CN107556312B - Novel fused ring compound with PARP inhibitory activity, preparation method and use thereof - Google Patents
Novel fused ring compound with PARP inhibitory activity, preparation method and use thereof Download PDFInfo
- Publication number
- CN107556312B CN107556312B CN201611245741.1A CN201611245741A CN107556312B CN 107556312 B CN107556312 B CN 107556312B CN 201611245741 A CN201611245741 A CN 201611245741A CN 107556312 B CN107556312 B CN 107556312B
- Authority
- CN
- China
- Prior art keywords
- substituted
- group
- fused ring
- pharmaceutically acceptable
- ring compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Abstract
The invention discloses a novel fused ring compound with PARP inhibitory activity, a preparation method and application thereof. The fused ring compound is shown as a formula I. The fused ring compound has PARP inhibitory activity, provides a new commercial choice for PARP inhibitors, and can be used for treating and/or preventing tumors, stroke, myocardial ischemia, inflammation, or diabetes.
Description
Technical Field
The invention belongs to the field of biomedicine, and relates to a series of novel fused ring compounds with PARP (para-amyloid peptide) inhibitory activity, in particular to a fused ring compound shown in a formula I with PARP inhibitory activity or pharmaceutically acceptable salt thereof.
Background
As targets for antitumor drugs, poly (ADP-ribose) polymerase (PARP) inhibitors have been actively explored for many years. The first PARP inhibitor Olaparib currently marketed globally by astrazen has been shown to be able to take advantage of defects in the DNA repair pathway to preferentially kill cancer cells. This mode of action, confers the potential of olaparib to treat a wide range of tumor types that are deficient in DNA repair. Olaparib has been used clinically to treat BRCA-mutated tumors, such as ovarian cancer and ovarian cancer. Clovis Oncology also announces the accelerated approval by the FDA of the U.S. New drug Rubraca (rucaparib) tablets as monotherapy for the treatment of advanced ovarian cancer carrying deleterious BRCA mutations (germline and/or somatic cells), these female patients having received two or more chemotherapeutic treatments. Another series of compounds, whether used as monotherapy or as combination therapy, is currently under clinical investigation, such as veliparib from Abbvie, niraparib from Tesaro, talazoparib from BioMarin (BMN-673), and others.
Therefore, the development of a novel PARP inhibitor drug for treating cancer with higher safety and efficiency has great social value and economic benefit, and is also a research hotspot of various medical enterprises at present. The novel compound with PARP inhibitory activity is searched, the drug resistance and the patent drug property of the antitumor drug are improved, the biological activity and the bioavailability are improved, and the compound has important significance for treating clinically relevant diseases. There is therefore a continuing need to develop new compounds having PARP inhibitory activity.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a fused ring compound with a novel structure, a pharmaceutical composition, a preparation method and application thereof. The fused ring compound has PARP inhibitory activity, provides a new commercial choice for PARP inhibitors, and can be used for treating and/or preventing tumors, stroke, myocardial ischemia, inflammation or diabetes.
The invention provides a fused ring compound shown in formula I, and pharmaceutically acceptable salt, solvate, metabolite, stereoisomer or prodrug thereof,
wherein the A ring is selected from C4-C8Cycloalkyl or 5-10 membered heterocyclyl; the 5-10 membered heterocyclic group contains 1-4 heteroatoms independently selected from O, S and N, and does not contain two adjacent O or S atoms; when ring a is a 5-membered heterocyclyl, the 5-membered heterocyclyl contains less than 4 heteroatoms;
the R is1Each independently selected from H, F, Cl, Br, I, CN, OH, SH, ═ O, C1-C6Alkyl radical, C1-C6Alkoxy radical, C2-C8Alkenyl, (C)1-C6) Alkoxy (C)1-C6) Alkyl radical, C1-C6Alkoxycarbonyl group, C1-C6Alkylcarbonyl group, C1-C6Alkyl carbonyl oxy, C1-C6Alkylthio radical, C1-C6Alkylthio group C1-C6Alkyl radical, C2-C8Alkynyl, carboxyl, AAcyl, halo (C)1-C6) Alkoxy, halo (C)1-C6) Alkyl and-NR8R9；
The R is3Selected from hydrogen, Br, Cl, F, I, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C1-C6Alkoxy, substituted or unsubstituted C1-C6Alkoxy (C)1-C6) Alkyl, or substituted or unsubstituted hydroxy (C)1-C6) An alkylene group; said "substituted C1-C6Alkyl group "," substituted C3-C8Cycloalkyl "," substituted C1-C6Alkoxy "," substituted C1-C6Alkoxy (C)1-C6) Alkyl group "," substituted hydroxy group (C)1-C6) Substituents on the "alkylene" are selected from one or more of the following groups: OH, NO2、CN、Br、Cl、F、I、C1-C6Alkyl and C3-C8A cycloalkyl group;
the R is4Is unsubstituted or substituted by R7Substituted 5-to 10-membered aryl, R7The number of (a) is from 1 to the total number of open valences on the aryl group;
the R is5Is unsubstituted or substituted by R7Substituted 5-10 membered aryl, or unsubstituted or substituted by R7Substituted 5-10 membered heteroaryl, R7From 1 to the total number of open valences on the aryl or heteroaryl group, wherein the heteroatoms in the heteroaryl group are from 1 to 4 and are independently selected from O, S and N;
the R is6Selected from hydrogen, Br, Cl, F, I, OH, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C1-C6Alkoxy, substituted or unsubstituted C1-C6Alkoxy radical C1-C6Alkyl, or substituted or unsubstituted hydroxy C1-C6An alkylene group; said "substituted C1-C6Alkyl group "," substituted C3-C8Cycloalkyl "," substituted C1-C6Alkoxy "," substituted C1-C6Alkoxy (C)1-C6) Alkyl group "," substituted hydroxy group (C)1-C6) Substituents on the "alkylene" are selected from one or more of the following groups: OH, NO2、CN、Br、Cl、F、I、C1-C6Alkyl and C3-C8A cycloalkyl group;
the R is7Selected from OH and NO2、CN、Br、Cl、F、I、C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C2-C8Heterocycloalkyl radical, C2-C6Alkenyl radical, C1-C6Alkoxy radical, C1-C6Alkoxy radical C1-C6Alkyl radical, C1-C6Alkylcarbonyl group, C1-C6Alkyl carbonyl oxy, C1-C6Alkylthio radical, C1-C6Alkylthio group C1-C6Alkyl radical, C1-C6Alkoxycarbonyl group, C1-C6Alkoxycarbonyl (C)1-C6) Alkyl radical, C2-C6Alkynyl, carbonyl, formyl, mercapto, 5-10 membered aryl (C)1-C6) Alkyl radical, C3-C8Cycloalkyl (C)1-C6) Alkyl, halo (C)1-C6) Alkoxy, halo (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkylene, ═ O, 5-10 membered heteroaryl (C)1-C6) Alkoxy, 5-to 10-membered heteroaryloxy, 5-to 10-membered heteroarylthio, 5-to 10-membered heteroaryl (C)1-C6) Alkylthio, 6-10 membered heterocycle (C)1-C6) Alkoxy radical, C2-C8Heterocyclylalkylthio, 6-10 membered heterocyclyloxy, 6-10 membered heterocyclylthio, NR8R9、N(R8)(R9)(C1-C6) Alkylene and N (R)8)(R9) A sulfonyl group;
the R is8And R9Independently selected from hydrogen, C1-C6Alkyl radical、C3-C8Cycloalkyl and C1-C6An alkylcarbonyl group; or R8And R9Together with the atoms to which they are attached form a substituted or unsubstituted 3-10 membered heterocyclyl group, said "3-10 membered heterocyclyl group" optionally having 1-3 heteroatoms or heterofunctional groups selected from: -O-, -NH-, -N (C)1-C6Alkyl) -, -NCO (C)1-C6Alkyl) -, -NCO (C)3-C8Cycloalkyl) -, -N (aryl-C)1-C6Alkyl) -, -N (substituted aryl-C)1-C6Alkyl) -, -N (heteroaryl-C)1-C6Alkyl) -, -N (substituted heteroaryl-C1-C6Alkyl) -, -S-or-S (O)q-, wherein q is 1 or 2;
the R is8And R9In (1), the substituent on the "substituted 3-to 10-membered heterocyclic group" is preferably one or more of the following groups: OH, NO2、CN、Br、Cl、F、I、C1-C6Alkyl radical, C3-C8Cycloalkyl radical, C2-C8Heterocycloalkyl radical, C2-C6Alkenyl radical, C1-C6Alkoxy radical, C1-C6Alkoxy radical C1-C6Alkyl radical, C1-C6Alkylcarbonyl group, C1-C6Alkyl carbonyl oxy, C1-C6Alkylthio radical, C1-C6Alkylthio group C1-C6Alkyl radical, C1-C6Alkoxycarbonyl group, C1-C6Alkoxycarbonyl (C)1-C6) Alkyl radical, C2-C6Alkynyl, carbonyl, formyl, mercapto, 5-10 membered aryl (C)1-C6) Alkyl radical, C3-C8Cycloalkyl (C)1-C6) Alkyl, halo (C)1-C6) Alkoxy, halo (C)1-C6) Alkyl, hydroxy (C)1-C6) Alkylene, ═ O, 5-10 membered heteroaryl (C)1-C6) Alkoxy, 5-to 10-membered heteroaryloxy, 5-to 10-membered heteroarylthio, 5-to 10-membered heteroaryl (C)1-C6) Alkylthio group, 6-10 membered heterocycle (C)1-C6) Alkoxy radical, C2-C8Heterocyclylalkylthio, 6-10 membered heterocyclyloxy, 6-10 membered heterocyclylthio, NR8R9、N(R8)(R9)(C1-C6) Alkylene and N (R)8)(R9) A sulfonyl group;
n is the total number of open valences on ring 0 to A.
