3,6-Disubstituted-2-pyridinealdehyde oxime skeleton

Abstract

The present invention relates to a compound of formula (I), or one of its pharmaceutically acceptable salts: wherein R1, R2 and -X-Y- have specific definitions. The present invention also relates to the use of such compounds in treatment; and a method for preparing such compounds.

Description

Technical Field

[0001] The present invention relates to novel compounds having a 3,6-disubstituted-2-pyridine aldehyde oxime skeleton. Such compounds can be used in many therapeutic and non-therapeutic applications. The present invention also relates to compositions, especially pharmaceutical compositions, comprising the compounds; and uses thereof. Background Art

[0002] Organophosphorus nerve agents (OPNAs) are highly toxic compounds including chemical warfare agents (CWAs), including sarin, soman, cyclosarin, Tabun, O-ethyl S-[2-(diisopropylamino)ethyl]methyl phosphorothioate (VX), and pesticides such as paraoxon, parathion, and tetraethyl pyrophosphate (TEPP). Their acute toxicity is due to irreversible inhibition of acetylcholinesterase (AChE) by its catalytic phosphorylation of serine, resulting in the enzyme's inability to hydrolyze acetylcholine (ACh). This neurotransmitter accumulates at cholinergic synapses, leading to permanent saturation of muscarinic and nicotinic receptors, ultimately leading to seizures and respiratory arrest. Depending on the type and dose of OPNA, death may occur within a few minutes.

[0003] Due to the similarities between the chemical precursors of chemical weapons and pesticides and the relatively simple chemistry involved in their synthesis, efforts to control the spread of these agents have proven to be of limited success. Therefore, the development of effective measures to combat OPNA poisoning remains a challenging problem for the protection and treatment of civilians and military personnel. Current treatments for OPNA poisoning include a combination of atropine (antimycin) and diazepam (anticonvulsant) and standard pyridine oximes (pradoxime or 2-PAM, trimethoxime, HI-6, orbidoxime or ) to reactivate acetylcholinesterase. Oxime acts on acetylcholinesterase inhibited by OPNA by attacking the phosphorus atom of phosphorylated serine, thereby removing phosphonate and restoring the catalytic activity of the enzyme. Hybrid reactivator compounds have a pyridine oxime structure that is coupled to a potential ligand of the enzyme's peripheral site called a peripheral site ligand (PSL). Its purpose is to increase the affinity of the activator for acetylcholinesterase (Mercey G. et al., Chemical Research Journal, 756-766, 2012, Vol. 45, No. 5).

[0004] The efficiency of the reactivator can be estimated from the second-order rate constant for reactivation Kr2, which is the product of the maximum reactivation rate constant (Kr) and the reactivator-inhibited acetylcholinesterase complex (K D) ratio of the apparent dissociation constants of OPNA. To date, no known oxime compound has the same efficacy against all acetylcholinesterases inhibited by OPNA.

[0005] Recently, WO2017 / 021319 disclosed bifunctional compounds containing a peripheral site-specific ligand (PSL) portion of an aminoquinoline functional group, which has an increased affinity for poisoned hAChE (thus, a lower KD), making it an effective reactivator of human acetylcholinesterase inhibited by any type of organophosphorus compound. However, these bifunctional compounds contain a hydroxyl group, which may be present in position 3 of the pyridine radical. This hydroxyl group needs to be protected and deprotected during the synthesis process. In addition, the hydroxyl group may be involved in the internal cyclization of the molecule.

[0006] Therefore, there is still a need for compounds that are effective in therapeutic applications, particularly compounds against OPNA poisoning, that are fast and easy to synthesize, have good yields, and can be produced on a higher scale. These compounds must be stable without any internal cyclization.

[0007] Surprisingly, the inventors have now found that specific pyridinidine aldoximes (carrying a hydrogen or a specific alkoxy group in the 3-position) meet these requirements. They can easily pass the blood-brain barrier, in particular because they are uncharged.

[0008] In fact, this compound is fast, simple and very easy to produce. The obtained compound does not show intramolecular cyclization and can be used for human therapy.

[0009] It is noteworthy that these compounds can act as antidotes for OPNA poisoning, or as antidotes for organophosphorus compounds, since they effectively and quickly reactivate hAChE. Without being bound by any theory, these molecules appear to bind selectively to the catalytic site of hAChE. They show in particular a very high reactivation efficiency of the inhibited acetylcholinesterase. The oxime of the compound can be regenerated once it has dephosphorylated a serine residue: the compound can therefore be used multiple times. These compounds are also agonists of adenosine 2A receptors. They can therefore be used to treat inflammation; for the treatment of neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease; for the treatment of cancer, especially due to the inhibitory activity of histone deacetylases (HDACs) in the treatment of diabetes and / or in the treatment of pain.

[0010] Therefore, a first object of the present invention is a compound of formula (I):

[0011]

[0012] Among them, the different groups are as defined in the detailed description below.

[0013] Another object of the present invention is a process for preparing compounds of formula (I), in particular by the Sonogashira reaction, as described below.

[0014] Another object of the invention is a pharmaceutical composition comprising at least one compound of formula (I) and at least one pharmaceutically acceptable carrier.

[0015] Another object of the present invention is the compounds according to the invention for use as medicaments.

[0016] Another object of the invention is the compounds according to the invention for use in the treatment of neurological and / or respiratory failure caused by poisoning by at least one organophosphorus nerve agent.

[0017] Another object of the present invention is the compounds according to the invention for use in the treatment of inflammation.

[0018] A further object of the present invention is the compounds according to the invention for use in the treatment of neurological diseases such as Alzheimer's disease or Parkinson's disease.

[0019] Another object of the present invention is the compounds according to the invention for use in the treatment of cancer.

[0020] Another object of the present invention is the compounds according to the invention for use in the treatment of diabetes.

[0021] Another object of the present invention is the compounds according to the invention for use in the treatment of pain.

[0022] A first object of the present invention is a compound of formula (I), or one of its pharmaceutically acceptable salts:

[0023]

[0024] in:

[0025] R1 is H, or a linear or cyclic (preferably aromatic) C1-C7 alkoxy radical, preferably R1 is methoxy or benzyloxy;

[0026] -XY-to-CH 2 -(CH 2 ) n -、-C≡C-、 or -XY- is Br, and R2 is absent;

[0027] n is an integer from 0 to 5;

[0028] R2 is a group selected from alkyl, aryl, aralkyl, heteroaryl, -R3-N(R4)(R5), free radical A, free radical B, free radical C and free radical D, wherein free radical A or free radical B or free radical C or free radical D can be connected to -YX- through an alkyl group, preferably an ethyl group:

[0029]

[0030] R3 is a C1-C4 alkyl group, and

[0031] R4 and R5 are the same or different and each independently represents H, a naphthyl radical, a 5-fluoroquinolin-4-yl radical, a quinolin-4-yl radical or an 8-methoxyquinolin-4-yl radical, or

[0032] R4 and R5 together with the nitrogen atom form a 4-benzylpiperazin-1-yl radical or a 3,7-dimethyl-2,6-dioxy-2,3,6,7-tetrahydro-1H-purin-1-yl radical.

[0033] For the definition of -XY-, the points of attachment of the triazole group are indicated by asterisks on each side of the triazole group:

[0034]

[0035] The point of attachment of any of the moieties A to D (in the definition of R2) to the remainder of the molecule of formula (I) is indicated by an asterisk:

[0036]

[0037] "Bz" in the free radical A represents benzoyl, that is, Ph-C(=O)-.

[0038] "Pharmaceutically acceptable salt" refers to any salt of a compound of formula (I) with an acid or base. A pharmaceutically acceptable salt may be a hydrochloride. The salt may be obtained using pyridine of formula (I) to obtain a pyridinium salt. For example, when R4 and / or R5 are identical or different and each independently represent a 5-fluoroquinoline-4-yl radical, a quinoline-4-yl radical or an 8-methoxyquinoline-4-yl radical, the radical may be complexed with HCl to obtain a 5-fluoroquinoline radical, a 4-quinoline radical or an 8-methoxy-4-quinoline radical, respectively. Preferred pharmaceutically acceptable salts are 5-fluoro-4-quinoline, 4-quinoline and 8-methoxy-4-quinoline radicals.

[0039] The oxime of the compound of formula (I) may be labeled with one or more isotopes, for example, 15 N. 18 O. 2 H or 3H. In fact, this stable, non-toxic, non-radioactive isotope will allow for in vivo and in vitro biological studies.

[0040] "Alkyl" refers to a linear hydrocarbon group preferably containing 1 to 20 carbon atoms, in particular 1 to 15 carbon atoms, or a branched or cyclic hydrocarbon group containing 3 to 20 carbon atoms. Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-tridecyl, cyclohexyl and cyclohexylmethyl, and preferably ethyl, propyl, n-hexyl, n-tridecyl, cyclohexyl or cyclohexylmethyl.

[0041] The C1-C4 alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

[0042] "Linear C1-C7 alkoxy radical" refers to the radical Rad-O-, wherein Rad is a linear C1-C7 alkyl radical. Preferably, the linear C1-C7 alkoxy radical is a methoxy radical. The so-called "cyclic (preferably aromatic) C1-C7 alkoxy radical" refers to the radical Rad-O-, wherein Rad is a cyclic, preferably aromatic C1-C7 alkyl radical. Preferably, the cyclic C1-C7 alkoxy radical is an aromatic C1-C7 alkoxy radical, and more preferably a benzyloxy radical.

[0043] "Aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon group which may be optionally substituted. Preferably, the aryl group is phenyl or a polycyclic aromatic hydrocarbon (PAH). The preferred polycyclic aromatic hydrocarbon is pyrene. The aryl group may be substituted by at least one alkyl group and / or by at least one cyano group (-CN). A preferred example of an aryl group is phenyl.

[0044] "Aralkyl" refers to an aryl group as described above, which is connected to the compound of formula (I) via an alkyl group. Preferably, the aralkyl group is phenylpropyl. The aralkyl group may be substituted on the aryl group by at least one alkyl group and / or by at least one cyano group (-CN). A preferred aralkyl group is phenylpropyl.

[0045] "Heteroaryl" refers to an aryl group in which at least one carbon atom of the aromatic ring is replaced by a heteroatom and may be optionally substituted. The heteroatom may be nitrogen, oxygen, phosphorus or sulfur. Preferably, the heteroatom is nitrogen. Examples of heteroaryl groups include pyrrole, thiophene, furan, pyridine, pyrimidine, pyrazine, triazine, imidazole, thiazole, oxazole and isoxazole groups. Preferably, the heteroaryl group is pyridyl, for example, 4- or 3-pyridyl. The heteroaryl group may be substituted by at least one alkyl group and / or at least one cyano group (-CN). Preferably, the heteroaryl group is in the form of a salt, preferably pyridyl, for example, 4- or 3-pyridine.

[0046] According to a first embodiment, in formula (I), preferably -XY- is Br and R2 is absent.

[0047] Therefore, the compound of formula (I) or one of its pharmaceutically acceptable salts has the following skeleton 1:

[0048]

[0049] Skeleton 1

[0050] wherein R1 is as defined above.

[0051] The compound of skeleton 1 is a compound in which R1 is H or a linear or cyclic (preferably aromatic) C1-C7 alkoxy radical. Preferably, the compound of skeleton 1 is a compound in which R1 is H, methoxy or benzyloxy.

[0052] According to the second embodiment, in formula (I), preferably -XY- is -CY- (skeleton 2):

[0053]

[0054] Skeleton 2

[0055] wherein R1 and R2 are as defined above.

[0056] The compound of skeleton 2 is a bifunctional compound.

[0057] Preferably, the compound of skeleton 2 is a compound in which R1 is selected from H and methoxy.

[0058] Preferably, the compound of skeleton 2 is the following compound, R2 is selected from free radical A, free radical B, free radical C and free radical D, preferably, free radical C or free radical D is connected to -YX- through an alkyl group, more preferably an ethyl group:

[0059]

[0060] Alternatively, preferably, the compound of skeleton 2 is the following compound, R2 is alkyl, heteroaryl, aralkyl or -R3-N(R4)(R5),

[0061] wherein R3 is a C1-C4 alkyl group, preferably R3 is selected from methyl, ethyl and n-propyl,

[0062] R4 is H, and

[0063] R5 is selected from a naphthyl radical, a 5-fluoroquinolin-4-yl radical, a quinolin-4-yl radical or a 8-methoxyquinolin-4-yl radical.

[0064] Alternatively, preferably, the compound of skeleton 2 is the following compound, R2 is -R3-N(R4)(R5), wherein R3 is a C1-C4 alkyl group, preferably R3 is selected from methyl, ethyl and n-propyl, and

[0065] R4 and R5 together with the nitrogen atom form a 4-benzylpiperazin-1-yl radical or a 3,7-dimethyl-2,6-dioxy-2,3,6,7-tetrahydro-1H-purin-1-yl radical.

[0066] Compared with compounds without triple binding and with -OH as R1 and with reference molecules such as pralidoxime (2-PAM) and HI-6, compounds with skeleton 2 have lower pKa and increased reactivation efficiency due to increased affinity (kr2 unit: mM -1 min -1 ).

[0067] According to a third embodiment, in formula (I), preferably -XY- is -CH 2 -(CH 2 ) n -, wherein n is an integer from 0 to 5 (skeleton 3):

[0068]

[0069] Skeleton 3

[0070] wherein R1 and R2 are as defined above.

[0071] The compound of skeleton 3 is a bifunctional compound.

[0072] Preferably, the compound of skeleton 3 is a compound in which R1 is selected from H and methoxy.

[0073] Preferably, the compound of skeleton 3 is the following compound, R2 is alkyl, aryl, aralkyl or -R3-N(R4)(R5),

[0074] Wherein, R3 is C1-C4 alkyl, preferably R3 is selected from methyl, ethyl and n-propyl,

[0075] R4 is H, and

[0076] R5 is selected from a naphthyl radical, a 5-fluoroquinolin-4-yl radical, a quinolin-4-yl radical or a 8-methoxyquinolin-4-yl radical.

[0077] Alternatively, preferably, the compound of skeleton 3 is the following compound, R2 is -R3-N(R4)(R5), wherein R3 is a C1-C4 alkyl group, preferably R3 is selected from methyl, ethyl and n-propyl, and

[0078] R4 and R5 together with the nitrogen atom form a 4-benzylpiperazin-1-yl radical.

[0079] According to a fourth embodiment, preferably -XY- in formula (I) is (Skeleton 4):

[0080]

[0081] Skeleton 4

[0082] wherein R1 and R2 are as defined above.

[0083] The compound of skeleton 4 is a trifunctional compound.

[0084] Preferably, the compound of skeleton 4 is a compound wherein R1 is selected from H, methoxy and benzyloxy; preferably, R1 is H.

[0085] Preferably, the compound of skeleton 4 is the following compound, R2 is selected from free radical A, free radical C and free radical D, preferably, free radical C or free radical D is connected to -YX- through an alkyl group, more preferably an ethyl group:

[0086]

[0087] Compounds of framework 4 selectively targeted the catalytic site of hAChE and exhibited good reactivation kinetics.

[0088] Preferably, the compound of formula (I) is selected from the following compounds and pharmaceutically acceptable salts thereof:

[0089] 6-Bromopyridine aldehyde oxime 2:

[0090]

[0091] 6-(5-phenylpent-1-yn-1-yl)pyridine aldehyde oxime 5:

[0092]

[0093] 6-(5-phenylpentyl)pyridine aldehyde oxime 7:

[0094]

[0095] 6-(Pentadecyl-1-yn-1-yl)pyridine aldehyde oxime 9:

[0096]

[0097] 6-Pentadecylpyridine aldehyde oxime 10:

[0098]

[0099] 6-(Pyridin-3-ylethynylene)pyridinealdehyde oxime 12:

[0100]

[0101] 2-((Hydroxyimino)methyl)-6-(pyridin-1-chloride-3-ylethynylene)pyridine-1-chloride 13:

[0102]

[0103] N-(4-{6-[(Hydroxyimino)methyl]pyridin-2-yl}but-3-yn-1-yl)naphthalen-1-amine 19:

[0104]

[0105] N-(4-{6-[(Hydroxyimino)methyl]pyridin-2-yl}but-3-yn-1-yl)naphthalen-1-amine 20:

[0106]

[0107] 6-(4-(Quinolin-4-ylamino)but-1-yn-1-yl)pyridine aldehyde oxime 25:

[0108]

[0109] 3-Hydroxy-6-(4-(quinolin-4-ylamino)butyl)picolinic acid methyl ester 26:

[0110]

[0111] 6-(4-((5-Fluoroquinolin-4-yl)amino)but-1-yn-1-yl)pyridine aldehyde oxime 30:

[0112]

[0113] 6-(4-((5-Fluoroquinolin-4-yl)amino)butyl)pyridinealdehyde oxime 31:

[0114]

[0115] 6-(4-((8-methoxyquinolin-4-yl)amino)but-1-yn-1-yl)pyridinealdehyde oxime 36:

[0116]

[0117] 6-(4-((8-methoxyquinolin-4-yl)amino)butyl)pyridinealdehyde oxime 37:

[0118]

[0119] 6-(3-(4-Benzylpiperazin-1-yl)prop-1-yn-1-yl)pyridinealdehyde oxime 42:

[0120]

[0121] 6-(3-(4-Benzylpiperazin-1-yl)propyl)pyridinealdehyde oxime 43:

[0122]

[0123] 6-(4-(4-Benzylpiperazin-1-yl)but-1-yn-1-yl)pyridinealdehyde oxime 47:

[0124]

[0125] 6-(4-(4-Benzylpiperazin-1-yl)butyl)pyridinealdehyde oxime 48:

[0126]

[0127] 6-(4-(3,7-dimethyl-2,6-dioxy-2,3,6,7-tetrahydro-1H-purin-1-yl)but-1-yn-1-yl)pyridine aldehyde oxime 51:

[0128]

[0129] (3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-N-(4-(6-(hydroxyimino)methyl)pyridin-2-yl)but-3-yn-1-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolane-4-carboxamide 56:

[0130]

[0131] (2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxy-N-(4-(6-(hydroxyimino)methyl)pyridin-2-yl)but-3-yn-1-yl)tetrahydrofuran-2-carboxamide 57:

[0132]

[0133] N-(9-((3aR,4R,6R,6aR)-6-(((3-(6-(hydroxyimino)methyl)pyridin-2-yl)prop-2-yn-1-yl)oxy)methyl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolan-4-yl)-9H-purin-6-yl)benzamide 60:

[0134] 6-(3-(((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolan-4-yl)methoxy)prop-1-yn-1-yl)pyridinealdehyde oxime 61:

[0135]

[0136] 3-Methoxy-6-(5-phenylpent-1-yn-1-yl)pyridine aldehyde oxime 64:

[0137]

[0138] 3-Methoxy-6-(5-phenylpentyl)pyridine aldehyde oxime 65:

[0139]

[0140] 3-Methoxy-6-(4-(quinolin-4-ylamino)but-1-yn-1-yl)pyridine aldehyde oxime 67:

[0141]

[0142] 4-((4-(6-((hydroxyimino)methyl)-5-methoxypyridin-2-yl)but-3-yn-1-yl)amino)quinoline-1-chloride 68:

[0143]

[0144] 3-Methoxy-6-(4-(quinolin-4-ylamino)butyl)pyridinealdehyde oxime 69:

[0145]

[0146] 4-((4-(6-((hydroxyimino)methyl)-5-methoxypyridin-2-yl)butyl)amino)quinoline-1-quaternary ammonium salt 70:

[0147]

[0148] (3aS, 4S, 6R, 6aR)-6-(6-amino-9H-purin-9-yl)-N-(4-(6-((hydroxyimino)methyl)-5-methoxypyridin-2-yl)but-3-yn-1-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolane-4-carboxamide 72:

[0149]

[0150] (3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-N-(2-(1-((6-((hydroxyimino)methyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolane-4-carboxamide 77:

[0151]

[0152] (2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxy-N-(2-(1-((6-((hydroxyimino)-methyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)tetrahydrofuran-2-carboxamide hydrochloride 78:

[0153]

[0154] N-(9-((3aR,4R,6R,6aR)-6-(((1-((6-((hydroxyimino)methyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)methyl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolan-4-yl)-9H-purin-6-yl)benzamide 79:

[0155]

[0156] More preferably, the compound of formula (I) is selected from the following compounds:

[0157] (2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxy-N-(4-(6-(hydroxyimino)methyl)pyridin-2-yl)but-3-yn-1-yl)tetrahydrofuran-2-carboxamide 57:

[0158]

[0159] 6-(4-(Quinolin-4-ylamino)but-1-yn-1-yl)pyridine aldehyde oxime 25:

[0160]

[0161] 3-Hydroxy-6-(4-(quinolin-4-ylamino)butyl)picolinic acid methyl ester 26:

[0162]

[0163] (2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxy-N-(2-(1-((6-((hydroxyimino)-methyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)tetrahydrofuran-2-carboxamide hydrochloride 78:

[0164]

[0165] Preparation of compounds of formula (I)

[0166] The compound of formula (I) according to the present invention or one of its pharmaceutically acceptable salts can be synthesized by any suitable method. For example, the compound of formula (I) or one of its pharmaceutically acceptable salts can be prepared according to the following scheme:

[0167]

[0168] The compound of formula (I) of skeleton 1 (ie, wherein XY is Br) is reacted with R2-XYH (wherein XY is -C≡C-) to obtain the compound of formula (I) of skeleton 2 (wherein XY is -C≡C-).

