 (CH 2) n-CR21(CONH 2) 2、(CH 2) n-CR21(COOH) 2、 (CH 2) n-CR21R22CO-O[(C 1-C 6)-alkyl], (CH2) n-CR21R22CONH 2、 (CH 2) n-CR21R22COOH、(CH 2) n-CO-R16、(CH 2) n-C(CH 3) 2-CO-O[(C 1-C 8)-alkyl], (CH2) n-C(CH 3) 2-CO-O[(C 3-C 8)-cycloalkyl], (CH2) n-C(CH 3) 2-CO-O-(CH 2) r-NH 2、(CH 2) n-C(CH 3) 2-CO-O-(CH 2) n-aryl, (CH2) n-C(CH 3) 2-CO-O-(CH 2) n-heteroaryl, (CH2) n-C(CH 3) 2-CO-NH 2、 (CH 2) n-C(CH 3) 2-CO-NH-[(C 1-C 8)-alkyl], (CH2) n-C(CH 3) 2-CO-NH-(CH 2) r-OH、(CH 2) n-C(CH 3) 2-CO-N[(C 1-C 8)-alkyl]2、(CH 2) n-C(CH 3) 2-CO-NH-[(C 3-C 8)-cycloalkyl], (CH2) n-C(CH 3) 2-CO-N[(C 3-C 8)-cycloalkyl]2、(CH 2) n-C(CH 3) 2-COOH、 (CH 2) n-CO-NH-C(CH 3) 2-CO-O[(C 1-C 8)-alkyl], (CH2) n-CO-NH-C(CH 3) 2-CONH 2、(CH 2) n-CO-NH-C(CH 3) 2-COOH, alkyl wherein, alkenyl, alkynyl and cycloalkyl, bicyclic alkyl, cycloalkenyl group and two cycloalkenyl groups can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C1-C 6)-alkyl, (C3-C 6)-cycloalkyl, O-(C1-C 6)-alkyl, S (O)m-(C 1-C 6)-alkyl, SO2-NH 2、COOH、CONH 2、 CO-O(C 1-C 6)-alkyl, CO-(C1-C 6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;R12 is H, (C 1-C 8)-alkyl, (C 3-C 8)-cycloalkyl, (CH 2) q-[(C 3-C 8)-cycloalkyl], (CH 2) n-[(C 7-C 12)-bicyclic alkyl], (CH 2) n-[(C 7-C 12)-tricyclic alkyl], (CH 2) n-aryl, (CH 2) n-heteroaryl, alkyl or cycloalkyl wherein can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C 1-C 6)-alkyl, O-(C 1-C 6)-alkyl, SO 2-NH 2, COOH, CONH 2, CO-O (C 1-C 6)-alkyl, CO-(C 1-C 6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;R13 is H, SO 2-[(C 1-C 8)-alkyl], SO 2-[(C 3-C 8)-cycloalkyl], SO 2-(CH 2) n-aryl, SO 2-(CH 2) n-heteroaryl, SO 2-(CH 2) n-NH-R12, SO 2-(CH 2) n-N (R12) 2, alkyl wherein and cycloalkyl can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, CF 3, (C 1-C 6)-alkyl, (C 3-C 6)-cycloalkyl, O-[(C 1-C 6)-alkyl], S (O) m-[(C 1-C 6)-alkyl], SO 2-NH 2, COOH, CONH 2, CO-[O (C 1-C 6)-alkyl], CO-(C 1-C 6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;R14 is H, (C 1-C 8)-alkyl, (C 3-C 8)-cycloalkyl, (CH 2) q-[(C 3-C 8)-cycloalkyl], (CH 2) n-aryl, (CH 2) n-heteroaryl, (CH 2) n-CO-[O-(C 1-C 8)-alkyl], (CH 2) n-CO-[O-(C 3-C 8)-cycloalkyl], (CH 2) n-CO-[O-(CH 2) n-aryl], (CH 2) n-CO-[O-(CH 2) n-heteroaryl], (CH 2) n-CO-[(C 1-C 8)-alkyl], (CH 2) n-CO-[(C 3-C 8)-cycloalkyl], (CH 2) n-CO-aryl, (CH 2) n-CO-heteroaryl, (CH 2) q-CO-NH 2, (CH 2) q-COOH, (CH 2) n-SO 2-NH 2, (CH 2) n-CO-NH-[(C 1-C 8)-alkyl], (CH 2) n-CO-N[(C 1-C 8)-alkyl] 2, (CH 2) n-CO-NH-[(C 3-C 8)-cycloalkyl], (CH 2) n-CO-N[(C 3-C 8)-cycloalkyl] 2, (CH 2) n-C (CH 3) 2-CO-O[(C 1-C 8)]-alkyl, (CH 2) n-C (CH 3) 2-CO-O[(C 3-C 8)]-cycloalkyl, (CH 2) n-C (CH 3) 2-CO-O-(CH 2) r-NH 2, (CH 2) n-C (CH 3) 2-CO-NH 2, (CH 2) n-C (CH 3) 2-CO-NH-(CH 2) r-OH, (CH 2) n-C (CH 3) 2-COOH, alkyl wherein and cycloalkyl can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C 1-C 6)-alkyl, (C 3-C 6)-cycloalkyl, O-(C 1-C 6)-alkyl, S (O) m-(C 1-C 6)-alkyl, SO 2-NH 2, COOH, CONH 2, CO-O (C 1-C 6)-alkyl, CO-(C 1-C 6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;R15 is H, (C 1-C 8)-alkyl, (C 3-C 8)-cycloalkyl, (CH 2) n-aryl, (CH 2) n-heteroaryl, (CH 2) n-CO-[O-(C 1-C 8)-alkyl], (CH 2) n-CO-[O-(C 3-C 8)-cycloalkyl], (CH 2) n-CO-[O-(CH 2) n-aryl], (CH 2) n-CO-[O-(CH 2) n-heteroaryl], CO-[(C 1-C 8)-alkyl], CO-[(C 3-C 8)-cycloalkyl], CO-aryl, CO-heteroaryl, (CH 2) n-CO-NH 2, (CH 2) q-COOH, (CH 2) n-SO 2-NH 2, (CH 2) n-CO-NH-[(C 1-C 8)-alkyl], (CH 2) n-CO-N[(C 1-C 8)-alkyl] 2, (CH 2) n-CO-NH-[(C 3-C 8)-cycloalkyl], (CH 2) n-C (CH 3) 2-CO-NH 2, (CH 2) n-C (CH 3) 2-COOH, alkyl wherein and cycloalkyl can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C 1-C 6)-alkyl, O-(C 1-C 6)-alkyl, SO 2-NH 2, COOH, CONH 2, CO-O (C 1-C 6)-alkyl, CO-(C 1-C 6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;R16 is ethylene imine-1-base, azetidine-1-base, 3-hydroxy azetidine-1-base, piperidines-1-base, 3-hydroxy piperidine-1-base, 4-hydroxy piperidine-1-base, 3-oxo-piperidine-1-base, 4-oxo-piperidine-1-base, tetramethyleneimine-1-base, 3-pyrrolidinol-1-base, 2-Cyanopyrolidine-1-base, morpholine-N-base, piperazine-1-base, 4-[(C 1-C 6)-alkyl] piperazine-1-base, piperazine-2-ketone-1-base, piperazine-2-ketone-4-base, piperazine-2,3-diketone-1-base, piperazine-2,6-diketone-1-base, piperazine-2,6-diketone-4-base, thiomorpholine-4-base, thiomorpholine-1,1-dioxide-4-base, NH-(CH 2) r-OH, NH-CH (CH 2OH) 2, NH-C (CH 2OH) 3, N[(C 1-C 6)-alkyl-OH] 2, N[(C 1-C 6)-alkyl] [(C 1-C 6)-alkyl-OH], D-glucosamine-N-base, N-methyl D-glucosamine-N-base, NH-[(C 1-C 8)-alkyl]-CO-O (C 1-C 6)-alkyl, NH-[(C 1-C 8)-alkyl]-COOH, NH-[(C 1-C 8)-alkyl]-CONH 2, N[(C 1-C 6)-alkyl] [(C 1-C 8)-alkyl]-CO-O (C 1-C 6)-alkyl, N[(C 1-C 6)-alkyl] [(C 1-C 8)-alkyl]-COOH, N[(C 1-C 6)-alkyl] [(C 1-C 8)-alkyl]-CONH 2, NH-[C (H) (aryl)]-CO-O (C 1-C 6)-alkyl, NH-[C (H) (aryl)]-COOH, NH-[C (H) (aryl)]-CONH 2, N[(C 1-C 6)-alkyl] [C (H) (aryl)]-CO-O (C 1-C 6)-alkyl, N[(C 1-C 6)-alkyl] [C (H) (aryl)]-COOH, N[(C 1-C 6)-alkyl] [C (H) (aryl)]-CONH 2, NH-[C (H) (heteroaryl)]-CO-O (C 1-C 6)-alkyl, NH-[C (H) (heteroaryl)]-COOH, NH-[C (H) (heteroaryl)]-CONH 2, N[(C 1-C 6)-alkyl] [C (H) (heteroaryl)]-CO-O (C 1-C 6)-alkyl, N[(C 1-C 6)-alkyl] [C (H) (heteroaryl)]-COOH, N[(C 1-C 6)-alkyl] [C (H) (heteroaryl)]-CONH 2, N[(C 1-C 6)-alkyl] [(C 3-C 8)-cycloalkyl]-CO-O (C 1-C 6)-alkyl, N[(C 1-C 6)-alkyl] [(C 3-C 8)-cycloalkyl]-COOH, N[(C 1-C 6)-alkyl] [(C 3-C 8)-cycloalkyl]-CONH 2, NH-[(C 3-C 8)-cycloalkyl]-CO-O (C 1-C 6)-alkyl, NH-[(C 3-C 8)-cycloalkyl]-COOH, NH-[(C 3-C 8)-cycloalkyl]-CONH 2, NH-(CH 2) r-SO 2-(C 1-C 6)-alkyl, NH-[(C 1-C 6)-alkyl]-SO 3H, NH-[(C 1-C 6)-alkyl]-SO 2-NH 2, N[(C 1-C 6)-alkyl] { [(C 1-C 6)-alkyl]-SO 3H}, alcohol wherein (OH) or ketone (C=O) functional group can be by F or CF 2Substitute;R17 