Improved inhibitors of insulin-like growth factor 2 mRNA binding proteins

Abstract

The present invention provides compounds of formula (I) or an enantiomer thereof, particularly the R-enantiomer, a diastereomer thereof, its hydrates, its solvates, its crystal forms, its tautomers or pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, X and A are as defined herein. Said compounds of formula (I) are inhibitors of insulin-like growth factor 2 mRNA binding proteins (IGF2BP). Provided are novel inhibitors of IGF2BPs and processes for manufacturing the same. The invention further relates to a compound of formula (I) or a pharmaceutical composition for use in the treatment of any malignant disorder, including primary disease, metastases or recurrent neoplasia, which exhibits expression of IGF2BP1 in a manner amenable to the therapeutic intervention.

Description

[0001] Improved inhibitors of insulin-like growth factor 2 mRNA binding proteins

[0002] Field of invention

[0003] The present invention relates to non-covalent, reversible inhibition of insulin-like growth factor 2 mRNA binding proteins (IGF2BP). Provided are novel inhibitors of IGF2BPs and processes for manufacturing the same. Efficacy of the new compounds is shown in four solid cancer models: Melanoma, Neuroblastoma, Ovarian and Pancreatic carcinoma.

[0004] Background of the invention

[0005] RNA-binding proteins (RBPs) are critical regulators in cancer progression and their expression correlates directly with poor patient prognosis. Due to their role in cancer, RBPs have attracted attention in drug development over the years (see US6004749A). Although targeting of RNA- binding proteins remains challenging due to the mostly non-enzymatic nature of RNA-protein association, various small molecule inhibitors disturbing protein-RNA association of oncogenic RBPs (oncoRBPs) have been reported (reviewed in: (1)).

[0006] The human IGF2 mRNA binding protein family (IGF2BPs) comprises a group of three canonical oncoRBPs (reviewed in: (2)). Two members, IGF2BP1 and 3, are considered bona fide oncofetal RBPs, characterized by substantial expression during embryogenesis, residual expression in some stem and progenitor cells in adult life, and severe de novo synthesis in various, mainly progressed malignancies (reviewed in: (2)). De novo synthesis of IGF2BPs in cancer is most strikingly observed for IGF2BP1 in anaplastic thyroid carcinoma (ATC). While IGF2BP1 is not present in healthy, adult thyroid tissue nor in papillary (PTC) or follicular carcinomas (FTC), de novo synthesis yielding diagnostic odd ratios greater 600 is observed exclusively in lethal ATC (3). IGF2BP2 is upregulated in various cancers as well, but shows ubiquitous, although moderate expression in healthy adult tissues (reviewed in: (2)). IGF2BP1 is the most conserved and potent oncogene of the IGF2BP family, promoting tumor cell vitality, invasion as well as tumor growth and metastasis in human as well as murine tumor models (4- 8). The IGF2BP-directed control of cancer hallmark pathways settles on the mRNA-binding properties of the proteins. Mainly demonstrated for IGF2BP1, mRNA-association of IGF2BPs results in the recruitment of transcripts in cytoplasmic mRNPs -mRNA-containing protein- RNA complexes. RNP-recruitment of target mRNA by IGF2BPs impairs their turnover, resulting in enhanced protein output (4,9,10). This regulatory role leads to the fostered expression of various oncogene targets of IGF2BP1, most prominently members of the MYC protein family. In concert with these factors, IGF2BP1 is sufficient to induce primary tumors and promotes metastasis in transgenic mouse models, as recently demonstrated for neuroblastoma (11). Collectively these findings indicate IGF2BPs, particularly IGF2BP1, to serve as oncogenes in various malignancies and suggest their RNA-binding activity as a bona fide target in cancer therapy. The first reported small molecule inhibitor impairing IGF2BP1 mRNA association and tumor cell vitality in vitro was BTYNB (12). Recent studies have demonstrated that BTYNB impairs the mRNA stabilizing role of IGF2BP1 in various solidcancer models (11,13). Most notably, it was observed that the inhibition of IGF2BP1 by BTYNB reduces tumor growth upon systemic but more prominently upon intra-tumoral application in vivo (11).

[0007] Accordingly, a first line of reversible IGF2BP1 inhibitors have been developed and patented (EP 4 008 717 A3). EP 4 008 717 A3 discloses inhibitors of IGF2BP and processes for manufacturing the same. Although the collective findings support the potential of BTYNB as a promising compound for impairing IGF2BP1 -driven oncogenesis in tumor cells and animal cancer models (11,13), recent studies have demonstrated that its chemical stability and selectivity and efficacy in vivo upon systemic application, e.g. BTYNB in neuroblastoma models (1), appeared to be insufficient.

[0008] It was demonstrated that this is largely due to insufficient affinity of IGF2BP-association as target engagement and / or off-target effects resulting in exceeding toxicity prohibiting in vivo application of these substances. Thus, the present invention relates to a second line of improved non-covalent IGF2BP1 protein inhibitors, which were designed and evaluated in respect to improved target engagement, which improves potency and reduces toxicity, probably due to increased target selectivity and the lack of IGFBP1 in most healthy cells and tissue. In terms of molecular cell biology, the present invention settles on the recent investigations demonstrating that IGF2BP1 is a bona fide oncogene in high-risk neuroblastoma. The deletion of the protein from high-risk neuroblastoma cell models (BE-2C) essentially impaired tumor initiation, here the subcutaneous (s.c.) xenograft growth in nude mice, due to a sever downregulation of the oncogene MYCN in cause of IGF2BP1 knockout (KO). Like IGF2BP1-KO, the ex vivo pretreatment of tumor cells by BTYNB substantially impaired the growth of neuroblastoma cells expressing IGF2BP1. However, the systemic, intraperitoneal (i.p.) application of BTYNB in mice with s.c. grafter patient-derived xenografts only showed moderate effects due to insufficient stability, potency, and / or efficacy of BTYNB. This limitation was overcome by direct, intra-tumoral (i.t.) application of BTYNB. Besides the indication of potency, efficiency, selectivity and / or serum stability of BTYNB (11,13) as well as the IGF2BP inhibiting compounds covered by EP 4008717 A3, compound improvement leading to elevated average efficacy is required to allow application of IGFBPli in clinical treatments. Efforts aim at IC₅₀ (half maximal inhibitory concentration) to remain in low micromolar or nanomolar range and avoid insufficient affinity of IGF2BP1 -association and / or potential off-target effects. The relevance of such efforts was demonstrated for various small molecule inhibitors, for example inhibitors of PTPNs. These show IC₅₀ values in the low nanomolar range resulting in elevated selectivity in impairing tumor but not immune cells (14). In line, conventional IGF2BP1 inhibitors with low potency are more prone to toxicological side effects, which are critical for advancing the development of solutions for treatments for malignancies driven by IGF2BP expression.

[0009] It is therefore the objective of the invention to provide compounds that overcome these limitations.Summary of the invention

[0010] To overcome the obstacles of prior art, the invention provides a compound of formula I

[0011]

[0012] Formula I

[0013] or an enantiomer thereof, particularly the A’-enantiomer, a diastereomer thereof, its hydrates, its solvates, its crystal forms, its tautomers or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, X and A are described herein.

[0014] In further embodiments, the present invention also provides pharmaceutical compositions comprising at least one compound according to above Formula I, or an enantiomer thereof, particularly the A’-enantiomer, a diastereomer thereof, its hydrates, its solvates, its crystal forms, its tautomers or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. It also provides pharmaceutical compositions comprising at least one compound according to above Formula I for use in methods of treating solid cancer, such as hepatocellular carcinoma, colorectal carcinoma, thyroid carcinoma and lung adenocarcinoma, preferably melanoma, neuroblastoma, ovarian and pancreatic carcinoma.

[0015] The present invention also provides a method of treatment or prophylaxis of the human or animal body comprising administering a therapeutically effective amount of the above compound or pharmaceutical composition to a subject in need thereof, and / or a compound or pharmaceutical composition for use in such a method.

[0016] The present invention also provides a method of treatment or prophylaxis of proliferative diseases like cancer, which is selected from the group consisting of solid, malignant tumors of epithelial or neuroectodermal cells like pancreatic cancer, melanoma, neuroblastoma, ovarian carcinoma, hepatocellular carcinoma, colorectal carcinoma, thyroid carcinoma and lung adenocarcinoma;

[0017] or any other malignant diseases of unknown origin that exhibit expression of IGF2BP1 in a manner amenable to the therapeutic intervention.Detailed description of the invention

[0018] The term “subject” as used herein, refers to an animal, preferably a mammal, most preferably a human, who is the object of treatment, observation or experiment.

[0019] The “ECso” value reflects the inhibitor concentration, which results in 50 % cell mortality in a cell cancer model.

[0020] The “IC50” value reflects the half-maximal inhibitory concentration, i.e. the concentration of a substance required to inhibit a biological target by 50 %.

[0021] The PBMC@ IC₅₀ refers to Peripheral Blood Mononuclear Cells (PBMCs) treated at the IC₅₀ concentration of a given compound, meaning that the PBMCs were exposed to the compound at a concentration corresponding to its IC₅₀ value, to assess cytotoxic effects of the compound on immune cells.

[0022] The term “IGF2BP inhibitor” or “inhibitor of IGF2 mRNA binding proteins” is known to a person skilled in the art and characterizes inhibitors, which inhibit the pharmacological activity of IGF2 mRNA binding proteins, especially the proliferative activity of IGF2BPs.

[0023] Molecular weight of IGF2BP inhibitors

[0024] In general, the IGF2BP inhibitors of the subject method or medical use will be small molecules, e.g. with molecular weights of 750 g / mole or less, 600 g / mole or less, preferably 500 g / mole or less, and even more preferably of 400 g / mole or less.

[0025] The term “therapeutically effective amount” as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal human being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. As used herein, the term “pharmaceutically acceptable” embraces both human and veterinary use: For example, the term “pharmaceutically acceptable” embraces a veterinary acceptable compound or a compound acceptable in human medicine and health care.

[0026] Throughout the description and the claims, the expression "alkyl", as used herein unless specifically limited, denotes a C1-12 alkyl group, suitably a C1-8 alkyl group, e.g. C1-6 alkyl group, e.g. C1-4 alkyl group. Alkyl groups may be straight chain or branched. Suitable alkyl groups include, for example, methyl, ethyl, propyl (e.g. n-propyl and isopropyl), butyl (e.g n-butyl, iso-butyl and tert-butyl), pentyl (e.g. n-pentyl), hexyl (e.g. n-hexyl), heptyl (e.g. n-heptyl) and octyl(e.g. n-octyl).

[0027] The expression "alk", for example in the expressions "alkoxy", "haloalkyl" and "thioalkyl” should be interpreted in accordance with the definition of "alkyl". Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g. n-propoxy), butoxy (e.g. n-butoxy), pentoxy (e.g. n-pentoxy), hexoxy (e.g. n-hexoxy), heptoxy (e.g. n-heptoxy) and octoxy. Exemplary thioalkyl groups include methylthio-. Exemplary haloalkyl groups include fluoroalkyl e.g. CF3, fluoroethyl, fluropropyl, fluorobutyl, difluoroethyl, difluoropropyl and difluorobutyl.The expression "alkynyl", unless specifically limited, denotes a C₂₋₁₂ alkynyl group, suitably a C₂₋₆ alkynyl group, e.g. a C₂₋₄ alkynyl group, which contains at least one triple bond at any desired location and may or may not also contain one or more double bonds. Alkynyl groups may be straight chain or branched. Exemplary alkynyl groups include propynyl and butynyl.

[0028] The expression “heterocyclyl”, unless specifically limited, refers to a carbocyclyl group wherein one or more (e.g. 1, 2 or 3) ring atoms are replaced by heteroatoms selected from N, S and O. A specific example of a heterocyclyl group is a cycloalkyl group (e.g. cyclopentyl or more particularly cyclohexyl) wherein one or more (e.g. 1, 2 or 3, particularly 1 or 2, especially 1) ring atoms are replaced by heteroatoms selected from N, S or O. Exemplary heterocyclyl groups containing one hetero atom include pyrrolidine, tetrahydrofuran and piperidine, and exemplary heterocyclyl groups containing two hetero atoms include morpholine, piperazine dioxolane and dioxane. A further specific example of a heterocyclyl group is a cycloalkenyl group (e.g. a cyclohexenyl group) wherein one or more (e.g. 1, 2 or 3, particularly 1 or 2, especially 1) ring atoms are replaced by heteroatoms selected from N, S and O. Examples of such a group are piperazinyl (e.g. piperazine- 1-yl-) and piperidinyl.

[0029] The expression “aryl”, unless specifically limited, denotes a C₆₋₁₂ aryl group, suitably a C₆₋₁₀ aryl group, more suitably a C₆₋₈ aryl group. Aryl groups will contain at least one aromatic ring (e.g. one, two or three rings). An example of a typical aryl group comprising one aromatic ring is phenyl. An example of a typical aryl group with two aromatic rings is naphthyl.

[0030] The expression “arylalkyl", unless specifically limited, denotes an aryl residue which is connected via an alkylene moiety, e.g., a C₁₋₄ alkylene moiety.

[0031] The expression “heteroaryl”, unless specifically limited, denotes an aryl residue, wherein one or more (e.g. 1, 2, 3, or 4, suitably 1, 2 or 3) ring atoms are replaced by heteroatoms selected from N, S and O, or else a 5-membered aromatic ring containing one or more (e.g. 1, 2, 3, or 4, suitably 1, 2 or 3) ring atoms selected from N, S and O. Exemplary monocyclic heteroaryl groups having one heteroatom include: five membered rings (e.g. pyrrole, furan, thiophene); and six membered rings (e.g. pyridine, such as pyridin-2-yl, pyridin-3-yl and pyridin-4-yl). Exemplary monocyclic heteroaryl groups having two heteroatoms include: five membered rings (e.g. pyrazole, oxazole, isoxazole, thiazole, isothiazole, imidazole, such as imidazol-l-yl, imidazol-2-yl imidazol-4-yl); six membered rings (e.g. pyridazine, pyrimidine, pyrazine). Exemplary monocyclic heteroaryl groups having three heteroatoms include: 1,2,3-triazole and 1,2,4-triazole. Exemplary monocyclic heteroaryl groups having four heteroatoms include tetrazole. Exemplary bicyclic heteroaryl groups include: indole (e.g. indol-6-yl), benzofuran, benzthiophene, quinoline, isoquinoline, indazole, benzimidazole, benzthiazole, quinazoline and purine.

[0032] The expression "heteroarylalkyl", unless specifically limited, denotes a heteroaryl residue which is connected via an alkylene moiety e.g. a C₁₋₄alkylene moiety.The expressions “alkoxyaryl”, “carboxyaryl”, “cyanoaryl”, “haloaryl”, “hydroxyaryl” and “heteroarylaryl”, unless specifically limited, denote an aryl residue which is substituted by at least one alkoxy, carboxy, cyano, halo, hydroxy and heteroaryl group, respectively.

[0033] The expressions “alkoxyarylalkyl”, “carboxyarylalkyl”, “cyanoarylalkyl”, “haloarylalkyl” and “hydroxyaryl” unless specifically limited, denote an alkoxy moiety attached to an aryl residue, which is further substituted with an alkyl group.

[0034] The term “heterocyclylacyl”, unless specifically limited, refers to a chemical moiety consisting of a heterocyclic ring connected to an acyl functional group.

[0035] The term “halo” comprises fluorine or fluoro (F), chlorine or chloro (Cl), bromine or bromo (Br) and iodine or iodo (I).

[0036] The term "nitro" refers to the group -NO2.

[0037] The expressions “(alkoxyaryl)methyl”, “(hydroxyaryl)methyl”, “(carboxyaryl)methyl”, “(heteroarylaryl)methyl” “(alkoxyheteroaryl)methyl”, “(hydroxyheteroaryl)methyl” and “(carboxyheteroaryl)methyl”, unless specifically limited, denote an alkoxyaryl, hydroxyaryl, carboxyaryl, heteroarylaryl, alkoxyheteroaryl, hydroxyheteroaryl and carb oxy heteroaryl residue, respectively, which is connected via a methylene moiety.

[0038] The terms “optionally has or have a substituent” and “substituted” refer to (optional) substitution by one or several groups independently selected from a halogen atom, a cyano group, a nitro group, a hydroxyl group and a carboxyl group. These terms also refer to (optional) substitution by one or several groups independently selected from –C(O)-O–(C₁₋₆ alkyl) group, a –C(O)-NH₂ group,

[0039]

[0040] a C₁₋₆ alkoxy and a C₁₋₆ aliphatic, aromatic or heterocyclic group, each of which may be further substituted by one or several halogen atoms, carboxyl, cyano, and / or hydroxyl groups.

[0041] The term stereoisomer relates to a chemical species that shares the same molecular formula and identical atom-to-atom connectivity with another compound but differs in the three-dimensional arrangement of its atoms in space. This difference in spatial configuration, rather than in bonding sequence, gives rise to distinct stereochemical forms, which may exhibit markedly different physicochemical, spectroscopic, or biological properties despite their constitutional identity. As used herein, the term “ / / -stereoisomer” refers to the / / -enantiomer, and the term “ / / -stereoisomer” refers to the 5-enantiomer of a compound having at least one stereogenic center. The present invention comprises all possible stereoisomers of the claimed compounds. Preferably, the present invention comprises the / / -stereoisomeric forms, in particular the R-enantiomers.

[0042] Following synthesis and biological testing, it was surprisingly and unexpectedly found that the / / -stereoisomers were the biologically active compounds whereas the S-stereoisomers were inactive or only weakly active compounds. It was thus demonstrated herein that the biological effect of the compounds of formula I is stereospecific and structure-specific.Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. As used herein, the compounds (5)-2-(naphthalen-2-yl)-2,3-dihydroquinazolin-4(lH)-one, referred to herein as reference 1A, was prepared solely as a reference compound for the purpose of determining the absolute configuration of the stereoisomers described herein (22). The absolute configuration of compound (5)-2-(naphthalen-2-yl)-2,3-dihydroquinazolin-4(lH)-one was determined by X-ray crystallography and was identified as the S -stereoisomer. Circular dichroism (CD) spectra were recorded for compound 1A and for further S -stereoisomers prepared by the same enantioselective synthetic route. Based on the comparison of these CD spectra, the absolute configuration of the stereoisomers obtained by chiral HPLC separation was assigned. 1A is used exclusively as a reference standard for stereochemical assignments and does not form part of the subject matter sought to be protected. In a most preferred embodiment, the present application is directed solely to the R-enantiomers exhibiting biological activity.

[0043] For selected potent inhibitors exhibiting EC₅₀ values below 2 μM, both enantiomers (e.g. the R-stereoisomer and the S-stereoisomer) were synthesized by stereoselective methods and their enantiomeric purity was confirmed by chiral HPLC. Comparative evaluation of the biological activity of the pure enantiomers demonstrated that the / / -stereoisomer is the active form, whereas the S-stereoisomer exhibits significantly reduced or negligible activity.

[0044] Preparation and isolation of stereoisomers:

[0045] Where the processes for the preparation of the compounds according to the invention give rise to a mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their components enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and / or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base, or by salt formation with an optically active base, such as quinine, quinidine, quinotoxine, cinkotoxine, (5)-phenylethylamine, (lA,2S)-ephedrine, (A)-phenylglycinol, (5)-2-aminobutanol, followed by fractional crystallization and regeneration of the free acid. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.

[0046] Polymorph crystal forms:

[0047] Furthermore, some of the crystalline forms of the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e. hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention. The compounds, includingtheir salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization.

[0048] As used herein, the term “tautomer” refers to the migration of protons between adjacent single and double bonds. The tautomerization process is reversible. Compounds described herein can undergo any possible tautomerization that is within the physical characteristics of the compound.

[0049] As used herein, the term "pharmaceutically acceptable" embraces both human and veterinary use. For example, the term "pharmaceutically acceptable" embraces a veterinarily acceptable compound or a compound acceptable in human medicine and health care.

[0050] Pharmaceutically acceptable salts:

[0051] In view of the close relationship between the free compounds and the compounds in the form of their salts, hydrates or solvates, whenever a compound is referred to in this context, a corresponding salt, solvate or polymorph is also intended, provided such is possible or appropriate under the circumstances.

[0052] Salts, hydrates and solvates of the compounds of Formula I and physiologically functional derivatives thereof which are suitable for use in medicine are those wherein the counter-ion or associated solvent is pharmaceutically acceptable. However, salts, hydrates and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds and their pharmaceutically acceptable salts, hydrates and solvates.

[0053] Suitable salts according to the invention include those formed with both organic and inorganic acids or bases. Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulfuric, nitric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, triphenylacetic, sulfamic, sulfanilic, succinic, oxalic, fumaric, maleic, malic, mandelic, glutamic, aspartic, oxaloacetic, methanesulfonic, ethanesulfonic, arylsulfonic (for example p-toluenesulfonic, benzenesulfonic, naphthalenesulfonic or naphthalenedisulfonic), salicylic, glutaric, gluconic, tricarballylic, cinnamic, substituted cinnamic (for example, phenyl, methyl, methoxy or halo substituted cinnamic, including 4-methyl and 4-methoxycinnamic acid), ascorbic, oleic, naphthoic, hydroxynaphthoic (for example 1- or 3 -hydroxy -2 -naphthoic), naphthaleneacrylic (for example naphthalene-2-acrylic), benzoic, 4 methoxybenzoic, 2- or 4-hydroxybenzoic, 4-chlorobenzoic, 4-phenylbenzoic, benzeneacrylic (for example 1,4-benzenediacrylic), isethionic acids, perchloric, propionic, glycolic, hydroxyethanesulfonic, pamoic, cyclohexanesulfamic, salicylic, saccharinic and trifluoroacetic acid. Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine.

[0054] All pharmaceutically acceptable acid addition salt forms of the compounds of the present invention are intended to be embraced by the scope of this invention.Protective Groups:

[0055] During any of the processes for preparation of the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, fully incorporated herein by reference. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

[0056] A protecting group or protective group is introduced into a molecule by chemical modification of a functional group to obtain chemoselectivity in a subsequent chemical reaction. Protecting groups are e.g. alcohol protecting groups, amine protecting groups, carbonyl protecting groups, carboxylic acid protecting groups and phosphate protecting groups.

[0057] Examples for alcohol protecting groups are acetyl (Ac), benzoyl (Bz), benzyl (Bn, Bnl) P-methoxyethoxymethyl ether (MEM), mimethoxytrityl [bis-(4-methoxyphenyl)phenylmethyl, DMT], methoxymethyl ether (MOM), methoxytrityl [(4-methoxyphenyl)diphenylmethyl, MMT), p-methoxybenzyl ether (PMB), methylthiomethyl ether, pivaloyl (Piv), tetrahydropyranyl (THP), trityl (triphenylmethyl, Tr), silyl ethers (such as trimethyl silyl ether (TMS), tert-butyldimethylsilyl ether (TBDMS), tert-butyldimethylsilyloxymethyl ether (TOM), and triisopropyl silyl ether (TIPS)); methyl ethers and ethoxyethyl ethers (EE).

[0058] Suitable amine protecting groups are selected from carbobenzyl oxy (Cbz), p-methoxybenzyl carbonyl (Moz or MeOZ), tert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-m ethoxyphenyl (PMP), tosyl (Ts), and other sulfonamides (Nosyl & Nps). Suitable carbonyl protecting groups are selected from acetals and ketals, acylals and dithianes. Suitable carboxylic acid protecting groups are selected from methyl esters, benzyl esters, tert-butyl esters, silyl esters, orthoesters, and oxazoline.

[0059] Examples for phosphate protecting groups are 2-cyanoethyl and methyl (Me).

[0060] As used herein, the term “composition” is intended to encompass a product comprising the claimed compounds in the therapeutically effective amounts, as well as any product which results, directly or indirectly, from combinations of the claimed compounds.

[0061] Carriers and Additives for galenic formulations:

[0062] Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives may advantageously include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules, gelcaps and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.

[0063] Carriers, which can be added to the mixture, include necessary and inert pharmaceutical excipients, including, but not limited to, suitable binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, coatings, disintegrating agents, dyes and coloring agents. Soluble polymers as targetable drug carriers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamide-phenol,or polyethyleneoxidepolyllysine substituted with palmitoyl residue. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polyactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid, polyorthoesters, polyacetals, polydihydropyrans, poly cyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.

[0064] Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or betalactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.

[0065] Disintegrators include, without limitation, starch-based disintegrators such as native starch and modified starches, superdisintegrators such as croscarmellose sodium, sodium starch glycolate or crospovidon, cellulose-based disintegrators such as methyl cellulose, microcrystalline cellulose or carboxymethylcellulose and natural gums, polysaccharide-based disintegrators such as alginates, guar gum, xanthan gum and clay-based disintegrants such as bentonite. Compounds of formula I

[0066] The present invention provides a compound of Formula I or an enantiomer thereof, particularly the A’-enantiomer, a diastereomer thereof, its hydrates, its solvates, its crystal forms, its tautomers or a pharmaceutically acceptable salt thereof,

[0067]

[0068] Formula I

[0069] wherein:

[0070] R1is H;

[0071] R2is H or a bond;

[0072] R3is H or is selected from the group consisting of aryl, haloalkyl, heteroaryl, haloheteroaryl, heteroarylalkyl, alkoxyaryl, alkoxyarylalkyl, wherein said haloalkyl, heteroaryl, haloheteroaryl, heteroarylalkyl, alkoxyaryl, alkoxyarylalkyl, optionally has at least one further substituent;R4is H or alkyl;

[0073] R4R4

[0074] X is selected from a group consisting of

[0075]

[0076] and;

[0077] A is a cyclic structure selected from the group consisting of unsubstituted heteroaryl and heteroaryl substituted by RTor is represented by RB, wherein RBis unsubstituted phenyl or structure IV

[0078]

[0079] wherein

[0080] RTis halo, or selected from the group consisting of alkyl, arylalkyl, haloarylalkyl, alkoxy, alkoxyaryl, alkoxyarylalkyl, haloalkoxy and haloalkoxyarylalkyl, wherein said alkyl, arylalkyl, haloarylalkyl, alkoxy, alkoxyaryl, alkoxyarylalkyl, haloalkoxy and haloalkoxyarylalkyl optionally has at least one further substituent; and

[0081] if RBis represented by structure IV, then at least one of Ra, Rb, Rc, and Rdis not H, wherein said at least one of Ra, Rb, Rc, and Rdwhich is not H is independently selected from the group consisting of halo, nitro, alkyl, heterocyclyl, heterocyclylacyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy and carbamoyl. The ring of structure IV has p substituents, wherein p is 1, 2, 3 or 4. Each of said alkyl, heterocyclyl, heterocyclylacyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy and carbamoyl optionally has at least one further substituent.

[0082] In some embodiments, R3is H or is selected from the group consisting of aryl, haloalkyl, heteroaryl, haloheteroaryl, heteroarylalkyl, alkoxyaryl, alkoxyarylalkyl, wherein each of said haloalkyl, heteroaryl, haloheteroaryl, heteroarylalkyl, alkoxyaryl, alkoxyarylalkyl can optionally has at least one substituent selected from the group consisting of alkyl, alkoxy, alkoxyaryl, heteroaryl, heteroarylalkyl, heteroaryl-heteroalkyl, carbamoyl, carbamoylalkyl, halo, azido and nitro. In a preferred embodiment, compounds according to any of the foregoing embodiments are present as ’-enantiomers.

[0083] In some embodiments, when RTis alkyl, arylalkyl, haloarylalkyl, alkoxy, alkoxyaryl, alkoxyarylalkyl, haloalkoxy, and haloalkoxyarylalkyl, each of said alkyl, arylalkyl, haloarylalkyl, alkoxy, alkoxyaryl, alkoxyarylalkyl, haloalkoxy, and haloalkoxyarylalkyl can optionally has at least one substituent selected from the group consisting of, alkyl, aryl, arylalkyl, haloalkoxy, alkoxyarlyl, alkoxyarylalkyl, and carbamoylalkyl. In a preferredembodiment, compounds according to any of the foregoing embodiments are present as R-enantiomers.

[0084] In some embodiments, ring A is RB, which is represented by unsubstituted phenyl. In a particularly preferred embodiment, the compounds according to this embodiment are present as the A’-enantiomer.

[0085] The following aspects refer to embodiments of compounds of formula I, wherein A is RB: In some embodiments, if RBis represented by structure IV, then at least one of Ra, Rb, Rc, and Rdis not H, wherein said at least one of Ra, Rb, Rc, and Rdwhich is not H is independently selected from the group consisting of halo, nitro, alkyl, heterocyclyl, heterocyclylacyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy and carbamoyl, wherein each of said alkyl, heterocyclyl, heterocyclylacyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy and carbamoyl, can optionally have at least one further substituent selected from the group consisting of alkyl, alkoxy, and halo. In a preferred embodiment, compounds according to any of the foregoing embodiments are present as A’-enantiomers.

[0086] In some embodiments, if RBis represented by structure IV, then two of Ra, Rb, Rc, and Rdare not H, wherein said two of Ra, Rb, Rc, and Rdwhich are not H are independently selected from the group consisting of halo, nitro, alkyl, heterocyclyl, heterocyclylacyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy and carbamoyl, wherein each of said alkyl, heterocyclyl, heterocyclylacyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy and carbamoyl, can optionally have at least one further substituent selected from the group consisting of alkyl, alkoxy, and halo. In a preferred embodiment, compounds according to any of the foregoing embodiments are present as A’-enantiomers.

[0087] In some embodiments, if RBis represented by structure IV, then three of Ra, Rb, Rc, and Rdare not H, wherein said three of Ra, Rb, Rc, and Rdwhich are not H are independently selected from the group consisting of halo, nitro, alkyl, heterocyclyl, heterocyclylacyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy and carbamoyl, wherein each of said alkyl, heterocyclyl, heterocyclylacyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy and carbamoyl, can optionally have at least one further substituent selected from the group consisting of alkyl, alkoxy, and halo. In a preferred embodiment, compounds according to any of the foregoing embodiments are present as A’-enantiomers.

[0088] In some embodiments, if RBis represented by structure IV, then four of Ra, Rb, Rc, and Rdare not H, wherein said four of Ra, Rb, Rc, and Rdwhich are not H are independently selected from the group consisting of halo, nitro, alkyl, heterocyclyl, heterocyclylacyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy and carbamoyl, wherein each of said alkyl, heterocyclyl, heterocyclylacyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy and carbamoyl, can optionally have at least one further substituent selected from the group consisting of alkyl, alkoxy, and halo. In a preferred embodiment, compounds according to any of the foregoing embodiments are present as A’-enantiomers.

[0089] As defined herein, If RBis represented by structure IV, then at least one of Ra, Rb, Rc, and Rdis not H. Said at least one of Ra, Rb, Rc, and Rdwhich is not H, is independently located at any available ring positions of the ring of structure IV.As defined herein, if RBis represented by structure IV, then two of Ra, Rb, Rc, and Rdare not H. Said two of Ra, Rb, Rc, and Rdwhich are not H, are independently located at any available ring positions of the ring of structure IV. This definition includes meta-, para- and orthopositions on the ring.

[0090] As defined herein, if RBis represented by structure IV, then three of Ra, Rb, Rc, and Rdare not H. Said two of Ra, Rb, Rc, and Rdwhich are not Hm are independently located at any available ring positions of the ring of structure IV.

