HK1175135B - Heterocylcic derivatives as inhibiyors of glutaminyl cyclase - Google Patents

Description

Heterocyclic derivatives as inhibitors of glutaminyl cyclase

Technical Field

The present invention relates to novel pyrrolidine derivatives as inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5). QC catalyzes the intramolecular cyclization of the N-terminal glutamine residue to pyroglutamic acid (5-oxo-prolyl, pGlu) under ammonia release, and the intramolecular cyclization of the N-terminal glutamic acid residue to pyroglutamic acid under water release.

Background

Glutaminyl cyclase (QC, EC 2.3.2.5) catalyses the intramolecular cyclization of the N-terminal glutamine residue to pyroglutamic acid (pGlu), releasing ammonia. QC was initially isolated by Messer in 1963 from the latex of the tropical plant papaya (Carica papaya) (Messer, m.1963 Nature 4874, 1299). After 24 years, the corresponding enzymatic activity was found in the animal pituitary (Busby, W.H. J.et al.1987J biol chem 262, 8532-. For mammalian QC, the conversion of Gln to pGlu by QC can be demonstrated by precursors of TRH and GnRH (Busby, W.H.J.et al.1987J Biol Chem 262, 8532-3636; Fischer, W.H.and Spiess, J.1987 Proc Natl Acad Sci U S A84, 3628-3632). Furthermore, initial localization experiments of QC showed co-localization with its putative catalytic product in bovine pituitary, further augmenting the proposed function in peptide hormone synthesis (Bockers, T.M.et al.1995 J.neuroendocrinol 7, 445-. In contrast, the physiological function of plant QC is less clear. In the case of enzymes from papaya (C.papaya), a role in the defense of plants against pathogenic microorganisms is proposed (El Moussaoui, A.et al.2001 Cell Mol Life Sci 58, 556-. Recently, putative QCs from other plants were identified by sequence comparison (Dahl, S.W.et al.2000protein Expr purify 20, 27-36). However, the physiological function of these enzymes is not yet clear.

Known QCs from plants and animals show a strict specificity for L-glutamine in the N-terminal position of the substrate and their kinetic behavior is found to follow the Michaelis-Menten equation (Pohl, T.et al 1991 Proc Natl Acad Sci U S A88, 10059-10063; Conssalvo, A.P.et al 1988 Anal Biochem 175,131-138; Gooloboov, M.Y.et al 1996 BiolChem Hoppe Seyler 377, 395-398). However, a comparison of the primary structure of QC from papaya with that of highly conserved QC from mammals does not show any sequence homology (Dahl, S.W.et al.2000 Protein Expr purify 20, 27-36). While plant QC appears to belong to a new enzyme family (Dahl, S.W.et al.2000 Protein Expr purify 20,27-36), mammalian QC was found to have significant sequence homology with bacterial aminopeptidases (Bateman, R.C.et al.2001biochemistry 40,11246-11250), leading to the conclusion that QC from plants and animals have different evolutionary origins.

Recently, it was demonstrated that recombinant human QC, as well as QC-activity from brain extracts, both catalyze N-terminal glutaminyl as well as glutamate cyclization. Most surprisingly, it was found that about pH6.0 favors cyclase-catalyzed Glu ₁-transformation, and Gln₁The conversion to pGlu-derivative takes place at an optimum pH of about 8.0. Since inhibition of QC-activity in recombinant human QC and from porcine pituitary extracts could inhibit the formation of pGlu- Α β -related peptides, the enzyme QC is a target for drug development for the treatment of alzheimer's disease.

Inhibitors of QC are described in WO 2004/098625, WO 2004/098591, WO2005/039548, WO 2005/075436, WO 2008/055945, WO 2008/055947, WO2008/055950, WO2008/065141, WO 2008/110523, WO 2008/128981, WO2008/128982, WO 2008/128983, WO 2008/128984, WO 2008/128985, WO2008/128986, WO 2008/128987 and WO 2010/026212.

EP 02011349.4 discloses polynucleotides encoding insect glutaminyl cyclase, as well as polypeptides encoded thereby and their use in methods of screening for agents reducing glutaminyl cyclase activity. Such materials are useful as pesticides.

Definition of

The term "k_i"or" K_I"and" K_D"is the binding constant, which describes the binding of the inhibitor to the enzyme and subsequent release from the enzyme. Another measure is "IC₅₀"value, which reflects the concentration of inhibitor that results in 50% enzyme activity at a given substrate concentration.

The term "DP IV-inhibitor" or "dipeptidyl peptidase IV inhibitor" is well known to those skilled in the art and refers to an enzyme inhibitor that inhibits the catalytic activity of DP IV or DP IV-like enzymes.

"DP IV-activity" is defined as the catalytic activity of dipeptidyl peptidase IV (DP IV) and DP IV-like enzymes. These enzymes are post-proline (to a lesser extent post-alanine, post-serine or post-glycine) cleaving serine proteases found in various tissues of the mammalian body, including kidney, liver and intestine, where they remove dipeptides from the N-terminus of a biologically active peptide with high specificity when proline or alanine form residues adjacent to the N-terminal amino acid in the sequence of the biologically active peptide.

The term "PEP-inhibitor" or "prolyl endopeptidase IV inhibitor" is well known to the person skilled in the art and denotes enzyme inhibitors which inhibit the catalytic activity of prolyl endopeptidase (PEP, prolyl oligopeptidase, POP).

"PEP-activity" is defined as the catalytic activity of an endoprotease capable of hydrolysing the post-proline bond in a peptide or protein, wherein the proline is located at the 3 rd or higher amino acid position counted from the N-terminus of the peptide or protein substrate.

As used herein, the term "QC" includes glutaminyl cyclase (QC) and QC-like enzymes. QC and QC-like enzymes have the same or similar enzymatic activity, further defined as QC activity. In this respect, QC-like enzymes may be completely different from QC in their molecular structure. Examples of QC-like enzymes are glutaminyl peptide cyclotransferase-like proteins (QPCTL) from humans (GenBank NM _017659), mice (GenBank BC058181), cynomolgus monkeys (macafascicularis) (GenBank AB168255), macaque (Macaca mulatta) (GenBank XM _001110995), dogs (Canis familiaris) (GenBank XM _541552), rattus norvegicus (Rattusnorvegicus) (GenBank XM _001066591), Mus musculus (Mus musculus) (GenBank BC058181) and cattle (bostaurus) (GenBank BT 026254).

As used herein, the term "QC activity" is defined as intramolecular cyclization of the N-terminal glutamine residue to pyroglutamic acid (pGlu) or intramolecular cyclization of the N-terminal L-homoglutamine or L- β -homoglutamine to cyclic pyroglutamic glutamine derivatives under release of ammonia. See therefore schemes 1 and 2.

Scheme 1: cyclization of glutamine by QC

Scheme 2: cyclization of L-homoglutamine by QC

As used herein, the term "EC" includes the activity of QC and QC-like enzymes as glutamate cyclases (ECs), further defined as EC activity.

As used herein, the term "EC activity" is defined as intramolecular cyclization of the N-terminal glutamic acid residue to pyroglutamic acid (pGlu) by QC. See scheme 3, therefore.

Scheme 3: uncharged glutamyl peptides are cyclized by QC (EC) N-terminal

The terms "QC inhibitor", "glutaminyl cyclase inhibitor" are well known to the person skilled in the art and denote enzyme inhibitors which inhibit the catalytic activity of glutaminyl cyclase (QC) or its glutamyl cyclase (EC) activity.

Potency of QC inhibition

In view of the relationship to QC inhibition, in preferred embodiments, the subject methods and medical uses of the present invention utilize QC-inhibited IC₅₀A substance of 10. mu.M or less, more preferably 1. mu.M or less, even more preferably 0.1. mu.M or less or 0.01. mu.M or less, or most preferably 0.001. mu.M or less. In fact, K is expected _iInhibitors with values in the lower micromolar, preferably nanomolar, and even more preferably picomolar range. Thus, although the active substance is described herein as a "QC inhibitor" for convenience, it should be understood that such nomenclature is not intended to limit the inventive subject matter to a particular mechanism of action.

Molecular weight of QC inhibitors

In general, QC inhibitors of the subject methods or medical uses of the invention are small molecules, e.g., having a molecular weight of 500 g/mole or less, 400 g/mole or less, preferably 350 g/mole or less, and even more preferably 300 g/mole or less, even 250 g/mole or less.

As used herein, the term "individual" refers to an animal, preferably a mammal, most preferably a human, who is the subject of treatment, observation or experiment.

As used herein, the term "therapeutically effective amount" means that amount of active compound or pharmaceutical agent that elicits the biological or medical response in a tissue system, animal or human that is 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" includes both human and veterinary uses: for example, the term "pharmaceutically acceptable" includes veterinarily acceptable compounds, or compounds that are acceptable in human medicine and health care.

Throughout the description and claims, unless otherwise specified, the expression "alkyl" denotes C_1-12Alkyl, suitably representing C_1-8Alkyl radicals, e.g. C_1-6Alkyl radicals, e.g. C_1-4An alkyl group. The alkyl group 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, isobutyl, sec-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). For example, in the expressions "alkoxy", "haloalkyl" and "thioalkyl", the expression "alkane" 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)Alkyl) and octyloxy (e.g., n-octyloxy). Exemplary thioalkyl groups include methylthio. Exemplary haloalkyl groups include fluoroalkyl groups, e.g., CF₃。

Unless specifically limited, the expression "alkenyl" denotes C_2-12Alkenyl, suitably represents C_2-6Alkenyl radicals, e.g. C_2-4Alkenyl comprising at least one double bond at any desired position and not comprising any triple bond. The alkenyl group may be straight-chain or branched. Exemplary alkenyl groups containing one double bond include propenyl and butenyl. Exemplary alkenyl groups containing two double bonds include pentadienyl, such as (1E,3E) -pentadienyl.

Unless specifically limited, the expression "alkynyl" denotes C_2-12Alkynyl, suitably represents C_2-6Alkynyl, e.g. C_2-4Alkynyl groups which contain at least one triple bond at any desired position and may or may not also contain one or more double bonds. The alkynyl group may be linear or branched. Exemplary alkynyl groups include propynyl and butynyl.

Unless specifically limited, the expression "alkylene" denotes the formula- (CH)₂)_nA chain of (a) wherein n is an integer, for example 2 to 5.

Unless specifically limited, the expression "cycloalkyl" denotes C_3-10Cycloalkyl (i.e. 3 to 10 ring carbon atoms), more suitably representing C_3-8Cycloalkyl radicals, e.g. C_3-6A cycloalkyl group. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The most suitable number of ring carbon atoms is 3 to 6.

Unless otherwise specified, the expression "cycloalkenyl" denotes C_5-10Cycloalkenyl (i.e. 5 to 10 ring carbon atoms), more suitably represents C_5-8Cycloalkenyl radicals, e.g. C_5-6A cycloalkenyl group. Exemplary cycloalkenyl groups include cyclopropenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Most suitably the number of ring carbon atoms is from 5 to 6.

Unless specifically limited, the expression "carbocyclyl" denotes any ring system wherein all ring atoms are carbon and which contains from 3 to 12 ring carbon atoms, suitably from 3 to 10 carbon atoms, and more suitably from 3 to 8 carbon atoms. Carbocyclyl groups may be saturated or partially unsaturated, but do not include aromatic rings. Examples of carbocyclyl groups include monocyclic, bicyclic and tricyclic ring systems, particularly monocyclic and bicyclic ring systems. Other carbocyclic groups include bridged ring systems (e.g., bicyclo [2.2.1] heptenyl). A specific example of carbocyclyl is cycloalkyl. Other examples of carbocyclyl are cycloalkenyl.

Unless otherwise specified, the expression "heterocyclyl" refers to a carbocyclic group in which one or more (e.g. 1, 2 or 3) ring atoms are replaced by a heteroatom selected from N, S and O. Specific examples of heterocyclyl groups are cycloalkyl groups (e.g. cyclopentyl or more particularly cyclohexyl) in which one or more (e.g. 1, 2 or 3, especially 1 or 2, especially 1) ring atoms are replaced by a heteroatom selected from N, S or O. Exemplary heterocyclic groups containing one heteroatom include pyrrolidine, tetrahydrofuran, and piperidine; while exemplary heterocyclic groups containing two heteroatoms include morpholine and piperazine. Other specific examples of heterocyclyl groups are cycloalkenyl groups (e.g. cyclohexenyl) wherein one or more (e.g. 1, 2 or 3, especially 1 or 2, especially 1) ring atoms are replaced by a heteroatom selected from N, S or O. An example of such a group is dihydropyranyl (e.g. 3, 4-dihydro-2H-pyran-2-yl-).

Unless otherwise specified, the expression "aryl" denotes C_6-12Aryl, suitably represents C_6-10Aryl, more suitably represents C_6-8And (4) an aryl group. The aryl group contains at least one aromatic ring (e.g., 1, 2, or 3 rings). An example of a typical aryl group having one aromatic ring is phenyl. An example of a typical aryl group having two aromatic rings is naphthyl.

Unless specifically limited, the expression "heteroaryl" denotes an aryl residue in which one or more (e.g. 1,2,3 or 4, suitably 1,2 or 3) ring atoms are replaced by a heteroatom selected from N, S and O, or a 5-membered aromatic ring comprising 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., pyridines 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, imidazoles, such as imidazol-1-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 tetrazoles. Exemplary bicyclic heteroaryls include: indoles (e.g., indol-6-yl), benzofurans, benzothiophenes, quinolines, isoquinolines, indazoles, benzimidazoles, benzothiazoles, quinazolines, and purines.

Unless otherwise specified, the expression "-alkylaryl" denotes a residue obtained by passing an alkylene moiety (e.g. C)_1-4Alkylene moiety) to an aryl residue.

Unless otherwise specified, the expression "-alkylheteroaryl" denotes a residue obtained by the reaction of an alkylene moiety (for example C)_1-4Alkylene moiety) to a heteroaryl residue.

The term "halogen" or "halo" includes fluorine (F), chlorine (Cl) and bromine (Br).

The term "amino" refers to the group-NH₂。

The term "phenyl substituted with phenyl" refers to biphenyl.

Term(s) forRepresents a single bond in which stereochemistry is undefined.

When the benzimidazolyl group is represented as a benzimidazol-5-yl group represented by the following formula:

those skilled in the art will appreciate that the benzimidazol-6-yl group represented by the formula:

are equivalent structures. As used herein, the term "benzimidazol-5-yl" encompasses both forms of benzimidazolyl.

Stereoisomers

All possible stereoisomers of the claimed compounds are included in the present invention.

When the compounds of the invention have at least one chiral center, they may accordingly exist as enantiomers. When the compounds have two or more chiral centers, they may also exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

Preparation and isolation of stereoisomers

When the process for preparing the compounds of the present invention produces 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 the individual enantiomers may be prepared by enantiospecific synthesis or by resolution. For example, the compounds may be resolved into their component enantiomers by standard techniques, for example, by salt formation with an optically active acid such as (-) -di-p-toluoyl-d-tartaric acid and/or (+) -di-p-toluoyl-l-tartaric acid to form diastereomeric pairs, followed by fractional crystallization and re-generation of the free base. The compounds may also be resolved by the formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds can be resolved using a chiral HPLC column.

Pharmaceutically acceptable salts

In view of the close relationship between the free compounds and the compounds in the form of their salts or solvates, whenever a compound is mentioned herein, the corresponding salt, solvate or polymorph is also meant, as far as this is possible or appropriate.

Salts and solvates of the compounds of formula (I) and physiologically functional derivatives thereof which are suitable for use in medicine are those in which the counter ion or related solvent is pharmaceutically acceptable. However, salts and solvates with non-pharmaceutically acceptable counter ions or related solvents are within the scope of the invention, for example, as intermediates in the preparation of other compounds and their pharmaceutically acceptable salts and solvates.

Suitable salts of the present invention include salts with organic and inorganic acids or bases. Pharmaceutically acceptable acid addition salts include those formed with the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, triphenylacetic acid, sulfamic acid, sulfanilic acid, succinic acid, oxalic acid, fumaric acid, maleic acid, malic acid, mandelic acid, glutamic acid, aspartic acid, oxaloacetic acid, methanesulfonic acid, ethanesulfonic acid, arylsulfonic acids (e.g., p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, or naphthalenedisulfonic acid), salicylic acid, glutaric acid, gluconic acid, tricarballylic acid, cinnamic acid, substituted cinnamic acids (e.g., phenyl, methyl, methoxy, or halogen substituted cinnamic acids, including 4-methylcinnamic acid and 4-methoxycinnamic acid), ascorbic acid, oleic acid, naphthoic acid, hydroxynaphthoic acid (e.g., 1-hydroxy-2-naphthoic acid or 3-hydroxy-2-naphthoic acid), Naphthacrylic acid (e.g., naphthalene-2-acrylic acid), benzoic acid, 4-methoxybenzoic acid, 2-or 4-hydroxybenzoic acid, 4-chlorobenzoic acid, 4-phenylbenzoic acid, phenylacrylic acid (e.g., 1, 4-benzenediacrylic acid), isethionic acid, perchloric acid, propionic acid, glycolic acid, isethionic acid, pamoic acid, cyclamic acid, salicylic acid, saccharinic acid, and trifluoroacetic acid. Pharmaceutically acceptable base salts include: an ammonium salt; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; and salts with organic bases such as dicyclohexylamine and N-methyl-D-glucosamine.

All pharmaceutically acceptable acid addition salt forms of the compounds of the present invention are intended to be included within the scope of the present invention.

Polymorphic crystalline forms

Moreover, some 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 included within the scope of the present invention. The compounds, including their salts, may also be obtained in the form of their hydrates or contain other solvents used for their crystallization.

Prodrugs

The present invention further includes within its scope prodrugs of the compounds of the present invention. In general, such prodrugs are functional derivatives of the compounds that are readily convertible in vivo into the desired therapeutically active compound. Thus, in these cases, the treatment methods of the present invention, the term "administering" shall include the treatment of the various stated conditions with a prodrug form of one or more of the claimed compounds, but which is converted in vivo to the compound described above after administration to the subject. Conventional methods for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of produgs", ed.h. bundgaard, Elsevier, 1985.

Protecting group

In any method of preparing a compound of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting Groups, such as those described by 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, which are incorporated herein in their entirety. The protecting group may be removed at a convenient subsequent stage using methods known in the art.

Protecting groups or protecting groups are introduced into the molecule by chemical modification of functional groups in order to obtain chemoselectivity in subsequent chemical reactions. Protecting groups such as alcohol protecting groups, amine protecting groups, carbonyl protecting groups, carboxylic acid protecting groups, and phosphoric acid protecting groups.

Examples of alcohol protecting groups are acetyl (Ac), benzoyl (Bz), benzyl (Bn, Bnl), β -Methoxyethoxymethyl Ether (MEM), dimethoxytrityl (mimotoxytrityl) [ bis- (4-methoxyphenyl) phenylmethyl, DMT ], methoxymethyl ether (MOM), methoxytrityl [ (4-methoxyphenyl) benzhydryl, MMT), p-methoxybenzyl ether (PMB), methylthiomethyl ether, pivaloyl (Piv), Tetrahydropyranyl (THP), trityl (triphenylmethyl, Tr), silyl ethers (e.g., trimethylsilyl ether (TMS), t-butyldimethylsilyl ether (TBDMS), t-butyldimethylsilyloxymethyl ether (TOM) and triisopropylsilyl ether (TIPS)); methyl ether and Ethoxyethyl Ether (EE).

Suitable amine protecting groups are selected from benzyloxycarbonyl (Cbz), p-methoxybenzylcarbonyl (Moz or MeOZ), tert-Butoxycarbonyl (BOC), 9-Fluorenylmethoxycarbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3, 4-Dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts) and other sulfonamides (Nosyl & Nps).

Suitable carbonyl protecting groups are selected from acetals and ketals, acylates and dithianes.

Suitable carboxylic acid protecting groups are selected from methyl esters, benzyl esters, t-butyl esters, silyl esters, ortho esters and oxazolines.

Examples of phosphoric acid protecting groups are 2-cyanoethyl and methyl (Me).

As used herein, the term "composition" is intended to include products comprising a therapeutically effective amount of the claimed compounds, as well as any product which results, directly or indirectly, from combination of the claimed compounds.

Carriers and additives for galenic formulations

Thus, for liquid oral preparations such as 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 formulations such as powders, capsules, soft capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.

Carriers that may 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, disintegrants, dyes and colorants.

Soluble polymers as targetable drug carriers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide phenol, polyhydroxyethylaspartamide-phenol, or polyethylene oxide polylysine substituted with palmitoyl residues. In addition, the compounds of the present invention may be coupled to a class of biodegradable polymers useful for achieving controlled release of a drug, such as polylactic acid, polyepsilon caprolactone, polyhydroxybutyric acid (polyhydroxybutyric acid), polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic hydrogel block copolymers.

Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta lactose, 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.

Disintegrants include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

Summary of The Invention

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers of said compound:

wherein:

R¹represents heteroaryl, -carbocyclyl-heteroaryl, -C_2-6Alkenyl heteroaryl, -C_1-6Alkyl heteroaryl or (CH)₂)_aCR⁵R⁶(CH₂)_bHeteroaryl, wherein a and b independently represent an integer from 0 to 5, with the proviso that a + b =0 to 5, and R⁵And R⁶Are taken together with the carbon to which they are attached to form C₃-C₅Alkylene groups of cycloalkyl groups;

wherein any of the above heteroaryl groups may be optionally selected from C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, -C_1-6Thioalkyl, -SOC_1-4Alkyl, -SO₂C_1-4Alkyl radical, C_1-6Alkoxy-, -O-C_3-8Cycloalkyl radical, C_3-8Cycloalkyl, -SO₂C_3-8Cycloalkyl, -SOC_3-6Cycloalkyl radical, C_3-6Alkenyloxy-, C_3-6Alkynyloxy-, -C (O) C_1-6Alkyl, -C (O) OC_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkyl-, nitro-, halogen-, cyano-, hydroxy, -C (O) OH, -NH₂、-NHC_1-4Alkyl, -N (C)_1-4Alkyl) (C_1-4Alkyl), -C (O) N (C)_1-4Alkyl) (C_1-4Alkyl), -C (O) NH₂、-C(O)NH(C_1-4Alkyl) and-C (O) NH (C)_3-10Cycloalkyl) substituted with one or more groups;

and wherein any of the above carbocyclic groups may optionally be selected from C_1-4Alkyl, oxo, halogen and C_1-4One or more groups of alkoxy;

R²Representation H, C_1-8Alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, -C_1-4Alkylaryl, -C_1-4Alkyl heteroaryl, -C_1-4Alkyl carbocyclyl or-C_1-4An alkyl heterocyclic group;

wherein any of the above aryl and heteroaryl groups may be optionally selected from C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, -C_1-6Thioalkyl, -SOC_1-4Alkyl, -SO₂C_1-4Alkyl radical, C_1-6Alkoxy-, -O-C_3-8Cycloalkyl radical, C_3-8Cycloalkyl, -SO₂C_3-8Cycloalkyl, -SOC_3-6Cycloalkyl radical, C_3-6Alkenyloxy-, C_3-6Alkynyloxy-, -C (O) C_1-6Alkyl, -C (O) OC_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkyl-, C_1-6alkoxy-C_1-6Alkoxy-, nitro-, halogen, halogeno-C_1-6Alkyl, halo C_1-6Alkoxy, cyano, hydroxy, -C (O) OH, -NH₂、-NHC_1-4Alkyl, -N (C)_1-4Alkyl) (C_1-4Alkyl), -N (C)_1-4Alkyl) (C_1-4Alkyl) -N (C)_1-4Alkyl) (C_1-4Alkyl), -C_1-4alkyl-N (C)_1-4Alkyl) (C_1-4Alkyl), -C_1-4alkoxy-N (C)_1-4Alkyl) (C_1-4Alkyl), -N (C)_3-8Cycloalkyl) (C)_3-8Cycloalkyl), -N (-C)_1-6alkyl-C_1-6Alkoxy) (-C_1-6alkyl-C_1-6Alkoxy), -C (O) N (C)_1-4Alkyl) (C_1-4Alkyl), -C (O) NH₂、-C(O)NH(C_1-4Alkyl) and-C (O) NH (C)_3-10Cycloalkyl) substituted with one or more groups;

and wherein any of the above carbocyclic and heterocyclic groupsEach may be optionally selected from C_1-4Alkyl, oxo, halogen, -C (O) C _1-6Alkyl and C_1-4One or more groups of alkoxy;

or R²Represents phenyl substituted by phenyl, phenyl substituted by monocyclic heteroaryl, phenyl substituted by phenoxy, phenyl substituted by heterocyclyl, wherein the heterocyclyl is substituted by phenyl, by-O-C_1-4Alkyl-heterocyclyl substituted phenyl, benzyloxy substituted phenyl, carbocyclyl substituted phenyl wherein said carbocyclyl is substituted with heterocyclyl, O-carbocyclyl substituted phenyl, phenyl substituted heterocyclyl, phenyl substituted carbocyclyl, phenyl fused to heterocyclyl, -C_1-4Alkyl (phenyl substituted by phenyl), -C_1-4Alkyl (phenyl substituted by monocyclic heteroaryl), -C_1-4Alkyl (phenyl substituted by monocyclic heterocyclyl), -C_1-4Alkyl (phenyl substituted by-O-carbocyclyl), -C_1-4Alkyl (phenyl substituted by benzyloxy), -C_1-4Alkyl (optionally substituted phenyl fused to an optionally substituted carbocyclyl) or-C_1-4Alkyl (optionally substituted phenyl fused to an optionally substituted heterocyclyl);

wherein any of the above phenyl, benzyloxy, and heteroaryl groups can be optionally selected from C _1-4Alkyl, halogen and C_1-4One or more groups of alkoxy;

and wherein any of the foregoing carbocyclyl and heterocyclyl groups may be optionally substituted with one or more substituents selected from methyl, phenyl, oxo, halogen, hydroxy and C_1-4One or more groups of alkoxy;

R³represents H, -C_1-4An alkyl or aryl group;

wherein the above aryl groups may optionally be selected from C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, -C_1-6Thioalkyl-SOC_1-4Alkyl, -SO₂C_1-4Alkyl radical, C_1-6Alkoxy-, -O-C_3-8Cycloalkyl radical, C_3-8Cycloalkyl, -SO₂C_3-8Cycloalkyl, -SOC_3-6Cycloalkyl radical, C_3-6Alkenyloxy-, C_3-6Alkynyloxy-, -C (O) C_1-6Alkyl, -C (O) OC_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkyl-, nitro-, halogen-, cyano-, hydroxy, -C (O) OH, -NH₂、-NHC_1-4Alkyl, -N (C)_1-4Alkyl) (C_1-4Alkyl), -C (O) N (C)_1-4Alkyl) (C_1-4Alkyl), -C (O) NH₂、-C(O)NH(C_1-4Alkyl) and-C (O) NH (C)_3-10Cycloalkyl) substituted with one or more groups;

or R²And R³Joined to form a C optionally substituted with one or more_1-2An alkyl-substituted carbocyclic ring;

or R²And R³Are linked to form a carbocyclic ring fused to a phenyl, wherein the carbocyclic group and/or the phenyl may optionally be selected from C_1-4Alkyl, halogen and C_1-4One or more groups of alkoxy;

or R ²And R³Are linked to form a carbocyclic ring fused to a monocyclic heteroaryl, wherein the carbocyclic and/or heteroaryl groups described above may optionally be selected from C_1-4Alkyl, halogen and C_1-4One or more groups of alkoxy;

x represents C = O, O, S, CR⁷R⁸、-O-CH₂-or-CH₂-CH₂-；

Y represents CHR⁹C = O or C = S;

z represents-N-R⁴O or CHR¹⁰So that when X represents O or S, Z must represent CHR¹⁰；

Or X and Z represent two adjacent carbon atoms of a phenyl ring which is fused at this position andsaid phenyl ring being optionally substituted by one or more halogens or C_1-2Alkyl substitution;

R⁴represents H, -C_1-8Alkyl, -C (O) C_1-6Alkyl or-NH₂；

R⁷And R⁸Independently represent H, -C_1-4An alkyl or aryl group;

wherein the above aryl group may be optionally substituted by C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, -C_1-6Thioalkyl, -SOC_1-4Alkyl, -SO₂C_1-4Alkyl radical, C_1-6Alkoxy-, -O-C_3-8Cycloalkyl radical, C_3-8Cycloalkyl, -SO₂C_3-8Cycloalkyl, -SOC_3-6Cycloalkyl radical, C_3-6Alkenyloxy-, C_3-6Alkynyloxy-, -C (O) C_1-6Alkyl, -C (O) OC_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkyl-, nitro-, halogen-, cyano-, hydroxy, -C (O) OH, -NH₂、-NHC_1-4Alkyl, -N (C)_1-4Alkyl) (C_1-4Alkyl), -C (O) N (C)_1-4Alkyl) (C_1-4Alkyl), -C (O) NH₂、-C(O)NH(C_1-4Alkyl) and-C (O) NH (C)_3-10Cycloalkyl) substituted;

R⁹And R¹⁰Independently represents H or methyl;

provided that the moiety-Y-Z-X-represents except C (= O) -N (-R)⁴) -C (= O) -or-C (= S) -N (-R)⁴) A moiety other than-C (= O) -.

Detailed Description

In a particular embodiment of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt, solvate or polymorph thereof, including all tautomers and stereoisomers of said compound:

wherein:

R¹represents heteroaryl, -carbocyclyl-heteroaryl, -C_2-6Alkenyl heteroaryl, -C_1-6Alkyl heteroaryl or (CH)₂)_aCR⁵R⁶(CH₂)_bHeteroaryl, wherein a and b independently represent an integer from 0 to 5, with the proviso that a + b =0 to 5, and R⁵And R⁶Are taken together with the carbon to which they are attached to form C₃-C₅Alkylene groups of cycloalkyl groups;

wherein any of the above heteroaryl groups may be optionally selected from C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, -C_1-6Thioalkyl, -SOC_1-4Alkyl, -SO₂C_1-4Alkyl radical, C_1-6Alkoxy-, -O-C_3-8Cycloalkyl radical, C_3-8Cycloalkyl, -SO₂C_3-8Cycloalkyl, -SOC_3-6Cycloalkyl radical, C_3-6Alkenyloxy-, C_3-6Alkynyloxy-, -C (O) C_1-6Alkyl, -C (O) OC_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkyl-, nitro-, halogen-, cyano-, hydroxy, -C (O) OH, -NH₂、-NHC_1-4Alkyl, -N (C)_1-4Alkyl) (C_1-4Alkyl), -C (O) N (C)_1-4Alkyl) (C_1-4Alkyl), -C (O) NH₂、-C(O)NH(C_1-4Alkyl) and-C (O) NH (C) _3-10Cycloalkyl) substituted with one or more groups;

and wherein any of the above carbocyclic groups may optionally be selected from C_1-4Alkyl, oxo, halogen and C_1-4One or more groups of alkoxy;

R²representation H, C_1-8Alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, -C_1-4Alkylaryl, -C_1-4Alkyl heteroaryl, -C_1-4Alkyl carbocyclyl or-C_1-4An alkyl heterocyclic group;

wherein any of the above aryl and heteroaryl groups may be optionally selected from C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, -C_1-6Thioalkyl, -SOC_1-4Alkyl, -SO₂C_1-4Alkyl radical, C_1-6Alkoxy-, -O-C_3-8Cycloalkyl radical, C_3-8Cycloalkyl, -SO₂C_3-8Cycloalkyl, -SOC_3-6Cycloalkyl radical, C_3-6Alkenyloxy-, C_3-6Alkynyloxy-, -C (O) C_1-6Alkyl, -C (O) OC_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkyl-, nitro-, halogen-, halogeno-C_1-6Alkyl, halo C_1-6Alkoxy, cyano, hydroxy, -C (O) OH, -NH₂、-NHC_1-4Alkyl, -N (C)_1-4Alkyl) (C_1-4Alkyl), -C (O) N (C)_1-4Alkyl) (C_1-4Alkyl), -C (O) NH₂、-C(O)NH(C_1-4Alkyl) and-C (O) NH (C)_3-10Cycloalkyl) substituted with one or more groups;

and wherein any of the aforementioned carbocyclyl and heterocyclyl groups may be optionally selected from C_1-4Alkyl, oxo, halogen and C_1-4One or more groups of alkoxy;

Or R²Represents phenyl substituted by phenyl, phenyl substituted by monocyclic heteroaryl, phenyl substituted by phenoxy, phenyl substituted by heterocyclyl, phenyl substituted by-O-C_1-4Alkyl-heterocyclyl substituted phenyl, benzyloxy substituted phenyl, fused to carbocyclyl, fused to heterocyclyl phenyl, -C_1-4Alkyl (phenyl substituted by phenyl), -C_1-4Alkyl (phenyl substituted by monocyclic heteroaryl), -C_1-4Alkyl (phenyl substituted by benzyloxy), -C_1-4Alkyl (optionally substituted phenyl fused to an optionally substituted carbocyclyl) or-C_1-4Alkyl (optionally substituted phenyl fused to an optionally substituted heterocyclyl);

wherein any of the above phenyl groupsBenzyloxy and heteroaryl groups may each optionally be selected from C_1-4Alkyl, halogen and C_1-4One or more groups of alkoxy;

and wherein any of the foregoing carbocyclyl and heterocyclyl may be optionally selected from methyl, phenyl, oxo, halogen and C_1-4One or more groups of alkoxy;

R³represents H, -C_1-4An alkyl or aryl group;

wherein the above aryl groups may optionally be selected from C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, -C_1-6Thioalkyl, -SOC_1-4Alkyl, -SO₂C_1-4Alkyl radical, C _1-6Alkoxy-, -O-C_3-8Cycloalkyl radical, C_3-8Cycloalkyl, -SO₂C_3-8Cycloalkyl, -SOC_3-6Cycloalkyl radical, C_3-6Alkenyloxy-, C_3-6Alkynyloxy-, -C (O) C_1-6Alkyl, -C (O) OC_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkyl-, nitro-, halogen-, cyano-, hydroxy, -C (O) OH, -NH₂、-NHC_1-4Alkyl, -N (C)_1-4Alkyl) (C_1-4Alkyl), -C (O) N (C)_1-4Alkyl) (C_1-4Alkyl), -C (O) NH₂、-C(O)NH(C_1-4Alkyl) and-C (O) NH (C)_3-10Cycloalkyl) substituted with one or more groups;

or R²And R³Joined to form a C optionally substituted with one or more_1-2An alkyl-substituted carbocyclic ring;

or R²And R³Are linked to form a carbocyclic ring fused to a phenyl, wherein the carbocyclic group and/or the phenyl may optionally be selected from C_1-4Alkyl, halogen and C_1-4One or more groups of alkoxy;

or R²And R³Are linked to form a carbocyclic ring fused to a monocyclic heteroaryl, whereinThe carbocyclyl and/or heteroaryl may optionally be selected from C_1-4Alkyl, halogen and C_1-4One or more groups of alkoxy;

x represents C = O, O, S, CR⁷R⁸、-O-CH₂-or-CH₂-CH₂-；

Y represents CHR⁹C = O or C = S;

z represents-N-R⁴O or CHR¹⁰So that when X represents O or S, Z must represent CHR¹⁰；

Or X and Z represent two adjacent carbon atoms of a phenyl ring, said phenyl ring being fused at this position and said phenyl ring optionally being substituted by one or more halogens or C _1-2Alkyl substitution;

R⁴represents H, -C_1-8Alkyl, -C (O) C_1-6Alkyl or-NH₂；

R⁷And R⁸Independently represent H, -C_1-4An alkyl or aryl group;

wherein the above aryl group may be optionally substituted by C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, -C_1-6Thioalkyl, -SOC_1-4Alkyl, -SO₂C_1-4Alkyl radical, C_1-6Alkoxy-, -O-C_3-8Cycloalkyl radical, C_3-8Cycloalkyl, -SO₂C_3-8Cycloalkyl, -SOC_3-6Cycloalkyl radical, C_3-6Alkenyloxy-, C_3-6Alkynyloxy-, -C (O) C_1-6Alkyl, -C (O) OC_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkyl-, nitro-, halogen-, cyano-, hydroxy, -C (O) OH, -NH₂、-NHC_1-4Alkyl, -N (C)_1-4Alkyl) (C_1-4Alkyl), -C (O) N (C)_1-4Alkyl) (C_1-4Alkyl), -C (O) NH₂、-C(O)NH(C_1-4Alkyl) and-C (O) NH (C)_3-10Cycloalkyl) substituted;

R⁹and R¹⁰Independently represents H or methyl;

provided that the moiety-Y-Z-X-represents other than-C (= O) -N (-R)⁴) -C (= O) -or-C (= S) -N (-R)⁴) A moiety other than-C (= O) -.

When carbocyclyl and heterocyclyl are substituted, they are typically substituted with 1 or 2 substituents (e.g., 1 substituent). Typically, the substituent is methyl. More typically, carbocyclyl and heterocyclyl are unsubstituted.

When aryl and heteroaryl groups are substituted, they are typically substituted with 1, 2 or 3 substituents (e.g., 1 or 2). The substituents for aryl and heteroaryl being selected from C _1-6Alkyl (e.g. methyl), C_2-6Alkenyl (e.g. buten-3-yl), C_2-6Alkynyl (e.g. butyn-3-yl), C_1-6Haloalkyl (e.g. fluoromethyl, trifluoromethyl), -C_1-6Thioalkyl (e.g. -S-methyl), -SOC_1-4Alkyl (e.g., -SO methyl), -SO₂C_1-4Alkyl (e.g., -SO)₂Methyl group), C_1-6Alkoxy- (e.g. methoxy, ethoxy), -O-C_3-8Cycloalkyl (e.g. -O-cyclopentyl), C_3-8Cycloalkyl (e.g. cyclopropyl, cyclohexyl), -SO₂C_3-8Cycloalkyl (e.g. -SO)₂Cyclohexyl), -SOC_3-6Cycloalkyl (e.g. -SO cyclopropyl), C_3-6Alkenyloxy- (e.g. -O-buten-2-yl), C_3-6Alkynyloxy- (e.g. -O-buten-2-yl), -C (O) C_1-6Alkyl (e.g., -C (O) ethyl), -C (O) OC_1-6Alkyl (e.g. -C (O) O-methyl), C_1-6alkoxy-C_1-6Alkyl- (e.g. methoxy-ethyl-), nitro, halogen (e.g. fluoro, chloro, bromo), cyano, hydroxy, -C (O) OH, -NH₂、-NHC_1-4Alkyl (e.g. -NH methyl), -N (C)_1-4Alkyl) (C_1-4Alkyl) (e.g., -N (methyl)₂)、-C(O)N(C_1-4Alkyl) (C_1-4Alkyl) (e.g., -C (O) N (methyl)₂)、-C(O)NH₂、-C(O)NH(C_1-4Alkyl) (e.g., -C (O) NH methyl), -C (O) NH (C)_3-10Cycloalkyl) (e.g., -C (O) NH cyclopropyl). More typically, the substituents are selected from C_1-6Alkyl (e.g. methyl), C_1-6Haloalkyl (e.g. C)_1-6Fluoroalkyl radicals, e.g. CF₃)、C_1-6Alkoxy (e.g., OMe), halogen, and hydroxy.

When R is¹Where heteroaryl is indicated, examples include monocyclic (e.g. 5-and 6-membered) and bicyclic (e.g. 9-and 10-membered, especially 9-membered) heteroaryl rings, especially rings containing nitrogen atoms (e.g. 1 or 2 nitrogen atoms). Suitable bicyclic heteroaryl rings are 9-membered heteroaryl rings containing 1 or 2 nitrogen atoms, particularly phenyl rings fused to a 5-membered ring containing 1 or 2 nitrogen atoms (e.g. 1H-benzimidazolyl). Most suitably, the point of attachment is through a phenyl ring, for example the group is 1H-benzimidazol-5-yl. The heteroaryl groups mentioned above may be unsubstituted (as is more typical) or may suitably be selected from alkyl (e.g. C)_1-4Alkyl, e.g. Me), alkoxy- (e.g. C)_1-4Alkoxy-, such as OMe) and halogen (e.g. F).

When R is¹represents-C_3-8When carbocyclyl-heteroaryl, examples of carbocyclyl include cycloalkyl (e.g., cyclohexyl) and cycloalkenyl (e.g., cyclohexenyl), and examples of heteroaryl include monocyclic (e.g., 5-or 6-membered, especially 5-membered), especially rings containing nitrogen atoms (e.g., 1 or 2 nitrogen atoms). The heteroaryl groups mentioned above may be unsubstituted (as is more typical) or may suitably be selected from alkyl (e.g. C)_1-4Alkyl, e.g. Me), alkoxy- (e.g. C) _1-4Alkoxy-, such as OMe) and halogen (e.g. F). Suitable heteroaryl groups are imidazol-1-yl. exemplary-C_3-8Carbocyclyl-heteroaryl is 3-imidazol-1-yl-cyclohexyl-.

When R is¹represents-C_2-6Alkenyl heteroaryl, C_2-6Examples of alkenyl groups include C_2-4Alkenyl, particularly propenyl, and examples of heteroaryl include monocyclic (e.g. 5-or 6-membered, particularly 5-membered), particularly nitrogen atom (e.g. 1 or 2 nitrogen atoms) containing rings. The above-mentioned heteroaryl groups may be unsubstituted (more typicallyType) or may suitably be selected from alkyl (e.g. C) groups_1-4Alkyl, e.g. Me), alkoxy- (e.g. C)_1-4Alkoxy-, such as OMe) and halogen (e.g. F). Suitable heteroaryl groups are imidazolyl, especially imidazol-1-yl. An exemplary-alkenylheteroaryl group is 3-imidazol-1-yl-prop-2-enyl.

When R is¹represents-C_1-6Alkyl heteroaryl, C_1-6Examples of alkyl groups include C_1-5Alkyl or C_1-4Alkyl, especially C_2-5Alkyl or C_2-4Alkyl, especially propyl, and examples of heteroaryl include monocyclic (e.g. 5-or 6-membered, especially 5-membered), especially nitrogen atom (e.g. 1 or 2 nitrogen atoms) containing rings. The heteroaryl groups mentioned above may be unsubstituted (as is most typical) or may suitably be selected from alkyl (e.g. C) _1-4Alkyl, e.g. Me), alkoxy- (e.g. C)_1-4Alkoxy-, such as OMe) and halogen (e.g. F). Suitable heteroaryl groups are imidazol-1-yl. A particularly suitable-alkylheteroaryl is 3-imidazol-1-yl-propyl-.

When R is¹represents-C_1-6Examples of alkyl heteroaryl groups, where the alkyl group is branched, include:

when R is¹Is represented by (CH)₂)_aCR⁵R⁶(CH₂)_bHeteroaryl, wherein a and b independently represent an integer from 0 to 5, with the proviso that a + b =0 to 5, and R⁵And R⁶Are taken together with the carbon to which they are attached to form C₃-C₅Examples of the alkylene group of the cycloalkyl group include:

R¹specific examples of heteroaryl groups include 5-membered rings containing 2 or 3 nitrogen atoms, which rings may be optionally substituted (e.g. with one or more groups, such as methyl, in particular), for example:

R¹other examples of heteroaryl groups include 9-membered bicyclic rings containing 2 nitrogen atoms, which rings may be optionally substituted, for example:

it is clear that the heteroaryl groups shown above can also be regarded as larger R¹Functional (e.g., -C)_3-8Carbocyclyl-heteroaryl, -C_2-6Alkenylheteroaryl or-C_1-6Alkylheteroaryl) are present.

When R is²represents-C_1-8Examples of alkyl groups include methyl, ethyl, propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl-, sec-butyl, isobutyl and tert-butyl), pentyl (e.g., n-pentyl, 3, -dimethylpropyl), hexyl, heptyl and octyl.

When R is²When an optionally substituted aryl group is represented, the aryl group may typically represent a phenyl group. Exemplary substituted phenyl groups include 3-methylphenyl-, 2, 3-dichlorophenyl-, 2, 3-difluorophenyl-, 2, 4-dichlorophenyl-, 2, 4-difluorophenyl-, 2, 4-dimethoxyphenyl-, 2, 4-dimethylphenyl-, 2, 4-bis (trifluoromethyl) phenyl-, 2,4, 6-trifluorophenyl-, 2,4, 6-trimethylphenyl-, 2, 6-dichlorophenyl-, 2, 6-difluorophenyl-, 2, 6-dimethoxyphenyl-, 2, 6-difluoro-4- (methoxy) phenyl-, 2-isopropyl-6-methylphenyl-, 3- (cyclopentyloxy) -4-methoxyphenyl-), 3,4, 5-trimethylOxyphenyl-, 3, 4-dimethoxyphenyl-, 3, 4-dichlorophenyl-, 3, 4-difluorophenyl-, 3, 4-dimethylphenyl-, 3,4, 5-trifluorophenyl-, 3, 5-bis (trifluoromethyl) phenyl-, 3, 5-dimethoxyphenyl-, 2-methoxyphenyl-, 3-methoxyphenyl-, 4- (trifluoromethyl) phenyl-, 4-bromo-2- (trifluoromethyl) phenyl-, 4-bromophenyl-, 4-chloro-3- (trifluoromethyl) phenyl-, 4-chlorophenyl-, 4-cyanophenyl-, 4-ethoxyphenyl-, 4-ethylphenyl-, 4-fluorophenyl-, 4-isopropylphenyl-, 4-methoxyphenyl-, 4-ethoxyphenyl-, 4-propoxyphenyl-, 4-butoxyphenyl-, 4-pentyloxyphenyl-, 4-isopropoxyphenyl-, 4-tetrafluoroethoxyphenyl-. Or, R ²May represent unsubstituted phenyl-. Other exemplary substituted phenyl groups include 2,3, 4-trifluorophenyl, 2, 3-difluoro-4-methylphenyl, 2-bromo-4-fluorophenyl-, 2-bromo-5-fluorophenyl-, 2-chlorophenyl-, 2-fluorophenyl-, 2-fluoro-5- (trifluoromethyl) phenyl-, 2-hydroxy-3-methoxyphenyl-, 2-hydroxy-5-methylphenyl-, 3-chlorophenyl-, 3-fluorophenyl-, 3-fluoro-4- (trifluoromethyl) phenyl-, 3-fluoro-5- (trifluoromethyl) phenyl-, 2-fluoro-4- (trifluoromethyl) phenyl-, 3-fluoro-4- (methoxy) phenyl-, 3-hydroxy-4-methoxyphenyl-, 4-bromo-2-fluorophenyl, 4-chloro-3- (trifluoromethyl) phenyl-, 4-chloro-3-methylphenyl, 4-chlorophenyl-, 4-fluorophenyl-, and 4-propoxyphenyl-.

When R is²When an optionally substituted aryl group is represented and an aryl group represents a naphthyl group, examples include unsubstituted naphthyl groups (e.g., naphthalen-1-yl, naphthalen-2-yl, naphthalen-3-yl) and substituted naphthyl groups (e.g., 4-methyl-naphthalen-2-yl-, 5-methyl-naphthalen-3-yl-, 7-methyl-naphthalen-3-yl-, and 4-fluoro-naphthalen-2-yl-).

When R is²When an optionally substituted heteroaryl group is represented, examples include monocyclic (e.g., 5-membered ring or 6-membered ring) and bicyclic (e.g., 9-membered ring or 10-membered ring), which may be optionally substituted. Exemplary 5-membered rings include pyrrolyl (e.g., pyrrol-2-yl) and imidazolyl (e.g., 1H-imidazol-2-yl or 1H-imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl), furyl (e.g., furan-2-yl), thiazolyl (e.g., thiazol-2-yl), thienyl (e.g., thiophen-2-yl, thiophen-3-yl). Exemplary 6-membered ring package Including pyridyl (e.g., pyridin-2-yl and pyridin-4-yl). Specific substituents which may be mentioned are one or more groups, for example 1,2 or 3 groups, selected from halogen, hydroxy, alkyl (e.g. methyl) and alkoxy- (e.g. methoxy-). Exemplary substituted 5-membered rings include 4, 5-dimethyl-furan-2-yl-, 5-hydroxymethyl-furan-2-yl-, 5-methyl-furan-2-yl-, and 6-methyl-pyridin-2-yl-. An exemplary substituted 6-membered ring is 1-oxy-pyridin-4-yl-. Exemplary 9-membered rings include 1H-indolyl (e.g., 1H-indol-3-yl, 1H-indol-5-yl), benzothienyl (e.g., benzo [ b ]]Thien-3-yl, especially 2-benzo [ b ]]Thiophen-3-yl), benzo [1,2,5 ]]Oxadiazolyl (e.g. benzo [1,2,5 ]]Oxadiazol-5-yl), benzo [1,2,5 ] l]Thiadiazolyl (e.g. benzo [1,2,5 ]]-thiadiazol-5-yl, benzo [1,2,5 ]]Thiadiazol-6-yl). Exemplary 10-membered rings include quinolinyl (e.g., quinolin-3-yl, quinolin-4-yl, quinolin-8-yl). Specific substituents which may be mentioned are one or more groups, for example 1,2 or 3 groups, selected from halogen, hydroxy, alkyl (e.g. methyl) and alkoxy- (e.g. methoxy-). Exemplary substituted 9-membered rings include 1-methyl-1H-indol-3-yl, 2-methyl-1H-indol-3-yl, 6-methyl-1H-indol-3-yl. Exemplary substituted 10-membered rings include 2-chloro-quinolin-3-yl, 8-hydroxy-quinolin-2-yl, oxo-chromen-yl (e.g., 4-oxo-4H-chromen-3-yl), and 6-methyl-4-oxo-4H-chromen-3-yl.

When R is²When a carbocyclic group is represented, examples include cycloalkyl and cycloalkenyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Examples of cycloalkenyl groups include cyclohexenyl (e.g., cyclohex-2-enyl, cyclohex-3-enyl). Examples of substituted carbocyclyl include 2-methyl-cyclohexyl-, 3-methyl-cyclohexyl-, 4-methyl-cyclohexyl-, 2-methyl-cyclohex-2-enyl, 2-methyl-cyclohex-3-enyl, 3-methyl-cyclohex-3-enyl.

When R is²Where heterocyclyl (which may be optionally substituted) is indicated, examples include tetrahydrofuranyl, morpholinyl, piperidinyl, 3, 4-dihydro-2H-pyranyl, pyrrolidinyl, methyltetrahydrofuranyl- (e.g. 5-methyltetrahydrofuran-2-yl-).

When R is²represents-C_1-4When the alkylaryl group, examples include-alkyl (substituted phenyl), for example, wherein the phenyl group is substituted with one or more groups selected from alkyl, fluoroalkyl, halogen, and alkoxy (e.g., methyl, trifluoromethyl, tert-butyl, chlorine, fluorine, and methoxy), and for example, the alkyl group is C_1-4An alkyl group. Another specific group is-alkyl (bicyclic aryl), for example, wherein bicyclic aryl is optionally substituted naphthyl. Another specific group is benzyl.

When R is²represents-C_1-4Examples of alkylheteroaryl groups, where the heteroaryl group is optionally substituted, include methylheteroaryl and-ethylheteroaryl (e.g. 1-heteroarylethyl-and 2-heteroarylethyl-), -propylheteroaryl and-butylheteroaryl, where the heteroaryl group is optionally substituted. Specific examples of (E) -alkylheteroaryl groups include pyridylmethyl-, N-methyl-pyrrole-2-methyl-, N-methyl-pyrrole-2-ethyl-, N-methyl-pyrrole-3-methyl-, N-methyl-pyrrole-3-ethyl-, 2-methyl-pyrrole-1-methyl-, 2-methyl-pyrrole-1-ethyl-, 3-methyl-pyrrole-1-methyl-, 3-methyl-pyrrole-1-ethyl-, 4-pyrido-methyl-, 4-pyrido-ethyl-, 2- (thiazol-2-yl) -ethyl-, pyridylmethyl-, N-methyl-pyrrole-2-ethyl-, N-methyl-pyrrole-3-methyl-, N-methyl-pyrrole-1-ethyl-, 4-pyrido-ethyl-, 2- (thiazol-2-yl) -ethyl, 2-ethyl-indol-1-methyl-, 2-ethyl-indol-1-ethyl-, 3-ethyl-indol-1-methyl-, 3-ethyl-indol-1-ethyl-, 4-methyl-pyridine-2-methyl-, 4-methyl-pyridin-2-yl-ethyl-, 4-methyl-pyridine-3-methyl-, 4-methyl-pyridine-3-ethyl-.

When R is²represents-C_1-4When the alkyl-carbocyclyl group (which may be optionally substituted), examples include-methyl-cyclopentyl, -methyl-cyclohexyl, -ethyl-cyclohexyl, -propyl-cyclohexyl, -methyl-cyclohexenyl, -ethyl-cyclohexenyl, -methyl (4-methylcyclohexyl), and-propyl (3-methylcyclohexyl).

When R is²represents-C_1-4Alkyl heterocyclyl (which may be optionally substituted); examples include-methyl-tetrahydrofuranyl (e.g. -methyl-tetrahydrofuran-2-yl, -methyl-tetrahydrofuran-3-yl), -ethyl-tetrahydrofuranyl, -methyl-a piperidinyl group.

When R is²Represents phenyl substituted by phenyl or phenyl substituted by a monocyclic heteroaryl, wherein any of the above phenyl and heteroaryl groups may be optionally substituted, typically the phenyl ring directly attached to the nitrogen atom is unsubstituted and the terminal phenyl ring or monocyclic heteroaryl ring is optionally substituted by 1, 2 or 3 substituents (e.g. 1 or 2, e.g. 1). Typically, the terminal phenyl or monocyclic heteroaryl is unsubstituted. Typically, the terminal phenyl or monocyclic heteroaryl group substitutes the other phenyl at the 4-position.

When R is²Represents phenyl substituted by phenyl, wherein any of the above phenyl groups may be optionally substituted, examples include-biphenyl-4-yl.

When R is²Represents phenyl substituted by a monocyclic heteroaryl group, wherein any of the above phenyl and heteroaryl groups may be optionally substituted, examples include 4- (oxazol-5-yl) phenyl-.

When R is²Represents a phenyl group substituted by a benzyloxy group, wherein any of the above-mentioned phenyl groups and benzyloxy groups may be optionally substituted, and examples include 4-benzyloxy-phenyl-, 4- (3-methylbenzyloxy) phenyl-, and 4- (4-methylbenzyloxy) phenyl-.

When R is²Examples of optionally substituted phenyl groups representing fused to optionally substituted carbocyclic groups include indanyl (e.g. indan-4-yl-, 2-methyl-indan-4-yl-), indenyl and tetrahydronaphthyl.

When R is²When an optionally substituted phenyl group which represents a fused to optionally substituted heterocyclic group is mentioned, examples include benzo [1,3 ]]Dioxo-4-yl-and 2, 3-dihydro-benzo [1,4 ]]Dioxin-4-yl-.

When R is²represents-C_1-4When alkyl (phenyl substituted with phenyl), examples include biphenyl-4-yl-methyl-.

When R is²represents-C_1-4Alkyl (monocyclic heteroaryl substituted benzene)Yl), examples include 4- (oxazol-5-yl) phenyl-methyl-.

When R is²represents-C_1-4Alkyl (phenyl substituted with benzyloxy), wherein any of the above-mentioned phenyl and benzyloxy can be optionally substituted, examples include 4-benzyloxy-phenyl-methyl-, 4- (3-methylbenzyloxy) phenyl-methyl-, and 4- (4-methylbenzyloxy) phenyl-methyl-.

When R is²represents-C_1-4When alkyl (optionally substituted phenyl fused to an optionally substituted carbocyclic group) examples include indanyl-methyl- (e.g. indan-4-yl-methyl-, 2-methyl-indan-4-yl-methyl-), indenyl-methyl-and tetrahydronaphthyl-methyl-.

When R is²represents-C_1-4When the alkyl group (an optionally substituted phenyl group fused to an optionally substituted heterocyclic group) is mentioned, examples include benzo [1,3 ]]Dioxo-4-yl-methyl-and 2, 3-dihydro-benzo [1,4 ]]Dioxin-4-yl-methyl-.

When R is³represents-C_1-4When the alkyl group is mentioned, examples include methyl, ethyl, propyl (e.g., n-propyl, isopropyl) and butyl (e.g., n-butyl-, sec-butyl, isobutyl and tert-butyl).

When R is³When an optionally substituted aryl group is represented, the aryl group may typically represent a phenyl group. Exemplary substituted phenyl groups include 2, 4-dichlorophenyl-, 2, 4-difluorophenyl-, 2, 4-dimethoxyphenyl-, 2, 4-dimethylphenyl-, 2, 4-bis (trifluoromethyl) phenyl-, 2,4, 6-trifluorophenyl-, 2,4, 6-trimethylphenyl-, 2, 6-dichlorophenyl-, 2, 6-difluorophenyl-, 2, 6-dimethoxyphenyl-, 2-isopropyl-6-methylphenyl-, 3- (cyclopentyloxy) -4-methoxyphenyl-, 3,4, 5-trimethoxyphenyl-, 3, 4-dimethoxyphenyl-, 3, 4-dichlorophenyl-, substituted phenyl groups, and substituted phenyl groups, 3, 4-dimethylphenyl-, 3,4, 5-trifluorophenyl-, 3, 5-bis (trifluoromethyl) phenyl-, 3, 5-dimethoxyphenyl-, 3-methoxyphenyl-, 4- (trifluoromethyl) phenyl-, 4-bromo-2- (trifluoromethyl) phenyl-, 4-bromophenyl-, 4-chloro-3- (trifluoromethyl) phenyl-, 4-chlorophenyl-, 4-cyanophenyl-, 4-ethoxyphenyl Phenyl-, 4-ethylphenyl-, 4-fluorophenyl-, 4-isopropylphenyl-, 4-methoxyphenyl-. Or, R³May represent unsubstituted phenyl-. Other exemplary substituted phenyl groups include 2-bromo-4-fluorophenyl-, 2-bromo-5-fluorophenyl-, 2-chlorophenyl-, 2-fluoro-5- (trifluoromethyl) phenyl-, 2-hydroxy-3-methoxyphenyl-, 2-hydroxy-5-methylphenyl-, 3-chlorophenyl-, 3-fluoro-4- (trifluoromethyl) phenyl-, 3-hydroxy-4-methoxyphenyl-, 4-chloro-3- (trifluoromethyl) phenyl-, 4-chlorophenyl-, 4-fluorophenyl-, and 4-propoxyphenyl-.

When R is²And R³Are linked to form a carbocyclic ring, optionally substituted with one or more C_1-2When alkyl is substituted, examples include cycloalkyl (e.g., cyclopropyl, cyclopentyl, and cyclohexyl) and cycloalkenyl (e.g., cyclohexenyl).

When R is²And R³When linked to form a carbocyclic ring fused to phenyl; examples include indanyl (e.g. indan-2-yl) and tetrahydronaphthyl.

When R is²And R³When linked to form a carbocyclic ring fused to a monocyclic heteroaryl; examples include 5-membered carbocyclyl fused to 6-membered heteroaryl, 6-membered carbocyclyl fused to 6-membered heteroaryl, 5-membered carbocyclyl fused to 5-membered heteroaryl, and 6-membered carbocyclyl fused to 5-membered heteroaryl. Monocyclic fused heteroaryl groups contain at least one heteroatom (e.g., 1, 2 or 3 heteroatoms, e.g., 1 or 2 heteroatoms, e.g., 1 heteroatom).

When R is⁴represents-C_1-8Examples of alkyl groups include methyl, ethyl, propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl-, sec-butyl, isobutyl and tert-butyl), pentyl (e.g., n-pentyl, 3, -dimethylpropyl), hexyl, heptyl and octyl.

When R is⁴represents-C (O) C_1-6When it is alkyl; examples include-C (O) C_1-4Alkyl groups, such as-C (O) methyl, -C (O) ethyl, -C (O) propyl and-C (O) butyl.

Suitably at the ground，R¹Represents heteroaryl or-C_1-6An alkyl heteroaryl group.

In one embodiment, R¹Represents a heteroaryl group. In another embodiment, R¹Represents unsubstituted heteroaryl or optionally substituted by one or more C_1-6Alkyl (e.g. methyl), halogen (e.g. fluorine) or C_1-6Haloalkyl (e.g., trifluoromethyl) substituted heteroaryl. In another embodiment, R¹represents-C_1-6An alkyl heteroaryl group.

When R is¹When represents a heteroaryl group, R¹Bicyclic heteroaryls are suitably represented, in particular 9-membered bicyclic heteroaryls. More suitably, R¹Denotes a bicyclic heteroaryl ring system, in particular a phenyl ring fused to a 5-membered heteroaryl ring containing one or more (e.g. 1 or 2, suitably 1, more suitably 2) nitrogen atoms or a pyridine ring fused to a 5-membered heteroaryl ring containing one or more (e.g. 1 or 2, suitably 1, more suitably 2) nitrogen atoms. When R is ¹When a bicyclic heteroaryl group is represented, it is preferred that the heteroaryl group does not contain an S atom. When R is¹When representing a benzene ring fused to a 5-membered heteroaryl ring, R is preferably¹Is linked to the core of formula (I) through the phenyl ring. When R is¹When a pyridine ring fused to a 5-membered heteroaryl ring is represented, R is preferably¹Linked to the core of formula (I) through the pyridine ring. Suitably, R¹Represents an unsubstituted heteroaryl group. In particular, R¹Suitably represents 1H-benzimidazolyl or imidazo [1,2-a ]]Pyridines, in particular 1H-benzimidazolyl, especially 1H-benzimidazol-5-yl.

When R is¹represents-C_1-6When alkylheteroaryl, the heteroaryl is suitably a monocyclic heteroaryl, especially a 5-membered monocyclic heteroaryl. More suitably, when R¹represents-C_1-6When an alkylheteroaryl group, the heteroaryl group is suitably a 5 membered heteroaryl ring containing one or more (e.g. 1 or 2, suitably 1, more suitably 2) nitrogen atoms. When R is¹represents-C_1-6When an alkylheteroaryl group is used, it is preferred that the heteroaryl group does not contain an S atom. When R is¹represents-C_1-6Alkyl heteroaromatic compoundsWhen substituted, heteroaryl represents a substituted or unsubstituted imidazolyl. In particular, when R¹represents-C_1-6When an alkylheteroaryl group, the heteroaryl group suitably represents a substituted or unsubstituted imidazol-1-yl group. When R is¹represents-C_1-6When the alkyl heteroaryl group and the heteroaryl group are substituted imidazol-1-yl, the imidazol-1-yl group is suitably substituted with a methyl group.

In one embodiment, R¹To represent

Wherein A represents unbranched C_1-6Alkylene chains (e.g. unbranched C)_1-5Alkylene chains, e.g. unbranched C_1-4Alkylene chains, e.g. unbranched C_1-3Alkylene chain) or A represents a branched C_1-6An alkylene chain (e.g. wherein one or more (e.g. 1 or 2) branches consist of one or more (e.g. 1 or 2) methyl groups at the same or different positions), or a represents (CH)₂)_aCR⁵R⁶(CH₂)_bAnd R is¹¹、R¹²And R¹³Independently represent H or C_1-2An alkyl group.

In a second embodiment, R¹To represent

Wherein B represents a bond, -CH₂-、-CH₂-CH₂-、-CH(Me)-、-CH(Me)-CH₂-or-CH₂-CH (Me) -, and

R¹⁴and R¹⁵Independently represent H, C_1-2Alkyl (e.g. methyl), halogen (e.g. fluorine) or C_1-6Haloalkyl (e.g., trifluoromethyl).

In a third embodiment, R¹To represent

Wherein C represents a bond, -CH₂-、-CH₂-CH₂-、-CH(Me)-、-CH(Me)-CH₂-or-CH₂-CH (Me) -, and

R¹⁶and R¹⁷Independently represent H, C_1-2Alkyl (e.g. methyl), halogen (e.g. fluorine) or C_1-6Haloalkyl (e.g., trifluoromethyl).

In a fourth embodiment, R¹To represent

Wherein D represents a bond, -CH₂-、-CH₂-CH₂-、-CH(Me)-、-CH(Me)-CH₂-or-CH₂-CH (Me) -, and

R¹⁸and R¹⁹Independently represent H, C_1-2Alkyl (e.g. methyl), halogen (e.g. fluorine) or C_1-6Haloalkyl (e.g., trifluoromethyl);

suitably, R¹To represent

In one embodiment, R ¹⁴Represents H, and R¹⁵Represents H. In another embodiment, R¹⁴Represents H, and R¹⁵Is represented by C_1-2An alkyl group. In a third embodiment, R¹⁴Is represented by C_1-2Alkyl, and R¹⁵Represents H. In a fourth embodiment, R¹⁴Represents a methyl group, and R¹⁵Represents H. In another embodiment, R¹⁴Represents H or methyl, and R¹⁵Is represented by C_1-2Alkyl (e.g., methyl) or halogen (e.g., fluorine).

Suitably, B represents a bond, -CH₂-or-CH₂CH₂-. In one embodiment, B represents a bond. In another embodiment, B represents-CH₂-. In a third embodiment, B represents-CH₂CH₂-。

Or, R¹To represent

R¹¹Suitably, it represents H, or a combination thereof,

R¹²suitably represents H or methyl.

R¹³Suitably represents H or methyl.

In one embodiment of the invention, R¹²Represents H, and R¹³Represents a methyl group. In another embodiment, R¹²Represents a methyl group, and R¹³Represents H. In a third embodiment, R¹²Represents H, and R¹³Represents H.

Suitably, A represents unbranched C_2-5An alkylene chain. In one embodiment, A represents- (CH)₂)₂-. In another embodiment, A represents- (CH)₂)₃-. In a third embodiment, A represents- (CH)₂)₄-. In another embodiment, A represents- (CH)₂)₅-. More suitably, A represents- (CH)₂)₂-、-(CH₂)₄-or- (CH)₂)₅-. In one embodiment, A represents- (CH) ₂)₃-. In another embodiment, A represents- (CH)₂)₄-。

Alternatively, A represents branched C_2-5An alkylene chain.

In one embodiment, A does not represent- (CH)₂)₃-。

When A represents C_2-5When the alkylene chain is substituted with two alkylene substituents at the same position, wherein the two alkylene substituents are linked to each other to form C_3-5Spiro-cycloalkyl, suitably said spiro-cycloalkyl is C₃Spiro-cycloalkyl groups.

Or, R¹To represent

In one embodiment, R¹⁶Represents H, and R¹⁷Represents H. In another embodiment, R¹⁶Represents H, and R¹⁷Is represented by C_1-2An alkyl group. In a third embodiment, R¹⁶Is represented by C_1-2Alkyl, and R¹⁷Represents H. In another embodiment, R¹⁶Represents H or methyl, and R¹⁷Is represented by C_1-2Alkyl (e.g., methyl) or halogen (e.g., fluorine).

Suitably, C represents a bond, -CH₂-or-CH₂CH₂-. In one embodiment, C represents a bond. In another embodiment, C represents-CH₂-. In a third embodiment, C represents-CH₂CH₂-。

Or, R¹To represent

In one embodiment, R¹⁸Represents H, and R¹⁹Represents H. In another embodiment, R¹⁸Represents H, and R¹⁹Is represented by C_1-2An alkyl group. In a third embodiment, R¹⁸Is represented by C_1-2Alkyl, and R¹⁹Represents H. In another embodiment, R ¹⁴Represents H or methyl, and R¹⁵Is represented by C_1-2Alkyl (e.g., methyl) or halogen (e.g., fluorine).

Suitably, D represents a bond, -CH₂-or-CH₂CH₂-. In one embodiment, D represents a bond. In another embodiment, D represents-CH₂-. In a third embodiment, D represents-CH₂CH₂-。

More suitably, R¹To represent

And more suitably R¹To represent

Most suitably, R¹To represent

Suitably, R²Representation H, C_1-8Alkyl radical, C_3-8Cycloalkyl, -C_1-4Alkyl carbocyclyl, aryl, heteroaryl, heterocyclyl, -C_1-4Alkylaryl, phenyl substituted by phenyl, phenyl substituted by phenoxy, phenyl substituted by heterocyclyl, wherein the heterocyclyl is optionally substituted by methyl or phenylSubstituted, phenyl substituted by carbocyclyl wherein said carbocyclyl is substituted by heterocyclyl, phenyl substituted by-O-carbocyclyl, heterocyclyl substituted by phenyl, carbocyclyl substituted by phenyl, -C_1-4Alkyl (phenyl substituted by monocyclic heterocyclyl), -C_1-4Alkyl (phenyl substituted by-O-carbocyclyl), by-O-C_1-4Alkyl-heterocyclyl substituted phenyl or phenyl fused to a heterocyclyl, the above aryl, heteroaryl, phenyl and heterocyclyl being optionally substituted.

More suitably, R ²Representation H, C_1-8Alkyl radical, C_3-8Cycloalkyl, aryl, heteroaryl, -C_1-4Alkylaryl, phenyl substituted by phenyl, phenyl substituted by phenoxy, phenyl substituted by heterocyclyl, wherein said heterocyclyl is optionally substituted by methyl or phenyl, by-O-C_1-4Alkyl-heterocyclyl substituted phenyl or phenyl fused to a heterocyclyl, the above aryl, heteroaryl, phenyl and heterocyclyl being optionally substituted.

And more suitably R²Is represented by C_1-8Alkyl radical, C_3-8Cycloalkyl, aryl, heteroaryl, -C_1-4Alkylaryl, phenyl substituted by phenyl, phenyl substituted by phenoxy, phenyl substituted by heterocyclyl, wherein said heterocyclyl is optionally substituted by methyl or phenyl, by-O-C_1-4Alkyl-heterocyclyl substituted phenyl or phenyl fused to a heterocyclyl, the above aryl, heteroaryl, phenyl and heterocyclyl being optionally substituted.

In one embodiment, R²Represents H.

In one embodiment, R²Is represented by C_1-8An alkyl group. When R is²Is represented by C_1-8When alkyl, R²Suitably represents an isopropyl or tert-butyl group.

In one embodiment, R²Represents a carbocyclic group. When R is²When represents a carbocyclic group, R²Suitably represents cyclohexyl.

In one embodiment, R²represents-C _1-4An alkyl carbocyclyl group. When R is²represents-C_1-4When there is an alkyl carbocyclic group, R²Suitably represents-CH₂-cyclohexyl.

In one embodiment, R²Represents an optionally substituted aryl group. When R is²When represents an optionally substituted aryl group, R²Suitably represents an optionally substituted phenyl or naphthyl group.

In one embodiment, R²Represents phenyl, optionally selected from C_1-6Alkyl (e.g. methyl), C_1-6Alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, pentoxy or isopropoxy), hydroxy, halo C_1-6Alkyl (e.g. trifluoromethyl), halo C_1-6Alkoxy (e.g. tetrafluoroethoxy), halogen (e.g. chloro or fluoro), C_1-6alkoxy-C_1-6Alkyl- (e.g., - (CH)₂)₃-OMe)、C_1-6alkoxy-C_1-6Alkoxy radicals- (e.g. -O- (CH)₂)₂-OMe)、-N(C_1-4Alkyl) (C_1-4Alkyl) -N (C)_1-4Alkyl) (C_1-4Alkyl) (e.g., -N (Me) - (CH)₂)₂-N(Me)₂)、-N(C_1-4Alkyl) (C_1-4Alkyl) (e.g., -N (ethyl)), -N (C)_3-8Cycloalkyl) (C)_3-8Cycloalkyl) (e.g., -N (cyclopropyl)), -C_1-4alkyl-N (C)_1-4Alkyl) (C_1-4Alkyl) (e.g., - (CH)₂)₃-N (methyl)), -C_1-4alkoxy-N (C)_1-4Alkyl) (C_1-4Alkyl) (e.g., -O (CH)₂)₂-N (methyl)), -N (-C)_1-6alkyl-C_1-6Alkoxy) (-C_1-6alkyl-C_1-6Alkoxy) (e.g., -N ((CH)₂)₂OMe)(CH₂)₂OMe) is substituted with one or more groups.

In another embodiment, R ²Represents phenyl, optionally selected from C_1-6Alkyl (e.g. methyl), C_1-6Alkoxy radical(e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy or isopropoxy), halo C_1-6Alkyl (e.g. trifluoromethyl), halo C_1-6Alkoxy (e.g., tetrafluoroethoxy) or halo (e.g., chloro or fluoro).

In another embodiment, R²Represents optionally selected from C_1-6Phenyl substituted with one or more groups of alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy, or isopropoxy). In another embodiment, R²Represents phenyl optionally substituted by propoxy.

When R is²When represents an optionally substituted phenyl group, R²Suitably represents a 3-methylphenyl group, a 2-methoxyphenyl group, a 3, 4-dimethoxyphenyl group, a 4-methoxyphenyl group, a 4-ethoxyphenyl group, a 4-propoxyphenyl group, a 4-butoxyphenyl group, a 4-pentyloxyphenyl group, a 4-isopropoxyphenyl group, a 4-tetrafluoroethoxyphenyl group, a 2-chlorophenyl group, a 3-chlorophenyl group, a 4-chlorophenyl group, a 2, 6-dichlorophenyl group, a 2, 3-dichlorophenyl group, a 3, 4-dichlorophenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, a 2, 6-difluorophenyl group, a 2, 3-difluorophenyl group, a 3, 4-difluorophenyl group, a 3-chloro-5-fluorophenyl group, a 3, 5-difluorophenyl group, a, 2,3, 5-trifluorophenyl group, 2-fluoro-5-trifluoromethylphenyl group, 3-fluoro-5-trifluoromethylphenyl group, 2-fluoro-4-trifluoromethylphenyl group, 3-fluoro-4-methoxyphenyl group, or 2, 6-difluoro-4-methoxyphenyl group. In an alternative embodiment, R ²Represents an unsubstituted phenyl group. In an alternative embodiment, R²Represents an unsubstituted naphthyl group.

In one embodiment, R²represents-C_1-4Alkylaryl, said aryl being optionally substituted. When R is²represents-C_1-4When it is an alkylaryl group, R²Suitably represents an optionally substituted one or more C_1-6Alkoxy (e.g., methoxy) or halo (e.g., chloro or fluoro) substituted benzyl. When R is²When represents an optionally substituted benzyl group, R²Suitably 4-methoxybenzyl, 4-chlorobenzyl or 4-fluorobenzyl. When R is²When represents an optionally substituted benzyl group, R²Also suitably represents 4-propoxybenzyl or 4-isopropoxybenzyl. In an alternative embodiment, R²Represents an unsubstituted benzyl group. When R is²represents-C_1-4When it is an alkylaryl group, R²Suitably represents-c, (h) phenyl. When R is²represents-C_1-4When it is an alkylaryl group, R²Suitably represents- (CH)₂)₂-phenyl.

In one embodiment, R²Represents an optionally substituted heteroaryl group. When R is²When represents an optionally substituted heteroaryl group, R²Suitably represents an optionally substituted thienyl group. In an alternative embodiment, R²Represents an unsubstituted thienyl group.

In one embodiment, R²Represents an optionally substituted heterocyclic group. When R is ²When represents an optionally substituted heteroaryl group, R²Suitably represents unsubstituted dihydrobenzodioxinyl or is substituted by-C (O) C_1-6Alkyl (i.e., -COMe) substituted piperidinyl.

In one embodiment, R²Represents a phenyl group substituted by a phenyl group, the above phenyl group being optionally substituted. When R is²Represents phenyl substituted by phenyl, R when the above phenyl is optionally substituted²Suitably represents a phenyl group substituted by a 3-phenyl group, a phenyl group substituted by a 4-phenyl group, a phenyl group substituted by a 3- (3-chlorophenyl) group, a phenyl group substituted by a 4- (3, 4-dichlorophenyl) group or a 3-fluorophenyl group substituted by a 4-phenyl group. In an alternative embodiment, when R²When represents a phenyl group substituted with a phenyl group, R²Suitably represents an unsubstituted phenyl group substituted by an unsubstituted phenyl group.

In one embodiment, R²Represents an optionally substituted phenyl group substituted by an optionally substituted phenoxy group. When R is²When represents an optionally substituted phenyl group substituted with an optionally substituted phenoxy group, R²Suitably represented by 4-phenoxyA substituted phenyl group.

In one embodiment, R²Represents an optionally substituted phenyl group substituted by an optionally substituted heterocyclic group. When R is ²When represents an optionally substituted phenyl group substituted by an optionally substituted heterocyclic group, R²Suitably represents 3-chlorophenyl substituted by 4-morpholinyl, phenyl substituted by 4-piperazinyl substituted by 4N-methyl, 2-chlorophenyl substituted by 4N-ethyl and 6-piperazinyl, phenyl substituted by pyrrolidinyl, phenyl substituted by 4N-methyl and piperidinyl, phenyl substituted by tetrahydropyranyl or phenyl substituted by morpholinyl.