is R18, R13, (CH 2) n-CO-[O-(C 1-C 8)-alkyl], (CH 2) n-CO-[O-(C 3-C 8)-cycloalkyl], (CH 2) n-CO-[(C 1-C 8)-alkyl], (CH 2) n-CO-[(C 3-C 8)-cycloalkyl], (CH 2) n-CO-aryl, (CH 2) n-CO-heteroaryl, (CH 2) n-CO-[O-(CH 2) n-aryl], (CH 2) n-CO-NH 2, (CH 2) q-COOH, alkyl wherein and cycloalkyl can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C 1-C 6)-alkyl, (C 3-C 6)-cycloalkyl, O-(C 1-C 6)-alkyl, S (O) m-(C 1-C 6)-alkyl, SO 2-NH 2, COOH, CONH 2, CO-[O (C 1-C 6)-alkyl], CO-(C 1-C 6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;R18 is (C 1-C 8)-alkyl, (C 3-C 8)-cycloalkyl, (CH 2) q-[(C 3-C 8)-cycloalkyl], (CH 2) n-aryl, (CH 2) n-heteroaryl, alkyl wherein and cycloalkyl can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C 1-C 6)-alkyl, O-(C 1-C 6)-alkyl, SO 2-NH 2, COOH, CONH 2, CO-[O (C 1-C 6)-alkyl], CO-(C 1-C 6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;R20 is H, (C 1-C 6)-alkyl, (C 3-C 8)-cycloalkyl, aryl, [(C 1-C 6)-alkyl]-aryl;R21 is H, F, CF 3, (C 1-C 6)-alkyl, (C 3-C 8)-cycloalkyl, OH, O-(C 1-C 6)-alkyl, O-(C 3-C 8)-cycloalkyl, O-(CH 2) n-aryl, O-(CO)-(C 1-C 6)-alkyl, O-(CO)-(C 3-C 8)-cycloalkyl, O-(CO)-O-(C 1-C 6)-alkyl, O-(CO)-O-(C 3-C 8)-cycloalkyl, NH-[(C 1-C 6)-alkyl]-aryl, NH 2, NH-(C 1-C 6)-alkyl, NH-(CO)-(C 1-C 6)-alkyl;R22 is H, CF 3, (C 1-C 6)-alkyl, aryl, [(C 1-C 6)-alkyl]-aryl. - 2. formula I compound as claimed in claim 1 with and the compatible salt of physiology, whereinEach (C naturally of R, R ' 1-C 6)-alkyl, wherein (C 1-C 6)-alkyl can be replaced by halogen; Perhaps R and R ' form the ring with 3 to 8 carbon atoms together;M is 0,1,2;N is 0,1,2,3,4;P is 1,2,3;Q is 1,2,3;R is 2,3,4;V is 0,1,2,3;A, D, E, G, L are C or N independently of one another, wherein when it is defined as N, do not have corresponding R1, R2, R3, R4, R5 substituting group;R1, R2, R3, R4, R5 are H, F, C1, Br, CN, NO independently of one another 2, CF 3, (C 1-C 8)-alkyl, (C 3-C 8)-cycloalkyl, (CH 2) q-[(C 3-C 8)-cycloalkyl], (CH 2) n-[(C 7-C 12)-bicyclic alkyl], (CH 2) n-[(C 7-C 12)-tricyclic alkyl], diamantane-1-base, diamantane-2-base, (CH 2) n-aryl, (CH 2) n-heteroaryl, OCF 3, O-R11, NR13R15, S (O) m-R12, SO 2-NH 2, SO 2-NH-[(C 1-C 8)-alkyl], SO 2-NH-[(C 3-C 8)-cycloalkyl], SO 2-NH-(CH 2) n-aryl, SO 2-N[(C 1-C 8)-alkyl] 2, SO 2-R16, SF 5, CO-O[(C 1-C 8)-alkyl], CO-O-(CH 2) r-NH 2, CO-NH 2, CO-NH-[(C 1-C 8)-alkyl], CO-N[(C 1-C 8)-alkyl] 2, C (=NH)-NH 2, C (=NH)-NHOH, C (=NH)-[NH-O-(C 1-C 6)-alkyl], C (=NH)-NR12R13, C (=NH)-R16, C (=NR13)-NR12R13, CO-NH-SO 2-R16, CO-NH-SO 2-NHR12, CO-R16, COOH, CO-(C 1-C 8)-alkyl, CO-(C 3-C 8)-cycloalkyl, CO-aryl, CO-heteroaryl, CH (OH)-aryl, CH (OH)-heteroaryl, CH[O-(C 1-C 6)-alkyl]-aryl, CH[O-(C 1-C 6)-alkyl]-heteroaryl, CHF-aryl, CHF-heteroaryl, CF 2-aryl, CH 2-O-R12, alkyl wherein, cycloalkyl, bicyclic alkyl and tricyclic alkyl can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C 1-C 6)-alkyl, (C 3-C 6)-cycloalkyl, O-(C 1-C 6)-alkyl, S (O) m-(C 1-C 6)-alkyl, SO 2-NH 2, COOH, CONH 2, CO-O (C 1-C 6)-alkyl, CO-(C 1-C 6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;R6, R7, R8, R9, R10 are R11, NR17-bicyclic heterocycles, NR17-aryl, NR17-heteroaryl independently of one another, aryl wherein or heteroaryl can be carbocyclic fused with 5-or 6-person's aromatics or non-aromatics, one or more CH or CH in described aromatics or the non-aromatic carbocyclic 2Group can be substituted by Sauerstoffatom and 5-wherein or 6-person's aromatics or non-aromatic carbocyclic can by F ,=O or-(C 1-C 6)-alkyl replaces, and bicyclic heterocycles wherein comprises 9 to 10 ring memberses and 5 CH or CH at the most 2Group can be independently of one another by N, NR20, O, S (O) mOr C=O substitutes, and aryl wherein or heteroaryl or bicyclic heterocycles can not be substituted or by following group list-or polysubstituted:R11、F、Cl、Br、CN、NO 2、CF 3、(CH 2) n-O-R11、(CH 2) n-O-(CH 2) r-OH、 (CH 2) n-O-CH(CH 2OH) 2、(CH 2) n-O-(CH 2) n-CO-O-(CH 2) r-NH 2、 (CH 2) n-O-sugar, (CH2) n-O-saccharic acid, (CH2) n-O-glucoside, (CH2) n-O-galactoside, (CH2) n-O-glucuronide, O-R13, OCF3、(CH 2) n-O-(CH 2) r-NH 2、 (CH 2) n-NH-R11、(CH 2) n-N[(CH 2) q-CO-O(C 1-C 6)-alkyl]2、 (CH 2) n-N[(CH 2) q-COOH] 2、(CH 2) n-N[(CH 2) q-CONH 2] 2、 (CH 2) n-NH-R13、(CH 2) n-N(R13) 2、(CH 2) n-NH-CN、 (CH 2) n-NH-SO 2-R16、(CH 2) n-NH-(CH 2) n-SO 2-R12、 (CH 2) n-NR12-CO-R16、(CH 2) n-NR12-CO-NR12R13、 (CH 2) n-NR12-CO-N(R12) 2、(CH 2) n-NR12-CO-NHR11、 (CH 2) n-NH-C(＝NH)-NH 2、(CH 2) n-NH-C(＝NH)-R16、 (CH 2) n-NH-C(＝NH)-NHR12、(CH 2) n-NR12-C(＝NR13)-NHR12、 (CH 2) n-NR12-C(＝NR12)-NR12R13、 (CH 2) n-NH-(CH 2) n-CO-O-(CH 2) r-NH 2、 (CH 2) n-NH-(CH 2) n-CO-NH-[(C 1-C 8)-alkyl], (CH2) n-NH-(CH 2) n-CO-NH-(CH 2) r-OH、 (CH 2) n-NH-(CH 2) n-CO-N[(C 1-C 8)-alkyl]2、 (CH 2) n-NH-(CH 2) n-CO-NH-[(C 3-C 8)-cycloalkyl], (CH2) n-NH-C(CH 3) 2-CO-O(C 1-C 8)-alkyl, (CH2) n-NH-C(CH 3) 2-CO-O-(CH 2) r-NH 2、 (CH 2) n-NH-C(CH 3) 2-CO-NH 2、 (CH 2) n-NH-C(CH 3) 2-CO-NH-(CH 2) r-OH、 (CH 2) n-NH-C(CH 3) 2-COOH、S(O) m-R12、SO 2-R16、 SO 2-N＝CH-N(CH 3) 2、SO 2-NH-CO-R12、SO 2-NHR12、 SO 2-NH-(CH 2) r-OH、SO 2-N[(C 1-C 8)-alkyl]2、SO 2-NH-(CH 2) r-NH 2、 SF 5、COOH、CO-NH 2、(CH 2) q-CN、(CH 2) n-CO-NH-piperidin-1-yl, (CH2) n-CO-NH-SO 2-NHR12、(CH 2) n-CO-NH-SO 2-R18、 (CH 2) n-C(＝NH)NH 2、(CH 2) n-C(＝NH)-NHOH、 C(＝NH)-[NH-O-(C 1-C 6)-alkyl], (CH2) n-C(＝NH)(R16)、 (CH 2) n-C(＝NR13)NHR12、(CH 2) n-C(＝NR12)NR12R13、 (CH 2) n-C(＝NH)O[(C 1-C 6)-alkyl], alkyl wherein and cycloalkyl can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C1-C 6)-alkyl, (C3-C 6)-cycloalkyl, O-(C1-C 6)-alkyl, S (O)m-(C 1-C 6)-alkyl, SO2-NH 2、COOH、 CONH 2、CO-O(C 1-C 6)-alkyl, CO-(C1-C 6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;F, Cl, Br, CN, CF 3, (CH 2) n-O-R11, (CH 2) n-O-(CCH 2) r-OH, (CH 2) n-O-sugar, (CH 2) n-O-saccharic