[0091] As defined herein, if RBis represented by structure IV, then four of Ra, Rb, Rc, and Rdare not H. Said two of Ra, Rb, Rc, and Rdwhich are not H, are independently located at any available ring positions of the ring of structure IV.

[0092] In a preferred embodiment, compounds according to any of the foregoing embodiments are present as A-enantiomers.

[0093] In another aspect of the present invention ring A is heteroaryl, to which the following embodiments relate to:

[0094] In one embodiment of the present invention, ring A is heteroaryl substituted by RT, wherein RTis H or selected from a group consisting of alkyl, arylalkyl, alkoxy, alkoxyaryl, haloarylalkyl, and haloalkoxy, wherein each of said alkyl, arylalkyl, alkoxy, alkoxyaryl, haloarylalkyl, and haloalkoxy can optionally have at least one further substituent. In a more preferred embodiment, compounds according to any of these embodiments are present as A’-enanti omers.

[0095] In another embodiment of the present invention, ring A is unsubstituted heteroaryl. In a particularly preferred embodiment, the compounds according to this embodiment are present as the A’-enantiomer.

[0096] The following aspects relates to preferred embodiments of the present invention:

[0097] In a further preferred embodiment of the present invention, A is RBrepresented by structure IV comprising at least one of Ra, Rb, Rc, and Rdwhich not H, wherein said at least one of Ra, Rb, Rc, and Rdwhich is not H, is independently selected from the group consisting of halo, nitro, alkyl, heterocyclyl, heterocyclylacyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy, and carbamoyl, wherein each of said alkyl, heterocyclyl, heterocyclylacyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy and carbamoyl optionally has at least one further substituent; R3is H or is selected from aryl and heteroaryl, wherein heteroaryl can optionally be substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, alkoxyaryl, carbamoyl,

[0098] R4R4

[0099] I

[0100] halo and nitro; X is——C —.or

[0101]

[0102] N jn aparticularly preferred embodiment, the compounds according to this embodiment are present as the A’-enantiomer.

[0103] In an even more particularly preferred embodiment of the foregoing embodiment, R3is heteroaryl, wherein said heteroaryl can optionally be substituted by one or more substituents selected from the group consisting of alkyl, alkoxy, alkoxyaryl, carbamoyl, halo and nitro, wherein if R3being a five-membered heteroaryl ring, said substituents are located on positions4 and 5. More preferably, when A is RBrepresented by structure IV comprising at least one of Ra, Rb, Rc, and Rdwhich not H, wherein said at least one of Ra, Rb, Rc, and Rdwhich is not H, is independently selected from halo.

[0104] In a more preferred embodiment of the present invention, A is RBrepresented by structure IV comprising at least one of Ra, Rb, Rc, and Rdwhich is not H, wherein said at least one of Ra, Rb, Rc, and Rdwhich is not H, is independently selected from the group consisting of halo, alkyl, haloalkyl, heterocyclyl, and heterocyclylacyl, wherein each of said alkyl, heterocyclyl, and heterocyclylacyl can optionally be further substituted; R3is aryl, which is substituted by one substituent a group consisting of alkyl, alkoxy or substituted alkoxy aryl and X is R4R4

[0105] I _ l _

[0106]

[0107] C or. A is RBrepresented by structure IV comprising at least one of Ra, Rb, Rc, and Rdwhich is not H, wherein said at least one of Ra, Rb, Rc, and Rdwhich is not H, is independently selected from

[0108] Most preferably, A is RBrepresented by structure IV comprising at least one of Ra, Rb, Rc, and Rdwhich not H, wherein said at least one of Ra, Rb, Rc, and Rdwhich is not H, is independently selected from fluoro, bromo, and chloro or is selected from a group consisting of Ci-6 alkyl, wherein said Ci-6 alkyl can optionally be further substituted; and R3is selected from R4R4

[0109] _ l _ I — unsubstituted phenyl and alkoxyphenyl and X is

[0110]

[0111] or, preferably R4

[0112] l _

[0113] N. In a particularly preferred embodiment, the compounds according to this embodiment are present as the A’-enantiomer.

[0114] Most preferably, A is heteroaryl substituted by RT, wherein said RTis selected from the group consisting of optionally further substituted alkyl, aryl, arylalkyl, alkoxyarlyl, alkoxyarylalkyl, carbamoylaryl or cabamoylarylalkyl group and R3is heteroaryl, which is substituted with a substituent selected from the group consisting of alkyl, alkoxy or substituted alkoxyaryl and X R4R4

[0115] isC=or— N— jn aparticularly preferred embodiment, the compounds according to this embodiment are present as the A’-enantiomer.

[0116] In another preferred embodiment, A is thienyl.

[0117] In one preferred embodiment, A is unsubstituted thienyl.

[0118] In a more preferred embodiment, A is substituted thienyl. When A is substituted thienyl, then the compound is represented by the following formula II

[0119]

[0120] (II),

[0121] wherein said substituted thienyl has a substituent RT, which is selected from a group consisting of Ci-6 alkyl, Ce-aryl, Ce- aryl-Ci-6-alkyl, halo-Ce- aryl-Ci-6-alkyl, Ci-6-alkoxy-Ce-arlyl, halo-Ci-6-alkoxy-Ce-arlyl, Ci-6-alkoxy-Ce-arlyl- Ci-6-alkyl, carbamoyl-Ce-aryl and cabamoyl-Ce-aryl-Ci-6-alkyl group, wherein each of said Ci-6 alkyl, Ce-aryl, Ce- aryl-Ci-6-alkyl, halo-Ce- aryl-Ci-6-alkyl, Ci-6-alkoxy-Ce-arlyl, halo-Ci-6-alkoxy-Ce-arlyl, Ci-6-alkoxy-Ce-arlyl- Ci-6-alkyl, carbamoyl-Ce-aryl and cabamoyl-Ce-aryl-Ci-6-alkyl group can optionally have at least one further substituent; R3is H. The ’-enantiomer of these embodiments are particularly preferred. In a more preferred embodiment, the compound is represented by formula II. According to formula II, ring A is substituted thienyl having a substituent RT, which is selected from a group consisting of Ci-6 alkyl, Ce-aryl, Ce- aryl-Ci-6-alkyl, halo-Ce- aryl-Ci-6-alkyl, Ci-6-alkoxy-Ce-arlyl, halo-Ci-6-alkoxy-Ce-arlyl, Ci-6-alkoxy-Ce-arlyl- Ci-6-alkyl, carbamoyl-Ce-aryl and cabamoyl-Ce-aryl-Ci-6-alkyl group, wherein each of said Ci-6 alkyl, Ce-aryl, Ce- aryl-Ci-6-alkyl, halo-Ce- aryl-Ci-6-alkyl, Ci-6-alkoxy-Ce-arlyl, halo-Ci-6-alkoxy-Ce-arlyl, Ci-6-alkoxy-Ce-arlyl-Ci-6-alkyl, carbamoyl-Ce-aryl and cabamoyl-Ce-aryl-Ci-6-alkyl group, can optionally have at least one further substituent; R3has a substituent, which is represented by structure V

[0122]

[0123] (V),

[0124] wherein said structure V is thienyl or substituted with a substituent R5, which is selected from the group consisting of alkyl, azidoalkyl, alkoxy, substituted alkoxyaryl heteroaryl,

[0125] R4 R4

[0126] I _ I —

[0127] heteroarylalkyl, and acylamido and X is

[0128]

[0129] - or. The A-enantiomer of these embodiments are particularly preferred.

[0130] Most preferably, when the compound is represented by formula II, then said thienyl group has a substituent RTwhich is selected from a group consisting of optionally further substituted Ci-6 alkyl, Ce-aryl, Ce- aryl-Ci-6-alkyl, halo-Ce- aryl-Ci-6-alkyl, Ci-6-alkoxy-Ce-arlyl, halo-Ci-6-alkoxy-Ce-arlyl, Ci-6-alkoxy-Ce-arlyl- Ci-6-alkyl, carbamoyl-Ce-aryl and cabamoyl-Ce-aryl-Ci-6-alkyl group, and has a substituent R3, which is represented by structure V, wherein said structure V has a substituent R5selected from the group consisting Ci-6 alkyl, triazol-l-yl, triazol-4-yl,Ci-6-azidoalkyl, acylamido, wherein said each of Ci-6 alkyl, triazol- 1-yl, triazol-4-yl, Ci-6-azidoalkyl, acylamido can have at least one further substituent selected from a group consisting of alkynyl, trizaol-l-yl, triazol-4-yl, Ci-6-alkoxy-Ci-6-alkoxy-triazol-l-yl, carbamoyl-Ci-6- R4

[0131] alkoxy-Ci-6-alkoxy -triazol- 1-yl and X is

[0132]

[0133] . The 7?-enantiomer of these embodiments are particularly preferred.

[0134] Most preferably, when the compound is represented by formula II, then said thienyl group has a substituent RTwhich is selected from a group consisting of optionally further substituted Ci-6 alkyl, Ce-aryl, Ce- aryl-Ci-6-alkyl, halo-Ce- aryl-Ci-6-alkyl, Ci-6-alkoxy-Ce-arlyl, halo-Ci-6-alkoxy-Ce-arlyl, Ci-6-alkoxy-Ce-arlyl- Ci-6-alkyl, carbamoyl-Ce-aryl and cabamoyl-Ce-aryl-Ci-6-alkyl group, and has a substituent R3, which is represented by structure V, wherein said structure V has a substituent R5selected from the group consisting fluoro, bromo, chloro and iodo and R4

[0135] nitro and X is

[0136]

[0137] . The 7?-enantiomer of these embodiments are particularly preferred. RTis suitably selected from the group consisting of optionally further substituted arylmethyl, alkoxyaryl(methyl), haloaryl(methyl), haloalkoxyaryl(methyl), carboalkoxyaryl(methyl), alkoxy carboalkoxyaryl(methyl), trifluoromethoxyphenyl (methyl);

[0138] [[[(alkoxyalkoxymethyl)]triazol-l-yl](methyl)], alkinylacylamidoaryl(methyl), alkylacylamidoaryl(methyl), heterocyclylaryl(methyl);

[0139] Preferably, RTis selected from a group consisting of phenyl(methyl), 3-methoxyphenyl(methyl), 4-methoxyphenyl(methyl), 2-chlorphenyl(methyl), 2,4-di chi orphenyl(m ethyl), 3- carbomethoxyphenyl(m ethyl), 4-carbomethoxyphenyl(m ethyl), 4-methyl-N-prop-2-ynyl-benzamide, 4-methyl-N-ethyl-benzamide, 2-methoxyethyl 4-methyl-benzoate, 4-trifluoromethoxyphenyl(methyl), 4-fluorophenyl(methyl), 5-chloro-2-methoxyphenyl(methyl), 3-chlorophenylmethyl, 2,5-dichlorophenyl(methyl), [[4-(2-m ethoxy ethoxymethyl)triazol- 1 -yl]methyl], 4-methyl-N-[[ 1 - [2-(2-methoxyethoxy)ethyl]triazol-4-yl]methyl]benzamide and 4-piperazine-4-yl-phenyl(methyl). The ’-enantiomer of these embodiments are particularly preferred.

[0140] In one preferred embodiment, A is RBrepresented by structure IV, wherein at least one of Ra, Rb, Rc, and Rdis not H and wherein each of the said at least one of Ra, Rb, Rc, and Rdis not H is suitably selected from a group consisting of Ci-6 alkyl, alkoxy, alkoxyalkyl, haloalkoxy, fluoro, bromo, chloro and nitro; R3is optionally substituted phenyl or alkoxyphenyl and X is - p4 R4

[0141] I _ I

[0142]

[0143] & or. The 7?-enantiomer of these embodiments are particularly preferred. In another preferred embodiment, A is RBrepresented by structure IV, wherein two of Ra, Rb, Rc, and Rdare not H and wherein each of the two substituents of Ra, Rb, Rc, and Rdare not H,are suitably selected from a group consisting of Ci-6 alkyl, alkoxy, alkoxyalkyl, haloalkoxy, fluoro, bromo, chloro and nitro; R3is optionally substituted phenyl or alkoxyphenyl and X is R4R4

[0144] Cor

[0145]

[0146] — N The / / -enantiomer of these embodiments are particularly preferred. In another preferred embodiment, A is RBrepresented by structure IV, wherein three of Ra, Rb, Rc, and Rdare not H and wherein each of the three of Ra, Rb, Rc, and Rdare not H, are suitably selected from a group consisting of Ci-6 alkyl, alkoxy, alkoxyalkyl, haloalkoxy, fluoro, bromo,

[0147] R4I

[0148] chloro and nitro; R3is optionally substituted phenyl or alkoxyphenyl and X is

[0149]

[0150] - or R4

[0151] _ l _

[0152] . The / / -enantiomer of these embodiments are particularly preferred.

[0153] More preferably, said RBrepresented by structure IV, wherein at least one of Ra, Rb, Rc, and Rdis not H and wherein each of the said at least one of Ra, Rb, Rc, and Rdis not H, is nitro or halo or selected from the group consisting of alkyl, heterocyclyl, heterocyclylacyl, alkoxy, alkoxyalkyl, haloalkoxy, wherein said alkyl, heterocyclyl, heterocyclylacyl, alkoxy, alkoxyalkyl, haloalkoxy are optionally further substituted and R3is halo or nitro or heteroaryl, wherein said heteroaryl is unsubstituted or substituted by a group consisting of alkyl,

[0154] R4R4_ I _ _ l _ (methoxyethoxymethyl)triazol-l-yl and propyltriazol-l-yl; X is or

[0155] The / / -enantiomer of these embodiments are particularly preferred.

[0156] More preferably, said RBrepresented by structure IV, wherein at least one of Ra, Rb, Rc, and Rdis not H and wherein each of the said at least one of Ra, Rb, Rc, and Rdis not H, is halo or selected from a group consisting of alkyl, alkoxy, alkoxyalkyl, and haloalkoxy, wherein said alkyl, alkoxy, alkoxyalkyl, and haloalkoxy can be optionally be further substituted with alkyl,

[0157] R4 R4

[0158] I _ l _

[0159] heterocyclyl, heterocyclylacyl or halo; R3is H, Xis

[0160]

[0161] — or. The / / -enantiomer of these embodiments are particularly preferred.

[0162] Most preferably, said RBrepresented by structure IV, wherein at least one of Ra, Rb, Rc, and Rdis not H and wherein each of the said at least of one Ra, Rb, Rc, and Rdis not H, is individually selected from a group consisting of halo alkyl, alkoxy, alkoxyalkyl, and haloalkoxy, wherein said alkyl, alkoxy, alkoxyalkyl, and haloalkoxy can be optionally be further substituted with alkyl, heterocyclyl, heterocyclylacyl or halo; R3is represented by structure V, which is substituted with a substituent R5selected from a group consisting of Ci-6 alkyl, fluoro,bromo, chloro iodo, nitro, (methoxyethoxymethyl)triazol-l-yl or propyltri azol -1-yl and X is - R4

[0163] I N The ^-enantiomer of these embodiments are particularly preferred.

[0164] Most preferably, said RBrepresented by structure IV, wherein two of Ra, Rb, Rc, and Rdare not H and wherein each of the said two substituents are individually selected from a group consisting of halo alkyl, alkoxy, alkoxyalkyl, and haloalkoxy, wherein said alkyl, alkoxy, alkoxyalkyl, and haloalkoxy can be optionally be further substituted with alkyl, heterocyclyl, heterocyclylacyl or halo; R3is represented by structure V, which is substituted with a substituent R5selected from a group consisting of Ci-6 alkyl, fluoro, bromo, chloro iodo, nitro,

[0165] R4

[0166] l _ (methoxyethoxymethyl)triazol-l-yl or propyltri azol -1-yl and X is

[0167]

[0168] . The / / -enantiomer of these embodiments are particularly preferred.

[0169] Preferably said RBrepresented by structure IV, wherein at least one of Ra, Rb, Rc, and Rdis not H and wherein each of the said at least one of Ra, Rb, Rc, and Rdis not H, is individually selected from a group consisting of Ci-6-alkyl, Ci-6-alkoxy, nitro, fluoro, chloro, bromo, iodo, trifluoromethoxy, acylcarbamat, acylalkylcarbamat and nitro. The / / -enantiomer of these embodiments are particularly preferred.

[0170] More preferably, said RBrepresented by structure IV, wherein at least one of Ra, Rb, Rc, and Rdis not H and wherein each of the said at least one of Ra, Rb, Rc, and Rdis not H, is individually selected from group consisting of methyl, ethyl, methoxy, ethoxy, trifluoromethoxy, fluoro, bromo, chloro, morpholine-4-carbonyl, chloro. The / / -enantiomer of these embodiments are particularly preferred.

[0171] In a particularly preferred embodiment, RBrepresented by structure IV comprises two substituents selected from Ra, Rb, Rc, and Rdwhich are not H, wherein the two substituents Ra, Rb, Rc, and Rdwhich are not H, are located at adjacent positions on RB. Most preferably, RBrepresented by structure IV comprises at least one substituent selected from Ra, Rb, Rc, and Rdwhich is not H, wherein said at least one substituent Ra, Rb, Rc, and Rdwhich is not H, is selected from a group consisting of 6-ethoxy, 7-fluoro, 6-methoxy, 6-(trifluoromethoxy), 7-methyl, 7-nitro, 6-chloro7-methoxy, 6-nitro, 8-methyl, 6-(morpholine-4-carbonyl), tert-butyl N- 6-oxo-hexyl]carbamate. In a particularly preferred embodiment, RBrepresented by structure IV comprises two substituents selected Ra, Rb, Rc, and Rdwhich are not H, wherein the two of Ra, Rb, Rc, and Rdwhich are not H, are 6,7-difluoro or 6-chloro-7-fluoro. The / / -enantiomer of these embodiments are particularly preferred.

[0172] In more preferred compounds of formula I and II, R3is structure V, R5is selected from the group consisting of Ci-6 alkyl, triazol-l-yl, triazol-4-yl, Ci-6-azidoalkyl, acylamido, wherein said each of Ci-6 alkyl, triazol-l-yl, triazol-4-yl, Ci-6-azidoalkyl, acylamido can have at least one further substituent selected from a group consisting of alkynyl, trizaol-l-yl, triazol-4-yl, Ci-6-alkoxy- triazol-l-yl, fluoro, bromo, chloro and nitro. The / / -enantiomer of these embodiments are particularly preferred.In more preferred compounds of formula I and II, R3is structure V, thienyl, R5is selected from or R5is fluoro, bromo, chloro and nitro. The / / -enantiomer of these embodiments are particularly preferred.

[0173] In further particularly preferred compounds of formula I and II, R3is structure V representing thienyl. The / / -enantiomer of these embodiments are particularly preferred.

[0174] In most preferred compounds of formula I and II, R3is structure V representingR5is selected from the group consisting of 5-methyl, 5-ethyl, 5-bromo, 5-chloro, 5-propyl, 5-isobutyl, [2-(2-m ethoxy ethoxy)ethyl]triazol-4-yl], 5-fluoro, 5-N-prop-2-ynyl-carboxamide, [2-(2-methoxyethoxy)ethyl]triazol-4-yl-2-carboxamide, (2-methoxyethyl), and 2-(m ethoxy ethoxy)ethyltriazol-4-yl. The / / -enantiomer of these embodiments are particularly preferred.

[0175] In most preferred compounds of formula I, wherein A is RB, R3is structure V representing thienyl.

[0176] In most preferred compounds of formula I, wherein A is RB, R3is structure V, R5is selected from the group consisting of 5-ethyl, 5-azidomethyl, 5-bromo, 5-propyl, 5-isobutyl, 5-nitro, 5-[(4-propyltriazol-l-yl)methyl], [4-(2-methoxyethoxymethyl)triazol-l-yl], The / / -enantiomer of these embodiments are particularly preferred.

[0177] Preferred compounds of formula II that show an IC50of 10 pM or below, more preferably of 5 pM or below, most preferably of 1 pM or below, in a cell-based proliferation test, such as the cell-based proliferation test which is described in detail in section “biological effects” hereinbelow, are compounds of formula II or a pharmaceutically acceptable salt form, solvate or polymorph thereof, including all tautomers and stereoisomers thereof, especially the R-enantiomer:

[0178] wherein R3is structure V representing thienyl or wherein R3is structure V and R5is selected R4

[0179] from alkyl and halo, R1, R2and R4are H, X is

[0180]

[0181] and RTis selected from alkyl, arylalkyl, alkoxyarylalkyl, haloarylalkyl, dihaloarylalkyl carboalkoxyarylalkyl, heteroalkylcarboalkoxyarylalkyl, alkinylacylamidoarylalkyl, alkylacylamidoarylalkyl, and heterocyclylarylalkyl. The / / -enantiomer of these embodiments are particularly preferred.. In a preferred embodiment of formula II, R3is structure V representing thienyl or R3is structure V and R5is selected from halo, wherein if R5is halo, then said R3preferably is bromo or chloro,

[0182] R4

[0183] I

[0184] R1, R2and R4are H, X is

[0185]

[0186] and RTis selected from alkyl, arylalkyl, carboalkoxyarylalkyl, alkylacylamidoarylalkyl, alkinylacylamidoarylalkyl. The A-enantiomer of these embodiments are particularly preferred.In yet a further preferred embodiment of formula II, R3is structure V, R5is Ci-6 alkyl or halo,

[0187] R4

[0188] l _ preferably methyl, ethyl or bromo, R1, R2and R4are H, X is and RTis alkoxyarylalkyl, heteroalkylcarboalkoxyarylalkyl, haloarylalkyl dihaloarylalkyl, haloalkoxyarylmethyl, carboalkoxyarylalkyl. The / / -enantiomer of these embodiments are particularly preferred.

[0189] Preferred compounds of formula I, wherein A is RBrepresented by structure IV comprising at least one substituent selected from Ra, Rb, Rc, and Rdwhich is not H, wherein p is 1 or 2, preferably two substituents from Ra, Rb, Rc, and Rdwhich are not H, more preferably one substituent from Ra, Rb, Rc, and Rdwhich is not H, selected from a group consisting of by Ci-6 alkyl, alkoxy, trihaloalkoxy, halo or nitro that show an IC50of 10 pM or below, more preferably of 5 pM or below, most preferably of 1 pM or below, in cell-based proliferation test such as the cell-based proliferation test which is described in detail in section “biological effects” hereinbelow, are compounds of formula I or a pharmaceutically acceptable salt form, solvate or polymorph thereof, including all tautomers and stereoisomers thereof, especially the R-enantiomer:

[0190] wherein R3is structure V, R5is C1-6 alkyl, halo, azidoalkyl, alkyltriazolmethyl, R1, R2is H or a R4R4

[0191] I I

[0192] bond, R

[0193]

[0194] 4is H, X is or

[0195] In a preferred embodiment of formula I, wherein A is RBis unsubstituted phenyl, R3is R4

[0196] I

[0197] optionally substituted benzyl, R1, R2and R4are H, X is

[0198]

[0199] N. The A-enantiomer of these embodiments are particularly preferred.

[0200] In another preferred embodiment of formula I, wherein A is RB.said RBrepresented by structure IV, wherein at least one of Ra, Rb, Rc, and Rdis not H and wherein each of the said at least one of Ra, Rb, Rc, and Rdis not H, is individually selected from a group consisting of R4_ l _ fluoro, bromo or chloro, R3is optionally substituted benzyl, R1, R2and R4are H, X is

[0201] In another preferred embodiment of formula I, wherein A is RB.said RBrepresented by structure IV, wherein two of Ra, Rb, Rc, and Rdare not H and wherein each of the said two ofRa, Rb, Rc, and Rdwhich are not H? are individually selected from a group consisting of fluoro,

[0202] R4

[0203] I

[0204] bromo or chloro, R3is optionally substituted benzyl, R1, R2and R4are H, X is

[0205]

[0206] In another preferred embodiment of formula I, wherein A is RBis unsubstituted phenyl, R3is structure V, R5is methyl, ethyl, bromo, chloro, azidomethyl, azidoalkyl, (propyltriazol-1- R4

[0207] I

[0208] yl)methyl, R

[0209]

[0210] 1, R2and R4are H, X is

[0211] In a more preferred embodiment of formula I, wherein A is RB. said RBrepresented by structure IV, wherein two of Ra, Rb, Rc, and Rdare not H and wherein each of the said two of Ra, Rb, Rc, and Rdare not H, are individually selected from a group consisting of methyl, ethyl alkoxymethyl, trifluormethoxy, fluoro, bromo, chloro and nitro, R3is structure V, R5is methyl, ethyl, bromo, chloro, azidomethyl, azidoalkyl, (propyltriazol- l-yl)methyl, R1, R2and R4are H, R4

[0212] X is N. The / / -enantiomer of these embodiments are particularly preferred.

[0213] In a most preferred embodiment of formula I, wherein A is RB.said RBrepresented by structure IV, wherein two of Ra, Rb, Rc, and Rdare not H and wherein each of the said two of Ra, Rb, Rc, and Rdare not H, are individually selected from a group consisting of alkoxymethly, trifluormethoxy and fluoro, R3is structure V, R5is ethyl or bromo, R1, R2and R4are H, X is R4

[0214] _ I _

[0215] . The / / -enantiomer of these embodiments are particularly preferred.

[0216] In one embodiment a suitable compound according to formula I is a compound selected from the group consisting of example compounds shown in the table below.

[0217] A suitable compound of formula II shows an IC50of 10 μM or below in a cell-based proliferation test such as the cell-based proliferation test which is described in detail in section “biological effects” hereinbelow, and is a compound or a pharmaceutically acceptable salt form, solvate or polymorph thereof, including individual tautomers and stereoisomers thereof, selected from the group consisting of:

[0218] 2-(5-ethyl-2-thienyl)-6-[(4-methoxyphenyl)methyl]-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-4-one;

[0219] 2-(5-bromothiophen-2-yl)-6-(5-chloro-2-methoxybenzyl)-2,3-dihydrothieno[2,3- d]pyrimidin-4(lH)-one;6-(4-methoxybenzyl)-2-(5-(2-methoxyethyl)thiophen-2-yl)-2,3-dihydrothieno[2,3-d]pyrimidin-4(lH)-one;

[0220] 6-(4-methoxybenzyl)-2-(5-propylthiophen-2-yl)-2,3-dihydrothieno[2,3-d]pyrimidin- 4(lH)-one;

[0221] 2-(5-ethylthiophen-2-yl)-6-(4-fluorobenzyl)-2,3-dihydrothieno[2,3-d]pyrimidin-4(lH)-one;

[0222] 2-(5-bromo-2-thienyl)-6-[(2-chlorophenyl)methyl]-2,3-dihydro-lH-thieno[2,3-d]pyrimidin-4-one;

[0223] 2-(5-bromo-2-thienyl)-6-[(4-methoxyphenyl)methyl]-2,3-dihydro-lH-thieno[2,3-d]pyrimidin-4-one;

[0224] methyl 3-[[2-(5-bromo-2-thienyl)-4-oxo-2,3-dihydro-lH-thieno[2,3-d]pyrimidin-6-yl]methyl]benzoate;

[0225] 2-(5-bromo-2-thienyl)-6-[(2,4-dichlorophenyl)methyl]-2,3-dihydro-lH-thieno[2,3-d]pyrimidin-4-one;

[0226] 2-methoxy ethyl 4-[[2-(5-bromo-2-thienyl)-4-oxo-2,3-dihydro-lH-thieno[2,3-d]pyrimidin-6-yl]methyl]benzoate;

[0227] 2-(5-bromo-2-thienyl)-6-[(3-methoxyphenyl)methyl]-2,3-dihydro-lH-thieno[2,3-d]pyrimidin-4-one;

[0228] 4-[[2-(5-bromo-2-thienyl)-4-oxo-2,3-dihydro-lH-thieno[2,3-d]pyrimidin-6-yl]methyl]-N-prop-2-ynyl-benzamide;

[0229] 2-(5-chloro-2-thienyl)-6-[(4-methoxyphenyl)methyl]-2,3-dihydro-lH-thieno[2,3-d]pyrimidin-4-one;

[0230] 4-[[2-(5-bromo-2-thienyl)-4-oxo-2,3-dihydro-lH-thieno[2,3-d]pyrimidin-6-yl]methyl]-N-ethyl-benzamide;

[0231] 2-(5-bromo-2-thienyl)-6-[(4-chlorophenyl)methyl]-2,3-dihydro-lH-thieno[2,3-d]pyrimidin-4-one;

[0232] 2-(5-bromo-2-thienyl)-6-methyl-2,3-dihydro-lH-thieno[2,3-d]pyrimidin-4-one;

[0233] 6-benzyl-2-(5-chloro-2-thienyl)-2,3-dihydro-lH-thieno[2,3-d]pyrimidin-4-one; methyl 4-[[2-(5-bromo-2-thienyl)-4-oxo-2,3-dihydro-lH-thieno[2,3-d]pyrimidin-6-yl]methyl]benzoate;

[0234] 6-benzyl-2-(5-bromo-2-thienyl)-2,3-dihydro-lH-thieno[2,3-d]pyrimidin-4-one; tert-butyl 4-[4-[[2-(5-bromo-2-thienyl)-4-oxo-2, 3 -dihydro- lH-thieno[2, 3-d]pyrimidin-6-yl]methyl] phenyl]piperazine-l -carboxylate;

[0235] 2-(5-chloro-2-thienyl)-6-methyl-2,3-dihydro-lH-thieno[2,3-d]pyrimidin-4-one;2-(5-bromo-2-thienyl)-6-[(2,5-dichlorophenyl)methyl]-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-4-one;

[0236] 2-(5-bromo-2-thienyl)-6-[(2-chlorophenyl)methyl]-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-4-one;

[0237] 2-(5-bromo-2-thienyl)-6-[(3-chlorophenyl)methyl]-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-4-one;

[0238] 2-(5-ethyl-2-thienyl)-6-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-lH- thieno[2,3-d]pyrimidin-4-one.

[0239] A particularly suitable compound of formula II shows an IC50of 10 μM or below in a cell-based proliferation test such as the cell-based proliferation test which is described in detail in section “biological effects” hereinbelow, and is a compound selected from the group consisting of:

[0240] (5)-2-(5-bromothiophen-2-yl)-6-(2,4-dichlorobenzyl)-2,3-dihydrothieno[2,3- d]pyrimidin-4(lH)-one;

[0241] (?)-2-(5-bromothiophen-2-yl)-6-(2,4-dichlorobenzyl)-2,3-dihydrothieno[2,3- d]pyrimidin-4(lH)-one;

[0242] (?)-2-(5-bromothiophen-2-yl)-6-(2-chlorobenzyl)-2,3-dihydrothieno[2,3-d]pyrimidin- 4(lH)-one.

[0243] Said ’-enantiomer of these embodiments are particularly preferred.

[0244] A suitable compound of formula I shows an IC50of 10 μM or below in a cell-based proliferation test such as the cell-based proliferation test which is described in detail in section “biological effects” hereinbelow, and is a compound or a pharmaceutically acceptable salt form, solvate or polymorph thereof, including all tautomers and stereoisomers thereof, selected from the group consisting of:

[0245] 2-(5-ethyl-2-thienyl)-7-fluoro-2,3-dihydro-lH-quinazolin-4-one;

[0246] 2-(5-ethylthiophen-2-yl)-6,7-difluoro-2,3-dihydroquinazolin-4(lH)-one;

[0247] 2-(5 -bromothiophen-2-yl)-6, 7-difluoro-2,3 -dihy droquinazolin-4( 1 H)-one;

[0248] 6-chloro-2-(5-ethylthiophen-2-yl)-7-fluoro-2,3-dihydroquinazolin-4(lH)-one;

[0249] 7-fluoro-2-(5-isobutylthiophen-2-yl)-2,3-dihydroquinazolin-4(lH)-one;

[0250] 2-(5-bromo-2-thienyl)-6-(trifluoromethoxy)-2,3-dihydro-lH-quinazolin-4-one;

[0251] 2-(5 -bromo-2-thienyl)-7-methyl-2, 3 -dihy dro- 1 H-quinazolin-4-one;

[0252] 2-(5-bromo-2-thienyl)-6-methoxy-2,3-dihydro-lH-quinazolin-4-one;

[0253] 2-(5 -bromo-2-thienyl)-7-chl oro-2, 3 -dihydro- 1 H-quinazolin-4-one;

[0254] 2-[5-(azidomethyl)-2-thienyl]-2,3-dihydro-lH-quinazolin-4-one;

[0255] 2-(5-bromo-2-thienyl)-7-nitro-2,3-dihydro-lH-quinazolin-4-one;2-(5-bromo-2-thienyl)-7-fluoro-2,3-dihydro-lH-quinazolin-4-one;

[0256] 6-chloro-2-phenyl-2,3-dihydro-lH-quinazolin-4-one;

[0257] 2-(5 -ethyl-2-thienyl)-7-nitro-2, 3 -dihydro- 1 H-quinazolin-4-one;

[0258] 2-(5 -bromo-2-thienyl)-7-m ethoxy-2, 3 -dihydro- 1 H-quinazolin-4-one;

[0259] 6-ethoxy-2-(5-ethyl-2-thienyl)-2,3-dihydro-lH-quinazolin-4-one;

[0260] 2-(5-ethyl-2-thi enyl)-6-(trifluoromethoxy)-2, 3 -dihydro- lH-quinazolin-4-one;

[0261] 2-(5-ethyl-2-thienyl)-6-methoxy-2,3-dihydro-lH-quinazolin-4-one;

[0262] 2-(5-bromo-2-thienyl)-7-fluoro-2,3-dihydro-lH-quinazolin-4-one.

[0263] A particularly suitable compound of formula I shows an IC50of 10 μM or below in cell-based proliferation test such as the cell-based proliferation test which is described in detail in section “biological effects” hereinbelow, and is a compound selected from the group consisting of:

[0264] (5)-2-(5 -Bromo-2-thienyl)-2, 3 -dihy dro-4( 1 H)-quinazolinone;

[0265] (?)-2-(5-Bromo-2-thienyl)-2,3-dihydro-4(lH)-quinazolinone;

[0266] (5)-6-Ethoxy-2-(5-ethyl-2-thienyl)-2,3-dihydro-4(lH)-quinazolinone;

[0267] (?)-6-Ethoxy-2-(5-ethyl-2-thienyl)-2,3-dihydro-4(lH)-quinazolinone;

[0268] (7?)-6-Methoxy-2-(5-bromo-2-thienyl)-2,3-dihydro-4(lH)-quinazolinone;

[0269] (5)-6-Methoxy-2-(5-Ethyl-2-thienyl)-2,3-dihydro-4(lH)-quinazolinone;

[0270] (7?)-6-Methoxy-2-(5-Ethyl-2-thienyl)-2,3-dihydro-4(lH)-quinazolinone;

[0271] (5)-6-Chloro-2-phenyl-2,3-dihydro-4(lH)-quinazolinone;

[0272] (?)-6-Chloro-2-phenyl-2,3-dihydro-4(lH)-quinazolinone;

[0273] (5)-2-(5-bromothiophen-2-yl)-7-methyl-2,3-dihydroquinazolin-4(lH)-one;

[0274] (7?)-2-(5-bromothiophen-2-yl)-7-methyl-2,3-dihydroquinazolin-4(lH)-one;

[0275] (5)-2-(5-bromothiophen-2-yl)-7-fluoro-2,3-dihydroquinazolin-4(lH)-one;

[0276] (?)-2-(5-bromothiophen-2-yl)-7-fluoro-2,3-dihydroquinazolin-4(lH)-one;

[0277] (5)-2-(5-bromothiophen-2-yl)-6-(trifluoromethoxy)-2,3-dihydroquinazolin-4(lH)-one; (A)-2-(5-bromothiophen-2-yl)-6-(trifluoromethoxy)-2,3-dihydroquinazolin-4(lH)-one; (5)-2-(5 -bromothiophen-2-yl)-6, 7-difluoro-2,3 -dihy droquinazolin-4( 1 H)-one;

[0278] (?)-2-(5-bromothiophen-2-yl)-6,7-difluoro-2,3-dihydroquinazolin-4(lH)-one;

[0279] (?)-2-(5-bromothiophen-2-yl)-6-(2-chlorobenzyl)-2,3-dihydrothieno[2,3-d]pyrimidin- 4(lH)-one;

[0280] (5)-(5-bromothiophen-2-yl)-7-methoxy-2,3-dihydroquinazolin-4(lH)-one;(A)-(5-bromothiophen-2-yl)-7-methoxy-2,3-dihydroquinazolin-4(lH)-one:

[0281] (5)-(5-bromothiophen-2-yl)-7-chloro-2,3-dihydroquinazolin-4(lH)-one;

[0282] (A)-(5-bromothiophen-2-yl)-7-chloro-2,3-dihydroquinazolin-4(lH)-one;

[0283] (5)-7-fluoro-2-(5-isobutylthiophen-2-yl)-2,3-dihydroquinazolin-4(lH)-one;

[0284] (7?)-7-fluoro-2-(5-isobutylthiophen-2-yl)-2,3-dihydroquinazolin-4(lH)-one.

[0285] Said ’-enantiomers of these embodiments are particularly preferred.

[0286] A suitable compound of formula I shows an IC50of 1.5 μM or below in cell-based proliferation test such as the cell-based proliferation test which is described in detail in section “biological effects” hereinbelow, and is a compound or a pharmaceutically acceptable salt form, solvate or polymorph thereof, including all tautomers and stereoisomers thereof, selected from the group consisting of:

[0287] 2-(5-ethyl-2-thienyl)-6-[(4-methoxyphenyl)methyl]-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-4-one;

[0288] 2-(5-bromothiophen-2-yl)-6-(5-chloro-2-methoxybenzyl)-2,3-dihydrothieno[2,3- d]pyrimidin-4(lH)-one;

[0289] 6-(4-methoxybenzyl)-2-(5-(2-methoxyethyl)thiophen-2-yl)-2,3-dihydrothieno[2,3- d]pyrimidin-4(lH)-one;

[0290] 2-(5-ethylthiophen-2-yl)-6,7-difluoro-2,3-dihydroquinazolin-4(lH)-one;

[0291] 2-(5 -bromothiophen-2-yl)-6, 7-difluoro-2,3 -dihy droquinazolin-4( 1 H)-one;

[0292] 6-(4-methoxybenzyl)-2-(5-propylthiophen-2-yl)-2,3-dihydrothieno[2,3-d]pyrimidin- 4(lH)-one;

[0293] 6-chloro-2-(5-ethylthiophen-2-yl)-7-fluoro-2,3-dihydroquinazolin-4(lH)-one;

[0294] 2-(5-ethyl-2-thienyl)-7-fluoro-2,3-dihydro-lH-quinazolin-4-one;

[0295] 2-(5-bromo-2-thienyl)-6-[(2-chlorophenyl)methyl]-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-4-one;

[0296] 2-(5-bromo-2-thienyl)-6-[(2,4-dichlorophenyl)methyl]-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-4-one;

[0297] methyl 3-[[2-(5-bromo-2-thienyl)-4-oxo-2,3-dihydro-lH-thieno[2,3-d]pyrimidin-6- yl]methyl]benzoate;

[0298] 2-(5-bromo-2-thienyl)-6-[(4-methoxyphenyl)methyl]-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-4-one;

[0299] 2-methoxy ethyl 4-[[2-(5-bromo-2-thienyl)-4-oxo-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-6-yl]methyl]benzoate;

[0300] 2-(5-bromo-2-thienyl)-6-(trifluoromethoxy)-2,3-dihydro-lH-quinazolin-4-one;2-(5-bromo-2-thienyl)-6-methoxy-2,3-dihydro-lH-quinazolin-4-one;

[0301] 2-(5-bromo-2-thienyl)-6-[(3-methoxyphenyl)methyl]-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-4-one;

[0302] 2-(5 -bromo-2-thienyl)-7-methyl-2, 3 -dihydro- 1 H-quinazolin-4-one;

[0303] 2-(5 -bromo-2-thienyl)-7-chl oro-2, 3 -dihydro- 1 H-quinazolin-4-one;

[0304] 4-[[2-(5-bromo-2-thienyl)-4-oxo-2,3-dihydro-lH-thieno[2,3-d]pyrimidin-6-yl]methyl]-N-prop-2-ynyl-benzamide;

[0305] 2-(5-chloro-2-thienyl)-6-[(4-methoxyphenyl)methyl]-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-4-one;

[0306] 4-[[2-(5-bromo-2-thienyl)-4-oxo-2,3-dihydro-lH-thieno[2,3-d]pyrimidin-6- yl]methyl]-N-ethyl-benzamide;

[0307] 2-(5-bromo-2-thienyl)-6-[(2,5-dichlorophenyl)methyl]-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-4-one;

[0308] 6-ethoxy-2-(5-ethyl-2-thienyl)-2,3-dihydro-lH-quinazolin-4-one;

[0309] 2-(5-ethyl-2-thi enyl)-6-(trifluoromethoxy)-2, 3 -dihydro- lH-quinazolin-4-one;

[0310] 2-(5-bromo-2-thienyl)-6-[(2-chlorophenyl)methyl]-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-4-one;

[0311] 2-(5-bromo-2-thienyl)-6-[(3-chlorophenyl)methyl]-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-4-one;

[0312] 2-(5-ethyl-2-thienyl)-6-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-lH- thieno[2,3-d]pyrimidin-4-one;

[0313] 2-(5-ethyl-2-thienyl)-6-methoxy-2,3-dihydro-lH-quinazolin-4-one.

[0314] A particularly suitable compound of formula I shows an IC50of 1.5 μM or below in cell-based proliferation test such as the cell-based proliferation test which is described in detail in section “biological effects” hereinbelow, and is a compound is a stereoisomer thereof, selected from the group consisting of:

[0315] (5)-6-Ethoxy-2-(5-ethyl-2-thienyl)-2,3-dihydro-4(177)-quinazolinone;

[0316] (?)-6-Ethoxy-2-(5-ethyl-2-thienyl)-2,3-dihydro-4(lJ7)-quinazolinone;

[0317] (A)-6-Methoxy-2-(5-bromo-2-thienyl)-2,3-dihydro-4(177)-quinazolinone;

[0318] (A)-6-Methoxy-2-(5-Ethyl-2-thienyl)-2,3-dihydro-4(177)-quinazolinone;

[0319] (?)-6-Chloro-2-phenyl-2,3-dihydro-4(177)-quinazolinone;

[0320] (?)-2-(5-bromothiophen-2-yl)-7-methyl-2,3-dihydroquinazolin-4(lJ7)-one;

[0321] (?)-2-(5-bromothiophen-2-yl)-7-fluoro-2,3-dihydroquinazolin-4(lH)-one;(7?)-2-(5-bromothiophen-2-yl)-6-(2,4-dichlorobenzyl)-2,3-dihydrothieno[2,3- d]pyrimidin-4(1H)-one;

[0322] (A)-2-(5-bromothiophen-2-yl)-6-(2-chlorobenzyl)-2,3-dihydrothieno[2,3-d]pyrimidin- 4(lH)-one;

[0323] (A)-2-(5-bromothiophen-2-yl)-6-(trifluoromethoxy)-2,3-dihydroquinazolin-4(177)-one; (A)-2-(5-bromothiophen-2-yl)-6-(2-chlorobenzyl)-2,3-dihydrothieno[2,3-d]pyrimidin- 4(lJ7)-one;

[0324] (A)-(5-bromothiophen-2-yl)-7-methoxy-2,3-dihydroquinazolin-4(177)-one;

[0325] (A)-(5-bromothiophen-2-yl)-7-chloro-2,3-dihydroquinazolin-4(177)-one;

[0326] (A)-7-fluoro-2-(5-isobutylthiophen-2-yl)-2,3-dihydroquinazolin-4(lH)-one.

[0327] Said ’-enantiomers of these embodiments are particularly preferred.

[0328] A suitable compound of formula I or II shows an IC50of 1.0 μM or below in cell-based proliferation test such as the cell-based proliferation test which is described in detail in section “biological effects” hereinbelow, and is a compound or a pharmaceutically acceptable salt form, solvate or polymorph thereof, including all tautomers and stereoisomers thereof, selected from the group consisting of:

[0329] 2-(5-ethyl-2-thienyl)-6-[(4-methoxyphenyl)methyl]-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-4-one;

[0330] 2-(5-bromothiophen-2-yl)-6-(5-chloro-2-methoxybenzyl)-2,3-dihydrothieno[2,3- d]pyrimidin-4(lH)-one;

[0331] 2-(5-ethylthiophen-2-yl)-6,7-difluoro-2,3-dihydroquinazolin-4(lH)-one;

[0332] 6-chloro-2-(5-ethylthiophen-2-yl)-7-fluoro-2,3-dihydroquinazolin-4(lH)-one;

[0333] 2-(5-ethyl-2-thienyl)-7-fluoro-2,3-dihydro-lH-quinazolin-4-one;

[0334] 2-(5-bromo-2-thienyl)-6-[(2-chlorophenyl)methyl]-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-4-one;

[0335] 2-(5-bromo-2-thienyl)-6-[(2,4-dichlorophenyl)methyl]-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-4-one;

[0336] methyl 3-[[2-(5-bromo-2-thienyl)-4-oxo-2,3-dihydro-lH-thieno[2,3-d]pyrimidin-6- yl]methyl]benzoate;

[0337] 2-(5-bromo-2-thienyl)-6-[(4-methoxyphenyl)methyl]-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-4-one;

[0338] 2-methoxy ethyl 4-[[2-(5-bromo-2-thienyl)-4-oxo-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-6-yl]methyl]benzoate;

[0339] 2-(5-bromo-2-thienyl)-6-(trifluoromethoxy)-2,3-dihydro-lH-quinazolin-4-one;

[0340] 2-(5-bromo-2-thienyl)-6-methoxy-2,3-dihydro-lH-quinazolin-4-oneethyl-benzamide;

[0341] 2-(5-bromo-2-thienyl)-6-[(2,5-dichlorophenyl)methyl]-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-4-one;

[0342] 6-ethoxy-2-(5-ethyl-2-thienyl)-2,3-dihydro-lH-quinazolin-4-one;

[0343] 2-(5-ethyl-2-thi enyl)-6-(trifluoromethoxy)-2, 3 -dihydro- lH-quinazolin-4-one;

[0344] 2-(5-bromo-2-thienyl)-6-[(2-chlorophenyl)methyl]-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-4-one;

[0345] 2-(5-bromo-2-thienyl)-6-[(3-chlorophenyl)methyl]-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-4-one;

[0346] 2-(5-ethyl-2-thienyl)-6-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-lH- thieno[2,3-d]pyrimidin-4-one;

[0347] 2-(5-ethyl-2-thienyl)-6-methoxy-2,3-dihydro-lH-quinazolin-4-one.

[0348] A particularly suitable compound of formula I or II shows an IC50of 1.0 μM or below in cell-based proliferation test such as the cell-based proliferation test which is described in detail in section “biological effects” hereinbelow, and is a compound selected from the group consisting of:

[0349] (5)-6-Ethoxy-2-(5-ethyl-2-thienyl)-2,3-dihydro-4(177)-quinazolinone;

[0350] (A)-6-Ethoxy-2-(5-ethyl-2-thienyl)-2,3-dihydro-4(177)-quinazolinone;

[0351] (A)-6-Methoxy-2-(5-bromo-2-thienyl)-2,3-dihydro-4(177)-quinazolinone;

[0352] (A)-6-Methoxy-2-(5-Ethyl-2-thienyl)-2,3-dihydro-4(177)-quinazolinone;

[0353] (?)-6-Chloro-2-phenyl-2,3-dihydro-4(lJ7)-quinazolinone;

[0354] (A)-2-(5-bromothiophen-2-yl)-7-fluoro-2,3-dihydroquinazolin-4(lH)-one;

[0355] (?)-2-(5-bromothiophen-2-yl)-6-(2,4-dichlorobenzyl)-2,3-dihydrothieno[2,3- d]pyrimidin-4(1H)-one;

[0356] (A)-2-(5-bromothiophen-2-yl)-6-(trifluoromethoxy)-2,3-dihydroquinazolin-4(177)-one; (?)-2-(5-bromothiophen-2-yl)-6-(2-chlorobenzyl)-2,3-dihydrothieno[2,3-d]pyrimidin- 4(lJ7)-one;

[0357] (?)-(5-bromothiophen-2-yl)-7-methoxy-2,3-dihydroquinazolin-4(lJ7)-one;

[0358] (?)-(5-bromothiophen-2-yl)-7-chloro-2,3-dihydroquinazolin-4(lJ7)-one;

[0359] (A)-7-fluoro-2-(5-isobutylthiophen-2-yl)-2,3-dihydroquinazolin-4(lH)-one.

[0360] Said ’-enantiomers of these embodiments are particularly preferred.

[0361] A suitable compound of formula I or II shows an IC50of 0.75 μM or below in cell-based proliferation test such as the cell-based proliferation test which is described in detail in section “biological effects” hereinbelow, and is a compound or a pharmaceutically acceptable salt form,solvate or polymorph thereof, including all tautomers and stereoisomers thereof, selected from the group consisting of:

[0362] 2-(5-ethyl-2-thienyl)-6-[(4-methoxyphenyl)methyl]-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-4-one;

[0363] 2-(5-ethylthiophen-2-yl)-6,7-difluoro-2,3-dihydroquinazolin-4(lH)-one;

[0364] 6-chloro-2-(5-ethylthiophen-2-yl)-7-fluoro-2,3-dihydroquinazolin-4(lH)-one;

[0365] 2-(5-ethyl-2-thienyl)-7-fluoro-2,3-dihydro-lH-quinazolin-4-one;

[0366] 2-(5-bromo-2-thienyl)-6-[(2-chlorophenyl)methyl]-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-4-one;

[0367] methyl 3-[[2-(5-bromo-2-thienyl)-4-oxo-2,3-dihydro-lH-thieno[2,3-d]pyrimidin-6- yl]methyl]benzoate;

[0368] 2-(5-bromo-2-thienyl)-6-[(4-methoxyphenyl)methyl]-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-4-one;

[0369] 2-(5-bromo-2-thienyl)-6-[(2,5-dichlorophenyl)methyl]-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-4-one;

[0370] 6-ethoxy-2-(5-ethyl-2-thienyl)-2,3-dihydro-lH-quinazolin-4-one;

[0371] 2-(5-ethyl-2-thi enyl)-6-(trifluoromethoxy)-2, 3 -dihydro- lH-quinazolin-4-one;

[0372] 2-(5-bromo-2-thienyl)-6-[(2-chlorophenyl)methyl]-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-4-one;

[0373] 2-(5-bromo-2-thienyl)-6-[(3-chlorophenyl)methyl]-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-4-one;

[0374] 2-(5-ethyl-2-thienyl)-6-[[4-(trifluoromethoxy)phenyl]methyl]-2,3-dihydro-lH- thieno[2,3-d]pyrimidin-4-one;

[0375] 2-(5-ethyl-2-thienyl)-6-methoxy-2,3-dihydro-lH-quinazolin-4-one.

[0376] A particularly suitable compound of formula I or II shows an IC50of 0.75 jiM or below in a cell-based proliferation test such as the cell-based proliferation test which is described in detail in section “biological effects” hereinbelow, and is a compound selected from the group consisting of:

[0377] (5)-6-Ethoxy-2-(5-ethyl-2-thienyl)-2,3-dihydro-4(177)-quinazolinone;

[0378] (7?)-6-Ethoxy-2-(5-ethyl-2-thienyl)-2,3-dihydro-4(177)-quinazolinone;

[0379] (7?)-6-Methoxy-2-(5-bromo-2-thienyl)-2,3-dihydro-4(177)-quinazolinone;

[0380] (7?)-6-Methoxy-2-(5-Ethyl-2-thienyl)-2,3-dihydro-4(177)-quinazolinone;

[0381] (7?)-2-(5-bromothiophen-2-yl)-7-fluoro-2,3-dihydroquinazolin-4(lH)-one;(7?)-2-(5-bromothiophen-2-yl)-6-(2,4-dichlorobenzyl)-2,3-dihydrothieno[2,3- d]pyrimidin-4(1H)-one;

[0382] (7?)-2-(5-bromothiophen-2-yl)-6-(trifluoromethoxy)-2,3-dihydroquinazolin-4(lJ7)-one; (7?)-(5-bromothiophen-2-yl)-7-chloro-2,3-dihydroquinazolin-4(lJ7)-one;

[0383] (7?)-7-fluoro-2-(5-isobutylthiophen-2-yl)-2,3-dihydroquinazolin-4(lH)-one.

[0384] Said / / -enantiomers of these embodiments are particularly preferred.

[0385] In a preferred embodiment, the compound of formula I is not a compound selected from the group consisting of:

[0386] Compound Vendor IUPAC name Name / Reference / CAS- number

[0387] a) Z355468370 8-methyl-2-(5-methyl-2- thi enyl)-2, 3 -dihydro- 1H- s. quinazolin-4-one I H i 4

[0388] if -Y

[0389] b) / Z369512236 7-chloro-2-(5-methyl-2- H? V furyl)-2, 3 -dihydro- 1H- quinazolin-4-one o

[0390] c) Z103377146 2-(5-bromo-2-thienyl)-3- Br methyl-1,2- H fA dihydroquinazolin-4-one

[0391] o

[0392] d) 2- [2-(2-furyl)thi azol -5- yl]-8-methyl-2,3- dihydro- 1 / 7-quinazolin- Z1898894100

[0393] 4-one

[0394] O

[0395] e) 304456-62-0 2-[[(5-bromo-2- thienyl)methylene]amino

[0396]

[0397] ] -benzamidef) 1262217-87-7 2-(5-Bromo-2-thienyl)- o 2,3 -dihy dro-4( 177)- quinazolinone ' ^NH

[0398] \ >z\

[0399] NH >rf \D

[0400] U - B1"

[0401] g) CN 119219 562 A, 2-(4-bromo-2-thienyl)- Compound 1n 2,3-dihydro-1H-

[0402] quinazolin-4-oneN H

[0403] HJL# / o

[0404] Br

[0405] h) / / CN 119219 562 A, 2-(3-bromothiophen-2- Compound 1u yl)-7-methyl-2,3- dihydroquinazolin- o c

[0406] frA^NH 4(lH)-one H3C'J^NAT\

[0407] HJL /

[0408] Br ' '

[0409] i) CN 101 190 899 A, 6-nitro-2-phenyl-2, 3 - dihydroquinazolin- Compound 1

[0410] 4(lH)-one 0

[0411] OjN^

[0412] H

[0413]

[0414] NO2Alaimo Robert et al 6-chloro-2-(5- " Anthelmintic 2-(5-nitro-2- nitrothi ophen-2 -yl)-2, 3- thienyl)-4- dihydroquinazolin- Ul [f 4(U7)-one (substituted

[0415] amino)quinazolines", JOURN

[0416] j)

[0417] AL OF MEDICINAL CHEMISTRY, vol. 15, no. 1,

[0418] 1 January 1972 (1972-01-01),

[0419] pages 108-109,

[0420] nitro analogue compound 3b

[0421] k) US 2015 / 166517 Al 2-(5-ethyl-2-thienyl)- 2, 3 -dihydro- 1H- H ft A. /

[0422] quinazolin-4-one

[0423] I) Lingayya Rajaka et al.

[0424] “Convenient and Scalable

[0425] Synthesis of 2,3- NR' Dihydroquinazolin-4(1 H )- one Derivatives and Their

[0426] Anticancer Activities”,

[0427] SYNTHETIC COMMUNICATIONS, vol.

[0428] wherein 45, no. 16, 8 June 2015 (2015- 1. X is Cl, Ri is H, R2 is phenyl; 06-08), pages 1893-1901

[0429] Compounds 3 m, 3p, 3q and 3r

[0430] 2. X is Cl, Ri is H, R2is 4- methoxyphenyl;

[0431] 3. X is Cl, Ri is H, R2is 3,4- dimethoxyphenyl;

[0432] 4. X is Cl, Ri is H, R2is 3,4,5- trimethoxyphenyl

[0433]

[0434] In one embodiment, only the racemates of the above compounds a) to 1) are excluded from the scope of formula I, but the S-stereoisomers and the R-stereoisomers of the above compounds a) to l) are not excluded from the scope of formula I.In one embodiment, the racemates and the S- stereoisomers of the above compounds a) to 1) are excluded from the scope of formula I, but the 7?-stereoisomers of the above compounds a) to 1) are not excluded from the scope of formula I.

[0435] In one embodiment, the racemates, the A'-stereoi somers and the ’-stereoi somers of the above compounds a) to 1) are excluded from the scope of formula I.

[0436] The compounds Z355468370, Z369512236, Z103377146, Z1898894100 are obtainable from ENAMINE GERMANY GmbH, Frankfurt am Main and are disclosed in the Enamine Catalogue as screening compounds without indication of a function or pharmaceutical use. Pharmaceutical uses

[0437] The compounds of formula I as described herein bind to an IGF2 (insulin-like growth factor 2) mRNA-binding protein and thereby inhibit the proliferative activity of said IGF2 mRNA-binding protein.

[0438] Accordingly, the invention further provides the compounds of formula I as described herein for use as a medicament.

[0439] The compounds of formula I as described herein may also be comprised in a pharmaceutical composition. In further embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula I as described herein, optionally in combination with further excipients and diluents.

[0440] As shown in the working examples below, the compounds of the present invention are useful for the treatment of cancer, tumor metastasis or tumor recurrence in a subject. Accordingly, in a preferred embodiment, the invention provides the compounds of formula I or the pharmaceutical composition comprising said compound of formula I for use in the prevention or treatment of cancer, tumor metastasis or tumor recurrence in a subject. Surprisingly, the R-enantiomer of the compounds of the present invention are particularly useful. Following synthesis and biological testing, it was surprisingly and unexpectedly found that the R-stereoisomers were the biologically active compounds whereas the S-stereoisomers were inactive or only weakly active compounds. It was thus demonstrated herein that the biological effect of the compounds of formula I is stereospecific and structure-specific.

[0441] In a further embodiment, the invention provides a method of treating a proliferative disease, such as cancer, tumor metastasis or tumor recurrence in a subject in need thereof, comprising administering to said subject in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutical composition comprising said compound of formula I.

[0442] Said proliferative disease is preferably selected from malignant tumors of epithelial, or neuroectodermal origin.

[0443] In a more preferred embodiment, said proliferative disease is cancer and is selected from the group consisting of malignant tumors of epithelial or neuroectodermal cells, pancreatic cancer, melanoma, neuroblastoma, ovarian carcinoma, hepatocellular carcinoma, colorectal carcinoma, thyroid carcinoma and lung adenocarcinoma as well as any malignant disorder of unknown origin that exhibits expression of IGF2BP1 in a manner amenable to the therapeutic intervention.Pharmaceutical compositions:

[0444] To prepare the pharmaceutical compositions of this invention, at least one compound of formula (I) optionally in combination with at least one of the other aforementioned agents can be used as the active ingredient(s). The active ingredient(s) is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules, gelcaps and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, though other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included.

[0445] Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient(s) necessary to deliver an effective dose as described above. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, from about 0.5-2 mg / kg of body weight (bw) and may be given at a dosage of about 100 mg / kg bw per day (preferred mg / kg per day) of each active ingredient or combination thereof. The dosages, however, may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.

[0446] Preferably these compositions are in unit dosage forms from such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pillsand capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.5 to about 100 mg / kg bw of each active ingredient or combinations thereof of the present invention.

[0447] The tablets or pills of the compositions of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of material can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

[0448] This liquid forms in which the compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

[0449] The pharmaceutical composition may contain between about 0.5 mg / kg bw and 500 mg / kg bw, preferably about 0.1mg / kg bw to 100 mg / kg bw, of each compound, and may be constituted into any form suitable for the mode of administration selected. Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixirs, emulsions, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.

[0450] Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

[0451] For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders; lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or betalactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.The liquid forms in suitable flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl -cellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.

[0452] The compounds or combinations of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

[0453] Compounds or combinations of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamid-ephenol, or polyethyl eneoxidepolyllysine substituted with palmitoyl residue. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polyactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.

[0454] Compounds or combinations of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of the addressed disorders is required.

[0455] The daily dosage of the products may be varied over a wide range from 0.5 to 7 g per mammal per day. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.15 g / kg bw to about 2g / kg of bw per day. Preferably, the range is from about 0.1g / kg bw to about 0.5g / kg bw per day. The compounds or combinations may be administered on a regimen of 1 to 4 times per day.

[0456] Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.

[0457] In a further aspect, the invention also provides a process for preparing a pharmaceutical composition comprising at least one compound of formula I, optionally in combination with at least one of the other aforementioned agents and a pharmaceutically acceptable carrier.

[0458] The compositions are preferably in a unit dosage form in an amount appropriate for the relevant daily dosage.

[0459] Suitable dosages, including especially unit dosages, of the compounds of the present invention include the known dosages including unit doses for these compounds as described or referred to in reference text such as the British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, ThePharmaceutical Press) (for example see the 31st Edition page 341 and pages cited therein) or the above mentioned publications.

