TW201249840A - Methods of using dihydropyridophthalazinone inhibitors of poly (ADP-ribose) polymerase (PARP) in the treatment of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) - Google Patents

Abstract

Disclosed herein are methods of treating MDS or AML with a compound of Formula I where R1, R2, R3, R4, R5, A, B, Y and Z are as defined herein. Also disclosed are methods of identifying a patient with MDS or AML who is sensitive to treatment with a compound of Formula I.

Description

201249840 VI. Description of the Invention: [Technical Field of the Invention] The present invention describes the use of poly(ADP-ribose) polymerase (PARP) dihydropyridine and hydrazine hydrolytic inhibitors for the treatment or prevention of myelodysplastic syndrome (MDS) (Myelodysplastic Syndrome; MDS) And acute myeloid leukemia (AML) method. The invention also relates to methods for determining the sensitivity of an individual to such PARP inhibitors based on the microsatellite instability (MSI) status. [Prior Art] The poly(ADP-nuclear) polymerase (PARP) family includes about 18 proteins, all of which exhibit a certain degree of homology in their catalytic domains, but in terms of their cellular functions. Different (Ame et al'

BioEssays, 26(8), 882-893 (2004)). PARP-1 and PARP-2 are unique members of this family because their catalytic activity is stimulated by the cleavage of DNA strands. PARP is involved in the signaling of DNA damage via its ability to identify and rapidly bind DNA single-strand or double-strand breaks (D'Amours et al.' Biochem J., 342, 249-268 (1999)). PARP is involved in a variety of DNA-related functions (including gene amplification, cell division, differentiation, apoptosis, DNA base excision repair) and also affects telomere length and chromosomal stability (d'Adda di Fagagna et al., Nature Gen) ., 23(1), 76-80 (1999)). Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are characterized by chromosomal instability, and leukemia cells have inherent defects in double-stranded DNA repair 156715.doc 201249840 (Gaymes et al., Cancer Res., 62). , 2791-2797 (2002)). Furthermore, PARP inhibitor studies using AML cell lines have shown that a certain proportion (15%) of cells derived from AML patients exhibit significant cytotoxic responses to PARP inhibitors (Gaymes et al., Haematologica, 94(5), 638-646. (2009)). Microsatellite instability (MSI) can be defined as an increase in the rate of uncorrected replication errors in microsatellite sequences (Han et al., Science, 97, 226_234 (2006)). Damage to the mismatch repair mechanism results in MSI and loss of mismatch repair, and the resulting MSI is observed in 12% of colorectal cancers. MSI is less well characterized in other cancers, but reports indicate mismatch repair defects and MSI in hematological malignancies (Han et al, Science, 97, 226-234 (2006); Gu et al, Oncogene, 21, 5758-5764 (2002)). Since the microsatellite sequence appears in the exon of the major DSB DNA repair gene, MSI may cause a frame shift mutation in the gene that confers sensitivity to the PARP inhibitor. The use of PARP inhibitors and PARP inhibitors in the treatment of certain cancers is well known in the art, as previously described in International Patent Publication No. WO 2010/01705 5 A2, the entire contents of which is incorporated herein by reference. . Methods for DNA profiling and analysis of MSI are also well known in the art, as previously described in Gaymes et al., C7zi· Cancer Res., 12, 5104-5111 (2006), the entire contents of which are incorporated herein by reference. in. We sought to find other PARP inhibitor therapies that could be used in certain cancers associated with MSI (eg, MDS and AML). An attempt was also made to find a candidate for the PARP inhibitor therapy 156715.doc 201249840 method via DNA repair path profiling and MSI analysis. SUMMARY OF THE INVENTION In one aspect, the invention features a method of treating MDS or AML in a patient with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) comprising administering a therapeutically effective amount to a patient with MDS or AML Compound of formula (1):

R3 Rs Formula (I), wherein: Y and Z are each independently selected from the group consisting of: a) an aryl group substituted by 1, 2 or 3 116 as needed; b) 1, 2 or 3 as needed a heteroaryl group substituted with R6; and c) a substituent independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkane , alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, ||alkyl, hydroxyalkyl, pendant oxy, heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl , arylcarbonyl, heteroarylcarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, (NRARB)alkyl, (NRarb)carbonyl, (NRaRb)carbonylalkyl, ( NRARB) sulfonyl and (nrarb) sulfonylalkylene; 156715.doc • 6 - 201249840

Ri, R_2 and R_3 are each independently selected from the group consisting of hydrogen, halogen, aryl, alkoxy, alkoxycarbonyl, alkyl, ring-based, alkynyl, cyano, alkoxy, Haloalkyl, hydroxy, hydroxyalkyl, succinyl, NRRAB, NRRAB alkylene and (NRARB)carbonyl; A and B are each independently selected from the group consisting of hydrogen, Br, C1, F, I, OH, CrCe An alkyl group, a C3-C8 cycloalkyl group, an alkoxy group and an alkoxyalkyl group, wherein the fluorene group, the CrC8 ring compound group, the alkoxy group and the alkoxyalkyl group are optionally at least one selected from the group consisting of Substituted substituents of the group: OH, N02, CN, Br, Cl, F, I, CVQ alkyl and C3_C8 cycloalkyl, wherein B is not OH;

Ra and Rb are independently selected from the group consisting of hydrogen, affiliary, cycloalkyl, and alkylcarbonyl; or Ra and Rb together with the atoms to which they are attached are formed, optionally having from 1 to 3, selected from the group consisting of a 3-10 membered heterocyclic ring of a hetero atom or a heterofunctional group of the group. -NH, _n(Ci_C6_烧美), -NCOA-CV alkyl)-, -N(aryl)·, _N(aryl_Ci_C6 _, 烧, _, -N (substituted aryl-CVC: 6-alkyl-)-, -n (heteroaryl), _N (heteroaryl-CVC: 6-alkyl-)-, _N ( Substituted heteroaryl*_Ci_C6_alkyl_)_ and _1 or S(0)q-, wherein q is 1 or 2 and the 3-10 membered heterocyclic ring is optionally substituted with one or more substituents; R4 and Rs Each is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxy, cycloalkyl, alkyl and (NRaRb)alkyl; and each core is selected from the group consisting of: 0H, N〇2, CN, Br, c, F, I, CVC6 alkyl, 〇3-(: 8-cycloalkyl, C2_C8 heterocyclic alkyl, & 156715.doc 201249840 alkenyl, alkoxy'alkane Oxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, c2-c6 alkynyl, aryl, arylalkyl, c3-c8 cycloalkyl Alkyl, haloalkoxy, li alkyl, hydroxyalkyl, pendant oxy, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylsulfide , heterocycloalkoxy, c2-c8 heterocycloalkylthio, heterocyclooxy, heterocyclic thio, NRRAB, (NRAROCrCdt alkyl, (NRARB) carbonyl, (NRARB) carbonyl alkylene, (NRARB Sulfosyl and (NRARB)sulfonylalkylene. In certain embodiments, the compound is administered as a single isomer, a stereoisomer or an enantiomer or a mixture thereof. In the embodiments, the compound is administered in the form of a salt, solvate, chemically protected form or prodrug thereof. In certain embodiments, the compound is in combination with a pharmaceutically acceptable diluent, excipient, and carrier. At least one of them is administered together. In some embodiments, the patient's malignant cells exhibit microsatellite instability (MSI) in the microsatellites. In some embodiments, the malignant cells are in at least one microsatellite Containing insertions or deletions. In some embodiments, the patient's malignant cells are in two, three, four The MSI is shown in five, six, seven or more microsatellites. In some embodiments, the MSI in at least one of the microsatellites comprises a plurality of insertions and/or deletions. In some embodiments, at least one The MSI in the microsatellite can be detected using primers designed to detect insertions or deletions in the microsatellite. In some embodiments, at least one of the microsatellite I lines NR21, NR22, NR24, Bat25, Bat26, Mono27 anti/DNA The microsatellite according to the present invention is repaired in the genes C77P, Mre/i, 3ΓΜ, 5LM, 156715.doc 201249840 and J77. In certain embodiments, the at least one microsatellite is selected from the group consisting of: see, , Mo«o2 7 and DNA repair genes CJ7P, Mreii, and 4, as described in the present invention. In some embodiments, the at least one microsatellite is selected from the group consisting of #7, iVi? In certain embodiments, the MSI comprises deletion or insertion of 3 or more base pairs in the microsatellite. In certain embodiments, the MSI comprises insertion or deletion of a base pair in the microsatellite, resulting in inactivation of the DNA repair function and/or a frameshift mutation in the double stranded DNA repair gene expression product. In certain embodiments, the DNA repair function is governed by a double-stranded DNA repair gene selected from the group consisting of: /ΓΜ and CHP. In certain embodiments, the method further comprises analyzing the MSI in at least one of the microsatellites of the patient's malignant cellular DNA. In certain embodiments, the compound is 5-fluoro-8-(4-fluorophenyl)-9-(1-indolyl-1H-1,2,4-triazol-5-yl)-8,9- Dihydro-2H-pyrido[4,3,2-de]indole-3(7H)-one or a pharmaceutically acceptable salt thereof. In certain embodiments, the invention features a method of treating AML in an AML patient comprising administering to the AML patient a therapeutically effective amount of a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof. In certain embodiments, the compound is 5-fluoro-8-(4-fluorophenyl)-9-indole-methyl-1H-1,2,4-triazol-5-yl)-8,9- Dihydro-2-indole-»pyridinyl[4,3,2-de]indole-3(7H)-one, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. In another aspect, the invention is illustrative of a compound of formula (1), or a salt, solvate, single isomer, stereoisomer, or enantiomer thereof, or a mixture of 156715.xloc -9-201249840, Or a chemically protected form or prodrug thereof for the treatment of MDS or AML in a patient with MDS or AML. In certain embodiments, the malignant cells in the patient exhibit MSI in the microsatellite. In certain embodiments, the malignant cells in the patient exhibit MSI in at least two, three, four, five, six or more microsatellites. In another aspect, the invention recites a compound of formula (I), or a salt, solvate, single isomer, stereoisomer, or enantiomer thereof, or mixture thereof, or a chemically protected form thereof, or Use of a prodrug in the formulation of a medicament for the treatment of MDS or AML in a patient with MDS or AML. In certain embodiments, the malignant cells in the patient exhibit MSI in the microsatellite. In certain embodiments, the malignant cells in the patient exhibit MSI in at least two, three, four, five, six or more microsatellites. In another aspect, the invention sets forth a method of identifying MSI in a patient with MDS or AML. In certain embodiments, the method comprises analyzing an MSI in at least one of the microsatellites of the patient's malignant DNA. In certain embodiments, the MSI comprises inserting or deleting three or more base pairs in the at least one microsatellite. In certain embodiments, the presence of an MSI-to-patient malignancy in at least one of the patient's malignant cellular DNA is identified as potentially responsive to the compound therapy of Formula I. In some embodiments, the MSI in the at least one microsatellite can be detected using primers designed to detect insertions or deletions in the microsatellite. In certain embodiments, the at least one of the 'defense I lines NR21, NR22, NR24, Bat25, Bat26, Mono27 anti/or ΌΝΑ repair genes CTiP, Mrell, ATM, Rad50, Chki, corpse and dri? The microsatellite of the present invention. In some embodiments, the at least one microsatellite is found in the R27, , , Mo«o27 or DNA repair gene C77 corpse, Mre" and J7W, the microsatellite according to the invention . In some embodiments, the at least one microsatellite is selected from the group consisting of and 5αί25. In certain embodiments, a microsatellite containing a base pair insertion or deletion results in inactivation of DNA repair function. In certain embodiments, the DNA repair function is mediated by a double-stranded DNA repair gene selected from the group consisting of Mre77, sputum, and C77 cadaver. In another aspect, the invention features methods of identifying a patient who may be responsive to treatment with a compound of formula (I). In certain embodiments, the compound of formula (I) is 5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1Η-1,2,4-triazol-5-yl) -8,9-Dihydro-2H-^b pyridine[4,3,2-de]indole-3(7Η)-one. In some embodiments, the method comprises analyzing an MSI in at least one of the microsatellites in the patient's malignant cellular DNA. In certain embodiments, the MSI comprises inserting or deleting three or more base pairs in at least one microsatellite in the patient's malignant cellular DNA. In certain embodiments, if MSI is present in at least one of the microsatellites of the patient's malignant DNA, this indicates that the patient's malignancy may be susceptible to treatment with the compound of formula (I). In some embodiments, the MSI in the at least one microsatellite can be detected using a primer designed to detect insertions or deletions in the microsatellite. In certain embodiments, the at least one scorpion 1 line NR2J, NR22, NR24, Bat25, Bat26, Mono27 and/or DNA repair genes C77P, Mre//, 3ΓΜ, C/zH, corpse, J: Microsatellites as described in TM and J77®. In certain embodiments, the at least one microsatellite, Μοπο27 or the DNA repair genes C77P, Mre77, and 3ΓΜ are microsatellites as described in the present invention. In certain embodiments, the at least one microsatellite is selected from the group consisting of and. In some embodiments, the at least one microsatellite contains a base pair insertion or deletion resulting in inactivation of the DNA repair function. In certain embodiments, the DNA repair function is governed by a double-stranded DNA repair gene selected from the group consisting of Mrei/, and CHi3. In certain embodiments, the method further comprises cytogenetic analysis of chromosomal abnormalities in the DNA of the patient's malignant cells. [Embodiment] Compounds of Formula (I) or Formula (II) In certain embodiments, the present invention discloses methods of treating MDS or AML in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), including A therapeutically effective amount of a compound having the structure of formula (I) or formula (II) is administered to a patient with MDS or AML. In certain embodiments, the methods comprise administering to a patient a pharmaceutically acceptable salt, solvate, ester, acid, and chemically protected form thereof, or a chemically acceptable form of a compound having the structure of Formula (I) and Formula (II) medicine. In certain embodiments, the methods comprise administering to a patient an isomer of a compound having the structure of Formula (I) and Formula (Π), including a single isomer, a stereoisomer, an enantiomer, Diastereomers or mixtures thereof. Formula (I) is as follows: 156715.doc 12 8 201249840

R3 r5 Υ Β Ζ Formula (1) wherein: Y and Z are each independently selected from the group consisting of: a) an aryl group substituted by 1, 2 or 3 R6 as needed; b) 1 or 2 as needed And 3 quaternary 6 substituted heteroaryl groups; c) substituents independently selected from the group consisting of hydrogen, alkenyl, methoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonyl Alkyl, alkyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, pendant oxy, heterocycloalkyl, heterocycloalkylalkyl, alkyl Carbonyl, arylcarbonyl, heterocyclyl, aryl, aryl, heteroarylsulfonyl, nrarb alkyl, nrarb carbonyl, nrarb carbonyl alkyl And (nrarb)sulfonyl and (nrarb)sulfonylalkyl; R!, R2 and R3 are each independently selected from the group consisting of hydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl, alkane Alkyl, cycloalkyl, alkynyl, cyano, dentate alkoxy, dentate alkyl, hydroxy, hydroxyalkyl, nitro, nrarb, nrarb alkyl and nrarb carbonyl; A and B are independent Ground selection Hydrogen, Br, C, F, I, OH, C丨-(: 6 alkyl, C3-C8 cycloalkyl, alkoxy, alkoxyalkyl) where Ci-C6 burns 156715.doc • 13- 201249840 The base, the alkyl group, the alkoxy group, the alkoxy group are optionally substituted with at least one substituent selected from the group consisting of OH, N02, CN, Br, C, F, I, Cl_C6 alkyl and C3_C8 cycloalkyl, wherein B Not 〇H; RA and Rb are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl and alkylcarbonyl; or Ra and Rb together with the atoms to which they are attached form 1 to 3 as desired 3-10 member heterocycles selected from heteroatoms or heterofunctional groups of the group consisting of: -Ο-, -NH, -alkyl)_, -NCOCCVCV ()-, -N(aryl)-, ν(aryl_Cl_C6_alkylidene, -N(substituted aryl-Ci-Ce-homo-)-, -N(heteroaryl)-, (heteroaryl-C!-C6-alkyl- )-, -N (substituted heteroaryl·Cl_c6_alkyl_)_ and _s_ or S(0)q- ' wherein q is 1 or 2 and the 3-10 member heterocyclic ring is required to pass one or more Substituted substituents; R4 and Rs are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, halomorph, hydroxy a stretching group and (NRaRb)alkyl group; and each R6 is selected from the group consisting of 〇H, N02, CN, Br, α, F, I, Ci-C6), a C3-C8 cycloalkyl group, C2-C8 Heterocyclic, C2-C6 alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, CrC6 alkynyl, aryl, arylalkyl, C3_C8 ring Alkylalkyl, haloalkoxy, dentate alkyl, hydroxyalkylene, pendant oxy, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkane Thiothio, heterocycloalkyloxy, C2-C8 heterocycloalkylthio, heterocyclooxy, heterocyclic thio, NRRAB, (NRARB)Ci_Cj alkyl, (NRaRb)carbonyl, (NRARB)carbonyl olefin (NRaRb)sulfonyl group & (NRaRb) sulfonyl ketone extension 156715.doc 8 -14 * 201249840 alkyl; or its isomers, salts, solvates, chemically protected forms and prodrugs. The formula (π) is as follows:

Formula (II); wherein: Y is an aryl or heteroaryl group which is optionally substituted with at least one R0; z is an aryl group which is optionally substituted with at least one r6; and A and B are each independently selected from hydrogen, Br, Cl , F, I, 〇n, (: 丨-(: 6 alkyl, CrC8 cycloalkyl, alkoxy, alkoxyalkyl, wherein (:1_(:6 alkyl, Cs-C: 8 naphthenic) The base, alkoxy, alkoxyalkyl group is optionally substituted with at least one substituent selected from the group consisting of OH, N〇2, CN, Br, C, F, I, CVC6 alkyl and C3-C8 cycloalkyl, wherein B is not oh; R6 is selected from OH, N〇2, CN, Br, Cl, F 'I, Cj-Ce alkyl, C3-Cs cycloalkyl, CrCg heterocycloalkyl, CrC6 alkenyl, alkoxy , alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, C2-C6 alkynyl, aryl, arylalkyl, CrC8 cycloalkylalkyl, functional alkoxy, alkyl , hydroxyalkylene, pendant oxy, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio 'heteroarylalkylthio, heterocycloalkoxy, C2_CS heterocycle Alkylthio, heterocyclooxy, heterocyclic thio, NRaRb, (NRaRUcvcM alkyl, (nrarb) carbonyl, (NRaRb) Carbonyl alkane 156715.doc •15·201249840 base, (NRARB) continuous sulfhydryl and (NRARB) synthetic base; R2 is selected from hydrogen, Br, α, I or F;

Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, C3-Cs cycloalkyl and alkylcarbonyl; or the ruler and Rb together with the atoms to which they are attached form 1 to 3 as desired A 3 - 10 member heterocyclic ring selected from the group consisting of heteroatoms or heterofunctional groups of the following composition: _〇_, _Nh, -NWrCe alkyl)_, -^[(^((^-(^))) 〇(C3_C8 cycloalkyl, -N(aryl)_, _N(aryl_Cl_C6 alkyl_)_, Ν(substituted aryl_Ci_C6 alkyl-)_, _N(heteroaryl)... _N(heteroaryl_c丨Qalkyl-b, -N(substituted heteroaryl_Cl_C6 alkyl_)_ and 4 or s(〇v, where ^ is 1 or 2 and 3H 3 -1 〇 The heterocyclic ring is optionally substituted with one or more substituents; or a pharmaceutically acceptable salt, solvate or prodrug thereof. In certain embodiments, the compound administered in the method of the present invention is a formula (1) a compound or a therapeutically acceptable salt thereof, wherein Ri, R2, and a heart are independently selected from the group consisting of hydrogen, an alkyl group, and a halogen; & is hydrogen and & is selected from the group consisting of hydrogen, alkyl, and ring. Alkyl, alkoxyalkyl, dentate alkyl, hydroxyalkylene and (nrarb) And/or independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl; or ampule and 1^ together with the atoms to which they are attached, forming from one to three A 3-10 membered heterocyclic ring selected from the group consisting of heteroatoms or heterofunctional groups of the following composition: _〇_, -ΝΗ,·Ν((:丨'C6·alkyl)-, -NCO(C 丨-C6-alkane Base, -, _N(aryl)_N(aryl-CVC6.alkyl.)_, _N (substituted aryl-Ci_C6 alkyl, ("square)-, (heteroaryl-C丨-C6 -alkyl-)-, -N (by heteroaryl Cl-C6-alkyl and -S- or S (〇V, where q is 1 or 2 and the 156715.doc 8 •16·201249840 3-10 The heterocyclic ring is optionally substituted with one or more substituents. In certain embodiments, the compound of the invention wherein the compound Y is an aryl group of the compound of formula (I). In another embodiment, An aryl phenyl group. In still another embodiment, the phenyl group is substituted with at least one Re selected from Br, d, F or Z. In one embodiment, Rs is F. In one embodiment, the phenyl group is At least one selected from the group consisting of (nrarb) Ci_C6 alkylene, (NRaRb) carbonyl, (nrarb) carbonyl alkylene, ( NRaRb) is substituted with R6 of the sulfonyl and sulfonylalkylene. In one embodiment, the Rs is (NRaRb)Ci_C6 alkyl. In another embodiment, the C1-C6 alkyl is selected from the group consisting of methylene and ethyl. , propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In a further embodiment, 'Cl-C6 alkyl is fluorenyl. In still another embodiment, ra and rb are each independently hydrogen, Ci_c6 alkyl or c3_c8 cycloalkyl. In one embodiment, Cl-C: 6 alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl, in one embodiment, CrC6 Alkyl methyl group. In another embodiment, the base is ethyl. In still another embodiment, the alkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. In another embodiment, the C3_C8 cycloalkyl is cyclopropyl. In still another embodiment, the r6 is a hydroxyl group alkyl group. In one embodiment, the » C, -C6 alkyl group is selected from the group consisting of CH2〇H, ch2ch2oh, CH2CH2CH2OH, CH(OH)CH3, CH(〇H)CH2CH3, CH2CH(OH)CH3, and CH2CH2CH2CH2〇H. In another embodiment, with Rb along with the gas to which it is attached, a heteroatom or heterofunctional group having one selected from the group consisting of -0, -NH or -N(C丨-C6 alkyl) is formed. 6-member heterocycle. In yet another embodiment, the heterofunctional group is Ν(^ν(:6 alkyl). In another embodiment 156715.doc -17-201249840 alkyl is selected from the group consisting of methyl, ethyl, n-propyl, and iso Propyl, n-butyl, isobutyl and tert-butyl. In still another embodiment, Ci-Ce alkyl is methyl. In one embodiment, 'Y is optionally substituted with at least one r6. Aryl. In another embodiment, the 'heteroaryl group is selected from the group consisting of furan, pyridine, pyrimidine, pyrazine, sodium, pyrazole, isothiazole, pyrazole, triazole, D-pyrrol, thiophene, oxazole , isoxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-triazine, anthracene, benzophenone, benzimidazole, benzopyrene In the other embodiment, the heteroaryl is imidazole. In another embodiment, the imidazole is inferior. Qin, 1,3,5-tripa, thienothiophene, quinoxaline, quinoline, and isoquineline. In still another embodiment, the heteroaryl is imidazole. Substituted by an alkyl group selected from the group consisting of decyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl iCl_c6. In still another embodiment, the CrCe alkyl is fluorenyl. In one embodiment, a heteroaryl furan. In another embodiment, An aryl thiazole. In still another embodiment, the heteroaryl is 1,3,4-. dioxin. In another embodiment, the 'heteroaryl is selected from the group consisting of methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, and tri-butyl-substituted CrC6 alkyl. In still another embodiment, 'Ci-C: 6 alkyl-methyl. In one embodiment, z-aryl In another embodiment, the aryl is phenyl. In still another embodiment, the 'phenyl is substituted with at least one R6 selected from the group consisting of Br, Cl, F or I. In yet another embodiment, the ruler 6 is F. In still another embodiment, I is ci. In one embodiment, the phenyl group is selected from at least one selected from the group consisting of (NRaRb^-C^ alkyl, (NRaRb)carbonyl, (nraRb)carbonylalkylene, (NRaRb) a sulfonyl group and a (NRaRb) sulfonylalkylene group substituted by r6. In another embodiment, the 'Re system (NRARJCrCe alkylene group. In still another embodiment, the Cl-C6 alkyl group is selected from the group consisting of methylene groups, Ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tri-butyl. In 156715.doc -18 - 201249840 In another embodiment, Cl-c: 6 alkyl Methylene group. In another embodiment, RA and Rb Independently hydrogen, Cl_CO alkyl or C3_C8 cycloalkyl. In one embodiment, CrC: 6 alkyl is selected from the group consisting of decyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and a third-butyl group. In another embodiment, the CrC6 alkyl group is methyl. In still another embodiment, with, together with the nitrogen to which it is attached, has one selected from the group consisting of '_NH or · NfrQ alkane. a 6-membered heterocyclic ring of a hetero atom or a heterofunctional group of the group. In another embodiment, the heterofunctional group is -N(Cl-C6 alkyl). In one embodiment, the dQ alkyl group is selected from the group consisting of methyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In still another embodiment, the Cl-C0 alkyl group is a fluorenyl group. In one embodiment, the 'Z" is optionally a heteroaryl group substituted with at least one r6. In another embodiment, the 'hetero square' is selected from the group consisting of β-flan, n-bite, and n-bite. Bismuth, taste beta, thiazole, isothiazole, pyrazole, triazole, pyrrole, thiophene, oxazole, isoxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1 2,4-triazine, anthracene, benzoporphin, benzimidazole, benzofuran, pyridazine, H5-triazine, thieno-septene, quinoxaline, quinoline and isoquinoline. In still another embodiment, the heteroaryl is saliva. In another embodiment, the imidazole is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl (^-(^alkyl substituted. In one embodiment, the Cl-C6 alkyl is decyl. In one embodiment, the heteroaryl is furan. In another embodiment, the heteroaryl is thiazole. In yet another embodiment, the 'heteroaryl system i,3,4-oxadiazole "In another embodiment, the heteroaryl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. C^-Ce alkyl substituted. In still another embodiment, 'CrC: 6 alkyl sulfhydryl. In another embodiment, r2 is hydrogen. In 156715.doc • 19· 201249840, an embodiment R2 is selected from the group consisting of F, α, Br, and I. In another embodiment, & F. In certain embodiments, the compound A in the process provided by the present invention is hydrogen (I) In another embodiment, a is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl. In another embodiment, A is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl. , a third-butyl group, a n-pentyl group, and a n-hexyl group. In still another embodiment Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl are required to pass through H, N〇2, CN, Br, Cl, F and I are substituted. In another embodiment, a is a methyl group. In still another embodiment 'A is selected from the group consisting of F, a, Br, and I. In another embodiment, 'A is a cycloalkyl group. In one embodiment, a is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In one embodiment, A is substituted with 〇H, n〇2 or CN. In another embodiment, 'BSCrC6 alkyl In another embodiment, B is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second-butyl, n-pentyl, and n-hexyl. In the examples, fluorenyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl are required to pass through H, n〇2, CN, Br. , Cl, F and I. In one embodiment, the compound to be administered is a compound of formula (I) wherein hydrogen is hydrogen. In another embodiment, B is a fluorenyl group. In yet another embodiment, 'B Selected from F, C, Br, and I. In another embodiment, b is a C3-C8 cycloalkyl group. In one embodiment, B is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In one embodiment 'A is substituted with 〇H, N〇2 or CN. In another embodiment' The compound is a compound of the following formula (1): wherein A is hydrogen and B is selected from the group consisting of Br, C, F, I, CVC6 alkyl, c3_c8 cycloalkyl, alkane 156715.doc • 20·8 201249840 oxy, alkoxyalkyl Wherein the CrC6 alkyl group, the c3-c8 cycloalkyl group, the alkoxy group, the alkoxyalkyl group are optionally subjected to at least one selected from the group consisting of OH, n〇2, CN, Br, a, F, I, CVC6 alkyl and : 3-0: 8 Substituted by a cycloalkyl group. In another embodiment, the compound administered is a compound of formula (1): wherein B is hydrogen and A is selected from the group consisting of Br, Cl, F, I ' (: 丨-(: 6 alkyl, c3-C8 cycloalkyl) , alkoxy, alkoxyalkyl, wherein the alkyl group, the C3-C8 cycloalkyl group, the alkoxy group, the alkoxyalkyl group are optionally at least one selected from the group consisting of 〇H, N〇2, CN, Br, Cl , F, I, CVC6 alkyl and (: 3 < 8 ring substituents substituted by the substituent. In a further embodiment card, both A and B are hydrogen. In another embodiment, A and B All selected from the group consisting of Br, Cl, F, I, CVC6 alkyl, qc:8 cycloalkyl, alkoxy, alkoxyalkyl, wherein Cl_c6 alkyl, C3_Cs cycloalkyl, alkoxy, alkoxy The alkyl group is optionally substituted with at least one substituent selected from the group consisting of hydrazine H, N02, CN, Br, C, F, I, CVC6 alkyl and C3-C8 cycloalkyl. In certain embodiments, the invention provides The compound to be administered in the method is a compound of the formula (II) wherein the aryl group is an aryl group. In another embodiment, the aryl group is a phenyl group. In still another embodiment, the phenyl group is selected from at least one selected from the group consisting of Br and C. 1 or J is replaced by Re. In one embodiment, R0 is F. In a real In one embodiment, the phenyl group is substituted with at least one R6 selected from the group consisting of (NRaROCVC alkylene, (NRARB) carbonyl, (nrarb)carbonylalkylene, (nrarb)sulfonyl and (NRaRb)sulfonylalkylene. In one embodiment, the Re system (NRaRb)Ci_C6 alkylene. In another embodiment, the CrC6 alkyl group is selected from the group consisting of an fluorenylene group, an ethylidene group, a propylidene group, an extended isopropyl group, an exobutyl group, and a stretch. Butyl and exemplified by the third-butyl 156715.doc -21 - 201249840. In still another embodiment, the CrC6 alkylene methylene group. In the re-embodiment, the RA & RB are each independently hydrogen, CfC : 6 alkyl or C 3 -C 8 cycloalkyl. In one embodiment, the CrC 6 alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In one embodiment, 'CrC6 alkyl is an alkyl group. In another embodiment, the group is an ethyl group. In still another embodiment, a C3_C8 cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. In another embodiment, the C3_C8 cycloalkyl is a cyclopropyl group. In still another embodiment, the R6 is a hydroxyalkyl group. In one embodiment, the hydroxyalkyl group is selected from the group consisting of ch2oh, CH2CH2OH, and ch. 2ch2ch2〇h, CH(OH)CH3, CH(〇H)CH2CH3, CH2CH(OH)CH3 and CH2CH2CH2CH2〇H. In another embodiment, the anti-eight and Rb together with the nitrogen to which they are attached form one A 6-membered heterocyclic ring of a hetero atom or a heterofunctional group of -O-, -NH or -N(C丨-C6 alkyl) is selected. In still another embodiment, a 'heterofunctional group-NerC6 alkyl group. In another embodiment, the dQ alkyl group is selected from the group consisting of decyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. In still another embodiment, d-Ce Alkyl methyl group. In one embodiment, Y is a heteroaryl group which is optionally substituted with at least one r6. In another consistent embodiment, the 'heteroaryl group is selected from the group consisting of oxime, oxime bite, mouth bite, alpha azine, and imipen. Sitting, thiophene. Sit, isothiazole, pyrazole, triazole, pyrrole, fensole, oxazole, iso. Evil 0 sitting, 1, 2, 4-° evil two sitting, 1,3,4-«> evil two. Sitting, ι, 2, 4-three calls, flowers, this and ° sputum, Ben and Mi 11 sitting, benzo-n-chew, chlorpyrifos, 1,3,5 _ three-call, sputum and sputum , wow, quinolin and isoquinoline. In still another embodiment, the hybrid 156715.doc" 8 201249840 aryl imidazole. In another embodiment, the sodium saliva is selected from the group consisting of decyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl and tert-butyl (: 1 - (: 6 alkyl substituted. In still another embodiment, Cl-(: 6 alkyl fluorenyl. In one embodiment, heteroaryl oxime). In another embodiment, the heteroaryl is sighed. Sitting β is in another embodiment a 'heteroaryl system, 1,3,4-oxadiazole. In another embodiment, the heteroatom is selected from the group consisting of a CrC:6 alkyl group substituted with a group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group and a third-butyl group. In still another embodiment, a 'CrC6 alkyl group is a methyl group. In another embodiment, z is an aryl group. In another embodiment, the phenyl group is a phenyl group. In still another embodiment, the phenyl group is substituted with at least one R6 selected from the group consisting of Br, Cl, F or I. In an embodiment, the system is F. In still another embodiment, R0 is C1. In one embodiment, the phenyl group is selected from at least one selected from the group consisting of (NRARJCVCe alkylene, (NRaRb) carbonyl, (NRARB) carbonyl alkylene , (NRaRb)sulfonyl and (nraRb)sulfonyl The alkyl group is substituted with r6. In another embodiment, the Re system (NRaRb)Ci_C6 is extended to an alkyl group. In the case of re-permeation red, the 'CrC6 extension base is selected from the group consisting of an anthracene group, an exoethyl group, an exo-propyl group, and a stretch. Isopropyl, n-butyl, exobutyl, and tert-butyl hydrazine. In still another embodiment, the CrC6 alkyl is fluorenylene. In another embodiment, Ra&Rb are each independently hydrogen. , alkyl or c3_c8 cycloalkyl. In a consistent example, the ten' CrC6 alkyl group is selected from the group consisting of decyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In one embodiment, the d. ce alkyl is decyl. In still another embodiment, the hexagram is formed together with the nitrogen to which it is attached, having one selected from the group consisting of -〇_, _nh!_n (Ci_C6 alkyl) a 6-membered heterocyclic ring comprising a hetero atom or a heterofunctional group of 156715.doc -23- 201249840. In another embodiment, the hetero group is a group of (Ci-C6.alkyl). In one embodiment , c"c6 is selected from the group consisting of decyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and second-butyl. In yet another embodiment, 'Ci-C6 alkyl group In another embodiment, 'R·2 is argon In still another embodiment, R2 is selected from the group consisting of F, C, and I. In another embodiment, the r2 is F 〇 In certain embodiments, the compound A administered in the method of the present invention is hydrogen. A compound of formula (II). In another embodiment, octane (^-〇6 alkyl. In another embodiment, A is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl Base, isobutyl, tert-butyl, n-pentyl and n-hexyl. In still another embodiment, mercapto, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, third - Butyl, n-pentyl and n-hexyl are optionally substituted with hydrazine H, N 〇 2, CN, Br, Cl, F and I. In another embodiment, a is a sulfhydryl group. In still another embodiment, A is selected from the group consisting of F, Cl, Br, and I. In another embodiment, the A is CpC: 8 cycloalkyl. In another embodiment, a is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In one embodiment, A is substituted with OH, N〇2 or CN. In one embodiment, the compound B is a compound of formula (II) wherein hydrogen is hydrogen. In another embodiment, the 8 series (: 1-(: 6 alkyl). In another embodiment, B is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , tri-butyl, n-pentyl and n-hexyl. In still another embodiment, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, positive Amyl and n-hexyl groups are required to pass OH, N〇2, CN, Br, 156715.doc -24- 8 201249840

Cl, F and I are substituted. In another embodiment, the B is a sulfhydryl group. In still another embodiment, B is selected from the group consisting of F, Cl, Br, and I. In another embodiment, b is a c3-C8 cycloalkyl group. In another embodiment 'B is a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group. In one embodiment, 'A is substituted with 〇H, N〇2 or CN. In another embodiment, the compound administered is a compound of the formula (A) wherein A is hydrogen and B is selected from the group consisting of Br, a, F, I, CVCe alkyl, C3-C8 cycloalkyl, alkoxy Alkoxyalkyl group wherein the CrC6 alkyl group, the c3-C8 cycloalkyl group, the alkoxy group, the alkoxy group is at least one selected from the group consisting of 〇H, N〇2, CN, Br, Cl, F, I. (VC6-based and (: 3-(: 8-ring-based substituent substitution). In another embodiment, the compound to be administered is a compound of the following formula (n): wherein B is hydrogen and A is selected from Br, C, F, I, CVC6 alkyl, C3-C8 cycloalkyl, alkoxy, alkoxyalkyl' wherein Cl_c6 alkyl, C3-C8 cycloalkyl, alkoxy, alkoxyalkyl If necessary, at least one substituent selected from the group consisting of 〇H, N02, CN, Bi·, CM, F, I, CVCe and (: 3-(:8 cycloalkyl) substituent. In still another embodiment 'A And B are both hydrogen. In another embodiment, 'A and B are both selected from the group consisting of Br, Cl, F, I, C!-C6 alkyl, Cs-c: 8 cycloalkyl, alkane An oxy, alkoxyalkyl group, wherein Ci_C6 alkyl, C8 cycloalkyl, alkoxy 'alkoxyalkyl is required to pass at least one Substituted from substituents of OH, N02, CN, Br, CM, F, I, Cl_C6, and C3_C8 cycloalkyl. In certain embodiments, the compounds administered in the methods provided herein are selected from the following Compound: 156715.doc •25- 201249840 s,

Or a pharmaceutically acceptable salt, solvate or prodrug thereof. In certain embodiments, the compound administered in the methods provided herein is selected from the group consisting of: 156715.doc -26 201249840

Or a pharmaceutically acceptable salt, solvate or prodrug thereof. In certain embodiments, the compound administered in the methods provided herein is selected from the group consisting of: 156715.doc -27· 201249840

Or a pharmaceutically acceptable salt, solvate or prodrug thereof. In certain embodiments, the compound administered in the methods provided herein is selected from the group consisting of: 156715.doc 28- 8 201249840

Or a pharmaceutically acceptable salt, solvate or prodrug thereof. In certain embodiments, the compounds administered in the methods provided herein are selected from the group consisting of: & (8S,9R)-5-fluoro-9-(1-methyl-1H-imidazole_2-yl 8·Phenyl·8 9 _hydrogen-2Η-"bipyridyl[4,3,2-de]呔耕-3(7Η)-one, (8R,9S)-5-fluoro-9-( 1-methyl-1Η-imidazol-2-yl)_8-phenyl_8,9·dihydro-2Η-β ratio bite [4,3,2-de] whistle ·-3(7H)-one '(8S,9R)-5 - It - 8-(4-Fluorophenyl)-9-(1-mercapto-1H-methane. Sodium-2.yl)-8,9-dihydro-2H-°比唆[4,3,2-de]Blowing-3(7H)- Stuffing 1, (8R,9S)-5-Fluoro-8-(4-fluorophenyl)-9-(1-indenyl -1H-imidazol-2-yl)-8,9-dihydro-2H.pyrido[4,3,2-de]indole-3(7H)-one, (8S,9R)-8-(4 -fluorophenyl)-9-(1-mercapto-1H-imidazol-2-yl)-8,9-dihydro-2H-° than pyridine[4,3,2-de]呔耕-3 ( 7H)-keto, (8R,9S)-8-(4-fluorophenyl)-9-(1-indolyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[ 4,3,2-de]呔耕-3(7H)-ketone, 156715.doc •29· 201249840 (8S,9R)-5-fluoro-Ml-methyl-1H-1,2,4-triazole -5-yl)·8-phenyl-8'9-dihydro-2H-. Bis-[4,3,2-de]呔耕-3(7H)-one, (8R,9S)-5-fluoro-9-(1-methyl-1H-1,2,4-triazole -5-yl)-8-phenyl-8,9-dihydro-2H-. Bis-[4,3,2-de] morphine-3(7H)-one, (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl- 1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3'2_de]indole-3(7H)-one, (8R,9S)- 5-fluoro-8-(4-fluorophenyl)-9-(1-indolyl-1H_1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4, 3,2_de]呔耕_3(7H)-ketone, (8S,9R)-8-(4-fluorophenyl)-9-(1-mercapto-1H-1,2,4-triazole_5 -yl)-8,9-dihydro-2H-pyrido[4,3,2-de]indole_3(7H)-one, (8R,9S)-8_(4-fluorophenyl)-9 -(1-methyl-1H_1,2,4-oxadiazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]indole_3(7H)-one , (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazole_5.yl)-8,9-di Hydrogen-2H-pyrido[4,3,2_de]呔耕-3(7H)-ketone' (8R,9S)-5-fluoro-8-(4-fluorophenyl)-9-(1-indenyl) -1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]indole-3(7H)-one' (8S, 9R)-8-(4-((Dimethylamino)indolyl)phenyl)_5_fluoro_9-(1-methyl-1H-1,2,4-triazol-5-yl)- 8,9-Di-argon-2H-pyrido[4,3,2-de]indole-3(7H)-one, and (8R,9S)-8-(4-((dimethylamino)) methyl) -5_fluoro_9_(1_mercapto-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido-3(7H)-one, or A pharmaceutically acceptable salt, solvate or prodrug thereof. 156715.doc -30- 8 201249840 'The method provided by the invention In certain embodiments having the formula:

Η (Compound I) or a pharmaceutically acceptable salt thereof. In some implementations, the compound administered by the method of the present invention is fluorophenyl) winter (1·methyl_ιΗ), 24·three-salt-5, and diter-2Η-ton [4,3,2_de] Blowing _ _3 (7 Η) _ (iv) Compound acceptable salts. In some embodiments, the compound administered in the method provided by the present invention is selected from the group consisting of the following: a group of mouths. 5. Sit. 5. (8S, 9R)-5_ Fluorine-8 · (4_ gas phenyl) winter (1-methyl-1Η-1,2,4-yl)-8,9' dihydro·2Η-° than bite and K3,2-de] Blowing well-3 (7Η )-ketone, (8R'9S)_5-fluoro+(4-fluorophenyl)-9-(1-indolyl-1Η·1,2,4-)'hydro-2Η-. Blowing [4,3,2-de] blown-3(7Η)-grinding|, or a pharmaceutically acceptable salt, solvate or prodrug thereof. ^ In certain embodiments, the compound of the genus Sylvestre (8S'9R)·5·fluoro-8-(4-fluorophenyl)-9-(1-methyl-1Η) administered in the method provided by the present invention · 1,2,4-triazol-5-yl)8'9-indol-2-indene-tonidine [4,3,2-de]indole-3(7Η)-one, or its drug Accepted salts, solvates or prodrugs.竿 匕 匕 & amp 设想 设想 设想 设想 设想 设想 设想 设想 设想 设想 设想 设想 设想 设想 设想 设想 设想 设想 设想 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 156 The entire contents of this application are incorporated herein by reference. Other compounds are disclosed in International Patent Publication No. WO 2010/017055 A2. Methods of Treatment The present invention provides a method of treating cancer comprising administering to a subject in need of treatment a therapeutically effective amount of a compound which is a modulator of PARP activity. In certain embodiments, the methods comprise administering to a subject in need of treatment a therapeutically effective amount of a PARP inhibitor, for example, a compound of formula (1) or (η). In certain embodiments, the cancer is leukemia. In certain embodiments, the cancer is myelodysplastic syndrome (MDS) or acute myeloid leukemia (Aml). In some embodiments, a system of MDS or AML patients. In certain embodiments, the cancer is AML. Thus, in one aspect, the invention features a method of treating MDS or AML in a patient with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), which comprises administering a therapeutically effective amount to a patient with MDS or AML ( J) Compound. In certain embodiments, the invention features a method of treating AML in a patient with acute myeloid leukemia (AML) comprising administering to a patient having a therapeutically effective amount of a compound of formula (1). In one embodiment, a compound of formula (I) or (π) is used to treat MDS or AML in a patient with MDS4 AML, or to prepare an agent for treating MDS or AML in a patient. In one embodiment, a compound of formula (1) or (11) is used to treat AML in an AML patient, or to prepare an agent for treating AML in an AML patient. Thus, yet another aspect is a method of treating a homologous recombination (HR)-dependent DNA double-strand break 156715.doc .32-8 201249840 split (DSB) repair path-defective cancer comprising administering to a subject in need of treatment An effective amount of a PARP inhibitor, for example, a compound of formula (I) or (II). In one embodiment, the compound of formula (I) or (II) is used to treat a cancer deficient in HR dependent DNA DSB repair activity, or to prepare an agent for treating the cancer. In one embodiment, the cancer comprises one or more cancer cells that have reduced or lost ability to repair DNA DSB by HR relative to normal cells. In another embodiment, the system encodes a heterozygous mutant of a gene that is part of the HR dependent DNA DSB repair pathway. In one embodiment, the cancer is leukemia. In one embodiment, the cancer is acute myeloid leukemia (AML). In another embodiment, the cancer is myelodysplastic syndrome (MDS). In another embodiment, the treatment further comprises administering ionizing radiation or a chemotherapeutic agent. The HR-dependent DNA DSB repair pathway repairs double-strand breaks (DSB) in DNA via a homologous mechanism to reform a continuous DNA helix. Components of the HR-dependent DNA DSB repair path include, but are not limited to, ATM (NM_000051), ATR (NM_001184), CTIP (NM-002894), BLM (NM_000057), RAD51 (NM_002875), RAD51L1 (NM_ 002877), RAD51C (NM) 002876), RAD51L3 (NM_ 002878), DMC1 (NM_007068), XRCC2 (NM_ 005431), XRCC3 (NM_005432), RAD52 (NM_ _002879), RAD54L (NM_003579), RAD54B (NM_012415), BRCA1 (NM_007295), BRCA2 I56715.doc 33- 201249840

(NM_000059), RAD50 (NM-005732), MRE11A (NM-005590), and NBS1 (NM_002485)» Other proteins involved in the HR-dependent DNA DSB repair pathway include regulatory factors such as EMSY. The HR component is also set forth in Wood et al, Science, 291, 1284-1289 (2001), the disclosure of which is incorporated herein by reference. KK Khanna and SP Jackson, Nat. Gewei. 27(3): 247-254 (2001); and Hughes-Davies et al, Cell, 115, pp. 523-535, the disclosure of which is incorporated herein by reference. in. In some embodiments, a cancer defective in HR-dependent DNA DSB repair comprises one or more cancer cells that have a reduced ability to repair DNA DSB via the pathway relative to normal cells, ie, HR-dependent DNA DSB repair pathway activity Decreased or disappeared in the one or more cancer cells. In certain embodiments, the activity of one or more components of the HR dependent DNA DSB repair pathway disappears in one or more cancer cells of an individual having a cancer deficient in HR dependent DNA DSB repair. HR-Dependent DNA The components of the DSB repair pathway include the components listed above. A further aspect is a method of treating a DNA mismatch repair (MMR) deficient cancer comprising administering to a subject in need of treatment a therapeutically effective amount of a PARP inhibitor, for example, a compound of formula (I) or (II). In one embodiment, the compound of Formula (I) or (II) is used to treat a MMR-deficient cancer, or to prepare an agent for treating a MMR-deficient cancer, the cancer having a defect in HR-dependent DNA DSB repair activity The main function of the DNA Mismatch Repair (MMR) system is to eliminate single base mismatches and insertion-deletion loops that may occur during DNA replication. The insertion-deletion loop is caused by the increase or loss of short repeat units within the microsatellite sequence of 156715.doc -34- 8 201249840, also known as microsatellite instability (MSI). At least six different MMR proteins are required. For mismatch identification, the MSH2 protein side forms a heterodimer with MSH6 or MSH3 depending on the type of damage to be repaired (MSH6 is required for correcting single base mismatches, while MSH3 and MSH6 can contribute to the correction of the insertion-deletion loop ). The heterodimer coordination mismatch between MLH1 and PMS2 identifies the interaction between the complex and other proteins required for MMR. Such other proteins may include (at least) exonuclease 1 (EX01), (possibly) helicase, proliferating cell nuclear antigen (PCNA), single-stranded DNA binding protein (RPA), and DNA polymerase δ and ε. In addition to PMS2, MLH1 is also heterodimerized with two other proteins, MLH3 and PMS1. Recent observations indicate that PMS2 is required for correcting single base mismatches, while both PMS2 and MLH3 can contribute to the correction of the insertion-deletion loop. Human MMR proteins are known to be other homologs required for functions other than MMR. Such proteins include MSH4 and MSH5 which are required for meiotic (and possibly mitotic) recombination but are presumed to be not involved in MMR. Mutations in the human MMR gene make it susceptible to hereditary non-polyposis colon cancer (HNPCC), one of the most common cancer syndromes in humans. Excessive colon cancer, which is diagnosed in the early years and inherited by autosomal dominant traits, and the defined extra-colonial cancer spectrum constitute the clinical definition of this syndrome. MSI is a hallmark of HNPCC that occurs in about 15% to 25% of the colorectal and other organ sporadic tumors. According to international standards, 'high-level MSI (MSI-high) is defined as two or more loci in five loci or 0% to 40% of loci in all microsatellite loci studied are unstable 'And fewer loci exhibit instability called MSI-low (MSI-156715.doc • 35·201249840 low). In non-HNPCC cancers (eg, breast cancer, prostate cancer, and lung cancer), MSI occurs in a significant proportion (2% to 50% of tumors). Based on the ratio of unstable markers, the species MSS, MSI-L and MSI-H can be distinguished in such cancers in a manner similar to HNPCC cancer. One embodiment is a method of treating a cancer that is mismatched by DNA repair path defects. Another embodiment is a method of treating cancers that exhibit microsatellite instability due to reduced or damaged DNA repair pathways. Another embodiment is a method of treating cancer that exhibits genomic instability due to reduced or damaged DNA repair pathways. The role of nuclear PTEN in maintaining chromatin stability has also been demonstrated in mouse and human systems (Shen et al, Cell 128: 157-170 (2007)). First, PTEN interacts with the centromere and maintains its stability. It is believed that PTEN performs this event via its C2 domain because the mutant PTEN that does not contain this C2 domain loses its ability to interact with the centromere. Second, PTEN may be necessary for DNA repair, as loss of PTEN results in high frequency double-strand breaks. PTEN affects double-strand breaks by regulating Rad51, a key component of homologous recombination repair of the Rad5 1 line DNA double-strand break. It has also been demonstrated that PTEN is physically linked to the integral component of the centromere in the nucleus, and its destruction leads to centromere cleavage and extensive chromosomal aberrations (Shen et al., Cell 128: 157-170 (2007)). List of human DNA repair genes associated with HR-dependent DNA DSB repair and MMR repair pathways described above, as well as other DNA repair pathways (eg, base excision repair (BER) and nucleotide excision repair (NER) pathways) In, for example, Wood et al, Science, 291, 1294 (2001), and updated 156715.doc -36-8, 201249840 in Wood et al, Mutation Res., 577, 275 (2005), the entire contents of each document Both are incorporated herein by reference. The protein sequences of the protein products of such DNA repair genes will be known to those skilled in the art and disclosed in publicly available databases, for example, GenPept, RefSeq, Swiss_Prot, PIR, PRF and PDB, for example, see The website of the National Center for Biotechnology Information (NCBI) (see www.ncbi.nlm.nih.gov). In certain embodiments, the patient's malignant cellular DNA exhibits microsatellite instability (MSI) in the microsatellite, wherein the MSI is explained in the definitions section of this application. In certain embodiments, the patient's malignant cellular DNA exhibits MSI in at least two microsatellites. Microsatellites displaying MSI may include, for example, any of the microsatellites known to those skilled in the art. The microsatellites may include, for example, the microsatellites identified in U.S. Patent No. 6,150,100 and U.S. Patent Publication No. 2009/03 178, the entire disclosure of each of which is incorporated herein by reference. . In certain embodiments, the MSI microsatellite NR21, NR22, NR24, Bat25, Bat26, Mono27 and/or DNA repair genes CTiP, Mrell 'ATM, Rad50, Chkl, BLM, PTEN, ATM, and ATR are displayed. The microsatellite of the present invention. In certain embodiments, the microsatellite according to the invention is a microsatellite NR21, NR22, Bat25, Bat26, Mono27 or a DNA repair gene CTiP, Mrell and ATM. In some cases, cancer-related mutations and polymorphisms are detected in the nucleic acid layer 156715.doc -37-201249840 by detecting the presence of a variant nucleic acid sequence or by detecting a mutation at the protein level (ie, mutation or etc.) The presence of a polypeptide variant is tested for its presence. In certain embodiments, the methods comprise administering to a subject in need of treatment a therapeutically effective amount of a compound of formula (1) and formula (II) with ionizing radiation, one or more chemotherapeutic agents, or a combination thereof. Certain embodiments provide methods of enhancing such treatment in an individual recognized to require MDS or AML cytotoxic cancer therapy comprising administering to the individual a therapeutically acceptable amount of a compound of formula (I) or (II) or a therapeutically acceptable thereof Accept the salt. In some embodiments, the invention provides a method of treating MDS or AML comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of formula (1) or (Π) in combination with ionizing radiation or one or more chemotherapeutic agents. In some embodiments, a system of MDS or AML patients. In some embodiments, the compounds of the invention are administered simultaneously with ionizing radiation or one or more chemotherapeutic agents. In other embodiments, the compounds of the invention are administered sequentially with ionizing radiation or one or more chemotherapeutic agents. In certain embodiments, the one or more chemotherapeutic agents are selected from the group consisting of alemtuzumab, antimony trioxide, aspartate (pegylated or non-PEGylated), bevacizole Antibiotic (bevacizumab), cetuximab, celebrity-based compounds (eg cisplatin), cladribine, daunorubicin/doxorubicin/Idabi Iriducin, irinotecan, udarabine, 5-fluorouracil, gemtuzumab, apterin - 8 201249840 (methotrexate), paclitaxel, Taxol®, temozolomide, thioguanine, and the following drug classes: hormones (antiestrogens) , antiandrogens, or gonadotropin-releasing hormone analogs), interferons (eg, alpha interferon), nitrogen mustard (eg, busulfan, melphalan, or It mustard) (mechlorethamine)), a retinoid (eg, retinoic acid) (tretinoin)), a topoisomerase inhibitor (eg, irinotecan or topotecan), a tyrosine kinase inhibitor (eg, gefitinib or imatinib) And agents for treating signs or symptoms induced by the therapy (including allopurinol, filgrastim, granisetron/ondansetron/palonos In some embodiments, the one or more chemotherapeutic agents are selected from the group consisting of alkylating agents such as methyl sulfonate (MMS), temozolomide, and dacarbazine. (dacarbazine) (DTIC); topoisomerase-1 inhibitors, such as topotecan, irinotecan, rubiconcan, exatecan, lurtotecan, Gimetecan, Diflomotecan (homocamptothecin), 7-substituted non-silatecan, 7-stone non-silatecan 7-silyl camptothecin and BNP 1350; non-camptothecin topology Isomerase-I inhibitors (such as carbazole); and dual topoisomerase-I and II inhibitors (such as benzophenazine, XR 11576/]^1^ 5 76 and benzopyridinium哚). 156715.doc -39- 201249840 Methods for identifying patients with MDS or AML who may be responsive to treatment In one aspect, the invention provides a method for identifying malignant cells having MSI in a patient with MDS or AML, which comprises analyzing a patient's malignant cell DNA MSI in one or more microsatellites where MSI is present in at least one of the microsatellites of the patient's malignant DNA is to identify the patient as likely to be sensitive to the regimen. In certain embodiments, the compound of Formula I or II is 5-fluoro-8-(4-fluorophenyl)-9-(1-indolyl-1H-1,2,4-tris-s--5-yl)- 8,9-dihydro-2H- ° ratio. And [4,3,2-de]呔耕-3(7H)-one or its stereoisomer. In certain embodiments, the methods comprise analyzing the MSI in at least one microsatellite of the patient's malignant cellular DNA. In certain embodiments, the methods comprise analyzing an MSI in at least two of the microsatellites of the patient's malignant cellular DNA. In certain embodiments, the methods comprise analyzing an MSI in at least three microsatellites of the patient's malignant cellular DNA. As explained in the definitions section of this application, the MSI comprises an insertion or deletion of one or more base pairs in the microsatellite of the patient's malignant DNA. Thus, in certain embodiments the 'MSI comprises one or more deletions in the microsatellite of the patient's malignant cell DNA, two or more deletions, or three or more deletions. Correct. As further explained in the definitions section of this application, low-level MSI (MSI-low) is defined as having 1 base pair (bp) deletion or insertion in the microsatellite; intermediate MSI (MSI-middle) is defined as being in the microsatellite There is a bp deletion or insertion in it, the southern MSI (MSI-direction) is defined as having 23 bp deletions or insertions in the microsatellite; and the MSI stability (MSI-stability) is defined as no 156715.doc in the microsatellite. ·40· 8 201249840 There are missing or inserted. Thus, in some embodiments, the MSI can be MSI-low. In other embodiments, the MSI can be in MSI-. In other embodiments, the MSI can be MSI-High. The methods disclosed herein contemplate that the presence of low-, medium-, or high-grade MSI in only one microsatellite of a patient's genomic DNA is to identify the patient as likely to respond to a compound of formula I or II therapy. However, the presence of MSI (low-, medium-, or high-) in other microsatellites of patient DNA may also facilitate identification in this patient. Thus, in certain embodiments, the presence of MSI in at least one of the microsatellites of the patient's malignant DNA is to identify the patient as likely to respond to the therapy of the compound of Formula I or II. In certain embodiments, the presence of MSI in at least two of the microsatellites of the patient's malignant DNA is to identify the patient as likely to respond to the compound therapy of Formula I or II. In certain embodiments, the presence of MSI in at least three microsatellites of the patient's malignant DNA is to identify the patient as likely to respond to the Formula I or II compound therapy. The presence or absence of MSI in the microsatellites in malignant cellular DNA can be assessed using methods well known to those skilled in the art. For example, fluorescence multiplex analysis using five sets of markers to analyze five near-single-state single-nucleotide microsatellite loci (NR2 1, NR24, Bat25, Bat26, and Mono27) is available from Promega (Madison, WI) ). See also, for example, Nardon et al, Diagn. Mol. Pathol., 19(4), 236-242 (2010); Bacher et al, Dis. Markers, 20 (4-5), 237-250 (2004); Patent Publication No. 2009/0317815. Definitions Unless otherwise defined, all technical and scientific terms used in the present invention 156715.doc -41 - 201249840 have the standard meanings of the claimed subject matter. In the present invention, when there are a plurality of definitions for a term, the definitions in this section take precedence. When referring to URLs or other such identifiers or addresses, it should be understood that such identifiers can be changed and specific information on the Internet can come and go, but the equivalent information can be found by searching the Internet. References to this confirm the availability of the information and public communication. It is to be understood that the foregoing general description, In the present application, the use of the singular includes the plural unless otherwise specified. It must be noted that the singular forms "a", "a", "the" and "the" In this application, the use of "or" means "and/or" unless otherwise stated. In addition, the use of the terms "including" and other forms (such as "rinclude", "^^心" and "included") is not limiting. Unless otherwise stated, conventional methods such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are used. Unless otherwise specified, standard nomenclature using analytical chemistry, synthetic organic chemistry, and medical and pharmaceutical chemistry, and its standard experiments to procedures and techniques are used. In some cases, standard techniques are used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation, and delivery, and patient treatment. In certain embodiments, 'recombinant nucleic acid methods, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection) use standard techniques. In some embodiments, the reaction and purification techniques are carried out, for example, using a manufacturer's instructions kit or a conventional method such as 156715.doc.42. 8 201249840 or as described herein. As used throughout this application and the scope of the accompanying claims, the following terms have the following meanings: The term "microsatellite" as used in the present invention means a repeat of 1-6 DNA base pairs, and is referred to in the industry. DNA sequences of single sequence repeats (SSR), short tandem repeats (STR), or variable number tandem repeats (VNTR). A repeat sequence can be, for example, one, two, three, four, five, or six nucleotides (mono-, di-, tri-, tetra-, pen-, and hexanucleotides, respectively) The sequence of repeats is composed and can be repeated, for example, 3 to 100 times. See, for example, Eckert et al, Mol Carcinog, 48(4), 379-388 (2009). In certain embodiments, the microsatellite single nucleotide repeat sequence, eg, TTTTTTTTT (SEQ ID N0.1), is referred to as (T)9; TTTTTTTTTTT (SEQ ID ΝΟ·2), termed (T)n TTTTTTTTTTTTTTT (SEQ ID ΝΟ·3), called (T)15; TTTTTTTTTTTTTTTTTTTTT (SEQ ID NO. 4), called (T)21; and AAAAAAAAAAAAAAAAAAAAA AAAAAA (SEQ ID ΝΟ·5), called (A)27 . In certain embodiments, the microsatellite dinucleotide repeat, eg, GTGTGTGTGTGT (SEQ ID NO. 6), is referred to as (GT)6. In certain embodiments, the microsatellite trinucleotide repeat, for example, CTGCTGCTGCTG (SEQ ID N0.7), is referred to as (Ctg)4. In certain embodiments, the microsatellite tetranucleoside 酉mann repeat, for example, ACACTACTCACTCACTC (SEQ ID N0.8)' is referred to as (ACTC)4. In certain embodiments, the microsatellite is single-state, or near-monomorphic, mononucleic acid repeats (eg, NR21, NR24, Bat25, 156715.doc • 43-201249840)

Bat26 and Mono27). For example, a microsatellite can contain one or up to six or seven, or more, nucleotides that interrupt a repeat within a microsatellite.

