Summary of the invention:
in a first aspect the present invention provides a compound of formula I:
and isomers, prodrugs, pharmaceutically acceptable salts, solvates or hydrates thereof, wherein:
x is-CH2-or-O-or-S-;
y is-CH2-or-CH2CH2-or-CO-;
R1selected from:
1)-H，
2)-C1-C6alkyl, optionally substituted with one or more halogens, and
3)-C3-C8cycloalkyl, optionally substituted with one or more halo;
R2selected from:
1)-H，
2)-C1-C6an alkyl group, a carboxyl group,
3)-C3-C8a cycloalkyl group,
4)-(C1-C6alkyl) -R7And are and
5)-Ar1，
wherein,
R7selected from:
1)-OR8，
2)-SR8，
3)-NR8R9，
4)-NCONR8R9，
5)-NCNNR8R9，
6)-COOR8，
7)-CONR8R9and are and
8)-Ar1，
Ar1selected from phenyl, arylheterocyclyl and heterobicyclyl, optionally substituted with one or more groups selected from:
1) the halogen(s) are selected from the group consisting of,
2) the nitro group(s),
3) the cyano group(s),
4)-CF3，
5)-R8，
6)-OR8，
7)-NR8R9and are and
8)-COOR8，
R8and R9Each independently selected from:
1)-H，
2)-(C1-C6alkylene radical)0-3Phenyl, wherein the phenyl is optionally substituted by one or more groups selected from-C1-C4Alkyl and halogen, and the like,
3)-C1-C6alkyl, optionally substituted with one or more halogens,
4)-C3-C8cycloalkyl, optionally substituted with one or more halogens,
5)-C2-C6alkenyl, which is optionally substituted with one or more halogens, and
6)-C2-C6alkynyl, optionally substituted with one or more halo;
R3selected from:
1)-H，
2)-C1-C6an alkyl group, a carboxyl group,
3)-C3-C8a cycloalkyl group,
4)-(C1-C6alkyl) -R10，
5)-Ar1，
Wherein,
R10selected from:
1)-OR8，
2)-SR8，
3)-NR8R9，
4)-NCONR8R9，
5)-NCNNR8R9，
6)-COOR8，
7)-CONR8R9and are and
8)-Ar1，
Ar1selected from phenyl, arylheterocyclyl and heterobicyclyl, optionally substituted with one or more groups selected from:
1) the halogen(s) are selected from the group consisting of,
2) the nitro group(s),
3) the cyano group(s),
4)-CF3，
5)-R8，
6)-OR8，
7)-NR8R9and are and
8)-COOR8，
R8and R9Each independently selected from:
1)-H，
2)-(C1-C6alkylene radical)0-3-phenyl, wherein the phenyl is optionally substituted by one or more groups selected from-C1-C4Alkyl and halogen, and the like,
3)-C1-C6alkyl, optionally substituted with one or more halogens,
4)-C3-C8cycloalkyl, optionally substituted with one or more halogens,
5)-C2-C6alkenyl, which is optionally substituted with one or more halogens, and
6)-C2-C6alkynyl, optionally substituted with one or more halo;
[ preferably, R3The carbon atoms to which they are attached may be of any optical configuration]
R4And R400Each independently selected from:
1)-H，
2)-C1-C6an alkyl group, a carboxyl group,
3)-C3-C8a cycloalkyl group,
4)-C2-C6alkenyl, and
5)-C2-C6an alkynyl group;
R5and R500Each independently selected from:
1)-H，
2)-C1-C6an alkyl group, a carboxyl group,
3)-C3-C8a cycloalkyl group,
4)-C2-C6alkenyl, and
5)-C2-C6an alkynyl group;
R6selected from:
1)-R11，
2)-OR11，
3)-NR11R12，
4)-SOR11and are and
5)-SO2R11，
wherein R is11And R12Each independently selected from:
1)-H，
2)-C1-C6an alkyl group, a carboxyl group,
3)-C3-C8a cycloalkyl group,
4)-C2-C6an alkenyl group, which is a radical of an alkenyl group,
5)-C2-C6an alkynyl group,
6)-COR8，
7)-Ar1，
8)-(C1-C6alkyl) -Ar1，
9)-CO-Ar1And are and
10)-CO-(C1-C6alkyl) -Ar1，
Wherein,
Ar1selected from phenyl, arylheterocyclyl and heterobicyclyl, optionally substituted with one or more groups selected from:
1) the halogen(s) are selected from the group consisting of,
2) the nitro group(s),
3) the cyano group(s),
4)-CF3，
5)-R8，
6)-OR8，
7)-NR8R9and are and
8)-COOR8，
R8and R9Each independently selected from:
1)-H，
2)-(C1-C6alkylene radical)0-3-phenyl, wherein the phenyl is optionally substituted by one or more groups selected from-C1-C4Alkyl and halogen, and the like,
3)-C1-C6alkyl, optionally substituted with one or more halogens,
4)-C3-C8cycloalkyl, optionally substituted with one or more halogens,
5)-C2-C6alkenyl, which is optionally substituted with one or more halogens, and
6)-C2-C6alkynyl, optionally substituted with one or more halo. A compound according to the first aspect of the invention is a compound of formula Ia:
and isomers, prodrugs, pharmaceutically acceptable salts, solvates or hydrates thereof, wherein X, R1、R2、R3、R4、R400、R5、R500And R6As defined for the compounds of formula I in the first aspect of the invention.