In the present invention, in the above-mentioned A, the above-mentioned "C" is mentioned4-C8Cycloalkyl radicals "preferably" C5-C7Cycloalkyl ", more preferably cyclohexyl.
In the present invention, in the above-mentioned a, the "heterocyclic group" is preferably a piperazinyl group, a furyl group, a pyrrolyl group, an imidazolyl group, a thiazolyl group, a pyrazolyl group, an isothiazolyl group, an isoxazolyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a 4, 5-dihydro-3-pyridazinonyl group, a pyrazinyl group or a thiadiazolyl group.
In the present invention, when n is not 0, R is1May be substituted at any open valency position on the a ring, as long as the resulting compound of formula I is stable.
In the present invention, when n is not 0, R is1Preferably ortho to the atoms common to the fusion of the a ring. Wherein said common atoms for fusion are the two carbon atoms shared by ring A and the benzene ring in the parent nucleus.
In the present invention, R is1Independently preferably selected from H, F, Cl, Br, I, C1-C6Alkyl or ═ O.
In the present invention, R is4Preferably unsubstituted or substituted by R7Substituted 6-10 membered aryl, more preferably unsubstituted or substituted by R7Substituted phenyl, or unsubstituted or substituted by R7Substituted naphthyl.
In the present invention, if R is4In presence of R7Substituted, then R7Preferably not substituted in the 2-position of the aryl group, i.e. not substituted by R in the position ortho to the atom to which the aryl group is attached to the rest of the molecule7And (4) substitution.
In the present invention, R is5The heteroaryl group is preferably furan, pyridine, pyrimidine, pyrazine, imidazole, thiazole, isothiazole, pyrazole, or the like,Triazole, pyrrole, thiophene, oxazole, isoxazole, 1,2, 4-oxadiazole, 1,3, 4-oxadiazole, 1,2, 4-triazine, indole, benzothiophene, benzimidazole, benzofuran, pyridazine, 1,3, 5-triazine, thienothiophene, quinoxaline, quinoline or isoquinoline.
In the present invention, R is5Preferably unsubstituted or substituted by R7Substituted 5-6 membered aryl, or unsubstituted or substituted by R7Substituted 5-6 membered heteroaryl containing 2-4 carbons.
In the present invention, R is5Preferably unsubstituted or substituted by R7Substituted phenyl, unsubstituted or substituted by R7Substituted naphthyl, unsubstituted or substituted by R7Substituted triazolyl, unsubstituted or substituted by R7Substituted tetrazolyl, unsubstituted or substituted by R7Substituted pyrazolyl, unsubstituted or substituted by R7Substituted imidazolyl or unsubstituted or substituted by R7A substituted pyrrolyl group; more preferably
In the context of the present invention, the "heteroaryl" group may be attached to the rest of the molecule via a heteroatom or a carbon atom, preferably via a carbon atom.
In the present invention, R7Wherein said "C" is1-C6Alkyl "is preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
In one embodiment, R4Is phenyl substituted by one or more selected from Br, Cl, F and I. In another embodiment, R4Is phenyl substituted by a single F. In one embodiment, R4Is p-fluorophenyl.
In one embodiment, the phenyl group is selected from N (R)8)(R9)(C1-C6) Alkylene and N (R)8)(R9) One or more of the sulfonyl groups.
In one embodiment, R7Is N (R)8)(R9)(C1-C6) Alkylene group of which "C1-C6Alkylene "is selected from methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene or tert-butylene. In another embodiment, C1-C6Alkylene is methylene.
In another embodiment, R8And R9Each independently is hydrogen, C1-C6Alkyl or C3-C8A cycloalkyl group. In one embodiment, C1-C6The alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In one embodiment, C1-C6Alkyl is methyl or ethyl. In another embodiment, C3-C8Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In another embodiment, C3-C8Cycloalkyl is cyclopropyl. In another embodiment, R8And R9Together with the nitrogen atom to which they are attached form a 6-membered heterocyclyl, the 6-membered heterocyclyl having 1 heteroatom or heterofunctional group selected from: -O-, -NH-or-N (C)1-C6Alkyl groups). In another embodiment, the heterofunctional group is-N (C)1-C6Alkyl groups). In another embodiment, C1-C6The alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.
In another embodiment, R6Is a hydroxyalkylene group. In one embodiment, the hydroxyalkylene group is selected from CH2OH、CH2CH2OH、CH2CH2CH2OH、CH(OH)CH3、CH(OH)CH2CH3、CH2CH(OH)CH3Or CH2CH2CH2CH2OH。
In another embodiment, R5Is a quilt C1-C6An alkyl substituted imidazole. In another embodiment, R5Is imidazole substituted by methyl. In another embodiment, R5Is a quilt C1-C6Alkyl-substituted heteroaryl. In another embodiment, R5Is heteroaryl substituted by methyl.
In one embodiment, R4Is phenyl substituted by one or more selected from Br, Cl, F and I. In another embodiment, R4Is phenyl substituted by F. In another embodiment, R4Is phenyl substituted by Cl. In one embodiment, R4Is represented by N (R)8)(R9)C1-C6Alkylene and N (R)8)(R9) Phenyl substituted with one or more of the sulfonyl groups. In another embodiment, R4Is represented by N (R)8)(R9)C1-C6Phenyl substituted by alkylene. In another embodiment, NR8R9Is azetidine.
In one embodiment, N (R)8)(R9)(C1-C6) In alkylene group "C1-C6Alkylene "is selected from methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene or tert-butylene.
In one embodiment, R8And R9Each independently is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
In one embodiment, R6Is C1-C6An alkyl group. In another embodiment, R6Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl. In one embodiment, R6Selected from the group consisting of OH, NO2Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl substituted by one or more of CN, Br, Cl, F and I. In one embodiment, R6Is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In one embodiment, R6The substituent on the (B) is OH and NO2And one or more of CN.
In one embodiment, R3Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butylButyl, n-pentyl or n-hexyl. In one embodiment, R3Selected from the group consisting of OH, NO2Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl substituted by one or more of CN, Br, Cl, F and I. In another embodiment, R3Is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In one embodiment, R6The substituent on the (B) is OH and NO2And one or more of CN.
In one embodiment, R6Is hydrogen, and R3Selected from Br, Cl, F, I, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C1-C6Alkoxy, substituted or unsubstituted C1-C6Alkoxy radical C1-C6Alkyl, wherein C is substituted1-C6Alkyl, substituted C3-C8Cycloalkyl, substituted C1-C6Alkoxy, substituted C1-C6Alkoxy radical C1-C6Alkyl is optionally selected from OH, NO2、CN、Br、Cl、F、I、C1-C6Alkyl and C3-C8At least one substituent in the cycloalkyl group.
