Preparation of Compounds and Compositions for Inhibiting the Activity of SHP2

Abstract

To provide a novel method of manufacturing (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, which has Src homology-2 phosphatase (SHP2) inhibitory action and is useful in treating various diseases, such as Noonan syndrome, LEOPARD syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and cancers of the breast, lung and colon.SOLUTION: A method of manufacturing a compound of the formula I is provided which comprises reacting a compound of the formula II with a compound of the formula III. (In the formulas, LG is Cl; A is Cl; m is 1; n is 1; and p is 2.)SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing a compound capable of inhibiting the activity of SHP2 and a method for producing a compound useful therein. This relates to intermediates. [Background technology]

[0002] Src homology-2 phosphatase (SHP2) regulates proliferation, differentiation, cell cycle maintenance, and migration. A non-receptor protein encoded by the PTPN11 gene contributes to multiple cellular functions, including SHP2 is a Ras mitogen-activated protein. kinase, JAK-STAT or phosphoinositol 3-kinase-AKT pathways Involved in signal transduction.

[0003] Formula I: [ka] Represented by (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridine) 4-(4-phenyl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro [4.5] The compound named decane-4-amine; and its pharma- ceutically acceptable salts. , which is described in the pamphlet of International Publication No. 2015 / 107495 A1 as an SHP2 inhibitor. Various therapeutic and treatment methods are also described.

[0004] Src homology-2 phosphatase (SHP2) regulates proliferation, differentiation, cell cycle maintenance, and migration. A non-receptor protein encoded by the PTPN11 gene contributes to multiple cellular functions, including SHP2 is a Ras mitogen-activated protein. kinase, JAK-STAT or phosphoinositol 3-kinase-AKT pathways Involved in signal transduction.

[0005] SHP2 contains two N-terminal Src homology 2 domains (N-SH2 and C-SH2), a catalytic The two SH2 domains are involved in the mitochondrial function of SHP2. The molecule regulates intracellular localization and function by binding to both N-SH2 and PTP domains. It exists in an inactive, autoinhibited conformation stabilized by a network of bonds involving residues For example, stimulation with cytokines or growth factors leads to exposure of the catalytic site, resulting in the S This results in the enzymatic activation of HP2.

[0006] Mutations in the PTPN11 gene and subsequently in SHP2 are responsible for several human diseases, e.g. For example, Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, and melanoma. It has been identified in ovarian tumors, acute myeloid leukemia, and cancers of the breast, lung, and colon. Therefore, SHP2 is a highly attractive target for the development of novel therapeutics for the treatment of various diseases. Compounds that can be prepared according to the present invention are small molecules that inhibit the activity of SHP2. Meet the need for.

[0007] WO 2015 / 107495 A1 describes the following reaction scheme: [ka] A process for the preparation of a compound of formula I is described, which can be characterized by:

[0008] The final compound obtained from step g above was then reacted as follows: [ka]

[0009] In this way, the compound of formula I is obtained (the last compound in the above scheme). The procedure requires at least nine steps as shown and is suitable for laboratory-scale synthesis.

[0010] This preparation is difficult, for example the diastereomeric Furthermore, many of the intermediates do not crystallize, so they require separation of the intermediates. It is necessary to use the higher purity without taking advantage of the higher purity.

[0011] In addition, a chromatography step is used in this process.

[0012] Furthermore, the aldehyde starting material for the reaction in Scheme 1 above is a compound known from the literature. However, it is not available in large quantities (e.g., commercially available from Aldlab Chemicals). (usually up to gram scale), which exhibits some inherent instability, so it is important to Advantageously, the synthesis can be carried out in large scale, for example in kilogram or larger quantities. A large amount is needed.

[0013] Further cyclization (step d in Scheme 1) involves the educt of the desired product, the tosylate, It has only moderate yields and further impurities are present, necessitating separation.

[0014] The ketone substrate product of step e of scheme 1) is obtained by condensing the enantiopure aldehyde starting material Even when used, it is partially racemized and step f (actually two steps, reduction and condensation) This resulted in the formation of four diastereomers in the 95:5 ratio of the two main This would result in the desired diastereomers, which would require further separation.

[0015] Further, the synthesis can be carried out according to the following scheme: [ka] As shown in Figure 1, it contains many oily intermediates and is therefore not ideal for purification.

[0016] Thus, although this process is particularly feasible on a laboratory scale, it is not feasible for larger scale manufacturing. is not ideal.

[0017] The compound added in reaction b in Scheme 2 is the compound disclosed in International Publication No. 2015 / 11074. According to the brochure No. 95 A1, this is obtained as "Intermediate 10" as follows: [ka]

[0018] This synthesis is feasible, but the amination step "a" only results in moderate yields (e.g., about 30-40%). 0%), some correction would be desirable. Summary of the Invention [Means for solving the problem]

[0019] In one aspect, the present invention provides a compound of formula I as described above, or a pharma- ceutically acceptable salt thereof. The present invention provides a method for producing an acid co-crystal, hydrate, or other solvate.

[0020] In a further aspect, the present invention relates to a compound of formula I as described above, or a pharma- ceutically acceptable salt thereof. The present invention relates to a method for preparing a salt, acid co-crystal, hydrate or other solvate of a compound according to the present invention, the method comprising the steps of: M: [ka] wherein LG is a leaving group, A is an anion of a protonic acid, and the salt of formula II is n, m and p are integers, preferably 1, 2 or 3, so that the compound is completely neutral. For example, m is 1, n is 1, and p is 2, and the compound of formula II is wherein the compound of formula II is preferably Preferably, the compound is of formula IV: [ka] (i) deprotecting or (ii) reducing the R1 is a secondary amino protecting group, R2 is a protected amino group, and R3 is hydrogen. or in the case of (ii), R1 is a secondary amino protecting group, R2 is amino, and R 3 is hydroxyl), and if necessary (i.e., an acid is added, e.g., for deprotection). (if not already present) to obtain a compound of formula III: [ka] Formula H n A is reacted with an acid to give a compound of formula II.

[0021] (i) and (ii) described immediately above and as a second preferred embodiment of the present invention In both cases, the preparation of the compound of formula II is carried out in a first step, preferably followed by the following In a further step defined by a further embodiment according to the invention defined in Compound of Formula V: [ka] (wherein R1 is a secondary amino protecting group and R4 is a carboxyl (-COOH) protecting group. In the presence of a strong base, L-lactide having the following formula: [ka] to produce a compound of formula VI: [ka] wherein R1 is as defined for compounds of formula IV and R5 is unsubstituted or or substituted alkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or substituted aryl. or formula VI * Compounds of: [ka] wherein R1 is as defined for the compound of formula IV.

[0022] Each of these two reaction variants is itself an embodiment of the present invention.

[0023] As a further embodiment of the present invention, or preferably as a further step, The compound of formula VI is cyclized with hydroxylamine, or a salt thereof, or the compound of formula V is I * The compound can be cyclized with hydroxylamine, or a salt thereof, to give the hydroxylamine of formula VII, Hydroxylamine compounds: [ka] where R1 is as defined for compounds of formula IV is obtained.

[0024] As a further embodiment of the present invention, or preferably in a further step, a compound of formula VII The compound is (ai) hydrogenated to produce an amino compound of formula VIII: [ka] where R1 is as defined for compounds of formula IV, or (a-ii) acylated under reducing conditions to give a compound of formula VIII * Compounds of: [ka] wherein R1 is as defined for compounds of formula IV; * R2 is acylated Amino (=acyl-protected amino) is obtained.

[0025] In another preferred embodiment of the present invention, or preferably, the reaction (a In a further step after -i), the compound of formula VIII is (bi) reduced to give Compound X: [ka] where R1 is as defined for the compound of formula IV, The product is a compound of formula IV, wherein R1 is a secondary amino protecting group and R2 is amino; R3 is hydroxyl; wherein the above pairs are included in the definition of the compound of formula IX. The reduction step (ii) described for the corresponding compound of formula IV is preferably carried out by itself As an embodiment of the present invention, or more preferably, in a further step, The reaction was carried out using ruthenium silane, and the reaction was carried out according to the formula H n After the subsequent addition of the acid A, A compound of formula II is obtained; or (ci) as an embodiment of the invention in itself or, preferably, as a further In step 2, a compound of formula X is reacted with a compound which inserts an amino protecting group to produce a compound of formula X: [ka] wherein R1 is as defined for compounds of formula IV and R2 is a protected is an amino group), and the compound of formula X can be represented as an embodiment of the present invention in its own right by Or preferably in a further step, a compound of formula XI: [ka] wherein R1 is as defined for compounds of formula IV and R2 is a protected The compound of formula XI is itself an embodiment of the present invention. Alternatively, or preferably in a further step, the hydroxy of the hydroxymethyl group (directly attached to the ring) is In the formula LG * A leaving group forming agent of -X (wherein LG * But it is combined X is an electrophilic group capable of forming a leaving group LG2 with the hydroxyl group to be added, ) to give a compound of formula XII: [ka] wherein R1 is as defined for compounds of formula IV and R2 is a protected LG2 is the leaving group); The compound of formula XII can then be used as an embodiment of the invention per se or preferably In a further step, cyclization under basic conditions gives a compound of formula XIII: [ka] where R1 is a secondary amino protecting group and R2 is a protected amino group. This is a compound of formula IV, where R1 is a secondary amino protecting group and R2 is a protected and R3 is hydrogen), wherein the above-mentioned The deprotection step (i) described for the corresponding compound of formula IV preferably proceeds by itself As an embodiment of the present invention, or more preferably in a further step, a compound of formula II Acid H as defined for the compound n A to form a compound of formula II as described above. You get something.

[0026] In another preferred embodiment of the present invention, or preferably, the reaction (a-ii) In a further step after the step of * The compound (b-ii) is a compound of itself. As an embodiment of the invention, or preferably as a further step, the chiral hydrogenation catalyst is hydrogenated in the presence of * Compounds of: [ka] wherein R1 is as defined for compounds of formula IV; * R2 is acylated amine group) is obtained, and a compound of formula X * The compound of formula (I) is as an embodiment of the present invention itself: Or preferably in a further step, * Compounds of: [ka] wherein R1 is as defined for compounds of formula IV; * R2 is acylated is reduced to the amine group; Formula XI * The compounds of formula (I) are suitable for use as embodiments of the present invention in their own right or preferably as further In the step of reacting the hydroxymethyl group with the hydroxy group (formula XI * Directly bonded to the middle ring In the formula LG * -X leaving group forming agent (wherein LG * However, the hydrochloride to which it is attached X is an electrophilic group capable of forming a leaving group LG2 with alkoxy, and X is a halogen. ) to give the compound of formula XII * Compounds of: [ka] wherein R1 is as defined for compounds of formula IV and R2 is a protected amino group and LG2 is the leaving group); Next, Equation XII * The compound of formula (I) is preferably used as an embodiment of the present invention in its own right. In a further step, the compound of formula XIII is cyclized under basic conditions to give * Compounds of: [ka] (Wherein R1 is a secondary amino protecting group; * R2 is an acylated amino group) This can be achieved by preparing a compound of formula IV, where R1 is a secondary amino protecting group and R2 is an acylated (=acyl-protected) amino group, R3 being hydrogen); II * of the compound of formula (i) as described above for the corresponding compound of formula IV. (In this specification, deprotection means deacylation) is preferably carried out in accordance with the present invention itself. In an obvious embodiment, or more preferably in a further step, a compound of formula II Acid H as defined for n A to give the compound of formula II shown above. can be.