acid, (CH 2) n-O-glucoside, (CH 2) n-O-galactoside, (CH 2) n-O-glucuronide, O-R13, OCF 3, (CH 2) n-NH-R11, (CH 2) n-NH-R13, (CH 2) n-NH-CN, (CH 2) n-NH-SO 2-R16, (CH 2) n-NH-(CH 2) n-SO 2-R12, (CH 2) n-NR12-CO-NR12R13, (CH 2) n-NR12-CO-N (R12) 2, (CH 2) n-NR12-CO-NHR11, (CH 2) n-NH-C (=NH)-NH 2, (CH 2) n-NH-C (=NH)-R16, (CH 2) n-NH-C (=NH)-NHR12, (CH 2) n-NR12-C (=NR13)-NHR12, (CH 2) n-NR12-C (=NR12)-NR12R13, (CH 2) n-NH-(CH 2) n-CO-NH-[(C 1-C 8)-alkyl], (CH 2) n-NH-(CH 2) n-CO-N[(C 1-C 8)-alkyl] 2, (CH 2) n-NH-C (CH 3) 2-CO-O (C 1-C 8)-alkyl, (CH 2) n-NH-C (CH 3) 2-CO-O (C 3-C 8)-cycloalkyl, (CH 2) n-NH-C (CH 3) 2-CO-NH 2, (CH 2) n-NH-C (CH 3) 2-CO-NH-(CH 2) r-OH, (CH 2) n-NH-C (CH 3) 2-CO-N[(C 1-C 8)-alkyl] 2, (CH 2) n-NH-C (CH 3) 2-COOH, S (O) m-R12, SO 2-R16, SO 2-NH-CO-R12, SO 2-NHR12, SO 2-NH-(CH 2) r-OH, SO 2-N[(C 1-C 8)-alkyl] 2, SF 5, (CH 2) n-COOH, (CH 2) n-CONH 2, (CH 2) q-CN, (CH 2) n-CO-NH-CN, (CH 2) n-CO-NH-SO 2-NHR12, (CH 2) n-CO-NH-SO 2-R18, (CH 2) n-C (=NH) NH 2, (CH 2) n-C (=NH) NHOH, (CH 2) n-C (=NH) (R16), (CH 2) n-C (=NR13) NHR12, (CH 2) n-C (=NR12) NR12R13, (CH 2) n-C (=NH) O[(C 1-C 6)-alkyl], alkyl wherein and cycloalkyl can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C 1-C 6)-alkyl, (C 3-C 6)-cycloalkyl, O-(C 1-C 6)-alkyl, S (O) m-(C 1-C 6)-alkyl, SO 2-NH 2, COOH, CONH 2, CO-[O (C 1-C 6)-alkyl] replace and alkyl wherein can be replaced by fluorine atom;Wherein at least one among radicals R 6, R7, R8, R9 and the R10 always is defined as NR17-aryl or NR17-bicyclic heterocycles or NR17-heteroaryl;Wherein four groups are to a pair of can the formation together in various situations-CH among R6 and R7 or R7 and R8 or R8 and R9 or R9 and the R10 2-CH 2-CH 2-or-CH 2-CH 2-CH 2-CH 2-group, wherein two-CH at the most 2-group can be substituted by-O-and wherein should-CH 2-CH 2-CH 2-or-CH 2-CH 2-CH 2-CH 2-group can by F, methyl or=O replaces;R11 is H, (C1-C 6)-alkyl, (C2-C 6)-alkenyl, (C2-C 6)-alkynyl, (C3-C 7)-cycloalkyl, (CH2) q-[(C 3-C 6)-cycloalkyl], (CH2) n-[(C 7-C 10)-bicyclic alkyl], (CH2) n-[(C 3-C 6)-cycloalkenyl group], (CH2) n-[(C 7-C 10)-two cycloalkenyl group], (CH2) n-[(C 7-C 12)-tricyclic alkyl], (CH2) n-aryl, (CH2) n-CO-[O-(C 1-C 6)-alkyl], (CH2) n-CO-[O-(C 3-C 6)-cycloalkyl], (CH2) n-CO-[(C 1-C 6)-alkyl], (CH2) n-CO-[(C 3-C 6)-cycloalkyl], (CH2) n-CO-aryl, (CH2) n-CO-heteroaryl, (CH2) n-CO-[O-(CH 2) v-aryl], (CH2) n-CO-[O-(CH 2) v-heteroaryl], (CH2) q-CO-NH 2、(CH 2) q-COOH、(CH 2) n-P(O)(OH)[O-(C 1-C 3)-alkyl], (CH2) n-P(O)[O-(C 1-C 3)-alkyl]2、(CH 2) n-P(O)(OH)(O-CH 2-aryl), (CH2) n-P(O)(O-CH 2-aryl)2、(CH 2) n-P(O)(OH) 2、(CH 2) n-SO 3H、 (CH 2) n-SO 2-NH 2、(CH 2) n-CO-NH-[(C 1-C 6)-alkyl], (CH2) n-CO-N[(C 1-C 6)-alkyl]2、(CH 2) n-CO-NH-[(C 3-C 6)-cycloalkyl], (CH2) n-CO-N[(C 3-C 6)-cycloalkyl]2、 (C 2-C 6)-alkenyl-CO-O[(C1-C 6)-alkyl], (C2-C 6)-alkenyl-CONH2、(C 2-C 6)-alkenyl-COOH, (C2-C 6)-alkynyl-CO-O[(C1-C 6)-alkyl], (C2-C 6)-alkynyl-CONH2、 (C 2-C 6)-alkynyl-COOH, (CH2) n-CR21[(CO-O(C 1-C 4)-alkyl)]2、 (CH 2) n-CR21(CONH 2) 2、(CH 2) n-CR21(COOH) 2、 (CH 2) n-CR21R22CO-O[(C 1-C 4)-alkyl], (CH2) n-CR21R22CONH 2、 (CH 2) n-CR21R22COOH、(CH 2) n-CO-R16、(CH 2) n-C(CH 3) 2-CO-O[(C 1-C 6)-alkyl], (CH2) n-C(CH 3) 2-CO-O[(C 3-C 6)-cycloalkyl], (CH2) n-C(CH 3) 2-CO-O-(CH 2) n-aryl, (CH2) n-C(CH 3) 2-CO-O-(CH 2) n-heteroaryl, (CH2) n-C(CH 3) 2-CO-NH 2、(CH 2) n-C(CH 3) 2-CO-NH-[(C 1-C 6)-alkyl], (CH2) n-C(CH 3) 2-CO-NH-(CH 2) r-OH、(CH 2) n-C(CH 3) 2-CO-N[(C 1-C 6)-alkyl]2、(CH 2) n-C(CH 3) 2-CO-NH-[(C 3-C 6)-cycloalkyl], (CH2) n-C(CH 3) 2-CO-N[(C 3-C 6)-cycloalkyl]2、(CH 2) n-C(CH 3) 2-COOH、 (CH 2) n-CO-NH-C(CH 3) 2-CO-O[(C 1-C 6)-alkyl], (CH2) n-CO-NH-C(CH 3) 2-CONH 2、(CH 2) n-CO-NH-C(CH 3) 2-COOH, alkyl wherein, alkenyl, alkynyl and cycloalkyl, bicyclic alkyl, tricyclic alkyl, cycloalkenyl group and two cycloalkenyl groups can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C1-C 6)-alkyl, (C3-C 6)-cycloalkyl, O-(C1-C 6)-alkyl, S (O)m-(C 1-C 6)-alkyl, SO2-NH 2、 COOH、CONH 2、CO-O(C 1-C 6)-alkyl, CO-(C1-C 6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;R12 is H, (C 1-C 6)-alkyl, (C 3-C 6)-cycloalkyl, (CH 2) q-[(C 3-C 6)-cycloalkyl], (CH 2) n-[(C 7-C 10)-bicyclic alkyl], (CH 2) n-[(C 7-C 10)-tricyclic alkyl], (CH 2) n-aryl, (CH 2) n-heteroaryl, alkyl wherein, cycloalkyl, bicyclic alkyl or tricyclic alkyl can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C 1-C 3)-alkyl, O-(C 1-C 3)-alkyl, SO 2-NH 2, COOH, CONH 2, CO-O (C 1-C 3)-alkyl, CO-(C 1-C 3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;R13 is H, SO 2-[(C 1-C 6)-alkyl], SO 2-[(C 3-C 6)-cycloalkyl], SO 2-(CH 2) n-aryl, SO 2-(CH 2) n-heteroaryl, SO 2-(CH 2) n-NH-R12, SO 2-(CH 2) n-N (R12) 2, alkyl wherein and cycloalkyl can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C 1-C 3)-alkyl, (C 3-C 6)-cycloalkyl, O-[(C 1-C 3)-alkyl], S (O) m-[(C 1-C 3)-alkyl], SO 2-NH 2, COOH, CONH 2, CO-[O (C 1-C 3)-alkyl], CO-(C 1-C 3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;R16 is ethylene imine-1-base, azetidine-1-base, piperidines-1-base, 3-hydroxy piperidine-1-base, 4-hydroxy piperidine-1-base, 3-oxo-piperidine-1-base, 4-oxo-piperidine-1-base, tetramethyleneimine-1-base, 3-pyrrolidinol-1-base, 2-Cyanopyrolidine-1-base, morpholine-N-base, piperazine-1-base, 4-[(C 1-C 3)-alkyl] piperazine-1-base, piperazine-2-ketone-1-base, piperazine-2-ketone-4-base, piperazine-2,6-diketone-1-base, piperazine-2,6-diketone-4-base, thiomorpholine-1,1-dioxide-4-base, NH-(CH 2) r-OH, NH-CH (CH 2OH) 2, NH-C (CH 2OH) 3, N[(C 1-C 6)-alkyl-OH] 2, D-glucosamine-N-base, N-methyl D-glucosamine-N-base, NH-[(C 1-C 6)-alkyl]-CO-O (C 1-C 3)-alkyl, NH-[(C 1-C 3)-alkyl]-COOH, NH-[(C 1-C 3)-alkyl]-CONH 2, N[(C 1-C 3)-alkyl] [(C 1-C 3)-alkyl]-CO-O (C 1-C 3)-alkyl, N[(C 1-C 3)-alkyl] [(C 1-C 