In one embodiment, R3Is hydrogen, R6Selected from Br, Cl, F, I, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C1-C6Alkoxy, substituted or unsubstituted C1-C6Alkoxy radical C1-C6Alkyl, wherein C is substituted1-C6Alkyl, substituted C3-C8Cycloalkyl, substituted C1-C6Alkoxy, substituted C1-C6Alkoxyalkyl optionally substituted by one or more substituents selected from OH, NO2、CN、Br、Cl、F、I、C1-C6Alkyl and C3-C8At least one substituent in the cycloalkyl group.
In another embodimentIn the embodiment, R3And R6Are all hydrogen.
In one embodiment, R3And R6Are all selected from Br, Cl, F, I, substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted C3-C8Cycloalkyl, substituted or unsubstituted C1-C6Alkoxy, substituted or unsubstituted C1-C6Alkoxy radical C1-C6Alkyl, wherein C is substituted1-C6Alkyl, substituted C3-C8Cycloalkyl, substituted C1-C6Alkoxy, substituted C1-C6Alkoxy radical C1-C6Alkyl is optionally selected from OH, NO2、CN、Br、Cl、F、I、C1-C6Alkyl and C3-C8At least one substituent in the cycloalkyl group.
In one embodiment, R3And R6Independently selected from hydrogen and C1-C6An alkyl group.
In one embodiment, R4Is unsubstituted aryl, and R5Selected from:
a) optionally substituted by 1,2 or 3R7Substituted phenyl;
b) optionally substituted by 1,2 or 3R7A substituted imidazolyl group;
c) optionally substituted by 1,2 or 3R7A substituted triazolyl group; and
d) hydrogen, C1-C6Alkoxy radical C1-C6Alkyl radical, C1-C6Alkoxycarbonyl radical C1-C6Alkyl radical, C1-C6Alkyl, 5-6 membered aryl C1-C6Alkyl, 4-10 membered cycloalkyl C1-C6Alkyl, halo C1-C6Alkyl, oxo, 4-10 membered heterocycloalkyl C1-C6Alkyl radical, C1-C6Alkylcarbonyl, 5-6 membered arylcarbonyl, 5-6 membered heteroarylcarbonyl or N (R)8)(R9)C1-C6An alkylene group.
In one embodiment, R4Is unsubstituted phenyl, and R5Selected from:
e) optionally substituted by 1,2 or 3R7Substituted phenyl;
f) optionally substituted by 1,2 or 3R7A substituted imidazolyl group;
g) optionally substituted by 1,2 or 3R7A substituted triazolyl group; and
h) hydrogen, C1-C6Alkoxy radical C1-C6Alkyl radical, C1-C6Alkoxycarbonyl radical C1-C6Alkyl radical, C1-C6Alkyl, 5-6 membered arylalkyl, 4-10 membered cycloalkyl C1-C6Alkyl, halo C1-C6Alkyl, oxo, 4-10 membered heterocycloalkyl C1-C6Alkyl radical, C1-C6Alkylcarbonyl, 5-6 membered arylcarbonyl, 5-6 membered heteroarylcarbonyl or N (R)8)(R9)C1-C6An alkylene group.
In one embodiment, R4Is substituted by 1,2 or 3R7Substituted phenyl, and R5Selected from:
i) optionally substituted by 1,2 or 3R7Substituted phenyl;
j) optionally substituted by 1,2 or 3R7A substituted imidazolyl group;
k) optionally substituted by 1,2 or 3R7A substituted triazolyl group; and
l) hydrogen, C1-C6Alkoxy radical C1-C6Alkyl radical, C1-C6Alkoxycarbonyl radical C1-C6Alkyl radical, C1-C6Alkyl, 5-6 membered aryl C1-C6Alkyl, 4-10 membered cycloalkyl C1-C6Alkyl, halo C1-C6Alkyl, oxo, 4-10 membered heterocycloalkyl C1-C6Alkyl radical, C1-C6Alkylcarbonyl, 5-6 membered arylcarbonyl, 5-6 membered heteroarylcarbonyl or N (R)8)(R9)C1-C6An alkylene group.
In the present invention, the solvate refers to a compound formed by combining a compound molecule and a solvent molecule and capable of stably existing, wherein the molar ratio of the compound molecule to the solvent molecule can be a common ratio of the solvate, and generally includes 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 and 1: 10. In the present invention, the solvent compound is preferably a hydrate, such as a monohydrate, a dihydrate or the like.
Thus, throughout this specification, the skilled person will be able to refer to the R in the compounds of formula I1、R3、R4、R5、R6And substituents thereof are selected to provide stable compounds of formula I as described in the examples of the invention, or pharmaceutically acceptable salts, solvates, metabolites or prodrugs thereof.
In the present invention, the fused ring compound represented by formula I is preferably any one of the following compounds:
in the present invention, the stereoisomers include enantiomers, diastereomers and mixtures of enantiomers or diastereomers.
The stereoisomer of the fused ring compound shown in the formula I is preferably of any structure as follows:
wherein each substituent is as defined above.
In the stereoisomers of the compounds of formula I as shown above, R1Is fluorine. In one embodiment, R5Is an imidazolyl group. In another embodiment, R5Is a quilt C1-C6An alkyl substituted imidazolyl group. In one embodiment, R5Is imidazolyl substituted with methyl. In one embodiment, R5Is a triazolyl group. In another embodiment, R5Is a quilt C1-C6An alkyl-substituted triazolyl group. In another embodiment, R5Is a triazolyl group substituted with a methyl group. In one embodiment, R5Is phenyl substituted by halogen. In one embodiment, R5Is phenyl substituted by F. In another embodiment, R5Is phenyl substituted by one or more of Br, Cl and I.
In one embodiment, R4Is phenyl substituted by one or more selected from the group consisting of F, Br, Cl and I. In one embodiment, R4Is phenyl substituted by F. In one embodiment, R4Is represented by N (R)8)(R9)C1-C6Alkylene substituted phenyl. In one embodiment, C1-C6Alkylene is methylene. In another embodiment, NR8R9Is azetidine.
The stereoisomer of the compound shown in the formula I is preferably any one of the following compounds:
the fused ring compound of the formula I can be prepared according to the conventional chemical synthesis method in the field, and the steps and the conditions can refer to the steps and the conditions of similar reactions in the field.
If a chiral pure compound of the fused ring compound of formula I according to the present invention is desired, chiral induction can be used in the art, for example, during the synthesis process, or after a mixture of stereoisomers of the target compound is obtained, the compound can be resolved by using a chiral resolution column or a chemical resolution method, which are conventional in the art, to obtain a chirally pure fused ring compound of formula I according to the present invention.
The reaction solvent used in each reaction step described in the present invention is not particularly limited, and any solvent that can dissolve the starting materials to some extent and does not inhibit the reaction is included in the present invention. Further, many equivalents, substitutions, or equivalents in the art to which this invention pertains, as well as different proportions of solvents, solvent combinations, and solvent combinations described herein, are deemed to be encompassed by the present invention.
The invention also provides a pharmaceutical composition which comprises a therapeutically effective amount of the fused ring compound of formula I and pharmaceutically acceptable excipients.
The pharmaceutically acceptable auxiliary material can be excipient.
The invention also provides application of the fused ring compound shown in the formula I, pharmaceutically acceptable salt, solvate, metabolite, stereoisomer or prodrug thereof, or the pharmaceutical composition in preparation of PARP inhibitors.
The invention also provides application of the fused ring compound shown in the formula I, pharmaceutically acceptable salt, solvate, metabolite, stereoisomer or prodrug thereof, or the pharmaceutical composition in preparing medicines for treating and/or preventing PARP-dependent or PARP-mediated diseases or symptoms.
The PARP inhibitors are useful in vivo; also useful in vitro, primarily for experimental purposes, for example: the kit can be used as a standard sample or a control sample for comparison, or can be prepared into a kit according to the conventional method in the field, so as to provide rapid detection for the inhibitory effect of PARP.
The invention also provides the fused ring compound shown in the formula I, and pharmaceutically acceptable salts, solvates, metabolites, stereoisomers or prodrugs thereof, or application of the pharmaceutical composition in preparation of drugs for treating tumors, stroke, myocardial ischemia, inflammation or diabetes.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is standard in the art to which the claimed subject matter belongs. In case there are multiple definitions for a term, the definitions herein control. When referring to a URL or other identifier or address, it should be understood that such identifier may change and that particular information on the internet may change, but equivalent information may be found by searching the internet. The reference demonstrates that such information is available and publicly disseminated.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Furthermore, the term "comprising" is open-ended and not closed-ended.