Those skilled in the art recognize that microsatellites are typically found in human genomic DNA. In some embodiments, microsatellites are located within genes (e.g., DNA repair genes). In certain embodiments, the microsatellite can, for example, be located, inter alia, within the following genes: ATM (NM_000051), ATR

(NM_001184), CTIP (NM_002894), BLM (NM_000057), RAD51 (NM_002875), RAD51L1 (NM-002877), RAD51C (NM_ 002876), RAD51L3 (NM_002878), DMC1 (NM_ 007068), XRCC2 (NM-005431), XRCC3 (NM_ _005432), RAD52 (NM_002879), RAD54L (NM_ _003579), RAD54B (NM_012415), BRCA1 (NM_ _007295), BRCA2 (NM—000059), RAD50 (NM_ 005732), MRE11A (NM—005590) or NBS1 (NM_002485) ° In certain embodiments, the microsatellite is located within the intron/exon splice junction of the gene. In certain embodiments, the microsatellite is located within an intron of the gene. In certain embodiments, the microsatellite is located outside the gene. In some embodiments, the microsatellite is located within one of the control elements of the gene (e.g., a gene promoter). In certain embodiments, the gene is a DNA repair gene. In certain embodiments, the gene is a gene other than a DNA repair gene. In certain embodiments, the microsatellite is located outside of the gene. As used herein, the term "microsatellite instability" (MSI) means a change in a microsatellite found in human genomic DNA as compared to a reference microsatellite, 156715.doc -44- 8 201249840 eg 'insertion or deletion one or Multiple test pairs. For example, MSI can be characterized in that the microsatellite length or repeat sequence is different from, for example, in genomic DNA (when the microsatellite is inherited), or, for example, with microsatellite lengths or repeats in a general human population. Compared to the difference. In certain embodiments, reference microsatellites are found in the following cellular genomes: cells from humans that do not have MDS or AML, or cells from a human population characterized by no cancer. As used in the present invention, a lower MSI (MSI-low) is defined as having one base pair (bp) deletion or insertion in a microsweet star; a mid-level msi (in MSI-) is defined as having 2 bp in a microsatellite Deletion or insertion; advanced msi (MSI_) is defined as having a bp deletion or insertion in the microsatellite; and msi-stable (MSI-stable) is defined as no deletion or insertion in the microsatellite. The term "alkenyl" as used in the present invention means a straight, branched, or cyclic group containing 2 to 1 carbon and containing at least one carbon-carbon double bond formed by removing two hydrogens (in this case). Hereinafter, it is also referred to as "cycloalkenyl" hydrocarbon. In some embodiments, the alkenyl group is a monovalent group or a divalent group (i.e., an 'alkenyl group'). In some embodiments, an alkenyl group is optionally substituted. Illustrative examples of dilute bases include, but are not limited to, ethylenyl, 2-propenyl, 2-indenyl-2-(tetra)yl, 3-butane, 4-pentenyl, 5-hexyl, 2·heptyl , 2-methyl_1_heptenyl, and 3-decenyl. The term "alkoxy" as used in this month means the alkyl group as defined in the present invention which is attached to the parent molecular moiety via an atom. Illustrative examples of alkoxy groups include, but are not limited to, capsid I ^ ^ methoxy, ethoxy, propoxy, 2-propoxy 'butoxy, second-butoxy, pentyloxy, and Oxygen. 156715.doc -45· 201249840 The term "shallow" as used in the present invention means a straight bond, a bond, or a ring containing (four) carbon atoms (in this case, also referred to as "ring-burning group"). Illustrative examples of thiol groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, second-butyl & sx^butyl, tert-butyl, n-pentyl, Isoamyl, neopentyl, n-hexyl, 3·hexylhexyl, 2,2-dimethylpentylmethylpentyl, n-heptyl, n-octyl, n-decyl and n-decyl. The term "Cl_C6_alkyl" as used in the present invention means a straight bond, a bond, or a ring (in this case, also referred to as "cycloalkyl") hydrocarbon containing one carbon atom. Illustrative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, second-butyl, tert-butyl, cyclobutyl, ruthenium Base, isopentyl, neopentyl, cyclopentyl and n-hexyl. As used herein, the term "ring-based" means a monocyclic or polycyclic group H containing only carbon and hydrogen, including those saturated, partially saturated or fully saturated. The cycloalkane f includes a group having 3 to 1 ring atoms. Representative examples of cyclic groups include, but are not limited to, the following:

Λ . , Λ , co . CO 〇〇, 〇〇, 〇〇 in '一. In some embodiments 156715.doc 8 •46-201249840, depending on the structure, the cycloalkyl group is a monovalent group or a divalent group (e.g., an exocyclic group). The term "cycloalkyl" as used in the present invention refers to a group which is optionally substituted with hydrazine, 2, 3, or 4 substituents selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxy. Carbonyl group, alkyl group, alkylcarbonyl group, alkylcarbonyloxy group, sulfur-burning group, alkylthioalkyl group, alkynyl group, carboxyl group, cyano group, formyl group, haloalkoxy group, functional alkyl group, dentate , hydroxy, hydroxyalkylene, sulfhydryl, pendant oxy, -NRARA, and (nrarb)carbonyl. The term "cycloalkylalkyl" as used in the present invention means a cyclosporin as defined in the present invention which is bonded to the parent molecular moiety through a thiol group as defined in the present specification. Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylindenyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and 4-cycloheptylbutyl. The term "carbocyclic ring" as used in the present invention refers to a compound which contains one or more covalently closed ring structures, and the atoms forming the ring main chain are all carbon atoms. The term "carbocyclic ring" as used in the present invention means a ring in which each atom forming a ring is a carbon atom. Carbocycles include those formed by three, four, five, six, seven, eight, nine or more carbon atoms. The carbon ring needs to be replaced. The term "alkoxyalkyl" as used in the invention means at least one alkoxy group as defined in the present invention which is bonded to the parent molecular moiety through an alkyl group as defined in the present invention. Illustrative examples of alkoxyalkyl include, but are not limited to, 2-methoxyethyl, 2-ethoxyethyl, tert-butoxyethyl, and methoxymethyl. As used herein, the term "oxygen ketone" means the 156715.doc as defined by the present invention.

S-47·201249840 The carbonyl group defined by the present invention is attached to the alkoxy group of the parent molecular moiety. Illustrative examples of alkoxy groups include, but are not limited to, methoxycarbonyl, ethoxylated, and tert-butoxycarbonyl. As used herein, the term "alkoxycarbonylalkyl" means an alkoxycarbonyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. The term "alkylcarbonyl" as used in the present invention means an alkyl group as defined in the present invention which is bonded to the parent molecular moiety through a carbonyl group as defined in the present invention. Illustrative examples of alkylcarbonyl groups include, but are not limited to, ethyl hydrazino, 1-sided oxy propyl, 2,2-diyl-1*, pendant oxypropyl, 1-sided oxybutyl, and 1- Side oxypentyl. As used herein, the term "alkylcarbonyloxy" means an alkylcarbonyl group as defined herein appended to the parent molecular moiety through an oxygen atom. Illustrative examples of alkylcarbonyloxy groups include, but are not limited to, ethenyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy. The term "alkylthio" or "thioalkoxy" as used in the present invention means an alkyl group as defined in the present invention which is bonded to the parent molecular moiety through a sulfur atom. Illustrative examples of alkylthio groups include, but are not limited to, methylthio, ethylthio, butylthio, tert-butylthio, and hexylthio. The term "alkylthioalkyl" as used in the present invention means an alkylthio group as defined in the present invention which is bonded to the parent molecular moiety through an alkyl group as defined in the present invention. Illustrative examples of alkylthioalkyl include, but are not limited to, sulfonylthio, 2-(ethylthio)ethyl, butylthiomethyl, and hexylthioethyl. As used herein, the term "alkynyl" means a straight-chain, branched hydrocarbon having 2 to 1 carbon and containing up to 1567 丨 5.d〇C, 48. 8 201249840 with one carbon-carbon triple bond. In some embodiments, , , and * are to be replaced. Illustrative examples of alkynyl groups include, but are not limited to, B-propyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl. As used herein, the term "aromatic" refers to a planar ring having a delocalized π-electron system containing (iv) paper electrons, where n is an integer. In some embodiments, the aromatic ring system is formed from 5, 6, 7, 8, 9, or more atoms. In other embodiments, the 'aromatic group' is optionally substituted. This term includes a monocyclic or fused ring polycyclic (i.e., the ring shares a pair of adjacent carbon atoms) groups. As used herein, the term "aryl" refers to an aromatic ring which forms a ring of carbon atoms. In some embodiments, the aromatic ring system consists of 5, 6 '7, 8, 9, or 9 The above carbon atoms are formed. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthryl, fluorenyl and fluorenyl. In some embodiments, the term "aryl" as used in the present invention means an aryl group which is optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of: Alkoxy group, alkoxy group, alkoxy group, alkoxycarbonyl group, alkyl group, alkylcarbonyl group, alkylcarbonyloxy group, thiol group, thiol group, block group, several groups, cyano group, Methyl ether, dentate oxy, ii alkyl, dentate, hydroxy, hydroxyalkyl, fluorenyl, nitro, -NRaRa, and (NRaRb) groups. As used herein, the term "arylalkyl" means an aryl group as defined herein appended to the parent molecular moiety through an alkyl group as defined herein. Illustrative examples of aryl groups include, but are not limited to, benzyl, 2-phenylethyl, -phenylpropyl, 156715.doc • 49-201249840 1-methyl-3-phenylpropyl, and 2-naphthalene -2-ylethyl. The term "carbonyl" as used in the present invention means a _C(〇)- group. The term "carboxy" as used in the present invention means a -COOH group. The term "cyano" as used in the present invention means a -CN group. The term "mercapto" as used in the present invention means a _C(0)H group. The term "halo" or "halogen" as used in the present invention means -I or -F. "Alkyl" means a -SH group. "Nitro" means a -N02 group. "Hydroxy" means an -OH group. "Sideoxy" means =0 group. "Key" or "single bond" means two atoms or two, in which case the atom to which the bond is bonded is considered to be a term used in connection with the present invention. The term used in the present invention. The term used in the present invention is used in the present invention. The term chemical moiety used between the parts is a part of the large substructure. The terms "dentate alkyl", "alkenyl", "dentate alkynyl" and "# alkoxy" as used in the present invention include alkyl, alkenyl, alkynyl groups in which at least one hydrogen is replaced by a halogen atom. And alkoxy structure. In some embodiments in which two or more hydrogen atoms are replaced by dentate atoms, all of the dentate atoms are identical to each other. In other embodiments in which two or more hydrogen atoms are replaced by a functional atom, not all of the south atoms are identical to each other. The terms "fluoroalkyl" and fluoroalkoxy" respectively include a dentate alkyl group of a dentate fluoro group and a dentate alkoxy group. In some embodiments, the acyl group is optionally substituted. The term "ester" refers to a chemical moiety having the formula -COOR wherein R is selected from alkylalkyl, aryl, heteroaryl (via ring carbon bonding) and heterocycloalkyl 156715.doc 201249840 (via ring carbon) Bond). In some embodiments, any of the hydroxyl groups, or carboxyl side chains, of the compounds of the invention are esterified. The terms "hetero (four)", "separation" and "hetero" in the present invention include - or a plurality of skeleton chain atoms selected from atoms other than carbon (for example, oxygen, nitrogen, sulfur, shi, disc or a combination thereof). The appearance of the substituted base, gynecyl and alkynyl groups. The term "hetero atom" as used in the present invention means an atom other than carbon or hydrogen. The heteroatoms are usually independently selected from the group consisting of oxygen, sulfur, nitrogen, and arsenic, but not: at the atoms. In the embodiment in which two or more hetero atoms are present, 'two or more hetero atoms are the same as each other, or some or all of the two or more hetero atoms are different from each other. = The term "ring" as used in the invention refers to a structure that is either covalently closed. Ring == (for example, aryl and cycloalkyl), heterocyclic (for example, heteroaryl and heterocycloalkyl), aristora (for example, aryl and heteroaryl) (for example, cycloalkyl and heterocyclic) alkyl). In this side, take the rod. / .^ ^ In the second embodiment, the surround is required to replace the part of the ring system in some embodiments. As used herein, the term "loop" means "..." means "two or more rings, or two or more rings that share the junction of one or more bonds:". "" means the two terms "heteroaryl" or alternatively - selected as "heteroaromatic one or more ring heteroatoms selected from nitrogen, oxygen and sulfur" 4 including aromatic or "heteroaryl" moieties Is a ring of at least two of the "heteroatom-containing aromatic groups. In some embodiments, the polycyclic L = atomic nitrogen is not fused. An illustrative example of a heteroaryl group is either fused or limited to the following : 156715.doc •51- 201249840 n^n 〇>,〇>, ύ,ύ ύ 'Ο Ο,Ο,〇

Ν In some embodiments, depending on the structure, a heteroaryl is a monovalent group or a divalent group (ie, a heteroaryl group). The term "heteroaryl" means hydrazine, 1, 2, 3. A heteroaryl group substituted with 4 or 4 substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, Alkylthio, alkylthioalkyl, alkynyl, carboxy, cyano, methionyl, dentate, alkoxy, hydroxy, hydroxyalkyl, decyl, nitro, - NRARB, and -(NRaRb)carbonyl. As used herein, the term "heteroarylalkyl" means a heteroaryl group as defined herein appended to the parent molecular moiety through an alkyl group as defined herein. Listed examples of heteroarylalkyl include, but are not limited to, pyridylmethyl. The term "heterocycloalkyl" or "non-aromatic heterocyclic ring" as used in the present invention is a non-aromatic ring which forms one or more atomic hetero atoms of the ring. The "heterocyclic group" or "non-aromatic heterocyclic" group means a cycloalkyl group including at least one hetero atom selected from nitrogen and sulfur. In some embodiments, the groups are fused to a base or heteroaryl. In some embodiments, the heterocycloalkyl ring system is composed of four, five, six, six, seven, eight, nine ', and anthracene atoms: 156715.doc • 52-201249840. In some embodiments, a heterocycloalkyl ring is optionally substituted. In certain embodiments, a heterocycloalkyl group contains one or more carbonyl or thiocarbonyl groups, for example, a group containing pendant and thio groups. Examples of heterocycloalkyl groups include, but are not limited to, indoleamine, lactone, cyclic quinone imine, cyclic thioimine, cyclic amino phthalate, tetrahydrothiopyran, 4H-pyran, tetra Hydropyran, hexahydropyridine, 1,3-dioxin, 1,3-dioxane, iota, dioxin, 1,4-dioxane, six Hydropyrazine, anthracene, % oxathiane, L4·oxathiane, 1,4-oxathiane, tetrahydro-hydrazine, 4-thiazine, 2Η-1,2 · Oxazine 'maleimide, amber imin, barbituric acid, thiobarbituric acid, diketopehydropyrazine, beta-urea urea, dihydrouracil, morpholine, dioxane , hexamethylene-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline, pyrazole, imidazoline, imidazolidinium , i 3_ dioxole, 1,3-dioxolane, 1,3-dithiol, anthracene, 3-dithiolane, isoxazoline, isoxazole, evil Oxazoline, oxazolidine, oxazolidinone thiazoline, thiazolidine and anthracene, 3-oxothiolane. Illustrative examples of heterocycloalkyl (also known as non-aromatic heterocycles) include, but are not limited to, 0

156715.doc 53- 201249840 Ο

Ο

00, ^, base also includes all rings > . The term heterocycloalkanediose and oligosaccharide t^carbohydrate, including but not limited to monosaccharides, = "heterocycle" refers to the heteroaryl and heterocycloalkyl groups used in the present invention, which are long, 曰B 1 to 4 Each of the heteroatoms selected from the group consisting of ruthenium, S&N, wherein each heterocyclic group has 4 to 〇 atoms in the support of the ring, the US group, and the premise that the soil does not contain two An adjacent 0 or S atom. In the present invention:::: the number of carbon atoms in the heterocycle (for example, the heart ^, etc., two other atoms (heteroatoms), such as the W heterocycle", the amount in the -= towel carbon family, Μ refers to the ring towel atom The total number of sub-""through the order, it should be understood that the 'heterocyclic ring has other heterogeneous numbers in the ring, m 4 6-membered heterocyclic ring" and the like refers to the total number of atoms contained in the ring = ie, 4 members, 5 members or 6 a member ring 'in which at least one atomic carbon precursor is Γ: an atomic hetero atom and the remaining 2 to 4 atomic carbon atoms or oxime in the embodiment 'in two or more heteroatoms, Two or more heteroatoms are the same or different from each other. In the -i embodiment, the heterocycle is optionally substituted. In some embodiments, at the heteroatom or via a carbon atom, the "heterocycloalkane" The group includes a group having only 4 atoms, but the heteroaryl group has 5 atoms in its ring system. The heterocyclic group includes a benzo-doping ring system. One example of the group 4 is a heterocyclic butyl group. (Derived from a gas-heterocyclic butyl burning) The 5th member of the heterozygous group is the winter sitting group. The example of the 6-membered heterocyclic group is t 156715.doc 8 •54· 2012498 Examples of the 40-group, and 1-membered heterocyclic group are quinolyl groups. Examples of heterocyclic leukosyl groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydron-decyl, tetraapyridyl, Dihydropyranyl, tetrahydrothiopyranyl, ruthenium-hexahydrogen, decyl, hydrazine-sulfonyl, hydrazine, hexahydro, hexanyl Cyclobutyl, oxetanyl, thioheterobutyl, high hexahydropyridyl, oxetanyl, thiomethyl, oxazolidinyl, diazepeq, thioxime, 1,2,3,6-tetrahydrogen ratio ° base, 2-. Ratio" each leaching base, 3-° Β 琳 琳, dihydro β 引 朵, 2Η- ° than 喃, 4Η- ° σ 南 、, ° 恶 恶, 1,3-dioxolyl, pyrazolinyl, dithiaalkyl, dithiolanyl, dihydropyranyl, dihydro sinyl, Dihydrofuranyl, pyridyl, azide, imidazolyl, imipenyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3 吲Examples of fluorenyl and quinone. Examples of heteroaryl are η-pyridyl, imidazolyl, pyrimidinyl, cyano. Tetras-sulphate, indoleyl, thiophene, iso-octagonal, sitting, ridge, stagnation, stagnation, stagnation, heterosexual beta, base ratio, ratio, base, porphyrin Quinolinyl, fluorenyl, benzimidazolyl, benzofuranyl, porphyrinyl, oxazolyl, pyridazinyl, hydrazine, pyridazinyl, triazinyl, isodecyl, acridine Base, mercapto, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazinyl, benzothienyl, benzothiazolyl, benzoxazolyl, porphyrinyl, quinoxalinyl , naphthyridinyl and furopyridinyl. In some embodiments, the above-described groups derived from the groups listed above are attached to or attached to c where possible. For example, in some embodiments In the case, the group derived from pyrrole is in the range of -1 -yl (attached to oxime) or ηbilor-3-yl (attached to c). Further 'in some embodiments' the group derived from imidazole is imidazolium- or oxazol-3-yl (both attached to ν) or imidaz-yl, imidazolyl or imi- 156715 .doc -55· 201249840 5-base (all attached to C). Heterocyclic groups include benzofused ring systems and ring systems substituted with one or two pendant oxy (= fluorene) moieties (eg, pyrrolidin-2-indole). In some embodiments, depending on the structure The heterocyclic group is a monovalent group or a divalent group (that is, a heterocyclic group). The heterocyclic ring of the present invention is substituted with hydrazine, i, 2, 3, or 4 substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, Alkylcarbonyl, alkylcarbonyloxy, alkylthio, alkylthioalkyl, alkynyl, carboxy, cyano, fluorenyl, dentate alkoxy, haloalkyl, _, hydroxy, hydroxy Alkyl, fluorenyl, nitro, _NRaRb, and -(NRaRb) groups. "Hypercycloalkoxy" means a heterocycloalkyl group as defined herein appended to the parent molecular moiety through an alkoxy group. -#Cycloalkylthio" refers to a heterocycloalkyl group as defined herein appended to the parent molecular moiety through a sulfur-burning group. The term "heterocyclooxy" refers to a heterocycloalkyl group as defined in the present invention which is attached to the parent molecular moiety through an oxygen atom. The term "heterocyclicthio" refers to a heterocycloalkyl group as defined in the present invention which is attached to the parent molecular moiety through a sulfur atom. The term "heteroaryl alkoxy" refers to a heteroaryl group as defined herein appended to the parent molecular moiety through a pendant oxy group. The term "heteroarylalkylthio" is defined as a heteroaryl group as defined herein appended to the parent molecular moiety through an alkanethiol. The term "heteroaryloxy" refers to a heteroaryl group attached to the parent molecular moiety through an oxygen atom. 1567I5.doc 8 -56 - 201249840 The term "heteroarylthio" refers to a heteroaryl group of the invention which is attached to the parent molecular moiety through a sulfur atom. New, in some embodiments, the term "member ring" encompasses any ring structure. ». "A member" is intended to mean the number of skeleton atoms that make up the ring. Thus, for example, 5' cyclohexyl...(4)" is a 5-membered ring of a cyclamate, a 6-membered ring, and a cyclic fluorenyl group, a 0-to-0, a furan, and a thiophene.丄:: The term "non-aromatic 5, 6, 7, 8, 9, 1 〇, " or ", 衣衣j" is used in the context of the invention as defined by two carbon rings (on the same carbon atom) (forms a spiro structure) or a different carbon atom (where two rings share - or a plurality of bonds) and consists of 5 to 12 originals in their overall ring system: (where one of the rings is formed Or a heterocyclic alkyl group of a plurality of atomic heteroatoms. Non-limiting examples of non-6^^^^, oxime or bicyclic heterocycles include, but are not limited to, 2 azabi, 7-azabicyclo[2.2 .1] heptyl, 2-azabicyclo[32〇]heptyl, 3-azabicyclo[32〇]heptyl, azaspiro[2·4]heptyl, 5-azaspiro[2_4]heptane Base, 2_oxa·5_azabis%[2·2.1]heptyl, 4·nitrogen off [2.5]octyl, 5-azaspiro[2.5]octylazinospiro[3.4]octyl, 6-Azaspiro[3.4]octyl, 4-oxa-7-azaspiro[2·5]octyl, 2·azabicyclo[2.2.2]octyl, 1,3-diazabicyclo [2.2.2] Octyl, % azaspiro[3.5]fluorenyl, 6-azaspiro[3·5]fluorenyl, 5_sideoxy_8_gashelix[3.5]fluorenyl, human hydrogen ring Ethylene [c]« is more specific than η, octahydroquinolinyl, 2,3,4,6, 7,9a-hexahydro-1Η-quinazinyl, decahydropyridinium S'2-amhyl, decahydro-1H-« than bite [l,2-a]azinyl, b azabis [2_2'1]1 base, 1 heterobicyclo[3.3.1] mercapto, quinuclidinyl, and 1_azabicyclo[4.4.0]decyl. 156715.doc 57· 201249840 The term used in the present invention By stretched yarn is meant at least one hydroxyl group attached to the parent molecular moiety through a stretch alkyl group as defined by the present invention as defined herein. Illustrative examples of hydroxyalkylene include, but are not limited to, hydroxyindenylene, 2-hydroxy- Ethyl, 3-hydroxyl-propyl and 4-hydroxyl-heptyl. The term "portion" as used in the present invention refers to a specific fragment or functional group of a molecule. The chemical moiety is generally considered to be embedded in or attached to the molecule. Chemical entity. The term "sulfonyl" as used in the present invention means _sb)2_R, wherein the ruler is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (via ring carbon bonds) And a heterocycloalkyl group (bonded via a ring carbon). The term "ethinyl" as used in the present invention refers to a group of the formula _c(=〇)CH3. The term "isocyanato group" as used in the present invention refers to a group of the formula _NC〇. The term "thiocyanato" as used in the present invention refers to a group of the formula -CNS. The term "isothiocyanato group" as used in the present invention refers to a group of the formula -NCS. As used herein, the substituent "R", which appears alone and without a numerical designation, is selected from alkyl, cycloalkyl, aryl, heteroaryl (via ring carbon linkage) and non-aromatic heterocycle (via a substituent of a ring carbon bond). The term "substituted" means that the group as referred to is optionally substituted (substituted or unsubstituted) with one or more other groups individually and independently selected from the group consisting of alkyl, cycloalkyl, aryl. , heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, sulfhydryl, thiol, arylthio, sulfathion, aryl sulfoxide, alkyl sulfone, aryl sulfone , cyano, halo, carbonyl, sulphur -58 - 156715.doc 8 201249840 oxime, isocyanate, thiocyanyl, isothiocyanate, nitro, fully dentate alkyl, perfluoroalkyl , a mercaptoalkyl group, and an amine group (including mono- and disubstituted amine groups), and protected derivatives thereof. For example, an optional substituent is LSRS, wherein each ^^ is independently selected from the group consisting of a bond, _〇_, =, _^, -s(=0)-, -S(=〇)2-, -NH- , -NHC(〇)-, _C(〇)NH_, S(=0)2NH-, -NHS(=0)2, -0C(0)NH·, -NHC(0)〇,·(substituted or Unsubstituted 2Cl-C6 alkyl) or (substituted or unsubstituted C2_Ce dilute); and each Rs is independently selected from hydrazine, (substituted or unsubstituted lower alkyl), (substituted Or an unsubstituted lower cycloalkyl), heteroaryl or heteroalkyl group means a removable group which can improve the reaction of a functional group (for example, a hydroxyl group, a ketone or an amine). Sexuality prevents undesired reactions from occurring during the synthesis procedure and subsequent removal. Examples of hydroxy protecting groups include, but are not limited to, methylthiomethyl, tris-dimethylformamidinyl, tert-butyldiphenylcarbamyl, ether (eg, decyloxymethyl), and esters. (including acetyl benzyl benzoyl, and the like). Examples of the ketone protecting group include, but are not limited to, acetal, hydrazine, hydrazine-substituted hydrazine (e.g., fluorenyl-benzyl hydrazine, fluorenyl-phenylthiomethyl hydrazine), 1-isopropylcyclohexyl hydrazine, and the like. Examples of amine protecting groups include, but are not limited to, tert-butoxycarbonyl (Boc) and benzyloxycarbonyl (Cbz). The term "optionally substituted" as defined herein means that the reference group is substituted with zero, one or more substituents as defined herein. In some embodiments, the compounds of the invention exist in stereoisomeric forms in which an asymmetric or palmar center is present. The stereoisomer is represented by (R) or 156715.doc -59-201249840 (S) depending on the configuration of the substituent around the palm carbon atom. The terms (8) and (s) used in the present invention are jupac 1974