3)-alkyl]-COOH, N[(C 1-C 3)-alkyl] [(C 1-C 3)-alkyl]-CONH 2, NH-[C (H) (aryl)]-CO-O (C 1-C 3)-alkyl, NH-[C (H) (aryl)]-COOH, NH-[C (H) (aryl)]-CONH 2, N[(C 1-C 3)-alkyl] [C (H) (aryl)]-CO-O (C 1-C 3)-alkyl, N[(C 1-C 3)-alkyl] [C (H) (aryl)]-COOH, N[(C 1-C 3)-alkyl] [C (H) (aryl)]-CONH 2, NH-[C (H) (heteroaryl)]-CO-O (C 1-C 3)-alkyl, NH-[C (H) (heteroaryl)]-COOH, NH-[C (H) (heteroaryl)]-CONH 2, N[(C 1-C 3)-alkyl] [C (H) (heteroaryl)]-CO-O (C 1-C 3)-alkyl, N[(C 1-C 3)-alkyl] [C (H) (heteroaryl)]-COOH, N[(C 1-C 3)-alkyl] [C (H) (heteroaryl)]-CONH 2, N[(C 1-C 3)-alkyl] [(C 3-C 6)-cycloalkyl]-CO-O (C 1-C 3)-alkyl, N[(C 1-C 3)-alkyl] [(C 3-C 6)-cycloalkyl]-COOH, N[(C 1-C 3)-alkyl] [(C 3-C 6)-cycloalkyl]-CONH 2, NH-[(C 3-C 6)-cycloalkyl]-CO-O (C 1-C 3)-alkyl, NH-[(C 3-C 6)-cycloalkyl]-COOH, NH-[(C 3-C 6)-cycloalkyl]-CONH 2, NH-(CH 2) r-SO 2-(C 1-C 3)-alkyl, NH-[(C 1-C 4)-alkyl]-SO 3H, NH-[(C 1-C 4)-alkyl]-SO 2-NH 2, N[(C 1-C 4)-alkyl] { [(C 1-C 4)-alkyl]-SO 3H}, alcohol wherein (OH) or ketone (C=O) functional group can be by F or CF 2Substitute;R17 is R18, R13, (CH 2) n-CO-[O-(C 1-C 3)-alkyl], (CH 2) n-CO-[O-(C 3-C 6)-cycloalkyl], (CH 2) n-CO-[(C 1-C 3)-alkyl], (CH 2) n-CO-[(C 3-C 6)-cycloalkyl], (CH 2) n-CO-aryl, (CH 2) n-CO-heteroaryl, (CH 2) n-CO-[O-(CH 2) n-aryl], (CH 2) n-CO-NH 2, (CH 2) q-COOH, alkyl wherein and cycloalkyl can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C 1-C 3)-alkyl, (C 3-C 6)-cycloalkyl, O-(C 1-C 3)-alkyl, S (O) m-(C 1-C 3)-alkyl, SO 2-NH 2, COOH, CONH 2, CO-[O (C 1-C 3)-alkyl], CO-(C 1-C 3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;R18 is (C 1-C 4)-alkyl, (C 3-C 6)-cycloalkyl, (CH 2) q-[(C 3-C 6)-cycloalkyl], (CH 2) n-aryl, (CH 2) n-heteroaryl, alkyl wherein and cycloalkyl can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C 1-C 3)-alkyl, O-(C 1-C 3)-alkyl, SO 2-NH 2, COOH, CONH 2, CO-[O (C 1-C 3)-alkyl], CO-(C 1-C 6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;R20 is H, (C 1-C 3)-alkyl, (C 3-C 6)-cycloalkyl, aryl, [(C 1-C 6)-alkyl]-aryl;R21 is H, F, CF 3, (C 1-C 3)-alkyl, (C 3-C 6)-cycloalkyl, OH, O-(C 1-C 3)-alkyl, O-(C 3-C 6)-cycloalkyl, O-(CH 2) n-aryl, O-(CO)-(C 1-C 3)-alkyl, O-(CO)-(C 3-C 6)-cycloalkyl, O-(CO)-O-(C 1-C 3)-alkyl, O-(CO)-O-(C 3-C 6)-cycloalkyl, NH 2, NH-[(C 1-C 3)-alkyl]-aryl, NH-(C 1-C 3)-alkyl, NH-(CO)-(C 1-C 3)-alkyl;R22 is H, CF 3, (C 1-C 3)-alkyl, aryl, [(C 1-C 6)-alkyl]-aryl.
- 3. formula I compound as claimed in claim 1 or 2 with and the compatible salt of physiology, whereinR, R ' are (C independently of one another 1-C 3)-alkyl, wherein (C 1-C 3)-alkyl can be replaced by halogen or R and R ' form the ring with 3 to 6 carbon atoms together;M is 0,1,2;N is 0,1,2,3;P is 1,2,3;Q is 1,2;R is 2,3,4;V is 0,1,2;A, D, E, G, L are C or N independently of one another, wherein when it is defined as N, do not have corresponding R1, R2, R3, R4, R5 substituting group;R1, R2, R3, R4, R5 are H, F, Cl, Br, CN, CF independently of one another 3, (C 1-C 4)-alkyl, (C 3-C 6)-cycloalkyl, (CH 2) q-[(C 3-C 6)-cycloalkyl], (CH 2) n-[(C 7-C 10)-bicyclic alkyl], (CH 2) n-[(C 7-C 10)-tricyclic alkyl], diamantane-1-base, diamantane-2-base, (CH 2) n-aryl, (CH 2) n-heteroaryl, OCF 3, O-(C 1-C 6)-alkyl, O-(C 3-C 7)-cycloalkyl, O-(CH 2) n-aryl, O-(CH 2) n-heteroaryl, NH-(C 1-C 4)-alkyl, N[(C 1-C 4)-alkyl] 2, NH-aryl, NH-heteroaryl, NH-SO 2-(C 1-C 4)-alkyl, NH-SO 2-aryl, S (O) m-(C 1-C 4)-alkyl, S (O) m-(C 3-C 6)-cycloalkyl, S (O) m-aryl, SO 2-NH 2, SO 2-NH-[(C 1-C 4)-alkyl], SO 2-NH-[(C 3-C 6)-cycloalkyl], SO 2-NH-(CH 2) n-aryl, SO 2-N[(C 1-C 4)-alkyl] 2, SF 5, CO-O[(C 1-C 4)-alkyl], CO-NH 2, CO-NH-[(C 1-C 4)-alkyl], CO-N[(C 1-C 4)-alkyl] 2, C (=NH)-NH 2, C (=N-OH) NH 2, COOH, CO-(C 1-C 6)-alkyl, CO-(C 3-C 6)-cycloalkyl, CO-aryl, CO-heteroaryl, CH (OH)-aryl, CH (OH)-heteroaryl, CH[O-(C 1-C 4)-alkyl]-aryl, CH[O-(C 1-C 4)-alkyl]-heteroaryl, CHF-aryl, CHF-heteroaryl, CF 2-aryl, alkyl wherein, cycloalkyl, bicyclic alkyl and tricyclic alkyl can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C 1-C 4)-alkyl, (C 3-C 6)-cycloalkyl, O-(C 1-C 4)-alkyl, S (O) m-(C 1-C 3)-alkyl, SO 2-NH 2, COOH, CONH 2, CO-O (C 1-C 3)-alkyl, CO-(C 1-C 3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;R6, R7, R8, R9, R10 are NR17-bicyclic heterocycles, NR17-aryl, NR17-heteroaryl independently of one another, aryl wherein or heteroaryl can be carbocyclic fused with 5-or 6-person's aromatics or non-aromatics, one or more CH or CH in described aromatics or the non-aromatic carbocyclic 2Group can be substituted by Sauerstoffatom and 5-wherein or 6-person's aromatics or non-aromatic carbocyclic can by F ,=O or-(C 1-C 6)-alkyl replaces, and bicyclic heterocycles wherein comprises 9 to 10 ring memberses and 5 CH or CH at the most 2Group can be independently of one another by N, NR20, O, S (O) mOr C=O substitutes, and aryl wherein or heteroaryl or bicyclic heterocycles can not be substituted or by following group list-or polysubstituted:R11、F、Cl、Br、CN、NO 2、CF 3、(CH 2) n-O-R11、(CH 2) n-O-(CH 2) r-OH、 (CH 2) n-O-CH(CH 2OH) 2、(CH 2) n-O-(CH 2) n-CO-O-(CH 2) r-NH 2、 (CH 2) n-O-saccharic acid, (CH2) n-O-glucoside, (CH2) n-O-galactoside, (CH2) n-O-glucuronide, OCF3、O-R13、(CH 2) n-O-(CH 2) r-NH 2、 (CH 2) n-NH-R11、(CH 2) n-N[(CH 2) q-CO-O(C 1-C 4)-alkyl]2、 (CH 2) n-N[(CH 2) q-COOH] 2、(CH 2) n-N[(CH 2) q-CONH 2] 2、 (CH 2) n-NH-R13、(CH 2) n-N(R13) 2、(CH 2) n-NH-SO 2-R16、 (CH 2) n-NH-(CH 2) n-SO 2-R12、(CH 2) n-NR12-CO-R16、 (CH 2) n-NR12-CO-NR12R13、(CH 2) n-NR12-CO-N(R12) 2、 (CH 2) n-NR12-CO-NHR11、(CH 2) n-NH-C(＝NH)-NH 2、 (CH 2) n-NH-C(＝NH)-R16、(CH 2) n-NH-C(＝NH)-NHR12、 (CH 2) n-NR12-C(＝NR13)-NHR12、 (CH 2) n-NR12-C(＝NR12)-NR12R13、 (CH 2) n-NH-(CH 2) n-CO-O-(CH 2) r-NH 2、 (CH 2) n-NH-(CH 2) n-CO-NH-[(C 1-C 8)-alkyl], (CH2) n-NH-(CH 2) n-CO-NH-(CH 