The present invention employs, unless otherwise indicated, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques or pharmacological detection, and the various steps and conditions may be referred to those conventional in the art. Unless otherwise indicated, the present invention employs standard nomenclature for analytical chemistry, organic synthetic chemistry, and medicinal chemistry, as well as standard laboratory procedures and techniques. In some cases, standard techniques are used for chemical synthesis, chemical analysis, drug preparation, formulation and drug delivery, and treatment of patients.
Definition and description of terms
The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from the compounds of the present invention found to have particular substituents, with relatively nontoxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and salts of organic acids including acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like; also included are salts of amino acids (e.g., arginine, etc.), and salts of organic acids such as glucuronic acid (see Berge et al, "Pharmaceutical salts," Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functionalities and can thus be converted to any base or acid addition salt. Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms by certain physical properties, such as solubility in polar solvents.
The term "pharmaceutically acceptable salts" as used herein pertains to derivatives of the compounds of the present invention wherein the parent compound is modified by salification with an acid or by salification with a base. Examples of pharmaceutically acceptable salts include, but are not limited to: inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound, for example, salts formed with non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic or organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, glycolic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannin, tartaric acid, and p-toluenesulfonic acid.
The "pharmaceutically acceptable salts" of the present invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, such salts are prepared by the following method: prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid, in water or an organic solvent or a mixture of the two. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the present invention. Any compound that can be converted in vivo to provide a biologically active substance (i.e., a compound of formula I) is a prodrug within the scope and spirit of the present invention. For example, compounds containing a carboxyl group may form physiologically hydrolyzable esters that act as prodrugs by hydrolyzing in vivo to give the compounds of formula I themselves. The prodrugs are preferably administered orally, since hydrolysis in many cases takes place mainly under the influence of digestive enzymes. Parenteral administration may be used when the ester itself is active or hydrolysis occurs in the blood. In addition, prodrugs can be converted to the compounds of the present invention in an in vivo environment by chemical or biochemical means.
Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in polycrystalline or amorphous form.
The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labelled with radioactive isotopes, such as tritium (A), (B), (C3H) Iodine-125 (125I) Or C-14(14C) In that respect Compounds of the inventionVariations in isotopic composition, whether radioactive or not, are included within the scope of the present invention.
In some embodiments, the compounds described herein exist as stereoisomers, wherein an asymmetric or chiral center is present. Stereoisomers are named according to the configuration of the substituents around the chiral carbon atom
Or (S). Terms used herein
And (S) is a configuration as defined in IUPAC 1974Recommendations for Section E, fundamentals Stereochemistry, Pure apply. chem, (1976),45:13-30, the contents of which are incorporated herein by reference. Embodiments described herein specifically include various stereoisomers and mixtures thereof. Stereoisomers include enantiomers, diastereomers and mixtures of enantiomers or diastereomers. In some embodiments, each stereoisomer of a compound is prepared synthetically from commercial starting materials containing asymmetric or chiral centers, or by preparing racemic mixtures followed by resolution. The resolution method comprises the following steps: (1) combining the mixture of enantiomers with a chiral auxiliary, and releasing the optically pure product from the auxiliary by recrystallization or chromatographic separation of the resulting mixture of diastereomers; or (2) directly separating the mixture of optical enantiomers on a chiral chromatography column.
The term "excipient" generally refers to a carrier, diluent, and/or vehicle necessary to formulate an effective pharmaceutical composition.
The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For oral dosage forms of the invention, an "effective amount" of one active agent in a composition is the amount required to achieve the desired effect when combined with another active agent in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.
The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.
The term "alkenyl" as used herein refers to a straight, branched, or cyclic (also referred to as "cycloalkenyl" in this case) hydrocarbon containing from 2 to 8 carbon atoms and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. In some embodiments, depending on the structure, an alkenyl group can be a subunit (i.e., alkenylene). Examples of "alkenyl" include, but are not limited to, ethenyl, 2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, and 3-decenyl.
The term "alkoxy" refers to an alkyl group, as defined herein, attached to the rest of the molecule through an oxygen atom. Examples of "alkoxy" include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, t-butoxy, pentoxy, and hexoxy.
The term "alkyl" refers to a straight or branched chain hydrocarbon group containing 1 to 6 carbon atoms. Examples of "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl. As used herein, "C" or "C" means1-C6Alkyl "refers to a straight or branched chain hydrocarbon group containing 1 to 6 carbon atoms.
The term "cycloalkyl" refers to monocyclic groups containing only carbon and hydrogen, including saturated, partially unsaturated, or fully unsaturated. "C4-C8Cycloalkyl "is meant to include groups having 4 to 8 carbon ring atoms. In some embodiments, cycloalkyl groups can be subunits (e.g., cycloalkylene groups), depending on the structure.
The term "cycloalkylalkyl" refers to a cycloalkyl group attached to the rest of the molecule through an alkyl group. As used herein, "C" or "C" means3-C8Cycloalkyl (C)1-C6) Alkyl "means a cycloalkyl group containing 3 to 8 carbon atoms through an alkyl group containing 1 to 6 carbon atomsAttached to the rest of the molecule. Examples of "cycloalkylalkyl" include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, and cyclohexylmethyl.
The term "alkoxyalkyl" refers to an alkoxy group attached to the rest of the molecule through an alkyl group, where the number of alkoxy groups can exceed one, but satisfies the maximum number of alkoxy groups that an alkyl group can carry. In the present invention, "C1-C6Alkoxy radical C1-C6Alkyl "refers to an alkoxy group having 1 to 6 carbons attached to the rest of the molecule through an alkyl group having 1 to 6 carbon atoms. It is understood that when the number of alkoxy groups exceeds one, the number of carbons refers to the sum of the number of carbons contained in all alkoxy groups. Examples of "alkoxyalkyl" groups include, but are not limited to, 2-methoxyethyl, 2-ethoxyethyl, t-butoxyethyl, and methoxymethyl.
The term "alkoxycarbonyl" refers to an alkoxy group attached to the rest of the molecule through a carbonyl group. As used herein, "C" or "C" means1-C6Alkoxycarbonyl "refers to an alkoxy group containing 1 to 6 carbons attached to the rest of the molecule through a carbonyl group. Examples of "alkoxycarbonyl" include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.
The term "alkoxycarbonylalkyl" refers to an alkoxycarbonyl group attached to the rest of the molecule through an alkyl group.
The term "alkylcarbonyl" refers to an alkyl group attached to the rest of the molecule through a carbonyl group. As used herein, "C" or "C" means1-C6Alkylcarbonyl "refers to an alkyl group containing 1-6 carbons attached to the rest of the molecule through a carbonyl group. Examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2-dimethyl-1-oxopropyl, 1-oxobutyl and 1-oxopentyl.
The term "alkylthio" refers to an alkyl group attached to the rest of the molecule through a sulfur atom. Examples of alkylthio include, but are not limited to, methylthio, ethylthio, butylthio, tert-butylthio, and hexylthio.
The term "alkynyl" refers to a compound containing 2 to 6 carbon atoms and at least one carbon-carbon triple bondStraight-chain, branched-chain hydrocarbon groups. As used herein, "C" or "C" means2-C6Alkynyl "refers to alkynyl groups containing 2-6 carbons. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.
The term "aryl" refers to an aromatic hydrocarbon ring in which each atom forming the ring is a carbon atom. In some embodiments, the aryl ring is formed from 5, 6, 7, 8, 9, or more than 9 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthracyl, fluorenyl, and indenyl.
The term "arylalkyl" refers to an aryl group attached to the rest of the molecule through an alkyl group. Herein, a 5-to 10-membered aryl group (C)1-C6) Alkyl means an aryl group having 5 to 10 ring atoms attached to the rest of the molecule through an alkyl group containing 1 to 6 carbon atoms. Examples of arylalkyl groups include, but are not limited to, benzyl, 2-phenylethyl, -phenylpropyl, 1-methyl-3-phenylpropyl, and 2-naphthalen-2-ylethyl.
