Synergy with ALC1 inhibitors and PARPI

Abstract

The present invention relates to small molecule compounds that allosterically inhibit ALC1 (CHD1L) and induce the capture of PARP1, PARP2 and / or PARP3 on chromatin or at sites of DNA damage. Disruption of the chromatin remodeling power of ALC1 by these agents allows highly selective treatments targeting the DNA damage function of the PARP enzyme in several proliferative diseases, especially BRCA-deficient cancers. The compounds are involved in the synthetic lethality between BRCA1 / 2 and ALC1 through inhibition of enzymatic activity. By capturing the PARP enzyme, ALC1 inhibitors enhance the cancer cell killing properties of PARP inhibitors, enabling therapeutic approaches in which ALC1 is amplified as an oncogene, allowing therapeutic overcoming of PARP inhibitor resistance mechanisms, and allowing alternative approaches to the treatment of germline or acquired BRCA1 / BRCA2 deficiencies, including tumors defined by "BRCAness" or other alterations in the DNA repair network.

Description

[Technical field]

[0001] The present invention relates to small molecule compounds that allosterically inhibit ALC1 (CHD1L) and induce the capture of PARP1, PARP2 and / or PARP3 on chromatin or at sites of DNA damage. Disruption of the chromatin remodeling power of ALC1 by these agents allows highly selective treatments targeting the DNA damage function of PARP enzymes in several proliferative diseases, especially BRCA-deficient cancers. The compounds are involved in synthetic lethality between mutations in HRD pathways such as BRCA1 / 2 and ALC1, through inhibition of enzymatic activity. By capturing the PARP enzyme, ALC1 inhibitors enhance the cancer cell killing properties of PARP inhibitors, enabling therapeutic approaches in which ALC1 is amplified as an oncogene, allowing therapeutically overcoming PARP inhibitor resistance mechanisms, and allowing alternative approaches to the treatment of germline or acquired BRCA1 / BRCA2 deficiencies, including tumors defined by "BRCAness" or other alterations in the DNA repair network. [Background technology]

[0002] For the recognition of single- and double-strand breaks (SSB / DSB), the nuclear poly-ADP-ribose polymerase (PARP) enzymes are early and critical participants in the DNA damage response (DDR). PARP-1 and PARP-2 act by catalyzing the metabolic product NAD + PARP-3 uses ADP-ribose to attach poly-ADP-ribose (PAR) chains to chromatin components and factors belonging to the DDR, whereas PARP-3 targets chromatin components via mono-ADP-ribosylation. PARP is recruited to DNA lesions by recognizing specifically altered DNA damage-induced structures, which turns on PARylation activity, thereby regulating the activity of PARP and other DDR and chromatin proteins, promoting the DDR (Ray Chaudhuri and Nussenzweig, 2017).

[0003] This catalytic activity is +These have become of particular interest and are clinically useful in genetically defined cancers, as they can be inhibited by analogs. In particular, so-called PARP inhibitors (PARPi) have been used to treat homologous repair (HR)-deficient and other cancers by targeting the synthetic lethality associated with BRCA1 or BRCA2 deficiency. This is thought to occur by a reduction in PARP activity and / or a biochemical "trapping" of PARP-1 / 2 / 3 on chromatin (Murai et al., 2012, 2014). Although the molecular definition of "trapping" remains unclear, the term usually defines an enhanced recruitment, binding, and / or retention of PARP-1 / 2 / 3 enzymes on damaged chromatin induced by treatment of the PARP-1 enzyme with PARP inhibitors (PARPi) or a reduced release of PARP-1 / 2 / 3 enzymes after the initial recruitment, resulting in their prolonged retention. Biochemically, this manifests as enhanced steady-state association / retention / binding ("complementation") of the PARP enzyme with the damaged genomic region / locus.

[0004] With the clinical advent of PARPi, PARP-1 has emerged as a powerful target in a growing list of cancers in all but one of many examples, including in combination with immuno-oncology therapies such as the current Lynparza / Keytruda trial, and furthermore, applications beyond frontline PARPi therapy and in settings other than germline BRCA-1 / 2 mutations are becoming possible.

[0005] Importantly, all clinical PARPi compounds have the substrate NAD + It binds to essentially the same location in the catalytic center of the active site by blocking the binding of NAD + The main reason is that poly(ADP-ribose) synthesis is prevented due to the structural similarity of the nucleotide moiety to nicotinamide.

[0006] However, PARPi show widely different clinical effects in tumor killing and patient outcomes in the clinic. One fundamental difference in the action of these PARPi is that they promote very different levels of PARP-1 / -2 trapping on chromatin. Currently, it is generally believed that the most potent and clinically effective PARPi trap PARP-1 at DNA break sites much more potently than less clinically useful PARPi. When PARP is trapped, DNA damage becomes more cytotoxic, especially in mutant tumor cells that have genetic or epigenetic defects in repairing DNA strand breaks, such as functionally HR-deficient BRCA-1 / 2 mutant tumor cells. Moreover, it is currently unclear what the relative or dominant contributions are made by PARP-1 versus PARP-2 versus PARP-3 enzymes, because all enzymes are involved in sensing DNA strand breaks and recruiting them to sites of DNA damage, and while both PARP-1 and PARP-2 promote PARylation of chromatin factors, all existing clinical PARPi molecules barely distinguish between the two related PAR polymerase enzymes, PARP-1 and PARP-2. PARP trapping is also believed to cause DNA replication stress, genomic instability, and cell death in cancer cells (Lord and Ashworth, 2012). For example, enhanced trapping of PARP1 is believed to lead to increased ability to kill cancer cells, especially cancers with defects in DNA repair pathways (Zandarashvili et al., 2020). Figure 1 shows the cytotoxicity mechanism of PARPi-mediated PARP trapping.

[0007] Thus, "PARP trapping" is described as the (enhanced) association of PARP-1 or PARP-2 or PARP-3 with chromatin in living cells. Using PARPi, the allosteric mechanisms that contribute to PARP-1 binding to DNA can be disrupted (Zandarashvili et al., 2020), with some PARPi contributing to retention and others promoting PARPi-DNA interaction, a PARP-1-based pro-release mechanism in vitro (Zandarashvili et al., 2020). Figure 3 shows the different mechanisms of PARPi on PARP trapping. U2OS cells treated with talazoparib show enhanced retention of GFP-tagged PARP2 at induced DNA lesions, whereas cells treated with veliparib show an overall less recruitment of PARP2 to DNA lesions.

[0008] PARP-1 or PARP-2 is required for sufficient recruitment of SSB repair proteins to the damage site, and through PARylation, chromatin remodeling or histone modifying enzymes are activated at the site of DNA damage, leading to changes in chromatin compaction (Luijsterburg et al., 2016; Mehrotra et al., 2011; Sellou et al., 2016; Smeenk et al., 2013; Timinszky et al., 2009).

[0009] Activation of PARP-1 and / or PARP-2 enzymes leads to the recruitment of many proteins, especially certain chromatin remodeling enzymes, including the macrodomain-containing nucleosome remodeler ALC1 (CHD1L) (Ahel et al., 2009; Gottschalk et al., 2009; Lehmann et al., 2017; Singh et al., 2017). Because macrodomains generally bind ADP-ribose, oligo-ADP-ribose, and poly-ADP-ribose (Karras et al., 2005), macrodomain-containing proteins are recruited in response to PARP activation sites on the genome, such as during DNA damage and in association with cancer. Importantly, PAR or oligo-ADP-ribose binding to the macrodomain of ALC1 potently turns on chromatin remodeling activity (Ahel et al., 2009; Gottschalk et al., 2009; Lehmann et al., 2017; Singh et al., 2017), revealing ALC1 as an allosterically regulated chromatin remodeling enzyme, the first of its kind and one of the very few enzymes whose catalytic activity is directly controlled by PAR. Furthermore, ALC1 is a validated oncogene and is often genetically amplified along with PARP1 in BRCA1 / 2-deficient ovarian and breast cancer samples (see Figure 2). ALC1 inhibitors, such as small molecules that inhibit the ATPase function and / or nucleosome remodeling function of ALC1, may potentiate the effects of PARPi, leading to enhanced cancer cell killing and / or reduced off-target effects, thereby reducing cytotoxicity in non-cancer cells.The fact that altering the expression levels of ALC1 (in this example, by CRISPR-based knockout) affects cancer cell sensitivity to PARP inhibitors also opens the possibility that PARP inhibitor resistance could be overcome by altering the activity levels of ALC1, since ALC1 reconstitution potently enhances the PARPi olaparib to levels sufficient to circumvent PARPi resistance upon restoration of a BRCA-deficient state (e.g., by internal deletion or loss of epigenetic BRCA1 / 2 gene silencing). Since it is generally accepted that cancer cell sensitivity to PARP inhibitors is due (also) to the ability of PARPi to trap PARP1 on chromatin (and possibly also PARP2 enzyme, although this has not been formally established in the field), we hypothesized that small molecule ALC1 inhibitors may mediate PARPi sensitization, circumvent PARPi resistance, and / or promote cancer cell killing through direct or indirect effects on PARP1 and / or PARP2 trapping. Specifically, we hypothesized that inhibition of ALC1 by small molecules might enhance PARP1 / 2 trapping at sites of DNA damage, thereby indirectly promoting DNA damage and cancer cell death.

[0010] Recently, the first small molecule inhibitor targeting ALC1 (CHD1L) was reported (Abbott et al., 2020). The paper revealed a role for ALC1 inhibitors in the progression of malignant colorectal cancer (CRC) through their oncogenic functions, specifically their impact on Wnt / TCF-induced epithelial-mesenchymal transition (EMT) in CRC. Analysis with one specific ALC1 inhibitor further showed evidence of significant DNA damage as measured by the DNA damage marker γH2AX. From this, the authors hypothesized that ALC1 may enhance the efficacy of DNA-damaging chemotherapy such as etoposide, the standard treatment for colorectal cancer, where it forms a ternary complex with DNA and topoisomerase II enzyme, preventing religation of DNA strands after DNA replication, leading to DNA strand breaks and cell death. Importantly, the paper presented neither a suggestion nor experimental evidence of the impact of ALC1 inhibitors on PARP-1 / 2 / 4 trapping.

[0011] To analyze the mechanism that causes the unique trapping effect, it was hypothesized that the chromatin remodeler ALC1 (CHD1L) regulates PARP retention. ALC1 contains a PAR-binding macrodomain and controls the recruitment of proteins to DNA lesions (Ahel et al., 2009; Gottschalk et al., 2009; Lehmann et al., 2017; Singh et al., 2017). As shown in Figure 5 and Figure 6, ALCi-mediated inhibition of ALC1 in U2OS cells resulted in specific retention of PARP-2 at DNA lesions.

[0012] As ALC1 is upregulated in several tumors and is a validated oncogene in hepatocellular carcinoma ( Cheng et al., 2013 ; Li et al., 2019 ; Su et al., 2014 ), inhibition of ALC1 with small molecule inhibitors that lead to PARP-2 trapping could lead to potent alterations in the DNA damage response.

[0013] We hypothesized that manipulation of ALC1 activity with small molecules may be sufficient to circumvent low- or high-level PARPi resistance, and thus ALC1 and PARP-2 may be exploited to improve PARP-targeted therapy in oncology.

[0014] This hypothesis led to part of the present invention, that ALC1 manipulation via small molecule inhibitors would affect the response to DNA damage via trapping of PARP-1, PARP-2 and / or PARP-3, as well as yet undescribed PARP family members associated with chromatin / DNA damage. These compounds were designed to inhibit the enzymatic activity of the ATP-dependent chromatin remodeler ALC1 (CHD1L), enhancing DNA damage accumulation and thus mediating synthetic lethality due to BRCA deficiency in vitro, which is well documented to be synthetic lethality with loss of BRCA-1 / 2 tumor suppressor function based on preclinical and clinical evidence, suppressing PARPi resistance mechanisms and enabling ALC1 inhibition as a therapeutic approach for cancers with intact HR pathways, and / or targeting ALC1 tumor amplification by disrupting ALC1 oncogene function, such as HCC, via promoting PARP-1 / 2 / 3 trapping. Also, because the ALC1 gene is a key mediator of PARP chromatin remodeling upon induced DNA damage ( Sellou et al., 2016 ), small molecules targeting ALC1 activity may affect the nucleus of DNA damage-related functions of PARP-1 / 2 / 3 in chromatin remodeling without affecting other roles of PARP-1 / 2 / 3 inside or outside the cell nucleus or even non-DNA damage-induced PARP enzymes, which may result in a “second generation PARPi” with reduced off-target effects and side effects.

[0015] The kinetics of enrichment of PARP-1, PARP-2 and PARP-3 at sites of DNA damage can be visualized using live cell imaging, as has been established for PARP-1 in the field (Ahel et al., 2009; Gottschalk et al., 2009). Wild-type PARP-1 and PARP-2 are rapidly recruited to DNA damage induced by laser microirradiation. We measured the effect of ALC1i on recruitment to and retention at sites of DNA damage via transient transfection of GFP-tagged PARP-1 and PARP-2 in immortalized cell lines.

[0016] The present inventors have succeeded in identifying an allosteric binding pocket in the ATPase domain of ALC1, and have used this information to model inhibitors of ALC1 activity. Taking into account the above-mentioned relevance of ALC1 for various proliferative diseases, particularly BRCA1 / 2 deficiency diseases. Thus, the present invention provides a novel class of compounds for treating or ameliorating tumor diseases, particularly tumor diseases characterized by increased ALC1 activity (e.g., increased expression).

[0017] Furthermore, the present inventors have confirmed that the effect of PARPi can be surprisingly enhanced by using a combination of PARPi and an ALC1 inhibitor, preferably an allosteric ALC1 inhibitor of the present invention.Thus, the present invention inter alia (i) provides an efficient treatment of tumors sensitive to PARPi, (ii) mediates PARPi sensitization, (iii) circumvents PARPi resistance, (iv) allows a reduction in the amount of PARPi administered, and / or (v) promotes the death of cancer cells through direct or indirect effects on PARP-1, PARP-2 and / or PARP-3 traps. Summary of the Invention

[0018] In a first aspect, the present invention relates to allosteric inhibitors of chromodomain helicase DNA-binding protein 1-like (ALC1), which specifically bind to an allosteric binding pocket formed by an amino acid stretch spanning amino acid residues 101 to 219 of SEQ ID NO:1.

[0019] In a further aspect, the present invention relates to a compound of formula (I): [ka] (I) [In the formula, X is N or S; A is C or N; R1 is -CO-OR6, -CO-R7, or -CO-NR6R A and preferably, R1 is -CO-OR6; R2 is -R7, -NHR8, -O-R7, -CO-R7, Br, -C 3-8 Cycloalkyl (preferably cyclopropyl), or -C 4-8 cycloalkenyl (preferably cyclohexenyl); or, R1 and R2 together form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, ═O, [—O—CH2—CH2]—NH—CH(OH)—O-tBu; R3 is H, =O, -OH, -O-R7, -R7, or -(CH2) m -L, where m is 0, 1 or 2, and L is a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, -hydroxyC 1-3optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, and =O; R4 is H or -C 1-3 alkyl, preferably H; R5 is -(CH2) m -L or -(CH2) m -(CH=CH)-L, where m is 0, 1 or 2, preferably 0 or 1, and L is a 5-, 6- or 7-membered carbocyclic or heterocyclic ring, adamantyl, C 1-4 alkyl, or -N(CH3)2, which are optionally substituted, preferably -OH, -NO2, -CN, -CO-OR6, -Br, -Cl, -F, -I, -R9, -O-R9, =O, and [-O-CH2-CH2]. q -NH-biotin (q is 1, 2, 3, or 4), or two adjacent substituents may form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; or, R4 and R5 together form a 5-, 6-, or 7-membered carbocyclic ring, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-R9, -R9, =CH-R A , and -CH2-R A and preferably R4 and R5 taken together are each independently selected from the group consisting of C 5-7 Forming a cycloalkyl; R6 is H, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 alkynyl, which may be optionally substituted, preferably, R6 is H; R7 is -C 1-3 Alkyl, -C 2-3 Alkenyl, -C 2-3alkynyl, which is optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -Br, -Cl, -F, -I, -CH3, -OCH3, or -SCH3; R8 is H or C 1-6 alkyl, preferably H; R9 is -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Alkyl-aryl, or C 1-6 Alkyl-heteroaryl (preferably isoxazole, thiazole, tetrazole, 1,2,4-thiadiazole, 1,2,3-thiadiazole, 1,2,5-thiadiazole, pyridine, 1,2,4-oxadiazole, pyrazine, or pyrazole), which is optionally substituted with -Br, -Cl, -F, -I, -NO2, -CN, -CONH2, -CONH-C 1-3 Alkyl (preferably -CONH-CH3), -NH-CO-C 1-3 Alkyl (preferably -NH-CO-CH3), -C 1-6 Alkyl (preferably -CH3, ethyl, propyl, t-butyl, or pentyl), -C 1-3 -haloalkyl (preferably -CF3 or -CHF2), -O-CHF2, -O-CF3, carbocycle (preferably cyclopropyl, cyclohexyl, or phenyl), -O-carbocycle (preferably phenoxy), heterocycle (preferably pyrazolyl), -CO-heterocycle (preferably -CO-(1-pyrrolidinyl)), -SO2-CH3, -SO2-N(CH3)2, -OC 1-4 Alkyl (preferably -OCH3), -OC 1-3 Alkyl-OC 1-3 alkyl (preferably -O-CH2-O-CH3), -SCH3, or R9 is -C 1-6When alkyl-aryl, two adjacent substituents of the aryl moiety may form an optionally substituted 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R A is H, a carbocycle or a heterocycle, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, R9, -O-R7, -O-(CH2) o and optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -R9 (wherein o is 0 or 1), -SO2NH2, and =O. and isomers, salts, solvates, chemically protected forms, and prodrugs thereof.

