Dioxazines and their use in the treatment of GBA-related disorders - Patents.com

Abstract

The present invention relates to dioxazines, their synthesis and their use to increase GBA activity and / or levels, as well as the treatment of GBA-related diseases, such as Parkinson's disease.

Description

[Technical field]

[0001] The present invention relates to dioxazines, their synthesis and their use to increase GBA activity and / or levels, as well as the treatment of GBA-related diseases, such as Parkinson's disease. [Background technology]

[0002] Lysosomes serve as vital reprocessing centers of human cells, breaking down proteins and fatty substances, such as glycosphingolipids, into their basic building blocks and then recycling them. A series of rare genetic disorders, called lysosomal storage diseases (LSDs), are the result of carrying distinct mutations in both copies of certain genes that code for various lysosomal enzymes. Gaucher disease, the most common lysosomal storage disease, is the result of 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 GCase activity, up to 95%. As a result of this profound loss of enzyme 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 serious health problems and organ pathology.

[0003] Many of these GBA mutations are also found in patients with Parkinson's disease (PD). Heterozygous mutations, such as those found in GBA mutation carriers (having one mutated GBA gene), have been found to predispose individuals to developing Parkinson's disease (Gan-Or et al., Neurology, 2015). GBA mutations are currently considered one of the main genetic risk factors for Parkinson's disease. It is estimated that at least 8% of Parkinson's disease patients have mutations in the GBA gene, including 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 function as GBA inducers with completely different structural species 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 (Ia): [ka] or a pharma- ceutically acceptable salt thereof, wherein: n is 1 or 2, R 1 , R 2 , and R 3 is independently selected from the group consisting of hydrogen, alkyl, and halogen; Y is a nitrogen-containing ring or chain; OrgB, sp 3 an organic base moiety attached to the rest of the compound via a hybridized carbon; OrgB and Y are optionally substituted.

[0007] In a second aspect, a pharmaceutical composition is provided 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 of treating a disease in a subject, the method comprising administering a compound as defined herein, wherein the disease is associated with decreased GBA levels and / or activity.

[0009] In a fourth aspect, there is provided a method of increasing GBA activity and / or levels, the method comprising contacting GBA with a compound as defined herein.

[0010] In a fifth 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

[0011] 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 from each other.

[0012] As used herein, the term "pharmaceutical acceptable salt" refers to salts commonly used in the pharmaceutical field. Examples of pharmaceutical acceptable salts include, but are not limited to, sodium salt, hydrochloride, magnesium salt, calcium salt, trifluoroacetate salt and potassium salt. In addition, 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.

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

[0014] The term "alkyl" refers to a straight or branched chain hydrocarbon chain radical composed of carbon and hydrogen atoms, which may be straight or branched, substituted or unsubstituted. In some preferred embodiments, the alkyl group may be composed of 1 to 12 carbon atoms, for example, up to and including 12 carbon atoms, such as 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc. 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, such as methyl (Me), ethyl (Et), n-propyl (Pr), 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and 3-methylhexyl, may be attached to the remainder of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted with one or more of any suitable substituents. The alkyl group can be monovalent, divalent, trivalent or tetravalent, as necessary to satisfy valence requirements.

[0015] The term "alkyl linker" as used herein refers to an alkyl, preferably a C1-C6 alkyl, that can link one portion of a molecule disclosed herein to another portion of the molecule. An example of an alkyl linker is "methylene". Thus, an alkyl linker may link, for example, a monocyclic ring, a bicyclic ring, or a tricyclic ring to a cyclic oxime of formula (Ia) disclosed herein.

[0016] In general, suitable substituents for the substituted groups disclosed herein include, independently, 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, in which each R a is independently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl.

[0017] The term "cycloalkyl" refers to a monocyclic or polycyclic radical containing carbon and hydrogen, which may be saturated or partially unsaturated. In some preferred embodiments, cycloalkyl groups include groups having 3 to 12 ring atoms (i.e., (C3 to C4)). 12 ) cycloalkyl or C(3~ 12 As used herein, any number range, such as (C3 to cycloalkyl), is also included. 12 ) cycloalkyl or C(3~ 12) "3-12" and the like in cycloalkyl refer to each integer in the given range, for example, "3 to 12 carbon atoms" means that the cycloalkyl group can 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.

[0018] The term "alkoxy" refers to an -O-alkyl group. In some preferred embodiments, alkoxy groups contain from 1 to 12 carbon atoms in a linear, branched, cyclic arrangement, 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.

[0019] 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. Acyl is attached to the parent structure through a carbonyl functionality.

[0020] The term “amino” or “amine” refers to —N(R a )2 radical group, where each R a is independently hydrogen, alkyl, (halo)alkyl, alkenyl, alkynyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, unless otherwise specified. a ) 2 groups, 2 R other than hydrogen aWhen substituted, they may be combined 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.

[0021] The term “amide” or “amido” refers to a group of the formula —(C═O)N(R d )2 or -NH(C=O)R d refers to a chemical moiety having the formula 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 are optionally substituted independently with one or more of the substituents as described herein as suitable substituents.

[0022] The term "haloalkyl" refers to an alkyl radical, as defined above, substituted with one or more halogen atoms. Thus, the term "alkyl" includes "haloalkyl." Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0023] The terms "halo", "halide", or alternatively "halogen", are intended to mean fluoro, chloro, bromo or iodo.

[0024] The term "aromatic" refers to an unsaturated, cyclic, 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 is an aromatic radical having 6 to 10 ring atoms (e.g., (C6- 10 ) aromatic or (C6~ 10 ) aryl) having at least one ring with a conjugated pi electron system that is carbocyclic (eg, phenyl, fluorenyl, and naphthyl).

[0025] The terms "aralkyl" or "arylalkyl" refer to an (aryl)alkyl radical, where aryl and alkyl are as disclosed herein.

[0026] The term "heteroaryl" or "heteroaromatic" refers to a 5- to 18-membered aromatic radical containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur (e.g., (C 13)heteroaryl) which may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system. Examples of heteroaryl include azepinyl, acridinyl, benzimidazolyl, benzoindolyl, 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, 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, isoindolinyl, 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-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).

[0027] The term "tautomers" refers to structurally distinct isomers that interconvert by tautomerization. "Tautomerization" is a form of isomerization and includes prototropy 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 with a change in bond order, often with the interconversion of a single bond with an adjacent double bond.

[0028] Symbols shown perpendicular to a bond TIFF2024537939000002.tif11129 indicates where the indicated moiety is attached to the remainder of the molecule.

[0029] The term "organic base moiety" refers to a combination of the terms "organic base" and "moiety." The term "moiety" refers to a portion of a molecule that is covalently bonded to the remainder of the molecule. An "organic base" is an organic compound that can act as a base. Organic bases usually contain a nitrogen atom that can be protonated, for example, amines have a lone pair of electrons on the nitrogen atom and can therefore act as a proton acceptor (base). Amines and nitrogen-containing heterocyclic compounds are organic bases. An example of an organic base is piperidine. Thus, an "organic base moiety" is an organic base that is a portion of a molecule with a basic functional group present with that portion. The organic base moiety is referred to herein as "OrgB."

[0030] compound In one embodiment, a compound of formula (Ia): [ka] or a pharma- ceutically acceptable salt thereof, wherein: n is 1 or 2, R 1 , R 2 , and R 3 is independently selected from the group consisting of hydrogen, alkyl, and halogen; Y is a nitrogen-containing ring or chain; OrgB, sp 3 an organic base moiety attached to the rest of the compound via a hybridized carbon; OrgB and Y are optionally substituted.

[0031] In one embodiment, the compound has formula (Ib): [ka] is a compound of During the ceremony, A is a monocyclic, bicyclic, or tricyclic ring, and A is sp 3 attached to the remainder of the compound via a hybrid bond, L is C 1~6 is an alkyl linker or L is absent, and if L is absent, A is directly attached to the cyclic oxime; A and Y are optionally substituted.

[0032] In one embodiment there is provided a compound as defined herein, wherein A is of formula (II): [ka] is a compound of the formula z 1 and z 2 is independently selected from the group consisting of 0, 1, 2, and 3; Q, [ka] is selected from the group consisting of R 4 is selected from the group consisting of hydrogen, alkyl, amino, alkoxy, acyl, amido, aralkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; R 5 is selected from the group consisting of hydrogen, alkyl, aralkyl, hydroxy, alkoxy, and amino; Each R 6 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxy, amino, amido, and halogen; Each R 7 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxy, amino, amido, and halogen; Each R 8 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxy, amino, amido, and halogen; Each R 9 are independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxy, amino, amido, and halogen.

[0033] In one embodiment, a compound is provided, wherein A is a compound of formula (II) and Q is a compound of formula (IIa).

[0034] In one embodiment, a compound is provided, wherein L is of formula (III): [ka] is a compound of the formula v is 0 or 1, and when v is 0, L is not present; Each R 10 is independently selected from the group consisting of hydrogen and alkyl; Each R 11 is independently selected from the group consisting of hydrogen and alkyl; R 10 and R 11 If both are alkyl, R 10 and R 11 can be arbitrarily combined to form C 3~6 It forms a ring.

[0035] In one embodiment, a compound is provided, wherein R 5 but, [ka] or any tautomer thereof; In the formula, 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 one, two, or three of the Subst. are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, alkoxy, amino, amido, acyl, cycloalkyl, and heterocycloalkyl.

[0036] In one embodiment, a compound is provided, wherein A is selected from the group consisting of monocyclic and bicyclic rings. In one embodiment, A is selected from the group consisting of monocyclic and bicyclic rings; b) containing 1, 2 or 3 nitrogen atoms, and / or c) contains 0, 1, 2 or 3 oxygen atoms.

[0037] In one embodiment, a compound is provided wherein A contains 1, 2 or 3 nitrogen atoms.In one embodiment, a compound is provided wherein A contains 0, 1, 2 or 3 oxygen atoms.

[0038] In one embodiment, a compound is provided, wherein A is a ring containing 5 to 10 ring atoms. 5~9 In one embodiment, A is a C heterocycle that includes pyrrolidine. 5~9 It is a bicyclic heterocycle.

[0039] In one embodiment, a compound is provided, wherein A is a compound of formula (II), L is a compound of formula (III), and L A is [ka] TIFF2024537939000010.tif231159TIFF2024537939000011.tif217159TIFF2024537939000012.tif57159.

[0040] In one embodiment, a compound is provided, wherein A is [ka] is selected from the group consisting of:

[0041] In one embodiment there is provided a compound as defined herein, wherein OrgB is [ka] is selected from the group consisting of:

[0042] In one embodiment, a compound is provided wherein Y is a nitrogen-containing ring, and the nitrogen-containing ring is monocyclic or bicyclic.

[0043] In one embodiment, a compound is provided wherein Y is an optionally substituted piperidine, such as piperidine substituted with 1, 2, 3 or 4 methyl groups.

[0044] In one embodiment, a compound is provided wherein Y is an optionally substituted pyrrolidine. In one embodiment, Y is an optionally substituted piperazine.

[0045] In one embodiment, a compound is provided, wherein Y is [ka] is selected from the group consisting of:

[0046] In one embodiment, a compound is provided, wherein R 1 , R 2 , and R 3 is independently selected from the group consisting of hydrogen and alkyl. In one embodiment, a compound is provided, 1 and R 2 are both hydrogen and R 3 C 1~6 It is an alkyl.

[0047] In one embodiment, a compound is provided, wherein R 3 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3 is selected from the group consisting of methyl, isopropyl, and cyclohexyl.

[0048] In one embodiment, a compound is provided, wherein R 4 is selected from the group consisting of hydrogen and alkyl. 4 is C 1~6 In one embodiment, R 4is selected from the group consisting of methyl, ethyl, propyl, butyl, isopropyl, sec-butyl, cyclopropyl, cyclobutyl, and cyclopentyl. 4 is methyl.

[0049] In one embodiment, a compound is provided, wherein R 5 is hydrogen or methyl.

[0050] In one embodiment, a compound is provided, wherein R 6 and R 7 are both hydrogen.

[0051] In one embodiment, a compound is provided, wherein R 8 and R 9 are both hydrogen.

[0052] In one embodiment, a compound is provided, wherein 1 and z 2 are both 2. In one embodiment, z 1 and z 2 are both 2, and R 6 , R 7 , R 8 , and R 9 is hydrogen. 1 and z 2 is 2, and R 6 , R 7 , R 8 , and R 9 is hydrogen, and R 5 is methyl.

[0053] In one particular embodiment, the compound is [ka] TIFF2024537939000017.tif210159TIFF2024537939000018.tif221159TIFF2024537939000019.tif237159TIFF2024537939000020.tif231159TIFF2024537939000021.tif227159TIFF2024537939000022.tif213159TIFF2024537939000023.tif86159.

[0054] GBA inducers The compounds of the present disclosure can induce glucocerebrosidase (GBA) enzyme activity and / or GBA level.Accordingly, the compounds of the present disclosure are GBA inducers, i.e., can induce an increase in GBA enzyme level and / or activity.In one embodiment, the compounds provided are GBA inducers.

[0055] In one embodiment, 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.

[0056] In one embodiment, a compound is provided that is capable of increasing said GBA activity 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, etc. In one embodiment, the method allows for increasing GBA activity 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.

[0057] In one embodiment, GBA activity is increased to greater than 50% of the hypothetical wild-type level, e.g., 50-60%, such as 60-70%, such as 70-80%, such as 80-90%, such as 90-100%, such as 100-110%, such as 110-120%, such as 120-130%, such as 130-140%, such as 140-150%, etc., of the hypothetical wild-type level.

[0058] In one embodiment, the EC 1.5is 150 μM or less, for example, 140 μM or less, such as 130 μM or less, such as 120 μM or less, such as 110 μM or less, such as 100 μM or less, such as 90 μM or less, such as 80 μM or less, such as 70 μM or less, such as 60 μM or less, and preferably EC 1.5 is 50 μM or less, for example, such as 40 μM or less, such as 30 μM or less, such as 20 μM or less, such as 10 μM or less, such as 9 μM or less, such as 8 μM or less, such as 7 μM or less, such as 6 μM or less, such as 5 μM or less, such as 4 μM or less, such as 3 μM or less, such as 2 μM or less, such as 1 μM.

[0059] In one embodiment, the Emax% of the compound is 80% or more, such as 100% or more, such as 120% or more, such as 140% or more, such as 160% or more, such as 180% or more, such as 200% or more, such as 220% or more, such as 240% or more, such as 260% or more, such as 280% or more, such as 300% or more.

[0060] Pharmaceutical Compositions In one embodiment, a pharmaceutical composition is provided comprising a compound as defined herein and one or more pharma- ceutically acceptable adjuvants, excipients, carriers, buffers and / or diluents.

[0061] Therapy The compounds of the present disclosure are important for use in therapy.In one embodiment, a method for treating a disease in a subject is provided, comprising administering a compound as defined herein, wherein the disease is associated with a decrease in GBA level and / or activity.

[0062] 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.

[0063] 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).

[0064] Terms 1. A compound of formula (Ia), [ka] or a pharma- ceutically acceptable salt thereof, n is 1 or 2, R 1 , R 2 , and R 3 is independently selected from the group consisting of hydrogen, alkyl, and halogen; Y is a nitrogen-containing ring or chain; OrgB, sp 3 an organic base moiety attached to the rest of the compound via a hybridized carbon; The compound wherein OrgB and Y are optionally substituted.

[0065] 2. The compound has formula (Ib), [ka] is a compound of During the ceremony, A is a monocyclic, bicyclic, or tricyclic ring, and A is sp 3 attached to the remainder of the compound via a hybrid bond, L is C 1~6 is an alkyl linker or L is absent, and if L is absent, A is directly attached to the cyclic oxime; The compound according to any one of the preceding clauses, wherein A and Y are optionally substituted.

[0066] 3. A is of formula (II): [ka] is a compound of the formula z 1 and z 2 is independently selected from the group consisting of 0, 1, 2, and 3; Q, [ka] is selected from the group consisting of R4 is selected from the group consisting of hydrogen, alkyl, amino, alkoxy, acyl, amido, aralkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; R 5 is selected from the group consisting of hydrogen, alkyl, aralkyl, hydroxy, alkoxy, and amino; Each R 6 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxy, amino, amido, and halogen; Each R 7 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxy, amino, amido, and halogen; Each R 8 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxy, amino, amido, and halogen; Each R 9 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxy, amino, amido, and halogen.

[0067] 4. The compound according to any one of the preceding clauses, wherein A is a compound of formula (II) and Q is a compound of formula (IIa).

[0068] 5. L is a compound of formula (III) [ka] is a compound of the formula v is 0 or 1, and when v is 0, L is not present; Each R 10 is independently selected from the group consisting of hydrogen and alkyl; Each R 11 is independently selected from the group consisting of hydrogen and alkyl; R 10 and R 11 If both are alkyl, R 10 and R 11 can be arbitrarily combined to form C 3~64. A compound according to any one of the preceding clauses, which forms a ring.

[0069] 6.R 5 but, [ka] or any tautomer thereof; In the formula, 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; The compound according to any one of the preceding clauses, wherein each one, two, or three substituents (Subst.) are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, alkoxy, amino, amido, acyl, cycloalkyl, and heterocycloalkyl.

[0070] 7. The compound according to any one of the preceding clauses, wherein A is selected from the group consisting of monocyclic and bicyclic rings.

[0071] 8. A compound according to any one of the preceding clauses, wherein A contains 1, 2 or 3 nitrogen atoms.

[0072] 9. A compound according to any one of the preceding clauses, wherein A contains 0, 1, 2 or 3 oxygen atoms.

[0073] 10. A compound according to any one of the preceding clauses, wherein A is a ring containing 5 to 10 ring atoms.

[0074] 11. A is C 5~9 4. The compound according to any one of the preceding clauses, which is a heterocycle.

[0075] 12.A is a compound containing pyrrolidine 5~9 4. A compound according to any one of the preceding clauses which is a bicyclic heterocycle.

[0076] 13. A is a compound of formula (II), L is a compound of formula (III) and LA is [ka] TIFF2024537939000031.tif229159TIFF2024537939000032.tif216159TIFF2024537939000033.tif57159.

[0077] 14. A: [ka] 4. The compound according to any one of the preceding clauses, selected from the group consisting of:

[0078] 15. OrgB, [ka] 4. The compound according to any one of the preceding clauses, selected from the group consisting of:

[0079] 16. A compound according to any one of the preceding clauses, wherein Y is a nitrogen-containing ring, said nitrogen-containing ring being monocyclic or bicyclic.

[0080] 17. A compound according to any one of the preceding clauses, wherein Y is an optionally substituted piperidine, such as piperidine substituted by 1, 2, 3 or 4 methyl groups.

[0081] 18. The compound according to any one of the preceding clauses, wherein Y is an optionally substituted pyrrolidine.

[0082] 19. The compound according to any one of the preceding clauses, wherein Y is an optionally substituted piperazine.

[0083] 20. Y: [ka] 4. The compound according to any one of the preceding clauses, selected from the group consisting of:

[0084] 21.R 1 , R 2 , and R 3 is independently selected from the group consisting of hydrogen and alkyl.

[0085] 22.R 1 and R 2 are both hydrogen and R 3 C 1~6 4. The compound according to any one of the preceding clauses, wherein:

[0086] 23.R 3 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0087] 24.R 3 is selected from the group consisting of methyl, isopropyl, and cyclohexyl.

[0088] 25.R 4 is selected from the group consisting of hydrogen and alkyl.

[0089] 26.R 4 is alkyl, e.g., C 1~6 The compound according to any one of the preceding clauses, wherein R is an alkyl group, R is an aryl group, and R is an aryl group.

[0090] 27.R 4 is selected from the group consisting of methyl, ethyl, propyl, butyl, isopropyl, sec-butyl, cyclopropyl, cyclobutyl, and cyclopentyl.

[0091] 28.R 4is methyl.

[0092] 29.R 5 is hydrogen or methyl.

[0093] 30.R 6 and R 7 and are both hydrogen.

[0094] 31.R 8 and R 9 and are both hydrogen.

[0095] 32.z 1 and z 2 and R are both 2.

[0096] 33.z 1 and z 2 are both 2, and R 6 , R 7 , R 8 , and R 9 is hydrogen.

[0097] 34.z 1 and z 2 is 2 and R 6 , R 7 , R 8 , and R 9 is hydrogen and R 5 is methyl.

[0098] 35. The compound, [ka] TIFF2024537939000038.tif220159TIFF2024537939000039.tif214159TIFF2024537939000040.tif232159TIFF2024537939000041.tif234159TIFF2024537939000042.tif221159TIFF2024537939000043.tif173159TIFF2024537939000044.tif93159.

[0099] 36. The compound according to any one of the preceding clauses, wherein the compound increases glucocerebrosidase (GBA) enzyme levels and / or GBA enzyme activity.

[0100] 37. The compound according to any one of the preceding clauses, wherein said compound is a GBA inducer.

[0101] 38. A compound according to any one of the preceding clauses for use in a method for increasing GBA level and / or activity.

[0102] 39. 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.

[0103] 40. A compound for use according to any one of the preceding clauses, wherein the GBA activity is increased to more than 50% of a hypothetical wild-type level, for example 50-60%, such as 60-70%, such as 70-80%, such as 80-90%, such as 90-100%, such as 100-110%, such as 110-120%, such as 120-130%, such as 130-140%, such as 140-150% of a hypothetical wild-type level.

[0104] 41.EC of the compound 1.5is 150 μM or less, for example, 140 μM or less, such as 130 μM or less, such as 120 μM or less, such as 110 μM or less, such as 100 μM or less, such as 90 μM or less, such as 80 μM or less, such as 70 μM or less, such as 60 μM or less, and preferably said EC 1.5 is 50 μM or less, such as 40 μM or less, such as 30 μM or less, such as 20 μM or less, such as 10 μM or less, such as 9 μM or less, such as 8 μM or less, such as 7 μM or less, such as 6 μM or less, such as 5 μM or less, such as 4 μM or less, such as 3 μM or less, such as 2 μM or less, such as 1 μM.