2) r-OH、 (CH 2) n-NH-(CH 2) n-CO-N[(C 1-C 8)-alkyl]2、 (CH 2) n-NH-(CH 2) n-CO-NH-[(C 3-C 8)-cycloalkyl], (CH2) n-NH-C(CH 3) 2-CO-O(C 1-C 8)-alkyl, (CH2) n-NH-C(CH 3) 2-CO-O-(CH 2) r-NH 2、 (CH 2) n-NH-C(CH 3) 2-CO-NH 2、 (CH 2) n-NH-C(CH 3) 2-CO-NH-(CH 2) r-OH、 (CH 2) n-NH-C(CH 3) 2-COOH、S(O) m-R12、SO 2-R16、 SO 2-N＝CH-N(CH 3) 2、SO 2-NH-CO-R12、SO 2-NHR12、 SO 2-NH-(CH 2) r-OH、SO 2-N[(C 1-C 8)-alkyl]2、SO 2-NH-(CH 2) r-NH 2、 SF 5、COOH、CO-NH 2、(CH 2) q-CN、(CH 2) n-CO-NH-piperidin-1-yl, (CH2) n-CO-NH-SO 2-NHR12、(CH 2) n-CO-NH-SO 2-R18、 (CH 2) n-C(＝NH)NH 2、(CH 2) n-C(＝NH)-NHOH、 C(＝NH)-[NH-O-(C 1-C 6)-alkyl], (CH2) n-C(＝NH)(R16)、 (CH 2) n-C(＝NR13)NHR12、(CH 2) n-C(＝NR12)NR12R13、 (CH 2) n-C(＝NH)O[(C 1-C 6)-alkyl], alkyl wherein and cycloalkyl can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C1-C 6)-alkyl, (C3-C 6)-cycloalkyl, O-(C1-C 6)-alkyl, S (O)m-(C 1-C 6)-alkyl, SO2-NH 2、COOH、 CONH 2、CO-O(C 1-C 6)-alkyl, CO-(C1-C 6)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;H, F, Cl, Br, CN, CF 3, (C 1-C 6)-alkyl, (C 2-C 6)-alkenyl, (C 2-C 6)-alkynyl, (C 3-C 7)-cycloalkyl, (CH 2) n-OH, (CH 2) n-O-(C 1-C 4)-alkyl, (CH 2) n-O-(C 3-C 6)-cycloalkyl, (CH 2) n-O aryl, (CH 2) n-O-glucoside, (CH 2) n-O-glucuronide, OCF 3, O-R13, (CH 2) n-NH-aryl, (CH 2) n-NH-SO 2-(C 1-C 4)-alkyl, (CH 2) n-NH-SO 2-aryl, (CH 2) n-NH-CO-NH 2, (CH 2) n-NH-CO-NH-(C 1-C 4)-alkyl, (CH 2) n-NH-CO-NH-(C 3-C 6)-cycloalkyl, (CH 2) n-NH-C (=NH)-NH 2, S (O) m-(C 1-C 4)-alkyl, S (O) m-aryl, SO 2-NH 2, SO 2-NH-(C 1-C 4)-alkyl, SO 2-N[(C 1-C 4)-alkyl] 2, SF 5, (CH 2) n-CO-[O-(C 1-C 4)-alkyl], COOH, (CH 2) q-COOH, CONH 2, (CH 2) q-CONH 2, (CH 2) n-C (=NH) NH 2, (CH 2) n(=NH) NHOH, alkyl wherein and cycloalkyl can be replaced by fluorine atom-C and aryl wherein or heteroaryl can be by halogen, CN, (C 1-C 3)-alkyl, (C 3-C 6)-cycloalkyl, O-(C 1-C 4)-alkyl, S (O) m-(C 1-C 3)-alkyl, SO 2-NH 2, COOH, CONH 2, CO-[O (C 1-C 3)-alkyl] replace and alkyl wherein can be replaced by fluorine atom;Wherein among radicals R 6, R7, R8, R9 and the R10 always is defined as NR17-aryl or NR17-bicyclic heterocycles or NR17-heteroaryl;R11 is H, (C1-C 4)-alkyl, (C2-C 3)-alkenyl, (C2-C 4)-alkynyl, (C3-C 5)-cycloalkyl, (CH2) q-[(C 3-C 4)-cycloalkyl], (CH2) n-[(C 7-C 10)-bicyclic alkyl], (CH2) n-[(C 3-C 6)-cycloalkenyl group], (CH2) n-[(C 7-C 8)-two cycloalkenyl group], (CH2) n-[(C 7-C 8)-tricyclic alkyl], (CH2) n-aryl, (CH2) n-CO-[O-(C 1-C 4)-alkyl], (CH2) n-CO-[O-(C 3-C 5)-cycloalkyl], (CH2) n-CO-[(C 1-C 3)-alkyl], (CH2) n-CO-[(C 3-C 5)-cycloalkyl], (CH2) n-CO-aryl, (CH2) n-CO-heteroaryl, (CH2) n-CO-[O-(CH 2) v-aryl], (CH2) n-CO-[O-(CH 2) v-heteroaryl], (CH2) q-CO-NH 2、(CH 2) q-COOH、 (CH 2) n-P(O)(OH)[O-(C 1-C 3)-alkyl], (CH2) n-P(O)[O-(C 1-C 3)-alkyl]2、 (CH 2) n-P(O)(OH)(O-CH 2-aryl), (CH2) n-P(O)(O-CH 2-aryl)2、 (CH 2) n-P(O)(OH) 2、(CH 2) n-SO 3H、(CH 2) n-SO 2-NH 2、 (CH 2) n-CO-NH-[(C 1-C 6)-alkyl], (CH2) n-CO-N[(C 1-C 4)-alkyl]2、 (CH 2) n-CO-NH-[(C 3-C 5)-cycloalkyl], (CH2) n-CO-N[(C 3-C 4)-cycloalkyl]2、(C 2-C 4)-alkenyl-CO-O[(C1-C 4)-alkyl], (C2-C 4)-alkenyl-CONH2、(C 2-C 4)-alkenyl-COOH, (C2-C 4)-alkynyl-CO-O[(C1-C 6)-alkyl], (C2-C 4)-alkynyl-CONH2、(C 2-C 4)-alkynyl-COOH, (CH2) n-CR21[(CO-O(C 1-C 4)-alkyl)]2、 (CH 2) n-CR21(CONH 2) 2、(CH 2) n-CR21(COOH) 2、 (CH 2) n-CR21R22CO-O[(C 1-C 4)-alkyl], (CH2) n-CR21R22CONH 2、 (CH 2) n-CR21R22COOH、(CH 2) n-CO-R16、(CH 2) n-C(CH 3) 2-CO-O[(C 1-C 3)-alkyl], (CH2) n-C(CH 3) 2-CO-O[(C 3-C 5)-cycloalkyl], (CH2) n-C(CH 3) 2-CO-NH 2、 (CH 2) n-C(CH 3) 2-CO-NH-[(C 1-C 3)-alkyl], (CH2) n-C(CH 3) 2-CO-NH-(CH 2) r-OH、(CH 2) n-C(CH 3) 2-CO-NH-[(C 3-C 5)-cycloalkyl], (CH2) n-CO-NH-C(CH 3) 2-CO-O[(C 1-C 4)-alkyl], (CH2) n-C(CH 3) 2-COOH、(CH 2) n-CO-NH-C(CH 3) 2-CONH 2、 (CH 2) n-CO-NH-C(CH 3) 2-COOH, alkyl wherein, alkenyl, alkynyl and cycloalkyl, bicyclic alkyl, cycloalkenyl group, two cycloalkenyl groups and tricyclic alkyl can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C1-C 4)-alkyl, (C3-C 6)-cycloalkyl, O-(C1-C 4)-alkyl, S (O)m-(C 1-C 4)-alkyl, SO2-NH 2、COOH、CONH 2、CO-O(C 1-C 4)-alkyl, CO-(C1-C 3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;R12 is H, (C 1-C 3)-alkyl, (C 3-C 5)-cycloalkyl, (CH 2) q-[(C 3-C 5)-cycloalkyl], (CH 2) n-[(C 7-C 8)-bicyclic alkyl], (CH 2) n-[(C 7-C 8)-tricyclic alkyl], (CH 2) n-aryl, (CH 2) n-heteroaryl, alkyl wherein, cycloalkyl, bicyclic alkyl or tricyclic alkyl can be replaced by fluorine atom, and aryl wherein or heteroaryl can be by halogen, CN, (C 1-C 3)-alkyl, O-(C 1-C 3)-alkyl, SO 2-NH 2, COOH, CONH 2, CO-O (C 1-C 3)-alkyl, CO-(C 1-C 3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;R13 is H, SO 2-[(C 1-C 3)-alkyl], SO 2-[(C 3-C 5)-cycloalkyl], SO 2-(CH 2) n-aryl, SO 2-(CH 2) n-heteroaryl, SO 2-(CH 2) n-NH-R12, SO 2-(CH 2) n-N (R12) 2, alkyl wherein and cycloalkyl can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C 1-C 3)-alkyl, (C 3-C 6)-cycloalkyl, O-[(C 1-C 3)-alkyl], S (O) m-[(C 1-C 3)-alkyl], SO 2-NH 2, COOH, CONH 2, CO-[O (C 1-C 3)-alkyl], CO-(C 1-C 3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;R16 is ethylene imine-1-base, azetidine-1-base, piperidines-1-base, 4-hydroxy piperidine-1-base, 3-oxo-piperidine-1-base, 4-oxo-piperidine-1-base, tetramethyleneimine-1-base, 3-pyrrolidinol-1-base, 2-Cyanopyrolidine-1-base, morpholine-N-base, piperazine-1-base, 4-[(C 1-C 3)-alkyl] piperazine-1-base, piperazine-2-ketone-1-base, piperazine-2-ketone-4-base, thiomorpholine-1,1-dioxide-4-base, NH-(CH 2) r-OH, NH-CH (CH 2OH) 2, NH-C (CH 2OH) 3, N[(C 1-C 3)-alkyl-OH] 2, D-glucosamine-N-base, N-methyl D-glucosamine-N-base, NH-[(C 1-C 3)-alkyl]-CO-O (C 1-C 3)-alkyl, NH-[(C 1-C 3)-alkyl]-COOH, NH-[(C 1-C 3)-alkyl]-CONH 2, NH-[C (H) (aryl)]-CO-O (C 1-C 3)-alkyl, NH-[C (H) (aryl)]-COOH, NH-[C (H) (aryl)]-CONH 2, NH-[C (H) (heteroaryl)]-CO-O (C 1-C 3)-alkyl, NH-[C (H) (heteroaryl)]-COOH, NH-[C (H) (heteroaryl)]-CONH 2, NH-[(C 3-C 6)-cycloalkyl]-CO-O (C 1-C 3)-alkyl, NH-[(C 3-C 6)-cycloalkyl]-COOH, NH-[(C 3-C 6)-cycloalkyl]-CONH 2, NH-(CH 2) r-SO 2-(C 1-C 3)-alkyl, NH-[(C 1-C 4)-alkyl]-SO 3H, NH-[(C 1-C 4)-alkyl]-SO 2-NH 2, N[(C 1-C 3)-alkyl] { [(C 1-C 4)-alkyl]-SO 3H}, alcohol wherein (OH) or ketone (C=O) functional group can be by F or CF 2Substitute;R17 is R18, H, SO 2-CH 3, SO 2-aryl, (CH 2) n-CO-[O-(C 1-C 3)-alkyl], (CH 2) n-CO-[(C 1-C 3)-alkyl], (CH 2) n-CO-aryl, (CH 2) n-CO-NH 2, (CH 2) q-COOH, alkyl wherein can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C 1-C 3)-alkyl, O-(C 1-C 3)-alkyl, S (O) m-(C 1-C 3)-alkyl, SO 2-NH 2, COOH, CONH 2, CO-[O (C 1-C 3)-alkyl], CO-(C 1-C 3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;R18 is (C 1-C 4)-alkyl, (C 3-C 4)-cycloalkyl, (CH 2) n-aryl, (CH 2) n-heteroaryl, alkyl wherein and cycloalkyl can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C 1-C 3)-alkyl, O-(C 1-C 3)-alkyl, SO 2-NH 2, COOH, CONH 2, CO-[O (C 1-C 3)-alkyl], CO-(C 1-C 3)-alkyl replaces, and alkyl wherein can be replaced by fluorine atom;R20 is H, (C 1-C 3)-alkyl, (C 3-C 6)-cycloalkyl, aryl, [(C 1-C 3)-alkyl]-aryl;R21 is H, F, CF 3, (C 1-C 3)-alkyl, (C 3-C 4)-cycloalkyl, OH, O-(C 1-C 3)-alkyl, O-(C 3-C 4)-cycloalkyl, O-(CH 2) n-aryl, O-(CO)-(C 1-C 3)-alkyl, O-(CO)-(C 3-C 4)-cycloalkyl, O-(CO)-O-(C 1-C 3)-alkyl, O-(CO)-O-(C 3-C 4)-cycloalkyl, NH 2, NH-[(C 1-C 2)-alkyl]-aryl, NH-(C 1-C 3)-alkyl, NH-(CO)-(C 1-C 3)-alkyl;R22 is H, CF 3, (C 1-C 3)-alkyl, aryl, [(C 1-C 3)-alkyl]-aryl.
- As one or multinomial described formula I compound in the claim 1 to 3 with and the compatible salt of physiology, whereinR, R ' are (C independently of one another 1-C 3)-alkyl; Perhaps R and R ' form the ring with 3 to 6 carbon atoms together;M is 0,1,2;N is 0,1,2;P is 1,2;Q is 1,2;R is 2,3;V is 0,1;A, D, E, G, L are C or N independently of one another, wherein when it is defined as N, do not have corresponding R1, R2, R3, R4, R5 substituting group;R1, R2, R3, R4, R5 are H, F, Cl, Br, CN, CF independently of one another 3, (C 1-C 4)-alkyl, (C 3-C 6)-cycloalkyl, (CH 2) q-[(C 3-C 6)-cycloalkyl], diamantane-1-base, diamantane-2-base, (CH 2) n-aryl, (CH 2) n-heteroaryl, OCF 3, O-(C 1-C 4)-alkyl, O-(C 3-C 6)-cycloalkyl, O-(CH 2) n-aryl, O-(CH 2) n-heteroaryl, NH-(C 1-C 4)-alkyl, N[(C 1-C 4)-alkyl] 2, NH-aryl, NH-heteroaryl, NH-SO 2-(C 1-C 4)-alkyl, NH-SO 2-aryl, S (O) m-(C 1-C 3)-alkyl, S (O) m-(C 3-C 6)-cycloalkyl, S (O) m-aryl, SO 2-NH 2, SO 2-NH-[(C 1-C 4)-alkyl], SO 2-NH-[(C 3-C 6)-cycloalkyl], SO 2-NH-(CH 2) n-aryl, SO 2-N[(C 1-C 4)-alkyl] 2, SF 5, CO-O[(C 1-C 4)-alkyl], CO-NH 2, CO-NH-[(C 1-C 3)-alkyl], CO-N[(C 1-C 3)-alkyl] 2, COOH, CO-(C 1-C 3)-alkyl, CO-(C 3-C 6)-cycloalkyl, CO-aryl, CO-heteroaryl, CH (OH)-aryl, CH (OH)-heteroaryl, CH[O-(C 1-C 4)-alkyl]-aryl, CH[O-(C 1-C 4)-alkyl]-heteroaryl, CHF-aryl, CHF-heteroaryl, CF 2-aryl, alkyl or cycloalkyl wherein can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C 1-C 3)-alkyl, O-(C 1-C 4)-alkyl, S (O) m-(C 1-C 3)-alkyl, SO 2-NH 2, COOH, CONH 2, CO-O (C 1-C 3)-alkyl, CO-(C 1-C 3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;R6, R7, R8, R9, R10 are NR17-bicyclic heterocycles, NR17-aryl, NR17-heteroaryl independently of one another, aryl wherein or heteroaryl can be carbocyclic fused with 5-or 6-person's aromatics or non-aromatics, one or more CH or CH in described aromatics or the non-aromatic carbocyclic 2Group can be substituted by Sauerstoffatom and wherein said 5-or 6-person's aromatics or non-aromatic carbocyclic can by F ,=O or-(C 1-C 3)-alkyl replaces, and wherein said bicyclic heterocycles comprises 9 to 10 ring memberses and 5 CH or CH at the most 2Group can be independently of one another by N, NR20, O, S (O) mOr C=O substitutes, and aryl wherein or heteroaryl or bicyclic heterocycles can not be substituted or by following group list-or polysubstituted:R11、F、Cl、Br、CN、NO 2、CF 3、(CH 2) n-O-R11、(CH 2) n-O-(CH 2) r-OH、 (CH 2) n-O-CH(CH 2OH) 2、(CH 2) n-O-(CH 2) n-CO-O-(CH 2) r-NH 2、 (CH 2) n-O-glucoside, (CH2) n-O-galactoside, (CH2) n-O-glucuronide, OCF3、O-R13、(CH 2) n-O-(CH 2) r-NH 2、(CH 2) n-NH-R11、 (CH 2) n-N[(CH 2) q-CO-O(C 1-C 4)-alkyl]2、(CH 2) n-N[(CH 2) q-COOH] 2、 (CH 2) n-N[(CH 2) q-CONH 2] 2、(CH 2) n-NH-R13、(CH 2) n-N(R13) 2、 (CH 2) n-NH-SO 2-R16、(CH 2) n-NH-(CH 2) n-SO 2-R12、 (CH 2) n-NR12-CO-R16、(CH 2) n-NR12-CO-NR12R13、 (CH 2) n-NR12-CO-N(R12) 2、(CH 2) n-NR12-CO-NHR11、 (CH 2) n-NH-C(＝NH)-R16、(CH 2) n-NR12-C(＝NR13)-NHR12、 (CH 2) n-NR12-C(＝NR12)-NR12R13、 (CH 2) n-NH-(CH 2) n-CO-O-(CH 2) r-NH 2、 (CH 2) n-NH-(CH 2) n-CO-NH-[(C 1-C 3)-alkyl], (CH2) n-NH-(CH 2) n-CO-NH-(CH 2) r-OH、 (CH 2) n-NH-(CH 2) n-CO-N[(C 1-C 3)-alkyl]2、 (CH 2) n-NH-(CH 2) n-CO-NH-[(C 3-C 5)-cycloalkyl], (CH2) n-NH-C(CH 3) 2-CO-O(C 1-C 4)-alkyl, (CH2) n-NH-C(CH 3) 2-CO-O-(CH 2) r-NH 2、 (CH 2) n-NH-C(CH 3) 2-CO-NH 2、 (CH 2) n-NH-C(CH 3) 2-CO-NH-(CH 2) r-OH、 (CH 2) n-NH-C(CH 3) 2-COOH、S(O) m-R12、SO 2-R16、 SO 2-N＝CH-N(CH 3) 2、SO 2-NH-CO-R12、SO 2-NHR12、 SO 2-NH-(CH 2) r-OH、SO 2-N[(C 1-C 3)-alkyl]2、SO 2-NH-(CH 2) r-NH 2、 SF 5、COOH、CO-NH 2、(CH 2) q-CN、(CH 2) n-CO-NH-piperidin-1-yl, (CH2) n-CO-NH-SO 2-NHR12、(CH 2) n-CO-NH-SO 2-R18、 (CH 2) n-C(＝NH)-NHOH、C(＝NH)-[NH-O-(C 1-C 3)-alkyl], (CH2) n-C(＝NH)(R16)、(CH 2) n-C(＝NR12)NR12R13、 (CH 2) n-C(＝NH)O[(C 1-C 3)-alkyl], alkyl wherein and cycloalkyl can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C1-C 3)-alkyl, (C3-C 6)-cycloalkyl, O-(C1-C 3)-alkyl, S (O)m-(C 1-C 3)-alkyl, SO2-NH 2、COOH、 CONH 2、CO-O(C 1-C 3)-alkyl, CO-(C1-C 3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;H, F, Cl, Br, CN, CF 3, (C 1-C 6)-alkyl, (C 3-C 7)-cycloalkyl, (CH 2) n-OH, (CH 2) n-O-(C 1-C 4)-alkyl, (CH 