[0169] Then, by selective hydrogenation (via H 2 ), the compound of formula (I) can be easily obtained, wherein XY is -CH 2 -CH 2 -(Skeleton 3).

[0170] To obtain compounds of skeleton 4, the alkyne R2-C≡CH is reacted with the corresponding linkable reactivating agent via linking chemistry.

[0171] The following examples illustrate these methods.

[0172] Preparation of compounds of formula (I)

[0173] The compound of formula (I) or one of its pharmaceutically acceptable salts according to the present invention can be synthesized by any suitable method known to those skilled in the art.

[0174] Preferably, the compound of formula (I) is synthesized according to the method described below. This method is chemoselective. In particular, it does not require any previous protection step for the oxime. The method comprises a minimum number of steps (one or two) and is carried out rapidly at ambient temperature.

[0175] Skeleton 1

[0176] Specifically, the compound of skeleton 1:

[0177]

[0178] Skeleton 1

[0179] It can be obtained by reacting a pyridine aldehyde precursor or a pyridine nitrile derivative with hydroxylamine hydrochloride, preferably in an organic solvent. In all cases, hydroxylamine hydrochloride can be used 15 N elements are marked.

[0180] Such a synthesis of 6-bromopyridine aldoxime 2 is illustrated in the examples.

[0181] Skeleton 2

[0182] Specifically, the method for synthesizing the compound of formula (I) (i.e., skeleton (2)) may include the later step of the Sonogashira coupling reaction between the compound of skeleton 1 (i.e., 6-bromopyridine aldehyde oxime) and the compound containing a terminal alkyne (see the above figure), preferably consisting of the later step of the Sonogashira coupling reaction between the compound of skeleton 1 (i.e., 6-bromopyridine aldehyde oxime) and the compound containing a terminal alkyne.

[0183] This type of Sonogashira coupling reaction can be carried out in a solvent such as tetrahydrofuran (THF), triethylamine (Et 3 N) or preferably a mixture thereof; in the presence of a catalyst such as Pd(PPh 3 ) 4 and the presence of CuI.

[0184] This Sonogashira coupling reaction is carried out without protecting the oxime moiety.

[0185] Skeleton 3

[0186] The obtained alkyne (Scenario 2) can then be reduced by reaction with hydrogen, for example in the presence of a palladium catalyst (eg, Pd / C), to afford the corresponding alkyl group (Scenario 3) in a selective hydrogenation step.

[0187] Likewise, the hydrogenation step was performed without protecting the oxime moiety.

[0188] Skeleton 4

[0189] As described above and as illustrated in the above schemes, to obtain compounds of skeleton 4, the alkyne R2-C≡CH is reacted with the corresponding linkable reactivating agent via linking chemistry.

[0190] The present invention therefore relates to a process for preparing compounds of formula (I) wherein -XY- is -CH 2 -CH 2 - or -C≡C-, R1 and R2 are as defined above, comprising a Sonogashira coupling reaction between 6-bromopyridine aldoloxime and a terminal alkyne-containing compound, optionally followed by a reduction step by reaction with hydrogen.

[0191] Medical uses of the compounds of the present invention

[0192] The compounds of the present invention can be used to treat neurological and / or respiratory failure caused by poisoning with at least one organophosphorus nerve agent, which can preferably be selected from warfare agents such as VX, Tabun, Sarin, Cyclosarin and Soman, and insecticides such as paraoxon, parathion and TEPP. The compounds of the present invention can be used to treat neurological and / or respiratory failure caused by poisoning with at least one organophosphorus nerve agent because they have the reactivation effect of organophosphorus inhibition of cholinesterase.

[0193] These compounds may alternatively be used to treat diseases involving reduced acetylcholine production, which can be overcome by administering acetylcholinesterase inhibitors. Examples of such diseases include in particular neurological diseases such as Alzheimer's or Parkinson's.

[0194] The compounds of the present invention are also agonists of adenosine 2A receptors. Therefore, they are useful for treating inflammation; for treating cancer; for treating diabetes; and / or for treating pain.

[0195] The compounds of the present invention are typically contained in a pharmaceutical composition comprising at least one compound of the present invention and a pharmaceutically acceptable carrier.

[0196] The amount of the compound of formula (I) or one of its pharmaceutically acceptable salts in the composition according to the invention may vary within a wide range depending on the patient, the mode of administration and the desired effect.

[0197] The compounds or compositions according to the invention can be administered orally or parenterally, for example, topically, parenterally, intramuscularly, intravenously, cutaneously, nasally or rectally.

[0198] The pharmaceutical composition of the present invention can be in different forms, including granules, powders, tablets, capsules, syrups, emulsions, suspensions and forms for non-oral administration, for example, injections, sprays, transdermal patches or suppositories. These pharmaceutical forms can be prepared by known conventional techniques.

[0199] For example, the preparation of a solid pharmaceutical form for oral administration can be carried out by adding an excipient (e.g., lactose, sucrose, starch or mannitol), a dehydrating agent (e.g., calcium carbonate, carboxymethylcellulose calcium, alginic acid, sodium carboxymethylcellulose, colloidal silicon dioxide, cross-linked carboxymethylcellulose sodium, cross-linked vinblastine, guar gum, magnesium aluminum silicate, microcrystalline cellulose, cellulose powder, pregelatinized starch, sodium alginate or glycol starch ester), a binder (e.g., α-starch, gum arabic, carboxymethylcellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose, alginic acid, carbomer, dextrin, ethyl cellulose, sodium alginate, maltodextrin, liquid glucose, magnesium aluminum silicate, hydroxyethyl cellulose, methyl cellulose or guar gum) and a lubricant (e.g., talc, magnesium stearate or polyethylene 6000) to the active compound, and then tableting the obtained mixture. If necessary, the tablets may be coated by known techniques to mask the taste (e.g., with cocoa powder, mint, borneol or cinnamon powder) or to allow enteric dissolution or sustained release of the active compound. Coating products that may be used are, for example, ethylcellulose, hydroxymethylcellulose, polyoxyethylene glycol, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate and (methacrylic acid-acrylic acid copolymer), (Hydroxypropylmethylcellulose+polyethylene glycol+titanium oxide+lactose monohydrate). A pharmaceutically acceptable colorant (eg, yellow iron oxide, red iron oxide, or quinoline yellow) may be added.

[0200] Liquid drug forms for oral administration include solutions, suspensions and emulsions. Aqueous solutions can be obtained by dissolving the active ingredient in water and then adding flavorings, colorants, stabilizers and / or thickeners (if necessary). In order to improve solubility, ethanol, propylene glycol or any other pharmaceutically acceptable non-aqueous solvent can be added. Oral aqueous suspensions can be obtained by dispersing the finely separated active ingredient in water using a viscous product (e.g., natural or synthetic gums or resins, methylcellulose or sodium carboxymethylcellulose).

[0201] For example, the injectable pharmaceutical form can be obtained by the following process. Using a dispersant (e.g., 80. 60 (Nikko Chemicals), polyethylene glycol, carboxymethyl cellulose or sodium alginate), preservatives (e.g., methyl paraben, propyl paraben, benzyl alcohol, chlorobutanol or phenol), isotonic agents (e.g., sodium chloride, glycerol, sorbitol or glucose) and optionally other additives such as solubilizers (e.g., sodium salicylate or sodium acetate) or stabilizers (e.g., human serum albumin), the active compound is dissolved, suspended or emulsified in an aqueous medium (e.g., distilled water, physiological saline or Ringer's solution) or an oil medium (e.g., olive oil, sesame oil, cottonseed oil, corn oil or propylene glycol).

[0202] External (epidermal application) drug forms can be obtained from solid, semi-solid or liquid compositions containing active compounds. For example, in order to obtain solid forms, active compounds can be treated with excipients (e.g., lactose, mannitol, starch, microcrystalline cellulose or sucrose) and thickeners (e.g., natural gum, cellulose derivatives or acrylic polymers) to convert them into powders. As previously mentioned, the preparation method of liquid pharmaceutical compositions is substantially the same as that of injection dosage forms. Semi-solid pharmaceutical dosage forms are preferably in the form of aqueous or oily gels or jams. These compositions can optionally include pH regulators (e.g., carbonic acid, phosphoric acid, citric acid, hydrochloric acid or sodium hydroxide) and preservatives (e.g., parabens, chlorobutanol or benzalkonium chloride).

[0203] Also described herein is a method for treating neurological and / or respiratory failure caused by poisoning by at least one organophosphorus nerve agent comprising administering at least one compound according to the invention.

[0204] Also described herein is a method for treating a neurological disease such as Alzheimer's or Parkinson's disease comprising administering at least one compound according to the invention.

[0205] Also described herein is a method for treating inflammation comprising administering at least one compound according to the invention.

[0206] Also described herein is a method for treating cancer comprising administering at least one compound according to the invention.

[0207] Also described herein is a method for treating diabetes comprising administering at least one compound according to the present invention.

[0208] Also described herein is a method for treating pain comprising administering at least one compound according to the present invention.

[0209] In the context of the present invention, the term "treatment" means therapeutic, symptomatic and / or preventive treatment. In particular, it may refer to slowing down the progression of a disease, reducing or inhibiting at least one symptom or complication, or improving the patient's health in any way.

[0210] Administration of a compound or composition according to the invention can be performed before, during or after exposure of the subject to an organophosphorus nerve agent.

[0211] In the present invention, the terms "subject" and "patient" are used interchangeably and refer to a human subject.

[0212] The amount of one of the formula (I) compound or its pharmaceutically acceptable salt to be used according to the present invention can change in a wide range according to the patient, mode of administration and expected effect. Specifically, the amount of one of the formula (I) compound or its pharmaceutically acceptable salt can be included between 200mg and 4000mg, and the daily dosage can reach 3 times.

[0213] The compounds or compositions according to the invention may be co-administered with at least one other active agent, for example, an antimycin agent (especially atropine), an anticonvulsant (especially diazepam or a prodrug thereof, for example, avizodone) and / or a biological scavenger such as human butyrylcholinesterase that is capable of capturing and / or degrading OPNA in the blood.

[0214] The term "co-administration" means that the administration of the compound or composition according to the present invention and the administration of other active agents may be simultaneous, sequential and / or separate.

[0215] Other uses of the compounds of the present invention

[0216] The compounds of the invention can further be used as tools for in vivo and / or in vitro biological studies. In the present application, the compound of formula (I) or one of its pharmaceutically acceptable salts may include one or more isotopes, which will allow its detection.

[0217] The following examples are offered as illustrative, non-limiting descriptions of the present invention. Example

[0218] Example 1: Synthesis of the compounds of the present invention

[0219] I-Synthesis of Bifunctional Pyridoxime Analogues

[0220] Synthesis of 6-(5-phenylpentyl)pyridine aldehyde oxime:

[0221] Scheme 1: Synthesis of 6-bromopyridine aldehyde oxime

[0222]

[0223] Scheme 2: Synthesis of 6-substituted pyridine aldehyde oximes

[0224]

[0225] Scheme 3: Alternative synthetic route to 6-substituted pyridine aldehyde oximes

[0226]

[0227] Scheme 4: Selective hydrogenation

[0228]

[0229] 6-Bromopyridine aldehyde oxime 2:

[0230]

[0231] This compound was prepared according to L. Zhang et al. 1 Synthesized according to published work; Hydroxylamine hydrochloride (2.24 g, 32.3 mmol) and sodium acetate (2.65 g, 32.3 mmol) were added to a solution of 6-bromopyridine aldehyde 1 (3.00 g, 16.1 mmol) in anhydrous ethanol (50 mL) at room temperature (rt). After addition, the colorless solution with white suspension was stirred at 90 ° C for 3 hours. The solution was cooled to room temperature and concentrated in vacuo. The obtained white solid was dissolved in EtOAc (50 mL). With H 2 The organic layer was washed with O (5 × 20 mL) and dried (MgSO 4 ), filtered and concentrated in vacuo to provide the title compound 2 (3.21 g, 16.0 mmol, 99%) as a white solid. The physical and spectral data were consistent with the reported values. 1 mp=168-170℃(literature value 2 164-166℃); IR (near infrared) V max 3203, 3084, 2912, 1546, 1158, 1119, 704cm -1 ; 1 HNMR (400 MHz, CDCl 3 ) δ11.90 (s, 1H, CHNOH), 8.04 (s, 1H, CHNOH), 7.82-7.74 (m, 2H, NCCHCHCH, NCCHCH), 7.63 (dd, J=6.8, 1.7Hz, 1H, NCCHCH); 13 C NMR (100 MHz, CDCl 3 )δ153.3, 147.5, 141.0, 140.1, 128.1, 119.3; C 6 H 5 Bn 2 O + HRMS (ESI) + m / z calculated: 200.9658, found: 200.9657.

[0232] References:

[0233] 1.Bioorg.Med.Chem.Lett.2016,26,778–781

[0234] 6-(5-phenylpent-1-yn-1-yl)pyridinecarboxaldehyde 4:

[0235]

[0236] To THF / Et 3 To a degassed solution of bromopicolinaldehyde 1 (568 mg, 3.056 mmol, 1.1 eq) in N (10 mL / 30 mL) was added Pd[PPh 3 ] 4 (482mg, 0.0.417mmol, 0.15 eq) and CuI (159mg, 0.834mmol, 0.3 eq). After the reaction mixture was degassed at room temperature for 5 minutes, alkyne 3 (400mg, 2.78mmol, 1 eq) was added dropwise, and the reaction mixture was stirred at room temperature for 16 hours. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (EtOAc / PE 6:94 to EtOAc / PE 1:9) to provide the desired coupled pyridine aldehyde 4 (500mg, 72%) in the form of a colorless oil. f (20% EtOAc + PE) 0.65; IR (near infrared) V max 3026, 2928, 2856, 2229, 1710, 1580, 1451, 1211, 987, 805, 698, 647, 542cm -1 ; 1 HNMR (400 MHz, CDCl 3 )δ(ppm)9.99(s,1H,H 18 ), 7.82-7.71(m,2H,H 3 , H 4 ), 7.53 (dd, J=7.5Hz, 1H, H 5 ), 7.26-7.10 (m, 5H, H 13 -H 17 ), 2.74 (t, J=7.5Hz, 2H, H 11 ), 2.43 (t, J=7.1Hz, 2H, H9), 1.92 (quintet, J=7.1, 7.5Hz, 2H, H 10 ); 13 C NMR (100 MHz, CDCl 3)δ(ppm)193.09(C18), 152.76(C2), 144.43(C6), 141.21(C12), 137.21(C4), 130.92(C5), 128.47(C14,C16), 128.41(C13,C17),126.02(C15),119.94(C3),92.32(C7),79.93(C8),34.90(C11),29.74(C10),18.81(C9);C 17 H 16 NO + HRMS (ESI + )m / z calculated was 250.1226, found was 250.1239.

[0237] 6-(5-phenylpent-1-yn-1-yl)pyridine aldehyde oxime 5:

[0238]

[0239] Method 1:

[0240] Acetaldehyde 4 (100 mg, 0.402 mmol, 1 eq.), hydroxylamine hydrochloride (56 mg, 0.803 mmol, 2 eq.) and CH 3 CO 2 A solution of Na (100 mg, 1.206 mmol, 3 eq.) in dry ethanol (6 mL) was stirred at reflux for 16 h. After completion (monitored by TLC), the solids were removed by filtration through a short pad of celite, the solvent was evaporated, and the residue was purified by column chromatography (EtOAc / PE 1:9) to provide oxime 5 (100 mg, 94%) in the form of a white solid. f (20% EtOAc + PE) 0.35; IR (near infrared) V max 3177, 3005, 2933, 2876, 2226, 1568, 1495, 1445, 1257, 1159, 985, 807, 734, 703, 657, 576, 490cm -1 ; 1 HNMR (400 MHz, CDCl 3 )δ(ppm)8.85(s,1H,OH),8.24(s,1H,H 18 ), 7.68 (dd, J=0.7, 7.8Hz, 1H, H 3 ), 7.56 (t, J=7.8Hz, 1H, H 4 ), 7.29 (dd, J=0.7, 7.7Hz, 1H, H 5 ), 7.29-7.08 (m, 5H, H13 -H 17 ), 2.71 (t, J=7.5Hz, 2H, H 11 ), 2.39 (t, J = 7.1H, 2H, H9), 1.89 (quintet, J = 7.1, 7.5Hz, 2H, H 10 ); 13 C NMR (100 MHz, CDCl 3 )δ(ppm)151.95(C2), 150.51(C18), 144.46(C6), 141.33(C12), 136.73(C4), 128.50(C14,C16), 128.35(C13, C17), 127.13(C5), 125.92(C15), 119.23(C3), 91.47(C7), 80.19(C8), 34.84(C11), 29.78(C10), 18.77(C9); C 17 H 17 N 2 O 1 + HRMS (ESI + )m / z calculated: 265.1335, found: 265.1360.

[0241] Method 2:

[0242] To THF / Et 3 To a degassed solution of oxime 2 (77 mg, 0.381 mmol, 1.1 equiv) in N (5 mL / 2 mL) was added Pd[PPh 3 ] 4 4-(4-(4-(4-(4-oxo-1-yl)-2-nitropropene)-2-nitropropene)-2-nitropropene)-3-nitropropene)-4-nitropropene)-3 ...