[0027] Each of the following novel intermediates is also an embodiment of the present invention.

[0028] Compounds of Formula II (salts): [ka] where A is the anion of a protonic acid, in particular Cl, and the salt of formula II is electrically neutral. Thus, n, m and p are integers, preferably 1, 2 or 3, and in particular where n and where m is 1 and p is 2.

[0029] Compound of formula VI: [ka] wherein R1 is a secondary amino protecting group, particularly tert-butyloxycarbonyl, and R 5 is unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, or unsubstituted or Most commonly substituted aryl, especially ethyl.

[0030] Equation VI * Compounds of: [ka] where R1 is a secondary amino protecting group, particularly tert-butoxycarbonyl.

[0031] Compound of formula VII: [ka] where R1 is a secondary amino protecting group, particularly tert-butoxycarbonyl.

[0032] Compound of formula VIII: [ka] where R1 is a secondary amino protecting group, particularly tert-butoxycarbonyl.

[0033] Compound of formula IX: [ka] where R1 is a secondary amino protecting group, particularly tert-butoxycarbonyl.

[0034] Formula VIII * Compounds of: [ka] wherein R1 is a secondary amino protecting group, in particular tert-butoxycarbonyl; * R2 but are acylated amino, especially acetylamino).

[0035] formula * Compounds of: [ka] wherein R1 is a secondary amino protecting group, in particular tert-butoxycarbonyl; * R2 but are acylated amino, especially acetylamino).

[0036] Formula XI * Compounds of: [ka] wherein R1 is a secondary amino protecting group, in particular tert-butoxycarbonyl; * R2 but are acylated amino, especially acetylamino).

[0037] Formula XII * Compounds of: [ka] wherein R1 is a secondary amino protecting group, in particular tert-butoxycarbonyl; * R2 is an acylated amino, particularly acetylamino, and LG2 is a leaving group, particularly toluenesulfonyl. (It is phenyloxy).

[0038] Formula XIII * Compounds of: [ka] wherein R1 is a secondary amino protecting group, in particular tert-butoxycarbonyl; * R2 is an acylated amino group, especially acetylamino).

[0039] Compound of formula X: [ka] wherein R1 is a secondary amino protecting group, particularly tert-butoxycarbonyl, and R2 is , a protected amino group, particularly tert-butoxycarbonylamino).

[0040] Compound of formula XI: [ka] wherein R1 is a secondary amino protecting group, particularly tert-butoxycarbonyl, and R2 is , a protected amino group, particularly tert-butoxycarbonylamino).

[0041] Compound of formula XII: [ka] wherein R1 is a secondary amino protecting group, particularly tert-butoxycarbonyl, and R2 is , a protected amino group, specifically tert-butoxycarbonylamino, and LG2 is eliminated. groups, particularly toluenesulfonyloxy).

[0042] Compound of formula XIII: [ka] wherein R1 is a secondary amino protecting group, particularly tert-butoxycarbonyl, and R2 is , a protected amino group, particularly tert-butoxycarbonylamino).

[0043] The compounds described may be used in free form or in combination with salt-forming groups (imido groups), to name just a few examples. When present, the salt form, particularly an acid addition salt, such as a halogenated hydroxyl group, is used. salts with inorganic acids such as HCl, sulfuric acid or phosphoric acid, and / or sulfonic acids, e.g. For example, methylsulfonic acid, ethylsulfonic acid, or toluenesulfonic acid, phosphonic acid Salts with organic acids such as acids or carboxylic acids, for example alkanoic acids, for example acetic acid or citric acid. It can exist as: DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0044] The following definitions are intended to define the more general features in a preferred and more specific manner. , one, two or more or all of the more general features of the variants of the invention = embodiments of the invention may be It is possible to substitute more specific definitions that define more specific embodiments of the invention. be.

[0045] The conditions for the above mentioned reactions are in particular selected as follows:

[0046] Reaction of compound II with a compound of formula III, wherein LG is a leaving group, preferably halo, In particular, the chloro or bromo moieties are preferably reacted at elevated temperatures, for example from 30° C. to the boiling point of the reaction mixture. in the range from 50 to 100°C, for example, in aprotic solvents such as N,N-alkanoic acids in a dialkylamide, such as dimethylacetamide or dimethylformamide, The reaction is preferably carried out in the presence of a base such as an alkali metal carbonate or metal hydrogen carbonate.

[0047] Reacting a compound of formula IV, where R1 is a secondary amino protecting group, to give a compound of formula II. (i) is deprotected by heating at 10° C., where R2 is a protected amino group and R3 is hydrogen. to the boiling point of the solvent, e.g., 20°C to 115°C (especially when R2 is acyl). At a preferred temperature, a solvent, such as an alcohol or a mixture of alcohols (particularly where R2 is benzyloxycarbonyl or especially alkoxycarbonyl, for example tert-butoxycarbonyl In the case of 1, the strong acid H n A, e.g., trifluoroacetic acid, trifluoromethane sulfonic acid or preferably an inorganic acid, such as sulfuric acid, phosphoric acid or especially a hydrogen halide, most especially In the presence of hydrogen chloride or water (especially when R2 is acyl, especially lower alkanoyl, e.g. It is preferably carried out in the presence of ethyl acetate (in which case it is cetyl).

[0048] A compound of formula IV, wherein R1 is a secondary amino protecting group, R2 is amino, and R3 is The alternative reduction (ii) of 2-(2-phenylpropanediol) (wherein 2-phenylpropanediol is a hydroxyl group) can be carried out in a suitable aprotic solvent, e.g. A strong inorganic acid or preferably a (strong) organic acid, especially trifluoroacetate, in ether or especially acetonitrile, In the presence of fluoromethanesulfonic acid, trialkylsilanes, particularly triethylsilane, were used. The reaction is preferably carried out with acid H n Subsequent addition of A produces a compound of formula II (salt or co-crystal) is obtained.

[0049] Formula VI or VI * The reaction of the compound of formula V with L-lactide to give a compound of formula Preferably, the reaction is carried out at low temperatures, for example in the range of -80 to -5°C, in a solvent, for example an acyclic or, in particular, a cyclic olefin. in ether, preferably tetrahydrofuran, with a strong base, in particular an alkyl-alkali metal, e.g. For example, n-butyllithium, and nitrogen bases, especially diisopropylamine or diethylamine. When the reaction is carried out at approximately -80°C, the result is a compound of formula VI If the reaction is carried out while increasing the temperature to approximately -5°C, the result is , Formula VI * It is a compound of the formula:

[0050] Cyclization of a compound of formula VI with hydroxylamine or a salt thereof, or synthesis of a compound of formula VII to the compound of formula VI * The reaction of the compound with hydroxylamine or its salt is At a preferred temperature in the range of 0 to 80°C, for example 10 to 50°C, a polar organic solvent, for example a In an alcohol, such as an alkanol, for example methanol or ethanol, a weak base, for example of hydroxylamine in the presence of an alkali metal alkanoate, e.g. sodium acetate. It is preferably carried out using an acid addition salt thereof, such as a hydrohalide salt thereof, such as a hydrochloride salt thereof. .

[0051] Hydrogenation of the hydroxylamine compound of formula VII to the corresponding amine of formula VIII (a -i) is a hydrogenation catalyst, such as platinum, palladium, rhodium or ruthenium, or Operates on lower temperatures (e.g. 0-40°C) and lower pressures (e.g. 1 bar) of H2 or other highly active catalysts, or at high temperatures and, for example, at 5 to 50 bar, e.g., 10 to 20 bar. At higher H2 pressures in the range, non-precious metal catalysts, especially nickel (Raney Nickel and Urushibara Nickel), It is preferably carried out as a heterogeneous hydrogenation in the presence of a catalyst based on nickel or the like. The reaction is carried out in a polar solvent, particularly an alcohol, such as an alkanol, for example ethanol or The reaction is carried out in methanol.

[0052] Formula VIII * Acylation of a hydroxyl compound of formula VII under reducing conditions to a compound of formula (a-ii) is preferably in the range of from 25° C. to the boiling point of the reaction mixture, for example 40 to 8 At elevated temperatures in the range of 0° C., inert organic solvents, such as hydrocarbons or aromatics, e.g. toluene. In benzene or xylylene, base metals such as zinc (e.g. zinc amalgam) are used as reducing agents. such as fluorine, and in particular iron, and acids, inorganic acids, such as hydrogen halides, e.g. hydrogen chloride, sulfuric acid, or an organic acid, such as a carboxylic acid corresponding to the anhydride, in particular an alkanoic acid, in particular acetic acid in the presence of an acylating agent, in particular an anhydride of a carboxylic acid, such as an alkanoic anhydride, in particular It is preferably carried out in the presence of acetic acid.

[0053] Acyl, in the context of the present invention, is the acyl rest itself, which is a carboxyl (- COOH) group, not on oxygen (such as tert-butoxycarbonyl), It refers to the part of an organic acid that is bonded to a carbon (for example, acetyl = H3CCOO-).

[0054] The reduction (bi) of the compound of formula VIII to the compound of formula IX is preferably carried out at a temperature of -100 At low temperatures in the range of -20°C, e.g. -80°C to -70°C, aprotic solvents such as ether In a cyclic ether, such as tetrahydrofuran, the oxo in formula VIII is reacted with A complex hydride that reduces the hydroxyl in IX, such as diisobutylaluminum hydride. This is preferably carried out using a

[0055] Next, the compound of formula IX corresponding to each compound of formula IV is reacted with the compound of formula I When the compound of formula I is reduced, the reduction is preferably carried out at a temperature of from 30° C. to the boiling point of the reaction mixture. At high temperatures, for example in the range of 50 to 95°C, aprotic solvents, such as hydrocarbons, esters or is particularly preferred in nitriles, e.g. acetonitrile, with acids, especially strong organic sulfonic acids, e.g. trifluoro In fluoromethanesulfonic acid, trialkylsilanes, especially triethylsilane, are used. This is often done. n Subsequent reaction with A in a protic, potentially aqueous solvent, e.g. It is preferably carried out in isopropyl alcohol.

[0056] Amino group inserting agents, especially dialkanoyl dicarbonates, especially di-tert-butyl dicarbonate (=B The reaction of the compound of formula VIII (ci) with the anhydride (oc) is carried out at a temperature of 0 to 50° C., for example at 20 to 40° C. At a preferred temperature in the range of 30° C., aprotic solvents, particularly halogenated hydrocarbons, such as dihydrocarbons, Tertiary amines, such as trialkylamines, especially diisopropyl ether, in chloromethane The reaction is preferably carried out in the presence of ethylamine to give a compound of formula X.

[0057] The reduction of the compound of formula X to the compound of formula XI is preferably carried out at a temperature of 0 to 50° C., for example at 20 to 40° C. At a temperature in the range of 30° C., an aprotic solvent, such as a linear ether or preferably a cyclic ether, is used. In an ether, such as tetrahydrofuran, the two hydroxy groups are used to prepare the lactone of formula X. A complex hydride, such as a boron hydride, capable of reducing the aryl group to the ring-opening of formula XI. It is preferably carried out in the presence of lithium.