In another embodiment, R²Represents an optionally substituted phenyl group substituted by an optionally substituted heterocyclic group. When R is²When represents an optionally substituted phenyl group substituted by an optionally substituted heterocyclic group, R²Suitably represents 3-chlorophenyl substituted by 4-morpholinyl, phenyl substituted by 4-piperazinyl substituted by 4N-methyl, phenyl substituted by 4-piperazinyl substituted by 4N-phenyl, phenyl substituted by 3-piperazinyl substituted by 4N-phenyl or 2-chlorophenyl substituted by 6-piperazinyl substituted by 4N-ethyl.

In one embodiment, R²Represents an optionally substituted phenyl group substituted by a heterocyclic group, wherein the heterocyclic group is substituted by a phenyl group. When R is²Represents an optionally substituted phenyl group substituted by a heterocyclic group, wherein when said heterocyclic group is substituted by a phenyl group, R ²Suitably represents a phenyl group substituted by a 4-piperazinyl group substituted by a 4N-phenyl group, a phenyl group substituted by a 3-piperazinyl group substituted by a 4N-phenyl group.

In one embodiment, R²Represents an optionally substituted phenyl group substituted by an optionally substituted carbocyclyl group, wherein said carbocyclyl group is substituted by an optionally substituted heterocyclyl group. When R is²Represents an optionally substituted phenyl group substituted by an optionally substituted carbocyclic group, wherein when said carbocyclic group is substituted by an optionally substituted heterocyclic group, R²Suitably represents a carbocyclic ring substituted by a heterocyclic group (i.e. morpholinyl)Phenyl substituted with a radical (i.e., cyclohexyl).

In one embodiment, R²Is represented by-O-C_1-4Alkyl-heterocyclyl substituted optionally substituted phenyl. When R is²Is represented by-O-C_1-4When alkyl-heterocyclyl-substituted optionally substituted phenyl, R²Suitably represented by 4-O- (CH)₂)₂Morpholinyl, 4-O- (CH)₂)₃Morpholinyl, 2-O- (CH)₂)₂Morpholinyl or 4-O- (CH)₂)₂-phenyl substituted by piperazinyl.

In one embodiment, R²Represents an optionally substituted phenyl group substituted by an optionally substituted carbocyclyl group. When R is²When represents an optionally substituted phenyl group substituted with an optionally substituted carbocyclyl group, R²Is suitably represented by C _3-8Cycloalkyl (e.g. cyclohexyl) substituted phenyl, wherein said C_3-8Cycloalkyl groups may optionally be substituted by one or more oxo, halogen (i.e. fluoro), hydroxy or C_1-4Alkoxy (i.e., methoxy) substitution.

In one embodiment, R²Represents an optionally substituted phenyl group substituted by an-O-carbocyclyl group. When R is²When represents an optionally substituted phenyl group substituted with an-O-carbocyclyl group, R²Suitably represented by-O-C_3-8Cycloalkyl (i.e., -O-cyclohexyl) substituted unsubstituted phenyl.

In one embodiment, R²Represents an optionally substituted heterocyclic group substituted by an optionally substituted phenyl group. When R is²When represents an optionally substituted heterocyclic group substituted with an optionally substituted phenyl group, R²Suitably represents an unsubstituted piperidinyl group substituted by an unsubstituted phenyl group.

In one embodiment, R²Represents an optionally substituted carbocyclyl substituted by an optionally substituted phenyl. When R is²When represents an optionally substituted carbocyclic group substituted with an optionally substituted phenyl group, R²Suitably represents unsubstitutedPhenyl-substituted unsubstituted C_3-8Cycloalkyl (i.e., cyclohexyl).

In one embodiment, R²Represents an optionally substituted phenyl group fused to an optionally substituted heterocyclic group. When R is ²When represents an optionally substituted phenyl group fused to an optionally substituted heterocyclic group, R²Suitably represents benzo-1, 3-dioxolanyl, 4-methoxy (benzo-1, 3-dioxolanyl), 6-methoxy (benzo-1, 3-dioxolanyl), 2-difluoro (benzo-1, 3-dioxolanyl) or benzo-1, 4-dioxanyl.

In one embodiment, R²represents-C_1-4Alkyl (phenyl substituted with monocyclic heterocyclyl). When R is²represents-C_1-4When alkyl (phenyl substituted by monocyclic heteroaryl), R²Suitably represents benzyl substituted by morpholinyl.

In one embodiment, R²represents-C_1-4Alkyl (phenyl substituted with-O-carbocyclyl). When R is²represents-C_1-4When alkyl (phenyl substituted by-O-carbocyclyl), R²Suitably represents a benzyl group substituted by an-O-carbocyclyl (i.e. -O-cyclohexyl).

Suitably, R³Represents H, or R²And R³Are linked to form a carbocyclic ring fused to the phenyl. Most suitably, R³Represents H.

Suitably, R⁴Represents H, -C_1-8Alkyl or-C (O) C_1-6An alkyl group. More suitably, R⁴Represents H or-C_1-8Alkyl, such as H or methyl. Most suitably, R⁴Represents H.

In one embodiment, X represents O, S or CR⁷R⁸Or X and Z represent two adjacent carbon atoms of a phenyl ring, said phenyl ring being fused at this position and said phenyl ring being optionally substituted by one or more halogens or C _1-2Alkyl substitution. In another embodiment, X represents O, S or CR⁷R⁸。

In one embodiment, X represents O. In an alternative embodiment, X represents S. In an alternative embodiment, X represents C = O. In an alternative embodiment, X represents S or CR⁷R⁸. In an alternative embodiment, X represents-O-CH₂-or-CH₂-CH₂-. In an alternative embodiment, X and Z are linked to form a carbocyclic ring, such as a 5-or 6-membered carbocyclic ring. In an alternative embodiment, X and Z represent two adjacent carbon atoms of a phenyl ring, said phenyl ring being fused at that position and said phenyl ring optionally being substituted with one or more halogens or C_1-2Alkyl substitution.

In one embodiment, R⁷And R⁸All represent hydrogen or-C_1-4Alkyl, or R⁷And R⁸One of them represents hydrogen and the other represents-C_1-4Alkyl or optionally substituted aryl. When R is⁷And R⁸One of them represents-C_1-4When alkyl, the group is suitably methyl. When R is⁷And R⁸When one of them represents an optionally substituted aryl group, said group is suitably unsubstituted phenyl or phenyl substituted by 4-propoxy. In one embodiment, R⁷And R⁸All represent hydrogen. In an alternative embodiment, R⁷And R⁸All represent-C_1-4An alkyl group. In an alternative embodiment, R ⁷And R⁸One of them represents hydrogen and the other represents-C_1-4Alkyl (e.g., methyl). In an alternative embodiment, R⁷And R⁸One of which represents hydrogen and the other represents an optionally substituted aryl group (e.g. unsubstituted phenyl or C_1-6Alkoxy substituted phenyl).

In one embodiment, Y represents C = O, C = S or CH₂. In an alternative embodiment, Y represents C = O. In an alternative embodiment, Y represents C = S. In an alternative embodiment, Y represents CH₂。

In one embodiment, Z represents-N-R⁴(e.g. -NH or-N-NH)₂) O or CHR¹⁰(e.g. CH)₂Or CH-methyl), or X and Z represent two adjacent carbon atoms of a phenyl ring, said phenyl ring being fused at this position and said phenyl ring being optionally substituted by one or more halogens or C_1-2Alkyl substitution. In one embodiment, Z represents-NH. In an alternative embodiment, Z represents-N-NH₂. In an alternative embodiment, Z represents O. In an alternative embodiment, Z represents CH₂. In an alternative embodiment, Z represents CH-methyl.

In one embodiment, X represents CR⁷R⁸Y represents C = O, and Z represents-N-R⁴. In another embodiment, X represents CH₂Y represents C = O, and Z represents-NH. In another embodiment, X represents CH-Me, Y represents C = O, and Z represents-NH. In another embodiment, X represents CH ₂Y represents C = O, and Z represents-N-NH₂。

When X represents CR⁷R⁸Y represents C = O, and Z represents-N-R⁴When R is¹Suitably represents 1H-benzo [ d]Imidazolyl or 1H-imidazo [1,2-a ]]A pyridyl group.

When X represents CR⁷R⁸Y represents C = O, and Z represents-N-R⁴When R is²Suitably represents:

C_1-8alkyl (e.g., tert-butyl);

carbocyclyl (e.g., cyclohexyl);

phenyl optionally substituted by one or more C_1-6Alkyl (e.g. methyl), C_1-6Alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, pentoxy or isopropoxy), halogen (e.g. fluorine or chlorine), halo C_1-6Alkyl (e.g. trifluoromethyl) or halo C_1-6Alkoxy (e.g., trifluoromethoxy) substitution;

optionally substituted phenyl fused to an optionally substituted heterocyclic group (e.g., 4-methoxybenzo [ d ] [1,3] dioxol-6-yl, 2-difluorobenzo [ d ] [1,3] dioxol-5-yl or 2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl);

optionally substituted phenyl substituted by optionally substituted heterocyclyl (e.g. by-O- (CH)₂)₂Phenyl substituted by morpholinyl or by-O- (CH)₂)₃-morpholinyl substituted phenyl);

optionally substituted phenyl substituted with optionally substituted phenyl; or

Optionally substituted phenyl substituted by an optionally substituted heterocyclic group (e.g., optionally substituted phenyl substituted by morpholinyl, optionally substituted phenyl substituted by phenyl-substituted piperazinyl, or optionally substituted phenyl substituted by ethyl-substituted piperazinyl).

When X represents CR⁷R⁸Y represents C = O, and Z represents-N-R⁴When R is³Suitably represents hydrogen.

When X represents CR⁷R⁸Y represents C = O, and Z represents-N-R⁴When R is³、R⁷And R⁸Each suitably represents hydrogen.

In one embodiment, X represents C = O and Y represents CHR⁹And Z represents-N-R⁴. In another embodiment, X represents C = O and Y represents CH₂And Z represents-NH.

When X represents C = O, Y represents CHR⁹And Z represents-N-R⁴When R is¹Suitably represents 1H-benzo [ d]An imidazolyl group.

When X represents C = O, Y represents CHR⁹And Z represents-N-R⁴When R is²Suitably represents phenyl optionally substituted by one or more halogen atoms (e.g. unsubstituted phenyl or 2,3, 5-trifluorophenyl).

When X represents C = O, Y represents CHR⁹And Z represents-N-R⁴When R is³Suitably represents hydrogen.

In an alternative embodiment, X represents CR⁷R⁸Y represents C = O, and Z represents O. In another embodiment, X represents CH ₂Y represents C = O, and Z represents O. In another embodiment, X represents C (Me)₂Y represents C = O, and Z represents O. In another embodiment, X represents CH-phenyl, Y represents C = O, and Z represents O.

When X represents CR⁷R⁸Y represents C = O, and when Z represents O, R¹Suitably represents 1H-benzo [ d]Imidazolyl or 1H-imidazo [1,2-a ]]A pyridyl group.

When X represents CR⁷R⁸Y represents C = O, and when Z represents O, R²Suitably represents:

C_1-8alkyl (e.g., isopropyl);

phenyl optionally substituted by one or more halogens (e.g. fluoro or chloro), C_1-6Alkoxy (e.g. propoxy) or halo C_1-6Alkyl (e.g., trifluoromethyl) substitution;

-C_1-4alkylaryl (e.g., benzyl);

optionally substituted phenyl fused to an optionally substituted heterocyclic group (e.g., 2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl or benzo [ d ] [1,3] dioxol-6-yl);

optionally substituted phenyl substituted by optionally substituted heterocyclyl (e.g. by-O- (CH)₂)₂-piperazinyl or-O- (CH)₂)₂-morpholinyl substituted phenyl);

optionally substituted phenyl substituted with optionally substituted phenyl; or

An optionally substituted phenyl group substituted with an optionally substituted heterocyclic group (e.g., an optionally substituted phenyl group substituted with a phenyl-substituted piperazinyl group or an optionally substituted phenyl group substituted with a methyl-substituted piperazinyl group).

When X represents CR⁷R⁸Y represents C = O, and when Z represents O, R³Suitably represents hydrogen.

In an alternative embodiment, X represents CR⁷R⁸Y represents CHR⁹And Z represents CHR¹⁰. In another embodiment, X represents CH₂Y represents CH₂And Z represents CH₂。

When X represents CR⁷R⁸Y represents CHR⁹And Z represents CHR¹⁰When R is¹Suitably represents 1H-benzo [ d]An imidazolyl group.

When X represents CR⁷R⁸Y represents CHR⁹And Z represents CHR¹⁰When R is²Suitably represents:

hydrogen;

phenyl optionally substituted by one or more halogens (e.g. fluoro or chloro), C_1-6Alkoxy (e.g., methoxy) substitution; or

Optionally substituted-C_1-4Alkylaryl groups (e.g. unsubstituted benzyl and substituted by halogen atoms (e.g. fluorine or chlorine) or C_1-6Alkoxy (e.g., methoxy) substituted benzyl).

When X represents CR⁷R⁸Y represents CHR⁹And Z represents CHR¹⁰When R is³Suitably represents hydrogen.

In an alternative embodiment, X represents S, Y represents C = O, and Z represents CHR¹⁰. In another embodiment, X represents S, Y represents C = O, and Z represents CH₂. In another embodiment, X represents S, Y represents C = O, and Z represents CH-methyl.

When X represents S, Y represents C = O, and Z represents CHR¹⁰When R is¹Suitably represents 1H-benzo [ d ]An imidazolyl group.

When X represents S, Y represents C = O, andz represents CHR¹⁰When R is²Suitably represents:

phenyl optionally substituted with one or more halogens (e.g., fluorine or chlorine);

optionally substituted naphthyl (e.g., unsubstituted naphthyl);

optionally substituted phenyl substituted with optionally substituted phenoxy; or

Optionally substituted heteroaryl (e.g., unsubstituted thienyl).

When X represents S, Y represents C = O, and Z represents CHR¹⁰When R is³Suitably represents hydrogen.

In an alternative embodiment, X represents S, Y represents C = S, and Z represents CHR¹⁰. In another embodiment, X represents S, Y represents C = S, and Z represents CH₂。

When X represents S, Y represents C = S, and Z represents CHR¹⁰When R is¹Suitably represents 1H-benzo [ d]An imidazolyl group.

When X represents S, Y represents C = S, and Z represents CHR¹⁰When R is²Suitably represents an optionally substituted phenyl group or an optionally substituted phenyl group substituted by an optionally substituted phenoxy group.

When X represents S, Y represents C = S, and Z represents CHR¹⁰When R is³Suitably represents hydrogen.

In an alternative embodiment, X represents CR⁷R⁸Y represents C = O, and Z represents CHR¹⁰. In another embodiment, X represents CH₂Y represents C = O, and Z represents CH ₂。

When X represents CR⁷R⁸Y represents C = O, and Z represents CHR¹⁰When R is¹Suitably represents 1H-benzo [ d]An imidazolyl group.

When X represents CR⁷R⁸Y represents C = O, and Z represents CHR¹⁰When R is²Suitably represents:

phenyl optionally substituted by one or more halogens (e.g. fluorine), C_1-6Alkoxy (e.g., methoxy or propoxy) substitution; or

Optionally substituted phenyl fused to an optionally substituted heterocyclyl (e.g. 2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl).

When X represents CR⁷R⁸Y represents C = O, and Z represents CHR¹⁰When R is³Suitably represents hydrogen.

In an alternative embodiment, X and Z represent two adjacent carbon atoms of a phenyl ring, said phenyl ring being fused at that position, and Y represents C = O. In another embodiment, X and Z represent two adjacent carbon atoms of a phenyl ring, said phenyl ring being fused at that position and said phenyl ring being substituted with one or more halogens or C_1-2Alkyl substituted, for example 2, 5-dichlorophenyl or 3, 4-dichlorophenyl, and Y represents C = O.

When X and Z represent two adjacent carbon atoms of a phenyl ring, said phenyl ring being fused at this position, and Y represents C = O, R represents¹Suitably represents 1H-benzo [ d]An imidazolyl group.

When X and Z represent two adjacent carbon atoms of a phenyl ring, said phenyl ring being fused at this position, and Y represents C = O, R represents ²Suitably represents:

phenyl optionally substituted by one or more halogens (e.g. fluoro or chloro), C_1-6Alkoxy (e.g., methoxy or propoxy) substitution;

optionally substituted phenyl substituted with optionally substituted phenyl;

optionally substituted phenyl fused to an optionally substituted heterocyclyl (e.g. benzo [ d ] [1,3] dioxol-6-yl); or

Optionally substituted phenyl substituted with optionally substituted phenoxy.

When X and Z represent two adjacent carbon atoms of a phenyl ring, said phenyl ring being fused at this position, and Y represents C = O, R represents³Suitably represents hydrogen.

In an alternative embodiment, X represents-O-CH₂-, Y denotes CO, and Z denotes CHR¹⁰. In another embodiment, X represents-O-CH₂-, Y represents CO, and Z represents CH₂(see, e.g., example 93).

When X represents-O-CH₂-, Y denotes CO, and Z denotes CHR¹⁰When R is¹Suitably represents 1H-benzo [ d]An imidazolyl group.

When X represents-O-CH₂-, Y denotes CO, and Z denotes CHR¹⁰When R is²Suitably represents optionally substituted by C_1-6Alkoxy (e.g., propoxy) substituted phenyl.

When X represents-O-CH₂-, Y denotes CO, and Z denotes CHR¹⁰When R is³Suitably represents hydrogen.

In an alternative embodiment, X represents-CH ₂-CH₂-, Y represents CO, and Z represents O.

When X represents-CH₂-CH₂-, Y represents CO, and Z represents O, R¹Suitably represents 1H-benzo [ d]Imidazolyl or 1H-imidazo [1,2-a ]]A pyridyl group.

When X represents-CH₂-CH₂-, Y represents CO, and Z represents O, R²Suitably represents optionally substituted by C_1-6Alkoxy (e.g., propoxy) substituted phenyl.

When X represents-CH₂-CH₂-, Y represents CO, and Z represents O, R³Suitably represents hydrogen.

In one embodiment, the compound of formula (I) is a compound selected from examples 1-235. In another embodiment, the compound of formula (I) is a compound selected from examples 1-147. In another embodiment, the compound of formula (I) is a compound selected from examples 12-14.

Method of producing a composite material

According to another aspect of the present invention there is provided a process for the preparation of a compound of formula (I), said process comprising:

(a) preparing a compound of formula (I) from a compound of formula (II):

wherein R is²、R³X, Y and Z are as defined above for compounds of formula (I). The methods generally include reacting a compound of formula (II) with a compound of formula R¹-L, wherein L represents a leaving group, for example a halogen atom, such as iodine. Non-limiting examples of methods of method (a) are described in methods 5-8 and 12 herein.

(b) Wherein R is prepared by hydrogenating a compound of formula (III)³Represents hydrogen, Y represents CO, Z represents-N-R⁴X represents CR⁷R⁸And R is⁸A compound of formula (I) representing hydrogen:

wherein R is¹、R²、R⁴And R⁷As hereinbefore defined for the compounds of formula (I). Process (b) generally comprises hydrogenation under suitable conditions, for example, 10% on carbon, 4 bar, 40 ℃ for 4 hours. Non-limiting examples of methods of method (b) are described in method 1 herein.

(c) Wherein R is prepared by hydrogenating a compound of formula (IV)³Represents hydrogen, Y represents CO, Z represents CH₂And X represents CH₂A compound of formula (I):

wherein R is¹And R²As hereinbefore defined for the compounds of formula (I). Process (c) generally comprises hydrogenation under suitable conditions, for example PdC, 10% on charcoal, 1-2 bar, at room temperature overnight. A non-limiting example of a method of method (c) is described in method 10 herein.

(d) Preparation of compounds of formula (V) wherein R³Represents hydrogen, Y represents CO, Z represents-N-R⁴And X represents CH₂A compound of formula (I):

wherein R is¹、R²And R⁴As hereinbefore defined for the compounds of formula (I). Method (d) typically comprises reaction with a suitable reagent, for example a compound of formula LCOL ', wherein L and L' represent leaving groups. An exemplary reagent is carbonyl diimidazole, which may be employed in the presence of a suitable solvent (e.g., methylene chloride). A non-limiting example of the method of method (b) is described in method 2 herein.

(e) Preparation of compounds of formula (VI) wherein R³Represents hydrogen, Y represents CH₂Z represents-N-R⁴And X represents CO, a compound of formula (I):

wherein R is¹、R²And R⁴As hereinbefore defined for the compounds of formula (I). Process (e) generally comprises the use of suitable reagentsFor example an activated formic acid derivative such as triethyl orthoformate, under suitable conditions such as reflux, and then reduced, for example with sodium borohydride. A non-limiting example of the method of method (e) is described in method 4 herein.

(f) Preparation of compounds of formula (VII) wherein R¹Represents 1H-benzo [ d ]]Imidazol-5-yl, R³Represents hydrogen, Y represents CO, Z represents-NH, and X represents CH₂A compound of formula (I):

wherein R is²As defined above for the compound of formula (I), and P¹Represents a suitable protecting group, such as p-methoxybenzyl. Method (f) generally comprises treating the compound of formula (IV) with an activated formic acid derivative, such as triethyl orthoformate. A non-limiting example of a method of method (f) is described in method 3 herein.

(g) Preparation of compounds of formula (VIII) wherein R³A compound of formula (I) representing hydrogen, Y represents CO, and X and Z are linked to form a carbocyclic ring, or X and Z represent two adjacent carbon atoms of a phenyl ring, said phenyl ring being fused at that position and said phenyl ring optionally being substituted by one or more halogens or C _1-2Alkyl substitution:

wherein R is¹、R²X and Z are as defined above for compounds of formula (I). Process (g) is essentially a dehydration reaction which generally involves the use of suitable reagents such as trifluoroacetic acid, triethylsilane and sodium bicarbonate. A non-limiting example of a method of method (g) is described herein as method 11.

(h) Preparation of compounds in which X represents OS a compound of formula (I), e.g. wherein R³Represents hydrogen, Y represents CO, Z represents-CH₂And X represents S. Method (h) typically involves the use of a suitable reagent, for example Lawesson's reagent. A non-limiting example of the method of method (h) is described in method 9 herein.

(i) From which R is removed by treatment with nitrite and subsequent reduction⁴Preparation of the corresponding compound of formula (I) wherein R represents H⁴represents-NH₂A compound of formula (I). In general, R is⁴The compound of formula (I) representing H is reduced by treatment with sodium nitrite (or potassium nitrite) in the presence of an acid (e.g. glacial acetic acid) followed by treatment with zinc dust. Non-limiting examples of methods of method (i) are described in example 65 herein.

(j) From which R is derived by treatment with an alkylating or alkanoylating agent⁴Preparation of the corresponding compound of formula (I) wherein R represents H ⁴represents-C_1-8Alkyl or-C (O) C_1-6Alkyl compounds of formula (I). Typical alkylating agents include those of the formula R⁴Compounds of formula (I) wherein L is a leaving group, e.g. iodine, and typical alkanoylating agents include activated acids, e.g. of formula (II)⁴A compound of-L, wherein L is a leaving group, such as halogen (e.g. chlorine) or the corresponding anhydride.

(k) Interconversion of compounds of formula (I). Examples of such interconversion include interconversion of a compound of formula (I) wherein Y represents CO to a compound of formula (I) wherein Y represents CS. Such interconversion may generally involve the use of suitable reagents, such as toluene and lawson's reagent. Non-limiting examples of methods of method (k) are described in method 9 herein; and

(l) Deprotecting the protected compound of formula (I).

Compounds of formula (I) and intermediate compounds may also be prepared using techniques analogous to those known to the skilled artisan or described herein.

One aspect of the present invention claims novel intermediates.

Therapeutic uses

Physiological substrates of QC (EC) in mammals are, for example, amyloid beta-peptide (3-40), (3-42), (11-40 and (11-42), ABri, ADAn, gastrin, neurotensin, FPP, CCL2, CCL 7, CCL 8, CCL 16, CCL 18, CXXXC chemotactic molecules, orexin A, [ Gln ] ³]-glucagon (3-29), [ Gln [ ]⁵]Substance P (5-11) and peptide QYNAD. See table 1 for further details. The compounds and/or combinations of the present invention as well as pharmaceutical compositions comprising at least one QC (ec) inhibitor may be used in the treatment of disease conditions which may be treated by modulation of QC activity.

Table 1: amino acid sequence of physiologically active peptide having N-terminal glutamine residue easily cyclized to final pGlu

Glutamate is present at positions 3, 11 and 22 of the amyloid β -peptide. Wherein the mutation of glutamic acid (E) in position 22 to glutamine (Q) (corresponding to amyloid precursor protein APP 693, Swissprot P05067) has been described as a so-called dutch-type cerebral arterial amyloid mutation.

Beta-amyloid peptides with pyroglutamic acid residues in positions 3, 11 and/or 22 have been reported to be more cytotoxic and hydrophobic than the amyloid beta-peptides 1-40(42/43) (Saido T.C.2000medical Hypotheses 54(3): 427-429).

A variety of N-terminal variants, such as A.beta.3-40, A.beta.3-42, A.beta.11-40 and A.beta.11-42, can be produced at different sites by beta-secretase beta-site amyloid precursor protein cleaving enzyme (BACE) (Huse J.T.et al 2002J.biol.chem.277(18): 16278-. In all cases, subsequent cyclization of the glutamic acid residue present at the N-terminus is catalyzed by QC.

Transepithelial transduction of cells, particularly gastrin (G) cells, coordinates gastric acid secretion when food enters the stomach. Recent studies have shown that multiple active products are produced from gastrin precursors, and that there are multiple control points in gastrin biosynthesis. Biosynthetic precursors and intermediates (progastrin and Gly-gastrin) are putative growth factors; gastrin, whose product is amidated, regulates epithelial cell proliferation, differentiation of acid-producing parietal cells and histamine-secreting enterochromaffin-like (ECL) cells, and expression of genes associated with histamine synthesis and storage in ECL cells, as well as strongly stimulating acid secretion. Gastrin also stimulates the production of members of the Epidermal Growth Factor (EGF) family, which in turn inhibits parietal cell function but stimulates the growth of surface epithelial cells. Plasma gastrin concentrations are elevated in individuals with Helicobacter pylori (Helicobacter pylori), which are known to be at increased risk of developing duodenal ulcer disease and gastric cancer (Dockray, G.J.1999J Physiol 15315-.

The peptide hormone gastrin released from G cells of the antrum is known to stimulate the synthesis and release of histamine from ECL cells in the acid-secreting mucosa via the CCK-2 receptor. Mobilizable histamine induces acid secretion by binding to H (2) receptors located on parietal cells. Recent studies have shown that both fully amidated and less processed forms of gastrin (progastrin and glycine-extended gastrin) are growth factors for the gastrointestinal tract. It has been determined that the main nutritional role of amidated gastrins is for the acid-secreting mucosa of the stomach, where it causes increased proliferation of gastric stem cells and ECL cells, resulting in increased parietal cell and ECL cell mass. On the other hand, the primary nutritional target for less processed gastrins (e.g., glycine-extended gastrins) appears to be the colonic mucosa (Koh, t.j.and Chen, d.2000regul Pept 9337-44).

Neurotensin (NT) is a neuropeptide associated with the pathophysiology of schizophrenia, which specifically regulates the neurotransmitter system, which has previously been shown to be dysregulated in this disorder. Clinical studies in which cerebrospinal fluid (CSF) NT concentrations have been measured reveal a sub-group of schizophrenic patients with reduced CSF NT concentrations that are restored by treatment with an effective antipsychotic. There is also considerable evidence to support the involvement of the NT system in the mechanism of action of antipsychotics. Centrally administered NTs have similar behavioral and biochemical effects as systemically administered antipsychotics, and antipsychotics increase NT neurotransmission. This series of findings leads to the following assumptions: NT acts as an endogenous antipsychotic. In addition, typical and atypical antipsychotics differentially alter NT neurotransmission in the nigrostriatal and mesolimbic dopamine-terminal regions, and these effects predict the propensity and efficacy of side effects, respectively (Binder, E.B. et al, 2001 Biol Psychiatry 50856-872).

The thyrotropin-releasing hormone (TRH) -related tripeptide Fertilization Promoting Peptide (FPP) is present in seminal plasma. Recent evidence obtained in vitro and in vivo indicates that FPP plays an important role in regulating sperm fertility. In particular, FPP initially stimulates unfertilized (unfertilized) sperm to "start up" and become fertile more quickly, but then stagnates capacitation so that the sperm do not undergo spontaneous acrosome detachment and thus lose fertilization potential. These responses are mimicked and indeed amplified by adenosine, which is known to regulate the Adenylate Cyclase (AC)/cAMP signal transduction pathway. Both FPP and adenosine have been shown to stimulate cAMP production in non-capacitated cells but inhibit its production in capacitated cells, while the FPP receptor interacts in some way with the adenosine receptor and G protein to effect modulation of AC. These events affect the tyrosine phosphorylation status of various proteins, some of which are important in the initial "priming", others may be involved in the acrosome reaction itself. Calcitonin and angiotensin II are also present in seminal plasma, have similar effects on non-capacitated sperm in vitro, and may amplify the response to FPP. These molecules have similar effects in vivo, affecting fertility by stimulating and then maintaining fertilization potential. Male infertility is due to reduced availability of FPP, adenosine, calcitonin and angiotensin II or their receptor defects (Fraser, l.r.and adooya-Osiguwa, s.a.2001 Vitam Horm 63, 1-28).

CCL2(MCP-1), CCL7, CCL8, CCL16, CCL18 and CXXXC chemotactic molecules play an important role in pathophysiological conditions such as inhibition of bone marrow progenitor cell proliferation, neoplasia, inflammatory host responses, cancer, psoriasis, rheumatoid arthritis, atherosclerosis, vasculitis, humoral and cell-mediated immune responses, leukocyte adhesion and migration processes at the endothelium, inflammatory bowel disease, restenosis, pulmonary fibrosis, pulmonary hypertension, liver fibrosis, liver cirrhosis, renal sclerosis, ventricular remodeling, heart failure, arterial disease after organ transplantation and failure of vein grafts.

Many studies have highlighted MCP-1 in particular against atherosclerosis (Gu, L., et al., (1998) mol. cell 2, 275-; rheumatoid arthritis (Gong, J.H., et al., (1997) J Exp.Med 186, 131-; pancreatitis (Bhatia, m., et al., (2005) am. jphysiol gastrointest. liver Physiol 288, G1259-G1265); alzheimer's disease (Yamamoto, m., et al, (2005) am.j pathol.166, 1475-1485); pulmonary fibrosis (Inoshima, i., et al., (2004) am.j Physiol Lung Cell mol. Physiol 286, L1038-L1044); important roles in the development of renal fibrosis (Wada, t., et al., (2004) J am. soc. nephrol.15,940-948), and graft rejection (Saiura, a., et al., (2004) ariioscope.thromb. vasc. biol.24, 1886-1890). In addition, MCP-1 may also play a role in gestational toxicosis (Katabuchi, H., et al., (2003) Med Electron Microsc.36,253-262), as a paracrine factor in tumor development (Ohta, M., et al., (2003) int.J Oncol.22,773-778; Li, S., et al., (2005) J exp.Med.202, 617 624), in neuropathic pain (White, F.A., et al., (2005) Proc.Natl.Acad.Sci.U.S.A.) and AIDS (Park, I.W., Wang, J.F., and DGrooan, J.E. (2001) Blood 97,352, 358; Coll, B., et al., (51-55).

MCP-1 levels are elevated in the CSF of AD patients and patients presenting with Mild Cognitive Impairment (MCI) (galimbetti, d., et al., (2006) arch. neuron.63, 538-543). Furthermore, MCP-1 shows elevated levels in the serum of patients with MCI and early AD (cleici, f., et al, (2006) neurobiol. aging 27, 1763-.

Several cytotoxic T lymphocyte peptide-based vaccines against hepatitis b, human immunodeficiency virus and melanoma have recently entered clinical trial studies. An interesting melanoma candidate vaccine, alone or in combination with other tumour antigens, is decapeptide ELA. This peptide is a Melan-A/MART-1 antigen immunodominant peptide analog with an N-terminal glutamic acid. It has been reported that amino and γ -carboxyl groups of glutamic acid and amino and γ -carboxamide groups of glutamine readily condense to form pyroglutamic acid derivatives. To overcome this stability problem, several pharmaceutically significant peptides have been developed with pyroglutamic acid instead of the N-terminal glutamine or glutamic acid without loss of pharmacological properties. Unfortunately, neither pyroglutamic acid derivatives (PyrELA) nor N-terminal acetyl-capped derivatives (AcELA) are able to elicit Cytotoxic T Lymphocyte (CTL) activity compared to ELA. Despite the introduction of significantly smaller modifications in PyrELA and AcELA, both derivatives are likely to have lower affinity for the specific class I major histocompatibility complex than ELA. Thus, in order to retain the full activity of ELA, PyrELA formation must be avoided (BeckA. et al.2001, J Pept Res 57(6): 528-38.).

Orexin a is a neuropeptide that may play an important role in regulating food intake and sleep-wakefulness by coordinating the complex behavioral and physiological responses of these complementary homeostatic functions. It also plays a role in energy metabolism, autonomic function, homeostatic regulation of hormonal balance, and regulation of body fluids.

Recently, it was confirmed that the level of pentapeptide QYNAD was increased in the cerebrospinal fluid (CSF) of patients suffering from multiple sclerosis or Guillain-Barre syndrome as compared with healthy individuals (Brinkmeier H.et al.2000, Nature Medicine 6, 808-. There is considerable controversy in the literature regarding the mechanism of action of the pentapeptide Gln-Tyr-Asn-Ala-Asp (QYNAD), particularly its potency to interact with and block sodium channels, leading to the escalation of axonal dysfunction, which is associated with inflammatory autoimmune diseases of the central nervous system. However, recently, it was demonstrated that rather than QYNAD, its cyclized pyroglutamic acid form, pEYNAD, is the active form that blocks sodium channels leading to an escalation of axonal dysfunction. Sodium channels are expressed at high density in myelinated axons and play an essential role in conducting action potentials along the axons within the mammalian brain and spinal cord. Thus, they are implicated in several aspects of the pathophysiology of inflammatory autoimmune diseases, in particular multiple sclerosis, guillain-barre syndrome and chronic inflammatory demyelinating polyradiculoneuropathy (chronic inflammatory demyelinating polyradiculoneuropathy).

Furthermore, QYNAD is a substrate for glutaminyl cyclase (QC, EC 2.3.2.5), which is also present in the mammalian brain, in particular in the human brain. Glutaminyl cyclase effectively catalyzes the formation of pEYNAD from its precursor QYNAD.

Accordingly, the present invention provides the use of a compound of formula (I) in the manufacture of a medicament for the prevention or alleviation or treatment of a disease selected from the group consisting of: mild cognitive impairment, alzheimer's disease, familial dementia of the british type, familial dementia of the danish type, neurodegeneration in down syndrome, huntington's disease, kennedy's disease, ulcer disease, duodenal cancer with or without infection by helicobacter pylori, colorectal cancer, zollinger-ellison syndrome, gastric cancer with or without infection by helicobacter pylori, pathogenic psychotic conditions, schizophrenia, infertility, neoplasia, inflammatory host response, cancer, malignant metastasis, melanoma, psoriasis, rheumatoid arthritis, atherosclerosis, pancreatitis, restenosis, impaired humoral and cell-mediated immune responses, leukocyte adhesion and migration processes in the endothelium, impaired food intake, impaired sleep-wake, impaired homeostatic regulation of energy metabolism, impaired autonomic nerve function, impaired hormone balance or humoral regulation, multiple sclerosis, Guillain-barre syndrome and chronic inflammatory demyelinating polyradiculoneuropathy.

In addition, the proliferation of bone marrow progenitor cells can be stimulated by administering the compounds of the present invention to a mammal.

In addition, administration of QC inhibitors of the present invention may result in inhibition of male fertility.

In a preferred embodiment, the invention provides the use of an inhibitor of qc (ec) activity in combination with other substances, in particular for the treatment of neuronal diseases, atherosclerosis and multiple sclerosis.

The present invention also provides a method of treating the above-mentioned diseases, comprising administering to a mammal, preferably a human, a therapeutically active amount of at least one compound of formula (I).

Most preferably, the method and corresponding use are for the treatment of a disease selected from the group consisting of: mild cognitive impairment, alzheimer's disease, familial dementia of the british type, familial dementia of the danish type, neurodegeneration in down syndrome, parkinson's disease and huntington's chorea, comprising administering a therapeutically active amount of at least one compound of formula (I) to a mammal, preferably a human.

Even more preferably, the present invention provides therapeutic methods and corresponding uses for the treatment of rheumatoid arthritis, atherosclerosis, pancreatitis and restenosis.

Pharmaceutical combination

In a preferred embodiment, the present invention provides a composition, preferably a pharmaceutical composition, comprising at least one QC inhibitor, optionally in combination with at least one further substance selected from the group consisting of: nootropic agents, neuroprotective agents, antiparkinsonian drugs, amyloid deposition inhibitors, beta amyloid synthesis inhibitors, antidepressants, anxiolytic agents, antipsychotic agents, and anti-multiple sclerosis agents.

Most preferably, said QC inhibitor is a compound of formula (I) of the present invention.

More specifically, the additional substance is selected from the group consisting of an amyloid beta antibody, a vaccine, a cysteine protease inhibitor, a PEP-inhibitor, LiCl, an acetylcholinesterase (AChE) inhibitor, a PIMT enhancer, a beta secretase inhibitor, a gamma secretase inhibitor, an aminopeptidase inhibitor, preferably a dipeptidyl peptidase inhibitor, most preferably a DP IV inhibitor, a neutral endopeptidase inhibitor, a phosphodiesterase-4 (PDE-4) inhibitor, a TNF alpha inhibitor, a muscarinic M1 receptor antagonist, an NMDA receptor antagonist, a sigma-1 receptor inhibitor, a histamine H3 antagonist, an immunomodulator, an immunosuppressant, an MCP-1 antagonist, or an antegren (natalizumab), Neurelan (slow release aminopyridine tablet), campath (alemtuzumab), IR 208, NBI 5788/MSP 771 (telimotide), paclitaxel, MS (AG284), SH636, davolvin (CD 271, adapalene), BAY 361677 (interleukin-4), matrix metalloproteinase-inhibitors (e.g., BB 76163), interferon-tau (trophoblastin), and SAIK-MS.

Furthermore, the other substance may be, for example, an anxiolytic or an antidepressant selected from the group consisting of:

(a) dinitrogen benzeneClasses, e.g. alprazolam, chlorazines(chloridizepoxide), clobazam, clonazepam, chlordiazepoxide(clorazepate), diazepam, fludiazepam, chlorofluoroEsters (loflazepate), lorazepam, mequinone, oxazepam, pramipepam, chlorideA potassium preparation, namely a potassium preparation,

(b) selective 5-hydroxytryptamine reuptake inhibitors (SSRI), such as citalopram, fluoxetine, fluvoxamine, escitalopram, sertraline, paroxetine,

(c) tricyclic antidepressants, such as amitriptyline, clomipramine, desipramine, doxepin, imipramine,

(d) (ii) a monoamine oxidase (MAO) inhibitor,

(e) azapirones (Azapirone), such as buspirone, tandospirone,

(f) 5-hydroxytryptamine-norepinephrine reuptake inhibitors (SNRI), such as venlafaxine, duloxetine,

(g) the administration of mirtazapine,

(h) norepinephrine Reuptake Inhibitors (NRIs), such as reboxetine,

(i) the content of the bupropion in the bupropion,

(j) the preparation method of the compound comprises the following steps of preparing nefazodone,

(k) a beta-blocker which is a mixture of beta-blockers,

(l) NPY-receptor ligands: an NPY agonist or antagonist.

In another embodiment, the other substance may be, for example, an anti-multiple sclerosis agent selected from:

a) Inhibitors of dihydroorotate dehydrogenase such as SC-12267, teriflunomide, MNA-715, HMR-1279 (synonymous with HMR-1715, MNA-279),

b) an autoimmune inhibitor, such as laquinimod,

c) the amount of paclitaxel is such that the amount of paclitaxel,

d) antibodies, such as AGT-1, anti-granulocyte-macrophage colony stimulating factor (GM-CSF) monoclonal antibodies, Nogo receptor modulators, ABT-874, alemtuzumab (CAMPATH), anti-OX 40 antibodies, CNTO-1275, DN-1921, natalizumab (synonymous with AN-100226, Antegren, VLA-4 Mab), daclizumab (synonymous with Zenepax, Ro-34-7375, SMART anti-Tac), J-695, priliximab (synonymous with Centara, CEN-000029, cM-T412), MRA, Dantes, anti-IL-12 antibodies,

e) peptide Nucleic Acid (PNA) preparations, such as reticulose,

f) interferon alpha, such as Alfaferone, human interferon alpha (synonymous with Omniferon, alphaleukaferon),

g) interferon beta, e.g., Frone, interferon beta-1 a such as Avonex, Betron (Rebif), interferon beta analogs, interferon beta transferrin fusion proteins, recombinant interferon beta-1 b such as Betaseron,

h) the concentration of the interferon-tau is,

i) peptides, for example AT-008, Angix. MS, Immunokine (. alpha. -Immunokine-NNSO3), cyclic peptides such as ZD-7349,

j) therapeutic enzymes, such as soluble CD8(sCD8),

k) Multiple sclerosis-specific autoantigen-encoding plasmids and cytokine-encoding plasmids, such as BHT-3009;

l) TNF-alpha inhibitors, such as BLX-1002, thalidomide, SH-636,

m) TNF antagonists, such as solirestat, lenacicept (synonymous with RO-45-2081, Tenefuse), onacept (sTNFR1), CC-1069,

n) TNF α, e.g. etanercept (synonymous with Enbrel, TNR-001)

o) CD28 antagonists, such as, for example, Albapulin,

p) an Lck tyrosine kinase inhibitor,

q) a cathepsin K inhibitor and a pharmaceutically acceptable salt thereof,

r) the membrane transporter taurine targeted to neurons and analogues of the calpain inhibitor leupeptin derived from plants, such as Neurodur,

s) chemokine receptor-1 (CCR1) antagonists, such as BX-471,

t) a CCR2 antagonist,

u) AMPA receptor antagonists, such as ER-167288-01 and ER-099487, E-2007, talampanel,

v) potassium channel blockers, such as aminopyridines,

w) a VLA-4/VCAM interacting tosyl-proline-phenylalanine small molecule antagonist, such as TBC-3342,

x) inhibitors of cell adhesion molecules, such as TBC-772,

y) antisense oligonucleotides, for example EN-101,

z) antagonists of free immunoglobulin light chains (IgLC) that bind to mast cell receptors, e.g.F-991,

aa) apoptosis-inducing antigens, such as Apogen MS,

bb) alpha-2 adrenoceptor agonists, such as tizanidine (synonymous with Zanaflex, Ternelin, Sirdalvo, Sirdaud, Mionidine),

cc) copolymers of L-tyrosine, L-lysine, L-glutamic acid and L-alanine, such as glatiramer acetate (synonymous with Copaxone, COP-1, copolymer-1),

dd) topoisomerase II modulators, for example mitoxantrone hydrochloride,

ee) adenosine deaminase inhibitors, such as cladribine (synonymous with Leustin, Mylinax, RWJ-26251),

ff) interleukin-10, such as ilo interleukin (synonymous with Tenovil, Sch-52000, CSIF),

gg) interleukin-12 antagonists, such as lisofylline (synonymous with CT-1501R, LSF, lisofylline),

hh) ethylammonium, such as SRI-62-834 (with CRC-8605, NSC-614383),

ii) immunomodulators, such as SAIK-MS, PNU-156804, alpha-fetoprotein peptide (AFP), IPDS,

jj) retinoid receptor agonists, such as adapalene (synonymous with davvin, CD-271),

kk) TGF-. beta.s, such as GDF-1 (growth and differentiation factor 1),

ll) TGF-. beta.2, such as BetaKine,

mm) MMP inhibitors, such as glycomed,

nn) phosphodiesterase 4(PDE4) inhibitors, such as RPR-122818,

oo) purine nucleoside phosphorylase inhibitors, such as 9- (3-pyridylmethyl) -9-deazaguanine, pefloxacin (synonymous with BCX-34, TO-200),

pp) alpha-4/beta-1 integrin antagonists, such as ISIS-104278,

qq) antisense alpha 4 integrins (CD49d), such as ISIS-17044, ISIS-27104,

rr) cytokine inducers, such as nucleosides, ICN-17261,

ss) an inhibitor of a cytokine,

tt) heat shock protein vaccines, such as HSPPC-96,

uu) neuregulin growth factors, such as GGF-2 (synonymous with neuregulin, glial growth factor 2),

vv) cathepsin S-inhibitors,

ww) analogs of brizopicline, such as PNU-56169, PNU-63693,

xx) inhibitors of monocyte chemoattractant protein-1, for example benzimidazoles, such as MCP-1 inhibitors, LKS-1456, PD-064036, PD-064126, PD-084486, PD-172084, PD-172386.

Furthermore, the present invention provides a pharmaceutical composition, e.g. for parenteral, enteral or oral administration, comprising at least one QC inhibitor, optionally in combination with at least one of the other substances mentioned above.

These combinations provide particularly beneficial effects. Such combinations are thus shown to be effective in and useful in the treatment of the above-mentioned diseases. Accordingly, the present invention provides methods for treating these disease conditions.

The method comprises co-administration of at least one QC inhibitor and at least one of the other substances, or sequential administration.

Co-administration includes administration of a formulation comprising at least one QC-inhibitor and at least one of the other substances, or administration of different formulations of the respective substances substantially simultaneously.

Beta-amyloid antibodies and compositions comprising beta-amyloid antibodies are described, for example, in WO/2009/065054, WO/2009/056490, WO/2009/053696, WO/2009/033743, WO/2007/113172, WO/2007/022416, WO 2006/137354, WO 2006/118959, WO 2006/103116, WO 2006/095041, WO 2006/081171, WO 2006/066233, WO 2006/066171, WO 2006/066089, WO 2006/066049, WO 2006/055178, WO 2006/046644, WO 2006/039470, WO 2006/036291, WO 2006/026408, WO 2006/016644, WO 2006/014638, WO 2006/014478, WO 2006/008661, WO 2005/123775, WO 2005/120571, WO 2005/105998, WO 2005/081872, WO 2005/080435, WO 2005/028511, WO 2005/025616, WO 2005/025516, WO 2005/023858, WO 2005/018424, WO 2005/011599, WO 2005/000193, WO 2004/108895, WO 2004/098631, WO 2004/080419, WO 2004/071408, WO 2004/069182, WO 2004/067561, WO 2004/044204, WO 2004/032868, WO 2004/031400, WO 2004/029630, WO 2004/029629, WO 2004/024770, WO 2004/024090, WO 2003/104437, WO 2003/089460, WO 2003/086310, WO 2003/077858, WO 2003/074081, WO 2003/070760, WO 2003/063760, WO 2003/055514, WO 2003/051374, WO 2003/048204, WO 2003/045128, WO 2003/040183, WO 2003/039467, WO 2003/016466, WO 2003/015691, WO 2003/014162, WO 2003/012141, WO 2002/088307, WO 2002/088306, WO 2002/074240, WO 2002/046237, WO 2002/046222, WO 2002/041842, WO 2001/062801, WO 2001/012598, WO 2000/077178, WO 2000/072880, WO 2000/063250, WO 1999/060024, WO 1999/027944, WO 1998/044955, WO 1996/025435, WO 1994/017197, WO 1990/014840, WO 1990/012871, WO 1990/012870, WO 1989/006242.

The β -amyloid antibody may be selected from, for example, polyclonal, monoclonal, chimeric (chimenic) or humanized antibodies. Furthermore, the antibodies can be used for the development of active and passive immunotherapy, i.e. vaccines and monoclonal antibodies.

Examples of suitable β -amyloid antibodies are ACU-5A5, huC091 (Acumen/Merck); PF-4360365, RI-1014, RI-1219, RI-409, RN-1219(RinatNeuroscience Corp (Pfizer Inc)); nanobody (nanobody) therapeutics of Ablynx/Boehringer Ingelheim; beta-amyloid-specific humanized monoclonal antibodies to Intellet neurosciens/IBL; m266, m266.2(Eli Lilly & Co.); AAB-02 (Elan); basizumab (Elan); BAN-2401(Bioarctic Neuroscience AB); ABP-102(Abiogen PharmaSpA); BA-27, BC-05 (Takeda); r-1450 (Roche); ESBA-212(ESBATech AG); AZD-3102(AstraZeneca) and the beta-amyloid antibody from Mindset Biopharmaceuticals Inc.

Particularly preferred are antibodies that recognize the N-terminus of the a β peptide. Suitable antibodies recognizing the A.beta. -N-terminus are, for example, Acl-24(AC Immune SA).

Monoclonal antibodies against beta-amyloid peptides are disclosed in WO 2007/068412, WO/2008/156621 and WO/2010/012004. Respective chimeric and humanized antibodies are disclosed in WO2008/011348 and WO/2008/060364. Vaccine compositions for the treatment of amyloid-related diseases are disclosed in WO/2002/096937, WO/2005/014041, WO 2007/068411, WO/2007/097251, WO/2009/029272, WO/2009/054537, WO/2009/090650WO/2009/095857, WO/2010/016912, WO/2010/011947, WO/2010/011999, WO/2010/044464.

Suitable vaccines for the treatment of amyloid-related diseases are for example Affinitops AD-01 and AD-02(GlaxoSmithKline), ACC-01 and ACC-02(Elan/Wyeth), CAD-106(Novartis/Cytos Biotechnology).

Suitable cysteine protease inhibitors are cathepsin B inhibitors. Cathepsin B inhibitors and compositions comprising such inhibitors are described, for example, in WO/2008/077109, WO/2007/038772, WO 2006/060473, WO 2006/042103, WO 2006/039807, WO 2006/021413, WO 2006/021409, WO 2005/097103, WO 2005/007199, WO2004/084830, WO 2004/078908, WO 2004/026851, WO 2002/094881, WO 2002/027418, WO 2002/021509, WO 1998/046559, WO 1996/021655.

Examples of suitable PIMT enhancers are 10-aminoaliphatic-dibenzo [ b, f ] oxepin (10-aminoaliphatic-dibenz [ b, f ] oxepine) described in WO 98/15647 and WO03/057204, respectively. Other useful examples according to the invention are the PIMT activity modulators described in WO 2004/039773.

Inhibitors of beta-secretase and compositions comprising such inhibitors are described, for example, in WO/2010/094242, WO/2010/058333, WO/2010/021680, WO/2009/108550, WO/2009/042694, WO/2008/054698, WO/2007/051333, WO/2007/021793, WO/2007/019080, WO/2007/019078, WO/2007/011810, WO03/059346, WO2006/099352, WO2006/078576, WO2006/060109, WO2006/057983, WO2006/057945, WO2006/055434, WO2006/044497, WO2006/034296, WO2006/034277, WO2006/029850, WO2006/026204, WO2006/014944, WO2006/014762, WO2006/002004, US 7,109,217, WO2005/113484, WO2005/103043, WO2005/103020, WO2005/065195, WO2005/051914, WO 2005/36, WO2005/044830, WO2005/032471, WO2005/018545, WO2005/004803, WO2005/004802, WO2004/062625, WO2004/043916, WO2004/013098, WO03/099202, WO03/043987, WO03/039454, US 6,562,783, WO02/098849 and WO 02/096897.

For the purposes of the present invention, examples of suitable beta-secretase inhibitors are WY-25105 (Wyeth); posiphen, (+) -phencycline (TorreyPines/NIH); LSN-2434074, LY-2070275, LY-2070273, LY-2070102(Eli Lilly & Co.); PNU-159775A, PNU-178025A, PNU-17820A, PNU-33312, PNU-38773, PNU-90530 (Elan/Pfizer); KMI-370, KMI-358, kmi-008(Kyoto University); OM-99-2, OM-003(Athenagen Inc.); AZ-12304146 (AstraZeneca/Astex); GW-840736X (GlaxoSmithKline plc.), DNP-004089(De Novo Pharmaceuticals Ltd.), and CT-21166(Comentis Inc.).

Inhibitors of gamma secretase and compositions comprising such inhibitors are described, for example, in WO/2010/090954, WO/2009/011851, WO/2009/008980, WO/2008/147800, WO/2007/084595, WO2005/008250, WO2006/004880, US7,122,675, US7,030,239, US 6,992,081, WO2005/097768, WO 2005/6,992,081, WO 2004/6,992,081, US 6,992,081, WO 6,992,081/6,992,081, WO 6,992,081, US 6,992,081, WO 2005/6,992,081, US 6,992,081, EP 6,992,081, WO 2004/362004, WO 2004/6,992,081, WO 6,992,081/6,992,081, WO 2004/6,992,081, WO 6,992,081/6,992,081, WO 2004/6,992,081, WO 6,992,081/6,992,081, WO 2004/6,992,081/, US 6,686,449, WO03/091278, US 6,649,196, US 6,448,229, WO01/77144 and WO 01/66564.

For the purposes of the present invention, examples of suitable gamma secretase inhibitors are GSI-953, WAY-GSI-A, WAY-GSI-B (Wyeth); MK-0752, MRK-560, L-852505, L-685-458, L-852631, L-852646(Merck & Co. Inc.); LY-450139, LY-411575, AN-37124(Eli Lilly & Co.); BMS-299897, BMS-433796(Bristol-Myers Squibb Co.); e-2012(Eisai co. ltd.); EHT-0206, EHT-206(ExonHit Therapeutics SA); NGX-555 (ToreyPines Therapeutics Inc.) and semaxatet (Semagacestat) (Eli Lilly).

DP IV inhibitors and compositions comprising such inhibitors are described, for example, in US, WO/61431, WO/67278, WO/67279, DE19834591, WO/40832, WO/15309, WO/19998, WO/46272, WO/68603, WO/40180, WO/55105, WO/34594, WO/072556, WO/000180, WO/000181, EP, WO/002553, WO/, WO 045977, WO/977, WO03/055881, WO03/057144, WO 057144/068748, WO 057144/068757, WO 057144/057144, WO2004/018467, WO 2004/057144, WO2004/071454, WO 2004/057144, WO 2004/362005, WO 2004/057144, WO 2004/362004/057144, WO 2004/362005/057144, WO 2004/362005, WO 2004/36, WO2005/023762, WO2005/025554, WO2005/026148, WO2005/030751, WO2005/033106, WO2005/037828, WO2005/040095, WO2005/044195, WO2005/047297, WO2005/051950, WO2005/056003, WO2005/056013, WO2005/058849, WO2005/075426, WO2005/082348, WO2005/085246, WO2005/087235, WO2005/095339, WO2005/095343, WO2005/095381, WO2005/108382, WO2005/113510, WO2005/116014, WO2005/116029, WO2005/118555, WO2005/120494, WO2005/121089, WO2005/121131, WO2005/123685, WO 2006/995613; WO 2006/009886; WO 2006/013104; WO 2006/017292; WO 2006/019965; WO 2006/020017; WO 2006/023750; WO 2006/039325; WO 2006/041976; WO 2006/047248; WO 2006/058064; WO 2006/058628; WO 2006/066747; WO2006/066770 and WO 2006/068978.

For the purposes of the present invention, suitable DP IV inhibitors such as sitagliptin, des-fluoro-sitagliptin (Merck & co.inc.); vildagliptin, DPP-728, SDZ-272-; ABT-279, ABT-341(Abbott Laboratories); digliptin, TA-6666(GlaxoSmithKline plc.); SYR-322(Takeda San Diego Inc.); tabostat (PointTherapeutics Inc.); ro-0730699, R-1499, R-1438(Roche Holding AG); FE-999011(Ferring Pharmaceuticals); TS-021(Taisho Pharmaceutical co.ltd.); GRC-8200(Glenmark Pharmaceuticals Ltd.); ALS-2-0426(Alantos pharmaceuticals Holding Inc.); ARI-2243(Arisaph Pharmaceuticals Inc.); SSR-162369 (Sanofi-Synthelabo); MP-513(Mitsubishi Pharma Corp.); DP-893, CP-867534-01(Pfizer Inc.); TSL-225, TMC-2A (Tanabe Seiyaku Co. Ltd.); PHX-1149(Phenomenix Corp.); saxagliptin (Bristol-Myers Squibb Co.); PSN-9301((OSI) Prosidion), S-40755 (Servier); KRP-104(ActivX biosciences Inc.); sulphostin (Zaidan Hojin); KR-62436(Korea Research Institute of chemical Technology); p32/98(Probiodrug AG); BI-A, BI-B (Boehringer Ingelheim Corp.); SK-0403(Sanwa Kagaku Kenkyusho Co. Ltd.); and NNC-72-2138(Novo Nordisk A/S).

Other preferred DP IV inhibitors are

(i) Dipeptide-like compounds, disclosed in WO 99/61431, such as N-valylprolinyl, O-benzoylhydroxylamine, alanylpyrrolidine, isoleucylthiazolidines, such as L-allo-isoleucylthiazolidine, L-threo-isoleucylpyrrolidine and their salts, in particular the fumarate salt, and L-allo-isoleucylpyrrolidine and its salts;

(ii) peptide structures, disclosed in WO 03/002593, such as tripeptides;

(iii) peptidyl ketones, disclosed in WO 03/033524;

(vi) substituted aminoketones, disclosed in WO 03/040174;

(v) topically active DP IV inhibitors, disclosed in WO 01/14318;

(vi) prodrugs of DP IV inhibitors, disclosed in WO 99/67278 and WO 99/67279; and

(v) DP IV inhibitors based on glutaminyl are disclosed in WO 03/072556 and WO 2004/099134.

For the purposes of the present invention, suitable amyloid-beta synthesis inhibitors are, for example, Bisnorcymserine (Axonyx Inc.); (R) -flurbiprofen (MCP-7869; Friladsan) (Myriadsgenetics); nitroflurbiprofen (NicOx); BGC-20-0406(Sankyo Co. Ltd.) and BGC-20-0466(BTG plc.), RQ-00000009(RaQuali Pharma Inc.).

For the purposes of the present invention, suitable amyloid deposition inhibitors are, for example, SP-233(Samaritan Pharmaceuticals); AZD-103(Ellipsis Neurotheliaceae Inc.); AAB-001 (Bapituzumab), AAB-002, ACC-001(Elan Corp plc.); colostrinin (ReGen Therapeutics plc); trimisate (Neurochem); AdPEDI- (amyloid- β 1-6)11) (Vaxin Inc.); MPI-127585, MPI-423948(Mayo Foundation); SP-08(Georgetown University); ACU-5A5 (Acumen/Merck); transthyretin (State University of New York); PTI-777, DP-74, DP 68, Exebryl (Proteo TechInc.); m266(Eli Lilly & Co.); EGb-761(D r. willmar Schwabe GmbH); SPI-014(Satori Pharmaceuticals Inc.); ALS-633, ALS-499(Advanced Life sciences Inc.); AGT-160(ArmaGen Technologies Inc.); TAK-070(takeda pharmaceutical co.ltd.); CHF-5022, CHF-5074, CHF-5096 and CHF-5105(Chiesi Farmaceutici SpA.), SEN-1176 and SEN-1329(Senexis Ltd.), AGT-160(ArmaGen Technologies), Davunetide (Allon Therapeutics), ELND-005 (Elancep/Transition Therapeutics), and nilvadipine (Archer Pharmaceuticals).

For the purposes of the present invention, suitable PDE-4 inhibitors are, for example, doxofylline (instituto biologico Chemioterapica ABC SpA.); idudilast eye drops, tulueast, ibudilast (Kyorin Pharmaceutical co. ltd.); theophylline (Elan Corp.); cilomilast (GlaxoSmithKline plc); atopik (Barrier Therapeutics Inc.); tolfrostat, CI-1044, PD-189659, CP-220629, PDE 4d inhibitor BHN (Pfizer Inc.); alotheine, LAS-37779(Almirall Prodesfara SA.); roflumilast, hydroxypermaphanid (Altana AG), tetomilast (Otska Pharmaceutical Co. Ltd.); tulueast, ibudilast (Kyorin Pharmaceutical), CC-10004(Celgene Corp.); HT-0712, IPL-4088(Inflazyme Pharmaceuticals Ltd.); MEM-1414, MEM-1917(MemoryPharmaceuticals Corp.); omilast, GRC-4039(Glenmark pharmaceuticals Ltd.); AWD-12-281, ELB-353, ELB-526 (ElbionAG); EHT-0202(ExonHitTherapeutics SA.); ND-1251(Neuro3d SA.); 4AZA-PDE4(4AZA bioscience nv.); AVE-8112 (Sanofi-Aventis); CR-3465 (Rottacharm SpA.); GP-0203, NCS-613(Centre National de la Recherche scientific); KF-19514 (kyowahako Kogyo co.ltd.); ONO-6126(ONO Pharmaceutical co.ltd.); OS-0217(Dainippon Pharmaceutical co.ltd.); IBFB-130011, IBFB-150007, IBFB-130020, IBFB-140301(IBFB Pharma GmbH); IC-485(ICOS Corp.); RBx-14016 and RBx-11082(Ranbaxy Laboratories Ltd.). A preferred PDE-4 inhibitor is rolipram.

MAO inhibitors and compositions comprising such inhibitors are described, for example, in WO2006/091988, WO2005/007614, WO2004/089351, WO01/26656, WO01/12176, WO99/57120, WO99/57119, WO99/13878, WO98/40102, WO98/01157, WO96/20946, WO94/07890 and WO 92/21333.

For the purposes of the present invention, suitable MAO inhibitors such as linezolid (pharmacia corp.); RWJ-416457(RW Johnson Pharmaceutical Research Institute); budesonide (Altana AG); GPX-325(BioResearch Ireland); isocarboxazid; phenelzine; tranylcypromine; indomethacin (Chiesi faceutici SpA); moclobemide (Roche Holding AG); SL-25.1131 (Sanofi-Synthelabo); CX-1370(Burroughs Wellcome Co.); CX-157(Krenitsky Pharmaceuticals Inc.); bangladine (desoxypeganine) (hfarzneimitelforschung GmbH & co. kg); diphenylmelem (Mitsubishi-Tokyo pharmaceuticals Inc.); RS-1636(Sankyo co.ltd.); sulfopurone (BASF AG); rasagiline (Teva Pharmaceutical Industries Ltd.); ladostigil (Hebrew university of jerusalem); saxatilide (Pfizer), NW-1048(Newron Pharmaceuticals SpA.), EVT-302 (Evotec).

For the purposes of the present invention, suitable histamine H3 antagonists are, for example, ABT-239, ABT-834(Abbott Laboratories); 3874-H1(Aventis Pharma); UCL-2173(Berlin Freeuniversity), UCL-1470(BioProjet, society Civille de Recherche); DWP-302(Daewoong Pharmaceutical Co Ltd); GSK-189254A, GSK-207040A (GlaxoSmithKline Inc.); cilarison, GT-2203 (Gliatch Inc.); ciprofloxacin (INSERM), 1S, 2S-2- (2-aminoethyl) -1- (1H-imidazol-4-yl) cyclopropane (hokkaido university); JNJ-17216498, JNJ-5207852(Johnson & Johnson); NNC-0038 0000 1049(Novo Nordisk A/S); and Sch-79687 (Schering-Plough).

PEP inhibitors and compositions comprising such inhibitors are described, for example, in JP 01042465, JP03031298, JP 04208299, WO 00/71144, US5,847,155; JP, JP10077300, JP, WO, EP0556482, JP, EP, US, JP, EP0268190, EP, US, EP, JP1226880, EP, US, EP, JP, US, JP, EP, JP, EP, JP, WO, EP0670309, EP, JP, US, EP0268281, US, EP, JP, US, EP, US, EP, US, EP, US4,772,587, EP 0372484, US5,028,604, WO 91/18877, JP 04009367, JP04235162, US5,407,950, WO 95/01352, JP 01250370, JP 02207070, US5,221,752, EP 0468339, JP 04211648, WO 99/46272, WO 2006/058720 and PCT/EP 2006/061428.

For the purposes of the present invention, suitable prolyl endopeptidase inhibitors are, for example, Fmoc-Ala-Pyrr-CN, Z-Phe-Pro-benzothiazole (Probiodrug), Z-321(Zeria pharmaceutical Co Ltd.); ONO-1603(Ono Pharmaceutical Co Ltd); JTP-4819(Japan Tobacco Inc.) and S-17092 (Servier).

Other suitable compounds which may be used in combination with QC inhibitors according to the invention are NPY, NPY mimetics or NPY agonists or antagonists, or ligands of the NPY receptor.

Antagonists of the NPY receptor are preferred according to the invention.

Suitable ligands or antagonists of the NPY receptor are compounds derived from 3a,4,5,9 b-tetrahydro-1 h-benzo [ e ] indol-2-ylamine as disclosed in WO 00/68197.

NPY receptor antagonists that may be mentioned include those disclosed in european patent applications EP 0614911, EP 0747357, EP 0747356 and EP 0747378; international patent applications WO 94/17035, WO 97/19911, WO 97/19913, WO96/12489, WO 97/19914, WO 96/22305, WO 96/40660, WO 96/12490, WO 97/09308, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 97/19682, WO 97/25041, WO 97/34843, WO 97/46250, WO 98/03492, WO 98/03493, WO 98/03494 and WO 98/07420; WO 00/30674, U.S. patent nos. 5,552,411, 5,663,192 and 5,567,714; 6,114,336, Japanese patent application JP 09157253; international patent applications WO 94/00486, WO 93/12139, WO 95/00161 and WO 99/15498; U.S. patent No. 5,328,899; german patent application DE 3939797; european patent applications EP 355794 and EP 355793; and NPY receptor antagonists of japanese patent applications JP 06116284 and JP 07267988. Preferred NPY antagonists include those specifically disclosed in these patent documents. More preferred compounds include amino acid and non-peptide based NPY antagonists. Amino acid and non-peptide based NPY antagonists that may be mentioned include those disclosed in european patent applications EP 0614911, EP 0747357, EP 0747356 and EP 0747378; international patent applications WO 94/17035, WO 97/19911, WO 97/19913, WO96/12489, WO 97/19914, WO 96/22305, WO 96/40660, WO 96/12490, WO 97/09308, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 97/19682, WO 97/25041, WO 97/34843, WO 97/46250, WO 98/03492, WO 98/03493, WO 98/03494, WO 98/07420 and WO 99/15498; U.S. patent nos. 5,552,411, 5,663,192, and 5,567,714; and the amino acid and non-peptide based NPY antagonists of japanese patent application JP 09157253. Preferred amino acid and non-peptide based NPY antagonists include those specifically disclosed in these patent documents.

Particularly preferred compounds include amino acid-based NPY antagonists. Amino acid-based compounds which may be mentioned include the compounds disclosed in the international patent applications WO 94/17035, WO 97/19911, WO97/19913, WO 97/19914 or preferably WO 99/15498. Preferred amino acid-based NPY antagonists include those specifically disclosed in these patent documents, such as BIBP3226, in particular (R) -N2- (diphenylacetyl) - (R) -N- [1- (4-hydroxy-phenyl) ethyl ] arginine amide (example 4 of international patent application WO 99/15498).

M1 receptor agonists and compositions comprising such inhibitors are described, for example, in WO2004/087158, WO 91/10664.

For the purposes of the present invention, suitable M1 receptor antagonists are, for example, CDD-0102(cognitive pharmaceuticals); cevimeline (Evoxac) (Snow Brand Milk Products Co. Ltd.); NGX-267(TorreyPines Therapeutics); sabcomeline (GlaxoSmithKline); atorvastatin (H Lundbeck A/S); LY-593093(Eli Lilly & Co.); VRTX-3 (VertexPharmaceutics Inc.); WAY-132983(Wyeth), CI-1017/(PD-151832) (Pfizer Inc.) and MCD-386(Mitridion Inc.).

Acetylcholinesterase inhibitors and compositions comprising such inhibitors are described, for example, in WO2006/071274, WO2006/070394, WO2006/040688, WO2005/092009, WO2005/079789, WO2005/039580, WO2005/027975, WO2004/084884, WO2004/037234, WO2004/032929, WO03/101458, WO03/091220, WO03/082820, WO03/020289, WO02/32412, WO01/85145, WO01/78728, WO01/66096, WO00/02549, WO01/00215, WO00/15205, WO00/23057, WO00/33840, WO00/30446, WO00/23057, WO00/15205, WO00/09483, WO00/07600, WO00/02549, WO99/47131, WO99/07359, WO98/30243, WO97/38993, WO97/13754, WO94/29255, WO94/20476, WO94/19356, WO93/03034 and WO 92/19238.

For the purposes of the present invention, suitable acetylcholinesterase inhibitors are, for example, donepezil (Eisai co. ltd.); rivastigmine (Novartis AG); (-) -Fencerine (TorreyPines Therapeutics); ladostigil (Hebrew University of Jerusalem); huperzine a (Mayo Foundation); galantamine (Johnson & Johnson); memoquin (university di bologna); SP-004(Samaritan Pharmaceuticals Inc.); BGC-20-1259(Sankyo co.ltd.); physostigmine (Forest Laboratories Inc.); NP-0361(Neuropharma SA); ZT-1 (Debiopharm); tacrine (Warner-Lambert Co.); metrazoxane esters (Bayer Corp.), INM-176(Whanin), huperzine A (Neuro-Hitech/Xel Pharmaceutical), Debiopharm (Debiopharm), and Dimebon (Medivation/Pfizer).

NMDA receptor antagonists and compositions comprising such inhibitors are described, for example, in WO2006/094674, WO2006/058236, WO2006/058059, WO2006/010965, WO2005/000216, WO2005/102390, WO2005/079779, WO2005/079756, WO2005/072705, WO2005/070429, WO2005/055996, WO2005/035522, WO2005/009421, WO2005/000216, WO2004/092189, WO2004/039371, WO 039371/010159, WO 039371/072542, WO 039371/039371, WO 039371/32640, WO 039371/10833, WO 039371/10831, WO 039371/039371, WO 3600197, WO 039371/039371, WO 0144872/039371, WO 360772/039371, WO 039371/039371, WO 360772/039371, WO 039371/039371, WO 360772/, WO98/10757, WO98/05337, WO97/32873, WO97/23216, WO97/23215, WO97/23214, WO96/14318, WO96/08485, WO95/31986, WO95/26352, WO95/26350, WO95/26349, WO95/26342, WO95/12594, WO95/02602, WO95/02601, WO94/20109, WO94/13641, WO94/09016 and WO 93/25534.

For the purposes of the present invention, suitable NMDA receptor antagonists are, for example, memantine (Merz & co.gmbh); topiramate (Johnson & Johnson); AVP-923(Neurodex) (Center for neurologic studio); EN-3231(Endo Pharmaceuticals Holdings Inc.); neramexane (MRZ-2/579) (Merz and Forest); CNS-5161(CeNeS Pharmaceuticals Inc.); deseprunox (HU-211; Sinnabidol; PA-50211) (Pharmos); EpiCept NP-1(Dalhousie university); indantadol (V-3381; CNP-3381) (Vernalis); peifex (EAA-090, WAY-126090, EAA-129) (Wyeth); RGH-896(Gedeon Richter Ltd.); troxolodine (CP-101606), Bessolodine (PD-196860, CI-1041) (Pfizer Inc.); CGX-1007(Cognetix Inc.); darussine (NPS-1506) (NPS Pharmaceuticals Inc.); EVT-101(Roche Holding AG); acamprosate (syncroneuron LLC.); CR-3991, CR-2249, CR-3394 (Rottacharm SpA.); AV-101 (4-Cl-kynurenine (4-Cl-KYN)), 7-chloro-kynurenic acid (7-Cl-KYNA) (Vistagen); NPS-1407(NPS Pharmaceuticals Inc.); YT-1006(Yaupon Therapeutics Inc.); ED-1812(Sosei R & D Ltd.); himantane (N-2- (adamantyl) -hexamethylene-imine hydrochloride) (RAMS); ranitidine (lancimine) (AR-R-15896) (AstraZeneca); EVT-102, Ro-25-6981 and Ro-63-1908(Hoffmann-La Roche AG/Evotec), Neramexane (Merz).

Furthermore, the present invention relates to a combination therapy useful for the treatment of atherosclerosis, restenosis or arthritis, the administration of a QC inhibitor in combination with another therapeutic agent selected from Angiotensin Converting Enzyme (ACE) inhibitors, to provide a beneficial or synergistic therapeutic effect relative to each of the monotherapy components alone; an angiotensin II receptor blocker; a diuretic; calcium Channel Blockers (CCBs); a beta-blocker; a platelet aggregation inhibitor; cholesterol absorption modulators; HMG-Co-A reductase inhibitors; high Density Lipoprotein (HDL) increasing compounds; a renin inhibitor; an IL-6 inhibitor; anti-inflammatory corticosteroids; an antiproliferative agent; a nitric oxide donor; an extracellular matrix synthesis inhibitor; growth factor or cytokine signal transduction inhibitors; MCP-1 antagonists and tyrosine kinase inhibitors.

Angiotensin II receptor blockers are understood as those active substances which bind to the AT 1-receptor subtype of the angiotensin II receptor but do not lead to activation of this receptor. Due to the blockade of the AT1 receptor, these antagonists may be used, for example, as antihypertensive agents.

Suitable angiotensin II receptor blockers that can be used in the combinations of the invention include AT1 receptor antagonists with different structural features, preferably those with non-peptidic structures. For example, compounds selected from valsartan (EP 443983), losartan (EP 253310), candesartan (EP 459136), eprosartan (EP 403159), irbesartan (EP 454511), olmesartan (EP503785), tasosartan (EP 539086), telmisartan (EP 522314), the compounds of formula named E-4177

A compound of the formula named SC-52458

And a compound of the formula designated ZD-8731

Or, in each case, a pharmaceutically acceptable salt thereof.

Preferred AT 1-receptor antagonists are those approved and marketed, most preferably valsartan, or a pharmaceutically acceptable salt thereof.

Blocking the enzymatic degradation of angiotensin to angiotensin II with ACE inhibitors is a successful variant for regulating blood pressure and thus also makes available therapeutic methods for the treatment of hypertension.

Suitable ACE inhibitors for the combination of the present invention are, for example, compounds selected from the group consisting of alacepril, benazepril, benazeprilat, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat (enaprilat), fosinopril, imidapril, lisinopril, moexipril (moveltopril), perindopril, quinapril, ramipril, spirapril, temocapril and trandolapril, or in each case a pharmaceutically acceptable salt thereof.

Preferred ACE inhibitors are those already on the market, most preferably benazepril and enalapril.

Diuretics are for example thiazine derivatives selected from the group consisting of chlorothiazide, hydrochlorothiazide, methyclothiazide and chlorothiazide. The most preferred diuretic is hydrochlorothiazide. Diuretics also include potassium sparing diuretics, such as amiloride or triameterene (triameterine), or pharmaceutically acceptable salts thereof.

CCB classes include essentially Dihydropyridines (DHP) and non-DHP, e.g. diltiazemType and verapamil type CCB.

CCB which can be used in said combination is preferably a DHP representative selected from amlodipine, a non-DHP representativeLodipine, ryosidine, isradipine, lacidipine, nicardipine, nifedipine, niguldipine, nilludipine, nimodipine, nisoldipine, nitrendipine, and nilvadipine (nivaldipine), and further preferably a non-DHP representative selected from flunarizine, prenylamine, diltiazemFendiline, gallopamil, mibefradil, anipamil, tiapamil and verapamil, and in each case, pharmaceutically acceptable salts thereof. All these CCBs are used therapeutically as, for example, antihypertensives, antianginals or antiarrhythmics. Preferred CCBs include amlodipine, diltiazemIsradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, and verapamil, or, for example, depending on the particular CCB, a pharmaceutically acceptable salt thereof. Particularly preferred as DHP is amlodipine or a pharmaceutically acceptable salt thereof, especially besylate. A particularly preferred non-DHP representative is verapamil or a pharmaceutically acceptable salt thereof, particularly the hydrochloride salt.

Beta-blockers suitable for use in the present invention include beta-adrenergic blockers (beta-blockers), which compete with adrenaline for beta-adrenergic receptors and interfere with the action of adrenaline. Preferably, the beta-blocker is selective for beta-adrenergic receptors compared to alpha-adrenergic receptors, and therefore has no significant alpha-blocking effect. Suitable beta-blockers include compounds selected from acebutolol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, and timolol. Wherein the beta-blocker is an acid or base, or is capable of forming a pharmaceutically acceptable salt or prodrug, such forms being contemplated herein, and it is to be understood that the compound may be administered in free form or in the form of a pharmaceutically acceptable salt or prodrug, such as a physiologically hydrolyzable and acceptable ester. For example, metoprolol is suitably administered as its tartrate salt, propranolol is suitably administered as its hydrochloride salt, and the like.

Platelet aggregation inhibitors include(clopidogrel hydrogensulfate), (cilostazol) and aspirin.

The cholesterol absorption regulator comprises(ezetimibe) and KT6-971(kotobuki pharmaceutical co.

HMG-Co-a reductase inhibitors (also known as beta-hydroxy-beta-methylglutaryl coenzyme a reductase inhibitors or statins) are to be understood as those active substances which can be used to reduce the lipid levels including cholesterol in the blood.