[0020] In yet another aspect, the present invention relates to a compound of formula (I): [ka] (I) [In the formula, X is N or S; A is C or N; R1 is -CO-OR6, -CO-R7, or -CO-NR6R A and preferably, R1 is -CO-OR6; R2 is -R7, -NHR8, -CO-R7; or, R1 and R2 together form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, and =O; R3 is H, =O, -OH, -O-R7, -R7, or -(CH2) m-L, where m is 0, 1 or 2, and L is a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, -hydroxyC 1-3 optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, and =O; R4 is H or -C 1-3 alkyl, preferably H; R5 is -(CH2) m -L or -(CH2) m -(CH=CH)-L, where m is 0, 1 or 2, preferably 0 or 1, and L is a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, or adamantyl, which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of -OH, -NO2, -CN, -CO-OR6, -Br, -Cl, -F, -I, -R9, -O-R9, and =O, or two adjacent substituents may form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; or, R4 and R5 together form a 5-, 6-, or 7-membered carbocyclic ring, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-R9, -R9, =CH-R A and preferably R4 and R5 taken together are each independently selected from the group consisting of C 5-7 Forming a cycloalkyl; R6 is H, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 alkynyl, which may be optionally substituted, preferably, R6 is H; R7 is -C 1-3 Alkyl, -C 2-3 Alkenyl, -C 2-3alkynyl, which may be optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -Br, -Cl, -F, -I, -CH3, -OCH3, or -SCH3; R8 is H or C 1-6 alkyl, preferably H; R9 is -C 1-6 Alkyl, -C 2-6 Alkenyl, or -C 1-6 alkyl-aryl, which may be optionally substituted with 1, 2 or 3 substituents selected from the group consisting of -Br, -Cl, -F, -I, -CH3, -OCH3, or -SCH3; R A is H, a carbocycle or a heterocycle, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, R9, -O-R7, -O-(CH2) o and optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -R9 (wherein o is 0 or 1), -SO2NH2, and =O. and isomers, salts, solvates, chemically protected forms, and prodrugs thereof.

[0021] In a second aspect, the present invention relates to a bifunctional compound comprising an allosteric inhibitor of ALC1 according to the first or further aspect of the invention and a compound that recruits an E3 ubiquitin ligase to ALC1 (E3 recruiter), wherein the allosteric inhibitor of ALC1 and the E3 recruiter are covalently linked, optionally via a linker.

[0022] In a third aspect, the present invention relates to a pharmaceutical composition comprising an allosteric inhibitor of ALC1 and a pharma- ceutically acceptable excipient.

[0023] In a fourth aspect, the present invention relates to an ALC1 inhibitor (ALC1i) for use in treating or ameliorating a proliferative disease in a patient, the method comprising administration of ALC1i and optionally administration of a poly(ADP-ribose)-polymerase inhibitor (PARPi).

[0024] In a fifth aspect, the present invention relates to a PARPi for use in the treatment or amelioration of a proliferative disease in a patient, the method comprising administration of a PARPi and administration of an ALC1i.

[0025] In a sixth aspect, the present invention relates to a kit comprising separately packaged PARPi and ALC1i, or a composition comprising PARPi and ALC1i, preferably with instructions for use for treating or ameliorating a proliferative disorder. [Brief description of the drawings]

[0026] The contents of the drawings attached hereto are described below, in which connection reference is also made to the above and / or following detailed description of the invention. [Figure 1] Cytotoxicity mechanism of PARPi on DNA repair pathways leading to PARP trapping. The upper pathway shows interference with DNA repair of single-strand breaks (SSBs) via DNA replication fork damage leading to repair by homologous recombination (HR) mechanism. The lower pathway shows trapping of PARP1 / 2 proteins on damaged DNA, leading to replication fork damage utilizing additional repair pathways such as Fanconi pathway (FA), template switching (TS), ATM, FEN1 (replicative flap endonuclease), and DNA polymerase β (Murai et al., 2012, S. 5591). [Diagram 2]The chromatin remodeler ALC1 (CHD1L) is frequently co-amplified with the PARP1 gene in human ovarian and breast cancer samples. Genomic alterations of ALC1 (CHD1L), PARP1, PARP2, BRCA1, BRCA2, and the most closely related chromatin remodeler CHD1 in the genomes of 10792 patients with breast, fallopian tube, and ovarian cancer (OncoPrint analysis performed on cBioPortal on 8 / 12 / 2020 - www.cbioportal.org). Percentage numbers indicate the percentage of alterations of a particular gene in all genomes where that particular gene was profiled. Gene amplifications (black), deep gene deletions (dark grey) are highlighted. Compared with CHD1, ALC1 is more frequently co-amplified with PARP1 (ALC1-PARP1: odds ratio (OR)=1.581, q-value=<0.001; CHD1-PARP1: OR=-0.125, q-value=0.250). When tumors show deep deletions or mutations in the BRCA1 or BRCA2 tumor suppressor genes, neither ALC1 nor PARP1 show deep deletions or frequent mutations (ALC1-BRCA1 / 2: OR=<-3 / -2.178, q-value=<0.001; PARP1-BRCA1 / 2: OR=<-3, q-value=<0.001). [Diagram 3] GFP-PARP2 association at sites of laser microirradiation in U2OS cells. U2OS cells were treated with the PARPi-veliparib (10 μM) and talazoparib (100 nM) and transfected with GFP-PARP2. Grey signal indicates PARP2 in the nucleus. Light lines indicate recruitment of PARP2 to sites of damage induced by laser microirradiation. Images were taken 1 and 15 min after irradiation. Treatment with talazoparib shows enhanced retention of PARP2 ("PARP trapping") at sites of induced damage, whereas treatment with veliparib results in less recruitment of PARP2 to sites of damage. [Figure 4]Schematic of the live-cell PARP trap assay. Cell nuclei were microirradiated with a 355 nm wavelength laser to induce DNA damage (black bar, left cell). Cells are then imaged for 15 min. Grey bars indicate recruitment of PARP1 / 2 to sites of induced DNA damage (middle cell). A) PARP2 signal decreases over time, indicating reduced PARP1 / 2 retention. B) Long-term retention of PARP2 is a live-cell imaging correlate showing molecular trapping of PARP2 at sites of induced DNA damage. [Diagram 5] Relative recruitment of PARP2 to sites of DNA damage following treatment with ALCi-9. Wild-type U2OS cells were stably transfected with GFP-PARP2. The kinetics of GFP-PARP2 recruitment to and dissociation from DNA lesions was measured over a 30 min period in the presence and absence of the compound ALCi-9. Treatment with ALCi-9 shows enhanced retention of PARP2 at sites of DNA damage compared to DMSO. Nine nuclei were analyzed in one biological replicate. Data are normalized to pre-damage GFP intensity at the microirradiated site and are presented as mean + SEM. [Figure 6] Relative recruitment of PARP2 to sites of DNA damage following treatment with ALCi-9. Wild-type U2OS cells were stably transfected with GFP-PARP2. The kinetics of GFP-PARP2 recruitment to and dissociation from DNA lesions was measured over a 30-minute period in the presence and absence of the compound ALCi-9. The upper nucleus was treated with DMSO and the lower nucleus with ALCi-9 (10 μM) for 1 hour. Time point 0 minutes shows nuclei before microirradiation, and time points 1 minute and 30 minutes show nuclei after irradiation. Treatment with ALCi-9 is shown to trap PARP2 at sites of DNA damage compared to DMSO. [Figure 7]PARP2 trapping after co-treatment with ALCi-9 and the PARPi veliparib. Wild-type U2OS cells were stably transfected with GFP-PARP2. The kinetics of GFP-PARP2 recruitment to and dissociation from DNA lesions was measured over a 30 min period in the presence and absence of veliparib, the compound ALCi-9, or a combination of both. Four to eleven nuclei were analyzed in one biological replicate. Data are normalized to pre-damage GFP intensity at the microirradiated site and are presented as mean + SEM. [Figure 8] Colony formation assay of BRCA positive and BRCA negative cells treated with ALCi. For MDA-MB-231 cells (BRCA1 / 2 wild type) and SUM-149-PT cells (BRCA1 negative), cells were seeded in 96-well plates and treated with various titrated concentrations of ALCi starting at 50 μM. Cells were cultured at 37 °C, 5% CO2 for 11 days, fixed with 10% TCA, and stained with sulforhodamine stain to analyze cell viability. Data are normalized to DMSO control, which represents 100% viability. Inhibitor vs. response curves with variable slope (four parameters) were fitted using GraphPad Prism. Error bars are shown for two technical replicates. [Figure 9]PARPi co-treatment colony formation assay of BRCA-negative cells. For SUM-149-PT cells (BRCA1 negative), cells were seeded in 96-well plates and treated with various concentrations of PARPi and various titrations of ALCi starting at 50 μM. Cells were cultured at 37°C, 5% CO2 for 11 days, fixed with 10% TCA, and stained with sulforhodamine stain to analyze cell viability. The top of the figure shows the survival curve of SUM-149-PT cells. The black curve shows the co-treatment of ALCi-x and PARPi-y. Treatment with ALCi-132 and ALCi-74 shows enhanced cell killing compared to treatment with veliparib alone or ALCi alone. The synergistic effect of veliparib and ALCi-x at the specified concentrations is shown in the bar graph, where control growth (%) with treatment with veliparib alone, treatment with ALCi-x alone, and co-treatment is shown in grey. [Figure 10] 1 shows structures for ALC1 inhibitors and codes for related compounds. [Figure 11] Nucleosome remodeling inhibition. IC50 (μM) of ALC1 inhibitors in FRET-based nucleosome remodeling assay. IC50 values ​​are represented by the following symbols: +++: IC50<25μM; ++: IC50=25~250μM; +: IC50>250μM; and, "-": compound has no activity (for SAR purposes). [Figure 12] Cell proliferation inhibition. EC50 (μM) of ALC1 inhibitors in a 5-day cell proliferation assay with SRB-based readout. EC50 values ​​are represented by the following symbols: +++: EC50<10 μM; ++: EC50=10-50 μM; +: EC50>50 μM; and "-": compound has no activity. [Figure 13] Surface cutaways of the first lobe of the ALC1 helicase domain in (A) "forward" and (B) "backward" orientation showing the newly identified allosteric binding pocket. The ATP binding site is indicated by a black circle. [Figure 14]Surface cross-sections of the first lobe of the ALC1 helicase domain in (A) the "forward" and (B) "backward" orientations, with regions colored according to their hydrophobicity, with darker colors indicating more hydrophilicity. [Figure 15] Surface cross-sections of the first lobe of the ALC1 helicase domain surface for ALCi-22 in (A) "forward" and (B) "backward" orientations, with regions colored according to hydrophobicity, with darker colors indicating more hydrophilicity. [Figure 16] Surface cross-sections of the first lobe of the ALC1 helicase domain in (A) "front" and (B) "back" orientations, with the van der Waals faces of the ligand ALCi-22 shown in white. [Figure 17] Surface cross-sections of the first lobe of the ALC1 helicase domain in (A) "front" and (B) "back" orientations, with a stick representation of the ligand ALCi-22 shown in white. [Figure 18] Ligplot of ALCi-22 bound to an allosteric site in the first lobe of the helicase domain of ALC1. [Figure 19] Surface cut surface of the first lobe of the ALC1 helicase domain in the "forward" orientation, with the ligand ALCi-22 shown in white and specific interactions with ASN165 and ARG135 indicated by black dashed lines. [Figure 20]PDB file of the novel allosteric pocket of ALC1. Structural coordinates of the key atoms of amino acids at the surface of the allosteric binding pocket of human ALC1, contained within the amino acid stretch spanning amino acids 101-219 of ALC1 according to SEQ ID NO:1. The allosteric ALC1 inhibitors of the invention interact with one or more of these key atoms to specifically bind to this pocket. The structure of the pocket of human ALC1 was determined by homology modeling with swissmodel. The residues shown are the minimal set of amino acids required to reproduce docking results initially performed on a larger ALC1 homology model generated with swissmodel. Specifically, the swissmodel model was used in the initial docking experiments. This pocket was selected due to its proximity to the ATP binding site and its novelty. These amino acids are necessary to form the pocket to enable docking, allowing faster calculations than when using the whole protein. [Figure 21] 1 is a table containing the suppliers used for each inhibitor. [Figure 22] 1 is a general synthesis scheme for inhibitors according to formula I. [Diagram 23] Table containing the percentage inhibition of ALC1 in the FRET-based nucleosome sliding assay at a compound concentration of 250 μM for each inhibitor. For some compounds, the concentration had to be reduced from 250 μM due to solubility issues, as indicated in the legend at the bottom of the table. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] Before the present invention is described in detail below, it should be understood that the present invention is not limited to the specific methodology, protocols and reagents described herein, which may vary.It should also be understood that the terms used herein are only for the purpose of describing specific embodiments, and do not limit the scope of the present invention, which is limited only by the appended claims.Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0028] Several documents are cited throughout the text of this specification. Each document cited herein, including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc., whether supra or infra, is hereby incorporated by reference in its entirety. Nothing herein should be construed as an admission that the present invention is not entitled to antedate its disclosure by virtue of prior invention. Some of the documents cited herein are characterized as being "incorporated by reference." In the event of a conflict between a definition or teaching of such an incorporated document and a definition or teaching set forth herein, the text of this specification shall control.

[0029] The configurations of the present invention are described below. These configurations are listed with specific embodiments, but it is understood that they can be combined in any manner and in any number to create additional embodiments. The various described examples and preferred embodiments should not be construed as limiting the invention to only the explicitly described embodiments. The description should be understood to support and encompass embodiments combining the explicitly described embodiments with any number of the disclosed configurations and / or preferred configurations. Furthermore, any permutation and combination of all configurations described in this application should be considered to be disclosed by the description of this application, unless the context indicates otherwise.

[0030] definition To practice the present invention, unless otherwise indicated, conventional methods of chemistry, biochemistry, and recombinant DNA technology described in the art are used (e.g., Molecular Cloning: A Laboratory Manual, 2nd Edition, J. Sambrook et al. eds., Cold Spring Harbor Laboratory Press, Cold Spring Harbor 1989).

[0031] Below are definitions of some of the terms frequently used herein, which will have their respective defined and preferred meanings throughout the remainder of the specification whenever they are used.

[0032] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise.

[0033] The term "chromodomain helicase DNA-binding protein 1-like", abbreviated CHD1L, refers to a protein also called ALC1. The amino acid sequence of human ALC1 is as specified in SEQ ID NO: 1. The 897 amino acid residue long protein is composed of an N-terminal Snf2-like DNA-dependent ATPase domain spanning amino acid residues 40-513, which contains a conserved helicase motif important for catalysis (Flaus et al., 2006). This domain is composed of two RecA-like lobes ranging from amino acid residues 48-261 and 351-513, respectively. The structure of the truncated N-terminal lobe of the ATPase domain has been determined by homology modeling to identify a putative allosteric binding site, and a minimal coordinate file of this model is provided as FIG. 20 to enable those skilled in the art to identify model compounds within the allosteric binding pocket defined for the first time by the present inventors. The allosteric binding pocket is spatially separated from the portion of ALC1 involved in binding ATP. The ATPase domain is followed by a linker region ranging from amino acid residues 514 to 703, which contains a putative coiled-coil region (amino acid residues 638 to 675), and a C-terminal macrodomain (amino acid residues 704 to 897). The macrodomain has been shown to directly interact with the ATPase domain, thereby inhibiting its catalytic function (Lehmann et al., 2017; Singh et al., 2017). This interaction is released upon binding of poly(ADP-ribose) to the macrodomain, resulting in activation of the chromatin-remodeling enzyme.

[0034] The term "alkyl" as used in the context of the present invention denotes a saturated straight or branched carbon chain. Preferably, the chain contains 1 to 10 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, such as methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl, sec-butyl, tert-butyl), pentyl, hexyl, heptyl, octyl, nonyl, decyl. Alkyl groups may be optionally substituted.

[0035] The term "heteroalkyl" as used in the context of the present invention denotes a saturated straight or branched carbon chain. Preferably, the chain contains 1 to 9 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, which is interrupted one or more times, such as 1, 2, 3, 4, 5 times, by the same or different heteroatoms. Preferably, the heteroatoms are selected from O, S and N, such as -(CH2) n -X-(CH2) m CH3, n=0, 1, 2, 3, 4, 5, 6, 7, 8, or 9, m=0, 1, 2, 3, 4, 5, 6, 7, 8, or 9, X=S, O, or NR', and R'=H or a hydrocarbon (e.g., C1-C6 alkyl). In particular, "heteroalkyl" includes O-CH3, -OC2H5, -CH2-O-CH3, -CH2-O-C2H5, -CH2-O-C3H7, -CH2-O-C4H9, -CH2-O-C5H 11 , -C2H4-O-CH3, -C2H4-O-C2H5, -C2H4-O-C3H7, -C2H4-O-C4H9, etc. Heteroalkyl groups may be optionally substituted.

[0036] The term "haloalkyl" refers to a saturated straight or branched carbon chain in which one or more hydrogen atoms have been replaced with a halogen atom, for example fluorine, chlorine, bromine or iodine. Preferably, the chain contains 1 to 10 carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. In particular, "haloalkyl" refers to -CH2F, -CHF2, -CF3, -C2H4F, -C2H3F2, C2H2F3, -C2HF4, -C2F5, -C3H6F, -C3H5F2, -C3H4F3, -C3H3F4, -C3H2F5, -C3HF6, -C3F7, CH2Cl, -CHCl2, -CCl3, -C2H4Cl, -C2H3Cl2, -C2H2Cl3, -C2HCl4, C2Cl5, -C3H6Cl, -C3H5Cl2, -C3H4Cl3, -C3H3Cl4, -C3H2Cl5, -C3HCl6, and -C3Cl7. Haloalkyl groups may be optionally substituted.

[0037] The term "5-, 6- or 7-membered carbocycle" is used in the context of the present invention to denote a "cycloalkyl", "cycloalkenyl" or "aryl" having 5, 6 or 7 carbon atoms forming the ring.

[0038] The term "cycloalkyl" includes cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl groups may be optionally substituted.

[0039] The term "cycloalkenyl" includes cyclopentenyl, cyclohexenyl, and cycloheptenyl. Cycloalkenyl groups can be optionally substituted.

[0040] The term "aryl" refers to phenyl, which may be optionally substituted, for example naphthyl.

[0041] The term "5-, 6- or 7-membered heterocycle" is used in the context of the present invention to denote a monocyclic "5-, 6- or 7-membered heterocycloalkyl" or a monocyclic "5-, 6- or 7-membered heteroaryl" in which 5, 6 or 7 atoms form the ring.