A compound according to the first aspect of the invention is a compound of formula Ib:
and isomers, prodrugs, pharmaceutically acceptable salts, solvates or hydrates thereof, wherein X, R1、R2、R3、R4、R400、R5、R500And R6As defined for the compounds of formula I in the first aspect of the invention.
A compound according to the first aspect of the invention is a compound of formula Ic:
and isomers, prodrugs, pharmaceutically acceptable salts, solvates or hydrates thereof, wherein R1、R2、R3、R8And R9As defined for the compounds of formula I in the first aspect of the invention.
A compound according to the first aspect of the invention is of formula Id:
and isomers, prodrugs, pharmaceutically acceptable salts, solvates or hydrates thereof, wherein R1、R2、R3、R8And R9As defined for the compounds of formula I in the first aspect of the invention.
A compound according to the first aspect of the invention which is a compound of formula Ic 1:
and isomers, prodrugs, pharmaceutically acceptable salts, solvates or hydrates thereof, wherein R1、R2、R3、R8And R9As defined for the compounds of formula I in the first aspect of the invention.
A compound according to the first aspect of the invention which is a compound of formula Id 1:
and isomers, prodrugs, pharmaceutically acceptable salts, solvates or hydrates thereof, wherein R1、R2、R3、R8And R9As defined for the compounds of formula I in the first aspect of the invention.
A compound according to the first aspect of the invention is a compound of formula Ie:
and isomers, prodrugs, pharmaceutically acceptable salts, solvates or hydrates thereof, wherein: r1、R2、R3And Ar1As defined for the compounds of the formula I in the first aspect of the invention, Ar2Selected from phenyl, arylheterocyclyl and heterobicyclic radicals, optionally substituted by one or more groups selected from
And (3) group substitution:
1) the halogen(s) are selected from the group consisting of,
2) the nitro group(s),
3) the cyano group(s),
4)-CF3，
5)-R8，
6)-OR8，
7)-NR8R9and are and
8)-COOR8，
wherein R is8And R9Each independently selected from:
1)-H，
2)-(C1-C6alkylene radical)0-3-phenyl, wherein the phenyl is optionally substituted by one or more groups selected from-C1-C4Alkyl and halogen, and the like,
3)-C1-C6alkyl, optionally substituted with one or more halogens,
4)-C3-C8cycloalkyl, optionally substituted with one or more halogens,
5)-C2-C6alkenyl, which is optionally substituted with one or more halogens, and
6)-C2-C6alkynyl, optionally substituted with one or more halo.
A compound according to the first aspect of the invention is a compound of formula If:
and isomers, prodrugs, pharmaceutically acceptable salts, solvates or hydrates thereof, wherein: r1、R2、R3And Ar1As defined for the compounds of the formula I in the first aspect of the invention, Ar2Selected from phenyl, arylheterocyclyl and heterobicyclyl, optionally substituted with one or more groups selected from:
1) the halogen(s) are selected from the group consisting of,
2) the nitro group(s),
3) the cyano group(s),
4)-CF3，
5)-R8，
6)-OR8，
7)-NR8R9and are and
8)-COOR8，
wherein R is8And R9Each independently selected from:
1)-H，
2)-(C1-C6alkylene radical)0-3-phenyl, wherein the phenyl is optionally substituted by one or more groups selected from-C1-C4Alkyl and halogen, and the like,
3)-C1-C6alkyl, optionally substituted with one or more halogens,
4)-C3-C8cycloalkyl, optionally substituted with one or more halogens,
5)-C2-C6alkenyl, which is optionally substituted with one or more halogens, and
6)-C2-C6alkynyl, optionally substituted with one or more halo.
A compound according to the first aspect of the invention which is a compound of formula Ie 1:
and isomers, prodrugs, pharmaceutically acceptable salts, solvates or hydrates thereof, wherein: r1、R2、R3And Ar1As defined for the compounds of the formula I in the first aspect of the invention, Ar2Selected from phenyl, arylheterocyclyl and heterobicyclyl, optionally substituted with one or more groups selected from:
1) the halogen(s) are selected from the group consisting of,
2) the nitro group(s),
3) the cyano group(s),
4)-CF3，
5)-R8，
6)-OR8，
7)-NR8R9and are and
8)-COOR8，
wherein R is8And R9Each independently selected from:
1)-H，
2)-(C1-C6alkylene radical)0-3-phenyl, wherein the phenyl is optionally substituted by one or more groups selected from-C1-C4Alkyl and halogen, and the like,
3)-C1-C6alkyl, optionally substituted with one or more halogens,
4)-C3-C8cycloalkyl, optionally substituted with one or more halogens,
5)-C2-C6alkenyl, which is optionally substituted with one or more halogens, and
6)-C2-C6alkynyl, optionally substituted with one or more halo.