The class of HMG-Co-A reductase inhibitors includes compounds having different structural features. For example, mention may be made of compounds selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin, or in each case a pharmaceutically acceptable salt thereof.

Preferred HMG-Co-A reductase inhibitors are those already on the market, most preferred being atorvastatin, pitavastatin or simvastatin, or a pharmaceutically acceptable salt thereof.

HDL increasing compounds include, but are not limited to, Cholesteryl Ester Transfer Protein (CETP) inhibitors. Examples of CETP inhibitors include JTT7O5 disclosed in example 26 of U.S. patent No. 6,426,365, granted on 30/7/2002, and pharmaceutically acceptable salts thereof.

Inhibition of interleukin 6-mediated inflammation may be achieved indirectly by modulation of endogenous cholesterol synthesis and isoprenoid depletion, or by direct inhibition of signal transduction pathways, using interleukin-6 inhibitors/antibodies, interleukin-6 receptor inhibitors/antibodies, interleukin-6 antisense oligonucleotides (ASONs), gp130 protein inhibitors/antibodies, tyrosine kinase inhibitors/antibodies, serine/threonine kinase inhibitors/antibodies, mitogen-activated protein (MAP) kinase inhibitors/antibodies, phosphatidylinositol 3-kinase (PI3K) inhibitors/antibodies, nuclear factor kappa B (NF-kappa B) inhibitors/antibodies, ikb kinase (IKK) inhibitors/antibodies, activin-1 (AP-1) inhibitors/antibodies, anti-inflammatory agents/antibodies, STAT transcription factor inhibitors/antibodies, altered IL-6, IL-6 or partial peptides of the IL-6 receptor, or SOCS (cytokine Signal transduction inhibitor) proteins, PPAR γ and/or PPAR β/δ activators/ligands or functional fragments thereof.

A suitable anti-inflammatory corticosteroid is dexamethasone.

Suitable antiproliferative agents are cladribine, rapamycin, vincristine and taxol.

A suitable extracellular matrix synthesis inhibitor is halofuginone.

Suitable growth factor or cytokine signal transduction inhibitors are for example the ras inhibitors R115777.

Suitable tyrosine kinase inhibitors are tyrosine phosphorylation inhibitors.

Suitable renin inhibitors are described, for example, in WO 2006/116435. A preferred renin inhibitor is aliskiren, preferably in the form of its hemi-fumarate salt.

The MCP-1 antagonist may, for example, be selected from the group consisting of an anti-MCP-1 antibody, preferably a monoclonal or humanized monoclonal antibody, an inhibitor of MCP-1 expression, a CCR2 antagonist, a TNF- α inhibitor, an inhibitor of VCAM-1 gene expression, and an anti-C5 a monoclonal antibody.

MCP-1 antagonists and compositions comprising such inhibitors are described, for example, in WO02/070509, WO02/081463, WO02/060900, US2006/670364, US2006/677365, WO2006/097624, US2006/316449, WO2004/056727, WO03/053368, WO00/198289, WO00/157226, WO00/046195, WO00/046196, WO00/046199, WO00/046198, WO00/046197, WO99/046991, WO99/007351, WO98/006703, WO97/012615, WO2005/105133, WO03/037376, WO2006/125202, WO2006/085961, WO2004/024921, WO 2006/074265.

Suitable MCP-1 antagonists such as C-243(Telik Inc.); NOX-E36(Noxxon Pharma AG); AP-761(Actimis Pharmaceuticals Inc.); ABN-912, NIBR-177(Novartis AG); CC-11006(Celgene Corp.); SSR-150106 (Sanofi-Aventis); MLN-1202(Millenium Pharmaceuticals Inc.); AGI-1067, AGIX-4207, AGI-1096 (Atherogenetics Inc.); PRS-211095, PRS-211092(Pharmos Corp.); anti-C5 a monoclonal antibodies, such as neutrazumab (G2 therapeutics Ltd.); AZD-6942(AstraZeneca plc.); 2-mercaptoimidazole (Johnson & Johnson); TEI-E00526, TEI-6122 (Deltagen); RS-504393(Roche Holding AG); SB-282241, SB-380732, ADR-7 (GlaxoSmithKline); anti-MCP-1 monoclonal antibody (Johnson & Johnson).

The combination of a QC inhibitor and an MCP-1 antagonist may be used generally to treat inflammatory diseases, including neurodegenerative diseases.

The combination of a QC inhibitor with a MCP-1 antagonist is preferably used for the treatment of alzheimer's disease.

Most preferably, said QC inhibitor is in combination with one or more compounds selected from the group consisting of:

PF-4360365, m266, basizumab, R-1450, Posiphen, (+) -phencycline, MK-0752, LY-450139, E-2012, (R) -flurbiprofen, AZD-103, AAB-001 (basizumab), trimipristal, EGb-761, TAK-070, doxofylline, theophylline, cilomilast, tofastonite, roflumilast, tetomilast, tyltelomilast, ibudilast, HT-0712, MEM-1414, Omilast, linezolid, budipine, isocarboxazid, phenelzine, tranylcypromine, indate, moclobemide, rasagiline, ladigy, sartoria, ABT-239, ABT-072,GSK-189254A, ciprofloxacin, JNJ-17216498, Fmoc-Ala-Pyrr-CN, Z-Phe-Pro-benzothiazole, Z-321, ONO-1603, JTP-4819, S-17092, BIBP3226, (R) -N2- (diphenylacetyl) - (R) -N- [1- (4-hydroxyphenyl) ethyl ] ethyl]Argininamide, cevimeline, sabcomeline, (PD-151832), donepezil, rivastigmine, (-) -phencycline, ladostigil, galantamine, tacrine, metrazine ester, memantine, topiramate, AVP-923, EN-3231, neramexane, valsartan, benazepril, enalapril, hydrochlorothiazide, amlodipine, diltiazem Isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, verapamil, amlodipine, acebutolol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol, esmolol, labetalol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, timolol,(clopidogrel hydrogensulfate),(cilostazol), aspirin,(ezetimibe) and KT6-971, statins, atorvastatin, pitavastatin or simvastatin, dexamethasone, cladribine, rapamycin, vincristine, taxol, aliskiren, C-243, ABN-912, SSR-150106, MLN-1202 and betalone.

In particular, the following combinations are considered:

-a QC inhibitor, preferably of formula (I), more preferably selected from any one of examples 1-235, in combination with atorvastatin for use in the treatment and/or prevention of atherosclerosis,

a QC inhibitor, preferably of formula (I), more preferably selected from any one of examples 1 to 235, in combination with an immunosuppressant, preferably rapamycin, for use in the prevention and/or treatment of restenosis,

-a QC-inhibitor, preferably of formula (I), more preferably selected from any one of examples 1 to 235, in combination with an immunosuppressant, preferably paclitaxel, for the prevention and/or treatment of restenosis,

-a QC inhibitor, preferably of formula (I), more preferably selected from any of examples 1-235, in combination with an AChE inhibitor, preferably donepezil, for the prevention and/or treatment of Alzheimer's disease,

-a QC inhibitor, preferably of formula (I), more preferably selected from any one of examples 1 to 235, in combination with an interferon, preferably Aronex, for use in the prevention and/or treatment of multiple sclerosis,

-a QC inhibitor, preferably of formula (I), more preferably selected from any one of examples 1 to 235, in combination with an interferon, preferably a betaxolone, for use in the prevention and/or treatment of multiple sclerosis,

-a QC inhibitor, preferably of formula (I), more preferably selected from any one of examples 1-235, in combination with an interferon, preferably Rebif, for use in the prevention and/or treatment of multiple sclerosis,

-a QC inhibitor, preferably of formula (I), more preferably selected from any one of examples 1 to 235, in combination with Copaxone, for use in the prevention and/or treatment of multiple sclerosis,

A QC inhibitor, preferably of formula (I), more preferably selected from any one of examples 1 to 235, in combination with dexamethasone, for use in the prevention and/or treatment of restenosis,

a QC inhibitor, preferably of formula (I), more preferably selected from any one of examples 1 to 235, in combination with dexamethasone, for use in the prevention and/or treatment of atherosclerosis,

-a QC inhibitor, preferably of formula (I), more preferably selected from any one of examples 1 to 235, in combination with dexamethasone, for use in the prevention and/or treatment of rheumatoid arthritis,

-a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any of examples 1-235, in combination with an HMG-Co-A-reductase inhibitor for use in the prevention and/or treatment of restenosis, wherein the HMG-Co-A-reductase inhibitor is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin,

-a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any of examples 1-235, in combination with an HMG-Co-A-reductase inhibitor for use in the prevention and/or treatment of atherosclerosis, wherein the HMG-Co-A-reductase inhibitor is selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin,

-a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any of examples 1-235, in combination with an HMG-Co-A-reductase inhibitor for use in the prevention and/or treatment of rheumatoid arthritis, wherein the HMG-Co-A-reductase inhibitor is selected from atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin,

-a QC inhibitor, preferably of formula (I), more preferably selected from any one of examples 1-235, in combination with an amyloid-beta antibody for use in the prevention and/or treatment of mild cognitive impairment, wherein said amyloid-beta antibody is Acl-24,

-a QC inhibitor, preferably of formula (I), more preferably a QC inhibitor selected from any of examples 1-235, in combination with an amyloid-beta antibody for use in the prevention and/or treatment of Alzheimer's disease, wherein said amyloid-beta antibody is Acl-24,

-a QC inhibitor, preferably of formula (I), more preferably a QC inhibitor selected from any of examples 1-235, in combination with an amyloid-beta antibody for use in the prevention and/or treatment of neurodegeneration in Down syndrome, wherein said amyloid-beta antibody is Acl-24,

-a QC inhibitor, preferably of formula (I), more preferably selected from any one of examples 1-235, in combination with a beta-secretase inhibitor for use in the prevention and/or treatment of mild cognitive impairment, wherein the beta-secretase inhibitor is selected from WY-25105, GW-840736X and CTS-21166,

-a QC inhibitor, preferably of formula (I), more preferably a QC inhibitor selected from any of examples 1-235, in combination with a beta-secretase inhibitor for use in the prevention and/or treatment of Alzheimer's disease, wherein said beta-secretase inhibitor is selected from WY-25105, GW-840736X and CTS-21166,

-a QC inhibitor, preferably a QC inhibitor of formula (I), more preferably a QC inhibitor selected from any of examples 1-235, in combination with a beta-secretase inhibitor for use in the prevention and/or treatment of neurodegeneration in Down syndrome, wherein said beta-secretase inhibitor is selected from the group consisting of WY-25105, GW-840736X and CTS-21166,

-a QC inhibitor, preferably of formula (I), more preferably selected from any of examples 1-235, in combination with a gamma-secretase inhibitor for use in the prevention and/or treatment of mild cognitive impairment, wherein the gamma-secretase inhibitor is selected from LY-450139, LY-411575 and AN-37124,

-a QC inhibitor, preferably of formula (I), more preferably selected from any one of examples 1 to 235, in combination with a gamma-secretase inhibitor for use in the prevention and/or treatment of Alzheimer's disease, wherein said gamma-secretase inhibitor is selected from LY-450139, LY-411575 and AN-37124,

-a QC inhibitor, preferably of formula (I), more preferably selected from any one of examples 1 to 235, in combination with a gamma-secretase inhibitor for use in the prevention and/or treatment of neurodegeneration in down syndrome, wherein the gamma-secretase inhibitor is selected from LY-450139, LY-411575 and AN-37124.

Such combination therapy is particularly useful for neurodegeneration in AD, FAD, FDD and down syndrome, as well as atherosclerosis, rheumatoid arthritis, restenosis and pancreatitis.

Such combination therapy may result in better efficacy (less proliferation and less inflammation, proliferation stimulation) than either substance alone.

For specific combinations of QC inhibitors with other compounds, reference is made in this respect in particular to WO2004/098625, which is incorporated herein by reference.

Pharmaceutical composition

For the preparation of the pharmaceutical compositions according to the invention, at least one compound of the formula (I), optionally in combination with at least one of the other substances mentioned above, may be used as active ingredient. The active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral, e.g., intramuscular. In preparing the compositions for oral dosage form, any of the conventional pharmaceutical media may be employed. Thus, for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral formulations such as powders, capsules, soft capsules 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. Tablets may be sugar coated or enteric coated by standard techniques, if desired. For parenteral formulations, the carrier will usually comprise sterile water, but may include other ingredients, for example, for purposes such as solubilization or preservation.

Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions of the present invention will contain per dosage unit (e.g., tablet, capsule, powder, injection, teaspoonful, etc.) the amount of active ingredient required to deliver an effective dose as described above. The pharmaceutical compositions of the present invention will contain from about 0.03mg to 100mg/kg (preferably 0.1 to 30mg/kg) per dosage unit (e.g., tablet, capsule, powder, injection, suppository, teaspoonful, etc.), and may be administered at a dosage of from about 0.1 to 300 mg/kg/day (preferably 1 to 50 mg/kg/day) of each active ingredient or combination thereof. However, the dosage may vary depending on the requirements of the patient, the severity of the disease condition being treated, and the compound being employed. Daily administration or post-periodic administration (post-periodicalization) may be employed.

Preferably, these compositions are in unit dosage forms, 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 in a form suitable for once weekly or once monthly administration; for example, an insoluble salt of the active compound, such as a decanoate salt, may be adapted to provide a depot formulation for intramuscular injection. To prepare 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 such as water, to form a solid preformulation composition comprising 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, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500mg of the various active ingredients of the present invention or combinations thereof.

Tablets or pills of the composition of the invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill may comprise an inner dosage component and an outer dosage component, the latter being in the form of a capsule covering the former. The two components may be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials may be used for such enteric layers or coatings, including a number of polymeric acids, and materials such as shellac, cetyl alcohol and cellulose acetate.

Liquid forms into which the compositions of the present invention may be incorporated for oral or administration by injection include: aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored 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, for example tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

The pharmaceutical composition may contain from about 0.01mg to 100mg, preferably from about 5 to 50mg of each compound and may be in any form suitable for the chosen mode of administration. 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.

Advantageously, the compounds of the present invention may be administered in a single daily dose, or the total daily dose may be divided into two, three or four daily doses. In addition, the compounds of the present invention may be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal patches well known to those skilled in the art. For administration in the form of a transdermal delivery system, the dosage administration is of course continuous rather than intermittent throughout the dosage regimen.

For example, for oral administration in the form of tablets or capsules, the active pharmaceutical ingredient may be mixed with an oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. In addition, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture, as desired or necessary. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta lactose, 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. Disintegrants include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

The liquid agents are formed in suitable flavored suspending or dispersing agents such as synthetic and natural gums, e.g., tragacanth, acacia, methyl-cellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. When intravenous administration is desired, isotonic formulations, which typically contain suitable preservatives, are employed.

The compounds or combinations of the present invention may 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.

The compounds or combinations of the present invention may also be delivered by using monoclonal antibodies conjugated to the compound molecules as separate carriers. The compounds of the invention may also be coupled to soluble polymers as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide polylysine substituted with palmitoyl residues. In addition, the compounds of the present invention may be coupled to a class of biodegradable polymers useful for achieving controlled release of a drug, such as polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic hydrogel block copolymers.

The compounds or combinations of the present invention may be administered in the form of any of the above-described compositions and according to art-established dosing regimens whenever treatment of the condition is desired.

The daily dosage of the product may vary widely from 0.01 to 1.000mg per mammal per day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the respective active ingredient or combination thereof for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug is typically provided at a daily dosage level of about 0.1mg/kg to about 300mg/kg of body weight. Preferably, the range is from about 1 to about 50mg/kg body weight per day. The compound or combination may be administered on a regimen of 1-4 times daily.

The optimal dosage to be administered can be readily determined by one skilled in the art and will vary with the particular compound used, the mode of administration, the strength of the formulation, the mode of administration and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, can result in the need to adjust the dosage.

In another aspect, the present invention also provides a process for the preparation of a pharmaceutical composition comprising at least one compound of formula (I), optionally in combination with at least one of the other agents mentioned above, and a pharmaceutically acceptable carrier.

The composition is preferably in unit dosage form in an amount suitable for the relevant daily dose.

Suitable dosages, including especially unit dosages, of The compounds of The invention include known dosages, including, for example, unit dosages of these compounds as described or mentioned in British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, Pharmaceutical Press) (see, for example, 31 th edition therein, page 341 and pages cited therein), or in The publications mentioned above.

Examples

General synthetic description:

method 1

Dissolving amine (1 equivalent) in CH₂Cl₂And TEA (3 equivalents) was added. Then adding the mixture dissolved in a small amount of CH₂Cl₂Bis (1H-imidazol-1-yl) methanone (1 equivalent). The mixture was stirred at r.t. for 2h, then a small amount of CH suspended in 2 equivalents of TEA was added₂Cl₂Corresponding aminoalkyl ketone hydrochloride in (1 eq). The mixture was stirred for 2-3h until complete formation of urea. The urea was isolated by preparative HPLC.

Urea was added to a mixture of AcOH and concentrated HCl (40/1, v/v)And kept under reflux for 1 h. The solvent was removed and the residue was redissolved in MeOH and a small amount of HCl (1-2%) was added. The solution was hydrogenated (PdC, 10% on charcoal, 4 bar, 40 ℃) for 4 h. By passingThe pad is filtered to remove the catalyst. The solvent was removed by preparative HPLC and purified.

Method 2

1 equivalent of aldehyde was dissolved in AcOH (5 mL in the case of 4mmol of starting material) and 1.1 equivalents of amine were added. Then 1 equivalent of TMSCN was added to the mixture. The mixture was then stirred at r.t. for 1.5 h.

The mixture was then poured onto ice/ammonia (12 mL of 25% NH in the case of 4mmol of starting material)₃Solution) above. The aqueous layer is replaced by CH₂Cl₂Extraction was performed 3 times, and the organic phases were combined and dried. The solvent was removed and the residue was added to MeOH and 1-2% concentrated HCl was added. The solution is hydrogenated (PdC 10%, H) ₂4 bar, 3h, RT). After filtration, the solvent was evaporated and the remaining oil was dissolved in CH₂Cl₂And TEA (2.2 eq) was added. After addition of carbonyldiimidazole (1.2eq), the mixture was kept at reflux for 18 h. Removing the solvent, adding the remaining oil to CH₂Cl₂Washed 2 times with water and with CHCl₃Column chromatography was performed with a MeOH gradient.

Method 3

Step A:

A1M solution of 1.34 equivalents of potassium tert-butoxide in THF or a suspension of 2 equivalents of n-butyllithium in 1.34 equivalents of methyltriphenylphosphonium bromide in THF is added at 0 ℃ under an argon atmosphere. The reaction was allowed to warm to ambient temperature and stirred for 10 minutes. The reaction was then cooled again to 0 ℃ and 1 equivalent of 4-propoxybenzaldehyde in THF was added. The reaction was stirred at ambient temperature until TLC control (heptane/chloroform 1:1) showed complete consumption of aldehyde. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The product was purified by flash chromatography (hexane/chloroform 8: 2).

And B:

tert-butyl carbamate (3.1eq) was dissolved in 1-propanol and 0.38M aqueous NaOH (3.1eq) was added. The reaction was stirred at ambient temperature for 5 minutes, 1, 3-dichloro-5, 5-dimethylimidazolidine-2, 4-dione (1.535 eq) was added, and the reaction was stirred at ambient temperature for 10 minutes. The reaction was cooled to 0 ℃ and (DHQ) dissolved in 1-propanol was added ₂PHAL (0.06 equiv.). Thereafter 1 equivalent of the corresponding styrene dissolved in 1-propanol was added followed by potassium osmate dihydrate (0.04 equivalent) suspended in a small amount of aqueous NaOH. The reaction was stirred at 0 ℃ until complete consumption of styrene (TLC control). Water was added, and the reaction mixture was extracted 3 times with ethyl acetate. Saturated aqueous sodium chloride solution had to be added until phase separation was observed. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The product was purified by flash chromatography using a heptane-ethyl acetate gradient (0 → 30%).

And C:

the product obtained from step B (1 eq) was dissolved in dichloromethane and the solution was cooled to 0 ℃. Tosyl chloride (1.05 eq) and triethylamine (1.4 eq) were added to the solution. The reaction was allowed to warm to ambient temperature and stirred for 14 hours, then the reaction mixture was transferred into water. The mixture was extracted 3 times with dichloromethane. The combined organic layers were washed with brine and dried (Na)₂SO₄) Go throughThe solvent was filtered and removed under reduced pressure. The product was purified by FPLC using a hexane-ethyl acetate gradient (0 → 30%).

Step D:

the product obtained from step C (1 eq) was dissolved in DMF and sodium azide (1.5 eq) was added. The reaction was stirred at 70 ℃ for 2 hours. The reaction was cooled to ambient temperature, then water was added and the mixture was extracted 3 times with 60mL ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by FPLC using a hexane-ethyl acetate gradient (0 → 30%).

Step E:

the product obtained from step D was dissolved in ethanol. The mixture was vented with argon, palladium on activated carbon (10%) was added and the mixture was hydrogenated using an autoclave at ambient temperature and 4 bar hydrogen pressure for 14 hours. By passingThe catalyst was filtered off through a pad, and the filtrate was concentrated under reduced pressure. The product first appeared as a colorless oil and crystallized after a few minutes.

The crude product obtained from the hydrogenation was dissolved in ethanol and p-anisaldehyde (1.2 equivalents) was added to the solution. The reaction was stirred at ambient temperature for 5 hours, then cooled to 0 ℃ and sodium borohydride (2.4 equivalents) was added. The mixture was stirred at ambient temperature for 14 hours. The solvent was removed under reduced pressure. The residue was suspended in saturated aqueous ammonium chloride solution and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine and dried (Na)₂SO₄) Filtered and concentrated under reduced pressure.

Step F:

the crude material obtained from step E was dissolved in dichloromethane and trifluoroacetic acid (20% V/V) was added. The reaction was stirred until complete consumption of the starting material (TLC control). Toluene was added, and the solvent and trifluoroacetic acid were removed under reduced pressure.

The crude material obtained from Boc-deprotection was dissolved in dichloromethane and triethylamine (2.2 equivalents) was added. Bis (1H-imidazol-1-yl) methanone (1.2 eq) was added to the stirred solution and the reaction was stirred at reflux for 1 hour. After the reaction mixture was cooled, the solvent was removed and water was added. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The product was purified by FPLC (hexane-ethyl acetate 0 → 100%).

Step G:

imidazolidin-2-one (1 equivalent), 4-iodobenzene-1, 2-diamine (1 equivalent), copper (I) iodide (0.1 equivalent) and cesium fluoride (2 equivalents) were added to a reaction flask vented with argon. Cyclohexane-1, 2-diamine (mixture of cis and trans 0.1 equiv.)]) Dissolved in anhydrous dioxane and solid obtained, the mixture was heated under argon atmosphere at 95 ℃ until TLC showed consumption of starting material. The reaction mixture was cooled to 45 ℃ and passedThe pad is filtered. The pad was washed several times with warm dichloromethane. The filtrate was concentrated under reduced pressure. The product was purified by FPLC using a chloroform-methanol gradient (0% → 10%).

Step H:

the product obtained from step G was dissolved in triethyl orthoformate and the reaction was stirred at reflux for 30 minutes. After cooling, the excess triethyl orthoformate was removed under reduced pressure and the residue was dissolved in trifluoroacetic acid. The reaction was stirred at ambient temperature for 14 hours. TFA was removed under reduced pressure, the residue was re-dissolved in buffer (pH7) and extracted 3 times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The final product was purified by FPLC using a methanol-chloroform gradient (0 → 10%).

Method 4

1 equivalent of aldehyde was dissolved in AcOH (5 mL in the case of 4mmol of starting material) and 1.1 equivalents of amine were added. Then 1 equivalent of TMSCN was added to the mixture. The mixture was then stirred at r.t. for 1.5 h.

The mixture was then poured onto ice/ammonia (12 mL of 25% NH in the case of 4mmol of starting material)₃Solution) above. The aqueous layer is replaced by CH₂Cl₂Extraction was performed 3 times, the organic phases were combined, dried, filtered and the solvent was removed. The residue was redissolved in concentrated HCl and kept at 40 ℃ overnight. Water was added and the solution was neutralized by the addition of NaOH. Using CH for the aqueous phase₂Cl₂Extraction was performed 3 times, and then the organic phases were combined and dried. The solvent was removed and the residue was added to triethyl orthoformate. The mixture was kept under reflux for 1 h. The orthoester was removed, the remaining oil was dissolved in MeOH, and NaBH was added₄(1.5 equiv.). The mixture was kept at ambient temperature for 1h, then at 60 ℃ for 1h, and the reaction was terminated by adding an aqueous solution of ammonia (12%). The aqueous layer is replaced by CH₂Cl₂Extraction was performed 3 times, and then the organic phases were combined and dried. The solvent was removed and the remaining mixture was subjected to preparative HPLC.

Method 5

Step A:

A1M solution of 1.34 equivalents of potassium tert-butoxide in THF or a suspension of 2.0 equivalents of n-butyllithium in 1.34 equivalents of methyltriphenylphosphonium bromide in THF is added at 0 ℃ under an argon atmosphere. The reaction was allowed to warm to ambient temperature and stirred for 10 minutes. The reaction was then cooled again to 0 ℃ and a solution of 1 equivalent of aldehyde in THF was added. The reaction was stirred at ambient temperature until TLC control (heptane/chloroform 1:1) showed complete consumption of aldehyde. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The product was purified by flash chromatography (hexane/chloroform 8: 2).

And B:

ethyl carbamate (3 equivalents) was dissolved in 1-propanol and 0.5M aqueous NaOH (3 equivalents) was added. The reaction was stirred at ambient temperature for 5 minutes, 1, 3-dichloro-5, 5-dimethylimidazolidine-2, 4-dione (1.5 equivalents) was added, and the reaction was stirred at ambient temperature for 10 minutes. Adding (DHQ) dissolved in 1-propanol₂PHAL (0.06 equiv.). Thereafter 1eq of the corresponding styrene obtained from step A dissolved in 1-propanol was added followed by potassium osmate dihydrate (0.04 eq) suspended in a small amount of 0.5M aqueous NaOH. The reaction was stirred at ambient temperature until complete consumption of styrene. (TLC control) water was added and the reaction mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The product was purified by flash chromatography using a heptane-ethyl acetate gradient.

Or:

tert-butyl hypochlorite (3eq) was added to a stirred solution of benzyl carbamate (3eq), 0.4M aqueous sodium hydroxide in 1-propanol at 0 ℃ and stirred for 15 min. Adding (DHQ)₂PHAL (0.05eq) in 1-propanol. The corresponding alkene in 1-propanol was then added followed by potassium osmate dihydrate (100mg,0.025eq) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched in saturated sodium sulfite solution and extracted with ethyl acetate (3 × 40 mL). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product. Silica gel (60-12) using 10% ethyl acetate in petroleum ether as eluent 0 mesh) to provide the product.

And C:

the product obtained from step B was dissolved in a 0.2M solution of sodium hydroxide in methanol. The reaction was stirred at reflux until TLC control showed complete consumption. The solvent was removed under reduced pressure and ethyl acetate was added. The organic layer was washed with brine, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The product was purified by FPLC using a heptane-ethyl acetate gradient (0 → 100%).

Step D:

3- (1H-benzo [ d ]]Imidazol-5-yl) oxazolidin-2-ones

1 equivalent of oxazolidin-2-one was added to the flask along with 4-iodobenzene-1, 2-diamine (1 equivalent), cesium fluoride (2 equivalents), and copper (I) iodide (0.1 equivalent). The flask was vented with argon and a solution of cyclohexane-1, 2-diamine (0.1 eq) in dioxane was added. The reaction was stirred at 95 ℃ until TLC showed consumption of oxazolidin-2-one. After cooling to 45 ℃ byThe reaction mixture was filtered through the pad, the pad was washed with warm dichloromethane, and the solution was concentrated under reduced pressure. The product was purified by FPLC using a chloroform-methanol gradient (0 → 10%).

The product obtained from the copper (I) -catalyzed coupling was dissolved in triethyl orthoformate and the reaction was stirred at reflux for 1 h. After cooling, the excess triethyl orthoformate was removed under reduced pressure. The final product was purified by FPLC using a chloroform-methanol gradient (0 → 10%).

3- (imidazo [1,2-a ]]Pyridin-7-yl) oxazolidin-2-one:

1 equivalent of oxazolidin-2-one and 7-bromoimidazo [1,2-a ]]Pyridine (1 equivalent), cesium fluoride (2 equivalents) and copper (I) iodide (0.1 equivalent) togetherThe flask was charged. The flask was vented with argon and a solution of cyclohexane-1, 2-diamine (0.1 eq) in dioxane was added. The reaction was stirred at 95 ℃ until TLC showed consumption of oxazolidin-2-one. After cooling to 45 ℃ byThe reaction mixture was filtered through the pad, the pad was washed with warm dichloromethane, and the solution was concentrated under reduced pressure. The final product was purified by FPLC using a chloroform-methanol gradient (0 → 10%).

Method 6

Step A:

potassium cyanide (1.2eq) was added to a stirred solution of the corresponding aldehyde (1eq), ammonium carbonate (3eq) in ethanol and water. The reaction mixture was heated at 60 ℃ overnight. The reaction mixture was then cooled to 0 ℃, and the precipitated solid was filtered and washed with water and petroleum ether. The residue was dried in vacuo.

And B:

a mixture of the product of step A (1eq) and 10% NaOH was refluxed overnight. The reaction mixture was extracted with ethyl acetate (3 × 30mL) and the aqueous layer was acidified to pH-2 with concentrated HCl. The aqueous layer was extracted with ethyl acetate, concentrated under vacuum and co-distilled with toluene. The crude product was used in the next step.

And C:

thionyl chloride was added to a stirred solution of the product of step B (1eq)) in methanol and refluxed overnight. The reaction mixture was concentrated in vacuo, the residue was dissolved in water and extracted with ethyl acetate. The aqueous layer was basified with solid sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate and concentrated in vacuo.

Step D:

the product of step C (1eq) was added portionwise to a suspension of sodium borohydride (3eq) in ethanol (100mL) at 0 ℃ and stirred at room temperature for 5 h. Excess ethanol was removed in vacuo and the residue was partitioned between water and ethyl acetate. The separated organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo.

Step E:

triethylamine (2eq), Boc anhydride (1.5eq) were added in succession to a stirred solution of the product of step D (1eq) in anhydrous dichloromethane and stirred at room temperature for 4 h. The reaction mixture was poured into water and extracted with dichloromethane. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate and concentrated in vacuo. It was purified by superfluid chromatography to obtain the R, S enantiomer.

Step F:

thionyl chloride (8eq) was added to a stirred solution of the product compound of step E (1eq) in tetrahydrofuran (75mL) at 0 ℃ and stirred at room temperature for 6 h. The reaction mixture was concentrated under reduced pressure to obtain crude compound. The crude product was purified by washing with n-pentane.

Step G:

a mixture of the product of step F (1eq), 1, 2-diamino 4-iodobenzene (1eq), cesium fluoride (1.5eq) in 1, 4-dioxane was sparged with argon for 15 min. 1, 2-diaminocyclohexane (0.1eq) and cuprous iodide (0.1eq) were added to the reaction mixture, the aeration was continued for an additional 5min, and stirred overnight at 120 ℃ in a sealed tube. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over anhydrous sodium sulfate and concentrated under vacuum to obtain crude compound. The crude product was purified by column chromatography using neutral alumina using 2% methanol in dichloromethane as eluent.

The mixture of the product of step G (1eq) and formic acid was heated at 70 ℃ for 1 h. The reaction mixture was cooled to 0 ℃ and basified with saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate, washed with brine solution and dried over anhydrous sodium sulfate. The compound was purified by preparative TLC or HPLC, 1M ether-HCl (0.57mL,0.57mmol) was added to a stirred solution of the product (150mg,0.47mmol) in dichloromethane (10mL) at 0 ℃ and stirred at room temperature for 30 min. The reaction mixture was filtered and washed with pentane.

Method 7

Step A:

malonic acid (1 eq) and ammonium acetate (2 eq) were dissolved in methanol. The corresponding aldehyde (1 eq) was added to the stirred solution and the reaction was stirred at reflux for 18 hours. The reaction was cooled to 0 ℃, the precipitate filtered off and washed with cold ethanol.

And B:

A2M solution of lithium aluminum hydride (1.5 equiv.) in THF was slowly added to the suspension of 3-aminopropionic acid in THF obtained from step A. The stirred solution was stirred at 50 ℃ for 2 hours. The reaction was cooled to 0 ℃ and quenched by the addition of water. The solution was extracted 3 times with ethyl acetate, the organic layers were combined, washed with brine, filtered and the solvent was removed under reduced pressure.

And C:

the product obtained from step B was dissolved in dichloromethane and bis (1H-imidazol-1-yl) methanone (1.2 eq) was added to the solution. The reaction was heated at reflux for 1 hour. The reaction was cooled to ambient temperature and washed with water. The organic layer was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The product was purified by FPLC using a heptane-ethyl acetate gradient (0 → 100%).

Step D:

3- (1H-benzo [ d ]]Imidazol-5-yl) -1, 3-oxazinan-2-ones

1 equivalent of 1, 3-oxazinan-2-one was added to the flask along with 4-iodobenzene-1, 2-diamine (1 equivalent), potassium carbonate (2 equivalents) and copper (I) iodide (0.1 equivalent). The flask was vented with argon and a solution of cyclohexane-1, 2-diamine (0.1 eq) in dioxane was added. The reaction was stirred at 95 ℃ until TLC showed consumption of 1, 3-oxazinan-2-one. After cooling to 45 ℃ by The reaction mixture was filtered through the pad, the pad was washed with warm dichloromethane, and the solution was concentrated under reduced pressure. The product was purified by FPLC using a chloroform-methanol gradient (0 → 10%).

The product obtained from the copper (I) -catalyzed coupling was dissolved in triethyl orthoformate and the reaction was stirred at reflux for 1 h. After cooling, the excess triethyl orthoformate was removed under reduced pressure. The final product was purified by FPLC using a chloroform-methanol gradient (0 → 10%).

3- (imidazo [1,2-a ]]Pyridin-7-yl) -1, 3-oxazinan-2-ones

1 equivalent of 1, 3-oxazinane-2-one and 7-bromoimidazo [1,2-a ]]Pyridine (1 equivalent), potassium carbonate (2 equivalents) and copper (I) iodide (0.1 equivalent) were added together to the flask. The flask was vented with argon and a solution of cyclohexane-1, 2-diamine (0.1 eq) in dioxane was added. The reaction was stirred at 95 ℃ until TLC showed consumption of 1, 3-oxazinan-2-one. After cooling to 45 ℃ byThe pad will be reversedThe mixture was filtered, the pad was washed with warm dichloromethane, and the solution was concentrated under reduced pressure. The final product was purified by FPLC using a chloroform-methanol gradient (0 → 10%).

Method 8

5(6) -bromobenzimidazole (200 mg; 1 mmol; 1eq.) and the respective pyrrolidine derivative (1.2 mmol; 1.2eq.) and 2-dicyclohexylphosphino-2' - (N, N-dimethylamino) biphenyl (9 mg; 0.024 mmol; 0.024 eq.; 2.4mol%) were reacted with Pd ₂dba₃(9 mg; 0.01 mmol; 0.01 eq.; 1mol%) was dissolved in THF (1 ml). After addition of lithium bis (trimethylsilyl) amide (1M solution in THF; 2.2 ml; 2.2 mmol; 2.2eq.) the mixture was stirred under argon at 65 ℃ for 24 h. After cooling to room temperature, 2N HCl was added until acidic pH and stirred for another 10 min. The mixture was poured into saturated sodium bicarbonate solution (20ml) and extracted with EtOAc (3 × 25 ml). The combined organic layers were washed with Na₂SO₄Dried and evaporated. Using Al₂O₃And CHCl₃The residue remaining was purified by flash chromatography with a MeOH gradient.

Method 9

Step A:

5-aminobenzimidazole (1eq) was dissolved in EtOH, followed by addition of the corresponding aldehyde (3eq) and piperidine (catalytic amount). The solution was stirred in a sealed tube at 80 ℃ overnight and under reflux for a further 1.5 h. The solvent was then removed, the residue was added to toluene, and mercaptoacetic acid (1.5eq) or 2-mercaptopropionic acid (1.5eq) was added. The solvent was removed and the product was purified by preparative HPLC.

And B:

the product of step B (1.0eq) was dissolved in toluene and lawson's reagent (5.0eq) was added. The mixture was kept under reflux for 6 h. The solvent was removed and the residue was added to CHCl₃Then with NaHCO₃Washing with a saturated solution of (a). The solvent was removed and the product was purified by preparative HPLC.

Method 10

Step A:

the respective 4-oxo-butyric acid (1eq.) was dissolved in dichloromethane (10 ml). Carbonyldiimidazole (1eq.) was added and the mixture was stirred at room temperature for 1 h. After addition of benzimidazole-5 (6) -amine (1eq.), the mixture was stirred overnight. The precipitated solid was collected by filtration and washed with dichloromethane to obtain the title compound used without further purification.

And step B and step C:

the respective 4-oxo-butyric acid amide was dissolved in a mixture of AcOH (3ml) and toluene (7ml) and refluxed overnight. The solvent was then removed by evaporation. The resulting residue was dissolved in AcOH (10ml) and hydrogenated overnight (PdC 10%; 1-2 bar; r.t.). After filtration through celite, the solvent was evaporated. Water was added to the remaining residue, adjusted to basic pH with 2N NaOH and extracted with EtOAc (3 × 25 ml). The combined organic layers were washed with Na₂SO₄Dried, evaporated, and used with CHCl₃The residue was purified by flash chromatography on silica gel with a MeOH gradient.

Method 11

Steps A, B and C:

the respective 2-oxobenzoic acid (1eq.) was dissolved in THF (5 ml in case of 1 mmol) and DCC (1eq.) was added. After stirring for 1h at r.t., benzimidazole-5 (6) -amine (1eq.) was added and stirring continued for 24h at r.t. The mixture was placed in a refrigerator for 2h and the precipitated solid was filtered off. The filtrate was concentrated in vacuo, redissolved in a mixture of AcOH and toluene (3ml and 7ml in the case of 1mmol batches) and refluxed overnight. After cooling, the solvent was evaporated. The resulting residue was dissolved in CH ₂Cl₂(10 ml in the case of 1mmol batch), cooled to 0 ℃ and treated with TFA (1ml (4 ml)/mmol). After stirring at r.t. for 10min, triethylsilane (2eq. (4eq.)) was added. The reaction was allowed to warm to room temperature and stirred for 3 h. After that time, the mixture was quenched with saturated sodium bicarbonate solution. The organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 25 ml). The combined organic layers were washed with Na₂SO₄Dried, concentrated in vacuo, and used silica gel and CHCl₃The residue remaining was purified by flash chromatography on a MeOH gradient.

Method 12

Step A:

methyl 2-formylbenzoate (3.28 g; 20 mmol; 1eq.) and p-toluenesulfonamide (3.42 g; 20 mmol; 1eq.) were suspended in tetraethylorthosilicate (4.69 ml; 21 mmol; 1.05eq.) and heated to reflux for 6 h. On cooling the mixture was diluted with warm EtOAc (70 ml). After treatment with n-pentane (250ml), the mixture was placed in a refrigerator overnight. The precipitate was collected by filtration and washed with n-pentane. Yield: 4.83g (76.2%); MS M/z 318.2[ M + H ]]⁺

Step B, C:

to prepare the 3S-enantiomer, the respective boronic acids (2eq.), [ RhCl (C) were used₂H₄)₂]₂Either (0.031eq.) and (3aS, 6aS) -3, 6-diphenyl-1, 3a,4,6 a-tetrahydropentalene (0.066eq.) were dissolved in toluene (2.5ml), or for the preparation of the 3R-enantiomer, (3aR,6aR) -3, 6-diphenyl-1, 3a,4,6 a-tetrahydropentalene (0.066eq.) was dissolved in toluene (2.5ml) and heated to 55 ℃ under an argon atmosphere. After 1h, methyl 2- (tosylimino-methyl) benzoate (1eq.) toluene (6ml) and TEA (2eq.) were added in that order with continued stirring for 5 h. The mixture was washed with saturated NaHCO ₃The solution was quenched and extracted with EtOAc (3 × 25 ml). The combined organic layers were washed with Na₂SO₄Dried and evaporated. The resulting residue was dissolved in THF (10 ml). After cooling to 0 ℃ the solution was subjected to Smi₂(1M solution in THF) until a dark blue color appeared. Stirring was continued for 1h, then the reaction was quenched with saturated sodium bicarbonate solution and CHCl₃Extraction (3 × 25 ml). The combined organic layers were washed with Na₂SO₄Dried and concentrated in vacuo. The residue was purified by flash chromatography using silica gel and a heptane/EtaOAc gradient.

Step D:

4-iodobenzene-1, 2-diamine (1eq.), each 3-phenylisoindolinone (1.1eq.), copper (I) iodide (0.1eq.), diaminocyclohexane (0.1eq.), and cesium fluoride (2eq.) were dissolved in dioxane (5ml) and heated to 95 ℃ under an argon atmosphere overnight. After cooling to rt, the reaction was quenched with saturated sodium bicarbonate solution and extracted with EtOAc (3 × 25 ml). The combined organic layers were washed with Na₂SO₄Dried and concentrated in vacuo. The remaining residue was dissolved in orthoformate (5ml) and heated to reflux for 2 h. The solvent was evaporated and the residue was purified by semi-preparative HPLC.

Synthesis of examples

Example 1: 5-tert-butyl-1- (1H-benzo [ d ] imidazol-5-yl) imidazolidin-2-one

This compound was synthesized as the hydrochloride salt by the following method.

Phenyl chloroformate (0.98mL,7.8mmol) was dissolved in CH₂Cl₂To 0 ℃ and 5-aminobenzimidazole (0.865g,6.5mmol) was slowly added. The mixture was held at 0 ℃ for 30min and then the mixture was allowed to warm to ambient temperature. The mixture was stirred at ambient temperature for 2 h. The resulting solid was aspirated, dried and added to a small amount of DMF. 1-amino-3, 3-dimethylbut-2-one (0.986,6.5mmol) and TEA (2.73mL,19.5mmol) were added to the solution. The mixture was kept at 40 ℃ for 2 h. The solvent was removed and purified by preparative HPLC. The residue was redissolved in MeOH and a small amount of HCl (1-2%) was added. The solution was hydrogenated (PdC, 10% on charcoal, 4 bar, 60 ℃) for 4 h. By passingThe pad was filtered to remove the catalyst and the residue was washed with water. The organic layer was dried, filtered and the solvent was removed to obtain the final product.

Yield: 0.087g (6.3%); MS M/z 259.4(M + H)⁺;¹H NMR(DMSO,400MHz):δ0.72(s,9H);3.23-3.27(m,H);3.46-3.50(m,H);4.37-4.41(m,H);6.84(bs,H);7.56(dd,H,³J=9.1Hz,⁴J=1.7Hz);7.70(d,H,J=9.1Hz);7.81(d,H,⁴J=1.7Hz);9.27(s,H),HPLC(λ=214nm,[B]:rt 6.83min(99%).

Example 2: 1- (1H-benzo [ d ] imidazol-5-yl) -5-cyclohexylimidazolidin-2-one

The compound was synthesized as the trifluoroacetate salt starting from 5-aminobenzimidazole (0.59g,4.4mmol), cyclohexanecarboxaldehyde (0.45g,0.485mL,4mmol), TMSCN (0.5mL,4mmol), PdC (10%,0.05g), bis- (imidazol-1-yl) methanone (0.64g,3.92mmol) as described in method 2. The product was purified by preparative HPLC using a water-acetonitrile gradient containing 0.04% trifluoroacetic acid.

Yield: 0.089g (5.6)%);MS m/z 285.1(M+H)⁺;¹H NMR(DMSO,400MHz):δ0.82-0.91(m,H);0.97-1.16(m,4H);1.39-1.42(m,H);1.52-1.69(m,5H);3.24-3.27(m,H);3.42-3.46(m,H);4.48-4.52(m,H);6.92(s,H);7.56-7.59(dd,H,³J=9.1Hz,⁴J=2.1Hz);7.73-7.75(d,H,³J=9.1Hz);7.94-7.95(d,H,⁴J=2.1Hz);9.24(s,H),HPLC(λ=214nm,[B]:rt 8.64min(99%).

Example 3: 1- (1H-benzo [ d ] imidazol-5-yl) -5-phenylimidazolidin-2-one

This compound was synthesized as described in method 2 starting from 5-aminobenzimidazole (1.46g,10mmol), benzaldehyde (1.06g,10mmol), TMSCN (1.25mL,10mmol), PdC (10%,0.05g), bis- (imidazol-1-yl) methanone (1.73,12 mmol).

Yield: 0.303g (10.9%); MS M/z 279.3(M + H)⁺;¹H NMR(DMSO,400MHz):δ3.08-3.11(m,H);3.85-3.89(m,H);5.54-5.58(m,H);7.19-7.33(m,6H);7.51-7.54(m,H);7.60(d,H,J=8.7Hz);7.84(d,H,4J=1.7Hz);9.15(s,H),HPLC(λ=214nm,[B]:rt 7.36min(96%).

Example 4: 1- (1H-benzo [ d ] imidazol-5-yl) -5-m-tolylimidazolidin-2-one

This compound was synthesized as the hydrochloride salt by the following method.

4-Nitrophenyl chloroformate (0.564g,3.5mmol) was dissolved in CH₂Cl₂To a solution, cool to 0 ℃ and slowly add 5-aminobenzimidazole (0.466g,3.5 mmol). The mixture was held at 0 ℃ for 30min and then the mixture was allowed to warm to ambient temperature. The mixture was stirred at ambient temperature for 2 h. The resulting solid was aspirated, dried and added to a small amount of DMF. Aminomethyl- (4-chloro-3-methylphenyl) ketone (0.774,3.5mmol) and TEA (1.46ml,10.5mmol) were added to the solution. The mixture was kept at 40 ℃ for 2 h. The solvent was removed and purified by preparative HPLC. The residue was redissolved in MeOH and a small amount of HCl (1-2%) was added. The solution was hydrogenated (PdC, 10% on charcoal, 4 bar, 60 ℃) for 4 h. By passing The pad was filtered to remove the catalyst and the solvent was removed and purified by preparative HPLC.

Yield: 0.008g (0.6%); MS M/z 293.4(M + H)⁺;¹H NMR(DMSO,400MHz):δ2.21(s,3H);3.05-3.09(m,H);3.83-3.87(m,H);5.49-5.53(m,H);7.01-7.10(m,2H);7.15(d,H,J=7.9Hz);7.19(s,H);7.52-7.55(m,H),7.60(d,H,J=8.7Hz);7.84(s,H);9.16(s,H),HPLC(λ=214nm,[B]:rt 8.05min(100%).

Example 5: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4-methoxyphenyl) imidazolidin-2-one

The compound was synthesized as the hydrochloride salt starting from 5-aminobenzimidazole (0.266g,2mmol), bis (1H-imidazol-1-yl) methanone (0.052g,2mmol), TEA (0.799mL,6mmol), aminomethyl- (4-methoxy) phenyl ketone hydrochloride (0.403g,2mmol), TEA (0.558mL,4mmol), PdC (10%,0.02g) as described in method 1.

Yield: 0.234g (37.8%); MS M/z 309.3(M + H)⁺;¹H NMR(DMSO,400MHz):δ3.09-3.12(m,H);3.67(s,3H);3.84-3.88(m,H);5.52-5.55(m,H);6.84-6.88(m,2H);7.23(s,H);7.25-7.29(m,2H);7.58(dd,H,³J=9.1Hz,⁴J=2.1Hz);7.65(d,H,J=9.1Hz);7.90(s,H);9.39(s,H),HPLC(λ=214nm,[B]:rt 7.84min(94%).

Example 6: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4-methoxyphenyl) imidazolidin-2-one enantiomer 1

Example 12, column: nucleocell Alpha RP-S,250 x 21mm (5 μm); eluent: 50/50 acetonitrile/water 30/70; the flow rate is 10 mL/min; second elution enantiomer rt: 20.2min (99.35)%.

Example 7: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4-methoxyphenyl) imidazolidin-2-one enantiomer 2

Example 12, column: nucleocell Alpha RP-S,250 x 21mm (5 μm); eluent: 50/50 acetonitrile/water 30/70; the flow rate is 10 mL/min; first eluting enantiomer, rt: 16.5min (99.75)%.

Example 8: (4R,5S) -1- (1H-benzo [ d ] imidazol-6-yl) -5- (4-methoxyphenyl) -4-methylimidazolidin-2-one

Step A:

tert-butyl carbamate (3.1 eq., 4.54g,38.75mmol) was dissolved in 50mL of 1-propanol and 99mL of 0.38M aqueous NaOH solution was added. The reaction was stirred at ambient temperature for 5 minutes, 1, 3-dichloro-5, 5-dimethylimidazolidine-2, 4-dione (1.535 eq., 3.78g,19.2mmol) was added, and the reaction was stirred at ambient temperature for 10 minutes. The reaction was cooled to 0 ℃ and added (DHQ) dissolved in 50mL of 1-propanol₂PHAL (0.06 eq, 0.585g,0.75 mmol). Then 1 equivalent of trans-anethole (1.85g,1.875mL,12.5mmol) dissolved in 100mL of 1-propanol was added followed by potassium osmate dihydrate (0.04 equivalent, 0.184g,0.5mmol) suspended in 1mL of 0.38M aqueous NaOH. The reaction was stirred at 0 ℃ until the trans-anethole was completely consumed (TLC control). 85mL of water was added and the reaction mixture was extracted 3 times with 150mL of ethyl acetate. Saturated aqueous sodium chloride solution had to be added until phase separation was observed. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The product was purified by FPLC using a heptane-ethyl acetate gradient (0 → 30%). The product was eluted at about 25% ethyl acetate. Yield: 1.54g (43.8%)

And B:

tert-butyl (1S,2S) -2-hydroxy-1- (4-methoxyphenyl) propylcarbamate (1 eq, 5.5mmol,1.54g) obtained from step B was dissolved in 20mL dichloromethane and the solution was cooled to 0 ℃. Tosyl chloride (1.05 eq, 1.10g,5.75mmol) and triethylamine (1.4 eq, 0.78g,1.07mL,7.7mmol) were added to the solution. The reaction was allowed to warm to ambient temperature and stirred for 18 hours, then the reaction was allowed to proceedThe mixture was transferred into 100mL of water. The mixture was extracted 3 times with 100mL dichloromethane. The combined organic layers were washed with brine and dried (Na)₂SO₄) Filtered and the solvent removed under reduced pressure. The product was purified by FPLC using a heptane-ethyl acetate gradient (0 → 40%). The product was eluted at 25% ethyl acetate. Yield: 1.79g (74.7%); MS M/z 436.4(M + H)⁺

(1S,2S) -1- (tert-Butoxycarbonylamino) -1- (4-methoxyphenyl) propan-2-yl 4-methylbenzenesulfonate (1 eq, 1.79g,4.1mmol) was dissolved in 20mL of DMF and sodium azide (1.5 eq, 0.4g,6.2mmol) was added. The reaction was stirred at 70 ℃ for 2 hours. The reaction was cooled to ambient temperature, then 50mL water was added and the mixture was extracted 3 times with 50mL ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by FPLC using a heptane-ethyl acetate gradient (0 → 30%). The product was eluted at about 15% ethyl acetate. Yield 0.75g (59.6%)

1 equivalent of (1S,2R) -2-azido-1- (4-methoxyphenyl) propylcarbamic acid tert-butyl ester (0.75g,2.45mmol) was dissolved in 20mL of ethanol. The mixture was vented with argon, palladium on activated carbon (10%) was added and the mixture was hydrogenated using an autoclave at ambient temperature and 4 bar hydrogen pressure for 24 hours. The catalyst was filtered off through a celite pad, and the filtrate was concentrated under reduced pressure. The product first appeared as a colorless oil and crystallized after a few minutes. Yield: 0.629g (91.9%)

And C:

2.24mmol of crude tert-butyl (1S,2R) -2-amino-1- (4-methoxyphenyl) propylcarbamate (1 eq, 0.629g) obtained from the hydrogenation were dissolved in 14mL of ethanol and p-anisaldehyde (1.2 eq, 0.366g,0.326mL,2.69mmol) was added to the solution. The reaction was stirred at ambient temperature for 4 hours, then the reaction was cooled to 0 ℃ and 5.38mmol sodium borohydride (2.4 eq, 0.203g) was added. The mixture was stirred at ambient temperature for 14 hours, then the solvent was removed under reduced pressure. The residue was suspended in 20mL of saturated chlorideAqueous ammonium solution and extracted 3 times with 40mL ethyl acetate. The combined organic layers were washed with brine and dried (Na)₂SO₄) Filtered and concentrated under reduced pressure. Yield: 0.97g

Step D:

0.97g of crude tert-butyl (1S,2R) -2- (4-methoxybenzylamino) -1- (4-methoxyphenyl) propylcarbamate (2.4mmol) is dissolved in 25mL of dichloromethane and 5mL of trifluoroacetic acid are added. The reaction was stirred at room temperature until complete consumption of the starting material (TLC control). Toluene was added, and the solvent and trifluoroacetic acid were removed under reduced pressure. Yield: 1.78g

Step E:

the crude (1S,2R) -N2- (4-methoxybenzyl) -1- (4-methoxyphenyl) propane-1, 2-diamine obtained from Boc-deprotection (step D) was dissolved in 30mL dichloromethane and triethylamine (2.2 eq, 1.04mL,7.5mmol) was added. Bis (1H-imidazol-1-yl) methanone (1.2 eq, 0.662g,4.08mmol) was added to the stirred solution and the reaction was stirred at reflux for 1 hour. After the reaction mixture was cooled, the solvent was removed and 60mL of water was added. The aqueous layer was extracted 3 times with 70mL ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The product was purified by FPLC (heptane/ethyl acetate 0 → 100%). The product was eluted at about 80% ethyl acetate. Yield: 0.29 g; MS M/z 327.4(M + H)⁺

Step F:

(4S,5R) -1- (4-methoxybenzyl) -4- (4-methoxyphenyl) -5-methylimidazolidin-2-one (1 eq, 0.29g,0.89mmol), 4-iodobenzene-1, 2-diamine (1 eq, 0.208g,0.89mmol), copper (I) iodide (0.1 eq, 0.017g,0.089mmol) and cesium fluoride (2 eq, 0.27g,1.78mmol) were added to a reaction flask and purged with argon. Cyclohexane-1, 2-diamine (mixture of cis and trans [0.1 eq, 0.01g,0.011 mL) ]) Dissolved in 4mL anhydrous dioxane to give a solid and the mixture heated under argon atmosphere at 95 ℃ for 3 days. The reaction mixture was cooled to 45 ℃ and filtered through a pad of celite. The pad was washed several times with warm dichloromethane. The filtrate was concentrated under reduced pressure. The product was purified by FPLC using a chloroform-methanol gradient (0% → 10%). The product eluted at about 4% methanol. Yield: 0.105g (27.3%); MS M/z 433.5(M + H)⁺

Step G:

(4R,5S) -1- (3, 4-diaminophenyl) -3- (4-methoxybenzyl) -5- (4-methoxyphenyl) -4-methylimidazolidin-2-one obtained from step F (0.105g,0.24mmol) was dissolved in 3mL triethyl orthoformate. The reaction was stirred at reflux for 30 minutes. After cooling, the solvent was removed and the residue was dissolved in 8mL of trifluoroacetic acid. The reaction was stirred at ambient temperature for 14 hours. TFA was removed under reduced pressure, the residue was re-dissolved in 20mL buffer (pH7) and extracted 3 times with 25mL dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The final product was purified by FPLC using a chloroform-methanol gradient (0 → 10%). The product eluted at about 5% methanol.

Yield: 0.048g (62%); MS M/z 323.3(M + H)⁺;¹H NMR(DMSO,400MHz):δ0.65-0.67(m,H);3.67(s,3H);4.06-4.13(m,3H);5.43-5.45(m,H);6.83-6.85(m,2H);6.97(bs,H);7.12-7.14(m,2H);7.19-7.25(m,H);7.30-7.47(m,H);7.50-7.69(m,H);8.05(s,H);12.19-12.24(m,H),HPLC(λ=214nm,[B]:rt 8.45min(98.7%).

Example 9: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (3-methoxyphenyl) imidazolidin-2-one

The compound was synthesized as the hydrochloride salt starting from 5-aminobenzimidazole (0.532g,4mmol), bis (1H-imidazol-1-yl) methanone (0.713g,4.4mmol), TEA (1.67mL,12mmol), aminomethyl- (3-methoxyphenyl) one hydrochloride (0.807g,4mmol), TEA (1.12mL,8mmol), PdC (10%,0.02g) as described in method 1.

Yield: 0.087g (6.3%); MS M/z 309.1(M + H)⁺;¹H NMR(DMSO,400MHz):δ3.07-3.11(m,H);3.66(s,3H);3.83-3.88(m,H);5.51-5.55(m,H;6.76-6.78(m,H);6.85-6.88(m,2H);7.17-7.21(m,H);7.24(bs,H);7.57(dd,H,³J=9.2Hz⁴J=1.8Hz);7.64(d,H,³J=9.2Hz);7.89(d,H,⁴J=1.8Hz);9.36(s,H),HPLC(λ=214nm,[B]:rt 7.79min(99%).

Example 10: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (2-methoxyphenyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from 5-aminobenzimidazole (0.585g,4.4mmol), 2-methoxybenzaldehyde (0.484mL,4mmol), TMSCN (0.5mL,4mmol), PdC (10%,0.02g), TEA (1.05mL,7.55mmol), bis- (imidazol-1-yl) methanone (0.667,4.12 mmol).

Yield: 0.184g (14.9%); MS M/z 309.3(M + H)⁺;¹H NMR(DMSO,400MHz):δ2.99-3.03(m,H);3.84-3.89(m,4H);5.66-5.69(m,H);6.79-6.83(m,H);6.91(s,H);7.02-7.07(m,2H);7.18-7.22(m,2H);7.40(bs,H);7.56(bs,H);8.06(s,H);12.21(bs,H),HPLC(λ=214nm,[B]:rt 7.81min(96%).

Example 11: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4-ethoxyphenyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from 5-aminobenzimidazole (0.585g,4.4mmol), 4-ethoxybenzaldehyde (0.601g,4mmol), TMSCN (0.5mL,4mmol), PdC (10%,0.02g), TEA (0.98mL,7.0mmol), bis- (imidazol-1-yl) methanone (0.622,3.84 mmol).

Yield: 0.126g (9.8%); MS M/z 323.3(M + H)⁺;¹H NMR(DMSO,400MHz):δ1.21-1.24(m,3H);3.03-3.07(m,H);3.75-3.79(m,H);3.87-3.92(m,2H);5.37-5.41(m,H);6.79(d,2H,J=8.7Hz);6.86(s,H);7.19-7.23(m,3H);7.35(d,H,J=8.7Hz);7.49(s,H);8.04(s,H);12.19(bs,H),HPLC(λ=214nm,[B]:rt8.40min(93%).

Example 12: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4-propoxyphenyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from 5-aminobenzimidazole (0.585g,4.4mmol), 4-propoxybenzaldehyde (0.632mL,4mmol), TMSCN (0.5mL,4mmol), PdC (10%,0.02g), TEA0.558mL,4mmol), bis- (imidazol-1-yl) methanone (0.648,4 mmol).

Yield: 0.135g (10.0%); MS M/z 337.0(M + H)⁺;¹H NMR(DMSO,400MHz):δ0.90-0.93(m,3H);1.61-1.70(m,2H);3.08-3.12(m,H);3.81-3.87(m,3H);5.49-5.53(m,H);6.85(d,2H,J=8.3Hz);7.19(s,H);7.25(d,2H,J=8.7Hz);7.55(dd,H,³J=9.1Hz,⁴J=2.1Hz);7.62(d,H,J=9.1Hz);7.86(d,H,⁴J=2.1Hz);9.21(s,H),HPLC(λ=214nm,[B]:rt 9.00min(99%).

Example 13: (R) -1- (1H-benzo [ d ] imidazol-5-yl) -5- (4-propoxyphenyl) imidazolidin-2-one

Example 12, column: nucleocell Alpha RP-S,250 x 21mm (5 μm); eluent: 50/50 acetonitrile/water 50/50; the flow rate is 10 mL/min; second elution enantiomer rt: 12.8min (98.35)%.

Example 14: (S) -1- (1H-benzo [ d ] imidazol-5-yl) -5- (4-propoxyphenyl) imidazolidin-2-one

Variant 1

The compound was synthesized according to method 3

Step A:

potassium tert-butoxide (41.7mL,41.7mmol), methyltriphenylphosphonium bromide (14.89g,41.7mmol), 4-propoxybenzaldehyde (4.915mL,31.1mmol), yield: 4.77g (94.6%)

And B:

tert-butyl carbamate (9.08g,77.5mmol), 0.38M aqueous NaOH solution (200mL,76mmol), 1, 3-dichloro-5, 5-dimethylimidazolidine-2, 4-dione (7.56g,38.4mmol), and (DHQ) ₂PHAL (1.17g,1.5mmol), 1-propoxy-4-vinylbenzene (4.055g,25mmol), potassium osmate dihydrate (0.368g,1mmol)

Yield: 5.49g (74.4%); MS M/z 296.3(M + H)⁺

And C:

the product obtained from step B (2.95g,10mmol), 4-methylbenzene-1-sulfonyl chloride (2g,10.5mmol), triethylamine (1.95mL,14mmol)

Yield: 2.59g (57.6%); MS M/z 450.3(M + H)⁺

Step D:

product obtained from step C (2.59g,5.76mmol), sodium azide (0.562g,8.64mmol)

Yield: 1.25g (67.8%); MS M/z 321.3(M + H)⁺

Step E:

the product obtained from step D (1.25g,3.9mmol), PdC (10%,0.02g), p-anisaldehyde (0.598mL,4.92mmol), sodium borohydride (0.372g,9.84mmol)

Yield: 1.68g (crude material)

Step F:

the crude material obtained from step E (1.63g,3.94mmol), trifluoroacetic acid (9.6mL), triethylamine (1.52mL,10.9mmol), bis (1H-imidazol-1-yl) methanone (0.963g,5.94mmol)

Yield: 1.05g (81.6%); MS M/z 341.1(M + H)⁺

Step G:

obtained from step F (S) -1- (4-methoxybenzyl) -4- (4-propoxyphenyl) imidazolidin-2-one (0.28g,0.82mmol), 4-iodobenzene-1, 2-diamine (0.192g,0.82mmol), copper (I) iodide (0.016g,0.08mmol), cesium fluoride (0.249g,1.64mmol), cyclohexane-1, 2-diamine (mixture of cis and trans [0.01mL,0.08mmol ])

Yield: 82mg (22.4%); MS M/z 447.5(M + H)⁺

Step H：

The product obtained from step G (0.082G,0.18mmol), triethyl orthoformate (5mL), trifluoroacetic acid (10mL)

Yield: 35mg (57.9%);

the total yield is as follows: 2.9%; MS M/z 337.2(M + H)⁺;HPLC(λ=214nm,[B]:rt 9.00min(97.4%)

Variant 2

Step A

Phenol (10g,106.1mmol) was added to a solution of powdered aluminum chloride (28.3g,212.2mmol) in dichloromethane (100mL) over a period of 15min at 0 deg.C, stirred for 30min, and ethyl oxalyl chloride (14.2mL,127.5mmol) was added dropwise to the reaction over a period of 30min, maintaining the temperature at 0 deg.C. Warm to room temperature and stir for 15 h. The reaction mass was quenched in cold water and the organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water then brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (60-120 mesh) using 20-22% ethyl acetate in petroleum ether afforded 7g (34%) of the product as a light yellow solid.

Step B

1-propyl bromide (4.9mL,53.73mmol) was added to a mixture of the product of step A (6.9g,35.82mmol) and potassium carbonate (9.9g,71.65mmol) in acetonitrile (100mL) and refluxed for 18 h. The reaction mass was filtered and washed with acetonitrile. The filtrate was concentrated under reduced pressure. The resulting residue was added to ethyl acetate and washed with water and then brine solution. Dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 6g (71%) of the product as a brown oil.

Step C

Hydroxylamine hydrochloride (1.6g,22.98mmol) was added to a mixture of the product of step B (3.6g,15.25mmol) and sodium acetate (2.5g,30.50mmol) in anhydrous ethanol (50mL) and refluxed for 18 h. Cooling the reaction mass to 0 ℃; filtered and washed with ethanol. The filtrate was concentrated under reduced pressure to give 3.6g (94%) of a pale yellow oily product which turned into a cream solid on standing.

Step D

Raney nickel (500mg) was added to a solution of the product of step C containing catalytic methanolic ammonia (3.6g,14.34mmol) in ethanol (60mL) and hydrogenated in a Parr apparatus at 85psi for 20 h. The reaction mass was filtered through celite and washed with ethanol. The filtrate was concentrated under reduced pressure to give 2.7g (79.5%) of the product as a light brown solid.

Step E

A solution of the product of step D (2.6g,10.97mmol) in tetrahydrofuran (15mL) was added at 0 ℃ to a suspension of lithium aluminum hydride (832mg,21.94mmol) in tetrahydrofuran (30 mL). The reaction mass was stirred at 15-20 ℃ for 1 h. The reaction mass was cooled again to 0 ℃, quenched with saturated sodium sulfate solution and filtered. The filtrate was washed with brine, dried over anhydrous sodium sulfate solution and concentrated in vacuo to afford the crude product. Trituration with petroleum ether provided 1.5g (58%) of the product as a yellow solid.

Step F

Triethylamine (1.42mL,10.2mmol) and di-tert-butyl dicarbonate (1.4mL,6.12mmol) are added successively to a solution of the product of step F (1.0g,5.10mmol) in dichloromethane at room temperature and stirred for 3 h. The reaction mass was poured into water and extracted with dichloromethane (2 × 30 mL). The combined organic layers were washed successively with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the crude compound. Purification by trituration with petroleum ether afforded 750mg (50%) of the product as a yellow solid.

Step (ii) ofG

10.0g of the product of step F was purified by chiral preparative HPLC using the following conditions: column: chiralpak IA (19x250mm)10 μ; mobile phase: hexane, ethyl acetate; 92: 8; flow rate: 16 mL/min; UV: 227 nm. The resulting ML from chiral preparative HPLC was concentrated in vacuo to afford 3.1g (31%) of the enantiomer as an off-white solid.

Variant 3

Example 12, column: nucleocell Alpha RP-S,250 x 21mm (5 μm); eluent: 50/50 acetonitrile/water 50/50; the flow rate is 10 mL/min; first eluting enantiomer, rt: 11.6min (99.15)%.

Example 15: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4-butoxyphenyl) imidazolidin-2-one

This compound was synthesized as the trifluoroacetate salt starting from 5-aminobenzimidazole (0.585g,4.4mmol), 4-butoxybenzaldehyde (0.691mL,4mmol), TMSCN (0.5mL,4mmol), PdC (10%,0.02g), TEA (1.03mL,7.4mmol), bis- (imidazol-1-yl) methanone (0.658,4.06mmol) as described in method 2. The product was purified by preparative HPLC.

Yield: 0.08g (4.3%); MS M/z 351.3(M + H)⁺;¹H NMR(DMSO,400MHz):δ0.84-0.88(m,3H);1.30-1.40(m,2H);1.56-1.63(m,2H);3.06-3.09(m,H);3.80-3.86(m,3H);5.47-5.50(m,H);6.82(d,2H,J=8.7Hz);7.15(s,H);7.22(d,2H,J=8.7Hz);7.51(d,H,J=9.1Hz);7.59(d,H,J=9.1Hz);7.82(s,H);9.15(s,H),HPLC(λ=214nm,[B]:rt 10.72min(99%).

Example 16: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4- (pentyloxy) phenyl) imidazolidin-2-one

This compound was synthesized as the trifluoroacetate salt starting from 5-aminobenzimidazole (0.585g,4.4mmol), 4-pentyloxybenzaldehyde (0.755mL,4mmol), TMSCN (0.5mL,4mmol), PdC (10%,0.02g), TEA (1.05mL,7.4mmol), bis- (imidazol-1-yl) methanone (0.667g,4.12mmol) as described in method 2. The product was purified by preparative HPLC.

Yield: 0.198g (13.6%); MS M/z 365.4(M + H)⁺;¹H NMR(DMSO,400MHz):δ0.80-0.83(m,3H);1.21-1.34(m,4H);1.57-1.64(m,2H);3.03-3.07(m,H);3.75-3.79(m,H);3.81-3.83(m,2H);5.37-5.41(m,H);6.78-6.80(d,2H,J=8.7Hz);6.86(s,H);7.20-7.22(d,2H,J=8.7Hz);7.28-7.35(m,2H);7.49(s,H);8.04(s,H);12.18(bs,H),HPLC(λ=214nm,[B]:rt 12.64min(98.2%).

Example 17: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4-isopropoxyphenyl) imidazolidin-2-one

This compound was synthesized as the trifluoroacetate salt starting from 5-aminobenzimidazole (0.585g,4.4mmol), 4-isopropoxybenzaldehyde (0.657g,4mmol), TMSCN (0.5mL,4mmol), PdC (10%,0.02g), TEA (0.889mL,6.38mmol), bis- (imidazol-1-yl) methanone (0.564,3.48mmol) as described in method 2. The product was purified by preparative HPLC.

Yield: 0.084g (4.7%); MS M/z 337.4(M + H)⁺;¹H NMR(DMSO,400MHz):δ1.18-1.20(m,6H);3.08-3.12(m,H);3.82-3.87(m,H);4.47-4.53(m,H);5.48-5.52(m,H);6.82-6.84(d,2H,J=8.7Hz);7.17(s,H);7.23-7.25(d,2H,J=8.7Hz);7.53-7.55(dd,H,³J=9.1Hz,⁴J=2.1Hz);7.61-7.63(d,H,³J=9.1Hz);7.85(d,H,⁴J=2.1Hz);9.17(s,H),HPLC(λ=214nm,[B]:rt 10.11min(100%).

Example 18: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4-methoxybenzo [ d ] [1,3] dioxol-6-yl) imidazolidin-2-one

The compound was synthesized as the trifluoroacetate salt starting from 5-aminobenzimidazole (0.585g,4.4mmol), 7-methoxybenzo [ d ] [1,3] dioxole-5-carbaldehyde (0.721g,4mmol), TMSCN (0.5mL,4mmol), PdC (10%,0.02g), TEA (0.521mL,3.74mmol), bis- (imidazol-1-yl) methanone (0.331g,2.04mmol) as described in method 2. The product was purified by preparative HPLC.

Yield: 0.022g (1.2%); MS M/z 353.5(M + H)⁺;¹H NMR(DMSO,400MHz):δ3.09-3.12(m,H);3.74(s,3H);3.78-3.83(m,H);5.43-5.47(m,H);5.87-5.89(m,2H);6.51(s,H);6.66(s,H);7.17(s,H);7.52-7.55(dd,H,³J=8.7Hz,⁴J=1.7Hz);7.61-7.63(d,H,J=8.7Hz);7.82(d,H,⁴J=1.7Hz);9.18(s,H),HPLC(λ=214nm,[B]:rt 7.55min(99.1%).

Example 19: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) imidazolidin-2-one

The compound was synthesized as the hydrochloride salt starting from 5-aminobenzimidazole (0.37g,2.78mmol), bis (1H-imidazol-1-yl) methanone (0.496g,3.06mmol), TEA (1.16mL,8.34mmol), aminomethyl- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) ketone hydrochloride (0.761g,2.78mmol), TEA (0.775mL,5.56mmol), pdcs (10%,0.02g) as described in method 1.

Yield: 0.014g (1.4%); MS M/z 337.1(M + H)⁺;¹H NMR(CD₃OD,400MHz):δ3.92-3.96(t,H,J=9.1Hz);4.10-4.16(m,5H);5.41-5.45(q,H,J=9.1Hz);6.51-6.85(m,5H);7.65(s,2H);7.86(s,H);9.18(s,H),HPLC(λ=214nm,[B]:rt 7.47min(100%).

Example 20: 5- (4- (1,1,2, 2-tetrafluoroethoxy) phenyl) -1- (1H-benzo [ d ] imidazol-5-yl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from 5-aminobenzimidazole (0.585g,4.4mmol), 4- (1,1,2, 2-tetrafluoroethoxy) benzaldehyde (0.888g,4mmol), TMSCN (0.5mL,4mmol), PdC (10%,0.02g), TEA (0.978mL,7.0mmol), bis- (imidazol-1-yl) methanone (0.621g,3.83 mmol). The product was purified by preparative FPLC.

Yield: 0.265g (16.8%); MS M/z 395.3(M + H)⁺;¹H NMR(DMSO,400MHz):δ3.05-3.09(m,H);3.25(s,H);3.80-3.85(m,H);5.52-5.56(m,H);6.70-6.72(m,H);6.94(bs,H);7.17-7.19(m,2H);7.37(bs,H);7.41-7.43(m,2H);7.54(bs,H);8.05(s,H);12.19(bs,H),HPLC(λ=214nm,[B]:rt 7.55min(93.9%).

Example 21: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (2, 2-difluorobenzo [ d ] [1,3] dioxol-5-yl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from 5-aminobenzimidazole (0.585g,4.4mmol), 2-difluorobenzo [ d ] [1,3] dioxole-5-carbaldehyde (0.744g,4mmol), TMSCN (0.5mL,4mmol), PdC (10%,0.02g), TEA (0.81mL,5.81mmol), bis- (imidazol-1-yl) methanone (0.514g,3.17 mmol). The product was purified by preparative FPLC.

Yield: 0.138g (9.6%); MS M/z 359.4(M + H)⁺;¹H NMR(DMSO,400MHz):δ3.10-3.14(m,H);3.81-3.85(m,H);5.55-5.58(m,H);6.99(s,H);7.19-7.21(dd,H,³J=8.3Hz,⁴J=2.1Hz);7.24-7.26(dd,H,³J=8.7Hz,⁴J=1.7Hz);7.30-7.32(d,H,³J=8.3Hz);7.41-7.43(m,2H);7.56-7.57(d,H,⁴J=1.7Hz);8.14(s,H),HPLC(λ=214nm,[B]:rt 10.25min(93.1%).

Example 22: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (3-fluoro-4-methoxyphenyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from 5-aminobenzimidazole (0.585g,4.4mmol), 3-fluoro-4-methoxybenzaldehyde (0.617g,4mmol), TMSCN (0.5mL,4mmol), PdC (10%,0.02g), TEA (0.524mL,3.76mmol), bis- (imidazol-1-yl) methanone (0.333g,2.05 mmol). The product was purified by preparative FPLC.

Yield: 0.04g (3.1%); MS M/z 327.5(M + H)⁺;¹H NMR(DMSO,400MHz):δ3.08-3.12(m,H);3.74(s,3H);3.78-3.82(m,H);5.43-5.47(m,H);6.93(s,H);7.04-7.12(m,2H);7.17-7.25(m,2H);7.39-7.41(m,H);7.52(s,H);8.08(s,H);12.22(bs,H),HPLC(λ=214nm,[B]:rt 8.54min(95%).

Example 23: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (2, 6-difluoro-4-methoxyphenyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from 5-aminobenzimidazole (0.585g,4.4mmol), 2, 6-difluoro-4-methoxybenzaldehyde (0.688mL,4mmol), TMSCN (0.5mL,4mmol), PdC (10%,0.02g), TEA (1.2mL,8.6mmol), bis- (imidazol-1-yl) methanone (0.761g,4.69 mmol). The product was purified by preparative FPLC.

Yield: 0.113g (8.2%); MS M/z 345.3(M + H)⁺;¹H NMR(DMSO,400MHz):δ3.31-3.35(m,H);3.65(s,3H);3.82-3.86(m,H);5.74-5.78(m,H);6.60(s,H);6.63(s,H);6.97(s,H);7.07(bs,H);7.44(s,2H);8.06(s,H);12.24(bs,H),HPLC(λ=214nm,[B]:rt 8.99min(93.6%).

Example 24: 5- (4- (2-morpholinoethoxy) phenyl) -1- (1H-benzo [ d ] imidazol-6-yl) imidazolidin-2-one

The compound was synthesized as the ditrifluoroacetate salt starting from 5-aminobenzimidazole (0.585g,4.4mmol), 4- (2-morpholinoethoxy) benzaldehyde (0.941g,4mmol), TMSCN (0.5mL,4mmol), PdC (10%,0.02g), TEA (1.34mL,9.6mmol), bis- (imidazol-1-yl) methanone (0.582g,3.6mmol) as described in method 2. The product was purified by preparative HPLC.