[0105] 42. The compound for use according to any one of the preceding clauses, wherein the Emax% of said compound is 80% or more, such as 100% or more, such as 120% or more, such as 140% or more, such as 160% or more, such as 180% or more, such as 200% or more, such as 220% or more, such as 240% or more, such as 260% or more, such as 280% or more, such as 300% or more.

[0106] 43. 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.

[0107] 44. 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 a decrease in GBA level and / or activity.

[0108] 45. The method of any one of the preceding clauses, wherein the disease is Parkinson's disease (PD).

[0109] 46. ​​A method for increasing GBA activity and / or level, comprising contacting GBA with a compound as defined in any one of the preceding clauses.

[0110] 47. The use of a compound as defined in any one of the preceding clauses for the manufacture of a medicament for the said treatment of Parkinson's disease (PD). EXAMPLES

[0111] [Table 1] TIFF2024537939000046.tif55159

[0112] Analytical and preparative equipment was used. One or more of the following instruments were used in the process of analyzing the composition of the isolated materials:

[0113] 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 DAD\ELSD Alltech 3300 and 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. Agilent 1260 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.

[0114] H-NMR Bruker AVANCE III 400 Varian UNITY INOVA 400

[0115] For chiral analysis or separation, the following instruments were used:

[0116] Analytical separation: Column: Chiralpak IA (250 * 4.6mm, 5mkm) HPLC equipment: Agilent Technologies HPLC system 1200 series equipped with a DAD detector (G1315B).

[0117] Preparative separation: Column: Chiralpak IA (250 * 20mm, 5km) HPLC equipment: Agilent Technologies HPLC Preparative System 1260 Infinity II Series equipped with a DAD detector (G7115B).

[0118] Component Synthesis Preparation of 1-(tert-butoxycarbonyl)-5-((tert-butoxycarbonyl)(methyl)amino)piperidine-3-carboxylic acid [ka] Step 1. Synthesis of 1-(tert-butyl) 3-methyl 5-(methylamino)piperidine-1,3-dicarboxylate 1-(tert-butyl)3-methyl 5-oxopiperidine-1,3-dicarboxylate (6 g, 23.32 mmol, 1 eq) was dissolved in dry DCE (100 ml) and then a solution of methanamine (20 wt%) in methanol (7.244 g, 46.64 mmol, 2 eq) was added to the resulting solution followed by acetic acid (1 ml). The reaction mixture was stirred at room temperature for 15 minutes and then sodium triacetoxyborane (14.828 g, 69.96 mmol, 3 eq) was added in portions with stirring. The reaction mixture was then left at room temperature overnight. After 14 hours the reaction mixture was poured onto distilled water (150 ml) and sodium hydrogen carbonate (11.754 g, 6 eq) was added in portions with stirring. After the addition was complete the organic layer was separated and washed with brine (100 ml), dried over anhydrous sodium sulfate and filtered. The collected filtrate was concentrated under reduced pressure to give the title product (5.25 g, 41.33%) as an orange oil which was used as is without any further purification.

[0119] Step 2. Synthesis of 1-(tert-butyl) 3-methyl 5-((tert-butoxycarbonyl)(methyl)amino)piperidine-1,3-dicarboxylate Starting crude 1-(tert-butyl)3-methyl 5-(methylamino)piperidine-1,3-dicarboxylate (6.05 g, 11.107 mmol, 1 eq) obtained in the previous experiment was dissolved in dry DCM (75 ml) and N,N-diethylethanamine (3.096 ml, 2.248 g, 22.215 mmol, 2 eq) was added to the resulting solution followed by dropwise addition of tert-butoxycarbonyl tert-butyl carbonate (2.667 g, 12.218 mmol, 1.1 eq). The reaction mixture was then left under stirring at room temperature until gas evolution ceased. The reaction mixture was then washed with distilled water (2 x 75 ml). The organic layer was separated, dried over anhydrous sodium sulfate and filtered. The collected filtrate was concentrated under reduced pressure to give 8 g of a crude brown oil, which was subjected to flash chromatography purification (Interchim, 220 g SiO2, petroleum ether / MtBE with 0-65% MtBE, flow rate = 100 ml / min) to give the title product (1.76 g, 40.42%) as an orange oil.

[0120] Step 3. Synthesis of 1-(tert-butoxycarbonyl)-5-((tert-butoxycarbonyl)(methyl)amino)piperidine-3-carboxylic acid 1-(tert-butyl)3-methyl 5-((tert-butoxycarbonyl)(methyl)amino)piperidine-1,3-dicarboxylate (1.76 g, 4.489 mmol, 1 eq), obtained in the previous experiment, was dissolved in anhydrous methanol (5 ml), followed by a solution of sodium hydroxide (0.539 g, 13.467 mmol, 3 eq) in distilled water (5 ml). The mixture was then heated to 50° C. and left under stirring overnight. After verifying complete conversion by LCMS analysis, the reaction mixture was concentrated under reduced pressure and the residue obtained was diluted with distilled water (10 ml). The aqueous solution obtained was washed with DCM (5 ml). The aqueous solution was separated and to it was added NaHSO4 (1.617 g, 3 eq) with stirring. An oily precipitate was formed, which was extracted with chloroform (3×7 ml). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The collected filtrate was concentrated under reduced pressure to give the title product (1.314 g, 77.58%) as a white foam. The crude product was used without further purification.

[0121] Preparation of rac-(3R,4R)-1-(tert-butoxycarbonyl)-4-(dimethylamino)pyrrolidine-3-carboxylic acid [ka] rac-(3R,4R)-4-amino-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (1 g, 4.34 mmol, 1 eq) was dissolved in a mixture of distilled water (10 ml) and methanol (10 ml). Formaldehyde 35% solution (1.49 g, 17.37 mmol, 4 eq) was added, followed by palladium on carbon 10% (0.231 g, 0.22 mmol, 0.05 eq). The reaction mixture was hydrogenated at room temperature under 10 atm hydrogen atmosphere for 12 h. The reaction mixture was then filtered and the catalyst was washed with methanol (10 ml). The filtrates were collected, combined and concentrated under reduced pressure to give the title product (1 g, 89.14%) as a white solid, which was used without further purification. LCMS [M + 1] + 259.2.

[0122] Preparation of tert-butyl 4-(3-chloropyridin-4-yl)-4-cyanopiperidine-1-carboxylate [ka] 2-(3-Chloro-4-pyridyl)acetonitrile (3.4 g, 22.28 mmol, 1 eq) was dissolved in dry DMF (70 ml). Sodium hydride 60% in mineral oil (2.67 g, 66.85 mmol, 3 eq) was added slowly in portions to the resulting solution at 0° C. under an inert atmosphere (argon inlet). tert-Butyl N,N-bis(2-chloroethyl)carbamate (5.4 g, 22.28 mmol, 1 eq) was added to the reaction mixture and left overnight with stirring at 80° C. After 14 h, the reaction mixture was quenched with saturated aqueous NH4Cl (50 ml) and the resulting mixture was extracted with DCM (3×30 ml). The organic layers were combined, washed with brine (2×50 ml), dried over anhydrous sodium sulfate and filtered. The collected filtrate was concentrated under reduced pressure to give the crude product (3.1 g), which was subjected to preparative HPLC purification to give 716 mg (10%) of the title product as a light brown solid. LCMS [M + 1] + 322.2.

[0123] Preparation of 2-hydroxy-2-methyl-4-azaspiro[3.5]nonan-4-ium chloride [ka] 2-(Chloromethyl)-2-methyl-oxirane (10 g, 93.853 mmol, 1 eq) was added dropwise to a solution of piperidine (7.993 g, 9.271 mL, 93.8 mmol, 1 eq) in methanol (100 ml), maintaining the temperature of the reaction mixture below 5° C. After complete addition, the reaction mixture was stirred at 0° C. for 1 h and then allowed to warm to room temperature. The reaction mixture was then refluxed for 24 h. The mixture was concentrated under reduced pressure to give the title product (19 g, 90%) as a yellow solid. LCMS [M] + 156.2. The crude product obtained was of sufficient purity to be used without any further purification.

[0124] Preparation of O-(4-methylpent-1-en-3-yl)hydroxylamine hydrochloride [ka] Step 1. Synthesis of 2-((4-methylpent-1-en-3-yl)oxy)isoindoline-1,3-dione [ka] 4-Methylpent-1-en-3-ol (6.5 g, 64.90 mmol, 1 eq) was dissolved in dry THF (400 ml). 2-Hydroxyisoindoline-1,3-dione (12.17 g, 74.63 mmol, 1.15 eq) was then added to the solution followed by triphenylphosphane (2.43 g, 77.88 mmol, 1.2 eq). The resulting reaction mixture was cooled using an ice bath and diisopropyl azodicarboxylate (DIAD) (15.75 g, 77.88 mmol, 1.2 eq) was added dropwise to the reaction mixture at 0° C. After the addition was complete, the cooling bath was removed and the mixture was allowed to warm to room temperature and left stirring overnight. After 14 hours, the solvent was evaporated off and the resulting crude oily residue was subjected to flash chromatography purification to give 8.1 g (48%) of the desired product as a white solid.

[0125] Step 2. Synthesis of O-(4-methylpent-1-en-3-yl)hydroxylamine hydrochloride [ka] 2-((4-Methylpent-1-en-3-yl)oxy)isoindoline-1,3-dione (7.5 g, 29.05 mmol, 1 eq), obtained in the previous experiment, was dissolved in a mixture of DCM (75 ml) and anhydrous methanol (75 ml), after which hydrazine hydrate (1.89 g, 1.80 ml, 37.77 mmol, 1.3 eq) was added to the resulting solution. The reaction mixture was then left under stirring at 50° C. for 5 h. The reaction mixture was then filtered and the precipitate was washed with further DCM (2×50 ml). The collected filtrates were combined and concentrated under reduced pressure to give a crude white solid residue, which was treated with 2N aqueous hydrochloric acid (10 ml). The resulting mixture was filtered and the collected filtrates were concentrated under reduced pressure (at 50° C.) to give the title product (2 g, 43%) as a white solid with sufficient purity.

[0126] 1. General synthesis using halocyclization Synthesis of rac-3-(2,2-dimethyl-4-piperidyl)-5-(1-piperidylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID705 [ka] Step 1.1 Synthesis of tert-butyl rac-4-(allyloxycarbamoyl)-2,2-dimethyl-piperidine-1-carboxylate [ka] Rac-1-tert-butoxycarbonyl-2,2-dimethyl-piperidine-4-carboxylic acid (1.0 g, 3.88 mmol, 1 eq) was dissolved in dry DCM (50 mL) followed by di(imidazol-1-yl)methanone (0.725 g, 4.47 mmol, 1.15 eq). The resulting mixture was left stirring at room temperature for 5 h. O-allylhydroxylamine hydrochloride (0.553 g, 5.05 mmol, 1.3 eq) was then added to the reaction mixture, which was left stirring at ambient temperature overnight. After 12 h, the reaction mixture was washed with water (2×25 mL) and brine (25 mL). The organic layer was isolated, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to give the title compound (1.096 g, 76.8%) as a yellow oil, which was used without further purification. LCMS [M − Boc + 1] + 213.4

[0127] Step 1.2 Synthesis of tert-butyl rac-4-[5-(bromomethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl]-2,2-dimethyl-piperidine-1-carboxylate [ka] tert-Butyl rac-4-(allyloxycarbamoyl)-2,2-dimethyl-piperidine-1-carboxylate (1096 mg, 3.33 mmol, 1 eq) was dissolved in dry acetonitrile (20 mL). 1-Bromo-2,5-pyrrolidinedione (889 mg, 4.99 mmol, 1.5 eq) was added to the solution. The reaction mixture was left stirring at room temperature overnight. After 12 h, the reaction mixture was evaporated under reduced pressure to give a residue which was diluted with DCM (40 mL) and washed with saturated aqueous sodium thiosulfate (2×25 mL), water (2×25 mL) and brine (25 mL). The organic layer was isolated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title product as a red oil (1.095 g) which was used without further purification. LCMS [M − t-Bu + 1] + 337.2

[0128] Step 1.3 Synthesis of tert-butyl rac-2,2-dimethyl-4-[5-(1-piperidylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl]piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-[5-(bromomethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl]-2,2-dimethyl-piperidine-1-carboxylate (1096 mg, 2.43 mmol, 1 eq) in dry acetonitrile (50 mL) was added dipotassium carbonate (1010 mg, 7.31 mmol, 3 eq) followed by piperidine (415 mg, 4.87 mmol, 2 eq). The reaction mixture was refluxed overnight and after 15 h cooled and then concentrated under reduced pressure. The residue was diluted with DCM (70 mL) and washed with water (3×50 mL) and brine (50 mL). The organic layer was isolated, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give 1.0 g of a red-brown oily residue. The residue was subjected to preparative HPLC (65-80%, 0-6 min, water-methanol, flow rate: 30 ml / min, loading pump 4 ml / min of methanol, target mass 396, column: SunFireC18, 100×19 mm, 5 um) to give the title product (411 mg, 42.64%) as a yellow oil. LCMS [M + 1] + 396.4

[0129] Step 1.4 Synthesis of rac-3-(2,2-dimethyl-4-piperidyl)-5-(1-piperidylmethyl)-5,6-dihydro-1,4,2-dioxazine [ka] tert-Butyl rac-2,2-dimethyl-4-[5-(1-piperidylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl]piperidine-1-carboxylate (411 mg, 1.039 mmol, 1 eq) was dissolved in dry DCM (6 mL) followed by dropwise addition of 2,2,2-trifluoroacetic acid (1184 mg, 10.39 mmol, 10 eq). The reaction mixture was left stirring at ambient temperature overnight. After 12 h, the reaction mixture was concentrated under reduced pressure to give an orange oily residue. This was diluted with DCM (20 mL) and washed with 30% aqueous potassium carbonate (2×15 mL). The organic layer was isolated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude product residue (132 mg, orange oil). The residue was subjected to preparative HPLC (95-95-40%, 0-1-5 min, acetonitrile-methanol, flow rate: 40 ml / min, loading pump acetonitrile at 4 ml / min, target mass 296, column Uptisphere Strategy HILIC-HIA 100 x 21.2 mm, 5 um) to give the title product (67.3 mg, 20.8%) as a yellow oil. LCMS [M + 1] + 296.4. 1 H NMR (400 MHz, CD3OD) δ 4.52 - 4.41 (m, 1H), 4.07 (dd, J = 11.5, 2.9 Hz, 1H), 3.69 (ddd, J = 11.6, 6.5, 1.8 Hz, 1H), 2.89 - 2.79 (m, 2H), 2.60 - 2.42 (m, 7H), 1.81 - 1.71 (m, 1H), 1.70 - 1.54 (m, 5H), 1.51 - 1.41 (m, 3H), 1.41 - 1.32 (m, 1H), 1.13 (s, 6H).

[0130] Synthesis of (rel-R)-3-((rel-trans-3aS,6aR)-hexahydrocyclopenta[b]pyrrole-3a(1H)-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID589 [ka] Using the general synthesis using halocyclization as described herein, rel-(R)-3-((3aS,6aR)-hexahydrocyclopenta[b]pyrrole-3a(1H)-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (single enantiomer of unknown absolute configuration, 113.9 mg, 53.04%) was obtained as a yellow oil from commercially available rel-trans-(3aS,6aR)-1-(tert-butoxycarbonyl)hexahydrocyclopenta[b]pyrrole-3a(1H)-carboxylic acid according to the synthesis described in 1.1-1.4. Chiral separation was applied after the step corresponding to reaction step 1.3 (BOC protected). LCMS [M + 1] + 294.2. 1 H NMR (400 MHz, CD3OD) δ 4.57 - 4.44 (m, 1H), 4.09 (dd, J = 11.5, 2.9 Hz, 1H), 3.85 - 3.78 (m, 1H), 3.71 (dd, J = 11.6, 6.5 Hz, 1H), 2.99 - 2.86 (m, 1H), 2.86 - 2.74 (m, 1H), 2.66 - 2.41 (m, 6H), 2.30 - 2.17 (m, 1H), 2.14 - 2.02 (m, 1H), 1.91 - 1.79 (m, 1H), 1.79 - 1.70 (m, 1H), 1.68 - 1.52 (m, 8H), 1.52 - 1.40 (m, 2H).

[0131] Synthesis of rel-(S)-3-rel-trans-((3aS,6aR)-hexahydrocyclopenta[b]pyrrole-3a(1H)-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID590 [ka] Using the general synthesis using halocyclization as described herein, rel-(S)-3-((3aS,6aR)-hexahydrocyclopenta[b]pyrrole-3a(1H)-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (118.4 mg, 48.67%) was obtained as a yellow oil from commercially available rel-trans-(3aS,6aR)-1-(tert-butoxycarbonyl)hexahydrocyclopenta[b]pyrrole-3a(1H)-carboxylic acid according to the synthesis described in 1.1-1.4. The material is a single enantiomer of unknown absolute configuration. Chiral separation was applied after the step corresponding to reaction step 1.3 (BOC protected). LCMS [M + 1] + 294.2. 1 H NMR (400 MHz, CD3OD) δ 4.55 - 4.45 (m, 1H), 4.09 (dd, J = 11.5, 2.9 Hz, 1H), 3.83 (dd, J = 7.3, 3.3 Hz, 1H), 3.71 (dd, J = 11.6, 6.5 Hz, 1H), 2.97 - 2.87 (m, 1H), 2.87 - 2.77 (m, 1H), 2.67 - 2.42 (m, 6H), 2.33 - 2.21 (m, 1H), 2.13 - 2.00 (m, 1H), 1.91 - 1.80 (m, 1H), 1.78 - 1.70 (m, 1H), 1.70 - 1.51 (m, 8H), 1.51 - 1.37 (m, 2H).

[0132] Synthesis of rac-3-rel-trans-((3aS,6aR)-hexahydrocyclopenta[b]pyrrole-3a(1H)-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID469 [ka] Using the general synthesis using halocyclization as described herein, rac-3-rel-trans-((3aR,6aS)-hexahydrocyclopenta[b]pyrrole-3a(1H)-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (139 mg, 39.36%) was obtained as a yellow oil from commercially available rel-trans(3aS,6aR)-1-(tert-butoxycarbonyl)hexahydrocyclopenta[b]pyrrole-3a(1H)-carboxylic acid according to the synthesis described in 1.1-1.4. This material is a mixture of four compounds. The hexahydrocyclopenta[b]pyrrole-3a(1H) core has a trans relationship and the dioxazine-C5 center can be in either the R or S configuration. LCMS [M + 1] + 294.2. 1 H NMR (400 MHz, cdcl3) δ 4.45 - 4.30 (m, 1H), 4.17 - 4.03 (m, 1H), 4.00 - 3.86 (m, 1H), 3.70 (dd, J = 11.4, 6.6 Hz, 1H), 3.44 - 2.76 (m, 4H), 2.54 - 2.43 (m, 4H), 2.43 - 2.36 (m, 2H), 2.36 - 2.19 (m, 2H), 2.11 - 1.99 (m, 1H), 1.91 - 1.82 (m, 1H), 1.80 - 1.54 (m, 7H), 1.50 - 1.31 (m, 2H).

[0133] Synthesis of rac-rel-trans-3-((3aS,6aR)-hexahydrocyclopenta[b]pyrrole-3a(1H)-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID584 [ka] Using the general synthesis using halocyclization as described herein, rac-rel-trans-3-rel-trans-((3aS,6aR)-hexahydrocyclopenta[b]pyrrole-3a(1H)-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (265.4 mg, 65.28%) was obtained as a yellow oil from commercially available rel-trans-(3aR,6aS)-1-(tert-butoxycarbonyl)hexahydrocyclopenta[b]pyrrole-3a(1H)-carboxylic acid according to the syntheses described in 1.1-1.4. The material is a mixture of two compounds containing a single fixed trans-hexahydrocyclopenta[b]pyrrole-3a(1H) core and a mixture of R and S configurations at the dioxazine-C5 center (piperidylmethyl substitution) or a mixture of a single stereoisomer at the dioxazine-C5 center and two trans-hexahydrocyclopenta[b]pyrrole-3a(1H) cores. Chiral separation was applied after the step corresponding to reaction step 1.3 (BOC-protected). LCMS [M + 1] + 294.2. 1 H NMR (400 MHz, CD3OD) δ 4.56 - 4.43 (m, 1H), 4.09 (dd, J = 11.7, 2.9 Hz, 1H), 3.82 (dd, J = 7.3, 3.3 Hz, 1H), 3.71 (dd, J = 11.6, 6.5 Hz, 1H), 2.96 - 2.87 (m, 1H), 2.87 - 2.76 (m, 1H), 2.68 - 2.40 (m, 6H), 2.32 - 2.20 (m, 1H), 2.15 - 2.01 (m, 1H), 1.90 - 1.80 (m, 1H), 1.80 - 1.69 (m, 1H), 1.69 - 1.52 (m, 8H), 1.52 - 1.34 (m, 2H).

[0134] Synthesis of rac-3-((2R,,6S)-2,6-dimethylpiperidin-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID633 [ka] Using the general synthesis using halocyclization as described herein, rac-3-((2R,,6S)-2,6-dimethylpiperidin-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (155 mg, 36.86%) was obtained as a yellow oil from commercially available (2R,,6S)-1-(tert-butoxycarbonyl)-2,6-dimethylpiperidine-4-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 296.4. 1 H NMR (400 MHz, CD3OD) δ 4.52 - 4.40 (m, 1H), 4.07 (dd, J = 11.7, 2.9 Hz, 1H), 3.69 (dd, J = 11.6, 6.4 Hz, 1H), 2.82 - 2.72 (m, 2H), 2.62 - 2.45 (m, 6H), 2.43 - 2.33 (m, 1H), 1.87 - 1.77 (m, 2H), 1.60 (p, J = 5.5, 5.5, 5.5, 5.5 Hz, 4H), 1.52 - 1.40 (m, 2H), 1.23 (ddd, J = 24.7, 13.5, 6.1 Hz, 2H), 1.13 (d, J = 6.3 Hz, 6H).