[0243] 6-(5-phenylpentyl)pyridine aldehyde 6:

[0244]

[0245] To a degassed solution of 6-substituted pyridine aldehyde 4 (200 mg, 0.802 mmol, 1 eq.) in dry EtOAc (4 mL) was added 10% Pd / C (21 mg, 0.201 mmol, 0.25 eq.). 2 After three rinses, the 2 The reaction mixture was stirred at 1 atm. for 90 minutes. After completion (monitored by TLC), the catalyst was removed by filtration through a short column of celite, the solvent was evaporated, and the residue was purified by column chromatography (EtOAc / PE 1:9) to provide oxime 6 (185 mg, 91%) as a colorless liquid; R f (20% EtOAc + PE) 0.70; IR (near infrared) V max 3026, 2929, 2856, 1709, 1591, 1455, 1213, 1089, 745, 689, 646, 570, 496cm -1 ; 1 HNMR (400 MHz, CDCl 3 )δ(ppm)9.97(s,1H,H 18 ), 7.73-7.63 (m, 2H, H 3 , H 4 ), 7.26 (dd, J=1.5, 7.7Hz, 1H, H 5 ), 7.24-7.05 (m, 5H, H 13 -H 17 ), 2.80 (t, J=7.7Hz, 2H, H7), 2.54 (t, J=7.7Hz, 2H, H11), 1.73 (quintet, J=7.7Hz, 2H, H8), 1.60 (quintet, J=7.7Hz, 2H, H 10 ), 1.35(quintet,J=7.3,7.8Hz,2H,H 9 ); 13 C NMR (100 MHz, CDCl 3 )δ(ppm)193.87(C18), 163.12(C6), 152.35(C2), 142.50(C12), 137.08(C4), 128.33(C14,C16), 128.20(C13, C17), 127.04(C5), 125.60(C15), 119.08(C3), 37.99(C7), 35.74(C11), 31.20(C10), 29.59(C8), 28.84(C9); C 17 H 20 NO + HRMS (ESI+ )m / z calculated: 254.1537, found: 254.1539.

[0246] 6-(5-phenylpentyl)pyridine aldehyde oxime 7:

[0247]

[0248] Acetaldehyde 6 (150 mg, 0.592 mmol, 1 eq.), hydroxylamine hydrochloride (82 mg, 1.184 mmol, 2 eq.) and CH 3 CO 2 A solution of Na (146 mg, 1.776 mmol, 3 eq.) in dry ethanol (12 mL) was stirred at reflux for 16 h. After completion (monitored by TLC), the solids were removed by filtration through a short pad of celite, the solvent was evaporated, and the residue was purified by column chromatography (EtOAc / PE 1:9) to provide the desired oxime 7 (135 mg, 85%) in the form of a white solid. f (20% EtOAc + PE) 0.40; IR (near infrared) V max 3080, 2926, 2856, 1720, 1575, 1452, 1269, 986, 780, 699, 658, 569, 458cm -1 ; 1 H NMR (400 MHz, CDCl 3 )δ(ppm)10.20(br s,1H,-OH),8.30(s,1H,H 18 ),7.59(br d,J=8.0Hz,1H,H 3 ),7.50(t,J=7.8Hz,1H,H 4 ),7.27-6.93(m,6H,H 5 ,H 13 -H 17 ),2.74(t,J=7.8Hz,2H,H 7 ),2.50(t,J=7.5Hz,2H,H 11 ),1.68(quintet,J=7.5,7.8Hz,2H,H 8 ),1.57(quintet,J=7.5Hz,2H,H 10 ),1.32(quintet,J=7.1,7.8Hz,2H,H 9 ); 13 C NMR (100 MHz, CDCl 3)δ(ppm)162.23,*160.10(C6),151.36,*150.73(C2),150.40(C18),142.61,*142.2 3(C12),*138.33,136.97(C4),*129.46,128.33(C14,C16),128.16(C13,C17),125. 61,*125.53(C5),*124.23,123.01(C15),*120.84,118.112(C3),37.86,*37.29(C7),35.75(C11),31.22,*31.10(C10),29.82(C8),28.91,*28.69(C9)(*cis and trans mixture); C 17 H 21 N 2 O + HRMS (ESI+) m / z calcd: 269.1648, found: 269.1670.

[0249] Synthesis of 6-pentadecylpyridine aldehyde oxime 10 :

[0250]

[0251] 6-(Pentadecyl-1-yn-1-yl)pyridine aldehyde oxime 9:

[0252]

[0253] To THF / Et 3 To a degassed solution of oxime 2 (51 mg, 0.252 mmol, 1.05 equiv) in N (4 mL / 2 mL) was added Pd[PPh 3 ] 4 (42mg, 0.036mmol, 0.15 eq) and CuI (14mg, 0.072mmol, 0.3 eq). After the reaction mixture was degassed at room temperature for 5 minutes, alkyne 8 (50mg, 0.240mmol, 1 eq) was added dropwise, and the reaction mixture was stirred at room temperature for 16 hours. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (EtOAc / PE6:94) to provide the desired coupling oxime 9 (65mg, 83%) in the form of a white solid. f (20% EtOAc + PE) 0.55; IR (near infrared) Vmax 3179, 3092, 2914, 2850, 2226, 1722, 1567, 1450, 1268, 1160, 992, 809, 733, 709, 657, 640, 549, 496 cm -1 ;1 H NMR (400 MHz, CDCl 3 )δ(ppm)8.50(s,1H,OH),8.26(s,1H,H 22 ),7.72(br d,J=7.8Hz,1H,H 3 ),7.61(t,J=7.8Hz,1H,H 4 ),7.23(br d,J=7.7Hz,1H,H 5 ),2.41(t,J=7.2Hz,2H,H 9 ),1.61(quintet,J=7.2Hz,2H,H 10 ),1.41(m,2H,H 11 ),1.24(s,18H,H 12 -H 20 ),0.85(t,J=6.5Hz,3H,H 21 ); 13 C NMR (100 MHz, CDCl 3 )δ(ppm)151.89(C2),150.73(C22),143.69(C6),136.64(C4),127.13(C5),125.92(C15),119.12(C3),92 .10(C7),79.76(C8),31.91,29.64,29.49,29.35,29.13,29.00,28.31,22.68,19.40,14.11(C9-C21);;C 21 H 33 N 2 O 1 + HRMS (ESI+) m / z calcd: 329.2587, found: 329.2549.

[0254] 6-Pentadecylpyridine aldehyde oxime 10:

[0255]

[0256] 10% Pd / C (3 mg, 0.027 mmol, 0.25 eq) was added to a degassed solution of oxime 9 (35 mg, 0.107 mmol, 1 eq) in dry EtOAc (2 mL). 2 After three rinses, the 2The reaction mixture was stirred at 40 °C (1 atm.) for 2 h. After completion, the catalyst was removed by filtration through a short column of celite, the solvent was evaporated, and the residue was purified by column chromatography (EtOAc / PE 6:94) to provide oxime 3 (30 mg, 85%) as a white solid; R f (20% EtOAc + PE) 0.65; IR (near infrared) ν max 3187,3083,2914,2849,1575,1457,1160,985,777,718,656,517,479cm -1 ; 1 H NMR (400 MHz, CDCl 3 )δ(ppm)8.36(br s,1H,OH),8.25(s,1H,H 22 ),7.61-6.54(m,2H,H 3 ,H 4 ),7.11(dd,J=2.5,6.1Hz,1H,H 5 ),2.78(t,J=7.2Hz,2H,H 7 ),1.70(m,2H,H 8 ),1.24(s,24H,H 12 -H 20 ),0.86(t,J=6.6Hz,1H,H 21 ); 13 C NMR (100 MHz, CDCl 3 )δ(ppm)162.71(C6),151.12(C2),151.02(C23),136.73(C4),123.09(C5),118.21(C 3),38.28,31.92,29.99,29.69,29.56,29.49,29.41,29.36,22.69,14.12(C7-C22). C 21 H 37 N 2 O + HRMS (ESI+) m / z calcd: 333.2900, found: 333.2918.

[0257] Synthesis of 2-((hydroxyimino)methyl)-6-(pyridin-1-chloride-3-ylethynylene)pyridine-1-chloride 13:

[0258]

[0259] 3-Fluoro-6-(pyridin-3-yl alkynylene)pyridine aldehyde oxime 12:

[0260]

[0261] To THF / Et 3 To a degassed solution of oxime 2 (211 mg, 1.05 mmol, 1.05 equiv) in N (3 mL / 3 mL) was added Pd[PPh 3 ] 4 (173 mg, 0.15 mmol, 0.15 eq) and CuI (57 mg, 0.30 mmol, 0.3 eq). After the reaction mixture was degassed at room temperature for 5 minutes, degassed alkyne 11 (103 mg, 1 mmol, 1 eq) in dry THF (3 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 16 hours. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (EtOAc / PE 45:55) to provide the desired coupled oxime 12 (200 mg, 90%) in the form of a white solid. f (60% EtOAc + PE) 0.35; IR (near infrared) ν max 3065,2764,1578,1561,1443,1288,1143,1042,990,981,798,697,637,563,499cm -1 ; 1 H NMR(400MHz,DMSO-d6)δ(ppm)11.84(s,1H,OH),8.83(br s,1H,H 14 ),8.65(br s,1H,H 12 ),8.11-8.04(m,2H,H 10 ,H 15 ),7.91(br t,J=7.8Hz,1H,H 4 ),7.83(br d,J=7.8Hz,1H,H 3 ),7.68(br d,J=7.8Hz,1H,H 5 ),7.50(dd,J=4.8,7.8Hz,1H,H 11 ); 13 C NMR(100MHz,DMSO-d6)δ(ppm)152.855(C2),151.93(C14),149.70(C12),148.34(C15),141.51(C6),13 9.03(C10),137.65(C4),127.50(C5),123.78(C11),119.84(C3),118.48(C9),91.27(C7),85.48(C8); C13 H 10 N 3 O + HRMS (ESI+) m / z calcd: 224.0818, found: 224.0840.

[0262] 2-((Hydroxyimino)methyl)-6-(pyridin-1-chloride-3-ylalkynylene)pyridine-1-chloride 13:

[0263]

[0264] Compound 12 (40 mg) in water (1 mL) was added with 1.2 N HCl (1 mL) and stirred for 2 minutes and at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to provide the hydrochloride salt 13 in quantitative yield as a white solid. IR (near infrared) max 3018,2970,2502,2080,1561,1465,1290,1005,813,726,674,548,499cm -1 ; 1 HNMR (400MHz, D 2 O)δ(ppm)9.05(br s,1H),8.83(br d,J=5.8Hz,1H),8.75(dt d,J=1.6,8.3Hz,1H),8.19(s,1H),8.15-8.04(m,2H),7.87(dd,J=0.6,8.0Hz,1H),7.81(br d,J=0.6,7.8Hz,1H); 13 C NMR (100MHz, D 2 O)δ(ppm)150.85,149.74,148.30,144.75,142.04,141.28,139.9,130.03,128.12,123.99,122.81,92.14,85.20; C 13 H 10 N 3 O + HRMS (ESI+) m / z calcd: 224.0818, found: 224.0826.

[0265] Synthesis of 6-(4-(naphthalen-1-ylamino)butyl)pyridine aldehyde oxime 20:

[0266]

[0267] 2-(Naphthylamino)-ethanol 15:

[0268]

[0269] According to Couty et al. 1 Procedure for the synthesis of substituted aromatic amines: A solution of 1-iodonaphthalene 14 (2.50 g, 9.8 mmol), 2-aminoethanol (1.78 mL, 29.5 mmol), cupric chloride (132 mg, 1.0 mmol) and freshly crushed KOH (1.10 g, 19.7 mmol) in dimethyl sulfoxide (2 mL) was stirred at room temperature for 18 h. Saturated NH 4 Cl aqueous solution (5 mL), and the solution was extracted (EtOAc, 3×20 mL). The combined extracts were washed (brine, 20 mL), dried (MgSO4), filtered and concentrated in vacuo. Silica gel chromatography (30% ethyl acetate in light petroleum ether) gave the title compound 15 (1.68 g, 9.0 mmol) as a beige oil. IR (near infrared) v max 3404,3051,2973,2869,1581,785cm -1 ; 1 HNMR (400MHz, CDCl 3 )δ(ppm)7.93-7.76(m,2H,ArH),7.52-7.29(m,4H,ArH),6.67(d,J=7.3Hz,1H,CHCNH),4.01(t,J=5.1Hz,2H,NHCH 2 CH 2 OH), 3.49(t, J=5.1Hz,2H,NHCH 2 CH 2 OH); 13 C NMR (101 MHz, CDCl 3 )δ(ppm)142.8,134.6,128.7,126.4,125.9,125.0,123.9,120.0,118.5,105.5,61.0,46.6.

[0270] 2-[(2-Hydroxyethyl)(naphthalen-1-yl)amino]acetonitrile 16:

[0271]

[0272] According to Couty et al. 1Procedure for N-cyanomethylation of aromatic aminoethanol; A solution of 2-(naphthylamino)-ethanol 15 (745 mg, 4.0 mmol) and paraformaldehyde (717 mg, 8.0 mmol) in MeCN (20 mL) was heated to 90 ° C for 18 hours. The white suspension was cooled to room temperature (rt), and TMSCN (1.06 mL, 8.0 mmol) and AcOH (0.46 mL, 8.0 mmol) were added to the reaction, and the light yellow reaction solution was stirred at 90 ° C for 18 hours. The reaction was cooled to room temperature, H 2 O (40 mL) and extract the aqueous mixture (CH 2 Cl 2 , 10 mL). The organic extract was washed with aqueous NaOH (1 M, 20 mL), brine (10 mL), and dried (MgSO 4 ), filtered and the organic extracts were concentrated in vacuo. Silica gel chromatography (30% ethyl acetate in light petroleum ether) afforded the title compound 16 (850 mg, 3.8 mmol, 94% yield over two steps) as a colorless solid. mp = 70-71 °C (literature value 1 =71-73°C); IR (near infrared) ν max 3422,3050,2956,2236,1705,1418,802cm -1 ; 1 HNMR (400MHz, CDCl 3 )δ(ppm)8.17(d,J=8.3Hz,1H,8-CH),7.91(d,J=7.6Hz,1H,2-CH),7.75(d,J=7.6Hz,1H,4-CH),7.61-7.42(m,4H,ArH),4.17(s,2H,CH 2 CN), 3.78 (br t, J = 5.0, 2H, NCH 2 CH 2 OH), 3.54(t, J=5.0Hz,2H,NCH 2 CH 2 OH); 13 C NMR (101 MHz, CDCl 3 )δ(ppm)145.8,134.8,129.7,128.5,126.2,126.1,125.8,125.7,122.9,119.1,116.0,61.1,55.1,44.7.

[0273] 1-(Naphthalene-1-yl)azetidine-2-carbonitrile 17:

[0274]

[0275] According to Couty et al. 1 Procedure for the formation of aromatic azetidines; add CH 2 Cl 2 2-[(2-Hydroxyethyl)(naphthalen-1-yl)amino]acetonitrile 16 (500 mg, 2.2 mmol) and Et 3 MsCl (0.21 mL, 2.6 mmol) was added dropwise to a solution of N (0.77 mL, 5.5 mmol). The colorless reaction solution was stirred at 0 °C for 30 min and slowly heated to room temperature. The reaction was stirred at room temperature for another 30 min. H 2 O (20 mL), separate the organic layer and extract the aqueous layer (CH 2 Cl 2 , 20 mL). In dry (MgSO 4 The combined extracts were washed with aqueous HCl (2M, 10 mL) and brine (10 mL) before filtration and concentration in vacuo. The pale yellow residue was directly carried to the next step and extracted in anhydrous THF (15 mL). At 0 °C, the solution was added t BuOK (297 mg, 2.6 mol). The reaction was slowly warmed to room temperature and H 2 O (20 mL). The solution was extracted (EtOAc, 3×20 mL), and the combined organics were washed with brine (20 mL), dried (MgSO 4 ), filtered and concentrated in vacuo. Silica gel chromatography (10% ethyl acetate in light petroleum ether) afforded the title compound 17 (850 mg, 3.8 mmol, 94% yield over two steps) as a colorless solid. mp = 129-131 °C (literature value 1 =130-131°C); IR (near infrared) ν max 3433,3045,2958,2248,1577,788cm -1 ; 1 HNMR (400MHz, CDCl 3 )δ(ppm)7.96-7.82(m,2H,ArH),7.56-7.38(m,4H,ArH),6.75(d,J=7.3Hz,1H,2-CH),4.93(dd,J=8.3,6.6Hz,1H,NCH 2 CH 2 CHCN),4.51(ddd,J=8.3,6.6,4.9Hz,1H,NCHHCH 2 CHCN),3.88(dt,J=8.3,6.8Hz,1H,NCHHCH 2CHCN), 2.91-2.80 (m, 1H, 2H, NCH 2 CHHCHCN), 2.78-2.66 (m, 1H, NCH 2 CHHCHCN); 13 C NMR (101 MHz, CDCl 3 )δ(ppm)145.0,134.7,128.6,126.1,125.6,125.2,125.1,122.9,122.5,118.4,109.5,54.3,51.0,22.7.

[0276] N-(3-Butyl-1-yl)naphthylamine 18:

[0277]

[0278] According to Couty et al. 2 Procedure for the formation of aromatic homopropargylamines from aromatic azetidines; To a solution of 1-(naphthalen-1-yl)azetidine-2-carbonitrile 17 (1.00 g, 4.8 mmol) in toluene (15 mL) were added dibutyltin oxide (298 mg, 1.2 mmol) and TMSN 3 (0.95 mL, 7.2 mmol) and stirred the reaction at 60 ° C for 96 hours. The brown reaction solution was cooled to room temperature and concentrated in vacuo. Silica gel chromatography (2% ethyl acetate in hexane) gave the title compound 18 (454 mg, 2.3 mmol, 48%) as a colorless oil. IR (near infrared) v max 3293,3050,2975,2117,1690,767cm -1 ; 1 HNMR (400MHz, CDCl 3 )δ(ppm)7.90-7.79(m,2H,5-CH,8-CH),7.57-7.29(m,4H,3-CH,4-CH,6-CH,7-CH),6.66(d,J=7.3Hz,1H,2-CH),3.50(t,J=6.5Hz,2H,NHCH 2 CH 2 CCH),2.69(td,J=6.5,2.7Hz,2H,NHCH 2 CH 2 CCH), 2.11(t, J=2.7, 1H, NHCH 2 CH 2 CCH); 13 C NMR (101 MHz, CDCl 3)δ(ppm)146.7,134.4,128.7,126.4,125.9,125.0,123.8,121.0,119.9,118.3,85.2,70.4,27.4,18.9.