2) n-O-(C 3-C 6)-cycloalkyl, (CH 2) n-O aryl, (CH 2) n-O-glucoside, (CH 2) n-O-glucuronide, OCF 3, O-R13, (CH 2) n-NH-aryl, (CH 2) n-NH-SO 2-(C 1-C 4)-alkyl, (CH 2) n-NH-SO 2-aryl, (CH 2) n-NH-CO-NH 2, (CH 2) n-NH-CO-NH-(C 1-C 3)-alkyl, (CH 2) n-NH-CO-NH-(C 3-C 6)-cycloalkyl, (CH 2) n-NH-C (=NH)-NH 2, S (O) m-(C 1-C 4)-alkyl, S (O) m-aryl, SO 2-NH 2, SO 2-NH-(C 1-C 3)-alkyl, SO 2-N[(C 1-C 3)-alkyl] 2, SF 5, (CH 2) n-CO-[O-(C 1-C 4)-alkyl], (CH 2) n-COOH, (CH 2) n-CONH 2, (CH 2) n-C (=NH) NH 2, alkyl wherein and cycloalkyl can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C 1-C 3)-alkyl, (C 3-C 6)-cycloalkyl, O-(C 1-C 4)-alkyl, S (O) m-(C 1-C 3)-alkyl, SO 2-NH 2, COOH, CONH 2, CO-[O (C 1-C 3)-alkyl] replace and alkyl wherein can be replaced by fluorine atom;Wherein at least one among radicals R 6, R7, R8, R9 and the R10 always is defined as NR17-aryl or NR17-bicyclic heterocycles or NR17-heteroaryl;R11 is H, (C1-C 4)-alkyl, (C3-C 5)-cycloalkyl, (CH2) q-[(C 3-C 4)-cycloalkyl], (CH2) n-[(C 7-C 8)-bicyclic alkyl], (CH2) n-[(C 7-C 8)-tricyclic alkyl], (CH2) n-aryl, (CH2) n-CO-[O-(C 1-C 4)-alkyl], (CH2) n-CO-[O-(C 3-C 5)-cycloalkyl], (CH2) n-CO-[(C 1-C 3)-alkyl], (CH2) n-CO-[(C 3-C 5)-cycloalkyl], (CH2) n-CO-aryl, (CH2) n-CO-heteroaryl, (CH2) n-CO-[O-(CH 2) v-aryl], (CH2) n-CO-[O-(CH 2) v-heteroaryl], (CH2) q-CO-NH 2、(CH 2) q-COOH、(CH 2) n-P(O)(OH)[O-(C 1-C 3)-alkyl], (CH2) n-P(O)[O-(C 1-C 3)-alkyl]2、(CH 2) n-P(O)(OH)(O-CH 2-aryl), (CH2) n-P(O)(O-CH 2-aryl)2、(CH 2) n-P(O)(OH) 2、(CH 2) n-SO 3H、 (CH 2) n-SO 2-NH 2、(CH 2) n-CO-NH-[(C 1-C 3)-alkyl], (CH2) n-CO-N[(C 1-C 3)-alkyl]2、(CH 2) n-CO-NH-[(C 3-C 5)-cycloalkyl], (C2-C 3)-alkenyl-CO-O[(C1-C 4)-alkyl], (C2-C 3)-alkenyl-CONH2、(C 2-C 3)-alkenyl-COOH, (C2-C 4)-alkynyl-CO-O[(C1-C 4)-alkyl], (C2-C 4)-alkynyl-CONH2、(C 2-C 4)-alkynyl-COOH, (CH2) n-CR21[(CO-O(C 1-C 4)-alkyl)]2、(CH 2) n-CR21(CONH 2) 2、 (CH 2) n-CR21(COOH) 2、(CH 2) n-CR21R22CO-O[(C 1-C 4)-alkyl], (CH2) n-CR21R22CONH 2、(CH 2) n-CR21R22COOH、(CH 2) n-CO-R16、 (CH 2) n-C(CH 3) 2-CO-O[(C 1-C 3)]-alkyl, (CH2) n-C(CH 3) 2-CO-O[(C 3-C 5)]-cycloalkyl, (CH2) n-C(CH 3) 2-CO-NH 2、(CH 2) n-C(CH 3) 2-CO-NH-[(C 1-C 3)-alkyl], (CH2) n-C(CH 3) 2-CO-NH-(CH 2) r-OH、(CH 2) n-C(CH 3) 2-CO-NH-[(C 3-C 5)-cycloalkyl], (CH2) n-C(CH 3) 2-COOH、(CH 2) n-CO-NH-C(CH 3) 2-CONH 2、 (CH 2) n-CO-NH-C(CH 3) 2-CO-O[(C 1-C 4)-alkyl], (CH2) n-CO-NH-C(CH 3) 2-COOH, alkyl wherein, cycloalkyl, bicyclic alkyl and tricyclic alkyl can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C1-C 4)-alkyl, (C3-C 6)-cycloalkyl, O-(C1-C 4)-alkyl, S (O)m-(C 1-C 4)-alkyl, SO2-NH 2、 COOH、CONH 2、CO-O(C 1-C 4)-alkyl, CO-(C1-C 3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;R12 is H, (C 1-C 3)-alkyl, (C 3-C 5)-cycloalkyl, (CH 2) n-aryl, (CH 2) n-heteroaryl, alkyl or cycloalkyl wherein can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C 1-C 3)-alkyl, O-(C 1-C 3)-alkyl, SO 2-NH 2, COOH, CONH 2, CO-O (C 1-C 3)-alkyl, CO-(C 1-C 3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;R13 is H, SO 2-[(C 1-C 3)-alkyl], SO 2-[(C 3-C 5)-cycloalkyl], SO 2-(CH 2) n-aryl, SO 2-(CH 2) n-heteroaryl, SO 2-(CH 2) n-NH-R12, SO 2-(CH 2) n-N (R12) 2, alkyl wherein and cycloalkyl can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C 1-C 3)-alkyl, (C 3-C 6)-cycloalkyl, O-[(C 1-C 3)-alkyl], S (O) m-[(C 1-C 3)-alkyl], SO 2-NH 2, COOH, CONH 2, CO-[O (C 1-C 3)-alkyl], CO-(C 1-C 3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;R16 is ethylene imine-1-base, azetidine-1-base, piperidines-1-base, 4-hydroxy piperidine-1-base, 3-oxo-piperidine-1-base, 4-oxo-piperidine-1-base, tetramethyleneimine-1-base, 3-pyrrolidinol-1-base, 2-Cyanopyrolidine-1-base, morpholine-N-base, piperazine-1-base, 4-[(C 1-C 3)-alkyl] piperazine-1-base, piperazine-2-ketone-1-base, piperazine-2-ketone-4-base, thiomorpholine-1,1-dioxide-4-base, NH-(CH 2) r-OH, NH-CH (CH 2OH) 2, NH-C (CH 2OH) 3, N[(C 1-C 3)-alkyl-OH] 2, D-glucosamine-N-base, N-methyl D-glucosamine-N-base, NH-[(C 1-C 3)-alkyl]-CO-O (C 1-C 3)-alkyl, NH-[(C 1-C 3)-alkyl]-COOH, NH-[(C 1-C 3)-alkyl]-CONH 2, NH-[C (H) (aryl)]-CO-O (C 1-C 3)-alkyl, NH-[C (H) (aryl)]-COOH, NH-[C (H) (aryl)]-CONH 2, NH-[C (H) (heteroaryl)]-CO-O (C 1-C 3)-alkyl, NH-[C (H) (heteroaryl)]-COOH, NH-[C (H) (heteroaryl)]-CONH 2, NH-[(C 3-C 6)-cycloalkyl]-CO-O (C 1-C 3)-alkyl, NH-[(C 3-C 6)-cycloalkyl]-COOH, NH-[(C 3-C 6)-cycloalkyl]-CONH 2, NH-(CH 2) r-SO 2-(C 1-C 3)-alkyl, NH-[(C 1-C 4)-alkyl]-SO 3H, NH-[(C 1-C 4)-alkyl]-SO 2-NH 2, N[(C 1-C 3)-alkyl] { [(C 1-C 4)-alkyl]-SO 3H}, wherein its alcohol (OH) or ketone (C=O) functional group can be by F or CF 2Substitute;R17 is H, R18, SO 2-CH 3, SO 2-aryl, (CH 2) n-CO-[O-(C 1-C 3)-alkyl], (CH 2) n-CO-[(C 1-C 3)-alkyl], (CH 2) n-CO-aryl, (CH 2) n-CO-NH 2, (CH 2) q-COOH, alkyl wherein and cycloalkyl can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C 1-C 3)-alkyl, O-(C 1-C 3)-alkyl, S (O) m-(C 1-C 3)-alkyl, SO 2-NH 2, COOH, CONH 2, CO-[O (C 1-C 3)-alkyl], CO-(C 1-C 3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;R18 is (C 1-C 4)-alkyl, (C 3-C 4)-cycloalkyl, (CH 2) n-aryl, (CH 2) n-heteroaryl, alkyl wherein and cycloalkyl can be replaced by fluorine atom and aryl wherein or heteroaryl can be by halogen, CN, (C 1-C 3)-alkyl, O-(C 1-C 3)-alkyl, SO 2-NH 2, COOH, CONH 2, CO-[O (C 1-C 3)-alkyl], CO-(C 1-C 3)-alkyl replaces and alkyl wherein can be replaced by fluorine atom;R20 is H, (C 1-C 3)-alkyl, (C 3-C 5)-cycloalkyl, aryl, [(C 1-C 2)-alkyl]-aryl;R21 is H, F, CF 3, (C 1-C 3)-alkyl, (C 3-C 4)-cycloalkyl, OH, O-(C 1-C 3)-alkyl, O-(C 3-C 4)-cycloalkyl, O-(CH 2) n-aryl, O-(CO)-(C 1-C 3)-alkyl, O-(CO)-O-(C 1-C 3)-alkyl, NH 2, NH-[(C 1-C 2)-alkyl]-aryl, NH-(C 1-C 3)-alkyl, NH-(CO)-(C 1-C 3)-alkyl;R22 is H, CF 3, (C 1-C 3)-alkyl, aryl, [(C 1-C 2)-alkyl]-aryl.