[0042] The term "5-, 6-, or 7-membered heterocycloalkyl" refers to a saturated monocyclic ring in which at least one of the carbon atoms is replaced by 1 or 2 (for 5-membered ring), or 1, 2, or 3 (for 6-membered ring), or 1, 2, 3, or 4 (for 7-membered ring) identical or different heteroatoms, preferably selected from O, N, and S. Preferred examples of heterocycloalkyl include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, or 2-piperazinyl. Heterocycloalkyl groups may be optionally substituted.

[0043] The term "heteroaryl" as used in the context of the present invention refers to a 5-, 6- or 7-membered aromatic monocyclic ring in which at least one of the carbon atoms is replaced by 1, 2, or 3 (in the case of a 5-membered ring) or 1, 2, 3, or 4 (in the case of a 6-membered ring) identical or different heteroatoms, preferably selected from O, N, and S. Examples of preferred heteroaryl are furanyl, thienyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl. Heteroaryl groups may be optionally substituted.

[0044] When two or more groups can be selected independently of each other, the term "independently" means that the groups can be the same or different.

[0045] In each instance, the term "optionally substituted" refers to halogen (especially F, Cl, Br, or I), -NO2, -CN, -OR''', -NR'R'', -COOR''', -CONR'R'', -NR'COR'', -NR''COR''', -NR'CONR'R'', -NR'SO2E, -COR''', -SO2NR'R'', -OOCR'''', -CR''''R''''OH, -R'''OH, and E; R' and R'' are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, and heteroaryl, or together form heteroaryl or heterocycloalkyl; R''' and R'''' are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and NR'R''; E is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocycloalkyl, alicyclic, aryl, and heteroaryl; which may be optionally substituted.

[0046] "Pharmaceutically acceptable" means approved by a regulatory agency of the Federal or state government, or listed in the United States Pharmacopeia (United States Pharmacopeia-33 / National Formulary-28 Reissue, published by the United States Pharmacopeia Convention, Inc., Rockville Md., publication date: April 2010), or other generally recognized pharmacopoeias for use in animals, especially humans.

[0047] The term "pharmaceutical acceptable salt" refers to a salt of the compound of the present invention. Suitable pharmaceutical acceptable salts of the compound of the present invention include acid addition salts, which can be formed, for example, by mixing a solution of the compound described herein or its derivative with a solution of a pharmaceutical acceptable acid, such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. In addition, when the compound of the present invention has an acidic moiety, suitable pharmaceutical acceptable salts thereof include alkali metal salts (e.g., sodium salt or potassium salt); alkaline earth metal salts (e.g., calcium salt or magnesium salt); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed with counter anions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkylsulfonates and arylsulfonates).Specific examples of pharma- ceutically acceptable salts include, but are not limited to, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecyl sulfate, and edetate. , edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride Salt, hydroiodide, 2-hydroxyethanesulfonate, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, lauryl sulfate, malate, malonate, mandelate, mesylate, methanesulfonate, methylsulfate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate) Salts, palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate / diphosphate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, acetate, succinate, tannate, tartrate, theoclate, tosylate, triethiodide, undecanoate, valerate, and the like (see, e.g., Berge, SM, et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19).Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0048] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for purposes of this invention.

[0049] In addition to salt forms, the present invention provides compounds in the form of prodrugs. Prodrugs of the compounds described herein are compounds that undergo easy chemical changes under physiological conditions to provide the compounds of formula (I) to formula (IV), particularly the compounds shown in FIG. 14. Prodrugs are active or inactive compounds that are chemically altered by in vivo physiological action, such as hydrolysis or metabolism, to provide the compounds of the present invention after administration of the prodrug to a patient. Additionally, prodrugs may be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs may be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with the appropriate enzyme. The suitability and techniques for making and using prodrugs are well known to those skilled in the art. For a general discussion of prodrugs, including esters, see Svensson LA and Tunek A. (1988) Drug Metabolism Reviews 19(2): 165-194 and Bundgaard H. "Design of Prodrugs", Elsevier Science Ltd. (1985). Examples of masked carboxylate anions include various esters, such as alkyl (e.g., methyl, ethyl), cycloalkyl (e.g., cyclohexyl), aralkyl (e.g., benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (e.g., pivaloyloxymethyl). Amines are masked as arylcarbonyloxymethyl-substituted derivatives that are cleaved by esterases in vivo to release the free drug and formaldehyde (Bundgaard H. et al. (1989) J. Med. Chem. 32(12): 2503-2507). Drugs containing acidic NH groups, such as imidazole, imide, and indole, are also masked with N-acyloxymethyl groups (Bundgaard H. "Design of Prodrugs", Elsevier Science Ltd. (1985)). Hydroxy groups are masked as esters and ethers.EP 0 039 051 A2 discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.

[0050] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain isotopes of, for example, tritium ( 3 H), iodine-125( 125 I) or carbon-14( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0051] As used herein, "para" when describing an aryl substituent means that the substituent occupies the position opposite to the position at which the aryl is attached to the backbone of the compound.

[0052] As used herein, a "patient" refers to any mammal or bird that may benefit from treatment with the compounds described herein. Preferably, the "patient" is selected from the group consisting of laboratory animals, livestock, or primates, including chimpanzees and humans. It is particularly preferred that the "patient" is a human.

[0053] As used herein, "treat," "treating," or "treatment" of a disease or disorder means achieving one or more of the following: (a) reducing the severity of the disorder; (b) limiting or preventing the onset of symptoms characteristic of the disorder being treated; (c) inhibiting the worsening of symptoms characteristic of the disorder being treated; (d) limiting or preventing the recurrence of the disorder in patients previously suffering from the disorder; and (e) limiting or preventing the recurrence of symptoms in patients previously suffering from symptoms of the disorder.

[0054] As used herein, "prevent", "preventing", "prevention", or "prevention" of a disease or disorder means preventing the disorder from occurring in a subject for a certain period of time. For example, when a compound described herein is administered to a subject for the purpose of preventing a disease or disorder, the disease or disorder is prevented at least on the day of administration, preferably for one or more days (e.g., 1 to 30 days, or 2 to 28 days, or 3 to 21 days, or 4 to 14 days, or 5 to 10 days) from the day of administration.

[0055] A "pharmaceutical composition" according to the invention may be in the form of a composition in which the different active ingredients and the diluents and / or carriers are mixed with one another, or it may take the form of a mixed preparation in which the active ingredients are partially or totally present in different forms. An example of such a combination or combined preparation is a kit of parts.

[0056] An "effective amount" is an amount of a therapeutic agent sufficient to achieve its intended purpose. The effective amount of a given therapeutic agent will vary depending on factors such as the nature of the agent, the route of administration, the size and species of the animal receiving the therapeutic agent, and the purpose of administration. The effective amount in a particular case can be empirically determined by one of ordinary skill in the art according to methods established in the art.

[0057] As used herein, the term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which a therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids, such as saline solutions of oil and water, including those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like. Saline solutions are preferred carriers when the pharmaceutical composition is administered intravenously. Saline solutions, aqueous dextrose, and glycerol solutions can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, and the like. The compositions can also contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents, if desired. These compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained release formulations, and the like. The composition can be formulated as a suppository using conventional binders and carriers such as triglycerides. The compounds of the present invention can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include salts formed with free amino groups, such as those derived from hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, tartaric acid, and the like, and salts formed with free carboxyl groups, such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxide, isopropylamine, triethylamine, 2-ethylaminoethanol, histidine, procaine, and the like. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by EW Martin. Such compositions contain a therapeutically effective amount of the compound, preferably in purified form, together with a suitable amount of carrier to provide the form for proper administration to the patient. The formulation should suit the mode of administration.

[0058] EMBODIMENTS OF THE PRESENT DISCLOSURE We have identified and characterized a pocket within ALC1 that appears to be involved in the allosteric control of ALC1 ATPase activity. Compounds that specifically bind to this pocket can inhibit the ATPase activity of ALC1. Compounds that bind to the ATPase site of ALC1 and block ATPase activity must compete with ATP for binding to the ATPase site. Because cellular ATP concentrations range from 1 to 10 mM depending on the cellular compartment, very high binding affinities in the low nanomolar range are required to successfully prevent ATP from binding to the ATPase site of ALC1. Allosteric inhibitors of ALC1 do not have this limitation, as they do not have to prevent ATP binding but rather prevent it by another mechanism to inhibit the ATPase activity of ALC1. We have identified compounds that can specifically bind to the allosteric pocket and determined the spatial and electronic requirements for compounds that fit into this pocket. Thus, by defining a "lock" (i.e., an allosteric binding pocket), the inventors can define "keys" (i.e., compounds) that fit into this lock, forming non-covalent or other stabilizing interactions that allow them to bind specifically within the pocket. Using this rational design approach, the inventors identified compounds that can inhibit the movement of ALC1 on chromatin, thereby triggering the so-called PARP trap. These compounds were also tested for their ability to kill two different tumor cell lines, one of which is BRCA-deficient.

[0059] Structure-based computational modeling of ligand-protein interactions is now a core component of modern drug discovery (Charifson and Kuntz, 1997). Computational methods play a key role in the drug discovery process for a growing number of marketed drugs, such as HIV protease inhibitors (Charifson and Kuntz, 1997; Greer et al., 1994; Jorgensen, 2004) and zanamivir (an antiviral neuraminidase inhibitor) (von Itzstein et al., 1993), and in the development of new drug candidates such as HIV integrase inhibitors (Hazuda et al., 2004; Schames et al., 2004), Hepatitis C protease inhibitors (Liverton et al., 2008; Thomson and Perni, 2006), and β-secretase inhibitors (BACE-1) (Stauffer et al., 2007). There are three main classes of physical-computational methods available in the field (listed from fastest to slowest and from least physical to most physical): (1) ultrafast molecular docking methods, including DOCK, Glide, AutoDock, FlexX, ICN, PMF, and GOLD; molecular dynamics-based free energy methods (MD), e.g., MM / GBSA, or MM / PBSA, in which the solvent, protein, and ligand are subjected to forces and thermal fluctuations that they exert on each other and move in iterative steps in response to these forces; and (4) absolute binding free energy (ABFE) methods, such as alchemical simulations, which involve physics in the most rigorous way currently in practical use, albeit at the most computationally expensive. ABFE methods start from structures of the unbound ligand and potentially the unbound protein and attempt to predict the structure, affinity, and thermal properties of a complex of interest. These strategies known in the art, and in particular the approach described in the experimental section, can be used to identify compounds that are allosteric inhibitors of ALC1 by binding to the allosteric binding pocket in ALC1 that was first identified by the inventors.

[0060] Thus, in a first aspect, the present invention provides allosteric inhibitors of ALC1 that specifically bind to an allosteric binding pocket formed by an amino acid stretch of human ALC1 spanning amino acid residues 101 to 219 of SEQ ID NO: 1. As used in this context, "specifically binds" refers to a compound that specifically binds to an allosteric binding pocket formed by an amino acid stretch of human ALC1 spanning amino acid residues 101 to 219 of SEQ ID NO: 1. D is 200 μM or less, preferably 100 μM, more preferably 50 μM, even more preferably 10 μM or less, more preferably 5 μM or less, even more preferably 1 μM, even more preferably 500 nM or less. Those skilled in the art are familiar with methods for measuring the dissociation constant of small molecules with respect to proteins, including surface plasmon resonance. Preferably, the K of the compounds of the invention is D is measured by immobilizing full-length human ALC1 on the surface of a chip and then applying a compound to the immobilized protein. Preferably, the measurement is performed at 37°C.

[0061] In a preferred embodiment of the invention, the allosteric inhibitor of ALC1 has an ID of 500 μM or less, preferably 250 μM or less, more preferably 100 μM or less, more preferably 50 μM or less, more preferably 10 μM or less, more preferably 5 μM or less, even more preferably 1 μM or less in a FRET-based nucleosome remodeling assay. 50 Indicates the value.

[0062] Not all amino acids in the amino acid stretch spanning amino acid residues 101-219 of SEQ ID NO:1 form the surface of the allosteric pocket of ALC1 available for binding to the compounds of the invention. This is due to the fact that some amino acids are buried in the pocket and difficult to access, while other amino acids are not even part of the pocket but are located on the interior or exterior surface of ALC1. Thus, in a preferred embodiment, the allosteric binding pocket to which the ALC1 inhibitors of the invention specifically bind is L101, Y153, C156, L157, A160, L163, K164, V173, D174, E175, A176, H177, R178, L179, S183, L186, H187, T189, L190, F193, L200, The binding pocket comprises or consists of the amino acids L201, T202, N208, S209, E212, L213, L216, and F219, more preferably the binding pocket comprises or consists of Y153, C156, L157, A160, L163, V173, E175, R178, L186, H187, L190, F193, L200, and E212 of SEQ ID NO: 1. To date, there is no 3D structure of ALC1 available, but structures of several homologous remodelers have been deposited in the Protein Data Bank (PDB). Thus, one skilled in the art can model the allosteric binding pocket of ALC1 based on its homology with other chromatin remodeling enzymes. Such models are also shown in Figures 13 to 19 with and without the compound of the invention in the pocket. In particular, the volume models of exemplary compounds of the present invention shown in Figures 16A and B show how one skilled in the art can visualize the suitability of a given compound to fit into the allosteric binding pocket. Figure 18 shows only the amino acids that may be utilized in the pocket to interact with the compounds of the present invention, providing further guidelines for the selection of compounds that meet the steric, hydrophobic, hydrophilic and charge requirements in the pocket. A minimal set of structural coordinates of the amino acids of ALC1 involved in binding to the compounds of the present invention is provided in Figure 20.

[0063] Based on their orientation within the pocket, the various amino acids accessible at the surface of the pocket can form various non-covalent bonds, in particular hydrogen bonds, ionic interactions, van der Waals interactions and hydrophobic interactions. Thus, in a preferred embodiment, the inhibitor forms a non-covalent bond with one or more amino acids of the allosteric binding pocket, preferably with the backbone of amino acids L157, A160, K164, V173, D174, H177, R178, L179, L186, N208, and / or E212 of ALC1, and / or with amino acids L101, Y153, C156, L157, A160, K164, V173, D174, H177, R178, L179, L186, N208, and / or E212 of ALC1. and more preferably with the main chains of D174, H177 and R178 of ALC1, and with the side chains of Y153, E175, R178, H187, T202, N208 and / or E212 of ALC1.

[0064] In a preferred embodiment, the inhibitor of ALC1 is: (i) an aromatic ring in the side chain of amino acid Y153 of ALC1, where the ring forms face-to-face or end-to-end π-π interactions with an aromatic carbon or heterocyclic substituent, or forms cation-π, polar-π, or halogen-π interactions with a polar, charged, or carbohalogen substituent; (ii) the terminal oxygen of the side chain of amino acid Y153 of ALC1, which bears a hydrogen bond donor group; (iii) the main chain carbonyl oxygen of H177 bearing a carbohalogen or hydrogen bond donor group; (iv) the main chain carbonyl oxygen of D174 bearing a carbohalogen or hydrogen bond donor group; (v) a side chain of E175 having a hydrogen bond donor or acceptor group; (vi) the side chain of R178 having a hydrogen bond donor or acceptor group; (vii) the main chain carbonyl oxygen of R178 bearing a carbohalogen or hydrogen bond donor group; (viii) a side chain of the H187 ring that forms face-to-face or end-to-end π-π interactions with aromatic carbon or heterocyclic substituents, or cation-π, polar-π, or halogen-π interactions with polar, charged, or carbohalogen substituents, or with hydrogen bond donor or hydrogen bond acceptor groups; (ix) a side chain of T202 having a hydrogen bond donor or acceptor group; (x) a side chain of N208 having a hydrogen bond donor or hydrogen bond acceptor group; and (xi) a side chain of E212 having a hydrogen bond donor or acceptor group; non-covalently bound to

[0065] In a preferred embodiment of the first aspect of the present invention, the allosteric inhibitor has formula (I): [ka] [In the formula, (i) R5 comprises an aromatic ring that is pi-stacked with the aromatic ring of amino acid Y153; and / or (ii) N is a hydrogen bond acceptor for the terminal OH of amino acid Y153; and / or (iii) R1 comprises a group that is a hydrogen bond donor group to the main chain carbonyl oxygen of amino acid H177 of ALC1; and / or (iv) R3 comprises a carbohalogen or hydrogen bond donor group attached to the main chain carbonyl oxygen of amino acid D174 of ALC1; and / or (v) R1 and R2 together form an aromatic or heteroaromatic monocyclic ring that contains, particularly at or near the R1 position, a hydrogen bond donor or acceptor group that can act as a hydrogen bond donor or acceptor group for the side chain of amino acid E175 of ALC1 and / or amino acid R178 of ALC1; and / or (vi) R1 and R2 together form a substituted carbocyclic or heterocyclic ring that contains a hydrogen bond donor or acceptor group, preferably at or near the R1 position, that is a hydrogen bond donor or acceptor group to the side chain of amino acid R178 of ALC1; and / or (vii) R3 is, in particular, an electron-deficient substituent that forms a polar-π or cationic-π interaction with the aromatic ring of amino acid H187 of ALC1 or contains an aromatic ring that is π-stacked with the aromatic ring of amino acid H187 of ALC1; and / or (viii) R1 and R2 together form an aromatic or heteroaromatic monocyclic ring that contains, particularly at or near the R2 position, a hydrogen bond donor or acceptor group that can act as a hydrogen bond donor or acceptor group for the side chain of amino acid T202 and / or amino acid N208 of ALC1; and / or (ix) R4 is H or -C 1-3 alkyl, preferably H; and / or (x) R5 is -(CH2) m -L or -(CH2) m -(CH=CH)-L, where m is 0, 1 or 2, preferably 0 or 1, and L is a 5-, 6- or 7-membered carbocyclic or heterocyclic ring or adamantyl, which is optionally substituted, preferably with 1, 2, 3 or 4 substituents independently selected from the group consisting of -OH, -NO2, -CN, -CO-OR6, -Br, -Cl, -F, -I, -R9, -O-R9, and =O, or two adjacent substituents may form a 5-, 6- or 7-membered carbocyclic or heterocyclic ring; and / or (xi) R4 and R5 together form a 5-, 6-, or 7-membered carbocyclic ring, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-R9, -R9, =CH-R A and preferably R4 and R5 taken together are each independently selected from the group consisting of C 5-7forming a cycloalkyl; and / or (xii) X is S or N; (xiii) A is N or C. It has the structure shown below.