[0279] N-(4-{6-[(Hydroxyimino)methyl]pyridin-2-yl}but-3-yn-1-yl)naphthalen-1-amine 19:

[0280]

[0281] N-(3-But-1-yl)naphthylamine 18 (400 mg, 2.0 mmol) was dissolved in anhydrous THF / Et 3 Pd(PPh 3 ) 4 (238 mg, 0.2 mmol) and CuI (78 mg, 0.4 mmol). A degassed solution of 6-bromopyridine aldehyde oxime 2 (453 mg, 2.2 mmol) in anhydrous THF (20 mL) was added dropwise to the resulting orange reaction mixture. The brown solution was stirred at room temperature for 16 hours. The reaction was concentrated in vacuo. Silica gel chromatography (hexanes to 10% ethyl acetate in hexanes) gave the title compound 19 (350 mg, 54%) as an orange solid: mp = 143-144 ° C; 1 HNMR (400MHz, CDCl 3 )δ(ppm)8.28(s,1H,NOH),7.95-7.73(m,4H,ArH),7.67(t,J=7.8Hz,1H,3-CH), 7.53-7.33(m,4H,ArH),6.70(d,J=7.8Hz,1H,2-CH),3.66(t,J=6.7Hz,2H,NHCH 2 CH 2 ),2.96(t,J=6.7Hz,2H,NHCH 2 CH 2 ); 13 C NMR (101 MHz, CDCl 3 )δ(ppm)152.0,150.5,143.1,142.1,136.8,134.4,128.7,127.8,127.3,126.4,125.9,125.0,12 3.8,120.0,119.8,105.2,88.6,81.4,42.6,19.8;IR(neat)ν3350,3152,3047,2864,2645,2200cm -1 , C 20 H18 N 3 O + HRMS (ESI) + m / z calculated: 316.1444, found: 316.1445.

[0282] N-(4-{6-[(Hydroxyimino)methyl]pyridin-2-yl}but-3-yn-1-yl)naphthalen-1-amine 20:

[0283]

[0284] To a degassed suspension of N-(4-{6-[(1E)-(hydroxyimino)methyl]pyridin-2-yl}but-3-yn-1-yl)naphthalen-1-amine 19 (173 mg, 0.5 mmol) in anhydrous methanol (10 mL) was added Pearlman catalyst (77 mg, 0.5 mmol). The reaction vessel was evacuated and flushed with hydrogen five times. The black reaction mixture was stirred at room temperature for 18 hours. The catalyst was removed by filtration through diatomaceous earth and the solvent was removed in vacuo. Silica gel chromatography (50% ethyl acetate in hexanes) afforded the title compound 20 (60 mg, 34%) as a colorless solid: mp = 151-152 °C; IR (near infrared) ν max 3351,3047,2867,2642,lcm -1 ; 1 HNMR (400MHz, CDCl 3 )δ(ppm)8.21(s,1H,NOH),7.77-7.67(m,2H,ArH),7.60-7.49(m,2H,ArH),7.41-7.30(m,2H,ArH),7.26(t,J=8.2Hz,1H,NCCHCH CH),7.15(d,J=8.2Hz,1H,NCCHCHCH),7.09(dd,J=7.1,1.7Hz,1H,7-CH),6.53(d,J=7.5Hz,1H,2-CH),3.26(t,J=6.9Hz,2H,NHCH 2 CH 2 CH 2 CH 2 ),2.85(t,J=6.7Hz,2H,NHCH 2 CH 2 CH 2 CH 2 ),2.00-1.65(m,4H,NHCH 2 CH 2 CH 2 CH 2 ); 13C NMR (101 MHz, CDCl 3 )δ(ppm)162.0,151.1,151.0,143.4,137.1,134.3,128.6,126.6,125.7,1 24.7,123.4,123.3,119.9,118.6,117.3,104.4,44.1,37.7,28.8,27.6; C 20 H 22 N 3 O + HRMS (ESI) + m / z calcd. 320.1757, found 320.1759.

[0285] References:

[0286] 1. Couty et al., J. Org. Chem, 2016, 81, 2899-2910;

[0287] 2. Couty et al., Chem. Comms, 52, 2016, pp. 10072-10075.

[0288] Synthesis of methyl 3-hydroxy-6-(4-(quinolin-4-ylamino)butyl)picolinate 26:

[0289]

[0290] 4-Bromoquinoline 22:

[0291]

[0292] According to Margolis et al. 1 Procedure for the synthesis of bromoquinolines; PBr 3 (3.34 mL, 35.5 mmol) was added dropwise to a solution of 4-quinolinol 21 (5.00 g, 34.4 mmol) in DMF (50 mL) at 60 °C. After addition, a color change from yellow to bright orange was observed with bubbles. The orange reaction mixture was stirred at 45 °C for 45 min. The solution was cooled to room temperature and washed with H 2 O (20 mL), and slowly add saturated NaHCO 3 The reaction mixture was basified to pH 10 using CH 2 Cl 2 (5 × 20 mL) extraction solution, and then the organic solution was combined and washed with H 2 O (20 mL), and dried (MgSO 4), filtered and concentrated in vacuo. Silica gel chromatography (EtOAc) afforded the title compound 22 (5.56 g, 26.7 mmol, 78%) as a cream solid. Physical and spectral data were consistent with reported values. mp = 28-29 °C (literature value 2 29.5-30.5℃); IR (near infrared) ν3062, 1615, 1058 cm –1 ; 1 HNMR (400 MHz, CDCl 3 )δ8.68(d,J=4.6 Hz,1H,NCH),8.20(dd,J=8.4,0.9Hz,1H,NCCHCHCHCH),8.11(d,J=8.4 Hz,1H,NCCHCHCHCH),7.78(ddd,J=8.4,7.0,1.4 Hz,1H,NCCHCH),7.71(d,J=4.6 Hz,1H,NCHCH),7.66(ddd,J=8.4,7.0,1.4Hz,1H,NCCHCHCH); 13 C NMR (100 MHz, CDCl 3 )δ149.9,149.0,134.2,130.4,129.9,127.9,127.9,126.8,125.1.

[0293] N-(But-3-yn-1-yl)quinolin-4-amine 24:

[0294]

[0295] According to Musonda et al. 3 Procedure for the synthesis of alkylated quinolines; Commercially available 3-n-butyl-1-amine 23 (4.72 mL, 57.7 mmol) was added to 4-bromoquinoline 22 (3.00 g, 14.4 mmol) to form a cream-colored paste. The paste was heated to 80° C. for 1 hour without stirring. The temperature was raised to 140° C. and the paste was heated for 18 hours with stirring. The viscous brown reaction mixture was cooled to room temperature and purified by silica gel chromatography (20% MeOH in EtOAc) to provide the title compound 24 (2.82 g, 14.4 mmol, 100%) as a cream solid: mp=165-166° C.; IR (near infrared) ν max 3281,3169,3067,1573,1151cm –1 ; 1 H NMR (400 MHz, DMSO-d 6)δ8.45(d,J=5.9Hz,1H,NCH),8.30(dd,J=8.3,1.2Hz,1H,NCCHCHCHCH),7.93(br.s,1H,NH),7.82(dd,J=8.3,1.2Hz,1H,NCCHCHCHCH),7.71(dd d,J=8.3,7.0,1.2Hz,1H,NCCHCHCHCH),7.51(ddd,J=8.3,7.0,1.2Hz,1H,NCCHCHCHCH),6.63(d,J=5.9Hz,1H,NCHCH),3.54(q,J=7.0Hz,2H,NHCH 2 CH 2 CCH), 2.91(t, J=2.7Hz,1H,NHCH 2 CH 2 CCH),2.58(td,J=6.8,2.7Hz,2H,NHCH 2 CH 2 CCH); 13 C NMR (100 MHz, DMSO-d 6 )δ151.3,148.2,145.1,130.2,126.4,124.7,122.1,118.1,98.3,82.1,72.6,41.4,17.8; C 13 H 13 N 2 + HRMS (ESI) + m / z calculated: 197.1073, found: 197.1072.

[0296] 6-(4-(Quinolin-4-ylamino)but-1-yn-1-yl)pyridine aldehyde oxime 25:

[0297]

[0298] N-(But-3-yn-1-yl)quinolin-4-amine 24 (1.00 g, 5.1 mmol) was dissolved in anhydrous THF / Et 3 Pd(PPh 3 ) 4(588 mg, 0.5 mmol) and CuI (194 mg, 1.0 mmol). A degassed solution (20 mL) of 6-bromopyridine oxime 2 (1.13 g, 5.6 mmol) in anhydrous THF was added dropwise to the resulting orange reaction mixture. The brown solution was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo. Silica gel chromatography (20% MeOH in EtOAc) gave the title compound 25 (1.55 g, 4.9 mmol, 96%) as an orange solid: mp = 202-203 ° C (decomposition); IR (near infrared) ν max 3291,3068,2947,2241,1617,1222,1051cm –1 ; 1 H NMR (400 MHz, DMSO-d 6 )δ11.90-11.69(m,1H,CHNOH),8.43(br d,J=5.4Hz,1H,NCH),8.23(d,J=8.3Hz,1H,NCCH),8.03(s,1H,CHNOH),7.85-7.65(m,4H ,ArH),7.52-7.38(m,3H,ArH),6.60(d,J=5.4Hz,1H,NCHCH),3.61(q,J=6.7Hz,2H,NHCH 2 CH 2 ),2.88(t,J=6.7Hz,2H,NHCH 2 CH 2 ); 13 C NMR (100 MHz, DMSO-d 6 )δ152.5,150.3,149.8,148.4,147.8,142.4,137.8,129.0,128.6,126.8,124.1,121.7,118.9,118.7,98.5,88.7,81.1,48.6,18.6; C 19 H 17 N 4 O + HRMS (ESI) + m / z calculated: 317.1397, found: 317.1396.

[0299] 3-Hydroxy-6-(4-(quinolin-4-ylamino)butyl)picolinic acid methyl ester 26:

[0300]

[0301] To a degassed suspension of (E)-6-(4-(quinolin-4-ylamino)but-1-yn-1-yl)pyridine aldehyde oxime 25 (575 mg, 1.8 mmol) in anhydrous methanol (20 mL) was added Pearlman catalyst (255 mg, 1.8 mmol). The reaction vessel was evacuated and flushed with hydrogen five times. The black reaction mixture was stirred at room temperature for 18 hours. The catalyst was removed by filtration through diatomaceous earth and the solvent was removed in vacuo to provide the title compound 26 (550 mg, 1.7 mmol, 94%) as a cream solid: mp = 218-219 ° C; IR (near infrared) v max 3145,3026,2985,1593,1224,1026,658cm –1 ; 1 H NMR (400 MHz, D 2 O)δ8.15(s,1H,CHNOH),8.01(d,J=7.1Hz,1H,NCH),7.89-7.49(m,7H,ArH),6.62(d,J=7.1Hz,1H,NCHCH),3.54(t,J=6.6Hz,2H,NHCH 2 CH 2 CH 2 CH 2 ),3.09(t,J=7.2Hz,2H,NHCH 2 CH 2 CH 2 CH 2 ),1.99-1.76(m,4H,NHCH 2 CH 2 CH 2 CH 2 ); 13 C NMR (100MHz, D 2 O) δ156.1,146.7,145.0,142.7,141.7,137.6,134.1,127.5,127.4,123.2,122.3,122.1,120.2,116.8,98.2,42.9,33.1,26.1,17.2; C 19 H 21 N 4 O + HRMS (ESI) + m / z calculated: 321.1710, found: 3321.1713.

[0302] References:

[0303] 1. Margolis, BJ et al., J. Org. Chem, 2007, 72, pp. 2232-2235;

[0304] 2. Charette, AB et al., J. Org. Chem, 2017, 82, 5046-5067.

[0305] 3.Musonda, CC et al., Bioorg.Med.Chem.Lett., 2007, Issue 17, pp. 4733-4736.

[0306] Synthesis of 6-(4-((5-fluoroquinolin-4-yl)amino)butyl)pyridine aldehyde oxime 31:

[0307]

[0308] 4-Bromo-5-fluoroquinoline 28:

[0309]

[0310] According to Kilpin-Guy et al. 1 Synthesis of substituted quinolines from aniline and Pulley et al. 2 Modified procedure for the synthesis of bromoquinoline from quinolinol; Meldrum's acid (9.49 g, 65.9 mmol) and triethyl orthoformate (21.3 mL, 128.0 mmol) were added to an ethanol (100 mL) solution of m-fluoroaniline 27 (6.00 g, 54.0 mmol) at room temperature. The yellow solution was stirred at 90 ° C for 2.5 hours. The solution was cooled to 0 ° C, and the resulting yellow solid was filtered and washed with cold ethanol (20 mL). The resulting light yellow solid was dried and slowly added to diphenyl ether (50 mL) refluxed at 280 ° C for more than 5 minutes. After addition, a large amount of white gas was observed, and the colorless solution turned orange / brown. Keep reflux for 5 minutes, and cool the reaction mixture to room temperature. During this period, the solution turned dark brown. Petroleum ether (50 mL) was added to the solution, and the resulting brown crystals were separated by filtration. Silica gel chromatography (10% methanol in EtOAc) provided an inseparable mixture of 5-fluoroquinolin-4-ol and 7-fluoroquinolin-4-ol (ca. 9:1 by 19F NMR, 7.76 g, 47.5 mmol). This mixture was directly carried forward to the next step.

[0311] To an inseparable mixture of 5-fluoroquinolin-4-ol and 7-fluoroquinolin-4-ol (4.00 g, 24.5 mmol) in DMF (30 mL) was added phosphorus tribromide (1.86 mL, 19.7 mmol) at 60°C, and the mixture was stirred at 45°C for 45 minutes. After cooling to room temperature, H 2 O (25 mL) and add saturated Na 2 CO 3 The obtained crystals were treated with H 2 O (10 mL). Silica gel chromatography (25% acetoacetic acid in hexanes) afforded only 4-bromo-5-fluoroquinoline 28 (2.50 g, 11.1 mmol, 61% yield over three steps) as an orange solid. mp = 89-90°C; IR (near infrared) ν 3091, 3041, 1621 cm –1 ; 1 HNMR (400MHz, CDCl 3 )δ8.67(d,J=4.6Hz,1H,NCH),8.22(dd,J=9.2,5.9Hz,1H,NCCH),7.75(dd,J=9.2,2.7Hz, 1H,NCCHCHCH),7.68(d,J=4.6Hz,1H,NCHCH),7.44(ddd,J=9.2,5.9,2.7Hz,1H,NCCHCH); 13 C NMR (100 MHz, CDCl 3 )δ161.9,150.6,149.6,133.7,128.9,124.7,124.1,118.0,113.1; 19 FNMR (376MHz, CDCl 3 )δ108.7; C 9 H 6 BrFN + HRMS (ESI) + m / z calculated: 225.9662, found: 225.9658.

[0312] N-(But-3-yn-1-yl)-5-fluoroquinolin-4-amine 29:

[0313]

[0314] Following the modified procedure used by Musonda et al. for the synthesis of alkylated quinolines 3; 3-Butyl-1-amine 23 (0.55 mL, 6.6 mmol) was added to 4-bromo-5-fluoroquinoline 28 (1.50 g, 6.6 mmol) to form an orange thin slurry. The slurry was heated to 100 ° C and stirred for 18 hours. The reaction was further heated to 120 ° C for 2 hours. The viscous, brown reaction mixture was cooled to room temperature and purified by silica gel chromatography (100% EtOAc to 20% MeOH in EtOAc) to provide the title compound 29 (1.06 g, 4.9 mmol, 75%) as a milky solid. mp = 225-226 ° C; IR (near infrared) v max 3079,2911,2240,1966cm -1 ; 1 HNMR (400 MHz, DMSO-d 6 )δ8.39(d,J=5.4Hz,1H,NCH),8.27(dd,J=10.8,8.3Hz,1H,NCCH),7.47(dd,J=10.8,2.5Hz,1H,NCCHCHCH),7.44-7.39(m,1H,NHCH 2 CH 2 CCH),7.35(ddd,J=10.8,8.3,2.5Hz,1H,NCCHCHCH),6.49(d,J=5.4Hz,1H,NCHCH),3.45(q,J=7.1Hz,2H,NHCH 2 CH 2 CCH), 2.88(t, J=2.7Hz,1H,NHCH 2 CH 2 CCH),2.55(td,J=7.1,2.7Hz,2H,NHCH 2 CH 2 CCH); 13 C NMR (100 MHz, DMSO-d 6 )δ163.4,160.9,151.9,149.7,124.5,115.8,113.5,112.2,98.2,82.2,72.4,41.2,17.7; 19 FNMR (376 MHz, DMSO-d 6 )δ112.1;C 13 H 12 FN 2 + HRMS (ESI) + m / z calculated: 215.0979, found: 215.0983 Da.

[0315] 6-(4-((5-Fluoroquinolin-4-yl)amino)but-1-yn-1-yl)pyridine aldehyde oxime 30:

[0316]

[0317] N-(But-3-yn-1-yl)-5-fluoroquinolin-4-amine 29 (0.50 g, 2.3 mmol) was dissolved in anhydrous THF / Et 3 Pd(PPh 3 ) 4 (270 mg, 0.2 mmol) and CuI (89 mg, 0.4 mmol). A degassed solution of 6-bromopyridine aldehyde oxime 2 (516 mg, 2.6 mmol) in anhydrous THF (20 mL) was added dropwise to the obtained orange reaction mixture. The brown solution was stirred at room temperature for 16 hours. The reactants were concentrated in vacuo. Silica gel chromatography (EtOAc) showed the title compound 30 (140 mg, 0.4 mmol, 18%) as a light cream solid: mp = 168-169 ° C; IR (near infrared) v max 3500,3435,3034,2960,2239,1966,1599,991cm -1 ; 1 H NMR (400 MHz, DMSO-d 6 )δ11.79(s,1H,CHNOH),8.42(d,J=5.4Hz,1H,NCHCH),8.30(dd,J=9.2,7.1Hz,1H,N CCHCHCHCF),8.02(s,1H,CHNOH),7.83-7.69(m,2H,ArH),7.53(t,J=5.6Hz,1H,NHCH 2 CH 2 ),7.48(dd,J=10.8,2.7Hz,1H,NCCHCHCH),7.41(d,J=7.1Hz,1H,NCCHCHCHCF),7.35( td,J=8.7,2.7Hz,1H,NCCHCHCH),6.58(d,J=5.4Hz,1H,NCHCH),3.66-3.51(m,2H,NHCH 2 CH 2 ),2.86(t,J=7.0Hz,2H,NHCH 2 CH 2 ); 13 C NMR (100 MHz, DMSO-d 6)δ163.4,160.9,152.4,151.9,149.8,148.4,142.4,137.3,126.9,124.5,119.0,115.9,113.5,112.2,98.4,88.7,81.1,41.0,18.6; 19 FNMR (376 MHz, DMSO-d 6 )δ111.9;C 19 H 16 FN 4 O + HRMS (ESI) + m / z calculated: 335.1303, found: 335.1298.