[0460] Examples of the invention

[0461] 1

[0462] Examples of compounds of formula I

[0463] Example MW

[0464] No. Compound IUPAC name

[0465] ° \ ( z — [g / mole]

[0466] \ I _

[0467] 1 2-(5-ethyl-2- thienyl)-6-[(4- methoxyphenyl)met

[0468] 383.8 hyl]-2,3-dihydro- lH-thieno[2,3- d]pyrimidin-4-one

[0469] 2 r 2-(5-bromo-2- thienyl)-6-[(2- S jry^Br chlorophenyl)methy

[0470] a \_ z ¥ T 1] -2,3 -dihydro- 1 H- V-k riH

[0471] thieno[2,3- d]pyrimidin-4-one

[0472] 2a / 17 1 \ (7?)-2-(5-bromo-2- o""

[0473] 1 thienyl)-6-[(2- \ _ -j- 1 chlorophenyl)methy

[0474] 437.6

[0475] 1] -2,3 -dihydro- 1 H- li X—Br thieno[2,3- d]pyrimidin-4-one

[0476] 2b / (5)-2-(5-bromo-2- thienyl)-6-[(2- chlorophenyl)methy

[0477] 1] -2,3 -dihydro- 1 H- J VI V_ Br thieno[2,3- d]pyrimidin-4-one

[0478] 3

[0479] 2-(5-bromo-2- thienyl)-6-[(4- methoxyphenyl)met

[0480] 433.7 hyl]-2,3-dihydro- lH-thieno[2,3- d]pyrimidin-4-one

[0481]

[0482] methyl 3-[[2-(5- o. / =x J' bromo-2-thienyl)-4- oxo-2,3-dihydro- 461.7 \ ' — £ V-K H ^N ■H lH-thieno[2,3- d]pyrimidin-6- 0 yl]methyl]benzoate

[0483] 2-(5-ethyl-2-hfX

[0484] X thienyl)-7-fluoro- 275.8 L ^NH2,3 -dihydro- 1H- quinazolin-4-one

[0485] o

[0486] Br 2-(5-bromo-2- H thienyl)-6- (trifluoromethoxy)- N H 2,3 -dihydro- 1H- 0CF3X^ / ^Y'

[0487] o quinazolin-4-one

[0488] a (7?)-2-(5-bromo-2- 392.0 thienyl)-6- (trifluoromethoxy)- Il.« 2,3 -dihydro- 1H- U_ quinazolin-4-one

[0489] b (5)-2-(5-bromo-2-. CL i thienyl)-6- (trifluoromethoxy)- 2,3 -dihydro- 1H- quinazolin-4-one

[0490] Br 2-(5-bromo-2- H thienyl)-6-methoxy-r^Z\xNxXw>2,3 -dihydro- 1H- ^n VXJX JTN Hquinazolin-4-one

[0491] o 337.8 a

[0492] (7?)-2-(5-bromo-2- thienyl)-6-methoxy- 2,3 -dihydro- 1H- II / v—

[0493] IU / quinazolin-4-one

[0494]

[0495] b

[0496] i! (0-2-(5-bromo-2- thienyl)-6-methoxy- 2,3 -dihydro- 1H- II '

[0497] 1 quinazolin-4-one o

[0498] X a 2-(5-bromo-2- thienyl)-6-[(2,4- / A

[0499] A^. X / r° - H J V-Br dichlorophenyl)met

[0500] CiHo hyl]-2,3-dihydro- lH-thieno[2,3- < O ZI= d]pyrimidin-4-one

[0501] a f z —

[0502] (7?)-2-(5-bromo-2-1L O thienyl)-6-[(2,4- dichlorophenyl)met hyl]-2,3-dihydro- 472.7 lH-thieno[2,3- L

[0503] , Z /

[0504] J » d]pyrimidin-4-one

[0505] X

[0506] b

[0507] a-s’ (5)-2-(5-bromo-2- / \ 0 >?*.•• thienyl)-6-[(2,4- dichlorophenyl)met

[0508] \ 0 _ l. I <! -“0T ‘NH

[0509] —\ 1 (S14 hyl]-2,3-dihydro- S X x

[0510] ^Br lH-thieno[2,3- O" 0 / d]pyrimidin-4-one

[0511] 0

[0512] 2-methoxyethyl 4- [[2-(5-bromo-2- thienyl)-4-oxo-2,3- dihydro-lH- 505.5 thieno[2,3- d]pyrimidin-6- yl]methyl]benzoate

[0513] 0

[0514] rQsH jAxBr 2-(5-bromo-2- thienyl)-6-[(3- ^H VYA I iJHsmethoxyphenyl)met 433.8 0 hyl]-2,3-dihydro- lH-thieno[2,3- d]pyrimidin-4-one

[0515] 1 2-(5-bromo-2- YY A T AZ® thienyl)-7-methyl- k A YH321.7

[0516] 2,3 -dihydro- 1H- quinazolin-4-one

[0517]

[0518] Ila a

[0519] (7?)-2-(5-bromo-2- [1 1 thienyl)-7-methyl- b 2,3- i"

[0520] 11b

[0521] (5)-2-(5-bromo-2- thienyl)-7-methyl- J1 l\. 2,3- L*__ / /

[0522] 12

[0523] H / T^— Br 2-(5-bromo-2- Cl / v A

[0524] thienyl)-7-chloro- L JL HI-I 2,3 -dihydro- 1H- quinazolin-4-one

[0525] 12a

[0526] m (7?)-2-(5-bromo-2- ii i ■ r thienyl)-7-chloro- 2,3 -dihydro- 1H- 341.6 “ 2 z — \ H z ■ - ■3rquinazolin-4-one

[0527] \ / O x=

[0528] 12b

[0529] (5)-2-(5-bromo-2- thienyl)-7-chloro- jC<r ° i ' i " r, 2,3 -dihydro- 1H- quinazolin-4-one

[0530] H

[0531] 13 4-[[2-(5-bromo-2- thienyl)-4-oxo-2,3- dihydro-lH- thieno[2,3- 484.9 d]pyrimidin-6- yl]methyl]-N-prop- 2-y ny 1 -b enzami de

[0532] 14 -°\ Cl 2-(5-chloro-2-HtA thienyl)-6-[(4- methoxyphenyl)met VJL / NH 389.8 hyl]-2,3-dihydro- 0 lH-thieno[2,3- d]pyrimidin-4-one

[0533]

[0534] 4-[[2-(5-bromo-2- thienyl)-4-oxo-2,3- ^NH dihydro-lH-O=^ Br thieno[2,3- 474.7 d]pyrimidin-6- S^NyW

[0535] yl]methyl]-N-ethyl- benzamide

[0536] O

[0537] H r*" ii 6-chloro-2-phenyl- 2,3 -dihydro- 1H- J JL NH quinazolin-4-one

[0538] CK

[0539] O

[0540] a

[0541] (7?)-6-chloro-2-1J 258.2 1 phenyl-2, 3 -dihy dro- 17 / -quinazolin-4- one

[0542] b w

[0543] c - 11 (S)-6-chloro-2- 1 4 T d i" phenyl-2, 3 -dihy dro- 17 / -quinazolin-4- ' il J one

[0544] Br

[0545] H2-(5-bromo-2- thienyl)-7-methoxy- k^JL / NF! 337.9

[0546] 2,3 -dihydro- \H- quinazolin-4-one

[0547] O

[0548] H ft rr^x _ / N32-[5-(azidomethyl)-s2-thienyl]-2,3- nr^ 284.9 dihydro-lH- 0 quinazolin-4-one

[0549]

[0550] Br

[0551] H 2-(5-bromo-2- thienyl)-7-nitro-2,3- 353.7 dihydro-lH- 0 quinazolin-4-one

[0552] Cl / O ZI=

[0553] Z ( — 2-(5-bromo-2- \ I thienyl)-6-[(4- \ / fj — Br

[0554] chlorophenyl)methy

[0555] s437.7

[0556] 1] -2,3 -dihydro- 1 H- 0 do thieno[2,3- d]pyrimidin-4-one

[0557] 2-(5-bromo-2- thienyl)-6-methyl- 2,3 -dihydro- 1H- 327.6 thieno[2,3- d]pyrimidin-4-one

[0558] \

[0559] o methyl 4-[[2-(5-O=^ Br bromo-2-thienyl)-4- oxo-2,3-dihydro- S^N^ J^Z 461.8 lH-thieno[2,3- ' VJL. NH d]pyrimidin-6- o yl]methyl]benzoate

[0560] H2-(5-ethyl-2- °2NXI<J#X^N'S>^ / thienyl)-7-nitro-2,3- 302.9 ksJL z'NH dihydro-lH- quinazolin-4-one

[0561] 0

[0562] 6-benzyl-2-(5- bromo-2-thienyl)- \_ / oH [T\ - Br 2,3 -dihydro- 1H- 404.4X

[0563] V-^X / NH thieno[2,3- o d]pyrimidin-4-one

[0564]

[0565] Boc^ tert-butyl 4-[4-[[2- (5-bromo-2- o > - N thienyl)-4-oxo-2,3- \ _ Br

[0566] dihydro-lH- thieno[2,3- 587.7 d]pyrimidin-6- yl]methyl]

[0567] o o

[0568] phenyl]piperazine- 1 -carboxylate

[0569] / O= ZI

[0570] ( / z O ZI—=

[0571] \ I

[0572] \ cn 2-(5-chloro-2- thienyl)-6-methyl- o 2,3 -dihydro- 1H- 284.3 thieno[2,3- d]pyrimidin-4-one

[0573] Cl 2-(5-bromo-2- thienyl)-6-[(2,5- O dichlorophenyl)met 471.5oPhyl]-2,3-dihydro- nlX

[0574] lH-thieno[2,3- o d]pyrimidin-4-one

[0575] 6-ethoxy-2-(5-ethyl- 2-thienyl)-2,3- dihydro-lH- quinazolin-4-one

[0576] a o (7?)-6-ethoxy-2-(5- '■v <CI ethyl-2-thienyl)-2,3-vfl fN“ dihydro-lH- cl • \ quinazolin-4-one 301.9 b

[0577] (5)-6-ethoxy-2-(5-Xethyl-2-thienyl)-2,3- ' ' 1 ’ 1 “ L dihydro-lH- quinazolin-4-one

[0578] " L / * \

[0579]

[0580] 2-(5-ethyl-2- H

[0581] thienyl)-6- (trifluoromethoxy)- 341.9F3 JC^ 'crJL^X- J'^LY ^'NH

[0582] 2,3 -dihydro- 1H- 0 quinazolin-4-one

[0583] O

[0584] 2-(5-bromo-2-QN thienyl)-6-[(3- JJ^Br

[0585] chlorophenyl)methy M T is1] -2,3 -dihydro- 1 H-1x < thieno[2,3- d]pyrimidin-4-one

[0586] T

[0587] a A (7?)-2-(5-bromo-2- u

[0588] I thienyl)-6-[(3- 437.7 chlorophenyl)methy

[0589] OX.zzzz - 1] -2,3 -dihydro- 1 H- thieno[2,3- d]pyrimidin-4-one

[0590] F..•- b Ci

[0591] / (5)-2-(5-bromo-2- J X thienyl)-6-[(3- w chlorophenyl)methy

[0592] s\_ "" ’ 1] -2,3 -dihydro- 1 H- _-'-. ■■X-C thieno[2,3- ■ L / d]pyrimidin-4-one

[0593] F3C-O

[0594] 2-(5-ethyl-2- thienyl)-6-[[4- U FV (trifluoromethoxy)p

[0595] shenyl]methyl]-2,3- 437.9 dihydro-lH- 0 thieno[2,3- d]pyrimidin-4-one

[0596] 2-(5-ethyl-2- thienyl)-6-methoxy- 2,3 -dihydro- 1H- 287.8 quinazolin-4-one

[0597]

[0598] a (7?)-2-(5-ethyl-2- o I thienyl)-6-methoxy- II I, 2,3 -dihydro- 1H-HJ, h \ quinazolin-4-one

[0599] b (5)-2-(5-ethyl-2- ^0^,< S.

[0600] ' TzM ' thienyl)-6-methoxy- 2,3 -dihydro- 1H- L •*’>x x_ c

[0601] hquinazolin-4-one

[0602] li

[0603] L / \

[0604] r-i 2-(5-bromo-2- i i "" thienyl)-7-fluoro- F tl 1-. 2,3 -dihydro- 1H- I. ‘S quinazolin-4-one

[0605] \

[0606] o

[0607] a (7?)-2-(5-bromo-2-. Il thienyl)-7-fluoro- o

[0608] 2,3 -dihydro- 1H- 325.8 quinazolin-4-one

[0609] r.1h- - •’

[0610] H

[0611] b 2 z — (5)-2-(5-bromo-2- xzzthienyl)-7-fluoro-. J- 2,3 -dihydro- 1H- \7

[0612] quinazolin-4-one

[0613] ■ Il - •

[0614] / — N S 2-[5-[(4- propyltriazol-1- yl)methyl]-2- 352.8 0 thienyl]-2,3- dihydro-lH- quinazolin-4-one

[0615] tert-butyl N-[6-[[2- (5-bromo-2- thienyl)-4-oxo-2,3- dihydro-lH- 398.7 quinazolin-6- yl] amino]- 6-oxo- hexyl]carbamate

[0616]

[0617] H ft _Rr

[0618] JLBr2-(5-bromo-2- rS

[0619] ML / NH thienyl)-8-methyl- 321.7 2,3 -dihydro- 1H- 0 quinazolin-4-one

[0620] H fA

[0621] 2-(l -methylpyrrol - UQH \ 2-yl)-2,3-dihydro- 327.0 lH-quinazolin-4- o

[0622] one

[0623] 2-(5-bromo-2- Br thienyl)-6- (morpholine-4-hiS 420.8 carbonyl)-2,3- dihydro-lH- OyCV

[0624] 0 0 quinazolin-4-one

[0625] Br tert-butyl N-[6-[[2- H H (5-bromo-2- thienyl)-4-oxo-2,3-BOC^N^ZXANX\NH dihydro-lH- 557.8

[0626] hs quinazolin-6- yl] amino]- 6-oxo- hexyl]carbamate

[0627] 4-[[2-(5-bromo-2- thienyl)-4-oxo-2,3- dihydro-lH- H / ?

[0628] hP\ / { Br thieno[2,3- J'i--v ' / d]pyrimidin-6- W=\sH Is" J^

[0629] yl]methyl]- N-[[l- 629.6 VUH [2-(2- methoxyethoxy)ethy l]triazol-4- yl]methyl]benzamid e

[0630]

[0631] 2-[5-[l-[2-(2- —0 methoxyethoxy)ethy l]triazol-4-yl]-2- V Y "sN=N thienyl]-6-[(4- " AJUH 525.0 methoxyphenyl)met

[0632] 0 hyl]- 2,3-dihydro- O J lH-thieno[2,3- d]pyrimidin-4-one

[0633] 5-[6-[(4- / o zx=

[0634] ( z — methoxyphenyl)met

[0635] - \ X o /

[0636] \ \ 7 — N H hyl]-4-oxo-2,3- \ w

[0637] \\ / ) H T X> dihydro-lH- \ / s~'^Nthieno[2,3- 436.9

[0638] "r '^ o

[0639] XVL ^NH d]pyrimidin-2-yl]- o N-prop-2-ynyl- thiophene-2- carb oxami de

[0640] N-[[l-[2-(2- methoxyethoxy)ethy l]triazol-4- _o <y^°' _

[0641] Z=\H / - * yl]methyl]-5-[6-[(4- V?. H jTY- / ~^

[0642] ' — < T i ^s° methoxyphenyl)met hyl]-4-oxo-2,3- 603.9 dihydro-lH- thieno[2,3- d]pyrimidin-2- yl]thiophene-2- carb oxami de

[0643] 2-(5-bromo-2- k jO^Br thienyl)-2,3- / ^TX|X^Sdihydro-lH- 313.6 \ OJL ^s>r,^NH

[0644] thieno[3,2- 0 d]pyrimidin-4-one

[0645] 6-benzyl-2-(5- chloro-2-thienyl)- 2,3 -dihydro- 1H- 359.8 thieno[2,3- d]pyrimidin-4-one

[0646]

[0647] □I 2-(5- bromothiophen-2- yl)-6-(5-chloro-2- ri'1' methoxybenzyl)- <^r -11' 2,3- 470.0 dihydrothieno[2,3- O ” d]pyrimidin-4(lH)- * X

[0648] Cl one

[0649] 6-(4- methoxybenzyl)-2- (5-(2- methoxyethyl)thiop hen-2 -yl) -2,3 - 414.3 t dihydrothieno[2,3- \ x#

[0650] / / I d]pyrimidin-4(lH)- one

[0651] yO^~

[0652] /

[0653] y.y CO

[0654] 2-(5-ethylthiophen- q-^4 2-yl)-6, 7 -difluoro- H r

[0655] 1 N '-, / 2,3- 293.8 I tI 1 l K MU1dihydroquinazolin- “ I; 4(lH)-one

[0656] 2-(5- Br

[0657] bromothiophen-2-cn • "‘>

[0658] F -jyl)-6,7-difluoro-2,3 - l:1 N- dihydroquinazolin-F:i

[0659] □ 4(lH)-one

[0660] 345.2 a (7?)-2-(5- bromothiophen-2- yl)-6,7-difluoro-2,3 - 4! M! ™

[0661] r" _ fi _ - ■« dihydroquinazolin- x_

[0662] 4(lH)-one

[0663]

[0664] b (5)-2-(5- bromothiophen-2- yl)-6,7-difluoro-2,3 - li. - ■> dihydroquinazolin- I-1-.'

[0665] Q 4(lH)-one

[0666] ^= /

[0667] % / 6-(4- ( Q ZI=

[0668] / methoxybenzyl)-2- - assZ

[0669] (5-propylthiophen- I I ff \

[0670] c N t

[0671] | 2-yl)-2,3- 398.3 ' Ml dihydrothieno[2,3-: « d]pyrimidin-4(lH)- one

[0672] 6-chloro-2-(5- ethylthiophen-2-yl)- 7-fluoro-2,3- 310.5 dihydroquinazolin- 4(lH)-one

[0673] 2-(5-ethylthiophen- H H 2-yl)-6-(4- s. N. >■>. /

[0674] fluorobenzyl)-2,3- / — >.- ’l■l1,..XN1372.3 / »»»»»»»> X H

[0675] z: x dihydrothieno[2,3- z—d]pyrimidin-4(lH)- F

[0676] one

[0677] 7-fluoro-2-(5- / J \

[0678] z \ isobutylthiophen-2- yl)-2,3- Fx^i. 304.3 dihydroquinazolin- \H

[0679] ¥ 4(lH)-one

[0680] 0

[0681]

[0682] 53a (A)-7-fluoro-2-(5- 0

[0683] isobutylthiophen-2- / NUNM

[0684] yl)-2,3- JL Jl (RJ. Q

[0685] dihydroquinazolin-HL / V- 4(lH)-one

[0686] 53b (5)-7-fluoro-2-(5- 0

[0687] isobutylthiophen-2- fi ^NHyl)-2,3- J! JLs

[0688] dihydroquinazolin-HtZV

[0689] 4(lH)-one

[0690] *Ref. 0 (A)-2-(5-Bromo-2- 2B thienyl)-2,3- 309.1 cOu dihydro-4(1H)- H fBr

[0691] quinazolinone

[0692]

[0693] *Reference

[0694] Synthesis of compounds of the Invention:

[0695] General synthesis description:

[0696] All materials and reagents were purchased from Sigma-Aldrich Co. Ltd., abcr GmbH and BLD GmbH. All solvents were analytically pure. Thin layer chromatography was carried out on aluminum sheets coated with silica gel 60 F254 (Merck, Darmstadt, Germany).

[0697] Analytical methods

[0698] Medium pressure liquid chromatography (MPLC) was performed in normal phase with an Isolera Flash chromatography System (Biotage INC) and SNAP Ultra columns (Biotage INC, particle size 25 pm) of different sizes (10, 25 and 50 g).

[0699] The purity of the final compounds was determined using HPLC based on UV absorbance at 254 nm. The HPLC consisted of a LiChrosorb® RP-18 (5 pm) 100-4.6 Merck column (Merck, Darmstadt, Germany), two LC10AD pumps, a SPD-M10A VP PDA detector, and a SIL-HT autosampler, all from the manufacturer Shimadzu (Kyoto, Japan). The absorption spectra were recorded with a SPDM10A diode array detector Shimadzu spectrophotometer (Kyoto, Japan). Mass spectrometry analyses were performed with a Finnigan MAT710C (Thermo Separation Products, San Jose, CA, USA) for the ESIMS spectra.

[0700] 1H NMR spectra were taken on a Varian Inova 400 using deuterated dimethyl sulfoxid (DMSO) as solvents. Chemical shifts are referenced to the residual solvent signals.Semi-preparative separation of racemic compounds was achieved with a chiral column Nucleocel delta RP S, 5 pm, 250 / 8 (Macher ey -Nagel, Germany) with acetonitrile / water (50:50, v / v) as mobile phase and a flow rate of 1.5 ml / min. Analytical determination of the enantiomeric purity of the fractions and final enantiomers was measured with a chiral column Nucleocel delta RP S, 5 pm, 250 / 4.6 (Macherey-Nagel, Germany) with acetonitrile / water (50:50, v / v) as mobile phase and a flow rate of 0.5 ml / min. The HPLC system consists of two LC-10AD pumps, and a SIL-HT autosampler, all from the manufacturer Shimadzu (Kyoto, Japan). The absorption spectra were recorded with a Shimadzu SPD-M10A diode array detector spectrophotometer (Kyoto, Japan) by UV absorbance at 254 nm.

[0701] Circular dichroism spectroscopy (CD) was performed on a Jasco J1599 CD spectrometer (Jasco, Easton, USA) using Spectra Manager 2 software (version 2.15.04) in the measure range 450 - 195 nm.

[0702] The following abbreviations and formulas for solvents and reagents were used: N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dichloromethane (DCM), N, N-diisopropylethylamine (DIPEA), O-(7-azabenzotriazol-l-yl)-N, N, N', N'-tetramethyluroniumhexafluorphosphate (HATU) and hydrochloric acid (HC1).

[0703] Synthetic schemes

[0704]

[0705] t ^3. _ 48; R: 6,7-difluoro, Rj R: 6-C1, R1: 49; R: 6,7-difluoro, Rj R: 6-C1, 7-F, R1: 18; R: H, R1: R: 7-F, R1:

[0706] R: 6-OCF3, R1: 37; R: H, R1:

[0707] R: 6-OCH3, R1: 17; R: 7-OCH3, R1: 12; R: 7-C1, R1: R: 6-OCH3, R1: 11; R: 7-CH3, R1: R: 6-OCF3, R1: 36; R: 8-CH3, R1: R: 6-OC2H5, R1: 19; R: 7-NO2, R1: R: 7-F, R1: 23; R: 7-NO2, R1: R: 7-F, R1:

[0708]

[0709] Scheme 1. Reagents and conditions: (a) cone. HC1 (cat.), ethanol, microwave, 90 °C, 2 hours; (b) i. acetic acid (cat.), ethanol, microwave, 90 °C, 2 hours, ii. NaH, DMF, RT, two minutes.

[0710]

[0711] Scheme 2. Reagents and conditions: (a) sodium ascorbate, CuSO4.5H2O, THF / H2O, Argon, RT, overnight; (b) NH2NH2.H2O, Fe(acac)3, ethanol, microwave, 150 °C, 10 minutes; (c) 6- ((tert-butoxycarbonyl)amino)hexanoic acid, HATU, DIPEA, DMF, RT, 2 hours; (d) i. methanol, cone. H2SO4 (cat.), reflux, overnight, ii. 5-bromothiophene-2-carboxaldehyde, cone. HC1 (cat.), ethanol, microwave, 90 °C, 2 hours; (e) i. LiOH, THF / H2O, RT, ii. morpholine, HATU, DIPEA, DMF, RT, 2 hours.

[0712]

[0713] Scheme 3. Reagents and conditions: (a) benzyltriethylammonium chloride, NaHCO3, Pd(OAc)2, allyl alcohol, DMF, argon, RT, overnight; (b) sulfur, cyanoacetamide, Et3N, DMF, RT, overnight; (c) i. acetic acid (cat.), ethanol, microwave, 90 °C, 2 hours, ii. NaH, DMF, RT, two minutes.

[0714]

[0715] Scheme 4. Reagents and conditions: (a) i. acetic acid (cat.), ethanol, microwave, 90 °C, 2 hours, ii. NaH, DMF, RT, two minutes.

[0716]

[0717] Scheme 5. Reagents and conditions: (a) benzyltriethylammonium chloride, NaHCO3, Pd(OAc)2, allyl alcohol, DMF, argon, RT, overnight; (b) sulfur, cyanoacetamide, Et3N, DMF, RT, overnight; (c) LiOH, THF / H2O, RT; (d) acetic acid (cat.), ethanol, microwave, 90 °C, 2 hours; (e) propargylamine, HATU, DIPEA, DMF, RT, 2 hours; (f) NaH, DMF, RT, two minutes; (g) sodium ascorbate, CuSO4.5H2O, THF / H2O, Argon, RT, overnight.

[0718]

[0719] Scheme 6. Reagents and conditions: (a) benzyltriethylammonium chloride, NaHCO3, Pd(OAc)2, allyl alcohol, DMF, argon, RT, overnight; (b) sulfur, cyanoacetamide, Et3N, DMF, RT, overnight; (c) i. 5-ethynyl-2-thiophenecarboxaldehyde, acetic acid (cat.), ethanol, microwave, 90 °C, 2 hours, ii. NaH, DMF, RT, two minutes; (d) 1 -(2-azidoethoxy)-2-methoxy ethane, sodium ascorbate, CuSO4.5H2O, THF / H2O, Argon, RT, overnight; (e) propargylamine, HATU, DIPEA, DMF, RT, 2 hours; (f) i. acetic acid (cat.), ethanol, microwave, 90 °C, 2 hours, ii. NaH, DMF, RT, two minutes

[0720]

[0721] Scheme 7. Reagents and conditions: (a) i. 1 mol% Sc(OTf)3, 2.5 % Ligand A, DCM, RT, 3h, ii. anthranilamide, benzaldehyde, RT, overnight; (b) i. 4 mol% Sc(OTf)3, 10 % Ligand A, DCM, RT, Argon, 3h, ii. anthranilamide derivate, aldehyde, argon, RT, overnight; (c) i. 4 mol% Sc(OTf)3, 10 % Ligand B, DCM, RT, 3h, ii. anthranilamide derivate, aldehyde, RT, overnight.

[0722] General synthetic methods

[0723] Method A: Cyclization using microwave and concentrated HC1

[0724] A mixture of the appropriate amine (1 mmol), carbonyl compound (1 mmol) in ethanol was placed in a microwave vial, and one drop of concentrated HC1 was added to the mixture. The vial was then heated in a microwave reactor, Monowave 450 (Anton Paar) at 90 °C for two hours. The reaction mixture was left to crystallize and the solid obtained was filtered, washed with ethanol, and air-dried. When the product remained dissolved, the solvent was removed under reduced pressure and the residue was purified by MPLC using n-heptane / ethyl acetate gradient to obtain the final compound. Yields ranged from 50-70%.Method B: Cyclization using microwave and sodium hydride

[0725] A mixture of the appropriate amine (1 mmol), aldehyde (1 mmol) in ethanol was placed in a microwave vial, and two drops of glacial acetic acid were added to the mixture. The vial was then heated in a microwave reactor, Monowave 450 (Anton Paar) at 90 °C for two hours. The precipitated Schiff base was filtered, washed with ethanol, air-dried and used without further purification.

[0726] To the appropriate Schiff base (0.3 mmol) in DMF (2 ml) was added sodium hydride (0.45 mmol). The reaction was stirred for 2 minutes and then quenched by the addition of distilled water. The reaction mixture was extracted with ethyl acetate and THF, washed two times with 4M sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by MPLC using n -heptane / ethyl acetate gradient to obtain the final compound. Yields ranged from 30-50%.

[0727] Method C: Cyclization using potassium tert, butoxide

[0728] To a mixture of 2-aminobenzonitril (1 mmol) and the appropriate ketone (2.7 mmol) in 99% tert, butanol was added potassium tert, butoxide (2 mmol). The reaction mixture was stirred under argon atmosphere for one hour at room temperature. The completed reaction was diluted with IM potassium hydrogen sulfate solution and extracted with ethyl acetate. The organic phase was washed with 4M sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by MPLC using n-heptane / ethyl acetate gradient to obtain the final compound. Yields ranged from 30-40%. Method D: Synthesis of substituted phenylpropanal derivatives

[0729] To a mixture of the appropriate iodobenzene (5 mmol), benzyltri ethylammonium chloride (5 mmol), sodium bicarbonate (12.5 mmol) and palladium acetate (1 mol %) were added allyl alcohol (0.4356 g) and DMF (20 ml) under argon. The mixture was then stirred at 50 °C for 5 hours and then filtered through Celite. Water was added to the filtrate and the mixture was extracted with ethyl acetate two times. The combined organic layers were washed two times with 4M sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by MPLC using n-heptane / ethyl acetate gradient to obtain the final compound. Yields ranged from 60-70%.

[0730] Method E: Synthesis of substituted 2-amino-5-benzylthiophen-3-carboxamides

[0731] To a mixture of the substituted phenylpropanal derivative (2 mmol), sulfur (2 mmol), and cyanoacetamide (2 mmol) in DMF was added dropwise triethylamine (EtsN, 2 mmol). The reaction mixture was stirred at room temperature overnight, quenched with a mixture of distilled water and ice, and then extracted with ethyl acetate. The organic phase was washed with 4M sodium chloride solution, concentrated, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by MPLC using n-heptane / ethyl acetate gradient to obtain the final compound. Yields ranged from 70-80%. Method F: Azide-alkyne click cycloaddition

[0732] An equimolar mixture of azide and propagyl containing compounds (1 mmol) was dissolved in a solvent mixture composed of THF and water (2:1). To that mixture were added sodiumascorbate (0.2 mmol) and copper (II) sulfate pentahydrate (0.2 mmol). After purging the reaction mixture with argon, the flask was placed in the dark and the mixture was stirred at room temperature overnight. After the completion of the reaction, ethyl acetate and IM aqueous ammonium chloride solution were added, and the organic layer was separated, washed with 4M sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by MPLC using DCM / methanol gradient to obtain the final compound. Yields ranged from 50-60%.

[0733] Method G: Amide bond formation using HATU

[0734] To a solution of the carboxylic acid (1 mmol), amine (1 mmol) and HATU (1.5 mmol) in DMF was added DIPEA (3 mmol) and the reaction was stirred for two hours at room temperature. After the completion of the reaction, ethyl acetate and IM aqueous ammonium chloride solution were added, and the organic layer was separated, washed with 4M sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by MPLC using DCM / methanol gradient to obtain the final compound. Yields ranged from 60-70%.

[0735] Method H: Reduction using hydrazine monohydrate

[0736] A mixture of the nitro compound (2 mmol), hydrazine monohydrate (3.5 mmol) and iron(III) acetyl acetonate (3 mol %) in ethanol (3 ml) was placed in a microwave vial which was then heated in a microwave reactor, Monowave 450 (Anton Paar) at 150 °C for ten minutes. The crude reaction mixture was then filtered through Celite and the solvent was removed under reduced pressure. The residue was used without further purification.

[0737] Method I: Ester hydrolysis using LiOH

[0738] A mixture of the appropriate ester (1 mmol) and lithium hydroxide monohydrate (5 mmol) in 1: 1 mixture of THF and water (5 ml) was heated at 50-60 °C in water bath until TLC confirmed total hydrolysis of the ester (usually after 2 hours). THF was then evaporated under reduced pressure, and the remaining aqueous solution was acidified with IM HC1. The precipitated acid was collected with filtration, washed with water, dried and used without further purification.

[0739] Method J: Synthesis of isoquinolin-1(2H)-ones (15)

[0740]

[0741] To a mixture of copper (I) bromide (0.2 mmol) and cesium carbonate (4 mmol) in DMSO was added 2-iodobenzamide (2 mmol) and the appropriate ketone (3 mmol). The reaction was stirred under argon for 24 hours at 80°C. The mixture was diluted with water, extracted with ethyl acetate. The organic phase was washed two times with 4M sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by MPLC using n-heptane / ethyl acetate gradient to obtain the final compound. Yields ranged from 20-30%.

[0742] Method K: Enantioselective synthesis of (M-2-(naphthalen-2-yl)-2.3-dihydroquinazolin-4(lH)-one (adapted from DOI: 10.1021 / ol300518m

[0743] Sc(OTf)3 (15 pmol, 7 mg) and inda-pybox-ligand B (CAS 185346-09-2, 37.5 μmol, 15 mg) was dissolved in 5 ml dry DCM, activated 200 mg mol sieve 4A was added and stirred 3 h at room temperature. 2-amino-benzamide (1.5 mmol, 204 mg) was dissolved in 5 ml dry DCMand added to catalyst solution. Subsequently, 2-naphthaldehyde (1.8 mmol, 281 mg) was added and the solution was stirred over night at room temperature. The resulting solution was filtered by using silica gel (60 mesh) and a fritted glass funnel with Büchener flask. The remaining solid was washed with a mixture of 150 ml n-heptane:ethylacetate (1:1). The solvents were evaporated under reduced pressure and the residue purified by gradient column chromatography (n-heptane: ethyl acetate, 100:0 to 30:70) to afford 297 mg (88.39 %) lAas a colourless solid.

[0744] Method L: Enantioselective synthesis of ( / ^-enantiomers (adapted from DOI:

[0745]

[0746] 10.1021 / ol300518m}

[0747] Sc(OTf)3 (40 μmol, 20 mg) and inda-pybox-ligand A (CAS 185346-09-2, 100 μmol, 39 mg) was dissolved in 5 ml dry DCM, activated 200 mg mol sieve 4A was added and stirred 3 h at room temperature under argon. 2-amino-benzamide derivates (1 mmol) and 5 ml dry DCM was added to catalyst solution. Subsequently, aldehyde (1.2 mmol) was added and the solution was stirred over night at room temperature under argon. The resulting solution was filtered by using silica gel (60 mesh) and a fritted glass funnel with Büchener flask. The remaining solid was washed with a mixture of 150 ml n-heptane: ethylacetate (2:8). The solvents were evaporated under reduced pressure and the residue purified by gradient column chromatography (n-heptane: ethyl acetate, 100:0 to 30:70) to afford dihydroquinazolinones as colourless or slightly yellow solids.

[0748] Method M: Enantioselective synthesis of CS')-enantiomers (adapted from DOI:

[0749]

[0750] 10.1021 / ol300518m}

[0751] Sc(OTf)3 (40 μmol, 20 mg) and inda-pybox-ligand A (CAS 357209-32-6, 100 μmol, 39 mg) was dissolved in 5 ml dry DCM, activated 200 mg mol sieve 4A was added and stirred 3 h at room temperature under argon. 2-amino-benzamide derivates (1 mmol) and 5 ml dry DCM was added to catalyst solution. Subsequenty, aldehyde (1.2 mmol) was added and the solution was stirred over night at room temperature under argon. The resulting solution was filtered by using silica gel (60 mesh) and a fritted glass funnel with Büchener flask. The remaining solid was washed with a mixture of 150 ml n-heptane: ethylacetate (2:8). The solvents were evaporated under reduced pressure and the residue purified by gradient column chromatography (n-heptane: ethyl acetate, 100:0 to 30:70) to afford dihydroquinazolinones as colourless or slightly yellow solids.

[0752] Synthesis of common intermediates

[0753] 4-(2-nitrobenzyloxy)-3 -methoxybenzaldehyde

[0754]

[0755] Potassium carbonate (3 mmol) was added to a mixture of vanillin (1 mmol) and 2-nitrobenzylbromide (1.1. mmol) in acetonitrile. The reaction mixture was refluxed until TLCshowed total consumption of the starting materials. The product was then precipitated by adding water and was then filtered, washed with water, and air-dried.

[0756] MS m / z: 288.3 [M+H]+

[0757] Yield (%) 45

[0758] ¹H NMR (400 MHz, dmso-d6) δ 9.83 (s, 1H), 8.16 – 8.11 (m, 1H), 7.83 – 7.73 (m, 2H), 7.65 – 7.59 (m, 1H), 7.52 (dd, J = 8.2, 1.9 Hz, 1H), 7.43 (d, J = 1.8 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 5.56 (s, 2H), 3.84 (s, 3H).

[0759] 5-(azidomethyl)thiophene-2-carbaldehyde

[0760]

[0761] This compound was prepared starting from the previously reported 5-(chloromethyl)thiophene-2-carbaldehyde (16).

[0762] A mixture of 5-(chloromethyl)thiophene-2-carbaldehyde (1 mmol), potassium iodide (1.5 mmol) and sodium azide (1.5 mmol) in a 1:1 solvent mixture of water and acetone was stirred at room temperature overnight. Ethyl acetate was then added and the organic layer was washed with 4M sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the product was used without further purification.

[0763] MS m / z: 168.0 [M+H]+

[0764] Yield: 72%

[0765] ¹H NMR (402 MHz, dmso-d6) δ 9.86 (s, 1H), 7.92 (d, J = 3.8 Hz, 1H), 7.29 (d, J = 3.8 Hz, 1H), 4.75 (s, 2H).

[0766] Synthesis and characterization of the final compounds

[0767] HPLC, rt: 12.53 min (96.25% purity)

[0768] Compound 1

[0769] 2-(5-ethylthiophen-2-yl)-6-(4-methoxybenzyl)-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-one

[0770]

[0771] The compound was synthesized starting from 1-iodo-4-methoxybenzene using method D to yield 3-(4-methoxyphenyl)propanal which was converted to 2-amino-5-(4-methoxybenzyl)thiophene-3-carboxamide using method E, followed by reaction with 5-ethylthiophen-2-carboxaldehyde using method B.

[0772] MS m / z: 384.80 [M+H]+¹H NMR (402 MHz, dmso-d6) δ 7.81 (d, J = 1.8 Hz, 1H), 7.73 (s, 1H), 7.11 (d, J = 8.7 Hz, 2H), 6.88-6.80 (m, 3H), 6.67 – 6.61 (m, 1H), 6.52 (s, 1H), 5.87 (t, J = 2.4 Hz, 1H), 3.81 (s, 2H), 3.69 (s, 3H), 2.75 – 2.66 (m, 2H), 1.16 (t, J = 7.5 Hz, 3H).

[0773] HPLC, rt: 14.14 min (95.10% purity)

[0774] Compound 2

[0775] 2-(5-bromothiophen-2-yl)-6-(2-chlorobenzyl)-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-one

[0776]

[0777] The compound was synthesized starting from 1-iodo-2-chlorobenzene using method D to yield 3-(2-chlorophenyl)propanal which was converted to 2-amino-5-(2-chlorobenzyl)thiophene-3-carboxamide using method E, followed by reaction with 5-bromothiophen-2-carboxaldehyde using method B.

[0778] MS m / z: 438.6 [M+H]+

[0779] 'H NMR (402 MHz, dmso-d6) 57.97 - 7.89 (m, 2H), 7.40 (dd, J= 7.5, 1.7 Hz, 1H), 7.35 (dd, J = 7.2, 2.0 Hz, 1H), 7.30 - 7.21 (m, 2H), 7.03 (d, J = 3.8 Hz, 1H), 6.89 (d, J = 3.8 Hz, 1H), 6.53 (s, 1H), 5.92 (t, J= 2.8 Hz, 1H), 3.99 (s, 2H).

[0780] HPLC, rt: 14.76 min (92.02% purity)

[0781] Compound 2a

[0782] (7?)-2-(5-bromothiophen-2-yl)-6-(2-chlorobenzyl)-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-one

[0783]

[0784] This compound was synthesized as described above as racemic mixture (Compound 2) and separated by chiral HPLC.

[0785] MS m / z: 438.6 [M+H]+

[0786] ¹H NMR (402 MHz, dmso-d6) δ 7.97 – 7.89 (m, 2H), 7.40 (dd, J = 7.5, 1.7 Hz, 1H), 7.35 (dd, J = 7.2, 2.0 Hz, 1H), 7.30 – 7.21 (m, 2H), 7.03 (d, J = 3.8 Hz, 1H), 6.89 (d, J = 3.8 Hz, 1H), 6.53 (s, 1H), 5.92 (t, J = 2.8 Hz, 1H), 3.99 (s, 2H).HPLC, rt: 14.76 min (92.02% purity)Chiral HPLC, rt = 29.18 min (ee 98.4%).Compound 2b

[0787] (S)-2-(5-bromothiophen-2-yl)-6-(2-chlorobenzyl)-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-one

[0788]

[0789] This compound was synthesized as described above as racemic mixture (Compound 2) and separated by chiral HPLC.

[0790] MS m / z: 438.6 [M+H]+

[0791] ¹H NMR (402 MHz, dmso-d6) δ 7.97 – 7.89 (m, 2H), 7.40 (dd, J = 7.5, 1.7 Hz, 1H), 7.35 (dd, J = 7.2, 2.0 Hz, 1H), 7.30 – 7.21 (m, 2H), 7.03 (d, J = 3.8 Hz, 1H), 6.89 (d, J = 3.8 Hz, 1H), 6.53 (s, 1H), 5.92 (t, J = 2.8 Hz, 1H), 3.99 (s, 2H).HPLC, rt: 14.76 min (92.02% purity)Chiral HPLC, rt = 25.65 min (ee 100.0%).

[0792] Compound 3

[0793] 2-(5-bromothiophen-2-yl)-6-(4-methoxybenzyl)-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-one

[0794]

[0795] The compound was synthesized starting from 1-iodo-4-methoxybenzene using method D to yield 3-(4-methoxyphenyl)propanal which was converted to 2-amino-5-(4-methoxybenzyl)thiophene-3-carboxamide using method E, followed by reaction with 5-bromothiophen-2-carboxaldehyde using method B.

[0796] MS m / z: 434.7 [M+H]+

[0797] ¹H NMR (402 MHz, dmso-d6) δ 7.92 (d, J = 2.6 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.11 (d, J = 8.6 Hz, 2H), 7.04 (d, J = 3.8 Hz, 1H), 6.89 (d, J = 3.8 Hz, 1H), 6.83 (d, J = 8.6 Hz, 2H), 6.53 (s, 1H), 5.92 (t, J = 2.7 Hz, 1H), 3.82 (s, 2H), 3.69 (s, 3H).

[0798] HPLC, rt: 14.27 min (94.60% purity)

[0799] Compound 4

[0800] Methyl 3-((2-(5-bromothi ophen-2 -yl)-4-oxo- 1,2,3, 4-tetrahydrothieno[2, 3 -d]pyrimidin-6-yl)methyl)benzoate

[0801]

[0802] The compound was synthesized starting from methyl 3 -iodobenzoate using method D to yield methyl 3-(3-oxopropyl)benzoate which was converted to methyl 3-((5-amino-4-carbamoylthi ophen-2 -yl)methyl)benzoate using method E, followed by reaction with 5-bromothiophen-2-carboxaldehyde using method B.

[0803] MS m / z: 462.7 [M+H]+

[0804] ¹H NMR (402 MHz, dmso-d6) δ 7.95 (d, J = 2.8 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.83 – 7.74 (m, 2H), 7.54-7.39 (m, 2H), 7.04 (d, J = 3.8 Hz, 1H), 6.90 (dd, J = 3.8, 0.6 Hz, 1H), 6.61 (s, 1H), 5.94 (t, J = 2.7 Hz, 1H), 3.99 (s, 2H), 3.81 (s, 3H).

[0805] HPLC, rt: 14.06 min (97.11% purity)

[0806] Compound 5

[0807] 2-(5-ethylthiophen-2-yl)-7-fluoro-2,3-dihydroquinazolin-4(1H)-one

[0808]

[0809] The compound was synthesized starting from 2-amino-4-fluorobenzamide and 5-ethylthiophene-2-carboxaldehyde using method A.

[0810] MS m / z: 276.8 [M+H]+

[0811] ¹H NMR (402 MHz, dmso-d6) δ 8.38 (s, 1H), 7.67 – 7.60 (m, 1H), 7.45 (s, 1H), 6.89 (d, J = 3.5 Hz, 1H), 6.66 (d, J = 3.4 Hz, 1H), 6.51 – 6.41 (m, 2H), 5.94 (s, 1H), 2.72 (q, J = 7.5 Hz, 2H), 1.16 (t, J = 7.5 Hz, 3H).

[0812] HPLC, rt: 12.55 min (89.92% purity)

[0813] Compound 6

[0814] 2-(5-bromothiophen-2-yl)-6-(trifluoromethoxy)-2,3-dihydroquinazolin-4(1H)-one

[0815]

[0816] The compound was synthesized starting from the previously reported 2-amino-5-(trifluoromethoxy)benzamide (19) and 5-bromothiophene-2-carboxaldehyde using method A.MS m / z: 393.0 [M+H]+

[0817] ¹H NMR (402 MHz, dmso-d6) δ 8.72 (d, J = 1.0 Hz, 1H), 7.58 (s, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.27 (ddd, J = 8.8, 2.9, 0.7 Hz, 1H), 7.06 (d, J = 3.8 Hz, 1H), 6.93 (dd, J = 3.8, 0.6 Hz, 1H), 6.85 – 6.81 (m, 1H), 6.01 (t, J = 2.2 Hz, 1H).

[0818] HPLC, rt: 13.88 min (94.97% purity)

[0819] Compound 6a

[0820] (R)-2-(5-bromothiophen-2-yl)-6-(trifluoromethoxy)-2,3-dihydroquinazolin-4(1H)-one

[0821] o

[0822]

[0823] This compound was synthesized as described above as racemic mixture (Compound 6) and separated by chiral HPLC.

[0824] MS m / z: 393.0 [M+H]+

[0825] ¹H NMR (402 MHz, dmso-d6) δ 8.72 (d, J = 1.0 Hz, 1H), 7.58 (s, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.27 (ddd, J = 8.8, 2.9, 0.7 Hz, 1H), 7.06 (d, J = 3.8 Hz, 1H), 6.93 (dd, J = 3.8, 0.6 Hz, 1H), 6.85 – 6.81 (m, 1H), 6.01 (t, J = 2.2 Hz, 1H).HPLC, rt: 13.88 min (94.97% purity)Chiral HPLC, rt = 22.68 min (ee 100.0%).

[0826] Compound 6b

[0827] CS')-2-(5-bromothiophen-2-yl)-6-(trifluoromethoxy)-2,3-dihydroquinazolin-4(1H)-one

[0828] o

[0829]

[0830] This compound was synthesized as described above as racemic mixture (Compound 6) and separated by chiral HPLC.

[0831] MS m / z: 393.0 [M+H]+

[0832] ¹H NMR (402 MHz, dmso-d6) δ 8.72 (d, J = 1.0 Hz, 1H), 7.58 (s, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.27 (ddd, J = 8.8, 2.9, 0.7 Hz, 1H), 7.06 (d, J = 3.8 Hz, 1H), 6.93 (dd, J = 3.8, 0.6 Hz, 1H), 6.85 – 6.81 (m, 1H), 6.01 (t, J = 2.2 Hz, 1H).HPLC, rt: 13.88 min (94.97% purity)Chiral HPLC, rt = 20.78 min (ee 100.0%).

[0833] Compound 72-(5-bromothiophen-2-yl)-6-methoxy-2,3-dihydroquinazolin-4(1H)-one

[0834]

[0835] The compound was synthesized starting from 2-amino-5-methoxybenzamide and 5-bromothiophene-2-carboxaldehyde using method B.

[0836] MS m / z: 338.8 [M+H]+

[0837] ¹H NMR (402 MHz, dmso-d6) δ 8.51 (d, J = 1.2 Hz, 1H), 7.11 (d, J = 3.0 Hz, 1H), 7.04 (d, J = 3.8 Hz, 1H), 6.95 – 6.88 (m, 3H), 6.72 (d, J = 8.8 Hz, 1H), 5.86 (t, J = 2.3 Hz, 1H), 3.65 (s, 3H). HPLC, rt: 12.13 min (97.28% purity)

[0838] Compound 7a

[0839] (7?)-6-Methoxy-2-(5-bromo-2-thienyl)-2,3-dihydro-4(1H)-quinazolinone

[0840]

[0841] The compound was synthesized starting from 2-amino-5-methoxy-benzamide and 5-bromothiophene-2-carbaldehyde using method L.

[0842] MS m / z: 338.8 [M+H]+,

[0843] 'H-NMR (600 MHz, DMSO-t / e) 8 8.53 - 8.48 (m, 1H), 7.11 (d, J = 3.0 Hz, 1H), 7.04 (d, J = 3.8 Hz, 1H), 6.95 - 6.88 (m, 3H), 6.72 (d, J= 8.8 Hz, 1H), 5.86 (t, J= 2.6 Hz, 1H), 3.66 (s, 3H) PPm,

[0844] HPLC, rt = 11.36 min (98.36% purity),

[0845] Chiral HPLC, rt = 25.66 min (ee 95.6%).

[0846] Compound 7b

[0847] (5)-6-Methoxy-2-(5-bromo-2-thienyl)-2,3-dihydro-4(1H)-quinazolinone

[0848]

[0849] The compound was synthesized starting from 2-amino-5-methoxy-benzamide and 5-bromothiophene-2-carbaldehyde using method M.

[0850] MS m / z: 338.8 [M+H]+,

[0851] 'H-NMR (402 MHz, DMSO-t / e) 8 8.53 - 8.48 (m, 1H), 7.11 (d, J = 3.0 Hz, 1H), 7.04 (d, J = 3.8 Hz, 1H), 6.95 - 6.88 (m, 3H), 6.72 (d, J= 8.7 Hz, 1H), 5.86 (t, J= 2.5 Hz, 1H), 3.66 (s, 3H) PPm,

[0852] HPLC, rt = 11.36 min (99.30% purity),

[0853] Chiral HPLC, rt = 23.14 min (ee 100.0%).

[0854] Compound 8

[0855] 2-(5-bromothiophen-2-yl)-6-(2,4-dichlorobenzyl)-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-one

[0856]

[0857] The compound was synthesized starting from 2,4-dichloro-1-iodobenzene using method D to yield 3-(2,4-dichlorophenyl)propanal which was converted to 2-amino-5-(2,4-dichlorobenzyl)thiophene-3-carboxamide using method E, followed by reaction with 5-bromothiophen-2-carboxaldehyde using method B.

[0858] MS m / z: 472.7 [M+H]+

[0859] ¹H NMR (402 MHz, dmso-d6) δ 7.95 (d, J = 2.9 Hz, 2H), 7.57 (d, J = 1.4 Hz, 1H), 7.43 – 7.32 (m, 2H), 7.04 (d, J = 3.8 Hz, 1H), 6.90 (dd, J = 3.8, 0.6 Hz, 1H), 6.56 (s, 1H), 5.94 (t, J = 2.7 Hz, 1H), 3.99 (s, 2H).

[0860] HPLC, rt: 15.63 min (93.53% purity)

[0861] Compound 8a

[0862] (R)-2-(5-bromothiophen-2-yl)-6-(2,4-dichlorobenzyl)-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-one

[0863]

[0864] This compound was synthesized as described above as racemic mixture (Compound 8) and separated by chiral HPLC.MS m / z: 472.7 [M+H]+

[0865] 1H NMR (402 MHz, dmso-d6) 57.95 (d, J = 2.9 Hz, 2H), 7.57 (d, J = 1.4 Hz, 1H), 7.43 - 7.32 (m, 2H), 7.04 (d, J = 3.8 Hz, 1H), 6.90 (dd, J = 3.8, 0.6 Hz, 1H), 6.56 (s, 1H), 5.94 (t, J = 2.7 Hz, 1H), 3.99 (s, 2H).

[0866] HPLC, rt: 15.63 min (93.53% purity)

[0867] Chiral HPLC, rt = 36.60 min (ee 100.0%).

[0868] Compound 8b

[0869] (S)-2-(5-bromothiophen-2-yl)-6-(2,4-dichlorobenzyl)-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-one

[0870]

[0871] This compound was synthesized as described above as racemic mixture Compound 8 and separated by chiral HPLC.

[0872] MS m / z: 438.6 [M+H]+

[0873] ¹H NMR (402 MHz, dmso-d6) δ 7.97 – 7.89 (m, 2H), 7.40 (dd, J = 7.5, 1.7 Hz, 1H), 7.35 (dd, J = 7.2, 2.0 Hz, 1H), 7.30 – 7.21 (m, 2H), 7.03 (d, J = 3.8 Hz, 1H), 6.89 (d, J = 3.8 Hz, 1H), 6.53 (s, 1H), 5.92 (t, J = 2.8 Hz, 1H), 3.99 (s, 2H).

[0874] HPLC, rt: 14.76 min (92.02% purity)

[0875] Chiral HPLC, rt = 26.06 min (ee 100.0%).

[0876] Compound 9

[0877] 2-(5-bromothiophen-2-yl)-6-methoxy-2,3-dihydroquinazolin-4(1H)-one

[0878]

[0879] The compound was synthesized starting from 2-methoxyethyl 4-iodobenzoate using method D to yield 2-methoxyethyl 4-(3-oxopropyl)benzoate which was converted to 2-methoxyethyl 4-((5-amino-4-carbamoylthiophen-2-yl)methyl)benzoate using method E, followed by reaction with 5-bromothiophen-2-carboxaldehyde using method B.

[0880] MS m / z: 506.5 [M+H]+¹H NMR (402 MHz, dmso-d6) δ 7.98 – 7.83 (m, 4H), 7.36 (d, J = 8.2 Hz, 2H), 7.04 (d, J = 3.8 Hz, 1H), 6.90 (d, J = 3.8 Hz, 1H), 6.61 (s, 1H), 5.93 (t, J = 2.8 Hz, 1H), 4.39 – 4.31 (m, 2H), 3.99 (s, 2H), 3.65 – 3.58 (m, 2H), 3.27 (s, 3H).

[0881] HPLC, rt: 13.87 min (96.69% purity)

[0882] Compound 10

[0883] 2-(5-bromothiophen-2-yl)-6-(3-methoxybenzyl)-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-one

[0884]

[0885] The compound was synthesized starting from 1-iodo-3-methoxybenzene using method D to yield 3-(3-methoxyphenyl)propanal which was converted to 2-amino-5-(3-methoxybenzyl)thiophene-3-carboxamide using method E, followed by reaction with 5-bromothiophen-2-carboxaldehyde using method B.

[0886] MS m / z: 434.8 [M+H]+

[0887] ¹H NMR (402 MHz, dmso-d6) δ 7.94 (d, J = 2.8 Hz, 1H), 7.90 (d, J = 1.9 Hz, 1H), 7.22 – 7.15 (m, 1H), 7.04 (d, J = 3.8 Hz, 1H), 6.90 (d, J = 3.8 Hz, 1H), 6.80-6.72 (m, 3H), 6.59 (s, 1H), 5.93 (s, 1H), 3.86 (s, 2H), 3.69 (s, 3H).

[0888] HPLC, rt: 14.21 min (96.30% purity)

[0889] Compound 11

[0890] 2-(5-bromothiophen-2-yl)-7-methyl-2,3-dihydroquinazolin-4(1H)-one

[0891]

[0892] The compound was synthesized starting from 2-amino-4-methylbenzamide and 5-bromothiophene-2-carboxaldehyde using method A.

[0893] MS m / z: 322.7 [M+H]+

[0894] ¹H NMR (402 MHz, dmso-d6) δ 8.38 (d, J = 1.3 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.18 (s, 1H), 7.04 (d, J = 3.8 Hz, 1H), 6.90 (dd, J = 3.8, 0.6 Hz, 1H), 6.56-6.48 (dd, J = 6.2, 4.4 Hz, 2H), 5.89 (t, J = 2.3 Hz, 1H), 2.18 (s, 3H).

[0895] HPLC, rt: 12.69 min (84.29% purity)

[0896] Compound Ila(R)-2-(5-bromothiophen-2-yl)-7-methyl-2,3-dihydroquinazolin-4(1H)-one

[0897]

[0898] This compound was synthesized as described above as racemic mixture (Compound 11) and separated by chiral HPLC.

[0899] MS m / z: 322.7 [M+H]+

[0900] ¹H NMR (402 MHz, dmso-d6) δ 8.38 (d, J = 1.3 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.18 (s, 1H), 7.04 (d, J = 3.8 Hz, 1H), 6.90 (dd, J = 3.8, 0.6 Hz, 1H), 6.56-6.48 (dd, J = 6.2, 4.4 Hz, 2H), 5.89 (t, J = 2.3 Hz, 1H), 2.18 (s, 3H).HPLC, rt: 12.69 min (84.29% purity)Chiral HPLC, rt = 13.39 min (ee 100.0%).

[0901] Compound 11b

[0902] (S)-2-(5-bromothiophen-2-yl)-7-methyl-2,3-dihydroquinazolin-4(1H)-one

[0903]

[0904] This compound was synthesized as described above as racemic mixture (Compound 11) and separated by chiral HPLC.

[0905] MS m / z: 322.7 [M+H]+

[0906] ¹H NMR (402 MHz, dmso-d6) δ 8.38 (d, J = 1.3 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.18 (s, 1H), 7.04 (d, J = 3.8 Hz, 1H), 6.90 (dd, J = 3.8, 0.6 Hz, 1H), 6.56-6.48 (dd, J = 6.2, 4.4 Hz, 2H), 5.89 (t, J = 2.3 Hz, 1H), 2.18 (s, 3H).HPLC, rt: 12.69 min (84.29% purity)Chiral HPLC, rt = 10.74 min (ee 90.7%).

[0907] Compound 12

[0908] 2-(5-bromothiophen-2-yl)-7-chloro-2,3-dihydroquinazolin-4(1H)-one

[0909]

[0910] The compound was synthesized starting from 2-amino-4-chlorobenzamide and 5-bromothiophene-2-carboxaldehyde using method A.

[0911] MS m / z: 342.6 [M+H]+

[0912] 1H NMR (402 MHz, dmso-d6) δ 8.60 (d, J= 1.2 Hz, 1H), 7.58 (d, J= 8.3 Hz, 1H), 7.53 (s, 1H), 7.06 (d, J = 3.8 Hz, 1H), 6.92 (d, J= 3.8 Hz, 1H), 6.78 (d, J = 2.0 Hz, 1H), 6.70 (dd, J = 8.3, 2.0 Hz, 1H), 5.99 (t, J = 2.3 Hz, 1H).HPLC, rt: 13.49 min (97.72% purity)Compound 12a

[0913] (R)-(5-bromothiophen-2-yl)-7-chloro-2,3-dihydroquinazolin-4(1H)-one

[0914]

[0915] This compound was synthesized as described above as racemic mixture Compound 12 and separated by chiral HPLC.

[0916] MS m / z: 342.6 [M+H]+

[0917] 1HNMR(402 MHz, dmso-d6) 58.60 (d, J= 1.2 Hz, 1H), 7.58 (d, J= 8.3 Hz, 1H), 7.53 (s, 1H), 7.06 (d, J = 3.8 Hz, 1H), 6.92 (d, J= 3.8 Hz, 1H), 6.78 (d, J = 2.0 Hz, 1H), 6.70 (dd, J = 8.3, 2.0 Hz, 1H), 5.99 (t, J = 2.3 Hz, 1H) ppm,

[0918] HPLC, rt: 13.49 min (97.72% purity),

[0919] Chiral HPLC, rt = 30.73 min (ee 98.5%).

[0920] Compound 12b

[0921] (S)-(5-bromothiophen-2-yl)-7-chloro-2,3-dihydroquinazolin-4(1H)-one

[0922]

[0923] This compound was synthesized as described above as racemic mixture Compound 12 and separated by chiral HPLC.MS m / z: 342.6 [M+H]+

[0924] 1HNMR(402 MHz, dmso-d6) 58.60 (d, J= 1.2 Hz, 1H), 7.58 (d, J= 8.3 Hz, 1H), 7.53 (s, 1H), 7.06 (d, J = 3.8 Hz, 1H), 6.92 (d, J= 3.8 Hz, 1H), 6.78 (d, J = 2.0 Hz, 1H), 6.70 (dd, J = 8.3, 2.0 Hz, 1H), 5.99 (t, J = 2.3 Hz, 1H) ppm,

[0925] HPLC, rt: 13.49 min (97.72% purity),

[0926] Chiral HPLC, rt = 27.13 min (ee 100.0%).

[0927] Compound 13

[0928] 4-((2-(5-bromothiophen-2-yl)-4-oxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)methyl)-N-(prop-2-yn-1-yl)benzamide

[0929]

[0930] The compound was synthesized starting from methyl 4-iodobenzoate using method D to yield methyl 4-(3-oxopropyl)benzoate which was converted to methyl 4-((5-amino-4-carbamoylthiophen-2-yl)methyl)benzoate using method E. Ester hydrolysis using method I afforded 4-((5-amino-4-carbamoylthiophen-2-yl)methyl)benzoic acid which was reacted with 5-bromothiophen-2-carboxaldehyde using the first step of method B to get (E)-4-((5-(((5-bromothi ophen-2 -yl)methylene)amino)-4-carbamoylthi ophen-2 -yl)methyl)benzoic acid. This intermediate was then reacted with propargylamine using method G and the obtained Schiff base was then converted to the final product using the second step of method B.

[0931] MS m / z: 485.9 [M+H]+

[0932] 'H NMR (402 MHz, dmso-d6) 5 8.82 (t, J= 5.5 Hz, 1H), 7.96 - 7.91 (m, 2H), 7.76 (d, J= 8.3 Hz, 2H), 7.30 (d, J= 8.3 Hz, 2H), 7.04 (d, J= 3.8 Hz, 1H), 6.90 (dd, J= 3.8, 0.8 Hz, 1H), 6.61 (s, 1H), 5.93 (t, J= 2.8 Hz, 1H), 4.00 (dt, J = 10.9, 5.4 Hz, 2H), 3.96 (s, 2H), 3.06 (t, J= 2.5 Hz, 1H).

[0933] HPLC, rt: 12.52 min (95.01% purity)

[0934] Compound 14

[0935] 2-(5-chlorothiophen-2-yl)-6-(4-methoxybenzyl)-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-one

[0936]

[0937] OThe compound was synthesized starting from l-iodo-4-methoxybenzene using method D to yield 3-(4-methoxyphenyl)propanal which was converted to 2-amino-5-(4-methoxybenzyl)thiophene-3-carboxamide using method E, followed by reaction with 5-chlorothiophen-2-carboxaldehyde using method B.

[0938] MS m / z: 390.8 [M+H]+

[0939] 'HNMR (402 MHz, dmso-d6) 57.93 (d, J= 2.6 Hz, 1H), 7.88 (d, J= 2.6 Hz, 1H), 7.14 - 7.08 (m, 2H), 6.93 (q, J = 3.9 Hz, 2H), 6.86 - 6.80 (m, 2H), 6.54 (s, 1H), 5.91 (t, J= 2.9 Hz, 1H), 3.82 (s, 2H), 3.69 (s, 3H).

[0940] HPLC, rt: 14.17 min (96.27% purity)

[0941] Compound 15

[0942] 4-((2-(5-bromothiophen-2-yl)-4-oxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)methyl)-N-ethylbenzamide

[0943]

[0944] The compound was synthesized starting from N-ethyl-4-iodobenzamide using method D to yield N-ethyl-4-(3-oxopropyl)benzamide which was converted to 2-amino-5-(4-(ethylcarbamoyl)benzyl)thiophene-3 -carboxamide using method E, followed by reaction with 5-bromothiophen-2-carboxaldehyde using method B.

[0945] MS m / z: 475.7 [M+H]+

[0946] 'H NMR (402 MHz, dmso-d6) 5 8.35 (t, J = 5.3 Hz, 1H), 7.94 (dd, J = 5.8, 2.8 Hz, 2H), 7.74 (d, J= 8.2 Hz, 2H), 7.28 (d, J= 8.2 Hz, 2H), 7.04 (d, J= 3.8 Hz, 1H), 6.90 (d, J= 3.7 Hz, 1H), 6.59 (s, 1H), 5.93 (t, J= 2.7 Hz, 1H), 3.95 (s, 2H), 3.27-3.19 (m, 2H), 1.08 (t, J = 7.2 Hz, 3H). HPLC, rt: 12.77 min (96.28% purity)

[0947] Compound 16

[0948] 6-chloro-2-phenyl-2,3-dihydroquinazolin-4(1H)-one

[0949]

[0950] O

[0951] The compound was synthesized starting from 2-amino-5-chlorobenzamide and benzaldehyde using method A.

[0952] MS m / z: 259.3 [M+H]+'H NMR (400 MHz, dmso-d6) 58.44 (s, 1H), 7.47 (ddd, J= 11.6, 8.3, 2.5 Hz, 3H), 7.39 - 7.32 (m, 3H), 7.32 - 7.28 (m, 1H), 7.25 (dd, J= 8.7, 2.6 Hz, 1H), 6.75 (d, J= 8.7 Hz, 1H), 5.74 (d, J= 13.6 Hz, 1H).

[0953] HPLC, rt: 12.51 min (95.34% purity)

[0954] Compound 16a

[0955] (7?)-6-Chloro-2-phenyl-2,3-dihydro-4(1H)-quinazolinone

[0956] o

[0957]

[0958] The compound was synthesized starting from 2-amino-5-chloro-benzamide and benzaldehyde using method L.

[0959] MS m / z: 259.3 [M+H]+,

[0960] 'H-NMR (402 MHz, DMSO-t / e) 8 8.44 (s, 1H), 7.47 (ddd, J= 11.6, 8.3, 2.5 Hz, 3H), 7.39 -7.32 (m, 3H), 7.32 - 7.28 (m, 1H), 7.25 (dd, J= 8.7, 2.6 Hz, 1H), 6.75 (d, J= 8.7 Hz, 1H), 5.74 (d, J= 13.6 Hz, 1H) ppm,

[0961] HPLC, rt = 12.04 min (98.17% purity),

[0962] Chiral HPLC, rt = 18.47 min (ee 96.1%).

[0963] Compound 16b

[0964] (5)-6-Chloro-2-phenyl-2,3-dihydro-4(1H)-quinazolinone

[0965] o

[0966]

[0967] The compound was synthesized starting from 2-amino-5-chloro-benzamide and benzaldehyde using method M.

[0968] MS m / z: 259.3 [M+H]+,

[0969] 'H-NMR (402 MHz, DMSO-tfc) 6 8.44 (s, 1H), 7.47 (ddd, J= 11.6, 8.3, 2.5 Hz, 3H), 7.39 -7.32 (m, 3H), 7.32 - 7.28 (m, 1H), 7.25 (dd, J= 8.7, 2.6 Hz, 1H), 6.75 (d, J= 8.7 Hz, 1H), 5.74 (d, J= 13.6 Hz, 1H) ppm,

[0970] HPLC, rt = 12.03 min (95.27% purity),

[0971] Chiral HPLC, rt = 16.18 min (ee 86.03%).Compound 17

[0972] 2-(5-bromothiophen-2-yl)-7-methoxy-2,3-dihydroquinazolin-4(1H)-one

[0973]

[0974] The compound was synthesized starting from the previously reported 2-amino-4-methoxybenzamide (18) and 5-bromothiophene-2-carboxaldehyde using method A.

[0975] MS m / z: 338.9 [M+H]+

[0976] 1H NMR (402 MHz, dmso-d6) δ 8.27 (d, J= 1.4 Hz, 1H), 7.50 (d, J= 8.6 Hz, 1H), 7.25 (s, 1H), 7.06 - 7.03 (m, 1H), 6.90 (d, J = 4.0 Hz, 1H), 6.28 (dd, J = 8.6, 2.4 Hz, 1H), 6.24 (d, J = 2.4 Hz, 1H), 5.89 (t, J= 2.3 Hz, 1H), 3.69 (s, 3H).

[0977] HPLC, rt: 12.13 min (97.48% purity)

[0978] Compound 18

[0979] 2-(5-(azidomethyl)thiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one

[0980] NH

[0981]

[0982] The compound was synthesized starting from anthranilic acid amide and 5-(azidomethyl)thiophene-2-carbaldehyde using method A.

[0983] MS m / z: 285.9 [M+H]+

[0984] 'H NMR (402 MHz, dmso-d6) 5 8.43 (s, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.27 - 7.16 (m, 2H), 6.96 (dd, J= 15.7, 3.4 Hz, 2H), 6.75 - 6.60 (m, 2H), 5.94 (s, 1H), 4.53 (s, 2H).

[0985] HPLC, rt: 10.82 min (96.23% purity)

[0986] Compound 19

[0987] 2-(5-bromothiophen-2-yl)-7-nitro-2,3-dihydroquinazolin-4(1H)-one

[0988] H /

[0989] N NH

[0990]

[0991] OThe compound was synthesized starting from 2-amino-4-nitrobenzamide and 5-bromothiophene-2-carboxaldehyde using method A.

[0992] MS m / z: 353.7 [M+H]+

[0993] 'HNMR (402 MHz, dmso-d6) 5 8.92 (s, 1H), 7.91 (s, 1H), 7.82 (d, J= 8.5 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.46 (dd, J= 8.5, 2.2 Hz, 1H), 7.08 (d, J= 3.8 Hz, 1H), 6.95 (d, J= 3.8 Hz, 1H), 6.12 (t, J= 2.2 Hz, 1H).

[0994] HPLC, rt: 12.99 min (99.35% purity)

[0995] Compound 20

[0996] 2-(5-bromothiophen-2-yl)-6-(4-chlorobenzyl)-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-one

[0997]

[0998] The compound was synthesized starting from l-iodo-4-chlorobenzene using method D to yield 3-(4-chlorophenyl)propanal which was converted to 2-amino-5-(4-chlorobenzyl)thiophene-3-carboxamide using method E, followed by reaction with 5-bromothiophen-2-carboxaldehyde using method B.

[0999] MS m / z: 438.7 [M+H]+

[1000] 'H NMR (402 MHz, dmso-d6) 57.98 - 7.90 (m, 2H), 7.37 - 7.29 (m, 2H), 7.23 (d, J= 8.4 Hz, 2H), 7.04 (d, J= 3.8 Hz, 1H), 6.91 - 6.88 (m, 1H), 6.59 (s, 1H), 5.93 (t, J = 2.7 Hz, 1H), 3.90 (s, 2H).

[1001] HPLC, rt: 14.89 min (94.43% purity)

[1002] Compound 21

[1003] 2-(5-bromothiophen-2-yl)-6-methyl-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-one

[1004]

[1005] This compound was synthesized starting from 2-amino-5-methylthiophen-3-carboxamide and 5-bromothiophen-2-carboxaldehyde using method B.

[1006] MS m / z: 328.6 [M+H]+

[1007] 1H NMR (402 MHz, dmso-d6) δ 7.93 (d, J = 3.0 Hz, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.04 (d, J = 3.8 Hz, 1H), 6.90 (dd, J = 3.8, 0.8 Hz, 1H), 6.52 (d, J = 1.3 Hz, 1H), 5.91 (t, J = 2.8 Hz, 1H), 2.21 (d, J= 1.2 Hz, 3H).

[1008] HPLC, rt: 12.47 min (94.10% purity)Compound 22

[1009] methyl 4-((2-(5-bromothiophen-2-yl)-4-oxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)methyl)benzoate

[1010]

[1011] The compound was synthesized starting from methyl 4-iodobenzoate using method D to yield methyl 4-(3-oxopropyl)benzoate which was converted to methyl 4-((5-amino-4-carbamoylthiophen-2-yl)methyl)benzoate using method E, followed by reaction with 5-bromothiophen-2-carboxaldehyde using method B.

[1012] MS m / z: 462.8 [M+H]+

[1013] 'HNMR (402 MHz, dmso-d6) 57.99 - 7.83 (m, 4H), 7.36 (d, J= 8.3 Hz, 2H), 7.04 (d, J= 3.8 Hz, 1H), 6.90 (d, J = 3.8 Hz, 1H), 6.62 (s, 1H), 5.94 (t, J = 2.8 Hz, 1H), 3.99 (s, 2H), 3.80 (s, 3H).

[1014] HPLC, rt: 14.12 min (93.46% purity)

[1015] Compound 23

[1016] 2-(5-ethylthiophen-2-yl)-7-nitro-2,3-dihydroquinazolin-4(1H)-one

[1017]

[1018] O

[1019] The compound was synthesized starting from 2-amino-4-nitrobenzamide and 5-ethylthiophene-2-carboxaldehyde using method A.

[1020] MS m / z: 303.9 [M+H]+

[1021] 'H NMR (402 MHz, dmso-d6) 5 8.79 (s, 1H), 7.85 - 7.76 (m, 2H), 7.56 (d, J = 2.2 Hz, 1H), 7.43 (dd, J= 8.6, 2.2 Hz, 1H), 6.91 (d, J= 3.5 Hz, 1H), 6.67 (d, J= 3.4 Hz, 1H), 6.07 (s, 1H), 2.72 (q, J= 7.5 Hz, 2H), 1.16 (t, J= 7.5 Hz, 3H).

[1022] HPLC, rt: 12.93 min (99.18% purity)

[1023] Compound 24

[1024] 6-benzyl-2-(5-bromothiophen-2-yl)-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-one

[1025]

[1026] The compound was synthesized starting from 3-phenylpropanal which was converted to 2- amino-5-benzylthiophene-3 -carboxamide using method E, followed by reaction with 5-bromothiophen-2-carboxaldehyde using method B.

[1027] MS m / z: 405.4 [M+H]+

[1028] 'HNMR (400 MHz, dmso-d6) 57.97 - 7.88 (m, 2H), 7.31 - 7.16 (m, 5H), 7.05 (d, J= 3.8 Hz, 1H), 6.90 (d, J= 3.8 Hz, 1H), 6.57 (s, 1H), 5.93 (t, J= 2.7 Hz, 1H), 3.90 (s, 2H).

[1029] HPLC, rt: 14.31 min (96.36% purity)

[1030] Compound 25

[1031] tert-butyl 4-(4-((2-(5-bromothiophen-2-yl)-4-oxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)methyl)phenyl)piperazine-1-carboxylate

[1032] Boc

[1033]

[1034] The compound was synthesized starting from tert-butyl 4-(4-iodophenyl)piperazine-1-carboxylate using method D to yield tert-butyl 4-(4-(3-oxopropyl)phenyl)piperazine-1-carboxylate which was converted to tert-butyl 4-(4-((5-amino-4-carbamoylthiophen-2-yl)methyl)phenyl)piperazine-1-carboxylate using method E, followed by reaction with 5-bromothiophen-2-carboxaldehyde using method B.

[1035] MS m / z: 588.7 [M+H]+

[1036] 'H NMR (402 MHz, dmso-d6) 57.92 (d, J= 2.8 Hz, 1H), 7.87 (d, J= 2.9 Hz, 1H), 7.17 - 6.98 (m, 3H), 6.92 - 6.81 (m, 3H), 6.52 (s, 1H), 5.91 (t, J = 2.8 Hz, 1H), 3.78 (s, 2H), 3.45 - 3.38 (m, 4H), 3.05 - 2.98 (m, 4H), 1.38 (s, 9H).

[1037] HPLC, rt: 15.24 min (92.72% purity)

[1038] Compound 26

[1039] 2-(5-chlorothiophen-2-yl)-6-methyl-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-one

[1040]

[1041] This compound was synthesized starting from 2-amino-5-methylthiophen-3-carboxamide and 5-chlorothiophen-2-carboxaldehyde using method B.

[1042] MS m / z: 285.3 [M+H]+

[1043] 'H NMR (400 MHz, dmso-d6) 57.94 (d, J= 2.5 Hz, 1H), 7.84 (d, J= 2.7 Hz, 1H), 6.94 (q, J= 3.9 Hz, 2H), 6.53 (d, J= 1.1 Hz, 1H), 5.90 (t, J= 3.1 Hz, 1H), 2.22 (d, J= 1.1 Hz, 3H).

[1044] HPLC, rt: 12.34 min (95.15% purity)

[1045] Compound 27

[1046] 2-(5-bromothiophen-2-yl)-6-(2,5-dichlorobenzyl)-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-one

[1047]

[1048] The compound was synthesized starting from 1,4-dichl oro-2 -iodobenzene using method D to yield 3-(2,5-dichlorophenyl)propanal which was converted to 2-amino-5-(2,5-dichlorobenzyl)thiophene-3-carboxamide using method E, followed by reaction with 5-bromothiophen-2-carboxaldehyde using method B.

[1049] MS m / z: 472.5 [M+H]+

[1050] 'H NMR (402 MHz, dmso-d6) 5 8.00-7.90 (m, 2H), 7.48 - 7.42 (m, 2H), 7.34 - 7.28 (m, 1H), 7.04 (d, J= 3.8 Hz, 1H), 6.89 (d, J= 3.8 Hz, 1H), 6.59 (s, 1H), 5.94 (s, 1H), 3.99 (s, 2H). HPLC, rt: 15.32 min (94.25% purity)

[1051] Compound 28

[1052] 6-ethoxy-2-(5-ethylthiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one

[1053]

[1054] The compound was synthesized starting from 2-amino-5-ethoxybenzamide and 5-ethylthiophene-2-carboxaldehyde using method A.

[1055] MS m / z: 302.9 [M+H]+‘H NMR (402 MHz, dmso-d6) 5 8.32 (s, 1H), 7.08 (d, J = 3.0 Hz, 1H), 6.91 - 6.84 (m, 2H), 6.77 (s, 1H), 6.68 (d, J = 8.7 Hz, 1H), 6.63 (d, J = 3.5 Hz, 1H), 5.81 (s, 1H), 3.89 (q, J = 7.0 Hz, 2H), 2.69 (q, J= 7.5 Hz, 2H), 1.24 (t, J= 6.9 Hz, 3H), 1.14 (t, J= 7.5 Hz, 3H).

[1056] HPLC, rt: 12.80 min (98.69% purity)

[1057] Compound 28a

[1058] (7?)-6-Ethoxy-2-(5-ethyl-2-thienyl)-2,3-dihydro-4(1H)-quinazolinone

[1059] o

[1060]

[1061] The compound was synthesized starting from 2-amino-5-ethoxy-benzamide and 5-ethylthiophene-2-carbaldehyde using method L.

[1062] MS m / z: 302.9 [M+H]+,

[1063] 'H-NMR (402 MHz, DMSO-t / e) 8 8.36 - 8.31 (m, 1H), 7.10 (d, J = 2.9 Hz, 1H), 6.91 - 6.85 (m, 2H), 6.78 (t, J= 1.8 Hz, 1H), 6.69 (d, J= 8.7 Hz, 1H), 6.66 - 6.61 (m, 1H), 5.82 (t, J= 2.3 Hz, 1H), 3.90 (q, J= 6.9 Hz, 2H), 2.70 (q, J= 1.0 Hz, 2H), 1.25 (t, J= 6.9 Hz, 3H), 1.15 (t, J= 7.5 Hz, 3H) ppm,

[1064] HPLC, rt = 12.75 min (97.71% purity),

[1065] Chiral HPLC, rt = 21.02 min (ee 87.9%),

[1066] CD (MeOH, 228.2 pM): Xmax (Mol. CD) = 208.5 (2.995), 238.5 (5.862), 290 (0.403) nm, CD (MeOH, 228.2 pM): Xmin (Mol. CD) = 223.5 (-1.251), 266 (-2.600), 370 (-2.018) nm.

[1067] Compound 28b

[1068] (5)-6-Ethoxy-2-(5-ethyl-2-thienyl)-2,3-dihydro-4(1H)-quinazolinone

[1069]

[1070] The compound was synthesized starting from 2-amino-5-ethoxy-benzamide and 5-ethylthiophene-2-carbaldehyde using method M.

[1071] MS m / z: 302.9 [M+H]+,

[1072] ‘H-NMR (402 MHz, DMSO-t / e) 6 8.36 - 8.31 (m, 1H), 7.10 (d, J = 2.9 Hz, 1H), 6.91 - 6.85 (m, 2H), 6.78 (t, J= 1.8 Hz, 1H), 6.69 (d, J= 8.7 Hz, 1H), 6.66 - 6.61 (m, 1H), 5.82 (t, J= 2.3Hz, 1H), 3.90 (q, J= 7.0 Hz, 2H), 2.70 (q, J= 1.0 Hz, 2H), 1.25 (t, J= 6.9 Hz, 3H), 1.15 (t, J= 7.5 Hz, 3H) ppm,

[1073] HPLC, rt = 12.76 min (97.45 %purity),

[1074] Chiral HPLC, rt = 19.50 min (ee 73.6%),

[1075] CD (MeOH, 261.3 pM): Xmax (Mol. CD) = 223.5 (1.146), 267.5 (2.613), 365.5 (2.161) nm, CD (MeOH, 261.3 pM): Xmin (Mol. CD) = 208 (-2.509), 239 (-5.038), 290 (-0,073) nm.

[1076] Compound 29

[1077] 2-(5-ethylthiophen-2-yl)-6-(trifluoromethoxy)-2,3-dihydroquinazolin-4(1H)-one

[1078]

[1079] The compound was synthesized starting from the previously reported 2-amino-5-(trifluoromethoxy)benzamide (19) and 5-ethylthiophene-2-carboxaldehyde using method A. MS m / z: 342.9 [M+H]+

[1080] 'H NMR (402 MHz, dmso-d6) 5 8.57 (s, 1H), 7.47 (s, 1H), 7.44 (d, J= 2.1 Hz, 1H), 7.24 (dd, J= 8.8, 2.7 Hz, 1H), 6.88 (d, J= 3.5 Hz, 1H), 6.79 (d, J= 8.8 Hz, 1H), 6.65 (d, J= 3.5 Hz, 1H), 5.95 (s, 1H), 2.71 (q, J= 7.5 Hz, 2H), 1.15 (t, J= 7.5 Hz, 3H).

[1081] HPLC, rt: 13.78 min (99.41% purity)

[1082] Compound 30

[1083] 2-(5-bromothiophen-2-yl)-6-(3-chlorobenzyl)-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-one

[1084]

[1085] The compound was synthesized starting from 1-iodo-3-chlorobenzene using method D to yield 3-(3-chlorophenyl)propanal which was converted to 2-amino-5-(3-chlorobenzyl)thiophene-3-carboxamide using method E, followed by reaction with 5-bromothiophen-2-carboxaldehyde using method B.

[1086] MS m / z: 438.7 [M+H]+

[1087] XH NMR (402 MHz, dmso-d6) 57.99 - 7.89 (m, 2H), 7.34 - 7.21 (m, 3H), 7.20 - 7.12 (m, 1H), 7.04 (d, J= 3.8 Hz, 1H), 6.89 (d, J= 3.8 Hz, 1H), 6.61 (s, 1H), 5.93 (t, J= 2.8 Hz, 1H), 3.91 (s, 2H).

[1088] HPLC, rt: 14.79 min (98.49% purity)Compound 30a

[1089] (7?)-2-(5-bromothiophen-2-yl)-6-(2-chlorobenzyl)-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-one

[1090] ci

[1091]

[1092] This compound was synthesized as described above as racemic mixture Compound 35 and separated by chiral HPLC.

[1093] MS m / z: 438.7 [M+H]+

[1094] 1H NMR (402 MHz, dmso-d6) 57.99 - 7.89 (m, 2H), 7.34 - 7.21 (m, 3H), 7.20 - 7.12 (m, 1H), 7.04 (d, J = 3.8 Hz, 1H), 6.89 (d, J = 3.8 Hz, 1H), 6.61 (s, 1H), 5.93 (t, J = 2.8 Hz, 1H), 3.91 (s, 2H) ppm,

[1095] HPLC, rt: 14.79 min (98.49% purity),

[1096] Chiral HPLC, rt = 31.75 min (ee 100.0%).

[1097] Compound 30b

[1098] (5)-2-(5-bromothiophen-2-yl)-6-(2-chlorobenzyl)-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-one

[1099] ci

[1100]

[1101] This compound was synthesized as described above as racemic mixture Compound 35 and separated by chiral HPLC.

[1102] MS m / z: 438.7 [M+H]+

[1103] 1H NMR (402 MHz, dmso-d6) 57.99 - 7.89 (m, 2H), 7.34 - 7.21 (m, 3H), 7.20 - 7.12 (m, 1H), 7.04 (d, J = 3.8 Hz, 1H), 6.89 (d, J = 3.8 Hz, 1H), 6.61 (s, 1H), 5.93 (t, J = 2.8 Hz, 1H), 3.91 (s, 2H) ppm,

[1104] HPLC, rt: 14.79 min (98.49% purity),

[1105] Chiral HPLC, rt = 25.72 min (ee 100.0%).

[1106] Compound 312-(5-ethylthiophen-2-yl)-6-(4-(trifluoromethoxy)benzyl)-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-one

[1107]

[1108] The compound was synthesized starting from 1-iodo-4-(trifluoromethoxy)benzene using method D to yield 3-(4-(trifluoromethoxy)phenyl)propanal which was converted to 2-amino-5-(4-(trifluoromethoxy)benzyl)thiophene-3-carboxamide using method E, followed by reaction with 5-ethylthiophen-2-carboxaldehyde using method B.

[1109] MS m / z: 438.9 [M+H]+

[1110] 'HNMR (402 MHz, dmso) 57.85 (s, 1H), 7.75 (s, 1H), 7.32 (d, J= 8.6 Hz, 2H), 7.25 (d, J= 8.5 Hz, 2H), 6.86 (d, J= 3.5 Hz, 1H), 6.63 (d, J= 3.4 Hz, 1H), 6.59 (s, 1H), 5.88 (t, J= 2.3 Hz, 1H), 3.92 (s, 2H), 2.70 (q, J= 7.5 Hz, 2H), 1.15 (t, J= 7.5 Hz, 3H).

[1111] HPLC, rt: 14.98 min (98.69% purity)

[1112] Compound 32

[1113] 2-(5-ethylthiophen-2-yl)-6-methoxy-2,3-dihydroquinazolin-4(1H)-one

[1114]

[1115] The compound was synthesized starting from 2-amino-5-methoxybenzamide and 5-ethylthiophene-2-carboxaldehyde using method B.

[1116] MS m / z: 288.8 [M+H]+

[1117] 'H NMR (402 MHz, dmso-d6) 5 8.34 (s, 1H), 7.10 (d, J = 3.0 Hz, 1H), 6.92 - 6.83 (m, 2H), 6.79 (s, 1H), 6.69 (d, J= 8.8 Hz, 1H), 6.63 (d, J= 3.4 Hz, 1H), 5.81 (s, 1H), 3.65 (s, 3H), 2.70 (q, J= 7.5 Hz, 2H), 1.14 (t, J= 7.5 Hz, 3H).

[1118] HPLC, rt: 12.07 min (99.28% purity)

[1119] Compound 32a

[1120] (7?)-6-Methoxy-2-(5-Ethyl-2-thienyl)-2,3-dihydro-4(1H)-quinazolinone

[1121]

[1122] The compound was synthesized starting from 2-amino-5-methoxy-benzamide and 5-ethylthiophene-2-carbaldehyde using method L.

[1123] MS m / z: 288.8 [M+H]+,

[1124] 1H-NMR (402 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.10 (d, J = 3.0 Hz, 1H), 6.92 - 6.83 (m, 2H), 6.79 (s, 1H), 6.69 (d, J= 8.8 Hz, 1H), 6.63 (d, J= 3.4 Hz, 1H), 5.81 (s, 1H), 3.65 (s, 3H), 2.70 (q, J= 7.5 Hz, 2H), 1.14 (t, J= 7.5 Hz, 3H) ppm,

[1125] HPLC, rt = 12.00 min (98.51% purity),

[1126] Chiral HPLC, rt = 19.92 min (ee 100.0%).

[1127] Compound 32b

[1128] (5)-6-Methoxy-2-(5-Ethyl-2-thienyl)-2,3-dihydro-4(1H)-quinazolinone

[1129]

[1130] The compound was synthesized starting from 2-amino-5-methoxy-benzamide and 5-ethylthiophene-2-carbaldehyde using method M.

[1131] MS m / z: 288.8 [M+H]+,

[1132] 1H-NMR (402 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.10 (d, J = 3.0 Hz, 1H), 6.92 - 6.83 (m, 2H), 6.79 (s, 1H), 6.69 (d, J= 8.8 Hz, 1H), 6.63 (d, J= 3.4 Hz, 1H), 5.81 (s, 1H), 3.65 (s, 3H), 2.70 (q, J= 7.5 Hz, 2H), 1.14 (t, J= 7.5 Hz, 3H) ppm,

[1133] HPLC, rt = 12.00 min (99.30% purity),

[1134] Chiral HPLC, rt = 16.95 min (ee 100.0%).

[1135] Compound 33

[1136] 2-(5-bromothiophen-2-yl)-7-fluoro-2,3-dihydroquinazolin-4(1H)-oneBr

[1137]

[1138] O

[1139] The compound was synthesized starting from 2-amino-4-fluorobenzamide and 5-bromothiophene-2-carboxaldehyde using method A.

[1140] MS m / z: 326.8 [M+H]+

[1141] 'H NMR (402 MHz, dmso-d6) 5 8.53 (s, 1H), 7.69 - 7.60 (m, 1H), 7.56 (s, 1H), 7.07 (d, J = 3.8 Hz, 1H), 6.93 (d, J= 3.8 Hz, 1H), 6.54-6.45 (m, 2H), 5.99 (s, 1H).

[1142] HPLC, rt: 12.55 min (99.24% purity)

[1143] Compound 33a

[1144] (R)-2-(5-bromothiophen-2-yl)-7-fluoro-2,3-dihydroquinazolin-4(1H)-one

[1145] o

[1146]

[1147] This compound was synthesized as described above as racemic mixture (Compound 38) and separated by chiral HPLC.

[1148] MS m / z: 326.8 [M+H]+

[1149] 'H NMR (402 MHz, dmso-d6) 5 8.53 (s, 1H), 7.69 - 7.60 (m, 1H), 7.56 (s, 1H), 7.07 (d, J = 3.8 Hz, 1H), 6.93 (d, J= 3.8 Hz, 1H), 6.54-6.45 (m, 2H), 5.99 (s, 1H).

[1150] HPLC, rt: 12.55 min (99.24% purity)

[1151] Chiral HPLC, rt = 15.85 min (ee 100.0%).

[1152] Compound 33b

[1153] (S)-2-(5-bromothiophen-2-yl)-7-fluoro-2,3-dihydroquinazolin-4(1H)-one

[1154]

[1155] This compound was synthesized as described above as racemic mixture Compound 38 and separated by chiral HPLC.

[1156] MS m / z: 326.8 [M+H]'H NMR (402 MHz, dmso-d6) 5 8.53 (s, 1H), 7.69 - 7.60 (m, 1H), 7.56 (s, 1H), 7.07 (d, J = 3.8 Hz, 1H), 6.93 (d, J= 3.8 Hz, 1H), 6.54-6.45 (m, 2H), 5.99 (s, 1H).

[1157] HPLC, rt: 12.55 min (99.24% purity)

[1158] Chiral HPLC, rt = 13.72 min (ee 99.3%).

[1159] Compound 34

[1160] 2-(5-((4-propyl-1H-1,2,3-triazol-1-yl)methyl)thiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one

[1161]

[1162] O

[1163] The compound was synthesized starting from 2-(5-(azidomethyl)thiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one (compound 18) and 1 -pentyne using method F.

[1164] MS m / z: 353.8 [M+H]+

[1165] 'HNMR (402 MHz, dmso-d6) 58.39 (s, 1H), 7.82 (s, 1H), 7.56 (dd, J= 7.7, 1.5 Hz, 1H), 7.23 - 7.17 (m, 2H), 6.95 (dd, J= 9.1, 3.7 Hz, 2H), 6.72 - 6.62 (m, 2H), 5.90 (t, J = 2.3 Hz, 1H), 5.63 (s, 2H), 2.52 (t, J= 7.5 Hz, 2H), 1.60 - 1.47 (m, 2H), 0.85 (t, J= 7.4 Hz, 3H).

[1166] HPLC, rt: 10.82 min (96.87% purity)

[1167] Compound 35

[1168] 2-(5-((4-((2-methoxyethoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)thiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one

[1169]

[1170] The compound was synthesized starting from 2-(5-(azidomethyl)thiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one (compound 18) and 3-(2-methoxyethoxy)prop-l-yne using method F.

[1171] MS m / z: 399.7 [M+H]+

[1172] 'HNMR (402 MHz, dmso-d6) 58.39 (s, 1H), 8.07 (s, 1H), 7.56 (dd, J= 7.7, 1.5 Hz, 1H), 7.23 - 7.15 (m, 2H), 7.00 (d, J= 3.5 Hz, 1H), 6.95 (d, J= 3.5 Hz, 1H), 6.74 - 6.61 (m, 2H), 5.90 (t, J= 2.1 Hz, 1H), 5.69 (s, 2H), 4.46 (s, 2H), 3.53 - 3.48 (m, 2H), 3.42 - 3.37 (m, 2H), 3.18 (s, 3H).

[1173] HPLC, rt: 09.36 min (99.38% purity)

[1174] Compound 36

[1175] 2-(5-bromothiophen-2-yl)-8-methyl-2,3-dihydroquinazolin-4(1H)-one

[1176]

[1177] The compound was synthesized starting from 2 -ami no-3 -methylbenzamide and 5-bromothiophene-2-carboxaldehyde using method A.

[1178] MS m / z: 322.7 [M+H]+

[1179] 'H NMR (402 MHz, dmso-d6) 58.55 (d, J= 3.3 Hz, 1H), 7.47 (d, J= 7.6 Hz, 1H), 7.14 (d, J= 6.7 Hz, 1H), 7.01 (d, J= 3.8 Hz, 1H), 6.85 (dd, J= 3.8, 0.9 Hz, 1H), 6.77 (d, J = 3.3 Hz, 1H), 6.63 (t, J = 7.5 Hz, 1H), 5.84 (t, J = 3.3 Hz, 1H), 2.09 (s, 3H).

[1180] HPLC, rt: 12.94 min (96.77% purity)

[1181] Compound 37

[1182] 2-(1-methyl-1H-pyrrol-2-yl)-2,3-dihydroquinazolin-4(1H)-one

[1183]

[1184] The compound was synthesized starting from anthranilic acid amide and 1 -methylpyrrole-2-carboxaldehyde using method A.

[1185] MS m / z: 228.0 [M+H]+

[1186] 'H NMR (402 MHz, dmso-d6) 5 8.10 (s, 1H), 7.61 (dd, J = 7.8, 1.4 Hz, 1H), 7.24 - 7.19 (m, 1H), 6.89 (s, 1H), 6.77 -6.63 (m, 3H), 6.04 (dd, J= 3.6, 1.9 Hz, 1H), 5.90 - 5.87 (m, 1H), 5.84 (s, 1H), 3.67 (s, 3H).

[1187] HPLC, rt: 09.72 min (95.45% purity)

[1188] Compound 38

[1189] 2-(5-bromothiophen-2-yl)-6-(morpholine-4-carbonyl)-2,3-dihydroquinazolin-4(1H)-one

[1190]

[1191] The compound was synthesized starting from the previously reported 4-amino-3-(aminocarbonyl)benzoic acid (21) which was converted to its methyl ester by refluxing in methanol overnight in the presence of catalytic amount of concentrated sulfuric acid. The resulting methyl 4-amino-3-(aminocarbonyl)benzoate was reacted with 5-bromothiophene-2-carboxaldehyde using method A followed by ester hydrolysis using method I to yield 2-(5-bromothiophen-2-yl)-4-oxo-l,2,3,4-tetrahydroquinazoline-6-carboxylic acid. This was reacted with morpholine using method G to get the desired compound.

[1192] MS m / z: 421.8 [M+H]+

[1193] 'H NMR (402 MHz, dmso-d6) 5 8.62 (s, 1H), 7.71 (s, 1H), 7.66 (d, J= 1.9 Hz, 1H), 7.35 (dd, J= 8.4, 2.0 Hz, 1H), 7.07 (d, J= 3.8 Hz, 1H), 6.94 (d, J= 3.8 Hz, 1H), 6.77 (d, J= 8.4 Hz, 1H), 6.02 (s, 1H), 3.59 - 3.51 (m, 4H), 3.51-3.42 (m, 4H).

[1194] HPLC, rt: 10.74 min (97.17% purity)

[1195] Compound 39

[1196] tert-butyl (6-((2-(5-bromothiophen-2-yl)-4-oxo-1,2,3,4-tetrahydroquinazolin-6-yl)amino)-6-oxohexyl)carbamate

[1197] Boc^

[1198]

[1199] The compound was synthesized starting from 2-(5-bromothiophen-2-yl)-6-nitro-2,3-dihydroquinazolin-4(1H)-one (compound 22) through reduction using method H to afford 6-amino-2-(5-bromothiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one which was reacted with 6-((tert-butoxycarbonyl)amino)hexanoic acid using method G to afford the desired compound. MS m / z: 558.8 [M+Na]+

[1200] 'H NMR (402 MHz, dmso-d6) 59.62 (s, 1H), 8.47 (s, 1H), 7.82 (d, J= 2.3 Hz, 1H), 7.45 (dd, J= 8.7, 2.4 Hz, 1H), 7.08 (s, 1H), 7.03 (d, J= 3.8 Hz, 1H), 6.90 (d, J= 3.8 Hz, 1H), 6.77 - 6.61 (m, 2H), 5.87 (s, 1H), 2.90 - 2.79 (m, 2H), 2.18 (t, 7.3 Hz, 2H), 1.51 (dt, J= 14.9, 7.5 Hz, 2H), 1.34 - 1.15 (m, 13H).

[1201] HPLC, rt: 13.26 min (97.34% purity)

[1202] Compound 40

[1203] 4-((2-(5-bromothiophen-2-yl)-4-oxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)methyl)-N-((1-(2-(2-methoxyethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)benzamide

[1204]

[1205] The compound was synthesized starting from 4-((2-(5-bromothiophen-2-yl)-4-oxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)methyl)-N-(prop-2-yn-1-yl)benzamide (Compound 13) and 1-(2-azidoethoxy)-2-methoxyethane using method F.

[1206] MS m / z: 630.60 [M+H]+'H NMR (402 MHz, dmso-d6) 5 8.94 (t, J = 5.8 Hz, 1H), 7.94 (dd, J = 4.8, 3.2 Hz, 2H), 7.88 (s, 1H), 7.79 (d, J= 8.3 Hz, 2H), 7.29 (d, J= 8.3 Hz, 2H), 7.04 (d, J= 3.8 Hz, 1H), 6.90 (dd, J = 3.8, 0.6 Hz, 1H), 6.59 (s, 1H), 5.93 (t, J= 2.8 Hz, 1H), 4.50-4.40 (m, 4H), 3.95 (s, 2H), 3.75 (t, J= 5.3 Hz, 2H), 3.49 - 3.43 (m, 2H), 3.35 - 3.31 (m, 2H), 3.12 (s, 3H).

[1207] Compound 41

[1208] 6-(4-methoxybenzyl)-2-(5-(1-(2-(2-methoxyethoxy)ethyl)-1H-1,2,3-triazol-4-yl)thiophen-2-yl)-2,3-dihydrothieno[2,3-d]pyrimidin-4(1H)-one

[1209]

[1210] The compound was synthesized starting from l-iodo-4-methoxybenzene using method D to yield 3-(4-methoxyphenyl)propanal which was converted to 2-amino-5-(4-methoxybenzyl)thiophene-3-carboxamide using method E, followed by reaction with 5-ethynyl-2-thiophenecarboxaldehyde using method B. The product was then reacted with 1-(2-azidoethoxy)-2-methoxyethane using method F.

[1211] MS m / z: 526.0 [M+H]+

[1212] 'H NMR (402 MHz, dmso-d6) 58.37 (s, 1H), 7.91 (d, J= 2.3 Hz, 2H), 7.21 (d, J= 3.6 Hz, 1H), 7.12 (d, J= 8.6 Hz, 2H), 7.04 (d, J= 3.7 Hz, 1H), 6.85 - 6.80 (m, 2H), 6.54 (s, 1H), 5.97 (t, J = 2.7 Hz, 1H), 4.50 (t, J= 5.2 Hz, 2H), 3.87 - 3.76 (m, 4H), 3.69 (s, 3H), 3.52 - 3.46 (m, 2H), 3.39-3.33 (m, 2H), 3.16 (s, 3H).

[1213] HPLC, rt: 12.62 min (95.61% purity)

[1214] Compound 42

[1215] 5-(6-(4-methoxybenzyl)-4-oxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-2-yl)-N-(prop-2-yn-1-yl)thiophene-2-carboxamide

[1216]

[1217] The compound was synthesized starting from 5-formyl-2-thiophenecarboxylic acid through reaction with propargylamine using method G to get 5-formyl-N-(prop-2-yn-1-yl)thiophene-2-carboxamide followed by reaction with 2-amino-5-(4-methoxybenzyl)thiophene-3-carboxamide using method B.

[1218] MS m / z: 437.9 [M+H]+XH NMR (402 MHz, dmso-d6) 5 8.86 (t, J= 5.5 Hz, 1H), 7.96 (d, J= 2.9 Hz, 1H), 7.92 (d, J= 2.8 Hz, 1H), 7.55 (d, J = 3.8 Hz, 1H), 7.11 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 3.8 Hz, 1H), 6.83 (d, J = 8.6 Hz, 2H), 6.52 (s, 1H), 5.95 (t, J = 3.1 Hz, 1H), 3.96 (dd, J = 5.5, 2.3 Hz, 2H), 3.81 (s, 2H), 3.69 (s, 3H), 3.09 (t, J = 2.3 Hz, 1H).

[1219] HPLC, rt: 12.09 min (98.25% purity)

[1220] Compound 43

[1221] 5-(6-(4-methoxybenzyl)-4-oxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-2-yl)-N-((1-(2-(2-methoxyethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide

[1222] " O

[1223]

[1224] O

[1225] The compound was synthesized starting from 5-(6-(4-methoxybenzyl)-4-oxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-2-yl)-N-(prop-2-yn-1-yl)thiophene-2-carboxamide (compound 54) and 1-(2-azidoethoxy)-2-methoxyethane using method F.

[1226] MS m / z: 604.9 [M+Na]+

[1227] 'HNMR (402 MHz, dmso-d6) 5 8.97 (t, J= 5.8 Hz, 1H), 7.96 (d, J= 3.2 Hz, 1H), 7.91 (d, J= 3.1 Hz, 1H), 7.87 (s, 1H), 7.56 (d, J = 3.8 Hz, 1H), 7.14 - 7.08 (m, 2H), 7.05 - 7.02 (m, 1H), 6.86 - 6.80 (m, 2H), 6.52 (s, 1H), 5.95 (t, J= 3.1 Hz, 1H), 4.47 - 4.36 (m, 4H), 3.81 (s, 2H), 3.74 (t, J= 5.3 Hz, 2H), 3.69 (s, 3H), 3.49 - 3.43 (m, 2H), 3.35 - 3.31 (m, 2H), 3.13 (s, 3H). HPLC, rt: 12.02 min (98.43% purity)

[1228] Compound 44

[1229] 2-(5-bromothiophen-2-yl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one

[1230]

[1231] O

[1232] This compound was synthesized starting from 3-aminothiophene-2-carboxamide and 5-bromothiophen-2-carboxaldehyde using method B.

[1233] MS m / z: 314.6 [M+H]+

[1234] 'H NMR (402 MHz, dmso-d6) 58.08 (d, J= 2.0 Hz, 1H), 7.64 (d, J= 5.2 Hz, 1H), 7.58 (d, J= 1.9 Hz, 1H), 7.05 (d, J = 3.8 Hz, 1H), 6.93 (d, J= 3.8 Hz, 1H), 6.61 (d, J = 5.2 Hz, 1H), 5.95 (t, J= 2.6 Hz, 1H).

[1235] HPLC, rt: 11.02 min (97.07% purity)Compound 45

[1236] 6-benzyl-2-(5-chlorothi ophen-2 -yl)-2,3-dihydrothieno[2, 3 -d]pyrimidin-4(U7)-one

[1237]

[1238] The compound was synthesized starting from 3-phenylpropanal which was converted to 2-amino-5-benzylthiophene-3 -carboxamide using method E, followed by reaction with 5-chlorothiophen-2-carboxaldehyde using method B.

[1239] MS m / z: 360.8 [M+H]+

[1240] 'H NMR (402 MHz, dmso-d6) 57.91 (dd, J= 14.5, 2.6 Hz, 2H), 7.32 - 7.14 (m, 5H), 6.95-6.91 (m, 2H), 6.57 (s, 1H), 5.91 (t, J = 2.8 Hz, 1H), 3.89 (s, 2H).

[1241] HPLC, rt: 11.31 min (95.55% purity

[1242] Compound 46

[1243] 2-(5-bromothi ophen-2 -yl)-6-(5-chl oro-2 -methoxybenzyl)-2,3-dihydrothieno[2, 3 -d]pyrimidin-4(lH)-one

[1244]

[1245] Cl

[1246] The compound was synthesized starting from 4-chl oro-2 -iodo- 1 -methoxybenzene using method D to yield 3-(5-chloro-2-methoxyphenyl)propanal which was converted to 2-amino-5-(5-chl oro-2 -methoxybenzyl)thiophene-3 -carboxamide using method E, followed by reaction with 5-bromothiophen-2-carboxaldehyde using method B.

[1247] MS m / z: 471.0 [M+H]+

[1248] 'H NMR (600 MHz, DMSO-6) δ 7.95 (d, = 3.1 Hz, 1H), 7.89 (d, = 3.0 Hz, 1H), 7.24 (dd, J= 8.7, 2.7 Hz, 1H), 7.20 (d, J= 2.7 Hz, 1H), 7.05 (d, J= 3.8 Hz, 1H), 6.99 (d, J= 8.7 Hz, 1H), 6.91 (dd, J = 3.8, 0.8 Hz, 1H), 6.58 (d, J= 1.2 Hz, 1H), 5.93 (td, J = 3.1, 0.9 Hz, 1H), 3.85 -3.80 (m, 2H), 3.78 (s, 3H).

[1249] HPLC, rt: 15.00 (96.84% purity)

[1250] Compound 47

[1251] 6-(4-methoxybenzyl)-2-(5-(2 -methoxy ethyl)thi ophen-2 -yl)-2,3-dihy drothieno[2, 3-d]pyrimidin-4(lH)-one

[1252]

[1253] The compound was synthesized starting from l-iodo-4-methoxybenzene using method D to yield 3-(4-methoxyphenyl)propanal which was converted to 2-amino-5-(4-methoxybenzyl)thiophene-3-carboxamide using method E, followed by reaction with 5-(2-m ethoxy ethyl)thiophene-2-carbaldehy de using method B.

[1254] MS m / z: 415.3 [M+H]+

[1255] 'H NMR (402 MHz, DMSO-6) δ 7.85 – 7.79 (m, 1H), 7.77 - 7.71 (m, 1H), 7.14 - 7.07 (m, 2H), 6.89 - 6.79 (m, 3H), 6.68 (d, J= 3.5 Hz, 1H), 6.52 (s, 1H), 5.87 (t, J = 2.7 Hz, 1H), 3.81 (s, 2H), 3.69 (s, 3H), 3.46 (t, J= 6.4 Hz, 2H), 3.20 (s, 3H), 2.91 (t, J= 6.4 Hz, 2H).

[1256] HPLC, rt: 13.26 (91.60% purity)

[1257] Compound 48

[1258] 2-(5 -ethylthi ophen-2 -y 1 ) -6, 7 -difluoro-2, 3 -dihy droquinazolin-4( 1 H)-one

[1259]

[1260] O

[1261] The compound was synthesized starting from 2-amino-4,5-difluorobenzamide and 5-ethylthiophene-2-carboxaldehyde using method A.

[1262] MS m / z: 294.8 [M+H]+

[1263] XH NMR (402 MHz, DMSO-6) δ 8.54 (s, 1H), 7.49 (dd, J= 10.8, 9.0 Hz, 1H), 7.37 (d, J= 2.2 Hz, 1H), 6.88 (d, J = 3.5 Hz, 1H), 6.73 - 6.62 (m, 2H), 5.93 (t, J = 2.3 Hz, 1H), 2.71 (qd, J = 7.5, 1.1 Hz, 2H), 1.15 (t,.7= 7.5 Hz, 3H).

[1264] HPLC, rt: 13.13 (99.65% purity)

[1265] Compound 49

[1266] 2-(5 -brom othi ophen-2 -y 1 ) -6, 7 -difluoro-2, 3 -dihy droquinazolin-4( 1 H)-one

[1267] Br

[1268]

[1269] O

[1270] The compound was synthesized starting from 2-amino-4,5-difluorobenzamide and 5-bromothiophene-2-carboxaldehyde using method A.MS m / z: 345.1; 347.1 [M+H]+

[1271] 'H NMR (402 MHz, DMSO-6) δ 8.70 – 8.65 (m, 1H), 7.54 – 7.45 (m, 2H), 7.06 (d, = 3.8 Hz, 1H), 6.95 – 6.89 (m, 1H), 6.71 (dd, = 12.0, 6.7 Hz, 1H), 5.98 (t, = 2.6 Hz, 1H).

[1272] HPLC, rt: 13.20 (98.99% purity)

[1273] Compound 49a

[1274] (7?)-2-(5 -brom othi ophen-2 -yl)-6, 7 -difluoro-2, 3 -dihy droquinazolin-4( 1 H)-one

[1275] o

[1276]

[1277] This compound was synthesized as described above as racemic mixture Compound 63 and separated by chiral HPLC.

[1278] MS m / z: 345.1; 347.1 [M+H]+

[1279] 'H NMR (402 MHz, DMSO-6) δ 8.70 – 8.65 (m, 1H), 7.54 – 7.45 (m, 2H), 7.06 (d, = 3.8 Hz, 1H), 6.95 – 6.89 (m, 1H), 6.71 (dd, = 12.0, 6.7 Hz, 1H), 5.98 (t, = 2.6 Hz, 1H) ppm, HPLC, rt: 13.20 (98.99% purity),

[1280] Chiral HPLC, rt = 27.99 min (ee 100.0%).

[1281] Compound 49b

[1282] (5)-2-(5 -brom othi ophen-2 -y 1 ) -6, 7 -difluoro-2, 3 -dihy droquinazolin-4( 1 H)-one

[1283] o

[1284]

[1285] This compound was synthesized as described above as racemic mixture Compound 63 and separated by chiral HPLC.

[1286] MS m / z: 345.1; 347.1 [M+H]+

[1287] 'H NMR (402 MHz, DMSO-6) δ 8.70 – 8.65 (m, 1H), 7.54 – 7.45 (m, 2H), 7.06 (d, = 3.8 Hz, 1H), 6.95 – 6.89 (m, 1H), 6.71 (dd, = 12.0, 6.7 Hz, 1H), 5.98 (t, = 2.6 Hz, 1H) ppm, HPLC, rt: 13.20 (98.99% purity),

[1288] Chiral HPLC, rt = 24.69 min (ee 100.0%).

[1289] Compound 50

[1290] 6-(4-methoxybenzyl)-2-(5-propylthi ophen-2 -yl)-2, 3 -dihy drothieno[2, 3 -d]pyrimidin-4(lH)-one

[1291]

[1292] The compound was synthesized starting from l-iodo-4-methoxybenzene using method D to yield 3-(4-methoxyphenyl)propanal which was converted to 2-amino-5-(4-methoxybenzyl)thiophene-3-carboxamide using method E, followed by reaction with 5-propylthiophene-2-carbaldehyde using method B.

[1293] MS m / z: 399.3 [M+H]+

[1294] 'H NMR (402 MHz, DMSO-6) δ 7.83 – 7.78 (m, 1H), 7.75 - 7.70 (m, 1H), 7.15 - 7.07 (m, 2H), 6.89 - 6.79 (m, 3H), 6.63 (dd, J = 3.5, 1.0 Hz, 1H), 6.53 (d, J= 1.3 Hz, 1H), 5.87 (t, J = 2.6 Hz, 1H), 3.81 (s, 2H), 3.69 (s, 3H), 2.66 (t, J= 7.7 Hz, 2H), 1.54 (h, J= 7.4 Hz, 2H), 0.87 (t, = 7.3 Hz, 3H).

[1295] HPLC, rt: 14.62 (96.89% purity)

[1296] Compound 51

[1297] 6-chloro-2-(5-ethylthi ophen-2 -yl)-7-fluoro-2, 3 -dihydroquinazolin-4(lH)-one

[1298]

[1299] O

[1300] The compound was synthesized starting from 2-amino-5-chloro-4-fluorobenzamide and 5-ethylthiophene-2-carboxaldehyde using method A.

[1301] MS m / z: 311.5 [M+H]+

[1302] 'H NMR (402 MHz, DMSO-6) δ 8.57 (s, 1H), 7.66 - 7.60 (m, 2H), 6.88 (d, J= 3.5 Hz, 1H), 6.70 - 6.63 (m, 2H), 5.97 (t, J= 2.3 Hz, 1H), 2.76 - 2.66 (m, 2H), 1.15 (t, J= 7.5 Hz, 3H). HPLC, rt: 13.85 (97.89% purity)

[1303] Compound 52

[1304] 2-(5-ethylthiophen-2-yl)-6-(4-fluorobenzyl)-2,3-dihydrothieno[2,3-d]pyrimidin-4(lH)-one

[1305]

[1306] The compound was synthesized starting from l-fluoro-4-iodobenzene using method D to yield 3-(4-fluorophenyl)propanal which was converted to 2-amino-5-(4-fluorobenzyl)thiophene-3-carboxamide using method E, followed by reaction with 5-ethylthiophene-2-carbaldehyde using method B.

[1307] MS m / z: 373.2 [M+H]+

[1308] 'H NMR (402 MHz, DMSO-6) δ 7.87 – 7.81 (m, 1H), 7.77 - 7.72 (m, 1H), 7.28 - 7.19 (m, 2H), 7.15 - 7.03 (m, 2H), 6.86 (d, J= 3.5 Hz, 1H), 6.64 (dd, J= 3.5, 1.0 Hz, 1H), 6.56 (d, J = 1.1 Hz, 1H), 5.88 (t, J= 2.6 Hz, 1H), 3.88 (s, 2H), 2.71 (q, J= 7.5 Hz, 2H), 1.16 (t, J= 7.5 Hz, 3H).

[1309] HPLC, rt: 14.00 (95.08% purity)

[1310] Compound 53

[1311] 7 -fluoro-2-(5-i sobutylthiophen-2-yl)-2, 3 -dihy droquinazolin-4( 1 H)-one

[1312] H /

[1313] IT NH

[1314]

[1315] O

[1316] The compound was synthesized starting from 2-amino-4-fluorobenzamide and 5-isobutylthiophene-2-carbaldehyde using method A.

[1317] MS m / z: 305.3 [M+H]+

[1318] XH NMR (402 MHz, DMSO-6) δ 8.37 (t, = 2.1 Hz, 1H), 7.62 (dd, = 8.5, 6.6 Hz, 1H), 7.44 (d, = 1.8 Hz, 1H), 6.89 (dd, = 3.5, 0.6 Hz, 1H), 6.65 – 6.60 (m, 1H), 6.51 – 6.40 (m, 2H), 5.94 (t, = 2.2 Hz, 1H), 2.56 (dd, = 7.0, 0.9 Hz, 2H), 1.74 (hept, = 6.7 Hz, 1H), 0.85 (dd, = 6.6, 0.6 Hz, 6H).

[1319] HPLC, rt: 14.00 (99.88% purity)

[1320] Compound 53a

[1321] (A)-7-fluoro-2-(5 -i sobutylthiophen-2-yl)-2, 3 -dihy droquinazolin-4( 1 H)-one

[1322] NH

[1323]

[1324] This compound was synthesized as described above as racemic mixture (Compound 67) and separated by chiral HPLC.

[1325] MS m / z: 305.3 [M+H]+

[1326] XH NMR (402 MHz, DMSO-6) δ 8.37 (t, = 2.1 Hz, 1H), 7.62 (dd, = 8.5, 6.6 Hz, 1H), 7.44 (d, = 1.8 Hz, 1H), 6.89 (dd, = 3.5, 0.6 Hz, 1H), 6.65 – 6.60 (m, 1H), 6.51 – 6.40 (m, 2H), 5.94 (t, = 2.2 Hz, 1H), 2.56 (dd, = 7.0, 0.9 Hz, 2H), 1.74 (hept, = 6.7 Hz, 1H), 0.85 (dd, = 6.6, 0.6 Hz, 6H).HPLC, rt: 14.00 (99.88% purity)

[1327] Chiral HPLC, rt = 29.17 min (ee 98.4%).

[1328] Compound 53b

[1329] (5)-7-fluoro-2-(5-isobutylthiophen-2-yl)-2,3-dihydroquinazolin-4(lH)-one

[1330] o

[1331]

[1332] This compound was synthesized as described above as racemic mixture (Compound 67) and separated by chiral HPLC.

[1333] MS m / z: 305.3 [M+H]+

[1334] 1H NMR (402 MHz, DMSO-6) δ 8.37 (t, = 2.1 Hz, 1H), 7.62 (dd, J= 8.5, 6.6 Hz, 1H), 7.44 (d, J= 1.8 Hz, 1H), 6.89 (dd, J= 3.5, 0.6 Hz, 1H), 6.65 - 6.60 (m, 1H), 6.51 - 6.40 (m, 2H), 5.94 (t, J= 2.2 Hz, 1H), 2.56 (dd, J= 7.0, 0.9 Hz, 2H), 1.74 (hept, J= 6.7 Hz, 1H), 0.85 (dd, J = 6.6, 0.6 Hz, 6H).

[1335] HPLC, rt: 14.00 (99.88% purity)

[1336] Chiral HPLC, rt = 25.66 min (ee 100.0%).

[1337] Reference 1A

[1338] (5)-2-(naphthalen-2-yl)-2,3-dihydroquinazolin-4(U7)-one

[1339] [Sc(OTf)3] [Ligand A] DCM over night, RT

[1340]

[1341] The compound was synthesized starting from 2-amino-benzamide and 2-naphthaldehyde using method K.

[1342] MS m / z: 274.8 [M]+,

[1343] 1H-NMR (402 MHz, DMSO-6): δ 8.32 (s, 1H), 7.95 - 7.85 (m, 4H), 7.66 (dd, J= 8.6, 1.7 Hz, 1H), 7.61 (dd, J = 7.8, 1.6 Hz, 1H), 7.54 - 7.43 (m, 2H), 7.22 (ddd, J = 8.1, 7.2, 1.6 Hz, 1H), 7.15 (s, 1H), 6.74 (dd, J= 8.2, 1.1 Hz, 1H), 6.70 - 6.61 (m, 1H), 5.91 (t, J= 1.7 Hz, 1H) ppm, HPLC, rt = 12.22 min (96.94% purity),

[1344] Chiral HPLC, rt = 31.95 min (ee 100.0%).

[1345] CD (MeOH, 174.8 μM): λmax(Mol. CD) = 208.5 (1.635), 228 (−3.333), 260 (4.342), 345 (2.258) nm,CD (MeOH, 174.8 μM): λmin(Mol. CD) = 203.5 (1.117), 220 (−7.037), 235.5 (−3.934), 284 (0.149) nm.

[1346] Reference 2A (5)-2-(5-Bromo-2-thienyl)-2,3-dihydro-4(1H)-quinazolinone

[1347] o

[1348]

[1349] The compound was synthesized starting from 2-amino-benzamide and 5-bromothiophene-2-carbaldehyde using method M.

[1350] MS m / z: 309.1 [M+H]+,

[1351] 1H-NMR (402 MHz, DMSO-6): δ 8.50 – 8.44 (m, 1H), 7.63 – 7.55 (m, 1H), 7.29 – 7.18 (m, 2H), 7.05 (d, = 3.8 Hz, 1H), 6.91 (d, = 3.8 Hz, 1H), 6.76 – 6.62 (m, 2H), 5.93 (t, = 2.5 Hz, 1H) ppm,

[1352] HPLC, rt = 11.75 min (98.16% purity),

[1353] Chiral HPLC, rt = 17.86 min (ee 94.5%),

[1354] CD (MeOH, 232.2 μM): λmax (Mol. CD) = 212.5 (1.716), 264 (−1.742), 345 (4.644) nm, CD (MeOH, 232.2 μM): λmin (Mol. CD) = 233.5 (−8.212), 279 (−3.550) nm.

[1355] Reference 2B CR)-2-(5-Bromo-2-thienvl)-2.3-dihvdro-4(TZ / )-auinazolinone

[1356] o

[1357]

[1358] The compound was synthesized starting from 2-amino-benzamide and 5-bromothiophene-2-carbaldehyde using method L.

[1359] MS m / z: 309.1 [M+H]+,

[1360] ‘H-NMR (402 MHz, DMSO-t / e): 6 8.50 - 8.44 (m, 1H), 7.63 - 7.55 (m, 1H), 7.29 - 7.18 (m, 2H), 7.05 (d, J= 3.8 Hz, 1H), 6.91 (d, J= 3.8 Hz, 1H), 6.76 - 6.62 (m, 2H), 5.93 (t, J= 2.5 Hz, 1H) ppm,

[1361] HPLC, rt = 11.75 min (98.09 %purity),

[1362] Chiral HPLC, rt = 21.65 min (ee 91.8%).

[1363] CD (MeOH, 212.2 μM): λmax (Mol. CD) = 234.5 (9.051), 277.5 (4.049) nm,CD (MeOH, 212.2 μM): λmin (Mol. CD) = 210.5 (−1.320), 264 (2.077), 344 (−4.442) nm.

[1364] Biological Effects (Potency, Efficacy and Toxicity)

[1365] For the improvement of IGF2BPli, two novel chemical series (series 1 and 2) were designed based on prior improvements (EP 4 008 717 A3) as well as improved potency and stability of the cyclized BTYNB isomer, termed EG212 (Reference 2). By stereoselective synthesis of both stereoisomers (Reference 2A and 2B), chiral HPLC separation and CD spectroscopy the enantiomers were separated and identified. Biological testing showed that the / / -isomer is active whereas the A- stereoisomer is inactive or weakly active. These compounds were evaluated for increased potency and efficacy in a panel of four cancer cell lines derived from cancers with validated oncogenic potential of IGF2BP1: pancreatic (PANC-1) and ovarian carcinoma (ES-2), melanoma (A375) as well as neuroblastoma (BE2C).

[1366] For determining the impact of novel, here presented compounds on cancer cell vitality, BE(2)C were cultured in a 1:1 mixture of DMEM / F12 (with HEPES, Gibco) and Minimum Essential Medium (MEM) with addition of non-essential amino acids (MEM NEAA). A375, ES-2 and PANC-1 cells were cultured in Dulbecco’s modified eagle medium (DMEM, Gibco). Media were supplemented with 10% (v / V) fetal bovine serum (FBS), 2mM GlutaMAX 25 (Sigma-Aldrich, Darmstadt, Germany) and contained phenol red, 4.5g / L D-Glucose and 0.11 g / L sodium pyruvate. Cells were maintained under humidified conditions at 37°C with 5% CO2. The relative potency of novel compounds was evaluated in a pre-screen by exposing cells to a fixed concentration of each compound: 5pMfor A375 andBE(2)C, 10pMforES-2 andPANC-1. In these analyses, the relative viability of tumor cells was compared to vitality determined upon the treatment with the cyclized BTYNB isomer (EG212) at the same concentration. Note that compounds with improved tumor cell toxicity were identified in comparison to EG212 by a reduced vitality ratio (smaller than 0.5), as depicted in Table I. Tumor cell killing was analyzed by seeding cells in 96 well plates and supplementing 50pL culture media per well. Cells were seeded at the following densities: lx 103cells per well for A375 and ES-2 cells and 2x 103cells per well for BE(2)C and PANC-1 cells. For each compound, four replicates were analyzed. After seeding (24h), cells were exposed to compounds for 72h in a final volume of lOOpl cell culture medium and a fixed concentration of 0.5% DMSO (v / V). Cells exposed to DMSO alone served as the normalization control. The viability of tumor cells post-treatment (72h) was determined by the CellTiter GLO (Promega) assay, according to the manufacturer’s instructions. The relative viability in comparison to cells exposed to DMSO alone is depicted for each of the 93 compounds analyzed in Table I. These analyses indicated xx compounds with improved or maintained tumor cell killing in comparison to EG212 (Viability ratio, VR: vitality compound / vitality DMSO ~ 0.4-0.6) over four analyzed cell lines.

[1367] The potency, indicated by the half-effective concentration (EC50) of these compounds was determined by seeding cells as indicated above. Cells were exposed to a serial dilution (1:1 dilution; highest concentration 50pM) of indicated compounds for 72h before determining cell vitality by CellTiter Gio (Promega), as described for pre-screening. Tumor cell vitality at each compound concentration was determined over four replicates. Vitality determined by the exposure to DMSO (0.5% v / V) alone served as control and was set to 1. The potency ofcompounds was determined by the half-effective concentration on vitality (EC50) determined in each of the four tumor cell lines analyzed. It is depicted as the average EC50 value in Table II. The average efficacy of compounds in tumor cell killing was determined by the maximal observed relative reduction of tumor cells upon 72h of compound exposure. Note that a 100% killing equals 1 in Table II. Graphpad Prism 10 was used for the quantitative and statistical evaluation of data.

[1368] For a series of the most potent racemic compounds, the R- and 5-enanti omers were produced by means of enantioselective synthesis or chiral HPLC separation and tested for their effect in the four cancer cell lines described, and the EC50 value was determined (Table III). Only the / / -enantiomers showed high potency; the R-enantiomers are inactive or weakly active. This is exemplarily shown for EG212 and compounds 2 and 11 in the figures, wherein:

[1369] Figure 1 shows the EC50 determination of racemic-EG212, (S)-EG212 and (R)-EG212 on four studied cancer cell lines;

[1370] Figure 2 shows the EC50 determination of racemic compound 2, the 5-enantiomer of compound 2 and the A-enantiomer of compound 2 on four studied cancer cell lines; and Figure 3 shows the EC50 determination of racemic compound 11, the 5-enantiomer of compound 11 and the A-enantiomer of compound 11 on four studied cancer cell lines.

[1371] The general toxicity of compounds on non-tumorous cells was assessed by exposing human PBMCs to the most potent compounds. Note that PBMCs comprise a variety of immune cells lacking IGF2BP1 expression (data not shown). PBMCs were cultured in RPMI (Gibco) under the same conditions applied for tumor cells and supplementation by IL2. For toxicity analyses, 2x 104PBMCs were seeded in 50 pL media per well in 96-well plates. The toxicity of the selected compounds was analyzed in triplicates at seven compound concentrations using a twofold serial dilution with an initial compound concentration of 50pM. After 72h, treated cells were examined via a MACS Quant Analyzer 10 Flow Cytometer by performing a live-dead cell count using Propidium Iodide (PI). This selectively labels dead cells due to corrupted membranes allowing the dye to enter the cell. Data were normalized to DMSO controls and analyzed via Graphpad Prism 10. Toxicity for the 39 compounds with improved potency (cf. Table I) is depicted as the percentage of dead PBMCs determined at the compound’s average EC50 concentration determined over four tumor cell lines (Table II).