A compound according to the first aspect of the invention which is a compound of formula If 1:
and isomers, prodrugs, pharmaceutically acceptable salts, solvates or hydrates thereof, wherein: r1、R2、R3And Ar1As defined for the compounds of the general formula I in the first aspect of the invention,Ar2selected from phenyl, arylheterocyclyl and heterobicyclic radicals, optionally substituted by one or more groups selected from
And (3) group substitution:
1) the halogen(s) are selected from the group consisting of,
2) the nitro group(s),
3) the cyano group(s),
4)-CF3，
5)-R8，
6)-OR8，
7)-NR8R9and are and
8)-COOR8，
wherein R is8And R9Each independently selected from:
1)-H，
2)-(C1-C6alkylene radical)0-3-phenyl, wherein the phenyl is optionally substituted by one or more groups selected from-C1-C4Alkyl and halogen, and the like,
3)-C1-C6alkyl, optionally substituted with one or more halogens,
4)-C3-C8cycloalkyl, optionally substituted with one or more halogens,
5)-C2-C6alkenyl, which is optionally substituted with one or more halogens, and
6)-C2-C6alkynyl, optionally substituted with one or more halo.
A compound according to the first aspect of the invention selected from:
and isomers, prodrugs, pharmaceutically acceptable salts, solvates or hydrates thereof.
In a second aspect, the present invention provides a process for the preparation of a compound according to any one of the first aspect of the invention, comprising the steps of:
a) reacting a compound of formula II
II (e.g. formula)Compounds of the formula) with a compound of the formula H-R6Reaction of the compound of formula (I) to give the compound of formula (II)The compound represented by formula (I), followed by removal of the group Z to give a compound of formula (II)A compound of (a);
b) make formulaA compound of the formulaReaction of the compound of formula (I) to give the compound of formula (II)The compound represented by the formula (I) is then hydrolyzed in the presence of a base to obtain the compound represented by the formula (II)To representA compound of (1);
c) in the presence of a suitable reagent (e.g., one or more of isobutyl chloroformate, triethylamine, and N-methylmorpholine)A compound of the formulaReaction of the compound of formula (I) to give the compound of formula (II)The compound represented, followed by removal of the group-Boc, to give the compound of formula I; and optionally (c) a second set of instructions,
d) forming the product of step c) into a pharmaceutically acceptable salt;
wherein, X, Y, R1、R2、R3、R4、R400、R5、R500And R6Z is selected from the group consisting of-H, -Boc, and-Cbz, as defined for the compound of formula I in any of the first aspects of the invention.
The method according to the second aspect of the invention, optionally having one or more of the following features:
in step a), the reaction conditions of the first step may adopt dried tetrahydrofuran, N-dimethylformamide or dichloromethane as solvent, preferably tetrahydrofuran, and may adopt a combination of DCC + HOBt or a combination of isobutyl chloroformate + tertiary amine as reaction auxiliary reagent, preferably a combination of DCC + HOBt, and the reaction temperature may be-15 ℃ to 25 ℃, preferably 0 ℃ to 10 ℃, and the reaction may be from 1 hour to 24 hours, preferably 12 hours; the deprotection in the second step can be carried out by using a dry organic solvent dissolved with 2-4N HCl, such as tetrahydrofuran, ethyl acetate, dioxane, 4N HCl/ethyl acetate, and the temperature can be-15-25 ℃, 0 ℃ and the reaction can be carried out for 1-8 hours, 2 hours;
in step b), the reaction conditions of the first step may adopt dried tetrahydrofuran, N-dimethylformamide or dichloromethane as solvent, preferably tetrahydrofuran, DCC + HOBt combination or isobutyl chloroformate + tertiary amine combination as reaction auxiliary reagent, preferably DCC + HOBt combination, the reaction temperature may be-15 ℃ to 25 ℃, preferably 0 ℃ to 10 ℃, and the reaction may be 1 hour to 24 hours, preferably 12 hours; the second step of deprotection can adopt a mixed methanol/water solution of 1-4N NaOH or LiOH, preferably a 50% methanol solution of 1N NaOH, the reaction temperature can be-15-25 ℃, preferably 0-10 ℃, and the reaction time can be 1-24 hours, preferably 3 hours; and
in step c), the reaction conditions in the first step may adopt dried tetrahydrofuran, N-dimethylformamide or dichloromethane as solvent, preferably tetrahydrofuran, preferably isobutyl chloroformate + N-methylmorpholine as reaction auxiliary reagent, the reaction temperature may be-15 ℃ to 25 ℃, preferably 0 ℃ to 10 ℃, and the reaction may be for 1 hour to 24 hours, preferably 12 hours; the deprotection in the second step can be carried out using a dry organic solvent in which 2-4N HCl is dissolved, such as tetrahydrofuran, ethyl acetate, dioxane, preferably 4N HCl/ethyl acetate, at a temperature of-15 ℃ to 25 ℃, preferably 0 ℃, for 1 hour to 8 hours, preferably 2 hours.