[0058] a leaving group forming agent LG to give a compound of formula XII * -X (wherein X is a halogen, Especially Chloro, LG * However, together with the hydroxyl to which it is attached, the leaving group LG2, specifically to form a sulfonyl halide, preferably toluenesulfonyl chloride, a compound of formula XI, which results in the introduction of a leaving group of formula LG2 using a compound of formula XI, which is a possible electrophilic group The reaction is carried out at a preferred temperature in the range of 0 to 50°C, e.g. 20 to 30°C, in an aqueous organic solvent, e.g. For example, in an aqueous halogenated hydrocarbon, such as dichloromethane, a base, such as an alkali metal ion It is preferably carried out in the presence of an oxide, for example sodium hydroxide.

[0059] At a preferred temperature in the range of 0 to 50° C., for example 20 to 30° C., an aqueous organic solvent, for example an aqueous In a halogenated hydrocarbon, such as dichloromethane, a base, in particular an alkali metal hydroxide, e.g. In the presence of a phase transfer catalyst, such as tetraalkylammonium halide, In the presence of a halogenide, such as tetra-n-butylammonium bromide, under basic conditions Cyclization of the compound of formula XII to the compound of formula XIII in

[0060] The deprotection of the compound of formula XIII can be carried out at a preferred temperature ranging from 0 to 50° C., for example from 20 to 30° C. at 100° C. in the presence of an amine base, such as isopropylamine, in a polar solvent, such as an alcohol , for example in an alkanol, such as ethanol or, in particular, methanol, to obtain a salt of formula II Acid H, which is part of n A is preferably used.

[0061] For example, chiral hydrogenation catalysts (usually based on, for example, ruthenium(I)) as defined below. Precatalysts based on bis(norbornadiene)rhodium(I) tetrafluoroborate and a chiral ligand, * to a compound of formula VII I * The hydrogenation of the compound is preferably carried out at a temperature ranging from 30 to 80° C., for example from 40 to 60° C. in a polar solvent, in particular 2,2,2-trifluoroethanol, for example at 3 to 50 bar, It is preferably carried out using hydrogen under high pressure, for example in the range of 20 to 40 bar. Hydrogenation is more generally carried out in the presence of a transition metal catalyst, preferably an organometallic complex and a chiral The reduction is carried out with hydrogen in the presence of a transition metal catalyst containing a ligand. The hydrogenation may be carried out under homogeneous hydrogenation conditions, preferably under homogeneous hydrogenation conditions. Thus, the transition metal catalyst is, for example, cobalt (Co ), Rhodium (Rh), Iridium (Ir), Nickel (Ni), Palladium (Pd) and and / or platinum (Pt).

[0062] Among the chiral catalysts, those of formula X * To generate the stereochemistry at the double bond in front of , formula VIII* are suitable all which allow hydrogenation of the double bond in the compound It is further preferred that the chiral ligand comprises a chiral ferrocene.

[0063] Preferred chiral ferrocenes have the formula: [ka] For example, the following formula: [ka] Any one of the others is also possible.

[0064] Mixtures of two or more such ligands, in particular those defined by the above formula, are also possible. It is Noh.

[0065] Typically, the active catalyst has a molecular weight of 0.9 to 1.2, preferably 1.0 to 1.1, and more preferably 1.0 to 1.05 moles of chiral ligand were added to 1.0 mole of transition metal catalyst. For example, when a dimeric transition metal catalyst is used, In this case, preferably, two moles of chiral ligand are reacted with one mole of It is reacted with a transition metal catalyst.

[0066] Chiral ligands are typically reacted in solution in the same solvent used in the reaction. Added to the mixture.

[0067] Formula XI under ring opening * to a compound of formula X * The reduction of the compound is preferably carried out in a range of 0 to 50 ° C., for example in the range of 20 to 30 ° C., in an aprotic solvent, for example a linear ether or Preferably in a cyclic ether, such as tetrahydrofuran, with two hydroxy groups , complex hydrides capable of reducing the lactone group in formula X to the ring opening in formula XI, e.g. For example, it is preferably carried out in the presence of lithium borohydride.

[0068] The amino protecting group is preferably a hydrogen halide, such as, for example, HCl, or a compound of formula II When the compound is a direct reaction product, it is represented by the formula H as defined for the compound of formula II. n Acids of A (particularly where n is 1 and A is a halide anion, especially a chloride anion) It is a group that can be cleaved by not too harsh acidic conditions in the presence of -fluorenylmethoxycarbonyl, allyloxycarbonyl or especially tert-butoxy It is dicarbonyl.

[0069] Formula XII * to give a compound of the formula: * -X (wherein X is a halogen) , especially Chloro, LG * But the hydroxyl group to which it is (will be) bound and electrophilic groups capable of forming a leaving group LG2, particularly sulfonyl halides. Introduction of a leaving group of formula LG2 using toluene, preferably toluenesulfonyl chloride which gives rise to Equation XI * The reaction of the compound is carried out at a temperature preferably in the range of 0 to 50°C, for example, 20 to 30°C. in an aqueous organic solvent, such as an aqueous halogenated hydrocarbon, such as dichloromethane, at a desired temperature. Preferably, the reaction is carried out in the presence of a base, such as an alkali metal hydroxide, for example sodium hydroxide. It can be done.

[0070] Formula XIII * to compound p of formula XII *The cyclization of the compound is carried out at 0 to 50° C., for example at 20 At a preferred temperature in the range of 30° C., an aqueous organic solvent, such as an aqueous halogenated hydrocarbon, e.g. For example, in dichloromethane, in the presence of a base, particularly an alkali metal hydroxide, e.g., sodium hydroxide. In the presence of a phase transfer catalyst, such as a tetraalkylammonium halide, e.g., tetra The reaction is preferably carried out under basic conditions in the presence of -n-butylammonium bromide.

[0071] Formula XIII * The deprotection of the compound is preferably carried out at elevated temperatures in the range of 50 to 120° C., e.g. For example, at 100 to 115°C, a polar solvent such as an alcohol, an alkanol, or an ethanol In alcohol or especially methanol, the acid H which is part of the resulting salt of formula II is n A is preferred This is often done.

[0072] The compound of formula III is, in a further embodiment according to the invention, As part of the total synthesis of a compound of formula I, according to one embodiment, a compound of formula XVIII: [ka] wherein LG is a leaving group, particularly a halogeno, such as chloro, by conversion of the aryl group to a halogeno group with a halogenating agent. , to give the compound of formula XIX. [ka] in which LG is a leaving group, in particular as defined immediately above, and Hal is a halogen, in particular chloro. is preferably obtained by obtaining

[0073] This reaction can be carried out using a halosuccinimide, e.g., preferably bromo, where Hal is bromo. The reaction is preferably carried out using bromosuccinimide. In the temperature range of 00°C, dichloromethane, acetonitrile, tetrahydrofuran, N,N- The reaction is carried out in one or more aprotic solvents, such as dimethylacetamide.

[0074] The compound of formula XIX is then or firstly reacted with a mercapto compound of formula XX: RO-C(=O)-CH2-CH2-SH (XX) wherein R6 is unsubstituted or substituted alkyl or unsubstituted or substituted aryl, particularly C 1-C6 alkyl, for example ethyl), to form a compound of formula XXI: [ka] wherein LG is a leaving group and R6 is an unsubstituted or substituted alkyl group, as particularly defined immediately above. aryl or unsubstituted or substituted aryl) is obtained.

[0075] The reaction is preferably carried out at elevated temperatures, for example from 30° C. to the boiling point of the reaction mixture, in a non-prototype reaction. In an amine solvent, such as an ester, preferably a cyclic ester, for example dioxane, a tertiary amine is Noble metals, particularly palladium and lithium, are reacted in the presence of an amine such as diisopropylethylamine. The reaction is preferably carried out in the presence of a noble metal complex, such as xantphos.

[0076] In a further embodiment, either alone or in combination, the compound of formula XXI is then Alkoxylates of alkaline metals, in particular lithium, potassium or most in particular sodium, in particular Upon treatment with a methoxylate or ethoxylate, a compound of formula XXII: [ka] where Mt is an alkali metal, in particular sodium. This reaction is preferred. or in a solvent, such as a mixture of alcohols, such as methanol, at a temperature in the range of 0 to 50°C. alcohol or ethanol (especially since the alkoxy group is the same as the organic compound in the alcohol) Alcohols compatible with the alkoxylates, and ethers, such as tetrahydrofuran. It is preferably carried out in any cyclic ether.

[0077] The compound of formula XXII is then reacted with a compound of formula XXIII: [ka] to produce a compound of formula III: [ka] in which LG is a leaving group as specifically defined above for compounds of formula III, Obtained.

[0078] The reaction is preferably carried out at elevated temperatures, for example in the range of from 30° C. to the boiling point of the reaction mixture, in a non- In protic solvents, such as ethers, e.g. cyclic ethers, especially dioxane, the ligand in the presence of, for example, Xantphos, and a tertiary nitrogen base, for example, diisopropylamine; In particular, it is preferably carried out in the presence of a noble metal complex formed from Pd2(dbba)2.

[0079] The compound of formula XXIII is preferably a compound of formula XXIV: [ka] can be obtained by reaction with iodine in the presence of a strong base.

[0080] The reaction is preferably carried out at low temperatures, for example in the range of -80 to -5°C, in a solvent, for example an acyclic or in particular in cyclic ethers, preferably tetrahydrofuran, strong bases, especially alkyl- an alkali metal, such as n-butyllithium, and a nitrogen base, in particular diisopropylamine or It is preferably carried out in the presence of diethylamine.

[0081] This provides a compound of formula XXV: [ka] which is then treated with ammonia to give the compound of formula XXIII.

[0082] The reaction is then carried out at elevated temperatures, preferably between 30° C. and the boiling point of the reaction mixture. at 85-95° C. in the presence of gaseous ammonia and an inert polar solvent, such as DMSO. This is preferably carried out in

[0083] As a preferred alternative to the synthesis from a compound of formula XVIII, a compound of formula XIX, al is chloro and LG is as defined above) is also preferably a compound of formula XX Compounds of VI: [ka] with ammonia to give a compound of formula XIX (wherein Hal is chloro). The reaction conditions are preferably as described immediately above for the reaction of a compound of formula XXV. ), and then reacting the compounds of formula III via the compounds of formulas XXI, XXII and XXIII above. (each as defined above) can.

[0084] In a further and most preferred embodiment, the compound of formula XXVI described immediately above is , reacted with ammonia (preferably in an aqueous medium at a temperature in the range of 0 to 80° C.), A compound of formula XIX, wherein Hal is halo, preferably chloro, is obtained, which is then reacted with It is preferably an anhydrous alkali metal sulfide of the formula MtS, where Mt is an alkali metal sulfide. a quaternary ammonium salt of the formula (alk)4NZ Halides (wherein each alk is independently alkyl, in particular n-alkyl, e.g. For example, C1-C6 alkyl and Z is halo, particularly chloro or more particularly bromo. Upon reaction, a compound of formula XXVII: [ka] (wherein, each alk is independently an alkyl, in particular an n-alkyl, such as a C1-C6 alkyl group. This is then preferably heated to -20 to 80°C, for example at 0 to 40°C. at a temperature in the range of °C in a suitable solvent, such as water or alcohol or mixtures thereof, preferably water and / or in methanol, ethanol or, in particular, isopropanol, preferably iodide In the presence of a copper(I) complex, such as CuI / phenanthroline, a compound of formula XXIII (preferably Preferably, it can be prepared as described above) to obtain a compound of formula III do.

[0085] In another embodiment, the compound of formula I, or a pharma- ceutically acceptable salt thereof, an acid co-crystal, water A method for preparing a dihydrate or other solvate comprising the steps of: [ka] wherein LG is a leaving group, A is an anion of a protonic acid, and the salt of formula II is wherein n, m and p are independently 1, 2 or 3, such that the compound is neutral to the formula The method comprises reacting a compound of formula II with a compound of formula III.