Yield: 0.015g (0.6%); MS M/z 408.5(M + H)⁺;¹H NMR(CD₃OD,400MHz):δ3.33-3.44(m,4H);3.55-3.58(m,2H);3.79-4.00(m,6H);4.29-4.31(m,2H);5.51-5.55(m,H);6.95(d,2H,J=8.7Hz);7.35(d,2H,J=8.7Hz);7.58-7.60(m,2H);7.90(s,H);9.13(s,H)HPLC(λ=214nm,[B]:rt 6.05min(90.5%).

Example 25: 5- (4- (3-Morpholinopropoxy) phenyl) -1- (1H-benzo [ d ] imidazol-5-yl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from 5-aminobenzimidazole (1.9g,14.45mmol), 4- (3-morpholinopropoxy) benzaldehyde (3g,12.05mmol), TMSCN (1.25g,12.05mmol), PdC (10%,0.40g), TEA (2.8mL,20.25mmol), bis- (imidazol-1-yl) methanone (1.6g,10.13 mmol). The product was purified by preparative HPLC.

Yield: 0.03g (5.79%); MS M/z 422.3(M + H)⁺;¹H NMR(400MHz,CD₃OD. delta.8.05 (s,1H),7.47(d,1H),7.44(d,1H),7.29-7.22(m,3H),6.83(d,2H),5.38(t,1H),3.97-3.91(m.3H),3.66(m,3H),3.35 (mixed with solvent, 2H),2.52-2.46(m,6H),1.95-1.88(m,2H), HPLC (. lamda =214nm, [ A, 1H ], [ A ], [ L ], [ 2 ] H ], HPLC, [ L ], []:rt 5.00min(100%).

Example 26: 5- (2- (2-morpholinoethoxy) phenyl) -1- (1H-benzo [ d ] imidazol-5-yl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from 5-aminobenzimidazole (679mg,5.11mmol), 2- (2-morpholinoethoxy) benzaldehyde (1g,4.26mmol), TMSCN (0.6mL,4.26mmol), PdC (10%,250mg), TEA (1.3mL,7.80mmol), bis- (imidazol-1-yl) methanone (220mg,1.31 mmol).

Yield: 40mg (7.5%); MS M/z 408.4(M + H)⁺;¹H-NMR(400MHz,DMSO-d₆):δ12.12(br s,H);8.07(s,H);7.65(s,H);7.42(s,H);7.36(s,H);7.21-7.17(m,2H);7.06-7.04(m,2H);6.94-6.89(m,H);6.83-6.79(m,H);5.68(br s,H);4.19-4.16(m,2H);3.90-3.86(m,H);3.60(s,4H);3.09-3.06(m,H);2.78-2.73(m,2H),HPLC(λ=214nm,[A]:rt 5.65min(100%)

Example 27: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4-fluorophenyl) imidazolidin-2-one

The compound was synthesized as the hydrochloride salt starting from 5-aminobenzimidazole (0.665g,5mmol), bis (1H-imidazol-1-yl) methanone (0.891g,5.5mmol), TEA (2.09mL,15mmol), aminomethyl- (4-fluorophenyl) ketone hydrochloride (0.948g,5mmol), TEA (1.39mL,10mmol), PdC (10%,0.02g) as described in method 1.

Yield: 0.02g (1.2%); MS M/z 297.3(M + H)⁺;¹H NMR(DMSO,400MHz):δ3.07-3.11(m,H);3.84-3.88(m,H);5.59-5.62(m,H);7.12-7.15(m,2H);7.26(bs,H);7.35-7.39(m,2H);7.54(dd,H,³J=9.2Hz⁴J=1.8Hz);7.63(d,H,³J=9.2Hz);7.89(d,H,⁴J=1.8Hz);9.35(s,H),HPLC(λ=214nm,[B]:rt 7.81min(97%).

Example 28: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (2-fluorophenyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from 5-aminobenzimidazole (0.585g,4.4mmol), 2-fluorobenzaldehyde (0.496g,4mmol), TMSCN (0.5mL,4mmol), PdC (10%,0.02g), TEA (1.04mL,7.5mmol), bis- (imidazol-1-yl) methanone (0.662,4.08 mmol).

Yield: 0.155g (13.1%); MS M/z 365.1(M + H)⁺;¹H NMR(DMSO,400MHz):δ3.16-3.19(m,H);3.88-3.93(m,H);5.73-5.76(m,H);7.00(s,H);7.08-7.20(m,2H);7.24-7.32(m,3H);7.40(s,H);7.56(s,H);8.08(s,H);12.20(bs,H),HPLC(λ=214nm,[B]:rt 7.23min(93%).

Example 29: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (3-fluorophenyl) imidazolidin-2-one

This compound was synthesized as the trifluoroacetate salt starting from 5-aminobenzimidazole (0.585g,4.4mmol), 3-fluorobenzaldehyde (0.496g,4mmol), TMSCN (0.5mL,4mmol), PdC (10%,0.02g), TEA (0.979mL,7.02mmol), bis- (imidazol-1-yl) methanone (0.621,3.83mmol) as described in method 2.

Yield: 0.023g (1.5%); MS M/z 297.4(M + H)⁺;¹H NMR(DMSO,400MHz):δ3.10-3.13(m,H);3.85-3.89(m,H);5.59-5.63(m,H);7.02-7.07(m,H);7.15-7.17(m,2H);7.24(s,H);7.31-7.36(m,H);7.52-7.55(dd,H,³J=8.7Hz,⁴J=1.7Hz);7.61-7.63(d,H,³J=8.7Hz);7.85(d,H,⁴J=1.7Hz);9.18(s,H),HPLC(λ=214nm,[B]:rt 8.25min(100%).

Example 30: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (2, 6-difluorophenyl) imidazolidin-2-one

The compound was synthesized as the trifluoroacetate salt starting from 5-aminobenzimidazole (0.585g,4.4mmol), 2, 6-difluorobenzaldehyde (0.431mL,4mmol), TMSCN (0.5mL,4mmol), PdC (10%,0.02g), TEA (1.15mL,8.22mmol), bis- (imidazol-1-yl) methanone (0.730,4.5mmol) as described in method 2.

Yield: 0.06g (3.9%); MS M/z 315.2(M + H)⁺;¹H NMR(DMSO,400MHz):δ3.38-3.42(m,H);3.93-3.98(m,H);5.97-6.01(m,H);7.02-7.06(m,2H);7.30-7-37(m,2H);7.47-7.50(dd,H,³J=8.7Hz,⁴J=1.7Hz);7.64-7.66(d,H,³J=8.7Hz);7.78(d,H,⁴J=1.7Hz);9.16(s,H),HPLC(λ=214nm,[A]:rt 8.24min(97.3%).

Example 31: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (3, 4-difluorophenyl) imidazolidin-2-one

The compound was synthesized as the hydrochloride salt starting from 5-aminobenzimidazole (0.585g,4.4mmol), bis (1H-imidazol-1-yl) methanone (0.713g,4.4mmol), TEA (1.84mL,13.2mmol), aminomethyl- (3, 4-difluorophenyl) ketone hydrochloride (0.911g,4.4mmol), TEA (1.23mL,8.8mmol), PdC (10%,0.02g) as described in method 1.

Yield: 0.048g (3.1%); MS M/z 315.2(M + H)⁺;¹H NMR(DMSO,400MHz):δ3.10-3.14(m,H);3.83-3.87(m,H);5.57-5.61(m,H);7.16-7.18(m,H);7.23(s,H);7.32-7.45(m,2H);7.49(dd,H,³J=8.7Hz,⁴J=1.7Hz);7.61(d,H,J=8.7Hz);7.82(d,H,4J=1.7Hz);9.14(s,H),HPLC(λ=214nm,[B]:rt 7.89min(96%).

Example 32: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (2-fluoro-5- (trifluoromethyl) phenyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from 2-fluoro-5- (trifluoromethyl) benzaldehyde (0.565mL,4mmol), 5-aminobenzimidazole (0.585g,4.4mmol), TMSCN (0.5g,4mmol), TEA (0.669mL,4.8mmol), PdC (10%,0.02g), bis (1H-imidazol-1-yl) methanone (0.778g,4.8 mmol).

Yield: 0.195g (13.4%); MS M/z 365.2(M + H) ⁺;¹H NMR(DMSO,400MHz):δ3.24-3.28(m,H);3.90-3.96(m,H);5.83-5.87(m,H);7.05-7.17(m,H);7.33-7.39(m,H);7.41-7.48(m,2H);7.53-7.60(m,H);7.63-7.70(m,2H);8.08-8.10(d,H,J=9.1Hz);12.25-12.31(m,H),HPLC(λ=214nm,[B]:rt 9.01min(100%).

Example 33: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (3-fluoro-5- (trifluoromethyl) phenyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from 5-aminobenzimidazole (0.585g,4.4mmol), 3-fluoro-5- (trifluoromethyl) benzaldehyde (0.768g,4mmol), TMSCN (0.5mL,4mmol), PdC (10%,0.02g), TEA (0.558mL,4mmol), bis- (imidazol-1-yl) methanone (0.648,4 mmol).

Yield: 0.143g (9.8%); MS m @z 365.2(M+H)⁺;¹H NMR(DMSO,400MHz):δ3.14-3.18(m,H);3.85-3.90(m,H);5.68-5.72(m,H);7.05(s,H);7.26(bs,H);7.42-7.43(m,H);7.51-7.60(m,4H);8.09(s,H);12.27(bs,H),HPLC(λ=214nm,[B]:rt 9.57min(95%).

Example 34: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (2-fluoro-4- (trifluoromethyl) phenyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from 5-aminobenzimidazole (0.457g,3.44mmol), 2-fluoro-4- (trifluoromethyl) benzaldehyde (0.600g,3.13mmol), TMSCN (0.39mL,3.13mmol), PdC (10%,0.02g), TEA (0.455mL,3.26mmol), bis- (imidazol-1-yl) methanone (0.529,3.26 mmol).

Yield: 0.100g (8.8%); MS M/z 365.2(M + H)⁺;¹H NMR(DMSO,400MHz):δ3.18-3.22(m,H);3.89-3.94(m,H);5.83-5.87(m,H);7.07(s,H);7.22-7.24(m,H);7.27-7.31(m,H);7.39-7.41(m,H);7.57(d,H,⁴J=2.1Hz);7.60-7.64(m,2H);8.07(s,H);12.31(bs,H),HPLC(λ=214nm,[B]:rt 9.36min(93%).

Example 35: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (3-fluoro-4- (trifluoromethyl) phenyl) imidazolidin-2-one

The compound was synthesized as described in method 2 starting from 5-aminobenzimidazole (0.585g,4.4mmol), 3-fluoro-4- (trifluoromethyl) benzaldehyde (0.768g,4mmol), TMSCN (0.5mL,4mmol), PdC (10%,0.02g), TEA (0.585mL,4.2mmol), bis- (imidazol-1-yl) methanone (0.681,4.2 mmol).

Yield: 0.123g (8.4%); MS M/z 365.1(M + H)⁺;¹H NMR(DMSO,400MHz):δ3.09-3.13(m,H);3.83-3.87(m,H);5.63-5.67(m,H);7.03(bs,H);7.20(bs,H);7.36(d,H,J=7.9Hz);7.39(bs,H);7.47-7.49(m,H);7.56(bs,H);7.70(t,H,J=7.9Hz);8.06(s,H);12.22(bs,H),HPLC(λ=214nm,[B]:rt 9.68min(91%).

Example 36: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (2-chlorophenyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from 5-aminobenzimidazole (0.585g,4.4mmol), 2-chlorobenzaldehyde (0.448mL,4mmol), TMSCN (0.5mL,4mmol), PdC (10%,0.02g), TEA (1.15mL,8.25mmol), bis- (imidazol-1-yl) methanone (0.700g,4.32 mmol).

Yield: 0.100g (8%); MS M/z 313.3(M + H)⁺;¹H NMR(DMSO,400MHz):δ3.06-3.1(m,H);3.94-3.99(m,H);5.78-5.81(m,H);7.04(s,H);7.22-7.29(m,4H);7.41-7.48(m,2H);7.55(s,H);8.08(s,H);12.29(bs,H),HPLC(λ=214nm,[B]:rt 9.16min(97%).

Example 37: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (3-chlorophenyl) imidazolidin-2-one

This compound was synthesized as the trifluoroacetate salt starting from 5-aminobenzimidazole (0.293g,2.2mmol), 3-chlorobenzaldehyde (0.227mL,2mmol), TMSCN (0.25mL,2mmol), PdC (10%,0.01g), TEA (0.613mL,4.4mmol), bis- (imidazol-1-yl) methanone (0.389g,2.4mmol) as described in method 2. The product was purified by preparative HPLC.

Yield: 0.049g (5.7%); MS M/z 313.3(M + H)⁺;¹H NMR(DMSO,400MHz):δ3.11-3.15(m,H);3.87-3-91(m,H);5.61-5.65(m,H);7.26(s,H);7.29-7.37(m,3H);7.42(s,H);7.53-7.56(dd,H,³J=7.1Hz⁴J=2.1Hz);7.63-7.65(d,H,J=8.7Hz);7.86-7.87(d,H,⁴J=2.1Hz);9.16(s,H),HPLC(λ=214nm,[B]:rt9.35min(92%).

Example 38: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (2, 6-dichlorophenyl) imidazolidin-2-one

The compound was synthesized as the trifluoroacetate salt starting from 5-aminobenzimidazole (0.585g,4.4mmol), 2, 6-dichloro-benzaldehyde (0.7g,4mmol), TMSCN (0.5mL,4mmol), PdC (10%,0.02g), TEA (0.4mL,2.8mmol), bis- (imidazol-1-yl) methanone (0.253g,1.56mmol) as described in method 2. The product was purified by preparative HPLC.

Yield: 0.03g (1.6%); MS M/z 347.1(M + H)⁺;¹H NMR(DMSO,400MHz):δ3.40-3.44(m,H);3.90-3.95(m,H);6.34-6.38(m,H);7.25-7.29(m,H);7.33-7.35(m,H);7.40-7.43(m,2H);7.48-7.50(m,H);7.63-7.65(m,H);7.71(m,H);9.15(s,H),HPLC(λ=214nm,[B]:rt 8.29min(93.6%).

Example 39: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (2, 3-dichlorophenyl) imidazolidin-2-one

The compound was synthesized as described in method 2 starting from 5-aminobenzimidazole (0.585g,4.4mmol), 2, 3-dichloro-benzaldehyde (0.700g,4mmol), TMSCN (0.5mL,4mmol), PdC (10%,0.02g), TEA (0.5mL,3.6mmol), bis- (imidazol-1-yl) methanone (0.308,1.9 mmol).

Yield: 0.014g (1%); MS M/z 347.2(M + H)⁺;¹H NMR(DMSO,400MHz):δ3.08-3.11(m,H);3.96-4.01(m,H);5.83-5.86(m,H);7.09(s,H);7.24-7.30(m,3H);7.44(s,H);7.52-7.56(m,2H);8.08(s,H);12.23(bs,H),HPLC(λ=214nm,[B]:rt 9.28min(94.1%).

Example 40: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (3, 4-dichlorophenyl) imidazolidin-2-one

The compound was synthesized as the hydrochloride salt starting from 5-aminobenzimidazole (1.18g,8.87mmol), bis (1H-imidazol-1-yl) methanone (1.58g,9.76mmol), TEA (3.71,26.61mmol), aminomethyl- (3, 4-dichlorophenyl) ketone hydrobromide (2.528g,8.87mmol), TEA (2.47mL,17.72mmol), PdC (10%,0.02g) as described in method 1.

Yield: 0.054g (1.6%); MS M/z 347.1(M + H)⁺;¹H NMR(DMSO,400MHz):δ3.10-3.14(m,H);3.84-3.88(m,H);5.60-5.64(m,H);7.27(s,H);7.30(dd,H,³J=8.3Hz⁴J=2.1Hz);7.50-7.57(m,2H);7.61-7.64(m,2H);7.85(s,H);9.18(s,H),HPLC(λ=214nm,[B]:rt 9.79min(100%).

Example 41: (S) -1- (1H-benzo [ d ] imidazol-5-yl) -5- (3, 4-dichlorophenyl) imidazolidin-2-one

Variant 1

This compound was synthesized according to method 3.

Step A

2.5M n-butyllithium (68.5mL,171.42mmol), methyltriphenylphosphonium bromide (61.2,171.42mmol), 3, 4-dichlorobenzaldehyde (15g,85.7mmol), yield 10g (66%)

Step B

1, 3-dichloro-5, 5-dimethylimidazolidine-2-dione (14.7g,75.0mmol), tert-butyl hypochlorite (15g,138.70mmol), tert-butyl carbamate (16.23g,138.72mmol), the product of step A (8g,46.24mmol), (DHQ)₂PHAL (1.44g;1.85mmol), potassium osmate dihydrate (680mg,1.85mmol), yield: 5g (35.4%)

Step C

Triethylamine (4.5mL,32.67mmol), p-toluenesulfonyl chloride (3.11g,16.33mmol), the product of step B, in dichloromethane (100 mL). Purification by flash column chromatography on silica gel using 20% ethyl acetate in petroleum ether, yield: 5.6g (75%).

Step D

Sodium azide (1.5g,23.41mmol), step C product (5.5g,11.95 mmol); yield: 4.0g (79%)

Step E

Step D, product (2.2g,6.65mmol), zinc powder (1.3g,19.96mmol) 3.3g (89%) yield, p-anisaldehyde (0.78mL,6.49mmol), sodium borohydride (870mg,23.6mmol), yield: 1.88g (75%)

Step F

Product of step E (1.8g,4.235mmol), yield 1.1g (80%)

N, N-carbonyl-di-imidazole (300mg,1.84mmol), triethylamine (0.64mL,4.615mmol), yield: 400mg (74%)

Step G

The product of step F (400mg,1.14mmol), 1, 2-diamino 4-bromobenzene (213mg,1.14mmol), cesium fluoride (347mg,2.28mmol), cuprous iodide (21mg,0.11mmol), 1, 2-diaminocyclohexane (13mg,0.11mmol), yield: 400mg (76%).

Step H

Product of step G (350mg,0.738mmol)

The product is then converted into the HCl salt

Trifluoroacetic acid (10mL) was added and the mixture was stirred at room temperature for 15 h. Excess trifluoroacetic acid was removed in vacuo and the crude compound was extracted with ethyl acetate. The combined organic layers were washed with 10% sodium carbonate, water, brine solution and dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum. Purification by column chromatography on silica gel (100-200 mesh) using a gradient of 5% methanol in chloroform as eluent afforded 200mg (76%) of product.

1M HCl in ether (0.56mL) was added to the above product dissolved in acetone (10mL) at 5 ℃ and stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, washed with n-pentane and dried in vacuo. Yield: 110mg (83%), MS M/z 347.1(M + H)⁺;¹H-NMR(400MHz,DMSO-d6):δ9.25(s,1H);7.93(s,1H);7.71-7.66(m,2H);7.58(d,1H);7.48(d,1H);7.35(dd,1H);5.63(q,1H);4.03(t,1H);3.33(t,1H,HPLC(λ=214nm,[A]:rt 10.56min(97.7%).

Example 42: 1- (1H-1, 3-Benzodiazol-5-yl) -5- (4-biphenylyl) imidazolidin-2-one

The compound was synthesized as the hydrochloride salt starting from 5-aminobenzimidazole (0.522g,3.92mmol), bis (1H-imidazol-1-yl) methanone (0.699g,4.31mmol), TEA (1.64mL,11.76mmol), aminomethyl- (4-biphenyl) ketone hydrobromide (1.14g,3.92mmol), TEA (1.09mL,7.8mmol), PdC (10%,0.02g) as described in method 1.

Yield: 0.033g (2.2%); MS M/z 355.3(M + H)⁺;¹H NMR(DMSO,400MHz):δ3.15-3.19(m,H);3.87-3.96(m,H);5.63-5.68(m,H);7.22(s,H);7.31-7.45(m,3H);7.57-7.62(m,7H);7.88(s,H);9.07(s,H),HPLC(λ=214nm,[B]:rt10.96min(94.1%).

Example 43: (S) -1- (1H-1, 3-Benzodiazol-5-yl) -5- (4-biphenylyl) imidazolidin-2-one

Variant 1

This compound was synthesized according to method 3.

Step A

2.5M n-butyllithium (44mL,109.89mmol), methyltriphenylphosphonium bromide (39.23g,109.89mmol), 4-phenylbenzaldehyde (10.0g,54.94mmol), yield: 9.0g (91%)

Step B

1, 3-dichloro-5, 5-dimethylimidazolidine-2-dione (14.7g,75.0mmol), tert-butyl carbamate (17.5g,150mmol), the product of step A (9.g,50.0mmol), (DHQ)₂PHAL (970mg;1.25mmol), potassium osmate dihydrate (736mg,2.0mmol), yield: 6.6g (42.3%)

Step C

Triethylamine (6.2mL,44.72mmol), p-toluenesulfonyl chloride (6.6g,31.94mmol), the product of step B (10.0g,31.94mmol) in dichloromethane (100 mL). Purification by flash column chromatography on silica gel using 20% ethyl acetate in petroleum ether, yield: 7.5g (50.3%).

Step D

Sodium azide (1.46g,23.41mmol), step C product (7.0g,11.95 mmol); yield: 4.0g (79%)

Step E

Product of step D (4.0g,11.83mmol), 10% PdC (400mg), yield 3.3g (89%)

P-anisaldehyde (1.3g,9.61mmol), sodium borohydride (711mg,19.23mmol), yield: 3.1g (74%)

Step F

Product of step E (3.0g,6.94mmol), yield 2.0g (86.9%)

N, N-carbonyl-di-imidazole (1.46g,9.03mmol), triethylamine (2.5mL), yield: 1.8g (83.7%)

Step G

The product of step F (1.0g,2.79mmol), 1, 2-diamino 4-bromobenzene (522mg2.79mmol), cesium fluoride (849mg,5.58mmol), cuprous iodide (53mg), 1, 2-diaminocyclohexane (32mg,0.28mmol), yield: 400mg (76%)

Step H

Product of step G (400mg,0.86mmol), yield: 350mg (85.7%)

The product is then converted into the HCl salt

Trifluoroacetic acid (10mL) was added and the mixture was stirred at room temperature for 15 h. Excess trifluoroacetic acid was removed in vacuo and the crude compound was extracted with ethyl acetate. The combined organic layers were washed with 10% sodium carbonate, water, brine solution and dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum. Purification by column chromatography on silica gel (100-200 mesh) using a gradient of 5% methanol in chloroform as eluent afforded 200mg (76%) of product.

1M HCl in ether (0.56mL) was added to the above product dissolved in acetone (10mL) at 5 ℃ and stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, washed with n-pentane and dried in vacuo. Yield: 190mg (86%). MS M/z 355.4(M + H) ⁺;¹H-NMR(400MHz,CD₃OD):δ9.23(s,H);7.95(s,H);7.74-7.66(br m,2H);7.59-7.41(br m,6H);7.39-7.37(m,2H);7.32-7.28(m,H);5.67-5.63(m,H);4.08-4.04(m,H);3.41-3.39(m,H),HPLC(λ=214nm,[B]:rt 10.85min(97.16%).

Variant 2

Example 42, column: nucleocell Alpha RP-S,250 x 21mm (5 μm); eluent: 50/50 acetonitrile/water 50/50; the flow rate is 10 mL/min; first eluting enantiomer, rt: 18.5min (98.35)%.

Example 44: (R) -1- (1H-1, 3-Benzodiazol-5-yl) -5- (4-biphenylyl) imidazolidin-2-one

Example 42, column: nucleocell Alpha RP-S,250 x 21mm (5 μm); eluent: 50/50 acetonitrile/water 50/50; the flow rate is 10 mL/min; first eluting enantiomer, rt: 22min (99.25)%.

Example 45: 1- (1H-1, 3-Benzodiazol-5-yl) -5- (3-fluoro-4-biphenylyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from 5-aminobenzimidazole (0.585g,4.4mmol), 3-fluoro-4-biphenylcarbaldehyde (0.801g,4mmol), TMSCN (0.5mL,4mmol), PdC (10%,0.02g), TEA (0.754mL,5.4mmol), bis- (imidazol-1-yl) methanone (0.479g,2.95 mmol).

Yield: 0.219g (14.7%); MS M/z 373.4(M + H)⁺;¹H-NMR(400MHz,DMSO-d6):3.14-3.18(m,H);3.86-3.90(m,H);5.59-5.63(m,H);7.00(bs,H);7.23-7.31(m,2H);7.38-7.45(m,7H);7.57(bs,H);7.64(bs,H);8.09(s,H);12.24(bs,H);HPLC(λ=214nm,[B]:rt 10.85min(96.7%).

Example 46: 1- (1H-benzo [ d ] imidazol-5-yl) -5- [4- (3-chlorophenyl) phenyl ] imidazolidin-2-one

This compound was synthesized as described in method 2, starting from 5-aminobenzimidazole (0.614mg,4.62mmol), 4- (3-chlorophenyl) phenyl ] carbaldehyde (1.0g,4.68mmol), TMSCN (0.93mL,6.93mmol), 10% PdC (200mg), TEA (1.31mL,8.76mmol), bis- (imidazol-1-yl) methanone (460mg,2.84 mmol).

Yield: 0.100g (5.5%); MS M/z 389.2(M + H)⁺;¹H NMR(400MHz,CD₃OD):δ8.06(s,1H),7.55(m,4H),7.47(m,4H),7.33(m,3H),5.53(t,1H),4.01(t,1H),3.4(t,2H).HPLC(λ=214nm,[B]:rt 13.15min(95.6%).

Example 47: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (3 ', 4' -dichloro-4-biphenyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from 5-aminobenzimidazole (0.53g,3.98mmol), 4-3 ', 4' -dichloro-4-biphenylcarbaldehyde (1.0g,3.98mmol), TMSCN (0.8mL,5.97mmol), 10% PdC (200mg), TEA (1.21mL,8.76mmol), bis- (imidazol-1-yl) methanone (426mg,2.63 mmol).

Yield: 0.100g (5.9%); MS M/z 423.2(M + H)⁺;1H-NMR(400MHz,CD₃OD):δ8.06(s,H);7.69(s,H);7.57-7.47(br m,8H);7.32-7..30(m,H);5.56-5.52(m,H);4.03-3.99(m,H);3.40-3.36(m,H);HPLC(λ=214nm),[A]:rt 14.35min(98.7%).

Example 48: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (3-phenylphenyl) imidazolidin-2-one

This compound was synthesized as described in method 2, starting from 5-aminobenzimidazole (526mg,3.95mmol), biphenyl-3-carbaldehyde (600mg,3.29mmol), TMSCN (654mg,6.59mmol), 10% PdC (100mg), TEA (1.5mL,11mmol), bis- (imidazol-1-yl) methanone (475mg,1.03 mmol).

Yield: 0.110g (7.13%); MS M/z 355.2(M + H)⁺;¹H NMR(400MHz,DMSO):δ9.10(bs,1H),7.87(s,1H),7.67-7.30(m,11H),7.25(s,1H),5.65(q,1H),3.92(t,1H),3.22-3.15(m,1H),HPLC(λ=214nm,[B]:rt 11.95min(97.02%).

Example 49: 1- (1H-benzo [ d ] imidazol-5-yl) -5- [3- (3-chlorophenyl) phenyl ] imidazolidin-2-one

This compound was synthesized as described in method 2, starting from 5-aminobenzimidazole (614mg,4.62mmol), 3- (3-chlorophenyl) benzaldehyde (1.0g,4.68mmol), TMSCN (0.93mL,6.93mmol), 10% PdC (200mg), TEA (1.31mL,8.76mmol), bis- (imidazol-1-yl) methanone (460mg,2.84 mmol).

Yield: 0.100g (6.13%); MS M/z 389.2(M + H)⁺;¹H NMR(400MHz,CD₃OD):δ8.056(s,1H),7.61(s,1H),7.56(s,2H),7.55-7.30(m,7H),5.57(q,1H),4.02(t,1H),3.41(t,1H),HPLC(λ=214nm,[B]:rt 13.20min(95.02%).

Example 50: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (3-chloro-4-morpholinophenyl) imidazolidin-2-one

This compound was synthesized as described in method 2, starting from 5-aminobenzimidazole (284mg,2.13mmol), 3-5- (3-chloro-4-morpholinophenyl) carbaldehyde (400mg,1.77mmol), TMSCN (352mg,3.55mmol), 10% PdC (200mg), TEA (0.82mL,5.92mmol), di- (imidazol-1-yl) methanone (168mg,1.03 mmol).

Yield: 0.04g (5.5%); MS M/z 398.1(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ12.24(bs,1H),8.09(s,1H),7.59(s,1H),7.50-7.37(m,3H),7.28(t,1H),7.19(d,1H),7.08(d,1H),6.95(d,1H),5.52-5.48(q,1H),3.81(t,1H),3.68(t,4H),3.09(t,1H),2.89(t,4H),HPLC(λ=214nm,[B]:rt 8.85min(100%)

Example 51: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4- (4-phenylpiperazin-1-yl) phenyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from 5-aminobenzimidazole (1.8g,13.98mmol), 5- (4- (4-phenylpiperazin-1-yl) phenyl) carbaldehyde (3.1g,11.65mmol), TMSCN (2.3mL,17.48mmol), 10% PdC (1.0g), TEA (5.3mL,36.64mmol), bis- (imidazol-1-yl) methanone (1.0g,6.06 mmol).

Yield: 0.04g (0.53%); MS M/z 439.4(M + H)⁺;¹H NMR(400MHz,DMSO-D₆): δ12.23(bs,1H),8.01(s,1H),7.53(s,1H),7.38(s,1H),7.19(t,5H),6.97-6.88(m,5H),6.78(t,1H),5.41-5.37(q,1H),3.80(t,1H),3.30.-3.16(m,8H),3.09(t,1H),HPLC(λ=214nm),[B]:rt 10.13min(97.77%).

Example 52: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (2-chloro-6- (4-ethylpiperazin-1-yl) phenyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from 5-aminobenzimidazole (0.95g,7.14mmol), 5-5- (2-chloro-6- (4-ethylpiperazin-1-yl) benzaldehyde (1.5g,5.95mmol), TMSCN (1.2g,11.9mmol), 10% PdC (0.04g), TEA (1mL,7.53mmol), bis- (imidazol-1-yl) methanone (284mg,1.75 mmol).

Yield: 0.02g (0.94%); MS M/z 425.4(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ12.19(bs,1H),8.03(s,1H),7.47(d,1H),7.35(t,2H),7.25-7.03(m,5H),6.32(d,1H),3.90(t,1H),3.55(d,1H),3.33-2.67(m,8H),2.47-2.38(m,3H),1.90(s,2H),1.09-1.05(t,3H),HPLC(λ=214nm),[B]:rt 6.24min(100.0%).

Example 53: 1- (H-imidazo [1,2-a ] pyridin-7-yl) -5-phenylimidazolidin-2-one

The compound was synthesized as described in method 2 starting from H-imidazo [1,2-a ] pyridin-7-yl-amine (0.85g,4.4mmol), benzaldehyde (0.48g,4.mmol), TMSCN (0.47g,4.8mmol), 10% PdC (0.04g), TEA (0.307mL,2.2mmol), bis- (imidazol-1-yl) methanone (0.195mg,1.25 mmol).

Yield: 0.035g (2.8%); MS M/z 279.3(M + H)⁺;¹H NMR(DMSO,400MHz):δ3.12-3.15(m,1H),3.94-3.99(m,1H),5.62-5.65(m,1H),7.27-7.42(m,5H),7.69-7.73(m,2H),7.77(s,1H),7.83-7.85(m,1H),7.99(m,1H),8.58-8.60(d,1H,3J=7.47Hz),HPLC(λ=214nm),[B]:rt 8.73min(73.8%).

Example 54: 1- (H-imidazo [1,2-a ] pyridin-7-yl) -5- (4-propoxyphenyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from H-imidazo [1,2-a ] pyridin-7-yl-amine (0.267g,2.0mmol), 4-propoxybenzaldehyde (0.328g,2.0mmol), TMSCN (0.300mL,2.4mmol), 10% PdC (0.04g), TEA (0.620,4.9mmol), bis- (imidazol-1-yl) methanone (0.4g,2.4 mmol).

Yield: 0.057g (5.7%); MS M/z 337.2(M + H)⁺;¹H-NMR(400MHz,DMSO-d6):δ0.91-0.95(t,3H),1.65-1.70(m,2H),3.11-3.14(m,1H),3.91-3.93(t,2H,),3.94-3.96(t,1H,),5.56-5.59(m,1H),6.90-6.93(d,2H,J=9Hz),7.24-7.27(d,2H,J=9Hz),7.73-7.75(dd,1H,J=2.0;7.0Hz),7.78-7.81(m,2H),7.90-7.91(d,1H,J=2.1Hz),8.03-8.04(d,1H,J=2.3Hz),8.62-8.64(d,1H,J=7.4Hz),HPLC(λ=214nm),([B]):rt 11.80min(99%).

Example 55: 5- (4-butoxyphenyl) -1- (H-imidazo [1,2-a ] pyridin-7-yl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from H-imidazo [1,2-a ] pyridin-7-yl-amine (0.267g,2.0mmol), 4-butoxybenzaldehyde (0.375g,2.0mmol), TMSCN (0.300mL,2.4mmol), 10% PdC (0.04g), TEA (0.620,4.9mmol), bis- (imidazol-1-yl) methanone (0.4g,2.4 mmol).

Yield: 0.062g (6.7%); MS M/z 351.0(M + H)⁺;1H-NMR(DMSO-d6,400MHz):δ0.88-0.91(t,3H,J=7.0),1.36-1.42(m,2H),1.61-1.66(m,2H),3.11-3.14(dd,1H,J=3.3,9.1Hz),3.89-3.96(m,3H),5.56-5.59(dd,1H,J=3.3,9.0Hz)，6.90-6.92(d，2H，J＝8，7)，7.25-7.27(d，2H，J＝8.7)，7.74-7.76(m.2H)，7.91(s，1H)，8.04(s，1H)，8.62-8.64(d，1H，J＝7，4)，13.64(br s，0.7H)，HPLC(λ＝214nm)，[B]：rt 13.00min(99％)

Example 56: 5- (2, 6-difluoro-4-methoxyphenyl) -1- (H-imidazo [1,2-a ] pyridin-7-yl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from H-imidazo [1,2-a ] pyridin-7-yl-amine (0.267g, 2.0mmol), 2, 6-difluoro-4-methoxybenzaldehyde (0.345g, 2.0mmol), TMSCN (0.300mL, 2.4mmol), 10% PdC (0.04g), TEA (0.620, 4.9mmol), bis- (imidazol-1-yl) methanone (0.4g, 2.4 mmol).

Yield: 0.067g (7.3%); MS M/z 345.2(M + H)⁺；1H-NMR(DMSO-d6，400MHz)：δ3.35-3.38(m，1H)，3.73(s，3H)，3.98(m，1H)，5.87-5.91(m，1H)，6.75-6.78(d，2H，J＝11.2Hz)，7.63(s，1H)，7.73-7.76(dd，1H，J＝7.6；2.4Hz)，7.93(d，1H，J＝2.0Hz)，7.95(s，1H)，8.06(d，1H，J＝2.0Hz)，8.66-8.68(d，1H，J＝8.0Hz)，HPLC(λ＝214nm)，[B]：rt 9.56min(99％)

Example 57: 1- (H-imidazo [1,2-a ] pyridin-7-yl) -5- (4-methoxybenzo [ d ] [1, 3] dioxol-6-yl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from H-imidazo [1,2-a ] pyridin-7-yl-amine (0.207g, 1.554mmol), (4-methoxybenzo [ d ] [1, 3] dioxol-6-yl) carbaldehyde (0.28g, 1.554mmol), TMSCN (0.195mL, 1.1.554mmol), 10% PdC (0.04g), TEA (0.49mL, 1.554mmol), bis- (imidazol-1-yl) methanone (0.311, 1.554 mmol).

Yield: 0.033g (4.5%); MS M/z 353.0(M + H)⁺；1H-NMR(DMSO-d6，400MH)δ3.14-3.17(dd，1H，J＝4.0；9.2Hz)，3.80(s，3H)，3.90-3.94(t，1H，J＝9Hz)，5.50-5.54(dd，1H，J＝9.2；4.2)，5.94-5.96(dd，2H，J＝0.8；7.2Hz)，6.54(d，1H，J＝1.2Hz)，6.70(d，1H，J＝1.6Hz)，7.76-7.82(m，3H)，7.93(d，1H，J＝2Hz)，8.06(d，1H，J＝2Hz)，8.64-8.66(d，1H，J＝7.6Hz)，HPLC(λ＝214nm)，[B]：rt9.20min (92％)

Example 58: 5- (4- (2-morpholinoethoxy) phenyl) -1- (H-imidazo [1,2-a ] pyridin-7-yl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from H-imidazo [1,2-a ] pyridin-7-yl-amine (0.267g,2.0mmol), 2-morpholinoethoxy) benzaldehyde (0.471g,2.0mmol), TMSCN (0.300mL,2.4mmol), 10% PdC (0.04g), TEA (0.620,4.9mmol), bis- (imidazol-1-yl) methanone (0.4g,2.4 mmol).

Yield: 0.016g (1.48%); MS M/z 408.4(M + H)⁺;1H-NMR(DMSO-d6,400MHz).:δ3.09-3.12(dd,1H,J=3.3;9.1Hz),3.51-3.53(t,2H,J=4.6Hz),3.61-4.00(br m,9H),4.28-4.30(t,2H,J=9.3Hz),5.59-5.62(dd,1H,J=8.9;3.3Hz),6.97-6.99(d,2H,J=8.8Hz),7.30-7.30(d,2H,J=8.8Hz),7.74-7.77(d,1H,J=2;9.7Hz),7.83(s,2H),7.92(d,1H,J=2.1Hz),8.05(d,1H,J=2.1Hz),8.64-6.66(d,1H,J=7.7Hz),HPLC(λ=214nm),[B]:rt 1.40min(86%)

Example 59: 5- (2, 6-difluorophenyl) -1- (H-imidazo [1,2-a ] pyridin-7-yl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from H-imidazo [1,2-a ] pyridin-7-yl-amine (0.267g,2.0mmol), 2, 6-difluoro-benzaldehyde (0.285g,2.0mmol), TMSCN (0.300mL,2.4mmol), 10% PdC (0.04g), TEA (0.620,4.9mmol), bis- (imidazol-1-yl) methanone (0.4g,2.4 mmol).

Yield: 0.0047g (0.55%); MS M/z 315.1(M + H)⁺;1H-NMR(DMSO-d6,400MHz):δ3.39-3.42(m,1H),3.99-4.04(t,1H,J=9.9Hz),5.98-6.01(dd,1H,J=4.1;10.4Hz),7.12-7.16(m,2H),7.41-7.45(m,1H),7.63(s,1H),7.76-7.78(dd,1H,J=2.2;7.7Hz),7.92(d,1H,J=2.1Hz),7.99(s,1H),8.05(s,1H),8.66-8.68(d,1H,J=7.7Hz),HPLC(λ=214nm),[B]:rt 8.40min(100%)

Example 60: 5- (biphenyl) -1- (H-imidazo [1,2-a ] pyridin-7-yl) imidazolidin-2-one

The compound was synthesized as described in method 2 starting from H-imidazo [1,2-a ] pyridin-7-yl-amine (0.267g,2.0mmol), biphenylcarboxaldehyde (0.365g,2.0mmol), TMSCN (0.300mL,2.4mmol), 10% PdC (0.04g), TEA (0.620,4.9mmol), bis- (imidazol-1-yl) methanone (0.4g,2.4 mmol).

Yield: 0.043g (4.6%); MS M/z 355.2(M + H) ⁺;1H-NMR(400MHz,DMSO-d6):δ3.19-3.22(m,H);3.98-4.03(m,H);5.70-5.73(m,H);7.32-7.38(m,H);7.42-7.46(m,4H);7.61-7.63(m,2H);7.68(d,J=8.4Hz,2H);7.78-7.81(m,H);7.84(s,H);7.88(s,H);7.92(d,J=2.0Hz,H);8.66(d,J=8.0Hz,H),HPLC(λ=214nm),[31/98]:rt 12.90min(99%)

Example 61: 5- (3-fluorobiphenyl) -1- (H-imidazo [1,2-a ] pyridin-7-yl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from H-imidazo [1,2-a ] pyridin-7-yl-amine (0.267g,2.0mmol), 3-fluorobiphenylcarboxaldehyde (0.401g,2.0mmol), TMSCN (0.300mL,2.4mmol), 10% PdC (0.04g), TEA (0.620,4.9mmol), bis- (imidazol-1-yl) methanone (0.4g,2.4 mmol).

Yield: 0.035g (0.036%); MS M/z 373.0(M + H)⁺;1H-NMR(400MHz,DMSO-d6):δ3.22-3.25(m,H);3.97-4.02(m,H);5.72-5.75(m,H);7.24-7.25(m,H);7.26-7.57(m,7H);7.80(dd,J=2.0Hz 7.6Hz,H);7.86(s,H);7.90(s,H);7.93(d,J=2.0Hz,H);8.06(d,J=2.4Hz,H);6.68(d,J=7.6Hz,H)HPLC(λ=214nm),([B])[31/98]):rt 13.20min(99%)

Example 62: 1- (H-imidazo [1,2-a ] pyridin-7-yl) -5- (4- (4-phenylpiperazin-1-yl) phenyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from H-imidazo [1,2-a ] pyridin-7-yl-amine (0.267g,2.0mmol), 4- (4-phenylpiperazin-1-yl) benzaldehyde (0.600g,2.0mmol), TMSCN (0.300mL,2.4mmol), 10% PdC (0.04g), TEA (0.620,4.9mmol), bis- (imidazol-1-yl) methanone (0.4g,2.4 mmol).

Yield: 0.011g (0.00126%); MS M/z 439.4(M + H)⁺;1H-NMR(400MHz,DMSO-d6):3.09-3.12(m,H);3.19-3.25(m,8H);3.88-3.93(m,H);5.50-5.54(m,H);6.75-6.78(m,H);6.93-6.97(m,4H);7.17-7.21(m,4H);7.73(dd,H,³J=7.5Hz ⁴J=2.1Hz);7.78(s,2H);7.89(d,H,⁴J=2.1Hz);8.01(d,H,⁴J=2.1Hz);8.61(d,H,³J=7.5Hz)

HPLC(λ=214nm),[31/98]):rt 10.93min(99%)

Example 63: 1- (1H-benzo [ d ] imidazol-5-yl) -5-phenylimidazolidin-4-one

As described in method 4, from 5-aminobenzimidazole (0.75g,5.61mmol), benzaldehyde (0.52mL,5.1mmol), TMSCN (0.64mL,5.1mmol), concentrated HCl (10mL), triethyl orthoformate (13mL, excess), NaBH₄(0.227g,6mmol) the synthesis of this compound was started.

Yield: 0.088g (6.2%); MS M/z 279.3(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ4.78-4.80(m,H);5.04-5.05(m,H);5.17-5.19(m,H);6.23(d,H,J=2.1Hz);6.79(dd,H,³J=9.1Hz,⁴J=2.1Hz);7.24-7.27(m,H);7.30-7.36(m,4H);7.59(d,H,J=9.1Hz);8.89(s,H);9.16(s,H),HPLC(λ=214nm),[B]:rt6.43min(97.8%).

Example 64: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (2,3, 5-trifluorophenyl) imidazolidin-4-one

As described in method 4, starting from 5-aminobenzimidazole (0.732g,5.5mmol), 2,3, 5-trifluorobenzaldehyde (0.57mL,5mmol), TMSCN (0.625mL,5mmol), concentrated HCl (15mL), triethyl orthoformate (30mL, excess), NaBH₄(0.157g,4.14mmol) the synthesis of this compound was started.

Yield: 0.037g (2.2%); MS M/z 333.2(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ4.77-4.78(m,H);5.19-5.21(m,H);5.43(s,H);6.67(d,H,J=1.7Hz);6.79-6.82(m,H);7.17-7.19(m,H);7.48-7.54(m,H);7.65(d,H,J=9.1Hz);9.13(s,H);9.18(s,H),HPLC(λ=214nm),[B]:rt 7.17min(98%).

Example 65: 1-amino-3- (1H-benzo [ d ] imidazol-5-yl) -4- (4-methoxyphenyl) imidazolidin-2-one

Example 5(0,35mmol) was dissolved in 5mL of glacial acetic acid and a sodium nitrite solution (0.46mmol (1.3eq.), water 0.25mL) was added. The solution was stirred at r.t. for 30min and subsequently cooled to 8 ℃. Thereafter, zinc powder (1,05mmol,3eq) was added in portions with stirring, so that the reaction temperature did not exceed 15 ℃. The mixture was stirred at 12-17 ℃ for a further 1 h. The solvent was then removed and the product was purified by semi-preparative HPLC.

Yield: 0.02g (10.3%); MS M/z 324.5[ M + H ]]⁺;¹H-NMR(400MHz,DMSO-d6):δ3.24-3.27(m,1H);3.64(s,3H);3.91-3.95(m,1H);5.46-5.49(m,H);6.84(d,2H,J=8,8Hz);7.27(d,2H,J=8.8Hz);7.53(dd,H,³J=8.8Hz⁴J=1.8Hz);7.66(d,H,³J=8,8Hz);7.84(d,H,⁴J=1,8Hz);9.21(s,H);HPLC(214nm):rt 6,51min(95,2%)[B]

Example 66: (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4-phenyloxazolidin-2-one

From (S) -4-phenyloxazolidin-2-one (1 eq, 0.163g,1mmol), 4-bromobenzene-1, 2-diamine (1 eq, 0.187g,1mmol) The compound was synthesized starting from copper (I) iodide (0.1 eq, 0.019g,0.1mmol), potassium carbonate (2 eq, 0.276g,2mmol), cyclohexane-1, 2-diamine (0.1 eq, 0.012mL,0.1 mmol). The solids were added together to a reaction flask, and the flask was vented with argon. A solution of cyclohexane-1, 2-diamine in 5mL dioxane was added to the flask. The reaction was stirred at reflux for 18 hours, then cooled to 45 ℃ and passedThe pad is filtered. The pad was washed with warm dichloromethane and the solution was concentrated under reduced pressure. The intermediate was purified by FPLC using a chloroform-methanol gradient (0 → 10%, product eluted at about 5%).

(S) -3- (3, 4-diaminophenyl) -4-phenyloxazolidin-2-one was dissolved in 2.5mL of 5N aqueous hydrochloric acid, and 0.25mL of formic acid was added to the solution. The reaction was stirred at reflux for 1h, then the reaction was cooled to 0 ℃ and the reaction mixture was neutralized with buffer (pH7) and concentrated aqueous ammonia. The aqueous layer was then extracted 3 times with 25mL of dichloromethane. The organic layers were combined, dried, filtered and the solvent was removed under reduced pressure. The final product was purified by FPLC using a chloroform-methanol gradient (0 → 10%). The product eluted at about 5% methanol.

Yield: 0.143g (51.3%); MS M/z 280.3(M + H) ⁺;¹H NMR(400MHz,DMSO-D₆):δ4.12-4.16(m,H);4.81-4.85(m,H);5.70-5.74(m,H);7.22-7.26(m,2H);7.30-7.33(m,2H);7.37-7.39(m,2H);7.45-7.47(m,H);7.58-7.59(m,H);8.14(s,H);12.37(bs,H),HPLC(λ=214nm),[B]:rt 7.87min(100%).

Example 67: (R) -3- (1H-benzo [ d ] imidazol-6-yl) -4-phenyloxazolidin-2-one

The compound was synthesized as described in method 5, step D, starting with (R) -4-phenyloxazolidin-2-one (1 eq, 0.163g,1mmol), 4-bromobenzene-1, 2-diamine (1 eq, 0.187g,1mmol), copper (I) iodide (0.1 eq, 0.019g,0.1mmol), potassium carbonate (2 eq, 0.276g,2mmol), cyclohexane-1, 2-diamine (0.1 eq, 0.012mL,0.1mmol), 5N HCl (3.4mL), formic acid (0.343 mL).

Yield: 0.056g (20.2%); MS M/z 280.3(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ4.10-4.13(m,H);4.78-4.83(m,H);5.68-5.72(m,H);7.20-7.23(m,2H);7.27-7.31(m,2H);7.35-7.37(m,2H);7.42-7.45(m,H);7.55-7.56(m,H);8.12(s,H);12.37(br s,H)HPLC(λ=214nm),[B]:rt 7.87min(100%).

Example 68: (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4-isopropyloxazolidin-2-one

The compound was synthesized as described in method 5, step D, starting from (S) -4-isopropyloxazolidin-2-one (0.065g,0.5mmol), 4-iodobenzene-1, 2-diamine (0.117g,0.5mmol), copper (I) iodide (0.010g,0.05mmol), cesium fluoride (0.276g,1mmol), cyclohexane-1, 2-diamine (0.006mL,0.05mmol), triethyl orthoformate (3 mL).

Yield: 0.012g (9.8%); MS M/z 246.3(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ0.71-0.72(m,3H);0.79-0.81(m,3H);1.85-1.90(m,H);4.20-4.24(m,H);4.38-4.42(m,H);4.55-4.59(m,H);7.25(bs,H);7.51-7.66(m,2H);8.20(s,H);12.41-12.45(m,H),HPLC(λ=214nm),[B]:rt 7.09min(96.7%).

Example 69: (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4-benzyl oxazolidin-2-one

The compound was synthesized as described in method 5, step D, starting from (S) -4-benzyloxazolidin-2-one (0.089g,0.5mmol), 4-iodobenzene-1, 2-diamine (0.117g,0.5mmol), copper (I) iodide (0.010g,0.05mmol), cesium fluoride (0.276g,1mmol), cyclohexane-1, 2-diamine (0.006mL,0.05mmol), triethyl orthoformate (3 mL).

Yield: 0.036g (24.5%); MS M/z 294.2(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ2.75-2.91(m,2H);4.11-4.15(m,H);4.33-4.37(m,H);4.88-4.91(m,H);7.13-7.26(m,5H);7.32-7.40(m,H);7.54-7.68(m,H);7.74-7.79(m,H);8.20-8.22(m,H);12.43-12.48(m,H),HPLC(λ=214nm),[B]:rt 8.93min(96.5%).

Example 70: (4S,5R) -3- (1H-benzo [ d ] imidazol-6-yl) -4, 5-diphenyloxazolidin-2-one

The compound was synthesized as described in method 5, step D, starting from (4S,5R) -4, 5-diphenyloxazolidin-2-one (0.479g,2mmol), 4-bromobenzene-1, 2-diamine (0.374g,2mmol), copper (I) iodide (0.038g,0.2mmol), potassium carbonate (0.553g,4mmol), cyclohexane-1, 2-diamine (0.024mL,0.2mmol), 5N HCl (5.8mL), formic acid (0.582 mL).

Yield: 0.235g (33.1%); MS M/z 356.2(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ6.09(d,H,J=8.3Hz);6.20(d,H,J=8.3Hz);6.95-7.16(m,10H);7.40(bs,H);7.49(d,H,J=8.7Hz);7.73(s,H);8.15(s,H);12.40(bs,H),HPLC(λ=214nm),[B]:rt 11.67min(94.9%).

Example 71: (4S,5S) -3- (1H-benzo [ d ] imidazol-6-yl) -5-methyl-4-phenyloxazolidin-2-one

Step A:

ethyl carbamate (2.14g,24mmol) was dissolved in 27mL of 1-propanol and 47.5mL of 0.5M freshly prepared aqueous NaOH solution was added. The reaction was stirred at ambient temperature for 5 minutes, 1, 3-dichloro-5, 5-dimethylimidazolidine-2, 4-dione (2.36g,12mmol) was added, and the reaction was stirred at ambient temperature for 10 minutes. Adding (DHQ) dissolved in 19mL of 1-propanol₂PHAL (0.156g,0.2mmol) and (E) -prop-1-enylbenzene (1.04mL,8mmol) were then added potassium osmate dihydrate (0.074g,0.2mmol) suspended in 0.56mL of 0.5M aqueous NaOH. The reaction was stirred at ambient temperature until complete consumption of (E) -prop-1-enylbenzene (TLC control). 60mL of water was added and the reaction mixture was extracted 3 times with 60mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The product was purified by FPLC using a heptane-ethyl acetate gradient.

Yield: 0.74g (4)1.5%);MS m/z 224.3(M+H)⁺;HPLC(λ=214nm),[B]:rt10.67min(95.5%).

And B:

2mmol of the product obtained from step A (0.446g) were dissolved in a 0.2M solution of sodium hydroxide in methanol. The reaction was stirred at reflux until TLC control showed complete consumption. The solvent was removed under reduced pressure and ethyl acetate was added. The organic layer was washed with brine, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure.

Yield: 0.335g (94.5%); MS M/z 178.3(M + H)⁺;HPLC(λ=214nm),[B]:rt11.41min(100%).

And C:

the product obtained from step B (0.335g,1.89mmol) was charged to a reaction flask along with 4-bromobenzene-1, 2-diamine (0.353g,1.89mmol), potassium carbonate (0.522g,3.78mmol) and copper (I) iodide (0.036g,0.19 mmol). The flask was vented with argon and a solution of cyclohexane-1, 2-diamine (0.022g,0.19mmol) in 10mL dioxane was added. The reaction was stirred at reflux for 14 h. After cooling to 45 ℃ byThe reaction mixture was filtered through the pad, the pad was washed with warm dichloromethane, and the solution was concentrated under reduced pressure. The product was purified by FPLC using a chloroform-methanol gradient (0 → 10%).

Yield: 0.362g (67.7%); MS M/z 284.1(M + H)⁺;HPLC(λ=214nm),[B]:rt9.53min(99.7%).

The product obtained from the copper (I) -catalyzed coupling was dissolved in 9.5mL of 5N aqueous HCl and 0.954mL of formic acid was added. The reaction was stirred at reflux for 1 hour. After cooling to 0 ℃. The final product was purified by FPLC using a chloroform-methanol gradient (0 → 10%).

Yield: 0.288g (78.7%);

the total yield is as follows:20.9%;MS m/z 294.2(M+H)⁺;¹H-NMR(400MHz,DMSO-d6):δ1.47(d,3H,J=5.8Hz);4.39-4.45(m,H);5.28(d,H,J=7.1Hz);7.14-7.23(m,2H);7.26-7.30(m,2H);7.37-7.46(m,3H);7.52(s,H);8.11(s,H);12.35(bs,H);HPLC(λ=214nm),[B]:rt 9.86min(100%).

example 72: (S) -3- (1H-benzo [ d ] imidazol-6-yl) -5, 5-dimethyl-4-phenyloxazolidin-2-one

This compound was synthesized as described in method 5, step D, starting from (S) -5, 5-dimethyl-4-phenyloxazolidin-2-one (0.25g,1.31mmol), 4-bromobenzene-1, 2-diamine (0.245g,1.31mmol), copper (I) iodide (0.025g,0.13mmol), potassium carbonate (0.362g,2.62mmol), cyclohexane-1, 2-diamine (0.015mL,0.13mmol), 5N HCl (6.5mL), formic acid (0.648 mL).

Yield: 0.155g (38.2%); MS M/z 308.2(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ0.90(s,3H);1.64(s,3H);5.46(s,H);7.25-7.34(m,5H);7.41(s,H);7.49-7.52(m,H);7.64-7.66(m,H);8.14(s,H);12.36(bs,H),HPLC(λ=214nm),[B]:rt 9.65min(99.6%).

Example 73: (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4- (4-propoxyphenyl) oxazolidin-2-one

Step A:

this compound was synthesized as described in method 5 starting from a 1M solution of 4-propoxybenzaldehyde (7.32g,44.6mmol), methyltriphenylphosphonium bromide (21.34g,59.75mmol), potassium tert-butoxide (potassium tert-butoxide) in THF (59.8mL,59.75 mmol).

Yield: 6.13g (84.7%)

And B:

the product obtained from step A (3g,18.48mmol), ethyl carbamate (4.94g,27.72mmol), 5-dimethylimidazolidine-2, 4-dione (5.46g,27.72mmol), (DHQ)₂PHAL(0.72g,0.92mmol)、K₂OsO₄x2H₂O (0.274g,0.74mmol), 0.5M aqueous NaOH (112.8mL,56.4mmol)

Yield: 3g (61%)

And C:

the product obtained from step B (3g,10.16mmol), 0.2M aqueous NaOH (300mL)

Yield: 1.21g (46%)

Step D:

the product obtained from step C (1.16g,5.25mmol), 4-bromobenzene-1, 2-diamine (0.982g,5.25mmol), copper (I) iodide (0.1g,0.525mmol), potassium carbonate (1.451g,10.5mmol), cyclohexane-1, 2-diamine (0.064mL,0.525mmol), 5N HCl (162mL), formic acid (3.02mL)

Yield: 0.650g (47.5%);

the total yield is as follows: 9.2% MS M/z 338.2(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ0.97(t,3H,J=7.5Hz);1.69-1.78(m,2H);3.81-3.84(m,2H);4.22-4.26(m,H);4.75-4.80(m,H);5.32-5.36(m,H);6.79-6.81(m,2H);7.16-7.21(m,3H);7.46(d,H,J=7.5Hz);7.60(d,H,J=2.1Hz);7.90(s,H),HPLC(λ=214nm),[B]:rt10.67min(98%).

Example 74: (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-7-yl) oxazolidin-2-one

This compound was synthesized according to method 5.

Step A

1.7M n-butyllithium (21.4mL,36.5mmol), triphenylphosphonium bromide (9.8g,27.43mmol), 2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-carbaldehyde (3.0g,18.29mmol), yield: 1.6g (54.05%)

Step B

Benzyl carbamate (4.3g,28.7mmol), 0.5M aqueous sodium hydroxide (1.1g in 55 mL), (DHQ)₂PHAL (360mg,0.46mmol), potassium osmate dihydrate (130mg,0.37mmol), the product from step A (1.5g,9.2 mmol)5mmol), yield 900mg (33%)

Step C

Thionyl chloride (1.6mL,21.88mmol), product from step B (900mg,2.73mmol), yield: 500mg (83.33%)

Step D

Product from step C (500mg,2.26mmol), 1, 2-diamino-4-iodobenzene (530mg,2.26mmol), cesium fluoride (515mg,3.39mmol), cuprous iodide (42mg,0.22mmol), 1, 2-diaminocyclohexane (27mg,0.22mmol), yield: 180mg (24.65%). The product was then isolated (100mg), formic acid (3mL), yield 75mg (75%)

Conversion to the HCl salt: free base in acetone (75mg,0.22mmol) and 1M HCl in ether (0.22mL), yield: 45mg (54.21%), MS M/z 338.2(M + H)⁺;¹H-NMR(400MHz,DMSO-d6):δ9.42(s,H);7.91(s,H);7.78-7.76(m,H);7.60-7.58(m,H);6.92(s,H);6.87-6.79(br m,2H);5.75-5.72(m,H);4.84-4.80(m,H);4.15-4.13(m,5H),HPLC(λ=214nm,[A]:rt 9.01min(99.49%).

Example 75: (S) -4- (benzo [ d ] [1,3] dioxol-6-yl) -3- (1H-benzo [ d ] imidazol-6-yl) oxazolidin-2-one

This compound was synthesized according to method 5.

Step A

1.5M n-butyllithium (28.95mL,66.60mmol), methyltriphenylphosphonium bromide (23.79g,66.60mmol), piperonal (5.0g,33.30mmol), yield: 3.6g (73%)

Step B

Benzyl carbamate (6.0g,40.5mmol), 0.5M aqueous sodium hydroxide solution (30mL), (DHQ)₂PHAL (530mg,0.5mmoL), potassium osmate dihydrate (200mg,0.4mmoL), the product from step A (2.0g,13.5mmoL), yield: 980mg (23%)

Step C

Thionyl chloride (1.66mL,22.85mmol), product from step B (0.9g,2.85mmol), yield: 450mg (76.2%)

Step D

Product from step C (450mg,2.17mmol), 1, 2-diamino-4-bromobenzene (406mg,2.17mmol), cesium fluoride (659mg,4.34mmol), cuprous iodide (62mg,0.32mmol), 1, 2-diaminocyclohexane (50mg,0.43mmol), yield: 250mg (36.7%). The product was then (230mg), formic acid (5mL), yield: (100mg,40%)

Conversion to the HCl salt: free base in acetone (100mg,0.31mmoL) and 1M HCl in ether (0.4mL,0.37mmoL), yield: 35mg, MS M/z 324.2(M + H) ⁺;¹H-NMR(400MHz,DMSO-d6):δ9.41(s,H);7.90(s,H);7.77-7.75(m,H);7.59-7.56(m,H);7.04(s,H);6.91-6.84(br m,2H);5-97-5.96(m,2H);5.78-5.74(m,H);4.85-4.81(m,H);4.19-4.15(m,H),HPLC(λ=214nm,[A]:rt 8.99min(98.77%).

Examples 76, 77: 3- (1H-benzo [ d ] imidazol-6-yl) -4, 5-bis (4-propoxyphenyl) oxazolidin-2-one, diastereomers 1 and 2

Step A

Thionyl chloride (5.75mL,77.30mmol) was added to a stirred solution of 2- (4-propoxyphenyl) acetic acid (3g,15.5mmol) in chloroform (30mL) at 0 ℃ and stirred overnight. The reaction mixture was concentrated under reduced pressure to obtain an acidic chloride as an oil. A stirred solution of aluminum trichloride (2.22g,16.7mmol) and propoxybenzene (1.75g,12.86mmol) in dichloromethane (30mL) was added dropwise to a solution of acid chloride (3g,14.15mmol) in dichloromethane at 0 ℃ and stirred at room temperature for 4 h. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The combined organic layers were washed successively with saturated sodium bicarbonate solution, water, brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude compound. It was purified by column chromatography on silica gel (60-120 mesh) using 10% ethyl acetate in petroleum ether as eluent to afford 2.5g (51.86%) of the product as a solid.

Step B

Tert-butyl nitrite (0.93mL,7.76mmol) was added dropwise to a stirred solution of the product of step A (2g,6.41mmol) in tetrahydrofuran (40mL) at 0 ℃ and stirred for 10 min. 5M HCl in iso-1-propanol (10mL) was added dropwise to the reaction mixture at 0 ℃ and stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The separated organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude compound. It was purified by column chromatography on silica gel (60-120 mesh) using 20% ethyl acetate in petroleum ether as eluent to afford 1.5g (68.80%) of the product as a solid.

Step C

10% PdC (800mg) was added to a stirred solution of the product of step B (1.5g,4.40mmol), chloroform (6.6mL,88.25mol) in ethanol (20mL) and hydrogenated in a par apparatus at 75psi overnight. The reaction mixture was filtered through a celite pad, washed with ethanol and the filtrate was concentrated under reduced pressure to obtain a solid compound. It was stirred in pentane for 15min, and the precipitated solid was filtered and dried in vacuo to afford 1.4g (97.22%) of the product as a solid.

Step D

Triphosgene (800mg,2.70mmol) was added to a stirred solution of the product of step C (1.75g,5.40mmol) in dichloromethane (20mL) at 10 ℃. Triethylamine (1.2mL,8.12mmol) was added to the reaction mixture at 0 ℃ and stirred at room temperature for 1 h. The reaction mixture was poured into ice water and extracted with dichloromethane. The combined organic layers were washed successively with saturated sodium bicarbonate solution, water and brine. Dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1.2g (63.82%) of the product as a white solid.

Step E

A mixture of the product of step D (750mg,2.11mmol), 1, 2-diamino 4-bromobenzene (400mg,2.11mmol), cesium fluoride (650mg,4.3mmol) and cuprous iodide (60mg,.32mmol) in 1, 4-dioxane (20mL) was sparged with argon for 15 min. 1, 2-diaminocyclohexane (40mg,.35mmol) was added to the reaction mixture, and the aeration was continued for 5min and stirred overnight at 110 ℃ and 115 ℃ in a sealed tube. The reaction mixture was filtered through a celite pad, washed with chloroform and concentrated under reduced pressure to obtain a crude compound. It was purified by column chromatography on silica gel (60-120 mesh) using 4% methanol in chloroform as eluent to afford 650mg (66.80%) of the product as a solid.

Step F

A mixture of the product of step E (650mg) and formic acid (10mL) was stirred at 70-80 ℃ for 1h, and the reaction mixture was concentrated under reduced pressure. The residue was partitioned between saturated sodium bicarbonate and chloroform. The separated organic layer was washed successively with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. It was purified by preparative HPLC. Yield: 170mg

Step G

140mg of the product of step F was purified by chiral HPLC.

Column: CHIRALPAK IA (250x4.6mm);5 μ

Mobile phase: hexane: ethanol (75:25)

Flow rate: 18mL/min

The obtained prep mL was concentrated under reduced pressure, and the residue was dissolved in chloroform and washed with water, brine. Dried over anhydrous sodium sulfate and concentrated under reduced pressure. Yield: 60mg (9%) of diastereomer 1, 60mg (9%) of diastereomer 2.

Diastereomer 1-HCl

A stirred solution of the free base from step G (60mg,0.13mmol) in acetone (3mL) was added 1M HCl in ether (.16mL) at 5 ℃ and stirred at room temperature for 30 min. The reaction mixture was concentrated in vacuo and co-distilled with water. Yield: 50mg (73.52%). MS M/z 472.4(M + H)⁺;¹H-NMR(400MHz,DMSO-d6):δ14.50(bs,1H);9.41(s,1H);8.06(d,1H);7.77(d,1H);7.66(d,1H);6.98(d,2H);6.87(d,2H);6.73(d,2H);6.64(d,2H);6.15-6.07(m,2H);3.82(t,2H);3.73(t,2H);1.66-1.58(m,4H);0.94-0.85(m,6H),HPLC(λ=214nm,[A]:rt 16.99min(100%).

Diastereomer 2-HCl

A stirred solution of the free base from step G (60mg,0.13mmol) in acetone (3mL) was added 1M HCl in ether (.16mL) at 5 ℃ and stirred at room temperature for 30 min. The reaction mixture was concentrated in vacuo and co-distilled with water. Yield 50mg (73.52%), MS M/z 472.4(M + H) ⁺,¹H-NMR(400MHz,DMSO-d6):δ14.50(bs,1H);9.34(s,1H);8.06(d,1H);7.76(d,1H);7.66(d,1H);6.98(d,2H);6.87(d,2H);6.73(d,2H);6.64(d,2H);6.15-6.07(m,2H);3.82(t,2H);3.73(t,2H);1.66-1.58(m,4H);0.94-0.85(m,6H),;HPLC(λ=214nm,[A]:rt 16.96min(100%)

Examples 78, 79: 3- (1H-benzo [ d ] imidazol-6-yl) -5-phenyl-4- (4-propoxyphenyl) oxazolidin-2-one

Step A

A mixture of 4-propoxylacetophenone (20g,0.12mol), sulphur (17.5g,0.27mol), morpholine (75mL,0.9mol) and p-toluenesulphonic acid (2g) was stirred at 130 ℃ for 5 h. The reaction mixture was poured into 500mL of ice water and stirred overnight. The precipitated solid was filtered and dried in vacuo to obtain crude compound. The crude compound in ethanol (400mL) and 10% potassium hydroxide were refluxed overnight. The ethanol was removed in vacuo. The residue was dissolved in water and acidified with 4N HCl (pH 2). The precipitated solid was filtered, washed with water and dried in vacuo to obtain crude compound. It was purified by column chromatography on silica gel (60-120 mesh) using 20% ethyl acetate in petroleum ether. Yield: 9g (40.90%)

Step B

Thionyl chloride (9.6mL,129mmol) was added to a stirred solution of the product of step A (5g,25.8mmol) in chloroform (60mL) at 0 ℃ and stirred overnight. The reaction mixture was concentrated under reduced pressure to obtain an acidic chloride as an oil. A stirred solution of aluminum trichloride (4g,30.66mmol) in benzene (30mL) was added dropwise to a solution of acid chloride (5g,23.6mmol) in benzene (20mL) at 0 ℃ and stirred at room temperature overnight. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The combined organic layers were washed successively with saturated sodium bicarbonate solution, water, brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude compound. It was purified by column chromatography on silica gel (60-120 mesh) using 10% ethyl acetate in petroleum ether as eluent to afford 2g of the product as a solid (30.75%).

Step C

Tert-butyl nitrite (1mL,8.5mmol) was added dropwise to a stirred solution of the product of step B (1.8g,7.08mmol) in tetrahydrofuran (40mL) at 0 ℃ and stirred for 10 min. 5M HCl in isopropanol (10mL) was added dropwise to the reaction mixture at 0 ℃ and stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The separated organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude compound. It was purified by column chromatography on silica gel (60-120 mesh) using 20% ethyl acetate in petroleum ether as eluent to afford 1.4g (70%) of the product as a solid.

Step D

10% PdC (700mg) was added to a stirred solution of the product of step C (1.4g,4.50mmol), chloroform (7.5mL,90mmol) in ethanol (20mL) and hydrogenated in a Parr apparatus at 75psi overnight. The reaction mixture was filtered through a celite pad, washed with ethanol and the filtrate was concentrated under reduced pressure to obtain a solid compound. It was stirred in pentane for 15min, and the precipitated solid was filtered and dried in vacuo to afford 1.3g (97.74%) of the product as a solid.

Step E

Triphosgene (720mg,2.34mmol) was added to a stirred solution of the product of step D (1.3g,4.8mmol) in dichloromethane (20 mL). Triethylamine (1mL,7.22mmol) was added to the reaction mixture at 0 ℃ and stirred at room temperature for 1 h. The reaction mixture was poured into ice water and extracted with dichloromethane. The combined organic layers were washed successively with saturated sodium bicarbonate solution, water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1g (70.42%) of the product as a white solid.

Step F

A mixture of the product of step F (750mg,2.53mmol), 1, 2-diamino 4-bromobenzene (480mg,2.53mmol), cesium fluoride (760mg,5mmol) and copper iodide (80mg,.42mmol) in 1, 4-dioxane (20mL) was purged with argon for 15 min. 1, 2-diaminocyclohexane (50mg,.43mmol) was added to the reaction mixture, and the aeration was continued for 5min and stirred overnight at 110 ℃ and 115 ℃ in a sealed tube. The reaction mixture was filtered through a celite pad, washed with chloroform and concentrated under reduced pressure to obtain a crude compound. It was purified by column chromatography on silica gel (60-120 mesh) using 4% methanol in chloroform as eluent to afford 700mg (70%) of the product as a solid.

Step G

A mixture of the product of step F (700mg) and formic acid (10mL) was stirred at 70-80 ℃ for 1h, and the reaction mixture was concentrated under reduced pressure. The residue was partitioned between saturated sodium bicarbonate and chloroform. The separated organic layer was washed successively with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. It was purified by preparative HPLC using the following conditions to obtain mixed diastereomers.

Column: gemini C18(50X30mm)10 mu

Mobile phase: 10M ammonium acetate (Aq)

Methanol

T%B：0/50,3/50,12/80,18/80,18.1/50

Flow rate: 35mL/Min.

The obtained prep mL was concentrated under reduced pressure, and the residue was dissolved in chloroform and washed with water, brine. Dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 200mg of the product as a solid. Separation of diastereomers

150mg of diastereomeric mixture was purified by chiral HPLC using the following conditions.

Column: CHIRALPAK IA (250x4.6mm);5 μ

Mobile phase: hexane ethanol (70:30)

Flow rate: 128mL/min

The obtained prep mL was concentrated under reduced pressure, and the residue was dissolved in chloroform and washed with water, brine. Dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 70mg (9.85%) of diastereomer 1 and diastereomer 2 as solids.

Conversion to the HCl salt

A stirred solution of diastereomer 1(70mg,0.17mmol) in acetone (3mL) was added 1M HCl (.2mL) in ether at 5 ℃ and stirred at room temperature for 30 min. The reaction mixture was concentrated in vacuo and co-distilled with water to afford 50mg (65.87%) of diastereomeric 1HCl as a solid.

¹H-NMR(400MHz,DMSO-d6):δ14.50(bs,1H);9.38(s,1H);8.06(s,1H);7.76(d,1H);7.67(d,1H);7.21-7.09(m,4H);6.88(d,2H);6.60(d,2H);6.22-6.14(q,2H);3.70(t,2H);1.60-1.55(m,2H);0.86(t,3H);MS=414(M+1)

A stirred solution of diastereomer 2(70mg,0.17mmol) in acetone (3mL) was added 1M HCl (.2mL) in ether at 5 ℃ and stirred at room temperature for 30 min. The reaction mixture was concentrated in vacuo and co-distilled with water to afford 50mg (65.87%) of diastereomer 2.HCl as a solid.

1H-NMR(400MHz,DMSO-d6):δ14.50(bs,1H);9.44(s,1H);8.07(s,1H);7.77(d,1H);7.67(d,1H);7.20-7.09(m,5H);6.88(d,2H);6.60(d,2H);6.22-6.14(q,2H);3.70(t,2H);1.62-1.53(m,2H);0.86(t,3H);MS=414(M+1);HPLC~98.88%.

Example 80: (S) -4- (4- (2- (piperazin-1-yl) ethoxy) phenyl) -3- (1H-benzo [ d ] imidazol-6-yl) oxazolidin-2-one

This compound was synthesized according to method 5.

Step A

1.5M n-butyllithium (5.7mL,11.97mmol), methyltriphenylphosphonium bromide (3.4g,9.58mmol), 4- (2- (4-tert-butoxycarbonyl-piperazin-1-yl) ethoxy) benzaldehyde (31.6g,4.79mmol), yield: 1.5g (94.32%)

Step B

Tert-butyl hypochlorite (1.6mL,20.93mmol), benzyl carbamate (2.1g,20.45mmol), 0.4M aqueous sodium hydroxide (0.55g in 34 mL), (DHQ)2PHAL (170mg,0.22mmol), potassium osmate dihydrate (66mg,0.28mmol), the product from step A (1.50g,4.518mmol), purified by preparative HPLC: column: chiral pak ADH (19 × 250mm)10 μ, mobile phase: hexane: isopropanol (80:20), flow rate: 15mL/min, yield: 1.0g of 76d (44.3%)

Step C

10% PdC (100mg), product of step B (600mg,1.2024mmol), hydrogen balloon 2 h.: 1, 1-carbonyldiimidazole (279mg,2.3012mmoL), yield: 420mg (92.4%)

Step D

Product from step C (420mg,1.0632mmoL), 1, 2-diamino-4-bromobenzene (200mg,1.06mmoL), cesium fluoride (240mg,1.59mmoL), 1, 2-diaminocyclohexane (20mg), cuprous iodide (20mg), yield: 110mg (22%)

The product (200mg,0.40mmol) was then dissolved in formic acid, yield: 150mg (73.9%)

Conversion to the HCl salt: free base in acetone (60mg,0.14mmol) and 1M HCl in ether (0.3mL,0.3242mmol), yield: 40mg, MS M/z 407.1(M-H)⁺1H-NMR 400MHz, CD3OD) < delta > 9.33(s,1H) < delta >, 7.99(s,1H) < delta >, 7.70(dd,2H) < delta >, 7.39(d,2H) < delta >, 7.02(d,2H) < delta >, 5.80(t,1H) < delta >, 4.88(2H, mixed with solvent) < delta >, 4.39(s,2H) < delta >, 4.26(t,1H) < delta >, 3.68-3.60(m,8H) < delta >, HPLC (. lambda. =214nm, [ A ] A]:rt 14.51min(100%).

Example 81: (S) -4- (4- (2-morpholinoethoxy) phenyl) -3- (1H-benzo [ d ] imidazol-6-yl) oxazolidin-2-one

The compound was synthesized according to method 5

Step A

1.5M n-butyllithium (11.4mL,17mmol), methyltriphenylphosphonium bromide (6.0g,17mmol), 4- (2-morpholinoethoxybenzaldehyde (2g,8.51mmol), yield 1.6g (80.8%)

Step B

Tert-butyl hypochlorite (2.3mL,20.93mmol), benzyl carbamate (3.20g,20.45mmol), 0.4M aqueous sodium hydroxide (0.1g in 6.4 mL), (DHQ)₂PHAL (270mg,0.34mmol), potassium osmate dihydrate (100mg,0.28mmol), the product from step A (1.60g,6.87mmol), yield: 1.0g (36.23%)

Step C

Thionyl chloride (1.5mL,20mmol), product from step B (1.0g,2.5mmol), yield: 400mg (54.79%)

Step D

Product from step C (400mg,0.73mmol), 4-bromo 1, 2-diaminobenzene (140mg,0.74mmol), cesium fluoride (166mg,1.09mmol), 1, 2-diaminocyclohexane (0.3mL), cuprous iodide (10mg), yield: 200mg (37.02%)

The product (150mg,0.376mmol) was then dissolved in formic acid, yield: 80mg (52.28%)

Conversion to the HCl salt: free base in acetone (80mg,0.2mmol) and 1M HCl in ether (0.43mL,0.43mmol), yield: 50mg (53.76%), MS M/z 409.3(M + H)⁺;(400MHz,DMSO-d6):δ9.39(s,1H);7.90(s,1H);7.74(d,1H);7.57(d,1H);7.38(d,2H);6.95(d,2H);5.80(t,1H);4.85(t,1H);4.37(s,2H);4.16(t,1H);3.84-3.89(bs,5H);3.48(t,3H);3.16(bs,2H),HPLC(λ=214nm,[A]:rt 4.64min(94.3%).