The method according to the second aspect of the present invention, whereinThe compound represented by the formulaThe compound represented is substituted to obtain an isomer of the compound of formula I.
In a third aspect, the present invention provides a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a compound according to any one of the first aspect of the present invention, and optionally a pharmaceutically acceptable carrier or excipient.
In a fourth aspect, the invention provides the use of a compound according to any one of the first aspect of the invention in the manufacture of a medicament for the treatment and/or prophylaxis of a disease associated with the overexpression of IAPs.
The use according to the fourth aspect of the invention, wherein the disease is selected from the group consisting of bladder cancer, breast cancer, pancreatic cancer, colon cancer, leukemia, lung cancer, lymphoma, multiple myeloma, ovarian cancer and cervical cancer, such as ovarian cancer and cervical cancer in particular.
In a fifth aspect, the present invention provides a method for the treatment and/or prophylaxis of a disease associated with the overexpression of IAPs in a mammal (e.g. a human) in need thereof, which method comprises administering to said mammal (e.g. a human) a therapeutically and/or prophylactically effective amount of a compound according to any one of the first aspect of the present invention.
The use according to the fifth aspect of the invention, wherein said disease is selected from the group consisting of bladder cancer, breast cancer, pancreatic cancer, colon cancer, leukemia, lung cancer, lymphoma, multiple myeloma, ovarian cancer and cervical cancer, such as ovarian cancer and cervical cancer in particular.
Detailed description of the invention:
in one embodiment of the compounds of the present invention, wherein said X is-O-.
In one embodiment of the compounds of the invention, wherein said X is-S-.
In one embodiment of the compounds of the invention, wherein Y is-CH2-。
In one embodiment of the compounds of the invention, wherein said Y is-CO-.
In one embodiment of the compounds of the present invention, wherein R is1Selected from: -H, -C optionally substituted by one or more halogens1-C6An alkyl group.
In one embodiment of the compounds of the present invention, wherein R is1Selected from: -H, and-C1-C6An alkyl group.
In one embodiment of the compounds of the present invention, wherein R is1Selected from: -H, and-C1-C4An alkyl group.
In one embodiment of the compounds of the present invention, wherein R is1Selected from: -H, methyl, ethyl, propyl, isopropyl.
In one embodiment of the compounds of the present invention, wherein R is1Selected from: -H, methyl.
In one embodiment of the compounds of the present invention, wherein R is2Selected from: -H, -C1-C6An alkyl group.
In one embodiment of the compounds of the present invention, wherein R is2Selected from: -H, -C1-C4An alkyl group.
In one embodiment of the compounds of the present invention, wherein R is2Selected from: -H, methyl, ethyl, propyl, isopropyl.
In one embodiment of the compounds of the present invention, wherein R is2Selected from: -H, methyl.
In one embodiment of the compounds of the present invention, wherein R is3Selected from: -H, -C1-C6Alkyl, -C3-C8Cycloalkyl, - (C)1-C6Alkyl) -R10Wherein R is10Selected from: -OR8、-SR8、-NR8R9、-NCONR8R9、-NCNNR8R9、-COOR8、-CONR8R9，R8And R9Each independently selected from: -H, - (C)1-C6Alkylene radical)0-3-phenyl, wherein the phenyl is optionally substituted by one or more groups selected from-C1-C4Alkyl and halogen radicals, optionally substituted by one or moreHalogen substituted-C1-C6Alkyl, -C optionally substituted by one or more halogens3-C8Cycloalkyl, -C optionally substituted by one or more halogens2-C6Alkenyl, and-C optionally substituted with one or more halogens2-C6Alkynyl.
In one embodiment of the compounds of the present invention, wherein R is3Selected from: -H, -C1-C6Alkyl, -C3-C8Cycloalkyl, - (C)1-C6Alkyl) -OR8Wherein R is8Selected from: -H, -C1-C6Alkyl, -C2-C6Alkenyl, and-C2-C6Alkynyl.
In one embodiment of the compounds of the present invention, wherein R is3Selected from: -H, -C1-C4Alkyl, -C4-C6Cycloalkyl, - (C)1-C4Alkyl) -OR8Wherein R is8Selected from: -C2-C6Alkynyl.
In one embodiment of the compounds of the present invention, wherein R is3Selected from: -H, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, 2-propynyloxy-ethyl.
In one embodiment of the compounds of the present invention, wherein R is4And R400Each independently selected from: -H, -C1-C4An alkyl group.
In one embodiment of the compounds of the present invention, wherein R is4And R400Each independently selected from: -H, methyl, ethyl, propyl, isopropyl.