The configuration defined in Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem" (1976), 45: 13-30 (incorporated herein by reference). The embodiments described herein specifically include various Stereoisomers and mixtures thereof. Stereoisomers include enantiomers, diastereomers, and mixtures of enantiomers or diastereomers. In some embodiments, synthetic The individual stereoisomers of the compounds are prepared from commercially available starting materials containing asymmetric or palmitic centers, or by preparative resolution of the racemic mixture. The resolution methods are illustrated as follows: (1) Attaching an enantiomeric mixture to a palmitic adjuvant, separating the resulting mixture of diastereomers by recrystallization or chromatography and releasing the optically pure product by a self-help agent, or (2) in the palm Direct separation of the mixture of optical enantiomers on a chromatography column. The methods and formulations of the present invention comprise an N-oxide, crystalline form (also known as a polymorph) of the compound of the invention. Or pharmaceutically acceptable salt, Active metabolites of such compounds having the same type of activity. In some cases the compounds are present as tautomers. All tautomers are encompassed within the scope of the compounds provided herein. In some embodiments The compounds of the present invention exist in the form of unsolvated forms and solvates with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds provided herein are also disclosed herein. Compounds and their substitutions throughout the specification, in some embodiments, to provide stable moieties and compounds. 156715.doc 201249840 Preparation of Compounds of the Invention In certain embodiments, A synthetic technique for the synthesis of the compounds of the invention' includes standard synthetic techniques and synthetic methods of the invention. In specific embodiments, the following synthetic methods are utilized: Synthetic reaction schemes are prepared in various ways in certain embodiments. a compound of formula (1) (including la to If), as described in the synthesis schemes in Figures 1 and 2. In each reaction diagram, the variables ( For example, R!, R2, r3 'r4, r5, γ, and z) correspond to the same definitions as those described above, and R is an alkyl group and γ is the same or different base defined by γ. Circles and Ζ' are the same or different groups defined by 。. In some embodiments, 'the compounds are synthesized using methods similar to those described in the following by using suitable alternative starting materials. In some embodiments The compound of the formula (Ia, and Ib) is synthesized according to the synthesis reaction scheme i (wherein Y is the same as Z). Therefore, by using the aldehyde 2 at an ambient temperature or a high temperature in the presence of a base (preferably a basic alkoxide) Intermediate 3 (wherein Rs is hydrogen) is prepared by subjecting 4-aminoisobenzofuran-i(3H)-one 1 to condensation in a suitable solvent such as ethyl acetate or ethyl propionate. The compound of formula la (wherein Rs is argon) is prepared by treating intermediate 3 with hydrazine hydrate at ambient or elevated temperature. The compound of formula 13 (wherein R5 alkyl or substituted alkyl) is prepared by reductive amination using KHO (wherein R7 is an alkyl group, substituted alkyl) from a compound of formula la (wherein R5 is hydrogen). In some embodiments, the compound of formula lb is prepared by further modifying la. A compound of formula lb having a different gamma and oxime at the 2- or 3-position can be obtained by carrying out a suitable functional group conversion on the gamma and oxime moieties. 156715.doc • 61 · 201249840 Synthesis Reaction Figure 1

In certain embodiments, the compound formula (Ic, and Id) is synthesized according to the synthesis reaction scheme 2. For example, the intermediate 5 is prepared by condensing the reagent i in the presence of a water absorbent (for example, sodium sulfate or magnesium sulfate) at a temperature of about 5 ° in the environment or at a high temperature in a base (preferably a base). This intermediate is subjected to a subsequent condensation reaction with another in the presence of a suitable alkoxide (e.g., ethyl acetate or ethyl propionate) to give intermediate 6 (where & hydrogen). The compound of formula Ic (where hydrogen is employed) is prepared by treating intermediate 6 with hydrazine hydrate at ambient or elevated temperature. Preparation of a compound of formula Ic (wherein Rs is an alkyl group, substituted alkyl group) by reductive amination using R7-CHO (wherein a determinant 7 alkyl group or a substituted alkyl group) from a compound of formula Ic (wherein R5 is hydrogen) ). In some embodiments, 'compounds of formula Id are prepared by further modification 1 (by formulating the appropriate functional group conversion of the Y and Z moieties, a compound of formula Ic having a different gamma and Z, at the 2 or 3 position, can be obtained. Synthesis reaction diagram 2

Example 2 - 159 of International Patent Publication No. WO 2010/017055 A2, the entire contents of which is incorporated herein by reference in its entirety, the disclosure of the disclosure of the entire disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of 156715.doc 8 -62· 201249840 Certain medical terms The term "acceptable" as used in relation to a formulation, composition or ingredient is meant to have no detrimental effect on the general health of the individual being treated. As used herein, the term "selective binding compound" refers to a compound that selectively binds to any portion of one or more target proteins. As used herein, the term "selectively binds" refers to the ability of a selectively bound sigma to bind to a target protein (e.g., PARP) with greater affinity than its affinity for binding to a non-target protein. In certain embodiments, the specific binding clasp is at least about 10 fold, about 50 fold, about 1 () 0 fold, about 250 fold, about 5 fold fold, about 1 fold greater than the affinity for the non-target. 〇 or more times the affinity binds to the target. As used herein, the term "dry protein" refers to a portion of a protein molecule or protein that selectively binds to a compound. In certain embodiments, the target protein-based enzyme poly(ADP-ribose) polymerase (pARp) ^ "the "treating" or "treatment" used in the present invention encompasses reactive and preventive measures. Either or both, for example, designed to suppress, delay or delay the onset of a disease or condition, to reduce or ameliorate a disease or condition, and/or to alleviate, ameliorate, attenuate, or cure a disease or condition and/or Or its symptoms. As used in this month, by administering a particular compound or pharmaceutical composition, the symptoms of a particular condition are attributable to the administration or persistence or temporary, persistence or association of the compound or composition. Any severity of transient loss, delayed onset, slowed progression, or reduced duration. I567I5.doc •63- 201249840 The term “modulator” as used in this month refers to a compound that alters the activity of a molecule. For example, a modulator includes an amount that causes the activity compared to the magnitude of a certain activity of a molecule in the absence of a modulator. A compound that increases or decreases in grade. In certain embodiments, the agent is an inhibitor that reduces the enthalpy of the molecule's activity or activities. In certain embodiments, the inhibitor completely blocks one or both of the molecules. In certain embodiments, the modulator is an activator that increases the amount of the molecule to the level of one activity. In certain embodiments, the presence of a conditioning agent results in an activity that is not present in the absence of a conditioning agent. The term "selective modulator J" as used in the present invention refers to a compound which selectively modulates the activity of a target. The term "PARP" as used in the present invention refers to a family of enzyme poly(ADp_ribose) polymerases comprising about 18 proteins, in particular Condensed (ADP_ribose) polypurin-1 (PARP-1) and poly(ADP-ribose) polymerase_2 (parp_2). As used herein, the term "selective pARp modulator" refers to a compound that selectively modulates at least one activity associated with enzymatic poly(ADP-ribose) polymerase (PARP). In various embodiments, a selective modulator will select Sexually modulates the activity of several members of the PARP-1, PARP_2, PARp_apARp_2 or enzyme poly(ADp ribose) polymerase (PARP) family. The term "method of inhibiting PARP" as used in the present invention refers to a method of inhibiting the activity of one or more of the enzyme poly(ADP-ribose) polymerase (PARP) family. The term "inhibiting PARP" as used in the present invention refers to the activity of inhibiting one or more of the enzyme poly(ADI ribose) polymerase (PARP) family. The term "regulating enzyme poly(ADP-ribose) polymerase activity" as used in the present invention refers to a regulatory enzyme poly(ADP-ribose) polymerase (PARP) family - or • 64-156715.doc 8 201249840 active. As used herein, the term "selective modulation" refers to the ability of a selective modulator to modulate the target activity to a greater extent than its ability to modulate non-target activity. In certain embodiments, the activity-free selectivity is adjusted, for example, by about 2 times up to about _ times, in some embodiments, about 2, 5, 10, 50, 1 〇〇, 15 〇, 2 〇〇. , 25G, 3〇G, 35G, complete, 45 () or greater than just double. As used herein, the term "cancer" refers to abnormal growth of cells that tend to proliferate in an uncontrolled manner and in some cases metastasize (diffuse). Types of cancer include, but are not limited to, solid tumors (eg, the following tumors: bladder, intestine, brain, breast, endometrium, heart, kidney, lung, lymphoid tissue (lymphoma), nest, gonads, or other endocrine organs) (thyroid), prostate, skin (melanoma) or hematological tumor (eg leukemia md^a. The term "carrier" as used in the present invention refers to a relatively non-toxic compound that facilitates the incorporation of a compound into a cell or tissue or The term "co-administered" or similar terms as used herein is intended to encompass the administration of a selected therapeutic agent to a single-patient, and is intended to include "the treatment of the agents with the same or different routes of administration or at the same or different times. The term "diluent" is used to mean a compound that is used to dilute a target compound prior to delivery. The dilution includes a chemical that is used to provide a more stable environment to stabilize the compound. In certain embodiments, the benefit is transferred to a buffer solution. a salt (which may also control or maintain pH) as a diluent, including but not limited to a salt buffered saline solution. The term "effective amount" as used herein Or "therapeutically effective amount" means sufficient to treat a disease or condition of being - or more symptoms - given the extent of the 156715.doc

S -65- 201249840 The amount of the agent or compound administered. The results include a reduction in disease signs, symptoms or causes and/or amelioration or any other desired change in the biological system. For example, for therapeutic use, the term "from a policing" causes the symptoms of the disease to be relieved in the presence of a bed that contains too much of the composition of the compound. Any suitable technique, such as dose escalation, is used to determine the appropriate "effective amount" in any particular situation. The term "enhance" ("enhance" or "-") used in the present invention means to increase the desired effect. Thus, for enhancing the effect of a therapeutic agent, the term "enhancement" refers to the ability to increase the effect or extend the duration of the effects of other therapeutic agents in the system. As used herein, "enhancing effective amount" refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system. As used herein, the term "enzymatic cleavage linker" refers to an unstable or decomposable linker that is decomposed by one or more enzymes. The term "PARp_mediated" as used in the present invention refers to a condition or disease which is ameliorated by one or more of the enzyme poly(ADp-ribose) polymerase (PARP) family. The "metabolite" of the compound disclosed in the present invention is a derivative of the compound which is formed upon metabolism of the compound. The term "active metabolite" refers to a biologically active derivative of a compound formed upon metabolism of a compound. The term "metabolism" as used in the present invention refers to the sum of the processes by which an organism changes a particular substance, including but not limited to, a hydrolysis reaction and a reaction catalyzed by an enzyme. Thus, in some cases, the enzyme causes a specific structural change in the compound. In some embodiments, the invention is identified by administering a compound to a host and analyzing the tissue from the host, 156, 715. doc, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compound. Metabolite of the compound. As used herein, the term "modulating" means directly or indirectly interacting with a target to alter the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or expanding the activity of the target. As used herein, "pharmaceutically acceptable" or "therapeutic" refers to a material that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, such as a carrier or diluent. In certain instances, non-toxic and non-eliminating materials include materials which, when administered to an individual, do not cause substantial, undesirable biological effects and/or are not in a detrimental manner with any of the compositions contained therein. A group of interactions. The term "pharmaceutically acceptable salt" or "therapeutically acceptable salt" refers to a formulation of a compound which does not cause significant irritation to the organism to which it is administered and which does not abrogate the biological activity and properties of the compound. In some cases, by reacting a compound of the present invention with a mineral acid (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-sulfonic acid, salicylic acid) And the like) react to obtain a pharmaceutically acceptable salt. In some cases, a pharmaceutically acceptable salt is obtained by reacting a compound having an acidic group of the present invention with a base to form a salt such as the following: an ammonium salt; an alkali metal salt such as a sodium salt or a potassium salt. a soil salt, for example, a calcium or magnesium salt; a salt of an organic base such as dicyclohexylamine 'N-methylglucamine, serotonylmethylamine; and with, for example, arginine, an amine A salt formed by an acid or the like such as an amino acid, or obtained by other methods as defined above. 156715.doc -67 · 201249840 The term "pharmaceutical combination" as used in the present invention means a product produced by mixing or combining more than one active ingredient, and includes both fixed and non-solid combinations of the active ingredients. The term "fixed combination" means that the active ingredient (e.g., a compound of the present invention) and the auxiliary agent are administered to the patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredient (eg, a compound of the present invention) is administered to the patient as a separate entity simultaneously, in parallel or sequentially and without specific time-limited restrictions, wherein the administration can be in the patient's body. The effective concentration of the two compounds is provided. The latter also applies to cocktails, such as the administration of three or more active ingredients. The term "pharmaceutical composition" means a mixture of a compound of the present invention and other chemical components. The other chemical components are, for example, carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, And / or excipients. The pharmaceutical composition facilitates administration of the compound to an organism. There are a variety of techniques for administering compounds in the industry including, but not limited to, intravenous, oral, aerosol, parenteral, transocular, transpulmonary, and topical administration. "Prodrug" means an agent that can be converted into a parent drug in vivo. Prodrugs are usually used because in some cases they are easier to administer than the parent drug. In some cases, prodrugs can be administered orally for biological use, while parent drugs are not. In some cases, the prodrug has improved solubility in the pharmaceutical composition over the parent drug. Non-limiting examples of prodrugs can be administered in the form of esters ("prodrugs") to facilitate transport across the cell membrane (where water soluble versus fluidity) but then metabolized to the human cell to metabolize the acid (active entity) Compounds of the invention (where water soluble, beneficial). Another example of a prodrug may be a short (polyamino acid) bonded to an acid group or an amine group, 156715.doc • 68 - 201249840