[0086] In a further embodiment, the compound of formula II is a compound of formula IV [ka] (i) deprotecting or (ii) reducing the R1 is a secondary amino protecting group, R2 is a protected amino group, and R3 is hydrogen. or in the case of (ii), R1 is a secondary amino protecting group, R2 is amino, and R 3 is hydroxyl), and, if necessary, the resulting compound of formula IVa: [ka] Formula H n A is reacted with an acid to give a compound of formula II.

[0087] In a further embodiment, a method for preparing a compound of formula II comprises the step of: [ka] (wherein R1 is a secondary amino protecting group and R4 is a carboxyl (-COOH) protecting group. In the presence of a strong base, L-lactide having the following formula: [ka] to produce a compound of formula VI: [ka] (Wherein, R1 is a secondary amino protecting group, R5 is an unsubstituted or substituted alkyl, or substituted cycloalkyl or unsubstituted or substituted aryl; Formula VI * Compounds of: [ka] wherein R1 is a secondary amino protecting group.

[0088] In a further embodiment, the method comprises reacting a compound of formula VI: [ka] (Wherein, R1 is a secondary amino protecting group, R5 is an unsubstituted or substituted alkyl, substituted or substituted cycloalkyl, or unsubstituted or substituted aryl, or a salt thereof; or * Compounds of: [ka] wherein R1 is a secondary amino protecting group, to give a compound of formula VII: [ka] wherein R1 is a secondary amino protecting group.

[0089] In a further embodiment, the method further comprises (ai) reacting a compound of formula VII: [ka] wherein R1 is a secondary amino protecting group, to afford an amino compound of formula VIII: [ka] (a-ii) obtaining a compound of formula VII, The compound can be acylated under reducing conditions to give a compound of formula VIII. * Compounds of: [ka] (Wherein R1 is a secondary amino protecting group; * R2 is an acylated amino The present invention further includes any one of the following:

[0090] In a further embodiment, the method comprises the step of: [ka] wherein R1 is a secondary amino protecting group; the compound is represented by the formula IV of claim 2. wherein R1 is a secondary amino protecting group, R2 is amino, and R3 is hydroxy. by reducing ethyl acetate to give a compound of formula IX: [ka] wherein R1 is a secondary amino protecting group; this compound may be prepared by reacting a compound of formula IV, is a secondary amino protecting group, R2 is amino, and R3 is hydroxyl. ) to obtain the corresponding compound of formula IV, which is then contained in formula IX, using a trialkylsilane. The compound of formula I according to claim 1 is subjected to a reduction step (ii) according to claim 2. A compound of formula I or a compound of formula V: [ka] Then, it is converted into the formula Hn An acid of A, where A is an acid anion and n is an integer. to the compound of formula II by treating with

[0091] In a further embodiment, the method comprises reacting an amino compound of formula VIII: [ka] wherein R1 is a secondary amino protecting group; reacting with an amino protecting group to give a compound of formula X thing: [ka] where R1 is a secondary amino protecting group and R2 is a protected amino group. This includes:

[0092] In a further embodiment, the method comprises the step of: [ka] wherein R1 is a secondary amino protecting group and R2 is a protected amino group, Compound XI: [ka] where R1 is a secondary amino protecting group and R2 is a protected amino group. the compound of formula XI is converted to a compound of formula LG at the hydroxy of the hydroxymethyl group; * -X Leaving group forming agent (wherein, LG * However, the leaving group LG2 is also attached to the hydroxyl group. and X is a halogen) to form a compound of formula XII Compound: [ka] (wherein R1 is a secondary amino protecting group, R2 is a protected amino group, and LG2 is a leaving group); then the compound of formula XII is cyclized under basic conditions to give the compound of formula XI Compound II: [ka] where R1 is a secondary amino protecting group and R2 is a protected amino group. wherein the compound of formula XIII is as defined in claim 2 for the compound of formula IV. The deprotection step (i) described is carried out with an acid H n This is done using A.

[0093] In a further embodiment, the method comprises reacting a compound of formula VIII * Compounds of: [ka] (Wherein R1 is a secondary amino protecting group; * R2 is acylated amino; by hydrogenation in the presence of a hydrogenation catalyst to obtain a compound of formula X * Compounds of: [ka] (Wherein R1 is a secondary amino protecting group; * R2 is an acylated amino group; formula * The compound of formula XI * Compounds of: [ka] (Wherein R1 is a secondary amino protecting group; * R2 is an acylated amino group) Let; Formula XI *The compound of formula LG * -X Leaving group forming agent (wherein, LG * However, the leaving group LG2 is also attached to the hydroxyl group. and X is a halogen) to form a compound of formula XII * Compounds of: [ka] (wherein R1 is a secondary amino protecting group, R2 is a protected amino group, and LG2 is a leaving group) to give the compound of formula XII * Compounds of formula XIII are cyclized under basic conditions to give compounds of formula XIII. * Compounds of: [ka] (Wherein R1 is a secondary amino protecting group; * R2 is an acylated amino group. and wherein the compound of formula XIII is * of the compound of the corresponding formula IV according to claim 2 The deprotection / deacylation step (i) for compound (I) is carried out with the acid H n This is done using A.

[0094] In another embodiment, the compound of formula III: [ka] wherein LG is a leaving group, by first reacting a compound of formula XIX: [ka] wherein LG is chloro and Hal is chloro, with a compound of formula XXVI: [ka] with ammonia to give a compound of formula XIX; is treated with an alkali metal sulfide of formula MtS, where Mt is an alkali metal. and then a quaternary ammonium halide of formula (alk)4NZ, where each alk is , each independently being alkyl and Z being halo, to produce a compound of formula XXVII compound: [ka] wherein each alk is independently alkyl, which is then reacted with a compound of formula XXIII Compounds of: [ka] to give a compound of formula III.

[0095] In a further embodiment of the method, the Mt alkali metal is sodium.

[0096] In another embodiment, (i) A salt compound of formula II: [ka] wherein A is the anion of a protonic acid, such that the salt of formula II is electrically neutral. n, m and p are selected from 1, 2 and 3; (ii) a compound of formula VI: [ka] (Wherein, R1 is a secondary amino protecting group, R5 is an unsubstituted or substituted alkyl, substituted or substituted cycloalkyl or unsubstituted or substituted aryl; (iii) Formula VI * Compounds of: [ka] (wherein R1 is a secondary amino protecting group); (iv) a compound of formula VII: [ka] (v) a compound of formula VIII: [ka] (wherein R1 is a secondary amino protecting group); (vi) a compound of formula IX: [ka] (vii) Formula VIII, wherein R1 is a secondary amino protecting group; * Compounds of: [ka] (Wherein R1 is a secondary amino protecting group; * R2 is an acylated amino; (vii i) Formula X * Compounds of: [ka] (Wherein R1 is a secondary amino protecting group; * R2 is an acylated amino; (ix) Formula XI * Compounds of: [ka] (Wherein R1 is a secondary amino protecting group; * R2 is an acylated amino; (x) formula XII* Compounds of: [ka] (Wherein R1 is a secondary amino protecting group; * R2 is an acylated amino group and LG2 is (xi) Formula XIII * Compounds of: [ka] (Wherein R1 is a secondary amino protecting group; * R2 is an acylated amino group; (xi i) A compound of formula X: [ka] (wherein R1 is a secondary amino protecting group and R2 is a protected amino group); (x iii) A compound of formula XI: [ka] (wherein R1 is a secondary amino protecting group and R2 is a protected amino group); (x iv) A compound of formula XII: [ka] (wherein R1 is a secondary amino protecting group, R2 is a protected amino group, and LG2 is a leaving group); and (xv) a compound of formula XIII: [ka] (wherein R1 is a secondary amino protecting group and R2 is a protected amino group). or a salt thereof.

[0097] In a further embodiment, A is Cl.

[0098] In a further embodiment, R1 is tert-butoxycarbonyl. EXAMPLES

[0099] The following examples are intended to illustrate, but are not intended to limit, the scope of the invention, unless otherwise defined herein. It serves to illustrate. Abbreviations used: Ac (acetate); AcOH (acetic acid); Ac 2O(acetic anhydride);Boc(tert-butoxycarbonyl);Boc2O(dicarbonic acid di- tert-Butyl; Brine (saturated sodium chloride solution at room temperature); n-Bu4NBr (Tetra-(n-butyl)ammonium bromide); n-BuLi (n-butyl lithium) );calcd(calculated value);DCM(dichloromethane);DIBAL-H(diisopropyl ether) butylaluminum;DIPEA (di(isopropyl)ethylamine);DMAc (di Methylacetamide; DMSO (dimethyl sulfoxide); DMSO-d6 (deuterated dimethyl sulfoxide; eq or equiv. (equivalent); Et (ethyl); EtOA c (ethyl acetate); HRMS (high resolution mass spectrometry); hrs. (hours); IPA (isopropyl alcohol); IT (internal temperature (of the reaction mixture)); LOQ (lower limit of quantification); MCC (micro Crystalline cellulose; Me (methyl); MeOH (methanol); MTBE (methyl terephthalate) rt-Butyl ether); NMR (nuclear magnetic resonance); i PrOH (isopropanol); i Pr2NH (diisopropylamine); Rt or RT (room temperature (approximately 20 to 25°C)); TB AB (Tetra-(n-butyl)ammonium bromide); Tf-OH (triflic acid); T HF (Tetrahydrofuran); TsCl (Tosyl chloride); Triflic acid (Trifluoromethan) sulfonic acid); and Xantphos (4,5-bis(diphenylphosphino)-9,9- Dimethylxanthene).

[0100] Experimental Procedure: Three basic procedures (Example 1 = Route B); Example 2 = Route C; and Example 3 = (corresponding to Route D) is summarized in the reaction overview scheme below.

[0101] Example 1 Route B [ka] Process a [ka] In a 500 mL three-neck round-bottom flask A under nitrogen atmosphere, diisopropylamine (9.4 The solution was charged with I Cool to T = -20 °C and add 2.4 M n-BuLi in hexane (38.9 mL, 1.2 equiv. ) was added dropwise over a period of 30 min. The reaction was stirred at -20°C for 30 min and then -7 Cool to 0° C. 1-(tert-butyl) 4-ethylpiperidinyl in THF (20 mL) 1,4-dicarboxylate (Jinan Welt Chem. Co., Ltd. , Jinan, China) (20.0 g, 77.7 mmol, 1.0 equiv.) The reaction was added dropwise over a period of 30 minutes while maintaining the temperature at -70°C to -60°C. Stirring at 0° C. for 30 min gave a pale yellow solution.

[0102] In a 500 mL three-neck round-bottom flask B under a nitrogen atmosphere, L-lactide (13.4 g, 9 The solution was charged with 1.2 eq. (3.3 mmol, 1.2 eq.) and THF (120 mL). The solution in flask A was cooled to 0°C. The solution in flask A was cooled to 30°C while maintaining the temperature at -70°C to -60°C. The reaction was slowly transferred to flask B via cannula over the course of 30 minutes at -70°C. The reaction solution was stirred for 30 minutes while maintaining the temperature at 0°C to 5°C. The mixture was transferred to flask C containing 3% HCl (300 mL) via The mixture was extracted with 400 mL of ethyl acetate and washed with 20% by weight salt water (200 mL). The organic layer was separated. The mixture was then dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to dryness to give B3 as a pale yellow solid. The oil (36.0 g, 71% by weight, 81% assay yield) was obtained which was further purified It was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ = 5.42 ( q,J=6.8Hz, 1H), 4.36-4.27(m,1H), 4.27-4.16( m,2H), 3.71-3.49(m,2H), 3.39-3.24(m,2H), 2. 81(br d,J=5.0Hz, 1H), 2.24-1.81(m,4H), 1.44 (s,15H), 1.27(t,J=7.1Hz, 3H).