In one embodiment of the compounds of the present invention, wherein R is4And R400Each independently selected from: -H, methyl.
In one embodiment of the compounds of the present inventionWherein R is5And R500Each independently selected from: -H, -C1-C4An alkyl group.
In one embodiment of the compounds of the present invention, wherein R is5And R500Each independently selected from: -H, methyl, ethyl, propyl, isopropyl.
In one embodiment of the compounds of the present invention, wherein R is5And R500Each independently selected from: -H, methyl.
In one embodiment of the compounds of the present invention, wherein R is6is-NR11R12。
In one embodiment of the compounds of the present invention, wherein R is6is-NR11R12Wherein R is11And R12Each independently selected from: -H, -C1-C4alkyl-C4-C6Cycloalkyl, -COR8、-Ar1、-(C1-C4Alkyl) -Ar1、-CO-Ar1and-CO- (C)1-C4Alkyl) -Ar1。
In one embodiment of the compounds of the present invention, wherein R is6is-NR11R12Wherein R is11And R12Each independently selected from: -H, -C1-C4alkyl-C4-C6Cycloalkyl, -COR8、-Ar1、-(C1-C4Alkyl) -Ar1、-CO-Ar1and-CO- (C)1-C4Alkyl) -Ar1Wherein Ar is1Is phenyl optionally substituted with one or more groups selected from: halogen, nitro, cyano, -CF3、-R8、-OR8、-NR8R9and-COOR8。
In one embodiment of the compounds of the present invention, wherein R is6is-NR11R12Which isIn R11And R12Each independently selected from: -H, -C1-C4alkyl-C4-C6Cycloalkyl, -COR8、-Ar1、-(C1-C4Alkyl) -Ar1、-CO-Ar1and-CO- (C)1-C4Alkyl) -Ar1Wherein Ar is1Is phenyl optionally substituted with one or more groups selected from: halogen, nitro, cyano, -CF3、-R8、-OR8、-NR8R9and-COOR8Wherein R is8And R9Each independently selected from: -H, - (C)1-C4Alkylene radical)0-3-phenyl, wherein the phenyl is optionally substituted by one or more groups selected from-C1-C4Alkyl and halogen, optionally substituted by one or more halogens, -C1-C4Alkyl, -C optionally substituted by one or more halogens4-C6Cycloalkyl, -C optionally substituted by one or more halogens2-C4Alkenyl, and-C optionally substituted with one or more halogens2-C4Alkynyl.
In one embodiment of the compounds of the invention, wherein
X is-O-or-S-;
y is-CH2-or-CO-;
R1selected from: -H, -C1-C4An alkyl group;
R2selected from: -H, -C1-C4An alkyl group;
R3-H、-C1-C6alkyl, -C3-C8Cycloalkyl, - (C)1-C6Alkyl) -OR8Wherein R is8Selected from: -H, -C1-C6Alkyl, -C2-C6Alkenyl, and-C2-C6An alkynyl group;
R4and R400Each independently selected from:-H、-C1-C4an alkyl group;
R5and R500Each independently selected from: -H, -C1-C4An alkyl group;
R6is-NR11R12Wherein R is11And R12Each independently selected from: -H, -C1-C4alkyl-C4-C6Cycloalkyl, -COR8、-Ar1、-(C1-C4Alkyl) -Ar1、-CO-Ar1and-CO- (C)1-C4Alkyl) -Ar1Wherein Ar is1Is phenyl optionally substituted with one or more groups selected from: halogen, nitro, cyano, -CF3、-R8、-OR8、-NR8R9and-COOR8Wherein R is8And R9Each independently selected from: -H, - (C)1-C4Alkylene radical)0-3-phenyl, wherein the phenyl is optionally substituted by one or more groups selected from-C1-C4Alkyl and halogen, optionally substituted by one or more halogens, -C1-C4Alkyl, -C optionally substituted by one or more halogens4-C6Cycloalkyl, -C optionally substituted by one or more halogens2-C4Alkenyl, and-C optionally substituted with one or more halogens2-C4Alkynyl.
All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.
The term "halogen" or "halo" as used herein refers to fluorine, chlorine, bromine, and iodine.
The term "hydrocarbyl" as used herein includes alkyl, alkenyl and alkynyl groups. These alkyl, alkenyl and alkynyl groups may be linear or may be branched.
The term "alkyl" as used herein is meant to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, e.g., C1-C6C in alkyl1-C6Are defined to include groups having 1, 2, 3, 4, 5, or 6 carbons arranged in a linear or branched arrangement. C as defined above1-C6Examples of alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl and hexyl.
The term "alkenyl" as used herein refers to an unsaturated, straight or branched chain hydrocarbon radical containing the specified number of carbon atoms, wherein at least two carbon atoms are connected to each other by a double bond, and having either the E or Z configuration, and combinations thereof. E.g. C2-C6C in alkenyl2-C6Are defined to include groups having 2, 3, 4, 5 or 6 carbons arranged in a linear or branched arrangement with at least two carbon atoms connected by a double bond. C2-C6Examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, and the like.
The term "alkynyl" as used herein refers to an unsaturated, straight or branched chain hydrocarbon radical containing the specified number of carbon atoms, and wherein at least two carbon atoms are joined together by a triple bond. E.g. C2-C6C in alkynyl2-C6Are defined to include groups having 2, 3, 4, 5, or 6 carbon atoms in the chain, at least two of which are linked together by a triple bond. Examples of such alkynyl groups include, but are not limited to: ethynyl, 1-propynyl, 2-propynyl and the like.
The term "cycloalkyl" as used herein refers to a monocyclic saturated aliphatic hydrocarbon group containing the specified number of carbon atoms therein, e.g. C3-C8C in cycloalkyl3-C8Are defined to include groups having 3, 4, 5, 6, 7, or 8 carbons in a single ring arrangement. C as defined above3-C8Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
The term "cycloalkenyl" as used herein refers to a monocyclic unsaturated aliphatic hydrocarbon group having the specified number of carbon atoms therein, e.g., C3-C8C in cycloalkenyl3-C8Are defined to include groups having 3, 4, 5, 6, 7, or 8 carbons in a single ring arrangement. C as defined above3-C8Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl and cyclohexenyl.
The term "halo" or "halogen" as used herein refers to fluoro, chloro, bromo and iodo.
The term "haloalkyl" as used herein means an alkyl group as defined above wherein each hydrogen atom may be replaced successively by a halogen atom. Examples of haloalkyl groups include, but are not limited to: -CH2F、-CHF2and-CF3。
The term "aryl", as used herein, whether alone or in combination with another group, refers to a carbocyclic aromatic monocyclic group containing 6 carbon atoms that may be further fused to a second 5-or 6-membered carbocyclic group that may be aromatic, saturated or unsaturated. Aryl groups include, but are not limited to, phenyl, 2, 3-indanyl, 1-naphthyl, 2-naphthyl, and tetrahydronaphthyl. The fused aryl group may be attached to a cycloalkyl ring or another group at an appropriate position on the aromatic ring.
The term "biphenyl" as used herein refers to two phenyl groups bonded together through any one of the available sites on the phenyl ring. The biphenyl group can be covalently linked to other groups from any available position on the phenyl ring.
The term "heteroaryl" as used herein refers to a monocyclic or bicyclic ring system having up to ten atoms, wherein at least one ring is aromatic and contains 1 to 4 heteroatoms selected from O, N and S. Heteroaryl substituents may be attached through one of the ring carbon atoms or through one of the heteroatoms. Examples of heteroaryl groups include, but are not limited to, thienyl, benzimidazolyl, benzo [ b ] thienyl, furyl, benzofuryl, pyranyl, isobenzofuryl, benzopyranyl, 2H-pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, 2, 3-naphthyridinyl, 1, 5-naphthyridinyl, quinoxalyl, quinazolinyl, cinnolinyl, pteridinyl, isothiazolyl, isobenzodihydropyranyl, chromanyl, isoxazolyl, furoryl, indolinyl, isoindolinyl, thiazolo [4, 5-b ] pyridine, and fluorescent derivatives.
The term "heterocycle", "heterocyclic" or "heterocyclyl" as used herein means a 5, 6 or 7 membered non-aromatic ring system containing 1 to 4 heteroatoms selected from O, N and S. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, pyrrolinyl, piperazinyl, imidazolidinyl, morpholinyl, imidazolinyl, pyrazolidinone, pyrazolinyl.
The term "heterobicyclic group" as used herein, refers to a heterocyclic ring as defined above fused to another ring, which may be a heterocyclic ring, an aryl group or any other ring defined herein. Examples of such heterobicyclics include, but are not limited to, coumarin, benzo [ d ] [1, 3] dioxetane, 2, 3-dihydrobenzo [ b ] [1, 4] dioxole, and 3, 4-dihydro-2H-benzo [ b ] [1, 4] dioxole (dioepine).
The present invention encompasses the compounds of the general formula I of the first aspect as well as the compounds of its various preferred or specific embodiments, and also encompasses the various isomers of these compounds. Some of the compounds of the invention may exist in the form of optical isomers or tautomers and the invention includes all the forms in which they exist, in particular the pure isomers. The different isomeric forms may be separated or resolved from the other isomeric forms by conventional means, or an isomer may be obtained by conventional synthetic methods or stereospecific or asymmetric syntheses. Since the compounds of formula I of the present invention are intended for pharmaceutical use, it will be appreciated that they are preferably provided in pure form, for example, at least 60% pure, more suitably at least 75% pure, even more suitably at least 85% pure, and most preferably at least 98% pure (% means weight percent).
The invention also relates to suitable pharmaceutically acceptable salts, solvates or hydrates of the compounds of the invention.