The peptide can be metabolized to display, and the inactive moiety. In certain embodiments, a more active biological 'medical or therapeutic form that is chemically converted to a compound by a post-prodrug is administered in vivo. In certain embodiments, the prodrug is enzymatically metabolized to the biological, pharmaceutical or therapeutically active form of the compound by - or multiple steps or processes. The pharmaceutically active compound is modified to produce a prodrug whereby the active compound is regenerated after administration in vivo. In some embodiments, the drug is used to alter the metabolic stability or transport characteristics of the drug, to mask side effects or toxicity, to improve the taste of the drug, or to alter the (four) nature or characteristics of the drug. The term "individual" or "patient" encompasses both mammals and non-mammals. Examples of mammals include, but are not limited to, any of the following mammalian members: humans, non-human primates, such as chimpanzees and other baboons and monkeys; agricultural animals such as cattle, horses, sheep, goats, and piglets, such as rabbits , dogs and cats, experimental animals, including rodents such as rats, mice and guinea pigs and the like. Examples of non-mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human. The term "treatment" ("treating", "treating" or "treatment" as used in the present invention includes prophylactic and/or therapeutic alleviation, reduction or amelioration of symptoms of a disease or condition, prevention of other symptoms, improvement or prevention of symptoms. Potential metabolic cause, inhibition of disease or condition 'eg, arresting a disease or condition, reducing a disease or condition, causing a disease or condition to resolve, reducing a condition caused by a disease or condition, or terminating a disease or condition Symptoms. Pharmaceutical Compositions/Formulations 156715.doc • 69· 201249840 The present invention provides pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable diluent, excipient, and/or carrier. Furthermore, in some embodiments, the compounds of the invention are administered in a pharmaceutical composition wherein the compound of the invention is mixed with other active ingredients, in a combination therapies. A pharmaceutical composition for use in the present invention refers to a mixture of a compound of the present invention and other chemical components, such as a carrier, a stabilizer, a diluent, a dispersing agent, a suspending agent, and a thickening agent. The l, in the embodiment of the agent, and/or the excipient m, facilitates administration of the compound to the organism. The treatment or use provided by the present invention in the practice of the present invention comprises administering or using a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein. In a particular embodiment, the invention provides a method of treatment comprising administering to a mammal having a disease or condition to be treated the pharmaceutical composition. In one embodiment the 'mammalian is a human. In some embodiments, the therapeutically effective amount varies widely depending on the severity of the disease, the age and relative health of the individual, the efficacy of the compound, and other factors. The compounds of the present invention are used alone or in combination with one or more therapeutic agents as a mixture component in various embodiments. In certain embodiments, the pharmaceutical compositions provided herein are formulated for intravenous injection. In some aspects, the intravenously injectable formulations provided by the present invention are formulated as aqueous solutions, and in some embodiments It is formulated into a physiologically compatible buffer (such as Hank (ss〇iuti〇n), Ringer's solution (Ringer, SS〇lution), or physiological saline buffer). In some implementations, the pharmaceutical compositions provided by the present invention are formulated for administration via 156715.doc -70·201249840 mucosal administration. In some aspects, the transmucosal formulation includes a penetrant suitable for passage through the barrier. In certain embodiments, the pharmaceutical compositions & compositions provided herein are formulated for other parenteral injections, and suitable formulations include aqueous or non-aqueous solutions, and (in the embodiment) physiologically compatible buffers. Liquid or excipient. In certain embodiments, the pharmaceutical compositions provided by the present invention are formulated; in some aspects, the oral formulations 匕s and peony-acceptable carriers or agents provided by the present invention are administered. The agents of the present invention formulated together are capable of formulating the compounds of the present invention into tablets, powders, pills, dragees, capsules, liquids, gels, syrups! |Liquid, suspension, and the like for oral ingestion by a patient to be treated. In some embodiments, the medical preparation for oral administration is obtained by mixing one or more solid excipients with one or more compounds of the invention, as needed, grinding the resulting mixture, and if necessary, adding The granule mixture is then treated with a suitable adjuvant to obtain a troche or dragee core and the excipients include, inter alia, fillers, such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as 'corn meal powder' , wheat glutinous rice, rice starch, potato starch, gelatin, tragacanth, bismuth fiber, alizarin micro-Ba cellulose, propyl methyl cellulose, methylated cellulose; or other traits For example, a polyethylene base ketone (pvp or pavigone (P〇V1d〇ne)) or a dish acid. ^ It is necessary to add a disintegrating agent as needed, for example, cross-linking cellulose, polyethylene bismuth, gluten, or alginic acid or a salt thereof (for example, sodium alginate). 156715.doc 201249840 In certain embodiments, the invention provides a pharmaceutical composition formulated as a dragee core having a suitable coating. In certain embodiments, a concentrated sugar solution is used to form a suitable coating, and the concentrated sugar solution optionally contains gum arabic, talc, polyethylene, carbopol gel, and carbopol gel. ), polyethylene glycol, and/or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. In some embodiments, dyes and/or pigments are added to the drag, dragee, and/or coating thereof to, for example, identify or characterize different combinations of active compound doses. In certain embodiments, the pharmaceutical preparations used include oral-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In some embodiments, the compounded inserts contain a filler (eg, lactose), a binder (eg, powder), and/or a slip agent (eg, talc or magnesium stearate) and, if desired, a stabilizer. The active ingredient of the mixture. In certain embodiments, in soft capsules, the active compounds are dissolved or suspended in a suitable liquid such as a fatty oil, liquid paraffin or liquid polyethylene glycol. In addition, stabilizers are added as needed. In certain embodiments, the formulation for oral administration is in a dosage form suitable for such administration. In certain embodiments, the pharmaceutical compositions provided by the present invention are formulated for buccal or sublingual administration. In certain embodiments, the buccal or sublingual composition is in the form of a conventionally adjusted wiring agent, diamond (tetra), or gel. In certain embodiments, a parenteral injection involves a bolus or continuous infusion. In some embodiments, the formulation for injection is in a unit dosage form, such as in an ampoule or in an ampoule. In the multi-dose container, (4) 156715.doc -72- 201249840 is added at the same time. In some embodiments, the pharmaceutical composition of the present invention is in a form suitable for parenteral injection in the form of a sterile suspension, solution or emulsion in an oily or aqueous vehicle, and optionally contains a suspending agent. a formulation such as a stabilizer, and/or a dispersant. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water soluble form. In some embodiments, a suspension of the active compound is prepared as a suitable oily injection suspension. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil or synthetic fatty acid esters such as ethyl oleate or triglycerides or liposomes. In certain embodiments, the aqueous injection suspensions contain materials which increase the viscosity of the suspension, such as sodium methacrylate, sorbitol or dextran. The suspension also contains suitable stabilizers or agents which increase the solubility of the compound, as needed, to permit the preparation of highly concentrated solutions. In an alternate embodiment, the active ingredient is in powder form for constitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to use. In some embodiments, the compounds of the invention are administered topically. In a particular embodiment, the compounds of the present invention are formulated into a variety of compositions for topical administration, such as solutions, suspensions, lotions, gels, creams, lotions, creams or ointments. These pharmaceutical compounds may optionally contain solubilizers, stabilizers, tonicity enhancing agents, buffers and/or preservatives. In certain embodiments, the pharmaceutical compositions provided herein are formulated for transdermal administration of a compound of the invention. In some embodiments, the compositions are administered using a transdermal delivery device and a transdermal delivery patch. In certain embodiments the composition is a lipophilic emulsion or a buffered aqueous solution dissolved and/or dispersed in a polymer or adhesive. Such patches include those that are configured for sustained, pulsatile or on-demand delivery of a pharmaceutical agent. In some embodiments, the compounds of the present invention are delivered transdermally by the use of iontophoretic patches and the like by 156715.doc • 73-201249840. In certain embodiments, a transdermal patch provides controlled delivery of a compound (e.g., a compound of formula (1) or (11)) provided herein. In some embodiments, the rate of absorption is slowed by the use of a rate controlling membrane or by trapping the compound in a polymer matrix or gel. Instead, use an augmentation enhancer as needed to increase absorption. Absorbing enhancers and carriers include pharmaceutically acceptable absorbable solvents that aid in the delivery of the compound through the skin. By way of example, the transdermal device is in the form of a bandage comprising a backing member, a reservoir containing the compound, optionally with a carrier, and optionally for delivering the compound at a controlled and predetermined rate for a prolonged period of time. The rate control barrier to the host skin and the means for securing the device to the skin. In certain embodiments, the pharmaceutical compositions provided herein are formulated for administration by inhalation. In certain embodiments, the compounds of the invention are in the form of an aerosol, mist or powder in such pharmaceutical compositions formulated for inhalation. In some embodiments, the pharmaceutical compositions of the present invention are typically delivered in a aerosol spray-off form from a pressurized pack or nebulizer using a suitable propellant, for example, two gas two. Fluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In some aspects of pressurized aerosol, the dosage unit is determined by providing a valve to deliver a metered amount. In certain embodiments, capsules and ejectors, such as, by way of example only, gelatin, for use in an inhaler or insufflator, are formulated to contain a compound of the invention and a suitable powder base f (eg, lactose or powder) a powder mixture. In a second embodiment, the compound of the invention is formulated in a rectal combination 156715.doc 201249840: for example, an enema, a rectal gel, a rectal foam, a rectal aerosol, a suppository, a fruit test, or a retention enema Agent. In certain embodiments, the rectal composition optionally contains a conventional tincture base (eg, cocoa butter or other glycerol vinegar and synthetic polymers (eg, polyethylate phase n and the like)" in certain suppository forms of the composition. Medium, low scented butterflies (such as, but not limited to, a mixture of fatty acid glycerides, if desired in combination with cocoa butter) are first melted. In various embodiments provided herein, one or more physiologically acceptable ones are used in a conventional manner. The vehicle is formulated with a pharmaceutical composition comprising excipients and auxiliaries which facilitate treatment of the active compound into a pharmaceutically acceptable formulation. In certain embodiments, suitable formulations are selected depending on the selected formulation. Depending on the route, in each of the examples, any of suitable techniques, carriers, and excipients are employed. In some embodiments, pharmaceutical compositions comprising the compounds of the invention are manufactured in a conventional manner, only For example, by conventional mixing, dissolving, granulating, dragee-making, grinding, emulsifying, encapsulating, encapsulating or compressing processes, in certain embodiments, pharmaceutical composition packs At least one pharmaceutically acceptable carrier, diluent or excipient and a compound of the invention (as an active ingredient, in the form of a free acid or a free base, or a pharmaceutically acceptable salt). Further, the present invention The methods and pharmaceutical compositions include the use of oxides, crystalline forms (also known as polymorphs), and active metabolites of such compounds having the same type of activity. In some cases, the compounds of the invention are mutually mutated The present invention is in the form of a solvate and an unsolvated form of the compound described in the present invention. The solvate compounds include those which are compatible with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvate forms of the compounds provided herein are also considered to be compounds disclosed herein. In the embodiments, the pharmaceutical composition of the present invention includes other medical or pharmaceutical agents, carriers, adjuvants, such as preservatives, stabilizers. Wetting or emulsifying agents, solution promoters, salts for regulating osmotic pressure, and/or buffers. In other embodiments, the pharmaceutical compositions of the present invention also contain other therapeutically valuable substances. A method of containing a composition of a compound of the invention comprises formulating the compound with - or a plurality of pharmaceutically acceptable inert excipients or carriers to form a solid, semi-solid or liquid. Solid compositions include, but are not limited to, Powders, troches, dispersible granules, capsules, pills, and suppositories. The liquid composition includes a solution in which the compound is dissolved, an emulsion containing the compound, or a liposome, micelle, or a nanoparticle comprising the compound disclosed herein. The semi-solid composition includes, but is not limited to, a gel, a suspension paste. In various embodiments, the composition is in the form of a tau: a liquid solution or suspension, a solid suitable for dissolution or in a liquid prior to use. Form, or lotion. These compositions optionally contain small amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like. In some embodiments, a composition comprising a compound of the invention is present in a solution, suspension or both in liquid form. In one embodiment, 'when the composition is administered as a solution or suspension, the first portion of the agent is present in solution and the second portion of the agent is in particulate form 156715.doc •76·201249840 in a liquid matrix In suspension. In some embodiments, the liquid composition includes a gel formulation. In other embodiments, the liquid composition is aqueous. Useful aqueous suspensions optionally contain one or more polymers as suspending agents. Useful polymers include water soluble polymers (e.g., cellulosic polymers such as 'propyl propylcellulose), and water insoluble polymers (e.g., crosslinked carboxyl containing polymers). Useful compositions optionally comprise a mucoadhesive polymer selected from, for example, methyl cellulose, carbomer (acrylic acid polymer), poly(decyl methacrylate), polyacrylamide 'Polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran. Useful compositions include solubilizing agents as needed to aid in the dissolution of the compounds of the present invention. The term "solubilizing agent" generally includes an agent which causes a colloidal solution or a true solution to form a medicament. Solubilizers include certain acceptable nonionic surfactants such as polysorbate 8 oxime, and ocularly acceptable diols, polyethylene glycols (eg, polyethylene glycol 400), and glycol ethers. . Useful compositions include, if desired, one or more pH adjusting or buffering agents, including acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, Acetic acid

Α, ~ή,, drink and 祀 are included in the amount needed for A

Or ammonium cations and gas ions, seed salts. Such salts include those having sodium, potassium citrate, ascorbate, borate, 156715.doc •77·201249840 phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anion; Salts include sodium chloride, potassium hydride, sodium thiosulfate, sodium hydrogen sulfite, and ammonium sulfate. Certain useful compositions include one or more preservatives as needed to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as stearic acid and sulphuric acid, and quaternary chlorine compounds, such as benzalkonium chloride, cetyltrimethylammonium bromide and west. Cetylpyridinium chloride. Some useful compositions include one or more surfactants as needed to enhance physical stability or for other purposes. Suitable nonionic surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, for example, polyoxyethylene (6 oxime) hydrogenated t sesame oil; and polyoxyethylene alkyl ethers and alkyl phenyl ethers, for example, octyl oxime Alcohol 10, octoxynol 40. If desired, certain useful compositions may contain one or more antioxidants as needed to enhance chemical stability. Suitable antioxidants include, by way of example only, ascorbic acid and sodium metabisulfite. In some embodiments, the aqueous suspension composition is packaged into a single dose non-reclosable container. In an alternate embodiment, a multi-dose recloseable container is used, in which case a preservative is typically included in the composition. In any of the examples, any delivery system for a hydrophobic pharmaceutical compound is used. Examples of delivery vehicles or carriers for hydrophobic drugs are liposomes and emulsions. In certain embodiments, certain organic solvents are used, such as N-decylpyrrolidone. In some embodiments, a compound such as cough 780715.doc 8 201249840 is delivered using a sustained release system (e.g., a semipermeable matrix of a solid hydrophobic polymer containing a therapeutic agent). In the present invention, you can use vv, T π with various sustained release materials. In the second embodiment, the compound is continuously released. In the case of “this”, J is released in the Q-day of the number—in the case, the chemical properties and biostability of the treatments are also using other protein stabilization strategies. In certain embodiments, the formulations or compositions of the present invention benefit from and/or optionally comprise an antioxidant, a metal nutrient, a thiol-containing compound, and other general stabilizers. Examples of such shots include, but are not limited to, (4) about 0.5. /. Up to about 2% w/v glycerol, (8) about 〇 to about (9) w/v of methionine, (4) about G 1% to about 2% w/v of monothioglycerol, (4) about 1 mM to about 10 blessings of bribes, (4) about genus to about w/v 疒 驮 (f) 0·003% to about % 2% w/v of polysorbate vinegar (9), (g) 0.001% to about 0· 05% w/v polysorbate 2〇, (8) arginine, (1) heparin, G) dextran sulfate, (k) cyclodextrin, (1) pentosan polysulfate s and other heparinoids, (m)= a combination of a valence cation (eg, a town and a word), or (η). Dosing method and treatment regimen Any of the above embodiments administered parenterally, parenterally, or both, and wherein: (a) administering an effective amount of the compound to the individual; (b) Administering a compound of effect 1 orally to an individual; (c) administering an effective amount of the compound intravenously to the individual; (d) administering an effective amount of the compound by inhalation; (e) administering by nasal administration And an effective amount of the compound; (0 an effective amount of the compound administered to the individual by injection; 156715.doc -79-201249840 (g) administering an effective amount of the compound to the individual (skin); (h) by eye Administration of an effective amount of a compound; and/or (1) administering an effective amount of a compound to the individual via rectal administration. Any of the above examples includes other embodiments of a single administration of an effective amount of a compound, including (1) once; Ii) multiple times within a one-day span; (Ui) uninterrupted; or (iv) other embodiments in which the compound is administered continuously to the individual. Any of the above embodiments includes multiple administrations of an effective amount of the compound. Embodiments include the following other embodiments: wherein (i) The compound is administered in a single dose; (Π) the interval between multiple administrations is 6 hours; (in) the compound is administered to the individual once every 8 hours. In other or alternative embodiments, the method includes a drug holiday, in which The administration of the compound is interrupted or the dose of the administered compound is temporarily lowered; the administration of the compound is resumed at the end of the drug holiday. In some embodiments, the length of the drug holiday varies from 2 days to 1 year. In the embodiments, the compounds of the invention are used to prepare or manufacture a medicament for the treatment of an enzyme poly(ADp_ribose) polymerase (pARp) mediated or inhibited enzyme poly(ADP_ribose) polymerase (pARp) a disease or condition that ameliorates a disease or condition. In some embodiments, a method of treating a disease or condition in a subject in need of treatment in a subject in need of treatment comprises administering to the individual a therapeutically effective amount of a pharmaceutical composition, The pharmaceutical compositions comprise at least one compound of the invention, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable N-oxide, a pharmaceutically active metabolite, a pharmaceutically acceptable prodrug, or a pharmaceutically acceptable Solvate. 156715.doc 201249840 In certain embodiments, a composition comprising a compound of the invention is administered for prophylactic and/or therapeutic treatment. In certain therapeutic applications, it will be violated. The composition is administered to a patient already suffering from the disease or condition in an amount sufficient to treat or at least partially arrest the symptoms of the disease or condition. In some embodiments, the amount effective for this application will depend on the disease or condition. Severity and duration, prior treatment, patient's health, weight and drug response, and the judgment of the treating physician. In some cases, we believe that the caregiver is suitable for routine experimentation (including but not limited to dose escalation) Clinical trials) to determine such therapeutically effective amounts. In certain prophylactic applications, a composition comprising a compound of the invention is administered to a patient susceptible to a particular disease, disorder or condition or at risk of a particular disease, condition or condition. In some embodiments, the amount administered is defined as "prophylactically effective amount or dose." In certain embodiments of this application, the exact amount of compound administered will depend on the health, weight and similar factors of the patient. In some embodiments, we believe that the caregiver is suitable for determining such prophylactically effective amounts by routine experimentation (e.g., a dose escalation clinical trial). In certain embodiments, when administered to a patient, the amount effective for this application will depend on the severity of the disease, condition or condition, the extent and duration of the disease, the prior therapy, the health of the patient and the drug's response, and the treating physician's Judging by judgment. In certain instances, after administration of a compound or composition of the invention, the condition of the patient is not improved or significantly improved, and as directed, long-term (i.e., longer period) administration as needed The administration of such compounds, including the duration of life through the heart, to improve or otherwise control or limit the symptoms of the patient's disease or condition. 156715.doc -81 - 201249840 In certain circumstances where the patient's condition does improve or does not materially improve, follow the doctor's advice and continue to administer the compound as needed; another option is to temporarily reduce or temporarily suspend the cast as needed. Dosage with the drug for a certain period of time (ie, "drug holiday"). In certain embodiments, the length of the drug holiday is between 2 days and 1 year, including (for example only) 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 2 days, 28 days, 35 days, 5 days, 70 days '1 day, 120 days, 15 days, 18 days, 2 days, 25 days, 280 days , 300 days, 320 days, 35 days or 365 days. The dose reduction during the drug holiday includes a reduction of from about 1% to about 1%, including, by way of example only, about 10%, about 15%, about 20%, about 25%, about 3%, About 35%, about 40 baht /. , about 45%, about 50%, about 55%, about 6%, about 65%, about 70%, about 75%, about 80 〇/〇, about 85%, about 9%, about 95%, or About 100%. In certain embodiments, 'when the patient's condition is improved, the dosage is administered as needed, and in some embodiments, the dosage (eg, maintenance dose) or frequency of administration or both is lowered depending on the symptoms. To the extent that the disease, condition or condition is improved. In certain embodiments, the patient will receive intermittent treatment as needed for a long-term recurrence. In certain embodiments, the amount of a given dose corresponding to an effective amount varies depending on, for example, the compound, the disease or condition, and the severity thereof, the characteristics of the individual or host in need of treatment (eg, Body weight In some embodiments, 'however' is determined according to the particular circumstances of this case, 'comprising (10) such as the particular agent administered, the route of administration, the condition being treated, and the individual or host being treated. In certain embodiments, however, the dose of 156715.doc 8 •82· 201249840 for treatment in an adult is between about 0.02 mg/day to about 5000 mg/day, which is about 1 mg/day in a particular embodiment. Up to about 15 〇〇 mg / day. In each of the embodiments, the desired doses of kansui and guanidine may conveniently be administered simultaneously (or in a short period of time) or at appropriate intervals in a single dose or in separate doses, such as twice daily, three-persons, four times or More sub-doses. In the second embodiment, the pharmaceutical composition of the present invention is in a unit dosage form suitable for a single dose of eight. In some instances, the formulation is divided into unit dosages containing appropriate quantities of one or more compounds in unit dosage form. In certain embodiments, the unit dose is in the form of a package containing a dispersion amount of the formulation. Non-limiting examples are packaged tablets or capsules, and powders stored in vials or ampoules. In some embodiments, the aqueous suspension composition is packaged in a single amount of non-reclosable towel. In an alternate embodiment, a multi-dose reclosable container is used, in which case a preservative is typically included in the composition. By way of example only, in some embodiments, formulations for parenteral injection are provided in unit dosage form (including but not limited to ampoules) or in multi-dose containers in which a preservative is added. In certain embodiments, the daily dosage suitable for use in the compounds of the invention is from about 0.01 mg/kg/body weight to about 2.5 mg/kg/body weight. In some embodiments, the specified daily dose in a larger individual (including but not limited to a human) is between about 〇5 mg to about 100 mg, conveniently in separate doses (including but not limited to up to daily Four times) or in the form of extended release. In certain embodiments, a suitable unit dosage form for oral administration comprises from about 1 mg to about 5 mg of the active ingredient. Since the number of variables for each treatment regimen is very large, the above ranges are only indicative and the deviations from these suggested values are quite large and 156715.doc •83-201249840 is not uncommon. In certain embodiments, the dosages vary according to a plurality of variables that are not limited to the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual, the disease or condition being treated The severity and judgment of the physician ^ In some implementations, the (s) treatment regimen and therapeutic efficacy are determined in cell culture or laboratory animals according to standard medical procedures, including but not limited to the determination of ld50 (causing 50%) The dose of death of the group) and ed5〇 (effective in the 5th body towel treatment (4)). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio of sputum to sputum. In certain embodiments, a compound exhibiting a higher therapeutic index is preferred. In some embodiments, the number obtained from cell culture assays and animal studies is (4) formulated for a dose range suitable for humans. In particular embodiments, the doses of the compounds are within a range of circulating concentrations that are less toxic (including EM. In certain embodiments, the dosage forms will be within this range depending on the dosage form employed and the administration used. Combination Therapy In certain instances, it may be appropriate to administer at least one of the compounds of the present invention in combination with another therapeutic agent. By way of example only, if a patient experiences a side effect after taking a compound of the invention, it is inflammation. In some embodiments, it is preferred to administer a combination of an anti-inflammatory agent and an initial therapeutic agent. In some embodiments, the efficacy of a compound of the invention is enhanced by administration of an adjuvant (ie, In some embodiments, the adjuvant itself has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced. In certain embodiments, by administering a method of the invention 156715.doc -84· 201249840 Compounds and other therapeutic agents (also including treatment regimens) that also have therapeutic benefits to increase the benefits experienced by the patient. In some embodiments, The overall benefit experienced by the combination therapy is additive or synergistic in the case of the disease, condition or condition being treated. In a second embodiment, the therapeutically effective dose will vary when the drug is used in a therapeutic combination. n In the examples, the therapeutically effective dose of the drug and other agents used in combination therapy regimens in any suitable manner is, for example, via the use of metronomic administration, i.e., more frequently at lower doses to minimize toxic side effects. In some embodiments, the combination treatment regimen of the present invention encompasses a treatment regimen comprising administering a PARp inhibitor of the invention prior to, during, or after treatment with the second agent described above, and continuing Until any time after the second agent treatment or after the second drug treatment is terminated. Also includes the treatment of administering a combination during the treatment time simultaneously or at different times and/or at intervals of decrease or increase. The PARP inhibitor of the present invention and the second agent are used. The combination therapy further includes multiple starts and stops to assist the patient in clinical care Periodic treatment. For example, in some embodiments, the PARP inhibitors of the invention are administered in combination with a combination of treatments: weekly, reduced to two weeks at the start of treatment, and further reduction if needed In certain embodiments, the present invention provides compositions and methods for combination therapy. According to one aspect, the pharmaceutical compositions disclosed herein are used to treat a PARP-mediated disease or condition or by inhibition A method for ameliorating a disease or condition of pARp. According to certain aspects, the pharmaceutical composition disclosed by the present invention is used to treat vascular disease, septic shock, ischemic injury, reperfusion injury I567l5.d〇c-85 - 201249840 Injury, neurotoxicity, hemorrhagic shock, inflammatory disease, multiple sclerosis, secondary effects of diabetes, and acute treatment of cytotoxicity after cardiovascular surgery. In one aspect, the pharmaceutical compositions disclosed herein are combined (simultaneously or sequentially) with ionizing radiation or one or more chemotherapeutic agents. In certain embodiments, the combination therapies of the invention are used as part of a particular treatment regimen intended to provide a beneficial effect from the synergistic effects of the PARP inhibitors of the invention and concurrent treatments. It will be appreciated that dosage regimens for the treatment, prevention or amelioration of conditions for which mitigation is sought may be tailored to a variety of factors as desired. . In certain combination therapies of the invention, the dosage of the co-administered compound will vary depending on the type of co-drug used, the particular drug employed, the condition or condition being treated, and the like. In some embodiments, when co-administered with - or a plurality of biological agents, the compounds provided herein can be administered simultaneously or sequentially with the bioactive agent. In some instances of sequential administration of the agent, the attending physician will determine the appropriate order of administration of the protein and the bioactive agent. In various embodiments, a plurality of therapeutic agents (-one of the compounds of the invention) are administered in either order or even simultaneously. In some cases, simultaneous administration and multiple therapeutic agents are provided as needed in a single, uniform form or in multiple forms (for example, in the form of a single pill or in the form of two separate pills - Λ-L·.. 丄In 歹', a therapeutic agent is administered in multiple doses, or both treatments are administered in the evening dose. 纟 Some cases τ, not simultaneous administration and multi-human dose time (for non-selective examples) For greater than zero weeks in four weeks. Tubu Bing: 匕, combination methods, compositions and formulations are not limited to the use of only two agents; also include the use of multiple therapeutic combinations. 156715.doc 8 •86- 201249840 in other In one embodiment, the compounds of the present invention are used in combination with a procedure that provides an additive or synergistic benefit to a patient. By way of example only, 'expected patients will have therapeutic and/or prophylactic benefits in the methods described in this month, among which Combinations of pharmaceutical compositions and/or other therapeutic agents of the presently disclosed compounds are combined with genetic testing to determine whether an individual is a carrier of a mutated group known to be associated with certain diseases or conditions. In certain embodiments The compounds of the invention and combination therapies are administered before, during or after the onset of the disease or condition. In certain embodiments, the time to administer the composition containing the compound will vary. Thus, for example, In some embodiments, the compounds are used in a prophylactic manner and are administered continuously to individuals with a predisposition to disease or disease to prevent the onset of the disease or condition. In some embodiments, during the onset of symptoms or as much as possible after the onset of symptoms The compounds and compositions are administered to the subject quickly. In certain embodiments, the administration of the compound begins within the first 48 hours of the onset of symptoms, within the first 6 hours of the onset of symptoms, or within 3 hours of the onset of symptoms. A practical approach to achieve initial administration, for example, intravenous injection, bolus injection, infusion over 5 minutes to about 5 hours, pills, capsules, transdermal patches, buccal delivery, and the like, or combinations thereof. In the case, the compound is administered as soon as possible after detecting or suspecting the onset of the disease or condition, and the time required to continue treating the disease, for example, about one month to Approximately 3 months. In certain embodiments, the length of time for treatment varies from individual to individual, and any standard is used to determine the length of time. In an exemplary embodiment, the compound or the compound is included The formulation is administered for at least 2 weeks 'about 1 month to about 5 years, or about 1 month to about 3 years. 156715.doc -87- 201249840 Other Combination Therapy In certain embodiments of the invention, the treatment A method of PARP mediated conditions or diseases (eg, proliferative disorders, including cancer) comprises administering to a patient a compound, pharmaceutical composition, or agent of the invention in combination with at least one other agent selected from the group consisting of: Alemtuzumab, = arsenic trioxide, aspartate (pegylated or non-PEGylated), bevacizumab, simixumab, platinum-based compounds (eg cisplatin), clad Bin, daunorubicin/doxorubicin/idabubicin, irinotecan, fludarabine, 5-fluorouracil, gemtuzumab, methotrexate, paclitaxel..., taxol, temozolomide, sulphur bird嘌呤, or include the following types of drugs: (anti-estrogen, antiandrogen, or gonadotropin-releasing hormone analog), interferon (eg, alpha interferon), nitroxan (eg, busulfan, melphalan or nitrogen), retinoid (eg, retinoic acid), a topoisomerase inhibitor (eg, irinotecan or topotecan), a tyrosine kinase inhibitor (eg, gefitinib or imatinib), or treatment induced by the therapy Signs or symptoms of the drug (including allopurinol, filgrastim, granisetron / ondansetron / palonosetron, and rhodamine). In certain embodiments, a compound, pharmaceutical composition, or agent of the invention is administered in combination with ionizing radiation, one or more chemotherapeutic agents, or a combination thereof. In certain embodiments, the chemotherapeutic agent is independently selected from the group consisting of: alemtuzumab, arsenic trioxide, PEGylated aspartate, non-PEGylated aspartate, bevacate Monoclonal Antibody, Rituzumab, Cisplatin, Cladribine, Daunorubicin/Doxorubicin/Idabubicin, 156715.doc ΟΛ • 〇〇- 8 201249840 Liticon, Fludarabine, 5-Fluorouracil , gemtuzumab, azathioprine, paclitaxel, paclitaxel, temozolomide, thioguanine, anti-estrogen hormone analogues, antiandrogen analogs, gonadotropin-releasing hormone analogues, alpha interferon, Busulfan, melphalan, nitrogen mustard, retinoic acid, irinotecan, topotecan, gefitinib, imatinib, allopurinol, filgrastim, granisetron/ondansetron / Palonosetron, and dronabinol. In certain embodiments, a compound, pharmaceutical composition, or agent of the invention is administered in combination with one or more of a chemotherapeutic agent, wherein each chemotherapeutic agent is independently an alkylating agent or a topologically different Constructase-1 inhibitor. In certain embodiments, a compound, pharmaceutical composition, or agent of the invention is administered in combination with one or more chemotherapeutic agents, wherein each chemotherapeutic agent is independently selected from the group consisting of: methanesulfonic acid Methyl ester, temozolomide, dacarbazine (DTIC), topotecan, irinotecan, rubiconcan, exacartan, letoticon, gimathycan, difluvomectone (hydantoin high hi tree Base), 7-substituted non-gibberelline, 7-carboxycylcamptothecin, BNP 1350, and XR li576/MLN 576. In certain embodiments, a compound, pharmaceutical composition, or agent of the invention is administered in combination with a chemotherapeutic agent, wherein the chemotherapeutic agent is irinotecan, cisplatin, or temozolomide. EXAMPLES The following examples are intended to illustrate various embodiments as defined in the accompanying claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference. Examples 1-4 are disclosed in the posters of December 4, 2010, 52nd a and _(10) listening to 156715.doc -89-201249840 of Hematology Annual Meeting and Exposition ’ Orlando, Florida. Example 1: Sensitivity of PARP Inhibitors in MDS/AML Cell Lines Associated with Presence of Advanced Microsatellite Instability (MSI) This example shows that MDS/AML cell lines sensitive to PARP inhibitors (Compound 1) exhibit advanced MSI . Figure 1 shows that the MDS/AML cell line displays a variable response to a PARP inhibitor (compound 1). The cell lines P39, KG-1 and Molm-13 exhibited significant cytotoxicity against Compound 1, while the MDS/AML cell lines Molt 4, NB4 and normal peripheral blood lymphocytes exhibited relatively insensitivity to Compound 1. MDS/AML cell lines were obtained from the American Type Culture Collection (ATCC). The group of 6 single nucleotide repeat markers (NR21, NR22, NR24, Bat25, Mono27, and Bat26) was used to estimate the MSI in each cell line » cell line sensitive to compound 1 (P39, KG-1, and Molm-) 13) Show advanced MSI (two loci with 23 nucleotide errors) (see Figures 2 and 3). For example, P39 shows a 5/6 single allelic variation in the MSI locus, while KG-1 and Molm-13 show a 5/6 single allele and a biallelic change in the MSI locus. Table 1 presents single nucleotide repeats (NR21, NR22, NR24, Bat25, Mono27, and Bat26) and MDS/AML cell lines (PBL, HL60, Jurkat, KG-1, Molm-13, Molt4, NB4, OCI- AML3, P39, Raji, REH, DS-1, U937 and DLD1). The equivalent value refers to the size of the fluorescent PCR product tested in the ABI Genetic Analyzer 3 13OXL 156715.doc • 90-8 201249840 inch (bp, base pair). The underlined and bold values are > 3 bp missing or added PCR products. Cell lines were classified into one of the following four groups: (1) MSI-stable, no abnormal MSI; (2) MSI-low, with an abnormal microsatellite; (3) MSI-, with 22 abnormalities Satellite locus; and (4) MSI-high (higher MSI) with three aberrant microsatellite loci (eg, P39, KG-1, NB4, and Molm-13). Table 1: Single nucleotide repeats and MDS/AML cell line cell line NR21 (bp) SLC7A8, 5'UTR NR22 (bp) TPPB5, 3'UTR NR24 (bp) ZNF-2, 3'UTR Bat25 (bp) C-kit, intron 16 Mono27 (bp) (map4K) intron Bat26 (bp) MSH2, intron 5 sensitivity to compound 1 PBL 98 136 126 126 139 116 HL60 98 135 126 125 140 104,116 - Jurkat 98 135 126 125 138 115 KG-1 90,92 128,132 125 119 130 104 + Molm- 13 90, 94 128, 132 125 120 130 105 + Molt 4 96 136 126 124 132 114 - NB4 90 129 125 119,125 130,136 104,116 - OCI - s. 116 - DLD1 98 135 123 122 132 113 Untested Example 2: MSI-high MDS/AML cell line in double-stranded DNA repair gene