[0066] In a further aspect, or in a preferred embodiment of the first aspect of the invention, the present invention provides a compound according to formula (I): [ka] (I) [In the formula, X is N or S; A is C or N; R1 is -CO-OR6, -CO-R7, or -CO-NR6R A and preferably, R1 is -CO-OR6; R2 is -R7, -NHR8, -O-R7, -CO-R7, Br, -C 3-8 Cycloalkyl (preferably cyclopropyl), or -C 4-8 cycloalkenyl (preferably cyclohexenyl); or, R1 and R2 together form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, ═O, [—O—CH2—CH2]—NH—CH(OH)—O-tBu; R3 is H, =O, -OH, -O-R7, -R7, or -(CH2) m -L, where m is 0, 1 or 2, and L is a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, -hydroxyC 1-3optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, and =O; R4 is H or -C 1-3 alkyl, preferably H; R5 is -(CH2) m -L or -(CH2) m -(CH=CH)-L, where m is 0, 1 or 2, preferably 0 or 1, and L is a 5-, 6- or 7-membered carbocyclic or heterocyclic ring, adamantyl, C 1-4 alkyl, or -N(CH3)2, which are optionally substituted, preferably -OH, -NO2, -CN, -CO-OR6, -Br, -Cl, -F, -I, -R9, -O-R9, =O, and [-O-CH2-CH2]. q -NH-biotin (q is 1, 2, 3, or 4), or two adjacent substituents may form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; or, R4 and R5 together form a 5-, 6-, or 7-membered carbocyclic ring, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-R9, -R9, =CH-R A , and -CH2-R A and preferably R4 and R5 taken together are each independently selected from the group consisting of C 5-7 Forming a cycloalkyl; R6 is H, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 alkynyl, which may be optionally substituted, preferably, R6 is H; R7 is -C 1-3 Alkyl, -C 2-3 Alkenyl, -C 2-3alkynyl, which is optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -Br, -Cl, -F, -I, -CH3, -OCH3, or -SCH3; R8 is H or C 1-6 alkyl, preferably H; R9 is -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Alkyl-aryl, or C 1-6 Alkyl-heteroaryl (preferably isoxazole, thiazole, tetrazole, 1,2,4-thiadiazole, 1,2,3-thiadiazole, 1,2,5-thiadiazole, pyridine, 1,2,4-oxadiazole, pyrazine, or pyrazole), which is optionally substituted with -Br, -Cl, -F, -I, -NO2, -CN, -CONH2, -CONH-C 1-3 Alkyl (preferably -CONH-CH3), -NH-CO-C 1-3 Alkyl (preferably -NH-CO-CH3), -C 1-6 Alkyl (preferably -CH3, ethyl, propyl, t-butyl, or pentyl), -C 1-3 -haloalkyl (preferably -CF3 or -CHF2), -O-CHF2, -O-CF3, carbocycle (preferably cyclopropyl, cyclohexyl, or phenyl), -O-carbocycle (preferably phenoxy), heterocycle (preferably pyrazolyl), -CO-heterocycle (preferably -CO-(1-pyrrolidinyl)), -SO2-CH3, -SO2-N(CH3)2, -OC 1-4 Alkyl (preferably -OCH3), -OC 1-3 Alkyl-OC 1-3 alkyl (preferably -O-CH2-O-CH3), -SCH3, or R9 is -C 1-6When alkyl-aryl, two adjacent substituents of the aryl moiety may form an optionally substituted 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R A is H, a carbocycle or a heterocycle, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, R9, -O-R7, -O-(CH2) o and optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -R9 (wherein o is 0 or 1), -SO2NH2, and =O. The present invention relates to an allosteric inhibitor compound having the structure:

[0067] In yet another aspect, or in a more preferred embodiment of the first aspect of the invention, the present invention provides a compound of formula (I): [ka] (I) [In the formula, X is N or S; A is C or N; R1 is -CO-OR6, -CO-R7, or -CO-NR6R A and preferably, R1 is -CO-OR6; R2 is -R7, -NHR8, -O-R7, -CO-R7; or, R1 and R2 together form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, and =O; R3 is H, =O, -OH, -O-R7, -R7, or -(CH2) m-L, where m is 0, 1 or 2, and L is a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, -hydroxyC 1-3 optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, and =O; R4 is H or -C 1-3 alkyl, preferably H; R5 is -(CH2) m -L or -(CH2) m -(CH=CH)-L, where m is 0, 1 or 2, preferably 0 or 1, and L is a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, or adamantyl, which is optionally substituted, preferably with 1, 2, 3, or 4 substituents independently selected from the group consisting of -OH, -NO2, -CN, -CO-OR6, -Br, -Cl, -F, -I, -R9, -O-R9, and =O, or two adjacent substituents may form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; or, R4 and R5 together form a 5-, 6-, or 7-membered carbocyclic ring, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -O-R9, -R9, =CH-R A and preferably R4 and R5 taken together are each independently selected from the group consisting of C 5-7 Forming a cycloalkyl; R6 is H, -C 1-6 Alkyl (i.e., C1-, C2-, C3-, C4-, C5-, or C6-alkyl), -C 2-6 alkenyl (i.e., C2-, C3-, C4-, C5-, or C6-alkenyl), -C 2-6 alkynyl (i.e. C2-, C3-, C4-, C5- or C6-alkynyl), which may be optionally substituted, preferably R6 is H; R7 is -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 alkynyl (i.e., C2-, C3-alkynyl), which may be optionally substituted, preferably with 1, 2, or 3 substituents independently selected from the group consisting of -Br, -Cl, -F, -I, -CH3, -OCH3, or -SCH3; R8 is H or C 1-6 alkyl, preferably H; R9 is -C 1-6 Alkyl (i.e., C1-, C2-, C3-, C4-, C5-, or C6-alkyl), -C 2-6 alkenyl (i.e., C2-, C3-, C4-, C5-, or C6-alkenyl), -C 2-6 Alkynyl (i.e., C2-, C3-, C4-, C5-, or C6-alkynyl), or -C 1-6 alkyl-aryl (i.e., C1-, C2-, C3-, C4-, C5-, or C6-alkyl-aryl), which may be optionally substituted with 1, 2, or 3 substituents selected from the group consisting of -Br, -Cl, -F, -I, -CH3, -OCH3, or -SCH3; R A is H, a carbocycle or a heterocycle, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -R9, -O-R7, -O-(CH2) o and optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of -R9 (wherein o is 0 or 1), -SO2NH2, and =O. The present invention relates to an allosteric inhibitor compound having the structure:

[0068] In a preferred embodiment of the first or further aspect of the invention, X is N.

[0069] In a preferred embodiment of the first or further aspect of the invention, A is C.

[0070] In a preferred embodiment of the first aspect of the present invention, R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-, alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably, R6 is H.

[0071] In a preferred embodiment of the first or further aspect of the invention, R1 is -CO-OH.

[0072] In a preferred embodiment of the first or further aspect of the invention, X is N and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably, R6 is H.

[0073] In a preferred embodiment of the first or further aspects of the invention, A is C and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably, R6 is H.

[0074] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is C and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably, R6 is H.

[0075] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is C and R1 is -CO-OH or -CO-NH2.

[0076] In a preferred embodiment of the first or further or yet another aspect of the invention, R2 is -NHR8, where R8 is H or C. 1-6 Alkyl, preferably H.

[0077] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N and R2 is -NHR8, where R8 is H or C. 1-6 Alkyl, preferably H.

[0078] In a preferred embodiment of the first or further or yet another aspect of the invention, A is C and R2 is -NHR8, where R8 is H or C 1-6 Alkyl, preferably H.

[0079] In a preferred embodiment of the first or further or yet another aspect of the invention, R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-, alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably R6 is H and R2 is -NHR8, where R8 is H or C 1-6 Alkyl, preferably H.

[0080] In a preferred embodiment of the first or further or yet another aspect of the present invention, R1 is -CO-OH and R2 is -NHR8, where R8 is H or C 1-6 Alkyl, preferably H.

[0081] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably R6 is H and R2 is -NHR8, where R8 is H or C 1-6 Alkyl, preferably H.

[0082] In a preferred embodiment of the first or further or yet another aspect of the present invention, A is C and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably R6 is H and R2 is -NHR8, where R8 is H or C 1-6 Alkyl, preferably H.

[0083] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is C and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 -alkyl (i.e., C1-, C2-, C3-alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably R6 is H and R2 is -NHR8, where R8 is H or C 1-6 Alkyl, preferably H.

[0084] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is C, R1 is -CO-OH or -CO-NH2 and R2 is -NHR8, where R8 is H or C. 1-6 Alkyl, preferably H.

[0085] In a preferred embodiment of the first or further or yet another aspect of the invention, R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 It may be substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, and =O, preferably -OH and =O.

[0086] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 It may be substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, and =O, preferably -OH and =O.

[0087] In a preferred embodiment of the first or further or yet another aspect of the invention, A is C and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 It may be substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, and =O, preferably -OH and =O.

[0088] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is C, and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 It may be substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, and =O, preferably -OH and =O.

[0089] In a preferred embodiment of the first or further or yet another aspect of the invention, R1 and R2 together form uracil or 3-deazauracil.

[0090] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N and R1 and R2 together form uracil or 3-deazauracil.

[0091] In a preferred embodiment of the first or further or yet another aspect of the invention, A is C and R1 and R2 together form uracil or 3-deazauracil.

[0092] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is C and R1 and R2 together form uracil or 3-deazauracil.

[0093] In a preferred embodiment of the first or further or yet another aspect of the invention, R3 is H, =O, -OH, -R7, or -(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0094] In a preferred embodiment of the first or further or yet another aspect of the present invention, R1 is -CO-OH and R3 is H, ═O, -OH, -R7, or -(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0095] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably, R6 is H and R3 is H, ═O, —OH, —R7, or —(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0096] In a preferred embodiment of the first or further or yet another aspect of the present invention, A is C and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably, R6 is H and R3 is H, ═O, —OH, —R7, or —(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted with -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0097] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is C and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 -alkyl (i.e., C1-, C2-, C3-alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably, R6 is H and R3 is H, ═O, —OH, —R7, or —(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted with -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0098] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is C, R1 is -CO-OH or -CO-NH2, and R3 is H, =O, -OH, -R7 or -(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0099] In a preferred embodiment of the first or further or yet another aspect of the invention, R2 is -NHR8, where R8 is H or C. 1-6 Alkyl, preferably H, and R3 is H, =O, -OH, -R7, or -(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted with -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0100] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N and R2 is -NHR8, where R8 is H or C. 1-6 Alkyl, preferably H, and R3 is H, =O, -OH, -R7, or -(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 and R3 is H, =O, -OH, -R7, or -(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0101] In a preferred embodiment of the first or further or yet another aspect of the invention, A is C and R2 is -NHR8, where R8 is H or C 1-6 Alkyl, preferably H, and R3 is H, =O, -OH, -R7, or -(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0102] In a preferred embodiment of the first or further or yet another aspect of the invention, R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-, alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably R6 is H and R2 is -NHR8, where R8 is H or C 1-6 Alkyl, preferably H, and R3 is H, =O, -OH, -R7, or -(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0103] In a preferred embodiment of the first or further or yet another aspect of the present invention, R1 is -CO-OH and R2 is -NHR8, where R8 is H or C 1-6 Alkyl, preferably H, and R3 is H, =O, -OH, -R7, or -(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0104] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably R6 is H and R2 is -NHR8, where R8 is H or C 1-6 Alkyl, preferably H, and R3 is H, =O, -OH, -R7, or -(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0105] In a preferred embodiment of the first or further or yet another aspect of the present invention, A is C and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably R6 is H and R2 is -NHR8, where R8 is H or C 1-6 Alkyl, preferably H, and R3 is H, =O, -OH, -R7, or -(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0106] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is C and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 -alkyl (i.e., C1-, C2-, C3-alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably R6 is H and R2 is -NHR8, where R8 is H or C 1-6 Alkyl, preferably H, and R3 is H, =O, -OH, -R7, or -(CH2) m-L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0107] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is C, R1 is -CO-OH or -CO-NH2 and R2 is -NHR8, where R8 is H or C. 1-6 Alkyl, preferably H, and R3 is H, =O, -OH, -R7, or -(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0108] In a preferred embodiment of the first or further or yet another aspect of the invention, R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Optionally, R3 is substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, and =O, preferably -OH and =O, and R3 is H, =O, -OH, -R7, or -(CH2) m-L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0109] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Optionally, R3 is substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, and =O, preferably -OH and =O, and R3 is H, =O, -OH, -R7, or -(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0110] In a preferred embodiment of the first or further or yet another aspect of the invention, A is C and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Optionally, R3 is substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, and =O, preferably -OH and =O, and R3 is H, =O, -OH, -R7, or -(CH2) m-L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0111] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is C, and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Optionally, R3 is substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, and =O, preferably -OH and =O, and R3 is H, =O, -OH, -R7, or -(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0112] In a preferred embodiment of the first or further or yet another aspect of the invention, R1 and R2 together form uracil or 3-deazauracil and R3 is H, ═O, —OH, —R7, or —(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0113] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, R1 and R2 together form uracil or 3-deazauracil, and R3 is H, ═O, —OH, —R7, or —(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 and R3 is H, =O, -OH, -R7, or -(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0114] In a preferred embodiment of the first or further or yet another aspect of the invention, A is C, R1 and R2 together form uracil or 3-deazauracil, and R3 is H, ═O, —OH, —R7, or —(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted with -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0115] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is C, R1 and R2 together form uracil or 3-deazauracil, and R3 is H, ═O, —OH, —R7, or —(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0116] In a preferred embodiment of the first or further or yet another aspect of the present invention, R3 is -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0117] In a preferred embodiment of the first or further or yet another aspect of the present invention, R1 is -CO-OH and R3 is -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m-L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0118] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably, R6 is H and R3 is -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0119] In a preferred embodiment of the first or further or yet another aspect of the present invention, A is C and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably, R6 is H and R3 is -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0120] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is C and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 -alkyl (i.e., C1-, C2-, C3-alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably, R6 is H and R3 is -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0121] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is C, R1 is -CO-OH or -CO-NH2, and R3 is -C1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0122] In a preferred embodiment of the first or further or yet another aspect of the invention, R2 is -NHR8, where R8 is H or C. 1-6 alkyl, preferably H; R3 is -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0123] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N and R2 is -NHR8, where R8 is H or C. 1-6 alkyl, preferably H; R3 is -C 1-3 -alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0124] In a preferred embodiment of the first or further or yet another aspect of the invention, A is C and R2 is -NHR8, where R8 is H or C 1-6 alkyl, preferably H; R3 is -C 1-3 -alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0125] In a preferred embodiment of the first or further or yet another aspect of the invention, R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-, alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably R6 is H and R2 is -NHR8, where R8 is H or C 1-6 alkyl, preferably H; R3 is -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3It may be substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl.

[0126] In a preferred embodiment of the first or further or yet another aspect of the present invention, R1 is -CO-OH and R2 is -NHR8, where R8 is H or C 1-6 alkyl, preferably H; R3 is -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0127] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably R6 is H and R2 is -NHR8, where R8 is H or C 1-6 alkyl, preferably H; R3 is -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0128] In a preferred embodiment of the first or further or yet another aspect of the present invention, A is C and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably R6 is H and R2 is -NHR8, where R8 is H or C 1-6 alkyl, preferably H; R3 is -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0129] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is C and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 -alkyl (i.e., C1-, C2-, C3-alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably R6 is H and R2 is -NHR8, where R8 is H or C1-6 alkyl, preferably H; R3 is -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0130] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is C, R1 is -CO-OH or -CO-NH2 and R2 is -NHR8, where R8 is H or C. 1-6 alkyl, preferably H; R3 is -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0131] In a preferred embodiment of the first or further or yet another aspect of the invention, R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 R3 is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, and =O, preferably -OH and =O; 1-3Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0 and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably NO, CN, Br, Cl, F, I, O, C 1-3 Alkyl, and -hydroxyC 1-3 and R3 is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0132] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N and R1, R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 R3 is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, and =O, preferably -OH and =O; 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 and R3 is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, -C1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0133] In a preferred embodiment of the first or further or yet another aspect of the invention, A is C and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 R3 is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, and =O, preferably -OH and =O; 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 and R3 is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted with -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0134] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is C, and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 R3 is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, and =O, preferably -OH and =O; 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 and R3 is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0135] In a preferred embodiment of the first or further or yet another aspect of the invention, R1 and R2 together form uracil or 3-deazauracil and R3 is -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2)m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 and R3 is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0136] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, R1 and R2 together form uracil or 3-deazauracil, and R3 is -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 R3 is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m-L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0137] In a preferred embodiment of the first or further or yet another aspect of the invention, A is C, R1 and R2 together form uracil or 3-deazauracil, and R3 is -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -O, -C 1-3 Alkyl, and -hydroxyC 1-3 and R3 is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0138] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is C, R1 and R2 together form uracil or 3-deazauracil, and R3 is -C 1-3Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0139] In a preferred embodiment of the first or further aspects of the invention, R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0140] In a preferred embodiment of the first or further or yet another aspect of the invention, R1 is -CO-OH and R3 is H, ═O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0141] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably, R6 is H and R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0142] In a preferred embodiment of the first or further or yet another aspect of the present invention, A is C and R1 is -CO-OR6 or -CO-NR6R Aand preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably, R6 is H and R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0143] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is C and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 -alkyl (i.e., C1-, C2-, C3-alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably, R6 is H and R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0144] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is C, R1 is -CO-OH or -CO-NH2 and R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H or CF3.

