3,6-Disubstituted-2-pyridinealdoxime skeleton

Abstract

To provide novel compounds having a 3,6-disubstituted-2- pyridinaldoxime scaffold.SOLUTION: The present invention relates to a compound of formula (I), or one of its pharmaceutically acceptable salts: (I) wherein R1, R2 and -X-Y- have specific definitions. The present invention also relates to the use of such a compound in therapy; and to a process for preparing it.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to novel compounds having a 3,6-disubstituted-2-pyridinealdoxime skeleton. These compounds may be useful in a variety of therapeutic and non-therapeutic applications. The present invention also relates to compositions, particularly pharmaceutical compositions, containing the compounds, and their uses. [Background technology]

[0002] Organophosphate nerve agents (OPNAs) are chemical warfare agents (CWAs) including sarin, soman, cyclosarin, tabun, O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate (VX), and paraoxon, parathion, and tetraethyl pyrophosphate. Highly toxic compounds include pesticides such as tetrachloroethylene (TEPP). Their acute toxicity results from irreversible inhibition of acetylcholinesterase (AChE) by phosphorylation of its catalytic serine, thereby preventing the enzyme from hydrolyzing acetylcholine (ACh). This accumulation of neurotransmitters occurs at the synapses of the brain, causing permanent saturation of muscarinic and nicotinic receptors, ultimately leading to seizures and respiratory arrest. Depending on the type and dose of OPNA, death can occur within minutes.

[0003] The chemical precursors of CWAs and pesticides and the relatively simple chemistry involved in their synthesis are similar. Because of this, efforts to control the spread of these agents have proven limited success. Therefore, developing effective countermeasures against OPNA poisoning remains a challenging task for protecting and treating both civilian and military populations. Current treatment for OPNA poisoning consists of administering a combination of atropine (an antimuscarinic drug) and diazepam (an anticonvulsant) and a standard pyridinium oxime (pralidoxime or 2-PAM, trimedoxime, HI-6, obidoxime, or HLo-7) to reactivate AChE. The oxime acts on OPNA-inhibited AChE by attacking the phosphorus atom of the phosphorylated serine, resulting in the elimination of the phosphonate and the restoration of the enzyme's catalytic activity. The hybrid reactivating compounds are potential ligands for the peripheral site of the enzyme, called peripheral site ligands (PSLs). The purpose of this reactivator is to increase the affinity of the reactivator for AChE (see Mercey G. et al., Accounts of Chemical Research, 756-766, 2012, Vol. 45, No. 5).

[0004] The efficiency of the reactivator can be estimated by the second-order rate constant for reactivation, kr2, The numbers are the maximum reactivation rate constant (kr) and the apparent dissociation constant (K) of the reactivator-inhibited AChE complex. D ) is the ratio.

[0005] At present, none of the known oximes have proven to be equally effective against all species of OPNA-inhibiting AChE.

[0006] Recent international application WO2017 / 021319 describes specific peripheral site ligands of the aminoquinoline functional group. The present invention discloses bifunctional compounds containing a (PSL) moiety, which inhibit the toxicity of hAChE (i.e., lower K D), enabling them to be potent reactivators of human AChE inhibited by any kind of organophosphorus compound. However, these bifunctional compounds contain a hydroxyl group that may be present at the 3-position of the pyridine group. This hydroxyl group must be protected and deprotected during synthesis. Furthermore, the hydroxyl group may be involved in the internal cyclization of the molecule.

[0007] Therefore, there remains a need for compounds that are effective for therapeutic use against OPNA poisoning, particularly compounds that are rapidly and easily synthesized in high yield and on a large scale. It needs to be stable and not erratic. Summary of the Invention

[0008] Surprisingly, the present inventors have now found that certain pyridine aldoxime compounds bearing hydrogen or a specific alkoxy group at position 3 meet these requirements, and because these compounds are not particularly charged, they can easily cross the blood-brain barrier.

[0009] Indeed, such compounds can be prepared quickly, simply and very easily, and the resulting compounds do not undergo intramolecular cyclization and can be used in human therapy.

[0010] In particular, these compounds prevent OPNA intoxication due to their effective and rapid reactivation of hAChE. These molecules can be used as antidotes to hAChE or as antidotes to organophosphorus compounds. Without being bound by any theory, these molecules selectively bind to the catalytic site of hAChE. These compounds appear to be particularly effective in reactivating inhibited AChE. The oximes of the compounds can be regenerated by dephosphorylation of the serine residue, allowing the compounds to be used repeatedly. These compounds are also agonists of the adenosine 2A receptor. As a result, these compounds can be used in the treatment of inflammation; neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease; and cancer, and, particularly through their inhibitory activity of histone deacetylases (HDACs), in the treatment of diabetes and / or pain.

[0011] Therefore, a first object of the present invention is to provide a compound of formula (I): [ka] wherein the various groups are as defined in the detailed description below. is a compound of

[0012] Another object of the present invention is a process for preparing compounds of formula (I), in particular by the Sonogashira reaction, as detailed below.

[0013] Another object of the present invention is a pharmaceutical composition comprising at least one compound of formula (I) and at least one pharmaceutically acceptable carrier.

[0014] Another object of the invention are the compounds of the invention for use as medicines.

[0015] A further object of the invention are the compounds of the invention for use in the treatment of neurological damage and / or respiratory failure due to poisoning with at least one organophosphorus nerve agent.

[0016] A further object of the invention are the compounds of the invention for use in the treatment of inflammation.

[0017] A further object of the invention is the compounds of the invention for use in the treatment of neurological diseases such as Alzheimer's disease or Parkinson's disease.

[0018] A further object of the invention is the compounds of the invention for use in the treatment of cancer.

[0019] A further object of the invention are the compounds of the invention for use in the treatment of diabetes.

[0020] A further object of the invention are the compounds of the invention for use in the treatment of pain.

[0021] A first object of the present invention is to provide a compound of formula (I): [ka] [In the formula, R1 is H or a linear or cyclic (preferably aromatic) C1-C7 alkoxy group. Preferably, R1 is methoxy or benzyloxy; -XY- is -CH2-(CH2) n -, -C≡C-, [ka] or -XY- is Br and R2 is absent; n is an integer from 0 to 5; R2 is a group selected from alkyl, aryl, aralkyl, heteroaryl, -R3-N(R4)(R5), A group, B group, C group, and D group shown below, wherein A group, B group, C group, or D group may be bonded to -YX- by an alkyl group, preferably an ethyl group; [ka] R3 is a C1-C4 alkyl group, and R4 and R5 are the same or different and each independently represent H, a naphthyl group, a 5-fluoroquinolin-4-yl group, a quinolin-4-yl group, or an 8-methoxyquinolin-4-yl group; or R4 and R5, together with the nitrogen atom, represent a 4-benzyl-piperazin-1-yl group or a 3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-1-yl group. forming an yl group] or one of the pharmaceutically acceptable salts thereof.

[0022] The points of attachment of the triazole group with respect to the -XY- definition are indicated by the asterisks on each side of the triazole group. [ka]

[0023] The point of attachment of any one of moieties AD (in the definition of R2) to the remainder of the molecule of formula (I) is indicated by an asterisk. [ka] The Bz in the A group represents benzoyl, i.e., Ph-C(=O)-. DETAILED DESCRIPTION OF THE INVENTION

[0024] "Pharmaceutically acceptable salt" refers to any salt of a compound of formula (I) with an acid or base. The pharmaceutically acceptable salt may be a hydrochloride salt.

[0025] Pyridine of formula (I) may be used as a salt to produce a pyridinium salt. For example, when R4 and / or R5 are the same or different and each independently represent a 5-fluoroquinolin-4-yl group, a quinolin-4-yl group, or an 8-methoxyquinolin-4-yl group, the group may be complexed with HCl to produce a 5-fluoro-4-quinolinium group, a 4-quinolinium group, or an 8-methoxy-4-quinolinium group, respectively. Preferred pharmaceutically acceptable salts are the 5-fluoro-4-quinolinium group, the 4-quinolinium group, and the 8-methoxy-4-quinolinium group.

[0026] The oxime of the compound of formula (I) 15 N, 18 O. 2 H, or 3 They may be labeled with one or more isotopes, such as H. Indeed, such stable, non-toxic and non-radioactive isotopes may enable in vivo and in vitro biological studies.

[0027] The term "alkyl" refers to a linear hydrocarbon group preferably containing 1 to 20 carbon atoms, particularly 1 to 15 carbon atoms, or a branched or cyclic hydrocarbon group containing 3 to 20 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-tridecyl, cyclohexyl, and cyclohexylmethyl groups, and preferred alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-tridecyl, cyclohexyl, and cyclohexylmethyl groups. Preferred examples include ethyl, propyl, n-hexyl, n-tridecyl, cyclohexyl, and cyclohexylmethyl groups.

[0028] C1-C4 alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.

[0029] A "straight chain C1-C7 alkoxy group" refers to the group Rad-O-, where Rad is a straight chain C1-C7 alkyl group. Preferably, the straight chain C1-C7 alkoxy group is methoxy.

[0030] A "cyclic (preferably aromatic) C1-C7 alkoxy group" refers to the group Rad-O-, where Rad is a cyclic (preferably aromatic) C1-C7 alkyl group. Preferably, the cyclic C1-C7 alkoxy group is an aromatic C1-C7 alkoxy group, more preferably benzyloxy.

[0031] "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). A preferred PAH is pyrene. The aryl may be substituted with at least one alkyl group and / or at least one cyano group (-CN). A preferred example of the aryl group is phenyl.

[0032] "Aralkyl" refers to an aryl group, as described above, linked to a compound of formula (I) by an alkyl group. Preferably, the aralkyl group is phenylpropyl. In the aralkyl, the aryl group may be substituted with at least one alkyl group and / or at least one cyano group (-CN). Preferably, the aralkyl is phenylpropyl.

[0033] "Heteroaryl" refers to an aryl group in which at least one carbon atom in the aromatic ring is replaced with a heteroatom, which 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 a pyridine group, such as 4- or 3-pyridino. The heteroaryl may be substituted with 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 a pyridinium group, such as 4- or 3-pyridinium.

[0034] According to a first embodiment, in formula (I), it is preferred that -XY- is Br and R2 is absent.

[0035] Thus, one of the compounds of formula (I) or a pharmaceutically acceptable salt thereof may have the following skeleton 1: [ka] wherein R1 is as defined above. It has.

[0036] In compounds of skeleton 1, R1 is H or a linear or cyclic (preferably aromatic) C1 Preferably, in compounds of Skeleton 1, R1 is H, methoxy, or or benzyloxy.

[0037] According to a second embodiment, in formula (I), -XY- is -C≡C- (skeleton 2): [ka] wherein R1 and R2 are as defined above. is preferred.

[0038] The compound of skeleton 2 is a bifunctional compound. Preferably, in compounds of Scaffold 2, R1 is selected from H and methoxy. Preferably, in the compound of skeleton 2, R2 is selected from the group A, group B, group C, and group D; [ka] Preferably, the C or D group is linked to -YX- by an alkyl group, more preferably an ethyl group.

[0039] Alternatively, preferably in compounds of Scaffold 2, R2 is alkyl, heteroaryl, aralkyl, or -R3-N(R4)(R5); R3 is a C1-C4 alkyl group, preferably R3 is selected from methyl, ethyl, and n-propyl; R4 is H, R5 is selected from a naphthyl group, a 5-fluoroquinolin-4-yl group, a quinolin-4-yl group, or an 8-methoxyquinolin-4-yl group.

[0040] Alternatively, preferably in compounds of Scaffold 2, R2 is -R3-N(R4)(R5) , R3 is a C1-C4 alkyl group, preferably R3 is selected from methyl, ethyl, and n-propyl; R4 and R5 together with the nitrogen atom form a 4-benzyl-piperazin-1-yl group or a 3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl group.

[0041] Compounds with scaffold 2 exhibit increased affinity, a lower pKa and increased reactivation efficiency (kr2: / mM·min), compared to compounds without a triple bond and with –OH as R1, and compared to reference molecules such as pralidoxime (2-PAM) and HI-6.

[0042] According to a third embodiment, in formula (I), -XY- is -CH2-(CH2) n -(here where n is an integer between 0 and 5) (skeleton 3): [ka] wherein R1 and R2 are as defined above. It is preferable that:

[0043] The compound of skeleton 3 is a bifunctional compound. Preferably, in compounds of Scaffold 3, R1 is selected from H and methoxy. Preferably, in compounds of Scaffold 3, R2 is alkyl, aryl, aralkyl, or -R3-N(R4)(R5), where: R3 is a C1-C4 alkyl group, preferably R3 is selected from methyl, ethyl, and n-propyl; R4 is H; R5 is selected from a naphthyl group, a 5-fluoroquinolin-4-yl group, a quinolin-4-yl group, or an 8-methoxyquinolin-4-yl group.

[0044] Alternatively, preferably in compounds of Scaffold 3, R2 is -R3-N(R4)(R5), where R3 is a C1-C4 alkyl group, preferably R3 is selected from methyl, ethyl, and n-propyl; and R4 and R5 together with the nitrogen atom form a 4-benzyl-piperazin-1-yl group.

[0045] According to a fourth embodiment, in formula (I), -XY- is [ka] (Skeleton 4): [ka] wherein R1 and R2 are as defined above. is preferred.

[0046] The compound of skeleton 4 is a trifunctional compound. Preferably, in compounds of skeleton 4, R1 is selected from H, methoxy, and benzyloxy; preferably, R1 is H. Preferably, in compounds of skeleton 4, R2 is selected from groups A, C, and D; [ka] Preferably, the C or D group is linked to -YX- by an alkyl group, more preferably an ethyl group.

[0047] Compounds of scaffold 4 selectively target the catalytic site of hAChE and show excellent reactivation. Show the dynamics.

[0048] Preferably, the compound of formula (I) is selected from the following compounds and their pharmaceutically acceptable salts: 6-Bromopicolinaldehyde oxime 2: [ka] 6-(5-phenylpent-1-yn-1-yl)picolinaldehyde oxime 5: [ka] 6-(5-phenylpentyl)picolinaldehyde oxime 7: [ka] 6-(pentadeca-1-yn-1-yl)picolinaldehyde oxime 9: [ka] 6-Pentadecylpicolinaldehyde oxime 10: [ka] 6-(Pyridin-3-ylethynyl)picolinaldehyde oxime 12: [ka] 2-((hydroxyimino)methyl)-6-(pyridin-1-ium-3-ylethynyl)pyridin-1-ium chloride 13: [ka] N-(4-{6-[(hydroxyimino)methyl]pyridin-2-yl}but-3-yn-1-yl)naphthalen-1-amine 19: [ka] N-(4-{6-[(hydroxyimino)methyl]pyridin-2-yl}but-3-yn-1-yl)naphthalen-1-amine 20: [ka] 6-(4-(quinolin-4-ylamino)but-1-yn-1-yl)picolinaldehyde oxime 25: [ka] 3-Hydroxy-6-(4-(quinolin-4-ylamino)butyl)methyl picolinate 26: [ka] 6-(4-((5-fluoroquinolin-4-yl)amino)but-1-yn-1-yl)picolinaldehyde oxime 30: [ka] 6-(4-((5-fluoroquinolin-4-yl)amino)butyl)picolinaldehyde oxime 31: [ka] 6-(4-((8-methoxyquinolin-4-yl)amino)but-1-yn-1-yl)picolinaldehyde oxime 36: [ka] 6-(4-((8-methoxyquinolin-4-yl)amino)butyl)picolinaldehyde oxime 37: [ka] 6-(3-(4-benzylpiperazin-1-yl)prop-1-yn-1-yl)picolinaldehyde oxime 42: [ka] 6-(3-(4-benzylpiperazin-1-yl)propyl)picolinaldehyde oxime 43: [ka] 6-(4-(4-benzylpiperazin-1-yl)but-1-yn-1-yl)picolinaldehyde oxime 47: [ka] 6-(4-(4-benzylpiperazin-1-yl)butyl)picolinaldehyde oxime 48: [ka] 6-(4-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)but-1-yn-1-yl)picolinaldehyde oxime 51: [ka] (3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-N-(4-(6-(hydroxyimino)methyl)pyridin-2-yl)but-3-yne-1- (yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide 56: [ka] (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: [ka] N-(9-((3aR,4R,6R,6aR)-6-(((3-(6-(hydroxyimino)methyl)pyridin-2-yl)prop-2-yn-1-yl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-yl)benzamide 60: [ka] 6-(3-(((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)prop-1-yn-1-yl)picolinaldehyde oxime 61: [ka] 3-Methoxy-6-(5-phenylpent-1-yn-1-yl)picolinaldehyde Kishim 64: [ka] 3-Methoxy-6-(5-phenylpentyl)picolinaldehyde oxime 65: [ka] 3-Methoxy-6-(4-(quinolin-4-ylamino)but-1-yn-1-yl)picolinaldehyde oxime 67: [ka] 4-((4-(6-((hydroxyimino)methyl)-5-methoxypyridin-2-yl)but-3-yn-1-yl)amino)quinolin-1-ium chloride 68: [ka] 3-Methoxy-6-(4-(quinolin-4-ylamino)butyl)picolinaldehyde oxime 69: [ka] 4-((4-(6-((hydroxyimino)methyl)-5-methoxypyridin-2-yl )Butyl)amino)quinolin-1-ium 70: [ka] (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-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide 72: [ka] (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-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide 77: [ka] (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: [ka] N-(9-((3aR,4R,6R,6aR)-6-(((1-((6-(-(hydroxyimino)methyl)pyridin-2-yl)methyl)-1H-1,2,3-triazole- 4-yl)methoxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-yl)benzamide 79: [ka] More preferably, the compound of formula (I) is selected from the following compounds: (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: [ka] 6-(4-(quinolin-4-ylamino)but-1-yn-1-yl)picolinaldehyde oxime 25: [ka] 3-Hydroxy-6-(4-(quinolin-4-ylamino)butyl)methyl picolinate 26: [ka] (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: [ka]

[0049] Preparation of Compounds of Formula (I)

[0050] The compound of formula (I) or one of its pharmaceutically acceptable salts according to the present invention 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: [ka]

[0051] Compounds of formula (I) in skeleton 1, i.e., compounds where XY is Br, are reacted with R2-XYH (XY is -C≡C-) to give compounds of formula (I) in skeleton 2, where XY is -C≡C-. Then, by selective hydrogenation (with H), a compound of formula (I) where XY is -CH-CH- is obtained. Any of the compounds (skeleton 3) can be easily obtained.

[0052] To obtain compounds of scaffold 4, the alkyne R2-C≡CH is reacted with the corresponding clickable reactivating agent via click chemistry. Such a method is exemplified below.

[0053] Preparation of Compounds of Formula (I) The compounds of formula (I) according to the present invention or one of its pharmaceutically acceptable salts may be synthesized by any suitable method known to those skilled in the art.

[0054] Preferably, compounds of formula (I) are synthesized as described below. This process is chemoselective. In particular, it does not require any prior protection step of the oxime. The process involves a minimum number of steps (one or two) and is carried out rapidly at ambient temperature.

[0055] Skeleton 1 In particular, compounds with skeleton 1 [ka] They can be obtained by reaction of either the picolinaldehyde precursor or the picolinonitrile derivative with hydroxylamine hydrochloride, preferably in an organic solvent. In all cases, hydroxylamine hydrochloride 15 It may be labeled with N element. This synthesis is illustrated for 6-bromopicolinaldehyde oxime 2 in the Examples.

[0056] Skeleton 2 In particular, the process for synthesizing Scaffold 2, a compound of formula (I), may include, and preferably includes, a late stage Sonogashira coupling reaction between a compound of Scaffold 1, i.e., 6-bromopyridine aldoxime, and a compound bearing a terminal alkyne. (See diagram above). The Sonogashira coupling reaction is carried out in the presence of a solvent such as tetrahydrofuran (THF), triethylamine (Et3N), or preferably a mixture thereof, and in the presence of Pd(PPh3)4 and The reaction may be carried out in the presence of a catalyst such as CuI. This Sonogashira coupling reaction is carried out without any protection of the oxime moiety.

[0057] Skeleton 3 The resulting alkyne (Scaffold 2) can then be reduced, for example by reaction with hydrogen in the presence of a Pd catalyst (such as Pd / C), to give the corresponding alkyl (Scaffold 3) in a selective hydrogenation step. In this case too, the hydrogenation step is carried out without any protection of the oxime moiety.

[0058] Skeleton 4 As described above and shown in the scheme above, the alkyne R2-C≡CH is reacted with the corresponding clickable reactivating agent via click chemistry to give compounds of scaffold 4.

[0059] An object of the present invention is therefore a process for preparing compounds of formula (I), in which -XY- is -CH2-CH2- or -C≡C-, and R1 and R2 are as defined above, comprising a Sonogashira coupling reaction between 6-bromopyridine aldoxime and a compound bearing a terminal alkyne, optionally followed by a reduction step by reaction with hydrogen.

[0060] Pharmaceutical Uses of the Compounds of the Invention The compounds of the present invention can be used to treat neurological damage and / or respiratory failure due to 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 pesticides such as paraoxon, parathion, and TEPP. Due to their ability to reactivate organophosphorus-inhibited cholinesterase, the compounds of the present invention can be used to treat neurological damage and / or respiratory failure due to poisoning with at least one organophosphorus nerve agent.

[0061] Alternatively, these compounds can be overcome by administering an acetylcholinesterase inhibitor. The compounds may also be used to treat diseases associated with reduced acetylcholine production, which can result in decreased production of acetylcholine. Examples of such diseases include neurological disorders such as Alzheimer's disease and Parkinson's disease, among others.

[0062] The compounds of the invention are also agonists of the adenosine 2A receptor, and as a result, they may be used in the treatment of inflammation, cancer, diabetes, and / or pain.

[0063] The compounds of the invention are typically included in pharmaceutical compositions comprising at least one compound of the invention and a pharmaceutically acceptable support.

[0064] The amount of the compound of formula (I) or one of its pharmaceutically acceptable salts in the composition of the present invention may vary widely depending on the patient, the mode of administration, and the desired effect.

[0065] The compounds or compositions of the present invention can be administered orally or parenterally, for example, via the topical, parenteral, intramuscular, intravenous, cutaneous, nasal, or rectal routes.

[0066] The pharmaceutical compositions of the present invention may be in various forms, including granules, powders, tablets, capsules, syrups, emulsions, suspensions, and forms used for parenteral administration, such as injections, sprays, transdermal patches, or suppositories, etc. These dosage forms may be prepared by known conventional techniques.

[0067] Orally administered solid dosage forms may be prepared, for example, by the following process: an excipient (e.g., lactose, sucrose, starch, or mannitol), a disintegrant (e.g., calcium carbonate, carboxymethylcellulose calcium, alginic acid, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, microcrystalline cellulose, cellulose powder, pregelatinized starch, sodium alginate, or starch glycolate), a binder (e.g., pregelatinized starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, alginic acid, carbomer, dextrin, ethyl cellulose, sodium alginate, maltodextrin, liquid glucose, magnesium aluminum silicate, hydroxyethyl cellulose, methylcellulose, or guar gum), and a lubricant (e.g., talc, magnesium stearate, or polyethylene 6000) are added to the active compound, and the resulting mixture is then tableted. 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 or sustained release of the active compound. Examples of coating products that can be used include ethyl cellulose, hydroxymethyl cellulose, polyoxyethylene glycol, cellulose acetophthalate, hydroxypropyl methylcellulose phthalate, and Eudragit® (methacrylic acid-acrylic acid copolymer), Opadry® (hydroxypropyl methylcellulose + macrogol + titanium dioxide + lactose monohydrate). Pharmaceutically acceptable coloring agents may be added (e.g., yellow iron oxide, red iron oxide, or quinoline yellow pigments).

[0068] Liquid dosage forms for oral administration include solutions, suspensions, and emulsions. Aqueous solutions may be obtained by dissolving the active ingredient in water and then adding flavorings, coloring agents, stabilizers, and / or thickeners as needed. To improve solubility, ethanol, propylene glycol, or other pharmaceutically acceptable non-aqueous solvents may be added. Oral aqueous suspensions may be obtained by dispersing finely divided active ingredients in water with viscous products such as natural or synthetic gums or resins, methylcellulose, or sodium carboxymethylcellulose.

[0069] Injectable dosage forms may be prepared, for example, by the following process: The active compound is dissolved, suspended, or emulsified in either an aqueous medium (e.g., distilled water, saline, or Ringer's solution) or an oily medium (e.g., olive oil, sesame seed oil, cottonseed oil, corn oil, or propylene glycol) together with a dispersing agent (e.g., Tween® 80, HCO® 60 (Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, or sodium alginate), a preservative (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, benzyl alcohol, chlorobutanol, or phenol), an isotonic agent (e.g., sodium chloride, glycerin, sorbitol, or glucose), and, if necessary, other additives such as a solubilizer (e.g., sodium salicylate or sodium acetate) or a stabilizer (e.g., human serum albumin).

[0070] Dosage forms for external use (topical use) may be obtained from solid, semi-solid, or liquid compositions containing the active compound. For example, to obtain a solid form, the active compound can be processed with excipients (e.g., lactose, mannitol, starch, microcrystalline cellulose, or sucrose) and thickeners (e.g., natural gums, cellulose derivatives, or acrylic polymers) and converted into powder. Liquid pharmaceutical compositions are prepared in substantially the same manner as injectable forms, as described above. Semi-solid pharmaceutical forms are preferably in the form of aqueous or oily gels, or in the form of pomades. These compositions may optionally contain pH adjusters (e.g., carbonic acid, phosphoric acid, citric acid, hydrochloric acid, or sodium hydroxide) and preservatives (e.g., p-hydroxybenzoic acid esters, chlorobutanol, or benzalkonium chloride).

[0071] Further described herein are methods for treating neurological damage and / or respiratory failure due to poisoning associated with at least one organophosphorus nerve agent, comprising administration of at least one compound of the present invention. Further described herein are methods for treating neurological disorders, such as Alzheimer's disease or Parkinson's disease, comprising administering at least one compound of the present invention. Further described herein are methods of treating inflammation comprising administering at least one compound of the present invention. Further described herein are methods of treating cancer comprising administering at least one compound of the present invention. Further described herein are methods of treating diabetes comprising administering at least one compound of the present invention. Further described herein are methods for treating pain comprising administering at least one compound of the present invention.

[0072] Within the context of the present invention, the term "treatment" refers to curative, symptomatic, and / or prophylactic treatment. In particular, the term may refer to slowing the progression of the disease, reducing or inhibiting at least one of its symptoms or complications, or improving the well-being of the patient in any way.

[0073] Administration of a compound or composition of the invention may occur before, during, or after the subject's exposure to an organophosphorus nerve agent.

[0074] As used herein, the terms "subject" and "patient" are used interchangeably and refer to a human subject.

[0075] The amount of the compound of formula (I) or one of its pharmaceutically acceptable salts administered according to the present invention may vary widely depending on the patient, the mode of administration, and the desired effect. ) or one pharmaceutically acceptable salt thereof may be included in an amount of 200 mg to 4000 mg, in up to three daily doses.

[0076] The compounds or compositions of the present invention may be co-administered with at least one other active agent that is, for example, an antimuscarinic agent (particularly atropine), an anticonvulsant (particularly diazepam or one of its prodrugs, such as Avizafone), and / or a bioscavenger, such as human butyrylcholinesterase, which can capture and / or degrade OPNA in the blood.

[0077] The term "co-administration" indicates that the administration of the compound or composition of the present invention and the administration of the other active agent may be simultaneous, sequential, and / or separate.

[0078] Other Uses of the Compounds of the Invention The compounds of the present invention may further be used as tools for in vivo and / or in vitro biological research, in which case the compound of formula (I) or one of its pharmaceutically acceptable salts may contain one or more isotopes that allow for their detection.

[0079] The following examples are offered by way of illustration of the present invention, but not by way of limitation. [Example]

[0080] Example 1: Synthesis of compounds of the present invention I - Synthesis of bifunctional pyridine aldoxime analogues Synthesis of 6-(5-phenylpentyl)picolinaldehyde oxime: [ka]

[0081] 6-Bromopicolinaldehyde oxime 2: [ka]

[0082] This compound was reported by L. Zhang et al. 1 It was synthesized according to the paper published by A solution of choline aldehyde 1 (3.00 g, 16.1 mmol) in absolute EtOH (50 mL) was added to hydroxybenzoate (HCl). Dimethylamine (2.24 g, 32.3 mmol) and sodium acetate (2.65 g, 32.3 mmol) were added at room temperature. After the addition, the colorless solution with a white suspension was stirred at 90° C. for 3 hours. The solution was then cooled to room temperature. The mixture was cooled to rt and concentrated in vacuo. The resulting white solid was dissolved in EtOAc (50 mL). The organic layer was washed with H2O (5 x 20 mL), dried (MgSO4), filtered, and concentrated in vacuo to give the title compound 2. (3.21 g, 16.0 mmol, 99%) was obtained as a white solid. Physical and spectroscopic data were as reported. 1 The melting point is 168-170°C (see literature). 2 164-166°C); IR (neat method) )ν max 3203, 3084, 2912, 1546, 1158, 1119, 704 cm -1 ; 1 H NMR(400 MHz, CDCl3)δ 11.90(s, 1H, CHNOH), 8.04(s, 1H, CHNOH), 7.82~7.74(m, 2H, NCCHCHCH, NCCHCHCH), 7.63(dd, J = 6.8, 1.7 Hz, 1H, NCCHCHCH; 13C NMR(100 MHz, CDCl3)δ 153.3, 147.5, 141.0, 140.1, 128.1, 119.3;HRMS(ESI) + C6H5BrN2O + The calculated m / z value is 200.9658 , the actual measured value is 200.9657. References: 1.Bioorg. Med. Chem. Lett. 2016, 26, 778-781

[0083] 6-(5-phenylpent-1-yn-1-yl)picolinaldehyde 4: [ka]

[0084] Bromopicone aldehyde 1 (568 mg, 3.056 mmol, 1.1 equiv.) was dissolved in degassed THF / EtN (10 mL / 30 mL). A solution of Pd[PPh3]4 (482 mg, 0.417 mmol, 0.15 equiv.) and CuI (159 mg, 0.834 After degassing the reaction mixture at room temperature for 5 min, alkyne 3 (400 mg, 2.78 mmol, 1 equiv.) was added dropwise and the reaction mixture was stirred at room temperature for 16 h. Completion (monitored by TLC) was confirmed. After completion, 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 give the desired conjugated piconaldehyde 4 as a colorless oil (500 mg, 72%). f (20% EtOAc + PE) 0.65; IR (neat) ν max 3026, 2928, 2856, 2229, 1710, 1580, 1451, 1211, 987, 805, 698, 647, 542 cm -1 ; 1 H NMR(400 MHz, CDCl3)δ(ppm)9.99(s, 1H, H 18), 7.82~7.71(m, 2H, H3, H4), 7.53(dd, J = 7.5 Hz, 1H, H5), 7.26~7.10(m, 5H, H 13 -H 17 ), 2.74(t, J = 7.5 Hz, 2H, H 11 ), 2.43(t, J = 7.1 Hz, 2H, H9), 1.92(quintet, J = 7.1, 7.5 Hz, 2H, H 10 ); 13 C NMR(100 MHz, CDCl3)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);HRMS (ESI) + C 17 H 16 NO + The calculated m / z value is 250.1226, and the measured value is 250.1239.

[0085] 6-(5-phenylpent-1-yn-1-yl)picolinaldehyde oxime 5: [ka]

[0086] Method 1: Aldehyde 4 (100 mg, 0.402 mmol, 1 equiv.), hydroxylamine hydrochloride (56 mg, 0.803 mmol, 2 equiv.), and CH3CO2Na (100 mg, 1.206 mmol, 3 equiv.) in dry ethanol (6 mL) was stirred at reflux for 16 h. Upon completion (as monitored by TLC), the solid was removed by centrifugation using a short column. The resulting mixture was filtered off through a pad of water, the solvent was evaporated and the residue was purified by column chromatography (EtOAc / PE 1:9) to give oxime 5 as a white solid (100 mg, 94%). f (20% 0.35 IR (neat method) max 3177, 3005, 2933, 2876, 2226, 1568, 1495, 1445, 1257, 1159, 985, 807, 734, 703, 657, 576, 490 cm -1 ; 1 H NMR(400 MHz, CDCl3)δ(ppm)8.85(s. 1H, OH), 8.24(s, 1H, H 18 ), 7.68(dd, J = 0.7, 7.8 Hz, 1H, H3), 7.56(t, J = 7.8 Hz, 1H, H4), 7.29(dd, J = 0.7, 7.7 Hz, 1H, H5), 7.29 ~7.08(m, 5H, H 13 -H 17 ), 2.71(t, J = 7.5 Hz, 2H, H 11 ), 2.39(t, J = 7.1 Hz, 2H, H9), 1.89(quintet, J = 7.1, 7.5 Hz, 2H, H 10 ); 13 C NMR(100 MHz, CDCl3)δ(ppm)151.95(C2), 150.51(C18), 144.46(C6), 141.33(C12), 136.73(C4), 128.50(C14, C16), 128.35(C13, HRMS (ESI) + C 17 H 17 N2O1 + The calculated m / z value is 265.1335, and the measured value is 265.1360.

[0087] Method 2: To a solution of oxime 2 (77 mg, 0.381 mmol, 1.1 equiv.) in degassed THF / Et3N (5 mL / 2 mL) was added Pd[PPh3]4 (60 mg, 0.052 mmol, 0.15 equiv.) and CuI (20 mg, 0.104 mmol, 0.3 equiv.). After the reaction mixture was degassed at room temperature for 5 min, alkyne 3 (50 mg, 0.347 mmol, 1 equiv.) was added dropwise and the reaction mixture was stirred at room temperature for 16 h. Upon completion (as monitored by TLC), the reaction mixture was After concentration under reduced pressure, the residue was purified by column chromatography (EtOAc / PE 1:9) to give The desired conjugated oxime 5 was obtained as a white solid (68 mg, 74%).

[0088] 6-(5-phenylpentyl)picolinaldehyde 6: [ka]

[0089] To a solution of 6-substituted piconaldehyde 4 (200 mg, 0.802 mmol, 1 equiv.) in degassed, dry EtOAc (4 mL) was added 10% Pd / C (21 mg, 0.201 mmol, 0.25 equiv.). After washing three times with H2, the reaction mixture was stirred at room temperature under H2 (1 atm) for 90 min. 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 give oxime 6 as a colorless liquid (185 mg, 91%). f (20% EtOAc + PE) 0.70; IR (neat) ν max 3026, 2929, 2856, 1709, 1591, 1455, 1213, 1089, 745, 689, 646, 570, 496 cm -1 ; 1 H NMR(400 MHz, CDCl3)δ(ppm)9.97 (s, 1H, H 18 ), 7.73~7.63(m, 2H, H 3,H4), 7.26(dd, J = 1.5, 7.7 Hz, 1H, H5), 7.24~7.05(m, 5H, H 13 -H 17 ), 2.80(t, J = 7.7 Hz, 2H, H7), 2.54(t, J = 7.7 Hz, 2H, H 11 ), 1.73 (quintet, J = 7.7 Hz, 2H, H8), 1.60 (quintet, J = 7.7 Hz, 2H, H 10 ), 1.35 (quintet, J = 7.3, 7.8 Hz, 2H, H9); 13 C NMR(100 MHz, CDCl3)δ(ppm)193.87(C18), 163.12(C6), 152.35(C2), 142.50(C12), 137.08(C4), 128.33(C14, C16), 128.20(C13, HRMS (ESI) + C 17 H 20 NO + The calculated m / z value is 254.1537, and the measured value is 254.1539.

[0090] 6-(5-phenylpentyl)picolinaldehyde oxime 7: [ka]

[0091] Aldehyde 6 (150 mg, 0.592 mmol, 1 equiv.), hydroxylamine hydrochloride (82 mg, 1.184 mmol, 2 equiv.), and CH3CO2Na (146 mg, 1.776 mmol, 3 equiv.) in dry ethanol (12 mL) was stirred at reflux for 16 h. After completion (monitored by TLC), the solid was 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 give the desired oxime 7 as a white solid (135 mg, 85%). f (20% EtOAc + PE) 0.40; IR (neat) ν max 3080, 2926, 2856, 1720, 1575, 1452, 1269 , 986, 780, 699, 658, 569, 458 cm -1 ; 1 H NMR(400 MHz, CDCl3)δ(ppm)10.20(br s, 1H, -OH), 8.30(s, 1H, H 18 ), 7.59(br d, J = 8.0 Hz, 1H, H3), 7.50(t, J = 7.8 Hz, 1H, H4), 7.27~6.93(m, 6H, H5, H 13 -H 17 ), 2.74(t, J = 7.8 Hz, 2H, H7), 2.50(t, J = 7.5 Hz, 2H, H 11 ), 1.68 (quintet, J = 7.5, 7.8 Hz, 2H, H8), 1.57 (quintet, J = 7.5 Hz, 2H, H 10 ), 1.32 (quintet, J = 7.1, 7.8 Hz, 2H, H9); 13 C NMR (100 MHz, CDCl3)δ(ppm)162.23, *160.10(C6), 151.36, *150.73(C2), 150.40 (C18), 142.61, *142.23(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) (*mixture of cis and trans); HRMS (ESI) + C 17 H 21 N2O + The calculated m / z value is 269.1648, and the measured value is 269.1670.

[0092] Synthesis of 6-pentadecylpicolinaldehyde oxime 10: [ka]

[0093] 6-(pentadeca-1-yn-1-yl)picolinaldehyde oxime 9: [ka]

[0094] To a solution of oxime 2 (51 mg, 0.252 mmol, 1.05 equiv.) in degassed THF / EtN (4 mL / 2 mL) was added Pd[PPh] (42 mg, 0.036 mmol, 0.15 equiv.) and CuI (14 mg, 0.072 mmol, 0.3 equiv.). After degassing the reaction mixture at room temperature for 5 min, alkyne 8 (50 mg, 0.240 mmol, 1 equiv.) was added dropwise, and the reaction mixture was stirred at room temperature for 16 h. Upon completion (monitored by TLC), the reaction mixture was After concentration under reduced pressure, the residue was purified by column chromatography (EtOAc / PE 6:94) to give The desired conjugated oxime 9 was obtained as a white solid (65 mg, 83%). f (20% EtOAc + PE) 0.55; IR (neat) ν max 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, CDCl3)δ(ppm)8.5 0(s, 1H, OH), 8.26(s, 1H, H22 ), 7.72(br d, J = 7.8 Hz, 1H, H3), 7.61(t, J = 7.8 Hz, 1H, H4), 7.23(br d, J = 7.7 Hz, 1H, H5), 2.41(t, J = 7.2 Hz, 2H, H9), 1.61(quintet, J = 7.2 Hz, 2H, H 10 ), 1.41(m, 2H, H1), 1.24(s, 18H, H 12 -H 20 ), 0.85(t, J = 6.5 Hz, 3H, H 21 ); 13 C NMR(100MHz, CDCl3)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);HRMS (ESI) + C 21 H 33 N2O1 + The calculated value is 329.2587 , the actual measured value is 329.2549.

[0095] 6-Pentadecylpicolinaldehyde oxime 10: [ka]

[0096] A solution of oxime 9 (35 mg, 0.107 mmol, 1 equiv.) in degassed, dry EtOAc (2 mL) was added to 10% Pd / C (3 mg, 0.027 mmol, 0.25 equiv) was added. After washing three times with H2, the reaction mixture was stirred at room temperature under H2 (1 atm) for 2 h. Upon 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). This gave oxime 3 as a white solid (30 mg, 85%); f (20% EtOAc + PE) 0.65; IR (neat) ν max 3187, 3083, 2914, 2849, 1575, 1457, 1160, 985, 777, 718, 656, 517 , 479 cm -1 ; 1 H NMR(400 MHz, CDCl3)δ(ppm)8.36(br s, 1H, OH), 8.25(s, 1H, H 22 ), 7.61~6.54(m, 2H, H 3, H4), 7.11(dd, J = 2.5, 6.1 Hz, 1H, H5), 2.78(t, J = 7.2 Hz, 2H, H7), 1.70(m, 2H, H8), 1.24(s, 24H, H 12 -H 20 ), 0.86(t, J = 6.6 Hz, 1H, H 21 ); 13 C NMR(100MHz, CDCl3)δ(ppm)162.71(C6), 151.12(C2), 151.02(C23), 136.73(C4), 123.09(C5), 118.21( C3), 38.28, 31.92, 29.99, 29.69, 29.56, 29.49, 29.41, 29.36, 22.69, 14.12 (C7-C22);HRMS (ESI) + C 21 H 37 N2O + The calculated m / z value is 333.2900, and the measured value is 333.2918.

[0097] Synthesis of 2-((hydroxyimino)methyl)-6-(pyridin-1-ium-3-ylethynyl)pyridin-1-ium chloride 13: [ka]

[0098] 3-Fluoro-6-(pyridin-3-ylethynyl)picolinaldehyde oxime 12: [ka]

[0099] To a solution of oxime 2 (211 mg, 1.05 mmol, 1.05 equiv) in degassed THF / Et3N (3 mL / 3 mL) was added Pd[PPh3]4 (173 mg, 0.15 mmol, 0.15 equiv) and CuI (57 mg, 0.30 mmol, 0.3 equiv). After the reaction mixture was degassed at room temperature for 5 min, a solution of alkyne 11 (103 mg, 1 mmol, 1 equiv.) in degassed, dry THF (3 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 16 h. Upon completion (as monitored by TLC), the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (EtOAc / PE Purification by HPLC (45:55) afforded the desired conjugated oxime 12 as a white solid (200 mg, 90%). f (60% EtOAc + PE) 0.35; IR (neat) ν max 3065, 2764, 1578, 1561, 1443, 1288, 1143, 1042, 990, 981, 798, 697, 637, 563, 499 cm -1 ; 1 H NMR(400 MHz, 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 = 7.8 Hz, 1H, H4), 7.83(br d, J = 7.8 Hz, 1H, H3), 7.68(br d, J = 7.8 Hz, 1H, H5), 7.50(dd, J = 4.8, 7.8 Hz, 1H, H 11 ); 13C NMR(100MHz, DMSO-d6)δ(ppm)152.855(C2), 151.93(C14), 149.70(C12), 148.34(C15), 141.51(C6), 139.03(C1 0), 137.65(C4), 127.50(C5), 123.78(C11), 119.84(C3), 118.48(C9), 91.27(C7), 85.48(C8);HRMS (ESI) + C 13 H 10 N3O + The calculated m / z value is 224.0818, and the measured value is 224.0840.

[0100] 2-((hydroxyimino)methyl)-6-(pyridin-1-ium-3-ylethynyl)pyridin-1-ium chloride 13: [ka]

[0101] To a solution (1 mL) of compound 12 (40 mg) in water, 1.2N HCl (1 mL) was added and stirred for 2 minutes. It was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to give the HCl salt 13 as a white solid in quantitative yield. IR (neat) ν max 3018, 2970, 2502, 2080, 1561, 1465, 1290 , 1005, 813, 726, 674, 548, 499 cm -1 ; 1 H NMR(400 MHz, D2O)δ(ppm)9.05(br s, 1H), 8.83(br d, J = 5.8 Hz, 1H), 8.75(dt d, J = 1.6, 8.3 Hz, 1H), 8.19(s, 1H), 8.15~8.04(m, 2H), 7.87(dd, J = 0.6, 8.0 Hz, 1H), 7.81(br d, J = 0.6, 7.8 Hz, 1H); 13C NMR(100 MHz, D2O)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;HRMS (ESI) + C 13 H 10 N3O + The calculated m / z value is 224.0818, and the measured value is 224.0826.

[0102] Synthesis of 6-(4-(naphthalen-1-ylamino)butyl)picolinaldehyde oxime 20: [ka]

[0103] 2-(Naphthylamino)ethanol 15: [ka]

[0104] For the synthesis of substituted aromatic amines, see Couty et al. 1 A solution of 1-iodonaphthalene 14 (2.50 g, 9.8 mmol) in DMSO (2 mL) containing 2-aminoethanol (1.78 mL, 29.5 mmol), copper chloride (132 mg, 1.0 mmol), and freshly ground KOH (1.10 g, 19.7 mmol) was stirred at room temperature for 18 h. A saturated aqueous solution of NH4Cl (5 mL) was added to the maroon solution, and the resulting mixture was stirred for 18 h. The solution was extracted (EtOAc, 3 x 20 mL). The combined extracts were washed (brine, 20 mL), dried (MgSO4), filtered and concentrated in vacuo. Chromatography on silica gel (powdered silica gel) Evaporation of the oil (30% EtOAc in ether) gave the title compound 15 (1.68 g, 9.0 mmol) as a beige oil. IR (neat) ν max 3404, 3051, 2973, 2869, 1581, 785 cm -1 ; 1H NMR(400 MHz, CDCl3)δ(ppm)7.93~7.76(m, 2H, ArH), 7.52~7.29(m, 4H, ArH), 6.67(d, J = 7.3 Hz, 1H, CHCNH), 4.01(t, J = 5.1 Hz, 2H, NHCH2CH2OH), 3.49(t, J = 5.1 Hz, 2H, NHCH2CH2OH); 13 C NMR(101 MHz, CDCl3)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.

[0105] 2-[(2-hydroxyethyl)(naphthalen-1-yl)amino]acetonitrile 16: [ka]

[0106] For the N-cyanomethylation of aromatic aminoethanols, Couty et al. 1 The procedure was followed. 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 at 90 °C for 18 h. The white suspension was cooled to room temperature, and the reaction mixture was added with TMSCN (1.06 mL, 8.0 mmol) and AcOH (0.46 mL, 8.0 mmol). The pale yellow reaction solution was stirred at 90°C for 18 hours. The reaction was cooled to room temperature and diluted with H2O (40 mL ) was added and the aqueous mixture was extracted (CH2Cl2, 10 mL). The organic extract was washed with aqueous NaOH (1 M, 20 mL), brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo. Column chromatography (30% EtOAc in light petroleum ether) afforded the title compound 16 (850 mg, 3.8 mmol, 94% over two steps) as a colorless solid. Melting point: 70-71 °C (literature 1 71 ~73°C); IR (neat method) max 3422, 3050, 2956, 2236, 1705, 1418, 802 cm -1 ; 1 H NMR(400 MHz, CDCl3)δ(ppm)8.17(d, J = 8.3 Hz, 1H, 8-CH), 7.91(d, J = 7.6 Hz, 1H, 2-CH), 7.75(d, J = 7.6 Hz, 1H, 4-CH), 7.61~7.42(m, 4H, ArH), 4.17 (s, 2H, CH2CN), 3.78(br t, J = 5.0, 2H, NCH2CH2OH), 3.54(t, J = 5.0 Hz, 2H, NCH2CH2OH); 13 C NMR(101 MHz, CDCl3)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.

[0107] 1-(Naphthalen-1-yl)azetidine-2-carbonitrile 17: [ka]

[0108] For the production of aromatic azetidines, Couty et al. 1 The procedure was followed. To a solution of 2-[(2-hydroxyethyl)(naphthalen-1-yl)amino]acetonitrile 16 (500 mg, 2.2 mmol) and EtN (0.77 mL, 5.5 mmol) in CHCl (10 mL) was added dropwise at 0 °C. The colorless reaction solution was stirred at 0 °C for 30 min and gradually warmed to room temperature. The reaction was stirred at room temperature for an additional 30 min. H2O (20 mL) was added, the organic layer was separated, and the aqueous layer was extracted (CHCl, 20 mL). The combined extracts were washed with aqueous HCl (2 M, 10 mL) and brine (10 mL), then dried (MgSO4), filtered, and concentrated in vacuo. The pale yellow residue was carried directly to the next step. This solution was added to anhydrous THF (15 mL) at 0°C. t BuOK (297 mg, 2.6 mol) The reaction was allowed to warm slowly to room temperature and H2O (20 mL) was added. The solution was extracted (with EtOAc , 3 × 20 mL), and the combined organics were washed with brine (20 mL), dried (MgSO4), filtered, and concentrated in vacuo. Chromatography on silica gel (10% EtOAc in light petroleum ether) afforded the title compound 17 (850 mg, 3.8 mmol, 94% over two steps) as a colorless solid. mp 129–131 °C (literature 1 130-131°C); IR (neat method) max 3433, 3045, 2958, 2248, 1577, 788 cm -1 ; 1 H NMR(400 MHz, CDCl3)δ(ppm)7.96~7.82(m, 2H, ArH), 7.56~7.38(m, 4H, ArH), 6.75(d, J = 7.3 Hz, 1H, 2-CH), 4.93(dd, J = 8.3, 6.6 Hz, 1H, NCH2CH2CHCN), 4.51(ddd, J = 8.3, 6.6, 4.9 Hz, 1H, NCHHCH2CHCN), 3.88( dt, J = 8.3, 6.8 Hz, 1H, NCHHCH2CHCN), 2.91~2.80(m, 1H, 2H, NCH2CHHCHCN), 2.78~2.66(m, 1H, NCH2CHHCHCN); 13 C NMR(101 MHz, CDCl3)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 .

[0109] N-(3-butyn-1-yl)naphthylamine 18: [ka]

[0110] For the production of aromatic homopropargylamines from aromatic azetidines, Couty et al. 1 To a solution of 1-(naphthalen-1-yl)azetidine-2-carbonitrile 17 (1.00 g, 4.8 mmol) in toluene (15 mL) was added dibutyltin oxide (298 mg, 1.2 mmol) and TMSN3 (0.95 mL, 7.2 mmol) was added and the reaction was stirred at 60 °C for 96 h. The brown reaction solution was cooled to room temperature and concentrated in vacuo. Chromatography on silica gel (2% EtOAc in hexanes) afforded the title compound 18 (454 mg, 2.3 mmol, 48%) as a colorless oil. IR (neat) v max 3293, 3050, 2975, 2117, 1690, 767 cm -1 ; 1 H NMR(400 MHz, CDCl3)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 = 7.3 Hz, 1H, 2-CH), 3.50(t, J = 6.5 Hz, 2H, NHCH2CH2CCH), 2.69(td, J = 6.5, 2.7 Hz, 2H, NHCH2CH2CCH), 2.11(t, J = 2.7, 1H, NHCH2CH2CCH); 13 C NMR(101 MHz, CDCl3)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.

[0111] N-(4-{6-[(hydroxyimino)methyl]pyridin-2-yl}but-3-yn-1-yl)naphthalen-1-amine 19: [ka]

[0112] To a solution of N-(3-butyn-1-yl)naphthylamine 18 (400 mg, 2.0 mmol) in degassed anhydrous THF / EtN (7 mL / 3 mL) was added Pd(PPh) (238 mg, 0.2 mmol) and CuI (78 mg, 0.4 mmol). To the resulting orange reaction mixture was added dropwise a solution of 6-bromopicolinaldehyde oxime 2 (453 mg, 2.2 mmol) in degassed anhydrous THF (20 mL). The brown solution was stirred at room temperature for 16 h. The reaction was concentrated in vacuo. Purification was performed by silica gel chromatography (H. The title compound 19 (350 mg, 54%) was obtained by distillation of toluene (from hexane to 10% EtOAc in hexane). It was obtained as an orange solid, melting point 143-144°C; 1 H NMR(400 MHz, CDCl3)δ(ppm)8.28(s, 1H, NOH), 7.95~7.73(m, 4H, ArH), 7.67(t, J = 7.8 Hz, 1H, 3-CH), 7.53~7.33(m, 4H, ArH), 6.70(d, J = 7.8 Hz, 1H, 2-CH), 3.66(t, J = 6.7 Hz, 2H, NHCH2CH2), 2.96(t, J = 6.7 Hz, 2H, NHCH2CH2); 13 C NMR(101 MHz, CDCl3)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 , 123.8, 120.0, 119.8, 105.2, 88.6, 81.4, 42.6, 19.8; IR (NEAT method) v 3350, 3152, 3047, 2864, 2645, 2200 cm -1 ;HRMS (ESI) + C 20 H 18 N3O + The calculated m / z value is 316.1444, and the measured value is 316.1445.

[0113] N-(4-{6-[(hydroxyimino)methyl]pyridin-2-yl}but-3-yn-1-yl)naphthalen-1-amine 20: [ka]

[0114] To a 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 degassed anhydrous methanol (10 mL) was added Pearlman's catalyst (77 mg, 0.5 mmol). The reaction vessel was evacuated and flushed with hydrogen gas five times. The black reaction mixture was stirred at room temperature for 18 h. Celite was added. The catalyst was removed by filtration through filtration and the solvent was removed in vacuo. Chromatography on silica gel (50% EtOAc in hexanes) afforded the title compound 20 (60 mg, 34%) as a colorless solid. Melting point 151-152°C; IR (neat) v max 3351, 3047, 2867, 2642 cm -1 ; 1 H NMR(400 MHz, CDCl3)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 = 8.2 Hz, 1H, NCCHCHCH), 7.15(d, J = 8.2 Hz, 1H, NCCHCHCH), 7.09(dd, J = 7.1, 1.7 Hz, 1H, 7-CH), 6.53(d, J = 7.5 Hz, 1H, 2-CH), 3.26(t, J = 6.9 Hz, 2H, NHCH2CH2CH2CH2), 2.85(t, J = 6.7 Hz, 2H, NHCH2CH2CH2CH2), 2.00~1.65(m, 4H, NHCH2CH2CH2CH2); 13 C NMR(101 MHz, CDCl3)δ(ppm)162.0, 151.1, 151.0, 143.4, 137.1, 134.3, 128.6, 126.6, 125.7, 124.7, 123.4, 123.3, 119.9, 118.6, 117.3, 104.4, 44.1, 37.7, 28.8, 27.6;HRMS (ESI) + C 20 H 22 N3O + The calculated m / z value is 320.1757, and the measured value is 320.1759. References: 1.Couty et al. J. Org. Chem. 2016, 81, 2899-2910 2.Couty et al. Chem. Comms. 2016, 52, 10072-10075

[0115] Synthesis of methyl 3-hydroxy-6-(4-(quinolin-4-ylamino)butyl)picolinate 26: [ka]

[0116] 4-Bromoquinoline 22: [ka]

[0117] For the synthesis of bromoquinolines, see Margolis et al. 1 The procedure was followed. To a solution of 4-quinolinol 21 (5.00 g, 34.4 mmol) in DMF (50 mL) was added PBr3 (3.34 mL, 35.5 mmol) dropwise at 60 °C. Upon addition, a color change from yellow to bright orange accompanied by effervescence was observed. The orange reaction mixture was stirred at 45 °C for 45 min. The solution was cooled to room temperature, diluted with H2O (20 mL), and saturated aqueous NaHCO3 was slowly added to basify the reaction mixture to pH 10. Solution The residue was extracted with CH2Cl2 (5 × 20 mL), and the organic solution was then mixed with HO (20 mL), washed, dried (MgSO4), filtered, and concentrated in vacuo. Chromatography on silica gel (EtOAc) afforded the title compound 22 (5.56 g, 26.7 mmol, 78%) as a cream solid. Physical and spectroscopic data are reported. 2 The melting point is 28-29°C (see literature). 2 29.5~30.5°C); IR (neat method) v 3062, 1615, 1058 cm -1 ; 1 H NMR(400 MHz, CDCl3)δ 8.68(d, J = 4.6 Hz, 1H, NCH), 8.20(dd, J = 8.4, 0.9 Hz, 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, 1.4 Hz, 1H, NCCHCHCHCH); 13 C NMR (100 MHz, CDCl3)δ 149.9, 149.0, 134.2, 130.4, 129.9, 127.9, 127.9, 126.8, 125.1.

[0118] N-(but-3-yn-1-yl)quinolin-4-amine 24: [ka]

[0119] For the synthesis of alkylated quinolines, see Musonda et al. 3 Commercially available 3-butyn-1-amine 23 (4.72 mL, 57.7 mmol) was converted to 4-bromoquinoline 22 (3.00 g, 14.4 mmol) according to the procedure in After addition, a thin cream-colored paste was formed, which was then heated at 80°C for 1 hour without stirring. The temperature was increased to 140°C and the paste was heated with stirring for 18 hours. The brown reaction mixture was cooled to room temperature and purified by chromatography on silica gel (20% MeOH in EtOAc) to give the title compound 24 (2.82 g, 14.4 mmol, 100%) as a cream solid. Melting point: 165-166°C; IR (neat method) max 3281, 3169, 3067, 1573, 1151 cm -1 ; 1 H NMR(400 MHz, DMSO-d6)δ 8.45(d, J = 5.9 Hz, 1H, NCH), 8.30(dd, J = 8.3, 1.2 Hz, 1H, NCCHCHCHCH), 7.93(br. s, 1H, NH), 7.82(dd, J = 8.3, 1.2 Hz, 1H, NCCHCHCHCH), 7.71(ddd, J = 8.3, 7.0, 1.2 Hz, 1H, NCCHCHCHCH), 7.51(ddd, J = 8.3, 7.0, 1.2 Hz, 1H, NCCHCHCHCH), 6.63(d, J = 5.9 Hz, 1H, NCHCH), 3.54(q, J = 7.0 Hz, 2H, NHCH2CH2CCH), 2.91(t, J = 2.7 Hz, 1H, NHCH2CH2CCH), 2.58(td, J = 6.8, 2.7 Hz, 2H, NHCH2CH2CCH); 13 C NMR(100 MHz, DMSO-d6)δ 151.3, 148.2, 145.1, 130.2, 126.4, 124.7, 122.1, 118.1, 98.3, 82.1, 72.6, 41.4, 17.8;HRMS (ESI) + C 13 H 13 N2 + The calculated m / z value is 197.1073, and the measured value is 197.1072.

[0120] 6-(4-(quinolin-4-ylamino)but-1-yn-1-yl)picolinaldehyde oxime 25: [ka]

[0121] To a solution of N-(but-3-yn-1-yl)quinolin-4-amine 24 (1.00 g, 5.1 mmol) in degassed anhydrous THF / EtN (50 mL / 15 mL) was added Pd(PPh) (588 mg, 0.5 mmol) and CuI (194 mg, 1.0 mmol). The resulting orange reaction mixture was treated with 6-bromopicolinyl chloride. A solution of degassed anhydrous THF (20 mL) containing dehydroxime 2 (1.13 g, 5.6 mmol) was added dropwise. The solution was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo. Chromatography on silica gel (20% MeOH in EtOAc) gave the title compound 25 (1.55 g, 4.9 mmol, 96%). It was obtained as a pale orange solid. Melting point: 202-203°C (after decomposition); IR (neat method) νmax: 3291, 3068, 2947, 2241, 1617, 1222, 1051 cm -1 ; 1 H NMR(400 MHz, DMSO-d6)δ 11.90~11.69(m, 1H, CHNOH), 8.43(br d, J = 5.4 Hz, 1H, NCH), 8.23(d, J = 8.3 Hz, 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 = 5.4 Hz, 1H, NCHCH, 3.61(q, J = 6.7 Hz, 2H, NHCH2CH2), 2.88(t, J = 6.7 Hz, 2H, NHCH2CH2); 13 C NMR(100MHz, DMSO-d6)δ HRMS (ESI) + C 19 H17 N4O + The calculated m / z value is 317.1397, and the measured value is 317.1396.

[0122] 3-Hydroxy-6-(4-(quinolin-4-ylamino)butyl)methyl picolinate 26: [ka]

[0123] (E)-6-(4-(quinolin-4-ylamino)but-1-yn-1-yl)picolinaldehyde oxime 25 (575 mg, 1.8 mmol) was suspended in degassed anhydrous methanol (20 mL). Pearlman's catalyst (255 mg, 1.8 mmol) was added, and the reaction vessel was evacuated and flushed with hydrogen gas five times. The black reaction mixture was stirred at room temperature for 18 h. The catalyst was removed by filtration through Celite, and the solvent was removed in vacuo to give the title compound 26 (550 mg, 1.7 mmol, 94%) as a cream solid. Melting point: 218-219°C; IR (neat method) max 3145, 3026, 2985, 1593, 1224, 1026, 658 cm -1 ; 1 H NMR(400 MHz, D2O)δ 8.15(s, 1H, CHNOH), 8.01(d, J = 7.1 Hz, 1H, NCH), 7.89~7.49(m, 7H, ArH), 6.62(d, J = 7.1 Hz, 1H, NCHCH), 3.54(t, J = 6.6 Hz, 2H, NHCH2CH2CH2CH2), 3.09(t, J = 7.2 Hz, 2H, NHCH2CH2CH2CH2), 1.99 ~1.76(m, 4H, NHCH2CH2CH2CH2); 13 C NMR(100 MHz, D2O)δ 156.1, 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; HRMS (ESI) + C 19 H 21 N4O + The calculated m / z value is 321.1710, and the measured value is 3321.1713. References: 1.Margolis, BJ et al. J. Org. Chem. 2007, 72, 2232-2235 2.Charette, AB, et al. J. Org. Chem. 2017, 82, 5046-5067 3.Musonda, C. C et al. Bioorg. Med. Chem. Lett. 2007, 17, 4733-4736

[0124] Synthesis of 6-(4-((5-fluoroquinolin-4-yl)amino)butyl)picolinaldehyde oxime 31: [ka]

[0125] 4-Bromo-5-fluoroquinoline 28: [ka]

[0126] For the synthesis of substituted quinolines from anilines, see Kilpin Guy et al. 1 The procedure and Kinorino For the synthesis of bromoquinolines of the formula, see Pulley et al. 2 Follow the procedure in m-Fluoroaniline To a solution of 27 (6.00 g, 54.0 mmol) in EtOH (100 mL) was added Meldrum's acid (9.49 g, 65.9 mmol) and triethyl orthoformate (21.3 mL, 128.0 mmol) at room temperature. The yellow solution was stirred at 90 °C for 2.5 h. The solution was cooled to 0 °C, and the resulting yellow solid was filtered and diluted with cold EtOH. The resulting pale yellow solid was dried and added slowly over 5 minutes to refluxing diphenyl ether (50 mL) at 280°C. Upon 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 allowed to cool to room temperature. During this time, the solution turned a much darker brown color. Petroleum ether (50 mL) was added to the solution. The resulting brown crystals were separated by filtration. Chromatography on silica gel (10% MeOH in EtOAc) gave an inseparable mixture of 5-fluoroquinolin-4-ol and 7-fluoroquinolin-4-ol ( 19 The yield was approximately 9:1 by F NMR, 7.76 g, 47.5 mmol), which was carried on directly to the next step.

[0127] To a DMF solution (30 mL) of an inseparable mixture of 5-fluoroquinolin-4-ol and 7-fluoroquinolin-4-ol regioisomers (4.00 g, 24.5 mmol), phosphorus tribromide (1.86 mL, 19.7 mmol) was added at 60° C., and the mixture was stirred at 45° C. for 45 min. After cooling to room temperature, H2O (25 mL) was added, and the pH of the solution was adjusted to 10 by adding a saturated aqueous solution of Na2CO3. The crystals were washed with HO (10 mL). Chromatography on silica gel (25% EtOAc in hexane) gave 4-bromo-5-fluoroquinoline 28 (2.50 g, 11.1 mmol, 61% over three steps). ) was obtained as an orange solid. Melting point: 89-90°C; IR (neat method) values: 3091, 3041, 1621 cm -1 ; 1 H NMR(400 MHz, CDCl3)δ 8.67(d, J = 4.6 Hz, 1H, NCH), 8.22(dd, J = 9.2, 5.9 Hz, 1H, NCCH), 7.75(dd, J = 9.2, 2.7 Hz, 1H,NCCHCHCH), 7.68(d, J = 4.6 Hz, 1H, NCHCH), 7.44(ddd, J = 9.2, 5.9, 2.7 Hz, 1H, NCCHCH); 13 C NMR(100 MHz, CDCl3)δ 161.9, 150.6, 149.6, 133.7, 128.9, 124.7, 124.1, 118.0, 113.1; 19 F NMR(376 MHz, CDCl3)δ 108.7;HRMS (ESI) + C9H6BrFN + The calculated m / z value is 225.9662 , the actual measured value is 225.9658.

[0128] N-(but-3-yn-1-yl)-5-fluoroquinolin-4-amine 29: [ka]

[0129] For the synthesis of alkylated quinolines, see Musonda et al. 3 The procedure was followed. 3-Butyn-1-amine 23 (0.55 mL, 6.6 mmol) was added to 4-bromo-5-fluoroquinoline 28 (1.50 g, 6.6 mmol) to produce a pale orange paste. The paste was heated to 100 °C with stirring for 18 h. The reaction was heated to 120 °C for an additional 2 h. The viscous brown reaction mixture was cooled to room temperature and purified by chromatography on silica gel (100% EtOAc to 20% MeOH in EtOAc) to give the title compound 29 (1.06 g, 4.9 mmol, 75%) as a cream solid. Melting point: 225-226°C; IR (neat method) max 3079, 2911, 2240, 1966 cm -1 ; 1 H NMR(400 MHz, DMSO-d6)δ 8.39(d, J = 5.4 Hz, 1H, NCH), 8.27(dd, J = 10.8, 8.3 Hz, 1H, NCCH), 7.47(dd, J = 10.8, 2.5 Hz, 1H, NCCHCHCH), 7.44~7.39(m, 1H, NHCH2CH2CCH), 7.35(ddd, J = 10.8, 8.3, 2.5 Hz, 1H, NCCHCHCH), 6.49(d, J = 5.4 Hz, 1H, NCHCH), 3.45 (q, J = 7.1 Hz, 2H, NHCH2CH2CCH), 2.88(t, J = 2.7 Hz, 1H, NHCH2CH2CCH), 2.55(td, J = 7.1, 2.7 Hz, 2H, NHCH2CH2CCH); 13 C NMR(100 MHz, DMSO-d6)δ 163.4, 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 F NMR(376 MHz, DMSO-d6)δ 112.1;HRMS (ESI) + C 13 H 12 FN2 + The calculated m / z value is 215.0979, and the measured value is 215.0983 Da.

[0130] 6-(4-((5-fluoroquinolin-4-yl)amino)but-1-yn-1-yl)picolinaldehyde oxime 30: [ka]

[0131] A solution of N-(but-3-yn-1-yl)-5-fluoroquinolin-4-amine 29 (0.50 g, 2.3 mmol) in degassed anhydrous THF / EtN (7 mL / 3 mL) was treated with Pd(PPh) (270 mg, 0.2 mmol) and To the resulting orange reaction mixture was added 6-bromopicolinaldehyde oxime 2 (516 mg, 2.6 mmol) in degassed anhydrous THF (20 mL). The brown solution was stirred at room temperature for 16 hours. The reaction was concentrated in vacuo. Silica gel chromatography (EtOAc) afforded the title compound 30 (140 mg, 0.4 mmol, 18%) as a pale cream solid. Melting point 168-169 °C; IR (neat) v max 3500, 3435, 3034, 2960, 2239, 1966, 1599, 991 cm -1 ; 1 H NMR(400 MHz, DMSO-d6)δ 11.79(s, 1H, CHNOH), 8.42(d, J = 5.4 Hz, 1H, NCHCH), 8.30(dd, J = 9.2, 7.1 Hz, 1H, NCCHCHCHCF), 8.02(s, 1H, CHNOH), 7.83~7.69(m, 2H, ArH), 7.53(t, J = 5.6 Hz, 1H, NHCH2CH2), 7.48(dd, J = 10.8, 2.7 Hz, 1H, NCCHCHCH), 7.41(d, J = 7.1 Hz, 1H, NCCHCHCHCF), 7.35(td, J = 8.7, 2.7 Hz, 1H, NCCHCHCH), 6.58(d, J = 5.4 Hz, 1H, NCHCH), 3.66~3.51(m, 2H, NHCH2CH2), 2.86(t, J = 7.0 Hz, 2H, NHCH2CH2); 13 C NMR (100 MHz, DMSO-d6)δ 163.4, 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 F NMR (376 MHz, DMSO-d6)δ 111.9;HRMS (ESI) + C 19 H 16 FN4O + The calculated m / z value of The actual measured value is 335.1298.

[0132] 6-(4-((5-fluoroquinolin-4-yl)amino)butyl)picolinaldehyde oxime 31: [ka]

[0133] To a suspension of 6-(4-((5-fluoroquinolin-4-yl)amino)but-1-yn-1-yl)picolinaldehyde oxime 30 (50 mg, 0.1 mmol) in degassed anhydrous methanol (5 mL) was added Pearlman's catalyst (21 mg, 0.1 mmol). The reaction vessel was evacuated and filled with hydrogen gas for 5 min. The black reaction mixture was stirred at room temperature for 18 h. The catalyst was removed by filtration through Celite, and the solvent was removed in vacuo to give the title compound 31 (50 mg, 0.1 mmol, 99%) as a cream solid. Melting point 206-207 °C; IR (neat) v max 3247, 2935, 2859, 1978, 1584, 806 cm -1 ; 1 H NMR(400 MHz, D2O)δ 8.44(t, J = 8.1 Hz, 1H, NCCHCHCH), 8.19(d, J = 7.3 Hz, 1H, NCHCH), 8.16~8.13(m, 2H, CHNOH, NHCH2CH2CH2CH2), 7.91~7.81(m, 2H, NCCHCHCHCF, NCCHCHCHCF), 7.70(d, J = 8.1 Hz, 1H, NCCHCHCH), 7.42~7.32(m, 2H, NCCHCHCH), 6.70(d, J = 7.3 Hz, NCHCH), 3.58(t, J = 6.8 Hz, 2H, NHCH2CH2CH2CH2), 3.12(t, J = 7.7 Hz, 2H, NHCH2CH2CH2CH2), 2.01~1.76(m, 4H, NHCH2CH2CH2CH2); 13 C NMR(100 MHz, D2O)δ 166.0, 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 F NMR(376 MHz, D2O)δ 103.1;HRMS (ESI) + C 19 H 22 FN4O + The calculated m / z value is 339.1980, and the measured value is 339.1980. References: 1.Kiplin Guy, R. et al. Bioorg. Med. Chem. Lett. 2005, 15, 1015-1018 2.Pulley et al. J. Org. Chem. 2007, 72, 2232-2235 3.Musonda, CC et al. Bioorg. Med. Chem. Lett. 2007, 17, 4733-4736

[0134] Synthesis of 6-(4-((8-methoxyquinolin-4-yl)amino)butyl)picolinaldehyde oxime 37: [ka]

[0135] 8-Methoxyquinolin-4-ol 33: [ka]

[0136] For the synthesis of substituted quinolines from anilines, see Kilpin Guy et al. 1 Follow the steps below. To a solution of nisidine 32 (2.50 g, 20.3 mmol) in EtOH (20 mL) was added Meldrum's acid (3.57 g, 24.8 mmol) and triethyl orthoformate (8.00 mL, 48.0 mmol) at room temperature. The 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 EtOH (20 mL). The resulting pale yellow solid was dried and added slowly over 5 minutes to refluxing diphenyl ether (50 mL) at 280°C. Upon 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 allowed to cool to room temperature. During this time, the solution turned a much darker brown color. Petroleum ether (50 mL) was added to the solution. The resulting yellow crystals were isolated by filtration. Chromatography on silica gel (5% MeOH in EtOAc) gave 8-methoxyquinolin-4-ol 33 (7.76 g, 47.5 mmol) as a pale orange solid, mp 168 °C (literature 2 : 168-169°C); IR (neat method) v 2921, 2851, 1272, 1041 cm -1 ; 1 H NMR(400 MHz, DMSO-d6)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-d6)δ(ppm)177.1, 149.0, 139.3, 130.5, 123.2, 119.1, 116.7, 111.4, 109.6, 56.6;HRMS (ESI) + C 10 H 10 NO2 + The calculated m / z value is 176.0706, and the measured value is 176.0707 .

[0137] 4-Bromo-8-methoxyquinoline 34: [ka]

[0138] For the synthesis of bromoquinolines from quinolinols, see Pulley et al. 3 Follow the steps in 8- A solution of methoxyquinolin-4-ol 33 (2.50 g, 14.3 mmol) in DMF (20 mL) was added at 60 °C. Phosphorus tribromide (1.54 mL, 16.4 mmol) was added, and the mixture was stirred at 45 °C for 45 min. After cooling to room temperature, HO (25 mL) was added, and the pH of the solution was adjusted to 10 with saturated aqueous NaCO. The resulting cream-colored crystals were filtered and washed with HO (10 mL) to give 4-bromo-5-fluoroquinoline 34 (2.58 g, 10.8 mmol, 76%) as a cream solid. Melting point 99-101°C. °C; IR (neat method) max 1252, 1085 cm -1 ; 1 H NMR(400 MHz, CDCl3)δ(ppm)8.69 (d, J=4.6 Hz, 1H, NCH), 7.78(d, J=8.1 Hz, 1H, BrCCCH), 7.75(d, J=4.8 Hz, 1H, BrCCH), 7.58(t, J=8.2 Hz, 1H, ArH), 7.14(d, J=8.0 Hz, 1H, ArH), 4.12(s, 3H, OMe); 13 C NMR(101 MHz, CDCl3)δ(ppm)155.5, 148.5, 134.1, 129.0, 128.0 , 125.8, 118.5, 108.5, 56.3; HRMS (ESI) + C 10 H9BrNO + The calculated m / z value is 237.9862, and the measured value is 237.9865.

[0139] N-(but-3-yn-1-yl)-8-methoxyquinolin-4-amine 35: [ka]

[0140] For the synthesis of alkylated quinolines, see Musonda et al. 4 3-Butyn-1-amine 23 (1.20 mL, 14.7 mmol) was added to 4-bromo-8-methoxyquinoline 34 (0.70 g, 2.9 mmol) to produce an orange / yellow paste. This paste was heated without stirring at 80 °C for 1 h. With stirring, the temperature was increased to 100°C over 18 hours. The colored 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 pale orange. It was obtained as an orange solid. Melting point: 154-155°C; IR (neat) max 3279, 2938, 2240, 753 cm -1 ; 1 H NMR(400 MHz, DMSO-d6)δ(ppm)8.36(d, J=5.4 Hz, 1H, NCH), 7.73(d, J=7.8 Hz, 1H, MeOCCHCHCH), 7.35(t, J=8.1 Hz, 1H, MeOCCHCH), 7.10(d, J=7.3 Hz, 1H, OMeCCH), 6.55(d, J=5.4 Hz, 1H, NCHCH), 3.91(s, 3H, OMe), 3.39~3.53(m, 2H, CH2CH2CCH), 2.89(t, J=2.6 Hz, 1H, CH2CH2CCH), 2.56(td, J=7.1, 2.7 Hz, 2H, CH2CH2CCH); 13 C NMR(101 MHz, DMSO-d6)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; HRMS (ESI) + C 14 H 15 N2O + The calculated m / z value is 227.1179, and the measured value is 227.1183.

[0141] 6-(4-((8-methoxyquinolin-4-yl)amino)but-1-yn-1-yl)picolinaldehyde oxime 36: [ka]

[0142] To a solution of N-(but-3-yn-1-yl)-8-methoxyquinolin-4-amine 35 (1.00 g, 4.4 mmol) in degassed anhydrous THF / EtN (7 mL / 3 mL) was added Pd(PPh) (511 mg, 0.4 mmol) and CuI (168 mg, 0.9 mmol). The resulting orange reaction mixture was treated with 6-bromo- Add dropwise a solution of 20 mL of degassed anhydrous THF containing 2 (977 mg, 4.8 mmol) of methylpicolinaldehyde oxime 2. The brown solution was stirred at room temperature for 16 hours. The reaction was concentrated in vacuo. Chromatography on alumina (basic) gel (10% MeOH in EtOAc) afforded the title compound 36 (400 mg, 1.1 mmol, 26%) as a yellow solid. Melting point 171-172 °C; IR (neat) v max 3084, 2900, 2236, 1617, 1277, 745 cm -1 ; 1 H NMR(400 MHz, DMSO-d6)δ 11.79(s, 1H, CHNOH), 8.35(d, J = 6.1 Hz, 1H, NCHCH), 7.98(m, 2H, NCC(OMe)CHCHCH, CHNOH ), 7.78(t, J = 7.8 Hz, 1H, NCCHCHCH), 7.72(d, J = 7.8 Hz, 1H, NCCHCHCH), 7.49(d, J = 8.2 Hz, 1H, NCC(OMe)CHCHCH), 7.39(d, J = 7.8 Hz, 1H, NCCHCHCH), 7.29(d, J = 8.2 Hz, 1H, NCC(OMe)CHCHCH), 6.84(d, J = 6.1 Hz, 1H, NCHCH), 3.99 (s, 3H, OMe), 3.71(br t, J = 7.0, 2H, NHCH2CH2), 2.90(t, J = 7.0 Hz, 2H, NHCH2CH2); 13 C NMR(100MHz, DMSO-d6)δ HRMS (ESI) + C 20 H 19 N4O2 + The calculated m / z value is 347.1503, and the measured value is 347.1506.

[0143] 6-(4-((8-methoxyquinolin-4-yl)amino)butyl)picolinaldehyde oxime 37: [ka]

[0144] To a suspension of 6-(4-((8-methoxyquinolin-4-yl)amino)but-1-yn-1-yl)picoline-aldehyde oxime 36 (110 mg, 0.3 mmol) in degassed anhydrous methanol (10 mL) was added Pearlman's catalyst (9 mg, 0.1 mmol). The reaction vessel was evacuated and filled with hydrogen gas. The black reaction mixture was stirred at room temperature for 18 hours. The catalyst was removed by filtration through Celite. The solvent was removed in vacuo to give the title compound 37 (40 mg, 0.1 mmol, 36%) as a cream solid. Melting point 107-108 °C; IR (neat) v max 2927, 1617, 1581, 980 cm -1 ; 11H NMR (400 MHz, MeOD-d6) δ 8.29 (d, J = 5.6 Hz, 1H, NCHCH), 8.08 (s, 1H, CHNOH), 7.71 - 7.57 (m, 3H, ArH), 7.34 (t, J = 8.2 Hz, 1H, NCC(OMe)CHCHCH), 7.24 - 7.19 (m, 1H, NCC(OMe)CHCHCH), 7.08 (d, J = 7.8 Hz, 1H, NCCHCHCH), 6.48 (d, J = 5.6 Hz, NCHCH), 3.98 (s, 3H, OMe), 3.36 (t, J = 7.1 Hz, 2H, NHCH2CH2CH2CH2 ), 2.83 (t, J = 7.1 Hz, 2H, NHCH2CH2CH2CH2), 1.94 - 1.66 (m, 4H, NHCH2CH2CH2CH2); 13 13C NMR (100 MHz, MeOD-d6) δ 163.2, 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: HRMS (ESI) + C 20 H 23 N4O2 + The calculated m / z value for C18H19N4O2 is 351.1816, and the measured value is 351.1817. References: 2. Kiplin Guy, R. et al. Bioorg. Med. Chem. Lett. 2005, 15, 1015 - 1018 3. Lauer et al. J. Am. Chem. Soc., 1946, 68, 1268 4. Pulley et al. J. Org. Chem. 2007, 72, 2232 - 2235 5. Musonda, C. C.; Little, S.; Yardley, V.; Chibale, K. Bioorg. Med. Chem. Lett. 2007, 17, 4733 - 4736

[0145] Synthesis of 6-(3-(4-benzylpiperazin-1-yl)propyl)picolinaldehyde oxime 43: [ka]

[0146] N-benzylpiperazine 39: [ka]

[0147] For the synthesis of benzylpiperazines, see Bozell and Biannic 1 To a solution of piperazine 38 (12.9 g, 149.0 mmol) in anhydrous CHCl (100 mL) was added benzyl bromide (3.56 mL, 29.8 mmol) dropwise at 0 °C. The reaction was stirred at 0 °C for 1 h. The pale yellow solution was diluted with saturated NaHCO The mixture was washed with aqueous solution (2 × 50 mL), dried (NaSO), filtered, and concentrated in vacuo. Pure EtOH was added and a white precipitate was filtered from the solution. The solution was concentrated in vacuo to give the title compound 39 (24.8 g, 141.0 mmol, 94%) as a viscous yellow oil. IR (neat) ν max 3289, 2990, 2960, 2120, 1120cm -1 ; 1 H NMR(400 MHz, CDCl3)δ(ppm)7.36~7.28 (m, 5H, ArH), 3.50(s, 2H, CH2Ph), 2.90(t, J = 4.9 Hz, 4H, CH2N(Bn)CH2), 2.55~2.30(m, 5H, CH2NHCH2); 13 C NMR (101 MHz, CDCl3) δ (ppm) 138.1, 129.2, 128.2, 127.0, 63.7, 54.5, 46.1.

[0148] 1-Benzyl-4-propargylpiperazine 41: [ka]

[0149] For propargyl substitution of piperazines, see Corey, M. 2 To a solution of N-benzylpiperazine 39 (1.75 g, 9.93 mmol) was added propargyl bromide 40 (80% in toluene) ( A solution of DIPEA (1.28 mL, 14.9 mmol) and DIPEA (3.28 mL, 19.9 mmol) in CHCl (50 mL) was stirred at room temperature for 18 h. HO (30 mL) was added and the aqueous phase was separated and extracted (3 × 20 mL). The combined organic layers were washed (brine, 30 mL), dried (NaSO), filtered and concentrated in vacuo. Chromatography on silica gel (50% EtOAc in hexanes) afforded the title compound 41 (2.04 g, 9.5 mmol, 96%) as an orange oil. IR (neat) v max 3290 , 3026, 2933, 2807, 2117, 697 cm- 1 ; 1 H NMR(400 MHz, CDCl3)δ(ppm)7.37~7.28 (m, 5H, ArH), 3.56(s, 2H, PhCH2), 3.30(d, J = 2.5 Hz, 2H, NCH2CCH), 2.73~2.44(m, 8H, PizCH2), 2.25(t, J = 2.5 Hz, 1H, NCH2CCH); 13 C NMR(101 MHz, CDCl3)δ(ppm)129.5, 129.3, 128.3, 127.2, 78.9, 73.20, 62.8, 52.8, 51.7, 46.8;HRMS (ESI) + C x H x N x + The calculated m / z value is 215.1543 and the measured value is 215.1542.

[0150] 6-(3-(4-benzylpiperazin-1-yl)prop-1-yn-1-yl)picolinaldehyde oxime 42: [ka]

[0151] A solution of 1-benzyl-4-propargylpiperazine 41 (1.30 g, 6.1 mmol) in degassed anhydrous THF / EtN (7 mL / 3 mL) was treated with Pd(PPh) (0.70 g, 0.6 mmol) and CuI (0.23 g, 1.2 mmol). ) was added. To the resulting orange reaction mixture was added dropwise a solution of 6-bromopicolinaldehyde oxime 2 (1.34 g, 6.7 mmol) in degassed anhydrous THF (20 mL). The brown solution was stirred at room temperature for 18 h. The reaction was concentrated in vacuo. Chromatography on silica gel (EtOAc) afforded the title compound 42 (750 mg, 2.2 mmol, 37%) as a cream solid. Melting point 143-145 °C; IR (neat) v max 3150, 3048, 2944, 2808, 2364, 734 cm -1 ; 1 H NMR (400 MHz, CDCl3)δ(ppm)12.17(s, 1H, NOH), 7.99(s, 1H, CHNOH), 7.71(dd, J = 8.0, 1.0 Hz, 1H, NCCHCHCH), 7.53(t, J = 8.0 Hz, 1H, NCCHCHCH), 7.43~7.20(m, 6H, ArH), 3.70(s, 2H, NCH2CC), 3.63(s, 2H, PhCH2), 3.08~2.36(m, 8H, PizCH2); 13 C NMR(101 MHz, CDCl3)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; HRMS (ESI) + C 20 H 23 N4O + The calculated m / z value is 335.1866, and the measured value is 335.1863.

[0152] 6-(3-(4-benzylpiperazin-1-yl)propyl)picolinaldehyde oxime 43: [ka]

[0153] 6-(3-(4-benzylpiperazin-1-yl)prop-1-yn-1-yl)picolinaldehyde oxime 42 (200 mg, 0.6 mmol) suspended in degassed anhydrous methanol (10 mL) To this was added Pearlman's catalyst (44 mg, 0.3 mmol). The reaction vessel was evacuated and flushed with hydrogen gas five times. The black reaction mixture was stirred at room temperature for 2 hours. The catalyst was removed by filtration through Celite. The solvent was removed in vacuo. Chromatography on silica gel (CH2Cl2 to 10% MeOH in CH2Cl2) afforded the title compound 43 as a pale yellow oil (53%). IR (neat) v max 3162, 3057, 2939, 2816, 808 cm -1 ; 1 H NMR(400 MHz, CDCl3)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, 2.2 Hz, 1H, NCCHCHCH), 3.55(s, 2H, PhCH2), 2.82(t, J = 7.8 Hz, 1H, NCH2CH2CH2), 2.72~2.35(m, 10H, PizCH2, NCH2CH2CH2), 2.02(quintet,, J = 7.8 Hz, NCH2CH2CH2); 13 C NMR(101 MHz, CDCl3)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;HRMS (ESI) + C 20 H 27 N4O+ The calculated m / z value is 339.2179, and the measured value is 339.2176. References 1.Bozell. JJ et al. Org. Lett. 2013, 15, 2730-2733 2.Corey, M., et al. WO2017 / 184996 A1 (2017)

[0154] Synthesis of 6-(3-(4-benzylpiperazin-1-yl)propyl)picolinaldehyde oxime 48: [ka]

[0155] 3-Butynyl p-toluenesulfonate 45: [ka]

[0156] For the generation of p-toluenesulfonyl protected alcohols, Winssinger et al. 1 Follow the steps in To a solution of 3-butyn-1-ol 44 (3.00 g, 42.8 mmol), DMAP (522 mg, 4.3 mmol), and EtN (55.6 mL, 7.70 mmol) in CHCl (15 mL) was added dropwise at 0 °C with TsCl solution (8.98 g, 47.1 mmol). The yellow reaction solution was allowed to warm to room temperature and stirred for 2 h. H2O (30 mL) was added and the reaction was stirred at room temperature for 20 min. The organic layer was separated and the aqueous layer was extracted (CHCl, 5 × 40 mL). The combined extracts were dried (NaSO), filtered, and concentrated in vacuo. This gave the title compound 45 (9.60 g, 42.8 mmol, 100%) as a red / brown oil. IR (neat) Law)ν max 3433, 3045, 2958, 2248, 1577, 788 cm -1 ; 1H NMR(400 MHz, CDCl3)δ(ppm)7.81(d, J = 8.3 Hz, 2H, ArH), 7.36(d, J = 8.3 Hz, 2H, ArH), 4.11(t, J = 7.1 Hz, 2H, TsOCH2CH2CCH), 2.56(td, J = 7.1, 2.7 Hz, 2H, TsOCH2TsOCH2CH2CCH) , 2.46(s, 3H, PhCH3), 1.98(t, J = 2.7 Hz, 1H, TsOCH2CH2CCH); 13 C NMR (101 MHz, CDCl3) δ (ppm) 145.0, 132.8, 129.9, 128.0, 78.3, 70.7, 67.4, 21.6, 19.4.

[0157] 1-Benzyl-4-(but-3-yn-1-yl)piperazine 46: [ka]

[0158] For the production of alkylated piperazines, Guarna et al. 2 Follow the procedure in p-Toluene To a solution of 3-butynyl benzoate 45 (2.30 mL, 10.3 mmol) in DMF (60 mL) was added Na2CO3 (1.20 g, 11.3 mmol) and N-benzylpiperazine 39 (2.00 g, 11.3 mmol). The orange solution was stirred at 80 °C overnight. The reaction mixture was quenched with HO (10 mL) and ether (10 mL). ) was added. The organic layer was separated, washed with H2O (5 × 10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Chromatography on silica gel (100% CH2Cl2 to 10% MeOH in CH2Cl2) afforded the title compound 46 (1.70 g, 7.4 mmol, 72%) as an orange oil. IR (neat) ν max 3291, 3026, 2939, 2807, 2119, 1676, 697 cm -1 ; 1H NMR(400 MHz, CDCl3)δ(ppm)7.35~7.28(m, 5H, ArH), 3.52(s, 2H, PhCH2), 2.61(t, J = 7.6 Hz, 2H, NCH2CH2CCH), 2.58~2.42(m, 8H, PizCH2), 2.41~2.34(m, 2H, NCH2CH2CCH), 1.97(t, J = 2.7 Hz, 1H, NCH2CH2CCH); 13 C NMR(101 MHz, CDCl3)δ(ppm)138.1, 129.2, 128.2, 127.0, 82.8, 69.0, 63.0, 57.0, 52.9 , 52.8, 16.8; HRMS (ESI) + CxHxNx + The calculated m / z value is 229.1699, and the measured value is 229.1695.

[0159] 6-(4-(4-benzylpiperazin-1-yl)but-1-yn-1-yl)picolinaldehyde oxime 47: [ka]

[0160] To a solution of 1-benzyl-4-(but-3-yn-1-yl)piperazine 46 (1.55 g, 6.8 mmol) in degassed anhydrous THF / EtN (7 mL / 3 mL) was added Pd(PPh) (1.16 g, 0.7 mmol) and CuI (0.19 g, 1.4 mmol). The resulting orange reaction mixture was treated with 6-bromopicoline. A solution of aldehyde oxime 2 (1.50 g, 7.47 mmol) in degassed anhydrous THF (20 mL) was added dropwise. The brown solution was stirred at room temperature for 18 h. The reaction was concentrated in vacuo. Chromatography on silica gel (50% EtOAc in hexanes to EtOAc) gave the title compound 47 (150 mg, 0.4%). 134-136°C; IR (neat) v max 3161, 3060, 2954, 2808, 2231, 740 cm-1 ; 1 H NMR(400 MHz, CDCl3)δ(ppm)11.48(s, 1H, NOH), 8.20(s, 1H, CHNOH), 7.76(dd, J = 8.0, 1.0 Hz, 1H, NCCHCHCH), 7.59(t, J = 8.0 Hz, 1H, NCCHCHCH), 7.35~7.27(m, 6H, ArH), 3.56(s, 2H, PhCH2), 2.82~2.41(m, 12H, PizCH2, NCH2CH2CC); 13 C NMR(101 MHz, CDCl3)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; HRMS (ESI) + C 21 H 25 N4O + The calculated m / z value is 349.2023, and the measured value is 349.2018. References 1.Winsinger et al. Chem. Comms. 2010, 46, 5476-5478 2.Guarna et al. J. Med. Chem. 2010, 53, 7119-7128

[0161] 6-(4-(4-benzylpiperazin-1-yl)butyl)picolinaldehyde oxime 48: [ka]

[0162] A suspension of 6-(4-(4-benzylpiperazin-1-yl)but-1-yn-1-yl)picolinaldehyde oxime 47 (60 mg, 0.2 mmol) in degassed anhydrous methanol (5 mL) was Palladium (10% on carbon, 4 mg, 0.04 mmol) was added. The reaction vessel was evacuated and flushed with hydrogen gas five times. The black reaction mixture was stirred at room temperature for 1.5 h. The catalyst was removed by filtration through Celite and the solvent was removed in vacuo to give the title compound 48 (53 mg, 0.2 mmol, 87%) as a yellow oil. IR (neat) ν max 3181, 3060, 2938, 2818, 791 cm -1 ; 1 H NMR(400 MHz, CDCl3)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, 1.4 Hz, 1H, NCCHCHCH), 5.31(s, 2H, PhCH2), 2.82(t, J = 7.3 Hz, 2H, NCH2CH2CH2CH2), 2.59~2.31(m, 10H, PizCH2, NCH2CH2CH2CH2CH2), 1.76(quintet, J = 7.3 Hz, NCH2CH2CH2CH2), 1.58(br s, 2H, NCH2CH2CH2CH2CH2); 13 C NMR(101 MHz, CDCl3)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; HRMS (ESI) + C 20 H 27 N4O + The calculated m / z value is 353.2336, and the measured value is 353.2332.

[0163] Synthesis of 6-(4-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)but-1-yn-1-yl)picolinaldehyde oxime 51: [ka]

[0164] 1-(but-3-yn-1-yl)-3,7-dimethyl-dihydro-1H-purine-2,6-dione 50: [ka]

[0165] For the synthesis of substituted amines by the Mitsunobu reaction, see Ito et al. 1 3-Butyn-1-ol 44 (0.10 mL, 1.4 mmol), theobromine 49 (500 mg, 2.8 mmol), To a solution of (728 mg, 2.8 mmol) and triphenylphosphine (728 mg, 2.8 mmol) in THF (15 mL) was added ADDP (700 mg, 2.8 mmol) at room temperature. The yellow reaction mixture was heated to 60 °C for 24 h. The orange-colored reaction solution was diluted (H2O, 50 mL) and the aqueous solution was extracted (EtOAc, 3 x 20 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The white residue was evaporated onto silica gel. Purification by gel chromatography (EtOAc) gave 1-(but-3-yn-1-yl) )-3,7-Dimethyl-dihydro-1H-purine-2,6-dione 50 (120 mg, 0.5 mmol, 37%) was obtained as a white solid. Melting point: 192-193 °C; IR (neat) v max 3228, 3107, 2951, 1697, 1651 cm -1 ; 1 H NMR(400 MHz, DMSO-d6)δ(ppm)8.00(s, 1H, NCHN), 3.99(t, J = 7.6 Hz, 2H, NCH2CH2CCH), 3.87(s, 3H, NCHN(CH3)), 3.40(s, 3H, NCON(CH3)), 2.84(t, J = 2.7 Hz, 1H, NCH2CH2CCH), 2.45(td, J = 7.6, 2.7 Hz, 1H, NCH2CH2CCH); 13 C NMR(101 MHz, DMSO-d6)δ(ppm)154.6, 151.1, 148.7, 143.5, 107.0, 81.5, 73.0, 40.6, 33.6, 29.8, 17.3;HRMS (ESI) + C11 H 13 N4O2 + The calculated m / z value of is 233.1033 and the measured value is 233.1035, C 11 H 12 N4NaO2 + The calculated m / z value is 255.0852 and the measured value is 255.0857.

[0166] 6-(4-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)but-1-yn-1-yl)picolinaldehyde oxime 51: [ka]

[0167] To a solution of 1-(but-3-yn-1-yl)3,7-dimethyl-dihydro-1H-purine-2,6-dione 50 (200 mg, 0.9 mmol) in degassed anhydrous THF / EtN (7 mL / 3 mL) was added Pd(PPh) (99 mg, 0.1 mmol) and CuI (33 mg, 0.2 mmol). The resulting orange reaction mixture To the reaction mixture was added dropwise a solution of 6-bromopicolinaldehyde oxime 2 (190 mg, 1.0 mmol) in degassed anhydrous THF (10 mL). The brown solution was stirred at room temperature for 16 hours. The reaction was concentrated in vacuo. Concentration at rt gave an orange solid as crude product. Chromatography on silica gel (from EtOAc to 10% MeOH in EtOAc) gave the title compound 51 (111 mg, 0.3 mmol, 36%). Obtained as a colorless solid. Melting point: 210-211°C; IR (neat) max 3178, 3087, 2872, 2230, 1700, 1647, 759 cm -1 ; 1H NMR(400 MHz, DMSO-d6)δ 11.75(s, 1H, CHNOH), 8.03(s, 1H, CHNOH), 8.00(s, 1H, NCHN), 7.79(t, J = 8.1 Hz, 1H, NCCHCHCH), 7.73(dd, J = 8.1, 1.0 Hz, 1H, NCCHCHCH), 7.39(dd, J = 8.1, 1.0 Hz, 1H, NCCHCHCH), 4.12(t, J = 7.5 Hz, 2H, NHCH2CH2), 3.88(s, 3H, NCHN(CH3)), 3.42(s, 3H, NCON(CH3)), 2.75(t, J = 7.5Hz, 2H, NHCH2CH2); 13 C NMR(100MHz, DMSO-d6)δ HRMS (ESI) + C 17 H 17 N6O3 + The calculated m / z value is 353.1357, and the measured value is 353.1358. References 1.Ito, S. et al. Tet. Letts., 1993, 34, 1639-1642

[0168] II - Synthesis of bifunctional Neca analogues [ka]

[0169] (3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-N-(but-3-yn-1-yl)-2,2-dimethyltetrahydro-furo[3,4-d][1,3]dioxole-4-carboxamide 54: [ka]

[0170] The synthesis of (3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid 53 was reported by Debnath, J. et al. 1 This was achieved using the procedure.

[0171] To a stirred solution of acid 53 (500 mg, 1.56 mmol, 1 equiv.) in dry pyridine (15 mL) was added 1-amino-3-butyne 22 (140 μL, 1.71 mmol, 1.1 equiv.) and EDCI (598 mg, 3.12 mmol, 2 equiv.). (amounts) were added successively and the reaction mixture was stirred overnight at room temperature under nitrogen atmosphere. After completion, the reaction mixture was directly concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc to 95:5 EtOAc / MeOH) to afford the desired amide 54 as a pale yellow solid (500 mg, 80%). R f (pure EtOAc) 0.18; IR (neat) ν max 3289, 3142, 1672, 1601, 1526, 1206, 1090, 1058, 868, 789, 645, 514 cm -1 ; 1 H NMR (400 MHz, CDCl) δ (ppm )8.32(s, 1H), 7.89(s, 1H), 7.28(m, 1H), 6.33(s, 2H), 6.13(d, J = 2.5 H z, 1H), 5.47(dd, J = 2.1, 6.2 Hz, 1H), 5.39(dd, J = 2.5, 6.2 Hz, 1H), 4.74 (d, J = 2.1 Hz, 1H), 3.21(m, 2H), 2.21(m, 1H), 2.10(m, 1H), 1.82(t, J = 2.6 Hz, 1H), 1.63(s, 3H), 1.40(s, 3H); 13C NMR(100MHz, CDCl3)δ(ppm)168.98, 155.86, 153.11, 148.99, 139.82, 120.21, 114.37, 9 1.70, 86.33, 83.59, 82.88, 80.81, 69.83, 37.49, 26.95, 25.07, 18.85;HRMS (ESI) + C 17 H 21 N6O4 + Calculated m / z value is 373.1575, and the actual measured value is 373.1619.

[0172] (3aS,4S,6R,6aR)-6-(6-amino-9H-purin-9-yl)-N-(4-(6-formylpyridin-2-yl)but-3-yn-1-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide 55: [ka]

[0173] To a solution of methyl 6-bromopicolinaldehyde 1 (275 mg, 1.478 mmol, 1.1 equiv.) in degassed THF / Et3N (10 mL / 8 mL) was added Pd[PPh3]4 (233 mg, 0.202 mmol, 0.15 equiv.) and CuI (77 mg, 0.403 mmol, 0.3 equiv.). The reaction mixture was degassed at room temperature for 5 min, then cooled to room temperature with ethanol. A degassed THF solution (10 mL) of quinone 54 (500 mg, 1.344 mmol, 1 equiv.) was added dropwise, and the reaction mixture was cooled to room temperature. The mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (pure EtOAc to 9:1 EtOAc / MeOH) to give the desired coupled picolinaldehyde 55 as a thick syrup (510 mg, 80%). IR (neat) v max 3318, 1638, 1582, 1452, 1209, 1078, 868, 797, 646, 509 cm -1 ; 1H NMR(400 MHz, CDCl3)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(100MHz, CDCl3)δ(ppm)192.88, 169.13, 155.67, 153.12, 152.63, 148.97, 143.63, 139.87, 137.20, 130.8 5, 120.19, 114.62, 91.94, 88.87, 85.74, 83.55, 82.54, 80.66, 37.41, 27.09, 25.11, 20.08;HRMS (ESI) + C 23 H 24 N7O5 + The calculated m / z value is 478.1806, and the measured value is 478.1833.

[0174] (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-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide 56: [ka]

[0175] A solution of picolinaldehyde 55 (80 mg, 0.168 mmol, 1 equiv.), hydroxylamine hydrochloride (23 mg, 0.336 mmol, 2 equiv.), and CH3CO2Na (41 mg, 0.503 mmol, 3 equiv.) in dry ethanol was The solution (5 mL) was refluxed and stirred for 16 hours. After concentration under reduced pressure, the crude product was washed with CH2Cl2 (5 * 10 mL) to remove all impurities. The compound present in the round-bottom flask was pico- The phosphoric aldehyde oxime 56 was obtained by drying under high vacuum (82 mg, quantitative yield). , 1 Confirmed by H NMR. f (EtOAc); IR (neat method) ν max 3186, 2925, 1643, 1579 , 1207, 1089, 980, 867, 797, 726, 649, 509 cm -1 ; 1 H NMR(400 MHz, CDCl3)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 = 2.7 Hz, 1H), 5.35(dd, J = 2.0, 6.2 Hz, 1H), 5.29(dd, J= 2.7, 6.2 Hz, 1H), 4.74(d,J = 2.0 Hz, 1H), 3.41(m, 2H), 2.57~2.33(m, 2H), 1.59(s, 3H), 1.433(s, 3H); 13 C NMR(100MHz, CDCl3)δ(ppm)169.14, 155.54, 152.89, 152.05, 149.16, 148.60, 142.61, 139.82, 1 36.66, 126.72, 119.58, 119.47, 114.74, 91.86, 88.15, 85.78, 83.45, 82.68, 81.13 37.45, 27.11, 25.14, 20.21;HRMS (ESI) + C 23 H 25 N8O5 + The calculated m / z value is 493.1901, and the measured value is 493.1942.

[0176] (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: [ka]

[0177] To a stirred solution of oxime 56 (30 mg, 0.061 mmol, 1 equiv.) in dry MeOH (5 mL), 1.2 N HCl (185 μL, 0.610 mmol, 10 equiv.) was added, and the reaction mixture was stirred at 55 °C for 5 h. Upon completion, the reaction mixture was directly concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography (1:4 MeOH / HO) to give salt 57 as a white solid in quantitative yield. IR (neat method) )ν max 3192, 2927, 1644, 1580, 1448, 1305, 1254, 1045, 989, 808, 726, 642, 533 cm -1 ; 1 H NMR(400 MHz, CD3OD)δ(ppm)8.26(s, 1H), 8.25(s, 1H), 7.90(s, 1H ), 7.68(br d, J = 7.8 Hz, 1H), 7.0(t, J = 7.8 Hz, 1H), 7.13(d, J = 7.5 Hz, 1H), 6.30(d, J = 7.9 Hz, 1H), 4.85(s, 1H), 4.54(s, 1H), 4.39(br d, J = 4.3 Hz, 1H), 3.63(m, 2H), 2.74(m, 2H); 13 C NMR(100MHz, CD3OD)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;HRMS (ESI) + C 23 H 25 N8O5 + The calculated m / z value is 493.1901, and the measured value is 493.1942. References 1. Debnath, J. et al. Bioorg. Med. Chem. 2010, 18, 8257-8263

[0178] III - Synthesis of Bifunctional Pseudo-Neca Analogues [ka]

[0179] N-(9-((3aR,4R,6R,6aR)-6-(((3-(6-formylpyridin-2-yl)prop-2-yn-1-yl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-yl)benzamide 59: [ka]

[0180] The synthesis of N-(9-((3aR,4R,6R,6aR)-2,2-dimethyl-6-((prop-2-yn-1-yloxy)methyl)-tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-yl)benzamide 58 was reported by Silvia, F. et al. 1 This was achieved using known procedures.

[0181] To a solution of 6-bromopicolinaldehyde 1 (91 mg, 0.490 mmol, 1.1 equiv.) in degassed THF / EtN (3 mL / 2 mL) was added Pd[PPh] (77 mg, 0.067 mmol, 0.15 equiv.) and CuI (25 mg, 0.134 mmol, 0.3 equiv.). After degassing the reaction mixture at room temperature for 5 min, a degassed THF solution (3 mL) of alkyne 58 (200 mg, 0.445 mmol, 1 equiv.) was added dropwise, and the reaction mixture was stirred at room temperature for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (4:1 EtOAc / petroleum ether) to afford the desired coupled picolinaldehyde 59 from the concentrated silica gel. (200 mg, 81%). IR (neat method) max 2935, 1704, 1609, 1580, 1452 , 1248, 1210, 1074, 864, 709, 645, 541 cm-1 ; 1 H NMR(400 MHz, CDCl3)δ(ppm)9.97(s, 1H), 8.76(s, 1H), 8.32(s, 1H), 7.94(d, J= 7.6 Hz, 2H), 7.85~7.77 (m, 2H), 7.63~7.51(m, 2H), 7.45(t, J= 7.6 Hz, 2H), 6.25(d, J = 2.1 Hz, 2H), 5.32(dd, J= 2.1, 6.2 Hz, 1H), 5.03(dd, J= 2.1, 6.2 Hz, 1H), 4.56(q, J= 2.9 Hz, 1H), 4.37(s, 2H), 3.89~3.77(m, 2H), 1.61(s, 3H), 1.37(s, 3H) ; 13 C NMR(100MHz, CDCl3)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:HRMS (ESI) + C 29 H 27 N6O6 + The calculated m / z value is 555.2005, and the measured value is 555.1987.

[0182] N-(9-((3aR,4R,6R,6aR)-6-(((3-(6-(hydroxyimino)methyl)pyridin-2-yl)prop-2-yn-1-yl)oxy)methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-yl)benzamide 60; and [ka] 6-(3-(((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)prop-1-yn-1-yl)picolinaldehyde oxime 61: [ka]

[0183] Picolinaldehyde 59 (200 mg, 0.361 mmol, 1 equiv.), hydroxylamine hydrochloride (50 mg, 0.722 mmol, 2 equiv.), and CH3CO2Na (89 mg, 1.083 mmol, 3 equiv.) were dissolved in dry ethanol. The resulting solution (10 mL) was stirred at reflux for 16 hours. After completion, the reaction mixture was After concentration, the residue was purified by column chromatography, first from DCM to MeOH / DCM (2:98 ) to give 60 as a white solid (80 mg, 39%). IR (neat) v max 3196, 2924, 1698, 1610, 1581, 1453, 1246, 1210, 1075, 907, 727, 644, 551 cm -1 ; 1 H NMR(400 MHz, CDCl3)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 = 2.3 Hz, 2H), 5.31(dd, J = 2.3, 6.0 Hz, 1H), 5.03(dd, J = 2.3, 6.1 Hz, 1H), 4.48(br q, J = 3.4 Hz, 1H), 4.37, 4.30(2d, J = 16.1 Hz, 2H), 3.88(dd, J = 3.4, 10.3 Hz, 1H), 3.76(dd,J = 4.0, 10.3 Hz, 1H), 1.62(s, 3H), 1.38(s, 3H); 13C NMR(100MHz, CDCl3)δ(ppm)165.11, 152.73, 152.22, 151.35, 149.67, 149.37, 141.87, 136.74, 133.45, 132.69, 128.63, 12 7.92, 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;HRMS (ESI) + C 29 H 28 N7O6 + The calculated m / z value is 570.2075 The actual measured value is 570.2096.

[0184] Further elution (5:95 MeOH / DCM) gave 61 as a white solid (75 mg, 45%). IR (NEAT method) ν max 3176, 2925, 1639, 1450, 1374, 1207, 1077, 978, 865, 796, 717, 648, 510 cm -1 ; 1 H NMR(400 MHz, CDCl3)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 = 1.8 Hz, 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(100MHz, CDCl3)δ(ppm)155.35, 152.55, 152.47, 149.34, 149.08, 141.96, 139.32, 136.75, 1 32.82, 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;HRMS (ESI) + C 22 H 24 N7O5 +The calculated m / z value is 466.1812, and the measured value is 466.1833. References 1.Silvia, F. et al. J. Med. Chem. 2015, 58, 8269-8284

[0185] IV - Synthesis of Bifunctional 3-Methoxypyridine Aldoxime Analogues Synthesis of 3-methoxy-6-(5-phenylpentyl)picolinaldehyde oxime 65: [ka]

[0186] 3-Methoxy-6-(5-phenylpent-1-yn-1-yl)picolinaldehyde 63: [ka]

[0187] A solution of commercially available 6-bromo-3-methoxypicolinaldehyde 62 (75 mg, 0.347 mmol, 1.0 equiv.) in degassed THF / Et3N (4 mL / 2 mL) was treated with Pd[PPh3]4 (60 mg, 0.052 mmol, 0.15 equiv.) and and CuI (20 mg, 0.104 mmol, 0.3 equiv.) were added. After degassing the reaction mixture at room temperature for 5 min, alkyne 3 (50 mg, 0.347 mmol, 1 equiv.) was added dropwise, and the reaction mixture was stirred at room temperature for 16 h. After completion (as monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography. Purification by chromatography (1:4 EtOAc / PE) gave the desired conjugated methoxypiconaldehyde 63 as a colorless liquid (80 mg, 83%). f (30% EtOAc + PE) 0.25; IR (neat) ν max 2941, 2230, 1709, 1552, 1466, 1267, 1007, 747, 699, 542 cm -1 ; 1 H NMR(400 MHz, CDCl3)δ(ppm)10.21(s, 1H, H 18), 7.52(d, J = 8.8 Hz, 1H, H4), 7.33(d, J = 8.8 Hz, 1H, H5), 7.28~7.13(m, 5H, H 13 -H 17 ), 3.93(s, 3H, -OMe), 2.74(t, J = 7.5 Hz, 2H, H 11 ), 2.39(t, J = 7.1 Hz, 2H, H9), 1.91(quintet, J = 7.1, 7.5 Hz, 2H, H 10 ); 13 C NMR(100 MHz, CDCl3)δ(ppm)195.52(C18), 156.25, 141.28 , 140.73, 136.02, 132.0, 128.44, 128.32, 125.91, 120.41(Ar), 90.27(C7), 79.4 4(C8), 56.03(-OMe), 34.86(C11), 29.76(C10), 18.72(C9);HRMS (ESI) + C 18 H 18 N1O2 + The calculated m / z value is 280.1332, and the measured value is 280.1348.

[0188] 3-Methoxy-6-(5-phenylpent-1-yn-1-yl)picolinaldehyde oxime 64: [ka]

[0189] Aldehyde 63 (45 mg, 0.161 mmol, 1 equiv.), hydroxylamine hydrochloride (22 mg, 0.322 A solution of (40 mg, 0.483 mmol, 2 equiv.) and CH3CO2Na (40 mg, 0.483 mmol, 3 equiv.) in dry ethanol (3 mL) was stirred at reflux for 16 h. After completion (monitored by TLC), the solid was removed by a short Celite pad. The solvent was removed by filtration through a filter, evaporated under reduced pressure, and the residue was purified by column chromatography (3 Purification with 1:7 EtOAc / PE gave oxime 64 as a white solid (45 mg, 95%). f (50% EtOAc + PE) 0.35; IR (neat) ν max 3247, 2938, 2234, 1564, 1463, 1263, 975, 828, 745, 698, 649, 487 cm -1 ; *1 H NMR(400 MHz, CDCl3)δ(ppm)10.42(br s, 1H, OH), 8.42, 8.10(2s, 1.2H, H 18 , H 18’ ), 7.46~7.19(m, 7.6 H, Ar), 3.94, 3.91(2s, 3.6H, -OMe), 2.81, 2.80(2t, J= 7.5 Hz, 2.4H, H 11 , H 11’ ), 2.47, 2.44(2t, J = 7.1 Hz, 2.4H, H9, H 9’ ), 2.02~1.92(m, 2.4H, H 10 , H 10’ ); *13 C NMR(100MHz, CDCl3)δ(ppm)153.54, 151.66, 147.87, 141.41, 141.17, 140.65, 140.23, 136.37, 135.53, 131.86, 129.18, 128.47, 12 8.34, 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)(*cis-tran) isomers in a 1:5 ratio); HRMS (ESI) + C 18 H 18 N2NaO2 + The calculated m / z value is 317.1260, and the measured value is 317.1256.

[0190] 3-Methoxy-6-(5-phenylpentyl)picolinaldehyde oxime 65: [ka]

[0191] Methoxypyridine aldoxime 64 (25 mg, 0.085 mmol, 1 equiv.) in degassed, dry EtOAc To the resulting solution (2 mL), 10% Pd / C (4.5 mg, 0.042 mmol, 0.5 equiv.) was added. After washing with H2 three times, The reaction mixture was then stirred under H2 (1 atm) at room temperature for 3 h. Upon completion (as 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 (1:9 EtOAc / PE) to give oxime 65 as a colorless liquid (24 mg, 95%). f (50% EtOAc + PE) 0.40; IR (neat) ν max 3253, 2927, 2855, 1570, 1464, 1269, 1127, 975, 746, 698 cm -1 ; *1 H NMR(400 MHz, CDCl3)δ(ppm)8.40, 8.02(2s, 1.2H, H 18 , H 18’ ), 7.24~6.96(m, 9.4 H, 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, H7, H 7’ ), 1.68~1.52(m, 5 H, H8, H 8’ , H 10 , H 10’ ), 1.35~1.28(m, 2.5H, H9, H 9’ ); *13 C NMR (100 MHz, CDCl3)δ(ppm)154.25, 152.57, 150.87, 150.67, 146.82, 142.71, 142.4 7, 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) (*cis-trans isomers in a 1:4 ratio); HRMS (ESI) + C 18 H 23 N2O2 + The calculated m / z value is 299.1754, and the measured value is 299.1740.

[0192] Synthesis of V-quinoline-derived methoxypyridine aldoxime analogues: [ka]

[0193] 3-Methoxy-6-(4-(quinolin-4-ylamino)but-1-yn-1-yl)picolinaldehyde 66: [ka]

[0194] A solution of commercially available 6-bromo-3-methoxypicolinaldehyde 62 (97 mg, 0.448 mmol, 1.1 equiv.) in degassed THF / EtN (3 mL / 3 mL) was treated with Pd[PPh] (71 mg, 0.061 mmol, 0.15 equiv.) and After degassing the reaction mixture at room temperature for 5 min, a solution of alkyne 24 (80 mg, 0.408 mmol, 1 equiv.) in THF (3 mL) was added dropwise, and the reaction mixture was heated at room temperature. After completion (as monitored by TLC), the reaction mixture was concentrated under reduced pressure to give the residue. The material was purified by column chromatography (1:9 MeOH / EtOAc) to give the desired conjugated methoxypiconaldehyde 66 as a pale yellow solid (126 mg, 93%). f (30% MeOH + EtOAc) 0.25; IR (neat) ν max 3281, 2926, 2233, 1704, 1582, 1434, 1267, 1126, 1009, 763, 694, 521, 494 cm -1 ; 1 H NMR(400 MHz, CDCl3)δ(ppm)10.21(s, 1H, H 18 ), 7.52(d, J = 8.8 Hz, 1H, H4), 7.33(d, J = 8.8 Hz, 1H, H5), 7.28~7.13(m, 5H, H1 3-H 17 ), 3.93(s, 3H, -OMe), 2.74(t, J = 7.5 Hz, 2H, H 11 ), 2.39(t, J = 7.1 Hz, 2H, H9), 1.91(quintet, J = 7.1, 7.5 Hz, 2H, H 10 ); 13 C NMR (100 MHz, CDCl3) δ(ppm)195.52(C18), 156.25, 141.28, 140.73, 136.02, 132.0, 128.44, 128.32, 125.91, 120.41(Ar), 90.27(C7), 79.44(C8), 56.03( -OMe), 34.86(C11), 29.76(C10), 18.72(C9);HRMS (ESI) + C 18 H 18 N1O2 + The calculated m / z value is 280.1332, and the measured value is 280.1348.

[0195] 3-Methoxy-6-(4-(quinolin-4-ylamino)but-1-yn-1-yl)picolinaldehyde oxime 67: [ka]

[0196] A solution of aldehyde 66 (100 mg, 0.362 mmol, 1 equiv.), hydroxylamine hydrochloride (50 mg, 0.724 mmol, 2 equiv.), and CH3CO2Na (89 mg, 1.086 mmol, 3 equiv.) in dry ethanol (5 mL) was stirred at reflux for 16 h. Upon completion (as monitored by TLC), the solid was After filtration through a pad of light, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography (1:9 MeOH / EtOAc) to give oxime 67 as a white solid (65 mg, 62%). Got it. R f (30% MeOH + EtOAc) 0.2; IR (neat) ν max 3319, 2924, 1897, 1586, 1460, 1242, 1115, 982, 829, 760, 649, 524 cm -1 ; 1 H NMR(500 MHz, DMSO-d6)δ(ppm)11.63(br s, 1H, OH), 8.41(d, J = 5.2 Hz, 1H, Ar), 8.22(s, 1H, -C-NOH), 8.21(d, J = 8.5 Hz, 1H, Ar), 7.79(d, J = 8.5 Hz, 1H, Ar), 7.61(t, J= 7.6 Hz, 1H, Ar), 7.50~7.36(m, 4 H, Ar), 6.58(d,J = 5.4 Hz, 1H, Ar), 3.85(s, 3H, -OMe), 3.58(q, J = 5.9, 7.1 Hz, 2H, H 10 ), 2.83(t, J= 7.1 Hz, 2H, H9); 13 C NMR (125 MHz, 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);HRMS (ESI) + C 20 H 19 N4O2 + The calculated m / z value is 347.1503, and the measured value is 347.1491.

[0197] 4-((4-(6-((hydroxyimino)methyl)-5-methoxypyridin-2-yl)but-3-yn-1-yl)amino)quinolin-1-ium chloride 68: [ka]

[0198] To a solution of compound 67 (9.5 mg) in MeOH / H2O (0.5 mL / 0.5 mL) was added 1.2 N HCl (0.1 mL). The mixture was stirred for 2 min and then allowed to stand at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure to give the HCl salt 68 as a white solid in quantitative yield. IR (neat) max 3186, 3099, 2838, 2237, 1615, 1593, 1449, 1277, 1007, 760, 649, 530, 491 cm -1 ; 1 H NMR(500 MHz, D2O)δ(ppm)*8.18~8.08(m, 3H, Ar), *7.96~7.91(m, 1.5 H, Ar), *7.74~7.70(m, 1.5 H, Ar), *7.62~7.54(m, 3H, Ar), *7.51~7.40(m, 4.5 H, Ar), *6.73~6.70(m, 1.5 H, Ar), *3.92(s, 1.5H, -OMe), *3.84(the, J = 6.6 Hz, 1H, H 10’ ), 3.80(s, 3H, -OMe), 3.75(t, J = 6.6 Hz, 2H, H 10 ), *2.98(t, J = 6.6 Hz, 1H, H 9’ ), 2.89(t, J = 6.6 Hz, 2H, H9);*13 C NMR(125 MHz, D2O)δ(ppm)156.49, 154.95, 142.15, 142.03, 141.86, 141.45, 140.04, 139.68, 138. 68, 137.60, 137.00, 134.19, 131.06, 130.37, 128.51, 128.26, 17.55, 127.52, 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 in a 1:2 ratio); HRMS (ESI) + C 20 H 20 ClN4O2 + The calculated m / z value is 347.1503, and the measured value is 347.1461.

[0199] 3-Methoxy-6-(4-(quinolin-4-ylamino)butyl)picolinaldehyde oxime 69: [ka]

[0200] Methoxypyridine aldoxime 67 (25 mg, 0.085 mmol, 1 equiv.) in degassed, dry EtOAc To the resulting solution (2 mL) was added 10% Pd / C (4.5 mg, 0.042 mmol, 0.5 equiv.). After washing with H2 three times, The reaction mixture was stirred under H2 (1 atm) at room temperature for 3 h. Upon completion (as monitored by TLC), the catalyst The HCl 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 (1:9 EtOAc / PE) to give oxime 69 as a colorless liquid (24 mg, 95% ) was obtained as R f (50% EtOAc + PE) 0.40; IR (neat) ν max3327, 2923, 2853, 1582, 1457, 1272, 1126, 968, 763, 694, 540, 473 cm -1 ; *1 H NMR (400 MHz, CDCl) δ (ppm) 8.42 (2s, 1H, H 18 , H 18’ ), 8.32(d, J = 5.7 Hz, 1H, Ar), 8.10(dd, J = 1.2, 8.6 Hz, 1H, Ar), 7.79(d, J = 1.2, 8.6 Hz, 1H, Ar), 7.64(m, 1 H, Ar), 7.44(m, 1H, Ar), 7.39(d, J = 8.7 Hz, 1H, Ar), 7.26(d, J = 8.7 Hz, 1H, Ar), 6.50(d, J = 5.8 Hz, 1H, Ar), 3.87(s, 3H, -OMe), 3.42(t, J = 6.9 Hz, 1H, H 10 ), 3.42(t, J = 6.9 Hz, 1H, H 10 ), 2.83(t, J = 7.5 Hz, 1H , H7), 1.87~1.77(m, 4H, H 8, H9); *13 C NMR (100 MHz, CDCl3) 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) (*cis-trans isomers in a 1:4 ratio); HRMS (ESI) + C 20 H 23 N4O2 + The calculated m / z value is 351.1816, and the measured value is 351.1827.

[0201] 4-((4-(6-((hydroxyimino)methyl)-5-methoxypyridin-2-yl)butyl)amino)quinolin-1-ium 70: [ka]

[0202] To a solution of compound 69 (8 mg) in MeOH / HO (0.5 mL / 0.5 mL) was added 1.2 N HCl (0.1 mL). The reaction mixture was concentrated under reduced pressure to give HCl salt 70 as a white solid. The solid was obtained in quantitative yield. max 3237, 3111, 2926, 1617, 1594, 1452, 1291, 1011, 764, 663, 592 cm -1 ; 1 H NMR(500 MHz, D2O)δ(ppm)8.20(s, 1H, H 18 ), 8.19(d, J = 8.6 Hz, 1H , Ar), 8.04(d, J = 8.6 Hz, 1H , Ar), 7.94-7.87 (m, 2H , Ar), 7.75(dd, J = 8.6, 18.8 Hz, 1H , Ar), 7.64(t, J = 8.8 Hz, 1H , Ar), 6.64(d, J = 7.2 Hz, 1H , Ar), 3.93(s, 3H, -OMe), 3.55(t, J = 6.5 Hz, 1H , H 10 ), 3.01(t, J = 6.8 Hz, 1H , H7), 1.95~1.80(m, 4H, H 8, H9); *13 C NMR (125 MHz, DO) 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) (*cis-trans isomers in a 1:2 ratio); HRMS (ESI) +C 20 H 23 N4O2 + The calculated m / z value is 351.1816, and the measured value is 351.1782.

[0203] (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-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide 72: [ka]

[0204] Commercially available 6-bromo-3-methoxypicolinaldehyde 62 (192 mg, 0.887 mmol, 1.1 equiv.) To a solution of alkyne 54 (240 mg, 0.806 mmol, 1 equiv.) in degassed THF / EtN (5 mL / 5 mL) was added Pd[PPh3]4 (140 mg, 0.121 mmol, 0.15 equiv.) and CuI (46 mg, 0.242 mmol, 0.3 equiv.). After degassing the reaction mixture at room temperature for 5 min, a THF solution (5 mL) of alkyne 54 (300 mg, 0.806 mmol, 1 equiv.) was added dropwise, and the reaction mixture was stirred at room temperature for 16 h. Upon completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The residue was then passed through a small filter column (5:95 MeOH / EtOAc) to give the desired conjugated methoxypiconaldehyde 71 (360 mg, 88%) as a pale yellow solid. , which was used directly in the next step without purification.

[0205] A solution of aldehyde 71 (220 mg, 0.433 mmol, 1 equiv.), hydroxylamine hydrochloride (60 mg, 0.867 mmol, 2 equiv.), and CHCONa (107 mg, 1.299 mmol, 3 equiv.) in dry ethanol (7 mL) was stirred at reflux for 16 h. After completion (monitored by TLC), the solid was separated by a short column. The solvent was removed by filtration through a pad of water, evaporated, and the residue purified by column chromatography (1:9 MeOH / EtOAc) to give oxime 72 as a white solid (180 mg, 78%). f (30% MeOH + EtOAc) 0.2; IR (neat) ν max 3185, 2926, 1640, 1464, 1264, 1209 , 1090, 971, 868, 797, 647, 510 cm -1 ; 1 H NMR(400 MHz, MeOD)δ(ppm)8.39~8.11(3s, 3H, Ar, -C=NOH), 7.37(d, J = 8.6, 1H, H4), 7.26(d, J = 8.6 Hz, 1H, H5 ), 6.34(br s, H, -CH), 5.57(dd, J = 1.8, 6.0 Hz, 1H, -CH), 5.41(br d, J = 6.0 Hz, 1H, -CH), 4.68(d, J = 1.8 Hz, 1H, -CH), 3.89(s, 3H, -OCH3), 3.21(m, 1H, -CH2), 3.09(m, 1H, -CH2), 2.27(m, 1H, -CH2), 2.10(m, 1H, -CH2), 1.57(s, 3H, -CH3), 1.37(s, 3H, -CH3); 13 C NMR (100 MHz, 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), 92.41(C16), 88.65( HRMS (ESI) + C 24 H 27 N8O6 + The calculated m / z value is 523.2048, and the measured value is 523.2038.

[0206] VI - Synthesis of trifunctional Neca compounds [ka]

[0207] 6-(Azidomethyl)picolinaldehyde 75: [ka]

[0208] The synthesis of methyl 6-(azidomethyl)picolinate 74 was reported by Harekrushna, B. et al. 1 Sufficiently certain This was achieved using established procedures.

[0209] To a solution of azidoester 74 (100 mg, 0.521 mmol, 1 equiv.) in dry CHCl (5 mL) at −78 °C, DIBAL-H (1 M solution in CHCl, 1.563 mL, 1.563 mmol, 3 equiv.) was added dropwise, and the reaction mixture The mixture was stirred at -78°C for 5 hours. After the reaction was completed, the reaction mixture was quenched with MeOH (3 mL) and the cooling bath was The mixture was warmed to room temperature, and the reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over MgSO4. 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 further purification. IR (neat) v max 2836, 2098, 1709, 1591, 1457, 1255, 990, 777, 641 cm -1 ; 1 H NMR(400 MHz, CDCl3)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, CDCl3)δ(ppm)193.07, 156.73, 152.59, 138.11, 126.05, 102.78, 55.15;HRMS (ESI) +C7H7N4O1 + The calculated m / z value was 163.0604, and the measured value was 163.0614.

[0210] 6-(Azidomethyl)picolinaldehyde oxime 76: [ka]

[0211] A solution of crude picolinaldehyde 75 (0.521 mmol, 1 equiv.), hydroxylamine hydrochloride (73 mg, 1.042, 2 equiv.), and CHCONa (128 mg, 1.563 mmol, 3 equiv.) in dry ethanol (5 The resulting mixture (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 (1:9 EtOAc / PE). Purification gave oxime 76 as a thick syrup (70 mg, 76%). IR (neat) max 3182, 3010, 2889, 2084, 1572, 1590, 1459, 12666, 1233, 1158, 994, 966, 782, 741, 651, 619, 501 cm -1 ; 1 H NMR(400 MHz, CD3OD)δ(ppm)8.10(s, 1H), 7.86~7.76(m, 2H), 7.40(dd, J = 1.8, 6.8 Hz, 2H), 4.48(s, 2H); 13 C NMR(100 MHz, CD3OD)δ(ppm)157.29, 153.94, 149.93, 139.26, 1323.66, 120.86, 56.16;HRMS (ESI) + C7H8N5O1 + The calculated m / z value is 178.0721, and the measured value is 178.0723508.1867.

[0212] (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-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide 77: [ka]

[0213] A stirred solution of oxime 76 (52 mg, 0.295 mmol, 1.1 equiv) in t-BuOH / HO (2 mL / 1.5 mL) To the resulting mixture, CuSO (17 mg, 0.107 mmol, 0.4 equiv.), sodium ascorbate (21 mg, 0.107 mmol, 0.4 equiv.), and alkyne 54 (100 mg, 0.268 mmol, 1 equiv.) were added. The reaction mixture was stirred at 80 °C for 6 h. Upon completion (as monitored by TLC), the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (5:95 MeOH / EtOAc) to give the desired triazole compound 77 as a white solid (85 mg, 58%). IR (neat) v max 3192, 2924, 1644, 1598, 1458, 1376, 1209, 1155, 1057, 992, 868, 797, 648, 511 cm -1 ; 1 H NMR(400 MHz, CD3OD)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 = 1.7 Hz, 1H), 5.62(s, 2H), 5.50(dd, J = 1.9, 6.1 Hz, 1H), 4.62(d, J = 1.9 Hz, 1H), 3.24~3.01(m, 2H), 2. 61~2.41(m, 2H), 1.57(s, 3H), 1.38(s, 3H); 13C NMR(100MHz, CD3OD)δ(ppm)171.91, 157.38, 156.08, 153.97, 150.27, 150.06, 146.45, 142.54, 13 9.28, 124.46, 123.53, 121.07, 120.55, 115.24, 92.65, 88.38, 85.28, 85.06, 56.09, 39.64, 27.31, 25.91, 25.55;HRMS (ESI) + C 24 H 28 N 11 O5 + The calculated m / z value is 550.2237, and the measured value is 550.2269.

[0214] (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: [ka]

[0215] To a stirred solution of triazole 77 (23 mg, 0.042 mmol, 1 equiv) in dry MeOH (2 mL) was added 1.2 N HCl (127 μL, 0.42 mmol, 10 equiv.) was added and the reaction mixture was stirred at 55°C for 4 h. After completion, the reaction mixture was directly concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography (3:7 MeOH / HO) to give the HCl salt 78 (15 mg, 72%) as a white solid. IR (neat) v max 3196, 1640, 1588, 1458, 1427, 1306, 1254, 1113, 1054, 997, 796, 647 cm -1 ; 11H NMR (400 MHz, CD3OD) δ (ppm) 7.99 (s, 1H), 8.89 (s, 1H), 7.83 (s, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.29 (t, J = 9.3 Hz, 1H), 7.20 (s, 1H), 7.13 (t, J = 7.8 Hz, 1H), 5.77 (d, J = 8.3 Hz, 1H), 5.44 - 5.38 ((2d, J = 14.8 Hz, 2H), 4.43 (s, 1H), 4.32 (br d, J = 5.0 Hz, 1H), 4.08 (dd, J = 4.8, 8.3 Hz, 1H), 3.61 (m, 1H), 3.35 (m, 1H), 3.08 - 299 (m, 1H), 3.96 - 288 (m, 1H); 13 13C NMR (100 MHz, CD3OD) δ (ppm) 172.32, 155.44, 153.78, 151.99, 150.84, 147.61, 142.13, 138.97, 124.62, 124.41, 121.56, 119.75, 89.21, 85.20, 73.72, 72.06, 55.28, 49.50 (MeOH), 39.92, 24.77; HRMS (ESI) + C 21 H 334 N 11 O5 + The calculated m / z value for C H 1.Harekrushna, B. et al. Chem. Eur. J. 2015, 21, 10179 - 10184

[0216] VII - Synthesis of trifunctional pseudo-Neca compounds

Chem.

[0217] 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-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H-purin-6-yl)benzamide 79: [ka]

[0218] A stirred solution of oxime 76 (44 mg, 0.245 mmol, 1.1 equiv) in t-BuOH / HO (2 mL / 1.5 mL) To the reaction mixture was added CuSO (17 mg, 0.045 mmol, 0.2 equiv), sodium ascorbate (18 mg, 0.045 mmol, 0.2 equiv), and alkyne 58 (100 mg, 0.223 mmol, 1 equiv). The reaction mixture was stirred at 80 °C for 6 h. After completion (as monitored by TLC), the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (pure EtOAc - 5:95 MeOH / EtOAc) to give The desired triazole compound 79 was obtained as a white solid (100 mg, 72%). IR (neat) ν max 2924, 1698, 1610, 1581, 1455, 1248, 1211, 1070, 994, 796, 709, 645, 563 cm -1 ; 1 H NMR(400 MHz, CD3OD)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 = 7.5 Hz, 1H), 6.25(d, J = 2.3 Hz, 1H), 5.63(s, 2H), 5.21(dd, J = 2.2, 5.9 Hz, 1H), 4.98(dd, J = 1.6, 5.9 Hz, 1H), 4.65~4.50(m, 3H), 3.82(dd, J = 2.2, 10.6 Hz, 1H), 3.70(dd, J = 3.0, 10.6 Hz, 1H), 1.61(s, 3H) , 1.37(s, 3H); 13 C NMR(100MHz, CD3OD)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;HRMS (ESI) + C 30 H 31 N 10 O6 + The calculated m / z value is 627.2414, and the measured value is 627.2423.

[0219] Example 2: In vitro inhibition of human acetylcholinesterase (hAChE) by compounds of the present invention Reactivation of Example 1: hAChE inhibited by O-ethyl S-[2-(diisopropylamino)ethyl]methylphosphonothioate (VX), tabun, sarin, or paraoxon Compounds 57, 78, 25, and 26 were tested for their activating properties.

[0220] 2-PAM (pralidoxime, or 2-[(E)-(hydroxyimino)methyl]-1- methylpyridinium) and HI6 (asoxime chloride, or [1-[(4-carbamoyl Pyridin-1-ium-1-yl)methoxymethyl]pyridin-2-ylidene]methyl-oxoazanium dichloride) was used as a comparative compound.

[0221] Procedurally, materials and methods were as previously described in International Application WO2017021319, European Journal of Medicinal Chemistry 2014, 78, 455-467, and J. Med. Chem. 2018, 61, 7630-7639.

[0222] I C 50 Measurement of Recombinant hAChE was produced and purified as previously described (see Carletti et al 2008 J Am Chem Soc 130(47): 1601 1-20). Compounds were dissolved in MeOH to make 5 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 spectrophotometrically (absorbance at 412 nm) in the presence of various concentrations of oxime in 1 mL of Ellman's 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 concentration tested. The concentration of compound that produces 50% of enzyme inhibition is called the standard IC 50 Formula:%Activity=100*IC 50 / (I C 50 +[Ox]) was determined by nonlinear approximation using ProFit (Quantumsoft).

[0223] Inhibition of hAChE by OPNA Recombinant hAChE was produced and purified as previously described (see http: / / www.ncbi.nlm.nih.gov / pubmed / 18975951). VX and tabun were provided by DGA maitrise NRBC (Vert le Petit, France). Stock solutions of VX, sarin, tabun, and paraoxon were 5 mM Inhibition of 120 μM hAChE was performed using a 5-fold excess of OPNA in Tris buffer (20 mM, pH 7.4, 0.1% BSA) at 25°C. Incubation was for 20 min. Afterwards, the inhibited hAChE was desalted on a PD-10 column (GE Healthcare).

[0224] Reactivation of hAChE inhibited by OPNA OPNA-inhibited hAChE was incubated at least 10 min in phosphate buffer (0.1 M, pH 7.4, 0.1% BSA). They were also incubated at 37°C with 4-fold or 5-fold concentrations of oxime. The reactivation rate was less than 2% and did not affect the stability of the enzyme. At time intervals ranging from 1 minute, 10 aliquots of each solution containing various concentrations of oxime were transferred to cuvettes containing 1 mM acetylthiocholine in 1 mL of Ellman's buffer (0.1 M phosphate, pH 7.4, 0.1% BSA, 0.5 mM DTNB, 25°C) for measurement of hAChE activity.

[0225] The enzyme activity in the control was kept constant throughout the experiment. The percentage of reactivated enzyme (% E react ) was calculated as the ratio of recovered enzyme activity to the control activity. The apparent reactivation rate constant for each oxime concentration, K, was calculated as the dissociation constant of the inhibited enzyme-oxime complex (E-POx). D , and the maximum reactivation rate constant kr were calculated by nonlinear fitting in ProFit (Quantumsoft) using the standard oxime concentration-dependent reactivation equation derived from

number

[0226] The results are as follows (Tables 1 and 2).

[0227] [Table 1]

[0228] Table 1 shows that compound 57 exhibits higher reactivation rates (kr / min) against VX, tabun, sarin, and paraoxon compared to the controls 2-PAM and HI6, and that compound 78 exhibits higher reactivation rates (kr / min) against VX, tabun, and sarin compared to the references 2-PAM and HI6.

[0229] Compounds 25 and 26 exhibited strong affinity for AChE, which is inhibited by VX or sarin. These compounds exhibited higher reactivation rates (kr / mM·min) than 2-PAM and HI6.

[0230] [Table 2]

[0231] Table 2 shows that compounds 25 and 26 exhibit very high affinity for AChE, which is higher than that of 2-PAM and HI6. Compound 25 exhibits the greatest affinity.

Claims

1. Formula (I): 【Chemical 1】 [In the formula, R1 is H, -X-Y- is -CH 2 - (CH 2 ) n - or -C≡C-, n is an integer from 0 to 5, R2 is a group selected from alkyl, aryl, aralkyl, heteroaryl, and —R3—N(R4)(R5), and R3 is C 1 -C 4 is an alkyl group, and R4 and R5 are the same or different and each independently represent H, a naphthyl group, a 5-fluoroquinolin-4-yl group, a quinolin-4-yl group, or an 8-methoxyquinolin-4-yl group; or R4 and R5 together with the nitrogen atom form a 4-benzyl-piperazin-1-yl group or a 3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl group. or a pharmaceutically acceptable salt thereof.

2. Skeleton 2 below: 【Chemistry 2】 wherein R1 and R2 are as defined in claim 1.

2. The compound of claim 1 having the formula:

3. R2 is alkyl, heteroaryl, aralkyl, or —R3-N(R4)(R5), where: R3 is C 1 -C 4 is an alkyl group, R4 is H, and The compound of claim 2, wherein R5 is selected from a naphthyl group, a 5-fluoroquinolin-4-yl group, a quinolin-4-yl group, or an 8-methoxyquinolin-4-yl group.

4. R2 is -R3-N(R4)(R5), where R3 is C 1 -C 4 is an alkyl group, and The compound according to claim 2, wherein R4 and R5 together with the nitrogen atom form a 4-benzyl-piperazin-1-yl group or a 3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl group.

5. Skeleton 3 below: 【Chemistry 3】 2. The compound of claim 1, having the formula: wherein R1 and R2 are as defined in claim 1, and n is an integer from 0 to 5.

6. R2 is alkyl, aryl, aralkyl, or —R3-N(R4)(R5), where: R3 is C 1 -C 4 is an alkyl group, R4 is H, and The compound of claim 5, wherein R5 is selected from a naphthyl group, a 5-fluoroquinolin-4-yl group, a quinolin-4-yl group, or an 8-methoxyquinolin-4-yl group.

7. R2 is -R3-N(R4)(R5), where R3 is C 1 -C 4 is an alkyl group, and The compound of claim 5, wherein R4 and R5 together with the nitrogen atom form a 4-benzyl-piperazin-1-yl group.

8. 8. The compound of claim 3, 4, 6, or 7, wherein R3 is selected from methyl, ethyl, and n-propyl.

9. The following skeleton 4: 【Chemistry 4】 wherein R1 and R2 are as defined in claim 1.

2. The compound of claim 1 having the formula:

10. The following compounds: 6-(5-phenylpent-1-yn-1-yl)picolinaldehyde oxime 5: 【Chemistry 5】 6-(5-phenylpentyl)picolinaldehyde oxime 7: 【Chemistry 6】 6-(pentadec-1-yn-1-yl)picolinaldehyde oxime 9: 【Chemistry 7】 6-Pentadecylpicolinaldehyde oxime 10: 【Chemistry 8】 6-(pyridin-3-ylethynyl)picolinaldehyde oxime 12: 【Chemistry 9】 2-((hydroxyimino)methyl)-6-(pyridin-1-ium-3-ylethynyl)pyridin-1-ium chloride 13: 【Chemistry 10】 N-(4-{6-[(hydroxyimino)methyl]pyridin-2-yl}but-3-yn-1-yl)naphthalen-1-amine 19: 【Chemistry 11】 N-(4-{6-[(hydroxyimino)methyl]pyridin-2-yl}but-3-yn-1-yl)naphthalen-1-amine 20: 【Chemistry 12】 6-(4-(quinolin-4-ylamino)but-1-yn-1-yl)picolinaldehyde oxime 25: 【Chemistry 13】 3-hydroxy-6-(4-(quinolin-4-ylamino)butyl)picolinate methyl ester ２６： 【Chemistry 14】 6-(4-((5-fluoroquinolin-4-yl)amino)but-1-yn-1-yl)picolinaldehyde oxime 30: 【Chemistry 15】 6-(4-((5-fluoroquinolin-4-yl)amino)butyl)picolinaldehyde oxime 31: 【Chemistry 16】 6-(4-((8-methoxyquinolin-4-yl)amino)but-1-yn-1-yl)picolinaldehyde oxime 36: 【Chemistry 17】 6-(4-((8-methoxyquinolin-4-yl)amino)butyl)picolinaldehyde oxime 37: 【Chemistry 18】 6-(3-(4-benzylpiperazin-1-yl)prop-1-yn-1-yl)picolinaldehyde oxime 42: 【Chemistry 19】 6-(3-(4-benzylpiperazin-1-yl)propyl)picolinaldehyde oxime 43: 【Chemistry 20】 6-(4-(4-benzylpiperazin-1-yl)but-1-yn-1-yl)picolinaldehyde oxime 47: 【Chemical 21】 6-(4-(4-benzylpiperazin-1-yl)butyl)picolinaldehyde oxime 48: 【Chemical 22】 6-(4-(3,7-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)but-1-yn-1-yl)picolinaldehyde oxime 51: 【Chemical 23】 3-Methoxy-6-(5-phenylpent-1-yn-1-yl)picolinaldehyde oxime 64: 【Chemistry 24】 3-Methoxy-6-(5-phenylpentyl)picolinaldehyde oxime 65: 【Chemistry 25】 3-Methoxy-6-(4-(quinolin-4-ylamino)but-1-yn-1-yl)picolinaldehyde oxime 67: 【Chemical Formula 26】 4-((4-(6-((hydroxyimino)methyl)-5-methoxypyridin-2-yl)but-3-yn-1-yl)amino)quinolin-1-ium chloride 68 【Chemical 27】 3-Methoxy-6-(4-(quinolin-4-ylamino)butyl)picolinaldehyde oxime 69: 【Chemical Formula 28】 4-((4-(6-((hydroxyimino)methyl)-5-methoxypyridin-2-yl)butyl)amino)quinolin-1-ium 70 【Chemical 29】 The compound according to any one of claims 1 to 9, selected from:

11. A process for preparing a compound of formula (I) according to any one of claims 1 to 10, comprising: In the formula, -X-Y- is -CH 2 -CH 2 - or -C≡C-, A method comprising a Sonogashira coupling reaction between 6-bromopyridine aldoxime and a compound containing a terminal alkyne, optionally followed by a reduction step by reaction with hydrogen.

12. A compound according to any one of claims 1 to 10 for use in therapy.

13. A compound according to any one of claims 1 to 10 for use in the treatment of neurological damage and / or respiratory failure due to poisoning with at least one organophosphorus nerve agent, and / or in the treatment of neurological diseases, and / or in the treatment of inflammation, and / or in the treatment of cancer, and / or in the treatment of diabetes, and / or in the treatment of pain.

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