The compounds of the present invention may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The phrase "pharmaceutically acceptable salt" refers to salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, s.m.berge, et al.j.pharmaceutical Sciences, 1977, 66: pharmaceutically acceptable salts are described in detail in 1. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the free base functionality of the compounds of the invention with a suitable organic acid. Pharmaceutically acceptable salts of the compounds of the present invention include, but are not limited to, salts of the compounds of formula I with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, phosphorous acid, hydrobromic acid, and nitric acid; and salts of the compounds of formula I with various organic acids such as maleic acid, fumaric acid, malic acid, fumaric acid, succinic acid, tartaric acid, citric acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, lactic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, cinnamic acid, mandelic acid, palmitic acid, salicylic acid, and the like. In addition, pharmaceutically acceptable salts of the compounds of the present invention include, but are not limited to, salts prepared from the compounds of formula I and inorganic bases, such as sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like; salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, where substituted amines include naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. The free base forms of the compounds of the invention differ slightly from their respective salt forms in certain physical properties (such as solubility in polar solvents), but for the purposes of the present invention, each acid salt is equivalent to their respective free base form (see, e.g., s.m. berge, et al., "Pharmaceutical Salts," j.pharm.sci., 66: 1-19(1977), which is incorporated herein by reference).
Some of the compounds of the present invention may be crystallized or recrystallized using water or various organic solvents, in which case various solvates may be formed. The present invention includes those solvates, including hydrates, in stoichiometric amounts, as well as compounds containing variable amounts of water formed when prepared by the low pressure sublimation drying method. In general, for the purposes of the present invention, the solvate forms with pharmaceutically acceptable solvents such as water, ethanol, etc. are equivalent to the non-solvate forms.
The compounds of the invention and their pharmaceutically acceptable salts may also be prodrugs or forms which release the active ingredient after metabolic changes in the body. The selection and preparation of suitable prodrug derivatives is well known to those skilled in the art.
The term "pharmaceutically acceptable carrier" or "excipient" as used herein refers to any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, emulsifier or encapsulating agent, such as a liposome, cyclodextrin, encapsulated polymeric delivery system, or polyethylene glycol matrix, which is acceptable for use in a subject, preferably a human.
The present invention relates to the use of compounds of general formula I, all possible isomers, prodrugs, pharmaceutically acceptable salts, solvates or hydrates thereof for the manufacture of a medicament which can be used for the treatment and/or prevention of associated diseases caused by the overexpression of IAPs. Such diseases include, but are not limited to, the following: bladder cancer, breast cancer, pancreatic cancer, colon cancer, leukemia, lung cancer, lymphoma, multiple myeloma, ovarian cancer and cervical cancer, such as ovarian cancer and cervical cancer, among others.
In another aspect, the compound of formula I of the present invention or a pharmaceutically acceptable salt thereof can be used alone or in combination with a pharmaceutically acceptable carrier or excipient in the form of a pharmaceutical composition, and when used in the form of a pharmaceutical composition, an effective dose of the compound of formula I of the present invention or a pharmaceutically acceptable salt or hydrate thereof and one or more pharmaceutically acceptable carriers or diluents are usually combined to prepare a suitable administration form or dosage form, and such procedure includes mixing, granulating, compressing or dissolving the components by a suitable manner. Accordingly, the present invention provides a pharmaceutical composition comprising a compound of formula I, all possible isomers, prodrugs, pharmaceutically acceptable salts, solvates or hydrates thereof, and at least one pharmaceutically acceptable carrier.
Pharmaceutical compositions of the compounds of the invention may be administered in any of the following ways: oral, aerosol inhalation, rectal, nasal, vaginal, topical, parenteral such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal or intracranial injection or infusion, or by means of an explanted reservoir, with oral, intramuscular, intraperitoneal or intravenous administration being preferred.
The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form. The administration dosage form can be liquid dosage form or solid dosage form. The liquid dosage forms can be true solutions, colloids, microparticles, emulsions, and suspensions. Other dosage forms such as tablet, capsule, dripping pill, aerosol, pill, powder, solution, suspension, emulsion, granule, suppository, lyophilized powder for injection, clathrate, implant, patch, liniment, etc.
The pharmaceutical composition of the present invention may further comprise conventional carriers, wherein the pharmaceutically acceptable carriers include, but are not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, beeswax, lanolin and the like. The carrier may be present in the pharmaceutical composition in an amount of 1% to 98% by weight, typically about 80% by weight. For convenience, the local anesthetic, preservative, buffer, etc. may be dissolved directly in the vehicle.
Oral tablets and capsules may contain excipients such as binding agents, for example syrup, acacia, sorbitol, tragacanth, or polyvinylpyrrolidone, fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, glycine, lubricants such as magnesium stearate, talc, polyethylene glycol, silica, disintegrants such as potato starch, or acceptable wetting agents such as sodium lauryl sulfate. The tablets may be coated by methods known in the art of pharmacy.