Example 82: (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4- (2, 3-difluorophenyl) oxazolidin-2-one

Synthesis of the Compound according to method 6

Step A

Potassium cyanide (5.7g,87.96mmoL), 2, 3-difluorobenzaldehyde (10.0g,70.368mmoL), ammonium carbonate (33.14g,211.10mmoL), water (125mL:75 mL). Yield: 10.0g (67.0%).

Step B

Product of step A (10g,25.64mmoL), 10% NaOH (100mL), yield 22.0g

Step C

Thionyl chloride (8mL), the product of step B (22.0g crude), methanol (100mL), yield: 5.0g (35.15%).

Step D

Product of step C (5g,24.87mmoL), sodium borohydride (2.8g,74.62mmoL), ethanol (100mL), yield: 4.0g (92.96%).

Step E

Triethylamine (6.4mL,46.24mmol), Boc anhydride (6.8mL,30mmol), the product of step D (4.0g,23.12mmol), dichloromethane (100 mL). Yield 4.5g of crude product.

Step F

Thionyl chloride (3.9mL,52.744mmol), the product of step E (1.8g,6.593mmol), tetrahydrofuran (75 mL). Yield: 1.2g (87.0%)

Step G

Step F product (500mg,2.51mmol), 1, 2-diamino 4-iodobenzene (460mg,2.51mmol), cesium fluoride (570mg,3.76mmol), 1, 4-dioxane (15mL), 1, 2-diaminocyclohexane (28mg,0.25mmol), cuprous iodide (45mg,0.25mmol), yield: 350mg (45.6%).

Product of step G (300mg,0.1mmol), formic acid (5 mL). Yield: 150mg (47.6%)

Conversion to the hydrochloride salt:

free base in 1M ether-HCl (0.57mL,0.57mmol), dichloromethane (10mL) (150mg,0.47mmol), yield: 140mg (84.9%), MS M/z 314[ M-1 ]];¹H-NMR(400MHz,DMSO-d6):δ9.35(s,1H);7.94(s,1H);7.77(d,1H);7.57(d,1H);7.41-7.14(m,3H);6.12(t,1H);4.92(t,1H);4.37(m,1H);HPLC([A]):rt 9.76min(100%)

Example 83: (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4- (3-fluorophenyl) oxazolidin-2-one

This compound was synthesized according to method 5.

Step B

Tert-butyl hypochlorite (5.6mL,49.25mmol), benzyl carbamate (7.42g,49.12mmol), 0.4M aqueous sodium hydroxide (2.0g in 125 mL), (DHQ)₂PHAL (637mg,0.82mmoL), 3-fluorostyrene (2.0g,16.37mmoL), potassium osmate dihydrate (240mg,0.65mmoL), yield 1.01g (21.13%)

Step C

Thionyl chloride (2.3mL,31.50mmol), product from step B (1.0g,3.46mmol), yield: 510mg (81.47%)

Step D

Product from step C (500mg,2.76mmol), 4-bromo 1, 2-diaminobenzene (516mg,2.76mmol), cesium fluoride (630mg,4.14mmol), 1, 2-diaminocyclohexane (47mg,0.41mmol), cuprous iodide (80mg,0.41mmol), yield: 130mg (39.39%). The product (450mg,1.56mmol) was then dissolved in formic acid, yield: 450mg (96.77%)

Conversion to the HCl salt: free base in acetone (440mg,1.48mmol) and 1M HCl in ether (1.8mL,1.8mmol), yield: 60mg (74%), MS M/z 298.2(M + H)⁺;¹H-NMR(400MHz,DMSO-d6):δ9.35(bs,1H);7.91(s,1H);7.75(d,1H);7.56(d,1H);7.25-7.41(m,3H);7.13-7.09(m,1H);5.88(t,1H);4.88(t,1H);4.21(q,1H);HPLC(λ=214nm,[A]:rt 8.93min(100%).

Example 84: (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4- (3-fluoro-5- (trifluoromethyl) phenyl) oxazolidin-2-one

This compound was synthesized according to method 6.

Step A

3-fluoro-5-trifluoromethylbenzaldehyde (200mg,1.041mmol), potassium cyanide (85mg,1.301mmol), ammonium carbonate (490mg,3.123mmol), ethanol (5mL), water (2 mL). Yield: 250mg (91.58%)

Step B

Compound from step a (250mg,0.954mmol) in 10% aqueous sodium hydroxide (5mL), yield: 900mg

Step C

Thionyl chloride (0.2mL,2.8489mmol), the product from step B (225mg,0.949mmol), methanol (5mL), yield 150mg (63.03%)

Step D

Sodium borohydride (45mg,1.195mmol), product from step C (100mg,0.398mmol), methanol (5mL), yield: 75mg (85.23%)

Step E

Triethylamine (3.1mL,22.422mmol), di-tert-butyl dicarbonate (2.8mL,12.332mmol), the product from step D (2.5g,11.211mmol), dichloromethane (50mL), chiral preparative HPLC: column: ChiralPakAD-H (250x4.6mm)5u, mobile phase: hexane IPA DEA (95:05:0.1), flow rate: 1.0mL/min. UV 265nm, temperature 25 ℃ yield 310mg (8.61%)

Step F

Thionyl chloride (0.55mL,7.678mmol), the product from step D (310mg,0.9598mmol), tetrahydrofuran (10mL), yield: 200mg (83.68%)

Step G

Product from step F (300mg,1.205mmol), 4-bromo-1, 2, diaminobenzene (225mg,1.205mmol), cesium fluoride (275mg,1.807mmol), cuprous iodide (23mg,0.121mmol), 1, 4-dioxane (10mL), 1, 2-diaminocyclohexane (14mg,0.121mmol), yield: 210mg (49.07%).

Product from step G (210mg,0.592mmol), formic acid (5mL), yield: 175mg (81.40%)

Conversion to the hydrochloride salt:

1M HCl in ether (0.20mL,0.247mmol), free base (75mg,0.206mmol), acetone (3mL), yield: 75mg (90.36%). MS M/z 366[ M + H]⁺;¹H-NMR(DMSO d₆,500MHz):δ9.36(bs,1H);7.93(s,1H);7.80-7.75(m,3H);7.74(d,1H);7.58(d,1H);6.07(t,1H);4.91(t,1H);4.25(t,1H);HPLC([A]):rt 8.72min(96.47%)

Example 85: (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4- (3-chlorophenyl) oxazolidin-2-one

This compound was synthesized according to method 5.

Step A

1.5M n-butyllithium (28.5mL,42.7mmol), methyltriphenylphosphonium bromide (11.44g,32.02mmol), 3-chlorobenzaldehyde (3g,21.35mmol), yield: 1.6g (54.20%)

Step B

Benzyl carbamate (5g,33.69mmol), 0.4M aqueous sodium hydroxide (1.3g in 79 mL), (DHQ)₂PHAL (420mg,0.54mmol), potassium osmate dihydrate (160mg,0.43mmol), the product from step A (1.5g,10.86mmol), yield: 850mg (25.75%)

Step C

Thionyl chloride (1.74mL,23.6mmol), product from step B (900mg,2.95mmol), yield: 450mg (77.58%)

Step D

Product from step C (330mg,1.67mmol), 1, 2-diamino 4-iodobenzene (390mg,1.67mmol), cesium fluoride (380mg,2.51mmol), 1, 2-diaminocyclohexane (21mg,15mmol), cuprous iodide (35mg,15mmol), yield: 110mg (22%). The product (70mg,0.23mmol) was then dissolved in formic acid, yield: 55mg (76.38%)

Conversion to the HCl salt: free base in acetone (55mg,0.17mmol) and 1M HCl in ether (0.17mL), yield: 35mg (57.37%), MS M/z 314.1(M + H)⁺;¹H-NMR(400MHz,DMSO-d6):δ9.42(br s,H);7.94(s,H);7.78-7.76(m,H);7.60-7.55(m 2H);7.39-7.36(br m,3H);5.91-5.87(m,H);4.91-4.86(m,H);4.24-4.20(m,H),,HPLC(λ=214nm,[A]:rt 10.51min(97.16%).

Example 86: (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4- (4-chlorophenyl) oxazolidin-2-one

This compound was synthesized according to method 5.

Step A

1.5M n-butyllithium (21mL,21.135mmol), methyltriphenylphosphonium bromide (19.06g,53.35mmol), 4-chlorobenzaldehyde (5g,35.56mmol), yield: 2.5g (50.9%)

Step B

Benzyl carbamate (1.5g,10.869mmol), 0.4M aqueous sodium hydroxide (1.3g in 81 mL), (DHQ) ₂PHAL (420mg,0.54mmoL), potassium osmate dihydrate (160mg,0.43mmoL), the product from step A (1.5g,10.869mmoL), yield: 1.2g (36.19%)

Step C

Thionyl chloride (2.3mL,31.47mmol), product from step B (1.2g,3.934mmol), yield: 0.6g (50.1%)

Step D

Product from step C (400mg,2.03mmol), 1, 2-diamino 4-iodobenzene (390mg,2.03mmol), cesium fluoride (460mg,3.04mmol), 1, 2-diaminocyclohexane (23mg,0.2mmol), cuprous iodide (38mg,0.203mmol), yield: 340mg (55.2%). The product (300mg,0.99mmol) was then dissolved in 5mL of formic acid, yield: 170mg (54.86%)

Conversion to the HCl salt: free base in acetone (170mg,0.54mmol) and 1M HCl in ether (0.65mL), yield: 120mg (63.5%%), MS M/z 314.1(M + H)⁺;¹H-NMR(400MHz,DMSO-d6):δ9.34(s,H);7.90(s,H);7.75-7.73(m,H);7.56-7.54(m,H);7.47-7.40(br m,4H);5.89-5.86(m,H);4.90-4.86(m,H);4.21-4.18(m,H),HPLC(λ=214nm,[A]:rt 10.56min(94.89%).

Example 87: (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4- [4- (3-chlorophenyl) phenyl ] oxazolidin-2-one

This compound was synthesized according to method 5.

Step A

1.5M n-butyllithium (31.2mL,46mmol), phenylmagnesiumbromide (16.50g,46mmol), 4- (3-chlorophenyl) benzaldehyde (5g,23mmol), yield: 3.5g (70.99%)

Step B

1, 3-dichloro-5, 5-dimethylimidazolidine-2-dione (2.8g,14.20mmol), tert-butyl carbamate (3.3g,28.30mmol), 0.5M aqueous sodium hydroxide solution (58mL), (DHQ) ₂PHAL (182mg,.25mmol), potassium osmate dihydrate (140mg,0.38mmol), the product from step A (2g,9.35mmol), yield: 600mg (18.51%)

Step C

Thionyl chloride (0.55mL,4.67mmol), product from step B (300mg,0.57mmol), yield: 150mg (65.21%)

Step D

The product from step C (260mg,0.73mmol), 1, 2-diamino 4-bromobenzene (140mg,.74mmol), potassium carbonate (250mg,1.85mmol), cuprous iodide (14mg)1,155mg (42.34%)

The product was then purified by chiral preparative HPLC (150mg), triethyl orthoformate (1mL), column: CHIRALPAK 1A (250X4.6mm), 5. mu. and mobile phase: hexane: EtOH: DEA (70:30:0.1), flow rate: 18mL/min, U.V. 254nm, yield: 55mg (36.66%), MS M/z390.2(M + H)⁺;¹H-NMR(400MHz,DMSO-d6):δ8.18(s,H);1.68-1.66(m,4H);7.59-7.57(m,H);7.51-7.49(m,3H);7.47-7.38(br m,2H);7.32-7.30(m,H);5.85--5.81(m,H);4.89-4.85(m,H);4.21-4.17(m,H),HPLC(λ=214nm,[A]:rt 14.40min(100%)

Example 88: (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4- [3- (3-chlorophenyl) phenyl ] oxazolidin-2-one

This compound was synthesized according to method 5.

Step A

1.5M n-butyllithium (31mL,46mmol), methylphenylmagnesium bromide (16.5mmol,46mmol), 3- (3-chlorophenyl) -benzaldehyde (5g,23mmol), yield: 3.6g (72.72%)

Step B

1, 3-dichloro-5, 5-dimethylimidazolidine-2-dione (1.4g,7.10mmol), tert-butyl carbamate (1.7g,14.50mmol), 0.5M aqueous sodium hydroxide solution (29mL), (DHQ)₂PHAL (95mg,.12mmol), potassium osmate dihydrate (70mg), product from step A (1g,4.6mmol), yield: 610mg (37.62%)

Step C

Thionyl chloride (1mL,13.78mmol), product from step B (600mg,1.73mmol), yield: 420mg (88.98%)

Step D

Product from step C (300mg,1.10mmol), 1, 2-diamino 4-iodobenzene (210mg,1.12mmol), cesium fluoride (340mg,2.20mmol), cuprous iodide (35mg,.15mmol), 1, 2-diaminocyclohexane (21mg,.15mmol), yield: 250mg (60%). Then the product above (230mg), triethyl orthoformate (.5mL), yield: 100mg (41.66%)

Conversion to the HCl salt: free base in acetone (80mg,.2mmol) and 1M HCl in ether (0.2mL), yield: 50mg (57.47%), MS M/z 390.2(M + H)⁺;¹H-NMR(400MHz,DMSO-d6):δ9.34(br s,H);7.94(s,H);7.84(s,H);7.75-7.73(m 2H);7.63-7.61(m,3H);7.51-7.42(br m,4H);5.95-5.91m,H);4.94-4.90(m,H);4.32-4.28(m,H),HPLC(λ=214nm,[A]:rt 14.32min(100%).

Example 89: (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4- (4- (4-phenylpiperazin-1-yl) phenyl) oxazolidin-2-one

This compound was synthesized according to method 5.

Step A

1.5M n-butyllithium (3.2M;12.9mL,41.35mmol), methyltriphenylphosphonium bromide (11.0g,31.01mmol), 4- (4-phenylpiperazin-1-yl) benzaldehyde (5.5g,20.67mmol), yield: 2.6g (47.7%)

Step B

Tert-butyl hypochlorite (2.9mL,25.41mmol), benzyl carbamate (3.9g,25.83mmol), 0.4M aqueous sodium hydroxide (1.0g in 58 mL), (DHQ)₂PHAL (320mg,0.41mmol), the product from step A (2.2g,8.33mmol), potassium osmate dihydrate (100mg,0.28 mmol). Further purification by preparative HPLC gave a yield of 550mg (15.32%)

Step C

Thionyl chloride (0.75mL,10.20mmol), product from step B (550mg,1.27mmol), yield: 280mg (68.29%)

Step D

Product from step C (250mg,0.77mmol), 1, 2-diamino 4-iodobenzene (180mg,0.77mmol), cesium fluoride (170mg,1.15mmol), 1, 2-diaminocyclohexane (10mg,0.09mmol), cuprous iodide (14mg,0.07mmol), yield: 130mg (39.39%)

The product (120mg,0.28mmol) was then dissolved in formic acid, yield: 80mg (66.66%)

Conversion to the HCl salt: free base in acetone (70mg,0.16mmol) and 1M HCl in ether (0.2mL,0.20mmol), yield: 60mg (74%),1H-NMR (400MHz, DMSO-d6):9.48(s,1H), 7.92(s,1H), 7.80(d,1H), 7.62(d,1H), 7.25-7.30(M,4H), 7.02-6.97(M,5H), 5.74(t,1H), 4.84(t,1H), 4.18(t,3H), 3.29(s,7H), MS =440(M +1)

Example 90: (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4- (4- (4-methylpiperazin-1-yl) phenyl) oxazolidin-2-one

This compound was synthesized according to method 5.

Step A

1.5M n-butyllithium (20mL,29.42mmol), methyltriphenylphosphonium bromide (110.50g,29.42mmol), 4- (4-methylpiperazin-1-yl) benzaldehyde (3g,14.70mmol), yield: 2g (67.3%)

Step B

Benzyl carbamate (4.48g,29.70mmol), 0.4M aqueous sodium hydroxide (60.5mL,30.2mmol)), (DHQ) ₂PHAL (385mg,0.50mmoL), the product from step A (2g,9.90mmoL), potassium osmate dihydrate (145mg,0.40 mmoL). Further purification by preparative HPLC gave a yield of 1g (27.39%)

Step C

Thionyl chloride (0.8mL,10.84mmol), product from step B (0.5g,1.35mmol), yield: 170mg (48.57%)

Step D

Product from step C (350mg,1.34mmol), 1, 2-diamino 4-iodobenzene (250mg,1.34mmol), cesium fluoride (300mg,2.01mmol), 1, 2-diaminocyclohexane (12mg,0.34mmol), cuprous iodide (25mg,0.134mmol), yield: 130mg (26.53%).

The product (120mg,0.32mmol) was then dissolved in formic acid, yield: 70mg (58.33%)

Conversion to the HCl salt: free base in acetone (70mg,0.18mmol) and 1M HCl in ether (0.4mL,0.408mL), yield: 55mg (67.07%), MS M/z 378.4(M + H)⁺,¹H-NMR(400MHz,CDCl₃):δ2.51(s,3H);2.76(s,2H);3.05-3.07(m,2H);3.42(s,2H);3.75-3.77(m,2H);4.14-4.18(m,H);4.82-4.86(m,H);5.74-5.78(m,H);6.94-6.96(m,2H);7.29-7.31(m,2H);7.59-7.61(m,H);7.76-7.78(m,H);7.92-7.93(m,H);9.55(s,H);11.25(bs,H),HPLC(λ=214nm),[A]:rt5.23min(96.7%)

Example 91: (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4- (3- (4-phenylpiperazin-1-yl) phenyl) oxazolidin-2-one

This compound was synthesized according to method 5.

Step A

N-butyllithium (1.3M;12mL,15.13mmol), methyltriphenylphosphonium bromide (5.40g,15.13mmol), 3- (4-phenylpiperazin-1-yl) phenyl) carbaldehyde (2.0g,7.52mmol), yield: 1.8g (92.78%)

Step B

Tert-butyl hypochlorite (2.3mL,20.45mmol), benzyl carbamate (3.10g,20.45mmol), 0.4M aqueous sodium hydroxide (830mg in 54 mL), (DHQ) ₂PHAL (265mg,0.34mmol), the product from step A (1.80g,6.80mmol), potassium osmate dihydrate (100mg,0.28 mmol). Further purification by preparative HPLC, yield: 425mg (14%)

Step C

Thionyl chloride (0.81mL,10.81mmol), product from step B (400mg,1.35mmol), yield: 200mg (68.96%)

Step D

Product from step C (200mg,0.62mmol), 1, 2-diamino 4-iodobenzene (115mg,0.62mmol), cesium fluoride (190mg,1.24mmol), 1, 2-diaminocyclohexane (10mg,0.09mmol), cuprous iodide (17mg,0.09mmol), yield: 130mg (50%)

The product (120mg,0.28mmol) was then dissolved in formic acid, yield: 100mg (81.96%)

Conversion to the HCl salt: free base in acetone (100mg,0.23mmol) and 1M HCl in ether (0.5mL,0.5mmol), yield: 65mg (56.53%), MS M/z 440.4(M + H)⁺,¹H-NMR(400MHz,DMSO-d₆):δ9.52(s,1H);7.96(s,1H);7.78(d,1H);7.65(t,3H);7.77-7.20(m,5H);7.02-6.96(m,2H);6.87(d,1H);5.79(t,1H);4.86(t,1H);4.19(t,1H);3.42(bs,8H),HPLC(λ=214nm),[A]:rt 11.36min(100%)

Example 92: (S) -3- (2-methyl-1H-benzo [ d ] imidazol-6-yl) -4-phenyloxazolidin-2-one

Starting from (S) -4-phenyloxazolidin-2-one (1 eq., 0.163g,1mmol), 4-iodobenzene-1, 2-diamine (1 eq., 0.234g,1mmol), copper (I) iodide (0.1 eq., 0.019g,0.1mmol), cesium fluoride (2 eq., 0.304g,2mmol), cyclohexane-1, 2-diamine (0.1 eq., 0.012mL,0.1mmol)The compound was synthesized as the trifluoroacetate salt. The solids were added together to a reaction flask, and the flask was vented with argon. A solution of cyclohexane-1, 2-diamine in 4mL dioxane was added to the flask. The reaction was stirred at 95 ℃ for 20 hours, then cooled to 45 ℃ and filtered through a pad of celite. The pad was washed with warm dichloromethane and the solution was concentrated under reduced pressure. The intermediate was purified by FPLC using a chloroform-methanol gradient (0 → 10%, product eluted at about 5%). Yield: 0.215g (80%); MS M/z 270.3(M + H) ⁺

(S) -3- (3, 4-diaminophenyl) -4-phenyloxazolidin-2-one was dissolved in 12mL triethyl orthoacetate and the reaction was stirred at 150 ℃ for 0.5h, then the reaction was cooled. Excess triethyl orthoacetate was removed under reduced pressure. The final product was purified by preparative HPLC using a chloroform-methanol gradient (0 → 10%) FPLC followed by a water-acetonitrile gradient containing 0.04% trifluoroacetic acid.

Yield: 0.095g (23.3%); MS M/z 294.2(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ2.67(s,3H);4.16-4.20(m,H);4.85-4.89(m,H);5.79-5.83(m,H);7.24-7.40(m,5H);7.49(dd,H,³J=9.1Hz,⁴J=2.1Hz);7.63(d,H,³J=9.1Hz);7.76(d,H,⁴J=2.1Hz),HPLC(λ=214nm),[B]:rt 8.69min(100%).

Example 93: (S) -4- (1H-benzo [ d ] imidazol-6-yl) -5- (4-propoxyphenyl) morpholin-3-one

Step A:

A1M solution of potassium tert-butoxide (41.7mL,41.7mmol) in THF was added to a suspension of methyltriphenylphosphonium bromide (14.89g,41.7mmol) in 100mL THF under an argon atmosphere at 0 ℃. The reaction was allowed to warm to ambient temperature and stirred for 10 minutes. The reaction was then cooled again to 0 ℃ and a solution of 4-propoxybenzaldehyde (4.92mL,31.1mmol) in 70mL THF was added. The reaction was stirred at ambient temperature until TLC control (heptane/chloroform 1:1) showed complete consumption of aldehyde. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The product was purified by flash chromatography (hexane/chloroform 8: 2).

Yield: 16.5g (94.6%)

And B:

tert-butyl carbamate (9.08g,77.5mmol) was dissolved in 100mL of 1-propanol and 0.38M aqueous NaOH (198mL,75.2mmol) was added. The reaction was stirred at ambient temperature for 5 minutes, then 1, 3-dichloro-5, 5-dimethylimidazolidine-2, 4-dione (7.56g,38.4mmol) was added and the reaction was stirred at ambient temperature for 10 minutes. Adding (DHQ) dissolved in 100mL of 1-propanol₂PHAL (1.17g,1.5 mmol). Thereafter, 1-propoxy-4-vinylbenzene obtained from step A (4.055g,25mmol) dissolved in 200mL of 1-propanol was added followed by potassium osmate dihydrate (0.368g,1mmol) suspended in 2mL of 0.38M aqueous NaOH (0.76 mmol). The reaction was stirred at ambient temperature until complete consumption of styrene (TLC control). Water (170mL) was added and the reaction mixture was extracted 3 times with 250mL ethyl acetate. The combined organic layers were washed with brine (50mL), dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The product was purified by flash chromatography using a heptane-ethyl acetate gradient. The product was eluted at about 25% ethyl acetate.

Yield: 5.49g (74.4%); MS M/z 296.3(M + H)⁺

And C:

tert-butyl (S) -2-hydroxy-1- (4-propoxyphenyl) ethylcarbamate (0.47g,1.59mmol) and cesium carbonate (0.673g,1.91mmol) were added to the reaction flask, and 15mL of acetonitrile was added. The mixture was stirred and ethyl 2-bromoacetate (0.332mL,3mmol) was added. The reaction was stirred at 100 ℃ for 2 hours. The reaction was cooled to ambient temperature and then 50mL of water and 15mL of buffer (pH7) were added. The mixture was neutralized with 1N aqueous hydrochloric acid. The aqueous layer was extracted 3 times with 50mL ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The product was purified by FPLC using a hexane-ethyl acetate gradient (0 → 40%).

Yield: 0.11g (18.1%); MS M/z 382.4(M + H)⁺

Step D:

ethyl (S) -2- (2- (tert-butoxycarbonylamino) -2- (4-propoxyphenyl) ethoxy) acetate (0.11g,0.29mmol) obtained from step C was dissolved in 3mL of dichloromethane and 0.6mL of trifluoroacetic acid was added to the stirred solution. Boc-deprotection was monitored by TLC. After the deprotection was complete the solvent was removed and the oil was added to 3mL THF and 0.725mL diisopropylethylamine and excess potassium carbonate were added to the solution. The reaction was stirred at 50 ℃ for 18 hours. The solvent was removed and the oil was taken up in 10mL of dichloromethane and washed with brine (5 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was removed under reduced pressure. The product was purified by FPLC using a heptane-ethyl acetate gradient (0 → 100%).

Yield: 0.044g (64.5%); MS M/z 236.2(M + H)⁺

Step E:

the final product in the form of trifluoroacetate was synthesized starting from (S) -5- (4-propoxyphenyl) morpholin-3-one (0.044g,0.19mmol), 4-iodobenzene-1, 2-diamine (0.044g,0.19mmol), copper (I) iodide (0.004g,0.019mmol), cesium fluoride (0.058g,0.38mmol), cyclohexane-1, 2-diamine (0.0025mL,0.019 mmol). The solids were added together to a reaction flask, and the flask was vented with argon. A solution of cyclohexane-1, 2-diamine in 2mL dioxane was added to the flask. The reaction was stirred at 95 ℃ for 4 days, then cooled to 45 ℃ and filtered through a pad of celite. The pad was washed with warm dichloromethane and the solution was concentrated under reduced pressure. The intermediate was purified by FPLC using a chloroform-methanol gradient (0 → 10%).

Yield of：0.01g(15%);MS m/z 342.2(M+H)⁺

(S) -4- (3, 4-diaminophenyl) -5- (4-propoxyphenyl) morpholin-3-one was dissolved in 0.5mL triethyl orthoformate and the reaction was stirred at 150 ℃ for 0.5h, then cooled. Excess triethyl orthoacetate was removed under reduced pressure. The final product was purified by HPLC using a water-acetonitrile gradient containing 0.04% trifluoroacetic acid.

Yield: 0.003g (0.26%); MS M/z 352.4(M + H)⁺;HPLC(λ=214nm),[B]:rt10.57min(100%).

Example 94: 3- (1H-benzo [ d ] imidazol-6-yl) -4- (4-propoxyphenyl) -1, 3-oxazinan-2-one

This compound was synthesized according to method 7.

Step A:

this compound was synthesized as the trifluoroacetate salt starting from 4-propoxybenzaldehyde (3.16mL,20mmol), malonic acid (2.08g,20mmol), ammonium acetate (3.08g,40 mmol). Yield: 2.17g (48.6%)

And B:

the product obtained from step a (2.15g,9.6mmol), a 2M solution of lithium aluminum hydride (7.2mL,14.4mmol), yield: 1.61g (80.1%)

And C:

the product obtained from step B (1.61g,7.7mmol), bis (1H-imidazol-1-yl) methanone (1.622g,10mmol), yield: 0.9g (49.7%)

Step D:

the product obtained from step C (0.45g,1.91mmol), 4-iodobenzene-1, 2-diamine (0.448g,1.91mmol), copper (I) iodide (0.036g,0.19mmol), potassium carbonate (0.528g,3.82mmol), cyclohexane-1, 2-diamine (0.023mL,0.19mmol), triethyl orthoformate (10mL), yield: 0.018g (2.7%);

General collectorRate: 0.52%, MS M/z 352.4(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ0.89-0.93(m,3H);1.60-1.69(m,2H);2.02-2.09(m,H);2.51-2.58(m,H);3.80-3.83(m,2H);4.25-4.31(m,H);4.36-4.41(m,H);5.23-5.25(m,H);6.80(d,2H,J=8.7Hz);7.24(d,2H,J=8.7Hz);7.37-7.39(m,H);7.61-7.67(m,2H);9.08(s,H),HPLC(λ=214nm),[B]:rt 10.63min(100%).

Example 95: (S) -3- (H-imidazo [1,2-a ] pyridin-7-yl) -4-phenyloxazolidin-2-one

The compound was synthesized as described in method 5, step D, starting from 7-bromoimidazo [1,2-a ] pyridine (0.099g,0.5mmol), copper (I) iodide (0.010g,0.05mmol), cesium fluoride (0.152g,1mmol), cyclohexane-1, 2-diamine (0.006mL,0.05 mmol).

Yield: 0.045g (32.2%); MS M/z 280.1(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ4.12-4.16(m,H);4.82-4.86(m,H);5.76-5.79(m,H);7.24-7.41(m,8H);7.76(s,H);8.41(d,H,J=7.5Hz),HPLC(λ=214nm),[B]:rt 7.73min(100%).

Example 96: (4S,5R) -3- (H-imidazo [1,2-a ] pyridin-7-yl) -4, 5-diphenyloxazolidin-2-one

The compound was synthesized as described in method 5, step D, starting from 7-bromoimidazo [1,2-a ] pyridine (0.099g,0.5mmol), copper (I) iodide (0.010g,0.05mmol), potassium carbonate (0.138g,1mmol), cyclohexane-1, 2-diamine (0.006mL,0.05 mmol).

Yield: 0.057g (32.1%); MS M/z 356.2(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ6.15(d,H,J=7.9Hz);6.24(d,H,J=7.9Hz);6.97-6.99(m,2H);7.03-7.16(m,8H);7.38(s,H);7.43-7.45(m,2H);7.81(s,H);8.48(d,H,J=7.1Hz),HPLC(λ=214nm),[B]:rt 12.07min(99.5%).

Example 97: (4S,5R) -3- (imidazo [1,2-a ] pyridin-6-yl) -4, 5-diphenyloxazolidin-2-one

The compound was synthesized as described in method 5, step D, starting from 6-bromoimidazo [1,2-a ] pyridine (0.197g,1mmol), copper (I) iodide (0.019g,0.1mmol), cesium fluoride (0.304g,2mmol), cyclohexane-1, 2-diamine (0.012mL,0.1 mmol).

Yield: 0.033g (9.3%); MS M/z 356.3(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ6.06(d,H,J=8.3Hz);6.25(d,H,J=8.3Hz);6.96-6.98(m,2H);7.01-7.16(m,8H);7.4(s,H);7.45-7.52(m,2H);8.00(s,H);8.96(bs,H),HPLC(λ=214nm),[B]:rt 11.28min(93.9%).

Example 98: (S) -3- (H-imidazo [1,2-a ] pyridin-7-yl) -4- (4-propoxyphenyl) oxazolidin-2-one

This compound was synthesized according to method 5.

Step A:

the compound was synthesized starting from 4-propoxybenzaldehyde (7.32g,44.6mmol), methyltriphenylphosphonium bromide (21.34g,59.75mmol), a 1M solution of potassium tert-butoxide in THF (59.8mL,59.75 mmol). Yield: 6.13g (84.7%)

And B:

the product obtained from step A (3g,18.48mmol), ethyl carbamate (4.94g,27.72mmol), 5-dimethylimidazolidine-2, 4-dione (5.46g,27.72mmol), (DHQ)₂PHAL(0.72g,0.92mmol)、K₂OsO₄x2H₂O (0.274g,0.74mmol), 0.5M aqueous NaOH (112.8mL,56.4mmol), yield: 3g (61%)

And C:

the product obtained from step B (3g,10.16mmol), 0.2M aqueous NaOH (300mL), yield: 1.21g (46%)

Step D:

the product obtained from step C (0.376g,1.7mmol), 7-bromoimidazo [1,2-a ] pyridine (0.335g,1.7mmol), copper (I) iodide (0.033g,0.17mmol), cesium fluoride (0.52g,3.4mmol), cyclohexane-1, 2-diamine (0.021mL,0.17mmol), yield: 0.335g (58.4%)

The total yield is as follows: 8.7%; MS M/z 338.2(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ0.92(t,3H,J=7.5Hz);1.62-1.70(m,2H);3.83-3.87(m,2H);4.12-4.16(m,H);4.80-4.84(m,H);5.71-5.74(m,H);6.89(d,2H,J=8.7);7.26(d,H,J=7.5Hz);7.31-7.38(m,3H);7.48(br s,H);7.83(br s,H);8.46(br s,H),HPLC(λ=214nm),[B]:rt 11.20min(95%).

Example 99: (S) -4- (4-chlorophenyl) -3- (H-imidazo [1,2-a ] pyridin-7-yl) oxazolidin-2-one

This compound was synthesized according to method 5.

Step A:

the compound was synthesized starting from 4-chlorobenzaldehyde (0.42g,3mmol), methyltriphenylphosphonium bromide (1.428g,4mmol), a 1M solution of potassium tert-butoxide in THF (4mL,4 mmol).

Yield: 0.12g (28.9%)

And B:

the product obtained from step A (0.12g,0.869mmol), ethyl carbamate (0.24g,2.695mmol), 5-dimethylimidazolidine-2, 4-dione (0.261g,1.326mmol), (DHQ)₂PHAL(0.034g,0.043mmol)、K₂OsO₄x2H₂O (0.034g,0.034mmol), 0.41M aqueous NaOH (6.5mL,2.652mmol)

Yield: 0.12g (56.8%)

And C:

the product obtained from step B (0.1g,0.411mmol), 0.2M methanol, NaOH (11.25mL,2.25mmol), yield: 0.07g (86.2%)

Step D:

the product obtained from step C (0.07g,0.355mmol), 7-bromoimidazo [1,2-a ] pyridine (0.07g,0.355mmol), copper (I) iodide (0.007g,0.036mmol), cesium fluoride (0.108g,0.71mmol), cyclohexane-1, 2-diamine (0.005mL,0.036mmol), yield: 0.098g (88%)

The total yield is as follows: 12.5%; MS M/z 314.0(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ4.12-4.15(m,H);4.80-4.85(m,H);5.78-5.82(m,H);7.23-7.25(m,H);7.30(s,H);7.38-7.44(m,5H);7.77(s,H);8.42(d,H,J=7.5Hz),HPLC(λ=214nm),[B]:rt 10.35min(96.8%).

Example 100: 3- (imidazo [1,2-a ] pyridin-7-yl) -4- (4-propoxyphenyl) -1, 3-oxazinan-2-one

This compound was synthesized according to method 7.

Step A:

this compound was synthesized starting from 4-propoxybenzaldehyde (3.16mL,20mmol), malonic acid (2.08g,20mmol), ammonium acetate (3.08g,40 mmol). Yield: 2.17g (48.6%)

And B:

the product obtained from step a (2.15g,9.6mmol), a 2M solution of lithium aluminum hydride (7.2mL,14.4mmol), yield: 1.61g (93.8%)

And C:

the product obtained from step B (1.61g,7.7mmol), bis (1H-imidazol-1-yl) methanone (1.499g,9.2mmol), yield: 0.9g (49.7%)

Step D:

the product obtained from step C (0.45g,1.91mmol), 7-bromoimidazo [1,2-a ] pyridine (0.376g,1.91mmol), copper (I) iodide (0.036g,0.19mmol), potassium carbonate (0.528g,3.82mmol), cyclohexane-1, 2-diamine (0.023mL,0.19mmol), yield: 0.210g (31.3%)

The total yield is as follows: 6.1%; MS M/z 352.3(M + H)⁺;¹H-NMR(400MHz,DMSO-d6):δ0.87-0.91(m,3H);1.58-1.67(m,2H);2.05-2.12(m,H);2.49-2.57(m,H);3.79-3.82(m,2H);4.20-4.26(m,H);4.35-4.40(m,H);5.45-5.47(m,H);6.81(d,2H,J=8.7Hz);7.24(d,2H,J=8.7Hz);7.47(d,H,J=7.9Hz);7.75(s,H);7.96(s,H);8.10(s,H);8.65(d,H,J=7.9Hz),HPLC(λ=214nm),[B]:rt9.73min(100%).

Example 101: 5- (2-phenylpyrrolidin-1-yl) -1H-benzo [ d ] imidazole

From 5(6) (200mg;1mmol;1eq.) bromobenzimidazole, 2-dicyclohexylphosphino-2' - (N, N-dimethylamino) biphenyl (9mg;0.024mmol;0.024eq.;2.4mol%), Pd, according to method 8₂dba₃(9mg;0.01mmol;0.01eq.;1mol%) and 4-phenylpyrrolidine (176mg;1.2mmol;1.2 eq.); yield: 0.071g (27.0%); MS M/z 264.4[ M + H ]]⁺;¹H-NMR(DMSO d₆,500MHz):1.76-1.81(m,1H);1.93-1.98(m,2H);2.35-2.44(m,1H);3.34-3.39(m,1H);3.71-3.75(m,1H);4.73-4.75(m,1H);6.39(br s,1H);6.42-6.44(m,1H);7.17-7.35(m,6H);7.83(s,1H);11.80(br s,1H);HPLC([A]):rt 13.23min(95.7%)

Example 102: 5- (2- (4-methoxyphenyl) pyrrolidin-1-yl) -1H-benzo [ d ] imidazole

From 5(6) (200mg;1mmol;1eq.) bromobenzimidazole, 2-dicyclohexylphosphino-2' - (N, N-dimethylamino) biphenyl (9mg;0.024mmol;0.024eq.;2.4mol%), Pd, according to method 8₂dba₃(9mg;0.01mmol;0.01eq.;1mol%) and 2- (4-methoxyphenyl) -pyrrolidine (214mg;1.2mmol;1.2eq.) the compound was synthesized; yield: 0.060g (20.5%); MS M/z 294.2[ M + H ] ]⁺;¹H-NMR(DMSO d₆,500MHz):δ1.74-1.77(m,1H);1.92-1.97(m,2H);2.32-2.38(m,1H);3.33-3.36(m,1H);3.68-3.72(m,4H);4.67-4.69(m,1H);6.39(br s,1H);6.43-6.44(m,1H);6.81-6.88(m,2H);7.13-7.15(m,2H);7.27-7.29(m,1H);7.83(s,1H);11.80(br s,1H);HPLC([A]):rt 13.39min(91.3%)

Example 103: 5- (2- (4-fluorophenyl) pyrrolidin-1-yl) -1H-benzo [ d ] imidazole

From 5(6) -bromobenzimidazole (200mg;1mmol;1eq.) and 2-dicyclohexylphosphino-2' - (N, N-dimethylamino) biphenyl (9 m) according to method 8g；0.024mmol；0.024eq.；2.4mol％)、Pd₂dba₃(9 mg; 0.01 mmol; 0.01 eq.; 1 mol%) and 2- (4-fluorophenyl) -pyrrolidine (199 mg; 1.2 mmol; 1.2 eq.); yield: 0.103mg (36.7%); MS m/z: 282.5[ M + H]⁺；¹H-NMR(DMSO d₆，500MHz)：1.73-1.79(m，1H)；1.91-1.97(m，2H)；2.35-2.43(m，1H)；3.33-3.38(m，1H)；3.71-3.74(m，1H)；4.74-4.76(m，1H)；6.38(br s，1H)；6.41-6.43(m，1H)；7.08-7.12(m，2H)；7.25-7.28(m，2H)；7.33-7.35(m，1H)；7.83(s，1H)；11.81(br s，1H)；HPLC([A])：rt 13.69min(95.6％)

Example 104: 5- (2- (4-chlorophenyl) pyrrolidin-1-yl) -1H-benzo [ d ] imidazole

From 5(6) (200mg;1mmol;1eq.) bromobenzimidazole, 2-dicyclohexylphosphino-2' - (N, N-dimethylamino) biphenyl (9 mg; 0.024 mmol; 0.024 eq.; 2.4 mol%), Pd, according to method 8₂dba₃(9 mg; 0.01 mmol; 0.01 eq.; 1 mol%) and 2- (4-chlorophenyl) -pyrrolidine (220 mg; 1.2 mmol; 1.2 eq.); yield: 0.083g (27.9%); MS m/z: 293.3[ M + H]⁺；¹H-NMR(DMSO d₆，500MHz)：δ1.76-1.80(m，1H)；1.91-2.00(m，2H)；2.36-2.42(m，1H)；3.33-3.38(m，1H)；3.71-3.74(m，1H)；4.73-4.75(m，1H)；6.42-6.44(m，2H)；7.25-7.27(m，2H)；7.30-7.32(m，1H)；7.33-7.35(m，2H)；7.88(s，1H)；11.90(br s，)；HPLC([A])：rt 14.66min(94.8％)

Example 105: 5- (2-Benzylpyrrolidin-1-yl) -1H-benzo [ d ] imidazole

From 5(6) (200mg;1mmol;1eq.) bromobenzimidazole, 2-dicyclohexylphosphino-2' - (N, N-dimethylamino) biphenyl (9 mg; 0.024 mmol; 0.024 eq.; 2.4 mol%), Pd, according to method 8₂dba₃(9 mg; 0.01 mmol; 0.01 eq.; 1 mol%) and 2-benzylpyrrolidine (194 mg; 1.2 mmol; 1.2 eq.); yield: 0.101g (36.5%); MS m/z: 278.2[ M + H ]⁺；¹H-NMR(DMSO d₆，500MHz)：δ1.78-1.83(m，2H)；1.88-1.90(m，2H)；2.53-2.55(m，1H)；2.96-2.99(m，1H)；3.11-3.16(m，1H)；3.36-3.40(m，1H)；3.91-3.94(m，1H)；6.65-6.67(m，2H)；7.21-7.24(m，1H)；7.28-7.34(m，4H)；7.45-7.46(m，1H)；7.90(s，1H)；11.89(br s，1H)；HPLC([A])：rt 13.93min (90.4％)

Example 106: 5- (2- (4-chlorobenzyl) pyrrolidin-1-yl) -1H-benzo [ d ] imidazole

From 5(6) -bromobenzimidazole (200mg;1mmol;1eq.), 2-dicyclohexylphosphino-2' - (N, N-dimethylamino) biphenyl (9mg;0.024mmol;0.024eq.;2.4mol%), Pd₂dba₃(9mg;0.01mmol;0.01eq.;1mol%) and 2- (4-chlorobenzyl) -pyrrolidine (234mg;1.2mmol;1.2eq.) to the synthesis of the compound; yield: 0.04g (1.3%); MS M/z 312.1[ M + H ]]⁺;HPLC[A]:rt 15.49(92.2%)

Example 107: 5- (2- (4-fluorobenzyl) pyrrolidin-1-yl) -1H-benzo [ d ] imidazole

From 5(6) (200mg;1mmol;1eq.) bromobenzimidazole, 2-dicyclohexylphosphino-2' - (N, N-dimethylamino) biphenyl (9mg;0.024mmol;0.024eq.;2.4mol%), Pd, according to method 8₂dba₃(9mg;0.01mmol;0.01eq.;1mol%) and 2- (4-fluorobenzyl) -pyrrolidine (216mg;1.2mmol;1.2 eq.); yield: 0.086g (29.1%); MS M/z 296.6[ M + H ]]⁺;¹H-NMR(DMSO d₆,500MHz):δ1.76-1.90(m,4H);2.54-2.59(m,1H);2.92-2.95(m,1H);3.10-3.15(m,1H);3.35-3.38(m,1H);3.91-3.94(m,1H);6.68-6.69(m,2H);7.11-7.15(m,2H);7.29-7.32(m,2H);7.43-7.45(m,1H);7.92(s,1H);11.91(br s,1H);HPLC([A]):rt 15.18(96.3%)

Example 108: 5- (pyrrolidin-1-yl) -1H-benzo [ d ] imidazole

From 5(6) -bromobenzimidazole (2) according to method 800mg, 1mmol, 1eq.), 2-dicyclohexylphosphino-2' - (N, N-dimethylamino) biphenyl (9mg, 0.024mmol, 0.024eq.;2.4mol%), Pd₂dba₃(9mg;0.01mmol;0.01eq.;1mol%) and pyrrolidine (91mg;0.077ml;1.2mmol;1.2 eq.); yield: 0.054g (28.9%); MS M/z 188.3[ M + H ] ]⁺;¹H-NMR(DMSO d₆,500MHz):δ1.95-1.97(m,4H);3.21-3.24(m,4H);6.55-6.56(m,2H);7.38-7.40(m,1H);7.96(s,1H);HPLC[A]):rt 8.72min(82.3%)

Example 109: 5- (2- (4-methoxybenzyl) pyrrolidin-1-yl) -1H-benzo [ d ] imidazole

From 5(6) -bromobenzimidazole (200mg;1mmol;1eq.), 2-dicyclohexylphosphino-2' - (N, N-dimethylamino) biphenyl (9mg;0.024mmol;0.024eq.;2.4mol%), Pd₂dba₃(9mg;0.01mmol;0.01eq.;1mol%) and starting with 2- (4-methoxybenzyl) -pyrrolidine oxalate (337mg;1.2mmol;1.2eq.) and lithium bis (trimethylsilyl) amide (1M solution in THF; 3.3ml;3.3mmol;3.3 eq.); yield: 0.06g (1.9%); MS M/z 308.2[ M + H [)]⁺HPLC (gradient 3): rt 14.07(98.9%)

Example 110: 3- (1H-benzo [ d ] imidazol-6-yl) -2- (4-chlorophenyl) thiazolidin-4-one

This compound was synthesized according to method 9, step A, starting from 5-aminobenzimidazole (0.133g,1.0mmol), p-chloro-benzaldehyde (0.141mL,1.0mmol), mercaptoacetic acid (0.138g,1.5mmol), piperidine. Yield: 194mg (58%), MS M/z:330.3(M + H)⁺,HPLC[A]):rt 5.82min(91%)

Example 111: 3- (1H-benzo [ d ] imidazol-5-yl) -2-phenylthiazolidin-4-one

This compound was synthesized according to method 9, step A, starting from 5-aminobenzimidazole (0.133g,1.0mmol), benzaldehyde (0.306mL,3.0mmol), mercaptoacetic acid (0.276g,2.0mmol), piperidine. Yield: 118mg (40%), MS M/z:296.3(M + H) ⁺,HPLC[A]):rt 5.72min(96%)

Example 112: 3- (1H-benzo [ d ] imidazol-6-yl) -2- (4-fluorophenyl) thiazolidin-4-one

This compound was synthesized according to method 9, step A, starting from 5-aminobenzimidazole (0.133g,1.0mmol), 4-fluoro-benzaldehyde (0.108mL,1.0mmol), mercaptoacetic acid (0.138g,1.5mmol), piperidine. Yield: 69mg (22%), MS M/z 314.3(M + H)⁺,HPLC[A]):rt 5.86min(97%)

Example 113: 3- (1H-benzo [ d ] imidazol-6-yl) -2- (naphthalen-1-yl) thiazolidin-4-one

This compound was synthesized according to method 9, step A, starting from 5-aminobenzimidazole (0.133g,1.0mmol), 4-naphthalen-1-ylcarboxaldehyde (0.157mL,1.0mmol), mercaptoacetic acid (0.157g,1.5mmol), piperidine. Yield: 54mg (15.6%), MS M/z 346.3(M + H)⁺,HPLC[A]):rt 6.86min(95%)

Example 114: 3- (1H-benzo [ d ] imidazol-6-yl) -2- (4-phenoxyphenyl) thiazolidin-4-one

This compound was synthesized according to method 9, step A, starting from 5-aminobenzimidazole (0.133g,1.0mmol), 4-4-phenoxybenzaldehyde (0.175mL,1.0mmol), mercaptoacetic acid (0.157g,1.5mmol), piperidine. Yield: 173mg (44.7%), MS M/z 388.3(M + H)⁺,HPLC[A]):rt 5.86min(99%)

Example 115: 3- (1H-benzo [ d ] imidazol-6-yl) -2- (2, 6-difluorophenyl) thiazolidin-4-one

This compound was synthesized according to method 9, step A, starting from 5-aminobenzimidazole (0.133g,1.0mmol), 2, 6-difluoro-benzaldehyde (0.142mg,1.0mmol), mercaptoacetic acid (0.157g,1.5mmol), piperidine. Yield: 208mg (62.8%), MS M/z 332.3(M + H) ⁺,HPLC[A]):rt 5.76min(97%)

Example 116: 3- (1H-benzo [ d ] imidazol-6-yl) -2- (thiophen-3-yl) thiazolidin-4-one

This compound was synthesized according to method 9, step A, starting from 5-aminobenzimidazole (0.133g,1.0mmol), 2, 6-2-thiophenecarboxaldehyde (0.092mL,1.0mmol), thioglycolic acid (0.157g,1.5mmol), piperidine. Yield: 203mg (70.7%), MS M/z:302.3(M + H)⁺,HPLC[A]):rt 5.68min(97%)

Example 117: 3- (1H-benzo [ d ] imidazol-6-yl) -5-methyl-2-phenylthiazolidin-4-one

This compound was synthesized according to method 9, step A, starting from 5-aminobenzimidazole (0.133g,1.0mmol), 2, 6-benzaldehyde (0.204mL,2.0mmol), 2-mercaptopropionic acid (0.280g,3.0mmol), DCC (0.248mg,1.2 mmol). Yield: 115mg (37.2%), MS M/z:310.3(M + H)⁺,HPLC[A]):rt 6.32min(100%)

Example 118: 3- (1H-benzo [ d ] imidazol-5-yl) -2-phenylthiazolidine-4-thione

The compound was synthesized according to method 9, step B, starting from example 110(0.122g,0.29mmol), Lawson's reagent (0.6g,1.45 mmol). Yield: 44mg (48.7%), MS M/z 312.3(M + H)⁺,HPLC[A]):rt 7.32min(87%)

Example 119: 3- (1H-benzo [ d ] imidazol-6-yl) -2- (4-phenoxyphenyl) thiazolidine-4-thione

The compound was synthesized according to method 9, step B, starting from example 113(0.122g,0.284mmol), lawson's reagent (0.575g,1.42 mmol). Yield: 58mg (50.7%), MS M/z:404.3(M + H) ⁺,HPLC[A]):rt 6.45min(87%)

Example 120: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4-fluorophenyl) pyrrolidin-2-one

This compound was synthesized according to method 10.

Step A

4- (4-fluorophenyl) -4-oxobutanoic acid (196mg;1mmol;1eq.), carbonyldiimidazole (162mg;1mmol;1eq.) and benzimidazole-5 (6) -amine (133mg;1mmol;1 eq.); yield: 0.189g (60.8%); MS M/z 312.2[ M + H ]]⁺;HPLC([A]):rt 10.45min(81.9%)

Step B, C

Yield: 0.048g (26.8%); MS M/z 296.2[ M + H ]]⁺;¹H-NMR(CD₃OD,400MHz):δ2.02-2.10(m,1H);2.67-2.82(m,3H);5.39-5.43(m,1H);6.95-6.99(m,2H);7.21(dd,1H,⁴J=2.1Hz,³J=8.7Hz);7.29-7.33(m,2H);7.47(d,1H,³J=8.7Hz);7.53(d,1H,⁴J=2.1Hz);8.10(s,1H);HPLC([A]):rt 11.47min(97.4%)

Example 121: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4-methoxyphenyl) pyrrolidin-2-one

This compound was synthesized according to method 10.

Step A

4- (4-methoxy) -4-oxobutanoic acid (208mg;1mmol;1eq.), carbonyldiimidazole (162mg;1mmol;1eq.) and benzimidazole-5 (6) -amine (133mg;1mmol;1 eq.); yield: 0.207g (64.1%); MS M/z 324.2[ M + H ]]⁺;HPLC([A]):rt 10.30min(93.5%)

Step B, C

Additional purification by semi-preparative HPLC; yield: 0.019g (9.7%); MS M/z 308.2[ M + H ]]⁺;¹H-NMR(CD₃OD,400MHz):δ2.03-2.11(m,1H);2.64-2.83(m,3H);3.69(s,3H);5.42-5.45(m,1H);6.79-6.82(m,2H);7.20-7.23(m,2H);7.58(dd,1H,⁴J=2.1Hz,³J=9.1Hz);7.67(d,1H,³J=9.5Hz);7.86(d,1H,⁴J=2.1Hz);9.17(s,1H);HPLC([A]):rt 9.65min(100%)

Example 122: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4-propoxyphenyl) pyrrolidin-2-one

This compound was synthesized according to method 10.

Step A

4-oxo-4- (4-propoxyphenyl) butyric acid (236mg;1mmol;1eq.), carbonyldiimidazole (162mg;1mmol;1eq.) and benzimidazole-5 (6) -amine (133mg;1mmol;1 eq.); yield: 0.215g (61.3%); MS M/z 352.3[ M + H [)]⁺;HPLC([A]):rt 13.13min(100%)

Step B, C

Additional purification by semi-preparative HPLC; yield: 0.023g (11.2%); MS M/z 336.1[ M + H ]]⁺;¹H-NMR (CD₃OD,400MHz):δ0.97(t,3H,³J=7.5Hz);1.67-1.75(m,2H);2.05-2.08(m,1H);2.66-2.80(m,3H);3.82(t,2H,³J=6.2Hz);5.41-5.44(m,1H);6.78-6.81(m,2H);7.18-7.21(m,2H);7.56(dd,1H,⁴J=2.1Hz,³J=9.1Hz);7.67(d,1H,³J=9.1Hz);7.85(d,1H,⁴J=2.1Hz);9.13(s,1H);HPLC([A]):rt 12.44min(100%)

Example 123: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) pyrrolidin-2-one

This compound was synthesized according to method 10.

Step A

4- (2, 3-dihydro-1, 4-benzodioxine-6-yl) -4-oxobutanoic acid (236mg;1mmol;1eq.), carbonyldiimidazole (162mg;1mmol;1eq.), and benzimidazole-5 (6) -amine (133mg;1mmol;1 eq.); yield: 0.209g (59.5%); MS M/z 352.3[ M + H ]]⁺;HPLC([A]):rt 10.25min(94.8%)

Step B, C

Additional purification by semi-preparative HPLC; yield: 0.028g (14.1%); MS M/z 336.1[ M + H ]]⁺;¹H-NMR (CD₃OD,400MHz):δ2.00-2.08(m,1H);2.64-2.83(m,3H);4.13(s,4H);5.36-5.39(m,1H);6.70-6.72(m,1H);6.74-6.76(m,2H);7.60(dd,1H,⁴J=1.7,³J=9.1Hz);7.69(d,1H,³J=9.1Hz);7.89(d,1H,⁴J=1.7Hz);9.19(s,1H);HPLC([A]):rt 9.77min(96.1%)

Example 124: 1- (1H-benzo [ d ] imidazol-5-yl) -5-phenylpyrrolidin-2-one

This compound was synthesized according to method 10.

Step A

4-oxo-4-phenylbutyric acid (178mg;1mmol;1 eq).) Carbonyldiimidazole (162mg;1mmol;1eq.) and benzimidazole-5 (6) -amine (133mg;1mmol;1 eq.); yield: 0.198g (67.6%); MSm/z 294.2[ M + H ]]⁺;HPLC([A]):rt 10.66min(87.9%)

Step B, C

Yield: 0.015g (7.4%); MS M/z 278.1[ M + H ]]⁺;¹H-NMR(CD₃OD,400MHz):δ2.94-2.10(m,1H);2.70-2.79(m,3H);5.41-5.42(m,1H);7.17-7.19(m,1H);7.23-7.29(m,6H);7.54-7.55(m,1H);8.09(s,1H);HPLC([A]):rt 9.64min(91.5%)

Example 125: 2- (1H-benzo [ d ] imidazol-5-yl) -3-phenylisoindolin-1-one

This compound was synthesized according to method 10.

2-Benzoylbenzoic acid (226mg;1mmol), DCC (206mg;1mmol), benzimidazole-5 (6) -amine (133mg;1mmol), TFA (1ml) and triethylsilane (0.322ml;2mmol;2 eq.); yield: 0.074g (22.8%); MS M/z 326.2[ M + H% ]⁺;¹H-NMR(DMSO d₆400MHz) < delta > 6.63(s,1H) < 7.15-7.19(m,1H) < 7.22-7.32(m,5H) < 7.48-7.50(m,2H) < 7.53-7.62(m,2H) < 7.84-7.86(m,2H) < 8.16(s,1H) < 12.42(br s,1H) < HPLC (gradient 3) < rt 11.89min < 96.2% >)

Example 126: 2- (1H-benzo [ d ] imidazol-5-yl) -3- (4-biphenyl) isoindolin-1-one

This compound was synthesized according to method 11.

2- (4-Phenylbenzoyl) benzoic acid (1.0g;3.3mmol), DCC (680mg;3.3mmol), benzimidazole-5 (6) -amine (440mg;3.3mmol), TFA (3.92ml) and triethylsilane (0.624ml;3.92mmol;4eq.), and was additionally purified by semi-preparative HPLC; yield: 0.120g (9.1%); MS M/z 402.1[ M + H ]]⁺;¹H-NMR(DMSO d₆,400MHz):δ6.79(s,1H);7.28-7.32(m,1H);7.36-7.40(m,5H);7.53-7.60(m,5H);7.63-7.66(m,1H);7.72-7.74(d,1H,³J=8.7Hz);7.76-7.79(dd,1H,⁴J=1.7Hz,³J=8.7Hz);7.89-7.91(m,1H);8.17-8.18(d,1H,⁴J =1.7Hz), 9.06(s,1H), HPLC (gradient 3)):rt15.20min(97.0%)

Example 127: 2- (1H-benzo [ d ] imidazol-5-yl) -3- (4-fluorophenyl) isoindolin-1-one

Synthesis of the Compound according to method 11

2- (4-fluorobenzoyl) benzoic acid (244mg;1mmol), DCC (206mg;1mmol), benzimidazole-5 (6) (133mg;1mmol), TFA (1ml) and triethylsilane (0.322ml;2mmol;2 eq.); yield: 0.055g (16.0%); MS M/z 344.1[ M + H ]]⁺;¹H-NMR(DMSO d₆400MHz) < delta > 6.65(s,1H) < 7.04-7.09(m,2H) < 7.30-7.33(m,2H) < 7.37-7.51(m,2H) < 7.54-7.63(m,3H) < 7.84-7.86(m,2H) < 8.17(s,1H) < 12.43(br s,1H) < HPLC (gradient 3) < rt 12.44min < 95.9%)

Example 128: 2- (1H-benzo [ d ] imidazol-5-yl) -3- (3-fluorophenyl) isoindolin-1-one

Synthesis of the Compound according to method 11

2- (4-fluorobenzoyl) benzoic acid (225mg;0.92mmol), DCC (189mg;0.92mmol), benzimidazole-5 (6) -amine (122mg;0.92mmol), TFA (0.25ml) and triethylsilane (0.08ml;0.5mmol;2 eq.); yield: 0.010g (2.7%); MS M/z 343.4[ M + H ]]⁺;¹H-NMR(DMSO d₆400 MHz:. delta.6.67-6.68 (m,1H), 6.99-7.02(m,1H), 7.11-7.12(m,1H), 7.16-7.18(m,1H), 7.27-7.31(m,1H), 7.36-7.37(m,1H), 7.40-7.47(m,1H), 7.53-7.58(m,2H), 7.60-7.63(m,1H), 7.85-7.86(m,2H), 8.17-8.18(m,1H), 12.44-12.45(m,1H), HPLC (gradient 3): rt 12.53min (93.6%)

Example 129: 2- (1H-benzo [ d ] imidazol-5-yl) -3- (3, 5-difluorophenyl) isoindolin-1-one

Synthesis of the Compound according to method 11

2- (3, 5-difluorobenzoyl) benzoic acid (900mg;3.4mmol), DCC (701mg;3.4mmol), benzimidazole-5 (6) -amine (453mg;3.4mmol), TFA (12ml) and triethylsilane (1.9ml;12mmol;4eq.), and was additionally purified by semi-preparative HPLC; yield: 0.020g (1.6%); MS M/z 361.3[ M + H ]]⁺;¹H-NMR(DMSO d₆,400MHz):δ6.77(s,1H);7.06-7.11(m,1H);7.13-7.15(m,2H);7.44(d,1H,³J=7.5Hz);7.58-7.61(m,1H);7.64-7.68(m,1H);7.76-7.79(m,2H);7.89(d,1H,³J =7.5Hz), 8.18(s,1H), 9.20(s,1H), HPLC (gradient 3): rt 13.07min (99.6%)

Example 130: 2- (1H-benzo [ d ] imidazol-5-yl) -3- (4-chlorophenyl) isoindolin-1-one

Synthesis of the Compound according to method 11

2- (4-chlorobenzoyl) benzoic acid (261mg;1mmol), DCC (206mg;1mmol), benzimidazole-5 (6) amine (133mg;1mmol), TFA (1ml) and triethylsilane (0.322ml;2mmol;2 eq.); yield: 0.032g (8.9%); MS M/z 360.2[ M + H ] ]⁺;¹H-NMR(DMSO d₆400MHz): delta 6.66(s,1H), 7.30-7.33(m,4H), 7.39-7.58(m,2H), 7.54-7.63(m,3H), 7.85-7.87(m,2H), 8.17(s,1H), 12.44(br s,1H), HPLC (gradient 3): rt 13.43min (100%)

Example 131: 2- (1H-benzo [ d ] imidazol-5-yl) -3- (3, 4-dichlorophenyl) isoindolin-1-one

Synthesis of the Compound according to method 11

2- (3, 4-Dichlorobenzoyl) benzoic acid (720mg;2.44mmol), DCC (503mg;2.44mmol), benzimidazole-5 (6) -amine (325mg;2.44mmol), TFA (9.6ml) and triethylsilane (1.53ml;9.6mmol;4eq.), and was additionally purified by semi-preparative HPLC; yield: 0.007g (0.73%); MS M/z 396.0[ M + H ]]⁺;¹H-NMR(DMSO d₆,400MHz):δ6.77(s,1H);7.24-7.27(m,1H);7.41(d,1H,³J=7.5Hz);7.49-7.51(m,1H);7.58-7.61(m,1H);7.64-7.68(m,1H);7.74-7.77(m,3H);7.89(d,1H,³J =7.5Hz), 8.14(br s,1H), 9.15(s,1H), HPLC (gradient 3) rt 14.24min (100%)

Example 132: 2- (1H-benzo [ d ] imidazol-5-yl) -3- (3-chloro-5-fluorophenyl) isoindolin-1-one

Synthesis of the Compound according to method 11

From 2- (3-chloro-5-fluorobenzoyl) benzoic acid (920mg;3.3mmol), DCC (681)mg;3.3mmol), benzimidazole-5 (6) -amine (439mg;3.3mmol), TFA (12ml) and triethylsilane (1.9ml;12mmol;4eq.) the synthesis of this compound was started and additional purification by semi-preparative HPLC; yield: 0.004g (0.3%); MS M/z 378.2[ M + H ]]⁺;¹H-NMR(DMSO d₆400 MHz:. delta.6.76 (s,1H), 7.22-7.29(m,2H), 7.35(s,1H), 7.42-7.44(m,1H), 7.58-7.62(m,1H), 7.64-7.68(m,1H), 7.73-7.76(m,2H), 7.88-7.90(m,1H), 8.13(s,1H), 9.06(s,1H), HPLC (gradient 3): rt 14.24min (100%)

Example 133: 2- (1H-benzo [ d ] imidazol-5-yl) -3- (4-methoxyphenyl) isoindolin-1-one

Synthesis of the Compound according to method 11

2- (4-methoxybenzoyl) benzoic acid (820mg;3.2mmol), DCC (660mg;3.2mmol), benzimidazole-5 (6) -amine (426mg;3.2mmol), TFA (12ml) and triethylsilane (1.9ml;12mmol;4eq.), and was additionally purified by semi-preparative HPLC; yield: 0.044g (3.9%); MS M/z 356.1[ M + H ]]⁺;¹H-NMR(DMSO d₆,400MHz):δ3.63(s,3H,);6.65(s,1H);6.78-6.81(m,2H);7.18-7.20(m,2H);7.32(d,1H,³J=7.5Hz);7.54-7.65(m,1H);7.61-7.65(m,1H);7.72-7.73(m,2H);7.87(d,1H,³J =7.5Hz), 8.12(br s,1H), 9.15(s,1H), HPLC (gradient 3) rt 12.39min (100%)

Example 134: 2- (1H-benzo [ d ] imidazol-5-yl) -3- (4-propoxyphenyl) isoindolin-1-one

Synthesis of the Compound according to method 11

2- (4-propoxybenzoyl) benzoic acid (430mg;1.5mmol), DCC (309mg;1.5mmol), benzimidazole-5 (6) -amine (200mg;1.5mmol), TFA (1.5ml) and triethylsilane (0.239ml;1.5mmol;4eq.), and was additionally purified by semi-preparative HPLC; yield: 0.030g (5.2%); MS M/z 384.0[ M + H ]]⁺;¹H-NMR (DMSO d₆,400MHz):δ0.84-0.91(m,3H);1.58-1.67(m,2H);3.77-3.80(m,2H);6.64(s,1H);6.77-6.80(m,2H);7.16-7.19(m,2H);7.31(d,1H,³J=7.5Hz);7.54-7.58(m,1H);7.61-7.65(m,1H);7.72(br s,2H);7.87(d,1H,³J=7.5Hz);8.11(br s,1H), 9.12(s,1H), HPLC (gradient 3): rt 14.00min (100%)

Example 135: 2- (1H-benzo [ d ] imidazol-5-yl) -3- (3-fluoro-4-methoxyphenyl) isoindolin-1-one

Synthesis of the Compound according to method 11

2- (3-fluoro-4-methoxybenzoyl) benzoic acid (390mg;1.42mmol), DCC (293mg;1.42mmol), benzimidazole-5 (6) -amine (189mg;1.42mmol), TFA (0.8ml) and triethylsilane (0.127ml;0.8mmol;4 eq.); yield: 0.020g (3.8%); MS M/z 374.2[ M + H ] ]⁺;¹H-NMR(DMSO d₆,400MHz):δ3.68(s,3H);6.54(s,1H);6.97-7.02(m,2H);7.07-7.10(m,1H);7.30(d,1H,³J =7.5Hz), 7.36-7.49(m,2H), 7.51-7.54(m,1H), 7.56-7.60(m,1H), 7.81-7.83(m,2H), 8.15(s,1H), 12.04(br s,1H), YIeld:0.020g (25.0%), HPLC (gradient 3): rt 12.94min (94.4%)

Example 136: 2- (1H-benzo [ d ] imidazol-5-yl) -3- (3, 4-dimethoxyphenyl) isoindolin-1-one

Synthesis of the Compound according to method 11

2- (3, 4-Dimethoxybenzoyl) benzoic acid (1.16g;4mmol), DCC (825mg;4mmol), benzimidazole-5 (6) -amine (533mg;4mmol), TFA (15ml) and triethylsilane (2.88ml;15mmol;4eq.), and was additionally purified by semi-preparative HPLC; yield: 0.140g (9.1%); MS M/z 385.4[ M + H ]]⁺;¹H-NMR(DMSO d₆400MHz): delta 3.62(s, 3H); 3.64(s,3H);6.61(s,1H);6.79-6.81(m,2H);6.88(s,1H);7.37-7.39(m,1H);7.54-7.58(m,1H);7.62-7.65(m,1H);7.76-7.79(m,2H);7.86-7.88(m,1H);8.13-8.14(m,1H);9.19(s,1H); HPLC (gradient 3): rt 11.51min (100%)

Example 137: 3- (benzo [ d ] [1,3] dioxol-6-yl) -2- (1H-benzo [ d ] imidazol-5-yl) isoindolin-1-one

Synthesis of the Compound according to method 11

2- (benzo [ d ]][1,3]Dioxol-6-yl) benzoic acid (1.44g;4.2mmol), DCC (870mg;4.2 mm)ol), benzimidazole-5 (6) -amine (560mg;4.2mmol), TFA (5.4ml) and triethylsilane (0.86ml;5.4mmol;4eq.), and additional purification by semi-preparative HPLC; yield: 0.125g (25.0%); MS M/z 370.0[ M + H ] ]⁺;¹H-NMR(DMSO d₆400 MHz:. delta.5.89-5.90 (m,2H), 6.62(s,1H),6.76-7.77(m,1H), 6.78-6.80(m,1H), 6.85-6.88(m,1H), 7.33-7.35(m,1H), 7.54-7.58(m,1H), 7.62-7.66(m,1H), 7.75-7.76(m,2H), 7.85-7.87(m,1H), 8.14(br s,1H), 9.21(s,1H), HPLC (gradient 3): rt 13.00min (100%)

Example 138: 2- (1H-benzo [ d ] imidazol-5-yl) -3- (4-phenoxyphenyl) isoindolin-1-one

Synthesis of the Compound according to method 11

2- (4-Phenoxybenzoyl) benzoic acid (1.0g;3.14mmol), DCC (648mg;3.14mmol), benzimidazole-5 (6) -amine (418mg;3.14mmol), TFA (12ml) and triethylsilane (1.9ml;12mmol;4eq.), and was additionally purified by semi-preparative HPLC; yield: 0.040g (3.1%); MS M/z 418.3[ M + H ]]⁺;¹H-NMR(DMSO d₆,400MHz):δ6.71(s,1H);6.84-6.86(m,2H);6.90-6.92(m,2H);7.10-7.14(m,1H);7.29-7.35(m,5H);7.55-7.59(m,1H);7.64-7.67(m,1H);7.75-7.76(m,2H);7.88(d,1H,³J =7.5Hz), 8.16(s,1H), 9.19(s,1H), HPLC (gradient 3): rt 15.53min (100%)

Example 139: 2- (1H-benzo [ d ] imidazol-5-yl) -4, 7-dichloro-3- (4-methoxyphenyl) isoindolin-1-one

This compound was synthesized according to method 11.

2- (4-methoxybenzoyl) -3, 6-dichlorobenzoic acid (430mg;1.32mmol), DCC (272mg;1.32mmol), benzimidazole-5 (6) -amine (176mg;1.32mmol), TFA (0.36ml) and triethylsilane (0.057ml;0.36mmol;4 eq.); yield: 0.010g (1.8%); MS M/z 424.1[ M + H ]]⁺;¹H-NMR(DMSO d₆,400MHz):δ3.60(s,3H);6.47-6.49(m,H);6.70-6.72(m,2H);7.09-7.11(m,2H);7.27-7.53(m,2H);7.61-7.62(m,2H);7.65-7.72(m,H);8.15(s,H);12.41(br s,H)

Example 140: 2- (1H-benzo [ d ] imidazol-5-yl) -5, 6-dichloro-3- (4-methoxyphenyl) isoindolin-1-one

This compound was synthesized according to method 11.

2- (4-methoxybenzoyl) -4, 5-dichlorobenzoic acid (495mg;1.52mmol), DCC (313mg;1.52mmol), benzimidazole-5 (6) -amine (202mg;1.52mmol), TFA (0.36ml) and triethylsilane (0.057ml;0.36mmol;4 eq.); yield: 0.010g (1.6%); MS M/z 424.1[ M + H ]]⁺;¹H-NMR(DMSO d₆,400MHz):3.61(s,3H);6.54(s,H);6.76-6.78(m,2H);7.15-7.17(m,2H);7.37-7.51(m,2H);7.56(s,H);7.77(s,H);8.04(s,H);8.15(s,H);12.43(br s,H)

Example 141: 2- (1H-benzo [ d ] imidazol-5-yl) -5, 6-dichloro-3- (4-propoxyphenyl) isoindolin-1-one

This compound was synthesized according to method 11.

2- (4-Propoxybenzoyl) -4, 5-dichlorobenzoic acid (15mg;0.04mmol), DCC (10mg;0.04mmol), benzimidazole-5 (6) -amine (5mg;0.04mmol), TFA (0.08ml) and triethylsilane (0.013ml;0.08mmol;4 eq.); yield: 0.005(27.7%); MS M/z 452.0[ M + H ]]⁺;¹H-NMR(DMSO d₆,400MHz):δ0.82-0.88(m,3H);1.51-1.63(m,2H);3.80-3.82(m,2H);6.53(s,H);6.74-6.76(m,2H);7.13-7.15(m,2H);7.34-7.54(m,2H);7.56(s,H);7.76(s,H);8.04(s,H);8.15(s,H)

Example 142: (S) -2- (1H-benzo [ d ] imidazol-5-yl) -3- (3, 4-dimethoxyphenyl) isoindolin-1-one

Synthesis of the Compound according to method 12

Step B, C

3, 4-Dimethoxyphenylboronic acid (724mg;4 mmol); [ RhCl (C)₂H₄)₂]₂(12mg;0.031mmol), (3aS, 6aS) -3, 6-diphenyl-1, 3a,4,6 a-tetrahydropentalene (17mg;0.066mmol), methyl 2- (tosylimino-methyl) benzoate (634mg;2mmol) and TEA (0.56ml;4 mmol); yield: 40mg (7.4%); MS M/z 270.4[ M + H [)]⁺;539.4[2M+H]⁺HPLC (gradient 3): rt 13.41min (94.4%)

Step D

4-iodobenzene-1, 2-diamine (23mg;0.1mmol), 3- (3, 4-dimethoxyphenyl) isoindolinone (29mg;0.11mmol), copper (I) iodide (2mg;0.01mmol), diaminocyclohexane (1mg;0.01mmol) and cesium fluoride (30mg;0.2 mmol); yield: 0.015g (39.0%); MS M/z 384.4[ M + H []⁺;¹H-NMR(DMSO d₆,400MHz):3.60(s,3H);3.61(s,3H);6.57(s,1H);6.75-6.77(m,2H);6.85-6.86(m,1H);7.35(d,1H,³J=7.1Hz);7.51-7.55(m,1H);7.58-7.62(m,1H);7.67-7.68(m,2H);7.84(d,1H,³J =7.5Hz), 8.04(s,1H), 8.94(br s,1H), HPLC (gradient 3) rt 11.52min (99.6%)

Example 143: (R) -2- (1H-benzo [ d ] imidazol-5-yl) -3- (3, 4-dimethoxyphenyl) isoindolin-1-one

Synthesis of the Compound according to method 12

Step B, C

3, 4-Dimethoxyphenylboronic acid (724mg;4 mmol); [ RhCl (C)₂H₄)₂]₂(12mg;0.031mmol), (3aR,6aR) -3, 6-diphenyl-1, 3a,4,6 a-tetrahydropentalene (17mg;0.066mmol), methyl 2- (toluenesulfonylimino-methyl) benzoate (634mg;2mmol) and TEA (0.56ml;4 mmol); yield: 150mg (27.9%); MS M/z 270.3[ M + H ]]⁺;539.5[2M+H]⁺HPLC (gradient 3): rt 13.57min (95.8%)

Step D

4-iodobenzene-1, 2-diamine (117mg;0.5 mmol); 3- (3, 4-Dimethoxyphenyl) isoindolinone (148mg;0.55mmol), copper (I) iodide (10mg;0.05 mm)ol), diaminocyclohexane (6mg;0.05mmol) and caesium fluoride (152mg;1 mmol); yield: 0.032g (16.6%); MS M/z 386.3[ M + H ]]⁺;¹H-NMR(DMSO d₆,400MHz):δ3.60(s,3H);3.62(s,3H);6.58(s,1H);6.77-6.79(m,2H);6.86(s,1H);7.35(d,1H,³J=7.5Hz);7.52-7.55(m,1H);7.59-7.63(m,1H);7.73-7.75(m,2H);7.84(d,1H,³J =7.5Hz), 8.11(s,1H), 9.15(br s,1H), HPLC (gradient 3) rt 11.46min (99.5%)

Example 144: (R) -2- (1H-benzo [ d ] imidazol-5-yl) -3- (4-propoxyphenyl) isoindolin-1-one

Synthesis of the Compound according to method 12

Step B, C

4-Propoxyphenylboronic acid (720mg;4 mmol); [ RhCl (C)₂H₄)₂]₂(12mg;0.031mmol), (3aR,6aR) -3, 6-diphenyl-1, 3a,4,6 a-tetrahydropentalene (17mg;0.066mmol), methyl 2- (toluenesulfonylimino-methyl) benzoate (634mg;2mmol) and TEA (0.56ml;4 mmol); yield: 152mg (28.5%); MS M/z 268.3[ M + H ]]⁺;535.6[2M+H]⁺HPLC (gradient 3): rt 18.67min (89.7%)

Step D

4-iodobenzene-1, 2-diamine (117mg;0.5 mmol); 3- (4-Propoxyphenyl) isoindolinone (147mg;0.55mmol), copper (I) iodide (10mg;0.05mmol), diaminocyclohexane (6mg;0.05mmol) and cesium fluoride (152mg;1 mmol); yield: 0.052g (27.2%); MS M/z 384.4[ M + H []⁺;¹H-NMR(DMSO d₆400 MHz:. delta.0.85-0.89 (m,3H), 1.59-1.63(m,2H), 3.76-3.78(m,2H), 6.62(s,1H), 6.76-6.78(m,2H), 7.15-7.17(m,2H), 7.29-7.30(m,1H), 7.54-7.61(m,2H), 7.72(s,2H), 7.84-7.86(m,1H), 8.10(s,1H), 9.15(s,1H), HPLC (gradient 3): rt 14.56min (99.3%)

Example 145: (S) -2- (1H-benzo [ d ] imidazol-5-yl) -3- (4-propoxyphenyl) isoindolin-1-one

Synthesis of the Compound according to method 12

Step B, C

From 4-propoxyphenylboronic acid (720mg;4 mmol); [ RhCl (C) ₂H₄)₂]₂(12mg;0.031mmol), (3aS, 6aS) -3, 6-diphenyl-1, 3a,4,6 a-tetrahydropentalene (17mg;0.066mmol), methyl 2- (toluenesulfonylimino-methyl) benzoate (634mg;2mmol) and TEA (0.56ml;4mmol) to begin the synthesis of this compound; yield: 72mg (13.5%); MS M/z 268.3[ M + H [)]⁺;535.4[2M+H]⁺HPLC (gradient 3): rt 18.57min (97.8%)

Step D

4-iodobenzene-1, 2-diamine (47mg;0.2 mmol); 3- (4-Propoxyphenyl) isoindolinone (59mg;0.22mmol), copper (I) iodide (4mg;0.02mmol), diaminocyclohexane (2mg;0.02mmol) and cesium fluoride (60mg;0.4 mmol); yield: 0.016g (20.5%); MS M/z 384.4[ M + H ]]⁺;¹H-NMR(DMSO d₆,400MHz):0.84-0.88(m,3H);1.55-1.64(m,2H);3.74-3.77(m,2H);6.51(s,H);6.73-6.76(m,2H);7.10-7.13(m,2H);7.26(d,1H,³J =7.5Hz), 7.40-7.42(m,1H), 7.47-7.59(m,3H), 7.80-7.82(m,2H), 8.15(s,1H), 12.41(br s,1H), HPLC (gradient 3): rt 14.35min (100%)

Example 146: (R) -2- (1H-benzo [ d ] imidazol-5-yl) -3- (4-chlorophenyl) isoindolin-1-one

Synthesis of the Compound according to method 12

Step B, C

4-Chlorophenylboronic acid (624mg;4mmol), [ RhCl (C)₂H₄)₂]₂(12mg;0.031mmol), (3aR,6aR) -3, 6-diphenyl-1, 3a,4,6 a-tetrahydropentalene (17mg;0.066mmol), methyl 2- (toluenesulfonylimino-methyl) benzoate (634mg;2mmol) and TEA (0.56ml;4 mmol); yield: 113mg (23.3%); MS M/z 244.4[ M + H%]⁺;487.5[2M+H]⁺HPLC (gradient 3): rt 17.05min (100%)

Step D

4-iodobenzene-1, 2-diamine (94mg;0.4 mmol); 3- (4-chlorophenyl) isoindolinone (107mg;0.44mmol), copper (I) iodide (8mg;0.04mmol), diaminocyclohexane (5mg;0.04mmol) and cesium fluoride (121mg;0.8 mmol); yield: 0.020g (13.9%); MS M/z 360.2[ M + H [)]⁺;¹H-NMR(DMSO d₆,400MHz):δ6.75(s,1H);7.30-7.37(m,H);7.56-7.60(m,1H);7.63-7.67(m,1H);7.73-7.75(m,2H);7.89(d,1H,³J =7.5Hz), 8.13(s,1H), 9.15(s,1H), HPLC (gradient 3): rt 13.60min (100%)

Example 147: (S) -2- (1H-benzo [ d ] imidazol-5-yl) -3- (4-chlorophenyl) isoindolin-1-one

Synthesis of the Compound according to method 12

Step B, C

4-Chlorophenylboronic acid (624mg;4mmol), [ RhCl (C)₂H₄)₂]₂(12mg;0.031mmol), (3aS,6aS) -3, 6-diphenyl-1, 3a,4,6 a-tetrahydropentalene (17mg;0.066mmol), methyl 2- (toluenesulfonylimino-methyl) benzoate (634mg;2mmol) and TEA (0.56ml;4 mmol); yield: 112mg (23.0%); MS M/z 244.3[ M + H [)]⁺;487.4[2M+H]⁺HPLC (gradient 3): rt 17.24min (100%)

Step D

4-iodobenzene-1, 2-diamine (94mg;0.4 mmol); 3- (4-chlorophenyl) isoindolinone (107mg;0.44mmol), copper (I) iodide (8mg;0.04mmol), diaminocyclohexane (5mg;0.04mmol) and cesium fluoride (121mg;0.8 mmol); yield: 0.029g (20.3%); MS M/z 360.2[ M + H []⁺;¹H-NMR (DMSO d₆,400MHz):6.72(s,1H);7.28-7.34(m,5H);7.54-7.57(m,1H);7.60-7.64(m,1H);7.68-7.73(m,2H);7.86(d,1H,³J=7.1Hz), 8.11(s,1H), 9.11(br s,1H), HPLC (gradient 3): rt 13.50min (99.1%)

Example 148: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4-phenylcyclohexyl) imidazolidin-2-one

This compound was synthesized as the trifluoroacetate salt as described in method 2 starting from 5-aminobenzimidazole (848mg,6.38mmol), phenylcyclohexylcarboxaldehyde (1.0g,5.31mmol), TMSCN (1.39mL,10.63mmol), PdC (10%,0.02g), bis- (imidazol-1-yl) methanone (812mg,5.01 mmol). The product was purified by preparative HPLC using a water-acetonitrile gradient containing 0.04% trifluoroacetic acid.