[0318] 6-(4-((5-Fluoroquinolin-4-yl)amino)butyl)pyridinealdehyde oxime 31:

[0319]

[0320] To a degassed suspension of 6-(4-((5-fluoroquinolin-4-yl)amino)but-1-yn-1-yl)pyridine aldehyde oxime 30 (50 mg, 0.1 mmol) in anhydrous methanol (5 mL) was added Pearlman's catalyst (21 mg, 0.1 mmol). The reaction vessel was evacuated and flushed with hydrogen five times. The black reaction mixture was stirred at room temperature for 18 hours. The catalyst was removed by filtration through diatomaceous earth, and the solvent was removed in vacuo to provide the title compound 31 (50 mg, 0.1 mmol, 99%) as a cream solid: mp = 206-207 ° C; IR (near infrared) v max 3247,2935,2859,1978,1584,806cm –1 ; 1 H NMR (400 MHz, D 2 O)δ8.44(t,J=8.1Hz,1H,NCCHCHCH),8.19(d,J=7.3Hz,1H,NCHCH),8.16-8.13(m,2H,CHNOH,NHCH 2 CH 2 CH 2 CH 2 ),7.91-7.81(m,2H,NCCHCHCHCF,NCCHCHCHCF),7.70(d,J=8.1Hz,1H,NCCHCHCH),7.42-7.32(m,2H,NCCHCHCH),6.70(d,J=7.3Hz,NCHCH),3.58(t,J=6.8Hz,2H,NHCH 2 CH2 CH 2 CH 2 ),3.12(t,J=7.7Hz,2H,NHCH 2 CH 2 CH 2 CH 2 ),2.01-1.76(m,4H,NHCH 2 CH 2 CH 2 CH 2 ); 13 C NMR (100MHz, D 2 O) δ166.0,136.5,161.5,159.1,155.8,146.5,141.9,139.0,127.0,125.6,124.0,116.2,113.5,105.1,98.0,42.8,39.9,26.9,25.9; 19 FNMR (376MHz, D 2 O)δ103.1;C 19 H 22 FN 4 O + (ESI) + m / z calcd. 339.1980, found 339.1980.

[0321] References:

[0322] 1. Kiplin Guy R et al., Bioorg. Med. Chem. Lett., 2005, No. 15, pp. 1015-1018;

[0323] 2. Pulley et al., J. Org. Chem., 2007, No. 72, pp. 2232-2235;

[0324] 3. Musonda, CC et al., Bioorg. Med. Chem. Lett., 2007, Issue 17, Pages 4733-4736.

[0325] Synthesis of 6-(4-((8-methoxyquinolin-4-yl)amino)butyl)pyridinealdehyde oxime 37:

[0326]

[0327] 8-Methoxyquinolin-4-ol 33:

[0328]

[0329] An adapted procedure from Kilpin-Guy et al. for the synthesis of substituted quinolines from anilines 1 ; At room temperature, McLaughlin's acid (3.57 g, 24.8 mmol) and triethyl orthoformate (8.00 mL, 48.0 mmol) were added to an ethanol (20 mL) solution of o-anisidine 32 (2.50 g, 20.3 mmol). The yellow solution was stirred at 90 ° C for 2.5 hours. The solution was cooled to 0 ° C, the resulting yellow solid was filtered and washed with cold ethanol (20 mL). The resulting light yellow solid was dried and slowly added to diphenyl ether (50 mL) refluxed at 280 ° C for more than 5 minutes. After addition, a large amount of white gas was observed and the colorless solution turned orange / brown. Reflux was maintained for 5 minutes, and the reaction mixture was cooled to room temperature. During this period, the solution was dark brown. Petroleum ether (50 mL) was added to the solution, and the resulting yellow crystals were isolated by filtration. Silica gel chromatography (5% methanol in EtOAc) afforded 8-methoxyquinolin-4-ol 33 (7.76 g, 47.5 mmol) as a light orange solid: mp = 168 °C (literature value 2 :168-169℃); IR (near infrared) ν2921,2851,1272,1041cm -1 ; 1 HNMR (400 MHz, DMSO-d 6 )δ(ppm)11.35(s,1H,OH),7.58-7.70(m,1H,NCH),7.38-7.43(m,1H,ArH),7.23-7.27(m,2H,OHCCCH,OMeCCH),6.95-7.08(m,1H,OHCCH),3.99(s,3H,OMe); 13 C NMR (101 MHz, DMSO-d 6 )δ(ppm)177.1,149.0,139.3,130.5,123.2,119.1,116.7,111.4,109.6,56.6; C 10 H 10 NO 2 + HRMS (ESI) + m / z calculated: 176.0706, found: 176.0707.

[0330] 4-Bromo-8-methoxyquinoline 34:

[0331]

[0332] Following an adapted procedure by Pulley et al. for the synthesis of bromoquinolines from quinolinols 3To a solution of 8-methoxyquinolin-4-ol 33 (2.50 g, 14.3 mmol) in DMF (20 mL) was added phosphorus tribromide (1.54 mL, 16.4 mmol), and the mixture was stirred at 45 °C for 45 min. After cooling to room temperature, H 2 O (25 mL) and add saturated Na 2 CO 3 The aqueous solution was added to adjust the pH of the solution to 10. The resulting milky white crystals were filtered and washed with H 2 O (10 mL) to obtain 4-bromo-5-fluoroquinoline 34 (2.58 g, 10.8 mmol, 76%) as a creamy white solid. mp = 99-101 °C; IR (near infrared) v max 1252,1085cm -1 ; 1 HNMR (400MHz, CDCl 3 )δ(ppm)8.69(d,J=4.6Hz,1H,NCH),7.78(d,J=8.1Hz,1H,BrCCCH),7.75(d,J=4.8Hz, 1H,BrCCH),7.58(t,J=8.2Hz,1H,ArH),7.14(d,J=8.0Hz,1H,ArH),4.12(s,3H,OMe); 13 C NMR (101 MHz, CDCl 3 )δ(ppm)155.5,148.5,134.1,129.0,128.0,125.8,118.5,108.5,56.3; C 10 H 9 BrNO + HRMS (ESI) + m / z calculated: 237.9862, found: 237.9865.

[0333] N-(But-3-yn-1-yl)-8-methoxyquinolin-4-amine 35:

[0334]

[0335] According to the modified procedure of Musonda et al. for the synthesis of alkylated quinolines 4; 3-Butyl-1-amine 23 (1.20 mL, 14.7 mmol) was added to 4-bromo-8-methoxyquinoline 34 (0.70 g, 2.9 mmol) to form an orange / yellow slurry. The slurry was heated to 80 ° C for 1 hour without stirring. The temperature was raised to 100 ° C for 18 hours by stirring. The viscous brown reaction mixture was cooled to room temperature and purified by alumina (basic) gel chromatography (10% MeOH in EtOAc) to give the title compound 35 (0.80 g, 2.9 mmol, 99%) as a light orange solid. mp = 154-155 ° C; IR (near infrared) v max 3279,2938,2240,753cm -1 ; 1 HNMR (400 MHz, DMSO-d 6 )δ(ppm)8.36(d,J=5.4Hz,1H,NCH),7.73(d,J=7.8Hz,1H,MeOCCHCH),7.35(t,J=8.1Hz,1H,MeOCCHC H),7.10(d,J=7.3Hz,1H,OMeCCH),6.55(d,J=5.4Hz,1H,NCHCH),3.91(s,3H,OMe),3.39-3.53(m,2H,CH 2 CH 2 CCH), 2.89(t, J = 2.6 Hz, 1H, CH 2 CH 2 CCH),2.56(td,J=7.1,2.7Hz,2H,CH 2 CH 2 CCH); 13 CNMR (101MHz, DMSO-d 6 )δ(ppm)155.2,149.9,148.8,139.6,124.3,119.6,113.3,108.5,99.1,82.5,72.6,55.8,41.5,18.0; C 14 H 15 N 2 O + HRMS (ESI) + m / z calculated: 227.1179, found: 227.1183.

[0336] 6-(4-((8-methoxyquinolin-4-yl)amino)but-1-yn-1-yl)pyridinealdehyde oxime 36:

[0337]

[0338] N-(But-3-yn-1-yl)-8-methoxyquinolin-4-amine 35 (1.00 g, 4.4 mmol) was dissolved in anhydrous THF / Et 3 Pd(PPh 3 ) 4 (511 mg, 0.4 mmol) and CuI (168 mg, 0.9 mmol). A degassed solution of 6-bromopyridine aldehyde oxime 2 (977 mg, 4.8 mmol) in anhydrous THF (20 mL) was added dropwise to the obtained orange reaction mixture. The brown solution was stirred at room temperature for 16 hours. The reaction was concentrated in vacuo. Chromatography on alumina (basic) gel (10% methanol in EtOAc) gave the title compound 36 (400 mg, 1.1 mmol, 26%) as a yellow solid: mp = 171-172 ° C; IR (near infrared) v max 3084,2900,2236,1617,1277,745cm -1 ; 1 H NMR (400 MHz, DMSO-d 6 )δ11.79(s,1H,CHNOH),8.35(d,J=6.1Hz,1H,NCHCH),7.98(m,2H,NCC(OMe)CHCHCH,CHNOH),7.78(t,J=7.8Hz,1H,NCCHCHCH),7.72(d,J=7.8Hz,1H,NCCHCHCH),7.49( d,J=8.2Hz,1H,NCC(OMe)CHCHCH),7.39(d,J=7.8Hz,1H,NCCHCHCH),7.29(d,J=8.2 Hz,1H,NCC(OMe)CHCHCH),6.84(d,J=6.1Hz,1H,NCHCH),3.99(s,3H,OMe),3.71(br t,J=7.0,2H,NHCH 2 CH 2 ),2.90(t,J=7.0Hz,2H,NHCH 2 CH 2 ); 13 C NMR (100 MHz, DMSO-d 6 )δ152.6,152.5,152.1,148.3,145.1,142.3,137.3,134.2,126.8,125.4,119.0,118.5,113.7,110.3,99.0,88.3,81.3,56.1,48.5,18.7; C 20 H 19 N 4 O2 + HRMS (ESI) + m / z calculated: 347.1503, found: 347.1506.

[0339] 6-(4-((8-methoxyquinolin-4-yl)amino)butyl)pyridinealdehyde oxime 37:

[0340]

[0341] To a degassed suspension of 6-(4-((8-methoxyquinolin-4-yl)amino)but-1-yn-1-yl)pyridine aldehyde oxime 36 (110 mg, 0.3 mmol) in anhydrous methanol (10 mL) was added Pearlman's catalyst (9 mg, 0.1 mmol). The reaction vessel was evacuated and flushed with hydrogen five times. The black reaction mixture was stirred at room temperature for 18 hours. The catalyst was removed by filtration through celite and the solvent was removed in vacuo to provide the title compound 37 (40 mg, 0.1 mmol, 36%) as a cream solid: mp = 107-108 ° C; IR (near infrared) v max 2927,1617,1581,980cm –1 ; 1 H NMR (400 MHz, MeOD-d 6 )δ8.29(d,J=5.6Hz,1H,NCHCH),8.08(s,1H,CHNOH),7.71-7.57(m,3H,ArH),7.34(t,J=8.2Hz,1H,NCC(OMe)CHCHCH),7.24-7.19( m,1H,NCC(OMe)CHCHCH),7.08(d,J=7.8Hz,1H,NCCHCHCH),6.48(d,J=5.6Hz,NCHCH),3.98(s,3H,OMe),3.36(t,J=7.1Hz,2H,NHCH 2 CH 2 CH 2 CH 2 ),2.83(t,J=7.1Hz,2H,NHCH 2 CH 2 CH 2 CH 2 ),1.94-1.66(m,4H,NHCH 2 CH 2 CH 2 CH 2 ); 13 C NMR (100 MHz, MeOD-d 6)δ163.2,156.2,153.3,152.7,150.0,149.6,140.4,138.8,125.8,124.5,121.1,119.3,113.8,109.3,99.9,56.4,43.8,38.4,28.9,28.7; C 20 H 23 N 4 O 2 + HRMS (ESI) + m / z calculated: 351.1816, found: 351.1817.

[0342] References:

[0343] 2. Kiplin Guy, R. et al., Bioorg. Med. Chem. Lett., 2005, 15, pp. 1015-1018.

[0344] 3. Lauer et al., J. Am. Chem. Soc., 1946, 68, p. 1268.

[0345] 4. Pulley et al., J. Org. Chem. 2007, 72, pp. 2232-2235.

[0346] 5. Musonda, CC; Little, S.; Yardley, V.; Chibale, K., Bioorg. Med. Chem. Lett. 2007, 17, pp. 4733-4736

[0347] Synthesis of 6-(3-(4-benzylpiperazin-1-yl)propyl)pyridinealdehyde oxime 43:

[0348]

[0349] N-Benzylpiperazine 39:

[0350]

[0351] Following the procedure of Bozell and Biannic for the synthesis of benzylpiperazine 1 At 0 °C, piperazine 38 (12.9 g, 149.0 mmol) was added to anhydrous CH 2 Cl 2 Benzyl bromide (3.56 mL, 29.8 mmol) was added dropwise to the solution in 100 mL of 1% ethanol. The reaction was stirred at 0°C for 1 hour. Saturated NaHCO 3 The pale yellow solution was washed with an aqueous solution (20 mm) and dried (Na2 SO 4 ), filtered and concentrated in vacuo. Anhydrous ethanol was added and the white precipitate was filtered from the solution. The solution was concentrated in vacuo to provide the title compound 39 (24.8 g, 141.0 mmol, 94%) as a viscous yellow oil. IR (near infrared) v max 3289,2990,2960,2120,1120cm -1 ; 1 HNMR (400MHz, CDCl 3 )δ(ppm)7.36-7.28(m,5H,ArH),3.50(s,2H,CH 2 Ph), 2.90(t, J=4.9Hz,4H,CH 2 N(Bn)CH 2 ),2.55-2.30(m,5H,CH 2 NHCH 2 ); 13 C NMR (101 MHz, CDCl 3 )δ(ppm)138.1,129.2,128.2,127.0,63.7,54.5,46.1.

[0352] 1-Benzyl-4-propynylpiperazine 41:

[0353]

[0354] Following the procedure of Corey, M. for propargyl substitution of piperazine 2 N-Benzylpiperazine 39 (1.75 g, 9.93 mmol), propargyl bromide 40 (80% in toluene) (1.28 mL, 14.9 mmol) and DIPEA (3.28 mL, 19.9 mmol) were mixed in CH 2 Cl 2 The solution in 50 mL was stirred at room temperature for 18 h. 2 O (30 mL) and the aqueous phase was separated and extracted (3 and separated and extracted). The combined organic layers were washed (brine, 30 mL), dried (Na 2 SO 4 ), filtered and concentrated in vacuo. Silica gel chromatography (50% ethyl acetate in hexanes) afforded the title compound 41 (2.04 g, 9.5 mmol, 96%) as an orange oil. IR (near infrared) v max 3290,3026,2933,2807,2117,697cm -1 ; 1 HNMR (400MHz, CDCl 3)δ(ppm)7.37-7.28(m,5H,ArH),3.56(s,2H,PhCH 2 ),3.30(d,J=2.5Hz,2H,NCH 2 CCH), 2.73-2.44 (m, 8H, PizCH 2 ),2.25(t,J=2.5Hz,1H,NCH 2 CCH); 13 CNMR (101MHz, CDCl 3 )δ(ppm)129.5,129.3,128.3,127.2,78.9,73.20,62.8,52.8,51.7,46.8; C x H x N x + HRMS (ESI) + m / z calculated: 215.1543, found: 215.1542.

[0355] 6-(3-(4-Benzylpiperazin-1-yl)prop-1-yn-1-yl)pyridinealdehyde oxime 42:

[0356]

[0357] 1-Benzyl-4-propynylpiperazine 41 (1.30 g, 6.1 mmol) was dissolved in anhydrous THF / Et 3 Pd(PPh 3 ) 4 (0.70 g, 0.6 mmol) and CuI (0.23 g, 1.2 mmol). A degassed solution of 6-bromopyridine aldehyde oxime 2 (1.34 g, 6.7 mmol) in anhydrous THF (20 mL) was added dropwise to the obtained orange reaction mixture. The brown solution was stirred at room temperature for 18 hours. The reactants were concentrated in vacuo. Silica gel chromatography (EtOAc) showed the title compound 42 (750 mg, 2.2 mmol, 37%) in the form of a cream solid: mp = 143-145 ° C; IR (near infrared) v max 3150,3048,2944,2808,2364,734cm -1 ; 1 HNMR (400MHz, CDCl 3)δ(ppm)12.17(s,1H,NOH),7.99(s,1H,CHNOH),7.71(dd,J=8.0,1.0Hz,1H,NCCHCHCH),7.53(t,J=8.0Hz,1H,NCCHCHCH),7.43-7.20(m,6H,ArH),3.70(s,2H,NCH 2 CC), 3.63(s,2H,PhCH 2 ),3.08-2.36(m,8H,PizCH 2 ); 13 C NMR (101 MHz, CDCl 3 )δ(ppm)152.7,149.0,142.2,136.4,136.3,129.9,128.4,127.6,127.1,119.1,85.3,84.3,63.2,52.9,50.5,47.2; C 20 H 23 N 4 O + HRMS (ESI) + m / z calculated: 335.1866, found: 335.1863.

[0358] 6-(3-(4-Benzylpiperazin-1-yl)propyl)pyridinealdehyde oxime 43:

[0359]

[0360] To a degassed suspension of 6-(3-(4-benzylpiperazin-1-yl)propyl-1-yn-1-yl)pyridinealdehyde oxime 42 (200 mg, 0.6 mmol) in anhydrous methanol (10 mL) was added Pearlman catalyst (44 mg, 0.3 mmol). The reaction vessel was evacuated and flushed with hydrogen five times. The black reaction mixture was stirred at room temperature for 2 hours. The catalyst was removed by filtration through diatomaceous earth and the solvent was removed in vacuo. Silica gel chromatography (CH 2 Cl 2 to 10% methanol in CH 2 Cl 2 The title compound 43 (53%) was obtained as a light yellow oil. IR (near infrared) max 3162,3057,2939,2816,808cm -1 ; 1 HNMR (400MHz, CDCl 3)δ(ppm)8.19(s,1H,CHNOH),7.58-7.51(m,2H,ArH),7.36-7.27(m,5H,ArH),7.10(dd,J=6.5,2.2Hz,1H,NCCHCHCH),3.55(s,2H,PhCH 2 ),2.82(t,J=7.8Hz,1H,NCH 2 CH 2 CH 2 ),2.72-2.35(m,10H,PizCH 2 ,NCH 2 CH 2 CH 2 ),2.02(quin,J=7.8Hz,NCH 2 CH 2 CH 2 ); 13 C NMR (101 MHz, CDCl 3 )δ(ppm)161.3,151.8,150.3,137.6,136.6,129.4,128.3,127.2,122.8,118.0,62.9,57.7,25.8,25.5,35.8,26.3; C 20 H 27 N 4 O + HRMS (ESI) + m / z calculated: 339.2179, found: 339.2176.

[0361] References

[0362] 1. Bozell. JJ et al., Org. Lett. 2013, 15, 2730-2733.

[0363] 2. Corey, M. et al., WO2017 / 184996A1 (2017).