[0103] Process b [ka] In a 250 mL round-bottom flask, add the above yellow oil (15.0 g, 71 wt. %, 26.5 mL) mol), hydroxylamine hydrochloride (9.3 g, 132.6 mmol, 5.0 equiv.), Sodium acetate (10.9 g, 132.6 mmol, 5.0 equiv.) and methanol (15 0 mL) was added. The mixture was stirred at 20-25°C for 24 hours. The resulting suspension was The mixture was filtered through HPLC-MS / ... The mixture was concentrated to 1 mL, and then water (60 mL) was added dropwise over a period of 15 min to give a white solid. The suspension was stirred overnight and filtered. The filter cake was diluted with MeOH (5 mL) and B4 was obtained as a white solid (4.9 g, 59%). 1 H NMR (400MHz, DMSO-d6)δ=11.45( s,1H), 5.33(q,J=6.6Hz, 1H), 3.73-3.58(m,2H) , 3.56-3.43(m,1H), 3.43-3.35(m,1H), 1.87-1. 65(m,4H), 1.52(d,J=6.7Hz, 3H), 1.41(s,9H).

[0104] Process c [ka] In a 1 L reactor equipped with an impeller stirrer under nitrogen atmosphere, Raney Ni (5 g) and Me OH (250 mL), followed by tert-butyl (S)-4-(hydroxyimino)-3- Methyl-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate The reactor was flushed with nitrogen three times and then with 100 mL of 100 mL of 100% ethanol. The mixture was purged with hydrogen three times at IT=80° C. under 20 bar hydrogen pressure for 16 h. The reaction mixture was filtered through microcrystalline cellulose and the filter cake was diluted with MeO The filtrate was concentrated to dryness to give a white solid (23.0 g). EtOAc (220 mL) was added to the solid and the resulting suspension was heated to reflux (JT=100 At 20° C., n-heptane (550 mL) was added in portions. The resulting clear solution was stirred for 2 h. After cooling to room temperature and allowing to stand overnight, B5 was separated into a colorless crystalline product (16.7 g, cis / trans>99 / 1, 70%). 1 H NMR (400MHz , CDCl3)δ=4.75-4.64(m,1H), 3.89-3.80(m,1H) , 3.68-3.58(m,1H), 3.48-3.33(m,3H), 1.92-1. 61(m,4H), 1.46(s,9H), 1.40(d,J=6.5Hz, 3H).

[0105] Process d [ka] In a 500 mL three-neck round-bottom flask under nitrogen, tert-butyl (3S,4S) -4-Amino-3-methyl-1-oxo-2-oxa-8-azaspiro[4.5]decane -8-Carboxylate B5 (6.0 g, 21.1 mmol) and THF (200 mL) The solution was cooled to IT = -78 °C and 1.0 M DIBAL (42.2 mL, 4 2.2 mmol, 2.0 equiv) was added dropwise over a period of 30 min. The reaction was incubated at -78 °C. The mixture was stirred for 30 minutes. A saturated aqueous solution of sodium and potassium tartrate (150 mL) was added at IT = -78°C to -6 The reaction was quenched by careful addition of 0° C. The mixture was cooled to room temperature and the two clear phases were The mixture was stirred vigorously at 20-25 °C until the desired product was obtained (approximately 1.5 h), and then it was dissolved in EtOAc (200 The combined organic extracts were extracted with 20% by weight salt water (200 mL). The mixture was washed with 500 ml of ethyl acetate, dried over Na2SO4, filtered and concentrated to give B6 as a viscous oil (6.1 g, 64% by weight, 65% assay yield) which was carried to the next step without further purification. Used. 1 H NMR (400MHz, CDCl3)δ=5.06(s,1H), 4. 39-4.29(m,1H), 3.68-3.57(m,2H), 3.35-3.24( m,2H), 3.18(d,J=4.4Hz, 1H), 1.98-1.85(m,1H) , 1.75-1.54(m,3H), 1.46(s,9H), 1.35(d,J=6.6 Hz, 3H).

[0106] Process e [ka] In a 100 mL round bottom flask, add 6.0 g of the above viscous oil and acetonitrile (150 mL). The flask was cooled in an ice-water bath and triethylsilane (7.4 g, 63. 3 mmol), triflic acid (9.5 g, 63.3 mmol) were added successively. Next, the reaction The mixture was stirred in an oil bath at 90° C. for 1 hour. The reaction mixture was then cooled to 20-25° C. and separated. The mixture was poured into a funnel and washed with n-heptane (100 mL x 2). The acetonitrile layer was separated and concentrated. Concentration to dryness gave a colorless oil which was diluted in EtOAc (150 mL). 6N HCl in ethanol (30 mL) was added dropwise with stirring, and a white solid precipitated. MTBE (150 mL) was added and the white suspension was stirred for 2 h and filtered. The catalyst was washed with EtOAc (50 mL × 2) to give a white solid, which was dissolved in MeOH (6 The mixture was dissolved in 1.0 mL of EtOAc and 18 mL of EtOAc was added dropwise with stirring. The resulting white suspension was filtered and washed with EtOAc (10 mL × 2) to give B7 as a white solid ( Obtained as 2.5 g, 81% by weight, 39% over two steps). 1 H NMR (400 MHz, D MSO-d6)δ=9.37(br s,1H), 9.25(br s,1H), 8.4 2(br s,3H), 4.26-4.17(m,1H), 3.72(ABq,J=9. 1Hz, 2H), 3.50-3.41(m,1H), 3.28-3.18(m,1H), 3.18-3.09(m,1H), 2.99-2.74(m,2H), 2.07-1.6 3(m,4H), 1.22(d,J=6.5Hz, 3H).

[0107] process f [ka] In a 10 mL Schlenk tube, add 3-((2-amino-3-chloropyridin-4-yl)thio (o)-6-chloropyrazine-2-amine Y7a (0.1 g, 0.347 mmol), (3 S,4S)-3-Methyl-2-oxa-8-azaspiro[4.5]decane-4-amine diamine Hydrochloride B7 (0.1g, 0.416mmol, 1.2eq), DMAc (0.6mL) and and 36 wt% K2CO3 aqueous solution (0.66 g, 1.735 mmol, 5.0 equiv.) were added. The mixture was stirred in a 100°C oil bath for 16 hours and cooled to 20-25°C. % brine (10 mL) was added and the mixture was extracted with EtOAc (20 mL x 2). The combined extracts were washed with 20 wt% brine (10 mL × 4) and solubilized over anhydrous Na2SO4. The mixture was dried at 40° C. and filtered. The filtrate was concentrated to dryness to give B8 as a yellow solid (121 mg, 83% ) was obtained. 1 H NMR (400MHz, DMSO-d6) δ=7.64(d,J= 6.2Hz, 1H), 7.62(s,1H), 6.26(s,2H), 6.13(s,2 H), 5.74(d,J=5.3Hz, 1H), 4.12-4.02(m,1H), 3. 90-3.78(m,2H), 3.67(d,J=8.4Hz, 1H), 3.49(d, J=8.4Hz, 1H), 3.33(s,2H), 2.91(d,J=5.1Hz, 1H ), 1.78-1.68(m,1H), 1.67-1.57(m,1H), 1.56-1 .41(m,2H), 1.08(d,J=6.5Hz, 3H).

[0108] Example 2 Route C [ka] Step a: [ka] In a 1 L three-necked round-bottom flask A under nitrogen atmosphere, diisopropylamine (10.2 g, The solution was cooled to IT = -20 °C. 2.5 M n-BuLi in hexane (37.3 mL, 93.3 mmol) was added to the The reaction was stirred at -20°C for 30 min and then cooled to -70°C. 1-(tert-butyl) 4-ethylpiperidine-1,4 in THF (30 mL) A solution of -dicarboxylate (20.0 g, 77.7 mmol) was heated at -70°C for 12 h. The mixture was added dropwise over 30 minutes while maintaining the temperature at 60° C. The reaction was stirred at −70° C. for 1 hour. A pale yellow solution was obtained. L-Lactide (13.4 g, 93.3 m) in THF (50 mL) was dissolved in 10 mL of ethyl acetate. mol, 1.2 equivalents) was added to the solution at -70°C to -60°C for 30 minutes. , was added dropwise. The reaction was stirred at -70°C for 1 h.

[0109] In a 500 mL three-neck round-bottom flask B under nitrogen, diisopropylamine (9.2 g, 90.9 mmol) and THF (180 mL). The solution was brought to IT = -20 °C. Cool and add 2.5 M n-BuLi in hexane (33.6 mL, 84.0 mmol) to 3 The reaction was stirred at -20°C for 30 min and then cooled to -70°C. 1-(tert-butyl)-4-ethylpiperidine-1, in THF (27 mL) A solution of 4-dicarboxylate (18.0 g, 70.0 mmol) was heated at IT = -70 °C to The mixture was added dropwise over 30 min while maintaining the temperature at -60° C. The reaction was stirred at -70° C. for 1 h. did.

[0110] The solution in flask B was incubated at -70°C to -60°C for 30 min. The reaction was slowly transferred to flask A via a centrifuge. The reaction was stirred at -70°C for 1 hour. The reaction was then gradually warmed to -10°C over 1 h and stirred at -10°C for 30 min. The reaction solution was diluted with 3% water via cannula for 30 min while maintaining IT = 0 °C to 5 °C. The mixture was transferred to flask C containing HCl (500 mL). ) and washed with 20 wt% brine (200 mL). The organic layer was separated and washed with anhydrous Na2 The mixture was dried over SO4 and filtered. The filtrate was concentrated to dryness to give a colorless oil, which was After standing overnight, it gradually solidified. The solid was recrystallized from n-heptane / EtOAc to give , affording C3 as a white solid (24.0 g, 57%). 1 H NMR (400 MHz, CDCl3)δ=4.83(q,J=7.0Hz, 1H), 3.78-3.62(m,4 H), 1.90-1.72(m,4H), 1.53(d,J=7.1Hz, 3H), 1. 47(s,9H).

[0111] Process b [ka] In a 500 mL round bottom flask, add tert-butyl (S)-3-methyl-1,4-dioxane So-2-oxa-8-azaspiro[4.5]decane-8-carboxylate C3(26. 5g, 93.5mmol, 1.0eq), hydroxylamine hydrochloride (7.8g, 112 .2 mmol, 1.2 eq.), sodium acetate (9.2 g, 112.2 mmol, 1.2 Equivalents) and methanol (200 mL) were added, and the mixture was stirred at 20-25° C. overnight. The reaction mixture was concentrated to dryness and the resulting solid was diluted in EtOAc (300 mL) and washed with water. (200 mL) and 20 wt% brine (200 mL). The organic phase was washed with Na2SO4 The mixture was dried over ice, filtered, and concentrated to dryness to give C4 as a white solid (27.9 g, 99%, partial (partially racemized) as 1 H NMR (400MHz, DMSO-d6) δ = 11.45 (s, 1H), 5.33 (q, J=6.6Hz, 1H), 3.73-3.58 (m,2H), 3.56-3.43(m,1H), 3.43-3.35(m,1H), 1 .87-1.65(m,4H), 1.52(d,J=6.7Hz, 3H), 1.41(s ,9H).