The term "halo" or "halogen" refers to-Cl, -Br, -I, or-F.
The term "oxo" refers to an ═ O group.
The term "bond" or "single bond" refers to a chemical bond between two atoms or between two moieties.
The terms "haloalkyl" and "haloalkoxy" include alkyl and alkoxy structures in which at least one hydrogen is replaced with a halogen atom. In some embodiments where two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are the same as each other. In other embodiments where two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are not the same as each other. The terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy, respectively, wherein halogen is fluorine.
The term "heteroatom" refers to an atom other than carbon or hydrogen. Heteroatoms are typically independently selected from oxygen, sulfur, and nitrogen, but are not limited to these atoms. In embodiments where two or more heteroatoms are present, the two or more heteroatoms are the same as one another, or some or all of the two or more heteroatoms are different from one another.
The term "ring" refers to any covalently closed structure. Rings include, for example, carbocycles (e.g., aryl and cycloalkyl), heterocycles (e.g., heteroaryl and heterocycloalkyl), aromatic groups (e.g., aryl and heteroaryl), and nonaromatic groups (e.g., cycloalkyl and heterocycloalkyl).
The term "ring system" refers to two or more rings, wherein two or more rings are fused. The term "fused" refers to a structure in which two or more rings share one or more bonds.
The term "heteroaryl" refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. An N-containing "heteroaryl" moiety refers to an aromatic group in which at least one backbone atom of the ring is a nitrogen atom.
The term "heteroarylalkyl" refers to a heteroaryl group attached to the rest of the molecule through an alkyl group. Examples of heteroarylalkyl include, but are not limited to, pyridylmethyl.
The term "heterocycloalkyl" refers to a non-aromatic cyclic group in which one or more of the atoms forming the ring is a heteroatom. "heterocycloalkyl" contains at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, a "heterocycloalkyl" ring is formed from 3,4, 5, 6, 7, 8, 9, or more than 9 atoms. In some embodiments, the heterocycloalkyl group contains one or more carbonyl or thiocarbonyl groups, e.g., oxygen or sulfur containing groups. Examples of "heterocycloalkyl" include, but are not limited to, lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, tetrahydrothiopyrans, 4H-pyrans, tetrahydropyrans, piperidines, 1, 3-dioxins, 1, 3-dioxanes, 1, 4-dioxins, 1, 4-dioxanes, piperazines, 1, 3-oxathianes, 1, 4-oxathianes, tetrahydro-1, 4-thiazines, 2H-1, 2-oxazines, maleimides, succinimides, barbituric acid, thiobarbituric acid, dioxopiperazines, hydantoins, dihydrouracils, morpholines, trioxanes, hexahydro-1, 3, 5-triazines, tetrahydrothiophenes, tetrahydrofuran, pyrrolines, hexahydro-1, 3, 5-triazines, tetrahydrothiophenes, and mixtures thereof, Pyrrolinones, pyrazolines, imidazolines, 1, 3-dioxoles, 1, 3-dioxolanes, 1, 3-dithioles, isoxazolines, oxazolines, oxazolinones, thiazolines, and 1, 3-oxathiolanes.
The term "heterocyclyl" includes monocyclic heteroaryls and monocyclic heterocycloalkyls, and refers to groups containing 1 to 4 heteroatoms each selected from O, S and N, wherein each heterocyclic group has 4 to 10 atoms in its ring system, provided that the ring of the group does not contain two adjacent O or S atoms. Here, when the number of carbon atoms present in the heterocyclic ring is specified (e.g., C)1-C6Heterocyclic ring), at least one other atom (heteroatom) must be present in the ring. The number of ring atoms in the "heterocyclic group" in the present invention is described by "membered", for example, "4-10 membered heterocyclic group" means that the heterocyclic group is composed of 4 to 10 (including: 4,5, 6, 7, 8, 9, 10) atoms, at least one of which is a carbon atom, at least one of which is a heteroatom, and the remaining 2 to 4 atoms are carbon atoms or heteroatoms, as long as the structural formula formed is chemically stable. In some embodiments, in a heterocyclyl having two or more heteroatoms, the two or more heteroatoms are the same or different from each other. In some embodiments, the "heterocyclyl" is attached to the rest of the molecule through a heteroatom or carbon atom. Heterocycloalkyl includes groups having only 4 atoms in the ring system, but heteroaryl groups must have at least 5 atoms in the ring system. Examples of the 4-membered heterocyclic group include: azetidinyl (derived from azetidine). Examples of 5-membered heterocyclic groups include: a thiazolyl group. Examples of the 6-membered heterocyclic group include: examples of pyridyl, 10-membered heterocyclic groups include: a quinolyl group. Examples of heterocycloalkyl are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thiaoxazolyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thietanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3, 6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dihydropyranylDihydrothienyl, dihydrofuryl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0]Hexyl, 3-azabicyclo [4.1.0]Heptyl, 3H-indolyl and quinolizinyl. Examples of "heteroaryl" include: pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuryl, cinnolinyl, indazolyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridyl. In some embodiments, a "heterocyclyl" is a group derived from imidazole that is imidazol-1-yl or imidazol-3-yl (all N-linked) or imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl (all C-linked). "heterocyclyl" includes ring systems substituted with one or two oxo (═ O) moieties, such as pyrrolidin-2-one. In some embodiments, the heterocyclic group may be a subunit (i.e., a heterocyclylene group), depending on the structure.
The term "heterocycloalkoxy" refers to a heterocycloalkyl group, as defined herein, attached to the rest of the molecule through an alkoxy group.
The term "heterocycloalkylthio" refers to a heterocycloalkyl group, as defined herein, attached to the rest of the molecule through an alkylthio group.
The term "heterocyclyloxy" refers to a heterocycloalkyl group, as defined herein, attached to the rest of the molecule through an oxygen atom.
The term "heterocyclylthio" refers to a heterocycloalkyl group, as defined herein, attached to the rest of the molecule through a sulfur atom.
The term "heteroarylalkoxy" refers to a heteroaryl group, as defined herein, attached to the rest of the molecule through an alkoxy group.
The term "heteroarylalkylthio" refers to a heteroaryl group, as defined herein, appended to the rest of the molecule through an alkylthio group.
The term "heteroaryloxy" refers to a heteroaryl group, as defined herein, attached to the rest of the molecule through an oxygen atom.
The term "heteroarylthio" refers to a heteroaryl group, as defined herein, attached to the rest of the molecule through a sulfur atom.
The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
In some embodiments, the term "cyclic ring" includes any cyclic structure. The term "member" refers to the number of backbone atoms that make up a ring. Thus, for example, cyclohexyl, pyridine, pyran and thiopyran are 6-membered rings and cyclopentyl, pyrrole, furan and thiophene are 5-membered rings.
The term "hydroxyalkylene" refers to at least one hydroxyl group attached to the rest of the molecule through an alkylene group. Examples of "hydroxyalkylene" include, but are not limited to, hydroxymethylene, 2-hydroxy-ethylene, 3-hydroxypropylene, and 4-hydroxyheptylene.
The term "NR8R9"refers to two groups R attached to the rest of the molecule through a nitrogen atom8And R9。R8And R9Each independently hydrogen, alkyl and alkylcarbonyl. NR (nitrogen to noise ratio)8R9Illustrative examples of (a) include, but are not limited to, amino, methylamino, acetylamino, and acetylmethylamino.
Term "(NR)8R9) Carbonyl "refers to R attached to the rest of the molecule through the carbonyl8R9A group. (NR)8R9) Examples of carbonyl groups include, but are not limited to, aminocarbonyl, (methylamino) carbonyl, (dimethylamino) carbonyl, and (ethylmethylamino) carbonyl.
The terms "optional", "optionally" mean optionally. For example: "is optionally selected from OH, NO2、CN、Br、Cl、F、I、C1-C6Alkyl and C3-C8By "at least one substituent in a cycloalkyl group" is meant that it may be substituted by a substituent selected from OH, NO2、CN、Br、Cl、F、I、C1-C6Alkyl and C3-C8Cycloalkyl is substituted with at least one substituent.
The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.
The term "total number of open valences" refers to the total number of hydrogens on the ring that may be replaced with other substituents, i.e., the maximum number of substituents that may be present on the ring. For example: the total number of open valences of the benzene rings is 6.