[0364] Synthesis of 6-(3-(4-benzylpiperazin-1-yl)propyl)pyridinealdehyde oxime 48:

[0365]

[0366] 3-Butyl p-toluenesulfonate 45:

[0367]

[0368] According to Winssinger et al. 1Procedure for forming p-toluenesulfonyl protected alcohol: At 0°C, a solution of TsCl (8.98 g, 47.1 mmol) was added dropwise to CH 2 Cl 2 3-n-Butane-1-ol 44 (3.00 g, 42.8 mmol), DMAP (522 mg, 4.3 mmol) and Et 3 N (55.6 mL, 7.70 mL mmol) solution. The yellow reaction solution was heated to room temperature and stirred for 2 h. H 2 O (30 mL), and stirred the reaction at room temperature for 20 minutes. The organic layer was separated and the aqueous layer (CH 2 Cl 2 The combined extracts were dried (Na 2 SO 4 ), filtered and concentrated in vacuo. This provided the title compound 45 (9.60 g, 42.8 mmol, 100%) as a red / brown oil. IR (near infrared) v max 3433,3045,2958,2248,1577,788cm -1 ; 1 HNMR (400MHz, CDCl 3 )δ(ppm)7.81(d,J=8.3Hz,2H,ArH),7.36(d,J=8.3Hz,2H,ArH),4.11(t,J=7.1Hz,2H,TsOCH 2 CH 2 CCH),2.56(td,J=7.1,2.7Hz,2H,TsOCH 2 TxOB 2 CH 2 CCH), 2.46(s,3H,PhCH 3 ),1.98(t,J=2.7Hz,1H,TsOCH 2 CH 2 CCH); 13 CNMR (101MHz, CDCl 3 )δ(ppm)145.0,132.8,129.9,128.0,78.3,70.7,67.4,21.6,19.4.

[0369] 1-Benzyl-4-(butyl-3-yn-1-yl)piperazine 46:

[0370]

[0371] According to Guarna et al. 2Procedure for the formation of alkylated piperazines; Na 2 CO 3 (1.20 g, 11.3 mmol) and N-benzylpiperazine 39 (2.00 g, 11.3 mmol) were added to a solution of 3-butyl p-toluenesulfonate 45 (2.30 mL, 10.3 mmol) in DMF (60 mL). The orange solution was stirred at 80 °C overnight. 2 The reaction mixture was quenched with 1% O (10 mL) and ether (10 mL) was added. The organic layer was separated and washed with H 2 The organic layer was separated by 0.5% O (520), washed with brine (10 mL) and dried (Na 2 SO 4 ), filtered and concentrated in vacuo. Silica gel chromatography (100% CH 2 Cl 2 to 10% MeOH in CH 2 Cl 2 The title compound 46 (1.70 g, 7.4 mmol, 72%) was obtained as an orange oil. IR (near infrared) max 3291,3026,2939,2807,2119,1676,697cm -1 ; 1 HNMR (400MHz, CDCl 3 )δ(ppm)7.35-7.28(m,5H,ArH),3.52(s,2H,PhCH 2 ),2.61(t,J=7.6Hz,2H,NCH 2 CH 2 CCH), 2.58-2.42 (m, 8H, PizCH 2 ),2.41-2.34(m,2H,NCH 2 CH 2 CCH), 1.97(t, J = 2.7 Hz, 1H, NCH 2 CH 2 CCH); 13 CNMR (101MHz, CDCl 3 )δ(ppm)138.1,129.2,128.2,127.0,82.8,69.0,63.0,57.0,52.9,52.8,16.8; C x H x N x + HRMS (ESI) + m / z calcd. 229.1699, found 229.1695.

[0372] 6-(4-(4-Benzylpiperazin-1-yl)but-1-yn-1-yl)pyridinealdehyde oxime 47:

[0373]

[0374] 1-Benzyl-4-(butyl-3-yn-1-yl)piperazine 46 (1.55 g, 6.8 mmol) was dissolved in anhydrous THF / Et 3 Pd(PPh 3 ) 4 (1.16 g, 0.7 mmol) and CuI (0.19 g, 1.4 mmol). A degassed solution of 6-bromopyridine oxime 2 (1.50 g, 7.47 mmol) in anhydrous THF (20 mL) was added dropwise to the obtained orange reaction mixture. The brown solution was stirred at room temperature for 18 hours. The reactants were concentrated in vacuo. Silica gel chromatography (50% acetoacetic acid in hexane to acetoacetic acid) gave the title compound 47 (150 mg, 0.4 mmol, 6%) as a cream solid. mp = 134-136 ° C; IR (near infrared) v max 3161,3060,2954,2808,2231,740cm -1 ; 1 HNMR (400MHz, CDCl 3 )δ(ppm)11.48(s,1H,NOH),8.20(s,1H,CHNOH),7.76(dd,J=8.0,1.0Hz,1H,NCCHCHCH),7.59(t,J=8.0Hz,1H,NCCHCHCH),7.35-7.27(m,6H,ArH),3.56(s,2H,PhCH 2 ),2.82-2.41(m,12H,PizCH 2 ,NCH 2 CH 2 CC); 13 C NMR (101 MHz, CDCl 3 )δ(ppm)152.9,149.7,143.1,137.4,136.5,129.5,128.3,127.3,126.7,119.1,89.1,80.8,63.0,56.6,52.6,52.5,17.4; C 21 H 25 N 4 O + HRMS (ESI) + m / z calculated was 349.2023, found was 349.2018.

[0375] References

[0376] 1. Winssinger et al., Chem. Comms., 2010, 46, 5476-5478.

[0377] 2. Guarna et al., J. Med. Chem, 2010, 53, 7119-7128.

[0378] 6-(4-(4-Benzylpiperazin-1-yl)butyl)pyridinealdehyde oxime 48:

[0379]

[0380] To a degassed suspension of 6-(4-(4-benzylpiperazine-1-yl)but-1-yn-1-yl)pyridinealdehyde oxime 47 (60 mg, 0.2 mmol) in anhydrous methanol (5 mL) was added palladium (10% on carbon, 4 mg, 0.04 mmol). The reaction vessel was evacuated and flushed with hydrogen five times. The black reaction mixture was stirred at room temperature for 1.5 hours. The catalyst was removed by filtration through diatomaceous earth, and the solvent was removed in vacuo to provide the title compound 48 (53 mg, 0.2 mmol, 87%) as a yellow oil. IR (near infrared) v max 3181,3060,2938,2818,791cm -1 , 1 HNMR (400MHz, CDCl 3 )δ(ppm)8.18(s,1H,CHNOH),7.62-7.50(m,2H,ArH),7.34-7.29(m,5H,ArH),7.11(dd,J=7.3,1.4Hz,1H,NCCHCHCH),5.31(s,2H,PhCH 2 ),2.82(t,J=7.3Hz,2H,NCH 2 CH 2 CH 2 CH 2 ),2.59-2.31(m,10H,PizCH 2 ,NCH 2 CH 2 CH 2 CH 2 ),1.76(quin,J=7.3Hz,NCH 2 CH 2 CH 2 CH 2 ),1.58(br s,2H,NCH 2 CH 2 CH2 CH 2 ); 13 C NMR (101 MHz, CDCl 3 )δ(ppm)161.9,151.5,150.6,136.7,136.6,129.3,128.2,127.1,122.9,118.1,63.0,58.4,53.0,52.7,37.9,27.6,26.1; C 20 H 27 N 4 O + HRMS (ESI) + m / z calculated: 353.2336, found: 353.2332.

[0381] Synthesis of 6-(4-(3,7-dimethyl-2,6-dioxy-2,3,6,7-tetrahydro-1H-purin-1-yl)but-1-yn-1-yl)pyridine aldehyde oxime 51:

[0382]

[0383] 1-(But-3-yn-1-yl)-3,7-dimethyldihydro-1H-purine-2,6-dione 50:

[0384]

[0385] according to et al. 1 Improved procedure for the synthesis of substituted amines via the Mitsunobu reaction; ADDP (700 mg, 2.8 mmol) was added to a solution of 3-butyl-1-ol 44 (0.10 ml, 1.4 mmol), theobromine 49 (500 mg, 2.8 mmol) and triphenylphosphine (728 mg, 2.8 mmol) in THF (15 ml) at room temperature. The yellow reaction was heated to 60°C for 24 hours. The cream-colored reaction solution (H 2 O, 50 mL), extracted with aqueous solution (EtOAc, 3 tOAc solution). The combined organic layers were dried (MgSO 4 ), filtered and concentrated in vacuo. The white residue was purified by silica gel chromatography (EtOAc) to give 1-(but-3-yn-1-yl)-3,7-dimethyl-1H-purine-2,6-dione 50 (120 mg, 0.5 mmol, 37%) as a white solid: mp = 192-193 °C; IR (near infrared) v max 3228,3107,2951,1697,1651cm -1 ; 1HNMR (400 MHz, DMSO-d 6 )δ(ppm)8.00(s,1H,NCHN),3.99(t,J=7.6Hz,2H,NCH 2 CH 2 CCH), 3.87(s,3H,NCHN(CH 3 )),3.40(s,3H,NCON(CH 3 )),2.84(t,J=2.7Hz,1H,NCH 2 CH 2 CCH),2.45(td,J=7.6,2.7Hz,1H,NCH 2 CH 2 CCH); 13 C NMR (101 MHz, DMSO-d 6 )δ(ppm)154.6,151.1,148.7,143.5,107.0,81.5,73.0,40.6,33.6,29.8,17.3; C 11 H 13 N 4 O 2 + HRMS (ESI) + m / z calculated was 233.1033, found was 233.1035, and C 11 H 12 N 4 NaO 2 + The m / z calculated for is 255.0852, found is 255.0857.

[0386] 6-(4-(3,7-dimethyl-2,6-dioxy-2,3,6,7-tetrahydro-1H-purin-1-yl)but-1-yn-1-yl)pyridine aldehyde oxime 51:

[0387]

[0388] 1-(But-3-yn-1-yl)-3,7-dimethyldihydro-1H-purine-2,6-dione 50 (200 mg, 0.9 mmol) was dissolved in anhydrous THF / Et 3 Pd(PPh 3 ) 4(99 mg, 0.1 mmol) and CuI (33 mg, 0.2 mmol). A degassed solution of 6-bromopyridine aldehyde oxime 2 (190 mg, 1.0 mmol) in anhydrous THF (10 mL) was added dropwise to the obtained orange reaction mixture. The brown solution was stirred at room temperature for 16 hours. The reactants were concentrated in vacuo to give an orange solid as a crude product. Silica gel chromatography (EtOAc to 10% MeOH in EtOAc) gave the colorless title compound 51 (111 mg, 0.3 mmol, 36%): mp = 210-211 ° C; IR (near infrared) ν max 3178,3087,2872,2230,1700,1647,759cm -1 , 1 H NMR (400 MHz, DMSO-d 6 )δ11.75(s,1H,CHNOH),8.03(s,1H,CHNOH),8.00(s,1H,NCHN),7.79(t,J=8.1Hz,1H,NCCHCHCH),7.7 3(dd,J=8.1,1.0Hz,1H,NCCHCHCH),7.39(dd,J=8.1,1.0Hz,1H,NCCHCHCH),4.12(t,J=7.5Hz,2H,NHCH 2 CH 2 ),3.88(s,3H,NCHN(CH 3 ),3.42(s,3H,NCON(CH3),2.75(t,J=7.5Hz,2H,NHCH 2 CH 2 ); 13 C NMR (100 MHz, DMSO-d 6 )δ154.2,152.4,150.7,148.4,148.3,143.1,142.3,137.3,126.8,119.0,118.9,106.5,87.4,81.3,33.2,29.4,17.7; C 17 H 17 N 6 O 3 + HRMS (ESI) + m / z calculated: 353.1357, found: 353.1358.

[0389] References

[0390] 1. S. et al., Tet. Letts., 1993, No. 34, pp. 1639-1642.

[0391] II-Synthesis of bifunctional ethylcarbazole analogs

[0392]

[0393] (3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-N-(but-3-yn-1-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolane-4-carboxamide 54:

[0394]

[0395] The synthesis of (3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolane-4-carboxylic acid 53 was performed by using Debnath, J. et al. 1 This is achieved through improved procedures.

[0396] To a stirred solution of acid 53 (500 mg, 1.56 mmol, 1 eq.) in dry pyridine (15 mL) were added 1-amino-3-butene 22 (140 mL, 1.71 mmol, 1.1 eq.) and EDCI (598 mg, 3.12 mmol, 2 eq.) successively and the reaction mixture was stirred at room temperature under nitrogen atmosphere overnight. Upon completion, the reaction mixture was directly concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc to EtOAc / MeOH 95:5) to provide the desired amide 54 (500 mg, 80%) as a light yellow solid. f (pure EtOAc) 0.18; IR (near infrared) ν max 3289,3142,1672,1601,1526,1206,1090,1058,868,789,645,514cm -1 ; 1 H NMR (400 MHz, CDCl 3 )δ(ppm)8.32(s,1H),7.89(s,1H),7.28(m,1H),6.33(s,2H),6.13(d,J=2.5Hz,1H),5.47(dd,J=2.1,6.2Hz,1H),5.39(dd,J=2 .5,6.2Hz,1H),4.74(d,J=2.1Hz,1H),3.21(m,2H),2.21(m,1H),2.10(m,1H),1.82(t,J=2.6Hz,1H),1.63(s,3H),1.40(s,3H); 13C NMR (100 MHz, CDCl 3 )δ(ppm)168.98,155.86,153.11,148.99,139.82,120.21,114.37,91.70,86.33,83.59,82.88,80.81,69.83,37.49,26.95,25.07,18.85; C 17 H 21 N 6 O 4 + HRMS (ESI + ) m / z calculated value is 373.1575, found value is 373.1619.

[0397] (3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-N-(4-(6-formylpyridin-2-yl)but-3-yn-1-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolane-4-carboxamide 55:

[0398]

[0399] Palladium Pd[PPh 3 ] 4 (233 mg, 0.202 mmol, 0.15 eq.) and CuI (77 mg, 0.403 mmol, 0.3 eq.) were added to THF / Et 3 Methyl 6-bromopyridine aldehyde 1 (275 mg, 1.478 mmol, 1.1 eq) in degassed solution of N (10 mL / 8 mL). After the reaction mixture was degassed at room temperature for 5 min, a degassed solution of alkyne 54 (500 mg, 1.344 mmol, 1 eq) in THF (10 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (neat EtOAc to EtOAc / MeOH 9:1) to provide the desired coupled pyridine aldehyde 55 (510 mg, 80%) in the form of a thick syrup. IR (near infrared) v max 3318,1638,1582,1452,1209,1078,868,797,646,509cm -1 ; 1 H NMR (400 MHz, CDCl 3)δ(ppm)9.90(s,1H),8.24(s,1H),7.85-7.65(m,3H),7.38(m,1H),6.40(s,1H),6.02(s, 1H),5.33(s,2H),4.70(s,1H),3.35(m,2H),2.60-2.32(m,2H),1.57(s,3H),1.31(s,3H); 13 C NMR (100 MHz, CDCl 3 )δ(ppm)192.88,169.13,155.67,153.12,152.63,148.97,143.63,139.87,137.20,130.85 ,120.19,114.62,91.94,88.87,85.74,83.55,82.54,80.66,37.41,27.09,25.11,20.08; C 23 H 24 N 7 O 5 + HRMS (ESI + )m / z calculated was 478.1806, found was 478.1833.

[0400] (3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-N-(4-(6-(hydroxyimino)methyl)pyridin-2-yl)but-3-yn-1-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolane-4-carboxamide 56:

[0401]

[0402] The following solution was stirred at reflux for 16 h: pyridine aldehyde 55 (80 mg, 0.168 mmol, 1 eq), hydroxylamine hydrochloride (23 mg, 0.336 mmol, 2 eq) and CH 3 CO 2 A solution of Na (41 mg, 0.503 mmol, 3 eq.) in dry ethanol (5 mL) was concentrated under reduced pressure and washed with CH 2 Cl 2 The crude product was washed with 50% pyridine aldehyde oxime (5 x 10 mL) to remove all impurities. The compound present in the round-bottom flask was pyridine aldehyde oxime 56, which was dried under high vacuum (82 mg, quantitative yield) and purified by 1 H NMR confirmed. f (EtOAc); IR (near infrared) ν max3186,2925,1643,1579,1207,1089,980,867,797,726,649,509cm -1 ; 1 H NMR (400 MHz, CDCl 3 )δ(ppm)8.20(s,1H),8.11(s,1H),7.92(m,2H),7.46(m,2H),7.02(m,3H),6.05(d,J=2.7Hz,1H),5.35(dd,J=2.0,6.2H z,1H),5.29(dd,J=2.7,6.2Hz,1H),4.74(d,J=2.0Hz,1H),3.41(m,2H),2.57-2.33(m,2H),1.59(s,3H),1.433(s,3H); 13 C NMR (100 MHz, CDCl 3 )δ(ppm)169.14,155.54,152.89,152.05,149.16,148.60,142.61,139.82,136.66,126.72,11 9.58,119.47,114.74,91.86,88.15,85.78,83.45,82.68,81.13,37.45,27.11,25.14,20.21; C 23 H 25 N 8 O 5 + HRMS (ESI + )m / z calculated: 493.1901, found: 493.1942.

[0403] (2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxy-N-(4-(6-(hydroxyimino)methyl)pyridin-2-yl)but-3-yn-1-yl)tetrahydrofuran-2-carboxamide 57:

[0404]

[0405] 1.2 N HCl (185 μL, 0.610 mmol, 10 eq) was added to a stirred solution of oxime 56 (30 mg, 0.061 mmol, 1 eq) in dry methanol (5 mL), and the reaction mixture was stirred at 55 °C for 5 h. Upon completion, the reaction mixture was directly concentrated under reduced pressure and purified by reverse phase column chromatography (MeOH / H 2 The residue was purified by HPLC (1:4) to afford salt 57 as a white solid in quantitative yield. IR (near infrared)max 3192,2927,1644,1580,1448,1305,1254,1045,989,808,726,642,533cm -1 ; 1 HNMR (400MHz, CD 3 OD)δ(ppm)8.26(s,1H),8.25(s,1H),7.90(s,1H),7.68(br d,J=7.8Hz,1H),7.0(t,J=7.8Hz,1H),7.13(d,J=7.5Hz,1H),6.30(d,J=7.9Hz,1H),4.85(s,1H),4.54(s,1H),4.39(br d,J=4.3Hz,1H),3.63(m,2H),2.74(m,2H); 13 C NMR (100MHz, CD 3 OD)δ(ppm)172.76,157.47,154.03,153.96,150.15,149.49,143.97,142.67,138.49 ,128.24,121.22,120.73,90.84,89.91,86.78,82.11,75.30,73.56,38.93,21.02; C 23 H 25 N 8 O 5 + HRMS (ESI + )m / z calculated: 493.1901, found: 493.1942.

[0406] References

[0407] 1. Debnath, J. et al., Bioorg. Med. Chem., 2010, 18, 8257-8263.

[0408] III-Synthesis of bifunctional pseudo-ethylcarbazole analogs

[0409]

[0410] N-(9-((3aR,4R,6R,6aR)-6-(((3-(6-formylpyridin-2-yl)prop-2-yn-1-yl)oxy)methyl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolan-4-yl)-9H-purin-6-yl)benzamide 59:

[0411]

[0412] The synthesis of N-(9-((3aR,4R,6R,6aR)-2,2-dimethyl-6-((prop-2-yn-1-yloxy)methyl)-tetrahydrofuran[3,4-d][1,3]dioxolan-4-yl)-9H-purin-6-yl)benzamide 58 was performed by using Silvia, F. et al. 1 This is accomplished using known procedures.