[0112] Process c [ka] In a 500 mL round bottom flask under nitrogen, tert-butyl-4-(hydroxyethyl) 3-Methyl-1-oxo-2-oxa-8-azaspiro[4.5]decane-8- Carboxylate C4 (27.9 g, 93.5 mol), toluene (150 mL), anhydrous Acetic acid (29.1 g, 280.6 mmol), acetic acid (16.8 g, 280.6 mmol) and Iron (10.4 g, 187.0 mmol) was then added. The mixture was heated in an oil bath at 70° C. The mixture was stirred vigorously for 4 hours and cooled to room temperature. The suspension was filtered through microcrystalline cellulose to obtain The solid residue was removed, which was then washed with EtOAc (150 mL x 2). The filtrate was cooled in an ice-water bath and added 5 wt.% NaHCO3 (300 mL) and 20 wt.% The organic layer was separated, dried over Na2SO4, filtered, and cooled to 37° C. for 1 hour. The filtrate was evaporated to dryness. The residue was purified by column chromatography (silica gel, EtOAc). C / n-heptane = 1 / 1 to 3 / 1, v / v), and purified by EtOAc / n-heptane C5 was further purified by recrystallization from ethanol to give white needle-like crystals (16.7 g, 55% yield). ) was obtained. 1 H NMR (400MHz, CDCl3)δ=7.43(s,1H), 4.10-3.78(m,2H), 3.55-3.38(m,2H), 2.10(s,3 H), 1.94(s,3H), 1.76-1.58(m,4H), 1.45(s,9H) .

[0113] Process d [ka] [Rh(NBD)2]BF4 (2.0 mg, 0.005 m mol), ligand L * (Johnson Matthey & Brandenburg ger AG (Zuerich, Schweiz)) (3.3 mg, 0.005 mmo l) and DCM (1 mL) were added. The resulting solution was stirred for 30 min and then the solvent was removed. A yellow solid was obtained by adding tert-butyl 4-acetamide to the vial under nitrogen. 3-Methyl-1-oxo-2-oxa-8-azaspiro[4.5]dec-3-ene 8-Carboxylate C5 (86 mg, 0.27 mmol) and 2,2,2-trifluoro Triethanolamine (TFE) (2.7 mL) was added. The vial was placed in a hydrogenation reactor. The reactor was purged three times with nitrogen and then three times with hydrogen. The mixture was heated at IT=50° C. for 30 min. The reaction mixture was stirred under hydrogen pressure for 16 h. The reaction mixture was cooled to 20-25 °C and a short silica gel pack was added. Filtration through a filter and concentration to dryness gave C6 as a white solid (86 mg, 100%). Ta. 1 H NMR (400MHz, DMSO-d6) δ=8.33(br d,J=10 .3Hz, 1H), 4.94-4.84(m,1H), 4.71-4.56(m,1H) , 3.78-3.65(m,2H), 3.22-3.02(m,1H), 2.87-2. 69(m,1H), 1.89(s,3H), 1.64-1.50(m,4H), 1.40 (s,9H), 1.19(d,J=6.7Hz, 3H).

[0114] Process e [ka] In a 10 mL Schlenk flask under nitrogen, tert-butyl (3S,4S)- 4-Acetamido-3-methyl-1-oxo-2-oxa-8-azaspiro[4.5]de Can-8-carboxylate C6 (300 mg, 0.919 mmol) and THF (3. 0.0 mL) was added. The flask was cooled in an ice-water bath. 2.0 M of 2.0M tetrahydrofuran in THF (0.7 mL) was added. LiBH4 was added dropwise and the reaction was stirred at 20-25 °C for 4 h. The mixture was cooled to room temperature and quenched by dropwise addition of 5 wt% NaHCO3 (1.0 mL). The mixture was separated and the aqueous layer was extracted with EtOAc (10 mL × 3). The combined extract was washed with 20 wt % brine (20 mL). The organic layer was separated and diluted with Na2S The mixture was dried over O4 and filtered. The filtrate was evaporated to dryness. The residue was purified by column chromatography. (silica gel, EtOAc / n-heptane = 1 / 1 to 1 / 3, v / v) This afforded C7 as a colorless viscous oil (258 mg, 85%). 1 H NMR (400M Hz, DMSO-d6)δ=7.48(br d,J=10.1Hz, 1H), 5.23 (br s,1H), 5.15(br s,1H), 4.09-4.04(m,1H), 3.92-3.82(m,1H), 3.75(d,J=10.1Hz, 1H), 3.56 (d,J=5.1Hz, 1H), 3.54-3.44(m,4H), 1.98(s,3H ), 1.68-1.57(m,2H), 1.52-1.46(m,2H), 1.44(s ,9H), 1.00(d,J=6.2Hz,3H).

[0115] [ka] In a 25 mL Schlenk flask under nitrogen, add NaOH (94 mg, 2.35 mmol) and water (5.0 mL) were added. The tube was cooled in an ice-water bath and diluted with DCM (5.0 mL). tert-Butyl 4-((1S,2S)-1-acetamido-2-hydroxypropyl )-4-(hydroxymethyl)piperidine-1-carboxylate C7 (650 mg, 1 A solution of TsCl (450 mg, 2.36 mmol) and TsCl (450 mg, 2.36 mmol) was added dropwise. The mixture was then stirred at 20-25°C for 16 h. n-Bu4NBr (65 mg, 0 0.202 mmol) was added, followed by NaOH (94 mg, 2.35 m The mixture was then stirred at 20-25° C. for 16 hours. The organic layer was separated. The mixture was washed with 20 wt% brine (5 mL), dried over Na2SO4, and filtered. Evaporation to dryness afforded C9 as a white solid (500 mg, 81%). 1 H NMR(4 00MHz, DMSO-d6)δ=7.82(br d,J=10.0Hz, 1H), 4 .18-4.06(m,2H), 3.65-3.56(m,1H), 3.55(ABq, J=8.7Hz, 2H), 3.32-3.11(m,3H), 1.89(s,3H), 1 .57-1.40(m,4H), 1.38(s,9H), 1.01(d,J=6.1Hz , 3H).

[0116] process f [ka] In a 10 mL sealed tube, add tert-butyl (3S,4S)-4-acetamido-3-methyl 2-oxa-8-azaspiro[4.5]decane-8-carboxylate C9 (25m g, 0.077 mmol) and 6N aqueous HCl (1.0 mL) were added. The reaction was stirred in an oil bath at 110° C. for 16 hours. The reaction was then cooled to 20-25° C. and concentrated to dryness. This afforded C10 as a white solid (17.0 mg, 90%). 1 H NMR(40 0MHz, DMSO-d6)δ=9.37(br s,1H), 9.25(br s,1 H), 8.42(br s,3H), 4.26-4.17(m,1H), 3.72(AB q,J=9.1Hz, 2H), 3.50-3.41(m,1H), 3.28-3.18( m,1H), 3.18-3.09(m,1H), 2.99-2.74(m,2H), 2. 07-1.63(m,4H), 1.22(d,J=6.5Hz, 3H).

[0117] Process g [ka] In a 10 mL Schlenk tube, add 3-((2-amino-3-chloropyridin-4-yl)thio (O)-6-chloropyrazine-2-amine Y10a (0.1 g, 0.347 mmol), ( 3S,4S)-3-Methyl-2-oxa-8-azaspiro[4.5]decane-4-amine Dihydrochloride C10 (0.1 g, 0.416 mmol, 1.2 equiv.), DMAc (0.6 mL ) and 36 wt % aqueous K2CO3 solution (0.66 g, 1.735 mmol, 5.0 equiv.) The mixture was stirred in an oil bath at 100°C for 16 hours and cooled to 20-25°C. 0 wt % brine (10 mL) was added and the mixture was extracted with EtOAc (20 mL×2). The combined extracts were washed with 20 wt% brine (10 mL × 4) and anhydrous NaSO The mixture was dried over 4 and filtered. The filtrate was concentrated to dryness to give C11 as a yellow solid (121 mg, The result was 83%). 1H NMR (400MHz, DMSO-d6) δ=7.64(d ,J=6.2Hz, 1H), 7.62(s,1H), 6.26(s,2H), 6.13( s,2H), 5.74(d,J=5.3Hz, 1H), 4.12-4.02(m,1H) , 3.90-3.78(m,2H), 3.67(d,J=8.4Hz, 1H), 3.49 (d,J=8.4Hz, 1H), 3.33(s,2H), 2.91(d,J=5.1Hz , 1H), 1.78-1.68(m,1H), 1.67-1.57(m,1H), 1.5 6-1.41(m,2H), 1.08(d,J=6.5Hz, 3H).

[0118] Example 3 Route D [ka] Step a: [ka] In a 500 mL three-neck round-bottom flask A under nitrogen atmosphere, diisopropylamine (9.4 The solution was charged with I Cool to T = -20 °C and add 2.4 M n-BuLi in hexane (38.9 mL, 1.2 equiv. ) was added dropwise over a period of 30 min. The reaction was stirred at -20°C for 30 min and then -7 Cool to 0° C. 1-(tert-butyl) 4-ethylpiperidinyl in THF (20 mL) 1,4-Dicarboxylate (D1) (20.0 g, 77.7 mmol, 1.0 equiv. A solution of 1,2-dichlorophenyl ether (1,2-dichlorophenyl ether) was added dropwise over a period of 30 minutes while maintaining the temperature at -70°C to -60°C. The reaction was stirred at -70°C for 30 min to give a pale yellow solution.

[0119] In a 500 mL three-neck round-bottom flask B under a nitrogen atmosphere, L-lactide (13.4 g, 9 The solution was charged with 1.2 eq. (3.3 mmol, 1.2 eq.) and THF (120 mL). The solution in flask A was cooled to 0°C. The solution in flask A was cooled to 30°C while maintaining the temperature at -70°C to -60°C. The reaction was slowly transferred to flask B via cannula over the course of 30 minutes at -70°C. The reaction solution was stirred for 30 minutes while maintaining the temperature at 0°C to 5°C. The mixture was transferred to flask C containing 3% HCl (300 mL) via The mixture was extracted with 400 mL of ethyl acetate and washed with 20% by weight salt water (200 mL). The organic layer was separated. The mixture was then dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to dryness to give D3 as a pale yellow solid. The oil (36.0 g, 71% by weight, 81% assay yield) was obtained which was further purified It was used in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ = 5.42 ( q,J=6.8Hz, 1H), 4.36-4.27(m,1H), 4.27-4.16( m,2H), 3.71-3.49(m,2H), 3.39-3.24(m,2H), 2. 81(br d,J=5.0Hz, 1H), 2.24-1.81(m,4H), 1.44 (s,15H), 1.27(t,J=7.1Hz, 3H).

[0120] Process b [ka] In a 250 mL round-bottom flask, add the above yellow oil (15.0 g, 71 wt. %, 26.5 mL) mol), hydroxylamine hydrochloride (9.3 g, 132.6 mmol, 5.0 equiv.), Sodium acetate (10.9 g, 132.6 mmol, 5.0 equiv.) and methanol (15 0 mL) was added. The mixture was stirred at 20-25°C for 24 hours. The resulting suspension was The mixture was filtered through HPLC-MS / ... The mixture was concentrated to 1 mL, and then water (60 mL) was added dropwise over a period of 15 min to give a white solid. The suspension was stirred overnight and filtered. The filter cake was diluted with MeOH (5 mL) and D4 was obtained as a white solid (4.9 g, 59%). 1 H NMR (400MHz, DMSO-d6)δ=11.45( s,1H), 5.33(q,J=6.6Hz, 1H), 3.73-3.58(m,2H) , 3.56-3.43(m,1H), 3.43-3.35(m,1H), 1.87-1. 65(m,4H), 1.52(d,J=6.7Hz, 3H), 1.41(s,9H).

[0121] Process c [ka] In a 1 L reactor equipped with an impeller stirrer under nitrogen atmosphere, Raney Ni (5 g) and Me OH (250 mL), followed by tert-butyl (S)-4-(hydroxyimino)-3- Methyl-1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate The reactor was flushed with nitrogen three times and then with 100 mL of ethyl acetate D4 (25.0 g, 83.80 mmol). The mixture was purged with hydrogen three times at IT=80° C. under 20 bar hydrogen pressure for 16 h. The reaction mixture was filtered through microcrystalline cellulose and the filter cake was diluted with MeO The filtrate was concentrated to dryness to give a white solid (23.0 g). EtOAc (220 mL) was added to the solid and the resulting suspension was heated to reflux (IT=100 At 20° C., n-heptane (550 mL) was added in portions. The resulting clear solution was stirred for 2 h. After cooling to room temperature and leaving it overnight, D5 turned out to be colorless crystals (16.7 g, cis / trans>99 / 1, 70%). 1 H NMR (400MHz, CDC l3)δ=4.75-4.64(m,1H), 3.89-3.80(m,1H), 3.6 8-3.58(m,1H), 3.48-3.33(m,3H), 1.92-1.61(m ,4H), 1.46(s,9H), 1.40(d,J=6.5Hz, 3H).

[0122] Process d [ka] In a 10 mL Schlenk tube, add tert-butyl (3S,4S)-4-amino-3-methyl 1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate D5 (100 mg, 0.352 mmol) and DCM (5.0 mL) were added. The mixture was cooled in an ice-water bath. Diisopropylamine (182 mg, 1.41 mmol) was added dropwise. After the addition of Boc2O (230 mg, 1.05 mmol), the reaction was then The mixture was stirred at 0 to 25° C. for 44 hours. The organic layer was separated and washed with 20% by weight brine (5 mL). The mixture was dried over Na2SO4 and filtered. The filtrate was evaporated to dryness to give D6 as a colorless oil (95 ml). g, 70%) which gradually solidified on standing. HRMS m / z C1 9H 33 N2O6[M+H] + Calculated value 385.2333, measured value 385.23 34.

[0123] Process e [ka] In a 10 mL Schlenk flask under nitrogen, tert-butyl (3S,4S)- 4-((tert-butoxycarbonyl)amino)-3-methyl-1-oxo-2-oxo Sa-8-azaspiro[4.5]decane-8-carboxylate D6 (126 mg, 0.3 35 mmol) and THF (3.0 mL) were added. The flask was cooled in an ice-water bath. 0.25 mL of 2.0 M LiBH4 in HF was added dropwise and the reaction was incubated at 20–25 °C. The reaction was stirred for 16 h. The reaction was cooled in an ice-water bath and 5 wt % NaHCO3 (1.0 mL) was added. The mixture was separated and the aqueous layer was diluted with EtOAc ( The combined extracts were then extracted with 20% by weight saline (20 mL). The organic layer was separated, dried over Na2SO4 and filtered. The filtrate was evaporated to dryness. This gave D7 as a colorless viscous oil (91 mg, 70%). HRMS m / z C1 9H 37 N2O6[M+H] + Calculated value 389.2646, measured value 389.26 28.

[0124] process f [ka] In a 25 mL Schlenk flask under nitrogen, add NaOH (14 mg, 0.34 mmol) and water (2.0 mL) were added. The tube was cooled in an ice-water bath and diluted with DCM (2.0 mL). tert-Butyl 4-((1S,2S)-1-((tert-butoxycarbonyl)acetate Amino)-2-hydroxypropyl)-4-(hydroxymethyl)piperidine-1-carbo D7 (110 mg, 0.283 mmol) and TsCl (65 mg, 0.34 mmol). A solution of 1 mmol) was added dropwise to the mixture, which was then stirred at 20-25 °C for 16 h. After adding n-Bu4NBr (9.1 mg, 0.028 mmol), NaOH (14 mg, 0.34 mmol) was added. The mixture was then incubated at 20–25 °C for 1 The mixture was stirred for 6 h. The organic layer was separated and washed with 20 wt % brine (2 mL) and diluted with Na2SO4 The mixture was dried over ice and filtered. The filtrate was evaporated to dryness to give D9 as a colorless oil (45 mg, 43%). HRMS m / z C 19 H 35 N2O5[M+H] + Calculated value for 37 1.2540, actual value 371.2533.

[0125] Process g [ka] In a 10 mL Schlenk tube, add tert-butyl(3S,4S)-4-((tert-butyl) (3-methyl-2-oxa-8-azaspiro[4.5]deca(2-methoxycarbonyl)amino 100 mg, 0.27 mmol) in isopropanol 6N HCl (1.0 mL) and methanol (3.0 mL) were added. The reaction mixture was stirred for 20-2 Stir at 5° C. for 16 h and concentrate to dryness to give D10 as a white solid (59 mg, 90%). I got it. 1 H NMR (400MHz, DMSO-d6)δ=9.37(br s,1H ), 9.25(br s,1H), 8.42(br s,3H), 4.26-4.17( m,1H), 3.72(ABq,J=9.1Hz, 2H), 3.50-3.41(m,1 H), 3.28-3.18(m,1H), 3.18-3.09(m,1H), 2.99- 2.74(m,2H), 2.07-1.63(m,4H), 1.22(d,J=6.5H z, 3H).

[0126] Process h [ka] In a 10 mL Schlenk tube, add 3-((2-amino-3-chloropyridin-4-yl)thio (O)-6-chloropyrazine-2-amine Y10a (0.1 g, 0.347 mmol), ( 3S,4S)-3-Methyl-2-oxa-8-azaspiro[4.5]decane-4-amine Dihydrochloride D10 (0.1 g, 0.416 mmol, 1.2 equiv.), DMAc (0.6 mL ) and 36 wt % aqueous K2CO3 solution (0.66 g, 1.735 mmol, 5.0 equiv.) The mixture was stirred in an oil bath at 100°C for 16 hours and cooled to 20-25°C. 0 wt % brine (10 mL) was added and the mixture was extracted with EtOAc (20 mL×2). The combined extracts were washed with 20 wt% brine (10 mL × 4) and anhydrous NaSO The mixture was dried over 4 and filtered. The filtrate was concentrated to dryness to give D11 as a yellow solid (121 mg, The result was 83%). 1 H NMR (400MHz, DMSO-d6) δ=7.64(d ,J=6.2Hz, 1H), 7.62(s,1H), 6.26(s,2H), 6.13( s,2H), 5.74(d,J=5.3Hz, 1H), 4.12-4.02(m,1H) , 3.90-3.78(m,2H), 3.67(d,J=8.4Hz, 1H), 3.49 (d,J=8.4Hz, 1H), 3.33(s,2H), 2.91(d,J=5.1Hz , 1H), 1.78-1.68(m,1H), 1.67-1.57(m,1H), 1.5 6-1.41(m,2H), 1.08(d,J=6.5Hz, 3H).

[0127] Example 4 (3-((2-amino-3-chloropyridin-4-yl)thio)-6-chloropyrazine- 2-Amine) The above mentioned compounds Y7a = Y10a (3-((2-amino-3-chloropyridine- 4-yl)thio)-6-chloropyrazine-2-amine) was obtained as follows: [ka] Process a [ka] 2,3,5-trichloropyrazine (70.50g, 384.36mmol, 1eq) and and ammonia solution (25 wt%, 364.00 g, 400 mL, 2.68 mol, 6.1 4 equiv.) was added to a 1 L sealed reactor. The mixture was heated to 80° C. and stirred for 24 h. The reaction was then completed. The reaction mixture was cooled to 30° C. and filtered to give a brown filter cake. The brown filter cake was dissolved in acetone (50 mL) and filtered. Petroleum ether (300 mL) was added. The suspension was stirred for 4 h and filtered to give the crude product. The crude product was purified by elution with a combined solvent of petroleum ether and acetone (10 / 1, 200 ml). L) and filtered to give product Y7d (51.00 g, 307.91 mmol). , 80% yield) was obtained as a pale yellow solid. 1H NMR (400MHz, DMSO- d6) δ = 7.63 (s, 1H). The advantage of this (and generalized) method is that it The advantage of this method is that no chromatography is required to obtain Y7d.

[0128] Process b [ka] In a 200 mL round-bottom flask, add Na2S (10.816 g, 44 wt. % including water of crystallization, 60.978 mmol) and toluene (100 mL) were added. The mixture was heated to reflux. Water was removed in a Dean-Stark trap (approximately 5-6 mL of water was removed by distillation). After cooling, the mixture was concentrated to dryness.

[0129] Into the above round-bottom flask, Y7d (5.000 g, 30.489 mmol) and 2-methyl Loubutan-2-ol (50 mL) was added and the reaction was heated to reflux and stirred for 36 hours. After cooling to 25°C, the mixture was filtered. The filtrate was diluted with n-heptane (5V * 3 times, Y The mixture was then exchanged with THF (based on 7d) and concentrated to a final residue of 1V. The residue was charged with THF / n-heptane (5 mL) at 25° C. and stirred. The suspension was filtered and diluted with THF / n-heptane (5 mL). mL / 5 mL) to give a brown solid (6.200 g).

[0130] In a separate 200 mL round bottom flask, add the brown solid (6,200 g), 10% salt water, and (25mL), Me-THF (30mL) and n-Bu4NBr (9.829g, 30. The mixture was stirred at room temperature for 0.5 h and the phases were separated. The organic phase was , washed with 20% brine (25 mL), and the solvent was removed with iso-propanol (5 mL). * 3 times, Y7d (based on Y7c) was replaced with Y7c (27,000 g, 99.2 by HPLC area). % purity, 58.08% assay yield) in iso-propanol. R(400MHz, DMSO-d6)δ=6.88(s,1H), 2.97-2.92( m,14H), 1.38-1.31(m,14H), 1.13-1.04(m,14H) , 0.73-0.69 (t, 21H). n-Bu4NBr (or other corresponding tert- The advantage of using alkylamino halides is easier work-up and purification.

[0131] Process c [ka] In a 25 mL round-bottom flask, add Y7c (4.7 g, 23.27 wt. %, in IPA, 2. 723mmol, 1.0eq), Y7b (1.052g, 4.085mmol, 1.5eq) amount), 1,10-phenanthroline (0.05 g, 0.272 mmol) and water (8 mL The mixture was purged with nitrogen gas three times and CuI (0.026 g, 0.136 m The mixture was heated to 65° C. and stirred for 3 hours to complete the reaction. The reaction was cooled to room temperature, filtered, and the filter cake was diluted with water (4 mL * 3) and washed. The filter cake was slurried in MTBE (6 mL) for 30 minutes and filtered. Wash with MTBE (6 mL), dry and prepare the product of step g) of Example 2 and step h) of Example 3. The compound Y7a=Z17a of formula Y10a described in The reaction is an alternative to the palladium-catalyzed coupling of Y7b and Y7c. It may be started with copper.