[0135] Synthesis of rac-6-isopropyl-5-(piperidin-1-ylmethyl)-3-(piperidin-4-yl)-5,6-dihydro-1,4,2-dioxazine, ID706 [ka] Using the general synthesis using halocyclization as described herein, rac-6-isopropyl-5-(piperidin-1-ylmethyl)-3-(piperidin-4-yl)-5,6-dihydro-1,4,2-dioxazine (84.2 mg, 53.17%) was obtained as a yellow oil from commercially available 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid following the synthesis described in 1.1-1.4 but using O-(1-isopropylallyl)hydroxylamine hydrochloride instead of O-allylhydroxylamine hydrochloride in experimental procedure 1.1. The synthesis of O-(1-isopropylallyl)hydroxylamine hydrochloride is described above. LCMS [M + 1] + 310.2. 1 H NMR (400 MHz, CD3OD) δ 4.46 - 4.35 (m, 1H), 3.44 (t, J = 5.4, 5.4 Hz, 1H), 3.10 - 2.98 (m, 2H), 2.74 - 2.60 (m, 2H), 2.60 - 2.43 (m, 6H), 2.40 - 2.21 (m, 1H), 2.02 (q, J = 6.6, 6.6, 6.6 Hz, 1H), 1.86 - 1.72 (m, 2H), 1.66 - 1.52 (m, 6H), 1.52 - 1.39 (m, 2H), 1.06 (d, J = 6.9 Hz, 3H), 0.98 (d, J = 6.7 Hz, 3H).

[0136] Synthesis of rac-3-(4-methylpiperidin-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID568 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(4-methylpiperidin-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (135.8 mg, 18.03%) was obtained as a yellow oil from commercially available 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 282.2. 1 H NMR (400 MHz, CDCl3) δ 4.40 - 4.28 (m, 1H), 4.05 (d, J = 10.7 Hz, 1H), 3.70 (dd, J = 11.4, 6.4 Hz, 1H), 2.93 - 2.72 (m, 4H), 2.55 - 2.42 (m, 4H), 2.41 - 2.31 (m, 2H), 2.07 - 1.83 (m, 4H), 1.54 - 1.46 (m, 3H), 1.45 - 1.26 (m, 4H), 1.15 (s, 3H).

[0137] Synthesis of rac-3-(3-methylpiperidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID476 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(3-methylpiperidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (194.2 mg, 65.82%) was obtained as a yellow oil from commercially available rac-1-(tert-butoxycarbonyl)-3-methylpiperidine-3-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 282.2. 1H NMR (400 MHz, CDCl3) δ 4.43 - 4.32 (m, 1H), 4.08 (td, J = 11.1, 11.0, 2.9 Hz, 1H), 3.74 (dt, J = 11.2, 5.6, 5.6 Hz, 1H), 3.28 - 3.17 (m, 1H), 3.01 - 2.86 (m, 1H), 2.69 - 2.57 (m, 1H), 2.57 - 2.44 (m, 4H), 2.44 - 2.35 (m, 3H), 2.19 - 1.94 (m, 3H), 1.57 - 1.51 (m, 3H), 1.50 - 1.43 (m, 2H), 1.43 - 1.36 (m, 2H), 1.36 - 1.26 (m, 1H), 1.05 (d, J = 2.8 Hz, 3H).

[0138] Synthesis of rac-6-methyl-5-(piperidin-1-ylmethyl)-3-(pyrrolidin-3-yl)-5,6-dihydro-1,4,2-dioxazine, ID616 [ka] Using the general synthesis using halocyclization as described herein, rac-6-methyl-5-(piperidin-1-ylmethyl)-3-(pyrrolidin-3-yl)-5,6-dihydro-1,4,2-dioxazine (177.7 mg, 16%) was obtained as a yellow oil from commercially available rac-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid following the synthesis described in 1.1-1.4 but using O-(1-methylallyl)hydroxylamine hydrochloride instead of O-allylhydroxylamine hydrochloride in experimental procedure 1.1. LCMS [M + 1] + 268.4. 1H NMR (400 MHz, CD3OD) δ 4.19 - 4.06 (m, 1H), 3.73 - 3.62 (m, 1H), 3.06 (dd, J = 11.5, 8.1 Hz, 1H), 3.02 - 2.92 (m, 2H), 2.92 - 2.81 (m, 2H), 2.61 (dt, J = 14.1, 2.8, 2.8 Hz, 1H), 2.58 - 2.39 (m, 5H), 2.08 - 1.87 (m, 2H), 1.68 - 1.53 (m, 4H), 1.53 - 1.39 (m, 2H), 1.27 (d, J = 6.2 Hz, 3H).

[0139] Synthesis of rel-(S)-3-(4-methylpiperidin-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID567 [ka] Using the general synthesis using halocyclization as described herein, rel-(S)-3-(4-methylpiperidin-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (178.4 mg, 53.9%) was obtained as a yellow oil from commercially available 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid according to the synthesis described in 1.1-1.4. Chiral separation was applied after the step corresponding to reaction step 1.3. LCMS [M + 1] + 282.4. 1H NMR (400 MHz, CDCl3) δ 5.02 - 4.80 (m, 2H), 4.44 - 4.27 (m, 1H), 4.07 (d, J = 10.9 Hz, 1H), 3.72 (dd, J = 11.3, 6.2 Hz, 1H), 3.17 - 3.04 (m, 2H), 3.01 - 2.88 (m, 2H), 2.64 - 2.40 (m, 5H), 2.40 - 2.30 (m, 2H), 2.10 (d, J = 13.8 Hz, 2H), 1.73 - 1.53 (m, 4H), 1.45 - 1.33 (m, 2H), 1.19 (s, 3H).

[0140] Synthesis of rac-6-methyl-3-(4-methylpiperidin-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID531 [ka] Using the general synthesis using halocyclization as described herein, rac-6-methyl-3-(4-methylpiperidin-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (261.6 mg, 52.24%) was obtained as a yellow oil from commercially available 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid following the synthesis described in 1.1-1.4 but using O-(1-methylallyl)hydroxylamine hydrochloride instead of O-allylhydroxylamine hydrochloride in experimental procedure 1.1. LCMS [M + 1] + 296.4. 1H NMR (400 MHz, CDCl3) δ 4.00 (q, J = 6.0, 6.0, 5.9 Hz, 1H), 3.69 (p, J = 6.2, 6.2, 6.2, 6.2 Hz, 1H), 2.96 - 2.80 (m, 4H), 2.69 - 2.53 (m, 4H), 2.51 - 2.34 (m, 6H), 2.08 - 1.98 (m, 2H), 1.50 - 1.34 (m, 5H), 1.29 (d, J = 6.3 Hz, 3H), 1.18 (s, 3H).

[0141] Synthesis of rac-3-(5-methylpyrrolidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID560 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(5-methylpyrrolidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (449.5 mg, 58.69%) was obtained as a yellow oil from commercially available rac-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-3-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 268.4. 1 H NMR (400 MHz, CD3OD) δ 4.57 - 4.46 (m, 1H), 4.14 - 4.04 (m, 1H), 3.82 - 3.64 (m, 1H), 3.29 - 3.11 (m, 2H), 3.08 - 2.98 (m, 1H), 2.98 - 2.87 (m, 1H), 2.67 - 2.57 (m, 2H), 2.57 - 2.42 (m, 4H), 2.30 - 2.10 (m, 1H), 1.70 - 1.59 (m, 4H), 1.58 - 1.51 (m, 1H), 1.51 - 1.41 (m, 2H), 1.29 - 1.17 (m, 3H).

[0142] Synthesis of rac-rel-trans(3aR,7aS)-3a-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)octahydropyrano[4,3-b]pyrrole di-2,2,2-trifluoroacetate, ID462 [ka] Using the general synthesis using halocyclization as described herein, rac-rel-trans(3aR,7aS)-3a-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)octahydropyrano[4,3-b]pyrrole di-2,2,2-trifluoroacetate (270 mg, 33.84%) was obtained as a colorless oil from commercially available rel-trans-(3aR,7aS)-1-(tert-butoxycarbonyl)hexahydropyrano[4,3-b]pyrrole-3a(4H)-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 310.4. 1 H NMR (400 MHz, CD3OD) δ 5.01 - 4.93 (m, 1H), 4.28 - 4.16 (m, 2H), 4.13 - 3.91 (m, 1H), 3.91 - 3.72 (m, 4H), 3.68 - 3.50 (m, 4H), 3.50 - 3.41 (m, 3H), 3.23 - 2.98 (m, 2H), 2.38 (q, J = 8.5, 8.5, 8.3 Hz, 2H), 2.17 - 2.04 (m, 1H), 2.01 - 1.73 (m, 6H), 1.70 - 1.46 (m, 1H).

[0143] Synthesis of rac-5-(piperidin-1-ylmethyl)-3-(2-(piperidin-3-yl)propan-2-yl)-5,6-dihydro-1,4,2-dioxazine di-2,2,2-trifluoroacetate, ID473 [ka] Using the general synthesis using halocyclization as described herein, rac-5-(piperidin-1-ylmethyl)-3-(2-(piperidin-3-yl)propan-2-yl)-5,6-dihydro-1,4,2-dioxazinedi-2,2,2-trifluoroacetate (117.2 mg, 49.61%) was obtained as a beige oil from commercially available rac-2-(1-(tert-butoxycarbonyl)piperidin-3-yl)-2-methylpropanoic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 310.4. 1 H NMR (400 MHz, D2O) δ 5.03 - 4.92 (m, 1H), 4.26 - 4.16 (m, 1H), 3.77 (dd, J = 11.9, 7.1 Hz, 1H), 3.71 - 3.62 (m, 1H), 3.60 - 3.53 (m, 1H), 3.50 - 3.31 (m, 4H), 3.17 - 3.04 (m, 2H), 2.93 - 2.75 (m, 2H), 2.05 - 1.92 (m, 4H), 1.88 - 1.72 (m, 4H), 1.72 - 1.59 (m, 1H), 1.56 - 1.45 (m, 1H), 1.44 - 1.31 (m, 1H), 1.29 - 1.02 (m, 6H).

[0144] Synthesis of rac-3-(3-methylpyrrolidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID465 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(3-methylpyrrolidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (74.1 mg, 18.43%) was obtained as a yellow oil from commercially available rac-1-(tert-butoxycarbonyl)-3-methylpyrrolidine-3-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 268.4. 1H NMR (400 MHz, cdcl3) δ 4.46 - 4.31 (m, 1H), 4.06 (d, J = 11.0 Hz, 1H), 3.79 - 3.66 (m, 1H), 3.33 - 3.20 (m, 1H), 3.12 - 2.83 (m, 2H), 2.71 - 2.32 (m, 10H), 2.27 - 2.16 (m, 1H), 1.54 - 1.45 (m, 3H), 1.44 - 1.35 (m, 0H), 1.31 - 1.16 (m, 3H).

[0145] Synthesis of rac-(1R,4R)-1-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)-2-oxa-5-azabicyclo[2.2.1]heptane, ID490 [ka] Using the general synthesis using halocyclization as described herein, rac-(1R,4R)-1-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (146.5 mg, 36.39%) was obtained as a yellow oil from commercially available (1R,4R)-5-(tert-butoxycarbonyl)-2-oxa-5-azabicyclo[2.2.1]heptane-1-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 282.2. 1H NMR (400 MHz, CDCl3) δ 4.51 - 4.39 (m, 1H), 4.18 (dt, J = 11.6, 2.9, 2.9 Hz, 1H), 4.01 (d, J = 6.8 Hz, 1H), 3.85 (q, J = 8.8, 8.8, 7.9 Hz, 2H), 3.73 (s, 1H), 3.29 - 3.15 (m, 2H), 2.69 - 2.54 (m, 2H), 2.54 - 2.43 (m, 2H), 2.43 - 2.33 (m, 2H), 2.05 (dd, J = 9.9, 4.1 Hz, 1H), 2.00 - 1.93 (m, 1H), 1.92 - 1.67 (m, 2H), 1.65 - 1.54 (m, 3H), 1.41 (q, J = 5.7, 5.7, 5.7 Hz, 2H).

[0146] Synthesis of rac-5-(piperidin-1-ylmethyl)-3-(piperidin-3-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID554 [ka] Using the general synthesis using halocyclization as described herein, (312.8 mg, 45.78%) was obtained as a yellow oil from commercially available rac-2-(1-(tert-butoxycarbonyl)piperidin-3-yl)acetic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 282.4. 1H NMR (400 MHz, CDCl3) δ 4.40 - 4.28 (m, 1H), 4.12 - 4.01 (m, 1H), 3.75 - 3.65 (m, 1H), 3.57 - 3.27 (m, 3H), 3.15 - 3.07 (m, 1H), 3.07 - 3.00 (m, 2H), 2.58 - 2.51 (m, 1H), 2.51 - 2.40 (m, 4H), 2.40 - 2.28 (m, 3H), 2.12 - 1.99 (m, 2H), 1.95 - 1.77 (m, 2H), 1.73 - 1.62 (m, 1H), 1.53 - 1.46 (m, 3H), 1.44 - 1.32 (m, 2H), 1.24 - 1.01 (m, 1H).

[0147] Synthesis of rac-3-(3-(2-methoxyethyl)pyrrolidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID685 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(3-(2-methoxyethyl)pyrrolidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (92 mg, 29.43%) was obtained as a yellow oil from commercially available rac-1-(tert-butoxycarbonyl)-3-(2-methoxyethyl)pyrrolidine-3-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 312.4. 1H NMR (400 MHz, CD3OD) δ 4.55 - 4.46 (m, 1H), 4.15 - 4.03 (m, 1H), 3.80 - 3.67 (m, 1H), 3.46 - 3.40 (m, 2H), 3.33 - 3.32 (m, 4H), 2.99 (t, J = 7.2, 7.2 Hz, 2H), 2.72 - 2.65 (m, 1H), 2.62 - 2.47 (m, 6H), 2.35 - 2.24 (m, 1H), 1.97 - 1.88 (m, 2H), 1.75 - 1.66 (m, 1H), 1.65 - 1.57 (m, 4H), 1.53 - 1.43 (m, 2H).

[0148] Synthesis of rac-rel-trans-3-((1R,5R)-3-azabicyclo[3.1.0]hexan-1-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID482 [ka] Using the general synthesis using halocyclization as described herein, rac-rel-trans-3-((1R,5R)-3-azabicyclo[3.1.0]hexane-1-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (31.5 mg, 6.34%) was obtained as a yellow oil from commercially available rel-trans-(1R,5R)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.1.0]hexane-1-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 266.4. 1H NMR (400 MHz, CD3OD) δ 4.52 - 4.38 (m, 1H), 4.17 - 4.05 (m, 1H), 3.74 - 3.66 (m, 1H), 3.66 - 3.31 (m, 1H), 3.21 - 2.63 (m, 4H), 2.61 - 2.38 (m, 6H), 1.91 - 1.78 (m, 1H), 1.67 - 1.52 (m, 4H), 1.50 - 1.34 (m, 2H), 1.29 - 1.12 (m, 1H), 0.87 - 0.61 (m, 1H).

[0149] Synthesis of rac-3-(4-methylpiperidin-4-yl)-5-((5-(trifluoromethyl)-1,4-diazepan-1-yl)methyl)-5,6-dihydro-1,4,2-dioxazine, ID500 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(4-methylpiperidin-4-yl)-5-((5-(trifluoromethyl)-1,4-diazepan-1-yl)methyl)-5,6-dihydro-1,4,2-dioxazine (23.4 mg, 11.69%) was obtained as a yellow oil from commercially available 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid following the synthesis described in 1.1-1.4 but using 5-(trifluoromethyl)-1,4-diazepane instead of piperidine in experimental procedure 1.3. LCMS [M + 1] + 365.2. 1H NMR (400 MHz,CDCl3) δ 4.36 - 4.28 (m, 1H), 4.09 - 4.01 (m, 1H), 3.81 - 3.72 (m, 1H), 3.42 - 3.33 (m, 1H), 3.09 - 3.02 (m, 1H), 2.93 - 2.80 (m, 6H), 2.73 - 2.67 (m, 2H), 2.61 - 2.53 (m, 1H), 2.22 - 1.99 (m, 7H), 1.89 - 1.82 (m, 1H), 1.43 - 1.34 (m, 2H), 1.17 (s, 3H).

[0150] Synthesis of rac-rel-trans-3-((3R,4R)-4-methylpyrrolidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID551 [ka] Using the general synthesis using halocyclization as described herein, rac-rel-trans-3-((3R,4R)-4-methylpyrrolidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (164.5 mg, 21.45%) was obtained as a yellow oil from commercially available rel-trans-(3R,4R)-1-(tert-butoxycarbonyl)-4-methylpyrrolidine-3-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 268.4. 1 H NMR (400 MHz, CDCl3) δ 4.40 - 4.33 (m, 1H), 4.12 - 4.03 (m, 1H), 3.77 - 3.66 (m, 1H), 3.23 - 3.14 (m, 1H), 3.14 - 2.81 (m, 2H), 2.58 - 2.48 (m, 2H), 2.48 - 2.29 (m, 7H), 2.29 - 2.19 (m, 1H), 1.58 - 1.49 (m, 4H), 1.45 - 1.34 (m, 2H), 1.13 - 1.02 (m, 3H).

[0151] Synthesis of rac-5-(piperidin-1-ylmethyl)-3-(3-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-5,6-dihydro-1,4,2-dioxazine, ID583 [ka] Using the general synthesis using halocyclization as described herein, rac-5-(piperidin-1-ylmethyl)-3-(3-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl)-5,6-dihydro-1,4,2-dioxazine (151.5 mg, 36.24%) was obtained as a yellow oil from commercially available rac-1-(tert-butoxycarbonyl)-3-(tetrahydro-2H-pyran-4-yl)pyrrolidine-3-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 338.2. 1 H NMR (400 MHz, CDCl3) δ 4.40 - 4.31 (m, 1H), 4.06 (dd, J = 11.6, 2.8 Hz, 1H), 4.01 - 3.93 (m, 2H), 3.77 - 3.68 (m, 1H), 3.41 - 3.25 (m, 3H), 3.03 - 2.93 (m, 1H), 2.93 - 2.83 (m, 1H), 2.61 (t, J = 12.0, 12.0 Hz, 1H), 2.57 - 2.48 (m, 2H), 2.47 - 2.34 (m, 5H), 2.29 - 2.20 (m, 1H), 1.83 - 1.71 (m, 1H), 1.68 - 1.58 (m, 1H), 1.58 - 1.43 (m, 8H), 1.43 - 1.30 (m, 2H).

[0152] Synthesis of rac-5-(piperidin-1-ylmethyl)-3-(2-(piperidin-4-yl)propan-2-yl)-5,6-dihydro-1,4,2-dioxazine di-2,2,2-trifluoroacetate, ID477 [ka] Using the general synthesis using halocyclization as described herein, rac-5-(piperidin-1-ylmethyl)-3-(2-(piperidin-4-yl)propan-2-yl)-5,6-dihydro-1,4,2-dioxazinedi-2,2,2-trifluoroacetate (497.3 mg, 51.17%) was obtained as a yellow oil from commercially available 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2-methylpropanoic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 310.2. 1 H NMR (400 MHz, D2O) δ 4.89 - 4.80 (m, 1H), 4.07 (dd, J = 11.9, 2.8 Hz, 1H), 3.65 (dd, J = 11.9, 6.9 Hz, 1H), 3.53 (d, J = 12.1 Hz, 1H), 3.47 - 3.41 (m, 1H), 3.37 - 3.30 (m, 4H), 3.03 - 2.91 (m, 2H), 2.87 - 2.76 (m, 2H), 1.89 - 1.64 (m, 8H), 1.40 (q, J = 12.7, 12.6, 12.6Hz, 3H), 1.11 - 0.95 (m, 6H).

[0153] Synthesis of rac-3-(2-methylmorpholin-2-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID480 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(2-methylmorpholin-2-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (145.7 mg, 25.28%) was obtained as a yellow oil from commercially available rac-4-(tert-butoxycarbonyl)-2-methylmorpholine-2-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 284.4. 1HNMR (400 MHz, CD3OD) δ 4.62 - 4.50 (m, 1H), 4.23 - 4.08 (m, 1H), 3.87 - 3.76 (m, 1H), 3.74 - 3.56 (m, 2H), 3.28 - 3.22 (m, 1H), 2.76 (d, J = 5.4 Hz, 2H), 2.68 - 2.43 (m, 7H), 1.67 - 1.54 (m, 4H), 1.52 - 1.41 (m, 2H), 1.27 (s, 3H).

[0154] Synthesis of rac-3-(2-methylpyrrolidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID559 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(2-methylpyrrolidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (46.6 mg, 19.99%) was obtained as a light brown oil from commercially available rac-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-3-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 268.2. 1 H NMR (400 MHz, CDCl3) δ 4.46 - 4.30 (m, 1H), 4.13 - 3.98 (m, 1H), 3.82 - 3.60 (m, 1H), 3.20 - 3.02 (m, 2H), 2.86 - 2.66 (m, 2H), 2.59 - 2.46 (m, 2H), 2.46 - 2.32 (m, 4H), 2.06 - 1.95 (m, 2H), 1.94 - 1.86 (m, 3H), 1.62 - 1.54 (m, 2H), 1.45 - 1.33 (m, 2H), 1.26 - 1.07 (m, 3H).

[0155] Synthesis of rac-5-(piperidin-1-ylmethyl)-3-(pyrrolidin-3-yl)-5,6-dihydro-1,4,2-dioxazine, ID508 [ka] Using the general synthesis using halocyclization as described herein, rac-5-(piperidin-1-ylmethyl)-3-(pyrrolidin-3-yl)-5,6-dihydro-1,4,2-dioxazine (523.7 mg, 31.25%) was obtained as a yellow oil from commercially available rac-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 254.4. 1 H NMR (400 MHz, CDCl3) δ 4.43 - 4.30 (m, 1H), 4.07 (d, J = 11.2 Hz, 1H), 3.76 - 3.66 (m, 1H), 3.58 - 3.36 (m, 2H), 3.19 - 2.98 (m, 3H), 2.97 - 2.81 (m, 2H), 2.57 - 2.29 (m, 6H), 2.07 - 1.88 (m, 2H), 1.55 - 1.47 (m, 3H), 1.44 - 1.31 (m, 2H).