In the context of the present invention, if a substituent comprises a plurality of groups, the last-described substituent comprises an atom which is bonded to the remainder of the molecule, for example an "alkoxyalkyl" group, which is bonded to the remainder of the molecule by an alkyl group.
In the context of the present invention, unless otherwise indicated, groups not indicated for substitution are all unsubstituted, e.g. "C1-C6Alkoxy "means unsubstituted C1-C6An alkoxy group.
In the present invention, the substituent R of ring A in the structure of formula I without indicating the substitution position1And then means that any open valence position on the A ring can be replaced by R1And (4) substitution. For example, the A ring is cyclohexyl, then
When n is 1, the following substitution cases are included:
that is, it may be substituted at the 2,3,4 or 5 position of cyclohexyl; if A is cyclopentyl, then
When n is 1, the following substitution cases are included:
when A is cycloheptyl, then
When n is 1, the following substitution cases are included:
similarly, when A is 3-pyridazinone, then
When n is 1, the following substitution cases are included:
then
When n is 1, the following substitution cases are included:
when n is greater than 1, a plurality of R1Which may be the same or different, have each independently defined.
Provided herein is a therapeutic agent comprising a packaging material, a compound provided herein within the packaging material, and a label, wherein the compound is effective for modulating the activity of PARP, or for treating, preventing or ameliorating one or more symptoms of a PARP-dependent or PARP-mediated disease or disorder, and wherein the label indicates that the compound or composition, or a pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is for treating, preventing or ameliorating one or more symptoms of a PARP-dependent or PARP-mediated disease or disorder. Any combination of the various variables described above is also within the scope of the description herein.
In one embodiment, disclosed herein are pharmaceutical compositions containing a compound of formula I or a stereoisomer thereof, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable prodrug thereof. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition further comprises a second pharmaceutically active ingredient.
The compound shown in the formula I has good PARP inhibitory activity, can be effectively used as a PARP inhibitor, is used for treating one or more diseases related to the PARP activity, is used for preparing a medicament with the PARP inhibitory activity, and has good clinical application and medical application.
The dynamic solubility test experiment of the compound shown in the formula I shows that the compound has good water-soluble property and is superior to the BMN-673 of the existing PARP inhibitor.
The test experiment of the in vitro metabolic stability of the compound shown in the formula I shows that the compound shows good metabolic stability and provides an important basis for further preclinical research.
The PARP inhibitors provided by the present invention may be used to treat a wide range of diseases including tumors, stroke, myocardial ischemia, inflammation and diabetes. Tumors that may be treated by PARP inhibitors include, but are not limited to, breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, clonal cancer, and leukemia, among others.
Some embodiments provide the use of a compound of formula I, or a therapeutically acceptable salt thereof, in the manufacture of a medicament for having PARP inhibitory activity in an individual in need of treatment.
Some embodiments provide the use of a compound of formula I, or a therapeutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor growth in a subject thought to be in need of treatment.
Some embodiments provide the use of a compound of formula I, or a therapeutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject deemed in need of treatment.
Some embodiments provide the use of a compound of formula I, or a therapeutically acceptable salt thereof, in the manufacture of a medicament for treating leukemia, colon cancer, glioblastoma, lymphoma in a subject deemed to be in need thereof.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the fused ring compound has PARP inhibitory activity, good water solubility and good stability, provides a new commercial choice for PARP inhibitors, and can be used for treating and/or preventing tumors, stroke, myocardial ischemia, inflammation or diabetes.
Detailed Description
The scheme of the invention will be explained with reference to the examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
The embodiment of the invention provides a compound shown in formula I or a pharmaceutically acceptable salt, hydrate, solvate, metabolite, stereoisomer or prodrug thereof, a method and an intermediate for preparing the compound shown in formula I or the pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or prodrug thereof, a pharmaceutical composition, and application of the compound and the pharmaceutical composition in preparing medicines.
EXAMPLE 1 preparation of Compound represented by formula I-1
Dissolving the compound represented by the formula I-1a (107 mg, 1.0 mmol), the compound represented by the formula I-1b (144 mg, 1.0 mmol) and potassium carbonate (415 mg, 3.0 mmol) in anhydrous methanol (10mL), heating to 80 ℃, stirring for 5 hours, monitoring the reaction by TLC, adding ethyl acetate for extraction (30 mL. times.3), combining organic layers, washing 3 times with saturated saline, separating, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain a crude compound represented by the formula I-1c (184 mg, 0.74 mmol, 74% yield) which can be directly used in the next reaction without purification.
Adding a compound shown as a formula I-1c (250 mg, 1.0 mmol) and acetaldehyde (66 mg, 1.5 mmol) into a dry reaction pot, keeping the temperature at 10 ℃, stirring, adding anhydrous aluminum trichloride (400 mg, 3.0 mmol) in batches, heating to a reflux state after adding, keeping the reflux state for 2 hours, cooling, pouring into a mixed solution of hydrochloric acid and crushed ice, separating out a solid, performing suction filtration, washing a filter cake for 3 times by using water to obtain a crude product of the compound shown as a formula I-1d, cooling the crude product by using anhydrous ethanol, recrystallizing, filtering, washing by using anhydrous ethanol, and drying to obtain the compound shown as a formula I-1d (176 mg, 0.77 mmol, yield 77%). ESI-MS (m/z): 230(M +1)+。
A mixture of the compound represented by formula I-1d (275 mg, 1.2 mmol) with hydrazine hydrate (1.5mL) and methanol (5mL) was heated to reflux for 2.5 hours. The mixture was then cooled to room temperature, diluted with water (30mL), extracted with ethyl acetate (30 mL. times.3), and the organic layers were combined, washed 3 times with saturated brine, separated, the organic phase dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the compound represented by formula I-1e (187 mg, 0.83 mmol, 69% yield). ESI-MS (m/z): 226(M +1)+。
The compound represented by the formula I-1e (270 mg, 1.2 mmol) was dissolved in 10ml of methanol, and 10% palladium on carbon (40 mg) was added. And (4) replacing by hydrogen, keeping the pressure at 3-4 atmospheres, and stirring overnight at room temperature in a hydrogen atmosphere. After TLC monitoring reaction is finished, filtering to remove carbon palladium, decompressing and concentrating mother liquor to obtain crude product of compound shown in formula I-1, cooling and recrystallizing the crude product by mixed solvent of methanol/acetone (V: V ═ 3:1),filtration, washing with a little acetone, and drying gave the compound represented by formula I-1 (177 mg, 0.78 mmol, yield 65%). ESI-MS (m/z): 228(M +1)+。
EXAMPLE 2 preparation of Compound represented by formula I-2
Example 2 the compound of formula I-2 was prepared as described in example 1.
ESI-MS(m/z)：242(M+1)+。
EXAMPLE 3 preparation of the Compound represented by formula I-3
Example 3 the compound of formula I-3 was prepared as described in example 1.
ESI-MS(m/z)：256(M+1)+。
EXAMPLE 4 preparation of the Compound represented by formula I-4
Example 4 the compound of formula I-4 was prepared as described in example 1.
ESI-MS(m/z)：246(M+1)+。
EXAMPLE 5 preparation of the Compound represented by formula I-5
Example 5 the compound of formula I-5 was prepared as described in example 1.
ESI-MS(m/z)：260(M+1)+。
EXAMPLE 6 preparation of the Compound represented by formula I-6
Example 6 the compound of formula I-6 was prepared as described in example 1.