[0413] To THF / Et 3 To a degassed solution of 6-bromopyridine aldehyde 1 (91 mg, 0.490 mmol, 1.1 eq) in N (3 mL / 2 mL) was added Pd[PPh 3 ] 4 (77 mg, 0.067 mmol, 0.15 eq) and CuI (25 mg, 0.134 mmol, 0.3 eq). After the reaction mixture was degassed at room temperature for 5 min, a degassed solution of alkyne 58 (200 mg, 0.445 mmol, 1 eq) in THF (3 mL) was added dropwise and the reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc / petroleum ether 4:1) to provide the desired coupled pyridine aldehyde 59 (200 mg, 81%) in the form of a thick syrup. IR (near infrared) v max 2935,1704,1609,1580,1452,1248,1210,1074,864,709,645,541cm -1 ; 1 H NMR (400 MHz, CDCl 3 )δ(ppm)9.97(s,1H),8.76(s,1H),8.32(s,1H),7.94(d,J=7.6Hz,2H),7. 85-7.77(m,2H),7.63-7.51(m,2H),7.45(t,J=7.6Hz,2H),6.25(d,J=2.1 Hz,2H),5.32(dd,J=2.1,6.2Hz,1H),5.03(dd,J=2.1,6.2Hz,1H),4.56(q ,J=2.9Hz,1H),4.37(s,2H),3.89-3.77(m,2H),1.61(s,3H),1.37(s,3H); 13 C NMR (100 MHz, CDCl 3)δ(ppm)192.58,164.85,152.75,152.59,151.49,149.28,142.85,141.91,137.53,13335,132.81,131.23, 128.78,127.81,123.24,120.91,114.32,91.61,85.94,85.47,85.20,84.55,70.32,59.09,27.12,25.28; C 29 H 27 N 6 O 6 + HRMS (ESI + )m / z calculated: 555.2005, found: 555.1987.

[0414] N-(9-((3aR,4R,6R,6aR)-6-(((3-(6-(hydroxyimino)methyl)pyridin-2-yl)prop-2-yn-1-yl)oxy)methyl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolan-4-yl)-9H-purin-6-yl)benzamide 60:

[0415] and

[0416] 6-(3-(((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolan-4-yl)methoxy)prop-1-yn-1-yl)pyridinealdehyde oxime 61:

[0417]

[0418] Pyridine aldehyde 59 (200 mg, 0.361 mmol, 1 eq.), hydroxylamine hydrochloride (50 mg, 0.722 mmol, 2 eq.) and CH 3 CO 2 A solution of Na (89 mg, 1.083 mmol, 3 eq.) in dry ethanol (10 mL) was stirred at reflux for 16 h. After completion, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography and eluted first with DCM to MeOH / DCM (2:98) to give the product 60 (80 mg, 39%) as a white solid. IR (near infrared) v max 3196,2924,1698,1610,1581,1453,1246,1210,1075,907,727,644,551cm -1 ; 1 H NMR (400 MHz, CDCl 3)δ(ppm)8.83(s,1H),8.38(s,1H),8.11(s,1H),7.99-7.89(m,2H),7.54-7.27(m,6H),6 .27(d,J=2.3Hz,2H),5.31(dd,J=2.3,6.0Hz,1H),5.03(dd,J=2.3,6.1Hz,1H),4.48(br q,J=3.4Hz,1H),4.37,4.30(2d,J=16.1Hz,2H),3.88(dd,J=3.4,10.3Hz,1H),3.76(dd,J=4.0,10.3Hz,1H),1.62(s,3H),1.38(s,3H); 13 C NMR (100 MHz, CDCl 3 )δ(ppm)165.11,152.73,152.22,151.35,149.67,149.37,141.87,136.74,133.45,132.69,128.63,127 .92,127.22,122.87,120.30,114.28,91.87,86.05,85.03,84.34,81.89,70.23,59.17,27.11,25.26; C 29 H 28 N 7 O 6 + HRMS (ESI + )m / z calculated was 570.2075, found was 570.2096.

[0419] Further elution (MeOH / DCM 5:95) afforded the product 61 (75 mg, 45%) as a white solid. IR (near infrared) v max 3176,2925,1639,1450,1374,1207,1077,978,865,796,717,648,510cm -1 ; 1 H NMR (400 MHz, CDCl 3 )δ(ppm)8.30(s,1H),8.21(s,1H),8.15(s,1H),7.64-7.52(m,2H),7.26(s,1H),7.01-6.87(m,2H),6.20(d,J= 1.8Hz,2H),5.35(m,1H),5.03(m,1H),4.57(m,1H),4.35(m,2H),3.88-3.76(m,2H),1.61(s,3H),1.38(s,3H);13 C NMR (100 MHz, CDCl 3 )δ(ppm)155.35,152.55,152.47,149.34,149.08,141.96,139.32,136.75,132.82,127.10 ,119.93,114.13,91.70,86.10,85.72,84.86,84.38,81.88,70.21,59.11,27.07,25.27; C 22 H 24 N 7 O 5 + HRMS (ESI + )m / z calculated: 466.1812, found: 466.1833.

[0420] References

[0421] 1. Silvia, F. et al., J. Med. Chem. 2015, No. 58, pp. 8269-8284

[0422] IV-Synthesis of bifunctional 3-methoxypyridine oxime analogs

[0423] Synthesis of 3-methoxy-6-(5-phenylpentyl)pyridine aldehyde oxime 65:

[0424]

[0425] 3-Methoxy-6-(5-phenylpent-1-yn-1-yl)pyridinecarboxaldehyde 63:

[0426]

[0427] Commercially available 6-bromo-3-methoxypyridine aldehyde 62 (75 mg, 0.347 mmol, 1.0 equiv) was dissolved in THF / Et 3 Pd[PPh 3 ] 4 (60 mg, 0.052 mmol, 0.15 eq) and CuI (20 mg, 0.104 mmol, 0.3 eq). After the reaction mixture was degassed at room temperature for 5 min, alkyne 3 (50 mg, 0.347 mmol, 1 eq) was added dropwise and the reaction mixture was stirred at room temperature for 16 h. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc / PE 1:4) to provide the desired coupled methoxypyridine aldehyde 63 (80 mg, 83%) as a colorless liquid. f(30% EtOAc + PE) 0.25; IR (near infrared) ν max 2941,2230,1709,1552,1466,1267,1007,747,699,542cm -1 ; 1 H NMR (400 MHz, CDCl 3 )δ(ppm)10.21(s,1H,H 18 ),7.52(d,J=8.8Hz,1H,H 4 ),7.33(d,J=8.8Hz,1H,H 5 ),7.28-7.13(m,5H,H 13 -H 17 ),3.93(s,3H,-OMe),2.74(t,J=7.5Hz,2H,H 11 ),2.39(t,J=7.1Hz,2H,H 9 ),1.91(quintet,J=7.1,7.5Hz,2H,H 10 ); 13 C NMR (100 MHz, CDCl 3 )δ(ppm)195.52(C18),156.25,141.28,140.73,136.02,132.0,128.44,128.32,125.91,1 20.41(Ar),90.27(C7),79.44(C8),56.03(-OMe),34.86(C11),29.76(C10),18.72(C9); C 18 H 18 N 1 O 2 + HRMS (ESI + )m / z calculated was 280.1332, found was 280.1348.

[0428] 3-Methoxy-6-(5-phenylpent-1-yn-1-yl)pyridine aldehyde oxime 64:

[0429]

[0430] Aldehyde 63 (45 mg, 0.161 mmol, 1 eq), hydroxylamine hydrochloride (22 mg, 0.322 mmol, 2 eq) and CH 3 CO 2A solution of Na (40 mg, 0.483 mmol, 3 eq.) in dry ethanol (3 mL) was stirred at reflux for 16 h. After completion (monitored by TLC), the solids were removed by filtration through a short pad of celite, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (EtOAc / PE 3:7) to provide oxime 64 (45 mg, 95%) as a white solid. f (50% EtOAc + PE) 0.35; IR (near infrared) ν max 3247,2938,2234,1564,1463,1263,975,828,745,698,649,487cm -1 ; *1 HNMR (400MHz, CDCl 3 )δ(ppm)10.42(br s,1H,OH),8.42,8.10(2s,1.2H,H 18 ,H 18' ),7.46-7.19(m,7.6H,Ar),3.94,3.91(2s,3.6H,-OMe),2.81,2.80(2t,J=7.5Hz,2.4H,H 11 ,H 11' ),2.47,2.44(2t,J=7.1Hz,2.4H,H 9 ,H 9' ),2.02-1.92(m,2.4H,H 10 ,H 10' );* 13 C NMR (100 MHz, CDCl 3 )δ(ppm)153.54,151.66,147.87,141.41,141.17,140.65,140.23,136.37,13 5.53,131.86,129.18,128.47,128.34,128.29,127.83,125.93,125.84,119. 29,118.69(Ar),90.98,89.24(C7),79.93,78.76(C8),55.93,55.70(-OMe),34.85,34.76(C11),29.86,29.73(C10),18.74,18.57(C9)(The ratio of cis isomer to trans isomer is 1:5 * );C 18 H 18 N 2 NaO 2 + HRMS (ESI +)m / z calculated: 317.1260, found: 317.1256.

[0431] 3-Methoxy-6-(5-phenylpentyl)pyridine aldehyde oxime 65:

[0432]

[0433] 10% Pd / C (4.5 mg, 0.042 mmol, 0.5 eq) was added to a degassed solution of methoxypyridine oxime 64 (25 mg, 0.085 mmol, 1 eq) in dry EtOAc (2 mL). 2 After rinsing three times, the 2 The reaction mixture was stirred at 40 °C (1 atm) for 3 h. After completion (monitored by TLC), the catalyst was removed by filtration through a short column of celite, the solvent was evaporated, and the residue was purified by column chromatography (EtOAc / PE 1:9) to provide oxime 65 (24 mg, 95%) as a colorless liquid; R f (50% EtOAc + PE) 0.40; IR (near infrared) ν max 3253,2927,2855,1570,1464,1269,1127,975,746,698cm -1 ; *1 H NMR (400 MHz, CDCl 3 )δ(ppm)8.40,8.02(2s,1.2H,H 18 ,H 18' ),7.24-6.96(m,9.4H,Ar),3.79,3.78(2s,3.6H,-OMe),2.70-2.62(m,2.5H,H 11 ,H 11' ),2.55-2.49(m,2.5H,H 7 ,H 7' ),1.68-1.52(m,5H,H 8 ,H 8' ,H 10 ,H 10' ),1.35-1.28(m,2.5H,H 9 ,H 9' );* 13 C NMR (100 MHz, CDCl 3)δ(ppm)154.25,152.57,150.87,150.67,146.82,142.71,142.47,140.12,139 .24,137.09,128.35,128.21,128.16,125.59,125.51,125.06,123.58,119.91, 119.18 (Ar), 55.82, 55.63 (-OMe), 37.23, 36.25 (C11), 35.78, 35.73 (C7), 31.25, 31.12 (C10), 29.85, 29.67 (C9), 28.90, 28.65 (C8) (* The ratio of cis-trans isomer to trans-isomer is 1:4); C 18 H 23 N 2 O 2 + HRMS (ESI + )m / z calculated: 299.1754, found: 299.1740.

[0434] Synthesis of V-quinoline-derived methoxypyridine oxime analogs :

[0435]

[0436] 3-Methoxy-6-(4-(quinolin-4-ylamino)but-1-yn-1-yl)pyridinecarbaldehyde 66:

[0437]

[0438] Commercially available 6-bromo-3-methoxypyridine aldehyde 62 (97 mg, 0.448 mmol, 1.1 eq.) was dissolved in THF / Et 3 Pd[PPh 3 ] 4 (71 mg, 0.061 mmol, 0.15 eq) and CuI (23 mg, 0.122 mmol, 0.3 eq). After the reaction mixture was degassed at room temperature for 5 min, alkyne 24 (80 mg, 0.408 mmol, 1 eq) in THF (3 mL) was added dropwise and the reaction mixture was stirred at room temperature for 16 h. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (MeOH / EtOAc 1:9) to provide the desired coupled methoxypyridine aldehyde 66 (126 mg, 93%) as a light yellow solid. f (30% MeOH + EtOAc) 0.25; IR (near infrared) ν max3281,2926,2233,1704,1582,1434,1267,1126,1009,763,694,521,494cm -1 ; 1 H NMR (400 MHz, CDCl 3 )δ(ppm)10.21(s,1H,H 18 ),7.52(d,J=8.8Hz,1H,H 4 ),7.33(d,J=8.8Hz,1H,H 5 ),7.28-7.13(m,5H,H 13 -H 17 ),3.93(s,3H,-OMe),2.74(t,J=7.5Hz,2H,H 11 ),2.39(t,J=7.1Hz,2H,H 9 ),1.91(quintet,J=7.1,7.5Hz,2H,H 10 ); 13 C NMR (100 MHz, CDCl 3 )δ(ppm)195.52(C18),156.25,141.28,140.73,136.02,132.0,128.44,128.32,125.91,1 20.41(Ar),90.27(C7),79.44(C8),56.03(-OMe),34.86(C11),29.76(C10),18.72(C9); C 18 H 18 N 1 O 2 + HRMS (ESI + )m / z calculated was 280.1332, found was 280.1348.

[0439] 3-Methoxy-6-(4-(quinolin-4-ylamino)but-1-yn-1-yl)pyridine aldehyde oxime 67:

[0440]

[0441] Aldehyde 66 (100 mg, 0.362 mmol, 1 eq), hydroxylamine hydrochloride (50 mg, 0.724 mmol, 2 eq) and CH 3 CO 2A solution of Na (89 mg, 1.086 mmol, 3 eq.) in dry ethanol (5 mL) was stirred at reflux for 16 h. After completion (monitored by TLC), the solids were removed by filtration through a short pad of celite, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (MeOH / EtOAc 1:9) to provide oxime 67 (65 mg, 62%) as a white solid. f (30% MeOH + EtOAc) 0.2; IR (near infrared) ν max 3319,2924,1897,1586,1460,1242,1115,982,829,760,649,524cm -1 ; 1 H NMR(500MHz,DMSO-d6)δ(ppm)11.63(br s,1H,OH),8.41(d,J=5.2Hz,1H,Ar),8.22(s,1H,-C-NOH),8.21(d,J=8.5Hz,1H,Ar),7.79(d,J=8.5Hz,1H,Ar),7.61 (t,J=7.6Hz,1H,Ar),7.50-7.36(m,4H,Ar),6.58(d,J=5.4Hz,1H,Ar),3.85(s,3H,-OMe),3.58(q,J=5.9,7.1Hz,2H,H 10 ),2.83(t,J=7.1Hz,2H,H 9 ); 13 C NMR(125MHz,DMSO-d6)δ(ppm)153.77,151.22,149.97,148.83,145.06,140.87,134.59,129.57,129.24,128.54 ,124.42,122.07,120.24,119.30,98.94,(Ar),87.06(C8),81.50(C7),56.46(-OMe),41.75(C10),19.08(C9);C 20 H 19 N 4 O 2 + HRMS (ESI + )m / z calculated was 347.1503, found was 347.1491.

[0442] 4-((4-(6-((hydroxyimino)methyl)-5-methoxypyridin-2-yl)but-3-yn-1-yl)amino)quinolin-1-ammonium chloride 68:

[0443]

[0444] To MeOH / H 2 1.2N HCl (0.1 mL) was added to compound 67 (9.5 mg) in 0.5 mL / 0.5 mL and stirred for 2 minutes and allowed to stand at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure to provide HCl salt 68 in the form of a white solid in quantitative yield. IR (near infrared) max 3186,3099,2838,2237,1615,1593,1449,1277,1007,760,649,530,491cm -1 ; 1 H NMR (500 MHz, D 2 O)δ(ppm)*8.18-8.08(m,3H,Ar),*7.96-7.91(m,1.5H,Ar),*7.74-7.70(m,1.5H,Ar),*7.62-7.54(m,3H ,Ar),*7.51-7.40(m,4.5H,Ar),*6.73-6.70(m,1.5H,Ar),*3.92(s,1.5H,-OMe),*3.84(t,J=6.6Hz,1H,H 10' ),3.80(s,3H,-OMe),3.75(t,J=6.6Hz,2H,H 10 ),*2.98(t,J=6.6Hz,1H,H 9' ),2.89(t,J=6.6Hz,2H,H 9 );* 13 CNMR(125MHz,D 2 O)δ(ppm)156.49,154.95,142.15,142.03,141.86,141.45,140.04,139.68,1 38.68,137.60,137.00,134.19,131.06,130.37,128.51,128.26,17.55,127.5 2,125.38,122.39,120.29,120.22,119.12,116.93,116.81,98.55,98.47(Ar ),94.74(C8),76.76(C7),57.71,57.22(-OMe),41.65,41.10(C10),19.5(C9)( * cis-trans isomers (1:2); C 20 H 20 C1N 4 O 2 + HRMS (ESI+ )m / z calculated was 347.1503, found was 347.1461.

[0445] 3-Methoxy-6-(4-(quinolin-4-ylamino)butyl)pyridinealdehyde oxime 69:

[0446]

[0447] 10% Pd / C (4.5 mg, 0.042 mmol, 0.5 eq) was added to a degassed solution of methoxypyridine oxime 67 (25 mg, 0.085 mmol, 1 eq) in dry EtOAc (2 mL). 2 After rinsing three times, the 2 The reaction mixture was stirred at 40 °C (1 atm) for 3 h. After completion (monitored by TLC), the catalyst was removed by filtration through a short column of celite, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (EtOAc / PE 1:9) to provide oxime 69 (24 mg, 95%) as a colorless liquid; R f (50% EtOAc + PE) 0.40; IR (near infrared) ν max 3327,2923,2853,1582,1457,1272,1126,968,763,694,540,473cm -1 ; *1 H NMR (400 MHz, CDCl 3 )δ(ppm)8.42(2s,1H,H 18 ,H 18' ),8.32(d,J=5.7Hz,1H,Ar),8.10(dd,J=1.2,8.6Hz,1H,Ar),7.79(d,J=1.2,8.6Hz,1H,Ar),7.64(m,1H,Ar),7.44(m,1H,Ar ),7.39(d,J=8.7Hz,1H,Ar),7.26(d,J=8.7Hz,1H,Ar),6.50(d,J=5.8Hz,1H,Ar),3.87(s,3H,-OMe),3.42(t,J=6.9Hz,1H,H 10 ),3.42(t,J=6.9Hz,1H,H 10 ),2.83(t,J=7.5Hz,1H,H 7 ),1.87-1.77(m,4H,H 8 ,H 9 );* 13 C NMR (100 MHz, CDCl 3)δ(ppm)155.21,154.35,153.13,150.73,148.33,145.93,140.73,138.63,130.85,128.33,125.82, 122.51,121.43,120.31,99.30(Ar),56.53(-OMe),43.86(C10),37.37(C7),28.95(C9),28.82(C8)( * The ratio of cis-trans isomers is 1:4): C 20 H 23 N 4 O 2 + HRMS (ESI+) m / z calcd: 351.1816, found: 351.1827.