The MSI in the microsatellite coding region has MSI 156715.doc -91 - 201249840 This example shows that the MSI-high MDS/AML cell line has MSI in the microsatellite coding region of the double-stranded repair genes Mrell, ATM and CTiP. Double-stranded DNA repair genes, Mrell, ATM, CTiP, CHK1, PTEN, BLM, and ATR, have specific microsatellites that produce frameshift mutations at the time of mutation. A set of MDS was tested using fluorescent PCR and Sanger sequencing. MSI at these loci in the /AML cell line. A single allele 1 bp deletion was observed in the MSI-high cell line P39, KG-1, NB4 and Molm-13 double-stranded DNA repair genes CTiP and Mrrell microsatellites (see Figure 4 and Figure 5, respectively; Table 2) ), and two bp deletions were observed in the microsatellite of the double-stranded DNA repair gene ATM (see Figure 7). These specific microsatellite deletions were not observed in the MSI-stabilized cell line (see Figure 6; Table 2). No microsatellite deletion was observed for any of the CHK1, Rad50, PTEN, BLM, and ATR cell lines. Table 2 presents double-stranded DNA repair genes (Rad50, Mrell, CTiP, CHK1, BLM, PTEN, ATM, and ATR) and MDS/AML cell lines (PBL, KG-1, Molm-13, Molt4, NB4, P39, and DLD1). ) MSI data. The equivalent value refers to the size (bp, base pair) of the fluorescent PCR product tested in the ABI Genetic Analyzer 3130XL. Underlined and in bold values are PCR products with 23 bp deletions or additions. Table 2: Microsatellite deletions in double-stranded DNA repair genes in various MDS/AML cell lines

Cell line Rad50 Mrell CTiP CHK1 BLM PTEN ATM ATR 156715.doc -92- 201249840 PBL 124 110/111 133 135 147 110,138 140 145 KG-1 124 109/111 132/133 135 147 110 138 144/145 Molm-13 124 109 /111 132/133 135 147 110 138 144/145 Molt 4 124 110/111 133 135 135 110 140 145 NB4 124 109/111 132/133 135 147 110 138 144/145 P39 124 109/111 132/133 135 147 110 139 144/145 DLD1 124 109 133 136 147 110 138 145 Example 3: Intron single nucleotide microsatellite mutations produce aberrant transcriptional splicing products in ATM (497del22) and Mrell (315d3el88) This example shows introns Nucleotide microsatellite mutations produce aberrant transcriptional splicing products only in the double-stranded DNA repair genes ATM (497del22) and Mrell (315d3el88) of the MSI-high MDS/AML cell line. PCR was performed on ATM exon 8 and exon 5 of Mrrell on the cDNAs of the cell lines DNL, Jurkat, K562, KG-1, Molm-13, Molt4, NB4 and P39. cDNA PCR from ATM exon 8 (Fig. 8) and Mrrell exon 5 (Fig. 9) showed abnormal splicing transcripts in the MSI-high cell lines P39, Molm-13 and KG-1.

Example 4: Cell display of high-risk MDS patients exhibits MSI associated with chromosomal instability This example shows that high-risk MDS patients exhibit MSI associated with chromosomal instability » high-risk MDS and chromosomal instability, possibility of AML transformation Increase is associated with poor prognosis. Groups of 6 single nucleotide repeat markers (NR21, NR22, NR24, Bat25, Mono27, and Bat26) were tested for high-risk MDS by Sanger sequencing and fluorescent PCT MSI analysis, and further tested 156715.doc - 93- 201249840 Try chromosomal instability and mutations in the CTiP DNA repair gene. Cellular genetics was determined in the middle of division using Giemsa staining. Single nucleotide polymorphism analysis (SNPA) was used to determine recessive chromosomal abnormalities that cannot be found using conventional cytogenetic analysis, for example, single parent dimorphism (UPD). The results are shown in Fig. 10 and Table 3. Of the 63 high-risk MDS patients, 13 (21%) showed MSI (9 MSI-low and 4 MSI-high). Of the 13 MSI-positive patients, 7 (4 MSI-high, 3 MSI-low) exhibited monomeric 7 and other complex chromosomal abnormalities (group 1); 2 (MSI-low) patients showed Monomer 7 was isolated (Group 2); and 4 (MSI-low) exhibited normal cytogenetics (Group 3). It is evident that Group 3 with MSI and normal cytogenetics exhibits a wide range of single parental dimorphism (UPD) and recessive chromosomal changes, as determined by single nucleotide polymorphism analysis (SNPA). In contrast, 12 (19%) of 63 high-risk MDS patients with cytogenetic normality and no UPD and genomic aberrations by SNPA did not display MSI. In addition, 3 patients with MSI-high (Group 1) and 1 patient with MSI-low (Group 3) displayed a single allele 1 bp deletion in the microsatellite encoding the CTiP exon (see figure) 10) This allows for the production of shortened CTiP gene transcripts. Table 3: Incidence of chromosomal instability in high-risk MDS patients Patient locus (number; mononucleotide repeat) Cytogenetic abnormality? SNPA/UPD? CTiP^m 1 1 ; NR21 No 2 2 ; NR21 +Bat25 is Yes 3 1 ; Bat25 No is 156715.doc -94- 8 201249840 4 1 ; NR21 No is 5 1 ; NR24 is Yes 6 2 ; NR21+Bat25 is Yes 7 1 ; NR21+ Bat25 is Yes 8 1; Bat25 is 9 1; Bat25 is 10 1; NR24 is 11 2; NR21 + Bat25 is 12 1; NR21 is 13 1; Bat25 is a differential group of MDS/AML patients with MSI will help Screen candidates for PARP inhibitor therapy. Example 5: Screening of MDS/AML patients for PARP inhibitor therapy This example provides an exemplary screening for MDS/AML patients for PARP inhibitor therapy. Microsatellite markers in genomic DNA from samples of MDS/AML patients (eg, tumor biopsy samples) can be isolated and isolated from genomic DNA isolated from normal tissues or cells of patients, or healthy reference individuals Satellite markers were compared to detect MSI. In particular, microsatellite loci can be amplified and genotyped. The specific procedure used in this example is provided below in the 试样 sample and DNA separation. The sample may be a histological sample, a biopsy sample, or a cytological sample, for example, a smear, a swab, a lotion, or a body fluid contained therein. The sample may contain a fixed or preserved sample, such as a cytological or histological sample. The sample may be a tumor biopsy tissue obtained by surgical resection. 156715.doc -95- 201249840 PCR and microsatellite analysis. A group of five near-monomorphic single nucleotide markers (N R21, NR22, NR24, Bat25, Bat26, and Mono27) can be used for MSI assays of genomic DNA in patients. This analysis may involve fluorescent polymerase chain reaction (PCR) and/or Sanger sequencing. Immunohistochemistry: Chromosomal abnormalities in patient samples can be analyzed using conventional cytogenetics. Single nucleotide polymorphism analysis (SNPA) can be used to analyze recessive chromosomal abnormalities in patient samples. Results: MSI containing > 3 bp deletions or insertions and associated with chromosomal instability in one or more of the patient's malignant DNA indicates that the patient may be responsive to treatment with a compound of formula I or II. Example 6: Stage II Clinical Trial of Safety and Efficacy of a Compound of Formula (I) or (II) This example provides an exemplary stage sputum test for the purpose of studying the side effects and optimal dosage of a compound of formula (I) or (II) And how the compound is suitable for treating MDS/AML patients with MSI in malignant cells. Objectives: First: A. Determination of the response rate to a compound of formula (1) or (II) in a MDS/AML patient with or without MSI B. Evaluate the toxicity of a compound of formula (I) or (II) in such patients: A. Assessing progression and overall survival in patients treated with a compound of formula (I) or (II) B. Studying the pharmacokinetics of a compound of formula (I) or (II) in such patients 156715.doc -96 · 8 201249840 C. Assessment of poly(ADP-ribose) polymerase (PARP) activity in peripheral blood lymphocytes from these patients. Third: A. Evaluation of PARP performance using quantitative Western blot immunoassay B. Study drug genome Studies, including CYP2D6 and CYP3A5, drug transporters, and polymorphisms in genes encoding the PARP enzyme itself. C. Analysis of mutations in DNA repair genes from initial diagnostic biopsy (if possible) D. Analysis of paraffin by immunohistochemistry Part of the DNA repair enzyme status (from biopsy, if possible) E. Analysis of DNA double-strand break repair pathway function from ascites or pleural fluid (if possible) for cells used in primary cell culture F. weight Complex sequence implementation of composite microsatellite analysis to determine MSI (from biopsy, if possible) G. Implementation of cytogenetic analysis to determine chromosomal abnormalities (from biopsy, if possible) H. Implementation of single nucleotide polymorphism analysis ( SNPA) to measure recessive chromosomal abnormalities (from biopsy, if possible) F. Analysis of PARP activity and PARP performance (from biopsy, if possible) Patients: Eligible individuals are males and females aged 18 and older: • Disease characteristics: ° has one of the following types of bone marrow disorders (eg by Laboratory of Pathology or Hematology 5 Clinical Center, National 156715.doc -97- 201249840

Patients at the Institutes of Health: MDS, AML, or chronic myelomonocytic leukemia, patients with leukemia undergo no more than 3 prior chemotherapy regimens, measurable disease, as defined by the RECIST standard and by X Patients with bone disease measured by ray, CT scan, or MRI must have other measurable disease for evaluation. Previously irradiated lesions cannot be used for measurable disease. No known brain metastases • Patient characteristics: 〇 WHO fitness status is 0-1 ° Life expectancy 212 weeks