ESI-MS(m/z)：274(M+1)+。
EXAMPLE 7 preparation of the Compound represented by formula I-7
Adding a compound shown as a formula I-7c (277 mg, 1.0 mmol) and acetaldehyde (66 mg, 1.5 mmol) into a dry reaction pot, keeping the temperature at 10 ℃, stirring, adding anhydrous aluminum trichloride (400 mg, 3.0 mmol) in batches, heating to a reflux state after adding, keeping the reflux state for 3 hours, cooling, pouring into a mixed solution of hydrochloric acid and crushed ice, separating out a solid, performing suction filtration, washing a filter cake for 3 times by using water to obtain a crude product of the compound shown as a formula I-7d, cooling the crude product by using anhydrous ethanol, recrystallizing, filtering, washing by using anhydrous ethanol, and drying to obtain the compound shown as a formula I-7d (185 mg, 0.72 mmol, yield 72%). ESI-MS (m/z): 258(M +1)+。
A mixture of the compound represented by formula I-7d (308 mg, 1.2 mmol) with hydrazine hydrate (2mL) and methanol (5mL) was heated to reflux for 3 hours. The mixture was then cooled to room temperature, diluted with water (30mL), extracted with ethyl acetate (30 mL. times.3), and the organic layers were combined, washed 3 times with saturated brine, separated, the organic phase dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the compound represented by formula I-7e (197 mg, 0.78 mmol, yield 65%). ESI-MS (m/z): 254(M +1)+。
The compound represented by the formula I-7e (304 mg, 1.2 mmol) was dissolved in 10ml of methanol, and 10% palladium on carbon (50 mg) was added. And (4) replacing by hydrogen, keeping the pressure at 3-4 atmospheres, and stirring overnight at room temperature in a hydrogen atmosphere. After TLC monitoring reaction is completed, filtering to remove carbon palladium, concentrating mother liquor under reduced pressure to obtain crude product of compound shown in formula I-7, making the crude product pass through mixed solvent of methanol/acetone (V: V ═ 3:1), cooling and recrystallizing, filtering, washing with a little acetone and drying so as to obtain the invented productA compound represented by I-7 (211 mg, 0.83 mmol, yield 69%). ESI-MS (m/z): 256(M +1)+。
EXAMPLE 8 preparation of the Compound represented by formula I-8
Example 8 the compound of formula I-8 was prepared as described in example 7.
ESI-MS(m/z)：256(M+1)+。
EXAMPLE 9 preparation of the Compound represented by formula I-9
To ethyl propionate (100 ml), a compound represented by formula I-9n (2.95 g, 10 mmol), anhydrous sodium sulfite (2.52 g, 20 mmol), and anhydrous sodium sulfate (4.26 g, 30 mmol) were added, stirred, the temperature was maintained at 10 ℃ or lower, and EtONa solution [ obtained by dissolving 0.7 g of sodium (30 mmol) in 50 ml of ethanol ] was slowly added dropwise, and after completion of the addition, the temperature was raised to 40 ℃, and stirring was maintained for 6 hours. Then, the mixture was cooled to room temperature, filtered to remove solids, extracted with ethyl acetate (200mL × 3), the organic layers were combined, washed 3 times with saturated brine, separated, the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give an oil, which was purified by column chromatography to give a compound represented by formula I-9m (1.35 g, 31 mmol, yield 31%).
A mixture of the compound represented by the formula I-9m (434 mg, 1 mmol) and hydrazine hydrate (1.5mL) and methanol (6mL) was stirred at 25 ℃ for 12 hours. The mixture was then cooled to room temperature, diluted with water (30mL), extracted with ethyl acetate (30 mL. times.3), and the organic layers were combined, washed 3 times with saturated brine, separated, the organic phase dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the compound represented by formula I-9 (242 mg, 0.6 mmol, yield 60%).
ESI-MS(m/z)：403(M+1)+。
Example 10 Compounds of formula I-10
ESI-MS(m/z)：417(M+1)+。
Example 11 Compounds represented by formula I-11
ESI-MS(m/z)：431(M+1)+。
Example 12 Compounds represented by formula I-12
ESI-MS(m/z)：421(M+1)+。
Example 13 Compounds represented by formula I-13
ESI-MS(m/z)：435(M+1)+。
Example 14 Compounds of formulae I-14
ESI-MS(m/z)：449(M+1)+。
Example 15 Compounds of formulae I-15
ESI-MS(m/z)：431(M+1)+。
Example 16 Compounds of formulae I-16
ESI-MS(m/z)：431(M+1)+。
Example 17 Compounds of formulae I-17
ESI-MS(m/z)：403(M+1)+。ee％：97％。
Example 18 Compounds of formulae I-18
ESI-MS(m/z)：417(M+1)+。ee％：97％。
Example 19 Compounds of formulae I-19
ESI-MS(m/z)：431(M+1)+。ee％：97％。
Example 20 Compounds of formulae I-20
ESI-MS(m/z)：421(M+1)+。ee％：97％。
Example 21 Compounds of formulae I-21
ESI-MS(m/z)：435(M+1)+。ee％：97％。
Example 22 Compounds of formula I-22
ESI-MS(m/z)：449(M+1)+。ee％：97％。
Example 23 Compounds represented by formula I-23
ESI-MS(m/z)：431(M+1)+。ee％：97％。
Example 24 Compounds of formulae I-24
ESI-MS(m/z)：431(M+1)+。ee％：97％。
Example 25 Compounds of formulae I-25
ESI-MS(m/z)：403(M+1)+。ee％：97％。
Example 26 Compounds represented by formula I-26
ESI-MS(m/z)：417(M+1)+。ee％：97％。
Example 27 Compounds of formulae I-27
ESI-MS(m/z)：431(M+1)+。ee％：97％。
Example 28 Compounds represented by formula I-28
ESI-MS(m/z)：421(M+1)+。ee％：97％。
Example 29 Compounds of formulae I-29
ESI-MS(m/z)：435(M+1)+。ee％：97％。
Example 30 Compounds of formulae I-30
ESI-MS(m/z)：449(M+1)+。ee％：97％。
Example 31 Compounds represented by formula I-31
ESI-MS(m/z)：431(M+1)+。ee％：97％。
Example 32 Compounds represented by formulas I-32
ESI-MS(m/z)：431(M+1)+。ee％：97％。
Example 33 in vitro study
Cellular PARylation assay
HCC1937 cells were plated in 96-well plates at 4X 104 cells/well and cultured overnight in a 37 ℃ incubator. After 30 minutes of treatment of the cells with the test compound, they were treated with 1mM hydrogen peroxide for 10 minutes. Cells were washed twice with 200UL pre-chilled PBS and fixed with 100UL pre-chilled methanol/acetone (7:3) for 30 minutes in an ice bath. After air drying, blocking was performed with 5% skim milk powder in PBS-Tween-20 blocking solution (0.05%) for 30 minutes at room temperature. Cells and anti-PAR 10H antibody were expressed as 1: 100 ratio in the blocking solution at room temperature 1 h incubation, then with PBS-Tween-20 washing three times, then added to contain sheep anti mouse fluorescein-5 (6) -isothiocyanate (FITC) -combined secondary antibody and 1 u g/mL DAPI blocking solution at room temperature and light protection temperature 1 h incubation. After three washes with PBS-Tween-20, data were analyzed using a fluorescence microplate counter (Flexstation III, molecular DNA).
PARP enzyme assay (according to HT generic PARP1 colorimetric assay kit instructions).
Histones were coated in 96-well plates and incubated overnight at 4 ℃. After washing the plate 3 times with 200UL PBST solution, it was blocked with blocking solution and after incubation for 30 minutes at room temperature, washed 3 times with PBST solution. The test compound treatment was added to the well plate, after which 20. mu.l of diluted PARP1(1nM) or 20. mu.l of PARP2(3nM) solution was added to the reaction and incubated for 1 or 2 hours. After 50. mu.l of streptavidin-HRP (1:50) mixture was added to the well plate and incubated for 30 minutes at room temperature, PBST buffer was washed three times. Mu.l of (HRP) (chemiluminescent substrate A and substrate B (1:1)) was added to the well plate. Read immediately on a microplate reader (Envision, PerkinElmer).
Antiproliferative assay
MDA-MB-436 and MDA-MB-231 cells were seeded in 96-well plates at a density of 500 and 2000 cells per well, respectively, and cultured overnight. The culture medium is RPMI 1640 containing 10% (V/V) FBS and 1% (V/V) penicillin-streptomycin. After addition of the test compound, the treatment is carried out for 8 days. Cell viability was measured by the CCK8 kit. The specific method is that 10UL CCK8 reagent is added into each hole, and the temperature is 37 ℃ and the CO content is 5 percent2Incubate and incubate for 3 hours. After shaking for 10 minutes, the light absorption (OD value) was measured at 450nm using Flexstation III (Molecular Device).
IC of PARP-1 inhibiting enzymes of the Compounds of the invention50And cellular PARylation IC50The data are provided in table 1 below. IC of the Compound50Labeled as +++, between 1 and 100 nM; IC of the Compound50IC of the compound, denoted as ++, between 101 and 1000nm50Greater than 1000nm is indicated as +.