[0448] 4-((4-(6-((hydroxyimino)methyl)-5-methoxypyridin-2-yl)butyl)amino)quinolin-1-amine 70:

[0449]

[0450] 1.2N HCl (0.1 mL) was added to compound 69 (8 mg) in methanol / water (0.5 mL / 0.5 mL) and stirred for 2 minutes and allowed to stand at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure to obtain HCl salt 70 in the form of a white solid in quantitative yield. IR (near infrared) max 3237,3111,2926,1617,1594,1452,1291,1011,764,663,592cm -1 ; 1 H NMR (500 MHz, D 2 O)δ(ppm)8.20(s,1H,H 18 ),8.19(d,J=8.6Hz,1H,Ar),8.04(d,J=8.6Hz,1H,Ar),7.94-7.87(m,2H,Ar),7.75(dd,J=8.6,18.8Hz, 1H,Ar),7.64(t,J=8.8Hz,1H,Ar),6.64(d,J=7.2Hz,1H,Ar),3.93(s,3H,-OMe),3.55(t,J=6.5Hz,1H,H 10 ),3.01(t,J=6.8Hz,1H,H 7 ),1.95-1.80(m,4H,H 8 ,H 9 );* 13C NMR (125MHz, D 2 O)δ(ppm)156.07,154.21,150.14,141.63,139.57,137.60,134.14,133.86,129.10,128.69,127.47,122.29,120.27,116.86,98.31(Ar),57.45(-OMe),42.83(C10),32.20(C7),26.12(C9),25.81(C8)(*The ratio of cis and trans isomers is 1:2); C 20 H 23 N 4 O 2 + HRMS (ESI+) m / z calcd. 351.1816, found 351.1782.

[0451] (3aS, 4S, 6R, 6aR)-6-(6-amino-9H-purin-9-yl)-N-(4-(6-((hydroxyimino)methyl)-5-methoxypyridin-2-yl)but-3-yn-1-yl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolane-4-carboxamide 72:

[0452]

[0453] Commercially available 6-bromo-3-methoxypyridine aldehyde 62 (192 mg, 0.887 mmol, 1.1 eq.) was dissolved in THF / Et 3 Pd[PPh 3 ] 4 4-(4-(4-(4-(4-(4-(4-oxo-1-yl)-2-nitropropene))-1-nitropropene ...

[0454] Aldehyde 71 (220 mg, 0.433 mmol, 1 eq.), hydroxylamine hydrochloride (60 mg, 0.867 mmol, 2 eq.) and CH 3 CO 2A solution of Na (107 mg, 1.299 mmol, 3 eq.) in dry ethanol (7 mL) was stirred at reflux for 16 h. After completion (monitored by TLC), the solids were removed by filtration through a short pad of celite, the solvent was evaporated, and the residue was purified by column chromatography (MeOH / EtOAc 1:9) to provide oxime 72 (180 mg, 78%) as a white solid. f (30% MeOH + EtOAc) 0.2; IR (near infrared) ν max 3185,2926,1640,1464,1264,1209,1090,971,868,797,647,510cm -1 ; 1 H NMR (400MHz, MeOD) δ (ppm) 8.39-8.11 (3s, 3H, Ar, -C=NOH), 7.37 (d, J=8.6, 1H, H 4 ),7.26(d,J=8.6Hz,1H,H 5 ),6.34(br s,H,-CH),5.57(dd,J=1.8,6.0Hz,1H,-CH),5.41(br d,J=6.0Hz,1H,-CH),4.68(d,J=1.8Hz,1H,-CH),3.89(s,3H,-OCH 3 ),3.21(m,1H,-CH 2 ),3.09(m,1H,-CH 2 ),2.27(m,1H,-CH 2 ),2.10(m,1H,-CH 2 ),1.57(s,3H,-CH 3 ),1.37(s,3H,-CH 3 ); 13 C NMR(100MHz,MeOD)δ(ppm)172.07,157.33,155.15,153.99,150.30,145.21,142.55,141.69,135.92,129.89,120.84,120.49,115.17(Ar),9 2.41(C16),88.65(C15),87.34(C8),85.36(C14),85.26(C13),81.58( C7),56.74(C30),38.79(C10),27.29(C28),25.54(C29),20.47(C9); C 24 H 27 N 8 O 6 +HRMS (ESI + )m / z calculated is 523.2048, found is 523.2038.

[0455] VI-Synthesis of trifunctional ethylcarbazole compounds

[0456]

[0457] 6-(Azidomethyl)pyridinealdehyde 75:

[0458]

[0459] The synthesis of methyl 6-(azidomethyl)picolinate 74 was by Harekrushna, B. et al. 1 This is achieved through well-established procedures.

[0460] DIBAL-H (1 M in CH) was stirred at -78 °C. 2 Cl 2 The solution in 2% ethyl acetate (100 mg, 0.521 mmol, 1 eq.) was added dropwise to the azidoester 74 (100 mg, 0.521 mmol, 1 eq.) in dry CH 2 Cl 2 (5 mL) and the reaction mixture was stirred at -78 °C for 5 h. After the reaction was complete, the reaction mixture was quenched with methanol (3 mL) and the cooling tank was removed. When the mixture was warmed to room temperature, H 2 The reaction mixture was diluted with O and extracted with EtOAc. The combined organic layers were concentrated in MgSO 4 The solid was filtered off and the solvent was evaporated to give aldehyde 75. The crude aldehyde 75 was used directly in the next step without purification. IR (near infrared) max 2836,2098,1709,1591,1457,1255,990,777,641cm -1 ; 1 H NMR (400 MHz, CDCl 3 )δ(ppm)10.04(s,1H),7.94-7.86(m,2H),7.56(m,2H),4.57(s,2H); 13 C NMR (100 MHz, CDCl 3 )δ(ppm)193.07,156.73,152.59,138.11,126.05,102.78,55.15; C 7 H 7 N 4 O 1 + HRMS (ESI +) m / z calculated value is 163.0604, found value is 163.0614.

[0461] 6-(Azidomethyl)pyridinealdehyde oxime 76:

[0462]

[0463] Crude pyridine carboxaldehyde 75 (0.521 mmol, 1 eq.), hydroxylamine hydrochloride (73 mg, 1.042, 2 eq.) and CH 3 CO 2 A solution of Na (128 mg, 1.563 mmol, 3 eq.) in dry ethanol (5 mL) was stirred at 80 °C for 16 h. After completion, the solids were removed by filtration through a short column of celite, the solvent was evaporated, and the residue was purified by column chromatography (EtOAc / PE: 1:9) to afford oxime 76 (70 mg, 76%) as a thick syrup. IR (near infrared) v max 3182,3010,2889,2084,1572,1590,1459,12666,1233,1158,994,966,782,741,651,619,501cm -1 ; 1 H NMR (400MHz, CD 3 OD)δ(ppm)8.10(s,1H),7.86-7.76(m,2H),7.40(dd,J=1.8,6.8Hz,2H),4.48(s,2H); 13 C NMR (100MHz, CD 3 OD)δ(ppm)157.29,153.94,149.93,139.26,1323.66,120.86,56.16; C 7 H 8 N 5 O 1 + HRMS (ESI + ) m / z calculated value is 178.0721, found value is 178.0723508.1867.

[0464] (3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-N-(2-(1-((6-((hydroxyimino)methyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolane-4-carboxamide 77:

[0465]

[0466] To t-BuOH / H 2 To a stirred solution of oxime 76 (52 mg, 0.295 mmol, 1.1 eq.) in 2 mL / 1.5 mL of 2% CO was added CuSO 4 (17 mg, 0.107 mmol, 0.4 eq.), sodium ascorbate (21 mg, 0.107 mmol, 0.4 eq.) and alkyne 54 (100 mg, 0.268 mmol, 1 eq.). The reaction mixture was stirred at 80 °C for 6 hours. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (MeOH / EtOAc: 5:95) to provide the desired triazole compound 77 (85 mg, 58%) as a white solid. IR (near infrared) v max 3192,2924,1644,1598,1458,1376,1209,1155,1057,992,868,797,648,511cm -1 ; 1 H NMR (400MHz, CD 3 OD)δ(ppm)8.20(s,1H),8.08(s,1H),8.05(s,1H),7.75-7.70(m,2H),7.12(m,1H),6.30(d,J=1.7Hz,1H),5.62(s,2H) ,5.50(dd,J=1.9,6.1Hz,1H),4.62(d,J=1.9Hz,1H),3.24-3.01(m,2H),2.61-2.41(m,2H),1.57(s,3H),1.38(s,3H); 13 C NMR (100MHz, CD 3 OD)δ(ppm)171.91,157.38,156.08,153.97,150.27,150.06,146.45,142.54,139.28,124.46,12 3.53,121.07,120.55,115.24,92.65,88.38,85.28,85.06,56.09,39.64,27.31,25.91,25.55; C 24 H 28 N 11 O 5 + HRMS (ESI + ) m / z calculated value is 550.2237, found value is 550.2269.

[0467] (2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxy-N-(2-(1-((6-((hydroxyimino)-methyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)tetrahydrofuran-2-carboxamide hydrochloride 78:

[0468]

[0469] To a stirred solution of triazole 77 (23 mg, 0.042 mmol, 1 eq.) in dry methanol (2 mL) was added 1.2 N HCl (127 μL, 0.42 mmol, 10 eq.) and the reaction mixture was stirred at 55 °C for 4 h. Upon completion, the reaction mixture was directly concentrated under reduced pressure and purified by reverse phase column chromatography (MeOH / H 2 The residue was purified by 4% paraformaldehyde (20:7) to afford the HCl salt 78 (15 mg, 72%) as a white solid. IR (near infrared) max 3196,1640,1588,1458,1427,1306,1254,1113,1054,997,796,647cm -1 ; 1 H NMR (400MHz, CD 3 OD)δ(ppm)7.99(s,1H),8.89(s,1H),7.83(s,1H),7.42(t,J=7.8Hz,1H),7.29(t,J=9.3Hz,1H),7.20(s ,1H),7.13(t,J=7.8Hz,1H),5.77(d,J=8.3Hz,1H),5.44-5.38(2d,J=14.8Hz,2H),4.43(s,1H),4.32(br d,J=5.0Hz,1H),4.08(dd,J=4.8,8.3Hz,1H),3.61(m,1H),3.35(m,1H),3.08-299(m,1H),3.96-288(m,1H); 13 C NMR (100MHz, CD 3 OD)δ(ppm)172.32,155.44,153.78,151.99,150.84,147.61,142.13,138.97,124.62,12 4.41,121.56,119.75,89.21,85.20,73.72,72.06,55.28,49.50(MeOH),39.92,24.77; C 21 H 334 N 11 O 5+ HRMS (ESI + )m / z calculated: 510.1957, found: 510.1956.

[0470] References

[0471] 1. Harekrushna B. et al., Chem. Eur. J. 2015, No. 21, pp. 10179-10184.

[0472] Synthesis of VII-Trifunctional Pseudoethylcarbazole Compounds

[0473]

[0474] N-(9-((3aR,4R,6R,6aR)-6-(((1-((6-((hydroxyimino)methyl)pyridin-2-yl)-1H-1,2,3-triazol-4-yl)methoxy)methyl)-2,2-dimethyltetrahydrofuran[3,4-d][1,3]dioxolan-4-yl)-9H-purin-6-ylbenzamide 79:

[0475]

[0476] To t-BuOH / H 2 To a stirred solution of oxime 76 (44 mg, 0.245 mmol, 1.1 eq.) in 2 mL / 1.5 mL of 2% CO was added CuSO 4 (17 mg, 0.045 mmol, 0.2 eq.), sodium carbonate (18 mg, 0.045 mmol, 0.2 eq.) and alkyne 58 (100 mg, 0.223 mmol, 1 eq.). The reaction mixture was stirred at 80 °C for 6 hours. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (pure EtOAc-MeOH / EtOAc: 5:95) to provide the desired triazole compound 79 (100 mg, 72%) as a white solid. IR (near infrared) v max 2924,1698,1610,1581,1455,1248,1211,1070,994,796,709,645,563cm -1 ; 1 H NMR (400MHz, CD 3OD)δ(ppm)10.88(br s,1H),9.31(br s,1H),8.77(s,1H),8.31(s,1H),8.14(s,1H),7.95-7.80(m,3H),7.51-7.28 (m,5H),6.99(d,J=7.5Hz,1H),6.25(d,J=2.3Hz,1H),5.63(s,2H),5.21(dd, J=2.2,5.9Hz,1H),4.98(dd,J=1.6,5.9Hz,1H),4.65-4.50(m,3H),3.82(dd, J=2.2,10.6Hz,1H),3.70(dd,J=3.0,10.6Hz,1H),1.61(s,3H),1.37(s,3H); 13 C NMR (100MHz, CD 3 OD)δ(ppm)165.35,154.38,152.69,151.64,151.44,150.02,149.19,143.91,141.90,137.62,133.31,128.56,12 7.93,124.13,122.78,122.07,120.42,114.09,92.26,86.27,85.28,81.85,70.67,64.47,55.03,27.11,25.24; C 30 H 31 N 10 O 6 + HRMS (ESI + )The calculated m / z is 627.2423.

[0477] Example 2: In vitro reactivation of human acetylcholinesterase (hAChE) by the compounds of the present invention

[0478] Compounds 57, 78, 25 and 26 of Example 1 were tested to determine their ability to activate hAChE inhibited by O-ethyl S-[2-(diisopropylamino)ethyl]methyl phosphorothioate (VX), taben, sarin or paraoxon.

[0479] 2-PAM (pralidoxime or 2-[(E)-(hydroxyimino)methyl]-1-methylpyridine) and HI6 (asoxime chloride or [1-[(4-carbamoylpyridin-1-ammonium-1-yl)methoxymethyl]pyridin-2-ylidene]methyloxazolidinone dichloride) were used as comparative compounds.

[0480] The medical plan is as follows:

[0481] Materials and methods have been described in WO2017021319, 2014 European Journal of Medicinal Chemistry, 78, 455-467, and Journal of Medicinal Chemistry, 2018, 61, 7630-7639.

[0482] IC50 measurement. Recombinant hAChE was produced and purified as previously described (Carletti et al., 2008, J Am Chem Soc 130 (47): 1601-20). The compounds were dissolved in methanol to form 5 mM or 10 mM stock solutions and further diluted in phosphate buffer (sodium phosphate 0.1 M, pH 7.4). The activity of recombinant hAChE was measured by spectrophotometry (absorbance at 412 nm) in the presence of different concentrations of oxime in 1 mL of Ellman buffer (sodium phosphate 0.1 M, pH 7.4, 0.1% BSA, 0.5 mM DTNB, 25°C). At least two measurements were performed for each test concentration. ProFit (Quantumsoft) nonlinear fitting was used, using the standard IC50 equation: % activity = 100*IC 50 / (IC 50 + [Ox]) to determine the compound concentration that produced 50% enzyme inhibition.

[0483] Inhibition of hAChE by OPNAs. Recombinant hAChE was produced and purified as described previously (see reference: http: / / www.ncbi.nlm.nih.gov / pubmed / 18975951). VX and taben were from DGA maitrise NRBC (Vert le Petit, France). Stock solutions of VX, sarin, taben and paraoxon were 5 mM in isopropanol. Inhibition of hAChE at 120 M was tested with a 5-fold excess of OPNAs and in Tris buffer (20 mM, pH 7.4, 0.1% BSA) at 25°C. After incubation for 20 min, the inhibited hAChE was desalted on a PD-10 column (GE Healthcare).

[0484] OPNAs inhibit the reactivation of hAChE. OPNA-inhibited hAChE was incubated with at least 4 or 5 concentrations of oxime in phosphate buffer (0.1 M, pH 7.4, 0.1% BSA) at 37°C. The final concentration of methanol in the mixed culture was less than 2%, which had no effect on the stability of the enzyme. At time intervals of 1 to 10 minutes (depending on the reactivation rate), 10 aliquots of each solution containing different concentrations of oxime were transferred to a test tube containing 1 mM acetylthiocholine and placed in 1 mL of Ellman's buffer (phosphate 0.1 M, pH 7.4, 0.1% BSA, 0.5 mM DTNB, 25°C) to measure the activity of hAChE.

[0485] The enzyme activity of the control group remained unchanged during the experiment. The percentage of reactivated enzyme (%E 反应 ) was calculated as the ratio of the recovered enzyme activity to the enzyme activity in the control. The apparent reactivation rate kobs, the dissociation constant K of the inhibitory enzyme oxime complex (E-POx) for each oxime concentration were calculated by nonlinear fitting with ProFit (Quantumsoft) using the standard oxime concentration-dependent reactivation equation derived from the following protocol: D and the maximum reactivation rate constant k r :

[0486]

[0487] EP = Enzyme

[0488] Ox = oxime compound

[0489] E-Pox = enzyme oxime complex

[0490] The test results are shown below (Table 1 and Table 2):

[0491] Table 1 Human hAChE reactivation performance against OP inhibition by oxime 2-PAM, HI6, 57, 78, 25 and 26

[0492]

[0493] Table 1 shows that compound 57 exhibited higher reactivation kinetics (k) for VX, taben, sarin, and paraoxon than the reference compounds 2-PAM and HI6. r , min -1 ); Compound 78 showed higher reactivation kinetics (k r , min -1 ).

[0494] Compounds 25 and 26 showed strong affinity for AChE inhibited by VX or sarin. These compounds showed higher reactivation than 2-PAM and HI6 (kr2 mM -1 min -1 ).

[0495] Table 2 shows the IC values ​​of oxime compounds: 2-PAM, HI6, 57, 78, 25 and 26 for AChE 50

[0496]

[0497] Table 2 shows that compounds 25 and 26 exhibit very high affinity for AChE, which is higher than the affinity of 2-PAM and HI6. Compound 25 exhibits the best affinity.

Claims

1. A compound of formula (I), or one of its pharmaceutically acceptable salts: in: R1 is H; -XY- is -CH2-(CH2) n -、-C≡C-、 wherein n is an integer from 0 to 5; R2 is a free radical D, wherein the free radical D is connected to -YX- through an ethyl group:

2. The compound according to claim 1, wherein The compound has the following skeleton 2: wherein R1 and R2 are as defined in claim 1.

3. The compound according to claim 1, wherein The compound has the following skeleton 3: wherein R1 and R2 are as defined in claim 1, and n is an integer from 0 to 5.

4. The compound according to claim 1, wherein The compound has the following skeleton 4: wherein R1 and R2 are as defined in claim 1.

5. The compound according to claim 4, wherein R2 is a free radical D, wherein the free radical D is connected to -YX- through an ethyl group:

6. The compound according to any one of claims 1 to 5, wherein The compound is selected from: (2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxy-N-(4-(6-(hydroxyimino)methyl)pyridin-2-yl)but-3-yn-1-yl)tetrahydrofuran-2-carboxamide 57: (2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxy-N-(2-(1-((6-((hydroxyimino)-methyl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)ethyl)tetrahydrofuran-2-carboxamide hydrochloride 78:

7. A method for preparing a compound of formula (I) according to any one of claims 1 to 6, wherein -XY- is -CH2-CH2- or -C≡C-, and the method comprises a Sonogashira coupling reaction between 6-bromopyridine aldehyde oxime and a compound comprising a terminal alkyne, optionally followed by a reduction step of reduction by reaction with hydrogen.

8. Use of a compound according to any one of claims 1 to 6 in the manufacture of a medicament for the treatment of a disease selected from neurological failure and / or respiratory failure due to poisoning by at least one organophosphorus nerve agent, a nervous system disease, inflammation, cancer, diabetes and pain.

9. The use according to claim 8, wherein the nervous system disease is Alzheimer's disease or Parkinson's disease.

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