° Hemoglobin > 9.0 g/dL 〇 Absolute neutrophils 21,500/mm3 〇 Platelets > 100,000/mm3 1.5 Serum bilirubin $ 1.5 times the normal upper limit (ULN) 2 ALT or ASTSULN 2_5 times (Because of tumor, SULN 5 times) glomerular glomerular rate (GFR) 250 mL/min ° Not pregnant or nursing 〇 pregnancy test is negative 4 4 weeks before completion of study therapy (female), period, and 6 After the month (male and female), fertile patients must use two highly effective forms of contraception (ie, oral, injection, or implanted hormonal contraception, intrauterine avoidance 156715.doc • 98-8 201249840 pregnancy device' condom plus Shielding method for spermicides, or sterilization by surgery) ° 忐 与 与 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 与 与 与 与 与 与, in situ treatment of basal cells in a conical biopsy or squamous cell carcinoma of the skin, or a cancer survivor of breast cancer and ovarian cancer, has implemented a potential cure for the previous malignant tumor, and has no such disease within 5 years. sign, Considered to be at low risk of recurrence. Patients with cardiovascular signs or symptoms of inactive or unstable heart disease or myocardial infarction in the past 6 months should undergo MUGA scan or cardiac ultrasonography (ech〇cardi〇gram). And their left ventricular ejection fraction (LVEF) below the prescribed limit of normal should be excluded. No other condition that appears to the investigator to cause the patient to be a good candidate for this study. Parallel therapy: • At least 4 weeks after previous radiation therapy (except palliative causes), endocrine therapy, immunotherapy or chemotherapy (6 weeks for nitrosourea and mitomycin C) • from previous chest and / or major abdominal surgery and recovery for at least 4 weeks • Allow parallel radiotherapy for bone pain or skin damage, but not within 5 days after the last dose of study drug 156715.doc •99- 201249840 • Allow parallel double Phosphonate, provided that the dose is stable and the treatment begins at least 2 weeks prior to enrollment • No unresolved toxicity from prior treatment (CTCAE level 21) (hair loss) Except) • No parallel anti-cancer therapies or research drugs • No parallel-type tetracyclic antibiotic therapy for extended duration (a short course of treatment for infections [5-7 days]) • Study design: This is followed by a public label A dose escalation study following a multicenter study. Patients were graded according to disease status (MDS vs. AML versus chronic myelomonocytic leukemia) and MSI status. The patient receives the compound of formula (I) or (II) (in one of several possible doses) once daily for 30 minutes on days 1-5. The treatment was repeated every 21 days in the absence of disease progression or unacceptable toxicity and continued for 12 courses. According to the principal investigator or the Drug Development Office (DDO), patients with stable or responsive disease can receive other treatments. Patient blood samples were collected periodically for pharmacokinetic and pharmacodynamic studies. The tumor marker of the sample was analyzed, the plasma content of the compound of formula (I) or (II) (via liquid chromatography/mass spectrometry/mass spectrometry), PARP activity, and PARP protein expression (via Western blot immunoassay). The paraffin-embedded portion from the initial diagnostic biopsy was also collected and analyzed for PARP protein expression by immunohistochemistry. The pleural fluid and ascites can be collected and analyzed for DNA DS fracture repair by immunohistochemical techniques. Some patients also underwent tumor biopsy and analyzed DNA repair enzyme mutations 156715.doc -100-8 201249840 status, PARP activity (via validated PARP immuno dot analysis), and chromosomal status (using conventional cytogenetic analysis) And SNPA analysis) After completing the study treatment, the patient will be followed for 28 days. MAIN OUTCOME MEASURES: • Evaluation of anti-tumor activity using clinically or radiologically measured tumor size using CT scans, MRI, X-ray film or other imaging techniques according to RECIST • Safety characteristics Secondary outcome measurements: • Progress and overall survival time • Plasma content by liquid chromatography/mass spectrometry/mass spectrometry • Validation of assays for in vitro measurement of aggregate (ADP-ribose) polymerase (PARP) activity • Use of quantitative Western ink PARP performance of point immunoassay • Pharmacogenomics, including CYP2D6 and CYP3A5, drug transporters, and polymorphisms in genes encoding the PARP enzyme itself • DNA repair enzyme mutation status, MSI status, PARP in tumor biopsy samples Activity, and PARP performance (if possible) • DNA repair enzyme status measured by immunohistochemical techniques in the paraffin fraction from the initial diagnostic biopsy/operating procedure (if possible) • Use of customary cytogenetic analysis and SNPA analysis Measured chromosomal status (if possible) • Obtained ascites or pleural fluid for primary cell culture (if possible) 156715.doc • 101 - 2 DNA double-strand break repair pathway function in cells of 01249840. Other objects, features, and advantages of the compounds, methods, and compositions of the present invention will be apparent from the description which follows. However, it should be understood that The specific examples are given by way of illustration only, and the various changes and modifications may be The entire contents of all of the references cited in the present application are hereby incorporated by reference in their entirety for all purposes inso The content is hereby incorporated by reference in its entirety for all purposes. [Simplified Schematic] Figure 1. Response to pARP inhibition in MDS/AML cell lines. Different concentrations of Compound 1 were continuously added to the MDS/AML cell line and peripheral blood lymphocytes (pbl) over 12-14 days. Cell viability was determined using soft agar colonization analysis. Figure 2. Single nucleotide repeats of NR21 (21 consecutive thymines in the 5'UTR of the solute vector gene SLC7A8) in cell lines ΝΒ4, KG-1 and Ρ39 compared to normal PBL cell lines, underlined in the legend Composite microsatellite analysis. Figure 3. Single nucleotide repeats of Mono27 in the cell lines KG-1, Molm-13, Molt 4, NB4 and P39 compared to normal pbl cell lines (27 consecutive intron adenines in MAP4K3, below Composite microsatellite analysis, shown in the legend). Figure 4. MSI-high cell line 3, 156715.doc -102-8, 201249840 KG-1 and P39 single nucleotide repeat CTiP (9 consecutive thymines in exon 11) compared to normal pbl cell lines , Composite microsatellite analysis, underlined in the legend). The fluorescent PCR image is shown on the left and the Sanger sequence is shown on the right. Figure 5. Single nucleotide repeats of MSI-high cell lines KG-1, NB4, P39 and Molm-13 in the MSI-high cell line compared to normal PBL cell lines. ll consecutive intron thymus bites, underlined in Composite microsatellite analysis in the legend). The fluorescent PCR image is shown on the left and the Sanger sequence is shown on the right. Figure 6. MSI-stable cell lines HL60, Jurkat, DNA ligase IV-1 (DNL), OCI-AML3 and U937 single nucleotide repeats Mrell (ll consecutive intron thymine, underlined in Composite microsatellite analysis in the legend). The fluorescent PCR image is shown on the left and the Sanger sequence is shown on the right. Figure 7. Cell line Jurkat, KG-1, DNA ligase IV small (DNL), NB4, P39, Molm-13 and OCI-AML3 single nucleotide repeat ATM (15 consecutive intron thymine, below The line is shown in the legend) for composite microsatellite analysis. The fluorescent PCR image is shown on the left and the Sanger sequence is shown on the right. Figure 8. PCR was performed on ATM exon 8 on the cDNA of cell lines DNL, Jurkat, K562, KG-1, Molm-13, Molt4, NB4 and P39. The intensity ratio (RI) of the anomalous band to the wild type band was measured using Adobe PhotoshopTM. Figure 9. PCR was performed on Mrell exon 5 on the cDNA of cell lines DNL, Jurkat, K562, KG-1, Molm-13, Molt4, NB4 and P39. The intensity of the anomalous band and the wild type band was measured using Adobe PhotoshopTM 156715.doc -103· 201249840 ratio (RI). Figure 10. Composite microsatellite analysis of CTiP (9 consecutive thymines in exon 11, underlined in the legend) in 5 patients with high-risk MDS. The fluorescent PCR image is shown on the left and the Sanger sequence is shown on the right. 156715.doc 104- 201249840 Sequence Listing <11〇> American Business O'Mallin Pharmaceuticals <120> Treatment of Bone Marrow with Poly(ADP-ribose) Polymerase (PARP) Dihydropyridine and Hydroquinone Inhibitor Method for developing snoring syndrome (MDS) and acute myeloid leukemia (AML) <130> 11808-151-228 <140> 100119730 <141> 2011-06-03 <160> 13 <170> FastSEQ For Windows Version 4,0 <210> 1 <211> 9 <212> DNA <213>Artificial Sequence<220><223> T9 Microsatellite Sequence <400> 1 ttttttttt 9 <210> 2 <211> 11 <212> DNA <213> artificial sequence <220><223> Til microsatellite sequence <400> 2 tttttttttt t 11 <210> 3 <211> 15 <212&gt DNA <213>Artificial Sequence<220><223> T15 Microsatellite Sequence <400> 3 tttttttttt ttttt 15 <210> 4 <211> 21 <212> DNA <213> Artificial Sequence 156715 - Sequence Listing.doc 201249840 <220><223> T21 Microsatellite Sequence <400> 4 tttttttttt tttttttttt t <210> 5 <211&g 27; <212> DNA <213> artificial sequence <220><223> A27 microsatellite sequence <400> 5 aaaaaaaaaa aaaaaaaaaa aaaaaaa <210> 6 <211> 12 <212> DNA <;213>Artificial sequence <220><223>(GT>6 microsatellite sequence <400> 6 gtgtgtgtgt gt <210> 7 <211> 12 <212> DNA <213> artificial sequence<220><223> (CTG)4 microsatellite sequence<_> 7 ctgctgctgc tg <210> 8 <211> 16 <212> DNA <213> artificial sequence <220><223> ACTC > 4 microsatellite sequence <400> 8 actcactcac tcactc <210> 9 <211> 120 <212> DNA <213> artificial sequence <220> 156715 - Sequence Listing.doc 201249840 <223> NR21 (SLCVAe^^TR) , T21 <400> 9 attccagccg gagtcgctgg cacagttcta tttttatatt taaatgtatg tctcccctgg 60 cctttttttt tttttttttt tttagcaaca cttttcttgt ttgtaaacgc gagtgaccag 120 <210> 10 <211> 115 <212> DNA <213> Artificial Sequence<220><223> Mono27(MAP4K3, A27) <400> 10 Tgcagtgagc tgagattgcg ccactgcact ccagcgtggg agacagagca agactctgcc 60 tcaaaaaaaa aaaaaaaaaa aaaaaaaaat cctggtttta cttttttttc ttttt 115 <210> 11 <211> 100 <212> DNA <213>Artificial sequence <220><223> CTiP (T9, exon) U) <400> 11 cagattttga tctagttttt tctaatctag atatacaagt gttgctaaaa gggagtgttt 60 tcagatgttt ttttttccca ggctgtaaaa aagaagggga 100 <210> 12 <211> 56 <212> DNA <213> artificial sequence <22Q><223> MreU TI1 (intron) <400> 12 tttaagtaac tttttttttt taaggtttcc atgggtgaac tatcaagatg gcaacc 56 <210> 13 <211> 70 <212> DNA <213> artificial sequence <220><223> ATM (15T, Intron) <_> 13 tacattttga tttttaaaaa atcatgacta ataatttttt ttttttttta agaattgttc 60 tctgtgtact 7〇156715 - Sequence Listing.doc

Claims (1)

6 201249840 VII. Patent application scope: 1. A compound of formula (1) The use of the formula (1), or a mono-isomer, a stereoisomer, or an enantiomer thereof, or a mixture thereof, is optionally in the form of a salt, a solvate, a chemically protected form or a prodrug, It is used to manufacture an agent for treating MDS or AML in patients with bone (4) malnutrition syndrome (MDS) or acute myeloid white disease (AML), wherein: Y and Z are each independently selected from the group consisting of : a) an aryl group which is optionally substituted by 1, 2 or 3 R6; b) a heteroaryl group which is optionally substituted by 1, 2 or 3 R6; and c) independently selected from the group consisting of Substituents: hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxy Ikylalkyl, alkyl, alkynyl, aryl, cycloalkyl, cycloalkyl , _ alkyl, hydroxyalkyl, pendant oxy, heterocycloalkyl, heterocycloalkylalkyl 'alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkylsulfonyl, aryl sulfonate Mercapto, heteroarylsulfonyl' (NRaRb)alkylene, (NRaRb)carbonyl, (NRaRb)carbonylalkylene, (NRaRb)sulfonyl, and (NRaRb)sulfonyl 156715 .doc 201249840 alkylene; Ri, R·2, and R3 are each independently selected from the group consisting of hydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, cycloalkyl, alkynyl , cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, NRRAB, NRRAB alkyl, and (NRaRb) groups; A and B are each independently selected from the group consisting of: Hydrogen, Br, cl, F, I, OH, CVCe alkyl, C3-C8 cycloalkyl, alkoxy, and alkoxyalkyl, wherein Ci-C6 alkyl, CrC8 cycloalkyl, alkoxy, And the alkoxyalkyl group is optionally substituted with at least one substituent selected from the group consisting of OH, N〇2, CN, Br, C1, F, ! , Ci_C6 alkyl, and c3-c8 cycloalkyl, wherein B is not OH; Ra, and RB are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl; or ~ and, together with The attached atoms together form a 3-10 membered heterocyclic ring having 1 to 3 heteroatoms or heterofunctional groups selected from the group consisting of: _〇·, _NH, _n (Ci_c6_alkyl b, -nco) (Ci-c6-alkyl), _N(aryl)_, Ν(aryl_Ci C6 alkyl, -N(substituted aryl-Cl_C6_alkyl)_, _N(heteroaryl)... n (heteroaryl-cvc6-hospital-)-, Ν (substituted heteroaryl_Ci_c6_alkyl + ' and -s- or S(〇)q-, where coffee or 2, and the 3_1〇 The heterocyclic ring is optionally substituted by one or more substituents; 1 and each are each independently selected from the group consisting of a group consisting of a fluorenyl group, a cycloalkyl group, a decyl group, a dentate group, a (4) stretching base, and (NRARB) stretching base; and CN, Br, Cl, and each R6 are selected from the group consisting of OH, N0 1567l5.doc 201249840 F, I, CVC6 alkyl, (: 3-(:8 ring alkyl, C2-c8 Heterocyclic, C2-C6 alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonyl Alkyl, CrC6, aryl, arylalkyl, c3-c8 cycloalkylalkyl, haloalkoxy, _alkyl, hydroxyalkyl, pendant oxy, heteroaryl, heteroaryl Alkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy, c2-c8 heterocycloalkylthio, heterocyclooxy, heterocyclic thio, NRaRb, (NRARB)Cl_Cd_alkyl, (NRaRb)carbonyl, (NRaRb)carbonylalkylene, (nraRb)sulfonyl, and (NRARB)sulfonylalkylene. 2. The use of claim 1 The dnA of the malignant cell of the patient exhibits microsatellite instability (MSI) in at least one microsatellite. 3. The use of claim 2, wherein the MSI comprises an insertion or deletion in the at least one microsatellite. The use of claim 1 wherein the MSI from at least one of the microsatellites in the patient's malignant cells is analyzed, wherein the analyzing comprises amplifying the at least one microsatellite nucleotide sequence using a primer. Use, wherein the at least one microsatellite system # and 27, NR22, NR24, Bat25, Bat26, Μοηο27, or selected fish a microsatellite in the gene of the group consisting of dm and C77K. 6. The use of claim 5, wherein the at least one microsatellite is selected from the group consisting of NR2I, NR24 and anti-Bat2H3L fluorine. 7. The use of claim 3, wherein The MSI comprises inserting or deleting 3 or more base pairs in the at least one microsatellite. 8. The use of claim 3, wherein the at least one microsatellite is located in a gene encoding a double 156715.doc 201249840 bond DNA repair protein 'and/or wherein the MSI causes DNA repair function to be inactivated' and/or wherein the MSI renders The double-stranded DNA repair gene exhibits a frame shift mutation. The use of claim 8, wherein the MSI results in inactivation of a DNA repair function, wherein the DNA repair function is controlled by a double-stranded DNA repair gene selected from the group consisting of: 3ΓΜ and C77P. 10. The use of claim 1, wherein the compound is 5-fluoro_8_(4-fluorophenyl)_9_(1-methyl-1H-1,2,4-triazol-5-yl)_8,9 - dihydro-2H-pyrido[4,3,2-de]indole-3(7H)-one, or a single isomer, a stereoisomer, or an enantiomer thereof, or a mixture thereof, Or a pharmaceutically acceptable salt thereof. 11. A compound of formula (I) R3 r5 Formula (1), or a single isomer, stereoisomer, or enantiomer thereof, or a mixture thereof, optionally in the form of a salt, solvate, chemically protected form or prodrug thereof, and additionally Desirably, at least one of a pharmaceutically acceptable diluent, excipient, and carrier for treating MDS or AML in a patient having MDS or AML, wherein: Y and Z are each independently selected from the group consisting of Group: a) aryl, substituted by 1, 2 or 3 scales 6 as needed; 156715.doc 4- 201249840 b) Heteroaryl, substituted by 1, 2 or 3 116 as required; and c) independently selected Substituents of the group consisting of: hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkyl, cycloalkyl , cycloalkylalkyl, haloalkyl, hydroxyalkyl, pendant oxy, heterocycloalkyl, heterocycloalkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkylsulfonium , arylsulfonyl, heteroarylsulfonyl, (NRaRb)alkyl, (NRaRb)carbonyl, (NRaRb)carbonylalkyl, (NRaRb)sulfonyl And (NRaRb)sulfonylalkylene; Ri, R.2, and R3 are each independently selected from the group consisting of hydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, cycloalkyl , alkynyl, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, nrarb, nrarb alkyl, and (NRaRb)carbonyl; A and B are each independently selected from the group consisting of Group: hydrogen, Βγ, cl, F, I, OH, CVC6 alkyl, C3-C8 cycloalkyl, alkoxy, and alkoxyalkyl group, wherein CrC6 alkyl, cycloalkyl, alkoxy, and The alkoxyalkyl group is optionally substituted with at least one substituent selected from the group consisting of OH, N〇2, CN, Br, Cl, F, I, alkyl, and C3-C8 cycloalkyl, wherein B Is not 〇H; Ra, and RB are independently selected from the group consisting of: hydrogen, alkyl, cycloalkyl, and alkyl group, or ra and rb together with the atoms to which they are attached, as desired A 3-10 membered heterocyclic ring selected from the group consisting of heteroatoms or heterofunctional groups consisting of: _〇_, _simple, _n(Ci_c6•alkyl)·156715.doc 201249840, -NC〇(Cl- c 6-alkyl)-,·Ν(aryl)_,·Ν(aryl_CiC6 alkyl)_, -N(substituted aryl-Cl_cv alkyl+, _N(heteroaryl), _N (heteroaryl-CVC6-alkyl-)-, _N(substituted heteroaryl·Ci_C6_alkyl_)-, and -S- or S(〇V' where coffee or 2, and the 31 〇 The ring is optionally substituted with one or more substituents; FU and Rs are each independently selected from the group consisting of hydrogen, alkyl 'cycloalkyl, alkoxyalkyl, alkyl, hydroxyalkyl, and (nrarb) alkyl group; and each R6 is selected from the group consisting of: OH, N〇2, CN, ΒΓ, α, F, I, (VCe alkyl, 〇: 3-(: 8-ring alkyl, c2 -C8 heterocycloalkyl, c2_c6 alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C^C:6 alkynyl, aryl, arylalkyl, ( ^/"裒alkylalkyl, dentate alkoxy, self-alkyl, hydroxyalkyl, pendant oxy, heteroaryl, heteroaryl alkoxy, heteroaryloxy, heteroaryl sulphide , heteroarylalkylthio, heterocycloalkoxy, C2_C8 heterocycloalkylthio, heterocyclooxy, heterocyclic thio, NRaRb, (NRaRb)Ci_Cm alkyl (NRaRb) several groups, (NRaRb) carbonyl group alkylene, (NRaRb) sulfo acyl, and (NRaRb) alkylene sulfonic acyl. 12. The compound of claim 11, wherein the malignant cells from the patient exhibit an MSI in the microsatellite. 13. The compound of claim 12, wherein the malignant cell exhibits an MSI in at least two of the microsatellites. 14. A method of identifying a MDS or AML patient who is responsive to a PARP inhibitor therapy for treating mdS or AML, comprising: 156715.doc, • 6.8 201249840 analyzing a malignant cell from a patient with the MDS or AML An MSI in at least one microsatellite; wherein the MSI comprises missing or inserting three or more base pairs in the at least one microsatellite; and wherein the presence of the MSI in the at least one microsatellite is to identify the patient as possible to PARP Inhibitor therapy responds. 15. The method of claim 14, wherein the PARP inhibitor is 5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazole-5- ,8,9-dihydro-2H-pyrido[4,3,2-de]indole-3(7H)-one, or a single isomer, stereoisomer, or enantiomer thereof The method of claim 14, wherein the analyzing comprises amplifying the at least one microsatellite nucleotide sequence using a primer. 17. The method of claim 14, wherein the at least one microsatellite, NR22, NR24, Bat25, Bat26, or a microsatellite selected from the group consisting of Mreii, 4ΓΜ, and C77P. 18. The method of claim 17, wherein the at least one microsatellite is selected from the group consisting of NR21, NR24, and anti-Bat25. 19. The method of claim 14, wherein the MSI results in a DNA repair function being inactivated. 20. The method of claim 19, wherein the DNA repair function is selected from the group consisting of a double-stranded DNA repair gene gene consisting of 4, and CTzT. 21. The method of claim 14, further comprising performing a cytogenetic analysis of the chromosomal abnormality of the 156715.doc 201249840 in the malignant cells. 22. The method of claim 14, wherein at least three of the microsatellites are analyzed for MSI. 23. The method of claim 14, wherein the at least one microsatellite is located in a double stranded DNA repair gene. 156715.doc