Oral liquids may be prepared as suspensions, solutions, emulsions, syrups or elixirs in water and oil, or as dry products, supplemented with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, sorbitol, cellulose methyl ether, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gelatin, hydrogenated edible fats and oils, emulsifying agents such as lecithin, sorbitan monooleate, gum arabic; or a non-aqueous carrier (which may comprise an edible oil), such as almond oil, an oil such as glycerol, ethylene glycol, or ethanol; preservatives, e.g. methyl or propyl p-hydroxybenzoates, sorbic acid. Flavoring or coloring agents may be added if desired.
Suppositories may contain conventional suppository bases which are solid at room temperature and melt at body temperature to release the drug, such as cocoa butter, other glycerides or beeswax.
For parenteral administration, the liquid dosage forms are generally prepared from the compound and a sterile vehicle. The carrier is preferably water. The compound can be dissolved in the carrier or made into suspension solution according to the concentration of the carrier and the drug, and the compound is firstly dissolved in water when made into the solution for injection, filtered and sterilized and then filled into a sealed bottle or ampoule.
When applied topically to the skin, the compounds of the present invention may be formulated in the form of a suitable ointment, lotion, or cream in which the active ingredient is suspended or dissolved in one or more carriers. Among the vehicles that may be used in the ointment formulation include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; lotions and creams may employ carriers including, but not limited to: mineral oil, sorbitan monostearate, tween 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The term "therapeutically effective amount" as used herein refers to a dose which, upon administration to the subject, e.g., a mammal, e.g., a human, produces a desired physiological response, particularly a physiological response associated with the diseases described herein. The term "therapeutically effective amount" is also used in a similar sense.
Depending on the mode of administration, the composition may contain 0.1% by weight, or more suitably 10-60% by weight of the active ingredient. However, where the components comprise unit doses, each unit preferably contains from 1 to 500 mg of active ingredient.
It is further noted that the specific dosage and method of administration of the compounds of the present invention for each individual patient will depend upon a variety of factors including the age, body weight, sex, physical condition, nutritional status, the activity level of the compounds, the time of administration, the metabolic rate, the severity of the condition, and the judgment of the attending physician. The dosage is preferably between 0.01 and 100mg/Kg body weight/day.
It will be appreciated that the optimum dosage and interval for administration of a compound of formula I will be determined by the nature of the compound and the external conditions, such as form, route and site of administration, and that such optimum dosage may be determined by conventional techniques. It will also be appreciated that the optimal course of treatment, i.e. the daily dosage of a compound of formula I over a nominal period of time, may be determined by methods well known in the art.
The present invention relates to a process for the preparation of a compound of formula I or a pharmaceutically acceptable salt, solvate or hydrate thereof. In the following general description of the process, the specific definitions of the variables or substituents are as defined for the compounds of the first aspect of the invention.
The compounds of the invention may be formed by coupling a compound represented by formula II:
wherein Z is selected from the group including, but not limited to: -H, -Boc, -Cbz, preferably Z is-Boc.
Preferred but not limiting structures for the compounds of formula II are as follows:
the IIa and IIb structures can be synthesized by directly using commercially available L-proline, 4-S-hydroxy-L-proline and Boc anhydride. The synthesis of IIc, IId, IIe, IIf is via the following scheme 1:
scheme 1
The general procedure for scheme 1 above is: selecting unsubstituted native cysteine, serine, or by R5、R500Substituted native cysteine, serine, by analogous routes as described above, with formaldehyde, acetaldehyde, acetone or with R4、R400And reacting the substituted aldehyde and ketone compounds to obtain the substituted/unsubstituted five-membered heterocyclic alkane with S, O atoms.
Using the Ie compound as an example, scheme 2 below illustrates how the invention proceeds from compounds of formula II to compounds of formula I.
Scheme 2
The general procedure for scheme 2 above is: after the amine fragment 2ii and the acid fragment 2iv are synthesized respectively, the condensation is carried out with IIc in sequence to obtain 2vii, and then the deprotection is carried out to obtain the final product Ie.
Scheme 3 below illustrates how the invention proceeds from compounds of formula II to compounds of formula I, using If compounds as an example.
Scheme 3
The general procedure of scheme 3 above differs from scheme 2 only in that after intermediate 2v is obtained, intermediate 3i is obtained by a suitable reduction method, followed by sequential condensation to give 3iii and deprotection to give If.
The compounds of formula I can be synthesized individually by conventional methods, or in pools (at least two, or 5-1000, preferably 10-100 compounds per pool) by combinatorial chemistry, mixed-split methods or parallel synthesis, either in liquid phase or solid phase. The various starting materials for the reaction are either prepared by the skilled worker on the basis of their knowledge, or can be prepared by methods known from the literature, or are commercially available. The intermediates, starting materials, reagents, reaction conditions, etc. used in the above reaction schemes may be appropriately modified according to the knowledge of those skilled in the art. For more detailed information on the preparation of the compounds of the formula I, reference is made to the detailed description below.