[0145] In a preferred embodiment of the first or further or yet another aspect of the invention, R2 is -NHR8, where R8 is H or C. 1-6 Alkyl, preferably H, and R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0146] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N and R2 is -NHR8, where R8 is H or C. 1-6 Alkyl, preferably H, and R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0147] In a preferred embodiment of the first or further or yet another aspect of the invention, A is C and R2 is -NHR8, where R8 is H or C 1-6 Alkyl, preferably H, and R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0148] In a preferred embodiment of the first or further or yet another aspect of the invention, R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-, alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably R6 is H and R2 is -NHR8, where R8 is H or C 1-6 Alkyl, preferably H, and R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0149] In a preferred embodiment of the first or further or yet another aspect of the present invention, R1 is -CO-OH and R2 is -NHR8, where R8 is H or C 1-6 Alkyl, preferably H, and R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0150] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably R6 is H and R2 is -NHR8, where R8 is H or C 1-6 Alkyl, preferably H, and R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0151] In a preferred embodiment of the first or further or yet another aspect of the present invention, A is C and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably R6 is H and R2 is -NHR8, where R8 is H or C 1-6 Alkyl, preferably H, and R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0152] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is C and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 -alkyl (i.e., C1-, C2-, C3-alkyl), -C2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably R6 is H and R2 is -NHR8, where R8 is H or C 1-6 Alkyl, preferably H, and R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0153] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is C, R1 is -CO-OH or -CO-NH2 and R2 is -NHR8, where R8 is H or C. 1-6 Alkyl, preferably H, and R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0154] In a preferred embodiment of the first or further or yet another aspect of the invention, R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 It may be substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, and =O, preferably -OH and =O, where R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0155] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3It may be substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, and =O, preferably -OH and =O, where R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0156] In a preferred embodiment of the first or further or yet another aspect of the invention, A is C and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 It may be substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, and =O, preferably -OH and =O, where R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0157] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is C, and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 It may be substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, and =O, preferably -OH and =O, where R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0158] In a preferred embodiment of the first or further or yet another aspect of the invention, R1 and R2 together form uracil or 3-deazauracil and R3 is H, =O, -OH, thiophenyl, phenyl, 3, 4, 5 hydroxymethylphenyl, CF2H, or CF3.

[0159] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, R1 and R2 together form uracil or 3-deazauracil and R3 is H, ═O, —OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0160] In a preferred embodiment of the first or further or yet another aspect of the invention, A is C, R1 and R2 together form uracil or 3-deazauracil, and R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0161] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is C, R1 and R2 together form uracil or 3-deazauracil, and R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0162] In a preferred embodiment of the first or further or yet another aspect of the present invention, A is N and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (ie, C2-, C3-), which may be optionally substituted, preferably, R6 is H.

[0163] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is N and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3-alkyl (i.e., C1-, C2-, C3-alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably, R6 is H.

[0164] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is N and R1 is -CO-OH or -CO-NH2.

[0165] In a preferred embodiment of the first or further or yet another aspect of the invention, A is N and R2 is -NHR8, where R8 is H or C. 1-6 Alkyl, preferably H.

[0166] In a preferred embodiment of the first or further or yet another aspect of the present invention, A is N and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably R6 is H and R2 is -NHR8, where R8 is H or C 1-6 Alkyl, preferably H.

[0167] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is N and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 -alkyl (i.e., C1-, C2-, C3-alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably R6 is H and R2 is -NHR8, where R8 is H or C 1-6 Alkyl, preferably H.

[0168] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is N, R1 is -CO-OH or -CO-NH2 and R2 is -NHR8, where R8 is H or C. 1-6 Alkyl, preferably H.

[0169] In a preferred embodiment of the first or further or yet another aspect of the invention, A is N and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 It may be substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, and =O, preferably -OH and =O.

[0170] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is N, and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 It may be substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, and =O, preferably -OH and =O.

[0171] In a preferred embodiment of the first or further or yet another aspect of the invention, A is N and R1 and R2 together form uracil or 3-deazauracil.

[0172] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is N and R1 and R2 together form uracil or 3-deazauracil.

[0173] In a preferred embodiment of the first or further or yet another aspect of the present invention, A is N and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably, R6 is H and R3 is H, ═O, —OH, —R7, or —(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0174] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is N and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 -alkyl (i.e., C1-, C2-, C3-alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably, R6 is H and R3 is H, ═O, —OH, —R7, or —(CH2) m-L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0175] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is N, R1 is -CO-OH or -CO-NH2, and R3 is H, ═O, -OH, -R7 or -(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0176] In a preferred embodiment of the first or further or yet another aspect of the invention, A is N and R2 is -NHR8, where R8 is H or C. 1-6 Alkyl, preferably H, and R3 is H, =O, -OH, -R7, or -(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0177] In a preferred embodiment of the first or further or yet another aspect of the present invention, A is N and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably R6 is H and R2 is -NHR8, where R8 is H or C 1-6 Alkyl, preferably H, and R3 is H, =O, -OH, -R7, or -(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0178] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is N and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 -alkyl (i.e., C1-, C2-, C3-alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably R6 is H and R2 is -NHR8, where R8 is H or C 1-6 Alkyl, preferably H, and R3 is H, =O, -OH, -R7, or -(CH2) m-L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0179] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is N, R1 is -CO-OH or -CO-NH2 and R2 is -NHR8, where R8 is H or C. 1-6 Alkyl, preferably H, and R3 is H, =O, -OH, -R7, or -(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0180] In a preferred embodiment of the first or further or yet another aspect of the invention, A is N and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Optionally, R3 is substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, and =O, preferably -OH and =O, and R3 is H, =O, -OH, -R7, or -(CH2) m-L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0181] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is N, and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Optionally, R3 is substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, and =O, preferably -OH and =O, and R3 is H, =O, -OH, -R7, or -(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0182] In a preferred embodiment of the first or further or yet another aspect of the invention, A is N, R1 and R2 together form uracil or 3-deazauracil, and R3 is H, ═O, —OH, —R7, or —(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0183] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is N, R1 and R2 together form uracil or 3-deazauracil, and R3 is H, ═O, —OH, —R7, or —(CH2) m -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0184] In a preferred embodiment of the first or further or yet another aspect of the present invention, A is N and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably, R6 is H and R3 is -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0185] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is N and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 -alkyl (i.e., C1-, C2-, C3-alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably, R6 is H and R3 is -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0186] In a preferred embodiment of the first or further or yet another aspect of the present invention, X is N, A is N, R1 is -CO-OH or -CO-NH2, and R3 is -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0187] In a preferred embodiment of the first or further or yet another aspect of the invention, A is N and R2 is -NHR8, where R8 is H or C. 1-6 alkyl, preferably H; R3 is -C 1-3 -alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0188] In a preferred embodiment of the first or further or yet another aspect of the invention, R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-, alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably R6 is H and R2 is -NHR8, where R8 is H or C 1-6 alkyl, preferably H; R3 is -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2 or 3 substituents selected from the group consisting of alkyl.

[0189] In a preferred embodiment of the first or further or yet another aspect of the present invention, R1 is -CO-OH and R2 is -NHR8, where R8 is H or C 1-6 alkyl, preferably H; R3 is -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0190] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably R6 is H and R2 is -NHR8, where R8 is H or C 1-6 alkyl, preferably H; R3 is -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0191] In a preferred embodiment of the first or further or yet another aspect of the present invention, A is N and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably R6 is H and R2 is -NHR8, where R8 is H or C 1-6 alkyl, preferably H; R3 is -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0192] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is N and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 -alkyl (i.e., C1-, C2-, C3-alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably R6 is H and R2 is -NHR8, where R8 is H or C 1-6 alkyl, preferably H; R3 is -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2)m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0193] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is N, R1 is -CO-OH or -CO-NH2 and R2 is -NHR8, where R8 is H or C. 1-6 alkyl, preferably H; R3 is -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0194] In a preferred embodiment of the first or further or yet another aspect of the invention, A is N and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 R3 is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, and =O, preferably -OH and =O; 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m-L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 and R3 is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0195] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is N, and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 R3 is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, and =O, preferably -OH and =O; 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -O, -C 1-3 Alkyl, and -hydroxyC 1-3 and R3 is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, -C 1-3Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0196] In a preferred embodiment of the first or further or yet another aspect of the invention, A is N, R1 and R2 together form uracil or 3-deazauracil, and R3 is -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -O, -C 1-3 Alkyl, and -hydroxyC 1-3 and R3 is optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0197] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is N, R1 and R2 together form uracil or 3-deazauracil, and R3 is -C 1-3 Alkyl (i.e., C1-, C2-, C3-alkyl) or -(CH2) m -L, where m is 0, and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO, -CN, -Br, -Cl, -F, -I, -OC 1-3 Alkyl, and -hydroxyC 1-3 It may be substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl.

[0198] In a preferred embodiment of the first or further or yet another aspect of the present invention, A is N and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably, R6 is H and R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0199] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is N and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 -alkyl (i.e., C1-, C2-, C3-alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably, R6 is H and R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0200] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is N, R1 is -CO-OH or -CO-NH2 and R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H or CF3.

[0201] In a preferred embodiment of the first or further or yet another aspect of the invention, A is N and R2 is -NHR8, where R8 is H or C. 1-6 Alkyl, preferably H, and R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0202] In a preferred embodiment of the first or further or yet another aspect of the present invention, A is N and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 Alkyl (i.e., C1-, C2-, C3-, alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably R6 is H and R2 is -NHR8, where R8 is H or C 1-6 Alkyl, preferably H, and R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0203] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is N and R1 is -CO-OR6 or -CO-NR6R A and preferably, R6 is H, -C 1-3 -alkyl (i.e., C1-, C2-, C3-alkyl), -C 2-3 Alkenyl (i.e., C2-, C3-alkenyl), -C 2-3 Alkynyl (i.e., C2-, C3-), which may be optionally substituted, preferably R6 is H and R2 is -NHR8, where R8 is H or C 1-6 Alkyl, preferably H, and R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0204] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is N, R1 is -CO-OH or -CO-NH2 and R2 is -NHR8, where R8 is H or C. 1-6 Alkyl, preferably H, and R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0205] In a preferred embodiment of the first or further or yet another aspect of the invention, A is N and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 It may be substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, and =O, preferably -OH and =O, where R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0206] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is N, and R1 and R2 together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably -OH, -NO2, -CN, -Br, -Cl, -F, -I, -OC 1-3 It may be substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, and =O, preferably -OH and =O, where R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0207] In a preferred embodiment of the first or further or yet another aspect of the invention, A is N, R1 and R2 together form uracil or 3-deazauracil, and R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0208] In a preferred embodiment of the first or further or yet another aspect of the invention, X is N, A is N, R1 and R2 together form uracil or 3-deazauracil, and R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3.

[0209] In a preferred embodiment of the first or further or yet another aspect of the invention, R5 is -(CH2) m-L, where m is 0 or 1; or -(CH)-(CH=CH)-L, where L is phenyl, 5- or 6-membered heteroaryl, or adamantyl, which is optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO, -CN, -CO-OR, -Br, -Cl, -F, -I, -R, -O-R, and =O, or two adjacent substituents may form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring.

[0210] In a preferred embodiment of the first or further or yet another aspect of the invention, R4 and R5 together form a 5- or 6-membered unsubstituted or monosubstituted heterocycloalkyl, which preferably has =CH-R at the R4 position. A is replaced by.

[0211] In a preferred embodiment of the first or further or yet another aspect of the invention, R A are -Br, -Cl, -F, -O-(CH2) o -R9 (wherein o is 0 or 1), or a substituted carbocycle having 1 or 2 substituents independently selected from the group consisting of -SCH3.

[0212] In a preferred embodiment of the first or further or yet another aspect of the invention, R4 and R5 together form a 5- or 6-membered unsubstituted or monosubstituted heterocycloalkyl, which preferably has =CH-R at the R4 position. A where R A are -Br, -Cl, -F, -O-(CH2) o -R9 (wherein o is 0 or 1), or a substituted carbocycle having 1 or 2 substituents independently selected from the group consisting of -SCH3.

[0213] In a preferred embodiment of the first or further or yet another aspect of the present invention, R9 is -C 1-4-alkyl (i.e., C1-, C2-, C3-, or C4-alkyl), -C 2-4 -alkenyl (i.e., C2-, C3-, or C4-alkenyl), or -C 1-6 -alkyl-aryl (i.e., C1-, C2-, C3-, C4-, C5-, or C6-alkyl-aryl), which may be optionally substituted with 1 or 2 substituents selected from the group consisting of -Cl, -CH3, -OCH3, or -SCH3.

[0214] In a preferred embodiment of the first or further or yet another aspect of the invention, R5 is -(CH2) m -L, where m is 0 or 1; or -(CH2)-(CH=CH)-L, where L is phenyl, 5- or 6-membered heteroaryl, or adamantyl, which is optionally substituted, preferably with 1, 2 or 3 substituents independently selected from the group consisting of -OH, -NO2, -CN, -CO-OR6, -Br, -Cl, -F, -I, -R9, -O-R9, and =O; or two adjacent substituents may form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, where R9 is -C 1-4 Alkyl (i.e., C1-, C2-, C3-, or C4-alkyl, -C 2-4 Alkenyl (i.e., C2-, C3-, or C4-alkenyl, or -C 1-6 Alkyl-aryl, i.e., C1-, C2-, C3-, C4-, C5-, or C6-alkyl-aryl, which may be optionally substituted with one or two substituents selected from the group consisting of -Cl, -CH3, -OCH3, or -SCH3.

[0215] In a particularly preferred embodiment of the first aspect of the invention, the allosteric inhibitor has formula (Ia): [ka] (Ia) [In the formula, A is C or N; R1 is -COOH; R2 is -CH3, or -NH2; or, R1 and R2 together form uracil, or 3-deazauracil; R3 is H, =O, -OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF2H, or CF3; R4 is H; R5 is L or -CH2-(CH=CH)-L, where L is a 6-membered carbocycle or heterocycle, or adamantyl, which may be optionally substituted with 1 or 2 substituents independently selected from the group consisting of -OH, -NO2, -Br, -Cl, -F, -CH3, -O-R9, and =O, or two adjacent substituents may form a 5- or 6-membered heterocycle; or, R and R together form a 5- or 6-membered unsubstituted or monosubstituted heterocycloalkyl, preferably =CH-R A is replaced by; R9 is -C 1-4 Alkyl (i.e., C1-, C2-, C3-, or C4-alkyl), -C 2-4 alkenyl (i.e., C2-, C3-, or C4-alkenyl), or -C 1-6 alkyl-aryl (i.e., C1-, C2-, C3-, C4-, C5-, or C6-alkyl-aryl), which may be optionally substituted with 1 or 2 substituents selected from the group consisting of -Cl, -CH3, -OCH3, or -SCH3; R A are -Br, -Cl, -F, -O-(CH2) o -R9 (wherein o is 0 or 1), or -SCH3. and isomers, salts, solvates, chemically protected forms, and prodrugs thereof.

[0216] In particularly preferred embodiments, the compounds of the first and further aspects of the invention have the specific structures shown in FIG.

[0217] The use of bifunctional compounds that recruit proteins involved in targeting proteins for degradation by the proteasome has emerged as a potential therapeutic strategy to degrade proteins involved in disease processes. This approach has attracted particular attention in cancer treatment (Khan S. et al., 2020 and Bushweller JH, 2019). Such bifunctional compounds are generally referred to as PROteolysis TArgeting Chimeras (PROTACs). The allosteric inhibitors of ALC1 of the first and further aspects of the present invention specifically bind to ALC1 and are therefore suitable for recruiting proteins that are part of the ubiquitination pathway to ALC1.

[0218] Thus, in a second aspect, the present invention relates to a bifunctional compound comprising an allosteric inhibitor of ALC1 according to the first or further aspect of the present invention and a compound that recruits a protein that is part of the ubiquitination pathway for ALC1, preferably an E3 ubiquitin ligase to ALC1 (E3 recruiter), where the allosteric inhibitor of ALC1 and the E3 recruiter are covalently linked, optionally via a linker. Of particular importance with respect to the bifunctional compound of the present invention is the ability of the allosteric inhibitor of ALC1 according to the first and further aspects of the present invention to specifically bind to ALC1. Thus, the allosteric inhibitor of ACL1 has a K of 50 μM, more preferably 10 μM or less, more preferably 5 μM or less, even more preferably 1 μM, more preferably 500 nM, more preferably 200 nM, even more preferably 100 nM or less for full-length human ALC1 having the amino acid sequence set forth in SEQ ID NO:1. D It is preferred to bond with

[0219] Proteins in the ubiquitination pathway can be bound by either small molecules or protein ligands, such as antibodies or antibody-like proteins that specifically bind to proteins in the ubiquitination pathway. Such protein ligands are described, for example, in U.S. Patent No. 7,223,556B1. Small molecule compounds that bind to proteins that are part of the ubiquitination pathway are well known in the art and can be used in the bifunctional compounds of the present invention. Examples of such molecules are described in EP3131588, WO2017 / 024317, US6,306,663, US7,041,298, US2016 / 0176916, US2016 / 0235730, US2016 / 0235731, US2016 / 0243247, WO2016 / 105518, WO2016 / 077380, WO2016 / 105518, WO2016 / 077375, WO2017 / 007612, and WO2017 / 024317.

[0220] The allosteric inhibitor of ALC1 is covalently linked to a compound that recruits a protein that is part of the ubiquitination pathway to ALC1. Preferably, the two components are covalently linked to each other via a linker. Suitable linkers are of various lengths and functions. Preferably, the linker is a carbon chain. In a preferred embodiment, the carbon chain may optionally contain one, two, three or more heteroatoms selected from N, O, and S. In a preferred embodiment, the carbon chain contains only saturated chain carbon atoms. In a preferred embodiment, the carbon chain may optionally contain two or more unsaturated chain carbon atoms (e.g., C=C or C≡EC). In certain embodiments, one or more chain carbon atoms in the carbon chain may be substituted with one or more substituents, preferably oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C3 alkoxy, OH, halogen, NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, CN, C3-C7 cycloalkyl, heterocyclyl, phenyl, and heteroaryl.

[0221] In certain embodiments, the linker comprises at least 5 chain atoms (e.g., C, O, N, and S). In certain embodiments, the linker comprises less than 20 chain atoms (e.g., C, O, N, and S). In certain embodiments, the linker comprises 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 chain atoms (e.g., C, O, N, and S). In certain embodiments, the linker comprises 5, 7, 9, 11, 13, 15, 17, or 19 chain atoms (e.g., C, O, N, and S). In certain embodiments, the linker comprises 5, 7, 9, or 11 chain atoms (e.g., C, O, N, and S). In certain embodiments, the linker comprises 6, 8, 10, 12, 14, 16, or 18 chain atoms (e.g., C, O, N, and S). In certain embodiments, the linker comprises 6, 8, 10, or 12 chain atoms (eg, C, O, N, and S).