[0156] Synthesis of rac-rel-trans-(3aR,6aR)-3a-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole, ID494 [ka] Using the general synthesis using halocyclization as described herein, rac-rel-trans-(3aR,6aR)-3a-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)hexahydro-1H-furo[3,4-c]pyrrole (19.8 mg, 7.7%) was obtained as a yellow oil from commercially available rel-trans-(3aR,6aR)-5-(tert-butoxycarbonyl)tetrahydro-1H-furo[3,4-c]pyrrole-3a(3H)-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 296.2. 1 H NMR (400 MHz, CDCl3) δ 4.45 - 4.37 (m, 1H), 4.11 (dt, J = 11.6, 3.3, 3.3 Hz, 1H), 3.94 (dd, J = 9.2, 3.4 Hz, 1H), 3.88 - 3.83 (m, 1H), 3.81 - 3.73 (m, 2H), 3.67 (dd, J = 9.0, 2.6 Hz, 1H), 3.31 (d, J = 11.8 Hz, 1H), 3.27 - 3.18 (m, 1H), 3.07 - 2.97 (m, 1H), 2.87 (d, J = 11.7 Hz, 1H), 2.73 (dd, J = 11.6, 4.5 Hz, 1H), 2.53 (d, J = 6.1 Hz, 2H), 2.52 - 2.45 (m, 2H), 2.45 - 2.36 (m, 2H), 1.61 - 1.50 (m, 5H), 1.47 - 1.39 (m, 2H).

[0157] Synthesis of rac-rel-trans-(3aR,7aR)-3a-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)octahydropyrano[3,4-c]pyrrole, ID461 [ka] Using the general synthesis using halocyclization as described herein, rac-rel-trans-(3aR,7aR)-3a-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)octahydropyrano[3,4-c]pyrrole (123.8 mg, 41.18%) was obtained as a yellow oil from commercially available rel-trans-(3aR,7aR)-2-(tert-butoxycarbonyl)hexahydropyrano[3,4-c]pyrrole-3a(4H)-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 310.2. 1 H NMR (400 MHz, CDCl3) δ 4.47 - 4.31 (m, 1H), 4.08 (d, J = 10.6 Hz, 1H), 3.97 - 3.83 (m, 1H), 3.80 - 3.53 (m, 4H), 3.33 - 3.04 (m, 2H), 3.01 - 2.77 (m, 2H), 2.75 - 2.53 (m, 2H), 2.52 - 2.22 (m, 8H), 2.07 - 1.82 (m, 1H), 1.63 - 1.51 (m, 3H), 1.45 - 1.32 (m, 2H).

[0158] Synthesis of rac-5-(piperidin-1-ylmethyl)-3-(1-(piperidin-4-yl)cyclopropyl)-5,6-dihydro-1,4,2-dioxazine, ID521 [ka] Using the general synthesis using halocyclization as described herein, rac-5-(piperidin-1-ylmethyl)-3-(1-(piperidin-4-yl)cyclopropyl)-5,6-dihydro-1,4,2-dioxazine (23.6 mg, 14.9%) was obtained as a yellow oil from commercially available 1-(1-(tert-butoxycarbonyl)piperidin-4-yl)cyclopropane-1-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 308.2. 1H NMR (400 MHz, CDCl3) δ 4.36 - 4.26 (m, 1H), 4.03 (dd, J = 11.5, 2.8 Hz, 1H), 3.66 (dd, J = 11.5, 6.5 Hz, 1H), 3.06 (d, J = 11.6 Hz, 2H), 2.58 - 2.44 (m, 6H), 2.39 - 2.33 (m, 2H), 2.24 - 2.02 (m, 2H), 1.70 - 1.59 (m, 2H), 1.53 - 1.44 (m, 4H), 1.43 - 1.37 (m, 2H), 1.27 (qd, J = 12.4, 12.4, 12.4, 3.9 Hz, 2H), 0.92 - 0.78 (m, 2H), 0.65 - 0.49 (m, 2H).

[0159] Synthesis of rac-3-(3-methoxypyrrolidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID606 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(3-methoxypyrrolidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (116.5 mg, 9.99%) was obtained as a yellow oil from commercially available rac-1-(tert-butoxycarbonyl)-3-methoxypyrrolidine-3-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 284.2. 1H NMR (400 MHz, CDCl3) δ 4.47 - 4.35 (m, 1H), 4.11 (dt, J = 11.6, 2.7, 2.7 Hz, 1H), 3.83 (ddd, J = 11.5, 5.9, 3.7 Hz, 1H), 3.21 (s, 3H), 3.15 - 3.00 (m, 3H), 3.00 - 2.89 (m, 1H), 2.60 - 2.52 (m, 2H), 2.52 - 2.43 (m, 2H), 2.43 - 2.34 (m, 2H), 2.19 - 2.11 (m, 2H), 2.01 - 1.91 (m, 1H), 1.62 - 1.45 (m, 4H), 1.45 - 1.30 (m, 2H).

[0160] Synthesis of rac-3-(5-methoxypiperidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID680 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(5-methoxypiperidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (411.8 mg, 20.77%) was obtained as a yellow oil from commercially available rac-1-(tert-butoxycarbonyl)-5-methoxypiperidine-3-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 298.4. 1H NMR (400 MHz, CD3OD) δ 4.51 (qd, J = 6.1, 6.1, 6.1, 2.9 Hz, 1H), 4.09 (dd, J = 11.7, 2.9 Hz, 1H), 3.78 - 3.67 (m, 1H), 3.38 - 3.36 (m, 3H), 3.31 - 3.29 (m, 1H), 3.21 (dd, J = 12.4, 3.8 Hz, 1H), 3.15 - 3.05 (m, 1H), 2.91 - 2.78 (m, 1H), 2.60 (d, J = 5.6 Hz, 2H), 2.59 - 2.44 (m, 6H), 2.30 - 2.14 (m, 1H), 1.75 - 1.65 (m, 1H), 1.65 - 1.58 (m, 4H), 1.53 - 1.39 (m, 2H).

[0161] Synthesis of rac-3-(2-azabicyclo[2.1.1]hexan-5-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID548 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(2-azabicyclo[2.1.1]hexane-5-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (28.3 mg, 9.26%) was obtained as a yellow oil from commercially available rac-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-5-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 266.2. 1H NMR (400 MHz, CDCl3) δ 4.34 - 4.28 (m, 1H), 4.09 - 4.02 (m, 1H), 3.79 - 3.73 (m, 1H), 3.73 - 3.67 (m, 1H), 2.91 (d, J = 7.9 Hz, 2H), 2.85 - 2.78 (m, 1H), 2.54 (dd, J = 13.3, 6.3 Hz, 1H), 2.51 - 2.14 (m, 11H), 1.49 - 1.32 (m, 3H), 1.19 (t, J = 7.7, 7.7 Hz, 1H).

[0162] Synthesis of rac-rel-trans-3-((1R,5R)-5-methyl-3-azabicyclo[3.1.0]hexan-1-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID481 [ka] Using the general synthesis using halocyclization as described herein, rac-rel-trans-3-((1R,5R)-5-methyl-3-azabicyclo[3.1.0]hexan-1-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (22.9 mg, 4.85%) was obtained as a yellow oil from commercially available rel-trans-(1R,5R)-3-(tert-butoxycarbonyl)-5-methyl-3-azabicyclo[3.1.0]hexane-1-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 280.4. 1H NMR (400 MHz, CD3OD) δ 4.55 - 4.42 (m, 1H), 4.13 - 4.03 (m, 1H), 3.78 - 3.66 (m, 1H), 3.19 (d, J = 11.5 Hz, 1H), 2.98 - 2.87 (m, 2H), 2.69 (d, J = 11.5 Hz, 1H), 2.64 - 2.35 (m, 7H), 1.64 - 1.56 (m, 4H), 1.51 - 1.43 (m, 2H), 1.28 - 1.18 (m, 3H), 1.12 - 1.01 (m, 1H), 0.97 - 0.81 (m, 1H).

[0163] Synthesis of rac-rel-trans-3-((1R,5R)-3-azabicyclo[3.2.0]heptan-1-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine di-2,2,2-trifluoroacetate, ID485 [ka] Using the general synthesis using halocyclization as described herein, rac-rel-trans-3-((1R,5R)-3-azabicyclo[3.2.0]heptan-1-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazinedi-2,2,2-trifluoroacetate (32.3 mg, 14.62%) was obtained as a yellow oil from commercially available rel-trans-(1R,5R)-3-(tert-butoxycarbonyl)-3-azabicyclo[3.2.0]heptane-1-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 280.4. 1H NMR (400 MHz, CDCl3) δ 4.46 - 4.39 (m, 1H), 4.18 - 4.06 (m, 1H), 3.84 - 3.72 (m, 1H), 3.07 - 2.93 (m, 3H), 2.91 - 2.85 (m, 2H), 2.66 - 2.48 (m, 5H), 2.48 - 2.34 (m, 3H), 2.24 - 2.13 (m, 1H), 2.10 - 1.61 (m, 5H), 1.50 - 1.40 (m, 3H).

[0164] Synthesis of rac-3-(3-methoxypiperidin-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID690 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(3-methoxypiperidin-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (42 mg, 2.47%) was obtained as a yellow oil from commercially available rac-1-(tert-butoxycarbonyl)-3-methoxypiperidine-4-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 298.2. 1 H NMR (400 MHz, CD3OD) δ 4.56 - 4.40 (m, 1H), 4.16 - 4.01 (m, 1H), 3.79 - 3.66 (m, 1H), 3.63 - 3.51 (m, 1H), 3.36 (s, 3H), 3.29 - 3.19 (m, 1H), 3.08 - 2.93 (m, 1H), 2.72 - 2.40 (m, 9H), 1.92 - 1.75 (m, 1H), 1.71 - 1.54 (m, 5H), 1.53 - 1.42 (m, 2H).

[0165] Synthesis of rac-3-(2-azabicyclo[2.1.1]hexan-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID527 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(2-azabicyclo[2.1.1]hexane-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (113.7 mg, 17.5%) was obtained as a yellow oil from commercially available rac-2-(tert-butoxycarbonyl)-2-azabicyclo[2.1.1]hexane-4-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 266.2. 1 H NMR (400 MHz, cdcl3) δ 4.41 - 4.34 (m, 1H), 4.12 (dd, J = 11.6, 2.7 Hz, 1H), 3.80 - 3.72 (m, 2H), 3.12 (s, 2H), 3.09 - 2.82 (m, 4H), 2.52 (d, J = 5.9 Hz, 2H), 2.50 - 2.44 (m, 2H), 2.41 - 2.32 (m, 2H), 2.07 - 1.99 (m, 2H), 1.61 - 1.55 (m, 3H), 1.40 (q, J = 5.5, 5.5, 5.4Hz, 2H).

[0166] Synthesis of rac-4-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)cyclohexan-1-amine, ID611 [ka] Using the general synthesis using halocyclization as described herein, rac-4-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)cyclohexan-1-amine (165.5 mg, 23.69%) was obtained as a yellow oil from commercially available 4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 282.2. 1 H NMR (400 MHz, CD3OD) δ 4.52 - 4.40 (m, 1H), 4.12 - 4.01 (m, 1H), 3.74 - 3.64 (m, 1H), 2.70 - 2.59 (m, 1H), 2.59 - 2.34 (m, 6H), 2.20 - 2.01 (m, 1H), 2.01 - 1.78 (m, 4H), 1.68 - 1.56 (m, 5H), 1.56 - 1.40 (m, 4H), 1.33 - 1.03 (m, 2H).

[0167] Synthesis of rac-5-(piperidin-1-ylmethyl)-3-(2-(pyrrolidin-3-yl)propan-2-yl)-5,6-dihydro-1,4,2-dioxazine, ID491 [ka] Using the general synthesis using halocyclization as described herein, rac-5-(piperidin-1-ylmethyl)-3-(2-(pyrrolidin-3-yl)propan-2-yl)-5,6-dihydro-1,4,2-dioxazine (71.6 mg, 23.48%) was obtained as a yellow oil from commercially available rac-2-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-methylpropanoic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 296.4. 1H NMR (400 MHz, CDCl3) δ 4.43 - 4.28 (m, 1H), 4.05 (d, J = 11.4 Hz, 1H), 3.68 (dd, J = 11.2, 6.3 Hz, 1H), 3.42 - 3.01 (m, 1H), 2.99 - 2.85 (m, 3H), 2.84 - 2.69 (m, 2H), 2.61 - 2.46 (m, 4H), 2.45 - 2.24 (m, 4H), 1.83 - 1.72 (m, 1H), 1.55 - 1.49 (m, 3H), 1.48 - 1.38 (m, 2H), 1.18 - 1.01 (m, 6H).

[0168] Synthesis of rac-1-(6-isopropyl-3-(pyrrolidin-3-yl)-5,6-dihydro-1,4,2-dioxazin-5-yl)-N,N-dimethylmethanamine, ID713 [ka] Using the general synthesis using halocyclization as described herein, rac-1-(6-isopropyl-3-(pyrrolidin-3-yl)-5,6-dihydro-1,4,2-dioxazin-5-yl)-N,N-dimethylmethanamine (36.8 mg, 98.48%) was obtained as a yellow oil from commercially available 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid following the synthesis described in 1.1-1.4 but using O-(1-isopropylallyl)hydroxylamine hydrochloride instead of O-allylhydroxylamine hydrochloride in experimental procedure 1.1 and N-methylmethanamine hydrochloride instead of piperidine in experimental procedure 1.3. LCMS [M + 1] + 256.2. 1H NMR (400 MHz, CD3OD) δ 4.46 - 4.34 (m, 1H), 3.51 - 3.40 (m, 1H), 3.10 - 2.91 (m, 3H), 2.91 - 2.78 (m, 2H), 2.65 - 2.55 (m, 2H), 2.34 (s, 6H), 2.11 - 1.78 (m, 3H), 1.07 (d, J = 6.8 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H).

[0169] Synthesis of rac-rel-cis-3-((3R,4R)-3,4-dimethylpyrrolidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID489 [ka] Using the general synthesis using halocyclization as described herein, rac-rel-cis-3-((3R,4R)-3,4-dimethylpyrrolidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (99 mg, 25.31%) was obtained as a colorless oil from commercially available rel-cis-(3R,4R)-1-(tert-butoxycarbonyl)-3,4-dimethylpyrrolidine-3-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 282.2. 1 H NMR (400 MHz,CDCl3) δ 4.42 - 4.30 (m, 1H), 4.12 - 4.02 (m, 1H), 3.75 - 3.64 (m, 1H), 3.41 - 3.32 (m, 1H), 3.24 - 3.15 (m, 1H), 2.69 - 2.63 (m, 1H), 2.63 - 2.53 (m, 2H), 2.53 - 2.43 (m, 5H), 2.43 - 2.33 (m, 3H), 1.55 - 1.49 (m, 3H), 1.47 - 1.35 (m, 2H), 1.08 (s, 3H), 1.00 - 0.86 (m, 3H).

[0170] Synthesis of rac-3-(4,4-dimethylpyrrolidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID688 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(4,4-dimethylpyrrolidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (251.5 mg, 22.65%) was obtained as an orange oil from commercially available rac-1-(tert-butoxycarbonyl)-4,4-dimethylpyrrolidine-3-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 282.4. 1 H NMR (400 MHz, CD3OD) δ 4.56 - 4.43 (m, 1H), 4.17 - 4.05 (m, 1H), 3.81 - 3.70 (m, 1H), 3.24 - 3.07 (m, 2H), 2.81 - 2.66 (m, 2H), 2.66 - 2.43 (m, 7H), 1.67 - 1.54 (m, 4H), 1.54 - 1.40 (m, 2H), 1.18 (d, J = 4.9 Hz, 3H), 1.06 (d, J = 4.6 Hz, 3H).

[0171] Synthesis of rac-5-(piperidin-1-ylmethyl)-3-(piperidin-4-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID479 [ka] Using the general synthesis using halocyclization as described herein, rac-5-(piperidin-1-ylmethyl)-3-(piperidin-4-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (390 mg, 35.25%) was obtained as a yellow oil from commercially available 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1]+ 282.2. 1 H NMR (400 MHz,CDCl3) δ 4.44 - 4.33 (m, 1H), 4.10 (dd, J = 11.4, 2.3 Hz, 1H), 3.75 (dd, J = 11.5, 6.4 Hz, 1H), 3.07 (d, J = 12.4 Hz, 2H), 2.59 (t, J = 12.2, 12.2 Hz, 2H), 2.55 - 2.45 (m, 4H), 2.45 - 2.36 (m, 2H), 2.11 (d, J = 7.0 Hz, 2H), 1.88 - 1.76 (m, 3H), 1.76 - 1.63 (m, 3H), 1.57 - 1.51 (m, 2H), 1.49 - 1.38 (m, 2H), 1.26 - 1.11 (m, 2H).

[0172] Synthesis of rac-3-(3-methylazetidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID549 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(3-methylazetidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (22.5 mg, 8.52%) was obtained as a yellow oil from commercially available rac-1-(tert-butoxycarbonyl)-3-methylazetidine-3-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 254.4. 1H NMR (400 MHz, CDCl3) δ 4.45 - 4.32 (m, 1H), 4.09 (dd, J = 11.6, 2.8 Hz, 1H), 3.95 (d, J = 7.3 Hz, 2H), 3.74 (dd, J = 11.6, 6.3 Hz, 1H), 3.29 (d, J = 7.9 Hz, 2H), 2.52 (d, J = 6.0 Hz, 2H), 2.50 - 2.42 (m, 2H), 2.42 - 2.32 (m, 2H), 2.02 - 1.76 (m, 4H), 1.53 - 1.48 (m, 4H), 1.45 - 1.35 (m, 2H).

[0173] Synthesis of rac-3-(2-methylpyrrolidin-2-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID566 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(2-methylpyrrolidin-2-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (570.5 mg, 92.25%) was obtained as a yellow oil from commercially available rac-1-(tert-butoxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 268.2. 1 H NMR (400 MHz, dmso) δ 4.49 - 4.40 (m, 1H), 4.01 (dt, J = 11.6, 2.3, 2.3 Hz, 1H), 3.74 - 3.64 (m, 1H), 2.95 - 2.87 (m, 2H), 2.48 - 2.31 (m, 7H), 2.17 - 2.06 (m, 1H), 1.79 - 1.68 (m, 2H), 1.56 - 1.42 (m, 5H), 1.40 - 1.32 (m, 2H), 1.28 (d, J = 2.9 Hz, 3H).

[0174] Synthesis of rac-3-(4-methoxy-2-methylpyrrolidin-2-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID565 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(4-methoxy-2-methylpyrrolidin-2-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (118.8 mg, 31.76%) was obtained as a yellow oil from commercially available rac-1-(tert-butoxycarbonyl)-4-methoxy-2-methylpyrrolidine-2-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 298.4. 1 H NMR (400 MHz, CDCl3) δ 4.43 - 4.30 (m, 1H), 4.11 - 4.00 (m, 1H), 3.95 - 3.85 (m, 1H), 3.76 - 3.65 (m, 1H), 3.28 - 3.18 (m, 3H), 3.18 - 3.03 (m, 1H), 3.03 - 2.94 (m, 1H), 2.62 - 2.47 (m, 3H), 2.47 - 2.40 (m, 2H), 2.40 - 2.25 (m, 4H), 1.79 - 1.58 (m, 1H), 1.54 - 1.46 (m, 3H), 1.45 - 1.25 (m, 5H).

[0175] Synthesis of rac-3-(3-azabicyclo[5.1.0]octan-7-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID519 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(3-azabicyclo[5.1.0]octan-7-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (14.4 mg, 10.19%) was obtained as a brown oil from commercially available rac-3-(tert-butoxycarbonyl)-3-azabicyclo[5.1.0]octane-7-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 294.4. 1 H NMR (400 MHz, CDCl3) δ 4.38 - 4.12 (m, 3H), 4.08 - 4.00 (m, 1H), 3.73 - 3.57 (m, 1H), 3.27 - 2.93 (m, 3H), 2.88 - 2.75 (m, 1H), 2.75 - 2.62 (m, 1H), 2.55 - 2.38 (m, 4H), 2.38 - 2.23 (m, 3H), 1.57 - 1.43 (m, 6H), 1.42 - 1.34 (m, 2H), 1.30 - 1.20 (m, 1H), 0.85 - 0.58 (m, 1H).

[0176] Synthesis of rac-3-(3-(methoxymethyl)pyrrolidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID594 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(3-(methoxymethyl)pyrrolidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (121.8 mg, 78.11%) was obtained as a yellow oil from commercially available rac-1-(tert-butoxycarbonyl)-3-(methoxymethyl)pyrrolidine-3-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 298.4. 1H NMR (400 MHz, CD3OD) δ 4.57 - 4.45 (m, 1H), 4.09 (dt, J = 11.6, 3.0, 3.0 Hz, 1H), 3.74 (ddd, J = 11.6, 6.4, 3.0 Hz, 1H), 3.62 - 3.53 (m, 1H), 3.49 - 3.41 (m, 2H), 3.34 (s, 3H), 3.19 - 3.06 (m, 2H), 3.00 (dd, J = 12.0, 2.1 Hz, 1H), 2.58 (d, J = 5.8 Hz, 3H), 2.53 - 2.43 (m, 3H), 2.29 - 2.18 (m, 1H), 1.96 - 1.84 (m, 1H), 1.65 - 1.54 (m, 4H), 1.54 - 1.41 (m, 2H).

[0177] Synthesis of rac-3-(4-methylazepan-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID542 [ka] Using the general synthesis using halocyclization as described herein, 3-(4-methylazepan-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (134.9 mg, 95.33%) was obtained as a yellow oil from commercially available rac-1-(tert-butoxycarbonyl)-4-methylazepane-4-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 296.4. 1H NMR (400 MHz, CD3OD) δ 4.57 - 4.48 (m, 1H), 4.15 - 4.07 (m, 1H), 3.79 - 3.66 (m, 1H), 3.27 - 3.23 (m, 2H), 3.20 - 3.16 (m, 2H), 2.71 - 2.40 (m, 7H), 2.37 - 2.29 (m, 1H), 2.27 - 2.17 (m, 1H), 1.93 - 1.82 (m, 2H), 1.76 - 1.68 (m, 1H), 1.64 - 1.56 (m, 5H), 1.51 - 1.42 (m, 2H), 1.21 (s, 3H).

[0178] Synthesis of rac-3-(4-(2-methoxyethyl)piperidin-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID726 [ka] Using the general synthesis using halocyclization as described herein, 3-(4-(2-methoxyethyl)piperidin-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (166.6 mg, 54.46%) was obtained as a yellow oil from commercially available 1-(tert-butoxycarbonyl)-4-(2-methoxyethyl)piperidine-4-carboxylic acid according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 326.4. 1H NMR (chloroform-d, 400 MHz): δ (ppm) 4.42 - 4.31 (m, 1H), 4.15 - 4.03 (m, 1H), 3.74 (dd, J=11.4, 6.5 Hz, 1H), 3.40 (t, J=6.9, 6.9 Hz, 2H), 3.29 (s, 3H), 2.94 - 2.66 (m, 4H), 2.55 - 2.44 (m, 4H), 2.43 - 2.34 (m, 2H), 2.08 - 1.99 (m, 2H), 1.99 - 1.92 (m, 1H), 1.77 (t, J=6.8, 6.8 Hz, 2H), 1.62 - 1.47 (m, 4H), 1.48 - 1.23 (m, 4H).

[0179] Synthesis of rac-N-methyl-5-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)piperidin-3-amine, ID756 [ka] Using the general synthesis using halocyclization as described herein, N-methyl-5-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)piperidin-3-amine (32.9 mg, 6.81%) was obtained as a yellow solid from the starting rac-1-(tert-butoxycarbonyl)-5-((tert-butoxycarbonyl)(methyl)amino)piperidine-3-carboxylic acid according to the syntheses described in 1.1-1.4. The synthesis of the starting building blocks is described above. LCMS [M + 1] + 297.2. 1H NMR (methanol-d4, 400 MHz): δ (ppm) 4.55 - 4.43 (m, 1H), 4.10 (d, J=13.2 Hz, 1H), 3.76 - 3.69 (m, 1H), 3.22 - 3.15 (m, 1H), 3.13 - 3.05 (m, 1H), 2.59 - 2.40 (m, 9H), 2.38 (s, 3H), 2.29 - 2.22 (m, 1H), 2.22 - 2.12 (m, 1H), 1.66 - 1.55 (m, 4H), 1.54 - 1.45 (m, 2H), 1.34 - 1.24 (m, 1H).

[0180] Synthesis of rac-3-(1-methylcyclohexyl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID478 [ka] Using the general synthesis using halocyclization as described herein, 3-(1-methylcyclohexyl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (388.2 mg, 37.28%) was obtained as a yellow oil from commercially available 1-methylcyclohexane-1-carboxylic acid according to the synthesis described in 1.1-1.3. LCMS [M + 1] + 281.4. 1 H NMR (400 MHz, CDCl3) δ 4.38 - 4.29 (m, 1H), 4.04 (dd, J = 11.4, 2.9 Hz, 1H), 3.68 (dd, J = 11.4, 6.5 Hz, 1H), 2.57 - 2.43 (m, 4H), 2.43 - 2.32 (m, 2H), 1.94 - 1.83 (m, 2H), 1.59 - 1.49 (m, 4H), 1.49 - 1.44 (m, 4H), 1.44 - 1.37 (m, 3H), 1.32 - 1.25 (m, 1H), 1.25 - 1.17 (m, 2H), 1.11 (s, 3H).

[0181] Synthesis of rac-(3aR,6aR)-3a-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide, ID486 [ka] Using the general synthesis using halocyclization as described herein, rac-(3aR,6aR)-3a-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)hexahydro-1H-thieno[3,4-c]pyrrole 2,2-dioxide (25.3 mg, 43.99%) was obtained as a yellow oil from commercially available (3aR,6aR)-5-(tert-butoxycarbonyl)tetrahydro-1H-thieno[3,4-c]pyrrole-3a(3H)-carboxylic acid 2,2-dioxide according to the synthesis described in 1.1-1.4. LCMS [M + 1] + 344.2. 1 H NMR (400 MHz, CDCl3) δ 5.54 - 4.81 (m, 1H), 4.54 - 4.38 (m, 1H), 4.22 - 4.10 (m, 1H), 3.90 - 3.78 (m, 1H), 3.76 - 3.67 (m, 1H), 3.59 - 3.39 (m, 2H), 3.39 - 3.24 (m, 2H), 3.13 - 3.00 (m, 2H), 3.00 - 2.85 (m, 2H), 2.69 - 2.49 (m, 3H), 2.49 - 2.41 (m, 3H), 2.12 - 1.69 (m, 2H), 1.64 - 1.58 (m, 2H), 1.50 - 1.39 (m, 3H).

[0182] Halocyclization + additional reductive amination Synthesis of rac-3-(1-methylpiperidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID648 [ka] Step 1.5 Synthesis of rac-3-(1-methylpiperidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine [ka] rac-3-(3-piperidyl)-5-(1-piperidylmethyl)-5,6-dihydro-1,4,2-dioxazine (200 mg, 0.7480 mmol, 1 eq), obtained in a similar manner with non-essential modifications according to the synthesis described in 1.1-1.4 from commercially available rac-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid, was dissolved in anhydrous methanol (2 mL) and then acetic acid (224.6 mg, 3.7401 mmol, 5 eq) was added, followed by paraform (235.84 mg, 2.6181 mmol, 3.5 eq) and sodium cyanoborane (164.52 mg, 2.6181 mmol, 3.5 eq). The reaction mixture was left stirring at ambient temperature overnight. After 24 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with DCM (5 mL) and washed with 30% aqueous potassium carbonate (2 x 3 mL). The organic layer was isolated and concentrated under reduced pressure to give a crude oily residue which was purified by preparative HPLC (40-80%, 0-5 min, water-methanol, flow rate: 30 ml / min (loading pump 4 ml / min methanol), target mass 317, column SunFireC18 100 x 19 mm 5 um) to give the title product (139.1 mg, 62.78%) as a yellow oil. LCMS [M + 1] + 282.2. 1H NMR (400 MHz, CD3OD) δ 4.54 - 4.44 (m, 1H), 4.10 (dd, J = 11.5, 2.9 Hz, 1H), 3.72 (dd, J = 11.6, 6.5 Hz, 1H), 3.00 - 2.89 (m, 1H), 2.87 - 2.75 (m, 1H), 2.60 - 2.40 (m, 7H), 2.29 (s, 3H), 2.11 - 2.00 (m, 1H), 2.00 - 1.85 (m, 2H), 1.83 - 1.72 (m, 1H), 1.66 - 1.54 (m, 5H), 1.52 - 1.42 (m, 2H), 1.42 - 1.26 (m, 1H).

[0183] Synthesis of rac-6-isopropyl-3-(1-methylpyrrolidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID707 [ka] Using the general synthesis using halocyclization as described herein, 6-isopropyl-3-(1-methylpyrrolidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (20 mg, 16.8%) was obtained as a yellow oil from commercially available rac-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid following the synthesis described in 1.1-1.5 but using O-(1-isopropylallyl)hydroxylamine hydrochloride instead of O-allylhydroxylamine hydrochloride in experimental procedure 1.1. LCMS [M + 1] + 310.2. 1H NMR (400 MHz, CD3OD) δ 4.48 - 4.37 (m, 1H), 3.53 - 3.42 (m, 1H), 3.05 - 2.94 (m, 1H), 2.94 - 2.83 (m, 1H), 2.79 - 2.71 (m, 1H), 2.66 (dd, J = 13.9, 4.2 Hz, 1H), 2.61 - 2.42 (m, 7H), 2.36 (s, 3H), 2.14 - 1.96 (m, 3H), 1.67 - 1.57 (m, 4H), 1.53 - 1.43 (m, 2H), 1.06 (d, J = 6.9 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H).

[0184] Synthesis of rac-3-(1,3-dimethylpiperidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID529 [ka] Using the general synthesis using halocyclization as described herein, 3-(1,3-dimethylpiperidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (94.2 mg, 25.07%) was obtained as a yellow oil from commercially available 1-(tert-butoxycarbonyl)-3-methylpiperidine-3-carboxylic acid according to the synthesis described in 1.1-1.5. LCMS [M + 1] + 296.4. 1H NMR (400 MHz, cdcl3) δ 4.48 - 4.32 (m, 1H), 4.08 (td, J = 11.6, 11.5, 2.9 Hz, 1H), 3.77 - 3.61 (m, 1H), 2.74 - 2.58 (m, 1H), 2.58 - 2.47 (m, 4H), 2.47 - 2.26 (m, 5H), 2.26 - 2.21 (m, 3H), 2.21 - 1.98 (m, 2H), 1.91 - 1.66 (m, 2H), 1.66 - 1.57 (m, 1H), 1.57 - 1.54 (m, 2H), 1.45 - 1.35 (m, 2H), 1.34 - 1.24 (m, 1H), 1.19 (s, 3H).

[0185] Synthesis of rac-3-(1-methylpyrrolidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID546 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(1-methylpyrrolidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (134.5 mg, 16.82%) was obtained as a light brown oil from commercially available rac-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid according to the synthesis described in 1.1-1.5. LCMS [M + 1] + 268.2. 1H NMR (400 MHz, CDCl3) δ 4.40 - 4.35 (m, 1H), 4.06 (dd, J = 11.5, 2.7 Hz, 1H), 3.77 - 3.68 (m, 1H), 3.04 - 2.91 (m, 1H), 2.78 (td, J = 9.0, 9.0, 4.2 Hz, 1H), 2.64 - 2.42 (m, 8H), 2.41 - 2.36 (m, 2H), 2.33 (s, 3H), 2.06 - 1.96 (m, 2H), 1.96 - 1.82 (m, 3H), 1.44 - 1.38 (m, 2H).

[0186] Synthesis of rac-3-(3-methoxy-1-methylpiperidin-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID720 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(3-methoxy-1-methylpiperidin-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (71.9 mg, 16.31%) was obtained as a yellow oil from commercially available rac-1-(tert-butoxycarbonyl)-3-methoxypiperidine-4-carboxylic acid according to the synthesis described in 1.1-1.5. LCMS [M + 1] + 312.2. 1 H NMR (methanol-d4, 400 MHz): δ (ppm) 4.60 - 4.40 (m, 1H), 4.11 (d, 1H), 3.80 - 3.60 (m, 2H), 3.37 (s, 3H), 3.32 - 3.28 (m, 1H), 3.28 - 3.15 (m, 1H), 2.93 - 2.84 (m, 1H), 2.71 - 2.36 (m, 7H), 2.29 (s, 3H), 2.16 - 1.95 (m, 3H), 1.69 - 1.59 (m, 4H), 1.56 - 1.33 (m, 2H).

[0187] Synthesis of rac-3-(1-methylpiperidin-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID770 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(1-methylpiperidin-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (73 mg, 52.72%) was obtained as a yellow oil from commercially available 1-(tert-butoxycarbonyl)-piperidine-4-carboxylic acid according to the synthesis described in 1.1-1.5. LCMS [M + 1] + 282.2. 1 H NMR (methanol-d4, 400 MHz): δ (ppm) 4.50 - 4.40 (m, 1H), 4.07 (dd, J=12.1, 3.1 Hz, 1H), 3.75 - 3.63 (m, 1H), 2.94 - 2.82 (m, 2H), 2.62 - 2.41 (m, 6H), 2.25 (s, 3H), 2.20 - 2.12 (m, 1H), 2.03 (t, J=11.9, 11.9 Hz, 2H), 1.91 - 1.79 (m, 2H), 1.80 - 1.66 (m, 2H), 1.64 - 1.54 (m, 4H), 1.49 - 1.36 (m, 2H).

[0188] Synthesis of rac-3-(4-methoxy-1-methylpiperidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID700 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(4-methoxy-1-methylpiperidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (31.3 mg, 7.47%) was obtained as a yellow oil from commercially available rac-1-(tert-butoxycarbonyl)-4-methoxypiperidine-3-carboxylic acid according to the synthesis described in 1.1-1.5. LCMS [M + 1] + 312.2. 1 H NMR (methanol-d4, 400 MHz): δ (ppm) 4.57 - 4.45 (m, 1H), 4.15 - 4.07 (m, 1H), 3.80 - 3.73 (m, 1H), 3.37 - 3.33 (m, 5H), 2.96 - 2.85 (m, 1H), 2.86 - 2.30 (m, 9H), 2.32 - 2.28 (m, 3H), 2.24 - 2.15 (m, 1H), 2.13 - 2.05 (m, 1H), 1.68 - 1.56 (m, 4H), 1.53 - 1.43 (m, 2H).

[0189] Synthesis of rac-3-(2-(1-methylpiperidin-3-yl)propan-2-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID595 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(2-(1-methylpiperidin-3-yl)propan-2-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (112.3 mg, 53.72%) was obtained as a yellow oil from commercially available rac-2-(1-(tert-butoxycarbonyl)piperidin-3-yl)-2-methylpropanoic acid according to the synthesis described in 1.1-1.5. LCMS [M + 1] + 324.2. 1H NMR (chloroform-d, 400 MHz): δ (ppm) 4.37 - 4.27 (m, 1H), 4.05 (dd, J=11.5, 2.8 Hz, 1H), 3.76 - 3.60 (m, 1H), 2.83 - 2.70 (m, 2H), 2.59 - 2.40 (m, 4H), 2.41 - 2.32 (m, 2H), 2.23 (s, 3H), 1.90 - 1.60 (m, 5H), 1.58 - 1.41 (m, 5H), 1.41 - 1.33 (m, 2H), 1.19 - 0.82 (m, 7H).

[0190] Synthesis of rac-3-(3-(2-methoxyethyl)-1-methylpyrrolidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID701 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(3-(2-methoxyethyl)-1-methylpyrrolidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (22.6 mg, 27.03%) was obtained as a yellow oil from commercially available rac-1-(tert-butoxycarbonyl)-3-(2-methoxyethyl)pyrrolidine-3-carboxylic acid according to the synthesis described in 1.1-1.5. LCMS [M + 1] + 326.2. 1H NMR (methanol-d4, 400 MHz): δ (ppm) 4.55 - 4.42 (m, 1H), 4.14 - 4.04 (m, 1H), 3.80 - 3.70 (m, 1H), 3.41 - 3.35 (m, 3H), 3.29 (s, 3H), 3.04 (d, J=10.1 Hz, 1H), 2.64 - 2.54 (m, 5H), 2.53 - 2.47 (m, 2H), 2.46 - 2.37 (m, 2H), 2.33 (s, 3H), 2.07 - 1.85 (m, 2H), 1.80 - 1.69 (m, 1H), 1.67 - 1.56 (m, 4H), 1.51 - 1.41 (m, 2H).

[0191] Synthesis of rac-3-(4-methoxy-1-methylpyrrolidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID821 [ka] Using the general synthesis using halocyclization as described herein, 3-(4-methoxy-1-methylpyrrolidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (15.4 mg, 3.75%) was obtained as a yellow oil from commercially available 1-(tert-butoxycarbonyl)-4-methoxypyrrolidine-3-carboxylic acid according to the synthesis described in 1.1-1.5. LCMS [M + 1] + 298.0. 1H NMR (methanol-d4, 600 MHz): δ (ppm) 4.56 - 4.46 (m, 1H), 4.18 - 3.97 (m, 2H), 3.78 - 3.67 (m, 1H), 3.36 - 3.25 (m, 5H), 3.06 - 2.97 (m, 1H), 2.91 - 2.87 (m, 1H), 2.85 - 2.80 (m, 1H), 2.66 - 2.51 (m, 4H), 2.49 - 2.44 (m, 2H), 2.30 (s, 3H), 1.65 - 1.52 (m, 4H), 1.51 - 1.37 (m, 2H).

[0192] Synthesis of rac-3-(1-isopropylpyrrolidin-3-yl)-6-methyl-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID621 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(1-isopropylpyrrolidin-3-yl)-6-methyl-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (168.1 mg, 19.71%) was obtained as a yellow oil from commercially available rac-1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid following the synthesis described in 1.1-1.5 but using O-(1-methylallyl)hydroxylamine hydrochloride instead of O-allylhydroxylamine hydrochloride in experimental procedure 1.1 and acetone instead of the paraform in experimental procedure 1.5. LCMS [M + 1] + 310.2. 1H NMR (400 MHz, MeOD) δ 4.15 - 4.05 (m, 1H), 3.73 - 3.59 (m, 1H), 3.09 - 2.90 (m, 2H), 2.90 - 2.79 (m, 1H), 2.67 - 2.60 (m, 1H), 2.60 - 2.45 (m, 7H), 2.44 - 2.36 (m, 1H), 2.14 - 1.91 (m, 2H), 1.65 - 1.50 (m, 4H), 1.50 - 1.36 (m, 2H), 1.26 (d, J = 6.2 Hz, 3H), 1.10 (d, J = 3.5 Hz, 6H).

[0193] Synthesis of rac-3-(1-isopropylpiperidin-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID719 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(1-isopropylpiperidin-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (439.9 mg, 61.57%) was obtained as a yellow oil from commercially available 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid by following the synthesis described in 1.1-1.5 but using acetone instead of the paraform in experimental procedure 1.5. LCMS [M + 1] + 310.2. 1H NMR (400 MHz, CD3OD) δ 4.55 - 4.43 (m, 1H), 4.09 (dd, J = 11.6, 3.1 Hz, 1H), 3.71 (dd, J = 11.6, 6.4 Hz, 1H), 2.98 - 2.88 (m, 2H), 2.78 - 2.67 (m, 1H), 2.64 - 2.44 (m, 6H), 2.27 - 2.11 (m, 3H), 1.94 - 1.79 (m, 2H), 1.79 - 1.67 (m, 2H), 1.67 - 1.59 (m, 4H), 1.53 - 1.36 (m, 2H), 1.08 (d, J = 6.6 Hz, 6H).

[0194] Synthesis of rac-3-(1-isopropyl-3-methoxypiperidin-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID714 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(1-isopropyl-3-methoxypiperidin-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (37.2 mg, 7.74%) was obtained as a yellow oil from commercially available rac-1-(tert-butoxycarbonyl)-3-methoxypiperidine-4-carboxylic acid by following the synthesis described in 1.1-1.5 but using acetone instead of the paraform in experimental procedure 1.5. LCMS [M + 1] + 340.4. 1H NMR (400 MHz, CD3OD) δ 4.56 - 4.45 (m, 1H), 4.15 - 4.04 (m, 1H), 3.78 - 3.67 (m, 2H), 3.36 (s, 3H), 3.26 - 3.14 (m, 1H), 2.90 - 2.81 (m, 1H), 2.81 - 2.68 (m, 1H), 2.66 - 2.38 (m, 7H), 2.32 - 2.20 (m, 1H), 2.20 - 2.10 (m, 1H), 2.05 - 1.89 (m, 1H), 1.72 - 1.55 (m, 5H), 1.55 - 1.40 (m, 2H), 1.09 (d, J = 6.7 Hz, 3H), 1.05 (d, J = 6.4 Hz, 3H).

[0195] Synthesis of rac-3-(1-isopropylpiperidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID709 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(1-isopropylpiperidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (102.4 mg, 42.03%) was obtained as a yellow oil from commercially available rac-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid by following the synthesis described in 1.1-1.5 but using acetone instead of the paraform in experimental procedure 1.5. LCMS [M + 1] + 310.2. 1H NMR (400 MHz, CD3OD) δ 4.54 - 4.43 (m, 1H), 4.09 (dd, J = 11.7, 3.0 Hz, 1H), 3.72 (dd, J = 11.7, 6.5 Hz, 1H), 3.05 - 2.93 (m, 1H), 2.90 - 2.81 (m, 1H), 2.81 - 2.70 (m, 1H), 2.64 - 2.37 (m, 7H), 2.28 - 2.07 (m, 2H), 1.97 - 1.85 (m, 1H), 1.82 - 1.71 (m, 1H), 1.67 - 1.52 (m, 5H), 1.52 - 1.42 (m, 2H), 1.42 - 1.27 (m, 1H), 1.15 - 0.97 (m, 6H).

[0196] Synthesis of rac-3-(1-isopropyl-3-methylpiperidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID539 [ka] Using the general synthesis using halocyclization as described herein, rac-3-(1-isopropyl-3-methylpiperidin-3-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (286 mg, 28.82%) was obtained as a yellow oil from commercially available rac-1-(tert-butoxycarbonyl)-3-methylpiperidine-3-carboxylic acid by following the synthesis described in 1.1-1.5 but using acetone instead of the paraform in experimental procedure 1.5. LCMS [M + 1] + 324.2. 1H NMR (400 MHz, CDCl3) δ 4.42 - 4.29 (m, 1H), 4.14 - 3.96 (m, 1H), 3.75 - 3.61 (m, 1H), 2.78 - 2.58 (m, 2H), 2.56 - 2.44 (m, 4H), 2.43 - 2.30 (m, 4H), 2.15 - 2.02 (m, 1H), 1.93 - 1.80 (m, 1H), 1.81 - 1.55 (m, 2H), 1.55 - 1.49 (m, 4H), 1.43 - 1.33 (m, 2H), 1.29 - 1.18 (m, 1H), 1.13 (s, 3H), 1.03 - 0.80 (m, 6H).

[0197] Synthesis of rac-N,N-dimethyl-4-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)bicyclo[2.2.2]octan-1-amine, ID640 [ka] Using the general synthesis using halocyclization as described herein, N,N-dimethyl-4-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)bicyclo[2.2.2]octan-1-amine (124.9 mg, 16.73%) was obtained as a yellow oil from commercially available 4-((tert-butoxycarbonyl)amino)bicyclo[2.2.2]octane-1-carboxylic acid according to the synthesis described in 1.1-1.5. LCMS [M + 1] + 336.2. 1H NMR (400 MHz, CD3OD) δ 4.42 (tdd, J = 6.7, 6.7, 4.7, 2.9 Hz, 1H), 4.03 (dd, J = 11.6, 2.9 Hz, 1H), 3.63 (dd, J = 11.6, 6.5 Hz, 1H), 2.58 (dd, J = 13.7, 4.8 Hz, 2H), 2.55 - 2.48 (m, 2H), 2.48 - 2.41 (m, 2H), 2.19 (s, 6H), 1.82 - 1.73 (m, 6H), 1.67 - 1.56 (m, 10H), 1.50 - 1.41 (m, 2H).

[0198] Synthesis of rac-rel-cis-(1S,4S)-N,N-dimethyl-4-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)cyclohexan-1-amine, ID569 [ka] Using the general synthesis using halocyclization as described herein, rac-rel-cis-(1S,4S)-N,N-dimethyl-4-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)cyclohexan-1-amine (417.1 mg, 55.43%) was obtained as a brown oil from commercially available rac-rel-cis-(1S,4S)-4-{[(tert-butoxy)carbonyl]amino}cyclohexane-1-carboxylic acid according to the synthesis described in 1.1-1.5. LCMS [M + 1] + 310.4. 1 H NMR (400 MHz, CD3OD) δ 4.56 - 4.44 (m, 1H), 4.10 (dd, J = 11.8, 3.0 Hz, 1H), 3.80 - 3.64 (m, 1H), 2.64 - 2.47 (m, 7H), 2.39 (s, 6H), 2.16 - 2.05 (m, 2H), 1.79 - 1.66 (m, 4H), 1.66 - 1.52 (m, 7H), 1.52 - 1.44 (m, 2H).

[0199] Synthesis of rac-N,N-dimethyl-2-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)ethan-1-amine, ID779 [ka] Using the general synthesis using halocyclization as described herein, rac-N,N-dimethyl-2-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)ethan-1-amine (76.3 mg, 7.04%) was obtained as a yellow oil from commercially available 3-((tert-butoxycarbonyl)amino)propanoic acid according to the synthesis described in 1.1-1.5. LCMS [M + 1] + 256.2. 1 H NMR (methanol-d4, 400 MHz): δ (ppm) 4.60 - 4.46 (m, 1H), 4.12 (dd, J=11.2, 3.3 Hz, 1H), 3.81 - 3.67 (m, 1H), 2.76 - 2.46 (m, 8H), 2.40 (t, J=7.4, 7.4 Hz, 2H), 2.27 (s, 6H), 1.70 - 1.55 (m, 4H), 1.53 - 1.43 (m, 2H).

[0200] Synthesis of rac-2-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)-N-(pyridin-3-ylmethyl)ethan-1-amine, ID797 [ka] Using the general synthesis using halocyclization as described herein, rac-2-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)-N-(pyridin-3-ylmethyl)ethan-1-amine (70.9 mg, 50.61%) was obtained as a yellow oil from commercially available 3-((tert-butoxycarbonyl)amino)propanoic acid following the synthesis described in 1.1-1.5 but using nicotinaldehyde instead of the paraform in experimental procedure 1.5. LCMS [M + 1] + 319.2. 1 H NMR (methanol-d4, 400 MHz): δ (ppm) 8.54 (s, 1H), 8.45 (d, J=4.9 Hz, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.43 (dd, J=7.8, 4.9 Hz, 1H), 4.56 - 4.46 (m, 1H), 4.11 (dd, J=11.7, 2.9 Hz, 1H), 3.83 (s, 2H), 3.74 (dd, J=11.6, 6.6 Hz, 1H), 2.83 (t, J=6.9, 6.9 Hz, 2H), 2.56 (d, J=6.5 Hz, 2H), 2.54 - 2.43 (m, 5H), 2.43 (t, J=7.0 Hz, 2H), 1.66 - 1.54 (m, 4H), 1.51 - 1.40 (m, 2H).

[0201] Synthesis of rac-N-((5-methoxypyridin-3-yl)methyl)-2-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)ethan-1-amine, ID806 [ka] In a generally similar manner with non-essential modifications, rac-N-((5-methoxypyridin-3-yl)methyl)-2-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)ethan-1-amine (29.8 mg, 29.12%) was obtained as a yellow oil from commercially available 3-((tert-butoxycarbonyl)amino)propanoic acid following the synthesis described in 1.1-1.5 but using 5-methoxynicotinaldehyde instead of the paraform in experimental procedure 1.5. LCMS [M + 1] + 349.2. 1 H NMR (methanol-d4, 400 MHz): δ (ppm) 8.13 (d, J=8.7 Hz, 2H), 7.47 (s, 1H), 4.55 - 4.46 (m, 1H), 4.11 (d, J=14.7 Hz, 1H), 3.90 (s, 3H), 3.81 (s, 2H), 3.74 (dd, J=11.6, 6.5 Hz, 1H), 2.83 (t, J=6.9, 6.9 Hz, 2H), 2.61 - 2.33 (m, 8H), 1.68 - 1.51 (m, 4H), 1.54 - 1.37 (m, 2H).

[0202] Synthesis of rac-N,N-dimethyl-1-(1-methyl-3-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)pyrrolidin-3-yl)methanamine, ID826 [ka] In a generally similar manner with non-essential modifications, rac-N,N-dimethyl-1-(1-methyl-3-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)pyrrolidin-3-yl)methanamine (85.3 mg, 35.26%) was obtained as a yellow oil from commercially available 1-(tert-butoxycarbonyl)-3-(((tert-butoxycarbonyl)amino)methyl)pyrrolidine-3-carboxylic acid according to the synthesis described in 1.1-1.5. LCMS [M + 1] + 325.2.1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 4.43 - 4.29 (m, 1H), 3.99 (dd, J=11.3, 3.3 Hz, 1H), 3.68 - 3.56 (m, 1H), 2.70 - 2.57 (m, 2H), 2.47 - 2.24 (m, 10H), 2.22 - 2.09 (m, 10H), 1.69 - 1.59 (m, 1H), 1.56 - 1.43 (m, 4H), 1.41 - 1.30 (m, 2H).

[0203] Halocyclization + additional N-acylation Synthesis of rac-(2S)-2-amino-1-(3-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)piperidin-1-yl)propan-1-one, ID718 [ka] Step 1.6 Synthesis of tert-butyl rac-((2S)-1-oxo-1-(3-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)piperidin-1-yl)propan-2-yl)carbamate [ka] (2S)-2-(tert-butoxycarbonylamino)propanoic acid (155.69 mg, 0.823 mmol, 1.1 eq) and [dimethylamino-(3-oxidotriazolo[4,5-b]pyridin-3-ium-1-yl)methylene]-dimethyl-ammonium hexafluorophosphate (312.86 mg, 0.823 mmol, 1.1 eq) were mixed together in dry DMF (1 mL) followed by N,N-diisopropylethylamine (212.69 mg, 1.646 mmol, 2.2 eq). The resulting clear solution was stirred at ambient temperature for 20 min, then rac-3-(3-piperidyl)-5-(1-piperidylmethyl)-5,6-dihydro-1,4,2-dioxazine (200 mg, 0.748 mmol, 1 eq), obtained in a similar manner with non-essential modifications from commercially available rac-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid according to the synthesis described in 1.1-1.4, was added in one portion. The reaction mixture was left stirring overnight at ambient temperature. After 14 h, the reaction mixture solution was subjected to preparative HPLC (50-100%, 0-5 min, water-methanol, flow rate: 30 ml / min (loading pump 4 ml / min methanol), target mass 439, column: SunFireC18 100×19 mm 5 um) without any workup to give the title product (197.3 mg, 57.14%) as a yellow oil. LCMS [M+1] + 439.2

[0204] Step 1.7 Synthesis of rac-(2S)-2-amino-1-(3-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)piperidin-1-yl)propan-1-one [ka] tert-Butyl rac-N-[(1S)-1-methyl-2-oxo-2-[3-[5-(1-piperidylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl]-1-piperidyl]ethyl]carbamate (197.3 mg, 0.4499 mmol, 1 eq) was dissolved in dry DCM (1 mL) followed by dropwise addition of 2,2,2-trifluoroacetic acid (512.95 mg, 4.499 mmol, 10 eq). The reaction mixture was left stirring overnight at room temperature. After 14 h, the reaction mixture was gently evaporated under reduced pressure at 40° C. to give a yellow colored oily residue which was diluted with DCM (3 mL) and washed with 30% aqueous potassium carbonate (2×3 mL). The organic layer was isolated and concentrated under reduced pressure to give 200 mg of crude oil, which was purified by preparative HPLC (40-80%, 0-5 min, water-methanol, flow rate: 30 ml / min (loading pump 4 ml / min of methanol), target mass 339, column: SunFireC18 100×19 mm 5 um) to give the title product (80.1 mg, 49.98%) as a yellow oil. LCMS [M + 1] + 339.2. 1 H NMR (400 MHz, CD3OD) δ 4.57 - 4.36 (m, 2H), 4.20 - 3.94 (m, 2H), 3.93 - 3.76 (m, 2H), 3.77 - 3.63 (m, 1H), 3.26 - 3.06 (m, 1H), 3.06 - 2.59 (m, 1H), 2.59 - 2.21 (m, 7H), 2.12 - 1.97 (m, 1H), 1.97 - 1.67 (m, 2H), 1.67 - 1.53 (m, 5H), 1.53 - 1.38 (m, 3H), 1.25 - 1.19 (m, 3H).

[0205] Synthesis of rac-2-amino-1-(3-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)pyrrolidin-1-yl)propan-1-one, ID691 [ka] rac-2-amino-1-(3-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)pyrrolidin-1-yl)propan-1-one (94.7 mg, 34.42%) as a yellow oil was prepared from commercially available rac-3-methylpyrrolidine-1,3-dicarboxylate 1-(tert-butyl) following the synthesis described in 1.1-1.4, 1.6, 1.7 but using rac-2-(tert-butoxycarbonylamino)propanoic acid instead of (2S)-2-(tert-butoxycarbonylamino)propanoic acid in experimental procedure 1.6. LCMS [M+1] + 325.4. 1 H NMR (400 MHz, CD3OD) δ 4.59 - 4.47 (m, 1H), 4.17 - 4.06 (m, 1H), 3.81 - 3.70 (m, 2H), 3.70 - 3.47 (m, 4H), 3.17 - 3.02 (m, 1H), 2.58 (d, J = 5.7 Hz, 2H), 2.56 - 2.43 (m, 4H), 2.26 - 2.18 (m, 1H), 2.18 - 2.07 (m, 1H), 1.67 - 1.55 (m, 4H), 1.55 - 1.44 (m, 2H), 1.29 - 1.16 (m, 3H).

[0206] Synthesis of rac-2-amino-1-(4-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)piperidin-1-yl)propan-1-one, ID748 [ka] rac-2-amino-1-(4-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)piperidin-1-yl)propan-1-one (69.5 mg, 45.1%) as a yellow oil was prepared from commercially available 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid following the synthesis described in 1.1-1.4, 1.6, 1.7 but using 2-(tert-butoxycarbonylamino)propanoic acid instead of (2S)-2-(tert-butoxycarbonylamino)propanoic acid in experimental procedure 1.6. LCMS [M + 1] + 339.4. 1 H NMR (methanol-d4, 400 MHz): δ (ppm) 4.57 - 4.41 (m, 2H), 4.20 - 4.05 (m, 1H), 3.99 (d, J=13.6 Hz, 1H), 3.93 - 3.85 (m, 1H), 3.73 (dd, J=11.6, 6.6 Hz, 1H), 3.23 - 3.11 (m, 1H), 2.87 - 2.70 (m, 1H), 2.72 - 2.29 (m, 7H), 1.99 - 1.84 (m, 2H), 1.72 - 1.50 (m, 6H), 1.50 - 1.36 (m, 2H), 1.25 - 1.14 (m, 3H).

[0207] Synthesis of rac-2-amino-1-(3-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)pyrrolidin-1-yl)ethan-1-one, ID699 [ka] rac-2-amino-1-(3-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)pyrrolidin-1-yl)ethan-1-one (64.5 mg, 25.01%) as a yellow oil was prepared from commercially available rac-3-methylpyrrolidine-1,3-dicarboxylate 1-(tert-butyl) following the synthesis described in 1.1-1.4, 1.6, 1.7 but using 2-(tert-butoxycarbonylamino)acetic acid instead of (2S)-2-(tert-butoxycarbonylamino)propanoic acid in experimental procedure 1.6. LCMS [M+1] + 311.2. 1 H NMR (400 MHz, CD3OD) δ 4.60 - 4.45 (m, 1H), 4.17 - 4.02 (m, 1H), 3.79 - 3.71 (m, 1H), 3.71 - 3.52 (m, 3H), 3.52 - 3.41 (m, 1H), 3.38 (s, 2H), 3.19 - 2.94 (m, 1H), 2.58 (d, J = 5.8 Hz, 2H), 2.56 - 2.43 (m, 4H), 2.28 - 2.01 (m, 2H), 1.69 - 1.52 (m, 4H), 1.54 - 1.41 (m, 2H).

[0208] Synthesis of rac-2-amino-1-(3-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)piperidin-1-yl)ethan-1-one, ID725 [ka] rac-2-amino-1-(3-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)piperidin-1-yl)ethan-1-one (232 mg, 86.38%) as a yellow oil was prepared from commercially available rac-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid following the synthesis described in 1.1-1.4, 1.6, 1.7 but using 2-(tert-butoxycarbonylamino)acetic acid instead of (2S)-2-(tert-butoxycarbonylamino)propanoic acid in experimental procedure 1.6. LCMS [M+1]+ 325.4. 1 H NMR (methanol-d4, 400 MHz): δ (ppm) 4.57 - 4.37 (m, 2H), 4.16 - 3.87 (m, 2H), 3.73 - 3.62 (m, 3H), 3.19 - 2.88 (m, 2H), 2.57 - 2.43 (m, 7H), 2.38 - 2.21 (m, 1H), 2.07 - 1.64 (m, 3H), 1.63 - 1.43 (m, 8H).

[0209] Synthesis of rac-2-amino-1-(4-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)piperidin-1-yl)ethan-1-one, ID787 [ka] rac-2-amino-1-(4-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)piperidin-1-yl)ethan-1-one (28.8 mg, 18.93%) as a yellow oil was prepared from commercially available 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid following the synthesis described in 1.1-1.4, 1.6, 1.7 but using 2-(tert-butoxycarbonylamino)acetic acid instead of (2S)-2-(tert-butoxycarbonylamino)propanoic acid in experimental procedure 1.6. LCMS [M+1]+ 325.4. 1H NMR (methanol-d4, 400 MHz): δ (ppm) 4.56 - 4.43 (m, 2H), 4.12 (d, J=2.7 Hz, 1H), 3.89 - 3.80 (m, 1H), 3.72 (dd, J=12.2, 5.8 Hz, 1H), 3.55 - 3.40 (m, 2H), 3.09 (t, J=11.0, 11.0 Hz, 1H), 2.85 - 2.74 (m, 1H), 2.75 - 2.32 (m, 7H), 1.93 - 1.85 (m, 2H), 1.77 - 1.50 (m, 6H), 1.52 - 1.39 (m, 2H).

[0210] Halocyclization + further N-alkylation Synthesis of rac-2-(3-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)piperidin-1-yl)acetamide, ID711 [ka] Step 1.8 Synthesis of rac-2-(3-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)piperidin-1-yl)acetamide [ka] rac-3-(3-piperidyl)-5-(1-piperidylmethyl)-5,6-dihydro-1,4,2-dioxazine (200 mg, 0.7480 mmol, 1 eq), obtained in a similar manner with non-essential modifications according to the synthesis described in 1.1-1.4 from commercially available rac-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid, was dissolved in dry DMF (0.6 mL), then 2-chloroacetamide (76.943 mg, 0.8228 mmol, 1.1 eq) was added to the resulting solution, followed by N,N-diisopropylethylamine (116.01 mg, 0.8976 mmol, 1.2 eq). The reaction mixture was heated at 85 °C overnight. After 24 hours, the reaction mixture was subjected to preparative HPLC (20-60%, 0-6 min, water-methanol, flow rate: 30 ml / min (loading pump 4 ml / min methanol), target mass 325, column SunFireC18 100×19 mm 5 um) without any workup to give the title product (94.5 mg, 36.99%) as a yellow oil. LCMS [M + 1] + 325.4. 1 H NMR (400 MHz, CD3OD) δ 4.53 - 4.42 (m, 1H), 4.15 - 4.03 (m, 1H), 3.72 (ddd, J = 11.7, 6.5, 3.3 Hz, 1H), 3.05 - 2.94 (m, 2H), 2.94 - 2.85 (m, 1H), 2.85 - 2.75 (m, 1H), 2.65 - 2.43 (m, 7H), 2.39 - 2.24 (m, 1H), 2.24 - 2.10 (m, 1H), 1.93 - 1.81 (m, 1H), 1.81 - 1.71 (m, 1H), 1.70 - 1.54 (m, 5H), 1.54 - 1.40 (m, 3H).

[0211] Synthesis of rac-N,N-dimethyl-2-(3-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)piperidin-1-yl)acetamide, ID710 [ka] rac-N,N-dimethyl-2-(3-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)piperidin-1-yl)acetamide (77.2 mg, 27.82%) as a yellow oil was prepared from commercially available rac-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid following the synthesis described in 1.1-1.4, 1.8 but using 2-chloro-N,N-dimethyl-acetamide instead of 2-chloroacetamide in experimental procedure 1.8. LCMS [M + 1] + 353.2. 1 H NMR (400 MHz, CD3OD) δ 4.52 - 4.41 (m, 1H), 4.09 (dd, J = 11.6, 3.0 Hz, 1H), 3.71 (ddd, J = 11.8, 6.6, 2.2 Hz, 1H), 3.27 - 3.18 (m, 2H), 3.11 (s, 3H), 3.05 - 2.98 (m, 1H), 2.94 (s, 3H), 2.90 - 2.81 (m, 1H), 2.64 - 2.42 (m, 7H), 2.22 - 2.02 (m, 2H), 1.95 - 1.85 (m, 1H), 1.81 - 1.70 (m, 1H), 1.68 - 1.56 (m, 5H), 1.53 - 1.43 (m, 2H), 1.43 - 1.29 (m, 1H).

[0212] Synthesis of rac-N-methyl-2-(3-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)piperidin-1-yl)acetamide, ID721 [ka] rac-N-methyl-2-(3-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)piperidin-1-yl)acetamide (171.8 mg, 64.47%) as a yellow oil was prepared from commercially available rac-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid following the synthesis described in 1.1-1.4, 1.8 but using 2-chloro-N-methylacetamide instead of 2-chloroacetamide in experimental procedure 1.8. LCMS [M + 1] + 339.2. 1 H NMR (methanol-d4, 400 MHz): δ (ppm) 4.54 - 4.45 (m, 1H), 4.10 (dd, J=11.6, 2.5 Hz, 1H), 3.79 - 3.65 (m, 1H), 3.05 - 2.93 (m, 2H), 2.79 (s, 4H), 2.76 - 2.68 (m, 1H), 2.63 - 2.43 (m, 7H), 2.40 - 2.30 (m, 1H), 2.22 (t, J=9.9, 9.9 Hz, 1H), 1.91 - 1.80 (m, 1H), 1.78 - 1.70 (m, 1H), 1.69 - 1.57 (m, 5H), 1.56 - 1.41 (m, 3H).

[0213] Halocyclization + additional TBDMS deprotection Synthesis of rac-rel-(3R,5R)-1-methyl-5-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)piperidin-3-ol, ID724 [ka] Step 1.9 Synthesis of rac-rel-(3R,5R)-1-methyl-5-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)piperidin-3-ol tert-Butyl-dimethyl-[[rac-rel-(3R,5R)-1-methyl-5-[5-(1-piperidylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl]-3-piperidyl]oxy]silane (600 mg, 1.11 mmol, 1 eq), obtained in a similar manner with non-essential modifications according to the synthesis described in 1.1-1.5 from rac-rel-(3R,5R)-1-(tert-butoxycarbonyl)-5-((2,3,3-trimethylbutan-2-yl)oxy)piperidine-3-carboxylic acid described in the literature, was dissolved in THF (4 mL) and then a 1 M THF solution of tetrabutylammonium fluoride (5 ml, 5 mmol, 4 eq) was added to the resulting solution. The reaction mixture was stirred at room temperature for 15 h. The solvent was then removed by evaporation to give crude rac-rel-(3R,5R)-1-methyl-5-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)piperidin-3-ol, which was subjected to preparative HPLC purification (15-60%, 0-5 min, 0.1% NH3-methanol, flow rate: 30 ml / min (loading pump 4 ml / min methanol), target mass 284, column: YMC Triart C18 100 x 20 mm, 5 um) to give the title product (30.5 mg, 8.72%) as a yellow oil. LCMS [M + 1] + 298.2. 1 H NMR

[0214] Synthesis of rac-rel-(1R,5S)-N,N-dimethyl-5-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)-3-azabicyclo[3.2.0]heptane-1-carboxamide, ID765 [ka] Step 1.10 Synthesis of rac-rel-cis(1R,5S)-3-(tert-butoxycarbonyl)-5-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)-3-azabicyclo[3.2.0]heptane-1-carboxylic acid [ka] 3-(tert-butyl)-1-methyl rac-rel-cis-(1R,5S)-5-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)-3-azabicyclo[3.2.0]heptane-1,3-dicarboxylate (2.9 g, 6.297 mmol, 1 eq), obtained in a similar manner with non-essential modifications according to the synthesis described in 1.1-1.3 from commercially available rel-cis(1R,5S)-3-(tert-butoxycarbonyl)-5-(methoxycarbonyl)-3-azabicyclo[3.2.0]heptane-1-carboxylic acid, was dissolved in methanol (30 ml) and then a solution of sodium hydroxide (755.61 mg, 18.89 mmol, 3 eq) in water (30 ml) was added to the resulting solution. The reaction mixture was heated at 80° C. for 3 days. After complete conversion of the starting material was detected by LCMS, the mixture was concentrated under reduced pressure and the resulting residue was diluted with water (30 ml). A 1N aqueous solution of sodium hydrogen sulfate (2267.9 mg, 18.89 mmol, 3 eq) was added to the aqueous solution of the reaction mixture to adjust p to 7. The formed precipitate was collected by filtration to give the title product (1.38 g, 49.16%) as a white solid. LCMS [M + 1] + 424.4.

[0215] Step 1.11 Synthesis of tert-butyl rac-rel-(1R,5S)-1-(dimethylcarbamoyl)-5-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)-3-azabicyclo[3.2.0]heptane-3-carboxylate [ka] rac-rel-(1R,5S)-3-tert-butoxycarbonyl-1-[5-(1-piperidylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl]-3-azabicyclo[3.2.0]heptane-5-carboxylic acid (300 mg, 0.6730 mmol, 1 eq), [dimethylamino-(3-oxidotriazolo[4,5-b]pyridin-3-ium-1-yl)methylene]-dimethyl-ammonium hexafluorophosphate (281.47 mg, 0.7403 mmol, 1.1 eq) were mixed together in dry DMF (1 ml), and then N,N-diisopropylethylamine (191.34 mg, 1.4805 mmol, 2.2 eq) was added to the resulting solution, which was stirred at room temperature for 20 minutes. N-methylmethanamine hydrochloride (60.361 mg, 0.7403 mmol, 1.1 eq) was then added to the reaction mixture, which was stirred at room temperature for another 14 h. The reaction mixture solution was then subjected to preparative HPLC purification (50-90%, 0-5 min, water-methanol, flow rate: 30 ml / min (loading pump 4 ml / min methanol), target mass 451, column: SunFireC18 100 x 19 mm 5 um) without any workup to give the title product (177.4 mg, 55.58%) as a yellow oil. LCMS [M + 1] + 451.4.

[0216] Step 1.12 Synthesis of rac-rel-(1R,5S)-N,N-dimethyl-5-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)-3-azabicyclo[3.2.0]heptane-1-carboxamide [ka] In a generally similar manner with non-essential modifications, rac-rel-(1R,5S)-N,N-dimethyl-5-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)-3-azabicyclo[3.2.0]heptane-1-carboxamide (34.6 mg, 25.08%) was obtained as a beige solid following the synthesis described in 1.4. LCMS [M + 1]+ 351.4. 1 H NMR (methanol-d4, 400 MHz): δ (ppm) 4.60 - 4.55 (m, 1H), 4.18 - 4.08 (m, 1H), 3.76-3.64 (m, 1H), 3.36 (s, 2H), 3.18 - 3.14 (m, 1H), 2.90 - 2.89 (m, 6H), 2.84-2.83 (m, 2H), 2.64 - 2.54 (m, 4H), 2.51 -2.46 (m, 2H), 2.27 - 2.15 (m, 1H), 2.09 - 2.03 (m, 1H), 1.89-.79 (m, 1H), 1.62-1.61 (m, 4H), 1,50-1,48 (m, 2H).

[0217] Synthesis of rac-(4-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)piperidin-4-yl)methanol, ID722 [ka] Step 1.13 Synthesis of tert-butyl 4-(hydroxymethyl)-4-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)piperidine-1-carboxylate [ka] Tert-butyl rac-4-(benzyloxymethyl)-4-[5-(1-piperidylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl]piperidine-1-carboxylate (1.52 g, 7.5262 mmol, 1 eq), obtained in a similar manner with non-essential modifications according to the synthesis described in 1.1-1.3 from commercially available 4-((benzyloxy)methyl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid, was dissolved in anhydrous methanol (50 ml) and then palladium on carbon 10% (80.094 mg, 0.0753 mmol, 0.01 eq) was added to the resulting solution. The reaction mixture was then evacuated and flushed with hydrogen three times, a balloon containing hydrogen was attached and the reaction mixture was heated at 55° C. for 14 hours with vigorous stirring. After that time the reaction mixture was cooled to room temperature and filtered. The catalyst was washed with methanol (50 ml) and the collected filtrate was concentrated under reduced pressure to give the title product (1.73 g, 35.85%) as a yellow oil. The product obtained was used in further experiments without any additional purification. LCMS [M + 1] + 398.4.

[0218] Step 1.14 Synthesis of rac-(4-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)piperidin-4-yl)methanol [ka] rac-(4-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)piperidin-4-yl)methanol (33.8 mg, 45.19%) was prepared as a yellow oil according to the synthesis described in 1.4. LCMS [M + 1] + 298.2. 1H NMR (methanol-d4, 400 MHz): δ (ppm) 4.81 - 4.71 (m, 1H), 4.21 - 4.12 (m, 1H), 3.88 (dd, J=11.7, 5.0 Hz, 1H), 3.65 - 3.50 (m, 2H), 3.28 - 3.19 (m, 3H), 3.14 (d, J=12.9 Hz, 1H), 3.05 - 2.93 (m, 1H), 2.93 - 2.68 (m, 5H), 2.25 (t, J=17.4, 17.4 Hz, 2H), 1.82 - 1.62 (m, 6H), 1.60 - 1.50 (m, 2H).

[0219] Halocyclization + reductive amination Synthesis of rac-5-((4,4-difluoropiperidin-1-yl)methyl)-3-(4-methylpiperidin-4-yl)-5,6-dihydro-1,4,2-dioxazine, ID673 [ka] Step 1.15 Synthesis of tert-butyl 4-[5-(bromomethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl]-4-methylpiperidine-1-carboxylate [ka] tert-Butyl 4-[5-(bromomethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl]-4-methylpiperidine-1-carboxylate (32 g, 96%) was prepared as a dark yellow oil from commercially available tert-butyl 4-(allyloxycarbamoyl)-4-methyl-piperidine-1-carboxylate according to the synthesis described in 1.1-1.2.

[0220] Step 1.16 Synthesis of tert-butyl rac-4-[5-(acetoxymethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl]-4-methyl-piperidine-1-carboxylate [ka] To a solution of tert-butyl rac-4-[5-(bromomethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl]-4-methyl-piperidine-1-carboxylate (19 g, 50.36 mmol, 1 eq) in DMF (80 ml) was added potassium acetate (9.88 g, 100.72 mmol, 2 eq). The resulting mixture was stirred at 60° C. for 14 h. The reaction mixture was then diluted with water (250 mL) and extracted with methyl tert-butyl ether (2×100 mL). The combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give crude tert-butyl rac-4-[5-(acetoxymethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl]-4-methyl-piperidine-1-carboxylate (16 g, 90% purity, 80% yield) (LCMS [M-butene+H] + 301), which was used directly in the next step without further purification.

[0221] Step 1.17 Synthesis of tert-butyl rac-4-[5-(hydroxymethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl]-4-methyl-piperidine-1-carboxylate [ka] Sodium hydroxide (4.84 g, 121.2 mmol) and tert-butyl rac-4-[5-(acetoxymethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl]-4-methyl-piperidine-1-carboxylate (16 g, 40.4 mmol) were suspended in methanol (100 ml) at 20° C. The resulting mixture was stirred at room temperature overnight. The resulting solution was concentrated under reduced pressure, water was added and extracted with EtOAc (2×100 ml). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give a pale yellow oil. The crude material was purified by silica gel column chromatography (Companion combiflash, 120 g SiO2, petroleum ether / MtBE with 0-100% MtBE, flow rate = 85 mL / min, Rv = 11 CV) to give tert-butyl rac-4-[5-(hydroxymethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl]-4-methyl-piperidine-1-carboxylate (9.5 g, 100% purity, 75% yield) as a pale yellow oil. LCMS [M - butene + H] + 259.2.

[0222] Step 1.18 Synthesis of tert-butyl rac-4-(5-formyl-5,6-dihydro-1,4,2-dioxazin-3-yl)-4-methyl-piperidine-1-carboxylate [ka] To a stirred solution of tert-butyl rac-4-[5-(hydroxymethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl]-4-methyl-piperidine-1-carboxylate (6.73 g, 21.40 mmol, 1 eq.) in CHCl at 10° C. was added (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzoiodoxol-3(1H)-one (9.98 g, 23.54 mmol, 1.1 eq.). The reaction mixture was left stirring at room temperature overnight. Saturated NaHCO3 solution (200 ml) was added to the reaction mixture and stirred for 2 h. The aqueous and organic solutions were filtered. The organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to give tert-butyl rac-4-(5-formyl-5,6-dihydro-1,4,2-dioxazin-3-yl)-4-methyl-piperidine-1-carboxylate N83-1 (6.5 g, 77.7% yield, 80% purity), which was used in the next step without further purification.

[0223] Step 1.19 Synthesis of tert-butyl rac-4-[5-[(4,4-difluoro-1-piperidyl)methyl]-5,6-dihydro-1,4,2-dioxazin-3-yl]-4-methyl-piperidine-1-carboxylate [ka] tert-Butyl rac-4-(5-formyl-5,6-dihydro-1,4,2-dioxazin-3-yl)-4-methyl-piperidine-1-carboxylate (500 mg, 1.60 mmol, 1 eq.) was dissolved in MeOH (20 mL) at room temperature, followed by the addition of 4,4-difluoropiperidine (639 mg, 5.28 mmol, 3.3 eq.), acetic acid (357 uL, 3.9 eq.) and NaCNBH3 (310 mg, 4.94 mmol, 3.09 eq.) and stirring overnight. The reaction mixture was concentrated to dryness and the residue was added to MtBE and 6N NaOH and extracted with MtBE. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give crude tert-butyl 4-[5-[(4,4-difluoro-1-piperidyl)methyl]-5,6-dihydro-1,4,2-dioxazin-3-yl]-4-methyl-piperidine-1-carboxylate (800 mg, pure) (LCMS [M + H] + 418.0), which was used in the next step without further purification.

[0224] Synthesis of rac-5-((4,4-difluoropiperidin-1-yl)methyl)-3-(4-methylpiperidin-4-yl)-5,6-dihydro-1,4,2-dioxazine, ID673 [ka] rac-5-((4,4-difluoropiperidin-1-yl)methyl)-3-(4-methylpiperidin-4-yl)-5,6-dihydro-1,4,2-dioxazine (175.9 mg, 40%) was prepared as a yellow oil from tert-butyl rac-4-[5-[(4,4-difluoro-1-piperidyl)methyl]-5,6-dihydro-1,4,2-dioxazin-3-yl]-4-methyl-piperidine-1-carboxylate according to the synthesis described in 1.4. LCMS [M + 1] + 318.2. 1H NMR (400 MHz, CD3OD) δ 4.52 (qd, J = 6.0, 6.0, 6.0, 2.8 Hz, 1H), 4.12 (dd, J = 11.7, 2.9 Hz, 1H), 3.80 (dd, J = 11.7, 6.0 Hz, 1H), 3.24 (dt, J = 13.3, 4.2, 4.2 Hz, 2H), 3.19 - 3.08 (m, 2H), 2.72 - 2.61 (m, 6H), 2.24 (s, 1H), 2.21 (s, 1H), 1.97 (tt, J = 12.8, 12.8, 5.6, 5.6Hz, 4H), 1.64 (ddd, J = 15.4, 11.8, 4.3 Hz, 2H), 1.27 (s, 3H).

[0225] 2. General synthesis using the Mitsunobu reaction Synthesis of rac-3-(4-((5-fluoropyridin-3-yl)methyl)piperidin-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID528 [ka] Step 2.1 Synthesis of 1-(tert-butyl)4-ethyl rac-4-((5-fluoropyridin-3-yl)methyl)piperidine-1,4-dicarboxylate [ka] To a solution of lithium bis(trimethylsilyl)azanide 1M (18 ml, 17.88 mmol, 2.3 eq) in THF (40 mL) in a round-bottomed three-neck flask was added a solution of 1-(tert-butyl)4-ethyl piperidine-1,4-dicarboxylate (2 g, 7.77 mmol, 1 eq) in THF (10 mL) at -78°C under an inert atmosphere (argon inlet). The mixture was stirred at -78°C for 30 min, after which 3-(bromomethyl)-5-fluoro-pyridine hydrobromide (2.316 g, 8.55 mmol, 1.1 eq) was added in portions directly into the system during 30 min. The reaction mixture was stirred at -78°C for a further 30 min, then allowed to warm to room temperature and stirred overnight at ambient temperature. After 14 h, the reaction mixture was quenched with saturated aqueous NH4Cl (100 mL) and extracted with ethyl acetate (3 x 30 mL). The organic layers were isolated, combined, washed with water (100 mL) and brine (100 mL), then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 3.65 g of a crude orange oil. The crude material obtained was purified by FC (Companion combiflash, 80 g SiO2, chloroform / acetonitrile with 0-35% acetonitrile, flow rate=60 mL / min, Rv=13 CV) to give the title product (530 mg, 16.75%) as a pale yellow oil with 90% purity, which was used without further purification. LCMS [M - butene + H] + 311.2

[0226] Step 2.2 Synthesis of rac-1-(tert-butoxycarbonyl)-4-((5-fluoropyridin-3-yl)methyl)piperidine-4-carboxylic acid [ka] 1-(tert-butyl)4-ethyl rac-4-((5-fluoropyridin-3-yl)methyl)piperidine-1,4-dicarboxylate (530 mg, 1.302 mmol, 1 eq) was dissolved in a mixture of distilled water (3 mL) and methanol (5 mL) and then sodium hydroxide (104.14 mg, 2.604 mmol, 2 eq) was added to the resulting solution. The reaction mixture was then heated to 75° C. and left under stirring. After 48 h, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to give a yellow semi-solid residue which was diluted with distilled water (7 mL) and extracted with DCM (2×5 mL). The aqueous layer was isolated and sodium hydrogen sulfate (312 mg, 2.604 mmol, 2 eq) was added to the solution under stirring. The resulting mixture was stirred at room temperature for an additional 30 min, then the formed precipitate was collected by filtration and dried at 65° C. to give the title product (300 mg, 68.11%) as a white solid, which was used without further purification. LCMS [M − 1] - 337.2.

[0227] Step 2.3 Synthesis of tert-butyl rac-4-((5-fluoropyridin-3-yl)methyl)-4-((2-hydroxy-3-(piperidin-1-yl)propoxy)carbamoyl)piperidine-1-carboxylate [ka] rac-1-tert-butoxycarbonyl-4-[(5-fluoro-3-pyridyl)methyl]piperidine-4-carboxylic acid (300 mg, 0.575 mmol, 1 eq) was dissolved in dry DMF (5 mL), then [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium hexafluorophosphate (371 mg, 0.975 mmol, 1.1 eq) was added to the resulting solution, followed by N,N-diisopropylethylamine (0.772 ml, 572.92 mg, 4.43 mmol, 5 eq) and 1-aminooxy-3-(1-piperidyl)propan-2-ol dihydrochloride (285 mg, 1.15 mmol, 1.3 eq). The reaction mixture was left stirring at ambient temperature overnight. After 14 hours, the reaction mixture solution was subjected to preparative HPLC (45-80%, 0-5 min, water-methanol, flow rate: 30 ml / min (loading pump 4 ml / min methanol), target mass 495, column: SunFire C18 100×19 mm, 5 um) without any workup to give the title product (254.2 mg, 52.17%) as a yellow oil with 90% purity, which was used in further experiments without additional purification. LCMS [M + 1] + 495.4

[0228] Step 2.4 Synthesis of tert-butyl rac-4-((5-fluoropyridin-3-yl)methyl)-4-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)piperidine-1-carboxylate [ka] tert-Butyl rac-4-[(5-fluoro-3-pyridyl)methyl]-4-[[2-hydroxy-3-(1-piperidyl)propoxy]carbamoyl]piperidine-1-carboxylate (254.2 mg, 0.463 mmol, 1 eq) was dissolved in dry THF (5 mL) and then triphenylphosphane (242.65 mg, 0.925 mmol, 2 eq) was added to the resulting solution followed by diisopropyl azodicarboxylate (DIAD) (187.07 mg, 0.925 mmol, 2 eq). The reaction mixture was left stirring at ambient temperature overnight. After 12 h, the reaction mixture was concentrated under reduced pressure to give a yellow colored oily residue (705 mg). The resulting crude material was purified by preparative HPLC (50-85%, 0-6 min, water-methanol, flow rate: 30 ml / min (loading pump 4 ml / min methanol), target mass 477, column: SunFireC18 100×19 mm 5 um) to give the title product as a yellow oil (129 mg, 53.84%) which was used without further purification. LCMS [M + 1] + 477.2

[0229] Step 2.5 Synthesis of rac-3-(4-((5-fluoropyridin-3-yl)methyl)piperidin-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID528 [ka] tert-Butyl rac-4-[(5-fluoro-3-pyridyl)methyl]-4-[5-(1-piperidylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl]piperidine-1-carboxylate (129 mg, 0.249 mmol, 1 eq) was dissolved in dry DCM (2 mL) followed by dropwise addition of 2,2,2-trifluoroacetic acid (308.6 mg, 2.49 mmol, 10 eq). The reaction mixture was left stirring at ambient temperature overnight. After 12 h, the reaction mixture was concentrated under reduced pressure to give a yellow colored oily residue which was diluted with DCM (10 mL) and washed with 30% aqueous potassium carbonate (2×10 mL). The organic layer was isolated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude product residue (120 mg, pale yellow oil). The resulting residue was subjected to preparative HPLC (95-95-75%, 0-1-6 min, water-acetonitrile, flow rate: 30 ml / min (loading pump 4 ml / min acetonitrile), target mass 377, column Uptisphere Strategy HILIC-HIA 100×21.2 mm 5 um) to give the title product (94.1 mg, 95.35%). LCMS [M + 1] + 377.4. 1 H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 7.23 - 7.17 (m, 1H), 4.37 - 4.28 (m, 1H), 4.04 (dd, J = 11.5, 2.7 Hz, 1H), 3.69 (dd, J = 11.7, 6.4 Hz, 1H), 3.14 (d, J = 12.8 Hz, 2H), 2.96 (t, J = 11.9, 11.9 Hz, 2H), 2.82 (s, 2H), 2.46 (d, J = 5.9 Hz, 2H), 2.44 - 2.33 (m, 4H), 2.22 - 2.11 (m, 2H), 1.79 - 1.62 (m, 2H), 1.59 - 1.48 (m, 4H), 1.47 - 1.35 (m, 2H).

[0230] Synthesis of rac-3-(4-((2-methylpyridin-3-yl)methyl)piperidin-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID561 [ka] rac-3-(4-((2-methylpyridin-3-yl)methyl)piperidin-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (153.1 mg, 76.34%) as a yellow oil was prepared from commercially available 1-(tert-butyl)4-ethyl piperidine-1,4-dicarboxylate following the synthesis described in 2.1-2.5 but using 3-(chloromethyl)-2-methyl-pyridine hydrochloride instead of 3-(bromomethyl)-5-fluoro-pyridine hydrobromide in experimental procedure 2.1. LCMS [M+1] + 373.2. 1 H NMR (400 MHz, CD3OD) δ 8.30 (d, J = 4.4 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.27 - 7.13 (m, 1H), 4.43 - 4.32 (m, 1H), 4.12 (dd, J = 11.7, 3.1 Hz, 1H), 3.61 (dd, J = 11.5, 7.5 Hz, 1H), 3.00 - 2.80 (m, 4H), 2.80 - 2.61 (m, 2H), 2.59 - 2.47 (m, 4H), 2.46 - 2.26 (m, 5H), 2.23 - 1.99 (m, 2H), 1.65 - 1.48 (m, 6H), 1.48 - 1.38 (m, 2H).

[0231] Synthesis of rac-5-(piperidin-1-ylmethyl)-3-(3-(pyridin-3-ylmethyl)pyrrolidin-3-yl)-5,6-dihydro-1,4,2-dioxazine, ID643 [ka] rac-5-(piperidin-1-ylmethyl)-3-(3-(pyridin-3-ylmethyl)pyrrolidin-3-yl)-5,6-dihydro-1,4,2-dioxazine (17.8 mg, 26.95%) as a yellow oil was prepared from commercially available 1-(tert-butyl)3-methyl pyrrolidine-1,3-dicarboxylate following the synthesis described in 2.1-2.5 but using 3-(chloromethyl)pyridine hydrochloride instead of 3-(bromomethyl)-5-fluoro-pyridine hydrobromide in experimental procedure 2.1. LCMS [M+1] + 345.4. 1 H NMR (400 MHz, CD3OD) δ 8.49 (d, J = 3.2 Hz, 1H), 8.45 (s, 1H), 7.77 (t, J = 6.3, 6.3 Hz, 1H), 7.48 - 7.40 (m, 1H), 4.77 - 4.67 (m, 1H), 4.15 - 4.08 (m, 1H), 3.78 - 3.61 (m, 2H), 3.56 - 3.46 (m, 1H), 3.41 - 3.34 (m, 1H), 3.33 - 3.30 (m, 2H), 3.28 - 3.19 (m, 2H), 3.17 - 3.09 (m, 1H), 3.00 - 2.89 (m, 2H), 2.87 - 2.81 (m, 3H), 2.58 - 2.47 (m, 1H), 2.18 - 2.05 (m, 1H), 1.82 - 1.69 (m, 4H), 1.66 - 1.52 (m, 2H).

[0232] Synthesis of rac-5-(piperidin-1-ylmethyl)-3-(4-(pyridin-3-ylmethyl)piperidin-4-yl)-5,6-dihydro-1,4,2-dioxazine, ID550 [ka] rac-5-(piperidin-1-ylmethyl)-3-(4-(pyridin-3-ylmethyl)piperidin-4-yl)-5,6-dihydro-1,4,2-dioxazine (100 mg, 83.07%) as a yellow oil was prepared from commercially available 1-(tert-butyl)4-ethyl piperidine-1,4-dicarboxylate following the synthesis described in 2.1-2.5 but using 3-(chloromethyl)pyridine hydrochloride instead of 3-(bromomethyl)-5-fluoro-pyridine hydrobromide in experimental procedure 2.1. LCMS [M+1] + 359.4. 1 H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 4.2 Hz, 1H), 8.37 (s, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.22 - 7.18 (m, 1H), 4.37 - 4.28 (m, 1H), 4.05 (dd, J = 11.6, 2.5 Hz, 1H), 3.68 (dd, J = 11.5, 6.5 Hz, 1H), 3.23 (d, J = 12.4 Hz, 2H), 3.08 - 2.97 (m, 2H), 2.87 - 2.78 (m, 2H), 2.45 (d, J = 6.0 Hz, 2H), 2.44 - 2.30 (m, 5H), 2.21 (d, J = 13.8 Hz, 2H), 1.83 (t, J = 13.7, 13.7 Hz, 2H), 1.61 - 1.45 (m, 5H), 1.43 - 1.35 (m, 2H).