Yield: 0.092g (4.0%); MS M/z 361.2(M + H)⁺;¹H NMR(DMSO,400MHz):δ8.53(d,1H);8.07(d,1H);7.29-7.14(m,5H);4.27(t,1H);4.15-4.10(m,2H);2.42(t,1H);1.83-1.62(m,5H);1.50-1.41(m,2H);1.37-1.21(m,1H),HPLC(λ=214nm,[A]:rt 13.01min(98.6%).

Example 149: 1- (1H-benzo [ d ] imidazol-6-yl) -5- (1-phenylpiperidin-4-yl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from 1H-benzo [ d ] imidazol-5-amine (0.400g,3mmol), 1-phenylpiperidine-4-carbaldehyde (0.570g,3mmol), TMSCN (0.375mL,3mmol), Pd/C (10%,0.02g), TEA1.05mL,7.5mmol), and di- (imidazol-1-yl) methanone (0.730g,4.5 mmol).

Yield: 0.082g (7.6%); MS M/z 362.3(M + H)⁺,181.7(M+2H)²⁺;1H-NMR(DMSO,400MHz):1.63-1.80(m,3H);1.81-1.89(m,H);2.03-2.15(m,H);2.90-3.00(m,H);3.03-3.15(m,H);3.42-3.49(m,H);3.59-3.73(m,3H);4.70-4.77(m,H);7.12-7.18(m,H);7.24(d,2H,³J=8.3Hz);7.35(t,2H,J=7.5Hz);7.66(dd,H;³J=9.1Hz,⁴J=1.7Hz);7.79(d,H,³J=9.1Hz);7.98(s,H);9.14(s,H);HPLC(λ=214nm,[A]:rt.5.87min(99%)

Example 150: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4- (3-methoxypropyl) phenyl) imidazolidin-2-one

From 4- (3-methoxypropyl) benzaldehyde (1.5g,8.42 mm) according to method 2ol), trimethylsilyl chloride (1.6mL,16.84mmol), 5-aminobenzimidazole (1.23g,9.26mmol), 10% Pd-C (300mg), triethylamine (5.8mL,41.97mmol), and 1, 1' -carbonyldiimidazole (0.84g,5.24 mmol). Yield: 0.055g (0.6%); MS M/z 293.4(M + H) ⁺;¹H NMR(DMSO,400MHz):δ2.21(s,3H);3.05-3.09(m,H);3.83-3.87(m,H);5.49-5.53(m,H);7.01-7.10(m,2H);7.15(d,H,J=7.9Hz);7.19(s,H);7.52-7.55(m,H),7.60(d,H,J=8.7Hz);7.84(s,H);9.16(s,H),HPLC(λ=214nm,[B]:rt 8.05min(100%).

Example 151: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4-hydroxyphenyl) imidazolidin-2-one

1- (1H-benzo [ d ] in an argon atmosphere]Imidazol-5-yl) -5- (4-methoxyphenyl) imidazolidin-2-one (308mg;1mmol;1eq.) dissolved in anhydrous CH₂Cl₂(20ml) and cooled to 0 ℃. Dropwise adding BBr₃(0.285ml;3mmol;3 eq.). After complete addition, the mixture was stirred at 0 ℃ for 1h and then allowed to warm to room temperature. The reaction was quenched with water and the organic layer was separated. The aqueous layer was neutralized by adding 1N NaOH. The resulting precipitate was filtered off, dried and used without further purification. Yield: 0.174g (59.2%); MS M/z 295.1[ M + H ]]⁺;¹H-NMR(400MHz,DMSO d6):3.04-3.06(m,1H);3.72-3.77(m,1H);5.30-5.33(m,1H);6.62-6.64(m,2H);6.84(s,1H);7.09-7.11(m,2H);7.17-7.19(m,1H);7.34-7.36(d,1H,³J=8.7Hz);7.46(s,1H);8.03(s,1H);HPLC(P31/98):rt 6.66min(100%)

Example 152: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (2-hydroxyphenyl) imidazolidin-2-one

This compound was synthesized as described in example 151, starting from 1- (1H-benzo [ d ] imidazol-5-yl) -5- (2-methoxyphenyl) imidazolidin-2-one (0.075g,0.243mmol) by treatment with boron tribromide (0.069mL,0.73 mmol).

Yield: 0.014g (19.6%); MS M/z 295.2(M + H)⁺,¹H-NMR(DMSO,400MHz):3.01-3.06(m,H);3.86(t,H,³J=8.7Hz);5.65(q,H,J=4.6Hz);6.63(t,H;³J=7.9Hz);6.83(d,H;³J=7.9Hz);6.92-6.95(m,H);6.98-7.04(m,H);7.06(s,H);7.44(dd,H;³J=9.1Hz,⁴J=1.7Hz);7.53(d,H;³J=9.1Hz);7.77(d,H,⁴J=1.7Hz);1.82(s,H);9.84(s,H);HPLC(λ=214nm,[A]:rt.8.14min(100%)

Example 153: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (2, 4-dihydroxyphenyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from 1H-benzo [ d ] imidazol-5-amine (0.400g,3mmol), 2, 4-dimethoxybenzaldehyde (0.5g,3mmol), TMSCN (0.375mL,3mmol), Pd/C (10%,0.02g), tea1.05ml,7.5mmol), di- (imidazol-1-yl) methanone (0.730g,4.5mmol) to obtain 1- (1H-benzo [ d ] imidazol-5-yl) -5- (2, 4-dimethoxyphenyl) imidazolidin-2-one (yield: 0.305g,0.9mmol, 30%). The title compound was obtained by treatment with boron tribromide (0.512mL,5.41mmol) as in example 151.

Yield: 0.050g (17.9%, all steps 5.4%); MS M/z 311.1(M + H)⁺,¹H-NMR(DMSO,400MHz):3.03-3.08(m,H);3.80(t,H,³J=8.7Hz);5.54(dd,H,³J=9.1Hz,⁴J=5Hz);6.07(dd,H,³J=8.3Hz,4J=2.5Hz);6.31(d,H,⁴J=2.1Hz);6.75(d,H,³J=8.3Hz);7.04(s,H);7.47(dd,H,³J=9.1Hz,⁴J=2.1Hz);7.57(d,H,³J=9.1Hz);1.79(d,H,J=1.7Hz);8.94(s,H);9.19(s,H);HPLC(λ=214nm,[A]:rt.6.16min(98%)

Example 154: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (3, 4-dihydroxyphenyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from 1H-benzo [ d ] imidazol-5-amine (0.400g,3mmol), 3, 4-dimethoxybenzaldehyde (0.5g,3mmol), TMSCN (0.375mL,3mmol), Pd/C (10%,0.02g), tea1.05ml,7.5mmol), di- (imidazol-1-yl) methanone (0.730g,4.5mmol) to obtain 1- (1H-benzo [ d ] imidazol-5-yl) -5- (3, 4-dimethoxyphenyl) imidazolidin-2-one (yield: 0.3g,0.89mmol, 29.7%). The title compound was obtained by treatment with boron tribromide (0.505mL,5.34mmol) as in example 151.

Yield: 0.011g (3.98)% all steps 1.18%); MS M/z 311.1(M + H)⁺,621.4(2M+H);HPLC(λ=214nm,[A]:rt.6.42min(99%)

Example 155: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (3-hydroxyphenyl) imidazolidin-2-one

This compound was synthesized as described in example 151, starting from 1- (1H-benzo [ d ] imidazol-5-yl) -5- (3-methoxyphenyl) imidazolidin-2-one (0.182g,0.59mmol) by treatment with boron tribromide (0.224mL,2.36 mmol).

Yield: 0.009g (4.95%); MS M/z 295.2(M + H)⁺;¹H-NMR(DMSO,400MHz):3.03-3.08(m,H);3.83(t,H,³J=9.5Hz);5.40-5.47(m,H);6.56-6.60(m,H);6.68(s,H);6.73(d,H,³J=7.9Hz);7.07(t,H,³J=7.9);7.14(s,H);7.50(m,H);7.55-7.59(m,H);7.79(s,H);9.01(s,H);9.39(s,H);HPLC(λ=214nm,[A]:rt.7.30min(100%)

Example 156: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4- (cyclohexyloxy) phenyl) imidazolidin-2-one

The compound was synthesized as the trifluoroacetate salt starting from 5-aminobenzimidazole (2.35g,17.64mmol), cyclohexyloxy) benzaldehyde (3.0g,14.70mmol), TMSCN (2.91g,29.40mmol), PdC (10%,0.2g), TEA (9.6mL,69.36mmol), bis- (imidazol-1-yl) methanone (1.40g,8.67mmol) as described in method 2. The product was purified by preparative HPLC.

Yield: 0.11g (1.7%); MS M/z 377.4(M + H)⁺;¹H NMR (400MHz, CDCl3): delta 7.88(s,1H), 7.63(s,1H), 7.47(s,1H), 7.25-7.21 (mixed with CDCl3, 3H), 6.80(d,2H), 5.28(t,2H), 4.70(s,1H), 4.16(d,1H), 3.93(t,1H), 3.39(t,1H), 1.93-1.75(m,4H), 1.55-1.28(m,6H), HPLC (. lamda =214nm, [ A, H ]]:rt 12.75min(97.3%).

Example 157: 5- (4- (2-methoxyethoxy) phenyl) -1- (1H-benzo [ d ] imidazol-5-yl) imidazolidin-2-one

The compound was synthesized as the trifluoroacetate salt starting from 5-aminobenzimidazole (1.3gmg,9.99mmol), 4- (2-methoxyethoxy) benzaldehyde (1.5g,8.33mmol), TMSCN (1.64mL,16.66mmol), 10% Pd-C (200mg), TEA (2.5mL,18.40mmol), bis- (imidazol-1-yl) methanone (1.192g,7.36mmol) as described in method 2. The product was purified by preparative HPLC.

Yield: 0.04g (1.3%); MS M/z 353.3(M + H)⁺;¹H NMR (400MHz, DMSO-d6): delta 12.24(s,1H), 8.08(d,1H), 7.55-7.24(m,5H), 6.96-6.84(m,3H), 5.44(s,1H), 3.99(d,2H), 3.81(s,1H), 3.58(s,2H), 3.30 (mixed with aqueous DMSO solution, 3H), 3.08(s,1H), HPLC (. lamda =214nm, [ A, 1H ] ]:rt 7.97min(92.93%).

Example 158: (S) -5- (4- (2- (dimethylamino) ethoxy) phenyl) -1- (1H-benzo [ d ] imidazol-5-yl) imidazolidin-2-one

This compound was synthesized as the trifluoroacetate salt starting from trimethylcyanosilane (1.88mL,20.72mmol), 5-aminobenzimidazole (0.82g,6.21mmol), 4- (3- (dimethylamino) propoxy) benzaldehyde (1.0g,5.18mmol), 10% Pd-C (250mg), triethylamine (7.5mL,51.91mmol), 1' -carbonyldiimidazole (1g,6.48 mmol). The product was further purified by preparative HPLC using the following conditions: column: ChiralpakAD-H; mobile phase: hexane ethanol (0.1% DEA); flow rate: 32mL/min, UV: 210nm, diluent: a mobile phase. The preparative fractions were concentrated in vacuo and partitioned between water and chloroform. The separated organic layer was washed with brine solution. Dried over anhydrous sodium sulfate and concentrated in vacuo to afford 50mg of the product as a brown solid.

Yield: 0.050g (2.6%); MS M/z 366.3(M + H)⁺;¹H NMR (400MHz, CDCl3): delta 10.40(Bs,1H), 7.86(s,1H), 7.54(s,1H), 7.32-7.16 (mixed with CDCl3, 5H), 6.80(d,2H), 5.25(t,1H), 4.83(s,1H), 4.00-3.90(m,3H), 3.38(t,1H), 2.68(d,2H), 2.35-2.15(m,6H), HPLC (lambda =214nm, [ A ] H]:rt 5.12min(88.53%).

Example 159: 3- (1H-benzo [ d ] imidazol-5-yl) -1-phenethyl-4- (4-propoxyphenyl) imidazolidin-2-one

Step A:

this compound was synthesized as described in method 13, starting from 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4-propoxyphenyl) imidazolidin-2-one (6.73g,20mmol), triethylamine (3.33ml,24mmol) and trityl chloride (6.7g,24mmol) in 50ml THF.

Yield: 10.2g (86%)

And B:

the product obtained from step A (0.145g,0.25mmol), sodium hydride (0.13g,5.42mmol), (2-bromoethyl) benzene (0.14ml,1 mmol). The product was purified by flash chromatography using chloroform as eluent.

Yield: 0.13g (77%)

And C:

the product obtained from step B (0.13g,0.19mmol), TFA (4ml in 20ml methanol)

Yield: 0.039g (46.6%)

The total yield is as follows: 30.9% MS M/z 441.4(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ0.87-0.91(m,3H);1.56-1.67(m 2H);2.78-2.82(m,2H);3.05-3.09(m,H);3.36-3.55(m,2H);3.77-3.81(m,3H);5.29-5.32(m,H);6.75-6.78(m,2H);7.12-7.27(m,8H);7.34-7.36(m,H);7.47(s,H);8.04(s,H);12.24(br s,H),HPLC(λ=214nm),[B]:rt 14.97min(96%).

Example 160: 3- (1H-benzo [ d ] imidazol-5-yl) -1- ((naphthalen-2-yl) methyl) -4- (4-propoxyphenyl) imidazolidin-2-one

Step A:

this compound was synthesized as described in method 13, starting from 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4-propoxyphenyl) imidazolidin-2-one (6.73g,20mmol), triethylamine (3.33ml,24mmol) and trityl chloride (6.7g,24mmol) in 50ml THF.

Yield: 10.2g (86%)

And B:

the product obtained from step A (0.145g,0.25mmol), sodium hydride (0.13g,5.42mmol), 2- (bromomethyl) naphthalene (0.055g,0.25mmol)

And C:

crude product from step B, TFA (4ml in 20ml methanol)

Yield: 0.005g (3.9% step B + C)

The total yield is as follows: 3.3% MS M/z 477.4(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ0.91-0.95(m,3H);1.60-1.71(m,2H);3.17-3.21(m,H);3.76-3.83(m,3H);4.65(s,2H);5.23-5.27(m,H);6.74(d,2H,J=8.7Hz);7.17(d,2H,J=8.7Hz);7.27-7.29(m,H);7.43-7.47(m,4H);7.55(bs,H);7.76-7.85(m,4H);8.07(br s,H),HPLC(λ=214nm),[B]:rt 16.16min(95.4%).

Example 161: 3- (1H-benzo [ d ] imidazol-5-yl) -1- (3-phenylpropyl) -4- (4-propoxyphenyl) imidazolidin-2-one

Step A:

this compound was synthesized as described in method 13, starting from 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4-propoxyphenyl) imidazolidin-2-one (6.73g,20mmol), triethylamine (3.33ml,24mmol) and trityl chloride (6.7g,24mmol) in 50ml THF.

Yield: 10.2g (86%)

And B:

the product obtained from step A (0.145g,0.25mmol), sodium hydride (0.13g,5.42mmol), (3-bromopropyl) benzene (0.038ml,0.25mmol)

And C:

crude product from step B, TFA (4ml in 20ml methanol)

Yield: 0.063g (55.4% step B + C)

The total yield is as follows: 42.7% MS M/z 455.4(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ0.86-0.90(m,3H);1.58-1.66(m,2H);1.73-1.80(m,2H);2.54-2.58(m,2H);3.08-3.12(m,H);3.21-3.24(m,2H);3.78-3.85(m,3H);5.31-5.35(m,H);6.80(d,2H,J=8.7Hz);7.12-7.25(m,8H);7.35-7.37(m,H);7.50(s,H);8.04(s,H);12.22(br s,H),HPLC(λ=214nm),[B]:rt 15.73min(99.3%).

Example 162: 3- (1H-benzo [ d ] imidazol-5-yl) -1-benzyl-4- (4-propoxyphenyl) imidazolidin-2-one

Step A:

this compound was synthesized as described in method 13, starting from 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4-propoxyphenyl) imidazolidin-2-one (6.73g,20mmol), triethylamine (3.33ml,24mmol) and trityl chloride (6.7g,24mmol) in 50ml THF.

Yield: 10.2g (86%)

And B:

the product obtained from step A (0.145g,0.25mmol), sodium hydride (0.13g,5.42mmol), benzyl bromide (0.03ml,0.25mmol)

And C:

crude product from step B, TFA (4ml in 20ml methanol)

Yield: 0.062g (58.1% step B + C)

The total yield is as follows: 50% MS M/z 427.3(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ0.86-0.89(m,3H);1.57-1.66(m,2H);2.97-3.00(m,H);3.69-3.74(m,H);3.76-3.80(m,2H);4.40(s,2H);5.36-5.40(m,H);6.77(d,2H,J=8.7Hz);7.18(d,2H,J=8.7Hz);7.23-7.34(m,6H);7.37-7.39(m,H);7.54(s,H);8.06(s,H);12.24(br s,H),HPLC(λ=214nm),[B]:rt 14.43min(99.8%).

Example 163: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4-fluoro-3-methoxyphenyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from 5-aminobenzimidazole (0.585g,4.4mmol), 4-fluoro-3-methoxybenzaldehyde (0.616g,4mmol), TMSCN (0.5mL,4mmol), PdC (10%,0.02g), TEA1.21mL,8.7mmol), bis- (imidazol-1-yl) methanone (0.767g,4.7 mmol).

Yield: 0.15g (11.5%); MS M/z 327.5(M + H)⁺;¹H NMR(DMSO,400MHz):δ3.08-3.12(m,H);3.75(s,3H);3.77-3.82(m,H);5.43-5.47(m,H);6.83-6.86(m,H);.6.91(s,H);7.04-7.09(m,H);7.14-7.16(m,H);7.21(s,H);7.37(s,H);7.51(s,H);8.05(s,H);12.21(br s,H),HPLC(λ=214nm,[B]:rt 8.97min(94.8%).

Example 164: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (3-fluoro-4-propoxyphenyl) imidazolidin-2-one

3-fluoro-4-propoxybenzaldehyde was synthesized starting from 3-fluoro-4-hydroxybenzaldehyde (0.83g,5.95mmol) and 1-iodopropane (1.16ml,11.9mmol) according to the reaction conditions described in Liou et al, j.med.chem.2004,47(11), 2903.

This compound was further synthesized as described in method 2 starting from 5-aminobenzimidazole (0.806g,6.1mmol), 3-fluoro-4-propoxybenzaldehyde (1.0g,5.5mmol), TMSCN (0.69mL,5.5mmol), PdC (10%,0.02g), TEA1.44mL,10.3mmol), di- (imidazol-1-yl) methanone (0.92g,5.6 mmol).

Yield: 0.106g (5%); MS M/z 355.2(M + H)⁺;¹H NMR(CD₃OD,400MHz):δ0.96-1.00(m,3H);1.68-1.78(m,2H);3.32-3.36(m,H);3.89-3.97(m,3H);5.37-5.41(m,H);6.93-6.97(m,H);7.07-7.09(m,H);7.11-7.14(m,H);7.24-7.26(m,H);7.46-7.50(m,2H);8.06(s,H)

HPLC(λ=214nm,[B]:rt 10.73min(96%).

Example 165: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (2-fluoro-4-propoxyphenyl) imidazolidin-2-one

2-fluoro-4-propoxybenzaldehyde was synthesized starting from 3-fluoro-4-hydroxybenzaldehyde (0.1g,0.7mmol) and 1-iodopropane (0.24g,1.4mmol) under the reaction conditions described in Liou et al, j.med.chem.2004,47(11), 2903.

This compound was synthesized as described in method 2 starting from 5-aminobenzimidazole (0.09g,0.67mmol), 2-fluoro-4-propoxybenzaldehyde (0.11g,0.6mmol), TMSCN (0.084mL,0.67mmol), PdC (10%,0.02g), TEA (0.184mL,1.32mmol), bis- (imidazol-1-yl) methanone (0.117g,0.72 mmol).

Yield: 0.012g (4.8%); MS M/z 355.4(M + H)⁺;¹H NMR(CD₃OD,400MHz):δ0.96-0.99(m,3H);1.68-1.76(m,2H);3.39-3.42(m,H);3.83-3.86(m,2H);3.97-4.02(m,H);5.71-5.75(m,H);6.63-6.65(m,2H);7.22-7.27(m,H);7.46-7.49(m,H);7.57-7.59(m,H);7.73(s,H);8.72(s,H),HPLC(λ=214nm,[B]:rt 10.95min(95.1%).

Example 166: (S) -1- (1H-benzo [ d ] imidazol-5-yl) -5- (4- (diethylamino) phenyl) imidazolidin-2-one

From 4- (diethylamino) benzaldehyde (2g,11.29mmol), 2.3M n-butyllithium (tert-butyl hypochlorite (1.9mL,17.42mmol), tert-butyl carbamate (2g,17.14mmol), sodium hydroxide (0.696g in 25mL water), (DHQ) according to method 3, modified as indicated above₂PHAL (222mg,0.285mmol), potassium osmate dihydrate (83mg,0.228mmol), diethyl azodicarboxylate (1.5mL,9.496mmol), phthalimide (1.023g,6.96mmol), triphenylphosphine (2.48g,9.49mmol), hydrazine hydrate (20mL), p-anisaldehyde (0.3mL,2.768mmol), sodium borohydride (366mg,9.68mmol), 6N HCl solution (15mL), triethylamine (0.7mL), and CDI (433mg,2.67mmol), 1, 2-diamino-4-bromobenzene (349mg,1.869mmol), cesium fluoride (516mg,3.398mmol), cuprous iodide (48mg), 2-diaminocyclohexane (0.03mL,0.254mmol), formic acid (5mL), trifluoroacetic acid (5mL) were initially synthesized.

Yield: 0.07g (1.6%); MS M/z 350.5(M + H)⁺;¹H-NMR(400MHz,DMSO-d6):δ12.26(Bs,1H);8.08(s,1H);7.52(s,1H);7.39(d,1H);7.25(s,1H);7.12(d,2H);6.88(d,3H);6.52(d,2H);5.32(q,1H);3.73(t,1H);3.39-3.32(m,4H);3.07(t,1H);1.10-0.99(m,6H);HPLC(λ=214nm,[A]:rt 4.44min(95.4%)

Example 167: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4-chlorophenyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from 5-aminobenzimidazole (0.585g,4.4mmol), 4-chlorobenzaldehyde (0.56g,4mmol), TMSCN (0.5mL,4mmol), PdC (10%,0.02g), TEA (1.93mL,13.9mmol), bis- (imidazol-1-yl) methanone (1.12g,6.9 mmol).

Yield: 0.045g (3.6%); MS M/z 313.1(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ3.04-3.08(m,H);3.79-3.84(m,H);5.49-5.52(m,H);6.93(s,H);7.33-7.38(m,5H);7.19-7.22(m,H);7.51(d,H,J=1.7Hz);8.05(s,H);12.22(br s,H),HPLC(λ=214nm,[B]:rt 9.62min(99.7%).

Example 168: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4-cyclohexylphenyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from 1H-benzo [ d ] imidazol-5-amine (0.400g,3mmol), 4-cyclohexylbenzaldehyde (0.565g,3mmol), TMSCN (0.375mL,3mmol), Pd/C (10%,0.02g), TEA (1.05mL,7.5mmol), bis- (imidazol-1-yl) methanone (0.730g,4.5 mmol).

Yield: 0.023g (2.1%); MS M/z 361.0(M + H)⁺;¹H-NMR(DMSO,400MHz):1.05-1.19(m,H);1.20-1.34(m,4H);1.59-1.76(m,5H);2.34-2.41(m,H);3.04(t,H,J=7.9Hz);3.78(q,H,J=6.2Hz);5.43(t,H,J=8.3Hz);6.83(s,0.5H);6.90(s,0.5H);7.10(d,2H,³J=7.9Hz);7.13-7-18(m,0.6H);7.19-7.25(m,2H);7.28-7.37(m,2H);7.40(d,0.6H,³J=8.7Hz);7.46(s,0.4H);7.56(s,0.5H);8.04(d,H,J=10.8Hz);12.14-12-25(m,0.9H);HPLC(λ=214nm,[A]:rt.15.00min(95%)

Example 169: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4- (4-morpholinocyclohexyl) phenyl) imidazolidin-2-one

The compound was synthesized as described in method 2 starting from 5-aminobenzimidazole (486mg,3.66mmol), 34- (4-morpholinocyclohexyl) benzaldehyde (1g,3.66mmol), TMSCN (0.98mL,7.32mmol), 10% Pd-C (200mg), TEA (9.16mL,90.60mmol), bis- (imidazol-1-yl) methanone (1.76g,10.88 mmol).

Yield: 0.040g (2.4%); MS M/z 446.5(M + H)⁺;¹H NMR (400MHz, CDCl3) < delta > 7.91(S,1H) < delta >, 7.64(S,1H) < delta >, 7.55(S,1H) < delta >, 7.25-7.15 (mixed with CDCl3, 5H) < delta >, 5.35(t,1H) < delta >, 4.81(t,1H) < delta >, 3.99(t,1H) < delta >, 3.57(S,4H) < delta >, 3.56-3.32(m,2H) < delta >, 2.85(S,1H) < delta >, 2.45(S,4H) < delta >, 2.21(S,1H) < delta >, 1H, < delta >, 1.99 (S,4H) < delta >, 3.56-3.]:rt 5.84min(99.4%).

Example 170: (S) -1- (1H-benzo [ d ] imidazol-5-yl) -5- (4- (1-methylpiperidin-4-yl) phenyl) imidazolidin-2-one

Step A

n-BuLi (2.3M in hexane; 18.4mL,42.39mmol) was added over a period of 10min to a solution of 1, 4-dibromobenzene (10g,42.39mmol) in THF (100mL) at-78 deg.C (solids separated on addition of n-BuLi). Stirring was carried out at the same temperature for 30min, n-methyl-4-piperidone (4.9mL,42.39mmol) was added, the temperature was slowly raised to room temperature and stirring was carried out at RT for 1 hr. The reaction mass was quenched with ammonium chloride solution and diluted with ethyl acetate. The organic layer was separated and washed with water and then brine solution. Dried over anhydrous sodium sulfate and concentrated to afford 8.5g (74%) of the product as an oily liquid, which was used without further characterization.

Step B

6N HCl (10mL) was added to the product of step A (500mg,1.85mmol) and stirred at reflux for 16 h. The RM was concentrated, the residue basified with saturated ammonium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with water then brine solution, dried over anhydrous sodium sulfate and concentrated to provide 350mg (75%) of the product as a white solid, which was used without further characterization.

Step C

10% Pd-C (2g) was added to a solution of the product of step B (8g,31.74mmol) in AcOH (80mL) and hydrogenated in a par apparatus for 19 h. The RM was filtered through celite bed and washed with ethyl acetate. The filtrate was concentrated to provide 7.5g (90%) of the oily liquid-like product, which was used without further characterization.

Step D

Oxalyl chloride (4.1mL,45.71mmol) was added to a solution of the product of step C (2g,11.42mmol) in DCM (20mL) at-30 ℃ followed by AlCl addition at the same temperature₃(6g,45.71 mmol). Stir at-30 ℃ for 1h and slowly warm to RT for 2 h. The RM was cooled to 0 ℃ and methanol (30mL) was added slowly (exothermically) at 15min (note: salt formation and RM was stirred to add more methanol until the solution cleared). The temperature was slowly raised to RT and stirred for 18 h. Adding RM with Na₂CO₃The aqueous solution was quenched and diluted with ethyl acetate. The salt was filtered off and washed with ethyl acetate until the salt was free of compound. The organic layer was separated from the filtrate and washed with water and then brine solution. Dried over anhydrous sodium sulfate and concentrated to give 1.3g (50%) of the product as a brown oil, which was used without further characterization.

Step E

LiAlH was added at 0 ℃ for a period of 15min₄(211mg,5.57mmol) A solution of the product of step D (1.3g,5.57mmol) in THF (20mL) was added. The temperature was slowly raised to RT and stirred for 1 h. The RM was quenched with saturated sodium sulfate solution and diluted with ethyl acetate. The salt was filtered off and washed with ethyl acetate. The organic layers were combined and washed with water then brine solution. Dried over anhydrous sodium sulfate and concentrated to afford 850mg (74.5%) of the product as an oil, which was used without further characterization.

Step F

PCC (1.05g,4.87mmol) was added to a solution of the product of step E (1g,4.87mmol) in DCM (10mL) and stirred for 30 min. The reaction mass was dissolved by addition of a small amount of methanol and purified by column chromatography on neutral alumina using 5% methanol in chloroform as eluent to afford 750mg (75%) of 4- (1-methylpiperidin-4-yl) phenyl) carbaldehyde as an oily solid, which precipitated slowly on standing for a long period of time and was used without further characterization.

The title compound was synthesized as described in method 2 starting from 5-aminobenzimidazole (393mg,2.95mmol), 3-54- (1-methylpiperidin-4-yl) phenyl) carbaldehyde (500mg,2.46mmol), TMSCN (0.5mL,4.92mmol), 10% Pd-C (150mg), TEA (2.23mL,16.04mmol), bis- (imidazol-1-yl) methanone (334mg,2.06 mmol).

The product was further purified by preparative HPLC using the following chiral conditions:

column: chiralpak ADH

Mobile phase: hexane ethanol 0.1% diethylamine

Flow rate: 32mL/min

UV:210nm

Diluent agent: mobile phase

The solvent was evaporated, co-distilled with toluene and washed with pentane to afford 25mg of the product as a brown solid.

Yield: 0.025g (2.2%); MS M/z 376.4(M + H)⁺;¹H NMR 400MHz, CDCl 3:. delta.9.56 (bs, 1H);. delta.9.56 (s, 1H);. 7.89(s, 1H);. 7.66(s, 1H);. 7.51(s, 1H);. 7.27-7.13 (with CDCl) ₃Mixture, 7H), 5.35-5.31(q,1H), 5.01-4.90(m,1H), 4.69(s,1H), 3.95(t,1H), 3.37(t,1H), 2.94(d,2H), 2.50-2.31(m,1H), 2.30(s,3H), 2.04-1.98(m,3H), 1.86-1.65(m,4H), HPLC (. lamda =214nm, [ B, 1H ]]:rt 5.04min(97.7%)

Example 171: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4- (tetrahydro-2H-pyran-4-yl) phenyl) imidazolidin-2-one

Step A

N-butyllithium (2.3M in hexane; 1.83mL,4.23mmol) was added at-78 ℃ to a solution of 1, 4-dibromobenzene (1g,4.23mmol) in anhydrous THF. The reaction mixture was stirred for 20min, then 1H-tetrahydro-4-one (0.4mL,4.23mmol) was added at the same temperature. The reaction mixture was slowly brought to room temperature over 2h, quenched with 5% citric acid solution (10mL) and extracted with ethyl acetate (3 × 25mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to obtain 900mg (91.8%) of the product as a colorless liquid, which was used without further characterization.

Step B

A suspension of the product of step A (2g,7.78mmol) in BF 3-etherate (10mL) was stirred at room temperature for 2 h. The reaction mixture was then washed with saturated NaHCO₃The solution was basified and extracted with ethyl acetate (3 × 50mL), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to afford 1.5g (81%) of the product, which was used without further characterization.

Step C

The product of step B (6.0g,25.01mmol) was added to a solution of 10% Pd-C (600mg,10%) in ethanol (50mL) at 80Psi in a hydrogenation vessel for 16 h. The reaction mixture was then filtered through a celite bed, the solvent was evaporated and dried to provide 3.42g (83.7%) of the product as a pale yellow liquid, which was used without further characterization.

Step D

Oxalyl chloride (9mL,98.76mmol) was added to a solution of the product of step C (4.0g,24.69mmol) in dichloromethane (50mL) at-20 ℃. The reaction mixture was stirred for 30min and AlCl was added at the same temperature₃(32.8g,246.9mmol) and stirred for a further 1h, then brought to room temperature in 2 h. Methanol (25mL) was then added to the reaction and left overnight. The reaction mixture was washed with saturated NaHCO₃The solution was basified, filtered and washed with ethyl acetate (100mL), the solution was partitioned between two layers, the organic layer was separated, washed with brine solution and the organic layer was evaporated to give 4.0g(74%) colorless liquid-like product, which was used without further characterization.

Step E

Lithium aluminum hydride (860mg,20.45mmol) was added to a solution of the product of step D (4.5g,20.45mmol) in dry THF (40mL) at 0 ℃. The reaction mixture was then allowed to warm to room temperature for 2h, cooled to 0 ℃ and saturated NH was used ₄The Cl solution (25mL) was quenched, and the mixture was filtered and washed with ethyl acetate (100 mL). The solution was partitioned between two layers, the organic layer was separated, washed with brine solution and evaporated to afford 3.2g (82%) of the product as a light yellow solid, which was used without further characterization.

Step F

Pyridinium chlorochromate (4.1g,19.27mmol) was added to a solution of the product of step E (3.7g,19.27mmol) in dichloromethane (40mL) at room temperature. The reaction mixture was stirred for 1h, neutral alumina (10g) was added and passed through a filter column containing 10% ethyl acetate in petroleum ether to obtain 2.2g (60.01%) of the product as a white solid, which was used without further characterization.

The title compound was synthesized as described in method 2 starting from 5-aminobenzimidazole (840mg,6.32mmol), 3- (4- (tetrahydro-2H-pyran-4-yl) benzaldehyde (1.0g,5.25mmol), TMSCN (1.15mL,10.52mmol), 10% Pd-C (250mg), TEA (3.6mL,26.7mmol), bis- (imidazol-1-yl) methanone (434mg,2.67 mmol).

Yield: 0.05g (2.1%); MS M/z 363.1(M + H)⁺;¹H NMR (400MHz, CDCl3): delta 12.25(d,1H), 8.07(d,1H), 7.59-7.17(m,6H), 6.90(d,1H), 5.50(d,1H), 3.87(t,2H), 3.39-3.11 (mixed with DMSO aqueous solution, 2H), 3.08(t,1H), 2.67(d,1H), 1.59(d,4H), HPLC (lambda =214nm, [ A ] A ]:rt 10.03min(99.38%)

Example 172: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4- (4-oxocyclohexyl) phenyl) imidazolidin-2-one

Step A

A mixture of 4- (4-cyanophenyl) cyclohexanone (3.0g,15.05mmol), ethylene glycol (2.1mL,37.64mmol) and catalytic p-toluenesulfonic acid (430mg,2.26mmol) in toluene (50mL) was heated at 125 ℃ and 130 ℃ for 24 h. The reaction mass was cooled to room temperature, diluted with toluene and washed successively with saturated sodium bicarbonate solution, water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the crude product. Purification by column chromatography on silica gel (60-120 mesh) using 5% ethyl acetate in petroleum ether as eluent afforded 3.36g of the product as a white solid.

Step B

25% diisobutylaluminum hydride in toluene (17.3mL,27.65mmol) was added to a solution of the product of step A (3.36g,13.83mmol) in anhydrous tetrahydrofuran (60mL) at-40 ℃. The reaction mass was allowed to warm to room temperature and stirred for 3.5 h. The reaction mass was cooled to 0 ℃ and quenched with saturated ammonium chloride solution. The salt was filtered and washed with ethyl acetate. The combined filtrate and washings were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3.36g of crude product as a pale yellow slurry. It was used in the next step without purification.

Step C

Tribenzonitrile silane (0.87mL,6.50mol) was added to a solution of 5-aminobenzimidazole (433mg,3.25mmol), the product of step B (800g,3.25mmol) in acetic acid (20mL) and stirred for 1h40 min. The reaction mass was quenched with cold aqueous ammonia and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 1.0g of crude product as a tan solid.

Step D

A solution of the product of step C (1.0g,2.58mmol) in acetic acid (50mL) was hydrogenated over 10% Pd-C (250mg) in a Parr apparatus at 80psi pressure for 20 h. The reaction mass was filtered through celite and washed with acetic acid. The combined filtrate and washings were concentrated in vacuo to afford 2.56g of the crude product as a brown liquid. The crude product was used directly in the next step without any purification.

Step E

Triethylamine (9.8mL,70.4mmol), carbonyldiimidazole (1.14,7.04mmol) were added successively to a solution of the crude product from step D (2.76g,7.04mmol) in tetrahydrofuran (50mL) and refluxed for 18.5 h. The reaction mass was cooled to room temperature, poured into water and extracted with ethyl acetate (2X50 mL). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the crude product. Purification by column chromatography on neutral alumina using 6-7% methanol in chloroform as eluent afforded 270mg of the product as a pale yellow solid. It was used directly in the next step.

Step F

Trifluoroacetic acid (2.5mL) was added to a solution of the product of step E (200mg,0.48mmol) in dichloromethane (10mL) at 0 ℃ and stirred at room temperature for 3.5 h. The volatiles were evaporated in vacuo; the resulting residue was dissolved in dichloromethane and washed successively with saturated sodium bicarbonate solution, water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the crude product. Purification by preparative TLC using 5% methanol in chloroform as eluent afforded 70mg (35.52%) of the product as a light yellow solid.

Yield: 70mg (35.52%); MS M/z 375.2(M + H)⁺,174.9(M+2H)²⁺1H-NMR (DMSO,400MHz) < delta > 12.24(Bs,1H) < delta > 8.06(s,1H) < delta > 7.57-7.21(m,6H) < delta > 6.91(s,1H) < delta > 5.49(t,1H) < delta > 3.82(t,1H) < delta > 3.40(t,1H) < delta > 3.16-2.98(m,2H) < delta > 2.55 (mixed with DMSO, 1H) < delta > 2.37-2.19(m,2H) < delta > 2.15-0.9(m,2H) < delta > 0.95-0.85(m,2H) < delta > HPLC (. lamda =214nm, [ A, 2H) < delta > 0]:rt.9.93min(94.77%)

Example 173: (S) -1- (1H-benzo [ d ] imidazol-5-yl) -5- (4- (4, 4-difluorocyclohexyl) phenyl) imidazolidin-2-one

Step A

DAST (2.6mL,19.84mmol) was added to a solution of 4- (4-cyanophenyl) cyclohexanone (2.0g,10.04mmol) in dichloromethane (50) at 0 ℃. The reaction mass was allowed to warm to room temperature and stirred for 2.5 h. The reaction mass was quenched in ice water and the organic layer was separated. The aqueous layer was extracted with dichloromethane (1 × 30 mL). The combined organic layers were washed with water (1x50mL), brine (1x50mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford the crude product. Purification by column chromatography on silica gel (60-120 mesh) using 10-12% ethyl acetate in petroleum ether as eluent afforded 1.5g (67.63%) of the product as an off-white solid, which was used without further characterization.

Step B

Diisobutylaluminum hydride (8.5mL,13.37mmol) was added to a solution of the product of step A (1.5g,6.79mmol) in anhydrous tetrahydrofuran (50mL) at-70 ℃. The reaction mass was allowed to warm to room temperature and stirred for 3 h. The reaction mass was cooled to 0 ℃ and quenched with saturated ammonium chloride solution. The salt was filtered and washed with chloroform. The combined filtrate and washings were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 1.5g (96.68%) of 4- (4, 4-difluorocyclohexyl) benzaldehyde as a pale yellow syrup, which was used without further characterization.

The title compound was synthesized as described in method 2, starting from 5-aminobenzimidazole (297mg,2.23mmol), 3-4- (4, 4-difluorocyclohexyl) benzaldehyde (500mg,2.23mmol), TMSCN (0.6mL,2.23mmol), 10% Pd-C (200mg), TEA (2.8mL,20.0mmol), bis- (imidazol-1-yl) methanone (486mg,3.0 mmol).

The title compound was further purified by chiral preparative HPLC using the following chiral preparative conditions:

column: CHIRALPAK ADH (30x250mm) 5 mu,

mobile phase: hexane IPA DEA (80:20:0.1),

flow rate: 35mL/min, [ lambda ] max:225nm,

solubility: a mobile phase.

The fractions were concentrated under reduced pressure. The resulting residue was dissolved in chloroform, washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure.

Yield: 0.04g (4.5%); MS M/z 397.2(M + H)⁺;¹H NMR DMSO-d₆):δ:12.29(d,1H);8.09(d,1H);7.60-7.17(m,7H);6.96(d,1H);5.49(s,1H);3.82(d,1H);3.07(t,1H);2.62(t,1H);2.62(s,1H);2.04-1.56(m,8H)HPLC(λ=214nm,[A]:rt 12.69min(100%)

Example 174: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (3- (pyrrolidin-1-yl) phenyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from 1H-benzo [ d ] imidazol-5-amine (0.400g,3mmol), 3- (pyrrolidin-1-yl) benzaldehyde (0.526g,3mmol), TMSCN (0.375mL,3mmol), Pd/C (10%,0.02g), TEA (1.05mL,7.5mmol), bis- (imidazol-1-yl) methanone (0.730g,4.5 mmol).

Yield: 0.061g (6.2%); MS M/z 348.2(M + H)⁺,174.9(M+2H)²⁺;1H-NMR(DMSO,400MHz):1.83-1.95(m,4H);3.04-3.20(m,5H);3.81(t,H,J=9.1Hz);5.38(q,H;J=8.7Hz);6.32-6.37(m,H);6.50(s,H);6.54(d,H,J=7.5Hz);6.87(s,H);7.04(t,H,J=7.9Hz);7.24-7.34(m,H);7.39(d,H,J=8.7Hz);7.51-7.55(m,H);8.06(s,H);12.23(br s,0.6H);HPLC(λ=214nm,[A]:rt.9.68min(99%)

Example 175: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4- (piperidin-1-yl) phenyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from 1H-benzo [ d ] imidazol-5-amine (0.400g,3mmol), 4- (piperidin-1-yl) benzaldehyde (0.570g,3mmol), TMSCN (0.375mL,3mmol), Pd/C (10%,0.02g), TEA (1.05mL,7.5mmol), bis- (imidazol-1-yl) methanone (0.730g,4.5 mmol).

Yield: 0.006g (0.5%); MS M/z 362.4(M + H)⁺,181.7(M+2H)²⁺;¹H-NMR(DMSO,400MHz):1.44-1.51(m,6H);3.00-3.06(m,5H);3.75(t,H,8,7Hz);5.35(q,H,J=8.7Hz);6.78(d,2H,J=8.7Hz);7.13(d,2H,J=8.7Hz);7.21-7.23(m,0.6H);7.35(d,H,J=8.7Hz);7.5(s,H);8.06(br s,0.6H);HPLC(λ=214nm,[A]:rt.5.47min(90%)

Example 176: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (3- (piperidin-1-yl) phenyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from 1H-benzo [ d ] imidazol-5-amine (0.400g,3mmol), 3- (piperidin-1-yl) benzaldehyde (0.570g,3mmol), TMSCN (0.375mL,3mmol), Pd/C (10%,0.02g), TEA (1.05mL,7.5mmol), bis- (imidazol-1-yl) methanone (0.730g,4.5 mmol).

Yield: 0.085g (8.3%); MS M/z 362.2(M + H)⁺,181.7(M+2H)²⁺;¹H-NMR(DMSO,400MHz):1.40-1.57(m,6H);2.95-3.09(m,5H);3.73-3.83(m,H);5.37(q,H,J=9.1Hz);6.63-6.73(m,2H);6.79-6.91(m,2H);7.05(t,H;J=7.8Hz);7.13-7.19(m,0.5H);7.27-7.37(m,H);7.38-7.43(m,0.5H);7.44-7.49(m,0.5H);7.53(s,0.5H);8.04(d,H;J=9.1Hz);12.15-12.25(m,H);HPLC(λ=214nm,[A]:rt.5.89min(99%)

Example 177: 1- (1H-benzo [ d ] imidazol-5-yl) -5- (4-morpholinophenyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from 1H-benzo [ d ] imidazol-5-amine (0.333g,2.5mmol), 4-morpholinobenzaldehyde (0.473g,2.5mmol), TMSCN (0.375mL,3mmol), Pd/C (10%,0.02g), TEA (1mL,7.2mmol), bis- (imidazol-1-yl) methanone (0.600g,3.7 mmol).

Yield: 0.048g (4.16%); MS M/z 364,0(M + H)⁺,182.9(M+2H)²⁺;¹H-NMR(400MHz,DMSO-D₆):3.01-3.04(m,4H);3.08-3.11(m,H);3.66-3.68(m,4H);3.82-3.86(m,H);5.46-5.50(m,H);6.85-6.87(m,2H);7.19-7.21(m,3H);7.57-7.66(m,2H);7.89(d,H,J=2.1Hz);9.33(s,H);HPLC(λ=214nm,[A]:rt 8.02min(89%)

Example 178: 5- (4-cyclohexylphenyl) -1- (H-imidazo [1,2-a ] pyridin-7-yl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from H-imidazo [1,2-a ] pyridin-7-amine (0.400g,3mmol), 4-cyclohexylbenzaldehyde (0.565g,3mmol), TMSCN (0.450mL,3.6mmol), Pd/C (10%,0.02g), TEA (1.05mL,7.5mmol), bis- (imidazol-1-yl) methanone (0.730g,4.5 mmol).

Yield: 0.067g (6.2%); MS M/z 361.0(M + H)⁺;1H-NMR(DMSO,400MHz):1.10-1.23(m,H);1.24-1.38(m,4H);1.6-1.76(m,5H);2.39-2.42(m,H);3.05-3.15(m,H);3.91(t,H,³J=9.1Hz);5.58(dd,H,³J=5.4Hz,⁴J=9.1Hz);7.17-7.24(m,4H);7.73(dd,H,³J=7.5Hz,⁴J=2.1Hz);7.76-7.79(m,2H);7.87(d,H,⁴J=2.1Hz);8.00(d,H,⁴J=2.1Hz);8.61(d,H,³J=7.9Hz);HPLC(λ=214nm,[A]:rt.15.73min(99%)

Example 179: 1- (H-imidazo [1,2-a ] pyridin-7-yl) -5- (4- (pyrrolidin-1-yl) phenyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from H-imidazo [1,2-a ] pyridin-7-amine (0.400g,3mmol), 4- (pyrrolidin-1-yl) benzaldehyde (0.530g,3mmol), TMSCN (0.455mL,3.6mmol), Pd/C (10%,0.02g), TEA (1.05mL,7.5mmol), bis- (imidazol-1-yl) methanone (0.730g,4.5 mmol).

Yield: 0.019g (1.8%); MS M/z 348.2(M + H)⁺,174,9(M+2H)²⁺;¹H-NMR(DMSO,400MHz):1.74-1.91(m,4H);3.06-3.17(m,5H);3.88(t,H;J=9.1Hz);5.42-5.47(m,H);6.46(d,2H,³J=8.3Hz);7.12(d,2H,³J=8.3Hz);7.70-7.76(m,2H);7.85(d,H,⁴J=2.1Hz);7.99(d,H,⁴J=2.1Hz);8.57-8.60(m,H);HPLC(λ=214nm,[A]:rt.9.40min(94%)

Example 180: 1- (H-imidazo [1,2-a ] pyridin-7-yl) -5- (3- (pyrrolidin-1-yl) phenyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from H-imidazo [1,2-a ] pyridin-7-amine (0.400g,3mmol), 3- (pyrrolidin-1-yl) benzaldehyde (0.530g,3mmol), TMSCN (0.375mL,3mmol), Pd/C (10%,0.02g), TEA (1.05mL,7.5mmol), bis- (imidazol-1-yl) methanone (0.730g,4.5 mmol).

Yield: 0.01g (0.8%); MS M/z 348.2(M + H)⁺,174.9(M+2H)²⁺;¹H-NMR(DMSO,400MHz):1.81-1.91(m,4H);3.03-3.20(m,5H);3.83(t,H,J=9.1Hz);5.39(q,H,J=9.1Hz);6.35-6.39(m,H);6.50(d,2H,J=7.9Hz);7.04-7.09(m,2H);7.23(s,H);7.31-7.34(m,H);7.50(dd,H,³J=7.9Hz,⁴J=2.5Hz);7.67(s,H);8.30(d,H,J=7.9Hz);HPLC(λ=214nm,[A]:rt.10.62min(100%)

Example 181: 1- (H-imidazo [1,2-a ] pyridin-7-yl) -5- (4- (piperidin-1-yl) phenyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from H-imidazo [1,2-a ] pyridin-7-amine (0.400g,3mmol), 4- (piperidin-1-yl) benzaldehyde (0.570g,3mmol), TMSCN (0.455mL,3.6mmol), Pd/C (10%,0.02g), TEA (1.05mL,7.5mmol), bis- (imidazol-1-yl) methanone (0.730g,4.5 mmol).

Yield: 0.11g (10.1%); MS M/z 362.0(M + H)⁺,181.0(M+2H)²⁺;¹H-NMR(DMSO,400MHz):1.67-1.78(m,2H);1.87-2.02(m,4H);3.22-3.28(m,H);3.45(t,4H,J=5.4Hz);4.07(t,H,9.1Hz);5.63-5.68(m,H);7.48-7.54(m,4H);7.76(d,H,J=2.5Hz);7.78-7.80(m,H);7.84(dd,11H,³J=7.9Hz,⁴J=2.1Hz);7.91(d,H,⁴J=2.5Hz);8.51(d,H,³J=7.9Hz);HPLC(λ=214nm,[A]:rt.5.51min(96%)

Example 182: 1- (H-imidazo [1,2-a ] pyridin-7-yl) -5- (3- (piperidin-1-yl) phenyl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from H-imidazo [1,2-a ] pyridin-7-amine (0.400g,3mmol), 3- (piperidin-1-yl) benzaldehyde (0.570g,3mmol), TMSCN (0.375mL,3mmol), Pd/C (10%,0.02g), TEA (1.05mL,7.5mmol), bis- (imidazol-1-yl) methanone (0.730g,4.5 mmol).

Yield: 0.019g (1.7%); MS M/z 362.3(M + H)⁺,181.7(M+2H)²⁺;¹H-NMR(DMSO,400MHz):1.40-1.61(m,6H);3.05-3.18(m,4H);3.89-3.96(m,H);5.53(dd,H;³J=9.5Hz;⁴J=3.3Hz);6.67-6.73(m,H);6.87-6.92(m,H);7.01(s,H);7.18(t,H;J=7.9Hz);7.74(dd,H;³J=7.5Hz,⁴J=2.1Hz);7.77(s,H);7.80(s,H);7.89(d,H,J=2.1Hz);8.02(d,H,J=2.1Hz);8.62(d,H;³J=7.9Hz);HPLC(λ=214nm,[A]:rt.6.20min(100%)

Example 183: 1- (H-imidazo [1,2-a ] pyridin-7-yl) -5- (1-phenylpiperidin-4-yl) imidazolidin-2-one

This compound was synthesized as described in method 2 starting from H-imidazo [1,2-a ] pyridin-7-amine (0.400g,3mmol), 1-phenylpiperidine-4-carbaldehyde (0.570g,3mmol), TMSCN (0.375mL,3mmol), Pd/C (10%,0.02g), TEA (1.05mL,7.5mmol), bis- (imidazol-1-yl) methanone (0.730g,4.5 mmol).

Yield: 0.007g (0.6%); MS M/z 362.3(M + H)⁺,181.7(M+2H)²⁺;¹H-NMR(DMSO,400MHz):1.38-1.49(m,3H);1.64-1.72(m,H);1.90-2.01(m,H);2.40-2.43(m,H);2.52-2.65(m,H);3.63-3.74(m,2H);4.64-4.69(m,H);6.70-6.76(m,H);6.89(d,2H,³J=7.5Hz);7.15(t,2H,²J=7.9Hz);7.62(s,H);7.83(dd,H,³J=7.5Hz,⁴J=2.1Hz);7.94(d,H,⁴J=2.1Hz);8.08(d,H,4J=2.1Hz);8.16(d,H,⁴J=2.1Hz);8.72(d,H,³J=7.9Hz);HPLC(λ=214nm,[A]:rt.7.02min(95%)

Example 184: (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (3-methoxypropyl) phenyl) oxazolidin-2-one

Step A

3-phenyl-propan-1-ol (5g,36.71mmol) in THF (40mL) was added to a suspension of sodium hydride 60% suspension (1.05g,44.05mmol) in mineral oil in THF (10mL) at 0 deg.C, then methyl iodide (6.85mL,110.31mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was quenched in ice and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and evaporated to dryness to obtain 5g of a colorless oily product.

Step B

Ethyl cloroxylate (4.54mL,39.99mmol) and AlCl were combined at-20 deg.C₃(5.33g,39.99mmol) A solution of the product of step A (2.0g,13.33mmol) in dichloromethane (25mL) was added. The mixture was stirred for 0.5h and warmed to room temperature for 5 h. Saturated NaHCO at 0 deg.C ₃The solution was quenched, filtered and washed with excess ethyl acetate (200mL), the organic layer was washed with water, brine, Na₂SO₄Dried and evaporated under reduced pressure to give 1.7g of the product as a brown liquid.

Step C

Hydroxylamine hydrochloride (1.66g,20mmol) and sodium acetate (1.64g,20mmol) were added to a solution of the product 166a from step B (2.5g,10mmol) in ethanol (25mL) and heated to 80 ℃ for 2.5 h. The reaction mixture was then cooled to room temperature and filtered, and the filtrate was evaporated to dryness to obtain crude compound. The crude compound was suspended in water and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness to obtain 2.7g of the product as a colorless liquid.

Step D

The product of step C (2.7g,10.18mmol) was added to a solution of 10% Pd-C (300mg,10%) in ethanol and hydrogenated at 80Psi overnight at room temperature. The catalyst was then filtered through a bed of celite and the solvent was evaporated to give 2.2g of the product as a colourless liquid.

Step E

Boc anhydride (2.1g,9.63mmol) was added to a solution of the product of step D (2.2g,8.76mmol) and triethylamine (1.06mL,14.44mmol) in dichloromethane (30mL) and stirred at room temperature for 1 h. The reaction mixture was washed with water (30mL) and extracted with dichloromethane (3 × 50 mL). The combined organic layers were washed with brine (20mL), dried over anhydrous sodium sulfate and evaporated to dryness to obtain the crude product. The crude compound was triturated with n-pentane and dried to yield 2.9g of product as a brown oil.

Step F

Sodium borohydride (1.25g,33.04mmol) was added to a solution of the product of step E (2.9g,8.26mmol) in ethanol (30mL) at RT and heated at 50 ℃ for 2 h. The solvent was evaporated under reduced pressure to obtain the crude product. The crude product was taken up in saturated NH₄The Cl solution (25mL) was quenched, diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine solution and evaporated to dryness to afford 2.2g of product as a solid. Chiral preparative HPLC purification using the following conditions: column: chiral pak IC (30x250mm)10 μ, mobile phase: hexane, ethanol (85: 15); flow rate: 34mL/min, UV:210nm, diluent: a mobile phase. The preparative fractions were concentrated in vacuo and partitioned between water and chloroform. The separated organic layer was washed with brine solution. Dried over anhydrous sodium sulfate and concentrated in vacuo to provide 670mg of the product as a brown solid.

Step G

Thionyl chloride (1.27mL,17.34mmol) was added to a solution of the product of step F (0.67g,2.16mmol) in tetrahydrofuran (10mL) at 0 ℃. The reaction mixture was then allowed to warm to room temperature for 12 h. The solvent was evaporated and saturated NaHCO₃The solution (10mL) was basified and extracted with chloroform (3 × 25mL), the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to afford 0.35g of the product as an off-white solid.

The product was further synthesized according to method 5, step D, starting from the product of step G (350mg,1.48mmol), 1, 2-diamino 4-bromobenzene (306mg,1.78mmol), cesium fluoride (450mg,2.96mmol) and cuprous iodide (42mg,0.22mmol), 1, 2-diaminocyclohexane (25mg,0.22mmol), formic acid (7 mL).

Yield: 0.280g (53.9.3%); MS M/z 352.2(M + H)⁺;¹H NMR(400MHz,CDCl3):δ10.26(Bs,1H);7.88(s,1H);7.62(s,1H);7.46(s,1H);7.23-7.12(m,4H);5.39(q,1H);4.81(t,1H);4.26(q,1H);3.35-3.30(m,4H);2.61(t,2H);1.85-1.78(m,2H),HPLC(λ=214nm),[A]Rt 11.38min (96.6%), chiral HPLC-96.40%.

Example 185: 3- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (3- (dimethylamino) propyl) phenyl) oxazolidin-2-one

Step A

Formaldehyde (75mL) was added to a solution of 3-phenylpropylamine (5g,36.97mmol) in formic acid (50mL) and stirred at reflux for 18 hr. The RM was concentrated, the residue basified with saturated bicarbonate solution and extracted with ethyl acetate. The organic layers were combined and washed with water then brine solution. Dried over anhydrous sodium sulfate and concentrated to give 3.4g (56%) of the product as an oily liquid.

Step B

Ethyloxalyl chloride (7mL,61.34mmol) was added to a solution of the product of step A in DCM (30mL) at-30 ℃ over a period of 10 min. AlCl was added at-30 ℃ over a period of 15min₃(8.18g,61.34mmol) was added to the clear solution in three portions. Stirring at-20 deg.C to-30 deg.C for 1 hr. The temperature was slowly raised to RT and stirred for 2 hr. Reaction mass is added to Na ₂CO₃Quenched in aqueous solution and extracted with ethyl acetate. The salt was filtered and washed with ethyl acetate until the precipitate was free of compound. The organic layer was separated from the filtrate and washed with water and then brine solution. Dried over anhydrous sodium sulfate and concentrated to give 1.2g (29.7%) of the product as a colorless oil.

Step C

Sodium acetate (748mg,9.12mmol) was added to the product of step B (1.2g,4.56mmol), a suspension of hydroxylamine HCl (634mg,9.12mmol) in ethanol (15mL) and stirred at reflux for 4 hr. Cool to RT, filter off the salts and wash the cake with ethanol. The filtrate was concentrated to give 1.48g of the product as a white semi-solid.

Step D

10% Pd-C (280mg) was added to a solution of the product of step C (1.4g,5.03mmol) in ethanol (30mL) and hydrogenated in a par apparatus at 80psi for 16-18 hr. The RM was filtered through celite and washed with ethanol. The filtrate was concentrated to give 1.2g (90%) of the product as an oily liquid.

Step E

Boc anhydride (1.2mL,5.49mmol) was added to a solution of the product of step D (1.2g,4.58mmol) in TEA (0.95mL,6.87mmol), DCM (20mL) and stirred for 2 hr. Water was added and the organic layer was separated. The organic layer was washed with water and then brine solution. Dried over anhydrous sodium sulfate and concentrated to give 1.2g (72%) of the product as a colorless oil.

Step F

Reacting NaBH₄(713mg,4.69mmol) A solution of the product of step E (1.7g,4.69mmol) in ethanol (20mL) was added, heated slowly to 50 ℃ and stirred to dissolve. Cooled to RT and stirred for 3 hr. The RM was concentrated and water was added to the residue, which was extracted with ethyl acetate. The organic layers were combined and washed with water then brine solution. Dried over anhydrous sodium sulfate and concentrated to provide g of oily product.

Step G

Thionyl chloride (2.5mL,29.81mmol) was added to a solution of the product of step F (1.2g,3.72mmol) in THF (10mL) and stirred at RT for hr. The RM was concentrated and the residue was basified with saturated bicarbonate solution. Extracted with ethyl acetate and the organic layer was washed with water then brine solution. Dried over anhydrous sodium sulfate and concentrated to give 610mg of crude product as an oil. The next step was carried out directly without any purification.

The compound was further synthesized according to method 5, step D, starting from the product of step G (600mg,2.41mmol), 4-bromo 1, 2-diaminobenzene (497mg,2.66mmol), and cuprous iodide (69mg,0.36mmol), 1, 2-diaminocyclohexane (41mg,0.362mmol), formic acid (3 mL).

Yield: 0.025g (2.8%); MS M/z 365.2(M + H)⁺;¹H NMR(400MHz,CD3OD):δ8.11(s,1H);7.60(s,1H);7.49(d,1H);7.33(d,3H);7.20(d,2H);5.63(q,1H);4.25(q,1H);2.77(t,2H);2.63-2.51(m,7H);2.04-1.83(m,3H);,HPLC(λ=214nm),[A]:rt 6.77min(96.6%).

Example 186: (S) -3- (7-methyl-1H-benzo [ d ] imidazol-5-yl) -4-phenyloxazolidin-2-one

The compound was synthesized starting from (S) -4-phenyloxazolidin-2-one (1 eq, 0.326g,2mmol), 5-bromo-3-methylbenzene-1, 2-diamine (1 eq, 0.402g,2mmol), copper (I) iodide (0.1 eq, 0.038g,0.2mmol), cesium fluoride (2 eq, 0.605g,4mmol), cyclohexane-1, 2-diamine (0.1 eq, 0.024mL,0.2 mmol). The solids were added together to a reaction flask, and the flask was vented with argon. A solution of cyclohexane-1, 2-diamine in 10mL dioxane was added to the flask. The reaction was stirred at 95 ℃ for 48 hours, then cooled to 45 ℃ and passedThe pad is filtered. The pad was washed with warm dichloromethane and the solution was concentrated under reduced pressure. The intermediate was purified by FPLC using a chloroform-methanol gradient (0 → 10%, product eluted at about 5%).

(S) -3- (3, 4-diamino-5-methylphenyl) -4-phenyloxazolidin-2-one was dissolved in triethyl orthoformate and refluxed for 30 minutes. After cooling, the excess triethyl orthoformate was removed under reduced pressure. The final product was purified by FPLC using a chloroform-methanol gradient (0 → 10%).

Yield: 0.014g (2.4%); MS M/z 294.1(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ2.40-2.43(m,3H);4.11-4.14(m,H);4.79-4.84(m,H);5.68-5.74(m,H);7.06-7.16(m,H);7.21-7.27(m,H);7.30-7.39(m,5H);8.08-8.14(m,H);12.40(br s,H),HPLC(λ=214nm),[B]:rt 9.57min(99.6%).

Example 187: (S) -3- (6-fluoro-1H-benzo [ d ] imidazol-5-yl) -4-phenyloxazolidin-2-one

The compound was synthesized starting from (S) -4-phenyloxazolidin-2-one (1 eq, 0.328g,2mmol), 4-bromo-5-fluorobenzene-1, 2-diamine (1 eq, 0.412g,2mmol), copper (I) iodide (0.1 eq, 0.040g,0.2mmol), cesium fluoride (2 eq, 0.608g,4mmol), cyclohexane-1, 2-diamine (0.1 eq, 0.024mL,0.2 mmol). Adding the dried solids together A flask was reacted, and the flask was vented with argon. A solution of cyclohexane-1, 2-diamine in 4mL dioxane was added to the flask. The reaction was stirred at 95 ℃ for 48 hours, then cooled to 45 ℃ and passedThe pad is filtered. The pad was washed with warm dichloromethane and the solution was concentrated under reduced pressure. The intermediate was purified by FPLC using a chloroform-methanol gradient (0 → 10%, product eluted at about 5%).

Yield: 0.078g (13.6%)

(S) -3- (4, 5-diamino-2-fluorophenyl) -4-phenyloxazolidin-2-one was dissolved in triethyl orthoformate and refluxed for 30 minutes. After cooling, the excess triethyl orthoformate was removed under reduced pressure. The final product was purified by FPLC using a chloroform-methanol gradient (0 → 10%). Further purification by semi-preparative HPLC (acetonitrile/water gradient with 0,04% TFA) was necessary.

The total yield is as follows: 0.003g (1.5%, calculated TFA salt); MS M/z 298.0(M + H)⁺;HPLC(λ=214nm),[B]:rt 9.06min(100%).

Example 188: (S) -3- (7-fluoro-1H-benzo [ d ] imidazol-5-yl) -4-phenyloxazolidin-2-one

The compound was synthesized starting from (S) -4-phenyloxazolidin-2-one (1 eq, 0.082g,0.5mmol), 5-bromo-3-fluorobenzene-1, 2-diamine (1 eq, 0.103g,0.5mmol), copper (I) iodide (0.1 eq, 0.010g,0.05mmol), cesium fluoride (2 eq, 0.152g,1mmol), cyclohexane-1, 2-diamine (0.1 eq, 0.006mL,0.05 mmol). The dried solids were added together to a reaction flask, and the flask was vented with argon. A solution of cyclohexane-1, 2-diamine in 4mL dioxane was added to the flask. The reaction was stirred at 95 ℃ for 48 hours, then cooled to 45 ℃ and passed The pad is filtered. The pad was washed with warm dichloromethane and the solution was concentrated under reduced pressure. Using chloroform-methanol gradient(0 → 10%, product eluted at about 5%) the intermediate was purified by FPLC.

(S) -3- (3, 4-diamino-5-fluorophenyl) -4-phenyloxazolidin-2-one was dissolved in triethyl orthoformate and refluxed for 30 minutes. After cooling, the excess triethyl orthoformate was removed under reduced pressure. The final product was purified by FPLC using a chloroform-methanol gradient (0 → 10%). Further purification by semi-preparative HPLC (acetonitrile/water gradient with 0,04% TFA) was necessary.

Yield: 0.008g (3.9%, Calcd. for TFA salt); MS M/z 298.0(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ4.11-4.15(m,H);4.80-4.85(m,H);5.72-5.76(m,H);7.21-7.25(m,H);7.29(s,H);7.31-7.32(m,2H);7.36-7.38(m,2H);7.44(s,H);8.46(s,H),HPLC(λ=214nm),[B]:rt 9.92min(100%).

Example 189: (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4- (cyclohexylmethyl) oxazolidin-2-one

Step A

Acetamidomalonic acid diethyl ester (10g,5.72mmol) was added to a freshly prepared sodium ethoxide solution by dissolving sodium metal (1.26g,5.72mmol) in ethanol (20mL) at 0 ℃ and stirred at room temperature for 30 min. A solution of bromomethylcyclohexane (5g,2.82mmol) in tetrahydrofuran (25mL) was added dropwise to the reaction mixture at 0 ℃ and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The separated organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude compound, which was purified by column chromatography on silica gel (100-200 mesh) by elution with 30% ethyl acetate in petroleum ether to obtain 5.1g (35%) of the product as a viscous solid, which was used without further characterization.

Step B

A mixture of the product of step A (5g,10.7mmol) and concentrated HCl (100mL) was refluxed overnight. The reaction mixture was concentrated under reduced pressure to afford 1.55g (71.5%) of the product as HCl salt, which was used without further characterization.

Step C

Thionyl chloride (1.1mL,15.1mmol) was added to a reaction mixture of the product of step B (1.5g,7.3mmol) in methanol (30mL) at 0 ℃ and refluxed overnight. The reaction mixture was concentrated under reduced pressure to obtain crude compound, which was dissolved in ethyl acetate and saturated NaHCO₃The solutions were partitioned. The separated organic layer was washed successively with water, brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and dried to afford 1.15g (85.18%) of the product as a solid, which was used without further characterization.

Step D

A stirred solution of the product of step C (1.1g,5.3mmol) in tetrahydrofuran (10mL) was added at-15 ℃ to a stirred solution of lithium aluminum hydride (340mg,8.7mmol) in tetrahydrofuran (20mL) and stirred at room temperature for 2 h. The reaction mixture was quenched with saturated sodium sulfate solution, filtered through a pad of celite, washed with ethyl acetate, and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 500mg (60%) of the product as a yellow solid, which was used without further characterization.

Step E

Benzyl chloroformate (3.65g,21.3mmol) was added to a stirred solution of the product of step D (2g,14.2mmol), triethylamine (4mL,28.4mmol) in dichloromethane (15mL) and stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude compound, which was purified by column chromatography on silica gel (100-200 mesh) using 50% ethyl acetate in petroleum ether as eluent to afford 1g (25.6%) of the product as a viscous solid, which was used without further characterization.

Step F

Thionyl chloride (2.2mL,28.4mmol) was added to a stirred solution of the product of step E (1g,3.6mmol) in tetrahydrofuran (15mL) at 0 ℃ and stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo to obtain crude compound. It was purified by column chromatography on silica gel (60-120 mesh) using 25% ethyl acetate in petroleum ether as eluent to afford 500mg (75.75%) of the product as a solid, which was used without further characterization.

Step G

A mixture of the product of step F (450mg,2.4mmol), 1, 2-diamino 4-iodobenzene (620mg,3.3mmol), cesium fluoride (730mg,4.8mmol) in 1, 4-dioxane (15mL) was purged with argon for 15 min. 1, 2-diaminocyclohexane (20mg) and cuprous iodide (35mg) were added to the reaction mixture, and aeration was continued for 5min and stirring overnight at 120 ℃ in a sealed tube. The reaction mixture was filtered through a pad of celite, washed with dioxane and concentrated under reduced pressure to give the crude product. It was purified by preparative TLC using 2% methanol in chloroform as eluent to provide 200mg (29%) of the product as a solid, which was used without further characterization.

Step H

A mixture of the product of step G (190mg,6.57mmol) in formic acid (2mL) was heated at 70 ℃ for 2 hours. The reaction mixture was cooled to 0 ℃ and basified with sodium bicarbonate solution. The compound was extracted with ethyl acetate (3 × 20mL), washed with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The compound was triturated with ether to provide 120mg (61.22%) of the product as a solid, which was used without further characterization.

Step I

1M HCl in ether (0.4mL) was added to a stirred solution of the product of step H (110mg,0.36mmol) in acetone (3mL) at 0 ℃ and stirred at room temperature for 30 min. The reaction mixture was filtered, washed with pentane and dried in vacuo to afford the product as a solid.

Yield: 96mg (78%), MS M/z 300.2(M + H)⁺;¹H-NMR(400MHz,DMSO-d6):δ9.43(d,1H);7.88(t,2H);7.61(d,1H);4.71(s,1H);4.62(d,1H);4.20(d,1H);1.80(d,1H);1.75-1.41(m,6H);1.38-1.07(m,4H);0.86-0.80(m,2H);HPLC(λ=214nm),[A]Rt 11.89min (100%), chiral HPLC 99.27%

Example 190: (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4-cyclohexyloxazolidin-2-one

Step A

Lithium aluminium hydride (0.84g,22.292mmol) was added in one portion to a solution of L- (+) cyclohexylglycine (1.0g,6.369mmol) in anhydrous tetrahydrofuran (15ml) under nitrogen and 0 ℃. The reaction mass was slowly heated to reflux at 70 ℃ for 5 hr. The reaction mass was quenched with ethyl acetate and washed successively with water and brine solution. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to afford 0.6g (65.9%) of the product as an off-white solid, which was used without further characterization.

Step B

Triethylamine (0.93g,9.23mmol) and di-tert-butyl dicarbonate (1.189g,5.454mmol) are added at 0 ℃ to a solution of the product of step A (0.6g,4.198mmol) in dichloromethane (6 ml). The reaction mass was stirred at room temperature for 4 hr. The reaction mass was diluted with dichloromethane, washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain crude compound. Purification by column chromatography on silica gel (60-120 mesh) using 15% ethyl acetate in petroleum ether as eluent afforded 0.6g (60%) of the product as a white solid, which was used without further characterization.

Step C

Thionyl chloride (1.77ml,24.69mmol) was slowly added dropwise to the product of step B at 0 ℃ and stirred at room temperature for 4 hr. Excess thionyl chloride was removed in vacuo and co-distilled twice with petroleum ether to afford the crude compound. Purification by column chromatography on silica gel (60-120 mesh) using 15% ethyl acetate in petroleum ether as eluent afforded 0.2g (47.9%) of the product as a yellow solid, which was used without further characterization.

Step D

A mixture of the product of step C (200mg,1.1834mmol), 1, 2-diamino-4-bromobenzene (220mg,1.1834mmol), cesium fluoride (350mg,2.366mmol) and cuprous iodide (22mg,0.1183mmol) in 1, 4-dioxane (5ml) was sparged with argon for 10 min. 1, 2-diaminocyclohexane (13mg,0.1183mmol) was added to the reaction mixture and the aeration was continued for a further 10 min. The reaction mass was stirred in a sealed tube at 95-100 ℃ for 18 h. The reaction mixture was filtered through celite, washed with dichloromethane and concentrated under reduced pressure to provide 300mg of crude compound. The crude compound showed 34.9% product by LC-MS. The crude compound was used directly in the next step.

Step E

A solution of the product of step D (300mg), formic acid (5mL) was stirred at 70 ℃ for 30min and the reaction mixture was concentrated under reduced pressure. The resulting residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed successively with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the crude compound. The crude compound was purified by column chromatography on silica gel (100-200 mesh) using 3% methanol in chloroform as eluent to provide 100mg of product 100 with a purity of 84%. Further purification was by preparative HPLC. The resulting prep mL was concentrated under reduced pressure and partitioned between chloroform and water. The separated organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to provide 40mg (37.3%) of the product as an off-white solid.

Step F

1M HCl in ether (0.16mL,0.16mmol) was added to a stirred solution of the product of step E (40mg,0.14mmol) in acetone (5mL) at 0 ℃ and stirred at room temperature for 30 min. A solid precipitated out. The solvent was distilled off completely under vacuum. The solid was dissolved in distilled water and lyophilized to provide 40mg of the product as an off-white solid.

Yield: 0.040g MS M/z 286.2(M + H)⁺;¹H-NMR (400MHz, D2O): delta 9.12(D,1H), 7.93-7.87(m,2H), 7.64(D,1H), 4.95-4.60 (mixed with D2O, 3H), 4.58-4.46(m,1H), 1.65-1.50(m,5H), 1.14-93 (m,5H), HPLC (. lamda =214nm), [ A ] A]Rt 8.85min (100%), chiral HPLC 99.61%

Example 191: (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4- (4-phenylcyclohexyl) oxazolidin-2-one

Step A

Ethyl isocyanoacetate (2g,20.68mmol) was added dropwise to a solution of potassium tert-butoxide (2.3g,20.68mmol) in THF (50mL) at 0 ℃ over a period of 20min, and stirred at room temperature for 30 min. 4-phenylcyclohexanone (3.0g;17.24mmol) in THF (50mL) was then added dropwise over a period of 30min, followed by stirring at room temperature overnight. At the completion of the reaction, the reaction mixture was quenched with crushed ice and then extracted in ethyl acetate. The combined ethyl acetate extracts were washed with water (3x100mL) then brine (2x100mL) and dried over anhydrous sodium sulfate to obtain the crude product. The crude product was purified by using neutral alumina column chromatography eluting with 50% ethyl acetate in petroleum ether to obtain (2.5g,62.5%) a brown liquid-like product, which was used without further characterization.

Step B

A solution of the product of step A (2.5g,8.73mmol) in ethanol (200mL) was hydrogenated over 10% Pd-C (2g) in a Parr apparatus at 80psi pressure for 18 h. The reaction mass was filtered through celite and washed with ethanol. The combined filtrate and washings were concentrated in vacuo to afford a brown slurry (2g,79.68%) which was used without further characterization.

Step C

A mixture of the product of step B (2g,6.97mmol) in hydrochloric acid (35%) (150mL) was refluxed for 16 h. The reaction mixture was then co-distilled 2 times with toluene, followed by washing with diethyl ether to remove organic impurities and concentration in vacuo to obtain 4g of the product as an off-white solid (1.5g,83.33%) which was used directly in the other steps.

The title compound was further synthesized according to method 6 starting from step C starting with thionyl chloride (1mL,12.87mmol), triethylamine (1.2mL,8.86mmol), di-tert-butyl dicarbonate (0.75mL,3.5mmol), sodium borohydride (2.7g,47.32 mmol). Then concentrated in vacuo to give 1.2g (76.15%) of the mixed stereoisomer as a pale yellow oily liquid. The isomers were separated by chiral preparative HPLC to obtain 600mg of each isomer.

Chiral preparative HPLC conditions

Column: chiralpak ADH (250X20mm) 5. mu.

Mobile phase: hexane ethanol DEA (95:5)

Flow rate: 18mL/min

Wavelength: 210nm

Diluent agent: EtOH-Hexane

The first eluting isomer was then further processed according to method 6 starting from chloride (0.44g,3.76mmol), 4-bromo-1, 2, diaminobenzene (0.358g,1.91mmol), cesium fluoride (0.58g,3.8mmol) and copper (II) iodide (54mg,0.28mmol), formic acid (5 mL).

Yield: 0.20g (8.6%); MS M/z 362.3(M + H)⁺;¹H NMR 400MHz,DMSO-d6):δ12.45(s,1H);8.24(d,1H);7.75-7.56(m,2H);7.30-7.11(m,6H);4.65(d,1H);4.49-4.37(m,2H);2.49-2.42(m,1H);1.77-1.62(m,5H);1.35-1.19(m,4H),HPLC(λ=214nm),[A]:rt 14.57min(95.25%).

Example 192: (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4- (1-phenylpiperidin-4-yl) oxazolidin-2-one

This compound was synthesized according to method 6 starting from 1-phenylpiperidine-4-carbaldehyde (5g,26.4mmol), potassium cyanide (2.57g,3.96mmol), ammonium carbonate (12.5g,79.3mmol), thionyl chloride (5mL,61.8mmol), di-tert-butyl dicarbonate (2g,2mL,9.6mmol), triethylamine (2.5mL,17.6mmol), and LAH (0.98g,25.86 mmol).

In step E, 1.5g of racemate are separated into isomers using chiral preparative HPLC. Column: chiralpak ADH (250X 20mm) 5. mu.

Mobile phase: hexane ethanol DEA (90:10:0.1)

Flow rate: 40mL/min

Wavelength: 210nm

Diluent agent: EtOH-Hexane

0.35g of the first eluting enantiomer was further treated according to method 6 starting from thionyl chloride (1.57g,2mL,13.24mmol), 1, 2-diamino-4-bromobenzene (0.25g,1.34mmol), cesium fluoride (0.37g,5.58mmol) and copper (I) iodide (35mg), formic acid (4 mL).

Yield: 0.060g (0.6%); MS M/z 363.2(M + H)⁺;¹H NMR 400MHz, DMSO-d 6:. delta.12.65 (Bs,1H);8.28(s,1H);7.59(s,1H);7.62(d,1H);7.36-7.33(q,1H);7.16(t,2H);6.87-6.70(m,3H);4.73(t,1H);4.48(q,1H);4.2(q,1H);3.66(s,2H);2.54-2.34 (mixed with DMSO, 2H);1.57-1.17(m, 5H); HPLC (. lamda =214 nm); [ A. ]:rt 4.80min(95.0%).

Example 193: (S) -4- (1-acetylpiperidin-4-yl) -3- (1H-benzo [ d ] imidazol-5-yl) oxazolidin-2-one

Step A

Adding SOCl at 0 ℃₂(6.7mL,92.90mmol) piperidine-4-carboxylic acid (4g,30.96mmol) in MeOH was added dropwise with stirring(40mL) and the resulting reaction mixture was heated to reflux for 16 hr. The reaction mixture was concentrated under reduced pressure to afford the product as an off-white solid (4.7g, 85%).

Step B

Et at 0 ℃₃N (14.4mL,103.35mmol) was added to a stirred suspension of the product of step A (3.7g,20.67mmol) in DCM (75mL), then BOC anhydride (13.3mL,62.01mmol) was added dropwise and the resulting reaction mixture was stirred at room temperature for 16 hr. Water (50mL) was added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude compound was purified by column chromatography on silica gel (100-200 mesh) using 2% methanol in chloroform as eluent to afford the product as a colorless liquid (5g, 99%).

Step C

The product of step B (5g,20.57mmol) in anhydrous tetrahydrofuran (25mL) was added dropwise to a stirred suspension of lithium aluminium hydride (937mg,24.69mmol) in anhydrous tetrahydrofuran (25mL) at 0 ℃ and the resulting reaction mixture was stirred at 0 ℃ for 2 hr. The reaction mixture was quenched with saturated sodium sulfate, and the resulting reaction mixture was stirred at room temperature for 1hr, filtered through a celite bed, and washed with ethyl acetate. The combined filtrates were dried over sodium sulfate and concentrated under reduced pressure to afford the compound, and the product was used as a white solid (3.5g,79%) in the next step without further purification.

Step D

IBX (9.1g,32.55mmol) was added to a stirred solution of the compound of step C (3.5g,16.279mmol) in DCM (70mL) and the resulting reaction mixture was stirred at room temperature for 48 h. The reaction mixture was filtered, and the filtrate was washed with water, brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain crude compound. It was purified by column chromatography on silica gel (100-200 mesh) using 50% ethyl acetate in petroleum ether to give 2g (58%) of a colorless viscous compound-like product.

This compound was further synthesized according to method 6.

Example 194: 3- (1H-benzo [ d ] imidazol-5-yl) -4- (1-phenylethyl) oxazolidin-2-one

Step A

Ethylacetamidomalonate diethyl ester (12.95g,59.6mmol) was added to a solution of sodium metal (1.86g,80.86mmol) in ethanol and stirred at room temperature for 30 minutes, after cooling the above reaction mass to 0 ℃, phenylmethyl bromide (10g,54.2mmol) was added slowly over 15 minutes and the reaction mass was heated to 75 ℃ for 14 hours. The reaction mass was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 8.0g (64%) of the product as a brown liquid.

Step B

A mixture of the product of step A (0.5g,2.16mmol) in 70% HCl 5.0ml,10.0vol) was heated to 100 ℃, held for 14hr, and the reaction mass was evaporated under reduced pressure to give 0.28g (77%) of product.

Step C

Thionyl chloride (0.75g,5.02mmol) was added to a solution of the product of step B (0.3g,1.6mmmol) in methanol (3mL) at 0 ℃ and heated at reflux for 15 h. The volatiles were removed in vacuo and the resulting residue was partitioned between chloroform and saturated sodium bicarbonate solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 0.26g (81.2%) of the product as a pale yellow liquid.

Step D

A solution of the product of step C (0.2g,1.0mmol) in tetrahydrofuran (2mL) was added to a suspension of lithium aluminum hydride (43mg,1.1mmol) in tetrahydrofuran (3mL) at 0 ℃ and stirred at room temperature for 15 min. The reaction mixture was quenched with saturated sodium sulfate and filtered through celite, washing with chloroform. The filtrate was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to provide 150mg (88.18%) of the product as a light brown liquid.

Step E

Triethylamine (2.6mL,16.6mmol) and di-tert-butyl dicarbonate (2.08mL,9.08mmol) are added successively to a solution of the product of step D (1.5g,9.0mmol) in dichloromethane (20mL) at room temperature and stirred for 15 h. RM was poured into water and extracted with dichloromethane (2 × 30 mL). The combined organic layers were washed successively with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the crude compound. It was purified by flash column chromatography on neutral alumina using 25% ethyl acetate in petroleum ether as eluent to afford 1.65g (66.5%) of a light yellow slurry product.

Step F

Thionyl chloride (1.64mL,17.8mmol) was added to a solution of the product of step E (0.56g,2.12 mmol) in tetrahydrofuran (10mL) at 0 ℃ and stirred at room temperature for 15 h. The volatiles were removed in vacuo and co-distilled twice with toluene to afford the crude compound. Purification by column chromatography on silica gel (60-120 mesh) using 50% ethyl acetate in petroleum ether as eluent afforded 340mg (86.8%) of a light brown slurry which crystallized on standing as a cream solid.

The compound was further synthesized according to method 5 starting from step D.

The product of step F (200mg,1.0mmol), 1, 2-diamino-4-bromobenzene (230mg,1.2mmol), cesium fluoride (228mg,1.5mmol) and cuprous iodide (13mg,0.15mmol), 1, 2-diaminocyclohexane (17mg,0.15mmol), formic acid (5 mL).

Yield: 0.055g (17.7.1%); MS M/z 308.2(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ14.5(s,1H);9.50(s,1H);8.10(d,1H);7.90(s,1H);7.78(d,1H);7.30(d,6H);7.22(s,2H);7.04(d,1H);5.02(s,1H);4.37-4.29(m,2H);3.19(s,1H);1.26(d,1H),1.17(d,3H);,HPLC(λ=214nm),[A]:rt 9.84min(100%).

Example 195: (S) -4- (4-propoxybenzyl) -3- (1H-benzo [ d ] imidazol-5-yl) oxazolidin-2-one

Step A

Thionyl chloride (8mL,110.3mmol) was added to a stirred solution of the compound 2-amino-3- (4-hydroxy-phenyl) -propionic acid (10g,55.19mmol) in methanol (100mL) and refluxed overnight. The reaction mixture was concentrated in vacuo, the residue was dissolved in water and extracted with ethyl acetate. The aqueous layer was basified with solid sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 10g (78%) of the product as a white solid.

Step B

Triethylamine (5.4mL,38.87mmol), BOC anhydride (2.9mL,12.95mmol) were added sequentially to a stirred solution of the compound step a product (3g,12.95mmol) in anhydrous dioxin (40mL) and stirred at room temperature for 4 h. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2g of the product as a solid (52%).

Step C

Bromopropane (0.4mL,4.40mmol), potassium carbonate (935mg,6.77mmol) were added sequentially to a stirred solution of the product of step A (1g,3.38mmol) in acetonitrile and refluxed overnight. The reaction mixture was filtered, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. The separated organic layer was washed successively with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1g (87%) of the product as an oil.

Step D

The product of step C (900mg,2.67mmoL) in tetrahydrofuran (10mL) was added dropwise to a suspension of lithium aluminium hydride (300mg,8.01mmoL) in tetrahydrofuran (10mL) at 0 ℃ and stirred at room temperature for 5 h. The reaction mixture was quenched with saturated sodium sulfate and extracted with ethyl acetate. The separated organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to provide 800mg (96%) of the product as an off-white solid.

Step E

Thionyl chloride (1.4mL,19.41mmol) was added to a stirred solution of the compound step D product (750mg,2.42mmol) in tetrahydrofuran (75mL) at 0 ℃ and stirred at room temperature for 6 h. The reaction mixture was concentrated under reduced pressure to obtain crude compound. The crude product was purified by washing with n-pentane to afford 505mg (87%) of the product as a light brown solid.

This compound was further synthesized as the hydrochloride salt starting from the product of step E (500mg,2.12mmol), 1, 2-diamino 4-iodobenzene (480mg,2.55mmol), cesium fluoride (580mg,3.82mmol), 1, 2-diaminocyclohexane (29mg,.25mmol) and cuprous iodide (49mg,.25mmol), formic acid (5mL) according to method 5.

Yield: 0.037g (4.1%); MS M/z 352.3(M + H) ⁺;¹H NMR 400MHz,DMSO-d6):δ9.53(d,1H);8.10(s,1H);7.91(d,1H);7.77(d,2H);7.06(d,2H);6.81(d,2H);5.00(s,1H);4.43(t,1H);4.22(q,1H);3.86(t,2H);2.89-2.77(m,2H);1.73-1.65(m,2H);0.98-0.94(m,3H),HPLC(λ=214nm),[A]:rt 11.33min(100%).

Example 196: (S) -4- (4-isopropoxybenzyl) -3- (1H-benzo [ d ] imidazol-5-yl) oxazolidin-2-one

Step A

2-iodopropane (.45mL,4.40mmol), potassium carbonate (1g,6.77mmol) were added in sequence to a stirred solution of tert-butyl (S) -1- (methoxycarbonyl) -2- (4-hydroxyphenyl) ethylcarbamate (1g,3.38mmol) in acetonitrile and refluxed overnight. The reaction mixture was filtered, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. The separated organic layer was washed successively with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 900g (78%) of an oily product.

Step B

The product of step A (600mg,2.61mmoL) in tetrahydrofuran (10mL) was added dropwise to a suspension of lithium aluminum hydride (300g,8.01mmoL) in tetrahydrofuran (10mL) at 0 ℃ and stirred at room temperature for 5 h. The reaction mixture was quenched with saturated sodium sulfate and extracted with ethyl acetate. The separated organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 600g (75%) of the product as an off-white solid.

Step C

Thionyl chloride (1.13mL,15.53mmol) was added to a stirred solution of compound 180b (600mg,1.94mmol) in tetrahydrofuran (15mL) at 0 ℃ and stirred at room temperature for 6 h. The reaction mixture was concentrated under reduced pressure to obtain crude compound. The crude product was purified by washing with n-pentane to afford 415mg (91%) of 180c as a light brown solid.

The compound was further synthesized as the hydrochloride salt starting from the product of step C (400mg,1.70mmol), 1, 2-diamino 4-iodobenzene (397mg,2.12mmol), cesium fluoride (485mg,3.19mmol), 1, 2-diaminocyclohexane (24mg,.21mmol), cuprous iodide (40mg,.21mmol), formic acid (5mL), 1M ether-HCl (0.18mL,0.18mmol) according to method 5 starting from step D.

Yield: 0.45g (7.5%); MS M/z 352.4(M + H)⁺;¹H NMR(400MHz,DMSO-d6):δ9.53(d,1H);8.09(s,1H);7.91(d,1H);7.76(d,1H);7.05(d,2H);6.77(d,2H);5.00(s,1H);4.55-4.42(m,2H);4.23(s,1H);2.89-2.76(m,2H);1.22(s,6H)HPLC(λ=214nm),[A]Rt 10.45min (100%), chiral HPLC 88.05%;

example 197: (S) -4- (4- (cyclohexyloxy) benzyl) -3- (1H-benzo [ d ] imidazol-5-yl) oxazolidin-2-one

Step A

A mixture of cyclohexyl bromide (30mL,163.06mmol), p-hydroxybenzaldehyde (20g,163.7mmol), catalytic amounts of tetrabutylammonium iodide (500mg) and potassium carbonate (113g,138.21mmol) in N, N-dimethylformamide (200mL) and stirred at 140 ℃ for 18 h. The reaction mixture was poured into ice-water and extracted with diethyl ether. The combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure to provide 18g (53.8%) of product.

Step B

Hippuric acid (3.17g,17.72mmol), sodium acetate anhydrous (1.45g,17.72mmol) were added sequentially to a solution of the product of step A (3.6g,17.72mmol) in acetic anhydride (20ML) and refluxed for 18 h. The reaction mixture was cooled to 0 ℃ and ethanol (20mL) was added and allowed to stand for 2 h. The precipitated solid was filtered, washed with ethanol and hot water and dried in vacuo to afford 2.6g (42.5%) of the product as a white solid.

Step C

A mixture of the product of step B (10g,28.82mmol) and 3N hydrochloric acid (100mL) was heated at reflux temperature for 12 h. The reaction mixture was concentrated under reduced pressure and dried in vacuo to afford 10g (95%) of step C as a brown solid.

Step D

A solution of the product of step C (10g,27.39mmol) in ethanol (120mL) was hydrogenated over 10% Pd-C (2g) in a Parr apparatus at 60psi for 6 h. The reaction mass was filtered through celite and washed with ethanol. The filtrate was concentrated under reduced pressure to give 5g (50%) of the product as a brown solid.

Step E

Thionyl chloride (3mL,40.87mmoL) was added to a solution of the product of step D (5.0g,13.62mmoL) in methanol (50mL) under an argon atmosphere at 0 ℃ and heated at 65 ℃ for 12 h. The reaction mixture was concentrated under reduced pressure, the residue was basified with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3 × 25 ml). The combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated in vacuo to afford the product as a white solid (5.0g, 96%).

Step F

Lithium aluminum hydride (550mg,13.12mmol) was added in three portions to a solution of the product of step E (5g,13.12mmol) in anhydrous THF (60mL) at 0 ℃ and stirred at room temperature for 12 h. The reaction mixture was cooled to 0 ℃ and saturated NH was used ₄The Cl solution was quenched and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude compound was purified by column chromatography using a 60-120 mesh silica column, eluting the pure compound with 2% methanol in chloroform to afford 3g (68.3%) of the product as a brown solid.

Step G

The product of step F (3.0g,8.84mmol) was added to a solution of 10% Pd-C (300mg,10%) in acetic acid (50mL) and hydrogenated in a par apparatus at 80Psi for 36 h. The catalyst was filtered through a pad of celite, concentrated in vacuo and dried to provide 1.5g (68.3%) of the product as a colorless liquid.

Step H

Boc anhydride (0.56mL,2.46mmol) was added to a solution of the product of step G (500mg,2.00mmol) and triethylamine (0.54mL,4.00mmol) in dichloromethane (10mL) and stirred for 3 h. The reaction mixture was washed with water (10mL) and extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 350mg (50%) of the product as a yellow liquid.

Step I

Thionyl chloride (0.6mL,8.02mmol) was added to a solution of the product of step H (350mg,1.00mmol) in tetrahydrofuran (10mL) at 0 ℃ and stirred at room temperature for 12H. The reaction mixture was concentrated in vacuo and taken up with saturated NaHCO ₃The solution was basified and extracted with chloroform. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 200mg (72.7%) of the product as a colorless liquid.

This compound was further synthesized as the hydrochloride salt starting from the product of step I (200mg,0.727mmol), 1, 2-diamino 4-bromobenzene (152mg,0.872mmol), cesium fluoride (165mg,1.08mmol) and cuprous iodide (20mg,0.109mmol), 1, 2-diaminocyclohexane (12mg,0.108mmol), formic acid (10mL) according to method 5 starting from step D.

Yield: 0.100g (35.1%); MS M/z 392.2(M + H)⁺;¹H NMR(400MHz,DMSO-d6):δ12.54(s,bs);8.25(s,1H);7.79(s,1H);7.79(s,1H);7.61(s,1H);7.39(d,1H);7.05(d,2H);6.81(d,2H);4.86(s,1H);4.40-4.14(m,3H);2.82-2.74(m,2H);1.87(s,2H);1.69(s,2H);1.36-1.23(m,6H);HPLC(λ=214nm),[B]:rt 14.61min(96.4%).

Example 198: 4- (4-morpholinobenzyl) -3- (1H-benzo [ d ] imidazol-5-yl) oxazolidin-2-one

Step A

A mixture of 4-fluorobenzonitrile (10g,0.82mmol) and morpholine (50mL) was stirred in a steel reaction kettle at 100 ℃ overnight. The reaction mixture was poured into water and extracted with diethyl ether. The combined organic layers were washed successively with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 7g of the product as a viscous solid.

Step B

A mixture of the product of step A (7g,37.23mmol) and concentrated HCl was refluxed overnight. The reaction mixture was concentrated under reduced pressure to obtain 8.3g (96.3%) of the product as HCl salt.

Step C

Thionyl chloride (5.8mL,80.30mmol) was added to a reaction mixture of the product of step B (8.3g,40.19mmol) in methanol (80mL) at 0 ℃ and refluxed overnight. The reaction mixture was concentrated under reduced pressure to obtain crude compound, which was taken up in EtOAC and saturated NaHCO₃The solutions were partitioned. The separated organic layer was washed with water, brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and dried to provide 6g (67.5%) of the product as a solid.

Step D

A solution of the product of step C (6g,27.32mmol) in tetrahydrofuran (50mL) was added to a suspension of lithium aluminium hydride (2g,54.21mmol) in tetrahydrofuran (20mL) at-15 ℃ and stirred at room temperature for 2 h. The reaction mixture was quenched with saturated sodium sulfate solution, filtered through a pad of celite, washed with ethyl acetate, and the filtrate was extracted with ethyl acetate. The combined organic layers were washed successively with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 4.12g (78.58%) of the product as a yellow solid.

Step E

A mixture of the product of step D (4.1g,21.2mmol), thionyl chloride (4.5mL,63.8mmol) in chloroform (25mL) was stirred at reflux overnight. The reaction mixture was concentrated under reduced pressure and dried to give 4g (91.3%) of the product as an oil.

Step F

Acetamidomalonic acid diethyl ester (12.64g,0.058mmol) was added to a freshly prepared sodium ethoxide solution by dissolving sodium metal (890mg,38.80mmol) in ethanol (20mL) at 0 ℃ and stirred at room temperature for 30 min. A solution of the product of step E (4g,19.42mmol) in tetrahydrofuran (25mL) was added dropwise to the reaction mixture at 0 ℃ and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The separated organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude compound, which was purified by column chromatography on silica gel (100-200 mesh) by elution with 30% ethyl acetate in petroleum ether to obtain 6g (81%) of the product as a viscous solid.

Step G

A mixture of the product of step F (6g,15.3mmol) and concentrated HCl was refluxed overnight. The reaction mixture was concentrated under reduced pressure to afford 3.5g (91.6%) of the product as HCl salt.

Step H

Thionyl chloride (1.56mL,21mmol) was added to a reaction mixture of the product of step G (3.5G,14mmol) in methanol (30mL) at 0 ℃ and refluxed overnight. The reaction mixture was concentrated under reduced pressure to obtain crude compound, which was taken up in EtOAC and saturated NaHCO ₃The solutions were partitioned. The separated organic layer was washed with water, brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and dried to provide 3g (81%) of the product as a solid.

Step I

A stirred solution of the product of step H (2g,7.57mmol) in tetrahydrofuran (20mL) was added at-15 ℃ to a stirred solution of lithium aluminum hydride (2g,7.57mmol) in tetrahydrofuran (20mL) and stirred at room temperature for 2H. The reaction mixture was quenched with saturated sodium sulfate solution, filtered through a pad of celite, washed with ethyl acetate, and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 1.6g (89.8%) of the product as a yellow solid.

Step K

Boc anhydride was added to a stirred solution of the product of step I (1.6g,6.77mmol), triethylamine (1.4mL,13.54mmol) in dichloromethane (15mL) and stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 700mg (30.83%) of the product as a viscous solid.

Step L

Thionyl chloride (0.7mL,0.96mmol) was added to a stirred solution of the product of step K (700mg,0.48mmol) in tetrahydrofuran (15mL) at 0 ℃ and stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo and taken up with saturated NaHCO ₃The solution was basified and extracted with chloroform. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude compound. It was purified by column chromatography on silica gel (60-120 mesh) using 25% ethyl acetate in petroleum ether as eluent to afford 200mg (38%) of the product as a solid.

This compound was further synthesized as the hydrochloride salt starting from the product of step L (175mg,0.67mmol), 1, 2-diamino 4-iodobenzene (140mg,0.8mmol), cesium fluoride (200mg,1.32mmol), 1, 2-diaminocyclohexane (20mg) and cuprous iodide (35mg), formic acid (2mL), 1M HCl in ether (0.2mL) according to method 5.

Yield: 0.035g (13.8%); MS M/z 379.4(M + H)⁺;¹H NMR(400MHz,DMSO-d6):δ9.58(s,1H);8.08(s,1H);7.87(d,1H);7.72(d,1H);4.98(q,1H);4.42(t,2H);4.20(q,2H);3.75(s,4H);3.09(s,4H);2.85-2.78(m,2H);HPLC(λ=214nm),[A]:rt 6.59min(99.18%)

Example 199: (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4-phenethyloxazolidin-2-one

Step A

Ethylacetamidomalonate diethyl ester (9.39g,43.22mmol) was added to freshly prepared sodium ethoxide obtained by adding sodium (2.49g,108.05mmol) to anhydrous ethanol (80mL) at 0 ℃. The RM was warmed to room temperature and stirred for 25 min. It was cooled to 0 ℃ and a solution of (2-bromoethyl) benzene (8.0g,43.22mmol) was added. The reaction mass was allowed to warm to room temperature and stirred for 1h, heated at reflux for 15 h. The solvent was evaporated in vacuo and the resulting residue partitioned between water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed successively with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the crude compound. Purification by column chromatography on silica gel (60-120 mesh) using 25% ethyl acetate in petroleum ether as eluent afforded 2.89g (20.83%) of the product as a cream solid.

Step B

A suspension of the product of step A (2.88g,8.97mmol) in concentrated hydrochloric acid (20mL) was heated at reflux for 26 h. The volatiles were evaporated in vacuo, co-evaporated with toluene and dried under reduced pressure to afford 1.46g (90.96%) of the product as an off-white solid.

Step C

Thionyl chloride (1.2mL,16.44mmol) was added to a solution of the product of step B (1.45g,8.10mmmol) in methanol (20mL) at 0 ℃. The reaction mixture was heated at reflux for 15 h. The volatiles were evaporated in vacuo and the resulting residue was partitioned between chloroform and saturated sodium bicarbonate solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 1.36g (87.2%) of the product as a pale yellow liquid.

Step D

A solution of the product of step C (1.05g,5.44mmol) in tetrahydrofuran (10mL) was added at 0 ℃ to a suspension of lithium aluminum hydride (206mg,5.44mmol) in tetrahydrofuran (30 mL). The reaction mass was stirred for 15 min. It was cooled again to 0 ℃ and quenched with saturated sodium sulfate solution. Filtered through celite and washed with chloroform. The combined filtrate and washings were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 800mg (89.18%) of the product as a light brown liquid.

Step E

Triethylamine (1.4mL,10.04mmol) and di-tert-butyl dicarbonate (1.4mL,6.10mmol) are added successively to a solution of the product of step D (800mg,4.84mmol) in dichloromethane (20mL) at room temperature and stirred for 15 h. RM was poured into water and extracted with dichloromethane (2 × 30 mL). The combined organic layers were washed successively with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the crude compound. Purification by flash column chromatography on neutral alumina using 25% ethyl acetate in petroleum ether as eluent afforded 800mg (62.5%) of a light yellow slurry.

Step F

Thionyl chloride (2.0mL,27.39mmol) was added to a solution of the product of step E (800mg,3.02mmol) in tetrahydrofuran (20mL) at 0 ℃. The reaction mass was allowed to warm to room temperature and stirred for 15 h. The volatiles were evaporated in vacuo and co-distilled twice with toluene to afford the crude product. Purification by column chromatography on silica gel (60-120 mesh) using 50% ethyl acetate in petroleum ether as eluent afforded 500mg (86.8%) of the product of step F as a light brown syrup which crystallized on standing as a cream solid.

This compound was further synthesized as the hydrochloride salt starting from the product of step F (480mg,2.51mmol), 1, 2-diamino-4-bromobenzene (470mg,2.51mmol), cesium fluoride (572mg,3.76mmol) and cuprous iodide (72mg,0.376mmol), 1, 2-diaminocyclohexane (43mg,0.376mmol), formic acid (5mL), 1M HCl in ether (0.39mL,0.39mmol) according to method 5.

Yield: 0.235g (10.3%); MS M/z 308.4(M + H)⁺;¹H NMR (400MHz, DMSO-d6): delta 9.47(s,1H), 7.99(s,1H), 7.85(d,1H), 7.58(d,1H), 7.22(t,2H), 7.16-7.10(m,3H), 4.76-4.75(m,1H), 4.60(t,1H), 4.36-4.32(m,1H), 2.61-2.50 (mixed with DMSO, 2H), 1.90-1.81(m,2H), HPLC (lambda =214nm), [ A ] (lambda =214nm)]:rt9.20min(100%).

Example 200: 3- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (cyclohexyloxy) phenyl) oxazolidin-2-one

From 4- (cyclohexyloxy) benzaldehyde (4g,19.60mmol), potassium cyanide (1.60g,24.5 mmol) according to method 60mmol), ammonium carbonate (5.64g,58.8mmol), 10% aqueous sodium hydroxide (80mL), 10% aqueous sodium hydroxide (120mL), di-tert-butyl dicarbonate (14.47g,66mmol), potassium carbonate (1.78g,129.94mmol), methyl iodide (1.46g,10.31mmol), sodium borohydride (1.13g,29.76mmol), thionyl chloride (20mL,273.9mmol), 4-bromo-1, 2-diaminobenzene (561mg,3.0mmol), cesium fluoride (912mg,6.0mmol), cuprous iodide (85mg,0.45mmol), and formic acid (5 mL). Yield: 120mg (1.6%), MS M/z 378.4(M + H)⁺;¹H-NMR(400MHz,CDCl3):δ7.91(s,1H);7.62(s,1H);7.48(d,1H);7.19(d,3H);6.81(d,2H);5.33(t,2H);4.79(t,1H);4.17(t,1H);4.14(s,1H);1.9(t,2H);1.75(d,2H);1.56-1.25(m,6H);HPLC(λ=214nm,[A]:rt 14.40min(100%).

Example 201: (S) -3- (7-methyl-1H-benzo [ d ] imidazol-5-yl) -4- (4-propoxyphenyl) oxazolidin-2-one

(S) -4- (4-propoxyphenyl) oxazolidin-2-one was used as starting material and the synthesis was described above.

The compound was synthesized starting from (S) -4-phenyloxazolidin-2-one (1 equivalent, 0.1g,0.45mmol), 5-bromo-3-methylbenzene-1, 2-diamine (1 equivalent, 0.091g,0.45mmol), copper (I) iodide (0.1 equivalent, 0.009g,0.045mmol), cesium fluoride (2 equivalent, 0.137g,0.9mmol), cyclohexane-1, 2-diamine (0.1 equivalent, 0.006mL,0.05 mmol). The dried solids were added together to a reaction flask, and the flask was vented with argon. A solution of cyclohexane-1, 2-diamine in 4mL dioxane was added to the flask. The reaction was stirred at 95 ℃ for 48 hours, then cooled to 45 ℃ and passedThe pad is filtered. The pad was washed with warm dichloromethane and the solution was concentrated under reduced pressure. The intermediate was purified by FPLC using a chloroform-methanol gradient (0 → 10%).

Yield: 0.092g (59.9%)

(S) -3- (3, 4-diamino-5-methylphenyl) -4- (4-propoxyphenyl) oxazolidin-2-one was dissolved in triethyl orthoformate and refluxed for 30 minutes. After cooling, the excess triethyl orthoformate was removed under reduced pressure. The final product was purified by FPLC using a chloroform-methanol gradient (0 → 10%).

Yield: 0.016g (16.9%)

The total yield is as follows: 10.1%; MS M/z 352.3(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ0.89-0.92(m,3H);1.60-1.71(m,2H);2.40-2.42(m,3H);3.81-3.84(m,2H);4.08-4.12(m,H);4.75-4.79(m,H);5.60-5.64(m,H);6.83-6.86(m,2H);7.04-7.13(m,H);7.26-7.35(m,3H);8.08-8.14(m,H);12.40(br s,H),HPLC(λ=214nm),[B]:rt 11.99min(93.8%).

Example 202: (S) -3- (6, 7-dimethyl-1H-benzo [ d ] imidazol-5-yl) -4- (4-propoxyphenyl) oxazolidin-2-one

(S) -4- (4-propoxyphenyl) oxazolidin-2-one was used as starting material and the synthesis was described above.

The compound was synthesized starting from (S) -4-phenyloxazolidin-2-one (1 eq, 0.1g,0.45mmol), 5-bromo-3, 4-dimethylbenzene-1, 2-diamine (1 eq, 0.097g,0.45mmol), copper (I) iodide (0.1 eq, 0.009g,0.045mmol), cesium fluoride (2 eq, 0.137g,0.9mmol), cyclohexane-1, 2-diamine (0.1 eq, 0.006mL,0.05 mmol). The dried solids were added together to a reaction flask, and the flask was vented with argon. A solution of cyclohexane-1, 2-diamine in 4mL dioxane was added to the flask. The reaction was stirred at 95 ℃ for 48 hours, then cooled to 45 ℃ and passedThe pad is filtered. The pad was washed with warm dichloromethane and the solution was concentrated under reduced pressure. The intermediate was purified by FPLC using a chloroform-methanol gradient (0 → 10%).

Yield: 0.020g (12.5%)

(S) -3- (4, 5-diamino-2, 3-dimethylphenyl) -4- (4-propoxyphenyl) oxazolidin-2-one was dissolved in triethyl orthoformate and refluxed for 30 minutes. After cooling, the excess triethyl orthoformate was removed under reduced pressure. The final product was purified by FPLC using a chloroform-methanol gradient (0 → 10%).

Yield: 0.008g (39.1%)

The total yield is as follows: 4.9%; MS M/z 366.4(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ0.89-0.93(m,3H);1.61-1.69(m,2H);2.16(br s,3H);2.39(br s,3H);3.78-3.86(m,2H);4.30-4.34(m,H);4.77-4.86(m,H);5.57-5.63(m,H);6.82-6.83(m,2H);7.29-7.31(m,2H);7.40-7.49(m,H);8.09(br s,H);12.36(br s,H),HPLC(λ=214nm),[B]:rt 11.71min(90.9%).

Example 203: (S) -4- (4- (2-methoxyethoxy) phenyl) -3- (1H-benzo [ d ] imidazol-5-yl) oxazolidin-2-one

Step A

A solution of tert-butyl (methoxycarbonyl) (4-hydroxyphenyl) methylcarbamate (1.2g,4.27mmol) in THF (20mL) was added to 2-methoxyethanol (0.389mg,5.12mmol) and triphenylphosphine (1.68g,6.4mmol), and the mixture was stirred for 10 min. DEAD (1.16g,6.4mmol) was added. Then heated to reflux overnight. When the starting material was completely consumed, the reaction mixture was cooled to room temperature. Then diluted with water and extracted 3 times in ethyl acetate. The combined ethyl acetate extracts were washed with water (3x100mL) then brine (2x100mL) and dried over anhydrous sodium sulfate. Then concentrated in vacuo to yield 800mg (57.14%) of the product as a pale yellow oily liquid.

Step B

Sodium borohydride (500mg,13.27mmol) was added portionwise to a solution of the product of step A (800mg,3.31mmol) in methanol (20mL) at 0 ℃ and stirred well for 16h at RT. The methanol was then distilled and the residue obtained was extracted in ethyl acetate. The combined ethyl acetate extracts were washed with water (3x100mL) then brine (2x100mL) and dried over anhydrous sodium sulfate. Then concentrated in vacuo to yield 700mg (97.22%) of a pale yellow oily liquid product.

Step C

Thionyl chloride (0.32mL,4.5mmol) was added to a solution of the product of step B (700mg,2.25mmol) in anhydrous THF (20mL) at 0 ℃ and stirred well for 16h at RT. The RM was then concentrated in vacuo to yield 450mg (84%) of the product as a light yellow solid.

This compound was further synthesized according to method 6 starting from the product of step C (0.45g,1.89mmol), 4-bromo-1, 2, diaminobenzene (0.355g,1.89mmol), cesium fluoride (0.577g,3.79mmol) and copper (II) iodide (54mg,0.28mmol), 2-diaminocyclohexane (32mg,0.28mmol), formic acid (5 mL). Yield: 0.2g (29.9%); MS M/z 354.3(M + H)⁺;¹H NMR (400MHz, DMSO-d6): delta 10.10(Bs,1H), 7.91(d,1H), 7.55(d,1H), 7.26-7.20 (with CDCl)₃Mixture, 3H), 6.85(d,2H), 5.35(q,1H), 4.79(t,1H), 4.26(q,1H), 4.05(t,2H), 3.71(t,2H)3.43(d,3H), HPLC (. lamda =214nm), [ A ] A]:rt 9.98min(96.48%).

Example 204: (S) -4- (4- (2- (dimethylamino) ethoxy) phenyl) -3- (1H-benzo [ d ] imidazol-5-yl) oxazolidin-2-one

The compound was synthesized according to method 5 starting from 4- (2- (dimethylamino) ethoxy) benzaldehyde (3g,15.70mmol), 2.3M n-butyllithium (13.65mL,15.7mmol), methyltriphenylphosphonium bromide (11.21g,17mmol), tert-butyl hypochlorite (2.7mL,22.32mmol), tert-butyl carbamate (2.66g,22.72mmol), 0.4M aqueous sodium hydroxide (0.9g in 57mL water), osmate dihydrate (100mg,0.29mmol), thionyl chloride (1.2mL,16.49mmol), 4-bromo 1, 2-diaminobenzene (0.31mg,0.1.672mmol), and cuprous iodide (44mg,0.228), 1, 2-diaminocyclohexane (26mg,0.228), formic acid (3 mL). Yield: 0.110g (2.0%); MS M/z 367.2(M + H) ⁺;¹H NMR (400MHz, CDCl3): delta 10.40(Bs,1H), 7.89(s,1H), 7.53(s,1H), 7.26-7.19 (mixed with CDCl3, 5H), 6.81(d,2H), 5.33(t,1H), 4.79(q,1H), 4.25(t,1H), 4.00(t,2H), 2.70(t,2H), 2.34-2.25(m,6H), HPLC (. lamda =214nm), [ A ] A]:rt 5.79min(94.7%).

Example 205: 3- (1H-benzo [ d ] imidazol-5-yl) -4- (2, 6-difluoro-4-methoxyphenyl) oxazolidin-2-one

The compound was synthesized according to method 6 starting from 2, 6-difluoro-4-methoxybenzaldehyde (4g,23.25mmol), potassium cyanide (1.8mg,27.90mmol), ammonium carbonate (10.95g,69.76mmol), 10% aqueous sodium hydroxide (50mL), thionyl chloride (2.6mL,36.86mmol), sodium borohydride (2.31g,64.37mmol), triethylamine (2.4mL,17.73mmol), di-tert-butyl dicarbonate (1.5mL,7.09mmol), thionyl chloride (3.3mL,46.2mmol), 4-bromo-1, 2, diaminobenzene (0.734g,3.93mmol), cesium fluoride (1.19g,7.86mmol) and copper (II) iodide (112mg,5.89mmol), 1, 2-diaminocyclohexane (67mg,5.89mmol), formic acid (5 mL). Yield: 175mg (2.2%). MS M/z 346.3(M + H)⁺;¹H-NMR(400MHz,CDCl3):δ9.45(bs,1H);7.97(s,1H);7.72(bs,1H);7.39(s,1H);7.26(s,1H);6.37(d,1H);5.87(s,1H);4.83(t,1H);4.47(t,1H);3.70(s,3H),HPLC(λ=214nm,[A]:rt 9.17min(100%).

Example 206: (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (diethylamino) phenyl) oxazolidin-2-one

This compound was synthesized according to method 6 starting from (R) -tert-butyl 1- (4- (diethylamino) phenyl) -2-hydroxyethyl carbamate (0.500g,21.623mmol), thionyl chloride (0.95mL,12.98mmol), 4-bromo 1, 2-diaminobenzene (219mg,1.175mmol), cesium fluoride (324mg,2.136mmole) and cuprous iodide (30mg,0.160mmole), 1, 2-diaminocyclohexane (0.02,0.1602mmole), formic acid (5 mL). Yield: 0.05g (0.6%). MS M/z 351.4(M + H) ⁺;¹H-NMR(400MHz,DMSO-d6):δ12.44(d,1H);8.17(d,1H);7.56-7.13(m,5H);6.55(d,2H);5.54(t,1H);4.75(t,1H);4.09(t,1H);3.39-3.20(m,4H);1.23-0.98(m,6H),HPLC(λ=214nm,[A]:rt 6.04min(97.7%).

Example 207: (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (bis (2-methoxyethyl) amino) phenyl) oxazolidin-2-one

From (R) -1- (4- (bis (2-methoxyethyl) amino) phenyl) -2-hydroxyethylcarbamic acid tert-butyl ester (0.350g,0.951mmol), thionyl chloride (0.55mL,7.608mmol), 4-bromo-1, 2 according to method 6The synthesis of this compound was started with diaminobenzene (111mg,0.598mmol), cesium fluoride (165mg,1.08 mmol) and cuprous iodide (15mg,0.081 mmol), 1, 2-diaminocyclohexane (0.06,0.598 mmol), formic acid (5 mL). Yield: 0.04g (10.8%). MS M/z 411.4(M + H)⁺;¹H-NMR 400MHz, CDCl 3:. delta.7.89 (d,1H);7.60-7.45(m,2H);7.26-7.11 (mixed with CDCl3, 3H);6.61(d,2H);5.60(t,1H);4.77(t,1H);4.33(t,1H);3.60-3.49(m,8H);3.32(s, 6H); HPLC (. lamda =214nm, [ A ] A]:rt 10.09min(96%).

Example 208: (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (dicyclopropylamino) phenyl) oxazolidin-2-one

Step A

A suspension of 4-fluorobenzonitrile (6g,0.0495mole), cyclopropylamine (10.3mL,0.1487mole) and potassium carbonate (34.21g,0.198mole) in DMSO (50mL) was refluxed for 6 hours. The reaction mass was cooled, poured into ice water (100ml) and extracted with ethyl acetate. The separated organic layer was washed with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide crude compound, which was purified by column chromatography on silica gel (60-120 mesh) using 10% ethyl acetate in petroleum ether as eluent to provide 5g of product as white solid.

Step B

Sodium cyanoborohydride (2.98g,47.4mmol) was added to a stirred solution of the product of step A (5g,31.64mmol) in acetic acid (40ml) and 1-ethoxycyclopropyloxytrimethylsilane at room temperature and heated to 85 ℃ for 3 hours. Cool to room temperature, dilute with dichloromethane, and wash with saturated sodium bicarbonate solution & brine solution. Dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude compound. It was purified by column chromatography on neutral alumina using 8% ethyl acetate in petroleum ether as eluent to afford 3g of the product as a white crystalline solid.

Step C

25% DIBAL in toluene (11.47ml,20.2mmol) was added dropwise to a solution of the product of step B (2g,10mmol) in anhydrous DCM (20ml) at-45 ℃ and stirred for 1.5h, the reaction mixture was quenched with saturated ammonium chloride solution (50ml) and extracted with ethyl acetate (200 ml). The organic layer was separated and washed with water, brine solution. Dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude compound, which was purified by column chromatography on alumina using 40% ethyl acetate in petroleum ether as eluent to afford 2g of the product as a yellow liquid.

From the product of step C (1.6g,7.96mmol) according to method 5, 2.3M n-butyllithium in hexane (6.19mL,14.92mmol), methyltriphenylphosphonium bromide (6.68g,15.92mmol), tert-butyl hypochlorite (2mL,18.85mmol), Boc carbamate (2.17g,18.60mmol), (DHQ) ₂Further synthesis of this compound was started with PHAL (240mg,0.309mmol), potassium osmate dihydrate (90mg,0.247mmol), thionyl chloride (0.439mL,6.024mmol), 4-bromo-1, 2-diaminobenzene (130mg,0.697mmol), cesium fluoride (212mg,1.395 mmol) and cuprous iodide (20mg,0.104 mmol), 1, 2-diaminocyclohexane (1mL), formamidine acetate (23mg,0.219 mmol). Yield: 0.03g (0.6%). MS M/z 375.3(M + H)⁺;¹H-NMR 400MHz,CDCl3):δ7.94(s,1H);7.67(s,1H);7.52(s,1H);7.15(d,3H);6.96(d,2H);5.34(q,1H);4.77(t,1H);4.27(q,1H);2.40-2.38(t,1H);0.88-0.80(m,4H);0.64-0.63(m,4H);,HPLC(λ=214nm,[A]:rt 14.39min(95%).

Example 209: (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4- (biphenyl-4-yl) oxazolidin-2-one

As described in method 5, from 4-vinylbiphenyl (1.55g, 8.6mmol), ethyl carbamate (2.38g,26.7mmol), 5-dimethylimidazolidine-2, 4-dione (2.6g,13.2mmol), (DHQ)₂PHAL(0.402g,0.52mmol)、K₂OsO₄x2H₂O (0.127g,0.34mmol), 0.38M aqueous NaOH (74mL,28mmol), 4-iodobenzene-1, 2-diamine (0.35g,1.5mmol), copper (I) iodide (0.029g,0.15mmol), cesium fluoride (0.456g,3mmol), cyclohexane-1, 2-diamine (0.018mL,0.15mmol), triethyl orthoformate(10ml) the synthesis of this compound was started.

Yield: 0.011g (0.4%); MS M/z 356.3(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ4.19-4.30(m,H);4.73-4.84(m,H);5.25-5.51(m,H);7.29-7.68(m,12H);7.94-8.22(m,H),HPLC(λ=214nm),[B]):rt 12.22min(100%).

Examples 210, 211, 212: 3- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (4-oxocyclohexyl) phenyl) oxazolidin-2-one, 3- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (4-methoxycyclohexyl) phenyl) oxazolidin-2-one, and 3- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (4-hydroxycyclohexyl) phenyl) oxazolidin-2-one

Step A

Sodium borohydride (0.54g,14.36mmol) was added to a solution of 4-phenylcyclohexanone (5.0g,28.73mmol) in ethanol (50mL) at RT and stirred for 0.5 h. The reaction mixture was evaporated, quenched with ammonium chloride solution and extracted with dichloromethane. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and evaporated to dryness to obtain 5.0g of the product as a white solid.

Step B

Tetrabutylammonium hydrogen sulfate (1.42g,4.21mmol) followed by dimethyl sulfate (14.15g,112.35mmol) was added to a solution of the product of step A (5.0g,28.08mmol) in a mixture of 50% NaOH: toluene in a 1:1 ratio and heated at 80 ℃ for 48 h. The reaction mixture was diluted with water, acidified with 10% HCl and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and evaporated to dryness to obtain crude compound. The crude compound was purified by column chromatography on silica gel (60-120 mesh) by elution in 2-4% ethyl acetate in petroleum ether to obtain 4.0g of a colorless oily product.

Step C

Ethyl cloroxylate (7.16mL,63.15mmol) and AlCl were combined at-20 deg.C₃(8.42g,63.15mmol) A solution of the product of step B (2.0g,13.33mmol) in dichloromethane (60mL) was added. The mixture was stirred for 1h and warmed to room temperature for 2 h. Saturated NaHCO at 0 deg.C ₃The solution was quenched, filtered and washed with excess ethyl acetate (200mL), the organic layer was separated, washed with water, brine, Na₂SO₄Dried and evaporated under reduced pressure to give 3.0g of the product as a brown liquid.

Step D

Hydroxylamine hydrochloride (1.44g,20.68mmol) and sodium acetate (1.69g,20.68mmol) were added to a solution of the product of step C (2.5g,10mmol) in ethanol (30mL) and heated at 80 ℃ for 2 h. The reaction mixture was then cooled to room temperature and filtered, and the filtrate was evaporated to dryness to obtain crude compound. The crude compound was suspended in water and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness to obtain 3.1g of the product as a colorless liquid.

Step E

The product of step D (3.1g,10.16mmol) was added to a solution of 10% Pd-C (0.62g,20%) in ethanol and hydrogenated at room temperature overnight at 80 Psi. The catalyst was then filtered through a bed of celite and the solvent was evaporated to give 3.0g of the product as a colourless liquid.

Step F

Boc anhydride (2.23g,10.3mmol) was added to a solution of the product of step E (3.0g,10.30mmol) and triethylamine (1.6mL,12.37mmol) in dichloromethane (30mL) and stirred at room temperature overnight. The reaction mixture was washed with water (30mL) and extracted with dichloromethane (3 × 50 mL). The combined organic layers were washed with brine (20mL), dried over anhydrous sodium sulfate and evaporated to dryness to give 2.9g of crude product as a brown oil.

Step G

Sodium borohydride (0.82g,21.48mmol) was added to a solution of the product of step F (2.1g,5.37mmol) in ethanol (30mL) at RT and heated at 50 ℃ for 3 h. Under reduced pressureThe solvent was evaporated to obtain the crude product. The crude product was taken up in saturated NH₄The Cl solution (25mL) was quenched, diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine solution and evaporated to dryness to afford 1.5g of product as a sticky mass.

Step H

Thionyl chloride (2.5mL,34.38mmol) was added to a solution of the product of step G (1.5G,4.29mmol) in tetrahydrofuran (20mL) at 0 ℃. The reaction mixture was then allowed to warm to room temperature for 12 h. The solvent was evaporated and saturated NaHCO₃The solution (10mL) was basified and extracted with chloroform (3 × 25mL), the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to afford 1.0g of the product as an off-white solid.

Step I

A mixture of the product of step H (1g,3.63mmol), 1, 2-diamino 4-bromobenzene (0.74g,3.99mmol), cesium fluoride (1.1g,7.26mmol) and cuprous iodide (0.1g,0.54mmol) in 1, 4-dioxane (15mL) was purged with argon for 15 min. 1, 2-diaminocyclohexane (61mg,0.22mmol) was added to the reaction mixture and the aeration was continued for a further 15 min. The reaction mass was stirred in a sealed tube at 120 ℃ for 24 h. The reaction mixture was filtered through celite, washed with dioxane and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography on neutral alumina by elution in 3% methanol in chloroform as eluent to afford 1g of the product as a light brown solid.

Example 211

A mixture of the product of step I (1.1g,2.62mmol), formic acid (10mL) was stirred at 900C for 1h, and the reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was basified with saturated sodium bicarbonate solution and extracted with chloroform. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude product. The crude product was triturated with n-pentane and dried to afford 1g of example 211. MS M/z 392.5(M + H)⁺,HPLC[A]:rt 12.00min(92.96%).

Example 212

A solution of 18-crown-6 (4.46g,16.87mmol) saturated with potassium iodide in dry dichloromethane (30mL) was added to the solution of example 211 (1.1g,2.81mmol), cooled to-30 ℃, to which was added boron tribromide (0.8mL,8.43mmol), and stirred at RT for 3 hours. The reaction mixture was quenched with sodium bicarbonate solution, diluted with water and extracted with dichloromethane. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and evaporated to dryness to obtain crude compound. The crude compound was purified by elution in 3-4% methanol in chloroform on neutral alumina to provide 450mg of example 212. MS M/z 378.4(M + H)⁺;HPLC[A]:rt 9.95min(93.81%)

Example 210

A solution of example 212(0.4g,1.06mmol) in dichloromethane (20mL) was added to a suspension of IBX (0.89g,3.18mmol) in DMSO (7mL) and stirred at room temperature overnight. The reaction mixture was filtered, washed with saturated sodium bicarbonate solution, water, brine, dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure to yield 300mg of PQPL-188 as an off white solid (HPLC-93%). 80mg was further purified by preparative TLC, by elution in 4% methanol in chloroform to obtain example 153 as an off-white solid, 50 mg.

Yield: 0.05g (12.0%), MS M/z 376.4(M + H)⁺;¹H-NMR (400MHz, DMSO-d6): delta 12.39(d,1H), 8.15(d,1H), 7.61-7.20(m,7H), 5.73(d,1H), 4.80(t,1H), 4.22(t,1H), 2.98(t,1H), 2.56 (mixed with DMSO, 1H), 2.21(d,2H), 1.99(d,2H), 1.78(d,2H), HPLC [ A, H ]]:rt 10.69min(94.8%)

Example 213: 3- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (4-morpholinocyclohexyl) phenyl) oxazolidin-2-one

From n-butyllithium (2.3M in hexanes; 3.66mL,7.32mmol), triphenylphosphonium bromide (2.6g,7.32mmol), 4- (4-morpholinocyclohexyl) benzaldehyde (1g,3.66mmol), tert-butyl hypochlorite (1.13mL,8.85mmol), Boc carbamate (1.03g,8.85mmol), 0.4M aqueous sodium hydroxide (360mg in 10mL), (DHQ) according to method 5₂PHAL (114mg, mmol), dihydrateThe compound was synthesized starting from potassium osmate (40mg,0.12mmol), thionyl chloride (0.6mL,8mmol), 1, 2-diamino-4-bromobenzene (160mg,0.84mmol) and cesium fluoride (190mg,1.26mmol), cuprous iodide (25mg,0.13mmol) and 1, 2-diaminocyclohexane (15mg,0.13mmol), formic acid (10 mL). Yield: 40mg (2.4%), MS M/z 447.4(M + H)⁺;¹H-NMR (400MHz, DMSO-d6): delta 12.38(s,1H), 8.15(s,1H), 7.60-7.16(m,6H), 5.69(t,1H), 4.8(t,1H), 4.13-4.10(q,1H), 3.57(t,4H), 2.56 (mixed with DMSO, 1H), 2.33(s,4H), 2.11(s,1H), 1.91-1.67(m,5H), 1.45-1.38(m,4H), HPLC (. lamda =214nm, [ A, 4H ] ]:rt 7.95min(97.87%)

Example 214: 3- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (pyrrolidin-1-yl) phenyl) oxazolidin-2-one

The compound was synthesized as described above, starting with:

step A

1-phenylpyrrolidine (1g,6.8mmol), ethyl 2-chloro-2-oxoacetate (0.84mL,7.5mmol), aluminum chloride (1.81g,13.6 mmol).

Step B

Hydroxylamine hydrochloride (0.17g,2.49 mmol); sodium acetate (0.27g,3.32 mmol).

Step C

PdC(10%,0.02g)。

Step D

A2M solution of lithium aluminum hydride in THF (1.3mL,2.62 mmol).

Step E

Bis- (imidazol-1-yl) methanone (0.2g,1.23mmol), further starting from 4-iodobenzene-1, 2-diamine (0.066g,0.28mmol), copper (I) iodide (0.006g,0.028mmol), cesium fluoride (0.085g,0.56mmol), cyclohexane-1, 2-diamine (0.004mL,0.028mmol), triethyl orthoformate (1mL) according to method 5 step D.

Yield: 0.007g (0.6%); MS M/z 349.2(M + H)⁺,175.4(M+2H)²⁺;¹H NMR(400MHz,CD₃OD):δ1.63-1.72(m,2H);1.90-1.98(m,4H);3.32-3.36(m,4H);4.29-4.33(m,H);4.85-4.89(m,H);5.61-5.65(m,H);7.42-7.44(m,2H);7.51-7.55(m,3H);7.61(d,H,J=2.1Hz);7.94(s,H);8.21(d,H,J=7.7Hz);8.49-8.51(m,H),HPLC(λ=214nm),[A]:rt 10.69min(84.7%).

Example 215: (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (piperidin-1-yl) phenyl) oxazolidin-2-one

This compound was synthesized according to method 5.

Step A:

the compound was synthesized starting from 4- (piperidin-1-yl) benzaldehyde (2g,10.6mmol), methyltriphenylphosphonium bromide (5.1g,14.3mmol), a 1.6M solution of butyllithium in THF (8.9mL,14.3 mmol).

Yield: 1.5g (75.7%)

And B:

the product obtained from step A (1.5g,8mmol), ethyl carbamate (2.22g,24.9mmol), 5-dimethylimidazolidine-2, 4-dione (2.41g,12.23mmol), (DHQ) ₂PHAL(0.312g,0.4mmol)、K₂OsO₄x2H₂O (0.118g,0.32mmol), 0.41M aqueous NaOH (60.2mL,24.5 mmol).

Yield: 0.38g (16.2%)

And C:

the product obtained from step B (0.38g,1.3mmol), 0.2M aqueous NaOH (35.75 ml).

Yield: 0.24g (75%)

Step D:

the product obtained from step C (0.24g,1mmol), 4-iodobenzene-1, 2-diamine (0.234g,1mmol), copper (I) iodide (0.019g,0.1mmol), cesium fluoride (0.304g,2mmol), cyclohexane-1, 2-diamine (0.013mL,0.1mmol), triethyl orthoformate (4 mL).

Yield: 0.010g (6.9%)

The total yield is as follows: 0.010g (0.7%); MS M/z 363.2(M + H)⁺,182.2(M+2H)²⁺;¹H NMR(400MHz,CDCl₃):δ1.52-1.54(m,2H);1.63(br s,4H);3.08-3.10(m,4H);4.22-4.26(m,H);4.73-4.77(m,H);5.30(br s,H);6.79-6.81(m,2H);7.13-7.19(m,3H);7.50(br s,H);7.61(br s,H);7.95(br s,H),HPLC(λ=214nm),[A]:rt 6.54min (97.8%).

Example 216: (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4- (3- (piperidin-1-yl) phenyl) oxazolidin-2-one

This compound was synthesized according to method 5.

Step A:

the compound was synthesized starting from 3- (piperidin-1-yl) benzaldehyde (1.5g,7.9mmol), methyltriphenylphosphonium bromide (3.83g,10.7mmol), a 1.6M solution of butyllithium in THF (6.7mL,10.7 mmol).

Yield: 1.1g (74%)

And B:

the product obtained from step A (1.1g,5.9mmol), ethyl carbamate (1.62g,18.21mmol), 5-dimethylimidazolidine-2, 4-dione (1.76g,8.96mmol), (DHQ)₂PHAL(0.229g,0.29mmol)、K₂OsO₄x2H₂O (0.087g,0.23mmol), 0.41M aqueous NaOH (44mL,17.9 mmol).

Yield: 0.2g (11.6%)

And C:

The product obtained from step B (0.2g,0.68mmol), 0.2M aqueous NaOH (18.8 ml).

Yield: 0.15g (89%)

Step D:

the product obtained from step C (0.15g,0.61mmol), 4-iodobenzene-1, 2-diamine (0.142g,0.61mmol), copper (I) iodide (0.011g,0.06mmol), cesium fluoride (0.183g,1.22mmol), cyclohexane-1, 2-diamine (0.008mL,0.06mmol), triethyl orthoformate (10 mL).

Yield: 0.010g (4.5%)

The total yield is as follows: 0.010g (0.3%); MS M/z 363.2(M + H)⁺,182.2(M+2H)²⁺;¹H NMR(400MHz,CDCl₃):δ1.51-1.55(m,2H);1.60-1.64(m,4H);3.04-3.12(m,4H);4.23-4.26(m,H);4.76-4.80(m,H);5.30-5.34(m,H);6.70-6.72(m,H);6.78-6.80(m,2H);7.12-7.16(m,H);7.29(br s,H);7.46(br s,H);7.66(br s,H);7.96(br s,H),HPLC(λ=214nm),[A]:rt 4.43min(88%).

Example 217: (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4- (4-morpholinophenyl) oxazolidin-2-one

This compound was synthesized according to method 5.

Step A:

the compound was synthesized starting from 4-morpholinobenzaldehyde (2g,10.5mmol), methyltriphenylphosphonium bromide (5.04g,14.12mmol), a 1.6M solution of butyllithium in THF (8.8mL,14.12 mmol).

Yield: 0.78g (58.6%)

And B:

the product obtained from step A (0.78g,4.1mmol), ethyl carbamate (1.14g,12.7mmol), 5-dimethylimidazolidine-2, 4-dione (1.24g,6.3mmol), (DHQ)₂PHAL(0.16g,0.21mmol)、K₂OsO₄x2H₂O (0.06g,0.16mmol), 0.41M aqueous NaOH (30.7mL,12.5 mmol).

Yield: 0.4g (33.1%)

And C:

the product obtained from step B (0.4g,1.4mmol), 0.2M NaOH in methanol (37.5 ml).

Yield: 0.285g (60.1%)

Step D:

the product obtained from step C (0.14g,0.56mmol), 4-iodobenzene-1, 2-diamine (0.13g,0.56mmol), copper (I) iodide (0.011g,0.06mmol), cesium fluoride (0.17g,1.13mmol), cyclohexane-1, 2-diamine (0.008mL,0.06mmol), triethyl orthoformate (4 mL).

Yield: 0.062g (30.2%)

The total yield is as follows: 3.5%; MS M/z 365.3(M + H)⁺,183.4(M+2H)²⁺;¹H NMR(400MHz,CDCl₃):δ3.07-3.09(m,4H);3.77-3.79(m,4H);4.21-4.25(m,H);4.74-4.79(m,H);5.30-5.34(m,H);6.78-6.80(m,2H);7.17-7.19(m,3H);7.42(br s,H);7.58(br s,H),7.87(br s,H)HPLC(λ=214nm),[A]:rt 7.31min(98.8%).

Example 218: (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4- (3-morpholinophenyl) oxazolidin-2-one

This compound was synthesized according to method 5.

Step A:

the compound was synthesized starting from 3-morpholinobenzaldehyde (2g,10.5mmol), methyltriphenylphosphonium bromide (5.04g,14.12mmol), a 2M solution of butyllithium in THF (8.8mL,14.12 mmol).

Yield: 1.16g (58.6%)

And B:

the product obtained from step A (1.16g,6.14mmol), ethyl carbamate (1.7g,19mmol), 5-dimethylimidazolidine-2, 4-dione (1.84g,9.36mmol), (DHQ)₂PHAL(0.239g,0.31mmol)、K₂OsO₄x2H₂O (0.09g,0.25mmol), 0.41M NaOH in waterLiquid (46.2mL,18.7 mmol).

Yield: 0.27g (14.9%)

And C:

the product obtained from step B (0.27g,0.92mmol), 0.2M aqueous NaOH (25.3 ml).

Yield: 0.180g (80%)

Step D:

the product obtained from step C (0.07g,0.28mmol), 4-iodobenzene-1, 2-diamine (0.066g,0.28mmol), copper (I) iodide (0.006g,0.03mmol), cesium fluoride (0.085g,0.56mmol), cyclohexane-1, 2-diamine (0.004mL,0.03mmol), triethyl orthoformate (2 mL).

Yield: 0.010g (10%)

The total yield is as follows: 0.010g (0.7%); MS M/z 365.2(M + H)⁺,183.4(M+2H)²⁺;¹H NMR(400MHz,CD₃OD):δ3.00-3.10(m,4H);3.74-3.76(m,4H);4.22-4.26(m,H);4.81-4.87(m,H);5.55-5.59(m,H);6.83-6.84(m,2H);6.93(s,H);7.16-7.20(m,H);7.37(s,H);7.87(br s,H),HPLC(λ=214nm),[A]:rt 8.56min(93.9%).

Example 219: 3- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (tetrahydro-2H-pyran-4-yl) phenyl) oxazolidin-2-one

Step A

Ethyl cloroxylate (5.5mL,49.38mmol) and AlCl were combined at-20 deg.C₃(6.5g,49.38mmol) A solution of tetrahydro-4-phenyl-2H-pyran (2.0g,12.34mmol) in dichloromethane (25mL) was added. The mixture was stirred for 1h and warmed to room temperature for 2 h. The mixture was then washed with saturated NaHCO at 0 deg.C₃The solution was quenched, filtered and washed with excess ethyl acetate (200mL) and the organic layer was washedSeparating with Na₂SO₄Dried and evaporated under reduced pressure to give 2.0g (62.5%) of the product as a brown liquid.

Step B

Hydroxylamine hydrochloride (1.65g,23.86mmol) and sodium acetate (1.95g,23.86mmol) were added to a solution of the product of step B (2.5g,9.54mmol) in ethanol (25mL) and heated to 80 ℃ for 12 h. The reaction mixture was then cooled to room temperature and filtered, and the filtrate was evaporated to dryness to obtain 2.42g (91%) of the product as a colorless liquid.

Step C

The product of step B (3.5g,12.63mmol) was added to a solution of 10% Pd-C (350mg,10%) in ethanol and kept in a hydrogenation vessel at room temperature for 24h at 80 Psi. The catalyst was then filtered through a bed of celite and the solvent was evaporated to yield 1.7g (51.5%) of the product as a colorless liquid.

Step D

Boc-anhydride (2.5mL,11.40mmol) was added to a solution of the product of step C (3.0g,11.40mmol) and triethylamine (2.4mL,11.40mmol) in dichloromethane (40mL) and stirred for 3 h. The reaction mixture was washed with water (30mL) and extracted with dichloromethane (3 × 50 mL). The combined organic layers were washed with brine (20mL), dried over anhydrous sodium sulfate and concentrated. The crude compound was purified by column chromatography using neutral alumina and the pure product was eluted with 15% ethyl acetate in petroleum ether as solvent to obtain 2.3g (56%) of the product as a yellow liquid.

Step E

Lithium aluminum hydride (150mg,3.57mmol) was added to a solution of the product of step C (1.3g,3.57mmol) in dry THF (40mL) at 0 ℃. The reaction mixture was then allowed to warm to room temperature for 2h, cooled to 0 ℃ and saturated NH₄The Cl solution (25mL) was quenched, and the mixture was filtered and washed with ethyl acetate (100 mL). The solution was partitioned between two layers, the organic layer was separated, washed with brine solution and evaporated to give 900mg (81.8%) of the product as a light yellow solid.

Step F

Thionyl chloride (1.5mL,19.93mmol) was added to a solution of the product of step E (800mg,2.49mmol) in tetrahydrofuran (10mL) at 0 ℃. The reaction mixture was then allowed to warm to room temperature for 12 h. The solvent was evaporated and saturated NaHCO ₃The solution (10mL) was basified and extracted with chloroform (3 × 25mL), the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to afford 480mg (78%) of the product as a pale yellow solid.

The product was further synthesized according to method 5, step D, starting from the product of step F (400mg,1.617mmol), 1, 2-diamino 4-bromobenzene (333mg,1.78mmol), cesium fluoride (490mg,3.22mmol), cuprous iodide (45mg,0.241mmol), formic acid (5 mL). Yield: 150mg (25.5%), MSm/z 364.3(M + H)⁺;¹H-NMR (400MHz, DMSO-d6): delta 12.38(s,1H), 8.15(s,1H), 7.60(s,1H), 7.55(bs,1H), 7.33-7.20(m,5H), 5.72(t,1H), 4.80(t,1H):4.12(t,1H), 3.88(d,2H), 3.37-3.29 (mixed with DMSO water, 2H), 2.60(d,1H), 1.60-1.23(m,4H), HPLC (lambda =214nm, [ A, H ], [ A, 4H ]]:rt 10.93min(98.93%).

Example 220: 3- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (1-methylpiperidin-4-yl) phenyl) oxazolidin-2-one

Step A

Ethyloxalyl chloride (13mL,114.28mmol) was added to a solution of 1-methyl-4-phenylpiperidine (5g,28.57mmol) in DCM (50mL) at-30 ℃ over a period of 5 min. Aluminium chloride (15.2g,114.28mmol) was added to the above solution in 3 portions over a period of 15 min. The RM was stirred at-30 ℃ for 1 h. The RM was slowly warmed to room temperature and stirred at room temperature for 2 h. Reaction mass is added to Na ₂CO₃The reaction solution was quenched with water and extracted with ethyl acetate. The salt was filtered off and washed with ethyl acetate. The organic layer was separated from the filtrate and washed with water and then brine solution. Dried over anhydrous sodium sulfate and concentrated to give 2.8g (35.8%) of a brown oily liquidAnd (3) obtaining the product.

Step B

Sodium acetate (596mg,7.27mmol), hydroxylamine HCl (505mg,7.27mmol) were added to the product of step A (1g,3.6mmol) in ethanol (8mL) in sequence and stirred at reflux for 2 h. The salt was isolated and washed with ethanol. The filtrate was concentrated to give 1.5g of crude product.

Step C

10% Pd-C (200mg) was added to a solution of the product of step B (1.5g,5.17mmol) in ethanol (25mL) and hydrogenated at 80psi for 15 h. The RM was filtered through celite and washed with ethanol. The filtrate was concentrated to give 1g (70.4%) of the product as a thick oil.

Step D

Triethylamine (0.6mL,4.34mmol) was added to a solution of the product of step C (1g,3.62mmol) in DCM (10mL) and stirred for 15 min. Addition (Boc)₂O (0.95mL,4.34mmol) and stirred at RT for 1 hr. Water was added and extracted in ethyl acetate. The organic layers were combined and washed with water then brine solution. Dried over anhydrous sodium sulfate and concentrated to give 700mg of crude product as an oil, which was used without further characterization.

Step E

LAH (90mg,2.39mmol) was added slowly to a solution of the product of step D (900mg,2.39mmol) in THF (15mL) at 0 ℃ over a period of 5 min. After stirring at 0 ℃ to 5 ℃ for 2h, the RM is quenched with saturated sodium sulfate solution and diluted with ethyl acetate. The salt was filtered off and washed with ethyl acetate. The organic layers were combined and washed with water then brine solution. Dried over anhydrous sodium sulfate and concentrated to provide 550mg of oily product.

Step F

Thionyl chloride (1mL,14.37mmol) was added to a solution of the product of step E (600mg,14.37mmol) in THF (10mL) at 0 deg.C, slowly warmed to RT and stirred for 18 hr. The RM was concentrated below 45 ℃, basified with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layers were combined and washed with water then brine solution. Dried over anhydrous sodium sulfate and concentrated to provide 290mg of the product as a yellow solid.

The product was further synthesized according to method 5, step D, starting from the product of step F (290mg,1.11mmol), 2-diamino-4-bromobenzene (229mg,1.22mmol), cesium fluoride (339mg,2.23mmol) and copper (I) iodide (31mg,0.167mmol), 1, 2-diaminocyclohexane (19mg,0.167mmol), formic acid (3 mL). Yield: 50mg (11.9%), MS M/z 377.4(M + H)⁺;¹H-NMR400MHz, CDCl 3:. delta.7.95 (s,1H);7.67(s,1H);7.51(s,2H);7.25-7.15 (mixed with CDCl3, 5H);5.42-5.39(q,1H);4.79(t,1H);4.25-4.22(q,1H);2.95(d,2H);2.49-2.39(m,1H);2.30(s,3H);2.06-1.99(m,2H);1.77-1.65(m, 4H); HPLC (. lamda =214nm, [ A ] A; 1.77-1.65(m, 4H); HPLC ]:rt 5.63min(94.45%).

Example 221: (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4- (3- (4-methylpiperazin-1-yl) phenyl) oxazolidin-2-one

The compound was synthesized according to method 6 starting from 3- (4-methylpiperazin-1-yl) benzaldehyde (11g,53.92mmol), KCN (3.5g,53.9mmol), ammonium carbonate (4.381g,67.40mmol), NaOH (12g,775.32mmol), thionyl chloride (22.74g,313.25mmol), di-tert-butyl dicarbonate (1.8g,11.59mmol), triethylamine (3.23mL,23.18mmol), sodium borohydride (2.45g,65.01mmol), thionyl chloride (0.864mL,11.54mmol), 1, 2-diamino-4-bromobenzene (181mg,0.969mmol), cesium fluoride (267mg,1.762mmol), cis-1, 2-diaminocyclohexane (0.015mL,0.132mmol), formic acid (5 mL). Yield: 50mg (0.25%), MS M/z 378.3(M + H)⁺,¹H-NMR(400MHz,DMSO-d6):δ12.39(d,1H);8.16(d,1H);7.59-7.11(m,4H);6.95(d,1H);6.28-6.72(m,2H);5.63-5.61(q,1H);4.8(t,1H);4.12(t,1H);3.07(d,4H);2.49-2.40(m,4H);2.19(s,3H),HPLC(λ=214nm),[A]:rt 6.53min(93.54%)

Example 222: (S) -3- (3-methyl H-imidazo [1,2-a ] pyridin-7-yl) -4-phenyloxazolidin-2-one

The compound was synthesized according to method 5, step D, starting from 7-bromo-3-methyl H-imidazo [1,2-a ] pyridine (84mg;0.4mmol;1eq.), dioxane (5ml), (S) -4-phenyloxazolidin-2-one (72mg;0.44mmol;1.1eq.), copper (I) iodide (8mg;0.04mmol;0.1eq.), cesium fluoride (121mg;0.8mmol;2eq.), diaminocyclohexane (5mg;0.04mmol;0.1 eq.).

Yield: 57mg (48%); MS M/z 294.2(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ2.37(s,3H);4.17(dd,1H,3J=8.7Hz,2J=2.9Hz);4.86(t,1H,3J=8.7Hz);5.81(dd,1H,3J=8.7Hz,2J=2.9Hz);7.23-7.37(m,6H);7.40-7.42(m,2H);8.17(d,1H,3J=7.5Hz);HPLC(λ=214nm),[B]:rt 10.78min(99.7%).

Example 223: (S) -3- (3- (trifluoromethyl) H-imidazo [1,2-a ] pyridin-7-yl) -4-phenyloxazolidin-2-one

The compound was synthesized according to method 5, step D, starting from 7-bromo-3- (trifluoromethyl) H-imidazo [1,2-a ] pyridine (80mg;0.3mmol;1eq.), dioxane (5ml), (S) -4-phenyloxazolidin-2-one (54mg;0.33mmol;1.1eq.), copper (I) iodide (6mg;0.03mmol;0.1eq.), cesium fluoride (91mg;0.6mmol;2eq.), diaminocyclohexane (4mg;0.04mmol;0.1 eq.).

Yield: 39mg (37%); MS M/z 348.0(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ4.21(dd,1H,3J=8.7Hz,2J=3.3Hz);4.90(t,1H,3J=8.7Hz);5.88(dd,1H,3J=8.7Hz,2J=3.7Hz);7.29-7.33(m,1H);7.36-7.40(m,2H);7.42-7.44(m,2H);7.56(d,1H,4J=2.1Hz);7.67(dd,1H,3J=7.5Hz,2J=2.1Hz);8.15(s,1H);8.52(d,1H,3J=7.5Hz);HPLC(λ=214nm),[B]:rt 14.43min(98.6%).

Example 224: (S) -4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -3- (H-imidazo [1,2-a ] pyridin-7-yl) oxazolidin-2-one

This compound was synthesized according to method 5.

Step A:

this compound was synthesized starting from 2, 3-dihydrobenzo [ b ] [1,4] dioxine-6-carbaldehyde (0.5g,3.05mmol), methyltriphenylphosphonium bromide (1.47g,4.11mmol), a 2M solution of butyllithium in THF (2.06mL,4.11 mmol).

Yield: 0.41g (82.9%)

And B:

the product obtained from step A (0.41g,2.4mmol), tert-butyl carbamate (0.91g,7.75mmol), 5-dimethylimidazolidine-2, 4-dione (0.75g,3.8mmol), (DHQ)₂PHAL(0.12g,0.15mmol)、K₂OsO₄x2H₂O (0.037g,0.1mmol), 0.38M aqueous NaOH (20mL,7.6 mmol).

Yield: 0.3g (40.6%)

And C:

the product obtained from step B (0.3g,1.3mmol) was dissolved in 40mL of dichloromethane and 5mL of TFA was added. After stirring for 1 hour at ambient temperature, the solvent was removed under reduced pressure. The residue was added to THF. Bis (1H-imidazol-1-yl) methanone (0.2g,1.22mmol) and triethylamine (0.17mL,1.22mmol) were added. The reaction was stirred at 50 ℃ for 48 hours, then the solvent was removed under reduced pressure. The remaining residue was taken up in ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered and the solvent was removed using a rotary evaporator. The product was purified by flash chromatography (ethyl acetate/heptane gradient).

Yield: 0.12g (53.4%)

Step D:

the product obtained from step C (0.12g,0.54mmol), 7-bromoimidazo [1,2-a ] pyridine (0.11g,0.55mmol), copper (I) iodide (0.011g,0.055mmol), cesium fluoride (0.17g,1.1mmol), cyclohexane-1, 2-diamine (0.007mL,0.055 mmol).

Yield: 0.030g (16.5%)

The total yield is as follows: 0.010g (3%); MS M/z 388.2(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ4.08-4.12(m,H);4.15(s,4H);4.75-4.79(m,H);5.63-5.66(m,H);6.78-6.89(m,3H);7.25-7.29(m,2H);7.43(s,H);7.77(s,H);8.42(d,H,J=7.5Hz),HPLC(λ=214nm),[A]:rt 7.55min(98.5%).

Example 225: (S) -4- (4-cyclohexylphenyl) -3- (H-imidazo [1,2-a ] pyridin-7-yl) oxazolidin-2-one

This compound was synthesized according to method 5.

Step A:

the compound was synthesized starting from 4-cyclohexylbenzaldehyde (2.3g,12.2mmol), methyltriphenylphosphonium bromide (5.9g,16.5mmol), a 2M solution of butyllithium in THF (8.25mL,16.5 mmol).

Yield: 2.08g (91.4%)

And B:

the product obtained from step A (2.08g,11.17mmol), ethyl carbamate (3.08g,34.61mmol), 5-dimethylimidazolidine-2, 4-dione (3.35g,17.03mmol), (DHQ)₂PHAL(0.434g,0.56mmol)、K₂OsO₄x2H₂O (0.165g,0.45mmol), 0.41M aqueous NaOH (84mL,34.05 mmol).

Yield: 1.35g (41.5%)

And C:

the product obtained from step B (1.35g,4.64mmol), 0.2M aqueous NaOH (128 ml).

Yield: 0.675g (59.3%)

Step D:

the product obtained from step C (0.2g,0.82mmol), 7-bromoimidazo [1,2-a ] pyridine (0.16g,0.82mmol), copper (I) iodide (0.016g,0.082mmol), cesium fluoride (0.25g,1.63mmol), cyclohexane-1, 2-diamine (0.010mL,0.082 mmol).

Yield: 0.160g (54%)

The total yield is as follows: 12.1%; MS M/z 362.2(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ1.13-1.31(m,6H);1.60-1.70(m,4H);2.38-2.42(m,H);4.10-4.14(m,H);4.78-4.82(m,H);5.71-5.75(m,H);7.17-7.19(m,2H);7.28-7.30(m,4H);7.41(br s,H);7.76(s,H);8.40-8.42(m,H),HPLC(λ=214nm),[A]:rt 15.01min(98.3%).

Example 226: (S) -3- (H-imidazo [1,2-a ] pyridin-7-yl) -4- (4- (piperidin-1-yl) phenyl) oxazolidin-2-one

This compound was synthesized according to method 5.

Step A:

the compound was synthesized starting from 4- (piperidin-1-yl) benzaldehyde (1.17g,6.18mmol), methyltriphenylphosphonium bromide (2.98g,8.35mmol), a 1.6M solution of butyllithium in THF (5.22mL,8.35 mmol).

Yield: 0.72g (62.2%)

And B:

the product obtained from step A (0.72g,3.85mmol), ethyl carbamate (1.14g,12.7mmol), 5-dimethylimidazolidine-2, 4-dione (1.24g,6.3mmol), (DHQ)₂PHAL(0.16g,0.21mmol)、K₂OsO₄x2H₂O (0.06g,0.16mmol), 0.41M aqueous NaOH (30.7mL,12.5 mmol).

Yield: 0.2g (17.8%)

And C:

the product obtained from step B (0.2g,0.69mmol), 0.2M aqueous NaOH (18.8 ml).

Yield: 0.165g (97.8%)

Step D:

the product obtained from step C (0.09g,0.37mmol), 7-bromoimidazo [1,2-a ] pyridine (0.07g,0.37mmol), copper (I) iodide (0.007g,0.037mmol), cesium fluoride (0.11g,0.73mmol), cyclohexane-1, 2-diamine (0.005mL,0.037 mmol).

Yield: 0.02g (15.1%)

The total yield is as follows: 1.6%; MS M/z 363.2(M + H)⁺;¹H NMR(400MHz,CDCl₃):δ1.63-1.72(m,2H);1.90-1.98(m,4H);3.32-3.36(m,4H);4.29-4.33(m,H);4.85-4.89(m,H);5.61-5.65(m,H);7.42-7.44(m,2H);7.51-7.55(m,3H);7.61(d,H,J=2.1Hz);7.94(s,H);8.21(d,H,J=7.7Hz);8.49-8.51(m,H),HPLC(λ=214nm),[A]:rt 3.87min(98%).

Example 227: (S) -3- (H-imidazo [1,2-a ] pyridin-7-yl) -4- (4-morpholinophenyl) oxazolidin-2-one

This compound was synthesized according to method 5.

Step A:

the compound was synthesized starting from 4-morpholinobenzaldehyde (2g,10.5mmol), methyltriphenylphosphonium bromide (5.04g,14.1mmol), a 1.6M solution of butyllithium in THF (8.8mL,14.1 mmol).

Yield: 0.78g (39.4%)

And B:

the product obtained from step A (0.78g,4.1mmol), ethyl carbamate (1.14g,12.7mmol), 5-dimethylimidazolidine-2, 4-dione (1.24g,6.3mmol), (DHQ)₂PHAL(0.16g,0.21mmol)、K₂OsO₄x2H₂O (0.06g,0.16mmol), 0.41M aqueous NaOH (30.6mL,12.5 mmol).

Yield: 0.4g (33.1%)

And C:

the product obtained from step B (0.4g,1.36mmol), 0.2M aqueous NaOH (37.5 ml).

Yield: 0.29g (84.5%)

Step D:

the product obtained from step C (0.14g,0.56mmol), 7-bromoimidazo [1,2-a ] pyridine (0.11g,0.56mmol), copper (I) iodide (0.011g,0.06mmol), cesium fluoride (0.17g,1.13mmol), cyclohexane-1, 2-diamine (0.008mL,0.06 mmol).

Yield: 0.05g (24.3%)

The total yield is as follows: 2.7%; MS M/z 365.3(M + H)⁺;¹H NMR(400MHz,CDCl₃):δ3.10-3.12(m,4H);3.79-3.81(m,4H);4.19-4.22(m,H);4.74-4.79(m,H);5.30-5.33(m,H);6.83(d,2H,J=8.7Hz);7.08(s,H);7.20(d,2H,J=8.7Hz);7.44(s,H);7.47(s,H);7.59-7.61(m,H);7.99-8.01(m,H),HPLC(λ=214nm),[A]:rt 7.23min(95.1%).

Example 228: (S) -3- (H-imidazo [1,2-a ] pyridin-7-yl) -4- (4- (4-phenylpiperazin-1-yl) phenyl) oxazolidin-2-one

This compound was synthesized according to method 5.

Step A:

the compound was synthesized starting from 4- (4-phenylpiperazin-1-yl) benzaldehyde (1.03g,3.87mmol), methyltriphenylphosphonium bromide (1.86g,5.22mmol), a 2M solution of butyllithium in THF (2.61mL,5.22 mmol).

Yield: 0.66g (64.5%)

And B:

the product obtained from step A (0.66g,2.5mmol), tert-butyl carbamate (0.91g,7.75mmol), 5-dimethylimidazolidine-2, 4-dione (0.75g,3.83mmol), (DHQ)₂PHAL(0.117g,0.15mmol)、K₂OsO₄x2H₂O (0.037g,0.1mmol), 0.38M aqueous NaOH (20mL,7.68 mmol).

Yield: 0.26g (26.2%)

And C:

the product obtained from step B (0.26g,0.66mmol) was dissolved in 40mL of dichloromethane and 5mL of TFA was added. After stirring for 1 hour at ambient temperature, the solvent was removed under reduced pressure. The residue was taken up in dichloromethane. Bis (1H-imidazol-1-yl) methanone (0.13g,0.79mmol) and triethylamine (0.11mL,0.79mmol) were added. The reaction was stirred at ambient temperature for 90 minutes, then the solvent was removed under reduced pressure. The remaining residue was taken up in ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, filtered and the solvent was removed using a rotary evaporator. The product was purified by flash chromatography (ethyl acetate/hexane gradient).

Yield: 0.08g (37.8%)

Step D:

the product from step C (0.08g,0.25mmol), 7-bromoimidazo [1,2-a ] pyridine (0.049g,0.25mmol), copper (I) iodide (0.005g,0.025mmol), cesium fluoride (0.076g,0.5mmol), cyclohexane-1, 2-diamine (0.003mL,0.025mmol) were obtained.

Yield: 0.004g (3.8%)

The total yield is as follows: 0.2%; MS M/z 440.4(M + H)⁺,220.9(2M+H)²⁺;¹H NMR(400MHz,CD₃OD):δ3.33-3.34(m,8H);4.28-4.31(m,H);4.89-4.92(m,H);5.68-5.70(m,H);6.92-6.95(m,H);7.05-7.08(m,4H);7.27-7.33(m,4H);7.76-7.78(m,H);7.84(d,H,J=2.1Hz);7.93(d,H,J=2.1Hz);7.99(d,H,J=2.1Hz);8.61(d,H,J=7.6Hz),HPLC(λ=214nm),[A]:rt 12.38min(93.6%).

Example 229: (S) -1- (1H-benzo [ d ] imidazol-5-yl) -5- (4- (bis (2-methoxyethyl) amino) phenyl) imidazolidin-2-one

Following modification 3 as indicated above, from 4- (bis (2-methoxyethyl) amino) benzaldehyde (1.180g,4.97mmol), 2.3M n-butyllithium (4.3mL,9.95mmol), methyltriphenylphosphonium bromide (3.5g,9.95mmol), tert-butyl hypochlorite (1mL,9.342mmol), tert-butyl carbamate (1.o75g,9.191mmol), sodium hydroxide (0.373g in 22mL water), (DHQ)₂PHAL (119mg,0.153mmol), potassium osmate dihydrate (45mg,0.122mmol), phthalimide (1.318g,8.967mmol), triphenylphosphine (3.2g,12.28mmol), diethyl azodicarboxylate (2ml,12.28mmol), hydrateThis compound was synthesized starting from hydrazine (30mL), p-anisaldehyde (0.32mL,2.656mmol), sodium borohydride (350mg,9.296mmol), triethylamine (0.539mL) and CDI (0.301g,1.86mmol), 1, 2-dibromo-4-bromobenzene (200mg,1.065mmol), cesium fluoride (300mg,1.936mmol), cuprous iodide (50mg), 1, 2-diaminocyclohexane (16mg,0.145mmol), formic acid (5mL), and trifluoroacetic acid (5 mL). Yield: 0.040g (1.96%); MS M/z 410.6(M + H) +;1H NMR (400MHz, CDCl3): delta 7.89(d,1H);7.60-7.45(M,2H);7.26-7.11 (mixed with CDCl3, 3H);6.61(d,2H);5.60(t,1H);4.77(t,1H);4.33(t,1H);3.60-3.49(M,8H);3.32(s,6H); HPLC (. lamda =214nm, [ A ] H; and ]:rt 8.46min(98.3%).

Example 230: 5- (4- (N- (2- (dimethylamino) ethyl) -N-methylamino) phenyl) -1- (1H-benzo [ d ] imidazol-5-yl) imidazolidin-2-one

Step A

A suspension of 4-fluorobenzonitrile (5g,41.3mmole) and trimethylethylamine (6ml,1.2vol) was refluxed for 16 hours. The reaction mass was cooled, diluted in cold water (100ml), extracted with ethyl acetate (3 × 100mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 5g (58.8%) of the product as a colourless liquid.

Step B

Raney nickel (Raney Ni) (1vol,5g) was added to a suspension of the product of step A (5g,24.27mmol) in 85% formic acid (10vol,50mL) at room temperature for 12 h. The reaction mixture was then filtered through a celite bed and washed with ethyl acetate (50 mL). The mixture was washed with saturated NaHCO₃The solution was basified and extracted with ethyl acetate (3 × 50 mL). Dried over anhydrous sodium sulfate and concentrated in vacuo to afford 196b as a colorless liquid, 4g (78.8%).

Step C

2.3M n-butyllithium (25.65mL,58.2mmol) was added to a stirred solution of methyltriphenylphosphonium bromide (20.78g,58.2mmol) in tetrahydrofuran (110mL) at-10 ℃ and stirred for 30 min. A solution of the product of step B (6g,29.12mmol) in tetrahydrofuran (30mL) was added dropwise to the reaction mixture at-10 ℃ and stirred at room temperature for 3 h. The reaction mixture was quenched with saturated ammonium chloride solution (50mL) and extracted with ethyl acetate (3 × 50 mL). The organic layer was washed with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product; it was purified by column chromatography on neutral alumina using 20% ethyl acetate in petroleum ether as eluent to afford 3.2g (54.2) of the product as a colorless liquid.

Step D

Tert-butyl hypochlorite (8.1mL,74.72mmol) was added to a stirred solution of tert-butyl carbamate (8.8g,75.98mmol) in 1-propanol (90mL) and 0.4M aqueous sodium hydroxide (2.98g in 157mL water) at 0 ℃ and stirred for 15 min. A solution of (DHQ)2PHAL (954mg,1.22mmol) in 1-propanol (90mL) was added. The product of step C (5.0g,24.50mmol) in 1-propanol (90mL) was then added followed by potassium osmate dihydrate (360mg,0.98mmol) and the reaction mixture stirred at room temperature for 0.5 h. The reaction mixture was quenched with saturated sodium sulfite solution (50mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 3.0g of crude product.

Step E

Diethyl azodicarboxylate (0.63mL,4.0mmol) was added to a mixture of phthalimide (431mg,2.93mmol), triphenylphosphine (1.04g,4.0mmol) and the product of step D (900mg,2.67mmol) in anhydrous THF (200mL) at 0 ℃ and heated at 90 ℃ overnight. The solvent was evaporated in vacuo to afford the crude product, which was purified by column chromatography on silica gel (60-120 mesh) using 20% ethyl acetate in petroleum ether as eluent to afford 900mg (72.5%) of the product as a pale yellow solid.

Step F

Hydrazine hydrate (10mL) was added to a solution of the product of step E (900mg,1.934mmol) in ethanol (5mL) at room temperature. The reaction was then stirred at 80 ℃ for 2h, the reaction was cooled to room temperature and evaporated to dryness, and the RM was diluted with water (50mL) and extracted with ethyl acetate (3 × 50 mL). The organic layer was separated and dried over anhydrous sodium sulfate, concentrated to afford crude compound, which was purified by 4% methanol in DCM as eluent in neutral alumina to afford 550mg (84.5%) of the product as a pale yellow solid.

Step G

P-anisaldehyde (0.4mL,3.27mmol) was added to a stirred solution of the product of step F (1.0g,2.97mmol) in anhydrous ethanol (10mL) and stirred at room temperature for 5 h. Cool to 0 ℃, add sodium borohydride (395mg,10.4mmol), and stir the reaction at room temperature for 10 h. The reaction mass was poured into saturated ammonium chloride solution and extracted with ethyl acetate (2 × 75 mL). The combined organic layers were washed successively with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 750mg (55.59%) of the product as a white solid.

Step H

A3N HCl solution (10mL) was added to a solution of the product of step G (750mg,1.64mmol) in tetrahydrofuran (10mL) at 0 ℃. The reaction mass was allowed to warm to room temperature and stirred for 15 h. THF was evaporated in vacuo and the residue was made basic using saturated sodium bicarbonate solution (20 mL). The mixture was extracted with dichloromethane (3 × 50 mL). The combined organic layers were washed successively with water (20mL), brine (20mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 500mg (85.47%) of the product as a viscous liquid.

Step I

Triethylamine (0.57mL,4.20mmol) and CDI (327mg,2.02mmol) were added sequentially to a solution of the product of step H (600mg,1.68mmol) in tetrahydrofuran (10mL) at room temperature. The reaction mass was heated to 70 ℃ and held for 2 h. The solvent was evaporated in vacuo and the residue was dissolved in ethyl acetate (50mL), washed successively with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the crude product. The crude compound was purified by passing through a column using neutral alumina. The pure compound was eluted in 2% methanol in chloroform as mobile phase to give 260mg (39.1%) of the product as a viscous liquid.

Step J

A mixture of the product of step I (200mg,0.523mmol), 1, 2-diamino-4-bromobenzene (107mg,0.575mmol), cesium fluoride (159mg,1.04mmol) and cuprous iodide (15mg,0.08mmol) in 1, 4-dioxane (5ml) was sparged with argon for 15 min. 1, 2-diaminocyclohexane (9mg,0.08mmol) was added to the reaction mixture and the aeration was continued for a further 10 min. The reaction mass was stirred in a sealed tube at 110 ℃ and 115 ℃ for 38 h. The reaction mixture was filtered through celite, washed with dioxane and concentrated under reduced pressure to afford the crude product. The crude compound was purified by column chromatography on neutral alumina using 2-3% methanol in chloroform as eluent to afford 80mg (31.3%) of the product as a brown solid.

Step K

Formamidine acetate (25mg,0.245mmol) was added to a solution of the product of step J (80mg,0.163mmol) in ACN (5mL) and heated at 70-75 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure. RM was dissolved in 10% methanol in 50mL chloroform, the organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 60mg (74%) of the product as a brown solid.

Step L

A solution of the product of step K (60mg,0.12mmol) in trifluoroacetic acid (4mL) was heated at 70 ℃ for 4h and then cooled to room temperature. Distilling the TFA; the crude compound was dissolved in ethyl acetate and washed with 10% sodium bicarbonate solution, water and brine solution. Dried over anhydrous sodium sulfate and evaporated in vacuo to afford the crude product, which was purified by preparative TLC using 6% methanol in chloroform as eluent to afford 25mg (56.4%) of the product as a brown solid.

Yield: 0.025g (55%); MS M/z 379.5(M + H)⁺;¹H NMR(400MHz,DMSO-d6):δ12.28(s,1H);8.11(s,1H);7.80-7.33(m,4H);7.21(d,2H);6.69-(d,2H);4.72(t,1H);4.23(t,1H);3.60(t,1H);3.41(t,2H);2.88(s,3H);2.35(t,2H);2.17(s,6H)HPLC(λ=214nm,[A]:rt 7.43min(91.9%).

Example 231: 3- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (4, 4-difluorocyclohexyl) phenyl) oxazolidin-2-one

This compound was synthesized from example 210.

Diethylaminosulfur trifluoride (0.25g,0.31mL,1.6mmol) was added to a solution of example 210(0.15g,0.4mmol) in dichloromethane (5mL) at 0 ℃ and heated at reflux for 48 h. The reaction mixture was quenched with ice, quenched with saturated bicarbonate solution and extracted with dichloromethane. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and evaporated to dryness to obtain 140mg of the product as a brown solid. Yield: 0.02g (15.0%), MS M/z 398.4(M + H) ⁺;¹H-NMR (400MHz, CDCl3): delta 7.98(s,1H),7.70(s,1H),7.52(s,1H),7.21-7.1 (mixed with CDCl3, 4H),5.45-5.41(q,1H),4.81(t,1H),4.25-4.22(q,1H),2.53(d,1H),2.17-2.02(m,2H),1.86-1.25(m,7H), HPLC (. lamda =214nm, [ A ] A]:rt 14.79min(99.3%)

Example 232: 2- (1H-benzo [ d ] imidazol-5-yl) -4, 7-difluoro-3- (4-propoxyphenyl) isoindolin-1-one

This compound was synthesized according to method 11.

2- (4-Propoxybenzoyl) -3, 6-difluorobenzoic acid (577mg;1.8mmol), DCC (371mg;1.8mmol), benzimidazole-5 (6) -amine (239mg;1.8mmol), TFA (1.28ml) and triethylsilane (0.204ml;1.28mmol;4eq.), and was additionally purified by semi-preparative HPLC.

Yield: 0.043g (5.6%); MS M/z 420.3[ M + H ]]⁺;¹H-NMR(DMSO d₆,400MHz):0.86(t,3H,3J=7,5Hz);1.55-1.64(m,2H);3.74-3.77(m,2H);6.65(s,1H);6.72-6.74(m,2H);7.14-7.16(m,2H);7.31-7.48(br m,4H);7.707-7.711(m,1H);8.15(s,1H);12.41(br s,1H);HPLC(λ=214nm),[B]:rt 14.98min(99.3%).

Example 233: 2- (H-imidazo [1,2-a ] pyridin-7-yl) -3- (3, 4-dimethoxyphenyl) isoindolin-1-one

Reacting 7-bromo H-imidazo [1,2-a ]]Pyridine (39mg;0.2mmol;1eq.) was dissolved in dioxane (5 ml). 3- (3, 4-Dimethoxyphenyl) isoindolin-1-one (59mg;0.22mmol;1.1eq.) copper (I) iodide (4mg;0.02mmol;0.1eq.), cesium fluoride (60mg;0.4mmol;2eq.) and diaminocyclohexane (3mg;0.02mmol;0.1 eq.) were added and the mixture was stirred under argon at 100 ℃ overnight. The reaction was quenched with saturated NaHCO₃The solution was quenched and extracted with EtOAc (3 × 25 ml). The combined organic layers were washed with Na ₂SO₄Dried, evaporated and washed with CHCl on silica₃The MeOH gradient was purified by flash chromatography.

Yield: 24mg (31%); MS M/z 386.3(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ3.61(s,3H);3.64(s,3H);6.56(s,1H);6.76-6.82(m,2H);6.908-6.913(m,1H);7.35(d,1H,3J=7.5Hz);7.45-7.62(br m,5H);7.68-7.69(m,1H);7.84(d,1H,3J=7.5Hz);8.44(d,1H,3J=7.5Hz);HPLC(λ=214nm),[B]:rt 11.93min(91.4%).

Example 234: (S) -2- (H-imidazo [1,2-a ] pyridin-7-yl) -3- (3, 4-dimethoxyphenyl) isoindolin-1-one

Reacting 7-bromo H-imidazo [1,2-a ]]Pyridine (39mg;0.2mmol;1eq.) was dissolved in dioxane (5 ml). (S) -3- (3, 4-dimethoxyphenyl) isoindolin-1-one (59mg;0.22mmol;1.1eq.) copper (I) iodide (4mg;0.02mmol;0.1eq.), cesium fluoride (60mg;0.4mmol;2eq.) and diaminocyclohexane (3mg;0.02mmol;0.1 eq.) are added and the mixture is stirred under argon at 100 ℃ overnight. The reaction was quenched with saturated NaHCO₃The solution was quenched and extracted with EtOAc (3 × 25 ml). The combined organic layers were washed with Na₂SO₄Dried, evaporated and purified by semi-preparative HPLC.

Yield: 21mg (27%); MS M/z 386.1(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ3.64(s,3H);3.67(s,3H);6.59(s,1H);6.81-6.86(m,2H);6.93(br s,1H);7.37-7.38(m,1H);7.48-7.57(m,4H);7.61-7.65(m,1H);7.71(br s,1H);7.81(s,1H);7.85-7.87(m,1H);HPLC(λ=214nm),[B]:rt 11.61min(98.4%).

Example 235: (S) -3- (3, 4-dimethoxyphenyl) -2- (3-methyl H-imidazo [1,2-a ] pyridin-7-yl) isoindolin-1-one

Reacting 7-bromo-3-methyl H-imidazo [1,2-a ]]Pyridine (42mg;0.2mmol;1eq.) was dissolved in dioxane (5 ml). (S) -3- (3, 4-dimethoxyphenyl) isoindolin-1-one (59mg;0.22mmol;1.1eq.) copper (I) iodide (4mg;0.02mmol;0.1eq.), cesium fluoride (60mg;0.4mmol;2eq.) and diaminocyclohexane (3mg;0.02mmol;0.1 eq.) are added and the mixture is stirred under argon at 100 ℃ overnight. The reaction was quenched with saturated NaHCO ₃The solution was quenched and extracted with EtOAc (3 × 25 ml). The combined organic layers were washed with Na₂SO₄Dried, evaporated and purified by semi-preparative HPLC.

Yield: 21mg (27%); MS M/z 400.2(M + H)⁺;¹H NMR(400MHz,DMSO-D₆):δ2.39(s,3H);3.64(s,3H);3.66(s,3H);6.60(s,1H);6.81-6.82(m,2H);6.91-6.93(m,1H);7.27(s,1H);7.35-7.38(m,1H);7.50-7.57(m,3H);7.69-7.79(m,1H);7.85-7.87(m,1H);8.18-8.20(m,1H);HPLC(λ=214nm),[B]:rt 12.13min(92.9%).

Activity screening

Fluorescence measurement

All measurements were performed at 30 ℃ using a BioAssay Reader HTS-7000plus (Perkin Elmer) for microplates. QC activity was assessed by fluorescence using H-Gln- β NA. The samples were prepared from 0.2mM fluorogenic substrate, 0.2M Tris/HCl containing 20mM EDTA, 0.25U pyroglutamylaminopeptidase (Unizyme,denmark) and an aliquot of QC diluted appropriately, in a final volume of 250 μ l. The excitation/emission wavelength was 320/410 nm. The assay reaction was initiated by adding glutaminyl cyclase. QC activity was determined from a standard curve of β -naphthylamine under assay conditions. 1 unit is defined as the amount of QC that catalyzes the formation of 1. mu. mol pGlu-beta NA by H-Gln-beta NA per minute under the conditions described.

In the second fluorescence measurement, QC is the activity measured using H-Gln-AMC as a substrate. The reaction was carried out at 30 ℃ using a NOVOStar reader (BMG labtechnologies) for microwell plates. The samples consisted of different concentrations of fluorogenic substrate, 0.05M Tris/HCl with 5mM EDTA, 0.1U pyroglutamylaminopeptidase (Qiagen) at pH 8.0 and suitably diluted aliquots of QC, in a final volume of 250. mu.l. The excitation/emission wavelength was 380/460 nm. The assay reaction was initiated by adding glutaminyl cyclase. QC activity was determined from a standard curve of 7-amino-4-methylcoumarin under assay conditions. Kinetic data were evaluated using GraFit software.

Spectrophotometric assay of QC

This new assay was used to determine the kinetic parameters of most QC substrates. QC activity was analyzed spectrophotometrically using a continuous method derived from a discontinuous assay before alteration using glutamate dehydrogenase as a helper enzyme (Bateman, r.c.j.1989J Neurosci Methods 30, 23-28). The sample consisted of each QC substrate, 0.3mM NADH, 14mM alpha-ketoglutarate and 30U/ml glutamate dehydrogenase, with a final volume of 250. mu.l. The reaction was started by adding QC and the decrease in absorbance at 340nm was monitored for 8-15 min.

The initial velocity was evaluated and the enzymatic activity was determined from a standard curve of ammonia under the assay conditions. All samples were assayed at 30 ℃ using a SPECTRAFluor Plus or Sunrise (both from TECAN) reader for microplates. Kinetic data were evaluated using GraFit software.

Inhibitor assay

For inhibitor testing, the sample compositions were the same as described above, except that the putative inhibitory compound was added. For a rapid assay of QC-inhibition, the samples contained 4mM of each inhibitor and a concentration of 1K_MA substrate of (a). Detailed study and K on inhibition_iValue determination, the effect of the inhibitor on the helper enzyme was first investigated. In each case, there was no effect on any of the enzymes detected, thus enabling QC inhibition to be reliably determined. Evaluation of inhibition frequency by fitting a set of progress curves to a general equation of competitive inhibition using GraFit software And (4) counting.

Results

Examples 2, 3, 5, 7-12, 14-30, 32-43, 45-51, 53-62, 65-66, 68, 70-92, 95-96, 98, 99, 102, 116, 118, 121-₅₀The value is obtained. Some specific values are given in the following table:

example numbering	hQC IC50[μM]	hQC Ki[μM]
			12	0.482	0.0625
13	30.2	7.25
			14	0.238	0.0374
43	0.254	0.0408
			55	0.397	0.075
60	0.882	0.149
			73	0.170	0.0336
89	0.160	0.0125
			142	0.297	0.0535
145	0.240	0.0588

Analytical method

HPLC：

Process [ A]: analytical HPLC System consisting of Merck-Hitachi apparatus (model)) Composition of, useRP 18(5 μm), analytical column (length: 125mm, diameter: 4mm) and Diode Array Detector (DAD) reporting wavelength λ =214 nm. Using gradients toAnalyzing the compound at a flow rate of 1 mL/min; wherein eluent (a) is acetonitrile and eluent (B) is water, both containing 0.1% (v/v) trifluoroacetic acid, using the following gradient: 0min-5min → 5% (A),5min-17min → 5-15% (A),15min-27min → 15-95% (A)27min-30min → 95% (A), method [ B ]]0min-15min → 5-60% (A),15min-20min → 60-95% (A),20min-23min → 95% (A), method [ C ]]:0min-20min→5-60%(A),20min-25min→60–95%(A).25min-30min→95%(A)。

Method [ B ]: analytical HPLC systems consisted of using Waters SunFire RP 18(2,5 μm), analytical column (length: 50mm, diameter: 2.1mm) and Diode Array Detector (DAD) reporting wavelength λ =254 nm. Compounds were analyzed using a gradient at a flow rate of 0.6 mL/min; wherein eluent (a) is acetonitrile, eluent (B) is water, and eluent (C) is 2% formic acid in acetonitrile, using the following gradient:

Time min	% solvent B	% solvent C
			0	90	5
2.5	10	5
			4	10	5
4.5	90	5
			6	90	5

The purity of all reported compounds was determined by the percentage of the peak area at 214 nm.

Mass spectrometry, NMR-spectroscopy:

ESI-mass spectra were obtained using a SCIEX API 365 spectrometer (Perkin Elmer) in positive ion mode.

Recording on BRUKER AC 500¹H NMR spectrum (500 MHz). Unless otherwise stated, the solvent is DMSO-D₆. Chemical shifts represent parts per million (ppm) of the low magnetic field direction from tetramethylsilane. The splitting pattern is specified as follows: s (singlet), d (doublet), dd (doublet), t (triplet), m (multiplet) and br (broad signal).

MALDI-TOF mass spectrometry

Matrix-assisted laser desorption/ionization mass spectrometry was performed using a Hewlett-Packard G2025LD-TOF system with a linear time-of-flight analyzer. The instrument was equipped with a 337nm nitrogen laser, a voltage acceleration source (5kV) and a 1.0m flight tube. The detector was operated in positive ion mode and the signal was recorded and filtered using a LeCroy 9350M digital storage oscilloscope connected to a personal computer. The sample (5. mu.l) was mixed with an equal volume of matrix solution. For the matrix solution, DHAP/DAHC prepared by dissolving 30mg of 2 ', 6' -dihydroxyacetophenone (Aldrich) and 44mg of diammonium hydrogen citrate (Fluka) in a solution of 1ml of acetonitrile/0.1% TFA in water (1/1, v/v) was used. A small volume (≈ 1 μ Ι) of matrix-analyte-mixture is transferred to the probe tip and immediately evaporated in a vacuum chamber (Hewlett-Packard G2024A sample preparation accessory) to ensure rapid and uniform sample crystallization.

For long-term testing of Glu 1-cyclization, A β -derived peptides were incubated in 100 μ l of 0.1M sodium acetate buffer, pH 5.2 or 0.1M Bis-Tris buffer, pH 6.5 at 30 ℃. The peptide was used at a concentration of 0.5mM [ A β (3-11) a ] or 0.15mM [ A β (3-21) a ], and 0.2U QC was added throughout 24 hours. In the case of A β (3-21) a, the assay contained 1% DMSO. At various times, samples were removed from the assay tubes, peptides were extracted using ZipTips (Millipore) according to the manufacturer's recommendations, mixed with the matrix solution (1:1v/v), and mass spectra were recorded. The negative control contained no QC or heat inactivated enzyme. For inhibitor studies, the sample composition was the same as described above except for the addition of the inhibiting compound (5mM or 2mM test compound of the invention).

The compounds and combinations of the present invention may have the advantage that they are, for example, more potent, more selective, have fewer side effects, have better formulation and stability properties, have better pharmacokinetic properties, better bioavailability, are able to cross the blood-brain barrier and are more effective in the brain of mammals, are more compatible or more effective in combination with other drugs, or are easier to synthesize than other compounds of the prior art.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer, step, group of integers or group of steps but not the exclusion of any other integer, step, group of integers or group of steps.

All patents and patent applications mentioned throughout the specification of this invention are incorporated herein by reference in their entirety.

The present invention includes all combinations of the above preferred and more preferred collections and embodiments of collections.

Abbreviations

(DHQ)₂PHAL HYDROQUININE 1, 4-DIAZANAPHTHALENE DIETHER

AcOH acetic acid

DAD diode array detector

DCC dicyclohexylcarbodiimide

DEA diethylamine

DHAP/DAHC dihydroxyacetone phosphate/dihydro-5-azacytidine

DMF dimethyl formamide

DMSO dimethyl sulfoxide

EDTA ethylenediamine-N, N, N ', N' -tetraacetic acid

EtOAc ethyl acetate

EtOH ethanol

FPLC fast high performance liquid chromatography

HPLC high performance liquid chromatography

IPA isopropyl alcohol

LD-TOF laser desorption time-of-flight mass spectrum

ML mother lye

MS mass spectrometry

NMR nuclear magnetic resonance

Pd₂dba₃Tris (dibenzylideneacetone) dipalladium

TEA Triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

TMSCN Trimethylcyanosilane

Claims (28)

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, including all tautomers and stereoisomers of said compound:

wherein:

R¹represents a heteroaryl group, wherein the heteroaryl group is a benzene ring fused to a 5-membered heteroaryl ring orAnd wherein R¹(ii) is attached to the core of formula (I) through the phenyl ring;

wherein any of the above heteroaryl groups may be optionally selected from C_1-6Alkyl radical, C_1-6A halogenated alkyl group,

C_1-6Alkoxy-and halogen-substituted with one or more groups;

R²is represented by C_1-8Alkyl radical, C_6-12Aryl, C having one or more ring atoms replaced by a heteroatom selected from N, S and O_6-12Aryl residue, 5-membered aromatic ring containing one or more heteroatoms selected from N, S and O, C_3-12Carbocyclyl, C having one or more ring atoms replaced by a heteroatom selected from N, S and O_3-12Carbocyclyl, -C_1-4alkyl-C_6-12Aryl radical, -C_1-4alkyl-C_6-12Aryl residue in which one or more ring atoms are replaced by a heteroatom selected from N, S and O, -C_1-4An alkyl-5 membered aromatic ring, wherein the 5 membered aromatic ring comprises one or more heteroatoms selected from N, S and O, -C_1-4alkyl-C_3-12Carbocyclic group or-C_1-4alkyl-C_3-12Carbocyclyl, wherein said C_3-12One or more ring atoms of the carbocyclyl group are replaced with a heteroatom selected from N, S and O;

wherein any of the above C _6-12Aryl, C having one or more ring atoms replaced by a heteroatom selected from N, S and O_6-12Both the aryl residue and the 5-membered aromatic ring containing one or more heteroatoms selected from N, S and O may optionally be selected from C_1-6Alkyl radical, C_1-6Alkoxy-, -O-C_3-8Cycloalkyl radical, C_3-8Cycloalkyl, -C (O) C_1-6Alkyl radical, C_1-6alkoxy-C_1-6Alkyl-, C_1-6alkoxy-C_1-6Alkoxy-, nitro-, halogen, halogeno-C_1-6Alkyl, halo C_1-6Alkoxy, cyano, hydroxy, -NH₂、-NHC_1-4Alkyl, -N (C)_1-4Alkyl) (C_1-4Alkyl), -N (C)_1-4Alkyl) (C_1-4Alkyl) -N (C)_1-4Alkyl radical)(C_1-4Alkyl), -C_1-4alkyl-N (C)_1-4Alkyl) (C_1-4Alkyl), -C_1-4alkoxy-N (C)_1-4Alkyl) (C_1-4Alkyl), -N (C)_3-8Cycloalkyl) (C)_3-8Cycloalkyl), -N (-C)_1-6alkyl-C_1-6Alkoxy) (-C_1-6alkyl-C_1-6Alkoxy) by one or more groups;

and wherein any of the above C_3-12Carbocyclyl and C having one or more ring atoms replaced by a heteroatom selected from N, S and O_3-12The carbocyclyl groups may each be optionally selected from C_1-4Alkyl, oxo, halogen, -C (O) C_1-6Alkyl and C_1-4One or more groups of alkoxy;

or R²Represents phenyl substituted by phenyl, C wherein one or more ring atoms of the monocyclic ring are replaced by a heteroatom selected from N, S and O_6-12Phenyl substituted with an aryl residue, phenyl substituted with a monocyclic 5-membered aromatic ring containing one or more heteroatoms selected from N, S and O, phenyl substituted with phenoxy, C substituted with one or more ring atoms replaced with a heteroatom selected from N, S and O _3-12Phenyl substituted by carbocyclyl, C with one or more ring atoms replaced by a heteroatom selected from N, S and O_3-12Carbocyclyl-substituted phenyl wherein said one or more ring atoms is replaced with a heteroatom selected from N, S and O_3-12The carbocyclic group being substituted by phenyl, by-O-C_1-4alkyl-C_3-12Carbocyclyl-substituted phenyl, wherein said C_3-12One or more ring atoms of the carbocyclic group being replaced by a heteroatom selected from N, S and O, phenyl substituted by benzyloxy, phenyl substituted by C_3-12Phenyl substituted by carbocyclic radicals, by C_3-12Carbocyclyl-substituted phenyl, wherein said C_3-12C having carbocyclic groups with one or more ring atoms replaced by heteroatoms selected from N, S and O_3-12Substituted by carbocyclic radicals, by-O-C_3-12Phenyl substituted by carbocyclyl, C having one or more of the ring atoms substituted by phenyl replaced by a heteroatom selected from N, S and O_3-12Carbocyclyl, C substituted by phenyl_3-12Carbocyclic radical, condensed to C_3-12Phenyl of carbocyclic radicals, condensed to oneOr C having more ring atoms replaced by heteroatoms selected from N, S and O_3-12Phenyl, -C of carbocyclic radicals_1-4alkyl-C with one or more ring atoms of the monocyclic ring replaced by a heteroatom selected from N, S and O_3-12Carbocyclyl-substituted phenyl;

c wherein any of the above phenyl, benzyloxy, one or more ring atoms is replaced by a heteroatom selected from the group consisting of N, S and O _6-12Both the aryl residue and the 5-membered aromatic ring containing one or more heteroatoms selected from N, S and O may optionally be selected from C_1-4Alkyl, halogen and C_1-4One or more groups of alkoxy;

and wherein any of the above C_3-12Carbocyclyl and C having one or more ring atoms replaced by a heteroatom selected from N, S and O_3-12The carbocyclyl groups may each be optionally selected from methyl, phenyl, oxo, halogen, hydroxy and C_1-4One or more groups of alkoxy;

R³represents H;

x represents CR⁷R⁸or-O-CH₂-；

Y represents CHR⁹Or C = O;

z represents-N-R⁴O or CHR¹⁰；

Or X and Z represent two adjacent carbon atoms of a phenyl ring, said phenyl ring being fused at this position and said phenyl ring optionally being substituted by one or more halogens or C_1-2Alkyl substitution;

R⁴represents H or-NH₂；

R⁷And R⁸Independently represent H or-C_1-4An alkyl group;

R⁹and R¹⁰Independently represents H or methyl.

2. The compound of claim 1, wherein R¹Represents unsubstituted heteroaryl or optionally substituted by one or more C_1-6Alkyl, halogen or C_1-6Haloalkyl-substituted heteroaryl.

3. As in claimThe compound of claim 1, wherein R¹To represent

4. The compound of any one of claims 1-3, wherein R²Is represented by C_6-12Aryl, C having one or more ring atoms replaced by a heteroatom selected from N, S and O _6-12An aryl residue, a 5-membered aromatic ring comprising one or more heteroatoms selected from N, S and O, phenyl substituted with phenyl or C fused to the replacement of one or more ring atoms by heteroatoms selected from N, S and O_3-12A carbocyclic phenyl group;

c above_6-12Aryl, C having one or more ring atoms replaced by a heteroatom selected from N, S and O_6-12An aryl residue, a 5-membered aromatic ring comprising one or more heteroatoms selected from N, S and O, phenyl and C wherein one or more ring atoms are replaced by a heteroatom selected from N, S and O_3-12Carbocyclyl is optionally substituted.

5. The compound of claim 4, wherein R²Represents optionally substituted C_6-12And (4) an aryl group.

6. The compound of claim 5, wherein R²Represents phenyl, optionally selected from C_1-6Alkyl radical, C_1-6Alkoxy, hydroxy, halogeno C_1-6Alkyl, halo C_1-6Alkoxy, halogen, C_1-6alkoxy-C_1-6Alkyl-, C_1-6alkoxy-C_1-6Alkoxy-, -N (C)_1-4Alkyl) (C_1-4Alkyl) -N (C)_1-4Alkyl) (C_1-4Alkyl), -N (C)_1-4Alkyl) (C_1-4Alkyl), -N (C)_3-8Cycloalkyl) (C)_3-8Cycloalkyl), -C_1-4alkyl-N (C)_1-4Alkyl) (C_1-4Alkyl), -C_1-4alkoxy-N (C)_1-4Alkyl) (C_1-4Alkyl), -N (-C)_1-6alkyl-C_1-6Alkoxy) (-C_1-6alkyl-C_1-6Alkoxy) is substituted with one or more groups.

7. The compound of claim 6, wherein R²Represents phenyl, optionally substituted by one or more substituents selected from hydroxy, trifluoromethyl, tetrafluoroethoxy, chloro, fluoro, - (CH)₂)₃-OMe、-O-(CH₂)₂-OMe、-N(Me)-(CH₂)₂-N(Me)₂N (ethyl), -N (cyclopropyl), -CH₂)₃-N (methyl), -O (CH)₂)₂-N (methyl), -N ((CH)₂)₂OMe)((CH₂)₂OMe) is substituted with one or more groups.

8. The compound of claim 6, wherein R²Optionally substituted by one or more C_1-6Alkoxy-substituted phenyl.

9. The compound of claim 8, wherein R²Represents phenyl, optionally substituted by one or more groups selected from methoxy, ethoxy, propoxy, butoxy, pentoxy or isopropoxy.

10. The compound of claim 9, wherein R²Represents phenyl optionally substituted by propoxy.

11. The compound of claim 10, wherein R⁴Represents H.

12. A compound according to claim 1, wherein X represents CR⁷R⁸Y represents C = O, and Z represents-N-R⁴。

13. A compound according to claim 1, wherein X represents CH₂Y represents C = O, and Z represents-NH.

14. A compound according to claim 1, wherein X represents CR⁷R⁸Y represents C = O, and Z represents O.

15. A compound according to claim 1, wherein X represents CR ⁷R⁸Y represents CHR⁹And Z represents CHR¹⁰。

16. A compound according to claim 1, wherein X represents CR⁷R⁸Y represents C = O, and Z represents CHR¹⁰。

17. A compound as claimed in claim 1, wherein X and Z represent two adjacent carbon atoms of a phenyl ring, said phenyl ring being fused at that position and said phenyl ring optionally being substituted with one or more halogens or C_1-2Alkyl substituted and Y represents C = O.

18. A compound according to claim 1, wherein X represents-O-CH₂-, Y denotes C = O, and Z denotes CHR¹⁰。

19. The compound of claim 1, wherein the compound is one of the following compounds or a pharmaceutically acceptable salt thereof, including all tautomers and stereoisomers

15-tert-butyl-1- (1H-benzo [ d ] imidazol-5-yl) imidazolidin-2-one,

21- (1H-benzo [ d ] imidazol-5-yl) -5-cyclohexylimidazolidin-2-one,

31- (1H-benzo [ d ] imidazol-5-yl) -5-phenylimidazolidin-2-one,

41- (1H-benzo [ d ] imidazol-5-yl) -5-m-tolylimidazolidin-2-one,

51- (1H-benzo [ d ] imidazol-5-yl) -5- (4-methoxyphenyl) imidazolidin-2-one,

61- (1H-benzo [ d ] imidazol-5-yl) -5- (4-methoxyphenyl) imidazolidin-2-one,

71- (1H-benzo [ d ] imidazol-5-yl) -5- (4-methoxyphenyl) imidazolidin-2-one,

8 (4R,5S) -1- (1H-benzo [ d ] imidazol-6-yl) -5- (4-methoxyphenyl) -4-methylimidazolidin-2-one,

91- (1H-benzo [ d ] imidazol-5-yl) -5- (3-methoxyphenyl) imidazolidin-2-one,

101- (1H-benzo [ d ] imidazol-5-yl) -5- (2-methoxyphenyl) imidazolidin-2-one,

111- (1H-benzo [ d ] imidazol-5-yl) -5- (4-ethoxyphenyl) imidazolidin-2-one,

121- (1H-benzo [ d ] imidazol-5-yl) -5- (4-propoxyphenyl) imidazolidin-2-one,

13 (R) -1- (1H-benzo [ d ] imidazol-5-yl) -5- (4-propoxyphenyl) imidazolidin-2-one,

14 (S) -1- (1H-benzo [ d ] imidazol-5-yl) -5- (4-propoxyphenyl) imidazolidin-2-one,

151- (1H-benzo [ d ] imidazol-5-yl) -5- (4-butoxyphenyl) imidazolidin-2-one,

161- (1H-benzo [ d ] imidazol-5-yl) -5- (4- (pentyloxy) phenyl) imidazolidin-2-one,

171- (1H-benzo [ d ] imidazol-5-yl) -5- (4-isopropoxyphenyl) imidazolidin-2-one,

181- (1H-benzo [ d ] imidazol-5-yl) -5- (4-methoxybenzo [ d ] [1,3] dioxol-6-yl) imidazolidin-2-one,

191- (1H-benzo [ d ] imidazol-5-yl) -5- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) imidazolidin-2-one,

205- (4- (1,1,2, 2-tetrafluoroethoxy) phenyl) -1- (1H-benzo [ d ] imidazol-5-yl) imidazolidin-2-one,

211- (1H-benzo [ d ] imidazol-5-yl) -5- (2, 2-difluorobenzo [ d ] [1,3] dioxol-5-yl) imidazolidin-2-one,

221- (1H-benzo [ d ] imidazol-5-yl) -5- (3-fluoro-4-methoxyphenyl) imidazolidin-2-one,

231- (1H-benzo [ d ] imidazol-5-yl) -5- (2, 6-difluoro-4-methoxyphenyl) imidazolidin-2-one,

245- (4- (2-morpholinoethoxy) phenyl) -1- (1H-benzo [ d ] imidazol-6-yl) imidazolidin-2-one,

255- (4- (3-morpholinopropoxy) phenyl) -1- (1H-benzo [ d ] imidazol-5-yl) imidazolidin-2-one,

265- (2- (2-morpholinoethoxy) phenyl) -1- (1H-benzo [ d ] imidazol-5-yl) imidazolidin-2-one,

271- (1H-benzo [ d ] imidazol-5-yl) -5- (4-fluorophenyl) imidazolidin-2-one,

281- (1H-benzo [ d ] imidazol-5-yl) -5- (2-fluorophenyl) imidazolidin-2-one,

291- (1H-benzo [ d ] imidazol-5-yl) -5- (3-fluorophenyl) imidazolidin-2-one,

301- (1H-benzo [ d ] imidazol-5-yl) -5- (2, 6-difluorophenyl) imidazolidin-2-one,

311- (1H-benzo [ d ] imidazol-5-yl) -5- (3, 4-difluorophenyl) imidazolidin-2-one,

321- (1H-benzo [ d ] imidazol-5-yl) -5- (2-fluoro-5- (trifluoromethyl) phenyl) imidazolidin-2-one,

331- (1H-benzo [ d ] imidazol-5-yl) -5- (3-fluoro-5- (trifluoromethyl) phenyl) imidazolidin-2-one,

341- (1H-benzo [ d ] imidazol-5-yl) -5- (2-fluoro-4- (trifluoromethyl) phenyl) imidazolidin-2-one,

351- (1H-benzo [ d ] imidazol-5-yl) -5- (3-fluoro-4- (trifluoromethyl) phenyl) imidazolidin-2-one,

361- (1H-benzo [ d ] imidazol-5-yl) -5- (2-chlorophenyl) imidazolidin-2-one,

371- (1H-benzo [ d ] imidazol-5-yl) -5- (3-chlorophenyl) imidazolidin-2-one,

381- (1H-benzo [ d ] imidazol-5-yl) -5- (2, 6-dichlorophenyl) imidazolidin-2-one,

391- (1H-benzo [ d ] imidazol-5-yl) -5- (2, 3-dichlorophenyl) imidazolidin-2-one,

401- (1H-benzo [ d ] imidazol-5-yl) -5- (3, 4-dichlorophenyl) imidazolidin-2-one,

41 (S) -1- (1H-benzo [ d ] imidazol-5-yl) -5- (3, 4-dichlorophenyl) imidazolidin-2-one,

421- (1H-1, 3-benzoxadiazol-5-yl) -5- (4-biphenyl) imidazolidin-2-one,

43 (S) -1- (1H-1, 3-benzodiazol-5-yl) -5- (4-biphenyl) imidazolidin-2-one,

44 (R) -1- (1H-1, 3-benzooxadiazol-5-yl) -5- (4-biphenyl) imidazolidin-2-one,

451- (1H-1, 3-benzoxadiazol-5-yl) -5- (3-fluoro-4-biphenyl) imidazolidin-2-one,

461- (1H-benzo [ d ] imidazol-5-yl) -5- [4- (3-chlorophenyl) phenyl ] imidazolidin-2-one,

471- (1H-benzo [ d ] imidazol-5-yl) -5- (3 ', 4' -dichloro-4-biphenyl) imidazolidin-2-one,

481- (1H-benzo [ d ] imidazol-5-yl) -5- (3-phenylphenyl) imidazolidin-2-one,

491- (1H-benzo [ d ] imidazol-5-yl) -5- [3- (3-chlorophenyl) phenyl ] imidazolidin-2-one,

501- (1H-benzo [ d ] imidazol-5-yl) -5- (3-chloro-4-morpholinophenyl) imidazolidin-2-one,

511- (1H-benzo [ d ] imidazol-5-yl) -5- (4- (4-phenylpiperazin-1-yl) phenyl) imidazolidin-2-one,

521- (1H-benzo [ d ] imidazol-5-yl) -5- (2-chloro-6- (4-ethylpiperazin-1-yl) phenyl) imidazolidin-2-one,

531- (H-imidazo [1,2-a ] pyridin-7-yl) -5-phenylimidazolidin-2-one,

541- (H-imidazo [1,2-a ] pyridin-7-yl) -5- (4-propoxyphenyl) imidazolidin-2-one,

555- (4-butoxyphenyl) -1- (H-imidazo [1,2-a ] pyridin-7-yl) imidazolidin-2-one,

565- (2, 6-difluoro-4-methoxyphenyl) -1- (H-imidazo [1,2-a ] pyridin-7-yl) imidazolidin-2-one,

571- (H-imidazo [1,2-a ] pyridin-7-yl) -5- (4-methoxybenzo [ d ] [1,3] dioxol-6-yl) imidazolidin-2-one,

585- (4- (2-morpholinoethoxy) phenyl) -1- (H-imidazo [1,2-a ] pyridin-7-yl) imidazolidin-2-one,

595- (2, 6-difluorophenyl) -1- (H-imidazo [1,2-a ] pyridin-7-yl) imidazolidin-2-one,

605- (biphenyl) -1- (H-imidazo [1,2-a ] pyridin-7-yl) imidazolidin-2-one,

615- (3-fluorobiphenyl) -1- (H-imidazo [1,2-a ] pyridin-7-yl) imidazolidin-2-one,

621- (H-imidazo [1,2-a ] pyridin-7-yl) -5- (4- (4-phenylpiperazin-1-yl) phenyl) imidazolidin-2-one,

631- (1H-benzo [ d ] imidazol-5-yl) -5-phenylimidazolidin-4-one,

641- (1H-benzo [ d ] imidazol-5-yl) -5- (2,3, 5-trifluorophenyl) imidazolidin-4-one,

651-amino-3- (1H-benzo [ d ] imidazol-5-yl) -4- (4-methoxyphenyl) imidazolidin-2-one,

66 (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4-phenyloxazolidin-2-one,

67 (R) -3- (1H-benzo [ d ] imidazol-6-yl) -4-phenyloxazolidin-2-one,

68 (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4-isopropyloxazolidin-2-one,

69 (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4-benzyl oxazolidin-2-one,

71 (4S,5S) -3- (1H-benzo [ d ] imidazol-6-yl) -5-methyl-4-phenyloxazolidin-2-one,

72 (S) -3- (1H-benzo [ d ] imidazol-6-yl) -5, 5-dimethyl-4-phenyloxazolidin-2-one,

73 (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4- (4-propoxyphenyl) oxazolidin-2-one,

74 (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-7-yl) oxazolidin-2-one,

75 (S) -4- (benzo [ d ] [1,3] dioxol-6-yl) -3- (1H-benzo [ d ] imidazol-6-yl) oxazolidin-2-one,

80 (S) -4- (4- (2- (piperazin-1-yl) ethoxy) phenyl) -3- (1H-benzo [ d ] imidazol-6-yl) oxazolidin-2-one,

81 (S) -4- (4- (2-morpholinoethoxy) phenyl) -3- (1H-benzo [ d ] imidazol-6-yl) oxazolidin-2-one,

82 (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4- (2, 3-difluorophenyl) oxazolidin-2-one,

83 (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4- (3-fluorophenyl) oxazolidin-2-one,

84 (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4- (3-fluoro-5- (trifluoromethyl) phenyl) oxazolidin-2-one,

85 (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4- (3-chlorophenyl) oxazolidin-2-one,

86 (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4- (4-chlorophenyl) oxazolidin-2-one,

87 (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4- [4- (3-chlorophenyl) phenyl ] oxazolidin-2-one,

88 (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4- [3- (3-chlorophenyl) phenyl ] oxazolidin-2-one,

89 (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4- (4- (4-phenylpiperazin-1-yl) phenyl) oxazolidin-2-one,

90 (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4- (4- (4-methylpiperazin-1-yl) phenyl) oxazolidin-2-one,

91 (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4- (3- (4-phenylpiperazin-1-yl) phenyl) oxazolidin-2-one,

92 (S) -3- (2-methyl-1H-benzo [ d ] imidazol-6-yl) -4-phenyloxazolidin-2-one,

93 (S) -4- (1H-benzo [ d ] imidazol-6-yl) -5- (4-propoxyphenyl) morpholin-3-one,

943- (1H-benzo [ d ] imidazol-6-yl) -4- (4-propoxyphenyl) -1, 3-oxazinan-2-one,

95 (S) -3- (H-imidazo [1,2-a ] pyridin-7-yl) -4-phenyloxazolidin-2-one,

98 (S) -3- (H-imidazo [1,2-a ] pyridin-7-yl) -4- (4-propoxyphenyl) oxazolidin-2-one,

99 (S) -4- (4-chlorophenyl) -3- (H-imidazo [1,2-a ] pyridin-7-yl) oxazolidin-2-one,

1003- (imidazo [1,2-a ] pyridin-7-yl) -4- (4-propoxyphenyl) -1, 3-oxazinan-2-one,

1015- (2-phenylpyrrolidin-1-yl) -1H-benzo [ d ] imidazole,

1025- (2- (4-methoxyphenyl) pyrrolidin-1-yl) -1H-benzo [ d ] imidazole,

1035- (2- (4-fluorophenyl) pyrrolidin-1-yl) -1H-benzo [ d ] imidazole,

1045- (2- (4-chlorophenyl) pyrrolidin-1-yl) -1H-benzo [ d ] imidazole,

1055- (2-benzylpyrrolidin-1-yl) -1H-benzo [ d ] imidazole,

1065- (2- (4-chlorobenzyl) pyrrolidin-1-yl) -1H-benzo [ d ] imidazole,

1075- (2- (4-fluorobenzyl) pyrrolidin-1-yl) -1H-benzo [ d ] imidazole,

1095- (2- (4-methoxybenzyl) pyrrolidin-1-yl) -1H-benzo [ d ] imidazole,

1201- (1H-benzo [ d ] imidazol-5-yl) -5- (4-fluorophenyl) pyrrolidin-2-one,

1211- (1H-benzo [ d ] imidazol-5-yl) -5- (4-methoxyphenyl) pyrrolidin-2-one,

1221- (1H-benzo [ d ] imidazol-5-yl) -5- (4-propoxyphenyl) pyrrolidin-2-one,

1231- (1H-benzo [ d ] imidazol-5-yl) -5- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) pyrrolidin-2-one,

1241- (1H-benzo [ d ] imidazol-5-yl) -5-phenylpyrrolidin-2-one,

1252- (1H-benzo [ d ] imidazol-5-yl) -3-phenylisoindolin-1-one,

1262- (1H-benzo [ d ] imidazol-5-yl) -3- (4-biphenyl) isoindolin-1-one,

1272- (1H-benzo [ d ] imidazol-5-yl) -3- (4-fluorophenyl) isoindolin-1-one,

1282- (1H-benzo [ d ] imidazol-5-yl) -3- (3-fluorophenyl) isoindolin-1-one,

1292- (1H-benzo [ d ] imidazol-5-yl) -3- (3, 5-difluorophenyl) isoindolin-1-one,

1302- (1H-benzo [ d ] imidazol-5-yl) -3- (4-chlorophenyl) isoindolin-1-one,

1312- (1H-benzo [ d ] imidazol-5-yl) -3- (3, 4-dichlorophenyl) isoindolin-1-one,

1322- (1H-benzo [ d ] imidazol-5-yl) -3- (3-chloro-5-fluorophenyl) isoindolin-1-one,

1332- (1H-benzo [ d ] imidazol-5-yl) -3- (4-methoxyphenyl) isoindolin-1-one,

1342- (1H-benzo [ d ] imidazol-5-yl) -3- (4-propoxyphenyl) isoindolin-1-one,

1352- (1H-benzo [ d ] imidazol-5-yl) -3- (3-fluoro-4-methoxyphenyl) isoindolin-1-one,

1362- (1H-benzo [ d ] imidazol-5-yl) -3- (3, 4-dimethoxyphenyl) isoindolin-1-one,

1373- (benzo [ d ] [1,3] dioxol-6-yl) -2- (1H-benzo [ d ] imidazol-5-yl) isoindolin-1-one,

1382- (1H-benzo [ d ] imidazol-5-yl) -3- (4-phenoxyphenyl) isoindolin-1-one,

1392- (1H-benzo [ d ] imidazol-5-yl) -4, 7-dichloro-3- (4-methoxyphenyl) isoindolin-1-one,

1402- (1H-benzo [ d ] imidazol-5-yl) -5, 6-dichloro-3- (4-methoxyphenyl) isoindolin-1-one,

1412- (1H-benzo [ d ] imidazol-5-yl) -5, 6-dichloro-3- (4-propoxyphenyl) isoindolin-1-one,

142 (S) -2- (1H-benzo [ d ] imidazol-5-yl) -3- (3, 4-dimethoxyphenyl) isoindolin-1-one,

143 (R) -2- (1H-benzo [ d ] imidazol-5-yl) -3- (3, 4-dimethoxyphenyl) isoindolin-1-one,

144 (R) -2- (1H-benzo [ d ] imidazol-5-yl) -3- (4-propoxyphenyl) isoindolin-1-one,

145 (S) -2- (1H-benzo [ d ] imidazol-5-yl) -3- (4-propoxyphenyl) isoindolin-1-one,

146 (R) -2- (1H-benzo [ d ] imidazol-5-yl) -3- (4-chlorophenyl) isoindolin-1-one,

147 (S) -2- (1H-benzo [ d ] imidazol-5-yl) -3- (4-chlorophenyl) isoindolin-1-one,

1481- (1H-benzo [ d ] imidazol-5-yl) -5- (4-phenylcyclohexyl) imidazolidin-2-one,

1491- (1H-benzo [ d ] imidazol-6-yl) -5- (1-phenylpiperidin-4-yl) imidazolidin-2-one,

1501- (1H-benzo [ d ] imidazol-5-yl) -5- (4- (3-methoxypropyl) phenyl) imidazolidin-2-one,

1511- (1H-benzo [ d ] imidazol-5-yl) -5- (4-hydroxyphenyl) imidazolidin-2-one,

1521- (1H-benzo [ d ] imidazol-5-yl) -5- (2-hydroxyphenyl) imidazolidin-2-one,

1531- (1H-benzo [ d ] imidazol-5-yl) -5- (2, 4-dihydroxyphenyl) imidazolidin-2-one,

1541- (1H-benzo [ d ] imidazol-5-yl) -5- (3, 4-dihydroxyphenyl) imidazolidin-2-one,

1551- (1H-benzo [ d ] imidazol-5-yl) -5- (3-hydroxyphenyl) imidazolidin-2-one,

1561- (1H-benzo [ d ] imidazol-5-yl) -5- (4- (cyclohexyloxy) phenyl) imidazolidin-2-one,

1575- (4- (2-methoxyethoxy) phenyl) -1- (1H-benzo [ d ] imidazol-5-yl) imidazolidin-2-one,

158 (S) -5- (4- (2- (dimethylamino) ethoxy) phenyl) -1- (1H-benzo [ d ] imidazol-5-yl) imidazolidin-2-one,

1631- (1H-benzo [ d ] imidazol-5-yl) -5- (4-fluoro-3-methoxyphenyl) imidazolidin-2-one,

1641- (1H-benzo [ d ] imidazol-5-yl) -5- (3-fluoro-4-propoxyphenyl) imidazolidin-2-one,

1651- (1H-benzo [ d ] imidazol-5-yl) -5- (2-fluoro-4-propoxyphenyl) imidazolidin-2-one,

166 (S) -1- (1H-benzo [ d ] imidazol-5-yl) -5- (4- (diethylamino) phenyl) imidazolidin-2-one,

1671- (1H-benzo [ d ] imidazol-5-yl) -5- (4-chlorophenyl) imidazolidin-2-one,

1681- (1H-benzo [ d ] imidazol-5-yl) -5- (4-cyclohexylphenyl) imidazolidin-2-one,

1691- (1H-benzo [ d ] imidazol-5-yl) -5- (4- (4-morpholinocyclohexyl) phenyl) imidazolidin-2-one,

170 (S) -1- (1H-benzo [ d ] imidazol-5-yl) -5- (4- (1-methylpiperidin-4-yl) phenyl) imidazolidin-2-one,

1711- (1H-benzo [ d ] imidazol-5-yl) -5- (4- (tetrahydro-2H-pyran-4-yl) phenyl) imidazolidin-2-one,

1721- (1H-benzo [ d ] imidazol-5-yl) -5- (4- (4-oxocyclohexyl) phenyl) imidazolidin-2-one,

173 (S) -1- (1H-benzo [ d ] imidazol-5-yl) -5- (4- (4, 4-difluorocyclohexyl) phenyl) imidazolidin-2-one,

1741- (1H-benzo [ d ] imidazol-5-yl) -5- (3- (pyrrolidin-1-yl) phenyl) imidazolidin-2-one,

1751- (1H-benzo [ d ] imidazol-5-yl) -5- (4- (piperidin-1-yl) phenyl) imidazolidin-2-one,

1761- (1H-benzo [ d ] imidazol-5-yl) -5- (3- (piperidin-1-yl) phenyl) imidazolidin-2-one,

1771- (1H-benzo [ d ] imidazol-5-yl) -5- (4-morpholinophenyl) imidazolidin-2-one,

1785- (4-cyclohexylphenyl) -1- (H-imidazo [1,2-a ] pyridin-7-yl) imidazolidin-2-one,

1791- (H-imidazo [1,2-a ] pyridin-7-yl) -5- (4- (pyrrolidin-1-yl) phenyl) imidazolidin-2-one,

1801- (H-imidazo [1,2-a ] pyridin-7-yl) -5- (3- (pyrrolidin-1-yl) phenyl) imidazolidin-2-one,

1811- (H-imidazo [1,2-a ] pyridin-7-yl) -5- (4- (piperidin-1-yl) phenyl) imidazolidin-2-one,

1821- (H-imidazo [1,2-a ] pyridin-7-yl) -5- (3- (piperidin-1-yl) phenyl) imidazolidin-2-one,

1831- (H-imidazo [1,2-a ] pyridin-7-yl) -5- (1-phenylpiperidin-4-yl) imidazolidin-2-one,

184 (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (3-methoxypropyl) phenyl) oxazolidin-2-one,

1853- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (3- (dimethylamino) propyl) phenyl) oxazolidin-2-one,

186 (S) -3- (7-methyl-1H-benzo [ d ] imidazol-5-yl) -4-phenyloxazolidin-2-one,

187 (S) -3- (6-fluoro-1H-benzo [ d ] imidazol-5-yl) -4-phenyloxazolidin-2-one,

188 (S) -3- (7-fluoro-1H-benzo [ d ] imidazol-5-yl) -4-phenyloxazolidin-2-one,

189 (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4- (cyclohexylmethyl) oxazolidin-2-one,

190 (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4-cyclohexyloxazolidin-2-one,

191 (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4- (4-phenylcyclohexyl) oxazolidin-2-one,

192 (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4- (1-phenylpiperidin-4-yl) oxazolidin-2-one,

193 (S) -4- (1-acetylpiperidin-4-yl) -3- (1H-benzo [ d ] imidazol-5-yl) oxazolidin-2-one,

1943- (1H-benzo [ d ] imidazol-5-yl) -4- (1-phenylethyl) oxazolidin-2-one,

195 (S) -4- (4-propoxybenzyl) -3- (1H-benzo [ d ] imidazol-5-yl) oxazolidin-2-one,

196 (S) -4- (4-isopropoxybenzyl) -3- (1H-benzo [ d ] imidazol-5-yl) oxazolidin-2-one,

197 (S) -4- (4- (cyclohexyloxy) benzyl) -3- (1H-benzo [ d ] imidazol-5-yl) oxazolidin-2-one,

1984- (4-morpholinobenzyl) -3- (1H-benzo [ d ] imidazol-5-yl) oxazolidin-2-one,

199 (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4-phenethyloxazolidin-2-one,

2003- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (cyclohexyloxy) phenyl) oxazolidin-2-one,

201 (S) -3- (7-methyl-1H-benzo [ d ] imidazol-5-yl) -4- (4-propoxyphenyl) oxazolidin-2-one,

202 (S) -3- (6, 7-dimethyl-1H-benzo [ d ] imidazol-5-yl) -4- (4-propoxyphenyl) oxazolidin-2-one,

203 (S) -4- (4- (2-methoxyethoxy) phenyl) -3- (1H-benzo [ d ] imidazol-5-yl) oxazolidin-2-one,

204 (S) -4- (4- (2- (dimethylamino) ethoxy) phenyl) -3- (1H-benzo [ d ] imidazol-5-yl) oxazolidin-2-one,

2053- (1H-benzo [ d ] imidazol-5-yl) -4- (2, 6-difluoro-4-methoxyphenyl) oxazolidin-2-one,

206 (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (diethylamino) phenyl) oxazolidin-2-one,

207 (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (bis (2-methoxyethyl) amino) phenyl) oxazolidin-2-one,

208 (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (dicyclopropylamino) phenyl) oxazolidin-2-one,

209 (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4- (biphenyl-4-yl) oxazolidin-2-one,

2103- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (4-oxocyclohexyl) phenyl) oxazolidin-2-one,

2113- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (4-methoxycyclohexyl) phenyl) oxazolidin-2-one,

2123- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (4-hydroxycyclohexyl) phenyl) oxazolidin-2-one,

2133- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (4-morpholinocyclohexyl) phenyl) oxazolidin-2-one,

2143- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (pyrrolidin-1-yl) phenyl) oxazolidin-2-one,

215 (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (piperidin-1-yl) phenyl) oxazolidin-2-one,

216 (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4- (3- (piperidin-1-yl) phenyl) oxazolidin-2-one,

217 (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4- (4-morpholinophenyl) oxazolidin-2-one,

218 (S) -3- (1H-benzo [ d ] imidazol-5-yl) -4- (3-morpholinophenyl) oxazolidin-2-one,

2193- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (tetrahydro-2H-pyran-4-yl) phenyl) oxazolidin-2-one,

2203- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (1-methylpiperidin-4-yl) phenyl) oxazolidin-2-one,

221 (S) -3- (1H-benzo [ d ] imidazol-6-yl) -4- (3- (4-methylpiperazin-1-yl) phenyl) oxazolidin-2-one,

222 (S) -3- (3-methyl H-imidazo [1,2-a ] pyridin-7-yl) -4-phenyloxazolidin-2-one,

223 (S) -3- (3-trifluoromethyl) H-imidazo [1,2-a ] pyridin-7-yl) -4-phenyloxazolidin-2-one,

224 (S) -4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) -3- (H-imidazo [1,2-a ] pyridin-7-yl) oxazolidin-2-one,

225 (S) -4- (4-cyclohexylphenyl) -3- (H-imidazo [1,2-a ] pyridin-7-yl) oxazolidin-2-one,

226 (S) -3- (H-imidazo [1,2-a ] pyridin-7-yl) -4- (4- (piperidin-1-yl) phenyl) oxazolidin-2-one,

227 (S) -3- (H-imidazo [1,2-a ] pyridin-7-yl) -4- (4-morpholinophenyl) oxazolidin-2-one,

228 (S) -3- (H-imidazo [1,2-a ] pyridin-7-yl) -4- (4- (4-phenylpiperazin-1-yl) phenyl) oxazolidin-2-one,

229 (S) -1- (1H-benzo [ d ] imidazol-5-yl) -5- (4- (bis (2-methoxyethyl) amino) phenyl) imidazolidin-2-one,

2305- (4- (N- (2- (dimethylamino) ethyl) -N-methylamino) phenyl) -1- (1H-benzo [ d ] imidazol-5-yl) imidazolidin-2-one,

2313- (1H-benzo [ d ] imidazol-5-yl) -4- (4- (4, 4-difluorocyclohexyl) phenyl) oxazolidin-2-one,

2322- (1H-benzo [ d ] imidazol-5-yl) -4, 7-difluoro-3- (4-propoxyphenyl) isoindolin-1-one,

2332- (H-imidazo [1,2-a ] pyridin-7-yl) -3- (3, 4-dimethoxyphenyl) isoindolin-1-one,

234 (S) -2- (H-imidazo [1,2-a ] pyridin-7-yl) -3- (3, 4-dimethoxyphenyl) isoindolin-1-one,

235 (S) -3- (3, 4-dimethoxyphenyl) -2- (3-methyl H-imidazo [1,2-a ] pyridin-7-yl) isoindolin-1-one.

20. The compound of claim 1, which is one of the following compounds or a pharmaceutically acceptable salt thereof, including all tautomers and stereoisomers

121- (1H-benzo [ d ] imidazol-5-yl) -5- (4-propoxyphenyl) imidazolidin-2-one,

13 (R) -1- (1H-benzo [ d ] imidazol-5-yl) -5- (4-propoxyphenyl) imidazolidin-2-one,

14 (S) -1- (1H-benzo [ d ] imidazol-5-yl) -5- (4-propoxyphenyl) imidazolidin-2-one.

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20, optionally in combination with one or more therapeutically acceptable diluents or carriers.

22. The pharmaceutical composition of claim 21, further comprising at least one compound selected from the group consisting of: neuroprotective agents, antiparkinsonian drugs, amyloid deposition inhibitors, beta amyloid synthesis inhibitors, antidepressants, anxiolytic drugs, antipsychotic drugs, and anti-multiple sclerosis drugs.

23. The pharmaceutical composition of claim 21 or 22, further comprising at least one compound selected from the group consisting of: PEP-inhibitors, inhibitors of LiCl, DP IV or DP IV-like enzyme inhibitors, acetylcholinesterase (AChE) inhibitors, PIMT enhancers, beta secretase inhibitors, gamma secretase inhibitors, neutral endopeptidase inhibitors, phosphodiesterase-4 (PDE-4) inhibitors, TNF α inhibitors, muscarinic M1 receptor antagonists, NMDA receptor antagonists, sigma-1 receptor inhibitors, histamine H3 antagonists, immunomodulators, immunosuppressants, or substances selected from the group consisting of antegren (natalizumab), Neurelan (amipridine extended release tablets), campath (alemtuzumab), NBI5788/MSP771 (telimotide), paclitaxel, davofvin (CD271, adapalene), BAY361677 (interleukin-4), matrix metalloproteinase-inhibitors and interferon-tau (laminin).

24. Use of a compound according to any one of claims 1 to 20 or a pharmaceutical composition according to any one of claims 21 to 23 in the manufacture of a medicament for the treatment of a disease selected from the group consisting of: kennedy's disease, zollinger-ellison syndrome, pathogenic psychotic conditions, schizophrenia, infertility, inflammatory host responses, cancer, malignant metastasis, melanoma, psoriasis, impaired humoral and cell-mediated immune responses, leukocyte adhesion and migration processes in the endothelium, impaired food intake, impaired sleep-wake, impaired homeostatic regulation of energy metabolism, impaired autonomic nerve function, impaired hormonal balance or humoral regulation, multiple sclerosis, guillain-barre syndrome, and chronic inflammatory demyelinating polyradiculoneuropathy.

25. Use of a compound according to any one of claims 1 to 20 or a pharmaceutical composition according to any one of claims 21 to 23 in the manufacture of a medicament for the treatment of a disease selected from the group consisting of: duodenal cancer with or without helicobacter pylori infection, colorectal cancer, gastric cancer with or without helicobacter pylori infection, and neoplasia.

26. Use of a compound according to any one of claims 1 to 20 or a pharmaceutical composition according to any one of claims 21 to 23 in the manufacture of a medicament for the treatment of a disease selected from the group consisting of: mild cognitive impairment, alzheimer's disease, familial dementia of the british type, familial dementia of the danish type, neurodegeneration in down syndrome and huntington's disease.

27. Use of a compound according to any one of claims 1 to 20 or a pharmaceutical composition according to any one of claims 21 to 23 in the manufacture of a medicament for the treatment of a disease selected from the group consisting of: rheumatoid arthritis, atherosclerosis, pancreatitis and restenosis.

28. A process for the preparation of a compound of formula (I) as defined in any one of claims 1 to 20, which process comprises:

(a) preparing a compound of formula (I) from a compound of formula (II):

wherein R is²、R³X, Y and Z are as defined in any one of claims 1 to 20;

(b) by reacting a compound of formula (III)Hydrogenation to produce R³Represents hydrogen, Y represents CO, Z represents-N-R⁴X represents CR⁷R⁸And R is⁸A compound of formula (I) representing hydrogen:

wherein R is¹、R²、R⁴And R⁷As defined in any one of claims 1 to 20;

(c) wherein R is prepared by hydrogenating a compound of formula (IV)³Represents hydrogen, Y represents CO, Z represents CH₂And X represents CH₂A compound of formula (I):

wherein R is¹And R²As defined in any one of claims 1 to 20;

(d) preparation of compounds of formula (V) wherein R³Represents hydrogen, Y represents CO, Z represents-N-R⁴And X represents CH₂A compound of formula (I):

wherein R is¹、R²And R⁴As defined in any one of claims 1 to 20;

(f) Preparation of compounds of formula (VII) wherein R¹Represents 1H-benzo [ d ]]Imidazol-5-yl, R³Represents hydrogen, Y represents CO, Z represents-NH, and X represents CH₂A compound of formula (I):

wherein R is²As defined in any one of claims 1 to 20, P¹Represents a suitable protecting group;

(g) preparation of compounds of formula (VIII) wherein R³A compound of formula (I) representing hydrogen, Y represents CO, and X and Z are linked to form a carbocyclic ring, or X and Z represent two adjacent carbon atoms of a phenyl ring, said phenyl ring being fused at that position and said phenyl ring optionally being substituted by one or more halogens or C_1-2Alkyl substitution:

wherein R is¹、R²X and Z are as defined in any one of claims 1 to 20;

(i) from which R is removed by treatment with nitrite and subsequent reduction⁴Preparation of the corresponding compound of formula (I) wherein R represents H⁴represents-NH₂A compound of formula (I);

(k) tautomerization of compounds of formula (I); or

(l) Deprotecting the protected compound of formula (I).