[0222] In certain embodiments, the linker is a carbon chain optionally substituted with non-bulky substituents, preferably oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C3 alkoxy, OH, halogen, NH2, -NH(C1-C3 alkyl), -N(C1-C3 alkyl), CN, C3-C7 cycloalkyl, and CN.

[0223] In certain embodiments, the linker has formula L(VI): [ka] (VI) [In the formula, p1 is an integer selected from 0 to 12; p2 is an integer selected from 0 to 12; p3 is an integer selected from 1 to 6; each W is independently absent, CH2, O, S, NH, or NR5; Z is absent, CH2, O, NH, or NR5; Each R5 is independently H, or C1-C3 alkyl, preferably C1-C3 alkyl; and Q is absent or -CHC(O)NH-; Here, the linker is covalently attached at the bond next to Q to a compound that recruits a protein that is part of the ubiquitination pathway, and at the bond next to Z to an allosteric inhibitor of ALC1, and the total number of chain atoms in the linker is less than 20. or an enantiomer, diastereomer, or stereoisomer thereof.

[0224] In a third aspect, the present invention relates to a pharmaceutical composition comprising an allosteric inhibitor of ALC1 and a pharma- ceutically acceptable excipient.

[0225] In a fourth aspect, the present invention relates to an ALC1 inhibitor (ALC1i) for treating or ameliorating a proliferative disease in a patient, preferably the ALC1 inhibitor of the first aspect of the present invention, which comprises the administration of ALC1i and the optional administration of a poly(ADP-ribose)-polymerase inhibitor (PARPi). The present inventors have discovered that the PARP scavenging activity of known PARPi can be enhanced by ALC1i. Due to this surprising synergistic effect, the combined use of PARPi and ALC1i in the treatment of various proliferative diseases is particularly advantageous. This synergistic effect is not limited to the allosteric inhibitors of the present invention, but will also be observed with inhibitors that inhibit ALCi, for example, by binding to the ATPase site or reducing its expression (e.g., siRNA targeted to ALC1).

[0226] ALC1 may be provided to the physician administering the antiproliferative therapy separately from the PARPi or as a kit of parts. Thus, in an embodiment where both are combined to obtain synergistic benefits, ALC1 may be provided with instructions to combine it with the PARPi, or in a fourth aspect, the PARPi may be provided with instructions to combine it with ALC1.

[0227] Thus, in a fifth aspect, the present invention relates to a PARPi for use in treating or ameliorating a proliferative disorder in a patient, the method comprising administration of a PARPi and administration of an ALC1i.

[0228] In a preferred embodiment of ALC1i for use in the fourth aspect of the present invention or PARPi for use in the fifth aspect of the present invention, PARPi reduces PARP activity and / or inhibits PARP1, PARP2 and / or PARP3, preferably PARP2 on chromatin.The latter phenomenon is also called PARP trap.Therefore, in a preferred embodiment, PARP1, PARP2 and / or PARP3, preferably PARP2, are trapped.

[0229] In a preferred embodiment, in the ALC1i for use in the fourth aspect of the present invention or the PARPi for use in the fifth aspect of the present invention, the PARPi is (i) reduces PARP activity and is selected from small interfering RNAs; (ii) a compound that inhibits PARP1, the compound being: (a) Formula (II): [ka] (II) [In the formula, A and B together represent an optionally substituted fused aromatic ring; X is NR X or CR X R Y and; X=NR X , n is 1 or 2, and X=CR X R Y where n is 1; R X is H, optionally substituted C 1-20 Alkyl, C 5-20 Aryl, C 3-20selected from the group consisting of heterocyclyl, amide, thioamide, ester, acyl, and sulfonyl groups; R Y is selected from H, hydroxy, amino; Or, R X and R Y Together, Spiro-C 3-7 may form a cycloalkyl or heterocyclyl group; R C1 and R C2 are independently hydrogen and C 1-4 alkyl or X is selected from the group consisting of CR X R Y If R C1 , R C2 , R X and R Y may be taken together with the carbon atom to which they are attached to form an optionally substituted fused aromatic ring; and R1 is selected from H and halo. and isomers, salts, solvates, chemically protected forms, and prodrugs thereof; and, (b) Formula (III): [ka] (III) [In the formula, Y and Z each independently represent the following group: 1. an aryl group optionally substituted with 1, 2, or 3 R6; 2. a heteroaryl group optionally substituted with 1, 2, or 3 R6; 3. Hydrogen, alkenyl (e.g., C 2-6 alkenyl), alkoxy (e.g. C 1-6 alkoxy), alkoxyalkyl (e.g., C 1-6 Alkoxy-C 1-6 alkyl), alkoxycarbonyl (e.g., C 1-6 Alkoxy-carbonyl), alkoxycarbonylalkyl (e.g., C1-6 Alkoxy-carbonyl-C 1-6 alkyl), alkyl (e.g. C 1-6 Alkyl), alkynyl (e.g., C 2-6 alkynyl), arylalkyl (e.g., aryl-C 1-6 alkyl), cycloalkyl (e.g., C 3-8 cycloalkyl), cycloalkylalkyl (e.g., C 3-8 Cycloalkyl-C 1-6 alkyl), haloalkyl (e.g., C 1-6 -haloalkyl), hydroxyalkylene (e.g., hydroxy-C 1-6 alkylene), oxo, heterocycloalkyl (e.g., C 2-8 -heterocycloalkyl), heterocycloalkylalkyl (e.g., C 2-8 -Heterocycloalkyl-C 1-6 alkyl), alkylcarbonyl (e.g., C 1-6 alkyl-carbonyl), arylcarbonyl, heteroarylcarbonyl, alkylsulfonyl (e.g., C 1-6 Alkyl sulfonyl), aryl sulfonyl, heteroaryl sulfonyl, (R A R B ) alkylene (e.g., (R A R B )-C 1-6 alkylene), (NR A R B ) carbonyl, (NR A R B ) carbonyl alkylene (e.g., (NR A R B )Carbonyl-C 1-6 alkylene), (NR A R B ) sulfonyl, and (R A R B )sulfonylalkylene (e.g., (R A R B )Sulfonyl-C 1-6 Substituents independently selected from the group consisting of: alkylene; (wherein each R6 is OH, NO2, CN, Br, Cl, F, I, C 1-6Alkyl, C 3-8 Cycloalkyl, C 2-8 -heterocycloalkyl; C 2-6 Alkenyl, alkoxy (e.g., C 1-6 alkoxy), alkoxyalkyl (e.g., C 1-6 Alkoxy-C 1-6 alkyl), alkoxycarbonyl (e.g., C 1-6 Alkoxy-carbonyl), alkoxycarbonylalkyl (e.g., C 1-6 Alkoxy-carbonyl-C 1-6 Alkyl), C 2-6 Alkynyl, aryl, arylalkyl (e.g., aryl-C 1-6 Alkyl), C 3-8 Cycloalkylalkyl (e.g., C 3-8 Cycloalkyl-C 1-6 alkyl), haloalkoxy (e.g., C 1-6 -haloalkoxy), haloalkyl (e.g., C 1-6 -haloalkyl), hydroxyalkylene (e.g., hydroxy-C 1-6 alkylene), oxo, heteroaryl, heteroarylalkoxy (e.g., heteroaryl-C 1-6 alkoxy), heteroaryloxy, heteroarylthio, heteroarylalkylthio (e.g., heteroaryl-C 1-6 alkylthio), heterocycloalkoxy (e.g., C 2-8 -heterocycloalkoxy), C 2-8 -Heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR A R B , (R A R B ) C 1-6 Alkylene, (NR A R B ) carbonyl, (R A R B ) carbonyl alkylene (e.g., (R A R B )Carbonyl-C 1-6 alkylene), (NR A R B )sulfonyl, and (NR A RB )sulfonylalkylene (e.g., (NR A R B )Sulfonyl-C 1-6 alkylene). selected from the group consisting of; R1, R2, and R3 are each independently hydrogen, halogen, alkenyl (e.g., C 2-6 alkenyl), alkoxy (e.g. C 1-6 alkoxy), alkoxycarbonyl (e.g., C 1-6 alkoxy-carbonyl), alkyl (e.g., C 1-6 alkyl), cycloalkyl (e.g., C 3-8 cycloalkyl), alkynyl (e.g., C 2-6 alkynyl), cyano, haloalkoxy (e.g., C 1-6 -haloalkoxy), haloalkyl (e.g., C 1-6 -haloalkyl), hydroxyl, hydroxyalkylene (e.g. hydroxy-C 1-6 alkylene), nitro, NR A R B , N.R. A R B Alkylene (e.g., NR A R B C 1-6 alkylene), and (R A R B ) carbonyl; A and B are each independently hydrogen, Br, Cl, F, I, OH, or C. 1-6 Alkyl, C 3-8 Cycloalkyl, alkoxy (e.g. C 1-6 alkoxy), alkoxyalkyl (e.g., C 1-6 Alkoxy-C 1-6 alkyl), where C 1-6 Alkyl, C 3-8 Cycloalkyl, alkoxy, and alkoxyalkyl are OH, NO2, CN, Br, Cl, F, I, and C. 1-6 Alkyl, and C 3-8 cycloalkyl, where B is not OH; R A and R B is hydrogen, alkyl (e.g., C 1-6 alkyl), cycloalkyl (e.g., C 3-8 cycloalkyl), and alkylcarbonyl (e.g., C 1-6 or R A and R B together with the atoms to which they are attached, -O-, -NH, -N(C 1-6 alkyl), -NCO(C 1-6 Alkyl), -N(aryl), -N(aryl-C 1-6 Alkyl), -N(substituted-aryl-C 1-6 alkyl-), -N(heteroaryl)-, -N(heteroaryl-C1-C6 alkyl-), N(substituted-heteroaryl-C 1-6 Alkyl-)- and -S- or S(O) q - (wherein q is 1 or 2), optionally having 1 to 3 heteroatoms or heterofunctional groups selected from the group consisting of, wherein the 3 to 10 membered heterocycle is optionally substituted with one or more substituents; R4 and R5 are each independently hydrogen, alkyl (e.g., C 1-6 alkyl), cycloalkyl (e.g., C 3-8 cycloalkyl), alkoxyalkyl (e.g., C 1-6 Alkoxy-C 1-6 alkyl), haloalkyl (e.g., C 1-6 -haloalkyl), hydroxyalkylene (e.g., hydroxy-C 1-6 alkylene), and (NR A R B ) alkylene (e.g., NR A R B C 1-6 alkylene). and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, selected from the group consisting of; (iii) a compound that inhibits PARP1 and PARP2, the compound being: (a) Formula (IV): [ka] (IV) [In the formula, R1 is hydrogen or fluorine; and R2 is hydrogen or fluorine. and isomers, salts, solvates, chemically protected forms, and prodrugs thereof; and, (b) Formula (V): [ka] (V) [In the formula, R1, R2, and R3 are independently hydrogen, alkenyl (e.g., C 1-6 alkenyl), alkoxy (e.g., C 1-6 alkoxy), alkoxycarbonyl (e.g., C 1-6 alkoxycarbonyl), alkyl (e.g., C 1-6 alkyl), alkynyl (e.g., C 1-6 alkynyl), cyano, haloalkoxy (e.g., C 1-6 -haloalkoxy), haloalkyl (e.g., C 1-6 -haloalkyl), halogen, hydroxy, hydroxyalkyl (e.g., C 1-6 -hydroxyalkyl), nitro, NR A R B , and (NR A R B ) carbonyl; A is a non-aromatic 4-, 5-, 6-, 7- or 8-membered ring which may contain one or two nitrogen atoms and optionally one sulfur or oxygen atom, where the non-aromatic ring is alkenyl (e.g., C 1-6 alkenyl), alkoxy (e.g., C 1-6 alkoxy), alkoxyalkyl (e.g., C1-6 Alkoxy-C 1-6 alkyl), alkoxycarbonyl (e.g., C 1-6 alkoxycarbonyl), alkoxycarbonylalkyl (e.g., C 1-6 Alkoxycarbonyl-C 1-6 alkyl), alkyl (e.g., C 1-6 alkyl), alkynyl (e.g., C 1-6 alkynyl), aryl, arylalkyl (e.g., aryl-C 1-6 alkyl), cycloalkyl (e.g., C 3-8 cycloalkyl), cycloalkylalkyl (e.g., C 3-8 Cycloalkyl-C 1-6 alkyl), cyano, haloalkoxy (e.g., C 1-6 -haloalkoxy), haloalkyl (e.g., C 1-6 -haloalkyl), halogen, heterocycle, heterocycle alkyl (e.g., heterocycle-C 1-6 alkyl), heteroaryl, heteroarylalkyl (e.g., heteroaryl-C 1-6 alkyl), hydroxy, hydroxyalkyl (e.g., C 1-6 -hydroxyalkyl), nitro, NR C R D , (NR C R D ) alkyl (e.g., (NR C R D )-C 1-6 alkyl), (NR C R D ) carbonyl, (NR C R D ) carbonylalkyl (e.g., (NR C R D )Carbonyl-C 1-6 alkyl), and (NR C R D ) sulfonyl; and R A , R B , R C and R D is hydrogen, alkyl (e.g., C1-6 alkyl), and alkylcarbonyl (e.g., C 1-6 alkylcarbonyl). and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, selected from the group consisting of; (iv) a compound that inhibits PARP1, PARP2, and PARP3, the compound having the formula (VI): [ka] (VI) [In the formula, R1 is H; halogen; cyano; optionally substituted alkyl (e.g., C 1-6 Alkyl), alkenyl (e.g., C 2-6 alkenyl), alkynyl (e.g., C 2-6 alkynyl), cycloalkyl (e.g., C 3-8 cycloalkyl), heterocycloalkyl (e.g., C 2-8 -heterocycloalkyl), aryl, or heteroaryl groups (e.g., aryl groups, alkyl groups (e.g., C 111, C 112, C 113, C 114, C 115, C 116, C 117, C 118, C 119, C 120, C 121, C 122, C 123, C 124, C 125, C 126, C 127, C 128, C 129, C 130, C 131, C 132, C 133, C 134, C 135, C 136, C 137, C 138, C 139, C 140, C 141, C 142, C 143, C 144, C 145, C 146, C 147, C 148, C 149, C 150, C 151, C 152, C 153, C 154, C 155, C 156, C 157, C 158, C 159, C 160, C 161, C 162, C 163, C 164, C 165, C 166, C 167, C 168, C 169, C 170, C 171, C 172, C 173, C 174, C 175, C 176, C 177, C 178, C 179, C 180, C 181, C 182, C 183, C 184, C 185, C 186, C 187, C 188, C 189, C 190 1-6 alkyl), alkoxy groups (e.g., C 1-6 alkoxy); and ether groups (such as O-aryl); or -C(O)-R 10 where R 10 is H; optionally substituted alkyl (e.g., C 1-6 Alkyl), alkenyl (e.g., C 1-6 alkenyl), alkynyl (e.g., C 1-6 alkynyl), cycloalkyl (e.g., C 3-8 cycloalkyl), heterocycloalkyl (e.g., C 2-8-heterocycloalkyl), aryl, or heteroaryl groups (e.g., unsubstituted; or substituted with one or more substituents selected from halogen, hydroxy, nitro, amino; and aryl groups, alkyl groups (e.g., C 1-6 alkyl); or OR 100 , or N.R. 100 R 110 where R 100 and R 110 are each independently H or optionally substituted alkyl (e.g., C 1-6 Alkyl), alkenyl (e.g., C 2-6 alkenyl), alkynyl (e.g., C 2-6 alkynyl), cycloalkyl (e.g., C 3-8 cycloalkyl), heterocycloalkyl (e.g., C 2-8 -heterocycloalkyl), aryl, or heteroaryl groups (e.g., alkyl (e.g., C 11 , C 21 , C 31 , C 41 , C 51 , C 61 , C 71 , C 81 , C 91 , C 101 , C 112 , C 121 , C 131 , C 141 , C 151 , C 161 , C 171 , C 181 , C 191 , C 201 , C 211 , C 221 , C 31 , C 41 , C 51 , C 61 , C 71 , C 81 , C 91 , C 191 1-6 alkyl), substituted with one or more substituents selected from aryl groups, 1-6 Alkyl), alkenyl (e.g., C 2-6 alkenyl), alkynyl (e.g. C 2-6 alkynyl), cycloalkyl (e.g., C 3-8 cycloalkyl), heterocycloalkyl (e.g., C 2-8 -substituted with one or more substituents selected from heterocycloalkyl, aryl, and heteroaryl groups; R2 is H or alkyl (e.g., C 1-6 alkyl); R3 is H or alkyl (e.g., C 1-6 alkyl); R4 is H, halogen or alkyl (e.g., C1-6 alkyl); X is O or S; Y is (CR5R6)(CR7R8) n or NC(R5); where n is 0 or 1; R5 and R6 are each independently H or an optionally substituted alkyl (e.g., C 1-6 Alkyl), alkenyl (e.g., C 2-6 alkenyl), alkynyl (e.g., C 2-6 alkynyl), cycloalkyl (e.g., C 3-8 cycloalkyl), heterocycloalkyl (e.g., C 2-8 -heterocycloalkyl), aryl, or heteroaryl groups (e.g., aryl groups, unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, amino, and lower alkoxy groups (e.g., C 1-4 alkoxy), or lower alkyl (e.g., C 1-4 alkyl) groups; and R7 and R8 are each independently H or an optionally substituted alkyl (e.g., C 1-6 Alkyl), alkenyl (e.g., C 2-6 alkenyl), alkynyl (e.g., C 2-6 alkynyl), cycloalkyl (e.g., C 3-8 cycloalkyl), heterocycloalkyl (e.g., C 2-8 -heterocycloalkyl), aryl, or heteroaryl groups (e.g., aryl groups, unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, amino, and lower alkoxy groups (e.g., C 1-4 alkoxy), and lower alkyl groups (e.g., C 1-4 alkyl); wherein when R1, R4, R5, R6, and R7 are each H, R8 is not unsubstituted phenyl. and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, Either:

[0230] In a preferred embodiment of an ALC1i for use in the fourth aspect of the invention or a PARPi for use in the fifth aspect of the invention, the PARPi is selected from the group consisting of Olaparib, Talazoparib, Niraparib, Rucaparib, and Veliparib, in particular from the group consisting of Veliparib, Olaparib, and Talazoparib.

[0231] In a preferred embodiment of an ALC1i for use in the fourth aspect of the invention or a PARPi for use in the fifth aspect of the invention, the ALC1i is a direct inhibitor of the ATPase activity of ALC1 or is an allosteric inhibitor of ALC1.

[0232] In a preferred embodiment of an ALC1i for use in the fourth aspect of the invention or a PARPi for use in the fifth aspect of the invention, the ALC1i is an inhibitor of ALC1 of either the first or further aspect of the invention, or a bifunctional compound of the second aspect.

[0233] In a preferred embodiment of ALC1i for use in the fourth aspect of the invention or PARPi for use in the fifth aspect of the invention, the proliferative disease is selected from BRCA1 and / or BRCA2 deficient tumors and tumors in which expression of PARP1, PARP2, PARP3 and / or ALC1 is increased compared to non-tumor cells.

[0234] In a preferred embodiment of the ALC1i for use in the fourth aspect of the present invention or the PARPi for use in the fifth aspect of the present invention, the tumor disease is selected from hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, and colorectal cancer.

[0235] In a preferred embodiment of an ALC1i for use in the fourth aspect of the present invention or a PARPi for use in the fifth aspect of the present invention, (i) the ALC1i enhances the cancer cell killing effect of the PARPi, (ii) the dosage of the PARPi is reduced, and / or (iii) PARPi resistance is avoided.

[0236] In a preferred embodiment of the ALC1i for use in the fourth aspect of the invention or the PARPi for use in the fifth aspect of the invention, the PARPi and the ALC1i are administered simultaneously or separately.

[0237] In a sixth aspect, the present invention relates to a kit comprising separately packaged PARPi and ALC1i, or a composition comprising PARPi and ALC1i, preferably with instructions for use for treating or ameliorating a proliferative disorder. EXAMPLES

[0238] Experimental Section Cell lines used The preferred cell line used in the examples is an osteosarcoma cell line designated U2OS. The U2OS cell line is a human cancer cell line established in 1964 by J. Ponten and E. Saksela from a moderately differentiated sarcoma in the tibia of a 15-year-old Caucasian female. (U-2 OS ATCC™ HTB-96 TM Homo sapiens bone osteosarcoma, 2016). It is available from a number of sources, including ATCC™ HTB-96™.

[0239] MDA-MB-231 cells were used as a BRCA wild-type cell line. The cells were established from an aneuploid human female. The cells were extracted from the mammary gland (breast) at the metastatic site as pleural effusion. (MDA-MB-231 (ATCC™ HTB-26 TM Homo sapiens epithelial mammary gland), which is ATCC™ HTB-26 TM It is available from a number of sources, including

[0240] As a BRCA-negative cell line, SUM-149-PT cells were used. This cell line is a triple-negative breast cancer (TNBC) cell line derived from a primary human invasive ductal carcinoma metastatic nodule of a 40-year-old woman. It harbors a hemizygous BRCA1 mutation (p.Pro724Leufs * 12) and are available from a number of sources, including bioIVT.

[0241] PARP-2 Trap U2OS cells were seeded in 4-well Nunc Lab-Tek chambers (Thermo Fisher Scientific) containing regular DMEM. Cells were cultured overnight at 37°C and transfected with GFP-tagged PARP2 plasmid using Lipofectamine. 24 hours after transfection, cells were imaged using a Zeiss AxioObserver Z1 confocal spinning disk microscope equipped with a sCMOS ORCA Flash 4.0 camera (Hamamatsu). Live cell imaging experiments were performed using a C-Apo 63× water immersion objective. During this time, cells were maintained in Leibovitz's L-15 medium (Gibco) supplemented with 10% FBS at 37°C in the absence of CO2. Cells with comparable transgene expression levels were selected for imaging and analysis of PARP-2 trap. DNA damage was induced along a line of 88 pixels exposed for 400 milliseconds (msec) with 20% laser power of a 355 nm laser operated via a single-point scanning head (UGA-42 firefly, Rapp OptoElectronics). Figure 4 shows a schematic diagram of the live-cell PARP-2 trapping assay.

[0242] Accumulation of fluorescently labeled proteins at the laser microirradiation sites was followed for 15–30 min. Cells were treated with the indicated inhibitor concentrations for 1 h at 37 °C prior to experimental analysis. As a control, cells were treated with the corresponding concentrations of DMSO. Accumulation of fluorescently labeled proteins at the microirradiation sites was quantified using a custom-made macro in Fiji / ImageJ. Damage areas of interest were selected, the mean nuclear fluorescence intensity was determined, and background signal was subtracted. Recruitment was calculated with the following formula: (damaged area (t) - background signal (t)) / (nuclear intensity (t) - background (t)).

[0243] Inhibitor versus response (cell viability) assay For validation of small molecule inhibitors, synthetic lethality of BRCA and ALC1 was investigated using MDA-MB-231 cells as a BRCA wild-type cell line and SUM-149-PT as a BRCA1-deficient cell line. Cells were seeded in 96-well plates (5000 cells / well) and treated with titrations of ALC1 inhibitors starting at 50 μM. DMSO was added to the cells as a "no treatment" control. Cells were cultured at 37°C and 5% CO2 for 5 days, then fixed with 10% TCA for 1 h and stained with sulforhodamine dye for 30 min. After washing the cells with 1% acetic acid, stained cells were solubilized using 10 mM Tris (pH 10.5) solution. Absorbance was measured at 492 nm using a SUNRISE TECAN, and data were normalized to cell number at time point 0 and 100% viability (=DMSO control) and analyzed using GraphPad Prism. Survival curves were fitted using four-parameter inhibitor vs. response curves with variable slope. Figure 8 shows the IC of ALC1 inhibitor treatment. 50 Indicates the value.

[0244] For further validation of the compounds, a colony formation assay was applied. Here, the number of cells seeded for the assay was reduced (100 cells / well). Cells were treated with ALC1 inhibitors or a combination of PARPi and ALC1 inhibitors for 11 days. Cells were fixed and data were analyzed as described above. Figures 8 and 9 show the results of treatment with ALC1 inhibitors.

[0245] FRET-based nucleosome sliding assay The assay utilizes intermediately positioned mononucleosomes that can monitor the sliding activity of the ALC1 remodeling enzyme with a FRET readout. Each nucleosome is labeled with two FRET dyes, where the octamer is labeled with Cy5 (Cy5-maleimide, which couples to H2B) and one of the DNA ends is labeled with Cy3. The DNA template contains a 147 bp 601 DNA position sequence flanked by DNA overhangs on each side. Other nucleosome position sequences, both artificially constructed and natural sequences, can also be used, even if they are less efficient than the 601 sequence in positioning nucleosomes. Nucleosomes are assembled by salt gradient dialysis using purified Cy5-labeled histone octamer and purified Cy3-labeled DNA template, resulting in FRET-labeled intermediately positioned nucleosomes. These nucleosomes start out with low FRET and, with the two fluorophores too far apart for efficient FRET, will result in low Cy5 fluorescent signal when excited at the Cy3 excitation maximum wavelength. As the ALC1 remodeling reaction progresses and the remodeling enzyme slides the octamer towards the DNA end, the distance between the two FRET dyes decreases, resulting in an increase in signal from Cy5 / FRET. Thus, the increase in FRET can be used directly as a readout for sliding.

[0246] Construction of DNA templates for mononucleosome reconstitution For the reconstitution of mononucleosomes, the non-natural Widom601 nucleosome positioning sequence was used as a high affinity binding site for histone octamers (see Lowary, PT & Widom, J. New DNA sequence rules for high affinity binding to histone octamer and sequence-directed nucleosome positioning. J. Mol. Biol. 276, 19-42 (1998)). Cy3-labeled DNA containing these 601 sequences can be constructed using methods including PCR amplification, restriction digestion of DNA plasmids followed by Klenow end-labeling reactions, or other standard molecular biology techniques.

[0247] Preparation of ALC1 and histone octamers Full-length human ALC1(1-897) or its truncated forms were expressed and purified from Escherichia coli (E. coli) as N-terminal 6×His-tagged fusion proteins as previously published ( Singh, HR, et al., 2017 ).

[0248] Human histone proteins were recombinantly expressed in E. coli (using either classical IPTG induction or autoinduction media) and purified from E. coli inclusion bodies. The purification scheme involved extraction / solubilization of the histones from the inclusion bodies using guanidinium chloride, followed by reversed-phase chromatography. The purified histones were lyophilized to yield the TFA salt of the purified histone proteins.

[0249] Preparation of nucleosomes To construct nucleosomes, template DNA (final concentration 250 μg / ml) was mixed with purified histone octamers in high salt buffer at various molar ratios of histone octamers to DNA. The ionic strength of this mixture was then reduced to below 600 mM NaCl by successive dialysis against low salt buffer at 4° C. Finally, the material was dialyzed against TEA-20 (10 mM triethanolamine-Cl, pH 7.5, 20 mM NaCl, 0.1 mM EDTA). The best molar ratio, i.e. the ratio resulting in complete assembly of DNA into nucleosomes, was selected and used for further assembly.

[0250] Alternatively, nucleosomes can be assembled by other methods such as deposition of histone octamers onto DNA using polyglutamic acid or histone chaperones, or by salt serial dilution.

[0251] A method for measuring ALC1-mediated sliding; ALC1 nucleosome sliding assay Sliding reactions were carried out in 384-well plates at RT in 10 mM Tris-HCl, pH 8.1, 75 mM KCl, 1 mM MgCl2, 1.0 mM EGTA, 10% glycerol, 0.5 mM dithiothreitol (DTT), 0.01% TritonX100, 0.02% NP40. Reaction mixtures contained either nucleosomes in the midposition, tri-ADP-ribose, or (ADP-ribose). n , and the ALC1 chromatin remodeling enzyme. Sliding was initiated by addition of ATP, followed by shaking the plate at 1450 rpm for 5 seconds and sealing the plate with foil compatible for fluorescence reading. FRET signals were recorded immediately using a fluorometer (BMG Reader, PheraStar FSX, Channel A: Excitation 520 nm, Emission 680 nm; Channel B: Excitation 520 nm, Emission 590 nm) and remodeling was allowed to proceed for 30 min unless otherwise stated.

[0252] The FRET signal was calculated by dividing the signal at 680 nm (Cy5 emission) by the signal at 590 nm (Cy3 emission) and multiplying by 10,000. To obtain the apparent rate of ALC1-mediated nucleosome sliding, the increase in FRET over time was plotted as a function of time, and the initial rate of ALC1-mediated nucleosome sliding was obtained by fitting the resulting kinetic traces by a linear curve fit.

[0253] High-throughput screening (HTS) and IC of molecules regulating ALC1-mediated sliding 50 Decision High-throughput screening (HTS) and IC of compounds that modulate the sliding activity of ALC1 50 To determine the degree of sliding, nucleosomes were incubated with ALC1 and triADP-ribose or (ADP-ribose) in the presence of a putative ALCi before initiating sliding by the addition of ATP. n The cells were incubated with 0.01% EDTA for 30 minutes as described above. The sliding velocity (initial velocity) was then determined as described above and compared to the sliding velocity in the absence of the putative modulator / compound (% inhibition). IC 50 For determination of , % inhibition observed (y-axis) was plotted against compound concentration (x-axis) using GraphPad Prism and fitted using a nonlinear regression model (four parameters).

[0254] In silico modeling of ALC1 inhibitors To identify the binding pocket for small molecule inhibitors of ALC1, we constructed a homology model of the ALC1 helicase domain for use in molecular docking and molecular dynamics simulations. Then, the homology model and all the ligands were prepared for molecular docking, and flexible docking was performed on the homology model by Intel(R) Xeon(R) Platinum 8268 CPU @2.90GHz cpu, and ALCi-22 was selected to carry out MD simulation, which showed good results in the IC in biochemical sliding assay and docking pose. 50 The low ΔG of the ALC1 ATP-binding site was due to its low ΔG of 33449405, which was located in a previously unidentified pocket in the ATPase domain and not in the ATP-binding site itself. MD was then initiated by an NVIDIA Tesla V100-SXM2-32gb GPU. After the MD simulation was completed, every 10th frame was taken from the trajectory. These frames were aligned to the initial pose and PCA was performed. A plot of the PCA was generated using the first two principal components. Eight clusters of protein conformations were manually identified. Random points near the center of each cluster were extracted as PDB files. These frames were manually inspected and frame number 33449405 was finally selected for use in the figure due to the close proximity of the ligand to the catalytic residues of the ALC1 ATP-binding site and occupying a previously undescribed binding pocket. This pocket is composed of the following amino acids in human ALC1: L101, Y153, C156, L157, A160, L163, K164, V173, D174, E175, A176, H177, R178, L179, S1 83, L186, H187, T189, L190, F193, L200, L201, T202, N208, S209, E212, L213, L216, F219.

[0255] SAR analysis of ALC1 inhibitors When examining the biochemical and cellular data, several clear trends emerge relating to ligand structure and activity. The ligand "tail" clearly shows that long hydrophobic bonds are favored, both with (ALCi-123, vs. ALCi-125) and without (ALCi-4, vs. ALCi-2, vs. ALCi-1, vs. ALCi-22) a terminal cyclopentane. Furthermore, hydrophilic substituents in the "tail" region are highly detrimental (ALCi-135). This is consistent with the modeling poses that show the "tail" of the molecule to be located in a more hydrophobic region of the binding pocket (Figures 14 and 15). Considering the pyridine ring, CF3 substitution opposite the N appears to be favored over CF2H substitution (ALCi-8, vs. ALCi-4), while the thiophene ring is favored over CF3 (ALCi-4, vs. ALCi-56). This is again well illustrated by the modeling poses which show that this region of the molecule interacts with the more hydrophobic region of the binding pocket (Figures 14 and 15). Furthermore, in the "head" region of the inhibitors, molecules with more hydrophilic substituents are favored over those with fewer hydrophilic substituents (ALCi-6 vs. ALCi-72). Furthermore, the highest potency appears to be obtained when a carboxylic acid is substituted in the "head" region (ALCi-132), which is predicted to directly interact with ARG135 and potentially ASN165 (Figure 19). Indeed, ALCi-31, ALCi-32, ALCi-33, and ALCi-34, which do not have corresponding hydrophilic groups in the head region, are all inactive (data not shown), so interactions with ARG165 may be important for inhibition or binding. Taken together, it is clear that the SAR of the compounds supports the prediction of binding sites in the novel binding pocket by in silico modeling.

[0256] Synthesis of selected ALC1 inhibitors The synthesis of ALCi-72 begins with the aldol condensation of 1-(4-bromophenyl)ethan-1-one with ethyl 2,2,2-trifluoroacetate in THF at temperatures between −78° C. and room temperature for 16 hours using LiHMDS as a base to give 1-(4-bromophenyl)-4,4,4-trifluorobutane-1,3-dione (see FIG. 22, R=Br). This product is then involved in pyridine formation with 2-cyanoethanethioamide in acetic acid and ethanol under reflux to give 6-(4-bromophenyl)-2-sulfanylidene-4-(trifluoromethyl)-2,3-dihydropyridine-3-carbonitrile. In step 3, 6-(4-bromophenyl)-2-sulfanylidene-4-(trifluoromethyl)-2,3-dihydropyridine-3-carbonitrile is subjected to cyclization to thiophenopyridine with ethyl 2-chloroacetate using sodium carbonate as base in ethanol under reflux conditions for over 12 hours, thereby giving ethyl 3-amino-6-(4-bromophenyl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylate. Finally, in step 5, ethyl 3-amino-6-(4-bromophenyl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylate is subjected to urea formation and cyclization in DCM and water under reflux with ClSO2NCO, followed by sodium hydroxide under reflux for 6 hours, respectively, to give the final product ALCi-72.

[0257] The synthesis of ALCi-117 begins with the aldol condensation of 1-(4-butoxyphenyl)ethan-1-one with ethyl 2,2,2-trifluoroacetate using NaH as base in THF at 0° C. to room temperature for 16 hours to give 1-(4-butoxyphenyl)-4,4,4-trifluorobutane-1,3-dione, which is then involved in pyridine formation with 2-cyanoethanethioamide in acetic acid and ethanol to give 6-(4-butoxyphenyl)-2-sulfanyl-4-(trifluoromethyl)pyridine-3-carbonitrile. In step 3, 6-(4-butoxyphenyl)-2-sulfanyl-4-(trifluoromethyl)pyridine-3-carbonitrile is subjected to cyclization to thiophenopyridine with ethyl 2-chloroacetate under reflux conditions in ethanol using sodium carbonate as a base, thereby obtaining ethyl 3-amino-6-(4-butoxyphenyl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylate. In step 4, it is subjected to Sandmeyer reaction with ethyl 3-amino-6-(4-butoxyphenyl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylate to obtain ethyl 3-bromo-6-(4-butoxyphenyl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylate. Ethyl 3-bromo-6-(4-butoxyphenyl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylate was then reacted with CH3BF3-K + The resulting product is then subjected to Suzuki coupling reaction with Cs2CO3, Pd(dppf)Cl2, DCM, and dioxane at 150 °C for 30 min to give ethyl 6-(4-butoxyphenyl)-3-methyl-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylate. Finally, in step 6, ethyl 6-(4-butoxyphenyl)-3-methyl-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxylate is hydrolyzed with sodium hydroxide to give product ALCi-117.