[0132] Example 5 (3-((2-amino-3-chloropyridin-4-yl)thio)-6-chloropyrazine- 2-Amine) Alternatively, compounds of formula Z17a=Y10a may be prepared according to the following reaction scheme: R: [ka] [ka] In a three-necked round-bottom flask, add Y7d (200 mg, 1.22 mmol, 1 equiv.), dioxane Xantphos (14 mL) was added. The solution was evacuated and purged with nitrogen gas three times. mg, 0.024 mmol, 0.02 eq), PdCl2(dppf) (8.9 mg, 0 .012 mmol, 0.1 equiv.), and DIPEA (0.32 g, 2.44 mmol, 2 0.0 equiv.) was added under a nitrogen atmosphere. The solution was heated to 85° C. overnight. The reaction was cooled and The residue was purified by column chromatography (eluent: ethyl acetate / heptane = 1 Purification by HPLC (HPLC-HPLC) at 37° C. / 1) afforded Z17d (259 mg, 0.99 mmol, 81%). 1 H NMR (400MHz, CDCl3)δ=7.83(s,1H), 4.88(bs ,2H), 3.73(s,3H), 3.47(t,J=9.2Hz, 2H), 2.79( t, J = 9.2 Hz, 2H).

[0133] [ka] Z17d (8.0 kg, assay 95%, 30.68 mol) in THF (70 L) To the solution, add EtONa (prepared from 776 g Na and 13.6 L EtOH) at room temperature. was added and the mixture was stirred at ambient temperature for 1 hour. The mixture was then cooled to room temperature, where it became a wet yellow solid. The mixture was concentrated by rotary evaporation to 100 mL and the residue was suspended in DCM (40 L). Stirred under N2 for 6 h. Collect the solid by vacuum filtration, the filtrate becomes colorless. The cake was washed with DCM (approximately 15 L) until the solid was completely dissolved in water (PSC-2). Drying gave Z17c (6.93 kg, qNMR 72%, yield 88%). 1 HN MR(400MHz, D2O)δ=7.37(s,1H).

[0134] [ka] Z17c (6.95 kg, assay 72%, 27. 23 mol) to a mixture of Xantphos (233 g, 411 mmol, 0.015 equiv.) , Pd2(dba)3 (186g, 206mmol, 0.0075 equivalent), Z17b(7 .13kg, 28.02mol) and DIPEA (7.02kg, 54.46mol) The system was evacuated and purged with nitrogen gas three times. The mixture was stirred under N2 for 16 h. The mixture was cooled to room temperature, water (50 L) was added, and the cake was filtered. The filtrate was extracted with EA (4×20 L). The organic phase was concentrated under reduced pressure. The crude product was then concentrated to give a crude product which was combined with the cake. DCM (60 L) was then added to the crude product. The mixture was added to the product and stirred at 25-30°C for 18 hours, and then filtered. The filter cake was stirred for 4 hours. The mixture was slurried with CH2Cl2 (30 L) for 16 hours and filtered. The filter cake was then slurried in CH2Cl2 (30 L) for 10 min and filtered. Drying under reduced pressure gave Z17a (9.1 kg, 84%) as a pale yellow solid. 1 HN MR (400MHz, DMSO-d6)δ=7.89(s,1H), 7.7(d,J=7 .6Hz, 1H), 7.18(bs,2H), 6.40(bs,2H), 5.97(d, J=7.6Hz, 1H)

[0135] Example 6 (3-((2-amino-3-chloropyridin-4-yl)thio)-6-chloropyrazine- 2-Amine) Alternatively, compounds of formula Z17a=Y10a may be prepared according to the following reaction scheme: R: [ka] In detail, the synthesis of compound Z17a was carried out as follows: Process a [ka] Under a nitrogen atmosphere, n-BuLi (2.5 M, 7.6 L) was dissolved in THF (15 L) at -78 °C. The resulting mixture was then added dropwise to a solution of 3-chloro-2-fluoropyridine (2 kg) in 10 mL of ethyl acetate. The resulting mixture was stirred for 1 h. Then, a solution of I2 (4.82 kg) in THF (6 L) was added was added dropwise. After the addition, the reaction mixture was stirred for 30 min and then saturated Na2SO3( 10 L) and warmed to 20-25° C. The phases were separated. The aqueous phase was washed with EA (2×10 The combined organic phase was extracted with saturated Na2SO3 (2×8 L), brine (8 L). ) and dried over Na2SO4. The organic phase was concentrated under reduced pressure. The residue was diluted with MeOH (4 L), filtered, dried and purified by filtration to give 3-chloro-2-fluoro-4-iodo Dopyridine 1c (2.2 kg, 68% yield) was obtained.

[0136] Process b [ka] A solution of compound 1c (8 kg) in DMSO (48 L) was added to NH3( Gas) was passed through. TLC showed the reaction was complete. The reaction mixture was cooled to room temperature. The reaction mixture was added to water (140 L). The solid was collected, washed with water (25 L) and dried. As a result, Z17b (6.91 kg, yield 87%) was obtained. 1 H NMR (400 MHz, C DCl3)δ=7.61(d,J=6.8Hz, 1H), 7.14(s,J=6.8Hz , 1H), 5.09(bs,2H).

[0137] Process c [ka] 2-Amino-6-chloro-pyrazine 1a (1 kg, 7.69 mo) in DCM (15 L) The solution of l) was heated to reflux and NBS (417 g) was charged to it in portions over a period of 1 hour. The reaction was cooled to room temperature. The reaction mixture was washed with water (3 L) and brine (3 L). The organic phase was evaporated and the residue was purified by column chromatography to give product Z1. 7f (3-bromo-6-chloropyrazine-2-amine) (180 g, 11% yield) was obtained. Ta.

[0138] Process d [ka] 3-Bromo-6-chloropyrazine-2-amine Z1 in 1,4-dioxane (40 L) A solution of 7f (6.0 kg, 28.78 mol) was added to Pd(OAc)2 at room temperature under nitrogen. (64.56g, 287.6mmol), Xantphos (333g, 575.6mmol ), and DIPEA (7.44 kg, 57.56 mol) were added. The mixture was then stirred at room temperature for another 30 minutes under nitrogen. After purging with nitrogen, methyl 3-mercaptopropanoate (3.81 kg, 31.70 mol ) was added, causing the orange mixture to darken. The mixture was heated to 90°C. LC showed complete conversion of the starting material. The mixture was cooled to about room temperature and then diluted with EtOAc. c (40 L). After aging for 30 min with stirring, the entire mixture was filtered. The solid was washed with EtOAc (3×15 L). The combined orange filtrate was concentrated. It was evaporated to dryness and the solid residue was suspended in DCM (45 L). The mixture was heated to 35-40 °C. The mixture was stirred for 1 hour until all solids were dissolved. Then, n-heptane (45 L) was added dropwise. After complete addition, the mixture was cooled to 15-20°C with stirring for 1 hour. The solid was collected by vacuum filtration and the solid was washed with cold 1:1 DCM / heptane (2 The solid was washed with hexane (25 L) (PSC-2) and then with heptane (25 L) (PSC-3). The solid was dried over the weekend. This gave Z17d (5.32 kg, 75% yield). 1 H NMR (400 MHz, CDCl3)δ=7.83(s,1H), 4.88(bs,2H), 3.73(s,3H ), 3.47(t,J=9.2Hz, 2H), 2.79(t,J=9.2Hz, 2H).

[0139] Process e [ka] Z17d (8.0 kg, assay 95%, 30.68 mol) in THF (70 L) To the solution, add EtONa (prepared from 776 g Na and 13.6 L EtOH) at room temperature. was added and the mixture was stirred at ambient temperature for 1 hour. The mixture was then cooled to room temperature, where it became a wet yellow solid. The mixture was concentrated by rotary evaporation to 100 mL and the residue was suspended in DCM (40 L). Stirred under N2 for 6 h. Collect the solid by vacuum filtration, the filtrate becomes colorless. The cake was washed with DCM (approximately 15 L) until the solid was completely dissolved in water (PSC-2). Drying gave Z17c (6.93 kg, qNMR 72%, yield 88%). 1 HN MR(400MHz, D2O)δ=7.37(s,1H).

[0140] process f [ka] To a mixture of Z17c (6.95 kg, assay 72%, 27.23 mol) in 1,4-dioxane (72 L) was added Xantphos (233 g, 411 mmol, 0.015 equiv), Pd2(dba)3 (186 g, 206 mmol, 0.0075 equiv), Z17b (7.13 kg, 28.02 mol) and DIPEA (7.02 kg, 54.46 mol). The system was evacuated and purged with nitrogen gas three times. The mixture was stirred at 65 °C under N2 for 16 h. The mixture was cooled to room temperature, water (50 L) was added and filtered. The cake was washed with EA (25 L). The filtrate was extracted with EA (4 x 20 L). The organic phase was concentrated under reduced pressure to give the crude product, which was combined with the cake. DCM (60 L) was then added to the crude product and stirred at 25-30° C. for 18 h, then filtered. The filter cake was slurried with CHCl (30 L) for 4 h and filtered. The filter cake was slurried in CHCl (30 L) for 16 h and filtered. The filter cake was then dried under reduced pressure to give Z17a (3-((2-amino-3-chloropyridin-4-yl)thio)-6-chloropyrazin-2-amine; 9.1 kg, 84%) as a pale yellow solid. 1 H NMR (400MHz, DMSO-d6) δ=7.89(s,1H), 7.7(d,J=7.6Hz, 1H), 7.18(bs,2H), 6.40(bs,2H), 5.97(d,J=7.6Hz, 1H). The present invention includes the following aspects. [1] A method for preparing a compound of formula I, or a pharma- ceutically acceptable salt, acid co-crystal, hydrate, or other solvate thereof, comprising the steps of: [ka] wherein LG is a leaving group, A is an anion of a protic acid, and n, m and p are independently 1, 2 or 3, such that the salt of formula II is electrically neutral. [2] The compound of formula II is a compound of formula IV [ka] (i) deprotecting or (ii) reducing R 1 is a secondary amino protecting group, R 2 is a protected amino group, and R 3 is hydrogen, or in the case of (ii), R 1 is a secondary amino protecting group, R2 is amino, and R 3 is hydroxyl), and, if necessary, the resulting compound of formula IVa:

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[10] Compounds of formula III:

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[11] The method according to

[10] , wherein the Mt alkali metal is sodium.

[12] (i) A salt compound of formula II:

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[13] The compound according to

[12] , wherein A is Cl.

[14] R 1

[12] , wherein

Claims

1. A method for preparing a compound of formula I, or a pharma- ceutically acceptable salt, acid co-crystal, hydrate, or other solvate thereof, comprising the steps of: 【Chemistry 1】 wherein LG is Cl, A is Cl, m is 1, n is 1, and p is 2, such that the salt of formula II is electrically neutral.

2. The compound of formula II is a compound of formula IV 【Chemistry 2】 (i) deprotecting or (ii) reducing R １ is a secondary amino protecting group, R ２ is a protected amino group, R ３ is hydrogen, or in the case of (ii), R １ is a secondary amino protecting group, R ２ is amino, R ３ is hydroxyl), and, if necessary, the resulting compound of formula IVa: 【Chemistry 3】 Formula H ｎ 2. The method of claim 1, wherein the compound of formula II is obtained by reacting A with an acid to obtain the compound of formula II.

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