- As one or multinomial described formula I compound in the claim 1 to 4 with and the compatible salt of physiology, whereinEach methyl naturally of R, R ';Perhaps R and R ' form cyclohexyl ring together;N is 0,1,2;P is 1;A, D, E, G, L are C or N independently of one another, wherein when it is defined as N, do not have corresponding R1, R2, R3, R4, R5 substituting group;R1, R2, R5 are H, F, Cl, Br, I, CN, CF independently of one another 3, (C 1-C 4)-alkyl, O-(C 1-C 4)-alkyl, phenyl ,-O-phenyl, SF 5, alkyl wherein can be replaced by fluorine atom and phenyl wherein can be replaced by F, Cl, Br, I;R3 is F, CN;R4 is CF 3, (C 1-C 4)-alkyl, O-(C 1-C 4)-alkyl;R6, R7, R8, R9, R10 are H, F, Cl, Br, I, (C independently of one another 1-C 4)-alkyl, O-(C 1-C 4)-alkyl, alkyl wherein can be replaced by fluorine atom, NR17-aryl, and aryl wherein can be by F, Cl, Br, I, (CH 2) n-CO-NH 2, NH 2,-SO 2-NH 2, COOH, (CH 2) n-P (O) is [O-(C (OH) 1-C 4)-alkyl], (CH 2) n-P (O) (OH) 2Replace;Wherein among radicals R 6, R7, R8, R9 and the R10 always is defined as the NR17-aryl;R17 is H, (C 1-C 4)-alkyl.
- As medicine as one or multinomial described compound in the claim 1 to 5.
- 7. comprise one or more as in the claim 1 to 5 one or multinomial as described in the medicine of compound.
- 8. comprise one or more as in the claim 1 to 5 one or multinomial as described in the medicine of compound and another kind of at least activeconstituents.
- 9. medicine as claimed in claim 8, it comprises one or more antidiabetic drugs as other activeconstituents, effective blood sugar reducing component, the HMG-CoA reductase inhibitor, cholesterol absorption inhibitor, the PPAR gamma agonist, the PPAR alfa agonists, PPAR α/gamma agonist, the PPAR delta agonists, the special class material of shellfish, the MTP inhibitor, the bile acide absorption inhibitor, the MTP inhibitor, the CETP inhibitor, the polymer-type bile acid adsorbent, the ldl receptor inductor, the ACAT inhibitor, antioxidant, the lipoprotein lipase inhibitor, ATP citrate lyase inhibitor, inhibitor for squalene synthetic enzyme, lipoprotein (a) antagonist, the HM74A receptor stimulant, lipase inhibitor, insulin type, sulfonylurea, biguanides, meglitinides, thiazolidinediones, alpha-glucosidase inhibitor, act on the activeconstituents of the ATP dependency potassium channel of β cell, glycogen phosphorylase inhibitors, glucagon receptor antagonist, the activator of glucokinase, the inhibitor of glyconeogenesis, fructose 1, the inhibitor of 6-diphosphatase, the conditioning agent of glucose transporter 4, glutamine: the inhibitor of fructose-6-phosphate esteramides transferring enzyme, the inhibitor of DPP IV, the inhibitor of 11-beta-hydroxysteroid dehydrogenase 1, the inhibitor of PTP 1B, sodium dependent glucose translocator 1 or 2 conditioning agent, the conditioning agent of GPR40, the inhibitor of hormone-sensitive lipase, the inhibitor of acetyl CoA carboxylase, the kinase whose inhibitor of enolpyruvate phosphate carboxyl, the inhibitor of glycogen synthase kinase-3 β, the inhibitor of protein kinase C β, endothelin-A receptor antagonist, the inhibitor of I kappa b kinase, the conditioning agent of glucocorticoid receptor, the CART agonist, the NPY agonist, the MC4 agonist, the aricine agonist, the H3 agonist, the TNF agonist, the CRF antagonist, CRF BP antagonist, the Urocortin agonist, β 3 agonists, the CB1 receptor antagonist, MSH (melanotropin hormone) agonist, the CCK agonist, serotonin reuptake inhibitors, plain energy of pooled serum and norepinephrine energy compound, the 5HT agonist, the bombesin agonist, the galanin antagonist, growth hormones, tethelin-release compound, the TRH agonist, uncoupling protein 2 or 3 conditioning agents, the Leptin agonist, DA agonist (bromocriptine, Doprexin), lipase/amylase inhibitor, the PPAR conditioning agent, RXR conditioning agent or TR-beta-2-agonists or amphetamine.
- 10. be used to prepare the purposes of the medicine for the treatment of metabolism syndrome as one or multinomial described compound in the claim 1 to 5.
- 11. be used to prepare the purposes of the medicine for the treatment of diabetes as one or multinomial described compound in the claim 1 to 5.
- 12. be used to prepare the purposes of the fat medicine of treatment as one or multinomial described compound in the claim 1 to 5.
- 13. be used to prepare the purposes of the medicine that reduces body weight as one or multinomial described compound in the claim 1 to 5.
- 14. be used to prepare the purposes of the medicine for the treatment of nicotine dependence as one or multinomial described compound in the claim 1 to 5.
- 15. be used to prepare the purposes of the medicine for the treatment of alcohol dependence as one or multinomial described compound in the claim 1 to 5.
- 16. be used to prepare the purposes of the medicine of treatment CNS illness as one or multinomial described compound in the claim 1 to 5.
- 17. be used to prepare the purposes for the treatment of schizoid medicine as one or multinomial described compound in the claim 1 to 5.
- 18. be used to prepare the purposes of the medicine for the treatment of alzheimer's disease as one or multinomial described compound in the claim 1 to 5.
- 19. be used for the purposes of the medicine of preparation treatment polycystic ovary syndrome (PCOS) as one or multinomial described compound in the claim 1 to 5.
- 20. preparation comprise one or more as in the claim 1 to 5 one or multinomial as described in the method for medicine of compound, it comprises and described activeconstituents is mixed with suitable medicinal carrier and makes this mixture become the form that is suitable for administration.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102006036930.0 | 2006-08-08 | ||
| DE102006036930 | 2006-08-08 | ||
| DE102006040592.7 | 2006-08-30 |
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| CN101501005A true CN101501005A (en) | 2009-08-05 |
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| CNA2007800294643A Pending CN101501005A (en) | 2006-08-08 | 2007-07-25 | Arylaminoaryl-alkyl-substituted imidazolidine-2,4-diones, processes for preparing them, medicaments comprising these compounds, and their use |
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| Country | Link |
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| CN (1) | CN101501005A (en) |
| DO (1) | DOP2007000121A (en) |
| ZA (1) | ZA200900101B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101875636A (en) * | 2010-05-18 | 2010-11-03 | 浙江大学 | Imidazoline-2,4-diketone derivative and preparation method and applications thereof |
| CN102617563A (en) * | 2012-01-19 | 2012-08-01 | 西安交通大学 | Compound and preparation method thereof |
| CN102617564A (en) * | 2012-01-19 | 2012-08-01 | 西安交通大学 | Compound and preparation method thereof |
| CN105873917A (en) * | 2013-12-19 | 2016-08-17 | 恩多研究公司 | Non-steroidal antiandrogens and selective androgen receptor modulators with pyridyl moiety |
| CN106573921A (en) * | 2013-12-31 | 2017-04-19 | 博福-益普生（天津）制药有限公司 | Novel imidazolidine-2, 4-dione derivatives |
| CN112759550A (en) * | 2019-11-04 | 2021-05-07 | 上海科技大学 | Smooth receptor antagonist |
-
2007
- 2007-07-25 CN CNA2007800294643A patent/CN101501005A/en active Pending
- 2007-08-06 DO DO2007000121A patent/DOP2007000121A/en unknown
-
2009
- 2009-01-06 ZA ZA200900101A patent/ZA200900101B/en unknown
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101875636A (en) * | 2010-05-18 | 2010-11-03 | 浙江大学 | Imidazoline-2,4-diketone derivative and preparation method and applications thereof |
| CN102617563A (en) * | 2012-01-19 | 2012-08-01 | 西安交通大学 | Compound and preparation method thereof |
| CN102617564A (en) * | 2012-01-19 | 2012-08-01 | 西安交通大学 | Compound and preparation method thereof |
| CN102617564B (en) * | 2012-01-19 | 2015-04-29 | 西安交通大学 | Compound and preparation method thereof |
| CN102617563B (en) * | 2012-01-19 | 2015-04-29 | 西安交通大学 | Compound and preparation method thereof |
| CN105873917A (en) * | 2013-12-19 | 2016-08-17 | 恩多研究公司 | Non-steroidal antiandrogens and selective androgen receptor modulators with pyridyl moiety |
| TWI639585B (en) * | 2013-12-19 | 2018-11-01 | 加拿大商安多瑞翠奇股份有限公司 | Non-steroidal antiandrogens and selective androgen receptor modulators with a pyridyl moiety |
| CN105873917B (en) * | 2013-12-19 | 2021-08-10 | 恩多研究公司 | Non-steroidal antiandrogens and selective androgen receptor modulators containing a pyridyl moiety |
| CN106573921A (en) * | 2013-12-31 | 2017-04-19 | 博福-益普生（天津）制药有限公司 | Novel imidazolidine-2, 4-dione derivatives |
| CN106573921B (en) * | 2013-12-31 | 2019-05-07 | 博福-益普生（天津）制药有限公司 | Imidazolidine -2,4- derovatives |
| CN112759550A (en) * | 2019-11-04 | 2021-05-07 | 上海科技大学 | Smooth receptor antagonist |
Also Published As
| Publication number | Publication date |
|---|---|
| DOP2007000121A (en) | 2008-02-15 |
| ZA200900101B (en) | 2010-01-27 |
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