[0258] The synthesis of ALCi-132 begins with the synthesis of the intermediate 4-[(4-chlorophenyl)methoxy]-3-methoxybenzaldehyde used in the final step via 1-(bromomethyl)-4-chlorobenzene; 4-hydroxy-3-methoxybenzaldehyde and 1-(bromomethyl)-4-chlorobenzene are mixed under reflux conditions using acetone and potassium carbonate. In step 1 of the synthesis, 2,4-diethyl 5-amino-3-methylthiophene-2,4-dicarboxylate is formed by formation of the thiophene using ethyl 3-oxobutanoate, ethyl 2-cyanoacetate, and S8 in ethanol and EtNH, which is then subjected to amide formation with oxolane-2,5-dione in a mixture of ether, benzene, and dioxane at room temperature to form 3-{[3-carbamoyl-5-(ethoxycarbonyl)-4-methylthiophen-2-yl]carbamoyl}propanoic acid. In step 3, 3-{[3-carbamoyl-5-(ethoxycarbonyl)-4-methylthiophen-2-yl]carbamoyl}propanoic acid is subjected to a Stecklich esterification to form ethyl 4-carbamoyl-5-(4-methoxy-4-oxobutanamido)-3-methylthiophene-2-carboxylate. Ethyl 4-carbamoyl-5-(4-methoxy-4-oxobutanamido)-3-methylthiophene-2-carboxylate is then subjected to a Zn(BH4)2 reduction reaction to form ethyl 4-carbamoyl-5-(4-hydroxybutanamido)-3-methylthiophene-2-carboxylate, which is then cyclized using sodium hydroxide under reflux conditions for 16 hours to form 2-(3-hydroxypropyl)-5-methyl-4-oxo-4H,4aH-thieno[2,3-d]pyrimidine-6-carboxylic acid. 2-(3-hydroxypropyl)-5-methyl-4-oxo-4H,4aH-thieno[2,3-d]pyrimidine-6-carboxylic acid is then esterified with EtOH and H2SO4 under reflux for 16 h to give ethyl 2-(3-hydroxypropyl)-5-methyl-4-oxo-4H,4aH-thieno[2,3-d]pyrimidine-6-carboxylate.Using the Mitsunobu reaction, ethyl 2-(3-hydroxypropyl)-5-methyl-4-oxo-4H,4aH-thieno[2,3-d]pyrimidine-6-carboxylate was converted to ethyl 4-methyl-2-oxo-6-thia-1λ at room temperature. 4 ,8-Diazatricyclo[7.3.0.0 3 , 7 ]dodeca-1(9),4,7-triene-5-carboxylate, which is finally subjected to aldol condensation with intermediate 4-[(4-chlorophenyl)methoxy]-3-methoxybenzaldehyde under reflux with AcO to give ALCi-132.

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Claims

1. 1. An allosteric inhibitor of chromodomain helicase DNA-binding protein 1-like (ALC1), and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, comprising: The allosteric inhibitor has the formula (I): 【Chemistry 1】 (I) [In the formula, X is N or S; A is C or N; R １ is -CO-OR ６ , -CO-R ７ or -CO-NR ６ R Ａ and R ２ is -R ７ , -NHR ８ , -O-R ７ , -C-O-R ７ , Br, -C ３－８ Cycloalkyl or -C ４－８ is cycloalkenyl; or, R １ and R ２ taken together form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring, which is optionally substituted with -OH, -NO ２ , -CN, -Br, -Cl, -F, -I, -OC １－３ Alkyl, ═O, [—O—CH ２ -CH ２ ]-NH-CH(OH)-O-tBu; R ３ is H, ═O, —OH, —O—R ７ , -R ７ , or -(CH ２ ) ｍ -L, where m is 0, 1 or 2 and L is a 5-, 6-, or 7-membered carbocycle or heterocycle, which may be optionally substituted; R ４ is H or -C １－３ is alkyl; R ５ is -(CH ２ ) ｍ -L or -(CH ２ ) ｍ -(CH=CH)-L, where m is 0, 1 or 2, and L is a 5-, 6- or 7-membered carbocyclic or heterocyclic ring, adamantyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or -N(CH ３ ) ２ which may be optionally substituted; or, R ４ and R ５ taken together form a 5-, 6-, or 7-membered carbocyclic ring, which may be optionally substituted; R ６ is H, -C １－６ Alkyl, -C ２－６ Alkenyl, -C ２－６ alkynyl, which may be optionally substituted; R ７ is -C １－３ Alkyl, -C ２－３ Alkenyl, -C ２－３ alkynyl, which may be optionally substituted; R ８ is H or C １－６ is alkyl; R ９ is -C １－６ Alkyl, -C ２－６ Alkenyl, -C ２－６ Alkynyl, -C １－６ Alkyl-aryl, or C １－６ Alkyl-heteroaryl, which is optionally substituted with -Br, -Cl, -F, -I, -NO ２ , -CN, -CONH ２ , -CONH-C １－３ Alkyl, -NH-CO-C １－３ Alkyl, -C １－６ Alkyl, -C １－３ -haloalkyl, -O-CHF ２ , -O-CF ３ , carbocycle, -O-carbocycle, heterocycle, -CO-heterocycle, -SO ２ -CH ３ , -SO ２ -N(CH ３ ) ２ , -O-C １－４ Alkyl, —O—C １－３ Alkyl-O-C １－３ Alkyl, and -SCH ３ or R ９ Ga-C １－６ When alkyl-aryl, two adjacent substituents of the aryl moiety may form an optionally substituted 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; R Ａ is H, a carbocycle or a heterocycle, which may be optionally substituted. The allosteric inhibitor of ALC1, which is a compound represented by the formula:

2. During the ceremony, R １ But -CO-OR ６ and R ２ But, -R ７ , -NHR ８ , -O-R ７ , -C-O-R ７ , Br, -C ３－８ Cycloalkyl (preferably cyclopropyl), or -C ４－８ cycloalkenyl (preferably cyclohexenyl); R ３ However, -OH, -NO ２ , -CN, -Br, -Cl, -F, -I, -OC １－３ Alkyl, -hydroxy C １－３ optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, and =O; R ４ is H or -C １－３ alkyl, preferably H; R ５ However, -OH, -NO ２ , -CN, -CO-OR ６ , -Br, -Cl, -F, -I, -R ９ , -O-R ９ , ═O, and [—O—CH ２ -CH ２ ] ｑ -NH-biotin (q is 1, 2, 3, or 4), or two adjacent substituents may form a 5-, 6-, or 7-membered carbocyclic or heterocyclic ring; or, R ４ and R ５ taken together form a 5-, 6-, or 7-membered carbocyclic ring, which is optionally substituted with -OH, -NO ２ , -CN, -Br, -Cl, -F, -I, -OR ９ , -R ９ , =CH-R Ａ , and -CH ２ -R Ａ and preferably R ４ and R ５ Together, C ５－７ Forming a cycloalkyl; R ６ But H, -C １－６ Alkyl, -C ２－６ Alkenyl, -C ２－６ Alkynyl, which may be optionally substituted, preferably R ６ is H; R ７ is -Br, -Cl, -F, -I, -CH ３ , -OCH ３ , or -SCH ３ and / or R Ａ However, -OH, -NO ２ , -CN, -Br, -Cl, -F, -I, R ９ , -O-R ７ , —O—(CH ２ ) ｏ -R ９ (wherein o is 0 or 1), -SO ２ N.H. ２ and ═O, The allosteric inhibitor of ALC1 according to claim 1.

3. R １ and R ２ taken together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably -OH, -NO ２ , -CN, -Br, -Cl, -F, -I, -OC １－３ optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, and ═O, preferably —OH and ═O; and R ３ H, ═O, —OH, —R ７ , or -(CH ２ ) ｍ -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO ２ , -CN, -Br, -Cl, -F, -I, -OC １－３ Alkyl, and -hydroxyC １－３ optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl; The allosteric inhibitor of ALC1 according to claim 1 or 2.

4. A is C, R １ and R ２ taken together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably -OH, -NO ２ , -CN, -Br, -Cl, -F, -I, -OC １－３ optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, and ═O, preferably —OH and ═O; and R ３ is H, ═O, —OH, —R ７ , or -(CH ２ ) ｍ -L, where m is 0, and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO ２ , -CN, -Br, -Cl, -F, -I, -OC １－３ Alkyl, and -hydroxyC １－３ optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl; An allosteric inhibitor of ALC1 according to any one of claims 1 to 3.

5. R １ and R ２ together to form uracil or 3-deazauracil, R ３ is H, ═O, —OH, —R ７ , or -(CH ２ ) ｍ -L, where m is 0 and L is phenyl or a 5-, 6-, or 7-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -OH, -NO ２ , -CN, -Br, -Cl, -F, -I, -OC １－３ Alkyl, and -hydroxyC １－３ optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl; An allosteric inhibitor of ALC1 according to any one of claims 1 to 4.

6. R １ and R ２ taken together form a 6-membered aryl or heteroaryl moiety, which is optionally substituted, preferably -OH, -NO ２ , -CN, -Br, -Cl, -F, -I, -OC １－３ optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, and ═O, preferably —OH and ═O; and R ３ But, -C １－３ Alkyl (i.e., C １ -, C ２ -, C ３ -alkyl), or -(CH ２ ) ｍ -L, where m is 0 and L is phenyl or a 5-membered heteroaryl, preferably phenyl, which is optionally substituted, preferably -NO ２ , -CN, -Br, -Cl, -F, -I, -OC １－３ Alkyl, and -hydroxyC １－３ optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl; An allosteric inhibitor of ALC1 according to any one of claims 1 to 5.

7. R ３ H, ═O, —OH, thiophenyl, phenyl, 3,4,5 hydroxymethylphenyl, CF ２ H, or CF ３ That is, An allosteric inhibitor of ALC1 according to any one of claims 1 to 6.

8. The allosteric inhibitor of ALC1 according to claim 1, wherein the allosteric inhibitor is represented by one of the following structures: 【Chemistry 2】 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemical 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 。

9. A bifunctional compound comprising an allosteric inhibitor of ALC1 according to any one of claims 1 to 8 and a compound that recruits E3 ubiquitin ligase to ALC1 (E3 recruiter), wherein the allosteric inhibitor of ALC1 and the E3 recruiter are covalently bonded, optionally via a linker.

10. A pharmaceutical composition comprising an allosteric inhibitor of ALC1 according to any one of claims 1 to 8 or a bifunctional compound according to claim 9, and a pharma- ceutically acceptable excipient.

11. 10. An ALC1 inhibitor (ALC1i) according to any one of claims 1 to 8 for use in a method for treating or ameliorating a proliferative disease in a patient, said method comprising administration of an ALC1i and optionally administration of a poly(ADP-ribose)-polymerase inhibitor (PARPi).

12. PARPi reduces PARP activity and / or inhibits PARP1, PARP2 and / or PARP3, preferably PARP2 on chromatin, wherein preferably PARPi: (i) reduces PARP activity and is selected from small interfering RNAs; (ii) a compound that inhibits PARP1, the compound being: (a) Formula (II): 【Chemistry 28】 (II) [In the formula, A and B together represent an optionally substituted fused aromatic ring; X is NR Ｘ or CR Ｘ R Ｙ and X=NR Ｘ In the case of Ｘ R Ｙ where n is 1; R Ｘ is H, optionally substituted C １－２０ Alkyl, C ５－２０ Aryl, C ３－２０ selected from the group consisting of heterocyclyl, amide, thioamide, ester, acyl, and sulfonyl groups; R Ｙ is selected from H, hydroxy, amino; Or, R Ｘ and R Ｙ Together, Spiro-C ３－７ may form a cycloalkyl or heterocyclyl group; R Ｃ１ and R Ｃ２ are independently hydrogen and C １－４ alkyl or X is selected from the group consisting of CR Ｘ R Ｙ If R Ｃ１ , R Ｃ２ , R Ｘ and R Ｙ may, together with the carbon atom to which they are attached, form an optionally substituted fused aromatic ring; and R １ is selected from H and halo. and isomers, salts, solvates, chemically protected forms, and prodrugs thereof; and, (b) Formula (III): 【Chemical Formula 29】 (III) [In the formula, Y and Z each independently represent the following group:

1. 1, 2, or 3 R ６ an aryl group optionally substituted with 2. 1, 2, or 3 R ６ a heteroaryl group optionally substituted with 3. Hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkylene, oxo, heterocycloalkyl, heterocycloalkylalkyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, (R Ａ R Ｂ ) alkylene, (NR Ａ R Ｂ ) carbonyl, (NR Ａ R Ｂ ) carbonylalkylene, (NR Ａ R Ｂ ) sulfonyl, and (R Ａ R Ｂ ) sulfonylalkylene; (Here, each R ６ OH, NO ２ ,CN,Br,Cl,F,I,C １－６ Alkyl, C ３－８ Cycloalkyl, C ２－８ -heterocycloalkyl; C ２－６ Alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C ２－６ Alkynyl, aryl, arylalkyl, C ３－８ Cycloalkylalkyl, haloalkoxy, haloalkyl, hydroxyalkylene, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycloalkoxy, C ２－８ -heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR Ａ R Ｂ , (R Ａ R Ｂ ) C １－６ Alkylene, (NR Ａ R Ｂ ) carbonyl, (R Ａ R Ｂ ) carbonylalkylene, (NR Ａ R Ｂ ) sulfonyl, and (NR Ａ R Ｂ ) sulfonylalkylene. selected from the group consisting of: R １ , R ２ , and R ３ are each independently hydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, cycloalkyl, alkynyl, cyano, haloalkoxy, haloalkyl, hydroxyl, hydroxyalkylene, nitro, NR Ａ R Ｂ , N.R. Ａ R Ｂ Alkylene, and (R Ａ R Ｂ ) carbonyl; A and B are each independently hydrogen, Br, Cl, F, I, OH, C １－６ Alkyl, C ３－８ cycloalkyl, alkoxy, alkoxyalkyl, wherein C １－６ Alkyl, C ３－８ Cycloalkyl, alkoxy, and alkoxyalkyl are OH, NO ２ ,CN,Br,Cl,F,I,C １－６ Alkyl, and C ３－８ cycloalkyl, where B is not OH, R Ａ and R Ｂ is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl; or R Ａ and R Ｂ together with the atom to which they are attached, are -O-, -NH, -N(C １－６ alkyl)-, -NCO(C １－６ Alkyl)-, -N(aryl)-, -N(aryl-C １－６ alkyl-), -N(substituted-aryl-C １－６ Alkyl-, -N(heteroaryl)-, -N(heteroaryl-C １ -C ６ Alkyl-, -N(substituted-heteroaryl-C １－６ Alkyl-)- and -S- or S(O) ｑ - (wherein q is 1 or 2), optionally having 1 to 3 heteroatoms or heterofunctional groups selected from the group consisting of, wherein the 3 to 10 membered heterocycle is optionally substituted with one or more substituents; R ４ and R ５ are each independently selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl, hydroxyalkylene, and (NR Ａ R Ｂ ) alkylene. and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, Selected from the group consisting of: (iii) a compound that inhibits PARP1 and PARP2, the compound being: (a) Formula (IV): 【Chemistry 30】 (IV) [In the formula, R １ is hydrogen or fluorine; and R ２ is hydrogen or fluorine. and isomers, salts, solvates, chemically protected forms, and prodrugs thereof; and, (b) Formula (V): 【Chemistry 31】 (V) [In the formula, R １ , R ２ , and R ３ is hydrogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkynyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, NR Ａ R Ｂ , and (NR Ａ R Ｂ ) carbonyl; A is a non-aromatic 4-, 5-, 6-, 7-, or 8-membered ring containing one or two nitrogen atoms and optionally one sulfur or oxygen atom, where the non-aromatic ring is selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkoxy, haloalkyl, halogen, heterocycle, heterocyclealkyl, heteroaryl, heteroarylalkyl, hydroxy, hydroxyalkyl, nitro, NR Ｃ R Ｄ , (NR Ｃ R Ｄ ) alkyl, (NR Ｃ R Ｄ ) carbonyl, (NR Ｃ R Ｄ ) carbonylalkyl, and (NR Ｃ R Ｄ ) sulfonyl; and R Ａ , R Ｂ , R Ｃ , and R Ｄ are independently selected from the group consisting of hydrogen, alkyl, and alkylcarbonyl. and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, Selected from the group consisting of: (iii) a compound that inhibits PARP1, PARP2, and PARP3, the compound having the formula (VI): 【Chemistry 32】 (V) [In the formula, R １ is H; halogen; cyano; an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group (e.g., unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, and amino; and aryl, alkyl, alkoxy groups, unsubstituted or substituted with one or more selected from halogen, hydroxy, nitro, carboxy, and optionally substituted amino groups; and ether groups (such as O-aryl); or -C(O)-R １０ where R １０ is H; an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group (e.g., unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, amino; and aryl groups, alkyl groups, unsubstituted or substituted with one or more substituents selected from halo, hydroxy, nitro, and amino); or OR １００ , or N.R. １００ R １１０ where R １００ and R １１０ are each independently H or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group (e.g., unsubstituted; or substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups, which are unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, amino, and aryl groups, and alkyl groups, which are unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, and amino groups, which may be optionally substituted); R ２ is H or alkyl, R ３ is H or alkyl, R ４ is H, halogen or alkyl, X is O or S; Y is (CR ５ R ６ ) (CR ７ R ８ ) ｎ , or N-C(R ５ ) where: n is 0 or 1; R ５ and R ６ are each independently H or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group (e.g., unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, amino, and aryl groups, lower alkoxy groups, or lower alkyl groups, which are unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, and amino); and R ７ and R ８ are each independently H or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group (e.g., unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, amino, and aryl groups, lower alkoxy groups, lower alkyl groups, unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, and amino); Here, R １ , R ４ , R ５ , R ６ , and R ７ are each H, then R ８ is not unsubstituted phenyl. and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, The ALC1i according to claim 11, which is any one of the following:

13. The ALC1i according to claim 11 or 12, wherein the PARPi is selected from the group consisting of olaparib, talazoparib, niraparib, rucaparib and veliparib, in particular from the group consisting of veliparib, olaparib and talazoparib.

14. The ALC1i according to any one of claims 11, 12 or 13, wherein the proliferative disease is selected from BRCA-1 and / or BRCA-2 deficient tumors and tumors in which expression of PARP-1, PARP-2, PARP-3 and / or ALC1 is increased compared to non-tumor cells; and / or the proliferative disease is selected from hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, colorectal cancer.

15. The ALC1i of any one of claims 11, 12, 13 or 14, wherein the PARPi and the ALC1i are administered simultaneously or separately.

16. 1. An allosteric inhibitor of chromodomain helicase DNA-binding protein 1-like (ALC1) for use in treating or ameliorating a proliferative disorder in a patient, comprising: The inhibitor specifically binds to an allosteric binding pocket formed by an amino acid stretch spanning amino acid residues 101 to 219 of SEQ ID NO:1; The treatment comprises administration of ALC1i and optionally administration of a poly(ADP-ribose)-polymerase inhibitor (PARPi); the proliferative disease is selected from BRCA-1 and / or BRCA-2 deficient tumors, wherein expression of PARP1, PARP2, PARP3, and / or ALC1 is increased compared to non-tumor cells, and the proliferative disease is hepatocellular carcinoma; An allosteric inhibitor of the chromodomain helicase DNA-binding protein 1-like (ALC1).

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