[0233] Synthesis of rac-3-(4-((1-methyl-1H-pyrazol-5-yl)methyl)piperidin-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID547 [ka] rac-3-(4-((1-methyl-1H-pyrazol-5-yl)methyl)piperidin-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (36.9 mg, 90.21%) as a yellow solid was prepared from commercially available 1-(tert-butyl)4-ethyl piperidine-1,4-dicarboxylate by following the synthesis described in 2.1-2.5 but using 5-(chloromethyl)-1-methyl-1H-pyrazole hydrochloride instead of 3-(bromomethyl)-5-fluoro-pyridine hydrobromide in experimental procedure 2.1. LCMS [M+1] + 362.2. 1 H NMR (400 MHz, DMSO-d6) δ 7.38 - 7.31 (m, 1H), 6.06 - 6.00 (m, 1H), 4.29 - 4.21 (m, 1H), 4.07 - 3.98 (m, 1H), 3.76 (s, 3H), 3.62 (dd, J = 10.9, 7.3 Hz, 1H), 2.90 - 2.82 (m, 2H), 2.81 - 2.73 (m, 4H), 2.47 - 2.35 (m, 4H), 2.35 - 2.25 (m, 3H), 2.11 - 2.02 (m, 2H), 1.49 - 1.46 (m, 3H), 1.42 - 1.31 (m, 5H).

[0234] Synthesis of rac-5-(piperidin-1-ylmethyl)-3-(quinuclidin-4-yl)-5,6-dihydro-1,4,2-dioxazine, ID642 [ka] rac-5-(piperidin-1-ylmethyl)-3-(quinuclidin-4-yl)-5,6-dihydro-1,4,2-dioxazine (149 mg, 34.76%) as a beige solid was prepared from commercially available quinuclidine-4-carboxylic acid according to the synthesis described in 2.3-2.4. LCMS [M + 1] + 294.2. 1H NMR (400 MHz, CD3OD) δ 4.86 - 4.84 (m, 2H), 4.50 - 4.40 (m, 1H), 4.05 (dd, J = 11.6, 3.0 Hz, 1H), 3.72 - 3.61 (m, 1H), 2.95 - 2.87 (m, 5H), 2.64 - 2.55 (m, 2H), 2.55 - 2.40 (m, 4H), 1.77 - 1.69 (m, 5H), 1.66 - 1.54 (m, 4H), 1.51 - 1.40 (m, 2H).

[0235] Synthesis of rac-3-(1-azabicyclo[2.2.1]heptan-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID641 [ka] rac-3-(1-azabicyclo[2.2.1]heptan-4-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (79.6 mg, 62.86%) as a yellow oil was prepared from commercially available 1-azabicyclo[2.2.1]heptane-4-carboxylic acid according to the synthesis described in 2.3-2.4. LCMS [M + 1] + 280.2. 1 H NMR (400 MHz, CD3OD) δ 4.68 - 4.60 (m, 1H), 4.18 (dd, J = 11.8, 2.9 Hz, 1H), 3.81 (dd, J = 11.7, 6.3 Hz, 1H), 3.58 - 3.43 (m, 2H), 3.31 - 3.25 (m, 4H), 2.76 (d, J = 5.7 Hz, 2H), 2.74 - 2.59 (m, 4H), 2.34 - 2.21 (m, 2H), 2.07 - 1.89 (m, 2H), 1.73 - 1.61 (m, 4H), 1.60 - 1.45 (m, 2H).

[0236] Synthesis of rac-3-(1-azabicyclo[3.2.1]octan-5-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID553 [ka] rac-3-(1-azabicyclo[3.2.1]octan-5-yl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (1185 mg, 28.04%) was prepared as a yellow oil from commercially available rac-1-azabicyclo[3.2.1]octane-5-carboxylic acid according to the synthesis described in 2.3-2.4. LCMS [M + 1] + 294.2 1 H NMR (400 MHz, CDCl3) δ 4.39 - 4.23 (m, 1H), 4.05 (d, J = 11.4 Hz, 1H), 3.75 - 3.59 (m, 1H), 3.07 - 2.97 (m, J = 11.6, 5.7 Hz, 1H), 2.91 - 2.57 (m, 6H), 2.55 - 2.42 (m, 4H), 2.36 (s, 2H), 2.05 - 1.92 (m, J = 11.7 Hz, 1H), 1.87 - 1.64 (m, 4H), 1.53 - 1.47 (m, 3H), 1.46 - 1.31 (m, 3H).

[0237] Synthesis of rac-5-(piperidin-1-ylmethyl)-3-(quinuclidin-3-yl)-5,6-dihydro-1,4,2-dioxazine, ID644 [ka] rac-5-(piperidin-1-ylmethyl)-3-(quinuclidin-3-yl)-5,6-dihydro-1,4,2-dioxazine (151.4 mg, 20.82%) was prepared as a yellow oil from commercially available rac-quinuclidine-3-carboxylic acid according to the synthesis described in 2.3-2.4. LCMS [M + 1] + 294.2. 1H NMR (400 MHz, CD3OD) δ 4.55 - 4.46 (m, 1H), 4.17 - 4.08 (m, 1H), 3.74 (dd, J = 11.5, 6.4 Hz, 1H), 3.20 - 3.14 (m, 1H), 3.01 - 2.72 (m, 5H), 2.66 - 2.56 (m, 3H), 2.56 - 2.43 (m, 5H), 2.09 - 2.04 (m, 1H), 1.91 - 1.78 (m, 1H), 1.73 - 1.69 (m, 1H), 1.64 - 1.58 (m, 4H), 1.51 - 1.42 (m, 3H).

[0238] Synthesis of rac-5-(piperidin-1-ylmethyl)-3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-7-yl)-5,6-dihydro-1,4,2-dioxazine, ID655 [ka] rac-5-(piperidin-1-ylmethyl)-3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-7-yl)-5,6-dihydro-1,4,2-dioxazine (54 mg, 7.76%) as a yellow oil was prepared from commercially available rac-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-7-carboxylic acid according to the synthesis described in 2.3-2.4. LCMS [M + 1] + 305.2. 1H NMR (400 MHz, CD3OD) δ 7.52 (s, 1H), 6.69 (s, 1H), 4.60 - 4.46 (m, 1H), 4.33 - 4.21 (m, 1H), 4.20 - 4.07 (m, 1H), 4.05 - 3.92 (m, 1H), 3.79 - 3.66 (m, 1H), 3.12 - 3.02 (m, 1H), 2.88 - 2.81 (m, 1H), 2.81 - 2.73 (m, 1H), 2.64 - 2.56 (m, 2H), 2.55 - 2.46 (m, 3H), 2.31 - 2.21 (m, 1H), 2.09 - 1.98 (m, 1H), 1.68 - 1.54 (m, 4H), 1.53 - 1.40 (m, 2H), 1.28 - 1.23 (m, 1H).

[0239] Synthesis of rac-5-(piperidin-1-ylmethyl)-3-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-5,6-dihydro-1,4,2-dioxazine, ID660 [ka] rac-5-(piperidin-1-ylmethyl)-3-(5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)-5,6-dihydro-1,4,2-dioxazine (76 mg, 16.1%) as a yellow oil was prepared from commercially available rac-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-carboxylic acid according to the synthesis described in 2.3-2.4. LCMS [M + 1] + 305.2. 1H NMR (400 MHz, CD3OD) δ 6.94 (s, 1H), 6.87 (s, 1H), 4.57 - 4.47 (m, 1H), 4.19 - 4.08 (m, 2H), 4.02 - 3.92 (m, 1H), 3.73 (dd, J = 11.7, 6.5 Hz, 1H), 3.11 - 2.98 (m, 1H), 2.98 - 2.83 (m, 2H), 2.61 - 2.55 (m, 2H), 2.52 - 2.45 (m, 3H), 2.33 - 2.23 (m, 1H), 2.13 - 2.02 (m, 1H), 1.60 (p, J = 5.7, 5.7, 5.6, 5.6 Hz, 4H), 1.52 - 1.40 (m, 2H), 1.29 - 1.21 (m, 1H).

[0240] Synthesis of rac-N,N-dimethyl-3-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)propan-1-amine, ID768 [ka] rac-N,N-dimethyl-3-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)propan-1-amine (127 mg, 44.85%) was prepared as a yellow oil from commercially available 4-(dimethylamino)butanoic acid according to the synthesis described in 2.3-2.4. LCMS [M + 1] + 270.4. 1H NMR (methanol-d4, 400 MHz): δ (ppm) 4.56 - 4.47 (m, 1H), 4.11 (dd, J=11.6, 2.7 Hz, 1H), 3.73 (dd, J=11.6, 6.5 Hz, 1H), 2.58 (d, J=5.8 Hz, 2H), 2.57 - 2.41 (m, 4H), 2.41 - 2.34 (m, 2H), 2.26 (s, 6H), 2.25 - 2.15 (m, 2H), 1.85 - 1.72 (m, 2H), 1.67 - 1.56 (m, 4H), 1.54 - 1.41 (m, 2H).

[0241] Synthesis of rac-3-(2-(piperidin-1-yl)ethyl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID816 [ka] rac-3-(2-(piperidin-1-yl)ethyl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (62.8 mg, 32.09%) was prepared as a yellow oil from commercially available 3-(piperidin-1-yl)propanoic acid according to the synthesis described in 2.3-2.4. LCMS [M + 1] + 296.4. 1 H NMR (chloroform-d, 400 MHz): δ (ppm) 4.51 - 4.35 (m, 1H), 4.12 (d, J=13.6 Hz, 1H), 3.78 - 3.70 (m, 1H), 2.78 - 2.68 (m, 1H), 2.64 - 2.14 (m, 11H), 1.82 - 1.34 (m, 12H), 1.32 - 0.92 (m, 1H).

[0242] Synthesis of rac-3-(2-(4-methylpiperazin-1-yl)ethyl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID823 [ka] rac-3-(2-(4-methylpiperazin-1-yl)ethyl)-5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazine (72.9 mg, 35.96%) was prepared as a yellow oil from commercially available 3-(4-methylpiperazin-1-yl)propanoic acid according to the synthesis described in 2.3-2.4. LCMS [M + 1] + 311.4. 1 H NMR (methanol-d4, 400 MHz): δ (ppm) 4.54 - 4.46 (m, 1H), 4.11 (dd, J=11.6, 2.9 Hz, 1H), 3.74 (dd, J=11.6, 6.5 Hz, 1H), 2.63 (t, J=7.4, 7.4 Hz, 3H), 2.58 (d, J=5.8 Hz, 2H), 2.58 - 2.43 (m, 10H), 2.41 (t, J=7.4, 7.4 Hz, 3H), 2.29 (s, 3H), 1.68 - 1.59 (m, 4H), 1.53 - 1.42 (m, 2H).

[0243] Synthesis of rac-rel-cis-(3R,4R)-N,N-dimethyl-4-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)pyrrolidin-3-amine, ID766 [ka] In a generally similar manner with non-essential modifications, rac-rel-cis-(3R,4R)-N,N-dimethyl-4-(5-(piperidin-1-ylmethyl)-5,6-dihydro-1,4,2-dioxazin-3-yl)pyrrolidin-3-amine (18 mg, 46.12%) was obtained as a yellow oil from the starting rac-rel-cis-1-(tert-butoxycarbonyl)-4-((R)-dimethylamino)pyrrolidine-3-(R) carboxylic acid according to the syntheses described in 2.3-2.4. The synthesis of the starting building blocks is described above. LCMS [M + 1] + 297.4. 1H NMR (methanol-d4, 400 MHz): δ (ppm) 4.61 - 4.50 (m, 1H), 4.16 - 4.06 (m, 1H), 3.77 (dd, J=11.7, 6.2 Hz, 1H), 3.31 - 2.85 (m, 4H), 2.87 - 2.68 (m, 2H), 2.65 - 2.58 (m, 2H), 2.55 - 2.37 (m, 4H), 2.31 (s, 6H), 1.69 - 1.59 (m, 4H), 1.54 - 1.45 (m, 2H).

[0244] 3. General synthesis using base-induced cyclization from chloroamidoximes Synthesis of rac-3-(1-methylcyclobutyl)-5-(1-piperidylmethyl)-5,6-dihydro-1,4,2-dioxazine ID423 [ka] Step 3.1 Synthesis of N'-hydroxy-1-methyl-cyclobutanecarboxamidine [ka] 1-Methylcyclobutanecarbonitrile (5.0 g, 52.55 mmol, 1 eq), hydroxylamine hydrochloride (7.30 g, 105.11 mmol, 2 eq) and N,N-diethylethanamine (10.64 g, 105.11 mmol, 2 eq) were dissolved in 75 ml of IPA. The mixture was stirred at 60° C. for 36 h, after which the isopropanol was removed in vacuo. The crude product (21 g) was then purified by flash column chromatography to give 1.32 g of pure title compound. LCMS [M +H] + 129.2)

[0245] Step 3.2 Synthesis of rac-N'-[2-hydroxy-3-(1-piperidyl)propoxy]-1-methyl-cyclobutanecarboxamidine [ka] Sodium hydroxide (0.406 g (10.14 mmol, 1 eq), 4-azoniaspiro[3.5]nonan-2-ol chloride (1.80 g (10.14 mmol, 1 eq), and N'-hydroxy-1-methyl-cyclobutanecarboxamidine 1.30 g (10.14 mmol, 1 eq) were mixed in 50 ml of IPA and stirred at 60 °C for 36 h. The solution was filtered and the isopropanol removed in vacuo to give the crude title product (2.70 g), which was used without further purification. LCMS [M + 1] + 270.2.

[0246] Step 3.3 Synthesis of rac-(1Z)-N-[2-hydroxy-3-(1-piperidyl)propoxy]-1-methyl-cyclobutanecarboximidoyl chloride [ka] A mixture of N'-[2-hydroxy-3-(1-piperidyl)propoxy]-1-methyl-cyclobutanecarboxamidine (1.70 g, 5.68 mmol, 1 eq), tBuONO (1.76 g, 17.04 mmol, 3 eq), and CuCl2 (2.29 g, 17.04 mmol, 3 eq) in MeCN (50 ml) was stirred at room temperature for 2 days while protected from light. The reaction mixture was concentrated under vacuum and the remaining residue was suspended in 2.0 M aqueous sodium carbonate (50 ml) and extracted with AcOEt (2 x 30 ml). The combined organic fractions were dried over sodium sulfate, filtered and evaporated to give 1.3 g of the title compound as a yellow viscous oil, which was used in the next step without further purification. LCMS: [M + 1] + 289.2)

[0247] Step 3.4 Synthesis of rac-3-(1-methylcyclobutyl)-5-(1-piperidylmethyl)-5,6-dihydro-1,4,2-dioxazine, ID423 [ka] The above (1Z)-N-[2-hydroxy-3-(1-piperidyl)propoxy]-1-methyl-cyclobutanecarboximidoyl chloride (800 mg, 2.77 mmol, 1 eq) was dissolved in anhydrous tert-BuOH (30 ml) followed by potassium 2-methylpropan-2-olate (932 mg, 8.31 mmol, 3 eq). The reaction mixture was then heated to 80° C. and stirred overnight. After 24 hours, the reaction mass was concentrated to dryness, diluted with water (30 ml) and extracted with ethyl acetate (3×20 ml). The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give the crude product as a pale yellow oil (0.5 g). The crude product was purified by HPLC to give 67 mg of pure title compound. LCMS [M + 1] + 253.4. 1 H NMR (500 MHz, cdcl3) δ 4.47 - 4.34 (m, 1H), 4.20 - 4.06 (m, 1H), 3.81 - 3.70 (m, 1H), 2.61 - 2.49 (m, 4H), 2.48 - 2.37 (m, 4H), 2.05 - 1.93 (m, 1H), 1.91 - 1.74 (m, 3H), 1.63 - 1.55 (m, 4H), 1.50 - 1.42 (m, 2H), 1.38 (s, 3H).

[0248] Example 2: Determination of Dioxazine Potency and Efficacy Using the GCase Assay material The human fibroblast cell line GM10915, harboring the L444P GBA mutation, was obtained from Coriell Biorepositories.

[0249] 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).

[0250] Compounds tested for GCase activity were dissolved in H2O or DMSO.

[0251] 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 plated at 10 in 100 μL of complete medium in 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. 4 Cells were seeded at a density of 1000 x 1000 cells / well. Crystal violet staining is performed to obtain quantitative information regarding the relative density of cells attached to the multi-well plates.

[0252] Assay of GCase activity The assay was adapted from Sawkar et al (2002) and is briefly described below: The day after cells were seeded, the medium was replaced with fresh medium containing the compound to be tested. Compounds were tested in duplicate at a dose range of eight serial dilutions 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 the basal level of GCase activity.

[0253] The cells were washed three times with 200 μL of PBS per well, 50 μL of 2.5 mM 4-MUG buffer (4-MUG was 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.

[0254] Crystal violet staining Cells were treated with compounds in a parallel setup identical to the setup for testing GCase activity. After 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 of 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 dye. 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).

[0255] calculation The fluorescence signal (F) obtained from the GCase measurement is normalized relative to the absorbance signal (A) obtained from crystal violet staining. The percent GCase activity obtained from compound treatment is calculated relative to the basal activity obtained from untreated cells.

number

[0256] Effect EC 1.5 is determined as the concentration of "percent GCase activity" = 150%, which corresponds to a 1.5-fold induction of GCase activity based on the dose-response effect of the compound. The maximum effect (Emax) of the compound is determined from the dose-response effect as the maximum "percent GCase activity" achieved in the dose range tested.

[0257] [Table 2] TIFF2024537939000187.tif238159TIFF2024537939000188.tif227159TIFF2024537939000189.tif24 0159TIFF2024537939000190.tif231159TIFF2024537939000191.tif228159TIFF2024537939000192.t if229159TIFF2024537939000193.tif221159TIFF2024537939000194.tif216159TIFF20245379390001 95.tif240159TIFF2024537939000196.tif230159TIFF2024537939000197.tif231159TIFF2024537939 000198.tif231159TIFF2024537939000199.tif238159TIFF2024537939000200.tif224159TIFF202453 7939000201.tif239159TIFF2024537939000202.tif228159TIFF2024537939000203.tif216159TIFF20 24537939000204.tif242159TIFF2024537939000205.tif239159TIFF2024537939000206.tif237159TI FF2024537939000207.tif236159TIFF2024537939000208.tif230159TIFF2024537939000209.tif25159

[0258] conclusion This example demonstrates that the dioxazines 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 dioxazines of the present disclosure promising candidates for the treatment of GBA-mediated disorders.

Claims

1. Formula (Ib): 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2; R １ , R ２ , and R ３ are independently selected from the group consisting of hydrogen, alkyl, and halogen; Y is a nitrogen-containing ring or a nitrogen-containing chain; A is a monocyclic, bicyclic, or tricyclic ring, and A is sp ３ is attached to the remainder of the compound through a hybridized carbon; L is a C 1-6 alkyl linker or is absent, and when L is absent, A is directly attached to the cyclic oxime; A and Y are substituted or unsubstituted; A compound or a pharmaceutically acceptable salt thereof.

2. A is selected from the group consisting of monocyclic and bicyclic rings; (b) contains 1, 2, or 3 nitrogen atoms; and / or (c) contains 0, 1, 2, or 3 oxygen atoms; The compound of claim 1.

3. A is a compound of formula (II): 【Chemistry 2】 wherein: z １ and z ２ are independently selected from the group consisting of 0, 1, 2, and 3; Q is, 【Chemistry 3】 is selected from the group consisting of R ４ is selected from the group consisting of hydrogen, alkyl, amino, alkoxy, acyl, amido, aralkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; R ５ is selected from the group consisting of hydrogen, alkyl, aralkyl, hydroxy, alkoxy, and amino; Each R ６ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxy, amino, amido, and halogen; Each R ７ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxy, amino, amido, and halogen; Each R ８ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxy, amino, amido, and halogen; Each R ９ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxy, amino, amido, and halogen; The compound according to any one of claims 1 to 2.

4. The compound of any one of claims 1 to 2, wherein A is of formula (II) and Q is of formula (IIa).

5. L is of formula (III): 【Chemistry 4】 wherein: v is 0 or 1, and when v is 0, L is absent; Each R １０ are independently selected from the group consisting of hydrogen and alkyl; Each R １１ are independently selected from the group consisting of hydrogen and alkyl; R １０ and R １１ When both of R １０ and R １１ are combined to form C ３～６ Forming a ring, The compound according to any one of claims 1 to 2.

6. R ５ but, 【Chemistry 5】 or any tautomer thereof, wherein a is 0, 1, 2, or 3; X １ , X ２ , X ３ , X ４ , and X ５ are independently selected from the group consisting of C, CH, and N; each one, two, or three substituents (Subst.) are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, alkoxy, amino, amido, acyl, cycloalkyl, and heterocycloalkyl; The compound of claim 3.

7. A is of formula (II), L is of formula (III), and L-A is 【Chemistry 6】 【change】 【change】 【change】 The compound according to any one of claims 1 to 2, selected from the group consisting of:

8. A is, 【Chemistry 7】 The compound according to any one of claims 1 to 2, selected from the group consisting of:

9. The compound according to any one of claims 1 to 2, wherein Y is a nitrogen-containing ring, and said nitrogen-containing ring is monocyclic or bicyclic.

10. Y is, 【Chemistry 8】 The compound according to any one of claims 1 to 2, selected from the group consisting of:

11. The compound is 【Chemistry 9】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 The compound according to any one of claims 1 to 2, selected from the group consisting of:

12. The compound according to any one of claims 1 to 2, wherein the compound is a GBA inducer and increases glucocerebrosidase (GBA) enzyme levels and / or GBA enzyme activity.

13. A pharmaceutical for use in treating Parkinson's disease (PD) in a subject, comprising a compound according to any one of claims 1 to 2.

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