[1372] In summary, all analyzed compounds showed improved potency (Table II), chemical stability, efficacy and / or reduced general toxicity.

[1373] Table I. All analyzed compounds indicated with compound number (No.) relative cell vitality ratio (VR: compound / DMSO), and statistical evaluation of determined vitality ratios (VR -Median; S. D., standard deviation).

[1374] 2-(5-bromo-2-thienyl)-2,3-dihydro-lH-quinazolin-4-one (cyclized BTYNB isomer) and BTYNB* (non-cyclized isomer) highlighted in grey are reference compounds.

[1375] No. VR- VR- VR- VR- VR- A375 BE2C ES-2 Panc-1 S. D.

[1376] |5gM] |5gM] [IOJLM] [IOJLM] Median

[1377] 1 0.02 0.03 0.05 0.38 0.04 0.15

[1378] 26

[1379]

[1380] 0.04 0.04 0.02 0.33 0.04 0.130.04 0.07 0.03 0.37 0.06 0.14 0.06 0.13 0.03 0.36 0.10 0.13 0.04 0.09 0.02 0.31 0.06 0.11 0.05 0.06 0.02 0.30 0.05 0.11 0.05 0.07 0.03 0.35 0.05 0.13 0.05 0.08 0.03 0.31 0.06 0.11 0.06 0.08 0.03 0.41 0.07 0.15 0.04 0.08 0.06 0.40 0.07 0.15 0.05 0.11 0.01 0.36 0.08 0.13 0.03 0.09 0.07 0.41 0.08 0.15 0.08 0.09 0.03 0.42 0.08 0.15 0.06 0.13 0.02 0.33 0.09 0.12 0.08 0.11 0.04 0.42 0.09 0.15 0.03 0.10 0.09 0.52 0.10 0.19 0.03 0.12 0.08 0.42 0.10 0.15 0.05 0.14 0.07 0.42 0.11 0.15 0.04 0.14 0.09 0.43 0.12 0.15 0.05 0.19 0.03 0.45 0.12 0.17 0.11 0.16 0.05 0.24 0.13 0.07 0.05 0.16 0.11 0.40 0.13 0.13 0.10 0.15 0.13 0.42 0.14 0.13 0.12 0.23 0.06 0.17 0.14 0.06 0.10 0.24 0.02 0.36 0.17 0.13 0.11 0.26 0.03 0.39 0.18 0.14 0.11 0.26 0.04 0.40 0.19 0.14 0.18 0.23 0.07 0.46 0.20 0.14 0.14 0.32 0.03 0.36 0.23 0.13 0.40 0.21 0.19 0.37 0.29 0.09 0.55 0.33 0.21 0.41 0.37 0.13 0.55 0.32 0.28 0.57 0.44 0.13 0.60 0.51 0.15 0.45 0.48 0.17 0.75 0.64 0.98 0.99 0.86 0.15 0.82 0.71 0.97 1.17 0.90 0.17 0.98 0.88 1.01 0.93 0.96 0.05 1.05 0.96 0.94 1.05 1.00 0.05 1.08 0.96 0.94 1.05 1.00 0.06 1.09 0.82 0.93 1.07 1.00 0.11 1.00 1.00 1.19 0.99 1.00 0.08 0.98 1.02 1.01 1.00 1.01 0.02 1.07 0.98 1.00 1.02 1.01 0.03 1.08 0.82 0.98 1.04 1.01 0.10 1.07 0.82 0.98 1.05 1.01 0.10 0.11 0.11 0.02 0.19 0.11 0.06 0.15 0.15 0.04 0.30 0.16 0.09 0.08 0.08 0.04 0.31 0.13 0.11 0.09 0.09 0.03 0.33 0.14 0.12

[1381]

[1382] 0.14 0.14 0.03 0.27 0.15 0.0951 0.08 0.08 0.02 0.30 0.12 0.10

[1383] 42 0.35 0.35 0.04 0.27 0.26 0.13

[1384] 53 0.18 0.18 0.05 0.33 0.18 0.10

[1385] cyclized

[1386] BTYXB

[1387] isomer

[1388] (Reference

[1389] BTYNB*

[1390] i Reference

[1391]

[1392] l i

[1393] Table II. Compounds with improved potency, efficacy or general toxicity (PBMC@IC₅₀). The average IC50concentration and efficacy (1 ~ 100%) were determined in four cancer cell lines. General toxicity was evaluated based on the percentage of PBMCs killed upon exposure to compound at EC50 / IC50concentration in cancer cells for 72h. Compounds are ranked based on IC50concentration.

[1394] Enantiomers of compounds with improved potency. The average EC₅₀ concentration and efficacy (1 ~ 100%) were determined in the four cancer cell lines described above.

[1395] No. Average EC₅₀ [μM] Average efficacy PBMC @ EC₅₀

[1396] toxicity

[1397] IC₅₀ SD Mean SD SD

[1398] (%)

[1399] 1 0.27 0.04 0.87 0.13 -0.06 0.00

[1400] 27 0.27 0.01 0.88 0.13.0.30 0.00

[1401] 28 0.40 0.33 0.90 0.16 -2.30 0.06

[1402] 28a 0.15 0.07 0.88 0.15

[1403] 28b 0.69 0.24 0.91 0.16

[1404] 29 0.49 0.11 0.86 0.14 -0.68 0.00

[1405] 2 0.57 0.21 0.89 0.14 0.50 0.00

[1406] 2a 0.41 0.16 0.88 0.13

[1407] 2b 11.47 4.49 0.94 0.33

[1408] 48 0.57 0.08 0.88 0.12 0.40 0.00

[1409] 30 0.58 0.06 0.92 0.13 0.10 0.00

[1410] 30a 0.81 0.46 0.86 0.14

[1411] 30b 11.26 6.11 0.89 0.37

[1412] 31 0.62 0.26 0.87 0.12 0.70 0.00

[1413] 51 0.63 0.10 0.89 0.11 -0.49 0.00

[1414] 3 0.67 0.14 0.89 0.10 0.12 0.05

[1415] 32 0.70 0.25 0.87 0.14 0.30 0.00

[1416] 32a 0.48 0.16 0.86 0.48

[1417] 32b 3.19 0.12 0.85 0.14

[1418] 4 0.72 0.12 0.89 0.09 3.20 0.00

[1419] 5 0.75 0.09 0.89 0.13 0.40 0.04

[1420] 6 0.84 0.11 0.86 0.15 0.50 0.00

[1421] 6a 1.30 0.38 0.89 0.18

[1422] 6b 2.72 0.42 0.78 0.21

[1423] 7 0.92 0.11 0.86 0.14 1.00 0.00

[1424] 7a 0.49 0.09 0.87 0.13

[1425] 7b 14.87 7.27 1.12 0.42

[1426]

[1427] 46 0.98 0.12 0.95 0.08 -0.42 0.018 0.99 0.30 0.95 0.03 7.48 0.04 8a 0.21 0.08 0.87 0.16

[1428] 8b 11.68 7.26 0.97 0.08

[1429] 9 0.99 0.54 0.90 0.15 4.27 1.00 10 1.01 0.20 0.90 0.13 0.41 0.09 11 1.01 0.29 0.88 0.11 -10.02 0.00 Ila 0.24 0.06 0.87 0.15

[1430] 11b 13.06 3.25 0.87 0.19

[1431] 12 1.01 0.17 0.90 0.13 4.98 0.32 12a 0.72 0.24 0.89 0.14

[1432] 12b 8.63 1.78 0.89 0.11

[1433] 13 1.08 0.13 0.90 0.17 7.00 0.00 49 1.11 0.29 0.90 0.12 -2.32 0.00 49a 0.60 00.15 0.90 0.16

[1434] 49b 4.41 1.15 0.89 0.10

[1435] 47 1.13 0.16 0.94 0.13 -0.99 0.02 14 1.21 0.17 0.88 0.14 5.20 0.00 50 1.23 0.31 0.91 0.12 0.02 0.01 15 1.30 0.64 0.82 0.17 0.45 0.07 16 1.50 0.31 0.92 0.10 -0.83 0.00 16a 0.82 0.22 0.84 0.14

[1436] 16b 1.74 0.42 0.80 0.15

[1437] 17 1.51 0.61 0.87 0.14 2.50 0.25 17a 0.75 0.15 0.88 0.15

[1438] 7b 4.45 4.68 0.16 14.51

[1439] 18 1.71 0.46 0.89 0.12 5.39 0.00 52 1.77 1.07 0.95 0.10 0.32 0.04 53 1.86 0.22 0.87 0.11 1.60 0.01 53a 7.54 4.98 0.69 0.22

[1440] 53b 0.51 0.06 0.84 0.17

[1441] 19 2.04 0.31 0.85 0.15 0.07 0.00 33 2.12 0.31 0.83 0.16 0.28 0.02 33a 1.23 0.43 0.84 0.14

[1442] 33b n.i.

[1443] 20 2.38 0.29 0.90 0.14 5.15 0.09 21 2.63 0.78 0.89 0.11 4.06 0.81 45 2.77 0.86 0.90 0.11 0.02 0.10 22 2.86 3.79 0.94 0.15 3.09 2.46 23 2.97 0.33 0.85 0.14 0.75 0.25 24 4.55 0.71 0.88 0.15 0.34 0.30 25 6.18 1.63 0.94 0.06 10.08 2.08

[1444]

[1445] 26 8.33 1.23 0.92 0.07 15.25 2.22 n.t. means not tested; n.i. means no inhibitionReferences

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[1448] 3. Haase, J., Misiak, D., Bauer, M., Pazaitis, N., Braun, J., Potschke, R., Mensch, A., Bell, J. L., Dralle, H., Siebolts, U. etal. (2021) IGF2BP1 is the first positive marker for anaplastic thyroid carcinoma diagnosis. Mod Pathol, 34, 32-41.

[1449] 4. Busch, B., Bley, N., Muller, S., Glass, M., Misiak, D., Lederer, M., Vetter, M., Strauss, H. G., Thomssen, C. and Huttelmaier, S. (2016) The oncogenic triangle of HMGA2, LIN28B and IGF2BP1 antagonizes tumor-suppressive actions of the let- 7 family. Nucleic Acids Res, 44, 3845-3864.

[1450] 5. Muller, S., Bley, N., Glass, M., Busch, B., Rousseau, V., Misiak, D., Fuchs, T., Lederer, M. and Huttelmaier, S. (2018) IGF2BP1 enhances an aggressive tumor cell phenotype by impairing miRNA-directed downregulation of oncogenic factors. Nucleic Acids Res, 46, 6285-6303.

[1451] 6. Muller, S., Glass, M., Singh, A. K., Haase, J., Bley, N., Fuchs, T., Lederer, M., Dahl, A., Huang, H., Chen, J. etal. (2019) IGF2BP1 promotes SRF-dependent transcription in cancer in a m6A- and miRNA-dependent manner. Nucleic Acids Res, 47, 375-390.

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Claims

CLAIMS1. A compound represented by the following formula I, or an enantiomer thereof, particularly the A’-enantiomer, a diastereomer thereof, its hydrates, its solvates, its crystal forms, its tautomers or pharmaceutically acceptable salt thereof,wherein:R1is H;R2is H or a bond;R3is selected from the group consisting of aryl, haloalkyl, heteroaryl, haloheteroaryl, heteroarylalkyl, alkoxyaryl, alkoxyarylalkyl, wherein said haloalkyl, heteroaryl, haloheteroaryl, heteroarylalkyl, alkoxyaryl, alkoxy aryl alkyl optionally has at least one further substituent;R4is H or alkyl;R4 R4I _ l _X is selected from a group consisting ofc— and;A is a cyclic structure selected from the group consisting of unsubstituted heteroaryl and heteroaryl substituted by RT;or is represented by RB, wherein RBis unsubstituted phenyl or structure IVwhereinRTis selected from the group consisting of halo, alkyl, arylalkyl, haloarylalkyl, alkoxy, alkoxyaryl, alkoxyarylalkyl, haloalkoxy and haloalkoxyarylalkyl, wherein said alkyl, arylalkyl, haloarylalkyl, alkoxy, alkoxyaryl, alkoxyarylalkyl, haloalkoxy and haloalkoxyarylalkyl groups optionally have at least one further substituent; and if RBis represented by structure IV, then at least one of Ra, Rb, Rc, and Rdis not H, wherein said at least one of Ra, Rb, Rc, and Rdis independently selected from the group consisting of halo, nitro, alkyl, heterocyclyl, heterocyclylacyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy and carbamoyl, wherein said alkyl, heterocyclyl, heterocyclylacyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy and carbamoyl optionally have at least one substituent.

2. The compound of formula I according to claim 1, which is represented by the following formula II:(II),whereinR1, R2, R3, R4, RTand X are defined as of claim 1.

3. The compound according to claim 2, whereinR4X is — N-,A is heteroaryl substituted by RT, wherein said RTis selected from a group consisting of, alkyl, aryl, arylalkyl, haloalkoxy, alkoxyarlyl, alkoxyarylalkyl, carbamoylaryl and cabamoylarylalkyl, wherein said alkyl, aryl, arylalkyl, haloalkoxy, alkoxyarlyl, alkoxyarylalkyl, carbamoylaryl and cabamoylarylalkyl optionally can be further substituted;R2is H;R3is selected from the group consisting of aryl,, heteroaryl, haloalkyl, arylalkyl, alkoxyarlyl and alkoxyarylalkyl, wherein said heteroaryl, haloalkyl, arylalkyl, alkoxyarlyl and alkoxyarylalkyl can optionally have at least one further substituent selected from the group consisting of alkyl, alkoxy, alkoxyaryl, heteroaryl, heteroarylalkyl, heteroaryl-heteroalkyl, carbamoyl, carbamoylalkyl, halo, azido and nitro; andR4is H.

4. The compound according to claim 1, whereinR4IX is — N-R1, R2and R4are H;RBis represented by structure IV, wherein at least one of Ra, Rb, Rc, and Rdis not H and wherein said at least one of Ra, Rb, Rc, and Rdis independently selected from halo; andR3is selected from the group consisting of aryl, heteroaryl, arylalkyl, alkoxyarlyl and alkoxyarylalkyl, wherein said, alkoxyarlyl and alkoxyarylalkyl can optionally have at least one further substituent selected from the group consisting of alkyl, alkoxy and substitued alkoxy aryl.; andR4is H.

5. The compound according to any one of claims 1 to 4, wherein R3is thienyl or represented by the following structure V,(V),wherein(i) R5is selected from a group consisting of alkyl, azidoalkyl, heteroaryl, heteroarylalkyl, acylamido, wherein said alkyl, azidoalkyl, heteroaryl, heteroarylalkyl, acylamido can optionally have at least one further substituent; or(ii) R5is selected from a group consisting of halo and nitro,wherein R3can optionally be further substituted.

6. The compound according to claim 5, wherein(i) R5is selected from C₁₋₆ alkyl, triazol-1-yl, triazol-4-yl, C₁₋₆-azidoalkyl, acylamido and C₁₋₆ alkoxyalkyl, wherein said C₁₋₆ alkyl, triazol-1-yl, triazol-4-yl, C₁₋₆-azidoalkyl, acylamido and C₁₋₆ alkoxyalkyl, wherein said C₁₋₆ alkyl, triazol-1-yl, triazol-4-yl, C₁₋₆-azidoalkyl, acylamido and C₁₋₆ alkoxyalkyl, wherein said C₁₋₆ alkyl, triazol-1-yl, triazol-4-yl, C₁₋₆-azidoalkyl, acylamido and C₁₋₆ alkoxyalkyl can optionally have at least one further substituent selected from a group consisting of alkynyl, trizaol-1-yl, triazol-4-yl, C₁₋₆-alkoxy-triazol-1-yl; or(ii) R5is selected from fluoro, bromo, chloro, iodo and nitro,wherein R3can optionally be further substituted.

7. The compound according to any one of claims 1, 2, 5, or 6, wherein RTis selected from the group consisting of arylmethyl, alkoxyaryl(methyl), haloaryl(methyl), haloalkoxyaryl(methyl), carboalkoxyaryl(methyl), alkoxycarboalkoxyaryl(methyl), trifluoromethoxyphenyl(methyl), [[[(alkoxyalkoxymethyl)]triazol- 1 -yl](methyl)], alkinylacylamidoaryl(methyl), alkylacylamidoaryl(methyl), and heterocyclylaryl(methyl).

8. The compound according to any one of claims 1, 2, 5, 6, 7 or 8, whereinRTis selected from a group consisting of phenyl(methyl), 3-methoxyphenyl(methyl), 4-methoxyphenyl(methyl), 2-chlorphenyl(methyl), 2,4-dichlorphenyl(methyl), 3-carbomethoxyphenyl(methyl), 4-carbomethoxyphenyl(methyl), 4-methyl-N-prop-2-ynyl-benzamide, 4-methyl-N-ethyl-benzamide, 2-methoxyethyl 4-methyl-benzoate, 4-trifluoromethoxyphenyl(methyl), 3-chlorophenylmethyl, 2,5-dichlorophenyl(methyl),, [[4-(2-methoxyethoxymethyl)triazol-1-yl]methyl], (5-chloro-2-methoxybenzyl), 6-(4-methoxybenzyl), 6-(4-fluorobenzyl), 4-methyl-N-[[1-[2-(2-methoxyethoxy)ethyl]triazol-4-yl]methyl]benzamide and 4-piperazine-4-yl-phenyl(methyl); andR5is selected from the group consisting of H, 5-methyl, 5-ethyl, 5-bromo, 5-chloro, 5-propyl, [2-(2-methoxyethoxy)ethyl]triazol-4-yl], 5-fluoro, 5-N-prop-2-ynyl-carboxamide, [2-(2 -methoxy ethoxy)ethyl]triazol-4-yl-2-carboxamide, (2-methoxyethyl), 2- (methoxyethoxy)ethyltriazol-4-yl, 5-azidomethyl, 5-nitro, 5-[(4-propyltriazol-l-yl)methyl], [4-(2 -methoxy ethoxymethyl)triazol- 1 -yl].

9. The compound according to any one of claims 1,2, or 5, wherein RTis H or C₁₋₆ alkyl, preferably methyl or ethyl, and R5is bromo.

10. The compound according to claim 1, wherein ring A is represented by the structure IVwhereinRais H or alkyl, preferably H;Rbis H or selected from a group consisting of, alkyl, alkoxy, alkoxyalkyl, haloalkoxy, halo, and nitro;Rcis H or selected from a group consisting of alkyl, alkoxy, alkoxyalkyl, haloalkoxy, halo and nitro;Rdis H.

11. The compound according to claim 10, whereinRbis selected from a group consisting of H, Ci-6-alkyl, Ci-6-alkoxy, nitro, fluoro, chloro, bromo, iodo;Rcis H or selected from a group consisting of, Ci-6-alkyl, Ci-6-alkoxy, preferably methoxy or ethoxy, trifluoromethoxy, Ci-12-alkyl-carbamte and nitro.

12. The compound according to any one of claims 5, 6 and 11, wherein R5is selected from a group consisting of C₁₋₆-alkyl, preferably methyl or ethyl; or halo, preferably bromo or chloro.

13. The compound formula I, wherein said compound of formula I is selected from the group consisting of:ExampleIUPAC nameNo.1 2-(5-ethyl-2-thienyl)-6-[(4-methoxyphenyl)methyl]-2,3-dihydro-lH- thieno[2,3-d]pyrimidin-4-one2 2-(5-bromo-2-thienyl)-6-[(2-chlorophenyl)methyl]-2,3-dihydro-lH- thieno[2,3-d]pyrimidin-4-one2a (7?)-2-(5-bromo-2-thienyl)-6-[(2-chlorophenyl)methyl]-2,3-dihydro-lH- thieno[2,3-d]pyrimidin-4-one2b (5)-2-(5-bromo-2-thienyl)-6-[(2-chlorophenyl)methyl]-2,3-dihydro-lH- thieno[2,3-d]pyrimidin-4-one3 2-(5-bromo-2-thienyl)-6-[(4-methoxyphenyl)methyl]-2,3-dihydro-lH- thieno[2,3-d]pyrimidin-4-one4 methyl 3-[[2-(5-bromo-2-thienyl)-4-oxo-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-6-yl]methyl]benzoate52-(5-ethyl-2-thi enyl)-7-fluoro-2, 3 -dihydro- lH-quinazolin-4-one6 2-(5-bromo-2-thienyl)-6-(trifluoromethoxy)-2,3-dihydro-lH- quinazolin-4-one6a (7?)-2-(5-bromo-2-thienyl)-6-(trifluoromethoxy)-2,3-dihydro-lH- quinazolin-4-one6b (5)-2-(5-bromo-2-thienyl)-6-(trifluoromethoxy)-2,3-dihydro-lH- quinazolin-4-one72-(5-bromo-2-thienyl)-6-methoxy-2,3-dihydro-lH-quinazolin-4-one7a(7?)-2-(5-bromo-2-thi enyl)-6-methoxy-2, 3 -dihydro- lH-quinazolin-4-one7b(5)-2-(5-bromo-2-thienyl)-6-methoxy-2,3-dihydro-lH-quinazolin-4-one8 2-(5-bromo-2-thienyl)-6-[(2,4-dichlorophenyl)methyl]-2,3-dihydro-lH- thieno[2,3-d]pyrimidin-4-one8a (7?)-2-(5-bromo-2-thienyl)-6-[(2,4-dichlorophenyl)methyl]-2,3-dihydro- lH-thieno[2,3-d]pyrimidin-4-one8b (5)-2-(5-bromo-2-thienyl)-6-[(2,4-dichlorophenyl)methyl]-2,3-dihydro- lH-thieno[2,3-d]pyrimidin-4-one9 2-methoxy ethyl 4-[[2-(5-bromo-2-thienyl)-4-oxo-2,3-dihydro-lH- thieno[2,3-d]pyrimidin-6-yl]methyl]benzoate10 2-(5-bromo-2-thienyl)-6-[(3-methoxyphenyl)methyl]-2,3-dihydro-lH- thieno[2,3-d]pyrimidin-4-one11 2-(5-bromo-2-thienyl)-7-methyl-2,3-dihydro-lH-quinazolin-4-one Ila (7?)-2-(5-bromo-2-thienyl)-7-methyl-2,3- 11b (5)-2-(5-bromo-2-thienyl)-7-methyl-2,3- 122-(5-bromo-2-thi enyl)-7-chl oro-2, 3 -dihydro- lH-quinazolin-4-one12a(7?)-2-(5-bromo-2-thi enyl)-7-chl oro-2, 3 -dihydro- lH-quinazolin-4-one12b(5)-2-(5-bromo-2-thienyl)-7-chloro-2, 3 -dihydro- lH-quinazolin-4-one13 4-[[2-(5-bromo-2-thienyl)-4-oxo-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-6-yl]methyl]-N-prop-2-ynyl-benzamide14 2-(5-chloro-2-thienyl)-6-[(4-methoxyphenyl)methyl]-2,3-dihydro-lH- thieno[2,3-d]pyrimidin-4-one4-[[2-(5-bromo-2-thienyl)-4-oxo-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-6-yl]methyl]-N-ethyl-benzamide6-chloro-2-phenyl-2,3-dihydro-lH-quinazolin-4-onea (R)-6-chloro-2-phenyl-2,3-dihydro-1H-quinazolin-4-oneb (S)-6-chloro-2-phenyl-2,3-dihydro-1H-quinazolin-4-one2-(5-bromo-2-thienyl)-7-methoxy-2,3-dihydro-1H-quinazolin-4-one2-[5-(azidomethyl)-2-thienyl]-2,3 -dihydro- lH-quinazolin-4-one2-(5-bromo-2-thi enyl)-7-nitro-2, 3 -dihydro- lH-quinazolin-4-one 2-(5-bromo-2-thienyl)-6-[(4-chlorophenyl)methyl]-2,3-dihydro-lH- thieno[2,3-d]pyrimidin-4-one2-(5-bromo-2-thienyl)-6-methyl-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-4-onemethyl 4-[[2-(5-bromo-2-thienyl)-4-oxo-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-6-yl]methyl]benzoate2-(5-ethyl-2-thienyl)-7-nitro-2,3-dihydro-lH-quinazolin-4-one 6-benzyl-2-(5-bromo-2-thienyl)-2,3 -dihydro- lH-thieno[2, 3 - d]pyrimidin-4-onetert-butyl 4- [4- [ [2- ( 5 -bromo-2-thienyl)-4-oxo-2, 3 -dihydro- 1 H- thieno[2,3-d]pyrimidin-6-yl]methyl] phenyl]piperazine-l -carboxylate 2-(5-chloro-2-thienyl)-6-methyl-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-4-one2-(5-bromo-2-thienyl)-6-[(2,5-dichlorophenyl)methyl]-2,3-dihydro-lH- thieno[2,3-d]pyrimidin-4-one6-ethoxy-2-(5-ethyl-2-thienyl)-2,3-dihydro-1H-quinazolin-4-onea (R)-6-ethoxy-2-(5-ethyl-2-thienyl)-2,3-dihydro-1H-quinazolin-4-oneb 5)-6-ethoxy-2-(5-ethyl-2-thienyl)-2,3-dihydro-1H-quinazolin-4-one2-(5-ethyl-2-thienyl)-6-(trifluoromethoxy)-2,3-dihydro-lH-quinazolin- 4-one2-(5-bromo-2-thienyl)-6-[(3-chlorophenyl)methyl]-2,3-dihydro-lH- thieno[2,3-d]pyrimidin-4-onea (R)-2-(5-bromo-2-thienyl)-6-[(3-chlorophenyl)methyl]-2,3-dihydro-1H-thieno[2,3-d]pyrimidin-4-oneb (5)-2-(5-bromo-2-thienyl)-6-[(3-chlorophenyl)methyl]-2,3-dihydro-lH- thieno[2,3-d]pyrimidin-4-one2-(5-ethyl-2-thienyl)-6-[[4-(trifluoromethoxy)phenyl]methyl]-2,3- dihydro-lH-thieno[2,3-d]pyrimidin-4-one2-(5-ethyl-2-thi enyl)-6-methoxy-2, 3 -dihydro- lH-quinazolin-4-onea (R)-2-(5-ethyl-2-thienyl)-6-methoxy-2,3-dihydro-1H-quinazolin-4-oneb (S)-2-(5-ethyl-2-thienyl)-6-methoxy-2,3-dihydro-1H-quinazolin-4-one2-(5-bromo-2-thienyl)-7-fluoro-2,3-dihydro-lH-quinazolin-4-onea (R)-2-(5-bromo-2-thienyl)-7-fluoro-2,3-dihydro-1H-quinazolin-4-oneb (5)-2-(5-bromo-2-thienyl)-7-fluoro-2,3-dihydro-lH-quinazolin-4-one2- [5 - [(4-propyl tri azol- 1 -yl)methyl] -2-thienyl] -2, 3 -dihydro- 1 H- quinazolin-4-onetert-butyl N- [ 6 - [ [2 -( 5 -bromo-2-thienyl)-4-oxo-2, 3 -dihydro- 1 H- quinazolin-6-yl]amino]- 6-oxo-hexyl]carbamate2-(5-bromo-2-thienyl)-8-methyl-2,3-dihydro-lH-quinazolin-4-one2-(l-methylpyrrol-2-yl)-2,3-dihydro-lH-quinazolin-4-one2-(5-bromo-2-thienyl)-6-(morpholine-4-carbonyl)-2,3-dihydro-lH- quinazolin-4-onetert-butyl N- [ 6 - [ [2 -( 5 -bromo-2-thienyl)-4-oxo-2, 3 -dihydro- 1 H- quinazolin-6-yl]amino]- 6-oxo-hexyl]carbamate4-[[2-(5-bromo-2-thienyl)-4-oxo-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-6-yl]methyl]- N-[[l -[2-(2 -methoxy ethoxy)ethyl]triazol -4- yl]methyl]benzamide2-[5-[l-[2-(2-methoxyethoxy)ethyl]triazol-4-yl]-2-thienyl]-6-[(4- methoxyphenyl)methyl]- 2,3-dihydro-lH-thieno[2,3-d]pyrimidin-4-one 5-[6-[(4-methoxyphenyl)methyl]-4-oxo-2,3-dihydro-lH-thieno[2,3- d]pyrimidin-2-yl]-N-prop-2-ynyl-thiophene-2-carboxamide N-[[l-[2-(2-methoxyethoxy)ethyl]triazol-4-yl]methyl]-5-[6-[(4- methoxyphenyl)methyl]-4-oxo-2,3-dihydro-lH-thieno[2,3-d]pyrimidin- 2-yl]thiophene-2-carboxamide2-(5-bromo-2-thienyl)-2,3-dihydro-lH-thieno[3,2-d]pyrimidin-4-one 6-benzyl-2-(5-chloro-2-thienyl)-2,3 -dihydro- lH-thieno[2, 3 - d]pyrimidin-4-one2-(5-bromothi ophen-2 -yl)-6-(5-chloro-2-methoxybenzyl)-2, 3- dihydrothieno[2,3-d]pyrimidin-4(lH)-one6-(4-methoxybenzyl)-2-(5-(2 -methoxy ethyl)thi ophen-2 -yl)-2, 3- dihydrothieno[2,3-d]pyrimidin-4(lH)-one2-(5-ethylthi ophen-2 -yl)-6,7-difluoro-2, 3 -dihydroquinazolin-4(lH)-one 2-(5-bromothi ophen-2 -yl)-6,7-difluoro-2, 3 -dihydroquinazolin-4(lH)- onea (R)-2-(5-bromothiophen-2-yl)-6,7-difluoro-2,3-dihydroquinazolin-4(1H)-oneb (5)-2-(5-bromothiophen-2-yl)-6,7-difluoro-2,3-dihydroquinazolin- 4(lH)-one6-(4-methoxybenzyl)-2-(5-propylthi ophen-2 -yl)-2,3-dihy drothieno[2, 3- d]pyrimidin-4(lH)-one6-chloro-2-(5-ethylthiophen-2-yl)-7-fluoro-2,3-dihydroquinazolin- 4(lH)-one2-(5-ethylthi ophen-2 -yl)-6-(4-fluorobenzyl)-2,3-dihydrothieno[2, 3- d]pyrimidin-4(lH)-one7-fluoro-2-(5-isobutylthiophen-2-yl)-2,3-dihydroquinazolin-4(lH)-one53a(R)-7-fluoro-2-(5-isobutylthiophen-2-yl)-2,3-dihydroquinazolin-4(1H)-one53b (5)-7-fluoro-2-(5-isobutylthiophen-2-yl)-2,3-dihydroquinazolin-4(lH)- oneReference 2B (A)-2-(5-Bromo-2-thienyl)-2,3-dihydro-4(177)-quinazolinone14. A pharmaceutical composition comprising a compound of formula I according to any of the preceding claims.

15. A compound of formula I according to any one of clams 1 to 13 or a pharmaceutical composition according to claim 14 for use in the treatment of a malignant disorder selected from the group consisting of treating solid cancer, such as hepatocellular carcinoma, colorectal carcinoma, thyroid carcinoma and lung adenocarcinoma, preferably melanoma, neuroblastoma, ovarian and pancreatic carcinoma.

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