TABLE 1
The test result shows that the compounds shown in the formula I have good PARP kinase inhibition activity, and the compounds can be used as PARP inhibitors, used for treating one or more than one tumor diseases related to the PARP activity and used for preparing tumor medicaments.
Example 34 kinetic solubility test:
the test of kinetic solubility is commonly used for high throughput screening of drugs during the drug discovery phase. In kinetic analysis, a good solubility should help to generate reliable data in vitro and in vivo. Since the kinetic solubility is pH-dependent, the pH of the aqueous phase is always specified, usually measured at pH 7.4 (physiological pH of body fluids).
The test method comprises the following steps: samples of the weighed quantification compound were dissolved in pure DMSO at a final concentration of 10mM, and the test compound and control compound (10mM DMSO stock, 10 μ L per well) were added to a 96-well plate containing 490 μ L buffer per well. After vortexing for 2 minutes, the sample plates were incubated for 24 hours at room temperature (22. + -. 2 ℃) on a shaker. Then transfer 200 μ L of sample to MultiScreen filter plate (polycarbonate membrane), filter with millipore vacuum manifold and collect the filtrate. The concentration of the compound in the filtrate was determined by HPLC-UV. The sample introduction was performed sequentially for 3 UV standard solutions of different concentrations and the solubility test samples. Each sample was inserted 2 times, and the concentration was calculated by substituting a standard curve and averaging.
The experimental result shows that the compound provided by the invention has good water-soluble property and is superior to the BMN-673 of the control sample.
Example 35 in vitro metabolic stability test:
in vitro metabolic stability experiments assess the clearance of a compound in one phase of metabolism and can predict its intrinsic clearance in hepatocytes and in vivo. We evaluated the metabolic stability of some compounds of the invention in human and rat liver microsomes by in vitro metabolic stability experiments. The control sample was BMN-673.
The specific operation steps of the experimental method are determined by the methods described in the references (Tangminghai, Wang Haishun, Wangchun, leaf Haoyu. anti-tumor compound E7 in vitro metabolism research of liver microsome enzymes of different species [ J ]. Chinese medicine J2016, 9 th stage, 1739-1743 page).
The experimental result shows that the compound of the invention shows good metabolic stability and provides an important basis for further preclinical research.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example" or "some examples" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made in the above embodiments by those of ordinary skill in the art without departing from the principle and spirit of the present invention.
Claims (14)
1. A fused ring compound or a pharmaceutically acceptable salt thereof, which is a compound represented by formula I or a stereoisomer thereof:
wherein the A ring is selected from C5-C7Cycloalkyl or 4, 5-dihydro-3-pyridazinonyl;
the R is1Each independently selected from H, F, Cl, Br and I;
the R is3Selected from hydrogen;
the R is4Is as a quilt R7Substituted 6-to 10-membered aryl, R7The number of (2) is 1;
the R is5Is composed of
The R is6Selected from hydrogen;
the R is7Selected from Br, Cl, F and I;
n is the total number of open valences on ring A from 0;
the stereoisomer of the compound shown in the formula I is:
or, the fused ring compound or the pharmaceutically acceptable salt thereof is any one of the following compounds:
2. the fused ring compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: the R is4Is as a quilt R7A substituted phenyl group.
3. The fused ring compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: r4Is phenyl substituted by one selected from Br, Cl, F and I.
4. The fused ring compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein: r4Is phenyl substituted by F or phenyl substituted by Cl.
5. The fused ring compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: when n is not 0, the R1Substituted ortho to the atoms common to the fusion of the A rings.
6. The fused ring compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: r4Is p-fluorophenyl.
7. The fused ring compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: the fused ring compound shown in the formula I is any one of the following compounds:
8. the fused ring compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: the stereoisomer of the compound shown in the formula I is any one of the following compounds:
9. a pharmaceutical composition comprising a therapeutically effective amount of a fused ring compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
10. Use of the fused ring compound of any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 9 for the preparation of a PARP inhibitor.
11. The use of claim 10, wherein:
the PARP inhibitor is used in vivo; or in vitro, as a laboratory use.
12. The use of claim 11, wherein: the experimental application is a kit.
13. Use of the fused ring compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9 for the preparation of a medicament for the treatment and/or prevention of PARP dependent or PARP mediated diseases or conditions.
14. Use of the fused ring compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9 for the preparation of a medicament for the treatment and/or prevention of tumors, stroke, myocardial ischemia, inflammation, or diabetes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611245741.1A CN107556312B (en) | 2016-12-29 | 2016-12-29 | Novel fused ring compound with PARP inhibitory activity, preparation method and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611245741.1A CN107556312B (en) | 2016-12-29 | 2016-12-29 | Novel fused ring compound with PARP inhibitory activity, preparation method and use thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107556312A CN107556312A (en) | 2018-01-09 |
| CN107556312B true CN107556312B (en) | 2020-04-10 |
Family
ID=60972635
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611245741.1A Active CN107556312B (en) | 2016-12-29 | 2016-12-29 | Novel fused ring compound with PARP inhibitory activity, preparation method and use thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107556312B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102171214A (en) * | 2008-08-06 | 2011-08-31 | 生物马林药物股份有限公司 | Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP) |
| WO2011130661A1 (en) * | 2010-04-16 | 2011-10-20 | Biomarin Pharmaceutical Inc. | Methods of using dihydropyridophthalazinone inhibitors of poly (adp-ribose)polymerase (parp) |
-
2016
- 2016-12-29 CN CN201611245741.1A patent/CN107556312B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102171214A (en) * | 2008-08-06 | 2011-08-31 | 生物马林药物股份有限公司 | Dihydropyridophthalazinone inhibitors of poly(ADP-ribose)polymerase (PARP) |
| WO2011130661A1 (en) * | 2010-04-16 | 2011-10-20 | Biomarin Pharmaceutical Inc. | Methods of using dihydropyridophthalazinone inhibitors of poly (adp-ribose)polymerase (parp) |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107556312A (en) | 2018-01-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3459952B1 (en) | Pyrimidine derivative, method for preparing same and use thereof in medicine | |
| KR102513448B1 (en) | CDK4/6 inhibitor | |
| CA2823401A1 (en) | Therapeutic compounds and compositions | |
| MX2012009606A (en) | Deuterated pyrrolopyrimidine compounds as inhibitors of cdk4/6. | |
| CN110914277B (en) | Imidazo [1,2-b ] pyrimido [4,5-d ] pyridazin-5 (6H) -one compounds and application thereof | |
| WO2017071516A1 (en) | Kinase inhibitor, and preparing method and pharmaceutical use thereof | |
| CN104910137A (en) | CDK kinase inhibitor | |
| AU2010321366B2 (en) | Compound, certain novel forms thereof, pharmaceutical compositions thereof and methods for preparation and use | |
| JP2018517763A (en) | Heterocyclic imidazole compounds, pharmaceutical compositions thereof, preparation methods and uses thereof | |
| CN107556312B (en) | Novel fused ring compound with PARP inhibitory activity, preparation method and use thereof | |
| CN107573341B (en) | Novel fused ring compound as PARP inhibitor, preparation method and application thereof | |
| CN110650961B (en) | PARP inhibitor, pharmaceutical composition, preparation method and application thereof | |
| CN117447449A (en) | PARP1 inhibitor and application thereof | |
| CN110283160B (en) | PDGFR kinase inhibitor | |
| EP3896059B1 (en) | Pan-kit kinase inhibitor having quinoline structure and application thereof | |
| CN107964012B (en) | Compounds as PARP inhibitors and uses thereof | |
| CN113350347A (en) | Novel use of indazole compound | |
| TWI827429B (en) | Carbonyl bridged heterocyclic compounds, compositions and applications thereof | |
| CN111138426B (en) | Indazole kinase inhibitor and application thereof | |
| CN115843296B (en) | CDK9 inhibitors and uses thereof | |
| EP4353724A1 (en) | Compound as cdk kinase inhibitor and use thereof | |
| WO2023001061A1 (en) | Cdk7 selective inhibitors as anticancer agents | |
| TW202321248A (en) | Tyrosine kinase inhibitors | |
| WO2019085860A1 (en) | Fgfr4 inhibitor and preparation method therefor | |
| CN116867491A (en) | Salts of 3, 4-dihydro-isoquinoline compounds and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |