Oximes and their use in the treatment of GBA-related disorders

Abstract

The present invention relates to oximes, their synthesis and their use for increasing GBA activity and / or levels and for treating GBA-related diseases, such as Parkinson's disease.

Description

[Technical field]

[0001] The present invention relates to oximes, their synthesis and their use for increasing GBA activity and / or levels and for treating GBA-related diseases, such as Parkinson's disease. [Background technology]

[0002] Lysosomes serve as vital reprocessing centers in human cells that break down and then recycle proteins and fatty substances, such as glycosphingolipids, into their basic building blocks. A series of rare genetic disorders, called lysosomal storage diseases (LSDs), arise due to carrying distinct mutations in both copies of specific genes that code for various lysosomal enzymes. Gaucher disease, the most common lysosomal storage disease, arises due to mutations in both copies of the GBA1 gene, which codes for the glucocerebrosidase (GCase) enzyme. Such homozygous mutations in both copies of the GBA1 gene cause a profound loss of up to 95% of GCase activity. As a result of this profound loss of enzymatic activity, the metabolism of certain glycosphingolipids is severely impaired in Gaucher disease patients, leading to the accumulation of glucosylceramide (GluCer), the substrate of the GCase enzyme. This accumulation leads to severe health problems and organ pathology.

[0003] Many of these GBA mutations are also found in patients with Parkinson's disease (PD). Heterozygous mutations (having one mutated GBA gene), such as those found in GBA mutation carriers, have been found to predispose to the development of Parkinson's disease (Gan-Or et al., Neurology, 2015). GBA mutations are now considered one of the major genetic risk factors for Parkinson's disease. It is estimated that at least 8% of patients with Parkinson's disease have mutations in the GBA gene (both mild and severe GBA mutations), including L444P heterozygotes. Secondary deficiencies in GBA activity may also be associated with Parkinson's disease.

[0004] The state of the art compounds, ambroxol and LTI-291, have been shown to increase GBA activity, an important effect in the treatment of GBA-mediated disorders. More and better compounds are needed to meet the medical need for the treatment of GBA-mediated disorders. Summary of the Invention

[0005] The present inventors have developed a series of compounds that effectively act as GBA inducers with completely different structural chemistry compared to the state of the art compounds ambroxol and LTI-291, making the disclosed compounds promising candidates for the treatment of GBA-mediated disorders.

[0006] In a first aspect, a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof is provided, R 1 , H, C 1-6 selected from the group consisting of alkyl, and halogen; Y is OH and C 1-6 alkoxy; X is selected from the group consisting of chlorine and bromine; J is an aliphatic ring containing at least one nitrogen atom, where the aliphatic ring is optionally substituted; A is the following: [ka] is selected from the group consisting of wherein each k is 1, 2, 3, or 4; R 2 and R 3 are independent of each other, C 1-6 Alkyl, C 1-6 Acyl, and CO2-C 1-6 selected from the group consisting of alkyl; n1, n2, u1, and u2 are independently selected from the group consisting of 1, 2, or 3; Each R 4 are independently H, halogen, and C 1-4 alkyl, wherein each methylene group is optionally replaced by -O-; Each R 5 are independently H, halogen, and C 1-4 alkyl, wherein each methylene group is optionally replaced by -O-; Each R 6 are independently H, halogen, and C 1-4 alkyl, wherein each methylene group is optionally replaced by -O-; Each R 7 are independently H, halogen, and C 1-4 alkyl, wherein each methylene group is optionally replaced by -O-; R 8 H, and C 1-4 selected from the group consisting of alkyl; G is -CH2-, -CH(R 9 )-, -C(R 9 )2-, -NH-, and -N(R 9 )- selected from the group consisting of; In the formula, each R 9 are independently hydrogen, halogen, C 1-4 alkyl, wherein each methylene group is optionally replaced by -O-; HetAr optionally contains one or more R 10 wherein each R is a heteroaryl substituted by 10 are independently hydrogen, C 1-6 Alkyl, halogen, hydroxy, C 1-6 Alkoxy, amino, amido, and C 1-6 acyl; T is: [ka] or any tautomers thereof; wherein a is 0, 1, 2, or 3; X 1 , X 2 , X 3 , X 4 , and X 5 is independently selected from the group consisting of C, CH, and N; each of the one, two, and three substituents is independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, alkoxy, amino, amido, acyl, cycloalkyl, and heterocycloalkyl, where each methylene group of the alkyl is optionally replaced by -O-; However, if X is chlorine, A is [ka] but [ka] But not.)

[0007] In a second aspect, there is provided a pharmaceutical composition comprising a compound as defined herein and one or more pharma- ceutically acceptable adjuvants, excipients, carriers, buffers and / or diluents.

[0008] In a third aspect, there is provided a method for treating a disease in a subject, the disease being associated with reduced GBA levels and / or activity, comprising administering a compound as defined herein.

[0009] In a fourth aspect, there is provided a method for treating a disease in a subject, the disease being associated with reduced GBA levels and / or activity, comprising administering a compound as defined herein.

[0010] In a fifth aspect, there is provided a method of increasing GBA activity and / or levels, the method comprising contacting GBA with a compound as defined herein.

[0011] In a sixth aspect, there is provided the use of a compound as defined herein for the manufacture of a medicament for the treatment of Parkinson's disease (PD). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] definition With reference to substituents, the term "independently" refers to a situation where more than one substituent is possible, the substituents may be the same or different.

[0013] The efficacy referred to herein is "EC 1.5 " is determined based on the dose-response effect of the compound as the concentration at which "percentage of GCase activity" = 150%, which corresponds to a 1.5-fold induction of GCase activity.

[0014] As used herein, the term "pharmaceutical acceptable salt" refers to salts typically used in the pharmaceutical field. Examples of pharmaceutical acceptable salts include, but are not limited to, sodium salt, hydrochloride salt, magnesium salt, calcium salt, trifluoroacetate salt, and potassium salt. Further exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

[0015] The term "alkyl" refers to a straight or branched hydrocarbon chain group consisting of carbon and hydrogen atoms, which may be straight or branched, substituted or unsubstituted. In some preferred embodiments, the alkyl group may consist of 1 to 12 carbon atoms, e.g., 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, up to and including 12 carbon atoms. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl. The alkyl moiety may be attached to the remainder of the molecule by a single bond, such as, for example, methyl (Me), ethyl (Et), n-propyl (Pr), 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and 3-methylhexyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted with one or more of any suitable substituents. An alkyl group may be monovalent, divalent, trivalent, or tetravalent, as necessary to satisfy valence requirements.

[0016] The term "aliphatic ring," as used herein, means a hydrocarbon ring that is either fully saturated or contains one or more units of unsaturation, but is non-aromatic. Unless otherwise specified, an aliphatic ring contains 1-20 aliphatic carbon atoms, and in some embodiments, an aliphatic ring contains 1-10 aliphatic carbon atoms. In other embodiments, an aliphatic ring contains 1-8 aliphatic carbon atoms. In yet other embodiments, an aliphatic ring contains 1-6 aliphatic carbon atoms, and in yet other embodiments, an aliphatic ring contains 1-4 aliphatic carbon atoms.

[0017] In general, suitable substituents for the substituents disclosed herein independently include, but are not limited to, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -OC(O)N(R a )2, -C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2, N(R a )C(NR a )N(R a )2, -N(R a )S(O) t R a , -N(R a )S(O)2R a , -S(O)OR a , -S(O)2OR a , -S(O)N(R a )2, -S(O)2N(R a )2, or PO3(R a ) 2, where each R a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0018] The term "cycloalkyl" refers to a monocyclic or polycyclic group containing carbon and hydrogen, which may be saturated or partially unsaturated. In some preferred embodiments, the cycloalkyl group includes groups having 3 to 12 ring atoms (i.e., (C3-12 ) cycloalkyl or C(3- 12 Whenever represented herein, (C-)cycloalkyl) is included. 12 ) cycloalkyl or C(3- 12 Numerical ranges such as "3 to 12" for cycloalkyl refer to each integer within the given range. For example, "3 to 12 carbon atoms" means that the cycloalkyl group may consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 12 carbon atoms. Illustrative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloseptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like.

[0019] The term "alkoxy" refers to an -O-alkyl group. In some preferred embodiments, alkoxy groups contain 1 to 12 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, and cyclohexyloxy.

[0020] The term "acyl" means R c -(C=O)-, where R c Examples of acyl include, but are not limited to, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, and heteroaryl. An acylation is attached to the parent structure through a carbonyl functionality.

[0021] The term “amino” or “amine” refers to —N(R a ) groups, where, unless otherwise specified, each R ais independently hydrogen, alkyl, (halo)alkyl, alkenyl, alkynyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl. a ) Two groups are non-hydrogen R a When substituted, they can combine with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -N(R a )2 is meant to include, but is not limited to, 1-pyrrolidinyl, 1-piperazinyl, and 4-morpholinyl.

[0022] The term “amide” or “amido” refers to a group of the formula —(C═O)N(R d )2 or -NH(C=O)R d where R d is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, carbocyclyl, carbocyclylalkyl, cycloalkyl, aryl, and heteroaryl. d )2R d may optionally form a 4-, 5-, 6-, or 7-membered ring together with the nitrogen to which it is attached. Unless otherwise specifically stated in the specification, amide groups may be optionally and independently substituted with one or more of the substituents as described herein as suitable substituents.

[0023] The term "haloalkyl" refers to an alkyl group, as defined above, substituted with one or more halogen atoms. Thus, the term "alkyl" includes "haloalkyl." Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0024] The terms "halo", "halide", or alternatively "halogen", are intended to mean fluoro, chloro, bromo, or iodo.

[0025] The term "aromatic" refers to an unsaturated, cyclic, and planar hydrocarbon group having a delocalized conjugated π system with 4n+2 π electrons, where n is an integer having values ​​of 0, 1, 2, 3, etc. In some embodiments, the aromatic group is an "aryl" (abbreviated as Ar), which refers to an aromatic group having 6 to 10 ring atoms (e.g., (C6- 10 ) aromatic or (C6- 10 ) aryl) having at least one ring having a conjugated pi electron system that is carbocyclic (eg, phenyl, fluorenyl, and naphthyl).

[0026] The terms "aralkyl" or "arylalkyl" refer to an (aryl)alkyl group, where the aryl and alkyl are as disclosed herein.

[0027] The term "heteroaryl" or "heteroaromatic" refers to a 5- to 18-membered aromatic group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur (e.g., (C5- 13)heteroaryl), which may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system. Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzodioxan ... ranyl, benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3]-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[ 6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoin dolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydroquinazolinyl, tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienyl).

[0028] The term "tautomers" refers to structurally distinct isomers that interconvert by tautomerization. "Tautomerization" is a form of isomerization, which includes prototropic tautomerization or proton shift tautomerization, which is considered a subset of acid-base chemistry. "Prototropic tautomerization" or "proton shift tautomerization" involves the migration of a proton, accompanied by a change in bond order, often swapping a single bond with an adjacent double bond.

[0029] Symbols displayed perpendicular to a bond [ka] indicates the point at which the indicated moiety is attached to the remainder of the molecule.

[0030] compound In one embodiment, the compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof is provided, R 1 , H, C 1-6 selected from the group consisting of alkyl, and halogen; Y is OH and C 1-6 alkoxy; X is selected from the group consisting of chlorine and bromine; J is an aliphatic ring containing at least one nitrogen atom, where the aliphatic ring is optionally substituted; A is the following: [ka] is selected from the group consisting of wherein each k is 1, 2, 3, or 4; R 2 and R 3 are independent of each other, C 1-6 Alkyl, C 1-6 Acyl, and CO2-C 1-6 selected from the group consisting of alkyl; n1, n2, u1, and u2 are independently selected from the group consisting of 1, 2, or 3; Each R 4 are independently H, halogen, and C 1-4 alkyl, wherein each methylene group is optionally replaced by -O-; Each R 5 are independently H, halogen, and C 1-4 alkyl, wherein each methylene group is optionally replaced by -O-; Each R 6 are independently H, halogen, and C 1-4 alkyl, wherein each methylene group is optionally replaced by -O-; Each R 7 are independently H, halogen, and C 1-4 alkyl, wherein each methylene group is optionally replaced by -O-; R 8 H, and C 1-4 selected from the group consisting of alkyl; G is -CH2-, -CH(R 9)-, -C(R 9 )2-, -NH-, and -N(R 9 )- selected from the group consisting of; In the formula, each R 9 are independently hydrogen, halogen, C 1-4 alkyl, wherein each methylene group is optionally replaced by -O-; HetAr optionally contains one or more R 10 wherein each R is a heteroaryl substituted by 10 are independently hydrogen, C 1-6 Alkyl, halogen, hydroxy, C 1-6 Alkoxy, amino, amido, and C 1-6 acyl; T is: [ka] or any tautomers thereof; wherein a is 0, 1, 2, or 3; X 1 , X 2 , X 3 , X 4 , and X 5 is independently selected from the group consisting of C, CH, and N; each of the one, two, and three substituents is independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, alkoxy, amino, amido, acyl, cycloalkyl, and heterocycloalkyl, where each methylene group of the alkyl is optionally replaced by -O-; However, if X is chlorine, A is [ka] but [ka] But not.)

[0031] In one embodiment, there is provided a compound as defined herein, wherein J is of formula (J1): [ka] (Wherein, n3 and n4 are independently 1, 2, or 3; Each R 11 are independently H, halogen, and C 1-4 alkyl, wherein each methylene group is optionally replaced by -O-; Each R 12 are independently H, halogen, and C 1-4 alkyl, wherein each methylene group is optionally replaced by -O-; Each R 13 are independently H, halogen, and C 1-4 alkyl, wherein each methylene group is optionally replaced by -O-; Each R 14 are independently H, halogen, and C 1-4 alkyl, wherein each methylene group is optionally replaced by -O-; Q is a bond, -CH2-, -CH(R 15 )-, -C(R 15 )2-, -NH-, and -N(R 15 )-; wherein each R 15 are independently hydrogen, halogen, C 1-4 alkyl, wherein each methylene group is optionally replaced by -O-; R 11 and R 13 and the pairs are optionally linked together to form a ring.

[0032] In one embodiment, a compound is provided in which Q is selected from the group consisting of a bond, -CH-, -CHF-, -N(Me)-, and -NH-. 11 , R 12 , R 13, and R 14 are all hydrogen.

[0033] In one embodiment, n3 and n4 are each 2.

[0034] In one embodiment, J is: [ka] A compound selected from the group consisting of:

[0035] In one embodiment, compounds are provided where Y is OH.

[0036] In one embodiment, R 1 Compounds are provided where is hydrogen or methyl.

[0037] In one embodiment, a compound is provided wherein A is of formula (Ia); [ka] (k is 2, R 3 is C 1-3 is alkyl, R 2 is C 1-3 alkyl or CO2tBu).

[0038] In one embodiment, a compound is provided wherein A is of formula (Ib); [ka] (wherein n1 and n2 are each 2; R 4 , R 5 , R 6 , and R 7 are each hydrogen, and R 8 is hydrogen or C 1-3 alkyl; T is of formula (T3); [ka] In the formula, a is 0 or 1; X 1 , X 2and / or X 3 is N and X 1 ~X 5 the remainder are independently C or CH; the one, two, or three substituents are each independently hydrogen, C 1-4 Alkyl, halogen, hydroxy, C 1-4 Alkoxy and C 1-4 acyl).

[0039] In one embodiment, only one substituent is present and it is methyl. In one embodiment, only one substituent is present and it is chlorine. In one embodiment, all of the substituents are each hydrogen.

[0040] In one embodiment, a compound is provided wherein A is of formula (Ib); [ka] (wherein n1 and n2 are each 2; R 4 , R 5 , R 6 , and R 7 are each hydrogen; R 8 is hydrogen or C 1-3 alkyl; T is of formula (T1); [ka] In the formula, a is 0 and the substituent is C 1-6 alkyl, where each methylene group is optionally replaced by -O-.

[0041] In one embodiment, a compound is provided wherein A is of formula (Ic); [ka] (wherein k is 1, 2, or 3; u1 and u2 are each 1 or 2; R 4 , R 5 , R 6 , and R 7 are each hydrogen; G is a bond, -CH2-, -NH-, and -N(C1-3 wherein the aryl group is selected from the group consisting of aryl, ...

[0042] In one embodiment, a compound is provided wherein A is of formula (Id); [ka] where HetAr is a C5- 13 heteroaryl, which is monocyclic, bicyclic, or tricyclic.

[0043] In one embodiment, A is: [ka] A compound selected from the group consisting of:

[0044] In one embodiment, the compound is: [ka] TIFF2024545840000023.tif207159.

[0045] GBA inducers The compounds of the present disclosure can induce glucocerebrosidase (GBA) enzyme activity and / or GBA level.Thus, the compounds of the present disclosure are GBA inducers, i.e., can induce increased GBA enzyme level and / or activity.In one embodiment, the compounds provided are GBA inducers.

[0046] In one embodiment, the compounds are provided for use in a method for increasing GBA levels and / or activity, which effect can be readily determined using the assay provided in Example 2.

[0047] In one embodiment, a compound is provided that can increase the GBA activity by at least 1.5 times, such as at least 2 times, such as at least 2.5 times, such as at least 3 times. In one embodiment, the method increases the GBA activity by at least 1.5 times, such as at least 2 times, such as at least 2.5 times, such as at least 3 times.

[0048] In one embodiment, GBA activity is increased to more than 50% of the hypothetical wild-type level, such as 50-60%, such as 60-70%, for example 70-80%, such as 80-90%, for example 90-100%, such as 100-110%, for example 110-120%, such as 120-130%, for example 130-140%, for example 140-150% of the hypothetical wild-type level.

[0049] In one embodiment, the EC 1.5 is 150 μM or less, such as 140 μM or less, for example 130 μM or less, for example 120 μM or less, such as 110 μM or less, for example 100 μM or less, such as 90 μM or less, for example 80 μM or less, such as 70 μM or less, for example 60 μM or less, preferably EC 1.5 is 50 μM or less, such as 40 μM or less, for example 30 μM or less, such as 20 μM or less, for example 10 μM or less.

[0050] In one embodiment, the Emax% of the compound is 80% or more, such as 100% or more, for example 120% or more, such as 140% or more, for example 160% or more, such as 180% or more, for example 200% or more, such as 220% or more, for example 240% or more, such as 260% or more, for example 280% or more, such as 300% or more.

[0051] Pharmaceutical Compositions In one embodiment, there is provided a pharmaceutical composition comprising a compound as defined herein and one or more pharma- ceutically acceptable adjuvants, excipients, carriers, buffers, and / or diluents.

[0052] Therapy The compounds of the present disclosure are important for use in therapy.In one embodiment, a method is provided for treating a disease in a subject, comprising administering a compound as defined herein, wherein the disease is associated with reduced GBA level and / or activity.

[0053] In one embodiment, a method is provided in which the disease being treated is Parkinson's disease (PD). In one embodiment, a compound as defined herein is provided for use in the treatment of Parkinson's disease.

[0054] In one embodiment there is provided the use of a compound as defined herein for the manufacture of a medicament for the treatment of Parkinson's disease (PD).

[0055] Terms 1. A compound of formula (I), [ka] or a pharma- ceutically acceptable salt thereof, R 1 , H, C 1-6 selected from the group consisting of alkyl, and halogen; Y is OH and C 1-6 alkoxy; X is selected from the group consisting of chlorine and bromine; J is an aliphatic ring containing at least one nitrogen atom, wherein said aliphatic ring is optionally substituted; A is the following: [ka] is selected from the group consisting of wherein each k is 1, 2, 3, or 4; R 2 and R 3 are independent of each other, C 1-6 Alkyl, C 1-6 Acyl, and CO2-C 1-6 selected from the group consisting of alkyl; n1, n2, u1, and u2 are independently selected from the group consisting of 1, 2, or 3; Each R 4 are independently H, halogen, and C 1-4 alkyl, wherein each methylene group is optionally replaced by -O-; Each R 5 are independently H, halogen, and C 1-4 alkyl, wherein each methylene group is optionally replaced by -O-; Each R 6 are independently H, halogen, and C 1-4 alkyl, wherein each methylene group is optionally replaced by -O-; Each R 7 are independently H, halogen, and C 1-4 alkyl, wherein each methylene group is optionally replaced by -O-; R 8 H, and C 1-4 selected from the group consisting of alkyl; G is -CH2-, -CH(R 9 )-, -C(R 9 )2-, -NH-, and -N(R 9 )- selected from the group consisting of; In the formula, each R 9 are independently hydrogen, halogen, C 1-4 alkyl, wherein each methylene group is optionally replaced by -O-; HetAr optionally contains one or more R 10 wherein each R is a heteroaryl substituted by 10 are independently hydrogen, C 1-6 Alkyl, halogen, hydroxy, C 1-6 Alkoxy, amino, amido, and C 1-6 acyl; T is: [ka] or any tautomers thereof; wherein a is 0, 1, 2, or 3; X 1 , X 2 , X 3 , X 4 , and X 5 is independently selected from the group consisting of C, CH, and N; each of the one, two, and three substituents is independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, alkoxy, amino, amido, acyl, cycloalkyl, and heterocycloalkyl, wherein each methylene group of said alkyl is optionally replaced by -O-; However, if X is chlorine, A is [ka] but [ka] But not.)

[0056] 2. The compound according to any one of the preceding clauses, wherein J is of formula (J1): [ka] (Wherein, n3 and n4 are independently 1, 2, or 3; Each R 11 are independently H, halogen, and C 1-4 alkyl, wherein each methylene group is optionally replaced by -O-; Each R 12 are independently H, halogen, and C 1-4 alkyl, wherein each methylene group is optionally replaced by -O-; Each R 13 are independently H, halogen, and C 1-4alkyl, wherein each methylene group is optionally replaced by -O-; Each R 14 are independently H, halogen, and C 1-4 alkyl, wherein each methylene group is optionally replaced by -O-; Q is a bond, -CH2-, -CH(R 15 )-, -C(R 15 )2-, -NH-, and -N(R 15 )-; wherein each R 15 are independently hydrogen, halogen, C 1-4 alkyl, wherein each methylene group is optionally replaced by -O-; R 11 and R 13 and the pairs are optionally linked together to form a ring.

[0057] 3. The compound according to any one of the preceding clauses, wherein Q is selected from the group consisting of a bond, -CH2-, -CHF-, -N(Me)-, and -NH-.

[0058] 4. R 11 , R 12 , R 13 , and R 14 are all hydrogen.

[0059] 5. A compound according to any one of the preceding clauses, wherein n3 and n4 are each 2.

[0060] 6. J: [ka] 2. The compound according to any one of the preceding clauses, selected from the group consisting of:

[0061] 7. The compound according to any one of the preceding clauses, wherein Y is OH.

[0062] 8. R 1 is hydrogen or methyl.

[0063] 9. The compound of any one of the preceding clauses, wherein A is of formula (Ia); [ka] (k is 2, R 3 is C 1-3 is alkyl, R 2 is C 1-3 alkyl or CO2tBu).

[0064] 10. The compound according to any one of the preceding clauses, wherein A is of formula (Ib); [ka] (wherein n1 and n2 are each 2; R 4 , R 5 , R 6 , and R 7 are each hydrogen, and R 8 is hydrogen or C 1-3 alkyl; T is of formula (T3); [ka] In the formula, a is 0 or 1; X 1 , X 2 and / or X 3 is N and X 1 ~X 5 the remainder are independently C or CH; the one, two, or three substituents are each independently hydrogen, C 1-4 Alkyl, halogen, hydroxy, C 1-4 Alkoxy and C 1-4 acyl).

[0065] 11. A compound according to any one of the preceding clauses, wherein only one substituent is present and it is methyl.

[0066] 12. A compound according to any one of the preceding clauses, wherein only one substituent is present and it is chlorine.

[0067] 13. A compound according to any one of the preceding clauses, wherein all of the substituents are each hydrogen.

[0068] 14. The compound according to any one of the preceding clauses, wherein A is of formula (Ib); [ka] (wherein n1 and n2 are each 2; R 4 , R 5 , R 6 , and R 7 are each hydrogen; R 8 is hydrogen or C 1-3 alkyl; T is of formula (T1); [ka] In the formula, a is 0 and the substituent is C 1-6 alkyl, where each methylene group is optionally replaced by -O-.

[0069] 15. The compound according to any one of the preceding clauses, wherein A is of formula (Ic); [ka] (wherein k is 1, 2, or 3; u1 and u2 are each 1 or 2; R 4 , R 5 , R 6 , and R 7 are each hydrogen; G is a bond, -CH2-, -NH-, and -N(C 1-3 wherein the aryl group is selected from the group consisting of aryl, ...

[0070] 16. The compound according to any one of the preceding clauses, wherein A is of formula (Id); [ka] where HetAr is a C5- 13 heteroaryl, which is monocyclic, bicyclic, or tricyclic.

[0071] 17. A: [ka] 2. The compound according to any one of the preceding clauses, selected from the group consisting of:

[0072] 18. The compound, [ka] TIFF2024545840000040.tif206159TIFF2024545840000041.tif102159.

[0073] 19. A compound according to any one of the preceding clauses, which increases glucocerebrosidase (GBA) enzyme levels and / or GBA enzyme activity.

[0074] 20. A compound according to any one of the preceding clauses which is a GBA inducer.

[0075] 21. A compound according to any one of the preceding clauses for use in a method for increasing GBA levels and / or activity.

[0076] 22. A compound for use according to any one of the preceding clauses, wherein said GBA activity is increased by at least 1.5-fold, such as at least 2-fold, such as at least 2.5-fold, such as at least 3-fold.

[0077] 23. A compound for use according to any one of the preceding clauses, wherein said GBA activity is increased to more than 50% of the hypothetical wild-type level, such as 50-60%, such as 60-70%, for example 70-80%, such as 80-90%, for example 90-100%, such as 100-110%, for example 110-120%, such as 120-130%, for example 130-140%, such as 140-150% of the hypothetical wild-type level.

[0078] 24. E.C. 1.5 is 150 μM or less, for example 140 μM or less, for example 130 μM or less, for example 120 μM or less, for example 110 μM or less, for example 100 μM or less, for example 90 μM or less, for example 80 μM or less, for example 70 μM or less, for example 60 μM or less, preferably 1.5 is 50 μM or less, such as 40 μM or less, for example 30 μM or less, such as 20 μM or less, for example 10 μM or less.

[0079] 25. A compound for use according to any one of the preceding clauses, wherein the Emax% is 80% or more, such as 100% or more, for example 120% or more, such as 140% or more, for example 160% or more, such as 180% or more, for example 200% or more, such as 220% or more, for example 240% or more, such as 260% or more, for example 280% or more, such as 300% or more.

[0080] 26. A pharmaceutical composition comprising a compound as defined in any one of the preceding clauses and one or more pharma- ceutically acceptable adjuvants, excipients, carriers, buffers and / or diluents.

[0081] 27. A method for treating a disease in a subject, comprising administering a compound as defined in any one of the preceding clauses, wherein said disease is associated with reduced GBA levels and / or activity.

[0082] 28. The method of any one of the preceding clauses, wherein the disease is Parkinson's disease (PD).

[0083] 29. A method for increasing GBA activity and / or level, comprising contacting GBA with a compound as defined in any one of the preceding clauses.

[0084] 30. Use of a compound as defined in any one of the preceding clauses for the manufacture of a medicament for the treatment of Parkinson's disease (PD). EXAMPLES

[0085] Example 1: Synthesis of oximes Materials and Abbreviations Abbreviations used: [Table 1]

[0086] A straight line to a chiral center in the following schemes and structures indicates that the material is racemic. Unless otherwise stated, the structures are racemic.

[0087] The salt stoichiometry is an assumption based on considerations of common acid-base reactions. The exact salt content has not been fully determined.

[0088] Analytical and Preparative Instruments Used: In the process of analyzing the composition of the isolated materials, one or more of the following instruments were used:

[0089] LC / MS Equipment Specifications: Agilent 1100 Series LC / MSD system equipped with DAD\ELSD Alltech 2000ES and Agilent LC\MSD VL(G1956B), SL(G1956B) mass spectrometers. Agilent 1200 Series LC / MSD system equipped with DAD\ELSD Alltech 3300 and Agilent LC\MSD G6130A, G6120B mass spectrometers. Agilent Technologies 1260 Infinity LC / MSD system equipped with a DAD\ELSD Alltech 3300 and an Agilent LC\MSD G6120B mass spectrometer. Agilent Technologies 1260 Infinity II LC / MSD system equipped with a DAD\ELSD G7102A 1290 Infinity II and an Agilent LC\MSD G6120B mass spectrometer. An Agilent 1200 Series LC / MSD system equipped with a DAD\ELSD and an Agilent LC\MSD (G6120B) mass spectrometer. UHPLC Agilent 1290 Series LC / MSD system equipped with a DAD\ELSD and an Agilent LC\MSD (G6125B) mass spectrometer. All LC / MS data was acquired using positive / negative mode switching.

[0090] H-NMR Bruker AVANCE III 400 Varian UNITY INOVA 400

[0091] The following instruments were used for chiral analysis or separation:

[0092] Analytical separation: Column: Chiralpak IA (250 x 4.6 mm, 5 mkm) HPLC equipment: Agilent Technologies HPLC Systems 1200 Series equipped with a DAD Detector (G1315B).

[0093] Preparative separation: Column: Chiralpak IA (250 x 20 mm, 5 mkm) HPLC equipment: Agilent Technologies HPLC Preparative Systems 1260 Infinity II Series equipped with a DAD Detector (G7115B).

[0094] General composition of building blocks Synthesis of 2-methyl-4-azoniaspiro[3.5]nonan-2-ol chloride [ka] To a solution of 8.5 g piperidine in 200 ml methanol was added 10.64 g 2-(chloromethyl)-2-methyl-oxirane. The mixture was stirred at 25° C. for 24 hours and then evaporated to dryness. The residue was triturated with ether three times and then dried in vacuum to give 16.5 g crude title compound, which was used as it is.

[0095] 1. General synthesis using quaternary salts Synthesis of N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-4-methylpiperidine-4-carbimidoyl chloride dihydrochloride, ID336 General Scheme [ka]

[0096] 1.1 Synthesis of tert-butyl 4-(N'-hydroxycarbamimidoyl)-4-methylpiperidine-1-carboxylate [ka] tert-Butyl 4-cyano-4-methyl-piperidine-1-carboxylate (29.0 g, 122.83 mmol) was dissolved in IPA (200 ml) and then hydroxylamine hydrochloride (12.80 g, 184.24 mmol, 1.5 equiv) was added to the resulting solution followed by sodium bicarbonate (15.48 g, 184.24 mmol, 1.5 equiv). The reaction mixture was then left overnight at 60° C. with stirring. After 24 hours the reaction mixture was diluted with water (500 ml). The solid formed was collected by filtration, washed with water (100 ml) and air-dried to give the title product (25 g, 75%) as a white solid. LCMS [M - t-Bu H] + 202.0. The resulting product was used as is without further purification.

[0097] 1.2 Synthesis of tert-butyl 4-(N'-(2-hydroxy-3-(piperidin-1-yl)propoxy)carbamimidoyl)-4-methylpiperidine-1-carboxylate [ka] tert-Butyl 4-(N'-hydroxycarbamimidoyl)-4-methylpiperidine-1-carboxylate (1.5 g, 5.54 mmol, 1 equiv.) was dissolved in IPA (50 ml), followed by sodium hydroxide (0.222 g, 5.54 mmol, 1 equiv.), and 4-azoniaspiro[3.5]nonan-2-ol chloride (0.98 g, 5.54 mmol, 1 equiv.). The reaction mixture was then stirred at 50°C for 24 hours, after which the inorganic precipitate was removed by filtration and the collected filtrate was concentrated under reduced pressure to give the title product (3 g, 95.15%) as a yellow oil. LCMS [M + 1] + 399.2.

[0098] 1.3 Synthesis of N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-4-methylpiperidine-4-carbimidoyl chloride dihydrochloride [ka] tert-Butyl 4-(N'-(2-hydroxy-3-(piperidin-1-yl)propoxy)carbamimidoyl)-4-methylpiperidine-1-carboxylate (3.0 g, 5.27 mmol, 1 eq.) obtained in the previous experiment was dissolved in a mixture of acetic acid (5 ml) and aqueous hydrochloric acid (4N, 5 ml) at 0°C. To the resulting solution was added sodium nitrite (727 mg, 10.54 mmol, 2 eq.) in small portions with cooling, maintaining a temperature interval of 0-5°C. After the addition was complete, aqueous hydrochloric acid (4N, 5 ml) was added to the reaction mixture at 0°C, which was left at 0°C for 1 hour with stirring. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature and then left with stirring overnight. After 12 hours, the mixture was concentrated under reduced pressure to give a crude semi-solid product (3.1 g) which was subjected to preparative HPLC purification with addition of HCl to give 386 mg (17.8%) of the title N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-4-methylpiperidine-4-carbimidoyl chloride dihydrochloride as a yellow oil (Method A). *In an alternative work-up and purification procedure, the mixture was concentrated under reduced pressure to give a crude semi-solid residue which was diluted with 30% aqueous potassium carbonate to adjust to pH 10 and then extracted with DCM (3 x 5 ml). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The collected filtrate was concentrated under reduced pressure to give a crude oil which was subjected to preparative HPLC with addition of trifluoroacetic acid (Method B LCMS [M - Cl - ] + 282.2. 1 H NMR (heavy water, 400 MHz): δ (ppm) 4.32 - 4.23 (m, 1H), 4.19 - 4.03 (m, 2H), 3.53 - 3.35 (m, 2H), 3.24 - 3.12 (m, 3H), 3.10 - 2.88 (m, 4H), 2.82 (t, J=12.1, 12.1 Hz, 1H), 2.23 (d, J=14.2 Hz, 2H), 1.88 - 1.74 (m, 2H), 1.75 - 1.57 (m, 5H), 1.44 - 1.30 (m, 1H), 1.17 (s, 3H).

[0099] Example 2 Synthesis of 4-ethyl-N-(2-hydroxy-3-(piperidin-1-yl)propoxy)piperidine-4-carbimidoyl chloride di-2,2,2-trifluoroacetate, NME200409 [ka] Following the same general synthesis as described in 1.1-1.3 without significant modifications, 4-ethyl-N-(2-hydroxy-3-(piperidin-1-yl)propoxy)piperidine-4-carbimidoyl chloride di-2,2,2-trifluoroacetate (254 mg, 29.6%) was prepared as a yellow oil from commercially available tert-butyl 4-cyano-4-ethylpiperidine-1-carboxylate. 1 H NMR (heavy water, 500 MHz): δ (ppm) 4.34 - 4.25 (m, 1H), 4.23 - 4.09 (m, 2H), 3.46 (dd, J=31.0, 11.7 Hz, 2H), 3.27 - 3.06 (m, 4H), 3.05 - 2.92 (m, 3H), 2.83 (t, J=12.1, 12.1 Hz, 1H), 2.27 (d, J=14.6 Hz, 2H), 1.88 - 1.77 (m, 2H), 1.72 - 1.61 (m, 5H), 1.60 - 1.49 (m, 2H), 1.46 - 1.34 (m, 1H), 0.67 (t, J=7.4, 7.4 Hz, 3H).

[0100] Example 3 Synthesis of N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-4-(pyridin-2-yl)piperidine-4-carbimidoyl chloride tri-2,2,2-trifluoroacetate, NME200415 [ka] Following the same general procedure as described in 1.1-1.3 without significant modifications, N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-4-(pyridin-2-yl)piperidine-4-carbimidoyl chloride tri-2,2,2-trifluoroacetate (115 mg, 12.46%) was prepared as a yellow oil from commercially available tert-butyl 4-cyano-4-(pyridin-2-yl)piperidine-1-carboxylate. LCMS [M - ·Cl - ] + 345.0. 1 H NMR (heavy water, 400 MHz): δ (ppm) 8.59 (d, J=4.9 Hz, 1H), 8.38 (t, J=8.4, 8.4 Hz, 1H), 7.95 (d, J=8.2 Hz, 1H), 7.81 (t, 1H), 4.35 - 4.24 (m, 2H), 4.16 (dd, 1H), 3.55 - 3.14 (m, 7H), 3.15 - 3.01 (m, 2H), 2.93 - 2.86 (m, 1H), 2.82 - 2.76 (m, 2H), 2.42 - 2.31 (m, 2H), 1.85 - 1.71 (m, 2H), 1.70 - 1.51 (m, 3H), 1.44 - 1.27 (m, 1H).

[0101] Example 4 General scheme for preparation of nitrile precursors [ka]

[0102] 1.4 Synthesis of tert-butyl 4-cyano-4-(3-pyridylmethyl)piperidine-1-carboxylate [ka] In a round bottom flask under nitrogen atmosphere, lithium bis(trimethylsilyl)azanilide (1.0M in THF / ethylbenzol, 21.4ml, 21.4mmol) was slowly added to a solution of tert-butyl 4-cyanopiperidine-1-carboxylate (1.5g, 7.13mmol) at -76°C. After the mixture was stirred at -76°C for 2 hours, 3-(bromomethyl)pyridine hydrobromide (1.98g, 10.46mmol) was added to the system. The reaction mixture was stirred for another 30 minutes, then warmed to room temperature and stirred overnight. The mixture was quenched with 50ml of saturated aqueous NH4Cl2, further diluted with water and extracted with EtOAc. The organic layer was washed with water and brine, then dried over sodium sulfate, filtered and concentrated to give the target compound (2.6g, 33%), which was used as is. LCMS: [M + H] + 302

[0103] Synthesis of N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-4-(pyridin-3-ylmethyl)piperidine-4-carbimidoyl chloride tri-2,2,2-trifluoroacetate, NME200419 [ka] Following the same general sequence as described in 1.1-1.3 and 1.4 respectively without significant modifications and using tert-butyl 4-cyano-4-(3-pyridylmethyl)piperidine-1-carboxylate instead of tert-butyl 4-cyanopiperidine-1-carboxylate, N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-4-(pyridin-3-ylmethyl)piperidine-4-carbimidoyl chloride tri-2,2,2-trifluoroacetate (720 mg, 33.19%) was prepared as a yellow oil. LCMS [M + 1] + 396.2. 1H NMR (chloroform-d, 400 MHz): δ (ppm) 8.48 (d, J=4.5 Hz, 1H), 8.37 (s, 1H), 7.44 (d, 1H), 7.23 - 7.17 (m, 1H), 4.46 - 4.31 (m, 1H), 4.05 (d, J=13.2 Hz, 1H), 3.68 (dd, J=11.6, 5.7 Hz, 1H), 3.38 - 3.22 (m, 2H), 3.16 - 2.98 (m, 2H), 2.88 - 2.74 (m, 2H), 2.66 - 2.24 (m, 6H), 2.27 - 2.15 (m, 2H), 1.91 (t, J=14.4, 14.4 Hz, 2H), 1.64 - 1.51 (m, 4H), 1.46 - 1.34 (m, 2H).

[0104] Example 5 Synthesis of 3-(dimethylamino)-N-(2-hydroxy-3-(piperidin-1-yl)propoxy)propanimidoyl chloride, NME200446 [ka] Following the same general synthesis described in 1.1-1.3 without significant modifications, 3-(dimethylamino)-N-(2-hydroxy-3-(piperidin-1-yl)propoxy)propanimidoyl chloride (445.2 mg, 41.56%) was prepared as a yellow oil from commercially available 3-(dimethylamino)propanenitrile. LCMS [M + 1] + 292.2. 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 4.67 - 4.58 (m, 1H), 4.08 - 4.00 (m, 1H), 3.99 - 3.92 (m, 1H), 3.88 - 3.75 (m, 1H), 2.64 - 2.56 (m, 2H), 2.49 - 2.45 (m, 2H), 2.42 - 2.31 (m, 4H), 2.29 - 2.21 (m, 2H), 2.13 (s, 6H), 1.52 - 1.42 (m, 4H), 1.39 - 1.28 (m, 2H).

[0105] Example 6 Synthesis of N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-4-(2-methoxyethyl)piperidine-4-carbimidoyl chloride di-2,2,2-trifluoroacetate, NME200448 [ka] Following the same general procedure as described in 1.1-1.3 without significant modifications, N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-4-(2-methoxyethyl)piperidine-4-carbimidoyl chloride di-2,2,2-trifluoroacetate (26.5 mg, 6.63%) was prepared as a yellow oil from commercially available tert-butyl 4-cyano-4-(2-methoxyethyl)piperidine-1-carboxylate. LCMS [M - Cl - ] + 326.2. 1 H NMR (methanol-d4, 400 MHz): δ (ppm) 4.38 - 4.28 (m, 1H), 4.22 (d, J=4.9 Hz, 2H), 3.64 - 3.51 (m, 2H), 3.40 (t, J=6.1, 6.1 Hz, 2H), 3.34 - 3.21 (m, 8H), 3.19 - 2.96 (m, 4H), 2.39 (d, J=14.5 Hz, 2H), 2.00 - 1.67 (m, 8H), 1.62 - 1.47 (m, 1H).

[0106] Example 7 Synthesis of N-(2-hydroxy-3-(piperidin-1-yl)propoxy)pyridazine-4-carbimidoyl bromide, NME200452 [ka] Following the same synthesis as described in 1.1-1.3 without significant changes, except for using hydrobromic acid instead of hydrochloric acid in experimental procedure 1.3, N-(2-hydroxy-3-(piperidin-1-yl)propoxy)pyridazine-4-carbimidoyl bromide (159.9 mg, 12.36%) was prepared as a brown oil from commercially available pyridazine-4-carbonitrile. LCMS [M + 1] + 345.2. 1 H NMR (chloroform-d, 400 MHz): δ (ppm) 9.57 (s, 1H), 9.24 (d, J=5.3 Hz, 1H), 7.78 (d, J=7.7 Hz, 1H), 4.39 (d, J=5.0 Hz, 2H), 4.12 - 4.02 (m, 1H), 3.53 (s, 1H), 2.65 - 2.55 (m, 2H), 2.46 - 2.40 (m, 2H), 2.38 - 2.28 (m, 2H), 1.63 - 1.50 (m, 4H), 1.47 - 1.38 (m, 2H).

[0107] Example 8 Synthesis of N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-2-methylthiazole-5-carbimidoyl chloride, NME200453 [ka] Following the same general synthesis as described in 1.1-1.3 without significant modifications, N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-2-methylthiazole-5-carbimidoyl chloride (136 mg, 21.28%) was prepared as a yellow oil from commercially available 2-methyl-1,3-thiazole-5-carbonitrile. LCMS [M + 1] + 318.2. 1H NMR (chloroform-d, 400 MHz): δ (ppm) 7.93 (s, 1H), 7.24 (s, 1H), 4.29 - 4.16 (m, 2H), 4.07 - 3.99 (m, 1H), 2.68 (s, 3H), 2.62 - 2.51 (m, 2H), 2.42 - 2.27 (m, 4H), 1.63 - 1.51 (m, 4H), 1.47 - 1.38 (m, 2H).

[0108] Example 9 Synthesis of 6-chloro-N-(2-hydroxy-3-(piperidin-1-yl)propoxy)nicotinimidoyl chloride, NME200466 [ka] Following the same general synthesis described in 1.1-1.3 without significant modifications, 6-chloro-N-(2-hydroxy-3-(piperidin-1-yl)propoxy)nicotinimidoyl chloride (239 mg, 23.82%) was prepared as a yellow oil from commercially available 6-chloronicotinonitrile. LCMS [M + 1] + 332.2. 1 H NMR (chloroform-d, 400 MHz): δ (ppm) 8.80 (d, J=2.3 Hz, 1H), 8.05 (dd, J=8.4, 2.4 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 4.31 - 4.25 (m, 2H), 4.08 - 4.01 (m, 1H), 3.47 (s, 1H), 2.66 - 2.57 (m, 2H), 2.40 - 2.29 (m, 4H), 1.60 - 1.53 (m, 4H), 1.44 - 1.39 (m, 2H).

[0109] Example 10 Synthesis of N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-3-methylisoxazole-5-carbimidoyl chloride, NME200475 [ka] Following the same general synthesis described in 1.1-1.3 without significant modifications, N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-3-methylisoxazole-5-carbimidoyl chloride (360 mg, 24.46%) was prepared as a yellow oil from commercially available 3-methylisoxazole-5-carbonitrile. LCMS [M + 1] + 302.2. 1 H NMR (chloroform-d, 400 MHz): δ (ppm) 6.50 (s, 1H), 4.31 (d, J=5.0 Hz, 2H), 4.09 - 4.01 (m, 1H), 3.76 (s, 1H), 2.65 - 2.54 (m, 2H), 2.42 - 2.25 (m, 7H), 1.64 - 1.48 (m, 4H), 1.47 - 1.36 (m, 2H).

[0110] Example 11 Synthesis of 6-chloro-N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-4-methylnicotinimidoyl chloride, NME200501 [ka] Following the same general synthesis described in 1.1-1.3 without significant modifications, 6-chloro-N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-4-methylnicotinimidoyl chloride (66.3 mg, 2.48%) was prepared as a yellow oil from commercially available 6-chloro-4-methylnicotinonitrile. LCMS [M + 1] + 346.2. 1 H NMR (chloroform-d, 400 MHz): δ (ppm) 8.44 (s, 1H), 7.20 (s, 1H), 4.26 (d, J=5.6 Hz, 2H), 4.08 - 4.00 (m, 1H), 3.76 (s, 1H), 2.62 - 2.55 (m, 2H), 2.44 (s, 3H), 2.41 - 2.29 (m, 4H), 1.62 - 1.52 (m, 4H), 1.46 - 1.38 (m, 2H).

[0111] Example 12 Synthesis of 6-chloro-N-(2-hydroxy-3-(piperidin-1-yl)propoxy)nicotinimidoyl bromide, NME200504 [ka] Following the same synthesis as described in 1.1-1.3 without significant changes, except for using hydrobromic acid instead of hydrochloric acid in experimental procedure 1.3, 6-chloro-N-(2-hydroxy-3-(piperidin-1-yl)propoxy)nicotinimidoyl bromide (421.8 mg, 18.49%) was prepared as a yellow oil from commercially available 6-chloronicotinonitrile. LCMS [M + 1] + 376.2. 1 H NMR (chloroform-d, 500 MHz): δ (ppm) 8.82 (s, 1H), 8.07 (d, J=10.6 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 4.48 - 4.27 (m, 2H), 4.13 - 4.04 (m, 1H), 2.74 - 2.54 (m, 2H), 2.51 - 2.24 (m, 4H), 1.64 - 1.52 (m, 4H), 1.49 - 1.36 (m, 2H).

[0112] Example 13 Synthesis of 3-(dimethylamino)-N-(2-hydroxy-3-(piperidin-1-yl)propoxy)propanimidoyl bromide, NME200532 [ka] Following the same synthesis as described in 1.1-1.3 without significant changes, except for using hydrobromic acid instead of hydrochloric acid in experimental procedure 1.3, 3-(dimethylamino)-N-(2-hydroxy-3-(piperidin-1-yl)propoxy)propanimidyl bromide (123.6 mg, 16.69%) was prepared as a yellow oil from commercially available 3-(dimethylamino)propanenitrile. LCMS [M + 1] + 337.8. 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 4.64 (s, 1H), 4.15 - 4.04 (m, 1H), 4.03 - 3.93 (m, 1H), 3.89 - 3.79 (m, 1H), 2.69 (t, J=6.7, 6.7 Hz, 2H), 2.49 - 2.43 (m, 2H), 2.40 - 2.20 (m, 6H), 2.14 (s, 6H), 1.54 - 1.42 (m, 4H), 1.40 - 1.30 (m, 2H).

[0113] Example 14 Synthesis of N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-4-(pyridin-3-yl)piperidine-4-carbimidoyl chloride tri-2,2,2-trifluoroacetate, NME200492 [ka] Following the same general procedure as described in 1.1-1.3 without significant modifications, N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-4-(pyridin-3-yl)piperidine-4-carbimidoyl chloride tri-2,2,2-trifluoroacetate (116.4 mg, 17.22%) was prepared as a yellow oil from commercially available tert-butyl 4-cyano-4-(pyridin-3-yl)piperidine-1-carboxylate. LCMS [M - ·Cl - ] + 345.4. 1H NMR (methanol-d4, 400 MHz): δ (ppm) 8.82 (s, 1H), 8.72 (d, J=4.2 Hz, 1H), 8.32 (d, J=8.1 Hz, 1H), 7.82 (dd, J=8.0, 5.3 Hz, 1H), 4.40 - 4.28 (m, 2H), 3.64 - 3.52 (m, 2H), 3.43 - 3.26 (m, 8H), 3.25 - 3.13 (m, 2H), 3.07 - 2.93 (m, 2H), 2.85 (d, J=14.9 Hz, 2H), 2.42 (t, J=12.8, 12.8 Hz, 2H), 1.96 - 1.87 (m, 2H), 1.85 - 1.75 (m, 2H), 1.59 - 1.47 (m, 1H).

[0114] Example 15 Synthesis of N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-4-((6-methylpyridin-3-yl)methyl)piperidine-4-carbimidoyl chloride tri-2,2,2-trifluoroacetate, NME200493 [ka] Following the synthesis described in 3.1-3.3 without significant changes, except for using 5-(bromomethyl)-2-methylpyridine hydrobromide instead of 3-(bromomethyl)-pyridine hydrobromide in experimental procedure 1.4, N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-4-((6-methylpyridin-3-yl)methyl)piperidine-4-carbimidoyl chloride tri-2,2,2-trifluoroacetate (108.2 mg, 27.64%) was prepared as a light brown oil. LCMS [M + 1] + 410.2. 1H NMR (heavy water, 400 MHz): δ (ppm) 8.26 (s, 1H), 8.06 (d, J=9.6 Hz, 1H), 7.68 (d, J=8.3 Hz, 1H), 4.18 - 4.06 (m, 1H), 4.02 - 3.86 (m, 2H), 3.40 (t, J=11.0, 11.0 Hz, 2H), 3.24 (d, J=13.2 Hz, 2H), 3.10 - 2.83 (m, 7H), 2.79 (t, J=12.0, 12.0 Hz, 1H), 2.60 (s, 3H), 2.22 (d, J=14.5Hz, 2H), 1.91 - 1.70 (m, 4H), 1.73 - 1.58 (m, 3H), 1.41 - 1.29 (m, 1H).

[0115] Example 16 Synthesis of N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-4-((6-methoxy-2-methylpyridin-3-yl)methyl)piperidine-4-carbimidoyl chloride tri-2,2,2-trifluoroacetate, NME200524 [ka] Following the synthesis described in 1.1-1.3 without significant changes, except for using 3-(chloromethyl)-6-methoxy-2-methylpyridine instead of 3-(bromomethyl)-pyridine hydrobromide in experimental procedure 1.4, N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-4-((6-methoxy-2-methylpyridin-3-yl)methyl)piperidine-4-carbimidoyl chloride tri-2,2,2-trifluoroacetate (102.5 mg, 18.89%) was prepared as a light brown oil by LCMS [M - ·Cl - ] + 403.2. 1H NMR (heavy water, 400 MHz): δ (ppm) 7.95 (d, J=9.0 Hz, 1H), 7.13 (d, J=9.0 Hz, 1H), 4.20 - 4.12 (m, 1H), 4.07 - 3.90 (m, 5H), 3.40 (t, J=11.3, 11.3 Hz, 2H), 3.23 (d, J=13.0 Hz, 2H), 3.10 - 2.98 (m, 2H), 2.96 - 2.74 (m, 6H), 2.42 (s, 3H), 2.27 (d, J=14.7 Hz, 2H), 1.85 - 1.73 (m, 4H), 1.70 - 1.58 (m, 3H), 1.39 - 1.26 (m, 1H).

[0116] Example 17 Synthesis of N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-4-((6-methoxy-4-methylpyridin-3-yl)methyl)piperidine-4-carbimidoyl chloride, NME200525 [ka] Following the synthesis described in 1.1-1.3 without significant changes, except for using 5-(chloromethyl)-2-methoxy-4-methylpyridine instead of 3-(bromomethyl)-pyridine hydrobromide in experimental procedure 1.4, N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-4-((6-methoxy-4-methylpyridin-3-yl)methyl)piperidine-4-carbimidoyl chloride (62.6 mg, 11.42%) was prepared as a yellow oil. LCMS [M + 1] + 439.2. 1H NMR (heavy water, 400 MHz): δ (ppm) 7.77 (s, 1H), 7.22 (s, 1H), 4.23 - 3.92 (m, 7H), 3.41 (t, J=12.8, 12.8 Hz, 2H), 3.27 - 3.20 (m, 2H), 3.10 - 3.01 (m, 2H), 2.94 - 2.86 (m, 4H), 2.83 - 2.76 (m, 1H), 2.38 (s, 3H), 2.29 (d, J=14.4 Hz, 2H), 1.89 - 1.75 (m, 4H), 1.71 - 1.56 (m, 3H), 1.42 - 1.28 (m, 1H).

[0117] Example 18 Synthesis of N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-4-(pyridin-2-yl)piperidine-4-carbimidoyl chloride tri-2,2,2-trifluoroacetate, NME200534 [ka] Following the same general procedure as described in 1.1-1.3 without significant modifications, N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-4-(pyridin-2-yl)piperidine-4-carbimidoyl chloride tri-2,2,2-trifluoroacetate (115 mg, 12.46%) was prepared as a yellow oil from commercially available tert-butyl 4-cyano-4-(pyridin-2-yl)piperidine-1-carboxylate. LCMS [M - ·Cl - ] + 345.2. 1H NMR (heavy water, 400 MHz): δ (ppm) 8.59 (d, J=4.9 Hz, 1H), 8.38 (t, J=8.4, 8.4 Hz, 1H), 7.95 (d, J=8.2 Hz, 1H), 7.86 - 7.78 (m, 1H), 4.34 - 4.22 (m, 2H), 4.19 - 4.11 (m, 1H), 3.47 - 3.21 (m, 6H), 3.15 - 2.98 (m, 2H), 2.96 - 2.86 (m, 1H), 2.85 - 2.75 (m, 3H), 2.36 (t, J=14.8, 14.8 Hz, 2H), 1.86 - 1.71 (m, 2H), 1.69 - 1.54 (m, 3H), 1.42 - 1.29 (m, 1H).

[0118] Example 19 Synthesis of 4-(3-chloropyridin-4-yl)-N-(2-hydroxy-3-(piperidin-1-yl)propoxy)piperidine-4-carbimidoyl chloride tri-2,2,2-trifluoroacetate, NME200535 [ka] Following the general synthesis described in 1.1-1.3 without significant changes, 4-(3-chloropyridin-4-yl)-N-(2-hydroxy-3-(piperidin-1-yl)propoxy)piperidine-4-carbimidoyl chloride tri-2,2,2-trifluoroacetate (65 mg, 13.72%) was prepared as a yellow oil from the starting material tert-butyl 4-(3-chloropyridin-4-yl)-4-cyanopiperidine-1-carboxylate. The synthesis of the starting material was described above. LCMS [M + 1] + 416.0. 1H NMR (heavy water, 400 MHz): δ (ppm) 8.59 (s, 1H), 8.52 (d, J=5.3 Hz, 1H), 7.72 (d, 1H), 4.33 - 4.19 (m, 3H), 3.51 - 3.26 (m, 6H), 3.20 - 3.02 (m, 2H), 2.95 - 2.76 (m, 4H), 2.41 - 2.25 (m, 2H), 1.87 - 1.75 (m, 2H), 1.72 - 1.56 (m, 3H), 1.46 - 1.30 (m, 1H).

[0119] Example 20 Synthesis of N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-3-(pyrrolidin-1-yl)propanimidoyl chloride, NME200562 [ka] Following the same general synthesis as described in 1.1-1.3 without significant modifications, N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-3-(pyrrolidin-1-yl)propanimidoyl chloride (168.1 mg, 31.57%) was prepared as a yellow oil from commercially available 3-(pyrrolidin-1-yl)propanenitrile. LCMS [M + 1] + 318.2. 1 H NMR (methanol-d4, 400 MHz): δ (ppm) 4.07 - 4.01 (m, 2H), 3.32 - 3.25 (m, 3H), 2.84 - 2.65 (m, 4H), 2.61 - 2.56 (m, 3H), 2.53 - 2.41 (m, 5H), 1.92 - 1.71 (m, 4H), 1.64 - 1.55 (m, 4H), 1.50 - 1.41 (m, 2H).

[0120] Example 21 Synthesis of N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-3-(piperidin-1-yl)propanimidoyl chloride, NME200563 [ka] Following the same general synthesis described in 1.1-1.3 without significant modifications, N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-3-(piperidin-1-yl)propanimidoyl chloride (119.3 mg, 23.71%) was prepared as a yellow oil from commercially available 3-(piperidin-1-yl)propanenitrile. LCMS [M + 1] + 332.2. 1 H NMR (methanol-d4, 400 MHz): δ (ppm) 4.14 - 3.95 (m, 3H), 3.30 (s, 2H), 2.75 - 2.60 (m, 4H), 2.51 - 2.37 (m, 8H), 1.68 - 1.52 (m, 8H), 1.50 - 1.36 (m, 4H).

[0121] Example 22 Synthesis of 6-chloro-N-(2-hydroxy-2-methyl-3-(piperidin-1-yl)propoxy)nicotinimidoyl chloride, NME200502 [ka] Following the same synthesis as described in 1.1-1.3 without significant changes, except for using the above 2-hydroxy-2-methyl-4-azaspiro[3.5]nonan-4-ium chloride instead of 2-hydroxy-4-azaspiro[3.5]nonan-4-ium chloride in experimental procedure 1.2, 6-chloro-N-(2-hydroxy-2-methyl-3-(piperidin-1-yl)propoxy)nicotinimidoyl chloride (433.3 mg, 38.85%) was prepared as a yellow oil from commercially available 6-chloronicotinonitrile. LCMS [M + 1] + 346.2. 1H NMR (chloroform-d, 400 MHz): δ (ppm) 8.80 (s, 1H), 8.05 (d, 1H), 7.33 (d, J=8.4 Hz, 1H), 4.20 - 4.11 (m, 2H), 3.75 (s, 1H), 2.61 - 2.47 (m, 5H), 2.24 (d, J=13.9 Hz, 1H), 1.58 - 1.50 (m, 4H), 1.45 - 1.35 (m, 2H), 1.20 (s, 3H).

[0122] Example 23 Synthesis of tert-butyl (3-chloro-3-((2-hydroxy-3-(piperidin-1-yl)propoxy)imino)propyl)(methyl)carbamate, NME200599 General Scheme [ka]

[0123] 3.4 Synthesis of tert-butyl (3-chloro-3-((2-hydroxy-3-(piperidin-1-yl)propoxy)imino)propyl)(methyl)carbamate [ka] Following the synthesis described in 1.1-1.2 generally similarly without significant changes, tert-butyl N-[3-amino-3-[2-hydroxy-3-(1-piperidyl)propoxy]imino-propyl]-N-methyl-carbamate (2 g, 3.12 mmol, 1 equiv.), obtained from commercially available tert-butyl (2-cyanoethyl)(methyl)carbamate, was dissolved in acetonitrile (50 ml), and then tert-butyl nitrite (0.97 g, 9.37 mmol, 3 equiv.) was added to the resulting solution, followed by CuCl2 (1.26 g, 9.37 mmol, 3 equiv.). The reaction mixture was left in the dark for 2 days at room temperature with stirring. After 48 h, the reaction mixture was concentrated under reduced pressure, diluted with 4.0 M aqueous sodium carbonate (50 ml), and extracted with ethyl acetate (2 x 30 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The collected filtrate was concentrated under reduced pressure to give a crude yellow oil (1 g), which was subjected to preparative HPLC purification to give the title product (95 mg, 7.6%) as a pink oil. LCMS [M + 1] + 378.4. 1 H NMR (chloroform-d, 400 MHz): δ (ppm) 4.20 - 4.02 (m, 2H), 4.01 - 3.88 (m, 1H), 3.58 - 3.31 (m, 2H), 2.84 (s, 3H), 2.74 - 2.47 (m, 4H), 2.43 - 2.27 (m, 4H), 1.71 - 1.45 (m, 6H), 1.43 (s, 9H).

[0124] 1. Method using nosyl epoxide Example 1 Synthesis of N-(3-(4-fluoropiperidin-1-yl)-2-hydroxypropoxy)-4-methylpiperidine-4-carbimidoyl chloride di-2,2,2-trifluoroacetate, NME200399 General Scheme [ka]

[0125] 1.1 Synthesis of tert-butyl 4-(N'-(3-(4-fluoropiperidin-1-yl)-2-hydroxypropoxy)carbamimidoyl)-4-methylpiperidine-1-carboxylate [ka] A suspension of tert-butyl 4-(N'-hydroxycarbamimidoyl)-4-methylpiperidine-1-carboxylate (2 g, 7.77 mmol, 1 eq.) in dry DMF (5 ml) was cooled to 0°C. 60% sodium hydride in mineral oil (0.311 g, 7.77 mmol, 1 eq.) was added and the reaction mixture was stirred at 0°C for 30 min. Oxiran-2-ylmethyl 3-nitrobenzenesulfonate (2.015 g, 7.77 mmol, 1 eq.) dissolved in dry DMF (5 ml) was then added and the mixture was allowed to warm to room temperature and stirred for a further 2 h. 4-Fluoropiperidine hydrochloride (1.085 g, 7.77 mmol, 1 eq.) and N,N-diethylethanamine (0.787 g, 7.77 mmol, 1 eq.) in dry DMF (5 ml) were added dropwise to the reaction mixture. The reaction was heated to 60°C and left under stirring for 48 hours, after which it was concentrated under reduced pressure, diluted with distilled water (20ml) and extracted with DCM (3x15ml). The organic layers were combined, washed with saturated sodium bicarbonate solution (aqueous, 2x15ml), dried over anhydrous sodium sulfate and filtered. The collected material was concentrated under reduced pressure to give a brown oil (3.5g). The resulting material was subjected to flash chromatography purification (Companion combiflash, SiO2 80g, acetonitrile / methanol with 0-25% methanol, flow rate = 60mL / min) to give the title product (1.515g, 44.5%) as a light brown oil in good condition. LCMS [M + 1] + 417.2.

[0126] 1.2 Synthesis of N-(3-(4-fluoropiperidin-1-yl)-2-hydroxypropoxy)-4-methylpiperidine-4-carbimidoyl chloride di-2,2,2-trifluoroacetate [ka] tert-Butyl 4-[N'-[3-(4-fluoro-1-piperidyl)-2-hydroxy-propoxy]carbamimidoyl]-4-methyl-piperidine-1-carboxylate (500 mg, 1.14 mmol, 1 equiv.) was dissolved in distilled water (2 ml) and acetic acid (1 ml). The resulting solution was cooled to 0° C. and 30% aqueous hydrochloric acid (0.603 ml, 692.97 mg, 5.7 mmol, 5 equiv.) was added dropwise to the reaction mixture, followed by the slow addition of a solution of sodium nitrite (157.37 mg, 2.28 mmol, 2 equiv.) in distilled water (1 ml). The reaction mixture was left at 0° C. with stirring for 2 hours and then allowed to warm to room temperature. 30% aqueous hydrochloric acid (0.603 ml, 692.97 mg, 5.7 mmol, 5 eq) was added to the reaction mixture after 6 hours, then left with stirring at room temperature overnight, reduced in volume and subjected to preparative HPLC to give the title product (290.7 mg, 42.95%) as a yellow oil. LCMS [M − ·Cl - ] + 301.0. 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 9.54 (s, 1H), 8.75 (s, 1H), 8.61 (s, 1H), 5.13 - 4.68 (m, 1H), 4.31 - 4.17 (m, 1H), 4.16 - 4.04 (m, 2H), 3.61 - 3.34 (m, 2H), 3.34 - 3.01 (m, 7H), 3.01 - 2.87 (m, 2H), 2.22 - 1.90 (m, 6H), 1.75 (t, J=13.3, 13.3 Hz, 2H), 1.24 (s, 3H).

[0127] Example 2 Synthesis of N-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-4-methylpiperidine-4-carbimidoyl chloride tri-2,2,2-trifluoroacetate, NME200402 [ka] Following the synthesis described in 4.1-4.2 without significant changes, except for using 1-methylpiperazine instead of 4-fluoropiperidine hydrochloride in experimental procedure 4.1, N-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-4-methylpiperidine-4-carbimidoyl chloride tri-2,2,2-trifluoroacetate (420 mg, 51.47%) was prepared as a yellow oil from commercially available tert-butyl 4-(N'-hydroxycarbamimidoyl)-4-methylpiperidine-1-carboxylate. LCMS [M - Cl - ] + 298.0. 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 8.80 (s, 1H), 8.67 (s, 1H), 4.25 - 4.01 (m, 3H), 3.69 - 3.34 (m, 5H), 3.29 - 3.12 (m, 4H), 3.13 - 3.06 (m, 1H), 3.06 - 2.84 (m, 4H), 2.55 - 2.49 (m, 6H), 2.22 - 2.07 (m, 2H), 1.83 - 1.62 (m, 2H), 1.24 (s, 3H).

[0128] Example 3 Synthesis of N-(3-(3-azabicyclo[3.1.0]hexan-3-yl)-2-hydroxypropoxy)-4-methylpiperidine-4-carbimidoyl chloride di-2,2,2-trifluoroacetate, NME200403 [ka] Following the synthesis described in 2.1-2.2 without significant changes, except for using 3-azabicyclo[3.1.0]hexane hydrochloride instead of 4-fluoropiperidine hydrochloride in experimental procedure 2.1, N-(3-(3-azabicyclo[3.1.0]hexane-3-yl)-2-hydroxypropoxy)-4-methylpiperidine-4-carbimidoyl chloride di-2,2,2-trifluoroacetate (89.5 mg, 15.50%) was prepared as a yellow oil from commercially available tert-butyl 4-(N'-hydroxycarbamimidoyl)-4-methylpiperidine-1-carboxylate. LCMS [M - Cl - ] + 280.0. 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 9.59 (s, 1H), 8.76 (s, 1H), 8.64 (s, 1H), 4.19 - 3.84 (m, 4H), 3.65 - 3.55 (m, 2H), 3.44 - 3.32 (m, 2H), 3.27 - 3.21 (m, 1H), 3.05 - 2.84 (m, 3H), 2.15 - 2.02 (m, 2H), 1.90 - 1.67 (m, 5H), 1.24 (s, 4H), 0.88 - 0.77 (m, 1H), 0.72 - 0.59 (m, 1H).

[0129] Example 4 Synthesis of N-(3-(2-azabicyclo[2.2.1]heptan-2-yl)-2-hydroxypropoxy)-4-methylpiperidine-4-carbimidoyl chloride di-2,2,2-trifluoroacetate, NME200410 [ka] Following the synthesis described in 2.1-2.2 without significant changes, except for using 2-azabicyclo[2.2.1]heptane hydrochloride instead of 4-fluoropiperidine hydrochloride in experimental procedure 2.1, N-(3-(2-azabicyclo[2.2.1]heptane-2-yl)-2-hydroxypropoxy)-4-methylpiperidine-4-carbimidoyl chloride di-2,2,2-trifluoroacetate (104 mg, 19.97%) was prepared as a light brown oil from commercially available tert-butyl 4-(N'-hydroxycarbamimidoyl)-4-methylpiperidine-1-carboxylate. LCMS [M - Cl - ] + 294.4. 1 H NMR (methanol-d4, 400 MHz): δ (ppm) 4.32 - 4.09 (m, 4H), 3.59 - 3.23 (m, 7H), 3.21 - 2.97 (m, 4H), 2.88 - 2.72 (m, 1H), 2.34 (d, J=14.4 Hz, 2H), 2.05 - 1.97 (m, 1H), 1.86 - 1.68 (m, 5H), 1.62 - 1.49 (m, 1H), 1.31 (s, 3H).

[0130] Example 5 Synthesis of (S)-N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-4-methylpiperidine-4-carbimidoyl chloride di-2,2,2-trifluoroacetate, NME200384 [ka] Following the same general synthesis as described in 2.1-2.2, except for using piperidine instead of 4-fluoropiperidine hydrochloride in experimental procedure 4.1 and [(2S)-oxiran-2-yl]methyl 3-nitrobenzenesulfonate instead of oxiran-2-ylmethyl 3-nitrobenzenesulfonate without any significant changes, (S)-N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-4-methylpiperidine-4-carbimidoyl chloride di-2,2,2 trifluoroacetate (93 mg, 20.57%) was prepared as a yellow oil from commercially available tert-butyl 4-(N'-hydroxycarbamimidoyl)-4-methylpiperidine-1-carboxylate. LCMS [M - ·Cl - ] + 282.0. 1 H NMR (heavy water, 400 MHz): δ (ppm) 4.32 - 4.23 (m, 1H), 4.17 - 4.03 (m, 2H), 3.51 - 3.37 (m, 2H), 3.22 - 3.11 (m, 3H), 3.09 - 2.97 (m, 3H), 2.95 - 2.86 (m, 1H), 2.82 (t, J=12.7, 12.7 Hz, 1H), 2.23 (d, J=15.2 Hz, 2H), 1.86 - 1.74 (m, 2H), 1.74 - 1.55 (m, 5H), 1.43 - 1.28 (m, 1H), 1.18 (s, 3H)

[0131] Example 6 Synthesis of (R)-N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-4-methylpiperidine-4-carbimidoyl chloride di-2,2,2-trifluoroacetate, NME200387 [ka] Following the same general synthesis as described in 2.1-2.2 without significant changes, except for using piperidine instead of 4-fluoropiperidine hydrochloride in experimental procedure 2.1 and [(2R)-oxiran-2-yl]methyl 3-nitrobenzenesulfonate instead of oxiran-2-ylmethyl 3-nitrobenzenesulfonate, (R)-N-(2-hydroxy-3-(piperidin-1-yl)propoxy)-4-methylpiperidine-4-carbimidoyl chloride di-2,2,2 trifluoroacetate (450 mg, 82.13%) was prepared as a yellow oil from commercially available tert-butyl 4-(N'-hydroxycarbamimidoyl)-4-methylpiperidine-1-carboxylate. LCMS [M - ·Cl - ] + 282.0. 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 9.35 (s, 1H), 8.86 (s, 1H), 8.68 (s, 1H), 4.26 - 4.19 (m, 1H), 4.16 - 4.05 (m, 2H), 3.47 - 3.38 (m, 2H), 3.26 - 2.73 (m, 9H), 2.11 (d, J=15.0 Hz, 2H), 1.80 - 1.58 (m, 7H), 1.43 - 1.34 (m, 1H), 1.23 (s, 3H)

[0132] Example 7 Synthesis of N-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-4-(pyridin-3-ylmethyl)piperidine-4-carbimidoyl chloride tetra-2,2,2-trifluoroacetate, NME200513 [ka] Following the synthesis described in 1.4, 1.1, 2.1-2.2 without significant changes, except for using 3-(bromomethyl)pyridine hydrobromide instead of 3-(bromomethyl)-5-fluoro-pyridine hydrobromide in experimental procedure 1.4 and using 1-methylpiperazine instead of 4-fluoropiperidine hydrochloride in experimental procedure 2.1, N-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-4-(pyridin-3-ylmethyl)piperidine-4-carbimidoyl chloride tetra-2,2,2-trifluoroacetate (344 mg, 23.14%) was prepared as a yellow oil from commercially available tert-butyl 4-cyanopiperidine-1-carboxylate. LCMS [M + 1] + 410.2. 1 H NMR (heavy water, 400 MHz): δ (ppm) 8.57 (d, J=5.5 Hz, 1H), 8.45 (s, 1H), 8.23 ​​(d, J=8.0 Hz, 1H), 7.87 (t, 1H), 4.23 - 4.13 (m, 1H), 3.99 - 3.93 (m, 1H), 3.92 - 3.87 (m, 1H), 3.83 - 3.57 (m, 4H), 3.54 - 3.29 (m, 4H), 3.26 - 3.18 (m, 4H), 3.08 (s, 2H), 2.95 - 2.86 (m, 5H), 2.22 (d, J=14.2 Hz, 2H), 1.81 (t, J=13.7, 13.7 Hz, 2H).

[0133] Example 2: Determination of potency and efficacy of oximes using the GCase assay material The human fibroblast cell line GM10915 carrying the L444P GBA mutation was obtained from Coriell Biorepositories. All chemicals (glacial acetic acid, glycine, 4-methylumbelliferyl bD-glucopyranoside (4-MUG), sodium acetate trihydrate, sodium hydroxide, crystal violet, SDS, ammonium hydroxide) were obtained from Sigma-Aldrich (Denmark). Compounds tested for GCase activity were dissolved in HO or DMSO.

[0134] method The GM10915 cell line was cultured under standard cell culture conditions (37°C and 5% CO2) in complete DMEM medium supplemented with non-essential amino acids (NEAA), 1% Pen-Strep, and 12% FCS. Cells were cultured at 10 4 The cells were seeded at a density of 10000 cells / well into one black 96-well plate for glucosylceramidase (GCase) activity measurement and one clear 96-well plate for crystal violet staining to correct for cell density, which is performed to obtain quantitative information about the relative density of cells attached to the multi-well plate.

[0135] Assay of GCase activity The assay was adapted from Sawkar et al (2002) and is briefly described below. The day after the cells were seeded, the medium was replaced with fresh medium containing the compound to be tested. Compounds were tested in duplicate at an 8-point dilution dose range to obtain a dose response. Cells were exposed to compounds for 5 days. Fresh compound was added every 2-3 days. PBS was included to define basal levels of GCase activity.

[0136] The cells were washed three times with 200 μL of PBS per well, 50 μL of 2.5 mM 4-MUG buffer (4-MUG dissolved in 0.2 M acetate buffer, pH 4.0) was added, and the cells were incubated at 37° C., 5% CO2 for 23 hours. The reaction was stopped by adding 150 μL of 0.2 M glycine buffer, pH 10.8. Fluorescence was measured using a Varioskan® Flash reader (Thermo Scientific) with excitation / emission settings of 365 / 445 nm.

[0137] Crystal violet staining Cells were treated with compounds in a parallel setup identical to the setup for testing GCase activity. At the end of compound treatment, cells were washed once with 200 μL PBS per well and 50 μL of 0.1% w / v crystal violet (in H2O) was added. After 10 min incubation, the crystal violet solution was removed, cells were washed three times with 200 μL PBS and 100 μL of 1% SDS was added to solubilize the stain. Plates were agitated for 10-30 min on an orbital shaker. Absorbance (A) is measured at 570 nM using a Varioskan® Flash reader (Thermo Scientific).

[0138] calculation The fluorescence signal (F) derived from the GCase measurement is normalized to the absorbance signal (A) derived from crystal violet staining. The percentage of GCase activity resulting from compound treatment is calculated relative to the basal activity obtained from untreated cells.

number

[0139] Potency, EC 1.5is determined based on the dose-response effect of the compound as the concentration at which the "percentage of GCase activity" = 150%, which corresponds to a 1.5-fold induction of GCase activity. The maximum effect of the compound (Emax) is determined from the dose-response effect as the maximum "percentage of GCase activity" achieved in the dose range tested.

[0140] result GBA potency and Emax were determined as described above in this example and the results are shown in Table 1 below. [Table 2] JPEG2024545840000084.jpg208159JPEG2024545840000085.jpg215159JPEG2024545840000086.jpg219159JPEG2024545840000087.jpg169159

[0141] conclusion This example demonstrates that the oximes of the present disclosure are highly potent and effective compared to state-of-the-art GBA inducers such as ambroxol and LTI-291. These effects make the oximes of the present disclosure promising candidates for the treatment of GBA-mediated disorders.

Claims

1. Formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein R １ is H, C １－６ selected from the group consisting of alkyl, and halogen; Y is OH and C １－６ selected from the group consisting of alkoxy; X is selected from the group consisting of chlorine and bromine; J is an aliphatic ring containing at least one nitrogen atom, wherein said aliphatic ring is substituted or unsubstituted; A is, 【Chemistry 2】 selected from the group consisting of: wherein each k is 1, 2, 3, or 4; R ２ and R ３ are mutually independent, C １－６ Alkyl, C １－６ Acyl, and CO ２ -C １－６ selected from the group consisting of alkyl; n1, n2, u1, and u2 are independently selected from the group consisting of 1, 2, or 3; Each R ４ are independently H, halogen, and C １－４ alkyl, wherein each methylene group may be replaced by -O-; Each R ５ are independently H, halogen, and C １－４ alkyl, wherein each methylene group may be replaced by -O-; Each R ６ are independently H, halogen, and C １－４ alkyl, wherein each methylene group may be replaced by -O-; Each R ７ are independently H, halogen, and C １－４ alkyl, wherein each methylene group may be replaced by -O-; R ８ is H, and C １－４ selected from the group consisting of alkyl; G is -CH ２ -, -CH(R ９ ) -, -C(R ９ ) ２ -, -NH-, and -N(R ９ )-selected from the group consisting of; In the formula, each R ９ are independently hydrogen, halogen, C １－４ alkyl, wherein each methylene group may be replaced by -O-; T is, 【Chemistry 3】 or any tautomer thereof, wherein a is 0, 1, 2, or 3; and X １ , X ２ , X ３ , X ４ , and X ５ are independently selected from the group consisting of C, CH, and N, and each of the one, two, or three substituents is independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, alkoxy, amino, amido, acyl, cycloalkyl, and heterocycloalkyl, wherein each methylene group of said alkyl is optionally replaced by —O—; The compound or a pharmaceutically acceptable salt thereof.

2. J is formula (J1): 【Chemistry 4】 2. The compound of claim 1, wherein: n3 and n4 are independently 1, 2, or 3; Each R １１ are independently H, halogen, and C １－４ alkyl, wherein each methylene group may be replaced by -O-; Each R １２ are independently H, halogen, and C １－４ alkyl, wherein each methylene group may be replaced by -O-; Each R １３ are independently H, halogen, and C １－４ alkyl, wherein each methylene group may be replaced by -O-; Each R １４ are independently H, halogen, and C １－４ alkyl, wherein each methylene group may be replaced by -O-; Q is a bond, —CH ２ -, -CH(R １５ ) -, -C(R １５ ) ２ -, -NH-, and -N(R １５ )—, and each R １５ are independently hydrogen, halogen, C １－４ alkyl, wherein each methylene group may be replaced by -O-; R １１ and R １３ and the pair may be linked together to form a ring; compound.

3. Q is a bond, —CH ２ The compound of claim 2, wherein the compound is selected from the group consisting of -, -CHF-, -N(Me)-, and -NH-.

4. J, 【Chemistry 5】 The compound according to any one of claims 1 to 3, selected from the group consisting of:

5. The compound according to any one of claims 1 to 3, wherein Y is OH.

6. A is of formula (Ia): 【Chemistry 6】 4. The compound according to claim 1, wherein k is 2 and R ３ is C １－３ alkyl, and R ２ is C １－３ Alkyl or CO ２ The compound is tBu.

7. A is of formula (Ib): 【Chemistry 7】 4. The compound according to any one of claims 1 to 3, wherein n1 and n2 are each 2; R ４ , R ５ , R ６ , and R ７ are each hydrogen, and R ８ is hydrogen or C １－３ is alkyl; T is the formula (T3): 【Chemistry 8】 wherein a is 0 or 1; X １ , X ２ , and / or X ３ is N and X １ ~X ５ the remainder are independently C or CH; and the one, two, or three substituents are each independently hydrogen, C １－４ Alkyl, halogen, hydroxy, C １－４ Alkoxy, and C １－４ acyl; compound.

8. If only one substituent is present, it is: a) methyl; or b) is chlorine; The compound according to any one of claims 1 to 3.

9. A is of formula (Ib): 【Chemistry 9】 4. The compound according to any one of claims 1 to 3, wherein n1 and n2 are each 2; R ４ , R ５ , R ６ , and R ７ are each hydrogen, and R ８ is hydrogen or C １－３ is alkyl; T is the formula (T1): 【Chemistry 10】 wherein a is 0 and the substituent is C １－６ alkyl, wherein each methylene group may be replaced by —O—; compound.

10. A is of formula (Ic): 【Chemistry 11】 4. The compound according to any one of claims 1 to 3, wherein k is 1, 2, or 3; u1 and u2 are each 1 or 2; R ４ , R ５ , R ６ , and R ７ are each hydrogen; G is a bond, —CH ２ -, -NH-, and -N(C １－３ selected from the group consisting of (alkyl); compound.

11. A is, 【Chemistry 12】 The compound according to any one of claims 1 to 3, selected from the group consisting of:

12. The compound is 【Chemistry 13】 【change】 2. The compound of claim 1 selected from the group consisting of:

13. 4. The compound of any one of claims 1 to 3, which is a GBA inducer and increases glucocerebrosidase (GBA) enzyme levels and / or GBA enzyme activity.

14. A pharmaceutical for use in treating Parkinson's disease (PD), comprising a compound according to any one of claims 1 to 3.

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